Substances Generally Recognized as Safe, 54959-55055 [2016-19164]
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Vol. 81
Wednesday,
No. 159
August 17, 2016
Part III
Department of Health and Human Services
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Food and Drug Administration
21 CFR Parts 20, 25, 170, et al.
Substances Generally Recognized as Safe; Final Rule
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Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations
FOR FURTHER INFORMATION CONTACT:
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 20, 25, 170, 184, 186, and
570
[Docket No. FDA–1997–N–0020 (formerly
97N–0103)]
RIN 0910–AH15
Substances Generally Recognized as
Safe
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Final rule.
The Food and Drug
Administration (FDA or we) is issuing a
final rule that amends and clarifies the
criteria in our regulations for when the
use of a substance in food for humans
or animals is not subject to the
premarket approval requirements of the
Federal Food, Drug, and Cosmetic Act
(the FD&C Act) because the substance is
generally recognized as safe (GRAS)
under the conditions of its intended use.
We also are amending our regulations to
replace the voluntary GRAS affirmation
petition process with a voluntary
notification procedure under which any
person may notify us of a conclusion
that a substance is GRAS under the
conditions of its intended use. The
clarified criteria for GRAS status should
help stakeholders draw more informed
conclusions about whether the intended
conditions of use of a substance in food
for humans or animals complies with
the FD&C Act, and the notification
procedure will enable stakeholders to be
aware of whether we have questioned
the basis of a conclusion of GRAS
status.
DATES: This rule is effective October 17,
2016. Submit comments on information
collection issues under the Paperwork
Reduction Act of 1995 by October 17,
2016 (see section XXIX, the ‘‘Paperwork
Reduction Act of 1995’’ section of this
document).
ADDRESSES: To ensure that comments on
the information collection are received,
the Office of Management and Budget
(OMB) recommends that written
comments be faxed to the Office of
Information and Regulatory Affairs,
OMB, Attn: FDA Desk Officer, FAX:
202–395–7285, or emailed to oira_
submission@omb.eop.gov. All
comments should be identified with the
OMB control number 0910–0342 and
titled ‘‘Substances Generally Recognized
as Safe.’’ Also include the FDA docket
number found in brackets in the
heading of this document.
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Table of Contents
Executive Summary
SUMMARY:
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Regarding substances that would be
used in human food: Paulette M.
Gaynor, Center for Food Safety and
Applied Nutrition (HFS–255), Food and
Drug Administration, 5001 Campus
Drive, College Park, MD 20740, 240–
402–1192. Regarding substances that
would be used in animal food: Geoffrey
K. Wong, Center for Veterinary
Medicine (HFV–224), Food and Drug
Administration, 7519 Standish Pl.,
Rockville, MD 20855, 240–402–5838.
SUPPLEMENTARY INFORMATION:
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Purpose and Coverage of the Rule
Summary of the Major Provisions of the Rule
Costs and Benefits
I. Introduction
A. History of FDA’s Approach to the GRAS
Provision of the FD&C Act
B. Report by the Government
Accountability Office and How We Are
Addressing Its Recommendations
C. Issues Regarding the Legal and
Regulatory Framework for Substances
Added to Food
D. Recent FDA Actions Related to GRAS
Criteria
E. Moving Forward Under This Final Rule
II. Background
A. The Proposed Rule
B. Interim Pilot Program
C. 2010 Report of the Government
Accountability Office
D. 2010 Notice Reopening the Comment
Period
E. Public Comments
F. Applicability of Discussions in This
Document to Both the Human Food
Regulations and the Animal Food
Regulations
G. Use of Pronouns in This Document
H. Summary of Principal Changes to the
Proposed Notification Procedure
III. Legal Authority
IV. General Comments on the Proposed Rule
V. Comments on the Definition of Scientific
Procedures
VI. Comments on the Criteria for Eligibility
for Classification as GRAS
A. General Criteria for Eligibility for
Classification as GRAS
B. Criteria for Eligibility for Classification
as GRAS Through Scientific Procedures
C. Criteria for Eligibility for Classification
as GRAS Through Experience Based on
Common Use in Food
D. Other Comments on the Criteria for
Eligibility for Classification as GRAS
E. GRAS Status of Certain Food Substances
VII. Comments on the Substitution of a GRAS
Notification Procedure for the GRAS
Affirmation Petition Process
A. Affirmation on the Initiative of the
Commissioner
B. Deletion of the GRAS Affirmation
Petition Process
C. General Comments on the Proposed
GRAS Notification Procedure
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D. Comments on Certain Terms Used in the
Proposed Regulatory Text
E. Comments on the Use of ‘‘Plain
Language’’ in the Regulatory Text
VIII. Definitions Applicable to a GRAS Notice
A. Definitions We Described in the 2010
Notice
B. Definition of ‘‘GRAS Notice’’
C. Other Terms We Are Defining in the
Rule
IX. Opportunity to Submit a GRAS Notice
X. Comments on Administrative Procedures
for Submission of a GRAS Notice
A. How to Send a GRAS Notice to FDA
B. Option for Submission of Electronic or
Paper Copies of a GRAS Notice
C. Incorporation into a GRAS Notice
XI. General Requirements Applicable to a
GRAS Notice
XII. Comments on Part 1 of a GRAS Notice:
Signed Statements and Certification
A. Exclusion of Trade Secret and
Confidential Commercial Information
From the Signed Statements
B. Name of the Notified Substance, Using
an Appropriately Descriptive Term
C. Intended Conditions of Use of the
Notified Substance
D. Statutory Basis for the Conclusion of
GRAS Status
E. Agreement to Make Data and
Information Available Upon Request
F. Statements and Any Applicable
Explanation Regarding Data and
Information That a Notifier Views as
Exempt From Disclosure Under FOIA
G. Certification Statement
H. Person Signing Part 1 of the GRAS
Notice
I. Authorization for FDA to Send Trade
Secret Information to FSIS
XIII. Comments on Part 2 of a GRAS Notice:
Identity, Method of Manufacture,
Specifications, and Physical or Technical
Effect
A. Scientific Information About the
Identity of a Notified Substance
B. Method of Manufacture
C. Specifications for the Notified Substance
D. Data and Information Bearing on the
Physical or Other Technical Effect of the
Notified Substance
XIV. Comments on Part 3 of a GRAS Notice:
Dietary Exposure
XV. Comments on Part 4 of a GRAS Notice:
Self-Limiting Levels of Use
XVI. Comments on Part 5 of a GRAS Notice:
Common Use in Food Before 1958
XVII. Comments on Parts 6 and 7 of a GRAS
Notice: Narrative and List of Supporting
Data and Information
XVIII. Comments on Steps a Notifier May
Take Before We Respond to a GRAS
Notice
A. Communicating With a Notifier Before
We Respond to a GRAS Notice
B. Submitting an Amendment
C. Notifier’s Request That We Cease To
Evaluate a GRAS Notice
XIX. Comments on What We Will Do With
a GRAS Notice
A. Filing Decision
B. Our Response to a GRAS Notice
C. Additional Correspondence as
Circumstances Warrant
D. Procedures If a Notifier Disagrees With
Our Response
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XX. Coordinating Our Evaluation of a GRAS
Notice With FSIS
XXI. Comments on Public Disclosure of a
GRAS Notice
A. Data and Information in a GRAS Notice
Are Available for Public Disclosure on
the Date That We Receive It
B. We Will Make a List of Filed GRAS
Notices and Our Responses to GRAS
Notices Readily Accessible
C. Public Disclosure of a GRAS Notice Is
in Accordance With Our Public
Information Regulations in Part 20
XXII. Submission of a Supplement
XXIII. Comments on the Administrative
Process for Pending GRAS Affirmation
Petitions
XXIV. Other Comments
A. GRAS Panels and Conflict of Interest
B. Guidance on Documenting Conclusions
of GRAS Status
C. Compliance With Other FDA
Regulations
D. Impact on Other Federal Agencies
E. Impact on International Trade
F. Audits
G. Lack of an Environmental Assessment
H. Substances Affirmed as GRAS With
Specific Limitations
XXV. Comments on Substances Intended for
Use in Animal Food
A. Issues in the 2010 Notice Specific to
Animal Food
B. Criteria for Eligibility for Classification
as GRAS for a Substance Intended for
Use in Animal Food (§ 570.30)
C. Part 1 of a GRAS Notice for a Substance
Intended for Use in Animal Food: Name
of the Notified Substance
(§ 570.225(c)(3))
D. Part 1 of a GRAS Notice for a Substance
Intended for Use in Animal Food:
Intended Conditions of Use
(§ 570.225(c)(4))
E. Part 2 of a GRAS Notice for a Substance
Intended for Use in Animal Food: Data
and Information Bearing on the Physical
or Other Technical Effect of the Notified
Substance (§ 570.230(d))
F. Part 3 of a GRAS Notice for a Substance
Intended for Use in Animal Food: Target
Animal and Human Exposures
(§ 570.235)
G. Data and Information in a GRAS Notice
About Safety for the Target Animal
(§ 570.250)
H. Data and Information in a GRAS Notice
About the Safety for Humans Consuming
Human Food Derived From a FoodProducing Animal (§§ 570.235 and
570.250)
I. Filing Decision, Opportunity for a
Notifier to Submit an Amendment, and
Asking Us to Cease to Evaluate a GRAS
Notice for a Substance Intended for Use
in Animal Food (§§ 570.260 and 570.265)
J. Opportunity for a Notifier to Submit a
Supplement to a GRAS Notice for a
Substance Intended for Use in Animal
Food (§ 570.280)
K. GRAS Affirmation Petitions for
Substances Used in Animal Food
XXVI. Editorial, Clarifying, and Conforming
Amendments
XXVII. Economic Analysis of Impacts
XXVIII. Analysis of Environmental Impact
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XXIX. Paperwork Reduction Act of 1995
XXX. Federalism
XXXI. References
Executive Summary
Purpose and Coverage of the Rule
Although we have premarket review
authority over food additives, a food
manufacturer can intentionally add a
substance to human food or animal food
without our premarket review or
approval if the substance is generally
recognized, among qualified experts, to
be safe under the conditions of its
intended use (GRAS). Since the 1970s,
we have had regulations clarifying the
statutory provision for eligibility for
classification as GRAS. We also have
had regulations governing a procedure
for any person to voluntarily submit to
us a petition asking us to affirm the
GRAS status of a substance under the
conditions of its intended use, and for
us to engage in an intensive rulemaking
process in response to that petition.
Experience has shown that our
regulations need further clarification to
help stakeholders understand when a
substance is eligible for classification as
GRAS in human food or animal food
under the conditions of its intended use.
Experience also has shown that
streamlining our evaluation of
conclusions of GRAS status will enable
us to evaluate more, and higher priority,
substances. We are issuing this final
rule to amend and clarify the criteria in
our regulations for when a substance is
GRAS under the conditions of its
intended use in human food or animal
food, and to replace the voluntary
administrative procedure for petitioning
us to affirm the GRAS status of a use of
a substance in human food or animal
food with a voluntary administrative
procedure for notifying us about a
conclusion that a substance is GRAS
under the conditions of its intended use
in human food or animal food.
Summary of the Major Provisions of the
Rule
The final rule clarifies the criteria for
the use of a substance to be eligible for
classification as GRAS and establishes a
new administrative procedure for any
person to notify us of the basis for a
conclusion that a substance is GRAS
under the conditions of its intended use.
With respect to criteria for eligibility for
classification as GRAS, in the final rule
we clarify that:
• A substance cannot be classified as
GRAS under the conditions of its
intended use if the available data and
information do not satisfy the safety
standard for a food additive under the
FD&C Act;
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• General recognition of safety
requires common knowledge,
throughout the expert scientific
community knowledgeable about the
safety of substances directly or
indirectly added to food, that there is a
reasonable certainty that the substance
is not harmful under the conditions of
its intended use;
• ‘‘Common knowledge’’ can be based
on either ‘‘scientific procedures’’ or on
experience based on common use of a
substance in food prior to January 1,
1958; and
• General recognition of safety
through scientific procedures must be
based upon the application of generally
available and accepted scientific data,
information, or methods, which
ordinarily are published, as well as the
application of scientific principles, and
may be corroborated by the application
of unpublished scientific data,
information, or methods.
With respect to the procedure for
submitting a GRAS notice, we provide:
• Definitions for certain terms,
including amendment, GRAS notice,
notified substance, notifier, qualified
expert, supplement, we/our/us, and
you/your;
• A clear statement of the opportunity
for any person to submit a GRAS notice;
• Information on available formats
(electronic and paper) and where to
send a GRAS notice;
• What data and other information
may be incorporated into a GRAS
notice;
• General provisions applicable to a
GRAS notice;
• Specific information you must
provide in your GRAS notice, including:
Æ Signed statements and a
certification (Part 1);
Æ The identity, method of
manufacture, specifications, and
physical or technical effect of the
notified substance (Part 2);
Æ Dietary exposure (Part 3);
Æ Self-limiting levels of use, in
circumstances where the amount of the
notified substance that can be added to
human food or animal food is limited
because the food containing levels of the
notified substance above a particular
level would become unpalatable or
technologically impractical (Part 4);
Æ The history of consumption of the
substance for food use by a significant
number of consumers (or animals in the
case of animal food) prior to January 1,
1958, if a conclusion of GRAS status is
based on common use of the substance
in food prior to 1958 (Part 5);
Æ A narrative that provides the basis
for your conclusion of GRAS status,
including why the scientific data,
information, methods, and principles
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described in the notice provide a basis
for your conclusion that the notified
substance is generally recognized,
among qualified experts, to be safe
under the conditions of its intended use
(Part 6); and
Æ A list of the data and information
that you discuss in the narrative of your
GRAS notice, specifying which of these
data and information are generally
available, and which of these data and
information are not generally available
(Part 7); and
• Process for you to submit an
amendment to your GRAS notice; and
• Process for you to request that we
cease to evaluate your GRAS notice.
With respect to our administration of
a GRAS notice, we specify:
• Information about how we will file
a GRAS notice, respond to it, and send
subsequent correspondence about it;
• Our commitment to respond within
180 days of filing of a GRAS notice,
with a potential to extend our response
timeframe by another 90 days;
• Our procedures in the event the
intended conditions of use of the
notified substance include use in a
product subject to regulation by the
Food Safety and Inspection Service
(FSIS) of the U.S. Department of
Agriculture (USDA); and
• Provisions governing the public
disclosure of a GRAS notice, including
the actions we take to make some
information regarding a GRAS notice
readily accessible to the public.
As of the effective date of the final
rule, we will close the docket for any
pending GRAS affirmation petition. The
petitioner may incorporate the
applicable petition into a new GRAS
notice.
Costs and Benefits
The final rule eliminates the petition
process to affirm that a substance is
GRAS under the conditions of its
intended use and replaces that petition
process with a GRAS notification
procedure. We estimate that over 10
years with a 7 percent discount rate, the
present value of the total costs of the
final rule range from $0.9 million to
$3.3 million; with a 3 percent discount
rate, the present value of the total costs
range from $0.9 million to $3.4 million.
The annualized costs of the rule range
from $0.1 million to $0.4 million with
a 7 percent discount rate and range from
$0.1 million to $0.5 million with a 3
percent discount rate. We do not
quantify the benefits of the final rule,
but assume that firms will only
participate in the GRAS notification
procedure when they expect to receive
a non-negative private benefit. The
GRAS notification procedure will allow
us to complete our evaluation within
the timelines specified in the final rule.
The following table includes a summary
of the benefits and costs of the final
rule.
SUMMARY OF BENEFITS AND COSTS OF THE FINAL RULE
Total benefits
Present value of total
costs with 7 percent
discount rate ($ mil)
Present value of total
costs with 3 percent
discount rate ($ mil)
Total annualized costs
over 10 years with 7 percent discount rate ($ mil)
Not estimated ....................
$0.9 to $3.3 .......................
$0.9 to $3.4 .......................
$0.1 to $0.4 .......................
Total annualized costs
over 10 years with 3 percent discount rate ($ mil)
$0.1 to $0.5.
TABLE OF ABBREVIATIONS AND ACRONYMS
Abbreviation/acronym
What it means
1958 amendment ...............
AAFCO ...............................
Affected petitioner ..............
BATF ..................................
CFSAN ...............................
CVM ....................................
EPA ....................................
FDA ....................................
FDAMA ...............................
FD&C Act ...........................
FOIA ...................................
FSIS ....................................
GAO ....................................
GRAS .................................
JECFA ................................
MOU ...................................
N/A ......................................
OMB ...................................
Pdf ......................................
Pending petition ..................
1958 Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act.
Association of American Feed Control Officials.
Any person who had submitted a pending petition.
Bureau of Alcohol, Tobacco, and Firearms.
Center for Food Safety and Applied Nutrition.
Center for Veterinary Medicine.
U.S. Environmental Protection Agency.
U.S. Food and Drug Administration.
1997 Food and Drug Administration Modernization Act.
Federal Food, Drug, and Cosmetic Act.
Freedom of Information Act.
Food Safety and Inspection Service of the U.S. Department of Agriculture.
Government Accountability Office.
Generally Recognized as Safe.
Joint Expert Committee on Food Additives.
Memorandum of Understanding.
Not Applicable.
Office of Management and Budget.
Portable document format.
A filed GRAS affirmation petition that is pending on the date that the petition process is replaced with a notification
procedure.
Partially hydrogenated oil.
Paperwork Reduction Act.
Alcohol and Tobacco Tax and Trade Bureau.
U.S. Department of Agriculture.
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PHO ....................................
PRA ....................................
TTB .....................................
USDA ..................................
I. Introduction
A. History of FDA’s Approach to the
GRAS Provision of the FD&C Act
In 1958, in response to public concern
about the increased use of chemicals in
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foods and food processing and with the
support of the food industry, Congress
enacted the Food Additives Amendment
(the 1958 amendment) to the FD&C Act.
The basic thrust of the 1958 amendment
was to require that, before a substance
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could be used in food, its sponsor
demonstrate the safety of the substance
to FDA, and that we establish a
regulation prescribing the conditions
under which the substance may be
safely used. The 1958 amendment
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defined the terms ‘‘food additive’’ (21
U.S.C. 321(s)) and ‘‘unsafe food
additive’’ (21 U.S.C. 348(a)), established
a premarket approval process for food
additives (21 U.S.C. 348(b) through (g)),
and amended the food adulteration
provisions of the FD&C Act to deem
adulterated any food that is, or bears or
contains, any food additive that is
unsafe within the meaning of 21 U.S.C.
348 (see 21 U.S.C. 342(a)(2)(C)).
Congress recognized that, under this
scheme, the safety of a food additive
could not be established with absolute
certainty, and thus provided for a
science-based safety standard that
requires sponsors of food additives to
demonstrate to a reasonable certainty
that no harm will result from the
intended use of an additive (Ref. 1). We
have incorporated this safety standard
into our regulations for food additives
and GRAS substances (§ 170.3(i)) (21
CFR 170.3(i)). (We note that although
this rule addresses substances intended
for use in animal food as well as
substances intended for use in human
food, in this introduction we describe
the history of the our GRAS regulations
from the perspective of human food
only.) If we find an additive to be safe,
based ordinarily on data submitted by
the sponsor to us in a food additive
petition, we promulgate a regulation
specifying the conditions under which
the additive may be safely used.
In enacting the 1958 amendment,
Congress recognized that many
substances intentionally added to food
would not require a formal premarket
review by FDA to assure their safety,
either because their safety had been
established by a long history of use in
food or by virtue of the nature of the
substance, its customary or projected
conditions of use, and the information
generally available to scientists about
the substance. Congress thus adopted, in
section 201(s) of the FD&C Act (21
U.S.C. 321(s)), a two-step definition of
‘‘food additive.’’ The first step broadly
includes any substance, the intended
use of which results or may reasonably
be expected to result, directly or
indirectly, in its becoming a component
or otherwise affecting the characteristics
of food. The second step, however,
excludes from the definition of ‘‘food
additive’’ substances that are generally
recognized, among experts qualified by
scientific training and experience to
evaluate their safety (‘‘qualified
experts’’), as having been adequately
shown through scientific procedures (or,
in the case of a substance used in food
prior to January 1, 1958, through either
scientific procedures or through
experience based on common use in
food) to be safe under the conditions of
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their intended use. Importantly, under
section 201(s) of the FD&C Act, it is the
use of a substance, rather than the
substance itself, that is eligible for
GRAS status. It is on the basis of the
GRAS provision within the food
additive definition that many
substances (such as vinegar, vegetable
oil, baking powder, and many spices,
flavors, gums, and preservatives) are
lawfully marketed today without a food
additive regulation. Under the 1958
amendment, a substance that is GRAS
for a particular use may be marketed for
that use without our review and
approval. However, when a use of a
substance does not qualify for GRAS
status or other exceptions provided
under section 201(s) of the FD&C Act,
that use of the substance is a food
additive use subject to the premarket
approval mandated by the FD&C Act. In
such circumstances, we can take
enforcement action to stop distribution
of the food substance and foods
containing it on the grounds that such
foods are or contain an unlawful food
additive.
Shortly after passage of the 1958
amendment, we clarified the regulatory
status of a multitude of food substances
that were used in food prior to 1958 and
amended our regulations to include a
list of food substances that, when used
for the purposes indicated and in
accordance with good manufacturing
practice, are GRAS. This list was
incorporated into our regulations as
§ 121.101(d) (21 CFR 121.101(d)) (now
part 182 (21 CFR part 182)) (24 FR 9368;
November 20, 1959). As part of that
rulemaking, however, we acknowledged
that it would be impracticable to list all
substances that are GRAS for their
intended use (§ 121.101(a); current
§ 182.1(a)).
Section 121.101(d) became commonly
referred to as ‘‘the GRAS list.’’ We
added other categories of substances
(e.g., spices, seasonings, and flavorings)
to the GRAS list in subsequent
rulemakings (25 FR 404, January 19,
1960; and 26 FR 3991, May 9, 1961).
Many substances that were
considered GRAS by the food industry
were not included in our GRAS list.
Under the 1958 amendment, a substance
that is GRAS under the conditions of its
intended use may be marketed for that
use without Agency review and
approval. Nonetheless, as a practical
matter, manufacturers who concluded
on their own initiative that use of a
substance qualified for GRAS status
frequently decided to obtain our
opinion on whether their conclusion
was justified. Many manufacturers
wrote to us and requested an ‘‘opinion
letter,’’ in which Agency officials would
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render an informal opinion on the
GRAS status of use of a substance.
Although convenient and expedient,
these opinion letters were often
available only to the requestor.
Moreover, these opinion letters were not
binding on us even at the time they
were issued and letters issued before
April 9, 1970, were in fact revoked (21
CFR 170.6; 35 FR 5810; April 9, 1970).
In 1969 (34 FR 17063; October 21,
1969), we deleted various cyclamate
salts, a family of nonnutritive
sweeteners, from the GRAS list because
they were implicated in the formation of
bladder tumors in rats (Ref. 2). In
response to the concerns raised by the
new information on cyclamates, thenPresident Nixon directed us to
reexamine the safety of GRAS
substances (Ref. 3), and we announced
that we were conducting a
comprehensive study of substances
presumed to be GRAS (35 FR 18623;
December 8, 1970). The purpose of the
study was to evaluate, by contemporary
standards, the available safety
information regarding substances
presumed to be GRAS and to
promulgate each item in a new (i.e.,
affirmed) GRAS list, a food additive
regulation, or an interim food additive
regulation pending completion of
additional studies.
In the notice announcing the
comprehensive review of presumed
GRAS substances, we proposed criteria
that could be used to establish whether
these substances should be listed as
GRAS, become the subject of a food
additive regulation, or be listed in an
interim food additive regulation
pending completion of additional
studies (35 FR 18623). These criteria
were incorporated into our regulations
as § 121.3 (precursor of current § 170.30)
(36 FR 12093; June 25, 1971).
We made a second announcement
that we were conducting a study of
presumed GRAS substances (36 FR
20546; October 23, 1971) and
subsequently instituted a rulemaking to
establish procedures that we could use,
on our own initiative, to affirm the
GRAS status of substances that were the
subject of that review and were found to
satisfy the criteria established in § 121.3
(proposed rule, 37 FR 6207, March 25,
1972; final rule, 37 FR 25705, December
2, 1972). These procedures were
subsequently codified at § 170.35(a) and
(b). Because the GRAS review did not
cover all GRAS substances (e.g., it did
not cover many substances that were
marketed based on a manufacturer’s
independent conclusion of GRAS
status), that rulemaking included a
mechanism (the GRAS affirmation
petition process; § 170.35(c)) whereby
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an individual could petition us to
review the GRAS status of substances
not being considered as part of our
GRAS review. We codified our
affirmations of GRAS status in current
parts 184 and 186 (21 CFR parts 184 and
186).
In 1974, we proposed to clarify the
criteria for GRAS status, the differences
between GRAS status and food additive
status, and the procedures being used to
conduct the current review of food
substances (39 FR 34194; September 23,
1974). The final regulations based on
this proposal amended § 121.3 (now
§ 170.30) to distinguish a conclusion of
GRAS status through scientific
procedures (§ 170.30(b)) from a
conclusion of GRAS status through
experience based on common use in
food (§ 170.30(c)) (41 FR 53600;
December 7, 1976). Those final
regulations also established definitions
for ‘‘common use in food’’ (now
§ 170.3(f)) and ‘‘scientific procedures’’
(now § 170.3(h)). We subsequently
added criteria (§ 170.30(c)(2)) for the
determination of GRAS status through
experience based on common use in
food when that use occurred exclusively
or primarily outside of the United States
(53 FR 16544; May 10, 1988).
To the extent that a person elected to
submit a GRAS affirmation petition, the
GRAS affirmation process could
facilitate awareness, by us as well as the
domestic and international food
industry, of independent conclusions of
GRAS status. However, the GRAS
affirmation petition process involved
the resource-intensive rulemaking
process. In the Federal Register of April
17, 1997 (62 FR 18938; the proposed
rule), we proposed to: (1) Clarify the
criteria for eligibility for classification as
GRAS; and (2) replace the GRAS
affirmation petition process with a
notification procedure whereby any
person may notify us of a conclusion
that a particular use of a substance is
GRAS. We explained that we would
evaluate whether the notice provides a
sufficient basis for a GRAS conclusion
and whether information in the notice
or otherwise available to us raises issues
that lead us to question whether use of
the substance is GRAS. We would
respond to the notifier in writing and
could advise the notifier that we had
identified a problem with the notice.
Although information in a notice would
be publicly available consistent with the
Freedom of Information Act (FOIA), we
would make readily accessible to the
public a basic description the notified
substance, the conditions of its intended
use, and the statutory basis for GRAS
status (i.e., through scientific
procedures or through experience based
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on common use in food), as well as our
response to the notice. In 2010, we
reopened the comment period for the
proposed rule to update comments and
to solicit comment on specific issues (75
FR 81536, December 28, 2010; the 2010
notice). (See section II.D for additional
information about this reopening of the
comment period).
In the proposed rule, we invited
interested persons to notify us about
their conclusions of GRAS status as
described in the proposed rule (62 FR
18938 at 18954; the ‘‘Interim Pilot
program’’). Our Center for Food Safety
and Applied Nutrition (CFSAN) filed its
first GRAS notice in 1998 and has filed
614 GRAS notices as of December 31,
2015. Our Center for Veterinary
Medicine (CVM) established its Interim
Pilot program more recently (75 FR
31800, June 4, 2010) and filed its first
GRAS notice in December 2010. As of
December 31, 2015, CVM has filed 18
GRAS notices.
B. Report by the Government
Accountability Office and How We Are
Addressing Its Recommendations
From 2008 to 2010, the Government
Accountability Office (GAO) conducted
a study related to ingredients used in
human food on the basis of the GRAS
provision in section 201(s) of the FD&C
Act. In 2010, GAO issued a report (Ref.
4; the GAO report) that included a
number of recommendations for FDA.
For example, the GAO report
recommended that we finalize the
proposed rule to establish a notification
program for GRAS substances, strive to
minimize the potential for conflict of
interest on ‘‘GRAS panels,’’ issue
guidance on how to document GRAS
conclusions, and obtain more
information about the use of engineered
nanomaterials. (As we note in section
VI.B, this document uses the term
‘‘GRAS panel’’ to mean a panel of
individuals convened for the purpose of
evaluating whether the available
scientific data, information, and
methods establish that a substance is
safe under the conditions of its intended
use in food.) Consistent with the
recommendations in the GAO report,
this document finalizes the GRAS
notification procedure as requested by
GAO. It also announces our intent to
issue guidance in the near future to: (1)
Provide recommendations regarding the
use of a ‘‘GRAS panel,’’ including the
potential for conflict of interest; and (2)
remind the food industry that the same
standards apply to a conclusion of
GRAS status regardless of whether the
conclusion is submitted to us as a GRAS
notice or is not submitted to us. (See
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Response 125, Response 128, and
Response 129).
In 2012, we made available a draft
guidance entitled ‘‘Draft Guidance for
Industry: Assessing the Effects of
Significant Manufacturing Process
Changes, Including Emerging
Technologies, on the Safety and
Regulatory Status of Food Ingredients
and Food Contact Substances, Including
Food Ingredients That Are Color
Additives’’ (Ref. 5) (77 FR 24722, April
25, 2012). We finalized this guidance in
2014 (Ref. 6) (79 FR 36533, June 27,
2014). The guidance includes
recommendations for assessing the
effect of a significant manufacturing
process change (including the use of
nanotechnology) on the safety and
regulatory status of substances used in
human food, including those that are
GRAS. In this guidance, we stated that,
at present, for nanotechnology
applications in food substances, there
are questions related to the technical
evidence of safety as well as the general
recognition of that safety, that are likely
to be sufficient to warrant formal
premarket review and approval by FDA,
rather than to satisfy criteria for GRAS
status. In addition, in 2011, we made
available a draft guidance entitled
‘‘Considering Whether an FDARegulated Product Involves the
Application of Nanotechnology’’ (Ref. 7)
(76 FR 34715, June 14, 2011). We
finalized this guidance in 2014 (Ref. 8)
(June 27, 2014, 79 FR 36534), which
describes our thinking on determining
whether FDA-regulated products
involve the application of
nanotechnology.
C. Issues Regarding the Legal and
Regulatory Framework for Substances
Added to Food
The GAO report discussed issues
fundamental to the legal and regulatory
framework for our oversight of the safety
of substances added to food, such as the
voluntary nature of the GRAS
affirmation petition process and the
proposed GRAS notification procedure.
In light of these issues, the GAO report
recommended that we ask any company
evaluating whether a substance is GRAS
under the conditions of its intended use
to provide us with basic information
about any conclusion of GRAS status
(Ref. 4). Some comments to this
rulemaking raise similar issues. For
example, some comments address the
voluntary nature of the GRAS
notification procedure or assert that we
have implied legal authority to require
that companies notify us of a conclusion
of GRAS status (see Comment 1 and
Comment 28). Some comments ask us to
require companies to maintain active
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and accurate listings for all GRAS
substances, not just those that are the
subject of a GRAS regulation or a GRAS
notice, in a public database (see
Comment 3). Some comments ask us to
require certain postmarket submissions
of exposure and safety data related to all
GRAS substances, to require
submissions for conclusions of GRAS
status that predate the final rule, and to
require any notifier who ‘‘withdraws’’ a
GRAS notice or receives an ‘‘insufficient
basis letter’’ to notify us about any use
of that substance (see Comment 30). One
comment asks us to exclude uses of
‘‘novel’’ substances from consideration
for eligibility for classification as GRAS
(see Comment 19).
Some comments discuss an industry
practice of convening a ‘‘GRAS panel’’
of ‘‘qualified experts’’ to provide an
opinion on whether a company’s
evaluation of the available data and
information support a conclusion that a
substance is safe under the conditions of
its intended use, and express concern
that such a ‘‘GRAS panel’’ may base its
opinion partly on confidential data and
information that are provided to the
GRAS panel, but not provided to us in
a submitted GRAS notice (see Comment
10 through Comment 14, Comment 69,
and Comment 78).
Some comments express concern that
the GRAS notification procedure would
be viewed as a ‘‘fast-track’’ option that
would tempt a company that should
submit a food additive petition to
submit a GRAS notice instead (see
Comment 32). A published critique of
the GRAS notification procedure (Ref. 9)
likewise expresses concern that industry
is simply using the GRAS notification
procedure as an alternative to the food
additive petition process, contrasting
the number of food additive petitions
filed in recent years with the number of
GRAS notices filed in recent years. This
report also expresses concern that there
are an indeterminate—but not
insignificant—number of industry
conclusions of GRAS status that are not
the subject of a GRAS notice to FDA.
In this document, we respond to such
comments in the context of our
proposed revisions to the criteria for
eligibility for classification as GRAS and
our proposal to replace one voluntary
administrative procedure, i.e., the GRAS
affirmation petition process, with a
different voluntary administrative
procedure, i.e., the GRAS notification
procedure. (See Response 1, Response 3,
Response 10 through Response 14,
Response 19, Response 28, Response 30,
Response 32, Response 69, and
Response 78). As we discuss in
Response 28, the broader issues raised
by these comments about the legal and
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regulatory framework for our oversight
of the safety of substances added to food
are outside the scope of this rulemaking.
Thus, this final rule does not address
the possibility that we might enhance
our oversight through additional
rulemaking or other actions based on
our current legal authority. Nonetheless,
we will continue to consider the broader
issues raised by these comments and
take further action as appropriate under
our existing authority through future
rulemaking. Importantly, however, this
final rule does establish uniform criteria
for describing the basis for a conclusion
that a substance is GRAS under the
conditions of its intended use, and those
uniform criteria apply to all conclusions
of GRAS status, not just conclusions of
GRAS status that are submitted to us as
a GRAS notice. As discussed in
Response 129, we are issuing a guidance
directed to any person who evaluates
whether the available data and
information regarding the safety of a
substance under the conditions of its
intended use satisfy GRAS criteria. The
purpose of the guidance is to: (1)
Remind such persons of their
responsibilities under the FD&C Act
regarding a conclusion of GRAS status,
regardless of whether the conclusion of
GRAS status is submitted to us as a
GRAS notice; and (2) refer such persons
to key resources, such as those
discussed in Response 128, for
evaluating the safety of the substance
under the conditions of its intended use
and for evaluating whether the available
data and information regarding safety
satisfy the criteria for eligibility for
classification as GRAS in § 170.30.
D. Recent FDA Actions Related to GRAS
Criteria
In the following paragraphs, we
describe two examples of steps we have
taken to address concerns about the
safety of certain substances marketed
under the GRAS provision. The first
example is partially hydrogenated oils
(PHOs), which are the primary dietary
source of industrially produced trans
fatty acids, or trans fat. The second
example is certain uses of caffeine.
Although we had not listed the most
commonly used PHOs in either part 182
or part 184, they had been used in food
for many years based on conclusions of
GRAS status by industry. In a notice
published in the Federal Register of
November 8, 2013 (78 FR 67169), we
described new scientific evidence and
the findings of expert scientific panels
regarding trans fat and requested
comments and scientific data and
information on our tentative
determination that PHOs are not GRAS
for any use in food based on current
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scientific evidence establishing the
health risks associated with the
consumption of trans fat. In the Federal
Register of June 17, 2015 (80 FR 34650),
we issued a declaratory order
announcing our final determination that
there is no longer a consensus among
qualified experts that PHOs are GRAS
for any use in human food.
The GRAS list in part 182 includes
the use of caffeine in cola-type
beverages at a maximum level of 0.02
percent (§ 182.1180). In 2010, we issued
four warning letters regarding the use of
caffeine under markedly different
conditions of use than the use listed in
§ 182.1180, i.e., the use of caffeine as an
added ingredient in alcoholic beverages
(Ref. 10 through Ref. 13). In our letters,
we stated that, based on the publicly
available literature, a number of
qualified experts have concerns about
the safety of caffeinated alcoholic
beverages. We described these concerns,
citing published literature. We further
stated that FDA is not aware of data or
other information to establish the safety
of caffeine as used in these products.
We therefore informed the companies
who were marketing these caffeinated
alcoholic beverages that caffeine, as
used in the companies’ products, is an
unsafe food additive, and therefore the
products are adulterated under section
402(a)(2)(C) of the FD&C Act (21 U.S.C.
342(a)(2)(C)). (The Alcohol and Tobacco
Tax and Trade Bureau (TTB) also
notified the four companies that if we
deem their caffeinated alcohol beverage
products adulterated under the FD&C
Act, TTB would consider them to be
mislabeled under the Federal Alcohol
Administration Act, making it a
violation for industry members to sell or
ship the products in interstate or foreign
commerce (Ref. 14).) The companies
subsequently ceased distribution of
these products.
In recent years, other food and
beverage products containing caffeine as
an added substance have been
introduced into the marketplace,
including so-called ‘‘energy drinks’’ that
are frequently marketed for their
stimulant properties. When there are
new uses of an added food substance
without FDA’s premarket engagement,
presumably because a manufacturer has
concluded that such a use is GRAS, we
must react to the new uses after they
emerge. In such cases, it can be
challenging for FDA to accurately assess
consumption patterns and intake levels
and to determine whether those new
uses are safe and lawful in light of all
of the available safety data. FDA has
engaged with the National Academies of
Science (Ref. 15), trade associations, and
other industry representatives, some of
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whom are conducting a systematic
review on the health effects associated
with the consumption of caffeine (Ref.
16 and Ref. 17).
E. Moving Forward Under This Final
Rule
We believe that our filing of more
than 600 GRAS notices for substances
used in human food is evidence that the
substitution of a GRAS notification
procedure for the GRAS affirmation
petition process has benefits for
consumers, FDA, the regulated industry,
and other stakeholders. We have
increased our awareness of the
composition of the nation’s food supply
and the dietary exposure to GRAS
substances, which helps us to ensure
the safe use of substances added to food.
The ongoing submission of GRAS
notices provides evidence that our
response to a GRAS notice can support
the marketing of a food substance by the
regulated industry. Notified substances
include substances that are intended to
address food safety problems (e.g.,
antimicrobial substances and substances
intended to reduce acrylamide
formation) and public health issues
(e.g., substances that would reduce
levels of sodium chloride in food). In
addition, the letters we issue responding
to GRAS notices demonstrate that we
inform notifiers of any scientific or
regulatory issues that call into question
a notifier’s conclusion of GRAS status,
and stakeholders have ready access to
those letters. As discussed in Response
81, we intend to increase the
transparency of our response letters
when a notifier asks us to cease to
evaluate a GRAS notice.
In the years since we published the
proposed rule, we have taken important
public health actions with respect to
substances used in food on the basis of
the GRAS provision of the FD&C Act.
For example, we recently announced an
initiative to establish voluntary shortterm and long-term goals for sodium
reduction in a variety of identified
categories of foods to address the
excessive intake of sodium in the
current population and promote
improvements in public health (81 FR
35363, June 2, 2016). In addition, we
recently held a public meeting in which
we invited public comment on what
should be included, changed, or even
excluded from our guidance entitled
‘‘Guidance for Industry and Other
Stakeholders: Toxicological Principles
for the Safety Assessment of Food
Ingredients’’ (79 FR 64603, October 30,
2014); that guidance is intended to help
interested parties understand our
expectations regarding how to
determine which toxicity studies are
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appropriate and regarding the design,
conduct, and reporting of the results of
toxicity studies and applies to assessing
the safety of GRAS substances. As
discussed in section I.D, we also have
taken key postmarket actions such as
issuing a declaratory order announcing
our final determination that there is no
longer a consensus among qualified
experts that PHOs are GRAS for any use
in human food, as well as issuing
warning letters regarding the use of
caffeine as an added ingredient in
alcoholic beverages.
For reasons such as those discussed in
this section, and after fully considering
comments submitted to this rulemaking,
this rule announces that we are
replacing the former GRAS affirmation
petition process with a GRAS
notification procedure.
We strongly encourage any company
considering the addition of a substance
to any food on the basis of a conclusion
of GRAS status to contact us and follow
the available procedures for FDA
oversight of such decisions. As we move
forward to implement the GRAS
notification procedure that is the subject
of this rulemaking, we intend to
continue to closely monitor and assess
the ramifications of the use of
substances without food additive
approval or evaluation by FDA through
the GRAS notification procedure. We
intend to take action as appropriate,
such as we did in the case of PHOs and
caffeinated alcoholic beverages,
particularly when the available data and
information raise a safety concern about
the use of a substance.
We advise any company that intends
to market a food substance on the basis
of an independent conclusion of GRAS
status (i.e., a conclusion of GRAS status
that would remain with the proponent
of the conclusion rather than be
submitted to us as a GRAS notice) to
carefully consider whether this use fully
satisfies the criteria for eligibility for
classification as GRAS and to carefully
review the discussions in this document
relevant to those criteria. Fundamental
to all conclusions of GRAS status is the
criterion that general recognition of
safety requires common knowledge
throughout the scientific community
knowledgeable about the safety of
substances directly or indirectly added
to food that there is reasonable certainty
that the substance is not harmful under
the conditions of its intended use (see
§ 170.30(a)). In addition, the criteria for
eligibility for classification as GRAS
through scientific procedures require
that general recognition of safety
through scientific procedures be based
upon the application of generally
available and accepted scientific data,
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information, or methods, which
ordinarily are published, as well as the
application of scientific principles
(§ 170.30(b)). Although general
recognition of safety through scientific
procedures may be corroborated by the
application of unpublished scientific
data, information, or methods
(§ 170.30(b)), to satisfy GRAS criteria
qualified experts must be able to
conclude that the substance is not
harmful under the conditions of its
intended use without access to
‘‘corroborative’’ information (see, e.g.,
Response 9). For example, as discussed
in Response 69 there could be no basis
for a conclusion of GRAS status if trade
secret information (or other non-public
information) is necessary for qualified
experts to reach a conclusion that the
notified substance is safe under the
conditions of its intended use.
We also advise any company who
intends to market a food substance on
the basis of an independent GRAS
conclusion that relies, in whole or in
part, on the opinion of a specially
convened ‘‘GRAS panel’’ to carefully
review the discussions in this document
regarding whether and how the opinion
of a GRAS panel can support an
independent conclusion of GRAS status.
For example, as discussed in Response
10 and Response 11 whether a
published ‘‘GRAS panel’’ opinion that
discusses data and information that are
available to the members of the GRAS
panel, but not generally available to
qualified experts, could support an
independent conclusion of GRAS status
would depend on factors such as
whether that publication includes
details similar to details that would be
included in a publication in the primary
scientific literature; the subject matter
expertise of the members of the GRAS
panel; and whether the members of the
GRAS panel would be considered
representative of experts qualified by
scientific training and experience to
evaluate the safety of the substance
under the conditions of its intended use.
For example, a published GRAS panel
opinion that includes a very general
statement that a study was conducted
and reported no adverse findings would
not suffice to make the study ‘‘generally
available’’ as required by the criteria for
eligibility for classification as GRAS and
would merely be a generally available
opinion about data and information that
are not generally available. As another
example, a ‘‘GRAS panel’’ opinion
published by scientists without
expertise appropriate to address the
applicable safety questions could not
provide evidence that the conclusions
in the publication are ‘‘generally
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accepted.’’ Unless both criteria, i.e.,
‘‘generally available’’ as well as
‘‘generally accepted’’, are satisfied, there
would be no basis for a conclusion of
GRAS status.
II. Background
A. The Proposed Rule
We proposed to: (1) Clarify the criteria
for eligibility for classification as GRAS;
and (2) replace the GRAS affirmation
petition process with a notification
procedure through which any interested
person may notify us of a determination
that a particular use of a substance is
GRAS (62 FR 18938). In the proposed
rule, we:
• Discussed the 1958 amendment,
including judicial decisions bearing on
GRAS criteria and the burden on the
proponent of a conclusion of GRAS
status to show that there is a consensus
of expert opinion regarding the safety of
the use of the substance (62 FR 18938
at 18939);
• Described the history of our
approach to the GRAS provision,
including: (1) A GRAS list, first
established in 1959, in which we
clarified the regulatory status of a
multitude of food substances that were
used in food prior to 1958; (2) opinion
letters in which Agency officials
rendered an informal, non-binding
opinion on the GRAS status of a use of
a substance; (3) an FDA-initiated GRAS
review to evaluate the available safety
information regarding substances
presumed to be GRAS; and (4) GRAS
criteria and the GRAS affirmation
petition process (62 FR 18938 at 18939
to 18940);
• Discussed ‘‘elements of the GRAS
standard,’’ in which we distinguished
the ‘‘technical element’’ of the GRAS
standard (i.e., safety) from the ‘‘common
knowledge element’’ of the GRAS
standard (i.e., general recognition) (62
FR 18938 at 18940 to 18941);
• Proposed the submission
requirements for the GRAS notification
procedure, including: (1) A ‘‘GRAS
exemption claim,’’ in which a notifier
would take responsibility for a GRAS
determination; (2) information about the
identity of the notified substance; (3)
information about any self-limiting
levels of use; and (4) a comprehensive
discussion of the basis for the GRAS
determination (proposed §§ 170.36 (c)
and 570.36(c));
• Proposed what we would do when
we received a GRAS notice, including:
(1) Acknowledge receipt of the GRAS
notice; (2) evaluate whether the notice
provides a sufficient basis for a GRAS
determination and respond to the
notifier in writing; (3) make readily
accessible to the public the notice’s
‘‘GRAS exemption claim’’ and our
response to the notice; and (4) disclose
other releasable information in a notice
in accordance with our regulations, in
part 20 (21 CFR part 20), implementing
the FOIA (proposed §§ 170.36 (d)
through (f) and 570.36(d) through (f));
and
• Proposed to: (1) Convert any GRAS
affirmation petition that was pending on
the effective date of the rule establishing
the notification procedure to a GRAS
notice; and (2) require the petitioner to
submit an amendment to the converted
petition to satisfy the procedural
requirements of the GRAS notification
procedure (proposed §§ 170.36(g) and
570.36(g)).
We requested comments on the
proposed rule by July 16, 1997.
B. Interim Pilot Program
In the proposed rule, we invited
interested persons who determine that a
54967
use of a substance is GRAS to notify us
of those determinations as described in
the proposed rule (62 FR 18938 at
18954). We explained that we would
administer the notices as described in
the proposed rule (i.e., we would
acknowledge receipt of the notice,
respond in writing to the notifier, and
make publicly accessible a copy of all
‘‘GRAS exemption claims’’ and our
response). Although we would make a
good faith effort to respond within the
proposed 90-day timeframe, we would
not be bound by such a timeframe. We
stated that we would determine whether
our experience in administering such
notices suggests modifications to the
proposed procedure.
CFSAN received its first GRAS notice
in 1998. CFSAN wrote a memorandum
documenting its experience in
evaluating GRAS notices during the
period 1998–2009 (Ref. 18, ‘‘CFSAN’s
2010 experience document’’) and added
that memorandum to the docket for this
rulemaking in 2010. Unless we say
otherwise, the discussions in this
document referring to FDA’s experience
during the Interim Pilot program refer to
CFSAN’s experience.
During the Interim Pilot program,
CFSAN’s response to a GRAS notice fell
into three categories as shown in table
1 in this document. We refer to these
categories of response throughout this
document. Table 1 in CFSAN’s 2010
experience document shows the
category of response for CFSAN’s GRAS
notices that came to closure by
December 31, 2009. CFSAN has now
written an updated memorandum
showing the category of response for
CFSAN’s GRAS notices that came to
closure by December 31, 2015 (Ref. 19).
TABLE 1—CATEGORIES OF LETTERS RESPONDING TO A GRAS NOTICE DURING THE INTERIM PILOT PROGRAM
Category of response letter
Typical text of the response
‘‘No questions letter’’ .......................
Based on the information provided by the notifier, as well as other information available to FDA, the Agency has no questions at this time regarding the notifier’s conclusion that the notified substance is GRAS
under the intended conditions of use. The Agency has not, however, made its own determination regarding the GRAS status of the subject use of the notified substance. As always, it is the continuing responsibility of the notifier to ensure that food ingredients that the firm markets are safe, and are otherwise in
compliance with all applicable legal and regulatory requirements.
FDA has evaluated the information that the notifier discusses in its GRAS notice as well as other data and
information that are available to us. The notice does not provide a sufficient basis for a determination
that the notified substance is GRAS under the conditions of its intended use.
In correspondence dated [month, day, year], you asked that we cease to evaluate your notice. We ceased
to evaluate your GRAS notice, effective the date we received your correspondence.
‘‘Insufficient basis letter’’ .................
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‘‘Cease to evaluate letter’’ ..............
In this document, we frequently cite
CFSAN’s experience during the Interim
Pilot program when responding to
comments asking us to clarify how we
intend to administer various provisions
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of the rule, as well as state our intent to
continue the applicable practice in the
future, because this experience is
relevant to our administration of the
GRAS notification program.
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Nonetheless, we intend to adapt our
practices, consistent with the provisions
of this rule, as circumstances warrant
and as necessary to administer the
GRAS notification program consistent
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with appropriate public health policy,
current scientific information, our
available resources, and the scientific
and regulatory issues raised by specific
GRAS notices. For example, as
discussed in Response 92 we intend to
continue to include standard language
such as that shown in table 1 in
responding to GRAS notices. However,
this language may evolve over time.
CVM established its Interim Pilot
program in June, 2010 (75 FR 31800,
Docket No. FDA–2010–N–0215) and
filed its first GRAS notice in December
2010. CVM did not have any experience
to document as of 2010 and, thus, had
not written its own experience
document at that time. As of December
31, 2015, CVM had responded to 18
GRAS notices, and has now
documented its experience with those
18 GRAS notices with respect to some
comments specifically directed to the
GRAS notification procedure
administered by CVM (Ref. 20; ‘‘CVM’s
experience document’’). We discuss
CVM’s experience with GRAS notices
submitted for substances intended for
use in animal food in section XXV.
We are ending both the CFSAN
Interim Pilot program announced in the
proposed rule, and the CVM pilot
program announced in Docket No.
FDA–2010–N–0215, as of October 17,
2016. On that date, the final rule
becomes effective and will govern the
GRAS notification procedure.
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C. 2010 Report of the Government
Accountability Office
As noted in section I.B, from 2008 to
2010 GAO conducted a study related to
ingredients used in human food on the
basis of the GRAS provision of section
201(s) of the FD&C Act. In 2010, GAO
issued a report (Ref. 4) that included a
number of recommendations for FDA.
We responded to the GAO’s
recommendations, and that response is
also included in the GAO report.
D. 2010 Notice Reopening the Comment
Period
As noted in section I.A, we reopened
the comment period for the proposed
rule to update comments (75 FR 81536).
We did so because of the length of time
that had elapsed since publication of the
proposed rule and because we had
identified a number of issues within the
scope of the proposed rule that may
require further clarification based on
CFSAN’s experience with GRAS notices
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during the Interim Pilot program,
comments we received on the proposed
rule, and GAO’s recommendations (75
FR 81536 at 81537). These issues related
to the proposed revisions to the criteria
for eligibility for classification as GRAS
(Issue 1), the proposed establishment of
a notification procedure (Issues 2
through 16), and the effect of the
proposed notification procedure on
existing GRAS affirmation petitions
(Issue 17). Accordingly, we requested
comments, by March 28, 2011, on the
entire proposed rule as well as on the
specific issues identified in the 2010
notice.
In Issue 2 in the 2010 notice, we
explained our reasons for tentatively
concluding that the terms ‘‘conclude’’
and ‘‘conclusion’’ would be more
appropriate in lieu of ‘‘determine’’ and
‘‘determination’’ and requested
comment on these terms. In the
remainder of this document, we
generally use the terms ‘‘conclude’’ and
‘‘conclusion’’ in lieu of ‘‘determine’’ and
‘‘determination’’ except when we are
describing provisions of the proposed
rule (see Response 41).
E. Public Comments
We received submissions, each
containing one or more comments, from
diverse members of the public,
including manufacturers; trade
organizations; consulting firms; law
firms; public advocacy groups; nonprofit organizations; individuals; a
Federal Agency; and other
organizations. In the remainder of this
document, we describe these comments,
respond to them, and explain any
revisions we made to the proposed rule.
Some comments address issues that
are outside the scope of this rule. For
example, some comments ask us to add
a new definition to part 170, to define
the term ‘‘harm’’ that is used in our
current definition of ‘‘safe’’ or ‘‘safety’’
(§ 170.3(e)(i)) (where ‘‘safe’’ or ‘‘safety’’
means that there is a reasonable
certainty in the minds of competent
scientists that the substance is not
harmful under the intended conditions
of use). We did not propose to add a
definition of the term ‘‘harm’’ or ask for
comment on whether we should do so,
and adding a new definition in the final
rule for a term that is used in the
definition of ‘‘safe’’ and ‘‘safety’’ would
broadly affect our regulations for food
additives and GRAS substances without
opportunity for public comment. As
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another example, one comment asks us
to prepare an alphabetical index of food
additive and GRAS regulations and cites
the alphabetical list in our
Investigations Operations Manual as
evidence that it is feasible to develop
such a list. Regardless of whether it is
feasible to develop such a list, doing so
is not within the scope of our proposal
to establish a notification procedure for
uses of substances that are not listed in
our regulations. We do not discuss such
comments in this document.
F. Applicability of Discussions in This
Document to Both the Human Food
Regulations and the Animal Food
Regulations
To simplify the discussion in this
document, in general we refer to
provisions of the proposed rule and the
2010 notice from the perspective of the
regulations that would be established in
part 170. Unless we say otherwise,
however, the issues discussed also
apply to the corresponding provisions
for part 570. Any reference to CFSAN
documents (such as guidance
documents) is specific to CFSAN. See
section XXV for a discussion of
comments and issues specifically
directed to substances used in animal
food.
G. Use of Pronouns in This Document
In this document, terms such as ‘‘we,’’
‘‘our,’’ and ‘‘us’’ refer to FDA. The
regulatory text of the final rule for the
GRAS notification procedure specifies
that the terms ‘‘you’’ and ‘‘your’’ refer to
a notifier (i.e., a person who is
responsible for a GRAS notice). To
simplify the discussion in this
document, in general we use pronouns
such as ‘‘you’’ and ‘‘your’’ to refer to a
notifier, even though some persons who
read this document may not be notifiers.
H. Summary of Principal Changes to the
Proposed Notification Procedure
In table 2, we briefly describe the
principal changes to the GRAS
notification procedure in the final rule
compared to the proposed rule. In the
remainder of this document, we discuss
each of these changes in more detail,
including our response to comments
relevant to these changes. See table 28
for principal changes that are specific to
the GRAS notification procedure for
substances used in animal food in part
570.
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TABLE 2—SUMMARY OF PRINCIPAL CHANGES TO THE PROPOSED NOTIFICATION PROCEDURE
Proposed rule
Final rule
Would not define any terms .....................................................................
Defines the terms ‘‘amendment,’’ ‘‘GRAS,’’ ‘‘GRAS notice,’’ ‘‘notified
substance,’’ ‘‘notifier,’’ ‘‘qualified expert,’’ ‘‘supplement,’’ ‘‘we, our,
and us,’’ and ‘‘you and your.’’
Refers to a ‘‘GRAS conclusion’’ or ‘‘conclusion of GRAS status.’’
Refers to the statutory GRAS provision as an ‘‘exclusion.’’
Uses ‘‘Plain Language’’ techniques such as pronouns and short regulatory sections.
Referred to a ‘‘GRAS determination’’ .......................................................
Referred to the statutory GRAS provision as an ‘‘exemption’’ ................
Would not use ‘‘Plain Language’’ techniques as outlined in a Presidential Memorandum dated June 1, 1998 (Ref. 21) and in ‘‘Improving
Electronic Dockets on Regulations.gov and the Federal Docket Management System: Best Practices for Federal Agencies’’ (Ref. 22).
Was silent on whether you could incorporate into your GRAS notice
specifically identified data and information previously submitted to
CFSAN or CVM.
Would not specify individual parts of a GRAS notice ..............................
Would require three paper copies of a GRAS notice ..............................
Referred to dated and signed statements in a GRAS notice as a
‘‘claim’’.
Assumed that a notice will not contain any information that is protected
from public disclosure under the FOIA.
Would require that you inform us of the ‘‘common or usual name’’ of
the notified substance.
Would not require that you state your view as to whether any data and
information in your GRAS notice are exempt from disclosure under
the FOIA.
Would not expressly require a signed certification regarding the representative and balanced nature of the GRAS notice.
For a notified substance of natural biological origin, would require
source information such as genus and species.
Would require the method of manufacture (excluding any trade secrets)
Would not expressly require relevant data and information bearing on
the physical or other technical effect the notified substance is intended to produce.
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Would require consideration of dietary exposure as part of a comprehensive discussion of the data and information that you rely on to
establish safety, using the statutory language of section 409(c)(5)(A)
and (B) of the FD&C Act.
Would require a ‘‘comprehensive discussion’’ of, and citations to, generally available and accepted scientific data, information, methods, or
principles that you rely on to establish safety.
Would not require consideration of dietary exposure as part of a comprehensive discussion of the data and information that you rely on to
establish safety for a conclusion of GRAS status through experience
based on common use in food.
Would require a comprehensive discussion of any reports of investigations or other information that may appear to be inconsistent with the
GRAS determination.
Would not require that you identify data and information that you view
as exempt from disclosure under the FOIA.
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Expressly provides for you to incorporate into your GRAS notice specifically identified data and information previously submitted to
CFSAN or CVM.
Specifies the seven parts of a GRAS notice.
Provides that you may submit a GRAS notice either in electronic format that is accessible for our evaluation or on paper. If you send
your GRAS notice on paper, a single paper copy is sufficient.
Refers to dated and signed statements in a GRAS notice as ‘‘signed
statements.’’
Specifies that you must not include any information that is trade secret
or confidential commercial information in certain sections of the
signed statements in your GRAS notice, but does not otherwise prohibit the submission of information that is protected from public disclosure under the FOIA.
Requires that you provide an ‘‘appropriately descriptive term’’ for the
notified substance.
Requires that you state your view as to whether any of the data and information in your GRAS notice are exempt from disclosure under the
FOIA (e.g., as trade secret or as commercial or financial information
that is privileged or confidential).
Expressly requires a signed certification that to the best of your knowledge, your GRAS notice is a complete, representative, and balanced
submission that includes unfavorable information, as well as favorable information, known to you and pertinent to the evaluation of the
safety and GRAS status of the use of the substance.
For a notified substance of natural biological origin, requires source information that includes applicable data and information at the subspecies level (e.g., variety, strain) in addition to genus and species.
Requires a description of the method of manufacture of the notified
substance in sufficient detail to evaluate the safety of the notified
substance as manufactured; you may include trade secret information.
When necessary to demonstrate safety, expressly requires relevant
data and information bearing on the physical or other technical effect
the notified substance is intended to produce, including the quantity
of the notified substance required to produce such effect.
Separates the statutory language of section 409(c)(5)(A) and (B) of the
FD&C Act into two distinct parts of the GRAS notice: (1) Part 3,
which addresses how much of the notified substance consumers
would eat as part of the total diet (including exposure from its intended use and all sources in the diet), as well as how much consumers would eat of other substances (e.g., contaminants or byproducts); and (2) Part 6, which requires that you address, in your
narrative, the safety of the notified substance, considering all dietary
sources and taking into account any chemically or pharmacologically
related substances in such diet.
Requires a narrative (Part 6 of a GRAS notice) and a list of supporting
data and information (Part 7 of a GRAS notice).
Expressly requires consideration of dietary exposure, regardless of
whether your conclusion of GRAS status is through scientific procedures or through experience based on common use in food.
Requires that you either: (1) Identify, discuss, and place in context,
data and information that are, or may appear to be, inconsistent with
your conclusion of GRAS status; or (2) state that you have reviewed
the available data and information and are not aware of any data
and information that are, or may appear to be, inconsistent with your
conclusion of GRAS status.
If you view any of the data and information in your notice as exempt
from disclosure under the FOIA, requires that you identify the specific data and information.
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TABLE 2—SUMMARY OF PRINCIPAL CHANGES TO THE PROPOSED NOTIFICATION PROCEDURE—Continued
Proposed rule
Final rule
Would not require that you explain how there could be a basis for a
conclusion of GRAS status if qualified experts generally do not have
access to non-public, safety-related data and information.
Would require that the comprehensive discussion include the basis for
concluding that there is consensus among qualified experts that
there is reasonable certainty that the substance is not harmful under
the intended conditions of use.
Was silent on whether you could submit an amendment to a GRAS notice.
Requires that you explain how there could be a basis for a conclusion
of GRAS status if qualified experts generally do not have access to
non-public, safety-related data and information.
Uses the term ‘‘generally recognized’’ rather than the term ‘‘consensus.’’
Considered that it was implicit that you could ask us to cease to evaluate a GRAS notice.
We would acknowledge receipt of a GRAS notice within 30 days of receipt.
We would respond to you in writing within 90 days of receipt of the notice.
Was silent on procedures that apply when the intended conditions of
use of a notified substance include use in a product or products subject to regulation by USDA’s FSIS.
We noted that, although the decision to submit a GRAS notice would
be voluntary, the provisions governing the GRAS notification procedure, including the information to be submitted, would be mandatory.
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Was silent on whether you could submit additional information to a
GRAS notice after we respond to it.
Would presumptively convert any filed, pending GRAS affirmation petition to a notice on the effective date of the rule. If we did not receive
an amendment from the petitioner within 90 days of the effective
date of the rule, with information and statements analogous to those
in the proposed ‘‘GRAS exemption claim,’’ we would consider the
converted petition to be inadequate as a notice and would send the
petitioner a letter to that effect..
III. Legal Authority
We are amending our regulations in
21 CFR parts 170 and 570 to replace the
voluntary GRAS affirmation petition
process with a voluntary GRAS
notification procedure and to clarify
when the intended conditions of use of
a substance are eligible for classification
as GRAS under our authority in sections
201, 402, 409, and 701 of the FD&C Act
(21 U.S.C. 321, 342, 348, and 371).
Section 701(a) of the FD&C Act
authorizes the Secretary of the
Department of Health and Human
Services (the Secretary) to issue
regulations for the efficient
administration of the FD&C Act; under
section 1003(d) of the FD&C Act (21
U.S.C. 393(d)), the Secretary is
responsible for executing the FD&C Act,
including section 701(a), through the
Commissioner of Food and Drugs. The
FD&C Act requires that all food
additives (as defined by section 201(s)
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Expressly provides for you to submit a timely ‘‘amendment’’ to a GRAS
notice before we respond to your GRAS notice or cease to evaluate
your GRAS notice.
Expressly provides that you may ask us to cease to evaluate your
GRAS notice, and expressly provides that we will inform you of our
decision regarding your request.
We will conduct an initial evaluation of your submission to determine
whether to file it as a GRAS notice for evaluation of your view that
the notified substance is GRAS under the conditions of its intended
use. If we file your submission as a GRAS notice, we will send you a
letter that informs you of the date of filing. If we do not file your submission as a GRAS notice, we will send you a letter that informs you
of that fact and provides our reasons for not filing the submission as
a GRAS notice.
Within 180 days of filing, we will respond to you by letter based on our
evaluation of your notice. We may extend the 180 day timeframe by
90 days on an as needed basis. If we extend the timeframe, we will
inform you of the extension as soon as practicable but no later than
within 180 days of filing.
Specifies procedures that apply when the intended conditions of use of
a notified substance in human food include use in a product or products subject to regulation by USDA’s FSIS.
The regulatory text of the final rule specifies that the data and information in a GRAS notice are considered a mandatory, rather than voluntary, submission for purposes of its status under the FOIA and our
public information requirements in part 20.
Expressly provides for you to submit a ‘‘supplement’’ to a GRAS notice
after we respond to your GRAS notice or cease to evaluate it.
On the effective date of the rule, we will close the docket for any
GRAS affirmation petition that is still pending. Any person who submitted a GRAS affirmation petition that is closed may submit a
GRAS notice and request that we incorporate the GRAS affirmation
petition.
of the FD&C Act) be approved by FDA
before they are marketed (sections
402(a)(2)(C) and 409 of the FD&C Act).
Section 201(s) excludes from the
definition of a food additive a substance
generally recognized, among experts
qualified by scientific training and
experience to evaluate its safety, as
having been adequately shown through
scientific procedures (or, in the case of
a substance used in food prior to
January 1, 1958, through either
scientific procedures or experience
based on common use in food) to be safe
under the conditions of its intended use.
These regulations will help FDA
administer efficiently the FD&C Act’s
various provisions that apply to the use
of substances added to food, specifically
on the question of whether a substance
is GRAS under the conditions of its
intended use or is a food additive
subject to FDA’s premarket review.
These regulations provide clarification
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of the GRAS criteria and provide a more
efficient procedure.
As an error, the authority citation that
we listed for the proposed amendments
to part 570 did not include an existing
authority citation, i.e., section 408 of the
FD&C Act (21 U.S.C. 346a). Nothing in
the proposed rule would alter the
citation to section 408. Therefore, the
authority citation for 21 CFR part 570
continues to include section 408.
As an error, the authority citation that
we listed for the proposed amendments
to part 170 stated that we were revising
the authority citation. Nothing in the
proposed rule would alter the authority
citation for part 170. Therefore, the
authority citation for 21 CFR part 170
states that the authority citation
‘‘continues to read’’ rather than ‘‘is
revised to read.’’
(Comment 1) Some comments state
that the proposed rule violates the 1958
amendment because FDA would not be
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fulfilling its statutory duty to oversee
food additives, and, therefore, FDA’s
interpretation of the GRAS provision is
arbitrary and capricious. The comments
state that the proposed rule violates the
1958 amendment because it would not
require companies to notify FDA of a
conclusion that the use of a substance
is GRAS. One comment states that
without mandatory submissions FDA
lacks a ‘‘comprehensive catalog’’ of such
substances and their dietary exposure,
and therefore cannot ‘‘police the border
between food additives and GRAS
substances’’ and that FDA and food
manufacturers do not have access to
accurate exposure data and cannot
assess the cumulative effect of similar
substances. The comment further states
that because the proposed rule
‘‘establishes no real oversight over the
safety of GRAS substances’’ it violates
the 1958 amendment.
(Response 1) We disagree that the
voluntary nature of the GRAS
notification procedure violates the 1958
amendment. The FD&C Act provides for
premarket review by FDA of a food
additive, and excludes from this review
any substance that is generally
recognized, among qualified experts, to
be safe under the conditions of its
intended use. Although the FD&C Act
specifically provides for our review of
food additives, it is silent with respect
to industry submissions to us on the use
of GRAS substances. To administer the
provisions of the FD&C Act with respect
to the use of GRAS substances, we are
retaining the voluntary nature of the
GRAS administrative procedure. This
rule replaces one longstanding
voluntary administrative procedure
with a different voluntary
administrative procedure.
IV. General Comments on the Proposed
Rule
(Comment 2) One comment states that
the rule does not give consumers an
opportunity to participate in the process
before a substance is used in food.
Another comment asserts that the lack
of an opportunity for public comment or
participation is a ‘‘major flaw’’ in the
rule.
(Response 2) We disagree that the
GRAS notification procedure does not
allow for public participation. We
proactively disclose to the public
information about each GRAS notice
that we have filed for evaluation,
including the name and address of the
notifier; the name of the notified
substance; the intended conditions of
use of the notified substance; and the
statutory basis for the conclusion of
GRAS status (i.e., through scientific
procedures or through experience based
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on common use in food). In the past,
outside parties who have accessed this
information have made us aware of
dissenting views about whether
available data and information support
a conclusion that a notified substance is
safe under the conditions of its intended
use (see sections III.C.2, III.E, and III.I.1
in CFSAN’s 2010 experience document)
(Ref. 18). We continue to welcome
substantive information from
stakeholders regarding the safety of a
notified substance. We advise
stakeholders who wish to provide us
with such substantive information to
submit it to the same address where a
notifier would send a GRAS notice and
ask us to add it to the administrative file
for the applicable GRAS notice. This
administrative file is maintained by the
responsible Center (i.e., CFSAN or
CVM). We would consider the
submitted information, along with other
information that is available to us, on a
case-by-case basis.
(Comment 3) One comment asks us to
require companies to maintain active
and accurate registrations for GRAS
substances in a public database.
(Response 3) We decline this request.
This comment is suggesting a process
not within our regulatory framework
and does not provide a legal basis
whereby we could require companies to
maintain registrations in a public
database for substances that are used in
food on the basis of the GRAS provision
in section 201(s) of the FD&C Act. We
note, however, that the final rule
provides a framework for making the
GRAS notices, and our responses to
these notices, available to the public.
(Comment 4) One comment asks us to
specify whether the notified substance
would be for human or animal
consumption. Another comment notes
that specifying whether the notified
substance is intended for human or
animal consumption is important
because food for humans is not
necessarily appropriate for animals and
vice versa.
(Response 4) We agree with these
comments. This rule establishes
requirements for a GRAS notice about
the intended use of a notified substance
in human food in part 170 and
establishes separate requirements for a
GRAS notice about the intended use of
a notified substance in animal food in
part 570. Regardless of whether the
notified substance would be used in
human food or in animal food, the
notifier must specify the intended
conditions of use (see §§ 170.225(c)(4)
and 570.225(c)(4)). As discussed in
Response 90, we include the intended
conditions of use in our publicly
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available letters responding to GRAS
notices.
(Comment 5) One comment notes that
the experience highlighted in CFSAN’s
experience document (Ref. 18) can
provide valuable learning that can be of
benefit to CVM and asks CFSAN and
CVM to strive for harmonization of their
requirements and policies in all areas,
so the process is not more stringent for
one industry than the other.
(Response 5) We agree that CFSAN
and CVM can learn from each other’s
experience with the implementation of
the GRAS notification procedure and
that procedural and scientific
requirements should be consistent as
much as is feasible and appropriate. As
noted in section II.B, CVM has now
documented its experience with 18
GRAS notices with respect to some
comments specifically directed to the
GRAS notification procedure
administered by CVM (Ref. 20).
(Comment 6) One comment urges
CFSAN and CVM to put forth similar
training and resources for staff assigned
to evaluate GRAS notices to decrease
the time necessary to complete the
evaluation of a GRAS notice.
(Response 6) We staff, equip, and
train our employees consistent with our
priorities and budgets, which are
specific to each Center. As a practical
matter, our current organizational
framework, in which CFSAN and CVM
are both components of the Office of
Foods and Veterinary Medicine,
promotes interactions between staff in
the two Centers.
V. Comments on the Definition of
Scientific Procedures
We proposed to amend the definition
of ‘‘scientific procedures’’ to specify that
scientific procedures include scientific
data (such as human, animal, analytical,
or other scientific studies), information,
methods, and principles, whether
published or unpublished, appropriate
to establish the safety of a substance. In
the 2010 notice, we described comments
relevant to this proposed amendment,
including comments that support it and
a comment that objected to it because,
under the proposed amendment, an
‘‘unpublished principle’’ could
inappropriately be considered a
sufficient scientific procedure for
demonstrating the safety of a food
substance. We also noted that we had
reviewed our use of the term ‘‘study’’ in
the proposed companion change to the
definition of scientific procedures and
explained our view that, to be a
‘‘procedure,’’ data, information,
methods, or principles would need to be
acquired or applied. We stated that we
were considering whether to revise the
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definition of scientific procedures in
§ 170.3(h) to include the application of
scientific data (including, as
appropriate, data from human, animal,
analytical, and other scientific studies),
information, and methods, whether
published or unpublished, as well as the
application of scientific principles,
appropriate to establish the safety of a
substance (see Issue 1, 75 FR 81536 at
81537–81538). We requested comment
on this issue.
Several comments support the
proposed amendment to the definition
of scientific procedures as described in
the proposed rule, with the potential
modifications described in the 2010
notice, because the revised definition
would more accurately reflect the state
of contemporary science than the
definition it would replace. Some
comments express the view that
specifying that it is ‘‘the application’’ of
unpublished scientific data,
information, or methods that would
corroborate GRAS status would make it
clear that a submission to us regarding
a conclusion of GRAS status may
include discussions of unpublished
studies. In the following paragraphs, we
discuss comments that suggest
additional changes to the definition of
‘‘scientific procedures.’’ After
considering these comments, we are
finalizing the definition of scientific
procedures as proposed, with the
modifications described in the 2010
notice and with editorial changes as
shown in table 29.
(Comment 7) One comment that
supports the potential modifications to
the definition of ‘‘scientific procedures’’
as described in the 2010 notice asks us
to incorporate an additional clarification
that ‘‘scientific principles appropriate to
establishing the safety of a substance’’
encompass consideration of both the
data supporting the safety of the
substance and the probable dietary
exposure.
(Response 7) To the extent that the
comment means that ‘‘scientific
procedures’’ (rather than ‘‘scientific
principles’’) encompass consideration of
both the data supporting the safety of
the substance and the probable dietary
exposure, we agree. However, it is not
necessary to revise the definition of
scientific procedures to make that clear.
The definition of ‘‘scientific
procedures’’ already specifies the
application of data from human, animal,
analytical, or other scientific studies,
and the definition of ‘‘safe’’ or ‘‘safety’’
in § 170.3(i) includes probable dietary
exposure as a factor that must be
considered in determining safety.
As discussed in the 2010 notice,
‘‘principle’’ can be defined as a
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fundamental cause or basis of
something; a primary element, force, or
law determining a particular result; or a
fundamental truth or proposition on
which others depend. Thus, a principle
is a different genre than data,
information, and methods. Therefore,
although we agree that ‘‘scientific
procedures’’ encompass consideration
of both the data supporting the safety of
the substance and the probable dietary
exposure, we disagree that the data
supporting the safety of the substance
and the probable dietary exposure are
‘‘scientific principles.’’
VI. Comments on the Criteria for
Eligibility for Classification as GRAS
Section 170.30 specifies three types of
criteria for eligibility for classification as
GRAS: (1) General criteria; (2) criteria
for classification as GRAS through
scientific procedures; and (3) criteria for
classification as GRAS through
experience based on common use in
food. We proposed to amend all three
criteria to: (1) Clarify that the safety
standard for a GRAS substance is
identical to the safety standard for a
food additive; (2) clarify the types of
technical evidence of safety that could
form the basis for classification as GRAS
through scientific procedures, and
clarify the role of publication in
establishing general recognition of
safety through scientific procedures;
and (3) make conforming changes to the
criteria for eligibility for classification as
GRAS through experience based on
common use in food. We proposed these
amendments in association with our
concurrent proposal to replace the
GRAS affirmation petition process with
a GRAS notification procedure. In the
2010 notice, we stated that we were
considering an additional revision to
correspond with the revision to the
definition of scientific procedures (see
section V in this document and Issue 1,
75 FR 81536 at 81537–81538 in the 2010
notice).
In the following sections, we discuss
comments that disagree with one or
more aspects of our proposal to amend
the criteria for eligibility for
classification as GRAS, with the
potential modifications described in the
2010 notice (see, e.g., Comment 9 and
Comment 13); ask us to clarify how we
will interpret the revised criteria or offer
suggestions for how we should interpret
the revised criteria (see, e.g., Comment
12, Comment 16, Comment 17, and
Comment 18); or suggest one or more
changes to the revised criteria (see, e.g.,
Comment 10, Comment 19, and
Comment 20). After considering these
comments, we are establishing the
criteria for eligibility for classification as
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GRAS for use of a substance in human
food as proposed, with the modification
we described in the 2010 notice and
with editorial, clarifying, and
conforming changes as shown in table
29. See section XXV.B for a description
of additional changes we made to the
criteria for eligibility for classification as
GRAS for use of a substance in animal
food.
A. General Criteria for Eligibility for
Classification as GRAS
We proposed to revise the final
sentence of § 170.30(a) to specify that
general recognition of safety requires
common knowledge throughout the
scientific community knowledgeable
about the safety of substances directly or
indirectly added to food that there is
reasonable certainty that the substance
is not harmful under the intended
conditions of use. As discussed in the
proposed rule, we proposed this
revision to clarify that the safety
standard for a GRAS substance is
identical to the safety standard for food
additives (see § 170.3(i)) and that a
GRAS substance is neither more safe,
nor less safe, than an approved food
additive (62 FR 18938 at 18942). We
received no comments that disagreed
with this proposed revision and are
finalizing § 170.30(a) as proposed with
conforming changes as shown in table
29.
See section XXV.B regarding revisions
to the general criteria for eligibility for
classification as GRAS for a substance
used in animal food.
B. Criteria for Eligibility for
Classification as GRAS Through
Scientific Procedures
We proposed to amend the criteria for
eligibility for classification as GRAS
through scientific procedures to: (1)
Require that the data and information
for general recognition of safety be
‘‘generally available and accepted,’’ and
(2) broaden the types of acceptable data
and information by replacing ‘‘studies’’
with ‘‘data, information, methods, or
principles.’’ In the 2010 notice, we
stated that we were considering whether
to revise these criteria with respect to
the types of acceptable data and
information to include ‘‘the
application’’ of generally available and
accepted scientific data, information, or
methods, as well as ‘‘the application’’ of
scientific principles’’ (see section V in
this document and Issue 1, 75 FR 81536
at 81537–81538 in the 2010 notice).
See section XXV.B regarding revisions
to the criteria for eligibility for
classification as GRAS through
scientific procedures for a substance
used in animal food.
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(Comment 8) One comment asserts
that the criterion for the generally
available data or information
establishing safety to ordinarily be
published is artificial. Other comments
point out that information that is not
published can nonetheless be
considered ‘‘generally available.’’ Some
comments object to the proposed
amendment to the criteria for eligibility
for classification as GRAS through
scientific procedures and assert that it
would de-emphasize or eliminate the
existing criterion for peer-reviewed
studies.
(Response 8) Regardless of whether
the data and information are published
or unpublished, under the revised
criteria a GRAS conclusion must be
based on data and information that are
generally available and accepted, and as
such, are publicly available. As we
stated in the proposed rule, the common
knowledge element of the GRAS
standard precludes a GRAS conclusion
if the data and information (e.g., as
evaluated by a ‘‘GRAS panel’’) are only
available in files that are not publicly
accessible, such as in confidential
industry files (62 FR 18938 at 18943).
We disagree that the criterion for the
generally available data or information
establishing safety to ordinarily be
published is artificial. Publication in a
peer-reviewed scientific journal is the
usual mechanism to establish that
scientific information is generally
available, provided that the journal is
representative of scientific publications
accessed by the expert scientific
community (62 FR 18938 at 18943).
Nonetheless, the revised criteria provide
flexibility for supporting a conclusion of
GRAS status through the application of
scientific data, information, or methods
that are generally available through a
mechanism other than publication in a
peer-reviewed scientific journal, such as
publication in a textbook and other
sources of technical literature. One
example of another source of technical
literature is the Joint Expert Committee
on Food Additives (JECFA, a joint
committee of the Food and Agriculture
Organization/World Health
Organization). We note, however, that
the mere fact that data and information
are published or otherwise publicly
available does not satisfy the criteria for
general recognition of safety. Regardless
of the mechanism of making data and
information generally available to
qualified experts, it must be plausible
that qualified experts would be
accessing those data and information
using that mechanism. For example,
scientists who routinely access peerreviewed journals in electronic form on
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the Internet may avoid Internet
‘‘publications’’ about a scientific topic
when the ‘‘publication’’ is not
associated with a reputable scientific
institution.
We have not changed our position on
the importance of peer review. The basis
for GRAS status continues to be the
application of generally available
scientific data, information, and
methods, which ordinarily are
published (and, thus, are subject to peer
review as part of the scientific
publication process for most journals).
We continue to believe that whether
scientific data, information, and
methods have been peer reviewed
before publication in a scientific journal
that is representative of scientific
publications accessed by the expert
scientific community is a factor that
bears on the objectivity and scientific
merit of study, and is a variable we
consider in determining whether
experts accept the report of a scientific
investigation as a credible report and
whether there is general knowledge of
the scientific investigation.
CFSAN’s 2010 experience document
(Ref. 18) provides factual information on
how CFSAN already has interpreted the
criteria for eligibility for classification of
GRAS status through scientific
procedures for GRAS notices CFSAN
received during the Interim Pilot
program (see section III.A.1 of CFSAN’s
2010 experience document), and we
intend to continue this approach in the
future. In most cases, a submitted GRAS
notice described a mixture of
information published in peer-reviewed
journals, information (such as in
textbooks) that was generally available
in a form other than a peer-reviewed
journal, and unpublished information.
As shown in table 1 in CFSAN’s 2016
experience document, CFSAN had no
questions about GRAS status based on
this mixture of information in
approximately 81 percent of the GRAS
notices CFSAN evaluated between 1998
and 2015 (Ref. 19). Importantly,
CFSAN’s evaluation of the basis for a
conclusion that a use of a food
substance is GRAS in addition to being
safe was a case-by-case evaluation. As
discussed in section III.A.4 of CFSAN’s
2010 experience document, in some
cases it was CFSAN’s view that the
available data and information were
sufficient to demonstrate safety, but not
GRAS status, and CFSAN established a
food additive regulation for the use of
the substance in response to a food
additive petition for that use (Ref. 18).
(Comment 9) Some comments state
that all available relevant data,
including unpublished data, should be
used in evaluating GRAS status. Some
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of these comments cited the placement
of the word ‘‘ordinarily’’ in the criteria
for classification as GRAS through
scientific procedures as support for this
interpretation. Several comments urge
us to interpret, in a flexible manner, the
proposed criteria for the scientific data,
information, methods or principles that
establish safety to be ‘‘generally
available and accepted’’ and ‘‘ordinarily
. . . published.’’
(Response 9) We agree that all
relevant data should be used in
evaluating GRAS status, including
unpublished data. However, regardless
of whether data and information are
published or unpublished, a GRAS
conclusion based on scientific
procedures must be based on data and
information that are generally available
and accepted, and as such, are publicly
available (see Response 8). The GRAS
criteria for scientific procedures, as
established in 1976, state that the
applicable data and information are
‘‘ordinarily’’ published and may be
‘‘corroborated’’ by unpublished data and
information, and this rule retains these
criteria. The common meaning of
‘‘corroborate’’ is to make more certain or
confirm (Ref. 23). Although
unpublished data and information can
confirm a conclusion of GRAS status, to
satisfy GRAS criteria qualified experts
must be able to conclude that the
substance is not harmful under the
conditions of its intended use without
access to ‘‘corroborative’’ information
(see § 170.30(a)). Under this rule, a
notifier is required to explain how there
could be a basis for a conclusion of
GRAS status if qualified experts do not
have access to non-public safety-related
data and information considered in
reaching a conclusion of GRAS status
(see § 170.250(e)).
Whether data and information are
corroborative of safety, rather than
establish safety, depends on what those
data and information are and how they
relate to the safety assessment, not just
whether they are published or otherwise
publicly available. Whereas
unpublished data and information that
have a bearing on a safety conclusion,
and therefore could help confirm a
safety conclusion based on other data
and information, in general, can only be
considered as corroborative in the
context of a GRAS conclusion,
published data and information may be
either the basis for a safety conclusion
or corroborative of a safety conclusion,
depending on the nature of the data and
information. For example, a published
90-day toxicology study could be the
basis for a safety conclusion, but a
preliminary toxicology study conducted
primarily for the purpose of selecting
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the doses to be used in that 90-day
toxicology study is unlikely to be the
basis for a safety conclusion, regardless
of whether that preliminary toxicology
study is published.
See also the discussion in Response
58 regarding the requirement for you to
submit a signed statement certifying
that, to the best of your knowledge, your
GRAS notice is a complete,
representative, and balanced submission
that includes unfavorable information,
as well as favorable information, known
to you and pertinent to the evaluation
of the safety and GRAS status of the use
of the substance (§ 170.225(c)(9)). See
also the discussion in section XVII
regarding the requirement for your
narrative to identify, and place in
context, data and information that are,
or may appear to be, inconsistent with
your conclusion of GRAS status,
regardless of whether those data and
information are generally available
(§ 170.250(c)).
(Comment 10) One comment asks us
to explicitly acknowledge publication of
information in the secondary scientific
literature as a mechanism to satisfy the
standard for general availability.
(Response 10) We decline this
request. In general, the secondary
scientific literature includes
publications (such as review articles,
textbooks, and compendia) which
disseminate the views of scientists who
are critically evaluating a primary body
of data and information already
published in peer-reviewed scientific
journals that are representative of
scientific publications accessed by the
expert scientific community (i.e., the
primary scientific literature). Whether a
publication in the secondary scientific
literature satisfies the criteria for GRAS
status through scientific procedures is a
case-by-case determination that depends
on the circumstances. See section III.A.1
of CFSAN’s 2010 experience document
(Ref. 18) for examples of how CFSAN
considered publications in the
secondary scientific literature during
the Interim Pilot program. When the
underlying data being reviewed in the
secondary scientific literature are
themselves generally available, a
publication in the secondary scientific
literature can provide evidence that the
data and information discussed in the
publication are generally accepted as
well as generally available. If a
publication in the secondary scientific
literature discusses data and
information that are available to the
authors, but not previously published in
the primary scientific literature,
whether that publication could satisfy
the ‘‘generally available’’ aspect of the
criteria for eligibility for GRAS status
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through scientific procedures would
depend on the nature and extent of the
discussion in the publication. For
example, a very general statement that
a study was conducted and reported no
adverse findings would not suffice to
make the study ‘‘generally available’’;
instead, such a statement would merely
be a generally available opinion about
data and information, in that study, that
are not generally available. Such a
publication may satisfy the ‘‘generally
accepted’’ aspect of the criteria for
GRAS status through scientific
procedures for that study, but would be
insufficient, by itself, to satisfy the
‘‘generally available’’ aspect of those
criteria. However, a comprehensive
description in the secondary scientific
literature of a previously unpublished
study, including details similar to
details that would be included in a
publication in the primary scientific
literature, may suffice to make the study
published in the secondary scientific
literature ‘‘generally available.’’ In such
circumstances, the publication in the
secondary scientific literature may be
able to satisfy both the ‘‘generally
available’’ and ‘‘generally accepted’’
aspects of the criteria for eligibility for
GRAS status through scientific
procedures for certain data and
information.
(Comment 11) One comment asks us
to recognize that publication of an
opinion of a specially convened ‘‘expert
panel’’ would satisfy the standard for
general availability because, in the
comment’s view, review by such a panel
would be equivalent to, or exceed, peer
review. (By ‘‘expert panel,’’ we assume
that the comment is referring to a
‘‘GRAS panel’’, i.e., a panel of
individuals convened for the purpose of
evaluating whether the available
scientific data, information, and
methods establish that a substance is
safe under the conditions of its intended
use in food. See the discussion in
section III.A.1 of CFSAN’s 2010
experience document (Ref. 18).)
(Response 11) We would consider
publication of an opinion of a specially
convened ‘‘GRAS panel’’ to be part of
the secondary scientific literature as
discussed in Response 10. As with any
publication in the secondary scientific
literature, when the underlying data
being reviewed in a published ‘‘GRAS
panel’’ opinion are themselves generally
available, a published ‘‘GRAS panel’’
opinion could provide evidence that the
data and information discussed in the
publication are generally accepted,
depending on factors such as the subject
matter expertise of the members of the
GRAS panel and whether the members
of the GRAS panel would be considered
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representative of experts qualified by
scientific training and experience to
evaluate the safety of the substance
under the conditions of its intended use.
For example, a ‘‘GRAS panel’’ opinion
published by scientists without
expertise appropriate to address the
applicable safety questions could not
provide evidence that the conclusions
in the publication are ‘‘generally
accepted.’’
If a published ‘‘GRAS panel’’ opinion
discusses data and information that are
available to the members of the GRAS
panel, but not generally available to
qualified experts, whether that
publication could satisfy the ‘‘generally
available’’ aspect of the criteria for
eligibility for GRAS status through
scientific procedures would depend on
the nature and extent of the discussion
in the publication (see Response 10).
Unless both criteria, i.e., ‘‘generally
available’’ and ‘‘generally accepted’’, are
satisfied, there would be no basis for a
conclusion of GRAS status based on a
published ‘‘GRAS panel’’ opinion.
(Comment 12) One comment states
that all available relevant data,
including unpublished data, should be
used in evaluating GRAS status, as long
as any unpublished data are generated
by appropriate and valid scientific
methods as judged and reviewed by an
external qualified GRAS panel and are
accessible to FDA for review.
(Response 12) We agree that all
available relevant data should be used
in evaluating whether a use of a
substance in food is GRAS through
scientific procedures. By ‘‘all relevant
data,’’ we mean data that support a
conclusion of GRAS status as well as
data that are inconsistent with a
conclusion of GRAS status, not just
whether the data are published. (See
§§ 170.225(c)(9) and 170.250(c) and the
discussion in Response 58, Response 69,
and Response 78.) We also agree that it
is appropriate for unpublished data to
be generated by valid scientific methods
and to be accessible to FDA for review
(e.g., when such data are cited in a
submission to FDA). In addition, we
have acknowledged the practice of
convening an external ‘‘GRAS panel’’ to
evaluate whether the available scientific
data, information, and methods
demonstrate that a substance is safe
under the conditions of its intended use
in food (see section III.A.1 of CFSAN’s
2010 experience document) (Ref. 18).
However, we disagree that information
that is not generally available to
qualified experts could be used as
evidence for a GRAS conclusion merely
because a GRAS panel has reviewed it.
Such information would need to be
considered, but generally would only be
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corroborative of safety. (See Response 9
and Response 11.)
(Comment 13) One comment asserts
that the proposed rule treats the
findings of GRAS panels as equivalent
to determinations by authoritative
bodies and peer reviewed published
articles.
(Response 13) We disagree. In the
proposed rule, we noted that the basis
for concluding there is expert consensus
about the safety of a substance under the
conditions of its intended use may be
quite varied, and described common
mechanisms that have been used to do
so. We stated that these common
mechanisms included publication in the
primary, peer-reviewed scientific
literature; publication in the secondary
scientific literature; documentation of
the opinion of an ‘‘expert panel’’ that is
specifically convened for this purpose;
and the opinion or recommendation of
an authoritative body such as the
National Academy of Sciences or the
Committee on Nutrition of the American
Academy of Pediatrics on a broad or
specific issue that is related to a
conclusion of GRAS status (62 FR 18938
at 18940–18941). We also stated that
there could be a basis to conclude that
there is expert consensus that the
published results of a particular safety
study (i.e., the primary scientific
literature) establish the safety of a
substance for its intended use if the
study raises no safety questions that
experts would need to interpret and
resolve (62 FR 18938 at 18943). In
addition, technical literature from
JECFA can provide evidence that
generally available safety data and
information are generally accepted (see
section III.A.1 of CFSAN’s 2010
experience document (Ref. 18)).
However, acknowledging that the
opinion of an ‘‘expert panel’’ (which we
now refer to as a ‘‘GRAS panel’’) has
been used to provide evidence that
safety data and information are
generally accepted does not mean that
these mechanisms are ‘‘equivalent.’’
Whether the findings of a GRAS panel,
a determination by an authoritative
body, or a peer-reviewed scientific
study provide sufficient evidence that
safety data and information are
generally accepted would depend on the
specific findings of the GRAS panel, the
specific determination by the
authoritative body, and the data and
information in the peer-reviewed
scientific study rather than on the
classification of the mechanism for
providing evidence that safety data and
information are generally accepted.
(Comment 14) One comment asks us
to develop and publish guidelines
regarding specific duties that would be
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expected of any GRAS panel. This
comment suggests that such guidelines
could include recommendations for: (1)
Number of panel members; (2) measures
of ‘‘general acceptance,’’ such as a
majority (rather than unanimous)
opinion and the impact of a dissenting
opinion; and (3) the content of a letter
from a GRAS panel.
(Response 14) See Response 125. We
intend to issue for public comment a
draft guidance to address GRAS panels.
(Comment 15) Some comments assert
it can be difficult to publish data and
information that do not raise an issue of
concern.
(Response 15) We infer this comment
to refer primarily to toxicology studies.
Toxicology studies are designed to
provide information about potential
adverse effects from exposure to a
substance and any dose-response
relationship. Although studies that fail
to identity any adverse effects may be
difficult to publish, some scientific
journals report the findings of such
studies. (See section III.A.1 of CFSAN’s
2010 experience document (Ref. 18)).
(Comment 16) One comment asks us
to require that both toxicology and
exposure data be published because a
safety assessment for the use of a
substance in food requires consideration
of both.
(Response 16) We agree that a safety
assessment for the use of a substance in
food requires consideration of both
safety information (such as toxicology
studies) and dietary exposure (i.e., the
amount of the substance that consumers
are likely to eat or drink). Toxicology
data are ordinarily published.
A premarket exposure assessment
typically would be calculated by
applying generally available and
accepted methods to two types of data
and information: (1) Generally available
and accepted data about food
consumption; and (2) specific food
categories, and levels of use in those
food categories, projected by the
sponsor of a food additive petition or by
the proponent of GRAS status (Ref. 24
and Ref. 25). Using generally available
and accepted data about food
consumption, a qualified expert who
has access to the specific food categories
and associated levels of use intended by
the proponent of GRAS status can
calculate an estimated dietary exposure.
When the proponent of GRAS status
submits a GRAS notice, the proponent
must: (1) Provide data and information
about dietary exposure (see § 170.235);
and (2) include a narrative that
addresses the safety of the notified
substance, considering all dietary
sources (see § 170.250). Those
calculations and discussions included
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in the GRAS notice are subject to the
public disclosure provisions of this rule
(see § 170.275) and, thus, would be
available to the expert scientific
community. However, when the
proponent of GRAS status does not
submit a GRAS notice, the expert
scientific community that does not have
access to the specific food categories
and associated levels of use would not
be able to calculate an estimated dietary
exposure. When the available data and
information suggest that the specific
food categories and associated levels of
use must be carefully chosen to keep
consumption of the substance in a safe
range (e.g., when fortifying food with
certain vitamins), the expert scientific
community that does not have access to
the specific food categories and
associated levels of use would not be
able to reach a conclusion about
whether the substance is safe under the
conditions of its intended use, and
GRAS criteria would not be satisfied.
After market entry of the substance, it
may be appropriate to re-assess dietary
exposure. For example, dietary exposure
may need to be reassessed when a key
assumption in the methodology is
changed; as dietary consumption
patterns change; when there is an
unresolved question about consumer
intake; when there is a small margin of
exposure; or when other new
information becomes available. As with
a premarket exposure assessment, a
postmarket exposure assessment
typically would be calculated by
applying generally available and
accepted methods to two types of data
and information: (1) Generally available
and accepted data about food
consumption; and (2) specific food
categories, and levels of use in those
food categories. In some cases,
postmarket exposure assessments have
been published so that the expert
scientific community has access to
them. For example, exposure
assessments have been published for
some sweeteners using relative
sweetness as the basis of the estimate
(Ref. 26). As another example, estimates
of dietary exposure to caffeine have
been published to address consumer
intake and patterns of use (Ref. 27
through Ref. 29). However, as with a
premarket exposure assessment, when a
postmarket exposure assessment is not
publicly available, the expert scientific
community that does not have access to
the specific food categories and
associated levels of use would not be
able to reach a conclusion about
whether the substance is safe under the
conditions of its intended use when the
available data and information suggest
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that the specific food categories and
associated levels of use must be
carefully chosen to keep consumption of
the substance in a safe range.
(Comment 17) One comment asks us
to recognize that published literature
does not need to address a specific
substance, but could involve
publications on a class of substances or
a related substance to support a
conclusion that the use of a substance
is GRAS through scientific procedures.
(Response 17) We agree that
published information for a specific
substance is not always necessary to
support a conclusion that the use of a
substance is GRAS through scientific
procedures. For example, there may be
situations where the safety of the use of
the substance in food can be
demonstrated by relevant published
information on a closely, structurally
related compound. In such cases, the
analysis leading to the conclusion of
GRAS status should explain how the
information on the closely, structurally
related compound is relevant to the
safety assessment of the substance being
evaluated. In other cases, there may a
body of information published in the
primary or secondary literature about a
class of substances, which reflect
generally available and accepted data
and information that can be called to
bear on the safety assessment of a
specific substance. For example,
generally available metabolism
information about commonly consumed
components of food, such as
carbohydrates, lipids, and proteins,
could support a conclusion that a
specific substance is GRAS under the
conditions of its intended use.
To help ensure that the data are, in
fact, relevant to the safety assessment of
the substance being evaluated, we
strongly encourage any person who
intends to rely on data and information
regarding a class of substances, or a
specific substance related to the
substance that would be added to food,
to submit any conclusion of GRAS
status to FDA via the GRAS notification
procedure.
(Comment 18) One comment states
that the use of an approved food
additive can, through the passage of
time, become GRAS as the substance
becomes widely used and as
information about the substance
becomes publicly available.
(Response 18) We disagree that
widespread use of an approved food
additive as time passes has any bearing
on the eligibility of this use for
classification as GRAS. Eligibility for
classification as GRAS through
scientific procedures would depend on
the status of the information—as
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generally available and generally
accepted—rather than on the amount of
time that a food additive has been used
in food. However, in general, much of
the data submitted for our review of a
food additive contains unpublished data
and trade secret or confidential
information that is neither published
nor otherwise generally available.
Although the safety data are available
for public disclosure under 21 CFR
171.1(h)(1), they typically are based on
unpublished studies sponsored by the
petitioner.
See also the discussion in Response
19 regarding the impact of the passage
of time and the discussion in Response
79 that the qualified experts who
evaluate the basis for a conclusion that
the notified substance is safe under the
conditions of its intended use must not
exclusively be ‘‘FDA’s experts.’’
(Comment 19) One comment asks us
to exclude uses of ‘‘novel’’ substances
from consideration for eligibility for
classification as GRAS. The comment
asserts that novel or newly discovered
uses of substances that are the subject of
a conclusion of GRAS status are in
conflict with the original intent of the
1958 amendment and the plain meaning
of ‘‘generally recognized,’’ because there
is no history of safe use for these
substances. The comment also states
that similar ‘‘general recognition’’
provisions for new drugs are not
interpreted to allow industry-made
safety determinations for new or novel
drugs.
(Response 19) We do not have a
regulatory definition for a ‘‘novel’’
substance. As a general matter, section
201(s) of the FD&C Act provides two
alternatives for general recognition of
safety—through scientific procedures, or
through experience based on common
use in food. Section 201(s) does not
limit eligibility, or otherwise exclude,
the use of a substance from
classification as GRAS through
scientific procedures if there is no
history of use. Likewise, section 201(s)
does not limit eligibility, or otherwise
exclude, the use of a substance from
classification as GRAS through
scientific procedures based on other
criteria, such as whether a substance or
its use in food is ‘‘novel’’ or ‘‘newly
discovered.’’ Unlike the definition of a
‘‘new drug’’ in section 201(p) of the
FD&C Act, section 201(s) does not
require that a food ingredient be used
‘‘to a material extent or for a material
time under such conditions’’ before it
can become GRAS. Rather, the criteria
for eligibility for classification as GRAS
depend on whether generally available
and accepted data and information
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establish that the substance is safe
under the conditions of its intended use.
However, a conclusion of GRAS status
must be based on common knowledge
throughout the scientific community
knowledgeable about the safety of
substances added to food that there is
reasonable certainty that the substance
is not harmful under the conditions of
its intended use (§ 170.30(a)), and a
substance cannot be considered GRAS
when its characteristics are known to
only a few experts (Final rule
establishing GRAS criteria, 41 FR 53600,
December 7, 1976). In addition, the
passage of time is relevant in an
evaluation of whether a substance is
GRAS under the conditions of its
intended use. In our 1974 proposed rule
on general recognition of safety and
prior sanctions for food ingredients, we
acknowledged that there would be at
least some gap between the gathering of
the scientific knowledge necessary to
provide the toxicological underpinning
for general recognition of safety and the
dissemination to and assimilation by the
scientific community of this material
that is necessary for general recognition
of safety to exist.’’ (39 FR 34194 at
34194, September 23, 1974). More
recently, the discussions in sections
III.A.4 and IV.K of CFSAN’s 2010
experience document (Ref. 18) show our
approach to the time gap between the
publication of safety data and the use of
the published safety data to support a
conclusion of GRAS status during the
Interim Pilot program. See also
Response 67 regarding nanotechnology
applications in food substances.
(Comment 20) One comment asserts
that we must define the extent of
agreement needed to establish a
consensus among qualified experts, and
that we must exclude from eligibility for
classification as GRAS any substance
whose safety has been called into
question by expert authorities or
authoritative entities within the
scientific community.
(Response 20) The proponent of a
GRAS conclusion for a food substance
must demonstrate that the conditions of
use of the substance satisfy the
definition of ‘‘safe’’ in our regulations
(i.e., that there is reasonable certainty
that the substance is not harmful under
the conditions of its intended use (see
§ 170.3(i)). The proponent of GRAS
status also must demonstrate that there
is common knowledge about this safety
throughout the knowledgeable scientific
community (§ 170.30(a)). Although
courts have established that general
recognition of safety requires a
consensus of expert opinion regarding
the safety of the use of the substance,
(see, e.g., United States v. Western
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Serum Co., Inc., 666 F.2d 335, 338 (9th
Cir. 1982) (citing Weinberger v. Hynson,
Westcott & Dunning, 412 U.S. 609, 629–
32 (1973)), we disagree that we must
define the extent of agreement needed to
establish such a consensus. Courts have
established that general recognition of
safety does not require unanimous
agreement. See, e.g., United States v.
Articles of Drug * * * 5,906 Boxes, 745
F.2d 105, 119 n. 22 (1st Cir. 1984);
United States v. Articles of Food and
Drug (Coli-Trol 80), 518 F.2d 743, 746
(5th Cir. 1975) (‘‘What is required is not
unanimous recognition but general
recognition’’). Importantly, general
recognition of safety does not exist if
there is a genuine dispute among
qualified experts that the use of a
substance is safe. See, e.g., Premo
Pharmaceutical Laboratories v. United
States, 629 F.2d 795, 803–4 (2nd Cir.
1980) (‘‘genuine dispute among
qualified experts’’ precludes finding of
general recognition, and no general
recognition existed as a matter of law
where there was a ‘‘sharp difference’’ of
expert opinion); United States v. Article
of Food * * * Coco Rico, 752 F.2d 11,
15 n 6 (1st Cir. 1985) (substance was not
GRAS as a matter of law based on
existence of ‘‘genuine dispute among
qualified experts’’ regarding safety of
use). For discussions of additional
judicial decisions bearing on the criteria
for eligibility for classification as GRAS,
see the notice of declaratory order
providing our final determination
regarding partially hydrogenated oils
(80 FR 34650).
A conclusion of GRAS status must be
based on the totality of the publicly
available and corroborative evidence
about the safety of the substance under
the conditions of its intended use,
including both favorable and potentially
unfavorable information. Thus, reports
of expert authorities or authoritative
entities within the scientific community
may indicate that there is no general
recognition of safety when the reports
call into question the safety of a
substance for use in food. However, we
disagree that the outcome of an
evaluation of such information can be
predetermined as suggested by the
comments. Regardless of whether
particular scientific data and
information lead experts to conclude
that a substance is safe under the
conditions of its intended use, or raise
questions about the safety of the
substance under the conditions of its
intended use, the evaluation of whether
a use of a substance in food is safe, and
whether safety is generally recognized,
is a case-by-case evaluation. For
example, data and information that lead
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expert authorities or authoritative
entities within the scientific community
to raise a concern about the safety of the
substance under the conditions of its
intended use in food would have
reduced significance if the concern was
related to a contaminant in the
substance and scientifically valid data
and information supplied by the
proponent of GRAS status provide
evidence that an improved method of
manufacture eliminates that
contaminant.
See also Response 77, in which we
explain that we proposed to provide the
judicial interpretation of section 201(s)
of the FD&C Act in the requirement for
the comprehensive discussion of the
notifier’s basis for a conclusion of GRAS
status to provide more context to
notifiers than merely repeating the
statutory language. However, as
discussed in Response 77, we have
decided to use the statutory language
(i.e., ‘‘generally recognized’’) rather than
the proposed term ‘‘consensus’’ in the
submission requirements for a GRAS
notice to mirror the GRAS criteria in
§ 170.30, which continue to use the
statutory language rather than the
consensus standard applied by the
courts in applying the statutory
language to specific situations.
(Comment 21) In the proposed rule,
we asked for comment on the potential
for a conclusion of GRAS status through
scientific procedures to be based in part
on the ‘‘substantial equivalence’’ of the
applicable substance to a substance that
is GRAS through experience based on
common use in food. One comment
agrees with the view, expressed in a
1996 JECFA Report (Ref. 30) and
reported in the proposed rule (62 FR
18938 at 18944), that ‘‘substantial
equivalence’’ embodies the concept that
if a new food component is found to be
substantially equivalent to an existing
food component, the food component
could be considered to be as safe as the
existing food component, after taking
into account any processing that the
food component may undergo as well as
the intended use and the intake by the
population. Several comments assert
that the concept of substantial
equivalence, although useful, is
nonetheless ambiguous. One comment
asks us to clearly state our interpretation
of this concept in the final rule.
(Response 21) We have decided not to
include the term ‘‘substantial
equivalence’’ in the regulatory text of
this rule, because whether, and to what
extent, similarity between two
substances could support a conclusion
of GRAS status depends on too many
situation-specific variables. As
discussed in section IV.N of CFSAN’s
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2010 experience document, GRAS
notices filed during the Interim Pilot
program that relied on the concept of
‘‘substantial equivalence’’ generally
addressed alternative sources of
enzymes already used in food (Ref. 18).
Most of these notices both emphasized
the similarities of the new enzyme
preparations to existing enzyme
preparations and explained the
differences between the new enzyme
preparation and currently used enzyme
preparations. However, none of these
GRAS notices relied solely on the
concept of ‘‘substantial equivalence.’’
Instead, these notices also described
other applicable data and information,
such as data and information about the
biological source of the enzyme
preparation; the method of manufacture
of the enzyme preparation; constituents
of the enzyme preparation that derive
from the source organism or the
manufacturing process; the technical
effect of the enzyme preparation; dietary
exposure to the enzyme preparation;
specifications for the enzyme
preparation; and applicable safety
studies.
C. Criteria for Eligibility for
Classification as GRAS Through
Experience Based on Common Use in
Food
We proposed to amend the criteria for
eligibility for classification as GRAS
through experience based on common
use in food (§ 170.30(c)(2)) to state that
persons who claim that use of a
substance is GRAS through experience
based on its common use in food
outside of the United States should
notify FDA of that claim in accordance
with the GRAS notification procedure.
We received no comments that
disagreed with this proposed
amendment and are finalizing it as
proposed, with conforming changes as
shown in table 29.
See section XXV.B regarding revisions
to the criteria for eligibility for
classification as GRAS through
experience based on common use in
food for a substance used in animal
food.
D. Other Comments on the Criteria for
Eligibility for Classification as GRAS
(Comment 22) One comment asserts
that the proposed rule would add
unnecessary complexity to continued
use of substances currently presumed to
be GRAS. This comment also asserts
that the proposed rule would remove
the ‘‘pre-1958 exemption’’ and, as a
result, would place an unnecessary
burden on food producers and
processors with respect to substances
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that are the subject of previous
conclusions of GRAS status.
(Response 22) These comments are
unclear. By ‘‘pre-1958 exemption’’ these
comments could mean a conclusion of
GRAS status through experience based
on common use in food, which requires
common use in food before January 1,
1958. Alternatively, these comments
could be referring to the statutory
exception from the definition of ‘‘food
additive’’ for a substance that is the
subject of a prior sanction within the
meaning of section 201(s)(4) of the
FD&C Act and part 181 (21 CFR part
181). Either way, nothing in this rule
would affect a lawful use of a food
substance that is GRAS based on
common use in food prior to January 1,
1958 or that is the subject of a prior
sanction. This rule does not remove
GRAS status based on common use in
food prior to January 1, 1958. Likewise,
the lawful use of a substance listed in
part 181 as being the subject of a prior
sanction is not affected by this rule.
However, any person who relies on a
conclusion of GRAS status through
experience based on common use in
food prior to 1958 or on a prior sanction
within the meaning of section 201(s)(4)
of the FD&C Act needs to consider
whether the conditions of use associated
with the applicable substance, such as
the foods in which the substance would
be used and the levels of use of the
substance, are within the scope of these
statutory provisions. As discussed in
section I.D, in 2010 we issued warning
letters informing four companies
marketing caffeinated alcoholic
beverages that caffeine, as used in the
companies’ products, is an unsafe food
additive, and therefore the products are
adulterated under section 402(a)(2)(C) of
the FD&C Act, and the companies
subsequently ceased distribution of
these products. Thus, we advise any
manufacturer or distributor to carefully
consider whether there is adequate
support for concluding that a substance
is GRAS under the conditions of its
intended use and to submit a GRAS
notice to us if it intends to manufacture
or distribute a food product containing
a substance that has been used in food
as a GRAS substance under conditions
of use different from those in the
manufacturer’s or distributor’s product.
In addition, new data and information
may call into question the safety of a
substance used in food as a GRAS
substance, whether the basis for a
conclusion of GRAS status is through
experience based on common use in
food or through scientific procedures.
As discussed in section I.A, in 1969 we
deleted various cyclamate salts from the
GRAS list because they were implicated
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in the formation of bladder tumors in
rats; as discussed in section I.D, we
recently issued a declaratory order
making a final determination that there
is no longer a consensus among
qualified experts that PHOs are GRAS
for any use in human food (80 FR
34650).
(Comment 23) One comment asks us
to require minimum safety or short-term
toxicology studies for all conclusions of
GRAS status, regardless of whether the
conclusion is through scientific
procedures or through experience based
on common use in food before 1958.
This comment explains that such
studies could corroborate safety when
GRAS status is based on common use on
food, e.g., by taking into account any
impact of the manufacturing process on
food safety.
(Response 23) We decline this
request. We agree that the method of
manufacture can impact safety,
regardless of whether GRAS status is
through experience based on common
use on food or through scientific
procedures. See, e.g., our guidance
entitled ‘‘Assessing the Effects of
Significant Manufacturing Process
Changes, Including Emerging
Technologies, on the Safety and
Regulatory Status of Food Ingredients
and Food Contact Substances, Including
Food Ingredients that Are Color
Additives’’ (Ref. 6). The rule requires
submission of a description of the
method of manufacture in sufficient
detail to evaluate the safety of the
notified substance as manufactured,
regardless of whether the basis for the
conclusion of GRAS status is through
scientific procedures or through
experience based on common use in
food (see § 170.230(b)). If the method of
manufacture has changed over time, a
new evaluation of GRAS status based on
scientific procedures may be warranted.
We advise any manufacturer of a
substance that is used in food based on
a conclusion of GRAS status to carefully
consider the impact of its method of
manufacture on the safety of the
substance before introducing the
substance into commerce.
We disagree that the rule must require
minimum safety or short-term
toxicology studies for all conclusions of
GRAS status because the kinds of data
and information needed to demonstrate
safety (or that could be used to
corroborate safety) will vary based on
the substance and its intended use. A
conclusion of GRAS status based on
scientific procedures must be based on
the same quantity and quality of
scientific evidence as is required to
obtain approval of a food additive
(§ 170.30(b)). We have issued guidance
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on the types of data and information in
support of a food additive petition, and
these types of data and information
would be useful in the evaluation of the
safety of a substance when the
proponent of the substance seeks to
demonstrate that the substance is GRAS
under the conditions of its intended use
(see Response 37 and Response 66).
For a safety assessment of a chemical,
the specific types of data and
information generally follow from the
chemical structure and estimated
dietary exposure of the substance. For
example, chemistry data, including
manufacturing information, as well as
information sufficient to estimate
exposure, are necessary to consider in
arriving at a conclusion of GRAS status.
Whether toxicological studies are
necessary to demonstrate safety depends
on the properties of the substance such
as the presence or absence of chemical
alerts, physical properties, and
physiological fate of the substance. For
example, well understood and accepted
metabolism information about a
substance that is a component of
commonly consumed foods (such as
vegetables or fruits) may provide
sufficient safety information to arrive at
a conclusion of GRAS status at a
specified level of the use of that
substance in food. As discussed in
section III.A.2 of CFSAN’s 2010
experience document, during the
Interim Pilot program it was CFSAN’s
view that toxicological studies were not
necessary to evaluate the safety of
substances such as carrot fiber and dried
orange pulp (Ref. 18). Likewise, for
simple substances (such as minerals and
their salts) that are readily dissociated to
components that have long been viewed
as GRAS (e.g., by a listing in part 182
or by a GRAS affirmation regulation in
part 184), toxicological studies would
likely not be necessary. As discussed in
section III.A.2 of CFSAN’s 2010
experience document, during the
Interim Pilot program it was CFSAN’s
view that toxicological studies were not
necessary to evaluate the safety of
substances such as potassium bisulfate
and seaweed-derived calcium (with
calcium carbonate as the major
component) (Ref. 18).
For a safety assessment of a substance
produced from a microorganism, the
specific types of data and information
generally follow from the identity of the
microorganism and how the substance
is produced from that microorganism in
addition to the substance itself. For
example, the safety of a substance
produced from a microorganism
generally considers generally available
microbiological data and information
about the potential toxigenicity and
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pathogenicity of the microorganism.
Whether toxicological studies would be
necessary to demonstrate the safety of
the substance as manufactured would
depend on what the substance is and its
intended use in food.
E. GRAS Status of Certain Food
Substances
We proposed to remove § 170.30(f),
which expresses our intent to review the
GRAS status of certain food substances.
We received no comments that
disagreed with our proposal to remove
§ 170.30(f) and are removing it as
proposed.
VII. Comments on the Substitution of a
GRAS Notification Procedure for the
GRAS Affirmation
Petition Process
Our regulations specify procedures for
us to affirm the GRAS status of the use
of a food substance, whether on our own
initiative (§ 170.35(a) and (b)) or on the
petition of an interested person
(§ 170.35(c)). We proposed to eliminate
the GRAS affirmation petition process
in § 170.35(c) and replace it with a
GRAS notification procedure (proposed
§ 170.36) in which any person may
notify us of a claim that a particular use
of a substance is exempt from the
statutory premarket approval
requirements based on the notifier’s
determination that such use is GRAS.
Under the proposed notification
procedure, we would evaluate whether
the submitted notice provides a
54979
sufficient basis for a GRAS
determination and whether information
in the notice or otherwise available to us
raises issues that lead us to question
whether use of the substance is GRAS.
We also proposed to presumptively
convert any filed GRAS affirmation
petition that is pending on the date that
the petition process is replaced with a
notification procedure (‘‘pending
petition’’) to a GRAS notice and provide
an opportunity for the person who had
submitted a pending petition (‘‘affected
petitioner’’) to amend the petition to
meet the requirements for a GRAS
notice.
In the 2010 notice, we discussed
several issues broadly applicable to the
proposed substitution of a GRAS
notification procedure for the GRAS
affirmation petition process (see table
3).
TABLE 3—ISSUES IN THE 2010 NOTICE BROADLY APPLICABLE TO THE PROPOSED SUBSTITUTION OF A GRAS
NOTIFICATION PROCEDURE FOR THE GRAS AFFIRMATION PETITION PROCESS
Issue
No.
Description of our request for comment
N/A ....
2 ........
Our intent to use ‘‘Plain Language’’ tools such as pronouns in the final rule .......................................
Our reasons for tentatively concluding that the terms ‘‘conclude’’ and ‘‘conclusion’’ would be more
appropriate in lieu of ‘‘determine’’ and ‘‘determination’’.
Alternative approach to administering pending GRAS affirmation petitions ..........................................
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17 ......
Several comments support the
proposed replacement of the GRAS
affirmation petition process with a
GRAS notification procedure. For
example, several comments support the
expectation we expressed in the
proposed rule (62 FR 18938 at 18941)
that the substitution of a GRAS
notification procedure for the GRAS
affirmation petition process would
result in our increased awareness of the
composition of the nation’s food supply
and the cumulative dietary exposure to
GRAS substances. Most of these
comments agree that such increased
awareness could be an advantage of the
notification procedure if manufacturers
view our response to a GRAS notice as
an incentive to participate in the
program. Many comments that support
the proposed replacement of the GRAS
affirmation petition process with a
GRAS notification procedure
nonetheless raise questions about how
we would administer the pending GRAS
affirmation petitions. We discuss those
comments in section XXIII.
In the following sections, we discuss
comments that disagree with one or
more aspects of our proposal to replace
the GRAS affirmation petition process
with a GRAS notification procedure
(see, e.g., Comment 24, Comment 25,
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Reference
and Comment 32); ask us to clarify how
we generally will administer the
proposed GRAS notification procedure
(see, e.g., Comment 31); or suggest one
or more general changes to the proposed
GRAS notification procedure (see, e.g.,
Comment 27, Comment 28, Comment
30, Comment 31, and Comment 36).
After considering these comments, we
are replacing the GRAS affirmation
petition process with a GRAS
notification procedure, using the terms
‘‘conclude’’ and ‘‘conclusion’’ as
described in the 2010 notice. As noted
in the 2010 notice, the final rule uses
Plain Language tools such as pronouns.
To improve clarity and readability we
used another Plain Language tool, i.e.,
the use of short regulatory sections that
have limited subparagraph designations.
To do so we redesignated the single
proposed section (i.e., proposed
§ 170.36) into several distinct, short
sections of regulatory text in a newly
established subpart E (GRAS Notice),
with editorial changes associated with
the new structure of the redesignated
regulations. See table 4 for the section
numbers and titles of the regulatory text
in subpart E. Many provisions of the
regulatory text in subpart E use singular
nouns when discussing the intended
use of the notified substance, e.g., the
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75 FR 81536 at 81537.
75 FR 81536 at 81538.
75 FR 81536 at 81542–81543.
definition of ‘‘GRAS notice’’ means a
submission that informs us of your view
that a specified use of a substance is not
subject to the premarket approval
requirements of the FD&C Act based on
your conclusion that such use is GRAS.
The singular term ‘‘use’’ is employed for
a simple and consistent presentation in
the regulatory text and does not mean,
for example, that you are limited to
notifying us about a single use of the
notified substance.
We also are establishing in new
subpart E the process we described in
the 2010 notice for administering
pending GRAS affirmation petitions.
Finally, we made editorial, clarifying,
and conforming changes as shown in
table 29. Because the editorial changes
associated with the redesignation of the
notification procedure in subpart E are
extensive, we do not list them in table
29.
A. Affirmation on the Initiative of the
Commissioner
We proposed to amend current
§ 170.35(a) to clarify that the
Commissioner would affirm the GRAS
status of a use of a substance, rather
than the substance itself, and to include
a grammatical change to place
§ 170.35(a) in the singular. The single
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comment that expressly addressed this
proposed amendment concurred with us
on this point and we are finalizing it as
proposed.
We also proposed to amend current
§ 170.35(a) to remove the provision that
we may review the GRAS status of a
substance added to food in response to
a petition from an interested party.
Under current § 170.35, such a petition
would be submitted in accordance with
the provisions of the GRAS affirmation
petition process established in current
§ 170.35(c). We are deleting this
provision as proposed. The comments
we received relevant to our proposed
deletion of the petition-related
provision in § 170.35(a) are directed to
our proposed deletion of the GRAS
affirmation petition process in current
§ 170.35(c), and we discuss those
comments in section VII.B.
B. Deletion of the GRAS Affirmation
Petition Process
We proposed to eliminate the GRAS
affirmation petition process in current
§ 170.35(c).
(Comment 24) Several comments
oppose our proposal to eliminate the
GRAS affirmation petition process. In
general, these comments assert that we
should provide manufacturers the
option of seeking GRAS affirmation
even though we would be establishing
a new notification procedure. The
comments assert that such an option is
essential to support the marketing of a
product in certain situations, such as
when recognition of GRAS status is
needed by international standard-setting
bodies.
(Response 24) We acknowledge that a
regulation listing the use of a substance
in food could provide some support for
marketing a product in certain
situations, but disagree that we should
retain the GRAS affirmation petition
process. We note that CFSAN filed more
than 600 GRAS notices during the time
period 1998 through 2015 (Ref. 19), for
an average of approximately 34 GRAS
notices per year, including 69 GRAS
notices filed during 2014 and 51 GRAS
notices filed during 2015. By contrast,
during that time CFSAN finalized six
GRAS affirmation regulations. We
believe that the ongoing submission of
GRAS notices is evidence that our
response to a GRAS notice can support
the marketing of a food substance.
(Comment 25) Some comments assert
that the proposed GRAS notification
procedure would be less protective of
food safety than the GRAS affirmation
petition process it would replace. Some
comments assert that our role in
ensuring the safety of food ingredients
is best carried out by a review of the
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data supporting the safety of the
ingredient and that the public should
also have access to these data. These
comments also assert that the GRAS
affirmation petition process, in which
we conduct a review of supporting data,
provides an incentive to manufacturers
to fully research each substance and that
removing this incentive would
compromise safety. Other comments
assert that the GRAS notification
procedure would be less thorough than
the GRAS affirmation petition process.
One comment states that consumers are
concerned about the safety and
wholesomeness of substances added to
food and criticizes the proposed rule as
not being ‘‘rigorous enough’’ and as not
creating a ‘‘meaningful process for
adequately reviewing the safety of
substances used in human and animal
food.’’
(Response 25) We disagree that the
notification procedure is less protective
of food safety than the affirmation
petition process. In the proposed rule,
we stated that our response to a GRAS
notice would not be equivalent to an
agency affirmation of GRAS status
because we would neither receive nor
review the detailed data and
information that support the GRAS
determination (62 FR 18938 at 18951).
These comments may have
misinterpreted that statement to mean
that we would not conduct a substantive
evaluation of the summary information
that we receive in a GRAS notice. This
is not the case. CFSAN’s 2010
experience document (Ref. 18)
demonstrates that we have conducted a
substantive evaluation of the GRAS
notices that we received during the
Interim Pilot program. For example,
section III.C.1 of CFSAN’s 2010
experience document describes
examples of situations in which we
contacted a notifier to request
clarification about data and information
in the notice. CFSAN’s 2010 experience
document also demonstrates that during
the period 1998–2009 CFSAN had
questions about 21 percent of GRAS
notices, such that CFSAN either
responded to the notifier that the
submitted GRAS notice did not provide
a basis for a conclusion of GRAS status
or the notifier asked us to cease to
evaluate the GRAS notice (see section
III.B of CFSAN’s 2010 experience
document). Furthermore, we believe
that the GRAS notification procedure
provides us with greater flexibility to
respond to safety concerns that may
arise about a substance that is the
subject of a GRAS notice, compared to
a substance that is the subject of a GRAS
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affirmation regulation, which would
require rulemaking to revoke.
We acknowledge that the term (i.e.,
‘‘evaluate’’) we use to describe our
actions when we receive a GRAS notice
is different from the term (i.e., ‘‘review’’)
we use to describe our actions when we
receive a petition (whether a food or
color additive petition or a GRAS
affirmation petition). We decided to use
a different term because, as already
noted, the data and information we will
receive in a GRAS notice (i.e., summary
data and discussions) are different from
the data and information we receive in
a petition (which generally includes the
underlying data from studies described
in the petition).
As discussed in Response 120, we
currently make a hyperlink to an
electronic copy of each GRAS notice
accessible from our Internet site and,
thus, the public has access to each
GRAS notice. We also make our
response to each GRAS notice accessible
from our Internet site (see § 170.275(b),
Response 115, and Response 116). We
acknowledge that supporting data and
information that are provided to us in
the form of a petition can provide the
public with ready access to such data
and information (e.g., through a FOIA
request), but disagree that substitution
of the GRAS notification procedure for
the GRAS affirmation petition process
has a fundamental impact on the
public’s access to supporting data and
information, because a conclusion of
GRAS status must be based on generally
available data and information. Under
the notification procedure, the publicly
accessible GRAS notice both
summarizes the available data and
information and provides a list of
publicly available data and information
(see §§ 170.250 and 170.255). Under the
GRAS affirmation petition process, we
placed a copy of each publication
provided by the petitioner to support a
conclusion of GRAS status in the public
docket for that petition, but our current
practice with respect to copyrighted
publications is to refer the public to the
primary records (see § 20.51, Referral to
primary source of records).
We cannot say whether a petition
process would provide an incentive for
a manufacturer to more fully research
the safety of a substance before sending
a GRAS notice to us. However, we
advise a manufacturer who intends to
submit a GRAS notice to expect a
substantive evaluation of that GRAS
notice by us. Likewise, we advise a
manufacturer who reaches a conclusion
that a substance is GRAS under the
conditions of its intended use, but does
not submit a GRAS notice to us, that
when a substance is not GRAS under
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the conditions of its intended use (or is
not otherwise excepted from the
definition of ‘‘food additive’’ in section
201(s) of the FD&C Act), that use of the
substance is a food additive use subject
to our premarket review as mandated by
the FD&C Act. In such circumstances,
we can take various actions, including
issuing a warning letter (which we make
public on our Web site) to companies
that manufacture or distribute the food
additive and/or food containing the food
additive; issuing a public alert; taking
enforcement action to stop distribution
of the food substance and foods
containing it on the grounds that such
foods are or contain an unlawful food
additive; and issuing a declaratory order
determining that the substance is not
GRAS under the conditions of its
intended use and is a food additive
subject to section 409 of the FD&C Act.
For example, as already discussed in
section I.D, we recently issued a
declaratory order making a final
determination that there is no longer a
consensus among qualified experts that
PHOs are GRAS for any use in human
food (80 FR 34650). As another example
discussed in section I.D, we have issued
warning letters informing four
companies marketing caffeinated
alcoholic beverages that caffeine, as
used in the companies’ products, is an
unsafe food additive, and therefore the
products are adulterated under section
402(a)(2)(C) of the FD&C Act (Ref. 10
through Ref. 13), and the companies
subsequently ceased distribution of
these products. Thus, we advise any
manufacturer or distributor to carefully
consider whether there is adequate
support for concluding that a substance
is GRAS under the conditions of its
intended use and to submit its
conclusion of GRAS status to us in the
form of a GRAS notice.
(Comment 26) A few comments
express skepticism that the substitution
of a GRAS notification procedure for the
GRAS affirmation petition process
would result in our increased awareness
of the composition of the nation’s food
supply and the cumulative dietary
exposure to GRAS substances. These
comments assert that the proposed
notification procedure offered a risk
(i.e., the risk of a publicly available
‘‘insufficient basis letter’’) without the
potential benefit that was available
under the petition process (i.e., a
regulation affirming GRAS status).
These comments predict that, unless we
modify the proposed rule substantially,
we likely would have less awareness of
GRAS substances under the notification
procedure than we currently have under
the GRAS affirmation petition process.
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One comment asserts that the
notification procedure would in no
manner be equivalent to the GRAS
affirmation petition process, and the
substitution of a notification procedure
for a petition process would be anything
but neutral. This comment asserts that
the proposed substitution of a
notification process for the affirmation
process would actually reduce the
incentive for producers to notify FDA,
because notification would invite
regulatory scrutiny without requiring
FDA to attest to a conclusion of GRAS
status.
(Response 26) We disagree that the
notification procedure we are
establishing in this rule will reduce the
incentive for producers to notify us. As
already noted in Response 24, CFSAN
has filed more than 600 GRAS notices
between 1998 and 2015, for an average
of approximately 34 GRAS notices per
year. In contrast, as discussed in section
IV.L of CFSAN’s 2010 experience
document (Ref. 18), between 1987 and
1996 CFSAN received a total of fewer
than 100 GRAS affirmation petitions,
with an average of approximately 8
GRAS affirmation petitions per year.
These data support the expectation we
expressed in the proposed rule that the
substitution of a GRAS notification
procedure for the GRAS affirmation
petition process would result in our
increased awareness of the composition
of the nation’s food supply and the
cumulative dietary exposure to GRAS
substances.
The comments that predict that we
would need to modify the final rule
substantially to achieve increased
awareness of the nation’s food supply
did not suggest specific modifications
for this purpose. However, this
document discusses the changes we
have made to the proposed notification
procedure as a result of comments,
described in this document and the
2010 notice, that raised specific issues
and concerns regarding the proposed
notification procedure. For example, the
final rule defines the term
‘‘amendment’’ (§ 170.203) and expressly
provides that a notifier may submit a
timely amendment to address our
questions (§ 170.260(a)). As another
example, the final rule expressly
provides that a notifier may ask us to
cease to evaluate a GRAS notice
(§ 170.260(b)). In addition, see Response
80 regarding our willingness to engage
with a notifier to clarify particular
aspects of the notice and Response 96
and Response 97 regarding comments
that raise concerns about a publicly
available insufficient basis letter. For a
summary of the principal changes to the
notification procedure in this final rule
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relative to the proposed rule, see table
2.
(Comment 27) One comment asks us
to require the submission of a GRAS
affirmation petition on a random basis
for 20 percent of the GRAS notices we
receive. This comment states that such
a requirement would be essential in
light of our concurrent proposal to
broaden the types of safety information
that could support GRAS status in the
criteria for eligibility for classification as
GRAS through scientific procedures.
The comment refers to this procedure as
a ‘‘verification audit’’ and describes a
‘‘verification audit’’ as a detailed
evaluation of the scientific data and
other technical information. The
comment asks that the final rule give
FDA such ‘‘verification authority’’ and
asserts that such a verification system
would give consumers greater
confidence that the new notification
system was not just a system of
deregulation.
(Response 27) We decline this
request. Both the GRAS notification
procedure and the GRAS affirmation
petition process that it is replacing are
voluntary procedures and, thus, the
comment’s position that we could
require a GRAS affirmation petition—on
a random or any other basis—is
incorrect. Moreover, we disagree that
the revised criteria for eligibility for
GRAS status through scientific
procedures have any bearing on whether
we should evaluate a conclusion of
GRAS status through a notification
procedure or a petition process. The
revised criteria reflect the nature of
substances being added to food, and the
fact that the quantity and quality of
scientific evidence required to
demonstrate safety vary considerably
depending upon the estimated dietary
exposure to the substance and the
chemical, physical, and physiological
properties of the substance. See
Response 23.
C. General Comments on the Proposed
GRAS Notification Procedure
(Comment 28) Some comments ask us
to require that companies notify us of a
conclusion of GRAS status and assert
that we have implied legal authority to
require such notification. These
comments express concern that
potentially dangerous substances could
enter the food supply without our
knowledge or supervision. Other
comments emphasize that the GRAS
notification procedure should remain
voluntary and assert that we lack
express statutory authority to require
companies to submit GRAS notices.
(Response 28) We agree that we lack
express statutory authority to require
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companies to submit GRAS notices. In
creating the premarket approval
requirement for food additives in the
1958 amendment, Congress excluded a
substance that is GRAS under the
conditions of its intended use from the
definition of food additive. The creation
of this GRAS provision reflected
Congress’ determination that many
substances intentionally added to food
for a specific use do not need premarket
review by FDA to ensure their safety,
either because their safety has been
established by a long history of use in
food, or because their safety has been
established by information that is
generally available to and accepted by
qualified experts, regarding the
intended conditions of use of a
substance in food. Subsequently, in
1997, the Food and Drug Administration
Modernization Act (FDAMA) amended
section 409 of the FD&C Act to require
the establishment of a mandatory food
contact notification program for human
food. By contrast, Congress has not
amended section 409 of the FD&C Act
to require the establishment of a
premarket GRAS notification
procedure—either voluntary or
mandatory.
We did not propose to require the
submission to FDA of notices
concerning all conclusions of GRAS
status. We recognize that some
comments suggest that such a
requirement might be within our legal
authority, even if not expressly required
by the FD&C Act. We will consider
these comments and our experience
under this final rule in evaluating what,
if any, further action is needed with
respect to ensuring the safety of the food
supply. However, mandating
submission of GRAS notices would
need to be done in a separate
rulemaking to ensure adequate notice
and comment.
(Comment 29) One comment notes
that the proposed rule did not
specifically ask members of the food
industry to notify us of all conclusions
of GRAS status. This comment suggests
that the final rule include such a
request, explaining that such a
provision would help us to achieve our
goal of increasing our awareness of
substances added to food.
(Response 29) We view our
establishment of the GRAS notification
procedure in this final rule, as well as
our announcement of the Interim Pilot
program in the proposed rule, as an
invitation to industry to submit GRAS
notices to us for evaluation. See also
§ 170.205, entitled ‘‘Opportunity to
submit a GRAS notice.’’ The ongoing
submission of GRAS notices during the
Interim Pilot program demonstrates that
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the food industry is actively submitting
GRAS notices. As already noted in
Response 26, we believe that our filing
of more than 600 GRAS notices for
substances used in human food is
evidence that we have increased our
awareness of the composition of the
nation’s food supply and the dietary
exposure to GRAS substances.
(Comment 30) Some comments ask us
to require certain postmarket
submissions of exposure and safety data
related to all GRAS substances, to
require submissions for conclusions of
GRAS status that predate the final rule,
and to require any notifier who
‘‘withdraws’’ a GRAS notice or receives
an ‘‘insufficient basis letter’’ to notify us
about any use of that substance.
(Response 30) We decline this request
for the same reasons that we discuss in
Response 28. See also the discussions in
Response 25 and Response 35 regarding
the responsibility of a manufacturer to
ensure that a substance added to food
complies with the FD&C Act, and the
potential that we may disagree with a
conclusion of GRAS status and take
regulatory action against use of the food
substance when we do so.
(Comment 31) Some comments ask us
to clarify all the information we expect
to be submitted in a GRAS notice. One
comment states its opposition for the
proposed GRAS notification procedure,
but also states that if we implement
such a program we should establish the
framework and criteria for the voluntary
submission of GRAS notices. Another
comment asks us to include core
requirements in the final rule. Another
comment asks us to provide more
explicit instructions concerning the
level of detail necessary within the
required elements of a GRAS notice.
(Response 31) Subpart E of part 170
(subpart E) establishes a comprehensive
framework for the submission of GRAS
notices, describing in detail ‘‘core
requirements’’ such as the seven distinct
parts of a GRAS notice. Subpart E also
includes provisions that will govern
what we will do when we receive a
GRAS notice, as well as provisions that
will govern disclosure of a GRAS notice.
Section 170.30 establishes the revised
criteria for eligibility for classification of
the food use of a substance as GRAS.
(Comment 32) One comment
expresses concern that the proposed
GRAS notification procedure would be
viewed as a ‘‘fast-track’’ option that
would tempt a company that should
submit a food additive petition to
submit a GRAS notice instead.
(Response 32) We recognize that there
is a possibility that some manufacturers
of food ingredients may decide that they
do not need to submit a food additive
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petition because they have concluded
that the substance is GRAS under the
conditions of its intended use; this
possibility exists regardless of how we
structure the GRAS notification
procedure. However, a manufacturer’s
decision that a food additive petition is
not required must be based on the
extent to which the manufacturer has
information both that the intended
conditions of use of a substance in food
are ‘‘safe,’’ and that there is ‘‘general
recognition’’ of that safety. In this rule,
we clarify the criteria (§ 170.30) that
govern when the intended conditions of
use of a substance in food are more
properly the subject of a food additive
petition than a GRAS notice.
The record of our actions during the
Interim Pilot program demonstrates that
we will, when appropriate, issue an
‘‘insufficient basis letter’’ or a ‘‘cease to
evaluate letter’’ signaling that a petition
to obtain a regulation is more
appropriate than a GRAS notice. As
described in sections III.A.4 and III.N.2
of CFSAN’s 2010 experience document
(Ref. 18), in several cases during the
Interim Pilot program the outcome of
CFSAN’s review of a GRAS notice was
the notifier’s subsequent submission of
a food additive petition.
(Comment 33) One comment
expresses the opinion that a GRAS
notice could be an appropriate
mechanism to inform us of a view that
an additional use of an approved food
additive is GRAS.
(Response 33) We agree, provided that
the available data and information
demonstrate that the criteria for GRAS
status are satisfied. Whether an
additional use of a food additive is
GRAS depends on both whether that
additional use is safe and on whether
the safety of that additional use is
generally recognized by qualified
experts. To support a conclusion of
GRAS status for the additional use of
the substance, there must be evidence
that qualified experts generally (not
solely FDA experts who conducted a
premarket review of a food additive
petition) have evaluated generally
available data and information about the
intended conditions of use of the
substance, and reached agreement that
those generally available data and
information establish the safety of the
additional use of the substance. During
the Interim Pilot program, CFSAN
received several GRAS notices
informing CFSAN of a conclusion that
an additional use of an approved food
additive is GRAS. As discussed in
section III.A.4 of CFSAN’s 2010
experience document (Ref. 18),
CFSAN’s response to these GRAS
notices has been a case-by-case response
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that depends on the circumstances. In
several cases, CFSAN had no questions
about the notifier’s conclusion of GRAS
status for an additional use of a food
additive; in one case, the GRAS notice
did not support GRAS status for the
additional use of the food additive, and
the notifier subsequently submitted a
food additive petition for the additional
use of the substance.
(Comment 34) One comment suggests
that the GRAS notification procedure
would shift the burden of proof to FDA
to demonstrate that a use of a substance
is not safe or not GRAS after the
substance is already on the market.
(Response 34) We disagree. Under the
FD&C Act, the burden of supporting a
conclusion that a substance is GRAS
under the conditions of its intended use
is on the proponent of this conclusion.
United States v. An Article of Food, 752
F.2d 11, 15 (1st Cir. P.R. 1985). This
burden of proof remains after the
substance is on the market regardless of
whether the proponent asks FDA to
evaluate that GRAS conclusion, and our
rule does not change this. By
establishing a process for the
submission of GRAS notices for FDA to
review, our rule encourages firms to
seek our evaluation of their conclusions,
before they introduce the substance into
the market.
(Comment 35) A few comments note
that a notifier who markets a food
substance before we issue our letter
responding to the notice runs the risk
that we may disagree with the
conclusion of GRAS status. One
comment expresses concern that we
would take regulatory action to remove
the substance from the food supply
rather than discuss our concerns with
the notifier.
(Response 35) The comments are
correct that a notifier who markets a
food substance before we issue our letter
based on our evaluation of the notice
runs the risk that we may disagree with
the conclusion of GRAS status. (We note
that a manufacturer who markets a food
substance without submitting a GRAS
notice runs a similar risk.) However, we
make every effort to evaluate the data
and information submitted on a timely
basis, and in this rule we commit to
responding to a GRAS notice within 180
days after filing the notice, with the
option to extend an additional 90 days
as needed. Because a substance that is
GRAS under the conditions of its
intended use is not subject to premarket
review as a food additive under the
FD&C Act, a notifier could decide to
introduce the substance into the market
without waiting for the letter; we could
subsequently determine that the
substance is an unapproved food
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additive, and we may take action to
remove the substance from the food
supply.
See also the discussion in Response
80. Our experience during the Interim
Pilot program demonstrates that we are
willing to contact a notifier to clarify
particular aspects of a GRAS notice. As
also discussed in Response 80, under
the final rule, we intend to contact a
notifier when we identify a safety
concern. However, whether the purpose
of the contact is to provide an
opportunity to address that concern
(e.g., in an amendment or in a newly
submitted GRAS notice), or to alert the
notifier to our concerns while we
prepare an ‘‘insufficient basis letter,’’
has been, and will continue to be, a
matter committed to our discretion
depending on the totality of the
circumstances.
(Comment 36) One comment suggests
that we ask notifiers who previously
received a ‘‘no questions letter’’ under
the Interim Pilot program to review their
prior submissions and align them with
the requirements of the final rule.
(Response 36) We decline this
suggestion. The final rule does not pose
any substantially different data
requirements than did the Interim Pilot
program in terms of data quality and
quantity to support the conclusion of
GRAS status. We do not anticipate, as a
general matter, the need to ask previous
notifiers who received a ‘‘no questions
letter’’ to provide any supplemental
information. However, if we become
aware of data or information that
questions the GRAS status of the use of
a substance that has been the subject of
a ‘‘no questions letter,’’ we may send the
notifier a subsequent letter advising the
notifier of those questions (see
§ 170.265(c)). Because we would make
the subsequent letter readily accessible
to the public (see § 170.275(b)(2)), other
stakeholders would have ready access to
those questions.
(Comment 37) One comment states
that GRAS ‘‘determinations’’ must be
evaluated based on adequate science
and recommends that GRAS
‘‘determinations’’ comply with our
guidance on food additive testing.
(Response 37) We agree that safe
use(s) of a substance must be supported
by adequate science. We do have
extensive guidance on food additive
testing (Ref. 31 through Ref. 35), and we
agree that this guidance on food
additive testing can be useful in the
evaluation of the safety of a substance
when the proponent of the substance
seeks to demonstrate that the substance
is GRAS under the conditions of its
intended use. As discussed in Response
128, as resources allow we intend to re-
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visit these scientific guidance
documents to determine whether and
how to modify them to clarify that our
guidance on evaluating the safety of a
food substance generally applies
regardless of whether the substance
would be used in food as a food additive
or as a GRAS substance.
Recently, we issued a notice (79 FR
64603, October 30, 2014) announcing a
public meeting, and requesting
comments, on our intent to update our
guidance entitled ‘‘Guidance for
Industry and Other Stakeholders:
Toxicological Principles for the Safety
Assessment of Food Ingredients’’ (Ref.
35; commonly referred to as our
‘‘Redbook’’). In that notice, we reiterated
that general recognition of safety based
upon scientific procedures requires the
same quantity and quality of evidence
as is required to approve a food
additive. We also asked for comment on
how we should balance the desire for
transparency and consistency in risk
assessment, as described in the
Redbook, with the goal of flexibility in
applying the most appropriate analysis
for specific contexts.
(Comment 38) One comment states
that the resource-intensive petition
process would be reserved for
ingredients not eligible to meet GRAS
criteria, or those which pose questions
necessitating indepth review by FDA
scientists, even though the safety
standard for GRAS ingredients and food
additives is the same.
(Response 38) The comment is correct
that a food additive petition would be
required for an ingredient that is not
eligible for classification as GRAS and is
not otherwise excepted from the
statutory definition of a food additive.
We agree that indepth review of the
safety of a substance under the
conditions of its intended use in food by
FDA scientists is necessary when there
is no basis for a conclusion that the
intended conditions of use have GRAS
status. However, see Response 25. Our
evaluation of a GRAS notice is a
substantive evaluation even though we
respond to a GRAS notice by letter
rather than by establishing a regulation.
(Comment 39) One comment asserts
that we tentatively concluded that the
proposed notification procedure would
allow us to direct our resources to the
more significant questions about GRAS
status, without further explaining what
these ‘‘more significant questions’’ are.
This comment further asserts that the
obvious conclusion is that we will
simply reduce the Federal layer of
oversight in the interests of efficiency
and in doing so ignore the history of
food law, which has repeatedly shown
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that the public suffers when FDA
declines to regulate.
(Response 39) See the actions we
describe in section I.D, on PHOs and
caffeinated alcoholic beverages, for
examples of what we mean by ‘‘more
significant questions.’’ We disagree that
directing our resources in such a
manner reduces our oversight; on the
contrary, such actions demonstrate that
we will take appropriate steps to
address concerns about the safety of
substances marketed under the GRAS
provision of the FD&C Act. The
comment provides no basis for its
assertion that the notification procedure
ignores the history of food law or that
the public will suffer.
(Comment 40) One comment points
out that our response to a GRAS notice
addresses the question of whether a
particular use of a notified substance is
GRAS, without limiting that question to
production of that food substance by a
specific manufacturer (e.g., the notifier
who submitted the GRAS notice). This
comment asks us to require that any
other food producer who uses the
substance in food on the basis of a
GRAS conclusion submitted to FDA in
a GRAS notice meet all requirements
and specifications in the submitted
GRAS notice, including use of the same
source for the production of the food
substance.
(Response 40) The comment is correct
that our response to a GRAS notice
would not limit a food producer other
than the notifier from relying on the
submitted GRAS notice, and our
response to that GRAS notice, when that
food producer concludes that a
substance is GRAS under the conditions
of its intended use in food. The method
of manufacture (including any source
specified for the production of the
notified substance) and specifications
identified in a GRAS notice are relevant
to both the identity of the substance and
its safety for use in food. We advise any
food producer who relies on a GRAS
notice submitted by another person to
carefully consider whether its
production process, and/or the intended
conditions of use of the notified
substance, fall within the parameters,
such as method of manufacture
(including a specified source) and
specifications, addressed by the
submitted GRAS notice. We recently
issued guidance to help food producers
to do so. See our guidance entitled
‘‘Assessing the Effects of Significant
Manufacturing Process Changes,
Including Emerging Technologies, on
the Safety and Regulatory Status of Food
Ingredients and Food Contact
Substances, Including Food Ingredients
that Are Color Additives’’ (Ref. 6).
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D. Comments on Certain Terms Used in
the Proposed Regulatory Text
1. Replacing the Terms ‘‘Determine’’
and ‘‘Determination’’ With the Terms
‘‘Conclude’’ and ‘‘Conclusion’’
In the 2010 notice, we explained our
reasons for tentatively concluding that
the terms ‘‘conclude’’ and ‘‘conclusion’’
would be more appropriate in lieu of
‘‘determine’’ and ‘‘determination’’ and
requested comment on these terms (see
Issue 2, 75 FR 81536 at 81538).
(Comment 41) Many comments
support replacing the terms
‘‘determine’’ and ‘‘determination’’ with
the terms ‘‘conclude’’ and ‘‘conclusion.’’
One comment disagrees with changing
the terms ‘‘determine’’ and
‘‘determination.’’ This comment asserts
that the terms ‘‘determine’’ and
‘‘determination’’ are more appropriate
because a determination is made based
on the sum of the total assembled data
and conclusions. This comment also
disagrees with changing the terms
because individuals who already are
involved in the GRAS notification
procedure as a result of the Interim Pilot
program are already familiar with the
terms and meanings of ‘‘determine’’ and
‘‘determination.’’
One comment observes that the terms
‘‘determined’’ and ‘‘determination’’ are
used in § 170.30 of our regulations
within the context of establishing GRAS
status. This comment asks us to clarify
how we would apply the terms
‘‘determined,’’ ‘‘determination,’’
‘‘conclude,’’ and ‘‘conclusion’’ and
whether we would limit how some
terms apply depending on whether a
substance is the subject of a GRAS
notice. This comment expresses concern
that such a distinction in terms could
lead to a misperception that a substance
that is the subject of a GRAS notice has
a more authoritative and/or superior
legal standing than a substance that
does not.
(Response 41) We are replacing the
term ‘‘determination’’ with
‘‘conclusion,’’ and referring to a
‘‘conclusion of GRAS status’’ rather than
to a ‘‘GRAS determination,’’ throughout
the regulatory text for the GRAS
notification procedure. We recognize
that notifiers involved with the GRAS
notification procedure may be more
familiar with the terms ‘‘determine’’ and
‘‘determination.’’ Nevertheless, we
believe that as notifiers gain more
experience with the GRAS notification
procedure set forth in this final rule,
notifiers will adjust to using
‘‘concludes’’ and ‘‘conclusion.’’
We are making conforming changes to
current regulations regarding the use of
GRAS substances in food to no longer
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use the terms ‘‘determine’’ and
‘‘determination’’ (see the changes to
§§ 170.3(k), 170.30(c)(1), and 170.30(e)
in table 29). We are making these
conforming changes to clarify that there
would be no distinction between a
conclusion of GRAS status submitted to
us as a GRAS notice and a conclusion
of GRAS status that remains with its
proponent as an independent
conclusion (formerly referred to as a
‘‘self-determination’’) of GRAS status.
2. The Terms ‘‘Exempt,’’ ‘‘Exemption,’’
and ‘‘Claim’’
Several provisions in the proposed
rule would use terms such as ‘‘exempt,’’
‘‘exemption,’’ and ‘‘claim.’’
(Comment 42) Several comments
object to some terms used in the
proposed procedure for submitting a
GRAS notice. Some comments object to
proposed title for the GRAS notification
procedure, i.e., ‘‘Notice of a claim for
exemption based on a GRAS
determination.’’ Most of these
comments also object to our
characterization of one of the proposed
provisions (proposed § 170.36(c)(1)) as a
‘‘GRAS exemption claim.’’ In general,
these comments assert that nothing in
the FD&C Act or in the legislative
history of the FD&C Act supports
designation of GRAS status as an
‘‘exemption.’’ In addition, several
comments object to our use of the term
‘‘claim’’ in various proposed provisions
because our use of this term implies that
we have legal authority to deny a claim
or that GRAS status is not operative
unless a claim is filed.
(Response 42) We have made the
following editorial changes throughout
the regulatory text to no longer use
terms such as ‘‘exempt,’’ ‘‘exemption,’’
and ‘‘claim.’’ First, we replaced the term
‘‘exempt’’ with the phrase ‘‘not subject
to.’’ Section 201(s) of the FD&C Act
provides that a substance that is GRAS
under the conditions of its intended use
is not within the definition of food
additive. Whether the statutory GRAS
provision in section 201(s) is an
‘‘exemption,’’ or, is an ‘‘exclusion,’’ is
not essential to this rulemaking and,
thus, we need not include any
variations of the term ‘‘exempt’’ in the
final rule. Second, we replaced the term
‘‘claim’’ (when used as a noun) with the
term ‘‘view.’’ In the past, we have used
the term ‘‘view’’ when describing a
statement or assertion that a use of a
substance is GRAS (see, e.g., 62 FR
36749, July 9, 1997). Finally, we
simplified the title of the regulatory text
to ‘‘Generally Recognized as Safe
(GRAS) Notice.’’
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E. Comments on the Use of ‘‘Plain
Language’’ in the Regulatory Text
In the 2010 notice, we noted our
intent to use ‘‘Plain Language’’ tools
such as pronouns in the final rule (75
FR 81536 at 81537). The use of ‘‘Plain
Language’’ tools in government writing,
now called ‘‘plain writing,’’ is
consistent with the government-wide
initiative to promote transparency,
public participation, and collaboration
throughout the Federal Government’s
programs and activities as set out in
‘‘Improving Electronic Dockets on
Regulations.gov and the Federal Docket
Management System: Best Practices for
Federal Agencies’’ (Ref. 22).
(Comment 43) One comment
recommends that we use Plain Language
throughout the regulatory text to foster
greater understanding about the
regulatory requirements and
expectations for the notification
54985
procedure, leading to a more effective
program.
(Response 43) We have used ‘‘Plain
Language’’ tools (such as short sections
and the use of pronouns) throughout the
regulatory text of subpart E, which
establishes the requirements for the
GRAS notification procedure. See table
4 for the section numbers and titles of
the redesignated regulatory text in
subpart E.
TABLE 4—REDESIGNATION OF THE GRAS NOTIFICATION PROCEDURE IN SUBPART E
Section
170.203
170.205
170.210
170.215
170.220
170.225
170.230
170.235
170.240
170.245
170.250
170.255
170.260
170.265
170.270
Title
.............
.............
.............
.............
.............
.............
.............
.............
.............
.............
.............
.............
.............
.............
.............
170.275 .............
170.280 .............
170.285 .............
Definitions.
Opportunity to submit a GRAS notice.
How to send your GRAS notice to FDA.
Incorporation into a GRAS notice.
General requirements applicable to a GRAS notice.
Part 1 of a GRAS notice: Signed statements and certification.
Part 2 of a GRAS notice: Identity, method of manufacture, specifications, and physical or technical effect.
Part 3 of a GRAS notice: Dietary exposure.
Part 4 of a GRAS notice: Self-limiting levels of use.
Part 5 of a GRAS notice: Experience based on common use in food before 1958.
Part 6 of a GRAS notice: Narrative.
Part 7 of a GRAS notice: List of supporting data and information in your GRAS notice.
Steps you may take before FDA responds to your GRAS notice.
What FDA will do with a GRAS notice.
Procedures that apply when the intended conditions of use of a notified substance include use in a product or products subject to regulation by FSIS.
Public disclosure of a GRAS notice.
Submission of a supplement.
Disposition of pending GRAS affirmation petitions.
VIII. Definitions Applicable to a GRAS
Notice
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A. Definitions We Described in the 2010
Notice
In the 2010 notice, we requested
comment on definitions for the terms
‘‘amendment,’’ ‘‘notified substance,’’
‘‘notifier,’’ ‘‘qualified expert,’’ and
‘‘supplement’’ (see Issue 3, 75 FR 81536
at 81538). We received several
comments that generally support adding
definitions for these terms, and we are
establishing a section in the regulatory
text of subpart E to define these and
other terms (see § 170.203).
B. Definition of ‘‘GRAS Notice’’
(Comment 44) Some comments
express concern about the potential for
confusion between the proposed GRAS
notification procedure and another FDA
‘‘notification program’’, i.e., the
premarket notification program for food
contact substances (in part 170, subpart
D) that we established under FDAMA.
These comments assert that this
confusion can lead to uncertainty about
the nature of the proposed GRAS
notification procedure, such as with
respect to market ‘‘exclusivity’’ for the
notified substance. One comment states
that the terms ‘‘GRAS notice’’ and
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‘‘GRAS notification’’ appear to be used
interchangeably in the 2010 notice and
asks whether it is our intention to use
‘‘notice,’’ ‘‘notification,’’ or both terms
with regard to the proposed procedure
for submission of a conclusion of GRAS
status for a use of a food substance.
Another comment notes that the
proposed rule to establish a GRAS
notification procedure was followed
soon thereafter by the rulemaking to
establish the premarket notification
program for food contact substances as
authorized by FDAMA (the FCN
program; proposed rule 65 FR 43269,
July 13, 2000; final rule 67 FR 35724,
May 21, 2002). This comment asserts
that although the proposed GRAS
notification procedure and the
established FCN program are distinct,
industry reasonably relied on the close
temporal proximity of the 1997
proposed rule to establish a GRAS
‘‘notification’’ procedure, and the
rulemaking to establish the FCN
program, as contemporaneous guidance
for the meaning of the term
‘‘notification’’ under FDAMA. Because
the FCN program provides market
‘‘exclusivity’’ for the food contact
substance, the comment asserts that it is
understandable why regulated industry
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would think that submitting a GRAS
notice likewise implies ‘‘exclusivity’’ for
the substance. The comment notes that
FDA is not responsible for
misinterpretations made by industry,
but asks us to recognize this lack of
transparency and clarity and remedy it
in a fair and equitable manner.
(Response 44) In the proposed rule
and in this final rule, we use the term
‘‘notice’’ as a noun to refer to the
submission that you send to us and we
use the term ‘‘notification’’ as an
adjective, e.g., to modify the noun
‘‘procedure.’’ In contrast, the FCN
program uses the term ‘‘notification’’ as
a noun in addition to using the term as
an adjective, consistent with FDAMA’s
use of the term as a noun. We continue
to use the term ‘‘notification’’ as an
adjective (e.g., GRAS notification
procedure) in this preamble discussion
of the requirements for submitting a
GRAS notice. However, in the
regulatory text we only use the term
‘‘notice,’’ and we have added a
definition of the term ‘‘GRAS notice’’ to
the regulatory text (see § 170.203).
The ‘‘exclusivity’’ within the FCN
program is provided by section
409(h)(2)(C) of the FD&C Act. See also
our implementing regulation at
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§ 170.100(a), which provides that a FCN
is effective for the food contact
substance manufactured or prepared by
the manufacturer or supplier identified
in the FCN submission. There is no
similar provision in the FD&C Act or
our regulations providing exclusivity for
a substance that is used in food based
on a conclusion that the substance is
GRAS under the conditions of its
intended use.
C. Other Terms We Are Defining in the
Rule
We are defining the abbreviation
‘‘GRAS’’ to mean ‘‘generally recognized
as safe’’ so that we can use that
abbreviation throughout the regulatory
text without defining it in each section
where it appears. To clarify how
pronouns apply in the regulatory text,
we also are specifying in the definition
section that ‘‘you’’ and ‘‘your’’ refer to
a notifier, and that ‘‘we,’’ ‘‘our,’’ and
‘‘us’’ refer to FDA.
IX. Opportunity To Submit a GRAS
Notice
We proposed to provide that any
person may notify FDA of a claim that
a particular use of a substance is exempt
from the statutory premarket approval
requirements based on the notifier’s
determination that such use is generally
recognized as safe (GRAS) (proposed
§ 170.36(a)). We are establishing this
statement of an opportunity to submit a
GRAS notice in § 170.205, with the
editorial changes described in Response
41 and Response 42.
X. Comments on Administrative
Procedures for Submission of a GRAS
Notice
We proposed that a notice of a ‘‘GRAS
exemption claim’’ be submitted in
triplicate to a specified address
(proposed § 170.36(b)). We also asked
for comment on whether it would be
appropriate to require or recommend
that the submission include an
electronic copy in addition to the three
paper copies (62 FR 18938 at 18946) or,
at a minimum, an electronic copy of the
proposed ‘‘GRAS exemption claim’’
(proposed § 170.36(c)(1); final § 170.225
(part 1 of a GRAS notice).
In the 2010 notice, we described
comments asking us to permit a notifier
to reference a previously submitted
GRAS notice to support a view that an
additional use of the applicable
substance is GRAS. We also discussed a
coordinated evaluation process with
FSIS when the use of a notified
substance includes use in products
subject to regulation by FSIS. (Note that
the discussion in the 2010 notice
referred to a ‘‘coordinated review
process.’’ As discussed in Response 25,
we are using the term ‘‘evaluation’’
rather than ‘‘review’’ in connection with
GRAS notices. In addition, in a
Memorandum of Understanding (MOU)
between FDA and FSIS (Ref. 36), we
specify that we will inform the notifier
in writing that the notice will also be
‘‘evaluated’’ by FSIS to determine the
suitability of the use of the substance in
the production of meat, poultry, or egg
products. Given the discussion in
Response 25 and the terms of the MOU
with FSIS, in this document, we use the
term ‘‘coordinated evaluation’’ rather
than ‘‘coordinated review.’’) We asked
for comment relevant to these
administrative procedures (see table 5).
TABLE 5—ISSUES IN THE 2010 NOTICE RELEVANT TO PROCEDURES FOR ADMINISTERING A GRAS NOTICE
Issue
No.
Description of our request for comment
4 ........
Whether the final rule should include a provision to expressly permit a notifier to incorporate into a
GRAS notice data and information that were previously submitted by the notifier, or public data
and information submitted by another party, when such data and information remain in our files.
Whether a notifier who submits a GRAS notice for such a substance should provide an additional
paper copy or an electronic copy of the GRAS notice that we could send to FSIS.
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13 ......
Several comments support the
administrative procedures that we
proposed or described in the 2010
notice. For example, several comments
support adding a provision to allow a
notifier to incorporate information into
a GRAS notice, including data and
information previously submitted by the
notifier and public data and information
submitted by another party, because
such a provision would be practical,
promote administrative efficiency, or
reduce paper. In the following sections,
we discuss comments that disagree with
one or more aspects of the
administrative procedures that we
proposed or described as potential
modifications in the 2010 notice (see,
e.g., Comment 45); ask us to clarify
these administrative procedures (see,
e.g., Comment 48 and Comment 49); or
suggest one or more changes to these
administrative procedures (see, e.g.,
Comment 47). After considering these
comments, we are providing that you
may submit a GRAS notice either in
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Reference
electronic format that is accessible for
our evaluation or on paper; for paper
submissions, a single paper copy of a
GRAS notice is sufficient.
We also are finalizing a provision to
allow for incorporation into a GRAS
notice of data and information as
described in the 2010 notice, with
clarification that the referenced data and
information must be specifically
identified. As discussed in the 2010
notice, the provision specifies that
incorporation into a GRAS notice
applies only when data and information
remain in our files. We do not retain
records indefinitely; rather, records may
be retired to a Federal Records Center
and subsequently disposed of in
accordance with our Records Control
Schedule.
A. How To Send a GRAS Notice to FDA
We proposed to specify in the
regulatory text the address where you
would send a GRAS notice. We are
finalizing this administrative provision
with updates to reflect the current
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75 FR 81536 at 81538.
75 FR 81536 at 81541–81542.
mailing address and the editorial
changes described in Response 42. See
the regulatory text in § 170.210(a).
(Comment 45) One comment asserts
that a single GRAS notice to either
CFSAN or CVM should suffice to inform
both Centers of a conclusion of GRAS
status.
(Response 45) We disagree. Our
regulations directed to human food are
established in subchapter B of 21 CFR
(i.e., Food For Human Consumption,
parts 100–199), whereas our regulations
directed to animal food are established
in subchapter E of 21 CFR (i.e., Animal
Drugs, Feeds, And Related Products,
parts 500–599). We have separately
established requirements applicable to
GRAS substances for use in human food
in subchapter B of 21 CFR (e.g., in parts
170, 182, 184, and 186) and
requirements applicable to GRAS
substances for use in animal food in
subchapter E of 21 CFR (e.g., in parts
570, 582, and 584). We also had
separately established requirements for
the GRAS affirmation petition process
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(which the GRAS notification procedure
is replacing) for substances for use in
human food in subchapter B of 21 CFR
(i.e., in § 170.35(c)) and requirements
applicable to the GRAS affirmation
petition process for substances for use
in animal food in subchapter E of 21
CFR (i.e., in § 570.35(c)). We address
food substances separately for human
use and for animal use because the
safety evaluation of a food substance
relates to the conditions of its intended
use, and the conditions of use of a
substance in human food can raise
different safety questions than the
conditions of use of that same substance
in animal food. For example, a
substance containing copper can be
safely used in human food and in food
for many animal species, but even small
amounts of copper can be toxic to
sheep. As another example, FDA has
affirmed that several uses of propylene
glycol in human food are GRAS
(§ 184.1666), but propylene glycol is
known to be toxic to cats and FDA has
prohibited its use in cat food (see
§ 589.1001). Therefore, the final rule
establishes separate (albeit parallel)
requirements for submission of a GRAS
notice to CFSAN for the use of a
substance in human food and for
submission of a GRAS notice to CVM for
the use of a substance in animal food.
B. Option for Submission of Electronic
or Paper Copies of a GRAS Notice
(Comment 46) Most of the comments
that responded to our request for
comment on the submission of an
electronic copy of a GRAS notice
encourage us to recommend, but not
require, submission of an electronic
copy, explaining that an electronic copy
would make our administration of the
notification procedure more efficient.
However, one comment notes that
electronic technology may not be
universally available. As discussed in
Comment 47, another comment
expresses concern about protection for
confidential information in an
electronic copy. One comment suggests
that if we use an electronic means to
make GRAS notices readily accessible to
the public, then we should require that
the submission include an electronic
copy. Comments that address Issue 13
support requiring the notifier to provide
an additional paper copy that we would
send to FSIS as part of this procedure.
(Response 46) We agree that an
electronic copy will make our
administration of the GRAS notification
procedure more efficient. For example,
an electronic copy generated from a
word processing format generally is
searchable without the need for Optical
Character Recognition techniques, but
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an electronic copy generated by
scanning a paper document into
‘‘Portable Document Format’’ (‘‘pdf’’)
requires Optical Character Recognition
before it can be searched electronically.
Furthermore, the Government
Paperwork Elimination Act of 1998
(Pub. L. 105–277, Title XVII) requires
Federal agencies to give persons who
correspond with these agencies the
option of doing so electronically when
practicable as a substitute for paper, and
to use electronic authentication
(electronic signature) methods to verify
the identity of the sender and the
integrity of the electronic content. We
acknowledge that technology may not
be available to every notifier and, thus,
the final rule does not require the
submission of an electronic copy.
Instead, the final rule provides that
when you submit your GRAS notice,
you may do so either in electronic
format that is accessible for our
evaluation or on paper (see
§ 170.210(b)). Because you have an
option to submit a GRAS notice either
electronically or on paper, an electronic
copy will essentially replace the need
for a paper copy. In 2010, CFSAN issued
draft guidance for how to transmit a
submission, including a GRAS notice, in
electronic format (Ref. 37).
We used electronic means to make
submitted GRAS notices accessible to
the public during the Interim Pilot
program, and intend to continue to do
so under the final rule. However, we
decline the request to require that the
submission include an electronic copy
solely because we are doing so. We
acknowledge that an electronic copy
will improve the efficiency with which
we make GRAS notices available to the
public (see the public disclosure
provisions of this rule in § 170.275).
However, during the Interim Pilot
program we made an electronic copy of
a submitted GRAS notice available on
the Internet by scanning the paper
GRAS notice to create an electronic pdf
document, and we intend to continue to
do so when you submit a GRAS notice
on paper under the final rule.
We have decided that a single copy of
a GRAS notice that is submitted on
paper is acceptable (rather than the
three copies that we proposed to
require) and have specified that a single
paper copy is sufficient in the regulatory
text (§ 170.210(b)). We proposed to
require three copies of a submitted
GRAS notice to make it easier to provide
a paper copy of the GRAS notice to all
members of our staff who will evaluate
the GRAS notice. However, in practice
during the Interim Pilot program we
developed internal procedures in which
we scan a GRAS notice submitted on
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54987
paper to create an electronic pdf version
of the GRAS notice, and we make the
electronic pdf document available to all
staff who will evaluate the GRAS notice.
This procedure has reduced the
resources needed to distribute the GRAS
notice to our staff, and we intend to
continue to use this procedure when we
receive a GRAS notice on paper. When
we coordinate our evaluation of a GRAS
notice with FSIS, we send an electronic
copy to FSIS and, thus, an additional
paper copy for use by FSIS is not
necessary.
(Comment 47) One comment
expresses concern about the security of
confidential information in an
electronic submission. This comment
asks us to allow a notifier to edit an
electronic copy to remove confidential
information and present that
information only in the paper copy.
Another comment asks us to provide the
same protections that would apply to
confidential information in written
records to confidential information in
electronic records.
(Response 47) We decline the request
to allow you to edit an electronic copy
of your GRAS notice such that the
electronic copy would differ from the
paper copy. If you have concerns about
the security of confidential information
in an electronic submission, you have
the option to send the GRAS notice on
paper (see Response 46). The
protections applicable to confidential
information are the same regardless of
whether the information is in written or
electronic form (see part 20, ‘‘Public
Information’’). In particular, under
§ 20.20(e), ‘‘Policy on disclosure of Food
and Drug Administration records,’’ the
term ‘‘record’’ (as well as any other term
used in § 20.20 in reference to
information) includes any information
that would be an agency record
maintained by the Agency in any
format, including an electronic format.
In addition, the final rule requires you
to state in writing your view as to
whether any of the data and information
in your GRAS notice are exempt from
disclosure under FOIA (e.g., as trade
secret or as commercial or financial
information that is privileged or
confidential) (see § 170.225(c)(8)). The
final rule also requires that if you view
any of the data and information in your
GRAS notice as exempt from disclosure
under FOIA, you must identify the
specific data and information
(§ 170.250(d)). Together, these
provisions will give us notice as to
whether we will need to evaluate
specific data and information under the
FOIA and take steps to protect
applicable data and information from
public disclosure.
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C. Incorporation Into a GRAS Notice
(Comment 48) One comment supports
adding a provision to allow a notifier to
incorporate data and information into a
GRAS notice as long as the notifier has
explicit first-hand knowledge of the
referenced files. Other comments
address the limitation, discussed in the
2010 notice, that data and information
that are submitted by a person other
than the notifier must be public, noting
that it would be difficult to prevent the
use of public information by others or
that incorporating such data and
information into a GRAS notice would
be consistent with the criteria for
general recognition of safety.
(Response 48) A notifier must have
sufficient knowledge of data and
information submitted by another party
to be able to identify the specific data
and information that would be
incorporated into a GRAS notice. To
make this clear, the provision we are
adding to the rule to allow for
incorporation of data and information
into a GRAS notice requires that such
data and information be specifically
identified. For example, we expect you
to provide a specific file number (e.g.,
for a GRAS notice or a food additive
petition) that contains the referenced
data and information, and to identify
the specific data and information in that
file (rather than to broadly incorporate
into a GRAS notice the entire file
without explaining which data and
information to incorporate). Although
you may also incorporate into a GRAS
notice a ‘‘food master file’’ (provided
that you specifically identify both the
file number and the data and
information in that file that you are
asking us to incorporate into a GRAS
notice), the regulatory text does not
include ‘‘food master file’’ as an
example of the type of file that you may
reference because we do not have a
regulatory definition for ‘‘food master
file.’’ See the discussion of ‘‘food master
file’’ in Response 49.
A notifier also must have sufficient
knowledge of data and information
submitted by another party to be able to
discuss these data and information in
the narrative that is required in part 6
of a GRAS notice (see § 170.250). This
narrative must explain the basis for the
notifier’s view that the notified
substance is safe under the conditions of
its intended use and that GRAS
criteria—for both general availability
and general acceptance—are satisfied. In
other words, a GRAS notice must
present the independent conclusions of
the notifier regarding the basis for GRAS
status, even if the data and information
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on which the notifier relies were
submitted by another person.
Consistent with the discussion in the
2010 notice, the provision we are
adding to allow for incorporation of data
and information into a GRAS notice
specifies that data and information
submitted by another party must be
‘‘public.’’ By ‘‘public,’’ we mean data
and information that we have provided
(or would provide) in response to a
request under the FOIA, or that are
otherwise publicly available (e.g., in a
docket). Consistent with the views
expressed in the comments, we see no
reason to preclude you from referring us
to such public information when we
already have such information in our
files, provided that you identify the
specific data and information and the
file(s) containing these data and
information. We would not, for
example, search our files to look for the
referenced data and information.
However, if you intend to incorporate
into a GRAS notice data and
information that were submitted by
another party, and that you believe to be
public information, we recommend that
you explain the basis for your view that
the data and information are public. If
we need to evaluate the status of the
data and information under the FOIA
(e.g., because the data and information
have not previously been disclosed to
the public), we may decline to file the
GRAS notice until we have evaluated
the status of the referenced data and
information under the FOIA. Doing so
would be appropriate in light of the
perspective of the comments, as
discussed in the 2010 notice, that the
process of incorporation would be
administratively efficient (75 FR 81536
at 81538) and the limited time (i.e., 180
days) that we have to respond after we
file a submission as a GRAS notice (see
§ 170.265(b)). A notifier who intends to
incorporate data and information that
we must evaluate under the FOIA before
we determine whether the data and
information can be disclosed under the
FOIA may find it advantageous to
request those data and information
under our public information
procedures (see part 20), and then either
include the data and information we
disclose in response to that request in
the submitted GRAS notice, or refer us
to administrative information
identifying the completed FOIA request
when asking us to incorporate the data
and information into a GRAS notice.
(Comment 49) One comment states its
presumption that a ‘‘food master file’’ is
not available for public viewing,
referring to a ‘‘long-standing center
policy’’ that such files are confidential.
This comment asks us to continue to
PO 00000
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Sfmt 4700
provide that a ‘‘food master file’’ be a
confidential repository for proprietary
data, such as utility and manufacturing
information.
(Response 49) We establish a ‘‘food
master file’’ for a variety of reasons. For
example, a person who submits a food
additive petition may need us to
evaluate data and information regarding
a substance that the petitioner
purchases from another party for use in
the manufacture of the food additive.
The petitioner may ask the
manufacturer of that substance to
provide the applicable data and
information to us, and we then place the
submitted data and information in a
food master file. Although some or all
of the data in such a food master file
may be exempt from public disclosure
(e.g., as trade secret information or
confidential commercial information), a
determination of whether specific data
and information in a food master file is
exempt from public disclosure is based
on the status of the data and information
under FOIA rather than on the type of
file in which we place the data and
information. We do not limit the type of
data and information that may be
included in a food master file to
proprietary data and information.
See also § 170.215 and Response 48.
Data and information submitted by a
party other than a notifier must be
public information. If you previously
submitted a food master file to us, and
you view the data and information in
your food master file as proprietary, you
must explain in part 6 of your GRAS
notice how GRAS criteria are satisfied
(see § 170.250(e)).
XI. General Requirements Applicable to
a GRAS Notice
The final rule specifies two general
provisions applicable to a GRAS notice
(see § 170.220). As discussed in
Response 43, we have redesignated the
single proposed section (i.e., proposed
§ 170.36) into several distinct, short
sections of regulatory text in a newly
established subpart E (GRAS Notice).
The first general provision specifies that
a GRAS notice has seven parts, refers
the user to the regulatory text for each
of these parts, and specifies that you
must submit the information specified
in each of these parts on separate pages
or sets of pages (§ 170.220 (a)).
Submitting the information on separate
pages or sets of pages is consistent both
with the guidance we developed for
preparation of a GRAS notice in
electronic format (Ref. 37) and with
long-standing requirements for other
regulatory submissions, such as a food
additive petition (see § 171.1(f)) and a
health claim petition (see § 101.70(g)).
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The second general provision
specifies that you must include each of
the seven parts; if a part is not included,
you must include an explanation of why
that part does not apply to your GRAS
notice (§ 170.220 (b)). We added this
provision because some parts of a GRAS
notice (e.g., Part 4 (self-limiting levels of
use) and Part 5 (experience based on
common use in food before 1958))
would not apply to most GRAS notices.
Specifying that Parts 4 and 5 do not
apply to a particular GRAS notice will
make it clear that a notifier is aware of
the requirements of those parts and has
acknowledged that they do not apply.
XII. Comments on Part 1 of a GRAS
Notice: Signed Statements and
Certification
We proposed that a GRAS notice must
include a dated and signed claim that a
particular use of a substance is exempt
from the premarket approval
requirements of the FD&C Act because
the notifier has determined that such
use is GRAS. The proposed ‘‘GRAS
exemption claim’’ would include: (1)
The name and address of the notifier; (2)
the common or usual name of the
notified substance; (3) the applicable
conditions of use of the notified
substance, including the foods in which
the substance is to be used, levels of use
in such foods, and the purposes for
which the substance is used, including,
when appropriate, a description of the
population expected to consume the
substance; (4) the basis for the GRAS
determination (i.e., through scientific
procedures or through experience based
on common use in food); and (5) a
statement that the data and information
that are the basis for the notifier’s GRAS
54989
determination are available for our
review and copying at reasonable times
at a specific address set out in the notice
or will be sent to us upon request
(proposed § 170.36(c)(1)). In the 2010
notice, we requested comment on
several issues relevant to the proposed
‘‘GRAS exemption claim’’ (see table 6).
As discussed in Response 42, we have
made editorial changes throughout the
rule to replace the term ‘‘exempt’’ with
the phrase ‘‘not subject to’’ and to
replace the term ‘‘claim’’ (when used as
a noun) with the term ‘‘view.’’ In light
of these editorial changes, in the
remainder of this section we generally
use the term ‘‘proposed signed
statements’’ (rather than ‘‘GRAS
exemption claim’’) when referring to the
provisions that we had proposed to
include in proposed § 170.36(c)(1)).
TABLE 6—ISSUES IN THE 2010 NOTICE REGARDING THE PROPOSED SIGNED STATEMENTS IN A GRAS NOTICE
Issue
No.
Description of our request for comment
6a ......
How to best ensure that the identity and authority of the person who is signing the GRAS notice is
made clear.
Whether to require that a notifier submit a statement that to the best of his knowledge, the GRAS
notice is a representative and balanced submission that includes unfavorable information, as well
as favorable information, known to him and pertinent to the evaluation of the safety of the substance.
Whether to require a notifier to certify to the statement (described in Issue 6a) regarding the representative and balanced nature of the GRAS notice.
Whether to require that the GRAS notice include the name of the notified substance, using an appropriately descriptive term, instead of the ‘‘common or usual name’’ of the notified substance.
Whether to explicitly require that the information submitted in the ‘‘GRAS exemption claim’’ exclude
non-public information.
Whether to require that a notifier who identifies one or more trade secret(s) in the GRAS notice explain why it is trade secret information and how qualified experts could conclude that the intended use of the notified substance is safe without access to the trade secret(s).
Whether to require that a notifier who identifies confidential commercial or financial information in
the GRAS notice explain why it is confidential commercial or financial information and how qualified experts could conclude that the intended use of the notified substance is safe without access
to such information.
Whether to make our coordinated evaluation process with FSIS explicit in the final rule ....................
6b ......
6b ......
7 ........
8 ........
9b * ....
9c * ....
13 ......
Reference
75 FR 81536 at 81539.
75 FR 81536 at 81539.
75 FR 81536 at 81539.
75 FR 81536 at 81539.
75 FR 81536 at 81539.
75 FR 81536 at 81540.
75 FR 81536 at 81540.
75 FR 81536 at 81541–81542.
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* In the 2010 notice, Issues 9b and 9c asked how qualified experts could conclude that the intended use of the notified substance is ‘‘GRAS’’
rather than ‘‘safe.’’ However, the qualified experts evaluate safety rather than GRAS status; the person who is responsible for the conclusion of
GRAS status considers the view of the qualified experts on safety in reaching the conclusion that GRAS criteria are satisfied. In the remainder of
this document, we describe Issues 9b and 9c with respect to whether qualified experts could conclude that the intended use of the substance is
‘‘safe’’ rather than ‘‘GRAS.’’
In general, comments directed to the
proposed signed statements agree that
we should modify the provisions as
discussed in Issues 6a, 6b, 7, 8, 9a, 9b,
9c, and 13 in the 2010 notice. In the
following sections, we discuss
comments that address the issues
discussed in the 2010 notice (see, e.g.,
Comment 50, Comment 51, Comment
57, Comment 58, and Comment 59);
address provisions of the proposed
signed statements that we did not
discuss in the 2010 notice (see, e.g.,
Comment 53); ask us to clarify how we
will interpret the provisions of the
proposed signed statements and
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potential modifications (see, e.g.,
Comment 54 and Comment 55); or
suggest one or more changes to the
proposed signed statements and
potential modifications (see, e.g.,
Comment 52, Comment 56, and
Comment 59). After considering these
comments, we are establishing
requirements for Part 1 of a GRAS notice
to include certain signed statements and
a certification as shown in table 7, with
editorial, clarifying, and conforming
changes as shown in table 29. (See
§ 170.225.) Table 7 identifies changes
we made relative to the proposed rule
or the description in the 2010 notice
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other than the editorial, clarifying, and
conforming changes shown in table 29
and the additional editorial changes
associated with the redesignation of
proposed § 170.36(c)(1) as § 170.225.
We did not receive comments
disagreeing with the proposed
requirement for a GRAS notice to: (1) Be
dated and signed by a responsible
official of your organization, or by your
attorney or agent; (2) provide your name
and address; and (3) provide the
applicable conditions of use of the
notified substance. Therefore, we are
establishing those requirements in the
rule (see § 170.225(c)(1), (2), and (4)).
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See Comment 42 for our discussion of
comments on the terms used in final
§ 170.225(c)(6), in which you inform us
of your view that the notified substance
is not subject to the premarket approval
requirements of the FD&C Act based on
your conclusion that the substance is
GRAS under the conditions of its
intended use; see Response 42 for the
editorial changes we made in response
to those comments.
TABLE 7—FINAL REQUIREMENTS FOR SIGNED STATEMENTS AND A CERTIFICATION IN PART 1 OF A GRAS NOTICE
Proposed
designation in the
regulatory text
(§ )
170.225(a) ..............
170.36(c)(1) ...........
N/A
170.225(b) ..............
N/A .........................
8
170.225(c)(1) ..........
N/A .........................
N/A
170.225(c)(2) ..........
170.36(c)(1)(i) ........
N/A
170.225(c)(3) ..........
170.36(c)(1)(ii) .......
7
170.225(c)(4) ..........
170.36(c)(1)(iii) ......
N/A
170.225(c)(5) ..........
170.36(c)(1)(iv) ......
N/A
170.225(c)(6) ..........
170.36(c)(1) ...........
2
170.225(c)(7) ..........
170.36(c)(1)(v) .......
N/A
170.225(c)(8) ..........
N/A .........................
9
170.225(c)(9) ..........
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Final designation in
the regulatory text
(§ )
170.36(c)(4) ...........
6b
170.225(c)(10) ........
170.36(c)(1) ...........
6a
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Issue No.
in the 2010
notice
PO 00000
Description. Part 1 of your
GRAS notice:
Must be dated and signed by a responsible official of your organization, or
by your attorney or agent.
Must not include any information that is
trade secret or confidential commercial information.
Informs us that you are submitting a
GRAS notice in accordance with subpart E.
Provides the name and address of your
organization.
Provides the name of the notified substance, using an appropriately descriptive term.
Describes the intended conditions of
use of the notified substance, including the foods in which the substance
will be used, the levels of use in such
foods, and the purposes for which the
substance will be used, including,
when appropriate, a description of a
subpopulation expected to consume
the substance.
Informs us of the statutory basis for
your conclusion of GRAS status (i.e.,
through scientific procedures or
through experience based on common use in food).
States your view that the notified substance is not subject to the premarket
approval requirements of the FD&C
Act based on your conclusion that the
substance is GRAS under the conditions of its intended use.
States your agreements regarding making data and information available to
us upon our request.
States your view as to whether any of
the data and information in Parts 2
through 7 of your GRAS notice are
exempt from disclosure under the
FOIA.
Certifies that, to the best of your knowledge, your GRAS notice is a complete, representative, and balanced
submission that includes unfavorable
information, as well as favorable information, known to you and pertinent
to the evaluation of the safety and
GRAS status of the use of the substance.
States both the name and position or
title of the person who signs the
GRAS notice.
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Revisions (other than editorial,
clarifying, and conforming changes)
relative to the proposed rule or the
2010 notice
N/A.
Makes an exception for § 170.225(c)(8),
which requires you to state your view
as to whether any of the data and information in Parts 2 through 7 of your
GRAS notice are exempt from disclosure under the FOIA.
N/A.
N/A.
N/A.
Uses the term ‘‘subpopulation’’ rather
than ‘‘population’’.
• Specifies that a conclusion of GRAS
status through scientific procedures is
in accordance with both § 170.30(a)
and (b).
• Specifies that a conclusion of GRAS
status through experience based on
common use in food is in accordance
with both § 170.30(a) and (c).
See Response 42.
You agree to a procedure in which we
can access data and information
‘‘during customary business hours’’
rather than ‘‘at reasonable times’’.
N/A.
Specifies that your GRAS notice is
‘‘complete’’ in addition to ‘‘representative’’ and ‘‘balanced’’.
N/A.
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TABLE 7—FINAL REQUIREMENTS FOR SIGNED STATEMENTS AND A CERTIFICATION IN PART 1 OF A GRAS NOTICE—
Continued
Proposed
designation in the
regulatory text
(§ )
170.225(c)(11) ........
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Final designation in
the regulatory text
(§ )
N/A .........................
Issue No.
in the 2010
notice
13
A. Exclusion of Trade Secret and
Confidential Commercial Information
From the Signed Statements
(Comment 50) Several comments
support a provision specifying that
information submitted in the signed
statements exclude non-public
information. One of these comments
states that the information in the signed
statements should be publicly disclosed
because public disclosure is critical to
the continued success of the GRAS
program, and that for the use of a
substance to be ‘‘generally recognized as
safe’’ the data and research supporting
a conclusion of GRAS status must be
available for public view. Other
comments disagree that non-public
information should be excluded from
the signed statements and assert that the
final rule should allow for the
submission of limited amounts of nonpublic information at the discretion of
the notifier or when necessary to clarify
the safety of the notified substance for
the purposes of our evaluation. These
comments emphasize we should take
care to remove such non-public
information from any public disclosure
or, or at a minimum, discuss or clear our
intent to disclose non-public
information with the notifier before
disclosing it.
(Response 50) Some of these
comments appear to misinterpret the
reach of our request for comment in
Issue 8 in the 2010 notice. We narrowly
directed Issue 8 to the signed statements
that would provide the name and
address of the notifier; the name of the
notified substance; the applicable
conditions of use of the notified
substance; the statutory basis for the
conclusion of GRAS status; and
agreement to make the data and
information that are the basis for the
notifier’s conclusion of GRAS status
available for our review and copying.
The signed statements provide
administrative information rather than
safety information and, as discussed in
the 2010 notice, we extract noticespecific information from the signed
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When applicable, states whether you:
(1) Authorize us to send any trade
secrets to FSIS; or (2) ask us to exclude any trade secrets from the copy
of the GRAS notice that we will send
to FSIS.
statements for the purpose of informing
the public about GRAS notices that we
are evaluating. However, some
comments seem to be addressing the
issue of whether other sections of a
GRAS notice (e.g., Part 2 of a GRAS
notice (in which a notifier describes the
method of manufacture of the notified
substance) and Part 6 of a GRAS notice
(in which a notifier discusses the safety
of the notified substance)) can include
non-public information.
Consistent with our request for
comment in Issue 8, the final rule
specifies that a notifier must not include
any information that is trade secret or
confidential commercial information in
Part 1 of a GRAS notice, except in the
statement in § 170.225(c)(8) (see
§ 170.225(b) and the discussion of
§ 170.225(c)(8) in Response 57). This
provision does not preclude a notifier
from including non-public information
in other parts of a GRAS notice.
However, if a notifier views any
submitted data and information as
exempt from disclosure under the FOIA
then that notifier must identify the
specific data and information, and
explain how there could be a basis for
a conclusion of GRAS status if qualified
experts generally do not have access to
those data and information (see
§ 170.250(d) and (e)). Section 170.250(d)
and (e) is consistent with the criteria for
eligibility for classification as GRAS,
because: (1) The criteria provide that
general recognition of safety may be
corroborated by unpublished
information; and (2) the notifier has a
burden to explain how GRAS criteria
are satisfied given that certain data and
information in the GRAS notice are
trade secret or confidential commercial
information.
See section XIII.B for a discussion of
comments regarding including nonpublic information in part 2 of a GRAS
notice (particularly with respect to the
method of manufacture). Regarding
whether we would ‘‘clear our intent’’ to
disclose non-public information with
the notifier before disclosing it, see
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Revisions (other than editorial,
clarifying, and conforming changes)
relative to the proposed rule or the
2010 notice
Description. Part 1 of your
GRAS notice:
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We added a statement communicating
how you want us to handle trade secret information in a copy of a GRAS
notice that we send to FSIS.
Response 70. Regarding how we treat
non-public information in a GRAS
notice, see section XXI regarding the
provisions of the final rule regarding
public disclosure of information in a
GRAS notice. Under § 170.275(c), we
will disclose information that is not
exempt from public disclosure in
accordance with part 20.
B. Name of the Notified Substance,
Using an Appropriately Descriptive
Term
(Comment 51) Some comments agree
that the signed statements should
identify the name of the notified
substance using an ‘‘appropriately
descriptive term’’ instead of the
‘‘common or usual name,’’ and also
agree with our statement in the 2010
notice that the ‘‘appropriately
descriptive term’’ may be the same as
the common or usual name of the
substance in some circumstances (75 FR
81536 at 81539). One comment
disagrees and asks us to continue to
specify that the signed statements in a
GRAS notice identify the name of the
notified substance using the common or
usual name of the notified substance.
This comment recommends that a
notifier work with us to establish the
common or usual name of the notified
substance if the common or usual name
is not known or well defined. This
comment also asks us to include the
common or usual name of the notified
substance in any ‘‘no questions letter’’
from us to make the common our usual
name clear to the public. A few
comments support requiring that the
signed statements include both the
common or usual name of the notified
substance, as well as an appropriately
descriptive term for the notified
substance. One comment asks us to
continue the practice, described in the
2010 notice (75 FR 81536 at 81539), of
reminding notifiers that our response to
a GRAS notice should not be considered
an endorsement for any given term for
the purpose of complying with the
labeling provisions of the FD&C Act.
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(Response 51) The final rule requires
that you provide the name of the
notified substance, using an
appropriately descriptive term, in Part 1
of your GRAS notice (§ 170.225(c)(3)).
The appropriately descriptive term may
be the same as the common or usual
name of the substance under our
labeling regulations (see 21 CFR 102.5).
We decline the request to use resources
that we are directing to the evaluation
of the safety and regulatory status of
food substances under sections 201 and
409 of the FD&C Act to also address the
labeling requirements of the FD&C Act
given the limited time (i.e., 180 days)
that we have to respond (see
§ 170.265(b)). You may consult with our
staff in operating divisions that address
the labeling requirements of the FD&C
Act, currently CFSAN’s Office of
Nutrition and Food Labeling (for human
food); however, doing so would be a
separate process from the GRAS
notification procedure. (See section
XXV.C for contact information for
CVM.)
C. Intended Conditions of Use of the
Notified Substance
We did not receive comments
disagreeing with the proposed
requirement for the signed statements in
a GRAS notice to include the applicable
conditions of use of the notified
substance, including the foods in which
the substance is to be used, levels of use
in such foods, and the purposes for
which the substance is used, including,
when appropriate, a description of the
population expected to consume the
substance, and we are establishing this
requirement in the final rule (see
§ 170.225(c)(4)). As noted in table 29,
the final rule refers to the ‘‘intended
conditions of use’’ rather than the
‘‘applicable conditions of use’’ for
consistency with other provisions in the
rule. The final rule also uses the term
‘‘subpopulation’’ rather than
‘‘population’’ to provide more context
about when it would be appropriate to
specify the expected consumers of a
food. Most foods are broadly available to
all consumers; a few are more
specifically targeted to particular
subpopulations, such as persons with
specific dietary needs (such as persons
on liquid diets or persons with
conditions like phenylketonuria),
infants consuming infant formula, and
persons seeking alternatives to
commonly used food ingredients (such
as persons on a gluten-free diet).
D. Statutory Basis for the Conclusion of
GRAS Status
(Comment 52) Some comments ask us
to modify the rule to provide that the
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statutory basis for a conclusion of GRAS
status may be through scientific
procedures, through experience based
on common use in food, or through both
scientific procedures and experience
based on common use in food. These
comments assert that many conclusions
of GRAS status are based on both
statutory criteria.
(Response 52) We disagree that this
modification is needed. The final rule
does not prevent you from basing your
conclusion of GRAS status on both
statutory criteria. Importantly, if you
assert that your conclusion of GRAS
status is based on both statutory criteria,
you must fully support each conclusion
and address all requirements of the rule
regarding each conclusion; partial
support for each of the two statutory
criteria for a conclusion of GRAS status
is not adequate. You could not, for
example, assert that a substance is
GRAS under the conditions of its
intended use through scientific
procedures, but ‘‘fill in data gaps’’ by
also asserting that the substance was
commonly used in food before 1958.
Likewise, you could not assert that a
substance is GRAS under the conditions
of its intended use through experience
based on common use in food if you
cannot provide evidence of a substantial
history of consumption of the notified
substance for food use by a significant
number of consumers prior to January 1,
1958.
These comments highlight the
importance of fully supporting a
conclusion of GRAS status through each
of the statutory criteria. Because the
general criteria in § 170.30(a), as well as
the specific criteria in § 170.30(b) or (c),
must be satisfied to support a
conclusion of GRAS status, the final
rule specifies that a conclusion of GRAS
status through scientific procedures is
in accordance with both § 170.30(a) and
(b) and that a conclusion of GRAS status
through experience based on common
use in food is in accordance with both
§ 170.30(a) and (c).
E. Agreement To Make Data and
Information Available Upon Request
(Comment 53) Some comments
recommend that there be a means for us
to request non-public information if we
deem it necessary for our evaluation of
the intended conditions of use of the
notified substance, provided that the
information can be considered as
confidential and protected from
disclosure.
(Response 53) These comments
appear to misinterpret the reach of the
proposed requirement to agree to
provide us access to data and
information that a notifier relies on to
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support a conclusion of GRAS status.
Some of the data and information that
we may ask to see during our evaluation
of a GRAS notice may be ‘‘public’’ data
and information in that it would be data
and information that we would provide
in response to a request under the FOIA
(see Response 48), even though it may
not have been disseminated to the
public (e.g., in the scientific literature or
on the Internet (e.g., when a sciencebased organization uses the Internet to
disseminate scientific or technical
information or recommendations)). If we
receive data and information that are
non-public, such data and information
would be protected from public
disclosure in accordance with part 20.
(Comment 54) One comment states
that the phrase ‘‘at reasonable times’’
refers not only to hours of a day, but
also to a reasonable amount of time
following the submission of a GRAS
notice. This comment recommends that
‘‘several years (for example, five years)’’
after submission of a GRAS notice
would be a reasonable time for notifiers
to retain such data and information in
their active files.
(Response 54) By ‘‘at reasonable
times,’’ we meant the time of day that
we would have access to data and
information you retained but did not
include in your GRAS notice. To clarify
that the requirement relates to the time
of day rather than to the timeframe for
retaining the data and information, the
final rule specifies that you agree to a
procedure in which we can access data
and information ‘‘during customary
business hours’’ rather than ‘‘at
reasonable times.’’
As previously discussed (62 FR 18938
at 18951), we may, at some point after
our response to a GRAS notice, receive
additional information about a notified
substance that raises questions about the
safety of that substance. To address this
possibility, the rule specifies that we
will send you a subsequent letter about
your GRAS notice if circumstances
warrant (see § 170.265(c)). Although the
rule does not specify any timeframe to
retain the data and information that
support your conclusion of GRAS
status, preservation of the data and
information that are the basis for the
conclusion of GRAS status represents
prudent practice for those who claim an
exclusion from a statutory requirement
regardless of whether the person
subsequently notifies us (62 FR 18938 at
18947).
(Comment 55) One comment asks us
to clarify that electronic records are
acceptable for documenting the data and
information that support a conclusion of
GRAS status.
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(Response 55) Electronic records are
acceptable for documenting the data and
information that support a conclusion of
GRAS status. If we ask you to send us
such data and information for a notified
substance that would be used in human
food, we recommend that you do so by
following the instructions in CFSAN’s
guidance entitled ‘‘Guidance for
Industry: Providing Regulatory
Submissions in Electronic or Paper
Format to the Office of Food Additive
Safety’’ (Ref. 37), which includes
instructions for making an electronic
submission through our Electronic
Submission Gateway, as well as on
media that we can access on our
network computers. CFSAN’s
procedures for making an electronic
submission through our Electronic
Submission Gateway use a form that
CFSAN developed for a GRAS notice
when a substance would be used in
human food (i.e., Form FDA 3667) (Ref.
38). Form FDA 3667 prompts a notifier
to include certain elements of a GRAS
notice in a standard format. The form,
and elements that would be prepared as
attachments to the form, may be
submitted in electronic format via the
Electronic Submissions Gateway, as
electronic files on physical media, or in
paper format. At this time, we cannot
accept media such as thumb drives,
which can present a security risk.
(Comment 56) One comment asks us
to develop criteria for the required
documentation underlying industry
conclusions of GRAS status.
(Response 56) We are not establishing
criteria in the rule for the
documentation a notifier would have
regarding a conclusion of GRAS status.
Regardless of whether a person who
concludes that a use of a food substance
is GRAS notifies us, the applicable
documentation would address the safety
of the substance as described in the
definition of ‘‘safe’’ or ‘‘safety’’ (see
§ 170.3(i)); as applicable, the definition
of ‘‘common use in food’’ (see § 170.3(f)
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and/or the definition of ‘‘scientific
procedures’’ (§ 170.3(h)); and the criteria
for general recognition of safety (see
§ 170.30)).
F. Statements and Any Applicable
Explanation Regarding Data and
Information That a Notifier Views as
Exempt From Disclosure Under FOIA
In Issue 9 in the 2010 notice (75 FR
81536 at 81539–81540), we discussed
three issues regarding confidential data
and information that are included in a
GRAS notice. See table 8. Most of the
comments that address Issue 9 address
Issue 9a, particularly with respect to
how we would protect trade secret or
confidential commercial information
from public disclosure. See sections
XIII.B and XXI.C for a discussion of
those comments, and our response to
those comments. In the following
paragraphs, we discuss comments on
Issues 9b and 9c, and respond to those
comments.
TABLE 8—ISSUES IN THE 2010 NOTICE REGARDING CONFIDENTIAL DATA AND INFORMATION IN A GRAS NOTICE
Issue
No.
Description of our request for comment
9a ......
Whether the final rule should stipulate that the method of manufacture exclude any trade secrets,
as we proposed.
Whether to require that a notifier who identifies one or more trade secret(s), as defined in
§ 20.61(a), in the GRAS notice explain why it is trade secret information and how qualified experts could conclude that the intended use of the notified substance is safe without access to the
trade secret(s).
Whether to require that a notifier who identifies confidential commercial or financial information, as
defined in § 20.61(b), in the GRAS notice explain why it is confidential commercial or financial information and how qualified experts could conclude that the intended use of the notified substance is safe without access to such information.
9b ......
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9c ......
(Comment 57) One comment supports
the recommendation we made in the
proposed rule for a notifier who
considers that certain information in a
submission should not be available for
public disclosure to identify as
confidential the relevant portions of the
submission for our consideration (62 FR
18938 at 18952). Those comments that
address Issues 9b and 9c agree with the
outcome of our discussion, in the 2010
notice, that we should require that a
notifier who identifies a trade secret or
confidential commercial information
explain why it is a trade secret or
confidential commercial information
and how qualified experts can conclude
that the use of a substance is safe
without access to the trade secret or
confidential commercial information.
(Response 57) The final rule requires
a notifier to state his view as to whether
any of the data and information in Parts
2 through 7 of a GRAS notice are
exempt from disclosure under the FOIA
(e.g., as trade secret or as commercial or
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Reference
financial information that is privileged
or confidential) (§ 170.225(c)(8)).
Requiring this statement in Part 1 of a
GRAS notice will give us notice as to
whether we will need to evaluate
specific data and information under the
FOIA and take steps to protect
applicable data and information from
public disclosure. See also § 170.250(d),
which requires that Part 6 of a GRAS
notice (a narrative) identify specific data
and information that a notifier views as
exempt from disclosure under the FOIA.
Whereas Part 1 of a GRAS notice only
requires that the signed statements in a
GRAS notice state the notifier’s view as
to whether any of the data and
information in Parts 2 through 7 of a
GRAS notice are exempt from disclosure
under the FOIA, in Part 6 of a GRAS
notice the notifier would specifically
identify the applicable data and
information.
During the Interim Pilot program, we
sometimes received a curriculum vitae
(e.g., of a GRAS panel member)
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75 FR 81536 at 81539–81540.
75 FR 81536 at 81539–81540.
75 FR 81536 at 81539–81540.
containing personal privacy information
that we needed to redact before we
could make the GRAS notice available
to the public. The rule does not require
that a notifier submit such information,
and redaction of unnecessary privacy
information takes resources that we
would otherwise use to evaluate the
GRAS notice. We ask that notifiers
exclude personal privacy information
from a GRAS notice whenever possible.
If a notifier does include such
information, in Part 1 of a GRAS notice
the notifier should state his view that
the GRAS notice contains personal
privacy information. In Part 6 of a GRAS
notice, the notifier should identify the
personal privacy information.
G. Certification Statement
(Comment 58) Several comments
support a requirement for a GRAS
notice to include a certification
statement similar to the certification
statement that had been required in a
GRAS affirmation petition. One
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comment agrees that the notifier should
submit a statement that the notice is a
representative and balanced submission,
but does not agree that the notifier
needs to certify the statement.
(Response 58) The final rule requires
a certification statement as described in
the 2010 notice, with one modification
(see § 170.225(c)(9)). We added that the
statement certify that the GRAS notices
is ‘‘complete’’ in addition to
‘‘representative’’ and ‘‘balanced,’’ to
emphasize your responsibility to
identify, discuss, and place in context,
data and information that are, or may
appear to be, inconsistent with a
conclusion of GRAS status, regardless of
whether those data and information are
generally available (see the
requirements of the narrative in Part 6
of a GRAS notice (§ 170.250, in
particular § 170.250(c))). The
certification is appropriate and
necessary to underscore your legal
responsibility for the conclusion of
GRAS status. As discussed in the 2010
notice, the specific text of the
certification statement that you must
include in a GRAS notice is consistent
with the specific text of the certification
statement in the GRAS affirmation
petition process that the notification
procedure is replacing. The use of
certification statements has become
routine in other submissions to FDA for
food programs (see, e.g., the certification
statement in Part V of Form FDA 3480
(for a food contact notification
submission) (Ref. 39); and the
certification statement in Section 13 of
Form FDA 3537 (for registration of a
food facility) (Ref. 40)).
By ‘‘complete,’’ we also mean that
your GRAS notice identifies, and places
in context, unpublished data and
information that you believe corroborate
GRAS status. For example, if you
conduct six toxicology studies, but only
publish three of the studies, it may be
that you consider the remaining three
studies to be corroborative of safety. As
an example, it may be that you were
dissatisfied with the study design of one
study, repeated that study with an
improved study design, and published
the study with the improved study
design. If you consider that the findings
of the unpublished studies corroborate
safety, even if they do not establish it,
a ‘‘complete, representative, and
balanced’’ submission would briefly
describe the unpublished studies. In
addition, we expect that you would
describe, and place in context,
unpublished data and information if
you consider that the findings of the
unpublished data and information
warrant sharing with any ‘‘GRAS panel’’
that you convene. See also the
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discussion in Response 69 and
Response 78.
(Comment 59) One comment asks us
to specify that the statement include the
date the statement was certified.
(Response 59) The rule requires that
Part 1 of a GRAS notice be dated and
signed by a responsible official of your
organization, or by your attorney or
agent (see § 170.225(a)). The
certification statement is included in
Part 1 of the GRAS notice; it is not
necessary to date each statement
included in Part 1.
H. Person Signing Part 1 of the GRAS
Notice
(Comment 60) Several comments
support a provision to require a GRAS
notice to clearly identify the person
signing the GRAS notice, such as by
printing or stating the name and the title
of the person signing the GRAS notice.
(Response 60) The final rule requires
you to state both the name and position
or title of the person who signs the
GRAS notice (see § 170.225(c)(10)).
I. Authorization for FDA To Send Trade
Secret Information to FSIS
In the 2010 notice, we described some
of the terms of a MOU, between FDA
and USDA’s FSIS, that provides for a
coordinated evaluation process with
FSIS when the intended conditions of
use of a notified substance include use
in a product or products subject to
regulation by USDA under statutes that
it administers (75 FR 81536 at 81541–
81542); in 2015 we amended that MOU
to include more details about the
procedures FDA and FSIS will follow to
do so (Ref. 36). We also asked for
comment on whether to make our
coordinated evaluation process with
FSIS explicit in the final rule (see Issue
13, 75 FR 81536 at 81541–81542).
In accordance with our public
information regulations in § 20.85
(Disclosure to other Federal government
departments and agencies), we can
share confidential commercial
information with another Federal
agency pursuant to a written agreement
that the record will not be further
disclosed. The amended MOU between
FDA and USDA’s FSIS now provides for
FDA to share with FSIS confidential
commercial information in a submission
such as a GRAS notice (Ref. 36). We
generally cannot share trade secret
information with other Federal agencies
under section 301(j) of the FD&C Act (21
U.S.C. 331(j)), and therefore we would
need your authorization to share this
information with FSIS. For efficiency in
administering the coordinated
evaluation of a GRAS notice with FSIS,
we have added a requirement for a
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notifier who submits a GRAS notice that
we would send to FSIS to include in
part 1 of the GRAS notice a statement
as to whether the notifier: (1) Authorizes
us to send any trade secrets to FSIS; or
(2) asks us to exclude any trade secrets
from the copy of the GRAS notice that
we will send to FSIS (see
§ 170.225(c)(11)). Under the provisions
that make the coordinated evaluation of
a GRAS notice with FSIS explicit, we
will exclude any trade secrets unless
you have authorized us to send trade
secret information to FSIS (see
§ 170.270). These provisions will enable
us, with your authorization, to share a
GRAS notice that includes trade secret
information with FSIS without first
redacting the GRAS notice to remove
the trade secret information and, thus,
will reduce the time it takes for us to
provide FSIS with a copy of the GRAS
notice. These provisions also will clarify
your expectations regarding whether we
should share trade secret information
with FSIS and, thus, require us to redact
the trade secret information from the
copy we send to FSIS when consistent
with your express wishes.
Note that our rule establishing the
requirements of the GRAS notification
procedure does not specify the data and
information that FSIS will need to
evaluate whether the intended use of
the notified substance complies with
applicable statutes and regulations, or, if
not, whether the use of the substance
would be permitted in products under
FSIS jurisdiction under specified
conditions or restrictions. We
recommend that you contact the
appropriate staff at FSIS regarding the
data and information that FSIS will
need you to provide. FSIS provides
contact information for its programs on
its Web site (Ref. 41).
XIII. Comments on Part 2 of a GRAS
Notice: Identity, Method of
Manufacture, Specifications, and
Physical or Technical Effect
We proposed to require that a GRAS
notice include detailed information
about the identity of the notified
substance, including, as applicable, its
chemical name, Chemical Abstracts
Service (CAS) Registry Number, Enzyme
Commission number, empirical formula,
structural formula, quantitative
composition, method of manufacture
(excluding any trade secrets and
including, for a substance of natural
biological origin, source information
such as genus and species),
characteristic properties, any content of
potential human toxicants, and
specifications for food-grade material
(proposed § 170.36(c)(2)). In the 2010
notice, we requested comment on
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several issues relevant to the proposed
requirements for detailed information
54995
about the identity of the notified
substance (see table 9).
TABLE 9—ISSUES IN THE 2010 NOTICE REGARDING THE PROPOSED REQUIREMENTS FOR DETAILED INFORMATION ABOUT
THE IDENTITY OF THE NOTIFIED SUBSTANCE
Issue
No.
Description of our request for comment
9a ......
Whether the final rule should continue to stipulate that the method of manufacture exclude any
trade secrets, as proposed.
What scientific information would be sufficient to identify the biological source ...................................
Whether to require that information about the identity of the notified substance specify any known
toxicants that could be in the source.
Whether the final rule should address, as part of identity, particle size and other chemical and
physical properties that may be used to characterize engineered materials.
10a ....
10b ....
10c ....
Some comments support the proposed
requirements, with the potential
modifications described in the 2010
notice, without change. For example,
most of the comments that address the
issue of scientific information sufficient
to identify a biological source support
requiring both taxonomic information
and the part of any animal or plant used
as a source. As another example, several
comments that address the issue of
scientific information sufficient to
identify a biological source support
Reference
requiring that this information specify
toxicants that could be in the source.
Most of the comments regarding our
proposal to require that a GRAS notice
include detailed information about the
identity of the notified substance
address the issues discussed in 2010
notice. In the following sections, we
discuss these and other comments. After
considering these comments, we are
establishing requirements for Part 2 of a
GRAS notice to include information
about the identity, method of
manufacture, specifications, and
75 FR 81536 at 81539–81540.
75 FR 81536 at 81540.
75 FR 81536 at 81540.
75 FR 81536 at 81540.
physical or technical effect of the
notified substance as shown in table 10,
with editorial, clarifying, and
conforming changes as shown in table
29. (See § 170.230). Table 10 identifies
changes we made relative to the
proposed rule or the description in the
2010 notice other than the editorial,
clarifying, and conforming changes
shown in table 29 and the additional
editorial changes associated with the
redesignation of proposed § 170.36(c)(2)
as § 170.230.
TABLE 10—FINAL REQUIREMENTS FOR DETAILED INFORMATION IN PART 2 OF A GRAS NOTICE ABOUT THE IDENTITY OF A
NOTIFIED SUBSTANCE
Proposed
designation in the
regulatory text
(§ )
170.230(a)(1) .........
170.36(c)(2) ...........
N/A
170.230(a)(1) .........
170.36(c)(2) ...........
10a
170.230(a)(2) .........
170.36(c)(2) ...........
10b
170.230(b) ..............
170.36(c)(2) ...........
9a
170.230(c) ..............
170.36(c)(2) ...........
N/A
170.230(d) ..............
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Final designation in
the regulatory text
(§ )
N/A .........................
N/A
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Issue No.
in the 2010
notice
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Description. Part 2 of your
GRAS notice:
Must include scientific data and information that identifies the notified substance.
Must include data and information sufficient to identify a biological source of
a notified substance.
Must include data and information sufficient to identify any known toxicants
that could be in the source.
Must include the method of manufacture of the notified substance in sufficient detail to evaluate the safety of
the notified substance as manufactured.
Must include specifications for foodgrade material.
When necessary to demonstrate safety,
must include relevant data and information bearing on the physical or
other technical effect the notified substance is intended to produce, including the quantity of the notified substance required to produce such effect.
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Revisions (other than editorial,
clarifying, and conforming changes)
relative to the proposed rule
or the 2010 notice
N/A.
• Must provide taxonomic information
at the sub-species level (e.g., variety,
strain) in addition to genus and species.
• Must specify the part of any plant or
animal used as the source.
N/A.
• No longer requires that the method of
manufacture exclude any trade secrets.
• Requires ‘‘sufficient detail to evaluate
the safety of the notified substance
as manufactured’’ rather than ‘‘detailed information.’’
N/A.
New requirement based on comments
that addressed experience during
CVM’s Interim Pilot program (see
section XXV.E).
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A. Scientific Information About the
Identity of a Notified Substance
1. Scientific Information Sufficient To
Identify a Biological Source
(Comment 61) One comment asserts
that the scientific information, beyond
the standard taxonomic information,
that is sufficient to identify a biological
source for a notified substance should
be determined on a case-by-case basis
consistent with established practice and
publicly available guidance. Another
comment asserts that identifying the
source organism by the genus and
species (without additional information
such as strain or variety) is sufficient
when the notified substance is an
enzyme preparation produced by a
microorganism. However, this comment
also asserts that if safety concerns for a
specific genus and species have been
addressed (i.e., by genetic modification
to remove a characteristic of concern)
for a specific strain within that species
then information about the strain would
be appropriate. This comment
emphasizes that the description of the
source of a biological material should be
based on the safety of that source and
consider all relevant information related
to safety.
(Response 61) The information,
beyond the standard taxonomic
information, that we discussed in the
2010 notice is consistent with
established practice (see section III.J.1 of
CFSAN’s 2010 experience document
(Ref. 18)) and the final rule specifies
that when the source of a notified
substance is a biological material, your
GRAS notice must include both
taxonomic information (e.g., genus,
species), including as applicable data
and information at the sub-species level
(e.g., variety, strain) and the part of any
plant or animal used as the source (see
§ 170.230(a)(2)). We agree that the
specific scientific information, beyond
the standard taxonomic information,
that is sufficient to identify a biological
source is determined on a case-by-case
basis, and section III.J.1 of CFSAN’s
2010 experience document
demonstrates that the specific scientific
information included in a GRAS notice
to describe a biological source varied on
a case-by-case basis. For example, when
the notified substance was derived from
a microorganism, the notifier specified a
particular strain or subspecies or stated
the strain was a nontoxigenic and
nonpathogenic strain; when the notified
substance was derived from a plant, the
notifier identified the specific part(s) of
the plant used as the starting material,
such as fruit, seeds or seed husks,
expressed oil, flowers, roots, leaves,
pulp, wood, or bark. However, we
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disagree that we should use guidance,
rather than the regulatory text of this
rule, to describe the types of data and
information that are necessary to
sufficiently identify the biological
source because the types of information
we are specifying are necessary—rather
than merely recommended—
information. For example, data and
information at the sub-species level
(e.g., variety, strain) is necessary for
source microorganisms because so many
microorganisms (e.g., Escherichia coli
and Saccharomyces cerevisiae) have
multiple strains, and although some
strains are both non-toxigenic and nonpathogenic, others are not. For example,
there are several pathogenic strains of
Saccharomyces cerevisiae, even though
nonpathogenic strains are commonly
used in food and in the production of
enzyme preparations. As another
example, both Aspergillus oryzae and
Aspergillus niger naturally produce
mycotoxins, but strains that do not
produce mycotoxins have been
developed and are used for production
of enzyme preparations. In addition, for
phage production some host strains
have been pathogens (e.g., Listeria
monocytogenes) and produce toxins.
Likewise, data and information about
the part of a plant used as a source is
necessary because some plants that have
edible parts also secrete toxins in nonedible parts. For example, the leaf stalks
(petioles) of rhubarb (Rheum
rhaponticum) are edible, but the leaves
contain notable quantities of oxalic acid.
As another example, the leaves and
stems of tomato (Solanum
lycopersicum) contain solanine.
We agree that the description of a
biological source should be based on the
safety of that source and consider all
relevant information related to safety.
The regulatory text requires taxonomic
information beyond genus and species,
such as variety or strain, ‘‘when
applicable’’ for a source microorganism
such as those used to produce enzyme
preparations. Examples of when
information such as variety or strain
would be applicable are those microbial
sources, such as some fungi, for which
there are multiple strains or subspecies
that have different properties with
respect to the ability to produce toxins,
antibiotics, or other substances that are
not suitable for use in food.
(Comment 62) One comment asks us
to specify that information identifying a
substance derived from a biological
source must include the breed of animal
or plant.
(Response 62) During the Interim Pilot
program we did not evaluate any GRAS
notices in which the breed of an animal
or plant source was a taxonomic
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descriptor necessary to sufficiently
identify that animal or plant source.
Therefore, although breed may be an
appropriate taxonomic descriptor in
some circumstances, the circumstances
are rare enough that we have not seen
it as necessary information in more than
15 years. Therefore, we are not
specifying it as an example of applicable
taxonomic information in the rule. In a
specific circumstance where breed is
necessary to adequately identify a
particular animal or plant source, and
you do not specify the breed, we intend
to ask you to amend your GRAS notice
to identify the breed.
(Comment 63) One comment asks us
to address substances produced from
microorganisms, particularly
bioengineered microorganisms. This
comment explains that the development
of a production microorganism through
bioengineering is, for the most part,
highly confidential and cannot be
disclosed publicly. In addition, the
production microorganism often is
modified on an ongoing basis, e.g., to
improve yield. This comment asks us to
specify the point at which subsequent
modification of a production
microorganism would trigger
submission of a new GRAS notice and
notes that in some cases subsequent
modification of a production organism
could be incorporated into the original
GRAS notice by ‘‘amendment’’ or by
reference. This comment also asserts
that submission of a new GRAS notice
should not be needed in the case of safe
strain lineage as described in the
scientific literature (Ref. 42).
Another comment asks us to specify
that information identifying a substance
derived from a biological source must
specify whether the plant or animal is
genetically engineered or cloned.
(Response 63) We recommend that
notifiers consult our guidance entitled
‘‘Assessing the Effects of Significant
Manufacturing Process Changes,
Including Emerging Technologies, on
the Safety and Regulatory Status of Food
Ingredients and Food Contact
Substances, Including Food Ingredients
that Are Color Additives’’ (Ref. 6). That
guidance lists a change in the source
microorganism (including a change in
strain) used for a food substance derived
from fermentation of a microorganism as
an example of a significant
manufacturing process change.
Whenever there has been a significant
manufacturing process change for a food
substance that is the subject of a
previous conclusion of GRAS status, the
guidance recommends that the
manufacturer consider whether the
GRAS status of the use of the food
substance would be affected; consult
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with us regarding the conclusions about
the impact of the significant
manufacturing change on the safety and
regulatory status of the use of the food
substance; and make an appropriate
regulatory submission to us as
circumstances warrant. In the specific
circumstance of a production
microorganism that is modified on an
ongoing basis, a modification that
results in a new strain would no longer
fall within the description of the source,
which must include information at the
sub-species level (see § 170.230(a)(2)(i)).
If a notifier concludes that a
modification that results in a new strain
has no impact on the conclusion of
GRAS status, one approach could be to
submit a supplement to the GRAS
notice. Doing so would be consistent
with CFSAN’s 2010 experience during
the Interim Pilot program. See section
IV.J of CFSAN’s 2010 experience
document (Ref. 18), in which CFSAN
discusses a GRAS notice in which a
notifier consulted with CFSAN about
mechanisms to inform CFSAN about its
conclusion that additional uses of the
notified substance are also GRAS. The
notifier supplemented its original GRAS
notice with a letter informing CFSAN of
the additional conclusion of GRAS
status and CFSAN issued a second ‘‘no
questions letter’’ to the notifier as
additional correspondence.
We decline the request to require that
information identifying a substance
derived from a biological source specify
whether the plant or animal is
‘‘genetically engineered’’ or ‘‘cloned.’’
We consider that the more general
requirement to identify a biological
source at the sub-species level is
adequate to identify the source. In
practice during the Interim Pilot
program, notifiers routinely informed us
about the use of such techniques in
describing production microorganisms,
particularly for GRAS notices about the
intended conditions of use of enzyme
preparations. (See, e.g., the list of
enzyme preparations in section IV.N of
CFSAN’s 2010 experience document
(Ref. 18).) The source microorganisms
for several of the listed enzyme
preparations were developed using
bioengineering techniques.
When confidential data and
information about the development of a
production microorganism through
bioengineering are necessary to provide
evidence that a notified substance
produced from that production
organism is safe under the conditions of
its intended use, the use of the notified
substance would not satisfy GRAS
criteria. See the discussion in Response
69, where we explain that it may be
possible to explain that confidential
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information (whether included in a
GRAS notice, or provided privately to a
GRAS panel) is corroborative of safety,
rather than necessary to demonstrate
safety, if, for example, the method of
manufacture included in a GRAS notice
meets the requirements of the rule to
provide sufficient detail to evaluate the
safety of the notified substance as
manufactured. Alternatively, the notifier
could describe the development of the
production microorganism in sufficient
detail to address any safety issues
associated with use of that production
microorganism. For enzyme
preparations that would be used in
human food, we recommend that
notifiers consult our guidance entitled
‘‘Guidance for Industry: Enzyme
Preparations: Recommendations for
Submission of Chemical and
Technological Data for Food Additive
Petitions and GRAS Notices’’ (Ref. 33),
and ‘‘Food-Processing Enzymes From
Recombinant Microorganisms—A
Review’’ (Ref. 43), for details about our
recommendations for safety information
regarding enzyme preparations derived
from bioengineered microorganisms.
2. Potential Toxicants in the Source of
the Notified Substance
(Comment 64) One comment agrees
that a review of known toxicants that
could be produced by the biological
source of a notified substance should be
part of the safety review, but
recommends that the depth of the
review be addressed on a case-by-case
basis and be tailored to the substance
and the source of the substance. This
comment asserts that it would be
difficult and impractical to define a
method for this review or to define the
specific toxicants that are required to be
reviewed for each particular substance.
(Response 64) We agree that the safety
review should be tailored to the
substance and its source because of the
diversity of toxicants that could be in
the biological source. It is your
responsibility to determine how to
conduct the safety review; the rule does
not prescribe any method for this review
or any specific toxicants that must be
reviewed for a particular substance or
source. In some cases (e.g., when it is
well established in the scientific
community that a source is nontoxigenic), citations to publicly
available information about a biological
source may be sufficient to address the
safety of the notified substance with
respect to potential toxicants in the
source. In other cases (e.g., when a
source is known to be toxigenic), the
information about the toxigenic source
would lead you to a discussion, in the
narrative required in Part 6 of a GRAS
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54997
notice, of how the method of
manufacture and specifications for the
notified substance lead you to conclude
that the notified substance as
manufactured is safe and that the
criteria for general recognition are
satisfied.
(Comment 65) One comment refers to
a statement we made, in the 2010
notice, that we have found that
information about substances known to
be toxicants is relevant regardless of the
state of the science regarding the
specific toxicity of the substance to
humans (75 FR 81536 at 81540). This
comment asserts that specifying that the
identity of the notified substance
include any known toxicants that could
be in the source does not fully address
whether the toxicants cause a safety
concern. Another comment states that
the ‘‘GRAS process’’ should contain a
safety/risk assessment for known
toxicants, not just identify the toxicants.
(Response 65) We agree that a GRAS
notice must address the safety concerns
associated with toxicants known to be
in a biological source, not just identify
the toxicants. See the requirements for
a GRAS notice to include the method of
manufacture of the notified substance
(§ 170.230(b)), specifications for foodgrade material (§ 170.230(c)), and a
narrative explaining why the data and
information in a GRAS notice provide a
basis for the notifier’s view that the
notified substance is safe under the
conditions of its intended use
(§ 170.250).
(Comment 66) One comment
recommends using our guidance
entitled ‘‘Recommendations for
Submission of Chemical and
Technological Data for Direct Food
Additive Petitions’’ (Ref. 31) as a more
‘‘holistic’’ approach to addressing
potential safety concerns regarding
known toxicants in a biological source,
because the guidance describes how to
use the manufacturing process to
control, reduce, or concentrate toxicant
levels and explains the importance of
establishing limits for any known
natural toxicants in or on food additives
derived from a natural source. The
comment asserts that this guidance
should apply to GRAS substances as
well as food additives because general
recognition of safety through scientific
procedures requires the same quantity
and quality of evidence as is required to
establish a food additive regulation for
the use of the substance, and therefore
the information about the identity of the
substance should be consistent with the
requirements for food additives. This
comment notes that section III.A of
‘‘Recommendations for Submission of
Chemical and Technological Data for
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Direct Food Additive Petitions’’ clearly
outlines the information needed for
‘‘allowing the unequivocal
identification and characterization of
the food additive’’ and that the
principles in specific sections in section
III.A of the guidance apply to GRAS
substances even though they are written
to specifically address food additives.
(Response 66) We agree that many of
the recommendations in our guidance
entitled ‘‘Recommendations for
Submission of Chemical and
Technological Data for Direct Food
Additive Petitions’’ (Ref. 31) could be
useful to a person who assesses whether
a substance is GRAS under the
conditions of its intended use. As the
comment points out, the guidance
currently is structured to address the
specific requirements in § 171.1
(particularly § 171.1(c)) for food additive
petitions. Consistent with available
resources, we will consider revising that
guidance to clarify how its
recommendations apply to an
evaluation of whether a substance is
GRAS under the conditions of its
intended use.
3. Particle Size
In the 2010 notice, we noted that
substances that have a small particle
size often have chemical, physical, or
biological properties that are different
from those of their larger counterparts
(75 FR 81536 at 81540). We requested
comment on whether the final rule
should address, as part of identity,
particle size and other chemical and
physical properties that may be used to
characterize engineered materials (see
table 9).
(Comment 67) Some comments
recommend that a GRAS notice discuss
particle size only if it is relevant to the
safety or effectiveness of the notified
substance. One comment recommends
that the rule not address particle size, at
least until this area is better understood.
Another comment asks us to clarify
what we mean by the term ‘‘small
particle size’’ if we include that term in
the rule.
One comment asks us to require
information about particle size and
other physical/chemical properties that
may be used to characterize engineered
materials. This comment asserts that
nanoparticles are not simply smaller
versions of materials; instead
nanoparticles are specifically
engineered to create new properties and
behaviors that give products certain
attributes and highly reactive
nanoparticles can exhibit a toxic
reaction with their environments,
including the cells of living organisms.
This comment also notes that the U.S.
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Environmental Protection Agency (EPA)
has already made case-by-case rulings
on the safety of certain nanoparticles.
Several comments assert that any
requirement for a GRAS notice to
address particle size and other chemical
or physical properties should apply
only to engineered nanomaterials, and
that it is not typically necessary to
address such properties for nonengineered materials. One comment
asserts that engineered nanomaterials
could never be eligible for classification
as GRAS because they either are new
materials with unfamiliar properties or
represent a significant new use of a
material.
(Response 67) The final rule requires
that a GRAS notice include scientific
information that identifies the notified
substance, and includes ‘‘characteristic
properties’’ in a list of examples of
appropriate information that a notifier
would include. We agree that data and
information about particle size, and any
chemical and physical properties
attributable to small particle size, are
appropriate for engineered
nanomaterials; a GRAS notice about an
engineered nanomaterial likely would
not provide an adequate basis for a
conclusion of GRAS status without such
information. We also agree that data and
information about particle size may not
be relevant for non-engineered materials
and, thus, we are including the broad
example of ‘‘characteristic properties’’
in the final rule without adding the
narrow example of ‘‘particle size’’ (see
§ 170.230(a)(1)).
We note that we have several
guidances applicable to significant
manufacturing changes in food,
including nanotechnology (Ref. 6; Ref.
8; and Ref. 44). Our guidance entitled
‘‘Guidance for Industry: Assessing the
Effects of Significant Manufacturing
Process Changes, Including Emerging
Technologies, on the Safety and
Regulatory Status of Food Ingredients
and Food Contact Substances, Including
Food Ingredients that are Color
Additives’’ (Ref. 6) states: ‘‘At present,
for nanotechnology applications in food
substances, there are questions related
to the technical evidence of safety as
well as the general recognition of that
safety, that are likely to be sufficient to
warrant formal premarket review and
approval by FDA, rather than to satisfy
criteria for GRAS status.’’ However, that
guidance reflects the generally available
data and information at present, and we
disagree that data and information
supporting the safety of engineered
nanomaterials could never satisfy GRAS
criteria. Whether the generally available
data and information supporting the
safety of the intended conditions of use
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of any substance—including an
engineered nanomaterial—satisfy GRAS
criteria is a case-by-case conclusion that
depends on whether the generally
available data and information support
a conclusion that the substance is
generally recognized, among qualified
experts, to be safe under the conditions
of its intended use. Section 201(s) of the
FD&C Act does not limit the eligibility
of a substance for classification as GRAS
based on factors such as its
characteristic properties.
4. Other Comments About the Identity
of the Notified Substance
(Comment 68) One comment asserts
that the criteria used to conclude that a
particular substance is GRAS, including
details regarding biological source,
known toxicants, particle size, etc.,
should be based on what qualified
experts determine to be necessary.
(Response 68) We disagree that the
role of qualified experts in a conclusion
of GRAS status means that the
requirements for a GRAS notice should
be silent on the types of data and
information that generally apply to any
conclusion of GRAS status—in this case,
data and information regarding the
identity of the substance. In the
narrative required by part 6 of a GRAS
notice, a notifier must explain why the
data and information in the notice
provide a basis for the notifier’s view
that the notified substance is safe under
the conditions of its intended use
(§ 170.250(a)(1)); identify what specific
data and information that the notifier
discusses to support his view that the
notified substance is safe under the
conditions of its intended use are
generally available, and what specific
data and information that the notifier
discusses are not generally available
(§ 170.250(a)(2)); and explain how the
generally available data and information
that a notifier relies on to establish
safety provide a basis for the notifier’s
conclusion that the notified substance is
generally recognized, among qualified
experts, to be safe under the conditions
of its intended use (§ 170.250(b)). The
narrative is the appropriate mechanism
for a notifier to explain how the view of
qualified experts supports his view that
the notified substance is GRAS under
the conditions of its intended use.
B. Method of Manufacture
(Comment 69) Several comments
address Issue 9a, i.e., whether the final
rule should continue to stipulate that
the method of manufacture exclude any
trade secrets, as proposed. Some of
these comments support stipulating that
the method of manufacture exclude any
trade secrets. The stated reasons varied.
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For example, some comments state that
in the past experience of notifiers, it is
generally possible to include sufficient
information on the manufacturing
process without disclosing trade secrets.
One comment states that transparency,
by both FDA and industry, and the use
of publicly available information is
critical to the continued success of the
GRAS notification procedure. One
comment states that the common
knowledge element of the GRAS
standard inherently limits the
submission of confidential information
and/or trade secrets by the notifier to
substantiate a conclusion of GRAS
status.
Other comments point to the
proposed requirement that a GRAS
notice include ‘‘detailed information
about the . . . method of manufacture
(excluding any trade secrets . . .)’’ and
question whether a method of
manufacture that excludes trade secrets
can be sufficiently detailed to meet the
requirements of a GRAS notice. One
comment recommends that we clarify
the rule by requiring that the notice
include appropriate information on the
method of manufacture, sufficient to
conduct an adequate safety review, so
that confidential information would not
be submitted when a very general and
non-confidential description suffices.
Several comments acknowledge that
there may be situations where trade
secret information is necessary to
complete the description of the method
of manufacture and recommend that the
final rule provide flexibility for a
notifier to provide trade secret
information when appropriate (e.g., to
help us evaluate the GRAS notice), and
for FDA to protect trade secrets or other
confidential information in a GRAS
notice from public disclosure, just as we
would in the case of submissions such
as food additive petitions. To promote
clarity and transparency, some of these
comments recommend revising the rule
to require that a notifier who includes
trade secret information explain why
the information is trade secret and why
the trade secret information has a
corroborative role in the safety
assessment. Some comments emphasize
that a notifier who submits trade secret
information must mark the information
as non-public. Other comments assert
that information identified as trade
secret or confidential information
should only be allowed if the
information is not critical to a
conclusion of GRAS status.
One comment suggests that a notifier
could provide trade secret information
to a GRAS panel for review on a
confidential basis because deliberations
of the panel would not necessarily be
subject to public disclosure. One
comment notes that supporting
information can be valuable to a GRAS
panel and allowing submission of
confidential information in a GRAS
notice could inform FDA of the full
range of information taken into
consideration by a GRAS panel.
Some comments cite our regulations
for new drugs, premarket notification
for medical devices, and premarket
approval of medical devices as evidence
that our regulations implementing FOIA
specifically regard methods of
manufacture as confidential and urge us
to adopt a similar approach for GRAS
notices.
54999
See also Comment 57.
(Response 69) See table 11, and the
regulatory text in §§ 170.230(b),
170.225(c)(8), 170.250(d), and
170.250(e), for a series of changes we
made to the rule to address these
comments about the method of
manufacture included in a GRAS notice,
including comments about trade secret
information associated with the method
of manufacture. Although the changes
in Parts 1 and 6 of a GRAS notice
broadly apply to any non-public
information, in this response we focus
on how these provisions apply to trade
secret information that you may include
in the description of the method of
manufacture. Collectively, these
changes: (1) Emphasize that the
description of the method of
manufacture must be in sufficient detail
to evaluate the safety of the notified
substance as manufactured, without
stipulating that the method of
manufacture exclude any trade secrets
(§ 170.230(b)); (2) require the notifier to
include a signed statement with his
view as to whether the method of
manufacture includes trade secret
information (§ 170.225(c)(8)); (3) require
the notifier to identify any trade secret
information in the method of
manufacture (§ 170.250(d)); and (4)
require the notifier to explain how there
could be a basis for a conclusion of
GRAS status if qualified experts do not
have access to trade secret information
that the notifier considered in
concluding that the substance is safe
under the conditions of its intended use
(§ 170.250(e)). See also Response 57,
Response 78, and section XVII.
TABLE 11—REQUIREMENTS THAT APPLY WHEN A NOTIFIER INCLUDES TRADE SECRET OR OTHER NON-PUBLIC
INFORMATION IN A GRAS NOTICE
Final designation in the
regulatory text
(§ )
Proposed designation
in the regulatory text
(§ )
170.230(b) ...................
Revision
170.36(c)(2) ................
In Part 2 of your GRAS notice, you must include a description of the method of manufacture in sufficient detail to evaluate the
safety of the notified substance as manufactured.
170.225(c)(8) ...............
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Description
N/A .............................
170.250(d) ...................
N/A .............................
In Part 1 of your GRAS notice, you must
state your view as to whether any of the
data and information in Parts 2 through 7
of your GRAS notice are exempt from disclosure under the FOIA (e.g., as trade secret or as commercial or financial information that is privileged or confidential).
In Part 6 of your GRAS notice (the narrative),
if you view any of the data and information
in your notice as exempt from disclosure
under the FOIA, you must identify the specific data and information.
• We replaced ‘‘detailed’’ with ‘‘sufficient detail to evaluate the safety of the notified
substance as manufactured’’.
• We no longer stipulate that the description
of the method of manufacture must exclude
trade secret information.
Requires a notifier who includes information
that the notifier views as non-public information to make FDA aware of that view.
See Response 57.
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Requires a notifier who includes information
that the notifier views as non-public information to identify the non-public information. See section XVII.
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TABLE 11—REQUIREMENTS THAT APPLY WHEN A NOTIFIER INCLUDES TRADE SECRET OR OTHER NON-PUBLIC
INFORMATION IN A GRAS NOTICE—Continued
Final designation in the
regulatory text
(§ )
Proposed designation
in the regulatory text
(§ )
170.250(e) ...................
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170.275(c) ...................
170.36(f)(1) .................
This rule establishes requirements for
the information that a notifier submits
to FDA in a GRAS notice. GRAS criteria
require that any conclusion of GRAS
status be based on common knowledge
(see § 170.30(a)) and, thus, there could
be no basis for a conclusion of GRAS
status if trade secret information (or
other non-public information) is
necessary for qualified experts to reach
a conclusion that the notified substance
is safe under the conditions of its
intended use. In the particular case of a
conclusion of GRAS status through
scientific procedures, GRAS criteria
require that the conclusion of GRAS
status be based on data, information,
and methods that are generally available
(see § 170.30(b)). Non-public
information may be used to corroborate
safety but cannot be used to establish
safety; as discussed in Response 9,
qualified experts must be able to
conclude that the substance is not
harmful under the conditions of its
intended use without access to
‘‘corroborative’’ information (see
§ 170.30(a)).
We believe that it will be rare for a
GRAS notice to include trade secret
information. Likewise, we expect it will
be rare that trade secret information
would warrant sharing with members of
a GRAS panel, because a notifier must
write a non-confidential description of
the method of manufacture to include in
the GRAS notice and could share this
non-confidential description, rather
than trade secret information, with the
GRAS panel. If the GRAS panel had
questions about that description of the
method of manufacture, we expect that
the notifier would revise the description
to address those questions rather than
provide the GRAS panel with trade
secret information to address those
questions. If, however, a notifier does
provide the GRAS panel with trade
secret information, we agree that the
notifier should inform us of the full
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Description
Revision
In Part 6 of your GRAS notice (the narrative),
you must explain how there could be a
basis for a conclusion of GRAS status if
qualified experts generally do not have access to non-public, safety-related data and
information.
We will disclose all remaining data and information that are not exempt from public disclosure in accordance with part 20.
Requires a notifier to place non-public information in the context of a conclusion of
GRAS status. See section XVII.
range of information taken into
consideration by the GRAS panel,
consistent with the signed statement
that the GRAS notice is a complete,
representative, and balanced submission
(see Response 58 and § 170.225(c)(9)).
The notifier could do so either by
including in his GRAS notice a nonconfidential description of the trade
secret information that was shared, or
by providing the trade secret
information shared with a GRAS panel.
Importantly, the notifier would be
required to explain how there could be
a basis for a conclusion of GRAS status
if qualified experts generally do not
have access to non-public, safety related
data and information (see Response 78
and § 170.250(e)). If the public
description of the method of
manufacture that a notifier includes in
a GRAS notice cannot provide sufficient
detail to evaluate the safety of the
notified substance as manufactured,
there could be no basis to support a
conclusion of GRAS status. However, if
that public description meets the
requirements of the rule to provide
sufficient detail to evaluate the safety of
the notified substance as manufactured
(see § 170.230(b)), it may be possible to
explain that trade secret information
that a GRAS panel evaluated is
corroborative of safety rather than
necessary to demonstrate safety.
Under § 20.61, trade secrets and
commercial or financial information
which is privileged or confidential are
exempt from public disclosure. Under
§§ 20.100(c)(7) and 171.1(h)(2)(i),
manufacturing methods or processes,
including quality control procedures,
are exempt from public disclosure
unless they have been previously
disclosed to the public (as defined in
§ 20.81) or they relate to a product or
ingredient that has been abandoned. If
a notifier believes that all information
about the method of manufacture
should be non-public, it is unlikely that
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Uses active voice to emphasize that we will
apply the protections from public disclosure
under the FOIA to non-public information
included in a GRAS notice.
the notifier has a basis to conclude that
the notified substance is GRAS under
the conditions of its intended use. The
use of the substance would be a food
additive use and, if the notifier submits
a food additive petition for that use, our
regulations governing a food additive
petition would protect the information
from public disclosure, as do our
regulations for new drugs, premarket
notification for medical devices, and
premarket approval of medical devices.
(Comment 70) Several comments
express concern about the possibility
that we would determine that
information a notifier identifies as a
trade secret or as confidential
commercial information is available for
public disclosure. One comment asserts
that if we choose to allow the
submission of confidential information
in a GRAS notice, we should not be the
party who determines whether
information should be publicly
disclosed. Another comment asks us to
provide an opportunity for a notifier to
make a ‘‘cease to evaluate’’ request
before we disclose confidential
information.
One comment asks us to allow the
submission of limited confidential
information to supplement (or
corroborate) the publicly available
information in a GRAS notice, such as
by providing sufficient information in a
GRAS notice to support a conclusion of
GRAS status but also including
additional, corroborating information in
a food master file. The comment
explains that the public GRAS notice
would be complete and sufficient to
form a conclusion of GRAS status, but
we would have access to additional,
confidential information that would
ensure that we are informed of new
manufacturing or technological
developments. This comment points out
that we have for many years employed
food, drug, and medical device master
files for the submission of confidential
information.
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(Response 70) We disagree that we
should not be the party who determines
whether information should be publicly
disclosed. Under our public information
regulations in part 20, we have the
responsibility to determine whether
information should be publicly
disclosed, regardless of whether a
person who submits the information has
marked it as non-public. Marking
records submitted to us as confidential,
or with any other similar term, raises no
obligation by FDA to regard such
records as confidential, to return them
to the person who has submitted them,
to withhold them from disclosure to the
public, or to advise the person
submitting them when a request for
their public disclosure is received or
when they are in fact disclosed (see
§ 20.27). We also disagree that providing
an opportunity for a notifier to ask us
to cease to evaluate a GRAS notice
would impact the public disclosure of
data and information that do not satisfy
the criteria in part 20 for exemption
from disclosure; under § 20.29 a GRAS
notice is available for public disclosure
in accordance with part 20.
Data and information submitted to us
are available for public disclosure based
on the nature of the data and
information, not the name of the file
where we store the data and
information. Thus, asking us to store
data and information that you view as
confidential in a specific type of file,
such as a ‘‘food master file,’’ would not
automatically protect the information
from public disclosure. Furthermore, in
Part 6 of your GRAS notice you would
be required to explain how there could
be a basis for a conclusion of GRAS
status if qualified experts generally do
not have access to the confidential data
and information in the separate file. We
also would expect that you provide a
statement in Part 1 of your GRAS notice
with your view that the additional data
and information in the separate file are
exempt from disclosure under the FOIA
(see § 170.225(c)(8)). Because part 20
already provides protection of nonpublic information from disclosure, and
because your GRAS notice would need
to both acknowledge the data and
information in the separate file and
explain how there could be a basis for
a conclusion of GRAS status if qualified
experts generally do not have access to
these data and information, we consider
it administratively inefficient to
maintain the data and information
submitted in support of a conclusion of
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GRAS status in two separate files, and
we may decide to decline to file a GRAS
notice that is accompanied by a separate
file containing data and information that
you view as non-public.
(Comment 71) Some comments assert
that many manufacturers will choose
not to notify us of a conclusion of GRAS
status because they expect that we will
determine that all information
submitted in a GRAS notice is available
for public disclosure in most
circumstances.
(Response 71) Our experience during
the Interim Pilot program does not
support the assertions in these
comments. As noted in Response 24 and
Response 26, CFSAN has filed more
than 600 GRAS notices between 1998
and 2015, for an average of
approximately 34 GRAS notices per
year.
(Comment 72) One comment states
that commercial and financial
information are not relevant to the
determination of safety of a notified
substance.
(Response 72) Confidential
commercial information may on
occasion be used to corroborate safety.
One example is an article that has been
accepted for publication, but has not yet
been published. This article would
likely be considered confidential until it
is published, but it could be used to
corroborate other published
information.
C. Specifications for the Notified
Substance
We received no comments that
disagreed with our proposed
requirement for a GRAS notice to
include specifications for food-grade
material and we are finalizing it as
proposed for a substance used in human
food. See table 29 for an editorial
change we made to the regulatory text
for specifications for a substance used in
animal food.
D. Data and Information Bearing on the
Physical or Other Technical Effect of the
Notified Substance
As discussed in section XXV.E,
several comments discuss their
experience with CVM’s practice, during
the Interim Pilot program, of asking a
notifier to provide data or information
demonstrating the effectiveness, or
utility, of the notified substance. After
considering these comments, we have
added a requirement for Part 2 of a
GRAS notice to include relevant data
and information bearing on the physical
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55001
or other technical effect the notified
substance is intended to produce,
including the quantity of the notified
substance required to produce such
effect, when necessary to demonstrate
safety (see § 170.230(d) and Response
144). Data and information bearing on
the physical or other technical effect the
notified substance is intended to
produce are only necessary when they
bear on safety. This relationship to
safety is consistent with the
requirements of the FD&C Act for a
petition to establish the safety of a food
additive (see section 409(b)(2)(C) of the
FD&C Act). An example of when such
data and information would be relevant
to safety is when the intended use of the
notified substance is as an antimicrobial
agent. For example, an antimicrobial
agent may change the microbiological
profile of food such that it suppresses
one group of pathogenic
microorganisms while allowing others
to proliferate, thereby creating a
potential health problem (Ref. 32).
XIV. Comments on Part 3 of a GRAS
Notice: Dietary Exposure
We proposed that a notice regarding
a conclusion of GRAS status through
scientific procedures include a
comprehensive discussion of, and
citations to, generally available and
accepted scientific data, information,
methods, or principles that the notifier
relies on to establish safety, including a
consideration of the probable
consumption of the substance and the
probable consumption of any substance
formed in or on food because of its use
and the cumulative effect of the
substance in the diet, taking into
account any chemically or
pharmacologically related substances in
such diet (proposed § 170.36(c)(4)(i)(A)).
In the 2010 notice, we requested
comment on several issues relevant to
the proposed requirements for a
comprehensive discussion that
considers the probable consumption of
the substance and the probable
consumption of any substance formed
in or on food because of its use and the
cumulative effect of the substance in the
diet, and noted that the simple term
‘‘dietary exposure’’ could be used in
place of the statutory language (i.e.,
derived from section 409(c)(5) of the
FD&C Act) we used in the proposed rule
(see table 12). See table 27 for issues in
the 2010 notice regarding dietary
exposure when a notified substance
would be added to animal food.
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TABLE 12—ISSUES IN THE 2010 NOTICE REGARDING DIETARY EXPOSURE WHEN A NOTIFIED SUBSTANCE WOULD BE
ADDED TO HUMAN FOOD
Issue
No.
Description of our request for comment
11a .....
Whether the final rule should continue to restate the statutory language of section 409(c)(5)
of the FD&C Act or whether this provision should be stated more clearly, for example, by
requiring information about dietary exposure (i.e., the amount of the notified substance that
consumers are likely to eat or drink as part of a total diet).
Whether a GRAS notice should be required to include information about dietary exposure to
contemporary consumers regardless of whether the determination of GRAS status is
through scientific procedures or through experience based on common use in food.
11b .....
In the following sections, we discuss
comments on the proposed
requirements applicable to dietary
exposure and the issues discussed in the
2010 notice. After considering these
comments, we are establishing
requirements for Part 3 of a GRAS notice
Reference
as shown in table 13, with editorial,
clarifying, and conforming changes as
shown in table 29. (See § 170.235).
Table 13 identifies changes we made
relative to the proposed rule or the
description in the 2010 notice other
than the editorial, clarifying, and
75 FR 81536 at 81540–81541.
75 FR 81536 at 81540–81541.
conforming changes shown in table 29
and the additional editorial changes
associated with the redesignation of
some of the regulatory text of proposed
§ 170.36(c)(4)(i)(A) as § 170.235.
TABLE 13—FINAL REQUIREMENTS FOR DATA AND INFORMATION ABOUT DIETARY EXPOSURE IN PART 3 OF A GRAS
NOTICE
Proposed
designation in the
regulatory text
(§ )
170.235 ..................
170.36(c)(4)(i)(A) ...
11a
11b
In Part 3 of your GRAS Notice, you
must provide data and information
about dietary exposure (i.e., the
amount of relevant substances that
consumers are likely to eat or drink
as part of a total diet), regardless of
whether your conclusion of GRAS
status is through scientific procedures
or through experience based on common use in food.
170.235(a) ..............
170.36(c)(4)(i)(A) ...
11a
170.235(b) ..............
170.36(c)(4)(i)(A) ...
11a
170.235(c) ..............
170.36(c)(4)(i)(A),
170.36(c)(2).
11a
170.235(d) ..............
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Final designation in
the regulatory text
(§ )
170.36(c)(4)(i)(A) ...
11a
170.235(e) ..............
170.36(c)(4)(i)(A) ...
11a
In Part 3 of your GRAS Notice, you
must provide data and information
about dietary exposure to the notified
substance that includes exposure
from its intended use and all sources
in the diet.
When applicable, in Part 3 of your
GRAS Notice you must provide data
and information about dietary exposure to any other substance that is
expected to be formed in or on food
because of the use of the notified
substance (e.g., hydrolytic products
or reaction products).
When applicable, in Part 3 of your
GRAS Notice you must provide data
and information about dietary exposure to any other substance that is
present with the notified substance either naturally or due to its manufacture (e.g., contaminants or by-products).
In Part 3 of your GRAS notice, you
must describe the source of any food
consumption data that you use to estimate dietary exposure.
In Part 3 of your GRAS notice, you
must explain any assumptions you
made to estimate dietary exposure.
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Revisions (other than editorial,
clarifying, and conforming changes)
relative to the proposed rule or the
2010 notice
• Uses the term ‘‘dietary exposure’’ and
describes it as meaning ‘‘the amount
of relevant substances that consumers are likely to eat or drink as
part of a total diet.’’
• Requires data and information about
dietary exposure regardless of whether your conclusion of GRAS status is
through scientific procedures or
through experience based on common use in food.
Uses the term ‘‘dietary exposure.’’
• Uses the term ‘‘dietary exposure.’’
• Gives examples of substances that
could be formed in or on food because of the use of the notified substance.
Requires an estimate of dietary exposure to substances such as contaminants and by-products as a means to
establish specifications for applicable
contaminants and by-products.
Specifies a necessary aspect of the
proposed ‘‘comprehensive discussion’’ of scientific data, information,
and methods.
Specifies a necessary aspect of the
proposed ‘‘comprehensive discussion’’ of scientific data, information,
and methods.
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TABLE 13—FINAL REQUIREMENTS FOR DATA AND INFORMATION ABOUT DIETARY EXPOSURE IN PART 3 OF A GRAS
NOTICE—Continued
Proposed
designation in the
regulatory text
(§ )
170.250(a)(1) .........
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Final designation in
the regulatory text
(§ )
170.36(c)(4)(i)(A) ...
Issue No.
in the 2010
notice
N/A
See section XXV.F for a discussion of
comments on the issues listed in table
27 regarding dietary exposure when a
notified substance would be added to
animal food and for changes we made
to the regulatory text regarding dietary
exposure when a notified substance
would be added to animal food.
(Comment 73) Some comments
support retaining the statutory language
derived from section 409(c)(5) of the
FD&C Act when stating the requirement
for a comprehensive discussion in a
GRAS notice that considers dietary
exposure. One of these comments states
that the proposed statutory language
regarding dietary exposure is consistent
with the criteria for general recognition
of safety through scientific procedures,
which requires the same quantity and
quality of scientific evidence necessary
for a food additive petition. Other
comments support revising the
proposed requirement as a means of
clarifying that the comprehensive
discussion in a GRAS notice must
consider dietary exposure.
(Response 73) We agree that: (1) The
requirements of the rule regarding what
a notifier must include in a GRAS notice
regarding dietary exposure must be
clear; and (2) the statutory language of
section 409(c)(5)(A) of the FD&C Act is
consistent with the criteria for general
recognition of safety through scientific
procedures, which requires the same
quantity and quality of scientific
evidence necessary for a food additive
petition. To meet both of these goals, the
final rule requires information about
dietary exposure (i.e., the amount of
relevant substances that consumers are
likely to eat or drink as part of a total
diet), as we suggested in the 2010
notice, but also retains the detailed
statutory direction as proposed (see
§ 170.235(a) through (c), § 170.250(a)(1),
and table 13). In addition to requiring an
estimate of dietary exposure to the
notified substance (§ 170.235(a)), the
rule requires, when applicable, that a
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In Part 6 of your GRAS notice, you
must explain why the data and information in your notice provide a basis
for your view that the notified substance is safe under the conditions of
its intended use, considering all dietary sources and taking into account
any chemically or pharmacologically
related substances in such diet.
notifier provide data and information
about dietary exposure to any other
substance that is expected to be formed
in or on food because of the use of the
notified substance (e.g., hydrolytic
products or reaction products)
(§ 170.235(b)). Example of such
substances are benzoates (which react
with ascorbic acid (such as in beverages)
to form benzene) and sulfur dioxide
(which reacts irreversibly with
thiamine, such that we have prescribed
limitations on the use of sulfur dioxide
in some food products (see § 182.3862)).
The rule also requires, when applicable,
that a notifier provide data and
information about dietary exposure to
any other substance that is present with
the notified substance either naturally
or due to its manufacture (e.g.,
contaminants or by-products). An
estimate of dietary exposure to
substances such as contaminants and
by-products is necessary to establish
specifications for applicable
contaminants and by-products (see
§ 170.230(c), which requires that a
GRAS notice include specifications for
food-grade material). See also Response
75.
(Comment 74) One comment asks us
to allow for a reasonable methodology
that does not overestimate dietary
exposure in the extreme.
(Response 74) The rule neither
prescribes the methodology you would
use to estimate dietary exposure nor
requires that you overestimate dietary
exposure. Consistent with the proposed
requirement for the consideration of
dietary exposure to be a
‘‘comprehensive discussion,’’ the rule
requires you to describe the source of
any food consumption data that you use
to estimate dietary exposure and any
assumptions you made to estimate
dietary exposure; such information is
necessary for the estimates of dietary
exposure to be scientifically sound and
provides an opportunity for you to
explain why the methodology you used
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clarifying, and conforming changes)
relative to the proposed rule or the
2010 notice
Description
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N/A.
is reasonable (see § 170.235(d) and (e)
and table 13). Our guidance entitled
‘‘Estimating Dietary Intake of
Substances in Food’’ provides general
recommendations for calculating and
submitting estimates of dietary intake to
support the documentation of the safety
of substances introduced into food
either intentionally to accomplish a
technical effect, adventitiously as a
component of an added substance, or
inadvertently through contamination
resulting from processing (Ref. 25).
(Comment 75) One comment
emphasizes that the requirement for
consideration of dietary exposure must
discuss the potential cumulative effect
of the notified substance.
(Response 75) We agree. We are
specifying that the narrative included in
Part 6 of a GRAS notice must address
the safety of the notified substance,
considering all dietary sources and
taking into account any chemically or
pharmacologically related substances in
such diet (see § 170.250(a)(1)).
(Comment 76) Some comments
support requiring that a GRAS notice
include information about dietary
exposure to contemporary consumers
when the conclusion of GRAS status is
through experience based on common
use in food prior to 1958, e.g., because
dietary exposure to contemporary
consumers serves as a baseline for
future studies/assessment. Other
comments do not support such a
requirement and assert that it is not
critical to update the exposure data if
consumption of the GRAS substance
was already widespread before 1958, or
that information about dietary exposure
to contemporary consumers would only
be necessary if the exposure has
significantly changed since 1958.
One comment questions the value of
requiring information about
contemporary dietary intake of an
ingredient that is GRAS through
experience based on common use in
foods. This comment asserts that the
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FD&C Act deems an ingredient to be
GRAS if it was commonly used in foods
prior to January 1, 1958, and that FDA
has long recognized that a conclusion of
GRAS status through experience based
on common use in food may be made
without the quantity or quality of
scientific procedures required for
establishment of a food additive
regulation. This comment asserts that
there is no requirement for a GRAS
ingredient to be consumed at the same
use level as in 1958 and that imposition
of such a new requirement may be
impracticable, e.g., because there may
not be any databases that would allow
for the calculation of dietary exposures
prior to 1958. This comment also asserts
that in many instances there may be
insufficient information to establish an
acceptable daily intake (ADI) for the
ingredient because studies that can be
used to calculate ADIs may not be
available for many of these ingredients,
and that without information about the
ADI it would be difficult to imagine the
relevance of the estimated daily intake,
which would be calculated through
dietary exposure.
Another comment asserts that
§§ 170.30(c) and 170.3(f) clearly provide
that for a substance to be GRAS through
experience based on common use in
food there must be a substantial history
of consumption of the substance in food
by a significant number of people prior
to 1958 and that the requirements for
information about consumption data in
a GRAS notice should be consistent
with those regulatory provisions. This
comment also asserts that requiring
information about dietary exposure to
contemporary consumers would
represent an additional regulatory
burden that would not impact the
original conclusion of GRAS status
through experience based on common
use in food if there are no safety
concerns when the notified substance is
used in accordance with the intended
conditions of use.
(Response 76) We are requiring that a
notifier provide data and information
about dietary exposure, regardless of
whether the conclusion of GRAS status
is through scientific procedures or
through experience based on common
use in food (see § 170.235). The FD&C
Act and our regulations do not provide
that a substance is necessarily GRAS
under the conditions of its intended use
merely because it was commonly used
in food prior to 1958. Rather, the FD&C
Act provides that such a substance must
be generally recognized, among experts
qualified by scientific training and
experience to evaluate its safety,
through experience based on common
use in food, to be safe under the
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conditions of its intended use. Under
both the FD&C Act and the definition of
‘‘safe’’ in our regulations, relevant
factors must be considered, including
the ‘‘probable consumption of the
substance and of any substance formed
in or on food because of its use’’ (see
section 409(c)(5)(A) of the FD&C Act
and § 170.3(i)(1)). We recognize that a
conclusion of GRAS status through
experience based on common use in
food does not require the same quantity
or quality of scientific information
required for establishment of a food
additive regulation; however, this
means that a conclusion of GRAS status
through experience based on common
use in food is not necessarily supported
by the same testing data as would be
required to support establishment of a
food additive regulation. See, for
example, the 1976 final rule establishing
GRAS criteria, which provides, ‘‘for
those substances that were widely used
before 1958, under the terms of the
statute FDA must consider available
data and may not prohibit use of a
substance merely because tests that
would be required for new food
additives have not been performed.’’ (41
FR 53600, December 7, 1976). Like a
conclusion of GRAS status based on
scientific procedures, a conclusion of
GRAS status through experience based
on common use in food requires that the
substance be ‘‘safe,’’ as defined in 21
CFR 170.3(i), under the conditions of its
intended use.
The rule requires that a notifier
provide evidence of substantial history
of consumption of the substance for
food use by a significant number of
consumers prior to January 1, 1958, but
does not require an estimate of dietary
exposure prior to 1958 (see § 170.245).
The rule requires that the narrative in
Part 6 of a GRAS notice explain why the
data and information in the notice
provide a basis for the notifier’s view
that the notified substance is safe under
the conditions of its intended use,
considering all dietary sources and
taking into account any chemically or
pharmacologically related substances in
such diet (§ 170.250(a)); to do so, the
notifier must consider the estimated
dietary exposure (which this comment
refers to as ‘‘estimated daily intake’’).
However, the rule does not specify that
a notifier must determine an
‘‘acceptable daily intake’’ as part of the
narrative.
XV. Comments on Part 4 of a GRAS
Notice: Self-Limiting Levels of Use
We proposed that a GRAS notice must
include information on any self-limiting
levels of use (proposed § 170.36(c)(3)).
We did not receive comments
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disagreeing with this proposed
requirement. Therefore, we are
establishing a requirement for you to
include in Part 4 of your GRAS notice
data and information on self-limiting
levels of use in circumstances where the
amount of the notified substance that
can be added to food is limited because
food containing levels of the notified
substance above a particular level
would become unpalatable or
technologically impractical (see
§ 170.240). We included an explanation
of the circumstances in which the level
of use is self-limiting for clarity.
XVI. Comments on Part 5 of a GRAS
Notice: Common Use in Food Before
1958
We proposed that a GRAS notice
include a comprehensive discussion of,
and citations to, generally available data
and information that the notifier relies
on to establish safety, including
evidence of a substantial history of
consumption of the substance by a
significant number of consumers, for a
conclusion of GRAS status through
experience based on common use in
food (proposed § 170.36(c)(4)(ii)(A)).
During the Interim Pilot program, we
received fewer than a dozen GRAS
notices where the statutory basis was
through experience based on common
use in food (Ref. 45).
We did not receive comments
disagreeing with this proposed
requirement and we are establishing a
requirement for you to include in Part
5 of your GRAS notice evidence of a
substantial history of consumption of
the notified substance for food use by a
significant number of consumers prior
to January 1, 1958 if the statutory basis
for your conclusion of GRAS status is
through experience based on common
use in food (see § 170.245). See table 29
for conforming changes for a substance
used in animal food.
XVII. Comments on Parts 6 and 7 of a
GRAS Notice: Narrative and List of
Supporting Data and Information
We proposed that a GRAS notice must
include a detailed summary of the basis
for the notifier’s determination that a
particular use of the notified substance
is exempt from the premarket approval
requirements of the FD&C Act because
such use is GRAS (proposed
§ 170.36(c)(4)). Regardless of whether
the conclusion of GRAS status was
based on scientific procedures or
through experience based on common
use in food, we proposed to require: (1)
A comprehensive discussion of, and
citations to, generally available and
accepted scientific data and information
that the notifier relies on to establish
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safety (proposed § 170.36(c)(4)(i)(A) and
170.36(c)(4)(ii)(A)); (2) a comprehensive
discussion of any reports of
investigations or other information that
may appear to be inconsistent with the
GRAS determination (proposed
§ 170.36(c)(4)(i)(B) and (c)(4)(ii)(B)); and
(3) the basis for concluding, in light of
the data and information in the GRAS
notice, that there is consensus among
experts qualified by scientific training
and experience to evaluate the safety of
substances added to food that there is
reasonable certainty that the substance
is not harmful under the intended
conditions of use (proposed
§ 170.36(c)(4)(i)(C) and (c)(4)(ii)(C)).
When the conclusion of GRAS status is
based on scientific procedures, we also
proposed that the discussion of
generally available and accepted
information that the notifier relies on to
establish safety include methods and
principles, and include a consideration
of the probable consumption of the
substance and the probable
55005
consumption of any substance formed
in or on food because of its use and the
cumulative effect of the substance in the
diet, taking into account any chemically
or pharmacologically related substances
in such diet (proposed
§ 170.36(c)(4)(i)(A)).
In the 2010 notice, we requested
comment on issues relevant to the
applicability of confidential data and
information to a conclusion that a
substance is GRAS under the conditions
of its intended use (see table 14).
TABLE 14—ISSUES IN THE 2010 NOTICE REGARDING THE APPLICABILITY OF CONFIDENTIAL DATA AND INFORMATION TO A
CONCLUSION OF GRAS STATUS
Issue
No.
Description of our request for comment
9b ......
Whether to require that a notifier who identifies one or more trade secret(s), as defined in
§ 20.61(a), in the GRAS notice explain why it is trade secret information and how qualified experts could conclude that the intended use of the notified substance is safe without access to the
trade secret(s).
Whether to require that a notifier who identifies confidential commercial or financial information, as
defined in § 20.61(b), in the GRAS notice explain why it is confidential commercial or financial information and how qualified experts could conclude that the intended use of the notified substance is safe without access to such information.
9c ......
In the following paragraphs, we
discuss comments on the proposed
requirements applicable to a detailed
summary of the basis for the notifier’s
conclusion of GRAS status and the
issues discussed in the 2010 notice.
After considering these comments, we
are establishing requirements for Part 6
of a GRAS notice to include a narrative
Reference
as shown in table 15, and for Part 7 of
a GRAS notice to include a list of
supporting data and information as
shown in table 16, with editorial,
clarifying, and conforming changes as
shown in table 29. (See §§ 170.250 and
170.255.)
Table 15 and table 16 identify changes
we made relative to the proposed rule
75 FR 81536 at 81539–81540.
75 FR 81536 at 81539–81540.
or the description in the 2010 notice
other than the editorial, clarifying, and
conforming changes shown in table 29
and the additional editorial changes
associated with the redesignation of
proposed § 170.36(c)(4) as §§ 170.250
and 170.255.
TABLE 15—FINAL REQUIREMENTS FOR A NARRATIVE IN PART 6 OF A GRAS NOTICE
Proposed
designation in the
regulatory text
(§ )
170.250 ..................
170.36(c)(4) ...........
N/A
170.250(a)(1) .........
170.36(c)(4) ...........
N/A
170.250(a)(2) .........
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Final designation in
the regulatory text
(§ )
170.36(c)(4) ...........
9a, 9b, and 9c
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Issue No. in
the 2010
notice
PO 00000
Description. Part 6 of your
GRAS notice:
You must include a narrative that provides the basis for your conclusion of
GRAS status.
You must explain why the data and information in your notice provide a
basis for your view that the notified
substance is safe under the conditions of its intended use, considering
all dietary sources and taking into account any chemically or pharmacologically related substances in such
diet.
You must identify what specific data
and information are generally available, and what specific data and information are not generally available,
by providing citations to the list of
data and information that you include
in Part 7 of your GRAS notice.
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Revisions (other than editorial,
clarifying, and conforming changes)
relative to the proposed rule or the
2010 notice
N/A.
N/A.
Requires that your narrative clarify the
status of all data and information that
you rely on to establish safety.
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TABLE 15—FINAL REQUIREMENTS FOR A NARRATIVE IN PART 6 OF A GRAS NOTICE—Continued
Final designation in
the regulatory text
(§ )
Proposed
designation in the
regulatory text
(§ )
170.250(b) ..............
170.36(c)(4) ...........
N/A
170.250(c) ..............
170.36(c)(4) ...........
6b
170.250(d) ..............
N/A .........................
9b and 9c
170.250(e) ..............
N/A .........................
9b and 9c
Issue No. in
the 2010
notice
Revisions (other than editorial,
clarifying, and conforming changes)
relative to the proposed rule or the
2010 notice
Description. Part 6 of your
GRAS notice:
You must explain how the generally
available data and information that
you rely on to establish safety provide
a basis for your conclusion that the
notified substance is generally recognized, among qualified experts, to be
safe under the conditions of its intended use.
You must either: (1) Identify, discuss,
and place in context, data and information that are, or may appear to be,
inconsistent with your conclusion of
GRAS status, regardless of whether
those data and information are generally available; or
(2) State that you have reviewed the
available data and information and
are not aware of any data and information that are, or may appear to be,
inconsistent with your conclusion of
GRAS status..
In Part 6 of your GRAS notice (the narrative), if you view any of the data
and information in your notice as exempt from disclosure under the FOIA,
you must identify the specific data
and information.
In Part 6 of your GRAS notice (the narrative), you must explain how there
could be a basis for a conclusion of
GRAS status if qualified experts generally do not have access non-public,
safety-related data and information.
Uses the term ‘‘generally recognized’’
rather than the term ‘‘consensus.’’
When applicable, requires an affirmative
statement that you have reviewed the
available data and information and
are not aware of any data and information that are, or may appear to be,
inconsistent with your conclusion of
GRAS status.
N/A.
Your explanation must address all nonpublic safety-related data and information, not just confidential data and
information included in your GRAS
notice.
TABLE 16—FINAL REQUIREMENTS FOR A LIST OF SUPPORTING DATA AND INFORMATION IN PART 7 OF A GRAS NOTICE
Proposed
designation in the
regulatory text
(§ )
Issue No. in
the 2010
notice
Description. Part 7 of your
GRAS notice:
170.255(a) ..............
• 170.36(c)(4)(i)(A)
• 170.36(c)(4)(ii)(A)
9a, 9b, and 9c
170.255(b) ..............
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Final designation in
the regulatory text
(§ )
• 170.36(c)(4)(i)(A)
• 170.36(c)(4)(ii)(A)
9a, 9b, and 9c
You must include a list of all of the data
and information that you discuss in
part 6 of your GRAS notice to provide
a basis for your view that the notified
substance is safe under the conditions of its intended use.
The data and information that you list
must specify which data and information are generally available, and
which data and information are not
generally available.
In the requirements for Parts 6 and 7
of the final rule, we made changes to
require that the narrative in Part 6 of
your GRAS notice, and the
accompanying list of supporting data
and information in Part 7 of your GRAS
notice, clarify the status of all data and
information that you rely on to establish
safety as to whether it is generally
available (see §§ 170.250(a)(2) and
170.255, table 15, and table 16). We
made these changes relative to the
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proposed requirements for a detailed
summary and comprehensive
discussion for consistency with: (1) The
criteria for eligibility for classification as
GRAS through scientific procedures
(which provide that a conclusion of
GRAS status may be corroborated by the
application of unpublished scientific
data, information, or methods (see
§ 170.30(b), Response 8, and Response
12)); and (2) the provisions of the rule
that allow you to include data and
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Revisions (other than editorial,
clarifying, and conforming changes)
relative to the proposed rule or the
2010 notice
Clarifies that the list includes all data
and information, not just generally
available data and information.
Requires that you characterize each
item in your list as to whether it is
generally available.
information that are not generally
available (see § 170.230(b) (which no
longer stipulates that the method of
manufacture must exclude trade secret),
§ 170.225(c)(8), Response 57 and
Response 69).
In the requirements for Part 6 of a
GRAS notice, we also made a change to
require that your narrative either: (1)
Identify, discuss, and place in context,
data and information that are, or may
appear to be, inconsistent with your
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conclusion of GRAS status, regardless of
whether those data and information are
generally available; or (2) state that you
have reviewed the available data and
information and are not aware of any
data and information that are, or may
appear to be, inconsistent with your
conclusion of GRAS status. See
§ 170.250(c) and table 15. We made this
change relative to the proposed
requirement for a comprehensive
discussion of any reports of
investigations or other information that
may appear to be inconsistent with a
conclusion of GRAS status to emphasize
your responsibility to seek out such
reports and information, as we do
during our evaluation of a GRAS notice.
See also § 170.225(c)(9) and Response
58, in which we discuss the
requirements for a statement certifying
that the GRAS notice is ‘‘complete’’ in
addition to ‘‘representative’’ and
‘‘balanced,’’ to emphasize your
responsibility to identify, discuss, and
place in context, data and information
that are, or may appear to be,
inconsistent with a conclusion of GRAS
status. Under §§ 170.225(c)(9) and
170.250(c), we expect you to describe
unpublished reports of investigations or
other information that may appear to be
inconsistent with a conclusion of GRAS
status, not just published reports. If we
identify relevant information that was
not discussed in the GRAS notice, we
may question the credibility of the
certification statements in the GRAS
notice and respond with an
‘‘insufficient basis letter.’’ As noted in
Response 58, the use of certification
statements has become routine in other
submissions to FDA for food programs,
and the certification statements in Form
FDA 3480 (for a food contact
notification submission) (Ref. 39) and in
Form FDA 3537 (for registration of a
food facility) (Ref. 40) remind the
submitter of criminal penalties under 18
U.S.C. 1001 for a materially false,
fictitious, or fraudulent statement to the
U.S. Government. Now that certification
statements will be required in a GRAS
notice, we intend to modify the form
that we make available for the
submission of a GRAS notice (i.e., Form
FDA 3667 (Ref. 38)) to likewise remind
any person who submits a GRAS notice
of the applicability of criminal penalties
for a materially false, fictitious, or
fraudulent statement to the U.S.
Government.
See also Response 78. We also expect
you to describe unpublished data and
information that you consider to be
corroborative of safety (e.g., if you
consider that the unpublished data and
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information warrant sharing with any
‘‘GRAS panel’’ that you convene).
(Comment 77) One comment asserts
that the proposed requirement for a
GRAS notice to include the basis for
concluding that there is consensus
among qualified experts about the safety
of the substance misstates the statutory
standard for general recognition in
section 201(s) of the FD&C Act. This
comment asserts that the term
‘‘consensus’’ denotes complete or near
unanimity, whereas the standard of
general recognition requires that
qualified experts predominantly, but not
unanimously, accept the safety of the
substance. Although the comment
acknowledges that the proposed rule
stated that the term ‘‘consensus’’ does
not imply unanimity (62 FR 18938 at
18941), the comment argues that the
example used in our explanation, about
whether a single published report
questioning the safety of use of a
substance in food would preclude
general recognition, wrongly implied
that general recognition requires near
unanimity (62 FR 18938 at 18941). The
comment asks us to revise the rule by
replacing the term ‘‘consensus,’’ which
does not appear in the statute, with the
phrase ‘‘general recognition,’’ which
derives from the statute itself.
(Response 77) As discussed in the
proposed rule (62 FR 18938 at 18939),
our interpretation that general
recognition requires consensus is
consistent with the case law on the
general recognition standard. See
United States v. Western Serum Co.,
Inc., 666 F.2d 335, 338 (9th Cir. 1982);
United States v. Articles of
Drug...Promise Toothpaste, 624 F.Supp.
776, 778 (N.D. Ill. 1985), aff’d 826 F.2d
564 (7th Cir. 1987); United States v.
Articles of Drug...Hormonin, 498
F.Supp.2d 424, 435 (D.N.J. 1980). See
also the discussion of the consensus
standard in Response 20.
We proposed to provide our
interpretation of section 201(s) of the
FD&C Act in the requirement for Part 6
of a GRAS notice to provide more
context to notifiers than merely
repeating the statutory language. We
disagree with the comment’s assertion
that the example we described in the
proposed rule requires ‘‘near
unanimity’’; CFSAN’s experience during
the Interim Pilot program demonstrates
that CFSAN’s ‘‘insufficient basis letters’’
did not apply a standard of ‘‘near
unanimity’’ when evaluating the
notifier’s basis for a conclusion of GRAS
status (see section III.A.3 of CFSAN’s
2010 experience document (Ref. 18)).
However, we have decided to use the
statutory language (i.e., ‘‘generally
recognized’’) rather than the proposed
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term ‘‘consensus’’ because the revised
GRAS criteria that we are establishing in
§ 170.30 continue to use the statutory
language rather than the consensus
standard applied by the courts in
applying the statutory language to
specific situations. Using the statutory
language in both the GRAS criteria and
the requirement for the submission of a
narrative in a GRAS notice will
emphasize your burden to explain how
the data and information in the notice
regarding the safety of the notified
substance under the conditions of its
intended use satisfy the GRAS criteria.
See also Response 128, in which we
respond to comments recommending
that we clarify that the same standards
apply to a conclusion of GRAS status
regardless of whether the conclusion is
submitted to us as a GRAS notice or is
not submitted to us. As noted in
Response 128, we believe that the
provisions of the GRAS notification
procedure will be a useful resource to
any person who intends to use a
substance in food based on a conclusion
of GRAS status, regardless of whether
the conclusion of GRAS status is
submitted to us in a GRAS notice. In
developing any recommendations (e.g.,
in guidance) that would broadly apply
to any conclusion of GRAS status, it is
simpler to consistently use the same
regulatory text in both the GRAS criteria
and the submission requirements for a
GRAS notice.
(Comment 78) One comment notes
that industry has various options for
handling confidential information. For
example, confidential agreements are
commonly used instruments to help
maintain the confidentiality of
proprietary trade secret information,
and therefore qualified experts on GRAS
panels can have access to such
information if it is necessary for a
conclusion of GRAS status. The
comment asks us to require that
notifiers indicate whether qualified
experts (such as on the notifier’s GRAS
panel) had access to trade secrets when
they concluded that the substance is
safe under the conditions of its intended
use.
(Response 78) The rule establishes no
requirements specific to a GRAS panel.
However, we agree that it is appropriate
for a notifier to indicate whether
qualified experts (such as on the
notifier’s GRAS panel) who reviewed
the data and information supporting
safety had access to safety-related trade
secrets in reaching a conclusion that the
notified substance is safe under the
conditions of its intended use.
Therefore, we are requiring that a
notifier explain how there could be a
basis for a conclusion of GRAS status if
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qualified experts generally do not have
access to non-public safety-related data
and information (see § 170.250(e)). This
requirement applies to all non-public
safety-related data and information, not
just trade secret information, and is not
limited to non-public safety-related data
and information that are included in the
notice. As requested by the comment,
this requirement would apply if the
notifier provided non-public safetyrelated information to outside experts
(such as on a GRAS panel). As already
discussed, if a GRAS panel considers
non-public safety-related information
that a notifier does not include in a
GRAS notice, we also expect the notifier
to inform us that the GRAS panel had
access to such information, consistent
with the notifier’s signed statement that
the GRAS notice is a complete,
representative, and balanced submission
(see § 170.225(c)(9)) (see Response 58
and Response 69).
See also table 11 and table 15. The
rule also requires that a notifier state his
view as to whether any of the data and
information in Parts 2 through 7 of a
GRAS notice are exempt from disclosure
under the FOIA (see § 170.225(c)(8)) and
identify what specific data and
information in the notice are generally
available, and what specific data and
information in the notice are not
generally available (see § 170.250(a)(2)
and (d)). Collectively, the requirements
in §§ 170.225(c)(8) and (9) and
170.250(a)(2), (d), and (e) address the
underlying issue in the comment’s
request, i.e., that there must be a basis
for a conclusion of GRAS status if some
safety-related data and information that
a notifier assesses in his deliberations
are non-public (e.g., trade secret
information or otherwise are
confidential information), regardless of
whether the notifier shares such
information with a GRAS panel. If a
GRAS notice does not provide a basis
for a conclusion that the notified
substance is safe under the conditions of
its intended use without access to such
information, we would respond to the
notice with an ‘‘insufficient basis
letter.’’ If we respond with a ‘‘no
questions letter,’’ and later determine
that the GRAS notice was not
‘‘complete’’ (e.g., because it did not
describe unpublished reports of
investigations that are, or may appear to
be, inconsistent with the conclusion of
GRAS status), we may send the notifier
a subsequent letter regarding the
omission; such a letter would be readily
accessible to the public (§§ 170.265(c)
and 170.275(b)(2)).
(Comment 79) One comment suggests
that if the qualified experts are FDA
reviewers, an option might be for the
notifier to submit a ‘‘sanitized’’ version
of the GRAS notice, excluding nonpublic information, together with a
separate appendix to the GRAS notice
where the notifier would include
relevant trade secrets or confidential
information needed to support the
conclusion of GRAS status.
Alternatively, we could require that a
notifier submit two versions of the
submission: (1) A sanitized version that
excludes non-public information; and
(2) a more detailed version including
the confidential information. The
comment states that these options
would both allow our reviewers access
to the information and facilitate the
process of promptly making GRAS
notices available for public disclosure.
(Response 79) In enacting the GRAS
provision, Congress clearly
contemplated a process of concluding
that a food substance is GRAS under the
conditions of its intended use as an
alternative to submission of a food
additive petition to FDA and
establishment of a regulation
prescribing the conditions under which
the substance may be safely used. It
follows that the qualified experts who
evaluate the basis for a conclusion that
the notified substance is safe under the
conditions of its intended use must not
exclusively be ‘‘FDA’s experts’’ (such as
our scientific staff who evaluate GRAS
notices). The suggestion of this
comment that a notifier could rely
exclusively on evaluation by FDA
experts to support his view that there is
a basis for concluding that there is
consensus among ‘‘qualified experts’’ is
inconsistent with the GRAS provision in
section 201(s) of the FD&C Act, which
requires general recognition among
qualified experts. See also the
discussion in Response 70, in which we
explain our reasons for why we may
decide to decline to file a GRAS notice
that is accompanied by a separate file
containing data and information that
you view as non-public.
XVIII. Comments on Steps a Notifier
May Take Before We Respond to a
GRAS Notice
In the 2010 notice, we described
comments regarding steps you may take
before we respond to your GRAS notice
(see table 17). As noted in section
VIII.A, we are establishing a definition
for ‘‘amendment’’ in the rule (see
§ 170.203). In the following paragraphs,
we discuss additional comments
regarding the issues in table 17. Some of
these comments agree that the rule
should have such a provision. Other
comments ask us to clarify how such a
provision would operate in practice
(see, e.g., Comment 82) or suggest one
or more changes to the provision as we
described it in the 2010 notice (see, e.g.,
Comment 80, Comment 81, and
Comment 83). After considering these
comments, we are establishing two
provisions regarding steps you may take
before we complete our evaluation of a
GRAS notice. The first provision
specifies that you may submit a timely
amendment to your filed GRAS notice,
to update your GRAS notice or in
response to a question from us, before
we respond to your notice by letter (see
the regulatory text of § 170.260(a)). The
second provision specifies that you may
ask us to cease to evaluate your GRAS
notice as described in the 2010 notice,
with clarifications as a result of
comments (see the regulatory text of
§ 170.260(b)). One clarification is that
such a request does not preclude you
from submitting a future GRAS notice
with respect to the notified substance. A
second clarification is that we will send
you a letter informing you of our
decision regarding your request (see the
regulatory text of § 170.265(b)(3)).
TABLE 17—ISSUES IN THE 2010 NOTICE REGARDING STEPS YOU MAY TAKE BEFORE WE RESPOND TO YOUR GRAS
NOTICE
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Issue
No.
Description of our request for comment
3a ......
Whether to define ‘‘amendment’’ to mean any data or other information that you submit regarding a
filed GRAS notice before we respond to the notice.
Whether the final rule should explicitly provide that you may request in writing that we cease to
evaluate your GRAS notice at any time during our evaluation of that GRAS notice.
5 ........
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75 FR 81536 at 81538–81539.
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See section XXV.I for a discussion of
comments regarding steps you may take
before we respond to your GRAS notice
for a substance used in animal food, and
for our response to those comments.
A. Communicating With a Notifier
Before We Respond to a GRAS Notice
(Comment 80) Several comments note
that the proposed rule did not say that
we would contact a notifier, before we
issue our publicly available response, to
provide preliminary feedback regarding
our evaluation of a GRAS notice. One of
these comments asks us to include a
provision specifying that we may
communicate with the notifier about
any aspect of a notice while the notice
is pending. Some comments express
concern that a letter listing answerable
and nonsubstantive questions about a
GRAS notice could cause confusion and
misunderstanding in the marketplace,
particularly if additional information,
clarification, or amendment would
address our concerns.
(Response 80) We decline the request
to include a provision specifying that
we may communicate with you about
any aspect of a notice while your notice
is pending. As discussed in section
III.C.1 of CFSAN’s 2010 experience
document (Ref. 18), during the Interim
Pilot program CFSAN contacted several
notifiers to request clarification about
data and information in the notice
under the framework of existing
regulations governing meetings and
correspondence (§ 10.65(g)). It is not
necessary to duplicate the existing
procedures in § 10.65(g) in the
requirements for the GRAS notification
procedure.
We infer that this comment is
specifically asking us to require that we
contact you to provide preliminary
feedback before we respond to your
GRAS notice with an ‘‘insufficient basis
letter.’’ As discussed in section III.C.1 of
CFSAN’s 2010 experience document
(Ref. 18), our experience during the
Interim Pilot program demonstrates that
we are willing to engage in a dialog with
a notifier to clarify particular aspects of
a GRAS notice. As discussed in section
IV.H.4 of CFSAN’s 2010 experience
document (Ref. 18), our experience
during the Interim Pilot program also
demonstrates that we do not issue an
‘‘insufficient basis letter’’ with
‘‘nonsubstantive questions.’’ Although
we have issued ‘‘insufficient basis
letters’’ due to an overall poor quality of
a submission, to conserve resources our
practices have evolved so that we
generally do not file such submissions
as GRAS notices (see section XIX.A
regarding filing decisions and section
III.K of CFSAN’s 2010 experience
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document (Ref. 18)). Although we
expect to contact you when we have
questions, whether we intend to provide
you with an opportunity to submit an
amendment to a GRAS notice before
responding to the notice has been, and
will continue to be, a matter committed
to our discretion.
In the following paragraphs, we
discuss some key factors we intend to
consider regarding the purpose of our
contact with you regarding your GRAS
notice, particularly with respect to
whether we intend to provide you with
an opportunity to submit an amendment
to a GRAS notice. These factors are: (1)
Whether our questions can be addressed
by a timely, clarifying amendment; (2)
whether our evaluation identifies a
safety concern; and (3) whether we
question whether GRAS criteria are
satisfied, even if our evaluation does not
identify a safety concern. See also the
discussion in Response 85 regarding
factors that could lead us to decline to
file a submission as a GRAS notice,
rather than to file it for our evaluation
of your view that the notified substance
is GRAS under the conditions of its
intended use and issue an ‘‘insufficient
basis letter.’’
We agree that an ‘‘insufficient basis
letter’’ listing answerable questions
about a GRAS notice could cause
confusion and misunderstanding in the
marketplace, particularly if additional
information, clarification, or
amendment would address our
concerns. Section III.C.1 of CFSAN’s
2010 experience document provides
examples of circumstances where
CFSAN contacted a notifier and
expected that the information
exchanged between CFSAN and the
notifier would clarify, rather than
substantively amend, the original
notice. We intend to continue
contacting notifiers in such
circumstances. By ‘‘clarify, rather than
substantively amend,’’ we mean that the
amendment would add or modify
specific sections in the notice, not that
the clarifying information would
necessarily be nonsubstantive in nature.
For example, as discussed in Response
96 during the Interim Pilot program we
contacted notifiers when the notice
contained insufficient information about
dietary exposure and when the notice
contained insufficient information to
adequately identify the substance. We
did so because it is efficient, for us as
well as the notifier, to bring a GRAS
notice to closure with a ‘‘no questions
letter’’ when it is likely that a timely,
clarifying amendment would resolve
our questions. For example, it is more
efficient for us to bring a GRAS notice
to closure while our reviewers are
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already immersed in the substantive
evaluation of the notice, rather than to
issue an ‘‘insufficient basis letter’’ and
begin the evaluation process anew when
the notifier addresses the questions in a
new GRAS notice. See section XVIII.B
for a discussion of what we mean by a
‘‘timely’’ amendment.
If we file your submission as a GRAS
notice and our evaluation of the
available data and information identifies
a safety concern, the purpose of our
contact with you would depend on
whether the safety concern could be
addressed by a timely, clarifying
amendment. For example, in some cases
the available data and information may
support safety only under modified
conditions of use relative to the
conditions of use described in your
GRAS notice, and our contact with you
would focus on your opportunity to
address the safety concern through a
timely amendment specifying modified
conditions of use. However, if we
believe that the safety concern could not
be addressed through a timely,
clarifying amendment or by resubmission of a new GRAS notice (e.g.,
after studies are conducted to address
the safety concern), we likely would
contact you to make you aware of our
concerns and then issue an ‘‘insufficient
basis letter’’ that clearly and fully
articulates our reasons for that safety
concern, including the full context of
the risk to human or animal health.
If we file your submission as a GRAS
notice and find that your narrative does
not support a conclusion of GRAS
status, even if the available data and
information support your view that the
notified substance is safe under the
conditions of its intended use (e.g.,
because data and information that are
necessary to establish safety are not
generally available), the purpose of our
contact with you would focus on your
opportunity to address the regulatory
status of the notified substance. For
example, it may be possible for you to
submit a new GRAS notice after
publishing applicable data and
information and allowing sufficient time
to allow the expert scientific community
to access the published information.
Alternatively, it may be more
appropriate for you to consider the
notified substance as a food additive
under the conditions of its intended use,
and to make a premarket submission
such as a food additive petition. For
examples of circumstances leading to
the options for addressing questions
about the regulatory status of the
substance when we have not identified
a safety concern, see section III.A.4 of
CFSAN’s 2010 experience document
(Ref. 18). Any letter we issue would
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include our view of the regulatory status
of the substance at the time that we
issued the letter, based on the generally
available data and information at that
time.
B. Submitting an Amendment
Comments support adding a provision
to clarify that you may submit an
amendment to your GRAS notice and,
thus, we are establishing a provision
specifying that you may submit a timely
amendment to your filed GRAS notice
(§ 170.260(a)). In some cases, you would
submit such an amendment after we
contact you to discuss our questions
about your GRAS notice. (See the
discussion in Response 80 regarding
contacting a notifier.) In other cases, you
may conclude that it is appropriate to
submit an amendment to update your
GRAS notice on your own initiative,
e.g., if new data and information about
the notified substance under the
conditions of its intended use become
available after we file your submission
as a GRAS notice. Depending on the
circumstances, you could then decide to
explain your view that the new data and
information do not alter the basis for
your conclusion of GRAS status;
alternatively, you could decide to ask us
to cease to evaluate your GRAS notice
while you evaluate the impact of the
new data and information on the GRAS
status of the notified substance under
the conditions of its intended use (see
§ 170.260(b)).
By timely, we mean that you submit
your amendment in a timeframe that
provides us with sufficient time to
evaluate it before we respond to your
GRAS notice. Given that the rule
requires us to end our evaluation and
respond to your GRAS notice within
180 days, with an extension of up to an
additional 90 days on an as needed
basis § 170.265(b)(1)), we reserve the
right to not consider your amendment if
you submit it so late in our evaluation
that it would impact our ability to
respond within our established
timeframes. Therefore, as a companion
provision, the rule also provides that we
will consider any timely amendment
that you submit to a filed GRAS notice,
to update your GRAS notice or in
response to a question from us, before
we respond to you by letter based on
our evaluation of your notice if we deem
that doing so is feasible within the
established timeframes (see
§ 170.265(a)(4)). If we deem that
considering your amendment is not
feasible within the established
timeframes, we will inform you that we
are not considering your amendment.
See also the discussion in Response
101, which emphasizes that the role of
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an amendment is to clarify questions
that we have about your conclusion of
GRAS status rather than to substantively
amend the GRAS notice.
C. Notifier’s Request That We Cease To
Evaluate a GRAS Notice
(Comment 81) Some comments ask us
to make public the reason for a notifier’s
request that we cease to evaluate a
notice. One comment asks that any new
information, or questions about the
scientific consensus about whether a
substance is safe, be made clear to the
public as well as FDA. Another
comment expresses concern that
companies ask FDA to cease evaluations
of their GRAS notices with ‘‘alarming
frequency.’’
(Response 81) We are establishing a
provision specifying that a notifier may
ask us to cease to evaluate his GRAS
notice (see § 170.260(b)). As a
companion provision, we are specifying
that if a notifier asks us to cease to
evaluate a GRAS notice, we will send
the notifier a letter informing the
notifier of our decision regarding that
request (see § 170.265(b)(3)). As
discussed in section III.E of CFSAN’s
2010 experience document (Ref. 18),
during the Interim Pilot program
CFSAN’s ‘‘cease to evaluate letters’’
generally repeated any reason specified
in a request letter, but may not have
otherwise described the reasons
underlying the request. If a notified
substance is marketed even though we
issue a ‘‘cease to evaluate letter,’’ there
could be confusion about the GRAS
status of the notified substance even
when the conditions of use in the
marketplace differ from the notified use
that was the subject of the ‘‘cease to
evaluate letter.’’ For example, a notifier
could ask us to cease to evaluate a
GRAS notice because we identified a
safety concern about the specified use
level of the notified substance in food
products, and then decide to market the
substance at a lower use level than the
level specified in the GRAS notice,
where we would no longer have that
concern. In addition, as discussed in the
proposed rule we proposed to make all
response letters readily accessible to the
public because such a system will
properly underscore a notifier’s
acceptance of responsibility for the
conclusion of GRAS status, and a GRAS
notice that is submitted to us is a public
notice (62 FR 18938 at 18953). A ‘‘cease
to evaluate letter’’ signals that a
submitted GRAS notice does not
provide an adequate basis for a
conclusion that the notified substance is
GRAS under the conditions of its
intended use, even though we do not
issue an ‘‘insufficient basis letter.’’
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Given the public nature of a GRAS
notice, it is appropriate for the reasons
leading to a ‘‘cease to evaluate letter’’ to
also be public. Therefore, as of October
17, 2016, we intend to change this
practice and increase transparency by
describing the reasons leading to any
‘‘cease to evaluate letter.’’
Table 1 in CFSAN’s 2010 experience
document (Ref. 18) shows that
approximately 16 percent of GRAS
notices that CFSAN responded to during
the 12-year period spanning 1998
through 2009 came to closure when the
notifier asked us to cease to evaluate a
GRAS notice. Table 1 in CFSAN’s 2010
experience document also shows that
CFSAN issued equal numbers of ‘‘cease
to evaluate letters’’ and ‘‘insufficient
basis letters’’ during the years 1998
through 2002 (i.e., 16 ‘‘cease to evaluate
letters’’ and 16 ‘‘insufficient basis
letters’’). However, during the years
2003 through 2009 CFSAN issued 31
‘‘cease to evaluate letters,’’ but no
‘‘insufficient basis letters.’’ In addition,
table 1 in CFSAN’s 2016 experience
document (Ref. 19) shows that during
the years 2010 through 2015 CFSAN
issued 48 ‘‘cease to evaluate letters’’ but
only one ‘‘insufficient basis letter.’’ We
acknowledge that there has been a
distinct shift between the ratio of the
number of ‘‘cease to evaluate letters’’
compared to the number of ‘‘insufficient
basis letters’’ issued during the years
1998 through 2002 and the
corresponding ratio for letters issued
during the years 2003 through 2015. We
consider that the data in the experience
document demonstrate an evolving
practice in which CFSAN has declined
to file some submissions as GRAS
notices when the notice lacks much of
the required data and information
necessary for us to evaluate a notifier’s
view that the notified substance is
GRAS under the conditions of its
intended use (see Response 85). In
addition, such a frequency demonstrates
that CFSAN has been willing to contact
notifiers with questions about a
conclusion that the notified substance is
GRAS under the conditions of its
intended use. As discussed in Response
80, when our questions cannot be
addressed by a timely amendment,
contacting the notifier provides the
notifier an opportunity to re-submit a
new GRAS notice or other regulatory
submission (such as a food additive
petition) that addresses our questions.
As discussed in section III.E of
CFSAN’s 2010 experience document
(Ref. 18), in many cases a notifier who
received a ‘‘cease to evaluate letter’’
resubmitted a new GRAS notice, and
CFSAN responded with a ‘‘no questions
letter.’’ For many GRAS notices, the
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questions we raised and discussed with
the notifier clearly addressed issues
other than a fundamental safety
concern. For example, some of the
letters that CFSAN lists in section III.E
of its 2010 experience document
provide reasons such as preparing a new
notice that will not contain any
confidential business information and
that will clarify that the statutory basis
for the conclusion of GRAS status is
through scientific procedures; needing
to revise an estimate of dietary
exposure; and clarifying and providing
additional information for a new notice.
However, CFSAN only made these
reasons transparent to the public
because the notifier chose to provide
these reasons in his request that we
cease to evaluate the GRAS notice. In
other circumstances, the public had no
way to know what the issue was until
we responded to the resubmitted notice.
We intend to continue to contact a
notifier to discuss our questions, and
provide an opportunity for the notifier
to ask us to cease to evaluate the GRAS
notice (e.g., so that the notifier can
submit a new GRAS notice that
addresses the issues). However, we also
intend to briefly describe these issues in
a ‘‘cease to evaluate letter’’ that follows
that contact. As CFSAN did during the
Interim Pilot program, we intend to
consider any reasons a notifier provides
for the request, and to include those
reasons in our ‘‘cease to evaluate letter.’’
If, however, we conclude that a
notifier’s explanation does not
adequately describe the reasons leading
to a ‘‘cease to evaluate’’ request, we
intend to explain the reasons for ceasing
to evaluate the notice from our point of
view. Doing so will both ensure clear
communication about the reasons and
make the reasons transparent to the
public.
As discussed in Response 80, if we
identify a safety concern and believe
that the safety concern could not be
addressed through a timely, clarifying
amendment, by re-submitting a new
GRAS notice, or by submitting another
premarket submission (such as a food
additive petition), we likely would issue
an ‘‘insufficient basis letter’’ even
though we would have contacted the
notifier to discuss our concerns.
Asking us to cease to evaluate a GRAS
notice does not guarantee that we will
honor that request. Depending on the
circumstances, we may decide to
decline the request and instead respond
with an ‘‘insufficient basis letter’’;
depending on the time remaining
between when we receive the request
and the timeframes by which we must
respond to the GRAS notice, we may
either send the notifier a separate letter
declining the request, or note in the
‘‘insufficient basis letter’’ that we had
declined the request. See the discussion
in section III.C.1 of CFSAN’s 2010
experience document (Ref. 18) for an
example of a situation in which CFSAN
responded with an ‘‘insufficient basis
letter’’ after a notifier asked CFSAN to
cease to evaluate its GRAS notice,
submitted a new GRAS notice, and
asked CFSAN to cease to evaluate the
second submitted GRAS notice.
(Comment 82) One comment asks us
to clarify that a notifier’s request that we
cease to evaluate a GRAS notice would
be without prejudice for future
submissions.
(Response 82) The final provision
specifies that your request that we cease
to evaluate a GRAS notice does not
preclude you from submitting a future
GRAS notice with respect to the notified
substance.
(Comment 83) One comment asks us
to specify that, if feasible, the files could
be returned to the notifier at the
notifier’s expense.
(Response 83) We decline this
request. As discussed in the 2010 notice
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(75 FR 81536 at 81538–81539), our
current regulations regarding public
information stipulate that no person
may withdraw records submitted to
FDA (see § 20.29), and those regulations
will apply to any GRAS notice that we
receive. To make this clear, the
provision we are establishing in the
final rule provides an opportunity for
you to ask us to ‘‘cease to evaluate’’ a
GRAS notice rather than ‘‘withdraw’’ a
GRAS notice.
(Comment 84) Some comments ask us
to specify that if a notifier requests that
we cease to evaluate a submitted GRAS
notice, such notices will remain in our
files and will be available for public
disclosure.
(Response 84) See § 20.29 and the
discussion of Issue 5 in the 2010 notice
(75 FR 81536 at 81538–81539). If a
notifier asks us to cease to evaluate a
submitted GRAS notice, the notice will
remain in our files and will be available
for public disclosure in accordance with
part 20. It is not necessary to repeat the
provisions of § 20.29 in the GRAS
notification procedure.
XIX. Comments on What We Will Do
With a GRAS Notice
We proposed that: (1) We would
acknowledge receipt of a notice, within
30 days of receipt, by informing the
notifier in writing of the date on which
the notice was received (proposed
§ 170.36(d)); (2) we would respond to
the notifier in writing within 90 days of
receipt of the notice (proposed
§ 170.36(e)); and (3) a copy of any
subsequent letter that we issued
regarding a GRAS notice would be
readily accessible for public review and
copying (proposed § 170.36(f)(2)(iii)). In
the 2010 notice, we asked for comment
on issues relating to what we will do
with a GRAS notice as shown in table
18.
TABLE 18—ISSUES IN THE 2010 NOTICE REGARDING WHAT WE WILL DO WITH A GRAS NOTICE
Issue
No.
Description of our request for comment
12 ......
Whether we should make explicit the process by which we make a filing decision, including the factors we would use to determine whether to file a submission as a GRAS notice.
Whether we should retain a set timeframe for us to respond to a GRAS notice, and, if so, whether it
should be 90 days or another timeframe.
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14 ......
In the following sections, we discuss
comments on what we will do when we
receive a GRAS notice. After
considering these comments, we are
establishing requirements in § 170.265
for what we will do when we receive a
GRAS notice as shown in table 19, with
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Reference
editorial, clarifying, and conforming
changes as shown in table 29. Table 19
identifies changes we made relative to
the proposed rule or the description in
the 2010 notice other than the editorial,
clarifying, and conforming changes
shown in table 29 and the additional
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75 FR 81536 at 81541.
75 FR 81536 at 81542.
editorial changes associated with the
redesignation of proposed § 170.36(d),
(e), and (f)(2)(iii) as § 170.265. See
section XXV.I for a discussion of
comments specific to a filing decision
for a substance used in animal food.
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TABLE 19—FINAL REQUIREMENTS FOR WHAT FDA WILL DO WITH A GRAS NOTICE
Final designation in
the regulatory text
(§ )
Proposed
designation in the
regulatory text
(§ )
170.265(a)(1) .........
N/A .........................
12
170.265(a)(2) .........
170.36(d) ...............
12
170.265(a)(3) .........
N/A .........................
12
170.265(a)(4) .........
N/A .........................
3a
170.265(b)(1) .........
170.36(e) ...............
14
170.265(b)(2) .........
N/A .........................
14
170.265(b)(3) .........
N/A .........................
5
170.265(c) ..............
170.36(f)(2)(iii) .......
N/A
Issue No. in
the
2010 notice
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A. Filing Decision
(Comment 85) One comment asks for
greater refinement, clarity, and
transparency when we decline to file a
GRAS notice. Some comments ask us to
communicate any questions or concerns
that could be quickly addressed upon
submission of a GRAS notice. Another
comment asks us to use specific criteria
for a ‘‘decline to file’’ determination
when format and general categories are
adequate. Another comment states that
an explicit process for how we will
make a filing decision need not be
detailed ‘‘in the public domain’’ even
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We will conduct an initial evaluation of
your submission to determine whether to file it as a GRAS notice for evaluation of your view that the notified
substance is GRAS under the conditions of its intended use.
If we file your submission as a GRAS
notice, we will send you a letter that
informs you of the date of filing.
If we do not file your submission as a
GRAS notice, we will send you a letter that informs you of that fact and
provides our reasons.
We will consider any timely amendment
that you submit to a filed GRAS notice, to update your GRAS notice or
in response to a question from us,
before we respond to you by letter
based on our evaluation of your notice if we deem that doing so is feasible within the established timeframes. If we deem that considering
your amendment is not feasible within
the established timeframes, or if we
have granted your request to cease
to evaluate your notice, we will inform
you that we are not considering your
amendment.
Within 180 days of filing, we will respond to you by letter based on our
evaluation of your notice. We may extend the 180 day timeframe by 90
days on an as needed basis.
If we extend the timeframe, we will inform you of the change in writing as
soon as practicable but no later than
within 180 days of filing.
If you ask us to cease to evaluate your
GRAS notice, we will send you a letter informing you of our decision regarding your request.
If circumstances warrant, we will send
you a subsequent letter about the notice.
though it would be beneficial to the
notifier.
Another comment asks us to specify
the criteria that we use to decide to
provide verbal feedback to a notifier
(e.g., by telephone) rather than send the
notifier a letter informing the notifier
that we have declined to file a
submission as a GRAS notice. This
comment expresses concern that our
refusal to explain the problem in a letter
could be interpreted to mean that we
have safety concerns. This comment
asserts that a process in which we
neither provide specific guidance, nor
provide written feedback, when we
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2010 notice
Description
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N/A.
N/A.
Clarifies that we would inform you by
letter if we do not file your submission
as a GRAS notice.
Clarifies that we will only consider an
amendment if we deem that doing so
is feasible within the established timeframes.
• Specifies that the timeframe for our
response is 180 days, rather than 90
days.
• Provides for an extension of our evaluation by 90 days on an as needed
basis.
Provides that we will inform you if we
extend the timeframe for our response.
Companion change in light of new regulatory text (in § 170.260(b)) expressly
providing that you may ask us to
cease to evaluate your GRAS notice.
Clarifies that we may send a subsequent letter, in addition to specifying
under the public disclosure provisions
of the rule that such a letter would be
readily available to the public (see
§ 170.275(b)(2)).
decline to file a submission as a GRAS
notice would both discourage voluntary
submissions of GRAS conclusions from
industry and conflict with GAO’s
recommendations (in their 2010 report)
that we should take steps to increase our
awareness of independent conclusions
of GRAS status.
(Response 85) These comments raise
a number of issues regarding the
importance of a written communication
from us to a notifier when we decline
to file a submission as a GRAS notice,
including transparency and the
potential that lack of a written
explanation for why we declined to file
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a submission as a GRAS notice could
lead to suppositions, such as whether
we have safety concerns. To address
these issues, the final rule provides that
if we do not file a submission as a GRAS
notice, we will send the notifier a letter
that informs the notifier of that fact and
provides our reasons for not filing the
submission as a GRAS notice (see
§ 170.265(a)(3)). We would not place
that letter ‘‘in the public domain’’ by
including it in our publicly available
Inventory of GRAS Notices, because the
submission had not been filed as a
GRAS notice and, thus, there would be
no entry where we would place the
letter. However, whether the letter
would be releasable in response to a
FOIA request would be a case-by-case
determination based on the contents of
the letter and the provisions of part 20.
We are not specifying in the
regulatory text the factors that could
lead us to decline to file a submission
as a GRAS notice, because the factors
that apply to a particular GRAS notice
may be very specific to that notice.
Importantly, a GRAS notice presents an
opportunity for a notifier to inform us
about a conclusion of GRAS status
rather than an opportunity for a notifier
to test a hypothesis that there is a
sufficient basis to reach a conclusion of
GRAS status. If our initial evaluation of
a submission demonstrates that it lacks
much of the required data and
information necessary for us to evaluate
the notifier’s view that the notified
substance is GRAS under the conditions
of its intended use, our current practice
is to decline to file it as a GRAS notice
(see § 170.265(a)(3)). By declining to file
a submission as a GRAS notice, we
would both conserve our own resources
and provide the notifier an opportunity
to submit a new GRAS notice, that
contains appropriate data and
information and an adequate narrative,
rather than move forward knowing that
an amendment necessary for us to
evaluate the notifier’s view that the
notified substance is GRAS under the
conditions of its intended use would be
so substantive as to make the original
submission largely irrelevant. For
additional examples of factors we have
considered in determining whether to
file a submission as a GRAS notice, see
the examples we provided in the 2010
notice (75 FR 81536 at 81541), the
discussion of filing decisions in section
III.K of CFSAN’s 2010 experience
document (Ref. 18), Response 48, and
Response 70. As discussed in Response
152, CVM intends to consider the same
factors that CFSAN considers regarding
whether to file a submission as a GRAS
notice.
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(Comment 86) In the 2010 notice, we
explained that we may decide to
respond to a submission as general
correspondence, rather than file it as a
GRAS notice, if the subject of the
submission is: (1) Already authorized
for use under our regulations; or (2) a
mixture of substances that are already
authorized for use under our
regulations. One comment asks us to
clarify how we would determine that
the use of a substance is authorized for
use under our regulations, with respect
to the similarity of factors such as: (1)
The substance; (2) the intended
conditions of use of the substance,
including food categories and use levels;
and (3) the manufacturing process.
(Response 86) We decline this request
because it is overly broad. We do not
have a ‘‘formula’’ that would apply in
all circumstances. Just as the factors that
apply to a particular GRAS notice may
be very specific to that notice, the
factors that would apply in determining
whether the intended conditions of use
of a notified substance are already
authorized by our regulations may be
very specific to that substance.
However, with regard to similarities in
the manufacturing process, we likely
would apply the same factors that we
have advised industry to apply when
assessing the effects of significant
manufacturing process changes on the
safety and regulatory status of food
ingredients (Ref. 6).
We note that we also may decide to
respond to a submission as general
correspondence, after communicating
with the submitter as appropriate, rather
than file it for evaluation as a GRAS
notice, if the subject of the submission
is: (1) Already the subject of a GRAS
notice, and we have responded to that
GRAS notice with a ‘‘no questions
letter’’; or (2) a mixture of substances
that already are the subject of GRAS
notices, and we have responded to those
GRAS notices with ‘‘no questions
letters.’’ In contrast to the statutory
provisions for the FCN program (section
409(h) of the FD&C Act), there is no
provision in the FD&C Act providing
exclusivity for a notifier for the use of
a substance on the basis that it is GRAS
under the conditions of its intended use.
(Comment 87) One comment asks us
to conduct a preliminary evaluation of
a GRAS notice to determine whether the
notice appears to be inadequate because
the intended conditions of use of the
notified substance raise ‘‘general
policy’’ issues.
(Response 87) It is not clear what the
comment means by ‘‘general policy’’
issues. However, we note that we would
not file a submission as a GRAS notice
if the intended conditions of use of the
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55013
notified substance are not eligible for
classification as GRAS because, for
example, the intended conditions of use
are excepted from the definition of
‘‘food additive’’ in section 201(s) of the
FD&C Act (and thus, from the GRAS
provision included in that definition of
‘‘food additive’’). See, for example, the
exception for a color additive in section
201(s)(3) of the FD&C Act, for a dietary
ingredient intended for use in a dietary
supplement in section 201(s)(6) of the
FD&C Act, and for a new animal drug
in section 201(s)(5) of the FD&C Act.
(Comment 88) Some comments ask us
to contact the notifier when our initial
evaluation of a GRAS notice raises
questions, and provide the notifier with
an opportunity to withdraw the notice
without prejudice before we begin a
substantive evaluation of the notice.
(Response 88) We agree that our
decision to not file a submission as a
GRAS notice would be without
prejudice to a future submission of a
GRAS notice for the notified substance.
However, see Response 70, Response
112, and the discussion in the 2010
notice at 75 FR 81536 at 81539. Just as
a filed GRAS notice is available for
public disclosure subject to the
procedures established in part 20, a
submission that you send to us is a
record that is available for public
disclosure subject to the procedures
established in part 20, regardless of
whether we file that submission as a
GRAS notice. Thus, you cannot
‘‘withdraw’’ a submission from our files
after you send it to us.
(Comment 89) One comment asks
whether ‘‘substantial equivalence’’
considerations are linked to ‘‘decline to
file’’ decisions or play a dominant role
in ‘‘decline to file’’ decisions. This
comment also asks us to issue a letter to
the notifier explaining the basis for a
‘‘decline to file’’ decision if ‘‘substantial
equivalence’’ is the reason.
(Response 89) As discussed in section
IV.N of CFSAN’s 2010 experience
document (Ref. 18), several GRAS
notices filed during the Interim Pilot
program relied, in part, on the concept
of ‘‘substantial equivalence’’; in each of
the listed examples CFSAN had no
questions about the notifier’s conclusion
of GRAS status. As discussed in
Response 21, whether, and to what
extent, similarity between two
substances could support a conclusion
of GRAS status depends on many
situation-specific variables. Thus, it
would be the complete evaluation
process, rather than the initial
evaluation that we conduct as part of a
filing decision, that would determine
whether a GRAS notice that relies on
the concept of ‘‘substantial equivalence’’
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provides a basis for a conclusion of
GRAS status. As discussed in Response
85, the final rule provides that if we do
not file a submission as a GRAS notice,
we will send the notifier a letter that
informs the notifier of that fact and
provide our reasons for not filing the
submission as a GRAS notice (see
§ 170.265(a)(3)); if problems with a
notifier’s use of the concept of
‘‘substantial equivalence’’ play a role in
our decision to not file a submission as
a GRAS notice, we intend to say so.
B. Our Response to a GRAS Notice
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1. Administrative Content of Our
Response to a GRAS Notice
(Comment 90) Several comments
address the administrative content of a
letter that responds to a GRAS notice. In
general, these comments ask us to
include the following items in the
response letter: (1) Name and address of
the notifier; (2) the date of our receipt
of the notice; (3) the common or usual
name of the notified substance; and (4)
the applicable conditions of use of the
notified substance. One comment states
that use of a standard format and
language in our letters would be
administratively efficient.
(Response 90) We agree that a
standard format and language in our
letters would be administratively
efficient and that the administrative
features suggested by these comments
are appropriate to include in our
response letter. During the Interim Pilot
program, we both developed a standard
format and language for our response
letters and included the administrative
features suggested by these comments
(see section III.H.1 of CFSAN’s 2010
experience document (Ref. 18)). We
intend to continue incorporating these
features in letters issued under the final
rule. However, as discussed in Response
51, the final rule requires that you
provide the name of the notified
substance, using an appropriately
descriptive term, rather than the
‘‘common or usual name’’ of the notified
substance (see § 170.225(c)(3)).
Therefore, CFSAN’s response letters
will include an appropriately
descriptive term for the notified
substance provided in a GRAS notice
submitted to CFSAN. See section XXV.C
regarding the name of the notified
substance provided in a GRAS notice
submitted to CVM.
2. Substantive Content of Our Response
to a GRAS Notice
(Comment 91) Several comments note
that the proposed rule did not specify
what we would say in a letter
responding to a GRAS notice and ask us
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to include in the final rule the specific
language for the response letter,
particularly when we do not raise any
questions about the notifier’s conclusion
of GRAS status. Some comments assert
that a notifier who invests resources in
a GRAS notice deserves a response that
is standardized and predictable and will
not change as personnel changes occur.
(Response 91) See table 1. During the
Interim Pilot program we developed
three categories of response letter: (1)
‘‘No questions letter’’; (2) ‘‘insufficient
basis letter’’; and (3) ‘‘cease to evaluate
letter.’’ As discussed in sections IV.H.1
through IV.H.7 of CFSAN’s 2010
experience document (Ref. 18), these
letters include some standard
information that is consistent across
those letters, such as opening and
closing paragraphs using a standard
format, and administrative information
(e.g., the date of our receipt of the GRAS
notice). They also include unique
features that depend upon the
circumstances, such as labeling issues
and whether the use of the substance
could require a color additive listing.
The content of the three categories of
response letter has evolved over time,
and may continue to evolve. In addition,
it is possible that in the future a
response to a GRAS notice may not fit
squarely within one of the current
categories of response letter. Therefore,
the final rule continues to specify that
we will respond to a GRAS notice but
does not specify any detail about the
nature of the response.
(Comment 92) Several comments
address the content of a ‘‘no questions
letter.’’ These comments ask that a ‘‘no
questions letter’’ be clear and definitive,
provide clear assurance that we
recognize the GRAS status of the
substance under the conditions of its
intended use, have some regulatory
significance, and be as affirmative as
possible. Some of these comments note
that our statements in the proposed rule
(62 FR 18938 at 18950) indicated that
we would evaluate a GRAS notice to
determine whether there is a sufficient
basis for the notifier’s conclusion of
GRAS status and suggest that our
response to a GRAS notice could reflect
those statements. Comments also
suggest the following specific
statements that could be included in a
‘‘no questions letter’’:
• ‘‘FDA at this time does not question
your determination that the notified
use(s) of this substance is (are)
Generally Recognized as Safe.’’
• ‘‘The Agency finds that there is
substantial evidence supporting both
the safety of the intended uses of the
substance and the fact that this safety is
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generally known and accepted by
qualified experts.’’
• ‘‘The notice provides a sufficient
basis for the notifier’s determination
that the substance is GRAS for its
intended use.’’
(Response 92) See table 1 for the
typical text of a ‘‘no questions letter’’
that we issued during the Interim Pilot
program. At this time, we intend to
continue including such text in our ‘‘no
questions letters.’’ We agree that the
regulatory significance of a ‘‘no
questions letter’’ should be clear. As
shown in table 1, during the Interim
Pilot program a typical ‘‘no questions
letter’’ made clear that: (1) It is the
information that is provided by the
notifier that forms the basis for our
response, and that the notifier (rather
than FDA) is responsible for the
conclusion of GRAS status; and (2) our
response must be considered in context
based on the knowledge and
information available to us at a point in
time, because scientific knowledge and
information about a particular
ingredient can evolve and sometimes
change over time.
The typical text of a ‘‘no questions
letter’’ issued during the Interim Pilot
program is similar to the specific
suggestion of one comment (i.e., FDA at
this time does not question your
determination that the notified use of
this substance is GRAS), except that
under the final rule we will use the term
‘‘conclusion’’ rather than
‘‘determination.’’ We disagree that a ‘‘no
questions letter’’ should state that we
‘‘find’’ that there is substantial evidence
supporting both the safety of the
intended conditions of use of the
notified substance and the fact that this
safety is generally known and accepted
by qualified experts; a GRAS notice
reflects the conclusion of the notifier,
not a finding by FDA. Likewise, we
disagree that a ‘‘no questions letter’’
should state that a notice ‘‘provides a
sufficient basis’’ for the notifier’s
conclusion that the notified substance is
GRAS under the conditions of its
intended use; the phrase ‘‘providing a
sufficient basis’’ would imply that we
are taking responsibility for the
notifier’s conclusion of GRAS status.
As discussed in Response 41, we are
replacing the term ‘‘determination’’ with
‘‘conclusion,’’ and referring to a
‘‘conclusion of GRAS status’’ rather than
to a ‘‘GRAS determination,’’ throughout
the regulatory text for the GRAS
notification procedure. We intend to
modify the typical text of our response
letters to refer to the ‘‘notifier’s
conclusion’’ (rather than the ‘‘notifier’s
determination’’) in letters issued under
the final rule (see table 20). We also
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intend to specify that we have not
affirmed the GRAS status of the notified
substance under the conditions of its
intended use, rather than to specify that
we have not made our own
determination. However, as noted in
section II.B, we intend to adapt our
practices, consistent with the provisions
of this rule, as circumstances warrant
and as necessary to administer the
GRAS notification program consistent
with appropriate public health policy,
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current scientific information, our
available resources, and the scientific
and regulatory issues raised by specific
GRAS notices. Thus, the text shown in
table 20 is for illustrative purposes only
and could evolve over time.
TABLE 20—CATEGORIES OF LETTERS RESPONDING TO A GRAS NOTICE UNDER THE FINAL RULE
Category of response letter
Typical text of for a response as modified to incorporate terms used in the rule
‘‘No questions letter’’ .......................
Based on the information provided by the notifier, as well as other information available to FDA, the Agency has no questions at this time regarding the notifier’s conclusion that the notified substance is GRAS
under the conditions of its intended use. By this letter, however, the Agency has not affirmed the GRAS
status of the notified substance under the conditions of its intended use in accordance with 21 CFR
170.35. As always, it is the continuing responsibility of the notifier to ensure that food ingredients that
the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.
FDA has evaluated the data and information in the GRAS notice as well as other available information.
The notice does not provide a sufficient basis for a conclusion that the notified substance is GRAS
under the conditions of its intended use.
In correspondence dated [month, day, year], you asked that we cease to evaluate your GRAS notice. We
ceased to evaluate your GRAS notice, effective the date we received your correspondence.
‘‘Insufficient basis letter’’ .................
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‘‘Cease to evaluate letter’’ ..............
(Comment 93) One comment suggests
that a written response need not assess
the quality of the submission but rather
could acknowledge whether the notice
was complete in addressing all key
issues.
(Response 93) We disagree that we
could acknowledge whether a notice is
‘‘complete’’ without assessing the
quality of the submission. Providing a
basis for whether the data and
information regarding the safety of a
substance under the conditions of its
intended use satisfy GRAS criteria is not
a matter of whether there is ‘‘something
behind each tab.’’ It would not be
appropriate, for example, for us to
acknowledge that a GRAS notice is
‘‘complete’’ because it included the
narrative required by Part 6 of a GRAS
notice without assessing the adequacy
of the narrative. Whether a notice is
‘‘complete’’ in addressing all key issues
depends on the nature and quality of the
submitted data and information.
(Comment 94) Some comments ask
that a ‘‘no questions letter’’ qualify that
we have not affirmed that the intended
conditions of use of the notified
substance are GRAS. Other comments
ask that a ‘‘no questions letter’’ qualify
that we have not conducted a
substantive review.
(Response 94) We agree that a ‘‘no
questions letter’’ should be clear that we
have not affirmed that the substance is
GRAS under the conditions of its
intended use. See table 20.
However, we disagree that a ‘‘no
questions letter’’ should state that we
did not conduct a substantive review of
the GRAS notice. See Response 25. Our
evaluation of a GRAS notice is a
substantive evaluation of the notifier’s
basis for concluding that the intended
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conditions of use of the notified
substance are safe and the criteria for
GRAS status are satisfied. In addition, as
circumstances warrant, we evaluate
information that is not included in the
notice but is otherwise available to us
(see section IV.G of CFSAN’s 2010
experience document (Ref. 18)).
(Comment 95) Some comments ask
that a ‘‘no questions letter’’ include a
positive statement that we have not
identified a problem with the notice
because finished food producers have
been reluctant to use a substance
without such documentation. These
comments both assert that the only
alternative available to manufacturers
whose customers require such a positive
statement would be to seek food
additive approval for an ingredient and
maintain that such approval is
unnecessary from a legal perspective.
(Response 95) Consistent with the
request of these comments, we intend to
continue including a statement that we
‘‘have no questions at this time’’ (see
table 1 and table 20). Whether a
manufacturer’s customer requires a
regulation prescribing the conditions
under which a substance may be safely
used in food, when there is a basis for
concluding that the substance is GRAS
under the conditions of its intended use,
is a business matter between the
manufacturer and the customer. If the
manufacturer submits a food additive
petition and we find, based on the data
and information submitted in the
petition, that the intended conditions of
use of the substance are safe, we would
issue a regulation prescribing the
conditions under which the food
additive may be safely used.
(Comment 96) Several comments
address the specific content of an
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‘‘insufficient basis letter’’ and ask us to
be specific about any deficiencies that
we identify in the notice. Some
comments assert that an ‘‘insufficient
basis letter’’ must clearly distinguish
between deficiencies that relate to safety
and those that relate to a technical
matter, such as the level of the
substance that is needed to accomplish
the intended technical effect. One
comment asks us to include in the final
rule guidelines that articulate clear
standards for issues that are of sufficient
magnitude to result in an ‘‘insufficient
basis letter.’’
(Response 96) We agree that we
should be specific about identified
problems and distinguish between
circumstances that lead to an
insufficient basis letter. Our experience
during the Interim Pilot program
demonstrates that we have done so, and
we intend to continue this practice
under the final rule. For example, as
discussed in sections IV.H.4 and IV.H.7
of CFSAN’s 2010 experience document
(Ref. 18), we have issued an insufficient
basis letter in cases where health effects
seen in toxicological or clinical studies
were not adequately explained or
because the notice did not describe
adequate toxicological studies; when the
notice contained insufficient
information about dietary exposure;
when the notice contained insufficient
information to adequately identify the
substance; when the notice contained
insufficient information to satisfy the
standard for demonstration of GRAS
status through experience based on
common use in food; and as a result of
the regulatory framework associated
with the substance. To date, we have
not issued an insufficient basis letter
solely as a result of insufficient
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evidence regarding the level of the
substance that is needed to accomplish
the intended technical effect. However,
CVM’s experience document
demonstrates that CVM has included
lack of information regarding the
intended technical effect as one of
several reasons leading to an
insufficient basis letter (Ref. 20). Some
‘‘no questions letters’’ issued by CFSAN
have discussed the level of the
substance that is needed to accomplish
the intended technical effect, e.g., when
CFSAN informed a notifier who
received a ‘‘no questions letter’’ that
FSIS needed information regarding the
lowest level necessary for the substance
to achieve its intended effect in meat,
meat food product, or poultry product
(see section III.L of CFSAN’s 2010
experience document (Ref. 18)).
Our experience during the Interim
Pilot program demonstrates that
whether a notice provides a sufficient
basis for a conclusion of GRAS status is
a case-by-case evaluation and that the
circumstances vary. Therefore, we
decline the request to specify standards
for issues that are of sufficient
magnitude to result in an ‘‘insufficient
basis letter.’’ See sections IV.H.4 and
IV.H.7 of CFSAN’s 2010 experience
document (Ref. 18) for information on
specific GRAS notices that received an
‘‘insufficient basis letter’’ from CFSAN,
and table 1 in CVM’s experience
document (Ref. 20) for information on
GRAS notices that received an
‘‘insufficient basis letter’’ from CVM.
Our letters responding to each of these
GRAS notices describe the problems in
more detail and are available on
CFSAN’s Web site (Ref. 46) and CVM’s
Web site (Ref. 47).
(Comment 97) Some comments ask
that an ‘‘insufficient basis letter’’
include a qualifying statement that we
have not conducted a substantive
review and have not concluded that the
intended conditions of use of the
notified substance are not GRAS. These
comments assert that a response that
does not include such a statement could
have the practical effect of challenging
the use of a substance in the absence of
a threshold determination that the
notified use is not GRAS.
(Response 97) We disagree that an
‘‘insufficient basis letter’’ should state
that we did not conduct a substantive
review of the GRAS notice. See
Response 25 and Response 94. Our
evaluation of a GRAS notice is a
substantive evaluation.
The typical text of an ‘‘insufficient
basis letter’’ specified that ‘‘the notice
does not provide a sufficient basis’’ for
a determination that the notified
substance is GRAS under the conditions
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of its intended use (see table 1), and we
intend to continue including such text
in letters issued under the final rule,
modified to refer to a ‘‘conclusion’’ of
GRAS status rather than a
‘‘determination’’ of GRAS status (see
table 20). This typical text addresses the
adequacy of the notice rather than the
regulatory status of the substance;
consistent with the request of these
comments, this text does not specify
that we have concluded that the
intended conditions of use of the
notified substance are ‘‘not GRAS.’’ In
several cases during the Interim Pilot
program, a notifier who received an
‘‘insufficient basis letter’’ submitted a
second GRAS notice and received a ‘‘no
questions letter’’ in response to the
second GRAS notice (see sections III.D
and IV.K of the experience document
(Ref. 18)). In these examples, CFSAN’s
response to the notifier’s first GRAS
notice made clear that the submitted
notice did not provide a basis for a
conclusion of GRAS status, but CFSAN
had no questions about the basis for
GRAS status provided by the second
notice.
3. Our Consideration of a Timely
Amendment
As discussed in section XVIII.B, the
rule provides that you may submit a
timely amendment to your filed GRAS
notice to update your GRAS notice or in
response to a question from us
(§ 170.260(a)). As a companion
provision, the rule also provides that we
will consider any timely amendment
that you submit to a filed GRAS notice,
to update your GRAS notice or in
response to a question from us, before
we respond to your notice based on our
evaluation of your notice if we deem
that doing so is feasible within the
established timeframes (see
§ 170.265(a)(4)). If we deem that
considering your amendment is not
feasible within the established
timeframes, we will inform you that we
are not considering your amendment
(see § 170.265(a)(4)). We also will
inform you that we are not considering
your amendment if we have granted
your request to cease to evaluate your
notice (i.e., if we send you a ‘‘cease to
evaluate letter’’). See § 170.265(b)) and
Response 98 for the timeframe
established in this rule for our response
to your GRAS notice.
4. Timeframe for Our Response to a
GRAS Notice
(Comment 98) Several comments
support retaining the proposed 90-day
timeframe. According to these
comments, a 90-day timeframe would
provide an incentive for a manufacturer
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to submit a GRAS notice. One comment
asserts that we should be held
accountable to the proposed 90-day
timeframe, whereas another comment
suggests that the proposed 90-day
timeframe provide a benchmark at
which we should make the notifier
aware of the current status of our
evaluation of the notice even if we have
not had sufficient time to completely
review the safety of the notified
substance.
One comment that asks us to retain
the proposed 90-day timeframe stresses
that we should have flexibility to take
additional time as needed. Another
comment agrees that it would be
appropriate for us to extend the
evaluation period, provided we do so
only in limited instances.
One comment asserts that the
requirements of the GRAS notification
procedure are similar to the
requirements of the GRAS affirmation
petition process and questions whether
we could respond to a GRAS notice
within 90 days because we did not
respond to a GRAS petition in such a
short timeframe. One comment that
stresses the importance of retaining a set
evaluation timeframe suggests that the
timeframe be 90–180 days based on
CFSAN’s experience during the Interim
Pilot program, and opposes a timeframe
greater than 180 days. Other comments
support a 180-day timeframe because it
would be realistic and reasonable,
would be sufficient to resolve all of the
issues raised by a GRAS notice with
procedural fairness, and could be
consistent and fair across both CFSAN
and CVM.
(Response 98) We are establishing a
timeframe of 180 days from the date of
filing for our response to a GRAS notice.
We also are providing that we may
extend the 180-day response timeframe
by 90 days on an as needed basis; if we
do so, we will inform you of the
extension in writing as soon as
practicable but no later than within 180
days of filing. (See the regulatory text of
§ 170.265(b)(1) and (2)). We agree that
the 180-day timeframe is realistic and
reasonable, would be sufficient to
resolve all of the issues raised by a
GRAS notice with procedural fairness in
most cases, and could be consistent and
fair across both CFSAN and CVM.
We disagree that we should establish
a 90-day timeframe merely because we
had proposed this timeframe before we
gained experience with evaluating
GRAS notices. As shown in section
III.M of CFSAN’s 2010 experience
document, less than 12 percent of the
response letters CFSAN issued as of
December 31, 2009, were sent within
the proposed 90-day timeframe (Ref.
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18). Importantly, section III.M of
CFSAN’s 2010 experience document
also shows that in many cases a dialog
between FDA and a notifier about
scientific issues associated with a GRAS
notice, with an ensuing amendment
from the notifier, played a role in the
timeframe for CFSAN’s response to a
GRAS notice. As discussed in the 2010
notice, several comments ask us to
allow a notifier to address questions we
have about a GRAS notice by submitting
an amendment to the notice (see Issue
3a, 75 FR 81536 at 81538), and the final
rule expressly provides that you may
submit an amendment to a filed GRAS
notice before we respond to the notice
(see § 170.260(a)). Although we are
including flexibility to take additional
time as needed, our goal is to do so in
only limited instances, such as when
the intended conditions of use of the
notified substance raise complex
scientific issues.
We have no basis to judge whether a
90-day timeframe, but not a 180-day
timeframe, would provide an incentive
to a manufacturer to submit a GRAS
notice. However, as noted in Response
24 CFSAN filed more than 600 GRAS
notices during the time period 1998
through 2015, including 69 GRAS
notices filed during 2014 and 51 GRAS
notices filed during 2015, even though
CFSAN rarely responded to a GRAS
notice within 90 days. We believe that
the ongoing submission of GRAS notices
is evidence that the 180-day timeframe
that is consistent with our experience
during the Interim Pilot program is not
a disincentive to a manufacturer.
We note that the procedural
requirements of the GRAS notification
procedure are very different from the
procedural requirements of the GRAS
affirmation petition process in that we
respond to a GRAS notice by letter
whereas we respond to a GRAS
affirmation petition through rulemaking.
As previously discussed (62 FR 18938 at
18941), the resource-intensive
rulemaking process includes: (1)
Publishing a filing notice in the Federal
Register; (2) requesting comment on the
petitioned request; (3) conducting a
comprehensive review of the petition’s
data and information and comments
received to the filing notice to
determine whether the evidence
establishes that the petitioned use of the
substance is GRAS; (4) drafting a
detailed explanation of why the use is
GRAS (as opposed to simply being safe);
and (5) publishing that explanation in
the Federal Register. Therefore, we
disagree with the perspective of one
comment that our experience in
responding to a GRAS affirmation
petition should have any bearing on the
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determination of an appropriate
timeframe for our response to a GRAS
notice.
(Comment 99) One comment
expresses concern that a 90-day
timeframe would be unrealistic unless
we allocate additional resources to the
program. This comment asks us to
consider a process similar to the process
for the FCN program, where there is a
fixed review period during which we
can ‘‘object to’’ a submitted notification.
If we do not object within the review
period or do not request an extension to
the review period, a notification
submitted to the FCN program is
considered effective.
(Response 99) We decline this
request. We disagree that the GRAS
notification procedure should be
modeled after the FCN program. Unlike
the GRAS notification procedure, the
FCN program is a mandatory process for
food contact substances under section
409(h) of the FD&C Act. Furthermore,
the statute provides that the FCN
program shall not operate unless it has
certain appropriated funds. See section
409(h)(5)(A)(i) of the FD&C Act and
§ 170.104(c)(3). There are no similar
statutory requirements applicable to our
evaluation of the basis for a conclusion
of GRAS status.
(Comment 100) One comment asserts
that we should respond to a GRAS
notice within 90 days unless we identify
a problem that warrants dialog with the
notifier and an ensuing amendment.
(Response 100) We disagree. The
suggestion of this comment could lead
to the unintended consequence of
seeking unnecessary amendments
merely to stay within an established
timeframe. We believe it is more
appropriate to establish a single
timeframe that would broadly apply to
all GRAS notices, with the potential to
extend the timeframe on an as needed
basis.
(Comment 101) One comment asks us
to stop the ‘‘review clock’’ when we
inform a notifier that we have questions
about a notice and then restart the
‘‘review clock’’ upon receipt of an
amendment that answers our questions.
(Response 101) We decline this
request. We acknowledge that there
could be an advantage to such a process,
because stopping the review clock
would reduce the time pressures on our
staff. However, the role of an
amendment is to clarify questions that
we have about your conclusion of GRAS
status rather than to substantively
amend the GRAS notice. A process in
which we stop and start a review clock
implies that the timeframe for you to
submit an amendment could be so long
as to significantly impact our ability to
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respond within an established
timeframe. Rather than a process in
which we stop and start a review clock
on a particular GRAS notice, we have
provided that you may ask us to cease
to evaluate a GRAS notice when your
preparation of an amendment would
impact our ability to respond within 180
days.
5. Responding to a GRAS Notice in All
Circumstances
In the proposed rule, we noted that
the GRAS notification procedure could
be structured so that we respond only
when we question the GRAS status of
the intended use of the substance and
requested comment on whether we
should, in all cases, provide a notifier
with a letter at the conclusion of our
evaluation of a notice (62 FR 18938 at
18951).
(Comment 102) Several comments
agree with our discussion in the
proposed rule that a written response
from us would give manufacturers an
incentive to notify us of their
conclusions of GRAS status; these
comments recommend that we respond
in writing in all circumstances. Other
comments suggest that we limit our
response to circumstances in which we
identify a problem with a notice because
such a limitation would make it easier
for us to respond within the proposed
90-day timeframe. One comment
expresses concern that a written
response could create a misperception
that we had undertaken an independent
review of the data described in the
GRAS notice; to prevent this
misperception, this comment suggests
that we respond in writing only if we
find a problem with the notice.
(Response 102) We acknowledge that
limiting our response to circumstances
in which we identify a problem with a
notice would reduce the number of
letters that we write. However, we
believe that it is important to publicly
document our evaluation of the GRAS
notice in light of all the comments
submitted to this rulemaking. (See, e.g.,
Comment 25 and the comments we
discuss in section VII.C). In addition, in
our experience it is the process of
evaluating a submission and reaching a
decision about whether the notice
provides a basis for a conclusion of
GRAS status, rather than the process of
drafting and issuing a letter, that
requires the most time.
We acknowledge the potential that a
‘‘no questions letter’’ could be
misinterpreted, e.g., to mean that FDA,
rather than the notifier, had reached a
conclusion of GRAS status. To mitigate
the potential for such misinterpretation,
the typical text of our response letters
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issued during the Interim Pilot program
referred to the notifier’s determination
and stated that we have not made our
own determination regarding the GRAS
status of the subject use of the notified
substance (see table 1). We intend to
continue including such typical text in
letters issued under the final rule,
modified as shown in table 20.
(Comment 103) One comment
suggests that we respond in writing only
at the notifier’s request.
(Response 103) We decline this
suggestion, which is contrary to
emphasis that the rule places on the
notifier’s acceptance of responsibility
for a conclusion of GRAS status (see the
discussion at 62 FR 18938 at 18953).
(Comment 104) One comment asserts
that a letter acknowledging receipt of a
GRAS notice would constitute a form of
response. Another comment suggests
that a letter acknowledging receipt of a
GRAS notice state whether the notice
meets the listed requirements for a
GRAS notice, eliminating the need for a
second letter responding to the notice
when we complete our evaluation. This
comment asserts that a second letter
would be unnecessary for two reasons.
First, the notifier has accepted full
responsibility for the conclusion of
GRAS status and does not require
premarket approval from us. Second,
under the terms of the rule a notifier
must agree to make all data and
information available to us.
(Response 104) The final rule
provides that we will inform you of the
date on which we filed your notice
rather than the date on which we
received it, as we had proposed. We
disagree that a letter informing you of
the date of filing in any way responds
to a GRAS notice or should state
whether the notice meets the listed
requirements for a GRAS notice. As
discussed in Response 93, we cannot
acknowledge whether a notice ‘‘meets
the listed requirements’’ without
assessing the quality of the submission,
which we do during the evaluation that
follows filing the submission as a GRAS
notice.
We acknowledge that submitting a
GRAS notice means that a notifier has
accepted full responsibility for the
conclusion of GRAS status. We also
acknowledge that the use of a GRAS
substance is not subject to our
premarket review. However, we disagree
that a relevant factor in determining
whether we should respond to a notifier
is the notifier’s agreement to make all
data and information available to us if
we question whether the notice
provides an adequate basis for a
conclusion of GRAS status. A GRAS
notice presents an opportunity for you
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to inform us about your conclusion of
GRAS status rather than an opportunity
for you to test a hypothesis that there is
a sufficient basis to reach a conclusion
of GRAS status.
(Comment 105) One comment
suggests that we issue a written
response only when we have reached a
conclusion regarding safety.
(Response 105) This comment may
have misunderstood the proposed
notification procedure. Under the
notification procedure, you analyze the
available data and information and
reach a conclusion about whether the
notified substance is safe under the
conditions of its intended use and
whether there is a basis to conclude that
the criteria for GRAS status are satisfied.
We evaluate your conclusions regarding
the available data and information.
During the Interim Pilot program, the
typical text of a ‘‘no questions letter’’
stated that we had not reached our own
determination regarding the GRAS
status of the notified substance under
the conditions of its intended use (see
table 1).
To the extent that the comment is
suggesting that we issue an ‘‘insufficient
basis letter’’ when the problem with the
notice relates to safety, but not to
general recognition, we disagree. It
would be inconsistent with the legal
basis of the GRAS standard for us to
only focus on safety, and we did not do
so during the Interim Pilot program.
(See section III.A.3 of CFSAN’s 2010
experience document (Ref. 18), where
CFSAN identifies ‘‘insufficient basis
letters’’ in which CFSAN had questions
about whether there was general
recognition of safety.)
C. Additional Correspondence as
Circumstances Warrant
(Comment 106) One comment
expresses the view that a ‘‘no questions
letter’’ should not affect our ability to
change our position if additional
information indicates that the use of the
substance raises any safety concerns.
(Response 106) We agree, and the
final rule expressly provides that we
will send the notifier a subsequent letter
about the notice if circumstances
warrant (see § 170.265(c)). The
circumstances may not relate to safety.
As discussed in section IV.J of CFSAN’s
2010 experience document (Ref. 18), as
of December 31, 2009, none of the
subsequent letters CFSAN issued during
the Interim Pilot program reflected a
change in CFSAN’s position and several
addressed issues other than the safety of
the use of the substance. For example,
CFSAN issued subsequent letters that:
(1) Clarified the intended conditions of
use; (2) clarified that the term CFSAN
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used to refer to the notified substance
for the purpose of the letter should not
be considered an endorsement of that
term for the purpose of declaring the
substance in the ingredient statement of
food products; (3) clarified FSIS’
position regarding the use of the
notified substance in meat, meat food
product or poultry product; and (4)
corrected a mistake in the original
response. CFSAN also sent a subsequent
letter as an administratively efficient
mechanism of responding to a notifier
who provided CFSAN with information
supporting a conclusion that an
additional use of the notified substance
satisfied GRAS criteria.
In addition, CFSAN has issued a
subsequent letter when CFSAN’s first
letter was an ‘‘insufficient basis letter’’
rather than a ‘‘no questions letter.’’ For
example, CFSAN did so when a notifier
who received an ‘‘insufficient basis
letter’’ submitted a new GRAS notice
that did not address the questions
CFSAN raised in the ‘‘insufficient basis
letter.’’ CFSAN also did so when a
notifier who received an ‘‘insufficient
basis letter’’ submitted a supplement to
its original GRAS notice rather than
submit a new GRAS notice. See section
IV.J of CFSAN’s 2010 experience
document (Ref. 18).
D. Procedures if a Notifier Disagrees
With Our Response
In the proposed rule, we explained
that there are existing processes that we
considered would be appropriate for a
notifier to use to engage us if the notifier
disagreed with our response (see 62 FR
18938 at 18952 and table 21). We also
noted that any person with concerns
about our response to a GRAS notice
may contact our Office of the Chief
Mediator and Ombudsman; that office
works on resolving issues and conflicts
that arise in any FDA component.
TABLE 21—EXISTING PROCEDURES IN
OUR REGULATIONS THAT CAN
APPLY IF A NOTIFIER DISAGREES
WITH OUR RESPONSE TO A GRAS
NOTICE
Regulatory
section
(§ )
10.25 ........
10.33 ........
10.65 ........
10.75 ........
Description
Initiation of administrative proceedings.
Administrative reconsideration of
action.
Meetings and correspondence.
Internal agency review of decisions.
(Comment 107) Several comments
express concern that the processes
discussed in the proposed rule would be
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available only after we sent, and made
readily accessible to the public, an
‘‘insufficient basis letter.’’ Other
comments express concern about the
practical effect of an ‘‘insufficient basis
letter’’ on the notifier’s ability to market
a notified substance while the notifier is
seeking review of our evaluation. Some
comments ask that our letter be
‘‘stayed’’ until any problems that we
identified in our response to the notice
are resolved under such a process.
(Response 107) We acknowledge the
concerns expressed in these comments
but are making no changes to the rule
to address these concerns. One of the
underpinnings of the GRAS notification
procedure is that making our response
readily accessible to the public will
properly underscore your responsibility
for the conclusion of GRAS status (62
FR 18938 at 18953). As discussed in
Response 104, a GRAS notice presents
an opportunity for you to inform us
about your conclusion of GRAS status
rather than for you to test a hypothesis
that there is a sufficient basis to reach
a conclusion of GRAS status. If we send
you an ‘‘insufficient basis letter,’’ we
advise you to carefully consider
whether marketing the notified
substance would be lawful. ‘‘Staying’’
an ‘‘insufficient basis letter’’ informing
you that there may not be a legal basis
to market the notified substance, e.g., so
that you could market the substance
while you are working to resolve the
issues that led us to send you an
‘‘insufficient basis letter’’, would not
change the legal status of the notified
substance.
(Comment 108) Several comments
assert that the processes we had
identified in the proposed rule are
cumbersome and do not provide
manufacturers with a clear framework
or timeline for responding to our
questions or concerns. In general, these
comments ask us to include in the final
rule a prompt, fair, and effective process
that would be specific to the GRAS
notification procedure. A few comments
suggest that such an appeal mechanism
also apply to subsequent
correspondence from us about a GRAS
notice.
Some comments provide specific
suggestions for how an appeals
mechanism specific to the GRAS
notification procedure could work, e.g.,
by specifying that a notifier may submit
additional data and information for our
evaluation, or by providing for an
independent advisory committee or an
FDA-certified third-party review
organization to review the matter and
issue an opinion. Some comments
suggest that an appeals mechanism
specify appeal steps and stressed the
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importance of timeframes for decisions
by our officials.
(Response 108) We decline the
request to include in the final rule an
appeals process that would be specific
to the GRAS notification procedure. We
agree that the process to contact us
about a response to a GRAS notice
should be clear. However, we disagree
that the existing procedures are unclear,
because our regulations fully describe
these procedures (§§ 10.25, 10.33, 10.65,
and 10.75). We acknowledge that the
listed procedures do not provide a clear
timeline and that some of the listed
procedures (e.g., §§ 10.25 and 10.33) are
more cumbersome than others (such as
requesting a meeting under § 10.65 or
requesting internal Agency review of a
decision under § 10.75). In practice
during the Interim Pilot program,
several notifiers who received an
‘‘insufficient basis letter’’ took steps to
resolve our questions and subsequently
submitted a new GRAS notice or a food
additive petition (see the discussion in
section III.K of CFSAN’s 2010
experience document (Ref. 18)). Given
the variety of circumstances that could
lead to an ‘‘insufficient basis letter,’’ we
believe that taking steps to resolve our
questions, and submitting a new GRAS
notice or a food additive petition, can be
an efficient mechanism for you to use in
lieu of the procedures we discussed in
the proposed rule. Doing so would be
consistent with the suggestion of some
comments that an appeals mechanism
specific to the GRAS notification
procedure could include submission of
additional data and information for our
evaluation, except that the data and
information would be submitted in a
new GRAS notice rather than be an
‘‘appeal’’ to the GRAS notice that
received an ‘‘insufficient basis letter.’’
We do not have an FDA-certified
third-party review organization that
could review the matter and issue an
opinion. We disagree that convening an
independent advisory committee would
be appropriate as an additional, routine
mechanism to appeal an ‘‘insufficient
basis letter.’’ Under our regulations in
part 14 governing advisory committees,
it would be FDA—not a notifier—who
decided to convene a meeting of our
Food Advisory Committee about the use
of a substance in food. We would have
little basis to convene a meeting of our
Food Advisory Committee as part of an
appeal to an ‘‘insufficient basis letter’’
unless the notifier had first used one or
more of the procedures listed in table
21.
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55019
XX. Coordinating Our Evaluation of a
GRAS Notice With FSIS
In the 2010 notice, we described some
of the terms of a MOU, between FDA
and USDA’s FSIS, that provides for a
coordinated evaluation process with
FSIS when the intended conditions of
use of a notified substance include use
in a product or products subject to
regulation by USDA under statutes that
it administers (75 FR 81536 at 81541–
81542). We also asked for comment on
whether to make our coordinated
evaluation process with FSIS explicit in
the final rule (see Issue 13, 75 FR 81536
at 81541–81542). In 2015, we amended
that MOU to include more details about
the procedures FDA and FSIS will
follow to do so (Ref. 36).
(Comment 109) Comments support
coordinating our evaluation of GRAS
notices with FSIS and including the
procedure for this coordination in the
final rule. Comments also support
requiring the notifier to provide an
additional paper copy that we would
send to FSIS as part of this procedure.
(Response 109) The final rule
includes procedures for coordinating
our evaluation of a GRAS notice with
FSIS when the use of the notified
substance includes use in a product or
products subject to regulation by FSIS
under statutes that it administers. (See
§ 170.270). If you send your GRAS
notice on paper, a single paper copy is
sufficient; we would send FSIS an
electronic copy. (See § 170.210(b) and
Response 46). Under § 170.270(d), we
will inform you of the advice we receive
from FSIS in the letter we send you in
accordance with § 170.265(b)(1), as
appropriate. By ‘‘as appropriate,’’ we
mean that in most circumstances we do
not intend to provide advice from FSIS
about the use of the notified substance
when we respond with an ‘‘insufficient
basis letter,’’ because doing so has the
potential to create confusion about the
regulatory status of a use of the notified
substance in products subject to
regulation by FSIS. Likewise, we do not
intend to provide advice from FSIS
about the use of the notified substance
when we respond with a ‘‘cease to
evaluate letter’’ and, thus, the procedure
described in § 170.270(d) does not
specify that we will inform you of the
advice we receive from FSIS in a letter
we send you in accordance with
§ 170.265(b)(3).
As we noted in section XII.I, this rule
does not specify the data and
information that FSIS will need to
evaluate whether the intended use of
the notified substance complies with
applicable statutes and regulations, or, if
not, whether the use of the substance
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would be permitted in products under
FSIS jurisdiction under specified
conditions or restrictions. We
recommend that you contact the
appropriate staff at FSIS regarding the
data and information that FSIS will
need you to provide. FSIS provides
contact information for its programs on
its Web site (Ref. 41).
(Comment 110) One comment agrees
that the evaluation of a GRAS notice
should be coordinated between FDA
and FSIS when ‘‘animal products’’ are
involved. This comment notes that FSIS
does not currently review the use of a
substance intended for use in animal
food and recommends that CVM be
involved in the safety review process of
the notice if the notice involves a
substance to be used in animal food.
(Response 110) This comment appears
to have misunderstood the purpose of
the coordinated evaluation process that
we discussed in the 2010 notice. That
process applies to the use of a substance
in human food products, such as meat
and poultry products, that are subject to
regulation by USDA and would be
evaluated by CFSAN; it does not apply
to the use of a substance in animal food.
FSIS, under the statutes it administers,
does not evaluate a substance intended
for use in animal food and, thus, the
process would not apply to a GRAS
notice received by CVM. See also
Response 45.
XXI. Comments on Public Disclosure of
a GRAS Notice
We proposed that a ‘‘GRAS exemption
claim’’ would be immediately available
for public disclosure on the date the
notice is received. All remaining data
and information in the notice would be
available for public disclosure, in
accordance with part 20, on the date the
notice is received (proposed
§ 170.36(f)(1)). We also proposed that
the following information would be
readily accessible for public review and
copying: (1) A copy of the ‘‘GRAS
exemption claim’’ (proposed
§ 170.36(f)(2)(i)); (2) a copy of our
response letter (proposed
§ 170.36(f)(2)(ii)); and (3) a copy of any
subsequent letter we issued regarding
the notice (proposed § 170.36(f)(2)(iii)).
In the 2010 notice, we noted that
although the decision to submit a GRAS
notice would be voluntary, the
provisions governing the GRAS
notification procedure, including the
information to be submitted, would be
mandatory (75 FR 81536 at 81540).
In the final rule, you include the
signed statements that we proposed be
in a ‘‘GRAS exemption claim’’ in Part 1
of your GRAS notice, and we no longer
use the term ‘‘GRAS exemption claim’’
(see Response 42). As discussed in
Response 50, the final rule stipulates
that you must not include any
information that is trade secret or
confidential commercial information in
Part 1 of your GRAS notice (see
§ 170.225(b)).
In the following sections, we discuss
comments on the proposed
requirements for public disclosure of a
GRAS notice. After considering these
comments, we are establishing
requirements applicable to the public
disclosure of a GRAS notice as shown
in table 22, with editorial, clarifying,
and conforming changes as shown in
table 29. (See § 170.275.) Table 22
identifies changes we made relative to
the proposed rule or the description in
the 2010 notice other than the editorial,
clarifying, and conforming changes
shown in table 29 and the additional
editorial changes associated with the
redesignation of proposed § 170.36(f) as
§ 170.275.
TABLE 22—FINAL REQUIREMENTS APPLICABLE TO PUBLIC DISCLOSURE OF A GRAS NOTICE
Proposed
designation in the
regulatory text
(§ )
170.275(a)(1) .........
N/A .........................
N/A
170.275(a)(2) .........
170.36(f)(1) ............
N/A
170.275(b)(1) .........
170.36(f)(2)(i) .........
N/A
170.275(b)(2) .........
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Final designation in
the regulatory text
(§ )
170.36(f)(2)(ii) ........
N/A
170.275(b)(3) .........
170.36(f)(2)(ii) ........
N/A
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Issue No. in
the 2010
notice
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Description
The data and information in a GRAS
notice (including data and information
submitted in any amendment or supplement to your GRAS notice or incorporated into your GRAS notice)
are considered a mandatory, rather
than voluntary, submission for purposes of its status under the FOIA
and part 20.
The data and information in a GRAS
notice (including data and information
submitted in any amendment or supplement to your GRAS notice or incorporated into your GRAS notice)
are available for public disclosure in
accordance with part 20 as of the
date that we receive your GRAS notice.
We will make readily accessible to the
public a list of filed GRAS notices, including the information described in
the signed statements you include in
§ 170.225(c)(2) through (c)(5).
We will make readily accessible to the
public the text of any letter that we
issue under § 170.265(b)(1) or (3)
(e.g., a ‘‘no questions letter’’ or an
‘‘insufficient basis letter’’); or under
§ 170.265(c) (a ‘‘subsequent letter’’).
We will make readily accessible to the
public the text of any letter that we
issue under § 170.265(b)(3) (e.g., a
‘‘cease to evaluate letter’’).
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Revisions (other than editorial,
clarifying, and conforming changes)
relative to the proposed rule or the
2010 notice
Clarify that a notice is considered a
mandatory, rather than voluntary,
submission for purposes of their status under the FOIA and part 20.
Clarify that part 20 applies to amendments and supplements as well as to
the GRAS notice as originally submitted.
Clarifies that the list of submissions that
we make publicly available are those
that we have ‘‘filed’’ as GRAS notices.
N/A.
Clarify that the provisions in which we
make certain letters readily accessible to the public apply to a ‘‘cease
to evaluate letter’’.
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55021
TABLE 22—FINAL REQUIREMENTS APPLICABLE TO PUBLIC DISCLOSURE OF A GRAS NOTICE—Continued
Proposed
designation in the
regulatory text
(§ )
170.275(c) ..............
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Final designation in
the regulatory text
(§ )
170.36(f)(2)(iii) .......
Issue No. in
the 2010
notice
N/A
A. Data and Information in a GRAS
Notice Are Available for Public
Disclosure on the Date That We Receive
It
(Comment 111) One comment asserts
that the releasability of the contents of
a GRAS notice should be governed by
§ 20.111 (data and information
submitted voluntarily to us) because the
FD&C Act does not require submission
of a GRAS notice. The comment asserts
that § 20.111 would affect the
releasability of the content of a GRAS
notice in three ways. First, while a
GRAS notice is pending, § 20.111 would
protect from disclosure safety data or
information about an ingredient under
development. Second, § 20.111 would
permanently protect from disclosure
any data or information relating to
manufacturing, production or sales, or
formulas. Third, § 20.111 would
establish that a notifier has the right to
request that we evaluate the notifier’s
position that specific data or
information in a GRAS notice are
protected from disclosure because these
data or information fall within the
exemption in § 20.61 for trade secrets
and commercial or financial
information, which is privileged or
confidential.
(Response 111) We disagree that the
provisions of § 20.111 apply to a GRAS
notice. Although your decision to
submit a GRAS notice is voluntary, the
information included in your GRAS
notice is required. To make that clear,
the final rule stipulates that the data and
information in a GRAS notice (including
data and information submitted in any
amendment or supplement to your
GRAS notice or incorporated into your
GRAS notice) are considered a
mandatory, rather than voluntary,
submission for purposes of its status
under the FOIA and part 20 (see
§ 170.275(a)(1)).
We agree that a notifier has a right to
request that we evaluate the notifier’s
position that specific data or
information in a GRAS notice are
protected from disclosure because these
data or information fall within the
exemption in § 20.61 for trade secrets
and confidential commercial
information. See § 170.225(c)(8), which
requires that you state your view as to
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We will disclose public information in
accordance with part 20.
whether any of the data and information
in Parts 2 through 7 of your GRAS
notice are exempt from disclosure under
the FOIA.
(Comment 112) Several comments
assert that a GRAS notice should not be
publicly available until after we have
completed our evaluation. These
comments also assert that a delay in
disclosure, coupled with an opportunity
for a notifier to amend the notice,
would: (1) Avoid the release of
information that we deemed to be
inadequate or incomplete; and (2) avoid
release of a notice that was withdrawn
if coupled with an opportunity for a
notifier to withdraw a notice.
(Response 112) We disagree that we
should refrain from disclosing the
existence of a GRAS notice, or the
contents of a GRAS notice, until after
we have completed our evaluation. As
previously discussed, immediate
disclosure of a GRAS notice underscores
a notifier’s responsibility for a
conclusion of GRAS status (62 FR 18938
at 18953). As discussed in Response 2,
immediate disclosure of a GRAS notice
also provides an opportunity for outside
parties to make us aware of dissenting
views about whether the available data
and information support a conclusion
that the notified substance is safe under
the conditions of its intended use, and
we did receive information from outside
parties during the Interim Pilot program.
Continuing to provide an opportunity
for public participation is consistent
with our substitution of the GRAS
notification procedure for the former
GRAS affirmation petition process, in
which there was a public comment
period.
As discussed in Response 83, our
current regulations regarding public
information stipulate that no person
may withdraw records submitted to
FDA (see § 20.29), and those regulations
will apply to a GRAS notice that you to
ask us to ‘‘cease to evaluate.’’
(Comment 113) One comment asks us
to make a GRAS notice available for
public disclosure only after we accept
the submission for review. Some
comments contrast our proposal for
immediate disclosure of a GRAS notice
with the provisions of: (1) The GRAS
affirmation petition process, in which a
PO 00000
Revisions (other than editorial,
clarifying, and conforming changes)
relative to the proposed rule or the
2010 notice
Description
Frm 00063
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N/A.
GRAS affirmation petition is disclosed
only after the petition has been accepted
for filing (former § 170.35(c)(2)); and (2)
the health claim petition process, in
which a health claim petition becomes
available for public disclosure only after
it is filed and a health claim petition
that is denied without filing is not
available for disclosure (21 CFR
101.70(j)).
(Response 113) The final rule
continues to specify that the data and
information in a GRAS notice are
available for public disclosure as of the
date of receipt (see § 170.275(a)(2)). The
former GRAS affirmation petition
process did not specify when a
submitted GRAS affirmation petition
would be available for public
disclosure. Instead, the former GRAS
affirmation petition process merely
specified that we would place the
petition on public file in the office of
the Division of Dockets Management
and publish a notice of filing in the
Federal Register within 30 days after
the date of filing. In addition, we
disagree that the public disclosure
provisions in § 101.70(j) applicable to
the health claim petition process should
apply to the GRAS notification
procedure. Those provisions derive
directly from the statutory provisions
that direct the health claim program
(section 403(r)(4)(A)(i) of the FD&C Act
(21 U.S.C. 343(r)(4)(A)(i))).
Under § 20.103, with few exceptions
all correspondence from members of the
public, organization or company
officials, or other persons, is available
for public disclosure at the time that we
receive it unless a different time for
such disclosure is specified in other
rules established or cross-referenced in
part 20. As noted in Comment 86 and
Response 86, we may decide to file and
respond to a submission as general
correspondence, rather than as a GRAS
notice, in certain circumstances; if we
do so, the data and information in the
submission would be available as of the
date of receipt. Retaining date of receipt
as the timeframe for when a submission
you transmit as a GRAS notice is
available for public disclosure is both
consistent with § 20.103 and a practical
approach to a situation in which we
receive a FOIA request for a GRAS
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submission before we have determined
whether to file the submission as a
GRAS notice. As a practical matter, we
believe that such situations will be rare,
and that in most cases a GRAS
submission will be disclosed after we
have determined whether to file it and
evaluate it as a GRAS notice, or to file
it and respond to it as general
correspondence.
(Comment 114) Some comments
disagree with the assumption we stated
in the proposed rule (62 FR 18938 at
18952) that submission of a GRAS
notice would not reflect the notifier’s
plans about the timing or the use of the
substance in a marketed product,
because a GRAS substance may be
marketed without prior approval.
(Response 114) We acknowledge that
immediate disclosure of a GRAS notice
could, in certain circumstances, provide
information about the timing of market
entry. However, when the data and
information regarding the safety of the
substance under the conditions of its
intended use satisfy GRAS criteria,
neither the law nor this rulemaking
would prevent you from marketing a
substance before submitting a GRAS
notice or during our evaluation of that
notice.
B. We Will Make a List of Filed GRAS
Notices and Our Responses to GRAS
Notices Readily Accessible
(Comment 115) Several comments
address our stated intention to maintain
an inventory of GRAS notices that we
receive, our response, and any
subsequent relevant correspondence.
(See the discussion at 68 FR 18938 at
18953.) Some of these comments agree
with the discussion in the proposed rule
that an inventory of GRAS notices
should be an adjunct to the proposed
rule rather than be included in the
regulatory text. Other comments
disagree and ask us to include the
creation and availability of the
inventory in the regulatory text. These
comments assert that a provision that
merely states that the inventory exists
and is available for public review would
address the concern that we identified
in the proposed rule about the need to
maintain flexibility regarding our
administration of the inventory.
(Response 115) The final rule
specifies that we will make the
following readily accessible to the
public: (1) A list of filed GRAS notices,
including the information described in
certain of the signed statements that are
included in Part 1 of a GRAS notice (i.e.,
§ 170.225(c)(2) through (c)(5)); and (2)
The text of any letter that we issue
under § 170.265(b)(1) (our response to a
GRAS notice based on our evaluation of
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the notice), § 170.265(b)(3) (a letter if we
grant a request that we cease to evaluate
a GRAS notice), or § 170.265(c) (a
subsequent letter that we send about a
GRAS notice). (See § 170.275(b).) We are
not specifying that the mechanism for
us to do so is through an ‘‘Inventory’’
because the procedure we used to make
this information readily accessible to
the public evolved over time during the
Interim Pilot program, and may
continue to evolve (see section III.I.1 in
CFSAN’s 2010 experience document
(Ref. 18)).
(Comment 116) In the proposed rule,
we stated our intention to initially
maintain a paper version of an
inventory at our Dockets Management
Branch (now Division of Dockets
Management) and asked for comment on
making an inventory available through
electronic means such as the Internet
(62 FR 18938 at 18953). Comments
support maintaining an inventory in
paper format, electronic format, or both
formats so that all members of the
public could have ready access to such
information regarding GRAS notices.
Some comments point out that
electronic access would be particularly
important to the international food
industry. Some comments support the
Division of Dockets Management as the
best location for an inventory
maintained in paper format.
(Response 116) As discussed in
section III.I.1 in CFSAN’s 2010
experience document (Ref. 18), the
procedure we used to make this
information readily accessible to the
public evolved over time during the
Interim Pilot program. It began as a
paper file (first maintained at the
Division of Dockets Management, and
then maintained in the public reading
room of our Freedom of Information
Staff), and evolved into its current
electronic format on our Internet site
(Ref. 46). We intend to continue using
the Internet as the principal means to
make the inventory readily accessible
because doing so is an efficient and
effective mechanism to disseminate
information to anyone who has access to
the Internet. The inventory on the
Internet can be accessed and printed
from computers in the public reading
room at Division of Dockets
Management, as well as from computers
located at businesses, at homes, and at
public locations such as libraries and
Internet cafes. If a person either does not
have access to the Internet or chooses
not to access the inventory through the
Internet, that person can request each
GRAS notice, and each letter listed in
§ 170.265(b)(1) or (3) or (c), under the
FOIA. It is no longer practical for us to
maintain a paper file at the Division of
PO 00000
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Dockets Management, because all new
information sent to the Division of
Dockets Management is maintained
electronically; paper submissions are
scanned to electronic form.
(Comment 117) One comment that
addresses the discussion in the 2010
notice about the reasons that may lead
us to decline to file a submission as a
GRAS notice, such as when the use is
covered by an existing regulation, asks
us to include those submissions in the
GRAS inventory so there will be no
confusion as to the status of the
ingredient.
(Response 117) We decline this
request. The purpose of the inventory of
GRAS notices is to provide a list of all
the GRAS notices that we have filed and
evaluated, not to interpret the uses
listed in our regulations or, as discussed
in Response 86, covered by an existing
GRAS notice.
(Comment 118) A few comments
suggest that a publicly available
inventory of GRAS notices could suffice
to document that certain notices raised
no significant issues.
(Response 118) We agree that a
publicly available inventory of GRAS
notices can document which notices
result in a ‘‘no questions letter, e.g., by
prominently listing the category of our
response. The Inventory of GRAS
Notices developed during the Interim
Pilot program prominently classifies
each response letter as ‘‘no questions,’’
‘‘insufficient basis,’’ and ‘‘cease to
evaluate’’ (Ref. 46). However, we
disagree that merely displaying the
category of our response, without
providing the full text of a letter that
places that category of response in
context, is appropriate, regardless of
whether the response to the GRAS
notice is ‘‘no questions,’’ ‘‘insufficient
basis,’’ or ‘‘cease to evaluate.’’ For
example, even when we answer ‘‘FDA
has no questions,’’ our response letter
highlights key safety considerations,
such as the importance of ensuring that
the method of manufacture removes
potential contaminants.
(Comment 119) One comment asks us
to provide ‘‘public notice’’ of all GRAS
notices and the information provided
therein. Another comment asks us to
make the ‘‘GRAS exemption claim’’
readily accessible to the public by
publishing information that would be in
the publicly accessible file in the
Federal Register in addition to placing
the ‘‘GRAS exemption claim’’ in a
readily accessible file. This comment
states that doing so would provide the
public with access to as much
information as possible about what
substances would be used in food on the
basis of the GRAS provision if FDA is
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going to ‘‘forgo its role’’ in the
evaluation of the safety of GRAS
substances. This comment also asks us
to publish the receipt of the notice and
all of our subsequent responses to the
notice in the Federal Register.
Another comment asks us to publish
semi-annually, either in a Federal
Register notice or by regulation, a list of
GRAS notices that receive a ‘‘no
questions letter’’ in addition to posting
the Inventory of GRAS notices on our
Web site. This comment explains that
questions are sometimes raised—
especially from outside the United
States—about the regulatory status of a
substance used in food on the basis of
the GRAS provision unless that use of
the substance is either incorporated into
the CFR or otherwise officially
published. This comment asserts that
periodic publications in the Federal
Register would assist in addressing this
concern.
(Response 119) By specifying that we
will make a list of filed GRAS notices
readily accessible (currently, through
the inventory on the Internet), the rule
requires us to actively disclose those
GRAS notices. There is a gap between
the date on which we receive a GRAS
notice and the date on which we add it
to the inventory, e.g., CFSAN currently
updates its inventory on an
approximately monthly basis. However,
in practice during the Interim Pilot
program there was ample public notice
of the receipt of the GRAS notice before
CFSAN responded to it (see the
discussion of the timeframe for
CFSAN’s response in section III.M of
CFSAN’s 2010 experience document
(Ref. 18)). In addition, the rule provides
that we may send a subsequent letter
about the GRAS notice if circumstances
warrant; such circumstances could
include data and information, received
from a member of the public, after we
responded to the GRAS notice.
We decline the requests to provide
public notice through an announcement
in the Federal Register. Publishing an
announcement in the Federal Register
requires an expenditure of our resources
(including time and cost of publication)
that would be inconsistent with our goal
of using our resources efficiently and
effectively. Even if we conserved
resources by publishing such a notice
only on a semi-annual basis, we
disagree that ‘‘officially publishing’’ a
list of GRAS notices that receive a ‘‘no
questions letter’’ in the Federal Register
would address concerns, in the
domestic or international community,
about the regulatory status of the use of
a substance when that use is not listed
in our regulations. It is the Code of
Federal Regulations, not the Federal
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Register, that is the official repository of
our regulations listing authorized uses
of food substances.
We disagree that we are forgoing our
role in the evaluation of the safety of
substances used in food on the basis of
the GRAS provision. See Response 25.
(Comment 120) One comment asks us
to place the entire GRAS notice, rather
than only the proposed ‘‘GRAS
exemption claim,’’ in a readily
accessible paper file, e.g., at the Division
of Dockets Management. In the
comment’s view, a simple provision that
a notifier submit one additional paper
copy would mitigate our concerns about
the administrative inefficiency of
maintaining duplicate files at both the
center and Agency levels. Another
comment asks us to make the entire
notice readily accessible in electronic
form.
(Response 120) We currently make a
hyperlink to an electronic copy of each
GRAS notice accessible from within the
entry for that GRAS notice in the
inventory, after appropriate redaction
(e.g., of privacy information,
copyrighted material, and any data and
information that are exempt from public
disclosure) (Ref. 18, footnote 3). As a
practical matter, placing paper files on
public display requires space, which is
finite, and our Division of Dockets
Management scans paper submissions
into electronic format.
C. Public Disclosure of a GRAS Notice
Is in Accordance With Our Public
Information Regulations in Part 20
(Comment 121) One comment agrees
that information submitted under the
proposed ‘‘GRAS exemption claim’’
should exclude from public disclosure
the non-public confidential information
with the exception of safety data.
(Response 121) This comment appears
to have misinterpreted the proposed
provisions regarding submission of nonpublic information and how the public
disclosure provisions of this rule apply
to non-public information. The
proposed ‘‘GRAS exemption claim’’ is
the precursor of Part 1 of a GRAS notice
(which we are establishing in
§ 170.225). The rule specifies that you
must not include any information that is
trade secret or confidential commercial
information in Part 1 of your GRAS
notice, except in the statement of your
view as to whether any of the data and
information in Parts 2 through 7 of your
GRAS notice are exempt from disclosure
under the FOIA. Part 1 of a GRAS notice
includes signed statements and a
certification, not ‘‘safety data.’’ The
‘‘safety data’’ would be included in
Parts 2 through 7 of the GRAS notice.
Consistent with the view of this
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comment, the rule provides that those
data and information are available for
public disclosure upon receipt (see
§ 170.275(a)(2)). See also Response 50.
(Comment 122) Some comments ask
us to alert the notifier, and grant the
notifier an option to withdraw the
notice, in order to protect information
designated as confidential from
disclosure.
(Response 122) We decline this
request. A person who submits a record
to us may not withdraw that record from
our files (§ 20.29). Rather, the
procedures that govern the release of
information that a notifier identifies as
confidential in a GRAS notice are
established in §§ 20.61 and 20.27. Under
§ 20.61(d), a person who submits
records to us may designate part or all
of the information in such records as
exempt from disclosure under
exemption 4 of FOIA. However, under
§ 20.27 marking records submitted to us
as confidential, or with any other
similar term, raises no obligation by
FDA to regard such records as
confidential, to return them to the
person who has submitted them, to
withhold them from disclosure to the
public, or to advise the person
submitting them when a request for
their public disclosure is received or
when they are in fact disclosed.
XXII. Submission of a Supplement
The rule provides that you may
submit a supplement to a GRAS notice
after we respond to your notice based on
our evaluation of your notice or cease to
evaluate your notice (§ 170.280).
However, if our response to your GRAS
notice raises questions about your
conclusion that the notified substance is
GRAS under the conditions of its
intended use, the appropriate
mechanism for you to address those
questions would be to submit a new
GRAS notice or other regulatory
submission (such as a food additive
petition) rather than to submit a
supplement. See section III.C.2 of
CFSAN’s 2010 experience document for
examples of supplements that CFSAN
received during the Interim Pilot
program (Ref. 18).
XXIII. Comments on the Administrative
Process for Pending GRAS Affirmation
Petitions
We proposed that any pending
petitions would be presumptively
converted to a GRAS notice on the date
the final rule becomes effective
(proposed § 170.36(g)(1)). An affected
petitioner would have an opportunity to
amend the converted petition to meet
the requirements of the GRAS
notification procedure by submitting a
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‘‘GRAS exemption claim’’ (proposed
§ 170.36(g)(2)). A GRAS affirmation
petition that is converted to a notice and
that the affected petitioner amends
would be reviewed and administered
according to the provisions of the GRAS
notification procedure; the date of
receipt of the amendment would be the
date of receipt of the notice (proposed
§ 170.36(g)(3)(i)). After 90 days from the
date of publication of the final rule, we
would inform any affected petitioner
who had not amended an applicable
petition that the converted petition is
inadequate as a GRAS notice.
In the 2010 notice, we requested
comments on three issues related to the
pending petitions as shown in table 23.
Although the 2010 notice classified all
of these issues as ‘‘Issue 17,’’ for
presentation purposes in this document
we classify the three issues as 17a, 17b,
and 17c.
TABLE 23—ISSUES IN THE 2010 NOTICE REGARDING PENDING GRAS AFFIRMATION PETITIONS
Issue
No.
Description of our request for comment
17a ....
How to reduce the impact on affected petitioners while retaining the principle that we will not devote
resources to pending petitions.
Whether an outcome of ‘‘withdrawal without prejudice’’ instead of ‘‘insufficient basis’’ would be more
appropriate when an affected petitioner simply chooses not to have the pending petition considered under the GRAS notification procedure.
Whether an affected petitioner could request that we incorporate into a GRAS notice a withdrawn
GRAS affirmation petition into a GRAS notice, and if so, if any requirements of the GRAS notification procedure should be waived.
17b ....
17c ....
In the following paragraphs, we
discuss comments regarding the
disposition of pending petitions in light
of the deletion of the GRAS affirmation
petition process. After considering these
comments, we are establishing
Reference
provisions for the pending petitions as
shown in table 24, with editorial,
clarifying, and conforming changes as
shown in table 29. (See § 170.285.)
Table 24 identifies changes we made
relative to the proposed rule or the
75 FR 81536 at 81542–81543.
75 FR 81536 at 81542–81543.
75 FR 81536 at 81542–81543.
description in the 2010 notice other
than the editorial, clarifying, and
conforming changes shown in table 29
and the additional editorial changes
associated with the redesignation of
proposed § 170.36(g) as § 170.285.
TABLE 24—FINAL REQUIREMENTS FOR DISPOSITION OF PENDING GRAS AFFIRMATION PETITIONS
Proposed
designation in the
regulatory text
(§ )
170.285(a) ..............
170.36(g)(1) ...........
17a and 17b
170.285(b) ..............
170.36(g)(2) ...........
17c
N/A .........................
170.36(g)(3)(i) ........
N/A
On the effective date of the rule, we will
close the docket for any GRAS affirmation petition that is still pending as
of that date.
Any person who submitted a GRAS affirmation petition that is pending as of
the date of the final rule may submit
a GRAS notice and request that we
incorporate the GRAS affirmation petition.
N/A .........................................................
N/A .........................
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Final designation in
the regulatory text
(§ )
170.36(g)(3)(ii) .......
17a and 17b
N/A .........................................................
Issue No. in
the 2010
notice
(Comment 123) Some comments to
the proposed rule support our proposal
to convert pending GRAS affirmation
petitions to GRAS notices on the
effective date of the rule. However, as
discussed in the 2010 notice, many
comments to the proposed rule object to
our proposal for administering the
pending petitions as being
fundamentally unfair, because an
affected petitioner had invested
considerable time and resources in the
petition process and should not be
penalized by our adoption of a new
GRAS notification procedure. Some of
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these comments state that, in most
cases, FDA also had dedicated
significant resources to the review of
these petitions and, in some cases, had
even arranged for an additional third
party to review the substance that was
the subject of the petition. These
comments suggest options such as
‘‘grandfathering’’ pending petitions, i.e.,
completing the rulemaking process for
them, particularly if we had completed
our scientific review with no
outstanding questions. Some comments
ask us to provide an affected petitioner
180 days, rather than 90 days, to amend
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clarifying, and conforming changes)
relative to the proposed rule or the
2010 notice
Description
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We administratively close the docket for
the GRAS affirmation petition rulemaking rather than convert the pending petition to a GRAS notice.
The affected petitioner submits a GRAS
notice rather than an amendment to a
‘‘converted petition’’.
No longer specifies the procedures for
FDA’s evaluation of a former pending
petition.
No longer treats a pending petition that
is not evaluated as a GRAS notice as
having an insufficient basis to support
GRAS status.
the converted petition to satisfy the
requirements of the GRAS notification
procedure. One of these comments
argues that there need not be any
urgency in closing the applicable files
because many of these petitions had
been pending for years, and the subjects
of the petitions had been marketed
during those years.
Some comments to the proposed rule
assert that more resources would be
needed to review a petition that is
converted to a GRAS notice than would
be needed to complete the review of
each pending petition and issue a
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regulation. One comment suggests that
it would be simpler and more efficient
administratively to allow an affected
petitioner an option to update a GRAS
affirmation petition to include
additional conditions of use or new
specifications than to require separate
GRAS notices for such changes.
Other comments ask us to clarify the
procedures we would use to convert a
GRAS affirmation petition to a GRAS
notice as well as procedures for
amending a petition that was converted
to a GRAS notice through an additional
submission. Some comments assert that
we should not require an affected
petitioner to submit such an amendment
because all of the pertinent information
would already be included in the
petition and argue that technical
adherence to the format of a GRAS
notice should not take precedence over
administrative efficiency and common
sense. Other comments express concern
that it was not clear that the proposed
additional submission (proposed
§ 170.36(g)(2)) was in fact a skeleton
notice that primarily would crossreference the original GRAS affirmation
petition.
Some comments to the 2010 notice
suggest that a pending petition could be
‘‘withdrawn without prejudice’’ or
‘‘suspended’’ so that it would no longer
require FDA resources to review it.
Other comments to the 2010 notice
express the view that a simple letter of
conversion should be adequate, but that
if an affected petitioner chose not do so
then the outcome of the converted
petition would more appropriately be
described as ‘‘withdrawn without
prejudice’’ rather than ‘‘insufficient’’ as
a GRAS notice. Other comments to the
2010 notice continue to express the
view that we should ‘‘grandfather’’ a
pending petition. One of these
comments asserts that failure to
grandfather those affirmation petitions
where FDA had completed its review
and no outstanding scientific issues
exist would be unfair because the GRAS
notification procedure results in a lower
level of authoritativeness than the GRAS
affirmation petition process, and the
affected petitioners had invested
considerable time and resources in the
petition process. This comment also
notes that after we published the
proposed rule we continued to review
GRAS affirmation petitions and
completed the process for six GRAS
affirmation petitions before
discontinuing further activity in 1999.
Comments that address Issue 17c
recommend that an affected petitioner
be allowed to incorporate information
from a ‘‘withdrawn’’ GRAS affirmation
petition into a GRAS notice.
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We received no comments asking us
to waive any of the requirements of the
notification procedure.
(Response 123) We have revised the
proposed provisions regarding the
disposition of pending petitions in light
of the concern of the comments that the
proposed process was unfair to affected
petitioners. The final rule provides that
on the effective date of the rule, we will
close the docket for any GRAS
affirmation petition that is still pending
as of that date (§ 170.285(a)). Any
person who submitted a GRAS
affirmation petition that is pending as of
the date of the final rule may submit a
GRAS notice and request that we
incorporate the GRAS affirmation
petition (§ 170.285(b)). We are closing
the docket for the petition by operation
of law because the process that would
be necessary to bring a petition to
closure (i.e., § 170.35(c)) no longer
exists. We decided to close the docket
for the petition, rather than classify the
petition as withdrawn without
prejudice, for two reasons. First, closing
the docket is an administrative option
that is open to us, whereas in our
petition processes withdrawing a
petition is an option that falls to the
petitioner (see, e.g., § 171.1(j) for
withdrawal of a food additive petition
without prejudice). Second,
‘‘withdrawal without prejudice’’
generally means ‘‘without prejudice to a
future filing,’’ and ‘‘future filing’’ refers
to the same type of filing; however, we
have eliminated the GRAS affirmation
petition process and, thus, an affected
petitioner could not submit another
GRAS affirmation petition.
Closing the docket is neutral with
respect to a conclusion by an affected
petitioner that the petitioned substance
is GRAS under the conditions of its
intended use, because closing the
docket does not result in a publicly
available ‘‘insufficient basis letter.’’ To
clarify that closing the petition is
without prejudice to eligibility for
classification of the use of the substance
as GRAS, the final rule specifically
provides that an affected petitioner may
incorporate the former GRAS
affirmation petition into a GRAS notice.
Given the passage of time since the
pending petitions were submitted, it is
likely that some of the data and
information in the petition would need
to be updated. In addition, the affected
petitioner would need to follow all
format requirements for a GRAS notice,
including the narrative required in Part
6 of a GRAS notice.
We acknowledge that our response to
a GRAS notice does not have the same
level of ‘‘authoritativeness’’ as a listing
in our regulations. However, some of the
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55025
comments that objected to the proposal
to convert a pending petition to a GRAS
notice assert that the substances that are
the subject of the pending petitions have
been marketed for years; clearly, these
affected petitioners are able to market
the substance without a listing in our
regulations.
We agree that it is appropriate to
extend the timeframe for an affected
petitioner to take action with respect to
a pending petition. Under final
§ 170.285(b), there is no limit on the
timeframe for an affected petitioner to
submit a GRAS notice that incorporates
a GRAS affirmation petition.
We decline the request to
‘‘grandfather’’ any pending petitions.
We simply do not have sufficient
resources to devote to the rulemaking
process that is required for GRAS
affirmation, regardless of whether we
already have completed our scientific
review. For example, even if we have
completed our scientific review, the
Administrative Procedures Act (5 U.S.C.
553) requires that we consider relevant
data, views, or arguments submitted to
us by interested persons and that we
publish a concise general statement of
the basis and purpose of the regulation.
In addition, Executive Order 12866
requires that we assess the costs and
benefits of available regulatory
alternatives when we conduct
rulemaking, and the Regulatory
Flexibility Act (5 U.S.C. 601–612)
requires that we consider alternatives
that would minimize the economic
impact of our regulations on small
entities. Thus, to complete the
rulemaking associated with the GRAS
affirmation petition process, we require
significant resources beyond those
associated with scientific review. Even
if we did ‘‘grandfather’’ a pending
petition, it is highly unlikely that we
would be able to devote resources to
this voluntary process in light of
competing programs that are required by
statute. For example, the resources that
could be directed to the GRAS
affirmation petition process must be
considered together with the resources
that are required to administer the food
and color additive petition processes
and the premarket notification process
for food contact substances, which are
required programs under sections 409
and 721 of the FD&C Act.
For the reasons discussed in the
previous paragraph, we disagree that we
would have needed more resources to
review a petition that is converted to a
GRAS notice than to complete the
review of each pending petition and
issue a regulation. We also disagree that
it would be simpler and more efficient
administratively to allow an affected
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petitioner an option to update a GRAS
affirmation petition. As discussed in
CFSAN’s 2016 experience document
(Ref. 19), during the 10-year period
extending from 1990 through 1999,
CFSAN completed the rulemaking
process for 24 GRAS affirmation
petitions, with an average elapsed time
of approximately 7.9 years (median
elapsed time approximately 6.9 years).
In contrast, under the final rule we will
respond to a GRAS notice in 180 days,
with an option to extend the timeframe
by an additional 90 days (see Response
98).
As of August 17, 2016 there are 45
pending GRAS affirmation petitions. We
intend to contact each affected
petitioner to inform the petitioner that:
(1) We are closing the affected docket as
of October 17, 2016; and (2) the
petitioner may submit a GRAS notice
that incorporates the former GRAS
affirmation petition.
(Comment 124) One comment asks us
to issue a regulation, to be included in
part 184, that lists the pending petitions.
The comment also asks us to include a
statement that the lack of an affirmation
regulation does not indicate that FDA
disagrees with the affected petitioner’s
GRAS determination.
(Response 124) We decline this
request. Our regulations in part 184
represent our own conclusions
regarding the GRAS status of a listed
substance under the conditions of its
intended use. It is inappropriate for our
regulations to become a catalog of
circumstances where we have not
reached our own conclusion regarding
GRAS status.
However, under final § 170.275(b), we
will make a list of filed GRAS notices
readily accessible to the public. The
inventory of GRAS notices that
currently makes this list available
includes a link to information about
each listed GRAS notice. When the
GRAS notice was originally submitted
as a GRAS affirmation petition, we have
included the petition number. We
intend to continue this practice under
the final rule.
We also have placed a list of the
pending petitions that we are closing in
the docket for this rule (Ref. 48).
XXIV. Other Comments
A. GRAS Panels and Conflict of Interest
In the 2010 notice, we explained that
the GAO report noted that we have not
issued any conflict of interest guidance
that companies can use to help ensure
that the members of their expert panels
are independent (75 FR 81536 at 81542).
The GAO report recommended that we
develop a strategy to minimize the
potential for conflicts of interest,
including taking steps such as issuing
guidance for companies on conflict of
interest and requiring information in
GRAS notices regarding expert
panelists’ independence. In the 2010
notice, we requested comments on three
issues related to GAO’s
recommendation regarding conflict of
interest as shown in table 25. Although
the 2010 notice classified all of these
issues as ‘‘Issue 15,’’ for presentation
purposes in this document we classify
the three issues as 15a, 15b, and 15c.
TABLE 25—ISSUES IN THE 2010 NOTICE REGARDING GUIDANCE ON CONFLICT OF INTEREST
Issue
No.
Description of our request for comment
15a ....
Whether companies would find it useful to have guidance on potential conflicts of interest of GRAS
expert panelists.
If guidance on potential conflicts of interest of GRAS expert panelists would be useful, what companies currently do to mitigate such a conflict.
Whether to require that GRAS notices include information regarding expert panelists’ independence
15b ....
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15c ....
(Comment 125) Most of the comments
that addressed Issues 15a and 15b ask us
to provide guidance regarding potential
conflicts of interest of GRAS panel
members. One of these comments
provided an example of a draft guidance
for our consideration. Other comments
provide criteria that they ask us to
consider in the guidance. One comment
asks us to provide an opportunity for
industry, academia, and the public to
comment on our proposed course of
action for the topic of conflict of
interest.
One comment asserts that there is no
need for guidance regarding potential
conflicts of interest of GRAS panel
members because industry is aware of
the importance of disclosing and
addressing potential conflicts of interest
and often has Standard Operating
Procedures delineating rules for
disclosure.
(Response 125) We have decided to
issue guidance regarding conflict of
interest. We will do so as Level 1
guidance within the framework of our
good guidance practices regulation (see
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Reference
§ 10.115(c) and (g)). Under that
framework, we prepare a draft of Level
1 guidance and then: (1) Publish a
notice in the Federal Register
announcing that the draft guidance
document is available; (2) post the draft
guidance document on the Internet and
make it available in hard copy; and (3)
invite public comment on the draft
guidance document. After providing an
opportunity for public comment on a
Level 1 guidance document, FDA will:
(1) Review any comments received and
prepare the final version of the guidance
document that incorporates suggested
changes, when appropriate; (2) publish
a notice in the Federal Register
announcing that the guidance document
is available; (3) post the guidance
document on the Internet and make it
available in hard copy; and (4)
implement the guidance document. We
will consider the recommendations and
draft guidance submitted in the
comments to this rule in developing our
draft guidance for public comment.
We acknowledge that some members
of industry are aware of the importance
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75 FR 81536 at 81542.
75 FR 81536 at 81542.
75 FR 81536 at 81542.
of disclosing and addressing potential
conflicts of interest. However, we
disagree that this awareness means that
we should not issue a guidance
regarding conflict of interest. A
guidance from us on conflict of interest
could promote consistency in
addressing conflict of interest by
different companies.
(Comment 126) One comment notes
that an external GRAS panel is not
required for a conclusion of GRAS
status when the conclusion is supported
by peer-reviewed literature or a ‘‘long
history of safe use.’’ (By ‘‘long history of
safe use,’’ we assume that the comment
is referring to the provision that GRAS
criteria may be satisfied through
experience based on common use in
food prior to January 1, 1958. See
§ 170.30(a) and (c)).
(Response 126) We agree that an
external GRAS panel is not required for
a conclusion of GRAS status. As we
previously noted, convening a GRAS
panel has historically been a way to
provide evidence that generally
available data and information are
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generally accepted by the expert
scientific community, but convening a
GRAS panel is not the only way to
provide such evidence (62 FR 18938 at
18943).
(Comment 127) Some comments
address Issue 15c and recommend that
a notifier include information on
independence of the panel members in
a submitted GRAS notice.
(Response 127) The rule neither
requires that a notifier convene a GRAS
panel nor establishes any other
requirements applicable to a GRAS
panel. Therefore, we are addressing
issues regarding a GRAS panel in
guidance rather than in the regulation.
See also Comment 14 and Response 14.
B. Guidance on Documenting
Conclusions of GRAS Status
In the 2010 notice, we explained that
the GAO report recommended that we
issue guidance on how to document a
conclusion of GRAS status (75 FR 81536
at 81542). We noted that there is
55027
guidance in the preamble to the
proposed rule and in our guidance for
industry entitled ‘‘Frequently Asked
Questions About GRAS’’ (Ref. 49). We
requested comments on two issues
related to guidance on documenting a
conclusion of GRAS status as shown in
table 26. Although the 2010 notice
classified both of these issues as ‘‘Issue
16,’’ for presentation purposes in this
document we classify the two issues as
16a and 16b.
TABLE 26—ISSUES IN THE 2010 NOTICE REGARDING GUIDANCE ON DOCUMENTING GRAS CONCLUSIONS
Issue
No.
Description of our request for comment
16a ....
Whether there is a need to clarify that our guidance applying to GRAS submissions also applies to
a GRAS conclusion that is not submitted to us in the form of a GRAS notice.
Whether there is a need for us to develop further guidance on documenting a GRAS conclusion
when the GRAS conclusion is not submitted to us as a GRAS notice.
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16b ....
(Comment 128) Most of the comments
that addressed Issue 16a recommend
that we clarify that the same standards
apply to a conclusion of GRAS status
regardless of whether the conclusion is
submitted to us as a GRAS notice or is
not submitted to us.
(Response 128) To reach a conclusion
of GRAS status, the proponent of GRAS
status must: (1) Establish that the
substance is safe under the conditions of
its intended use within the meaning of
section 409(c)(5) of the FD&C Act and
our implementing regulation in
§ 170.3(i); and (2) establish that the
safety of the substance under the
conditions of its intended use is
generally recognized within the
meaning of section 201(s) of the FD&C
Act and our regulations in § 170.30
governing the eligibility for
classification as GRAS. See the
discussion in section I.C of the proposed
rule of the elements of the GRAS
standard, where we described the
evaluation of safety as the ‘‘technical
element’’ of the GRAS standard and the
evaluation of general recognition as the
‘‘common knowledge element’’ of the
GRAS standard. In considering whether
GRAS criteria are satisfied because the
available data and information
demonstrate that the use of a substance
is safe and the safety is generally
recognized, we do not distinguish
between a conclusion of GRAS status
submitted to us as a GRAS notice and
an independent conclusion of GRAS
status that remains with the proponent.
As discussed in Response 41, in this
rulemaking we made conforming
changes to current regulations regarding
the use of GRAS substances in food, and
our affirmation of GRAS status on our
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Reference
own initiative, to emphasize that point
(see the changes to §§ 170.3(i) and (k),
170.30(c), 170.30(e), and 170.35(a) and
(b) in table 29). As already noted in
section I.E of this document, we advise
any company that intends to market a
food substance on the basis of an
independent conclusion of GRAS status
to carefully consider whether this use
fully satisfies the criteria for eligibility
for classification as GRAS and to
carefully review the discussions in this
document relevant to those criteria,
such as the discussion in Response 9
regarding the role of corroborative data
and information, the discussions in
Response 10 and Response 11 regarding
the limitations of a published report of
a GRAS panel, and the discussion in
Response 69 regarding the ramifications
of providing trade secret information (or
other non-public information) to a
GRAS panel.
Our 2004 guidance entitled
‘‘Frequently Asked Questions About
GRAS’’ generally applies to a
conclusion of GRAS status regardless of
whether that conclusion of GRAS status
is submitted to us as a GRAS notice.
Exceptions include current questions
specific to the notification procedure as
it operated during the Interim Pilot
program, such as ‘‘Where do I send my
GRAS notice? ’’ We are modifying that
guidance to update it in light of the
publication of this rule.
We believe that the provisions of the
GRAS notification procedure in part
170, subpart E will be a useful resource
to any person who intends to use a
substance in food based on a conclusion
of GRAS status, regardless of whether
the conclusion of GRAS status is
submitted to us in a GRAS notice or is
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75 FR 81536 at 81542.
75 FR 81536 at 81542.
an independent GRAS conclusion that
is not submitted to us. For example, the
requirements in Part 3 of a GRAS notice
make clear that a conclusion of GRAS
status requires consideration of dietary
exposure. Likewise, the requirements in
Part 6 of a GRAS notice demonstrate the
importance of a complete and balanced
evaluation of all applicable data and
information, including data and
information that are, or may appear to
be, inconsistent with a conclusion of
GRAS status. Therefore, we recommend
that any person who intends to use a
substance in food based on a conclusion
of GRAS status, but does not intend to
submit a GRAS notice to us, use the
provisions of part 170, subpart E as
guidance. We also recommend that such
persons organize the data and
information that support an
independent conclusion of GRAS status
according to the organization presented
by Parts 1 through 7 of a GRAS notice.
Doing so would facilitate our evaluation
of that independent conclusion of GRAS
status if circumstances warrant, e.g., if
we have cause to question the
independent conclusion of GRAS status.
Because we make information about
GRAS notices readily accessible to the
public, we also recommend that you
make the basis for your independent
GRAS conclusion publicly available
(e.g., by making publicly available a
document analogous to the narrative of
a GRAS notice, a report of a GRAS panel
(if you convene a GRAS panel), or both
a narrative and a report of a GRAS
panel).
General recognition of safety based
upon scientific procedures requires the
same quantity and quality of scientific
evidence as is required to obtain
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approval of a food additive regulation
for the ingredient (§ 170.30(b)). We
address scientific issues associated with
demonstrating the safety of a food
substance in a series of guidance
documents on our Internet (Ref. 6, Ref.
25, and Ref. 32 through Ref. 35).
Currently, some of these scientific
guidance documents are expressly
directed to evaluation of the safety of
food additives. For example, in
Response 66 we noted that our guidance
entitled ‘‘Recommendations for
Submission of Chemical and
Technological Data for Direct Food
Additive Petitions’’ (Ref. 31) currently is
structured to address the specific
requirements of a food additive petition,
even though many of the
recommendations in that guidance
could nonetheless be useful to any
person who evaluates whether a
substance is GRAS under the conditions
of its intended use. As resources allow,
we intend to re-visit these scientific
guidance documents to determine
whether and how to modify them to
clarify that our guidance on evaluating
the safety of a food substance generally
applies regardless of whether the
substance would be used in food as a
food additive or as a GRAS substance.
Regardless of any implication, in the
title or text of these guidance
documents, that the subject of the
document applies to a food additive, we
recommend that you consider that the
scientific recommendations in these
guidance documents may also apply to
substances that would be used in food
on the basis of a GRAS conclusion.
Some scientific guidance documents
already do make clear that they apply
regardless of the regulatory status of a
substance (e.g., as a food additive, color
additive, food contact substance, or
GRAS substance) (Ref. 6). In addition, as
discussed in Response 37, we recently
issued a notice announcing a public
meeting, and requesting comments, on
our intent to update our guidance
entitled ‘‘Guidance for Industry and
Other Stakeholders: Toxicological
Principles for the Safety Assessment of
Food Ingredients’’ (79 FR 64603), and
reiterated that general recognition of
safety based upon scientific procedures
requires the same quantity and quality
of evidence as is required to approve a
food additive.
(Comment 129) Some comments
support issuing additional guidance on
documenting a conclusion of GRAS
status, particularly for a GRAS
conclusion that is not submitted to us.
One comment asserts that there is no
need for us to develop additional
guidance on documenting a conclusion
of GRAS status that is not submitted to
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us. One comment agrees with the
recommendation in the GAO report that
we take steps to ensure that companies
maintain proper documentation to
support a conclusion of GRAS status.
(Response 129) We agree that
companies should maintain proper
documentation to support a conclusion
of GRAS status. As we discussed in the
proposed rule (62 FR 18938 at 18947),
any person who concludes that a
substance is GRAS under the conditions
of its intended use should have
assembled and evaluated the evidence
that forms the basis of that conclusion,
regardless of whether the person
subsequently notifies us. Preserving the
applicable data and information
represents prudent practice for those
who assert that the statutory premarket
review requirements do not apply to the
use of a substance in food.
To emphasize the importance of
maintaining the data and information
that support an independent conclusion
of GRAS status, we are issuing a
guidance directed to any person who
evaluates whether the available data and
information regarding the safety of a
substance under the conditions of its
intended use satisfy GRAS criteria. The
purpose of the guidance is to: (1)
Remind such persons of their
responsibilities under the FD&C Act
regarding a conclusion of GRAS status,
regardless of whether the conclusion of
GRAS status is submitted to us as a
GRAS notice; and (2) refer such persons
to key resources, such as those
discussed in Response 128, for
evaluating the safety of the substance
under the conditions of its intended use
and for evaluating whether the available
data and information regarding safety
satisfy the criteria for eligibility for
classification as GRAS in § 170.30. We
believe that such guidance is
appropriate in light of the
recommendations of the GAO report.
C. Compliance With Other FDA
Regulations
We proposed that a GRAS notice
would not constitute compliance with
the requirements for a health claim
petition in § 101.14(b)(3)(ii) or for a new
infant formula submission in
§ 106.120(b)(6)(ii). We specified that any
person who submits a health claim
petition, or who submits a new infant
formula submission, must comply in
full with the requirements of the
applicable program (proposed
§ 170.36(a)(2)).
(Comment 130) Several comments
object to the perceived implication that
a GRAS notice could never be used to
support a health claim petition or a new
infant formula submission. In general,
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the comments maintain we should
consider, on a case-by-case basis,
whether a particular GRAS notice is
sufficient to comply with the
requirements of the applicable program
rather than categorically disallow a
GRAS notice as a means for satisfying
the requirements of the applicable
program.
(Response 130) We are not including
this proposed provision in the final rule
because it is not necessary to do so. Any
person who submits a health claim
petition, or who submits a new infant
formula submission, must comply in
full with the requirements of the
applicable program whether this rule
says so or not. An FDA office that
evaluates a health claim petition or a
new infant formula submission will take
into account our response to a GRAS
notice when evaluating the health claim
petition or new infant formula
submission. In practice during the
Interim Pilot program, an FDA office
evaluated a health claim petition or a
new infant formula submission for
several substances that were the subject
of a previously submitted GRAS notice.
In each case, FDA’s evaluation of the
health claim petition or new infant
formula submission had an outcome
that was consistent with our response to
that GRAS notice (see section IV.A of
CFSAN’s 2010 experience document
(Ref. 18)).
D. Impact on Other Federal Agencies
In our discussion in the proposed rule
of the proposed procedures for making
information about GRAS notices readily
accessible to the public, we stated our
belief that there would be considerable
interest, from a broad segment of the
public, including other Federal
agencies, in notices received under the
proposed notification procedure (62 FR
18938 at 18952). We also stated our
expectation that such groups will likely
want to know whether we are aware that
a substance is being used in food on the
basis of the GRAS provision and
whether we have advised a notifier that
we have identified a problem with the
notice.
(Comment 131) The Bureau of
Alcohol, Tobacco and Firearms (BATF)
(in the U.S. Department of the Treasury
(now TTB) submitted a comment stating
that it has no major problem with our
proposal to replace the GRAS
affirmation petition process with a
notification procedure, but that there are
two ways in which the proposed rule
would impact TTB. First, TTB’s wine
regulations in 27 CFR 24.250
(Application for use of new treating
material or process) require that a
proprietor who wishes to use a new
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wine treating material submit to TTB an
application that includes documentary
evidence of FDA’s approval of the
material under the conditions of its
intended use. If we issue a final rule to
establish a GRAS notification
procedure, TTB would need to amend
this requirement to state that TTB needs
either evidence of FDA approval or
evidence that FDA has been notified of
a conclusion of GRAS status and has no
questions about that conclusion.
Second, certain alcoholic beverage
products require formula approval by
TTB due to the ingredients (such as
colors, flavors, herbs, and spices) in the
products. Currently, TTB requires that
these ingredients be approved by FDA
before TTB approves the formula. If we
issue a final rule to establish a GRAS
notification procedure, TTB would still
check the ingredients in these formulas
before approving the formula, but could
accept evidence that FDA has been
notified of a conclusion of GRAS status
and has no questions about that
conclusion.
TTB asks us to include the conditions
of use in our response to a GRAS notice
so that TTB would know the parameters
that FDA evaluated in considering the
GRAS notice (i.e., the foods and
beverages and the amounts in those
foods and beverages). TTB also asks us
to publish and update a list of GRAS
notices on a frequent basis, and to
include the conditions of use that FDA
evaluated in this list.
(Response 131) The provisions of this
rule are consistent with TTB’s requests.
The rule specifies that we will make a
list of filed GRAS notices, including the
information described in § 170.225(c)(2)
through (c)(5), readily accessible to the
public (see § 170.275(b)(1)). The
information the rule specifies will be
readily accessible includes the intended
conditions of use of the notified
substance, including the foods in which
the substance will be used, the levels of
use in such foods, and the purpose(s) for
which the substance will be used (see
§ 170.225(c)(4)). The response letters
that we issued during the Interim Pilot
program described the conditions of use
of the notified substance, and we intend
to continue describing the conditions of
use of the notified substance in letters
issued under the final rule.
(Comment 132) Some comments
assert that our affirmation of GRAS
status established a clear standard that
was needed by other Federal agencies to
carry out their own regulatory
responsibilities. The comments cite
BATF (now TTB), FSIS (in USDA), and
EPA as examples of such Federal
agencies. In general, these comments
maintain that the applicable Federal
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agency must be able to accept our
response to a GRAS notice in lieu of a
regulation affirming GRAS status. One
comment notes that the proposed rule
did not explicitly address the impact of
the proposed rule on other Federal
agencies and urges us to consult with
the cited Federal agencies prior to
issuing the final rule.
(Response 132) None of the Federal
agencies cited by these comments have
advised us that the absence of a
regulation affirming GRAS status for the
use of a food substance would preclude
the applicable Agency from carrying out
its statutory responsibilities. As
discussed in the following paragraphs,
we have interacted with each of these
agencies as requested.
TTB. As discussed in section IV.B of
CFSAN’s 2010 experience document
(Ref. 18), during the Interim Pilot
program CFSAN received and filed
several GRAS notices for substances
intended for use in alcoholic beverage
products. These notices demonstrate
that manufacturers of alcoholic beverage
products are aware of the GRAS
notification procedure and are using
GRAS notices as a means to satisfy
TTB’s regulations. As also discussed in
section IV.B of CFSAN’s 2010
experience document (Ref. 18), on
September 29, 2005, representatives of
TTB met with representatives of CFSAN
in the offices of CFSAN’s Office of Food
Additive Safety. At that meeting,
representatives of CFSAN described the
GRAS notification procedure that was
operating under the framework of the
proposed rule. CFSAN provided a copy
of TTB’s comments to these
representatives, and none of TTB’s
representatives expressed any concern
about the operation of the program.
FSIS. As discussed in section III.L of
CFSAN’s 2010 experience document
(Ref. 18), during the period 1998
through 2009 more than 25 percent of
GRAS notices filed by CFSAN described
use of the notified substance in meat,
meat food products, or poultry products.
During CFSAN’s review of these GRAS
notices, CFSAN consulted with FSIS
regarding the use of the applicable
substance. FSIS provided feedback to
CFSAN about the use of the notified
substance in products regulated by FSIS
and requested that CFSAN provide this
feedback to the notifier. In 2000, FDA
and FSIS formalized this process of
inter-agency consultation in a MOU (65
FR 33330, May 23, 2000). Subsequently,
FDA and FSIS have amended the MOU
to include simultaneous evaluation of
substances subject to regulation by
USDA under the Egg Products
Inspection Act (21 U.S.C. 1033(a)(2))
(Ref. 36). The final rule includes the
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55029
procedures CFSAN will use when
coordinating its evaluation of a GRAS
notice with FSIS (see § 170.270).
EPA. CFSAN has discussed the
concerns raised by these comments with
representatives from EPA (Ref. 50). The
representatives from EPA deferred to
CFSAN regarding the appropriate
process for voluntary interaction
between us and the regulated industry
with respect to GRAS substances.
E. Impact on International Trade
In the proposed rule, we requested
comment on whether the proposed
substitution of a GRAS notification
procedure for the GRAS affirmation
petition process would have any impact
on international trade (62 FR 18938 at
18955).
(Comment 133) Comments that
responded to this request for comment
express the view that whether the
proposed substitution of a GRAS
notification procedure for the GRAS
affirmation petition process would have
a positive, neutral, or negative impact
on international trade would depend on
the nature of our response to a GRAS
notice, particularly when we do not
question the notifier’s basis for a
conclusion of GRAS status. The
comments explain that the proposed
rule could have a positive or neutral
impact on international trade if our
response is clear and definitive,
provides regulatory significance, and is
as affirmative as possible, but could
have a negative impact on international
trade if our response is neutral or vague.
One comment expresses the opinion
that any impact on international trade
would be minimal because JECFA
frequently assesses uses of a food
ingredient, and foreign regulatory
agencies frequently reach a decision to
allow uses of a food ingredient, before
we complete our rulemaking under the
GRAS affirmation petition process.
(Response 133) The ‘‘no questions
letters’’ we issued during the Interim
Pilot program make clear that the
notifier (rather than FDA) is responsible
for the conclusion of GRAS status, and
place our statement that we have no
questions about the notifier’s conclusion
of GRAS status in the contexts of both
time and the available data and
information (see table 1). These features
of the ‘‘no questions letters’’ make the
letters clear and definitive and provide
regulatory significance (i.e., regulatory
status), and we intend to retain these
features in letters we issue under the
final rule. Moreover, the fact that many
GRAS notices were submitted by foreign
firms demonstrates that foreign firms
see value in submitting GRAS notices to
us (Ref. 51).
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Under the final rule, we will respond
to a GRAS notice within 180 days after
we file a submission as a GRAS notice,
with an option to extend the timeframe
by an additional 90 days as needed (see
§ 170.265(b)(1)). As discussed in
Response 123, during the ten year
period extending from 1990 through
1999, we completed the rulemaking
process for 24 GRAS affirmation
petitions, with an average elapsed time
of approximately 7.9 years (median
elapsed time approximately 6.9 years).
Thus, we believe that the GRAS
notification procedure will come to
closure more quickly than the GRAS
affirmation petition process.
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F. Audits
In the proposed rule, we stated that it
would be prudent for us monitor
compliance with the essence of the
statutory requirements for GRAS status
(i.e., that there is common knowledge
among qualified experts that there is
reasonable certainty that the substance
is not harmful under the conditions of
its intended use) and announced that
we intended to conduct random audits
of data and information maintained by
the notifier (62 FR 18938 at 18947). In
addition, because the proposed
substitution of a GRAS notification
procedure for the GRAS affirmation
petition process would allow us to
direct our resources to priority
questions about GRAS status, we might
conduct an audit on a broad issue or
class of products if the issue or use of
a class of products raises important
public health issues.
(Comment 134) One comment asks us
to renew our commitment to random
auditing to ensure that companies
maintain proper recordkeeping
practices.
(Response 134) As discussed in
section IV.C of CFSAN’s 2010
experience document (Ref. 18), during
the Interim Pilot program, CFSAN did
not conduct any random audits of data
and information maintained by the
notifier. However, CFSAN did not
hesitate to ask a notifier to provide
certain data or information as an
amendment to a GRAS notice. (See also
the discussion in section III.C.1 of
CFSAN’s 2010 experience document
regarding amendments to GRAS
notices.) In essence, CFSAN used its
resources to seek access to data and
information on a priority, rather than a
random, basis. At this time, we intend
to continue directing our resources on a
priority basis under the final rule.
(Comment 135) One comment asks us
to provide a notifier with the option of
converting a GRAS notice to a GRAS
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affirmation petition if we audit the data
supporting a GRAS notice.
(Response 135) As discussed in
Response 24 and Response 123, we have
eliminated the former GRAS affirmation
petition process. Therefore, the
administrative process requested by
these comments is no longer operative.
(Comment 136) One comment asks us
to incorporate two procedures to avoid
any uncertainty regarding the results of
the audit. First, the comment asks us to
provide the notifier with a letter
confirming that the audit is completed
and we have no basis to question the
conclusion of GRAS status if that is the
outcome of our audit. Second, the
comment asks us to apply any appeal
mechanism specified by the rule to
circumstances in which we question a
conclusion of GRAS status based on an
audit.
(Response 136) We decline these
requests. If we have no questions about
the notifier’s conclusion of GRAS status,
we would respond with a ‘‘no questions
letter’’ based on our evaluation of the
entire GRAS notice, not based solely on
the results of an audit of the data and
information maintained by the notifier
to support the notifier’s GRAS notice.
As discussed in Response 108, the rule
does not include an appeals process that
would be specific to the GRAS
notification procedure.
(Comment 137) One comment
suggests that our audit examine the
same ‘‘quantum of evidence’’ as we
would review to affirm GRAS status,
and asserts that a strong statement of
confidence, if not outright affirmation,
would be appropriate after successful
completion of this type of an indepth
review.
(Response 137) The purpose of the
audit would be to verify that a notifier
maintains the data and information
specified in the notice, not to conduct
a full scientific evaluation of those data
and information (62 FR 18938 at 18947).
Therefore, we decline the request to
examine the same ‘‘quantum of
evidence’’ as we would review to affirm
GRAS status. Because the purpose of an
audit would be to verify compliance
with the statutory requirements for
GRAS criteria, we disagree our response
to a GRAS notice following a favorable
audit should result in a ‘‘strong
statement of confidence’’ rather than a
‘‘no questions letter.’’ However, we
intend that our response letter would
mention any audit that we conduct
before responding to a GRAS notice.
G. Lack of an Environmental
Assessment
(Comment 138) One comment
suggests that a GRAS notice is ideal in
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circumstances where our evaluation of
an environmental assessment, which is
required for a food additive petition,
precludes timely action by us on a
petition.
(Response 138) We advise potential
notifiers that the lack of a requirement
to submit an environmental component
(e.g., an environmental assessment) with
a GRAS notice does not eliminate a
notifier’s responsibility to comply with
applicable Federal, State, tribal, and
local law or requirements regarding
protection of the environment.
H. Substances Affirmed as GRAS With
Specific Limitations
(Comment 139) One comment asks us
to ‘‘modernize the standard’’ in
§ 184.1(b)(2) to allow expedited review
under the notification program of new
uses of substances affirmed as GRAS
under § 184.1(b)(2). (Section 184.1(b)(2)
specifies that if an ingredient is affirmed
as GRAS with specific limitation(s), it
shall be used in food only within such
limitation(s), including the category of
food(s), the functional use(s) of the
ingredient, and the level(s) of use, and
any use of such an ingredient not in full
compliance with each such established
limitation shall require a food additive
regulation.)
(Response 139) We decline the
request to amend § 184.1(b) beyond the
editorial, clarifying, and conforming
changes listed in table 29. The comment
provides no basis for us to do so. As
discussed during the rulemaking to
establish § 184.1(b)(2) (41 CFR 53600 at
53601, December 7, 1976), that
regulation does not require that a
subsequent use be covered by a food
additive regulation even though it may
be GRAS. As an alternative to a food
additive regulation, the regulation
affirming a substance as GRAS with
specific limitations on the conditions of
use may be amended to cover additional
uses that have become GRAS.
Importantly, both mechanisms (i.e., food
additive regulation and GRAS
affirmation regulation) require
rulemaking, and the appropriate
mechanism for a manufacturer to
lawfully use a substance outside the
limitations established in a regulation
affirming specific uses of the substance
as GRAS with specific limitations is to
submit a petition to us. A manufacturer
may submit a food additive petition
asking us to conduct rulemaking that
results in a food additive regulation;
alternatively, now that the GRAS
affirmation petition process is no longer
operative, the manufacturer may submit
a citizen petition in accordance with
§ 10.30 asking us to conduct rulemaking
that amends the regulation affirming a
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substance as GRAS with specific
limitations on the conditions of use.
(See also Ref. 4.58 to CFSAN’s 2010
experience document).
See section III.N.2 of CFSAN’s 2010
experience document (Ref. 18) for a
discussion of a GRAS affirmation
petition to amend a specific regulation
that affirmed a substance as GRAS with
specific limitations on the conditions of
use; we converted that GRAS
affirmation petition to a food additive
petition and authorized the additional
conditions of use in a food additive
regulation. We advise persons who wish
to petition us to provide for additional
uses of substances that have been
affirmed as GRAS with specific
limitations that under § 10.30(e) we may
advise that we are denying the request
to initiate rulemaking to amend the
GRAS affirmation regulation, but note
that we could accommodate the request
to conduct rulemaking through the food
additive petition process.
XXV. Comments on Substances
Intended for Use in Animal Food
A. Issues in the 2010 Notice Specific to
Animal Food
In the 2010 notice, we discussed
several issues associated with the
requirements for a GRAS notice for an
intended use in animal food to consider
dietary exposure (see table 27).
Although we discussed these issues in
a section entitled ‘‘Dietary exposure,’’
these issues broadly applied to several
55031
provisions of the rule (see, e.g.,
§§ 570.30, 570.225(c)(4), 570.235,
570.245, and 570.250). In the following
sections, we discuss how comments on
these issues, and associated conforming
changes, lead to specific revisions to the
regulatory text. See table 28 for the
principal changes specific to the
proposed animal food rule other than
the editorial, clarifying, and conforming
changes shown in table 29 and the
additional editorial changes associated
with the redesignation of the proposed
notification procedure (proposed
§ 570.36) as part 570, subpart E. Table
28 does not include those changes that
we made to the proposed requirements
when we made an analogous change to
the human food regulations in part 170.
TABLE 27—ISSUES IN THE 2010 NOTICE SPECIFIC TO ANIMAL FOOD
Issue
No.
Description of our request for comment
11c ....
Whether it is necessary to clarify that the GRAS notification procedure is applicable to substances
used in both food and drinking water of animals and, if so, whether it would be necessary to clarify this in the provisions of the proposed notification procedure.
Whether it is necessary to clarify proposed § 570.36(c)(1)(iii) to explicitly require submission of information about the animal species expected to consume the substance.
Whether it is necessary to clarify applicable sections of the proposed rule to explicitly require, for
substances intended for use in the food of an animal used to produce human food, the submission of information about both target animal and human safety.
11d ....
11e ....
Reference
75 FR 81536 at 81541.
75 FR 81536 at 81541.
75 FR 81536 at 81541.
TABLE 28—SUMMARY OF PRINCIPAL CHANGES SPECIFIC TO THE PROPOSED ANIMAL FOOD RULE
Regulatory section in the final rule
Change
§ 570.30(a), (b), and (c) ..................
Specify that general recognition of safety is based on data and information that addresses safety for both
the target animal and for humans consuming human food derived from food-producing animals.
Requires you to describe the intended conditions of use of a notified substance in animal food by specifying the levels of use in foods or drinking water.
In part 3 of your GRAS notice, you must provide data and information about exposure to the target animal
and to humans consuming human food derived from food-producing animals.
You must explain how the generally available data and information in your notice provide a basis for your
view that the notified substance is generally recognized as safe, among qualified experts, under the conditions of its intended use for both the target animal and for humans consuming human food derived
from food-producing animals.
§ 570.225(c)(4) ................................
§ 570.235 .........................................
§ 570.250(a) and (b) .......................
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B. Criteria for Eligibility for
Classification as GRAS for a Substance
Intended for Use in Animal Food
(§ 570.30)
(Comment 140) Comments that
address Issue 11e agree that data and
information in a GRAS notice must be
sufficient to address safety for both the
target animal and for humans
consuming human food derived from
food-producing animals (see Comment
150 and Comment 151).
(Response 140) We have modified
several provisions of the GRAS
notification procedure to specify how
the notifier must provide data and
information to address the safety of the
notified substance under the conditions
of its intended use for both the target
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animal and for humans consuming
human food derived from foodproducing animals (see §§ 570.225(c)(4),
570.235, 570.245, and 570.250). To
clarify that the submission requirements
reflect the GRAS criteria for the use of
a substance in animal food, we also
have modified § 570.30(a), (b), and (c) to
specify that general recognition of safety
is based on data and information that
addresses safety for both the target
animal and for humans consuming
human food derived from foodproducing animals. See the regulatory
text of § 570.30. See also Response 141
regarding the definition of common use
in food in § 570.3(f).
(Comment 141) One comment notes
that the proposed human food
regulations, but not the proposed animal
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food regulations, include specific
criteria for eligibility for classification as
GRAS through experience based on
common use in food prior to 1958 when
that use occurred exclusively or
primarily outside the United States (see
§ 170.30(c)(2)). This comment asks us to
maintain parallel criteria for eligibility
for classification as GRAS through
experience based on common use in
food in the human food regulations and
the animal food regulations by
amending § 570.30(c) of the animal food
regulations to include a provision
analogous to § 170.30(c)(2).
(Response 141) We are amending
§ 570.30(c) to include a provision
analogous to § 170.30(c)(2). See the
regulatory text of § 570.30(c)(1) and (2).
For consistency with the clarifying
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amendment to the general criteria in
§ 570.30(a), we also are revising
§ 570.30(c) to clarify that general
recognition of safety through experience
based on common use in food shall
address safety for both the target animal
and for humans consuming human food
derived from food-producing animals.
For consistency with the clarifying
amendment to the general criteria in
§ 570.30(a), we also are revising the
definition of common use in food to
mean a substantial history of
consumption of a substance by a
significant number of animals of the
species to which the substance is
intended to be fed (and, for foodproducing animals fed with such
substance, also means a substantial
history of consumption by humans
consuming human foods derived from
those food-producing animals), prior to
January 1, 1958 (see § 570.3(f) and table
29).
C. Part 1 of a GRAS Notice for a
Substance Intended for Use in Animal
Food: Name of the Notified Substance
(§ 570.225(c)(3))
As shown in table 6, in the 2010
notice we asked for comment on
whether to require that the GRAS notice
include the name of the notified
substance, using an appropriately
descriptive term, instead of the
‘‘common or usual name’’ of the notified
substance (Issue 7). The final rule
requires that Part 1 of a GRAS notice for
an intended use of a notified substance
in animal food include the name of the
notified substance, using an
appropriately descriptive term
(§ 570.225(c)(3)). The appropriately
descriptive term may be the same as the
common or usual name of the
substance. You may consult with CVM’s
staff in operating divisions that address
the labeling requirements of the FD&C
Act, currently CVM’s Division of
Animal Feeds, regarding any common
or usual name for a substance used in
animal food. In addition, for substances
used in animal food, the Association of
American Feed Control Officials
(AAFCO) annually publishes its Official
Publication, a handbook which
contains, among other things, Official
Feed Terms, which define many of the
terms commonly used in the animal
food manufacturing industry. It also
contains Official and Tentative
Definitions of Feed Ingredients, a set of
definitions for ingredients commonly
used in animal food. Under CVM’s
Compliance Policy Guide CPG 665.100
(Common or Usual Names for Animal
Feed Ingredients), the definitions, as
they appear in the AAFCO Official
Publication, are generally regarded as
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constituting the common or usual name
for animal food ingredients, including
pet food (Ref. 52).
D. Part 1 of a GRAS Notice for a
Substance Intended for Use in Animal
Food: Intended Conditions of Use
(§ 570.225(c)(4))
(Comment 142) One comment asks us
to require that a notifier specify whether
the intended use of the notified
substance is in food or in drinking
water. Another comment asks CVM to
accept the anticipated consumption
levels by animals that are based upon
general formulation principles that
consider the availability of
contemporary feedstuffs.
(Response 142) The final
requirements for Part 1 of a GRAS notice
require you to describe the intended
conditions of use of a notified substance
in animal food by stating whether the
substance will be added to food
(including drinking water) for animals
in which the substance will be used,
and by identifying the foods to which it
will be added and the levels of use in
such foods (see § 570.225(c)(4)). In
describing the levels of use of the
notified substance, you may base the
levels of use upon general formulation
principles that consider the availability
of contemporary feedstuffs. See also
Response 148 regarding the calculation
of target animal exposure.
(Comment 143) Some comments ask
us to specifically require submission of
information about the animal species
expected to consume the substance. One
comment states that specifying the
target animal is as important as
specifying whether the substance would
be consumed by humans in human food
derived from the animal. Another
comment suggests that requiring
submission of information about the
animal that would consume the
substance would avoid the unnecessary
delays associated with CVM’s questions
that result in an amendment to the
notice with information about the
animal species expected to consume the
substance.
(Response 143) The final
requirements for Part 1 of a GRAS notice
require you to describe the intended
conditions of use of a notified substance
in animal food, including the animal
species for which the foods are
intended. In addition, the final
requirements for Part 1 of a GRAS notice
specify that in describing the intended
conditions of use of a notified substance
in animal food, you must, when
appropriate, describe any
‘‘subpopulation’’ expected to consume
the notified substance; the life stage of
an animal is an example of what we
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mean by ‘‘subpopulation.’’ The
physical, physiologic, and absorption/
distribution/metabolism/elimination
characteristics of a given animal species
may vary based on life stages within the
same animal species. A substance that is
safe for use in an animal species at one
stage of life may not be safe for use in
the same animal species at a different
stage of life. See also Response 51.
E. Part 2 of a GRAS Notice for a
Substance Intended for Use in Animal
Food: Data and Information Bearing on
the Physical or Other Technical Effect of
the Notified Substance (§ 570.230(d))
(Comment 144) Several comments
discuss CVM’s practice, during the
Interim Pilot program, of asking a
notifier to provide data or information
demonstrating the effectiveness, or
utility, of the substance. Some
comments ask us to limit the
notification procedure to the
information necessary to conduct an
appropriate safety assessment, without
submission of additional data and
information to demonstrate the
technical effect of the substance within
animal food in cases where the
technical effect has no impact on safety.
Some comments agree that the intended
conditions of use of the notified
substance in animal food must be
described and supported in the notice,
but assert that the need for utility data
generated from target animal feeding
studies is inappropriate and
unnecessary because the pivotal issue is
whether the ingredient is safe to feed to
animals.
(Response 144) We have added a
requirement for Part 2 of a GRAS notice
to include relevant data and information
bearing on the physical or other
technical effect the notified substance is
intended to produce, including the
quantity of the notified substance
required to produce such effect, when
necessary to demonstrate safety (see
§ 570.230(d)). We agree that data and
information bearing on the physical or
other technical effect the notified
substance is intended to produce are
only necessary when they bear on
safety. This relationship to safety is
consistent with the requirements of the
FD&C Act for a petition to establish the
safety of a food additive (see section
409(b)(2)(C) of the FD&C Act).
The physical or other technical effects
of substances added to animal food fall
into two main categories: (1) Substances
fed for a nutritive effect in the animal
(e.g., providing one or more nutrients or
other nutritive effect); and (2)
substances that have technical effects in
the food (e.g., anti-caking agents,
binders, emulsifiers, enzymes, mixing
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aids, preservatives, processing aids,
stabilizers, and substances added for
aroma, flavor, or other technical effects)
rather than nutritive effects in the
animal. As discussed in the following
paragraphs, a substance added for either
a nutritive effect or for a technical effect
in animal food can have an impact on
safety for the target animal.
Nutritive effect in the animal. Data
and information bearing on the nutritive
effect of a substance may be necessary
to demonstrate safety because animals
(e.g., food-producing animals,
companion animals) typically are fed
the same diet formula for long periods
of their life. These diets are formulated
to supply all of the animal’s daily
nutrient needs for a specific life stage
(e.g., growth, reproduction, adult
maintenance). The diet must provide
appropriate amounts of all nutrients the
animal requires in a form that the
animal can use and consume daily;
otherwise, a nutrient deficiency or
toxicity can result, causing adverse
effects to animal health, including poor
growth, excessive weight loss, organ
system failures, and death. Under these
constraints of how animals are fed, a
substance intended to provide one or
more nutrients becomes unsafe if the
nutrients are, in fact, not provided in a
form usable by the animals consuming
the diet.
The typical approach to support the
nutritive effect of a substance intended
for use in animal food is to combine
generally available and accepted data
and information about the general
function of the substance with animal
feeding studies demonstrating that the
substance acts as intended. When an
appropriate animal feeding study (i.e.,
an animal feeding study that is relevant,
properly designed, and well-controlled)
is already generally available (e.g., in
the peer-reviewed scientific literature),
it can be possible to support the
nutritive effect of a substance without
conducting a new study. If an
appropriate animal feeding study is not
already generally available, an animal
feeding study specifically conducted to
support the nutritive effect would
ordinarily be published and, as
discussed in Response 19, there would
be a time gap between the publication
of the study and the use of the
published study to support a conclusion
of GRAS status. (As discussed in
Response 9, unpublished studies can be
used to corroboratively support the
intended nutritive effect of the
substance under the conditions of its
intended use.) In addition, for any
animal feeding study a factor to be
considered is whether data and
information obtained from a feeding
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study conducted in one animal species
(or in one stage of life of an animal
species) can be used to support safety in
another animal species (or in a different
stage of life in the same animal species).
See Response 145 for a discussion of
when data and information that are
obtained from an animal study and bear
on the nutritive effect of a substance
could be extrapolated from one animal
species to another animal species, or to
a different stage of life of the same
animal species. In the following
paragraphs, we provide examples of
when data and information bearing on
the nutritive effect of a substance
intended for use in animal food could
be established through the use of
generally available and accepted data
and information, or likely would need
to be established through an animal
feeding study that specifically supports
the nutritive effect of the substance
under the conditions of its intended use.
For some types of substances,
generally available and accepted data
and information about the function of a
substance may be adequate to support
the nutritive effect of the substance
without also relying on an animal
feeding study. For example, generally
available and accepted data and
information about the function of fat
and carbohydrates as sources of dietary
energy often can be used for substances
providing fat intended as a source of
dietary energy (rather than as a source
of essential fatty acids) and for
substances providing carbohydrates
intended as a source of dietary energy.
Likewise, generally available and
accepted data and information about the
nutritive content of human food can
provide support for the nutritive effect
of unsalable human food products (such
as bruised produce) being collected for
animal food use for their nutritional
content rather than entering landfills or
being incinerated.
For other types of substances, an
animal feeding study (whether
previously published or newly
conducted) is the norm to support the
nutritive effect of the substance. For
example, for an ingredient that is
intended to supply an essential mineral
(such as phosphorus or zinc), generally
available data and information can
provide support that the mineral is an
essential nutrient for the animal, but the
bioavailability of the mineral in the
ingredient that would be added to
animal food generally needs to be
determined in an animal feeding study
conducted with that specific ingredient,
because data regarding the amount of
the mineral that is added to the feed in
the ingredient (or that can be detected
analytically in the feed or in the
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ingredient) would not provide evidence
that the mineral is in a form that is
available to the animal. However, for an
ingredient that is intended to provide an
essential amino acid, the need for an
animal feeding study can depend on the
form and composition of the ingredient.
For example, it can be possible to rely
on published literature to establish that
a crystalline amino acid will be
bioavailable to an animal (and, thus,
functional). However, if a complex
matrix, such as a biomass composed of
microbial cells or a processed oilseed
meal, is intended to be a source of
amino acids, an animal feeding study
generally would be needed to provide
evidence that the bioavailability of the
amino acids has not been adversely
impacted by the other substances
present in the complex matrix.
Technical effect in the food (rather
than nutritive effect in the animal). As
with a substance intended to provide a
nutritive effect in the animal, data and
information bearing on a substance’s
technical effect in the food (e.g.,
substances such as anti-caking agents,
binders, emulsifiers, enzymes, mixing
aids, preservatives, processing aids,
stabilizers, and substances added for
aroma, flavor or other technical effects)
may be necessary to demonstrate safety
because of the physical form and
properties of animal diets. Although
generally available and accepted data
and information can provide evidence
of a technical effect in the food, it is
common for studies to be conducted
with the animal food to demonstrate the
intended technical effect. Depending on
the intended technical effect, an animal
feeding study (whether previously
published or newly conducted) may be
also needed to demonstrate the intended
technical effect of the substance. In the
following paragraphs, we provide
examples of when animal feeding
studies may be needed to support the
intended technical effect of the
substance. We also provide examples of
when an intended technical effect in
animal food could be established
through the use of generally available
and accepted data and information
about the technical effect and the
studies conducted with the intended
animal food matrix. As with a substance
intended to provide a nutritive effect in
the animal, when an appropriate study,
which may be an animal feeding study,
is already generally available (e.g., in
the peer-reviewed scientific literature),
it can be possible to support the
technical effect of a substance in the
food without conducting a new study. If
an appropriate study is not already
generally available, a study conducted
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to support the technical effect in the
food would ordinarily be published and,
as discussed in Response 19, there
would be a time gap between the
publication of the study and the use of
the published study to support a
conclusion of GRAS status.
Enzymes are often added to animal
food to alter the bioavailability of
nutrients already in the food. For
example, it is well known that the
enzyme phytase increases the
bioavailability to animals of the
phosphorus present in grain (Ref. 53),
and substances that provide phytase
activity are often added to diets for
poultry and swine. Poultry and swine
diets are typically formulated with the
minimal amount of phosphorus. If the
phytase enzyme does not carry out the
effect of improving phosphorus
availability to the animal as intended,
the consequence will be a diet that is
deficient in phosphorus and therefore
results in adverse impacts on animal
health in the form of decreased growth,
increased orthopedic disease (e.g.,
rickets), and suffering animals (Ref. 54).
As another example, protease enzymes
can be added to an animal food to affect
the digestibility of proteins in the food
(Ref. 55). Both animal feeding studies
and stability studies (to assess the
stability of the enzyme in the food and,
thus, its ability to perform its intended
technical effect) are the norm when
enzymes are added to animal food.
However, when the function of an
enzyme in animal food is well known,
it is also common to use generally
available and accepted data and
information about the function of the
enzyme in combination with animal
feeding studies and stability studies to
support the function of the enzyme (see
section IV in CVM’s experience
document (Ref. 20)).
Substances such as binders,
lubricants, and pelleting agents are
added to animal food that will be fed as
pellets. In some cases, such substances
are added to ensure that the pellet
retains its desired form and that the
individual ingredients remain
agglomerated, making it more difficult
for an animal to select only those
ingredients it prefers. In aquaculture
foods, such substances are added to
prevent the pellet from dissolving or
prevent the nutrients from leaching out
of the pellet. Depending on the
circumstances, either technical effect
studies conducted with the animal food,
or generally available and accepted data
and information about the function of
the substance, can be used to support
the intended technical effect, such as
that of a binder, lubricant, or pelleting
agent, etc., when added to animal food.
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Flavors are added to animal food for
certain species, generally for specific
life stages of that species. For example,
flavors can be added to animal food
intended for consumption by piglets
being transitioned from a milk-based
diet to a commercial growth diet to
increase consumption of the commercial
growth diet. Flavors also are added to
commercial animal food intended for
aquaculture to attract newly hatched
fish (fish fry) to the commercial food
when the commercial food does not
resemble the food that fish fry would
consume in nature. If the fish fry are not
attracted to the commercial food, the
fish fry can starve to death. Animal
feeding studies are the norm to support
the function of the substance as a flavor
when added to animal food.
Substances such as emulsifiers and
stabilizers are added to animal food to
ensure that an animal consumes all of
the ingredients in the correct
proportions in order to meet its
nutritional needs. Inconsistent nutrient
content and delivery of a diet to the
animal can cause either nutrient
deficiency diseases, or toxicities. For
example, liquid cattle foods are often
available to the animal at all times and
cattle simply lick the feeding device to
obtain the food. If the minerals present
in the liquid fall out of suspension and
settle to the bottom, the first animals to
access the feeder will consume lower
nutrient levels than expected, while
those animals that access the feeder
later and consume the bottommost
material may be at risk of toxicity due
to higher nutrient levels. For dry
ingredients, the ingredients in the
formulated diet must be uniformly
dispersed and mixed, remain mixed
during handling, and be physically
stable as a formulated animal diet is
moved through augers and conveyors,
and transported in bulk in trucks, which
can result in the loss of nutrients
through sifting or ‘‘unmixing.’’ These
effects are assessed on the diet itself
through appropriate studies.
(Comment 145) One comment asks us
to accept reasonable arguments as to the
worst-case exposures (inclusion levels)
if the substance or class of substances
has well-established use patterns rather
than require utility data to support the
intended nutritional effect. This
comment also asks us to be flexible
when utility data are warranted to
support an entirely new use in animal
feeds when utility data from one
representative species would be
sufficient to address utility in the target
animal.
(Response 145) When animal feeding
studies are necessary to provide data
and information bearing on the nutritive
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effects of a substance intended for use
in animal food, the potential to
extrapolate from the conclusions of a
feeding study conducted in one animal
species to another animal species
depends on the similarities of their
digestive systems, physiology, and diets.
For example, when a bioavailability
study for selenium present in selenium
yeast is conducted in cattle (which have
a fermentative digestive tract), it can be
possible to extrapolate the conclusions
of that bioavailability study to other
animal species that have fermentative
digestive tracts. However, when a
bioavailability study for copper is
conducted in a ruminant animal
species, it may not be appropriate to
extrapolate the conclusions of that
bioavailability study to sheep, even
though sheep are ruminants, because
sheep physiology is such that sheep are
much more sensitive to copper toxicity
than other ruminant species. In
addition, when a bioavailability study
for a nutrient is conducted in animals
other than fish, it may not be possible
to extrapolate the conclusions of that
bioavailability study to aquaculture-fed
fish, because aquaculture diets that are
consumed in the water present special
challenges, particularly for slow-feeding
or bottom-feeding aquaculture species,
where the diet pellet must retain its
form and nutrient content until the
pellet is consumed. For example, it is
possible for nutrients that are soluble in
water to dissolve out of the pellet before
consumption, preventing the
aquaculture animal from accessing all
the required nutrients.
See Response 144 for a discussion of
circumstances where generally available
and accepted data and information can
be used to provide evidence bearing on
the nutritive effects of a substance
intended for use in animal food (e.g., for
substances providing fat intended as a
source of dietary energy, for substances
providing carbohydrates intended as a
source of dietary energy, for unsalable
human food products, and when a
crystalline amino acid is added to
animal food). See also Response 150 for
additional discussion of limitations on
the use of generally available and
accepted data and information, such as
a weight of evidence approach, for the
extrapolation of available data and
information from an animal species
other than the target animal.
Regardless of whether the intended
use of the notified substance is to
provide nutritive value or technical
effect, any person who concludes that
the available data and information
regarding the safety of a notified
substance under the conditions of its
intended use satisfy GRAS criteria must
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have a basis for the conclusion of GRAS
status, irrespective of whether that
person notifies us of that conclusion in
a GRAS notice. If you submit your
conclusion of GRAS status to FDA, you
must explain how the data and
information in your GRAS notice
provide the basis for your conclusion,
e.g., in Part 2 of the GRAS notice (where
you would describe the applicable data
and information), in the narrative in
Part 6 of your GRAS notice, or in both
Parts 2 and 6 of your GRAS notice. We
would then evaluate whether the data,
information, and narrative in your
GRAS notice support your conclusion.
When data and information bearing on
the physical or other technical effect of
the notified substance are necessary to
support safety, we could conclude that
a GRAS notice that does not discuss
such data and information is
incomplete, and either contact a notifier
to request an amendment discussing
such data and information, or issue an
insufficient basis letter.
(Comment 146) One comment asserts
that a requirement for proof of utility,
with subsequent publication of utility
data, is unnecessary, and that a
requirement for utility data to be
documented by means of a peerreviewed publication would burden the
industry with additional cost, not only
to conduct the studies but also to
prepare the manuscript and have it
accepted for publication. This comment
also asserts that finding a journal
willing to publish such germane studies
may be challenging because the
manuscript may be viewed as serving
the manufacturer’s interest rather than
providing any new scientific
information. As alternatives to
publication of a target animal feeding
study, this comment suggests means
such as documenting the chemical
nature of the substance in relation to
same (or similar) substance with ample
public information, and placing
unpublished studies conducted by the
notifier in the context of published
literature about the use of the substance
or related substances. This comment
also asserts that CVM and industry
resources could be better utilized to
demonstrate the safety of the intended
use of the substance with a focus on
establishing the worst-case exposure
and relating it to available safety
information to establish a margin of
safety.
(Response 146) See Response 15, in
which we respond to comments
asserting it can be difficult to publish
data and information that do not raise
an issue of concern. Consistent with
CFSAN’s experience during the Interim
Pilot program, we believe that some
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journals directed to food safety would
be willing to publish data and
information bearing on the physical or
other technical effect the notified
substance is intended to produce when
those data and information are
necessary to demonstrate safety (see
section III.A.1 of CFSAN’s 2010
experience document (Ref. 18)).
See also Response 144 for a
discussion of circumstances where
generally available and accepted data
and information can be used to provide
evidence bearing on the nutritive effects
of a substance intended for use in
animal food. There may be situations
where sufficient generally available and
accepted data and information on
exposure to the substance or class of
substances can satisfy GRAS criteria
without publication of specific data and
information bearing on the physical or
other technical effect the notified
substance is intended to produce. For
example, as discussed in section IV of
CVM’s experience document during the
Interim Pilot program CVM responded
with a ‘‘no questions letter’’ when the
use of published information for
technical effects such as nutrient,
enzyme, and component of a defoamer
was used, in whole or in part, to support
such technical effects (Ref. 20). As
discussed in Response 12, GRAS status
may be corroborated by unpublished
scientific data, information, or methods,
and there may be some unpublished
scientific data, information, or methods
regarding the safety of a use of a food
substance. As discussed in Response 8,
the criteria for GRAS status through
scientific procedures provide for the
application of ‘‘generally available and
accepted’’ scientific data, information,
or methods, which ‘‘ordinarily’’ are
published and, thus, provide flexibility
for supporting a conclusion of GRAS
status through the application of
scientific data, information, or methods
that are generally available through a
mechanism other than publication in a
peer-reviewed scientific journal.
See the discussion in Response 150
regarding the evaluation of safety
studies, including the applicability of
worst-case exposure on a case-by-case
basis.
F. Part 3 of a GRAS Notice for a
Substance Intended for Use in Animal
Food: Target Animal and Human
Exposures (§ 570.235)
1. Substances Intended for Use in Food
or Drinking Water for Animals
(Comment 147) Comments that
address Issue 11c support clarifying that
the GRAS notification procedure is
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applicable to substances used in both
food and drinking water of animals.
(Response 147) The final
requirements for Part 3 of a GRAS notice
specify that ‘‘animal food’’ includes
‘‘drinking water.’’ See also Response
142.
2. Data and Information About the
Dietary Exposure for the Target Animal
(Comment 148) One comment states
that exposure information can usually
be obtained from published data sources
and that if a worst-case exposure cannot
be established without new data, then
data for one representative animal
species are sufficient, especially if the
selected species represents a worst-case
scenario. As an example, the comment
suggests that data from one
representative poultry species would be
sufficient to address the conditions of
use of a notified substance intended for
poultry. As noted in Comment 142,
another comment asks CVM to accept
the anticipated consumption levels by
animals that are based upon general
formulation principles that consider the
availability of contemporary feedstuffs.
(Response 148) See the regulatory text
of § 570.235(a) for the requirements for
what you must provide in Part 3 of a
GRAS notice regarding exposure to the
target animal. The regulatory text
addressing the types of exposure to the
target animal parallels the regulatory
text for dietary exposure to a notified
substance in the human food regulations
(see § 170.235). As noted in Response
142, you may base the levels of use
upon general formulation principles
that consider the availability of
contemporary feedstuffs. We agree that
exposure information may be available
from published data sources. If exposure
cannot be established without new data,
then data for one representative animal
species may be sufficient if the selected
species represents a worst-case scenario.
(Comment 149) One comment asks
that any restatement of the regulatory
text regarding dietary exposure consider
how to use the word ‘‘consumer,’’
because ‘‘consumers’’ are humans for
the purpose of part 170 but are
‘‘animals’’ for the purpose of part 570.
(Response 149) To reduce the
potential for confusion, the final
requirements for part 3 of a GRAS notice
for a substance intended for use in
animal food do not use the term
‘‘consumer.’’
G. Data and Information in a GRAS
Notice About Safety for the Target
Animal (§ 570.250)
(Comment 150) Comments that
address Issue 11e agree that data and
information in a GRAS notice must be
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sufficient to address safety for the target
animal. However, most of these
comments express concern about the
standard for demonstrating safety to the
target animal, specifically whether
safety must be established through
feeding studies specific to the target
animal or could be extrapolated from
data and information regarding species
other than the target animal. Although
one comment asserts that a notifier must
submit evidence that the substance is
safe for all the species in question if a
substance is expected to be consumed
by different animal species, other
comments emphasize that safety could
be established through either feeding
studies in the target animal or through
extrapolation of data obtained from
species other than the target animal.
Some comments suggest that the rule
require a clear and concise written
explanation of how studies in non-target
species relate to the target animal rather
than require safety data in the target
animal species.
One comment disagrees that the
GRAS notification procedure should
establish any absolute requirement for
data addressing safety for the target
species. This comment asserts that CVM
should not require species-specific data
for all substances and species covered
by the intended use of the notified
substance because recognized scientific
procedures, such as a weight of
evidence approach, allow for the
extrapolation of data and that these
types of scientific procedures can be
applied to notified substances. This
comment also asserts that a CVM
requirement for safety data in the target
animal, rather than a written
explanation of how studies in non-target
species relate to the target animal,
cannot be scientifically justified and
will put the animal feed industry at a
disadvantage for obtaining recognition
of new GRAS substances, and that the
additional cost and time will stifle
innovation and reduce growth in the
U.S. feed industry and animal
agriculture.
(Response 150) Whether speciesspecific data and information (such as
feeding studies) are necessary to satisfy
GRAS criteria depends on the intended
use of the notified substance. We
recognize that there may be situations
where scientific procedures, such as a
weight of evidence approach, allow for
the extrapolation of available data and
information from an animal species
other than the target animal. For
example, CVM had no questions
regarding an enzyme preparation
intended for use in food for turkeys,
broiler chickens, and laying hens, when
the feeding studies used to support
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target animal safety were conducted
only on broiler chickens (Ref. 20). In
such cases, you would explain the
relevance of the available data to the
target species in the narrative required
in Part 6 of a GRAS notice rather than
describe species-specific data and
information.
However, extrapolating data from one
animal species to another is not always
appropriate because a substance that is
safe for use in one animal species may
not be safe for use in another species or
in the same species at a different stage
of life. For example, a substance that is
safe for use in a species that is a
ruminant animal (e.g., cattle) may not be
safe for use in a species considered a
monogastric animal (e.g., swine)
because of the difference in their
digestive systems and different nutrient
requirements. For example, in ruminant
animals, non-protein nitrogen
compounds (e.g., urea and biuret)
release ammonia, which is then
metabolized by rumen microorganisms
into microbial proteins. These microbial
proteins are a useful source of protein
to ruminant animals. However, in
monogastric animals, the liberated
ammonia from non-protein nitrogen
compounds is absorbed directly by the
animal, resulting in adverse
toxicological events, and possibly death.
Even within the same species of animal,
or for different species in the same class
of animals (e.g., chicken, duck, turkey),
extrapolating safety data may not be
appropriate. For example, a substance
that is safe for laying hens may not be
safe for use in broilers because of the
different nutrient requirements, such as
the higher calcium level in a laying hen
diet (which is intended to meet the
nutrient demand for egg production). If
that high level of calcium is consumed
by broiler chickens, the potential
calcification of soft tissue such as that
of kidneys could become detrimental to
the broiler chickens. Likewise, a
substance that is safe for chickens may
not be safe for ducks or turkeys because
the nutrient requirements for different
species of poultry vary widely. Feeding
a diet intended for one species of
poultry to another species could cause
nutrient imbalances, deficiencies, or
excesses, which could have adverse
consequences ranging from loss of
production to damages to tissues and
organs and even to death. When
extrapolating data and information from
another animal species is not
appropriate, in Part 6 of your GRAS
notice you would discuss data and
information developed specifically for
the target animal, or for the stage of life
in the same animal species, rather than
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explain how you extrapolated available
data and information from an animal
species other than the target animal, or
how you extrapolated available data and
information from the same animal
species to a different life stage of that
animal species.
Any person who concludes that the
available data and information regarding
the safety of a notified substance under
the conditions of its intended use satisfy
GRAS criteria must have a basis for the
conclusion of GRAS status, regardless of
whether that person notifies us of that
conclusion in a GRAS notice. A
resource that may help determine when
it could be appropriate to extrapolate
species-specific data and information
from one animal species to another
animal species is our guidance entitled
‘‘Guidance for Industry:
Recommendations for Preparation and
Submission of Animal Food Additive
Petitions’’ (# 221) (June 2015) (Ref. 56).
Section G.2 of that guidance (on target
animal safety) recommends that target
animal safety studies be conducted
using the life stage and animal species
for which the food additive will be
marketed. In cases where the food
additive is intended for multiple animal
species or life stages, the food additive
should be tested in the most sensitive
life stage and/or species. The guidance
recommends using current scientific
literature to identify the most sensitive
life stage and/or species. As with
guidance documents prepared by
CFSAN, CVM’s scientific
recommendations in a guidance
directed to food additives can be
applied to the evaluation of whether a
substance is GRAS under the conditions
of its intended use (see Response 66).
Another resource is a book entitled
‘‘Safety of Dietary Supplements for
Horses, Dogs, and Cats’’ by the National
Research Council (Ref. 57), which
identifies five factors to consider when
selecting appropriate surrogates for
horses, dogs and cats. In addition, it
advises considering nutritional,
metabolic, pharmacokinetic, and natural
dietary patterns when selecting
appropriate animal model species.
Although the material is directed to
only three target animals, some aspects
of its approach can be generalized.
If you submit your conclusion of
GRAS status to FDA, you must explain
how the data and information in your
GRAS notice provide the basis for your
conclusion; we would then evaluate
whether the data, information, and
narrative in your GRAS notice support
your conclusion.
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H. Data and Information in a GRAS
Notice About the Safety for Humans
Consuming Human Food Derived From
a Food-Producing Animal (§§ 570.235
and 570.250)
(Comment 151) Some comments
support clarifying the rule to explicitly
require the submission of information
about safety for both the target animal
and for humans consuming human food
derived from food-producing animals.
One comment states that the safety and
wholesomeness of food given to animals
that eventually end up in human food
must be held to the same standard as for
a substance intended for use in human
food. Another comment asks us to
specify that the submission of data and
information about both target animal
and human safety is required when such
data and information are developed for
food-producing animals.
One comment states that it is the
responsibility of the notifier to
determine the extent of the safety
assessment of a substance intended for
use in the food of a food-producing
animal. This comment asserts that there
is no need to set explicit standards for
addressing both target animal and
human food safety in applicable
sections of the rule, because whether
new data, such as tissue residue data,
would be warranted would be
determined through application of
general scientific principles from the
fields of animal nutrition and
metabolism.
Another comment asserts that neither
human feeding studies nor tissue
residue accumulation data should be
required when available scientific
information can be used to draw
conclusions using a weight of the
evidence approach, as CFSAN does for
human food substances. This comment
asserts that CVM must clarify what data
need to be provided regarding safety for
humans consuming human food derived
from food-producing animals before
industry could agree to the requirement.
(Response 151) We are clarifying the
requirement to address safety for
humans consuming human food derived
from food-producing animals in Parts 3
and 6 of a GRAS notice.
In the requirements for Part 3 of a
GRAS notice for a substance intended
for use in animal food, we have
modified the title of the regulatory text
to specify that Part 3 addresses
exposures to both the target animal and
to humans consuming human food
derived from food-producing animals
(see § 570.235). When the intended use
of the notified substance is in food for
food-producing animals, you must
provide: (1) The potential quantities of
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any residues that humans may be
exposed to in edible animal tissues; and
(2) the data and information you rely on
to establish the potential quantities of
such residues (see § 570.235(b)). These
requirements parallel the requirements
for target animal exposure, but are
directed to the quantity of potential
residues of the notified substance, and
of any other substance that is expected
to be formed in or on the animal food
because of the use of the notified
substance, and those residues from any
other substances present with the
notified substance, whether naturally,
due to its manufacture (e.g.,
contaminants or by-products), or
produced as a metabolite in edible
animal tissues when the notified
substance is consumed by a foodproducing animal. It is well established
that substances consumed by foodproducing animals, and substances such
as metabolites produced by a foodproducing animal, can accumulate in
edible animal tissues and have an
adverse impact on public health. For
example, aflatoxin M1 is a metabolite of
aflatoxin B1 that is produced during
normal biological processes of animals
ingesting the toxin (e.g., from food
contaminated with aflatoxin B1) and has
been shown to cause liver cancer in
certain animals (Ref. 58). As another
example, there can be human food
safety concerns about the level of
selenium in animal tissues when foodproducing animals consume large
amounts of a substance that contains
selenium in their diets.
We agree that the specific data and
information that are necessary to
determine the safety for humans
consuming human food derived from a
food-producing animal would be
determined through the application of
general scientific principles from the
fields of animal nutrition and
metabolism and that it is the notifier’s
responsibility to determine what those
specific data and information are.
Therefore, we have modified the
requirements for the narrative in Part 6
of a GRAS notice to clarify that the
narrative must address the safety for
both the target animal and for humans
consuming human food derived from
food-producing animals (see
§ 570.250(a)(1) and (b)).
I. Filing Decision, Opportunity for a
Notifier To Submit an Amendment, and
Asking Us To Cease To Evaluate a
GRAS Notice for a Substance Intended
for Use in Animal Food (§§ 570.260 and
570.265)
(Comment 152) Some comments
express concern about differences in
how CFSAN and CVM administered
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GRAS notices during the Interim Pilot
program. Some comments describe
CFSAN’s practice of using conference
calls to obtain a clarification or
additional information, with a
reasonable period of time for the notifier
to provide the clarification or additional
information. These comments assert that
CVM’s practice is different from
CFSAN’s practice because CVM does
not contact a notifier to discuss CVM’s
questions after a submission has been
accepted for filing. One comment asserts
that CVM has informally indicated that
once a GRAS notice is accepted for
filing, there will be no further
communication with the notifier and
the GRAS notice will be judged solely
on what was accepted for filing. This
comment further asserts that such a
process is unreasonable because the
error or omission may be trivial and/or
easily remedied. This comment also
asserts that allowing informal contacts
(including telephone, email, and fax) to
address minor issues would be
consistent with how FDA has handled
a wide range of submissions that require
review. Another comment asserts that
CVM’s practice of not contacting the
notifier is a major concern for the
industry and that CVM’s reviewers may
have questions that could be easily
answered by the notifier, if contacted.
Some comments ask CVM to engage
in the same informal practice as CFSAN,
with respect to contacting the notifier
and allowing remedial action, if such
action may be completed in a reasonable
period of time. Some comments ask the
Centers to establish a uniform system of
contact and communication after a
submission (and/or agreeing to evaluate
an amendment to a GRAS notice) to
prevent delays or other inefficiencies
over issues that could easily be clarified
and resolved. Some comments note that
uniformity between CFSAN and CVM in
the submission and handling of requests
to cease to evaluate a GRAS notice is of
great importance in maintaining
transparency and efficiency in the
GRAS notification procedure.
(Response 152) The regulatory text
governing what CVM will do with a
GRAS notice (§ 570.265) is the same as
the regulatory text governing what
CFSAN will do with a GRAS notice
(§ 170.265). In addition, the regulatory
text that provides for a notifier who
submits a GRAS notice to CVM to
submit a timely amendment to a filed
GRAS notice, and to ask us to cease to
evaluate a GRAS notice (§ 570.260), is
the same as the regulatory text that
provides for a notifier who submits a
GRAS notice to CFSAN to submit a
timely amendment to a filed GRAS
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notice, and to ask us to cease to evaluate
a GRAS notice (§ 170.260).
We disagree that CVM did not contact
notifiers during the Interim Pilot
program. As shown in table 1 in CVM’s
experience document (Ref. 20), CVM
contacted the notifier regarding 9 of 18
GRAS notices during its evaluation
process. CVM issued ‘‘no questions
letters’’ to seven of these nine notices
after the notifiers provided clarifying
amendments.
Moving forward under the final rule,
CVM intends to consider the same
factors that CFSAN considers regarding
whether to file a submission as a GRAS
notice (see Response 85), the purpose of
contacting a notifier (including whether
to provide an opportunity for a notifier
to ask us to cease to evaluate a GRAS
notice) (see Response 80), and the
transparency of the reasons for a ‘‘cease
to evaluate letter’’ (see Response 81).
Because our factors regarding the
purpose of contacting a notifier, and the
provisions that provide an opportunity
for a notifier to submit an amendment,
consider whether an amendment is (or
could be) timely, the final rule does, as
requested by the comments, consider
whether an amendment could be
prepared and submitted in a reasonable
period of time. Importantly, as
discussed in Response 101, the role of
an amendment is to clarify questions
that we have about your conclusion of
GRAS status, rather than to
substantively amend the notice.
Whether we will evaluate an
amendment to a GRAS notice before
responding to the notice is a matter that
we will consider on a case-by-case basis.
J. Opportunity for a Notifier To Submit
a Supplement to a GRAS Notice for a
Substance Intended for Use in Animal
Food (§ 570.280)
(Comment 153) One comment asks
CVM to adopt CFSAN’s approach of
allowing a notifier to submit
information to a GRAS notice after FDA
responds to the notice.
(Response 153) The rule provides
that, if circumstances warrant, a notifier
who submits a GRAS notice to CVM
may submit a supplement to a filed
GRAS notice after we respond to your
notice by letter or cease to evaluate your
notice (§ 570.280). As discussed in
section VI of CVM’s experience
document (Ref. 20), as of December 31,
2015, CVM had not received any
supplements to a GRAS notice.
K. GRAS Affirmation Petitions for
Substances Used in Animal Food
CVM has no pending GRAS
affirmation petitions and, thus, the final
animal food regulations do not include
provisions for the disposition of
pending GRAS affirmation petitions for
substances used in animal food.
XXVI. Editorial, Clarifying, and
Conforming Amendments
The revised regulatory text includes
several changes that we have made to
make the requirements more clear and
improve readability. The revised
regulatory text also includes several
conforming changes that we have made
when a change to one provision affects
other provisions. We summarize the
principal editorial and conforming
changes in table 29.
TABLE 29—PRINCIPAL EDITORIAL, CLARIFYING, AND CONFORMING CHANGES
Designation in the
regulatory text
(§ )
§ 20.100(c)(46) .....................
§ 25.20(k) .............................
§ 25.32(f) ..............................
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§ 25.32 (i), (j), (k), and (r) ....
§ 170.3(h), § 570.3(h) ...........
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Revision
Explanation
Add new paragraph (c)(46) to clarify applicability of
§ 20.100 (the handling of FDA records upon a request for public disclosure) to GRAS notices in
§§ 170.36(h) and 570.36(h).
• Replace ‘‘Affirmation of a food substance as GRAS
for humans or animals, on FDA’s initiative or in response to a petition, under parts 182, 184, 186, or
582 of this chapter’’ with ‘‘Establishment or amendment of a regulation for a food substance as GRAS
under the conditions of its intended use for humans
or animals under parts 182, 184, 186, 582, or 584 of
this chapter’’.
• Replace ‘‘unless categorically excluded in § 25.32(f),
(k), or (r)’’ with ‘‘unless categorically excluded in
§ 25.32(f), (i), (j), (k), or (r)’’.
Replace ‘‘Affirmation of a food substance as GRAS for
humans or animals on FDA’s initiative or in response
to a petition, under parts 182, 184, 186, or 582 of
this chapter’’ with ‘‘Establishment or amendment of a
regulation for a food substance as GRAS under the
conditions of its intended use for humans or animals
under parts 182, 184, 186, 582, or 584 of this chapter’’.
Replace ‘‘or GRAS affirmation petition’’ with ‘‘establishment or amendment of a regulation for a food substance as GRAS under the conditions of its intended
use for humans or animals under parts 182, 184,
186, 582, or 584 of this chapter’’.
• Specify ‘‘data from human, animal, analytical, or
other scientific studies’’ rather than ‘‘data from
human, animal, analytical, and other scientific studies’’.
• Replace ‘‘appropriate to establish the safety of a substance’’ with ‘‘appropriate to establish the safety of a
substance under the conditions of its intended use’’.
Conforming change in light of the new GRAS notification procedures established in §§ 170.36 and 570.36.
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• Conforming change in light of the deletion of the
GRAS affirmation petition process.
• Correct the list of applicable categorical exclusions
that apply to include the categorical exclusions listed
in § 25.32(i) and (j).
• Clarify that GRAS affirmation applies to the intended
conditions of use of a substance, not the substance
itself.
• Conforming change in light of the deletion of the
GRAS affirmation petition process.
• Clarify that GRAS affirmation applies to the intended
conditions of use of a substance, not the substance
itself.
• Conforming change in light of the deletion of the
GRAS affirmation petition process.
• Clarify that the four listed types of studies (human,
animal, analytical, and other) do not necessarily
apply in all circumstances.
• Include statutory language from section 201(s) of the
FD&C Act to clarify that GRAS status applies to the
intended conditions of use of a substance, not the
substance itself.
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TABLE 29—PRINCIPAL EDITORIAL, CLARIFYING, AND CONFORMING CHANGES—Continued
Designation in the
regulatory text
(§ )
Revision
Explanation
170.3(i) .................................
In the definition of ‘‘safe’’ or ‘‘safety,’’ replace ‘‘under
the intended conditions of use’’ with ‘‘under the conditions of its intended use’’.
§ 170.3(k) .............................
Replace ‘‘General recognition of safety shall be determined in accordance with 170.30’’ with ‘‘General recognition of safety shall be in accordance with
§ 170.30’’.
Replace ‘‘§ 186.1’’ with ‘‘part 186’’ ..................................
Conforming change to consistently use the exact statutory language in section 201(s) ‘‘under the conditions
of its intended use’’ rather than variations (such as
under the intended conditions of use).
Conforming change. See Response 41.
Throughout § 170.30 ............
§ 170.30(a) ...........................
§ 170.30(b), § 570.30(b) .......
§ 170.30(c)(1), § 570.30(c)(1)
§ 170.30(c)(2) .......................
170.30(c)(2), 170.38(a),
570.38(a).
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§ 170.30(e) ...........................
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Replace the proposed regulatory text ‘‘there is reasonable certainty that the substance is not harmful under
the intended conditions of use’’ with ‘‘there is reasonable certainty that the substance is not harmful under
the conditions of its intended use’’.
Replace ‘‘General recognition of safety based upon scientific procedures shall require the same quantity
and quality of scientific evidence as is required to obtain approval of a food additive regulation for the ingredient’’ with ‘‘General recognition of safety based
upon scientific procedures shall require the same
quantity and quality of scientific evidence as is required to obtain approval of a food additive’’.
Replace ‘‘General recognition of safety through experience based on common use in food prior to January
1, 1958, may be determined without the quantity or
quality of scientific procedures required for approval
of a food additive regulation’’ with ‘‘General recognition of safety through experience based on common
use in food prior to January 1, 1958, may be
achieved without the quantity or quality of scientific
procedures required for approval of a food additive’’.
• Replace ‘‘if the information about the experience establishes that the use of the substance is safe within
the meaning of the act (see § 170.3(i))’’ with ‘‘if the
information about the experience establishes that the
substance is safe under the conditions of its intended
use within the meaning of section 201(u) of the Federal Food, Drug, and Cosmetic Act (see also
§ 170.3(i))’’.
• Replace ‘‘in this country’’ with ‘‘in the United States’’
Replace ‘‘the act’’ with ‘‘the Federal Food, Drug, and
Cosmetic Act’’ in any provision that we otherwise revised.
• Replace ‘‘Beginning in 1969, the Food and Drug Administration has undertaken a systematic review of
the status of all ingredients used in food on the determination that they are GRAS or subject to a prior
sanction’’ with ‘‘Beginning in 1969, the Food and
Drug Administration has undertaken a systematic review of the status of all ingredients used in food
based on the view that they are GRAS under the
conditions of their intended use or subject to a prior
sanction’’.
• Replace ‘‘All determinations of GRAS status or food
additive status or prior sanction status pursuant to
this review shall be handled pursuant to §§ 170.35,
170.38, and 180.1 of this chapter. Affirmation of
GRAS status shall be announced in part 184 or
§ 186.1 of this chapter’’ with ‘‘All affirmations of
GRAS status or determinations of food additive status or prior sanction status pursuant to this review
shall be handled pursuant to §§ 170.35, 170.38, and
180.1 of this chapter. Affirmation of GRAS status
shall be announced in part 184 or part 186 of this
chapter’’.
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Correction to clarify that the provision applies to all of
part 186, not just § 186.1.
Conforming change to consistently use the exact statutory language in section 201(s) ‘‘under the conditions
of its intended use’’ rather than variations (such as
under the intended conditions of use).
• Clarify that FDA approves a food additive, not a
‘‘food additive regulation’’.
• Clarify that the same quantity and quality of scientific
evidence is required regardless of whether the substance is intended for use as an ‘‘ingredient’’.
• Conforming change. See Response 41.
• Clarify that FDA approves a food additive, not a
‘‘food additive regulation’’.
• Conforming change to consistently use the exact
statutory language in section 201(s) ‘‘under the conditions of its intended use’’ rather than variations
(such as ‘‘the use of the substance’’).
• Clarify that the applicable section of the FD&C Act is
section 201(u). Section 170.3(i) is in our regulations,
not in the FD&C Act.
• Editorial change to include the full name of the statute.
• Editorial change to be specific that ‘‘this country’’
means ‘‘the United States’’.
Editorial. It is now our practice to include the full name
of this statute when we refer to it.
• See Response 41.
• Include statutory language from section 201(s) of the
FD&C Act to clarify that GRAS status applies to the
intended conditions of use of a substance, not the
substance itself.
• Clarify that GRAS status pursuant to parts 184 and
186 is affirmed by FDA.
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TABLE 29—PRINCIPAL EDITORIAL, CLARIFYING, AND CONFORMING CHANGES—Continued
Designation in the
regulatory text
(§ )
§ 170.30(l) ............................
§ 170.35(a), § 570.35(a) .......
§ 170.35(b)(1),
§ 570.35(b)(1).
§ 170.35(b)(3),
§ 570.35(b)(3).
§ 170.35(b)(4),
§ 570.35(b)(4).
§ 170.38(a), § 570.38(a) .......
• Throughout part 170, subpart E.
• Throughout part 570, subpart E.
• Throughout part 170, subpart E.
• Throughout part 570, subpart E.
• Throughout part 170, subpart E.
• Throughout part 570, subpart E.
§ 170.203, § 570.203 ............
§ 170.225(c)(4) .....................
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§ 184.1(a) .............................
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Revision
Explanation
Replace ‘‘Any change in part 182, part 184, or § 186.1
of this chapter shall be accomplished pursuant to
§ 170.38’’ with ‘‘Any change to the GRAS status of a
food ingredient in part 182, part 184, or part 186 of
this chapter shall be accomplished pursuant to
§ 170.38’’.
Replace ‘‘may affirm the GRAS status of substances’’
with ‘‘may affirm that a substance that directly or indirectly becomes a component of food is GRAS under
the conditions of its intended use’’.
Replace ‘‘If the Commissioner proposes on his own initiative that a substance is entitled to affirmation as
GRAS’’ with ‘‘If the Commissioner proposes on his
own initiative that a substance is entitled to affirmation as GRAS under the conditions of its intended
use’’.
• Replace ‘‘convincing evidence that the substance is
GRAS’’ with ‘‘convincing evidence that the substance
is GRAS under the conditions of its intended use’’.
• Replace ‘‘listing the substance as GRAS in part 182,
part 184, or part 186 of this chapter’’ with ‘‘listing the
GRAS conditions of use of the substance in part 184
or part 186 of this chapter’’.
Replace ‘‘there is a lack of convincing evidence that the
substance is GRAS’’ with ‘‘there is a lack of convincing evidence that the substance is GRAS under
the conditions of its intended use’’.
• Replace ‘‘may, in accordance with § 170.35(b)(4) or
(c)(5), publish a notice in the Federal Register determining that a substance is not GRAS’’ with ‘‘may, in
accordance with § 170.35(b)(4), publish a notice in
the Federal Register determining that a substance is
not GRAS under the conditions of its intended use’’.
• Replace ‘‘may, in accordance with § 570.35(b)(4) or
(c)(5), publish a notice in the Federal Register determining that a substance is not GRAS’’ with ‘‘may, in
accordance with § 570.35(b)(4), publish a notice in
the Federal Register determining that a substance is
not GRAS under the conditions of its intended use’’.
Replace variations of ‘‘data or other information’’ with
‘‘data and information’’.
Clarify the applicability of the requirement.
• Editorial change to use the singular.
• Include statutory language from section 201(s) of the
FD&C Act to clarify that GRAS affirmation applies to
the intended conditions of use of a substance, not
the substance itself.
Include statutory language from section 201(s) of the
FD&C Act to clarify that GRAS affirmation applies to
the intended conditions of use of a substance, not
the substance itself.
• Include statutory language from section 201(s) of the
FD&C Act to clarify that GRAS affirmation applies to
the intended conditions of use of a substance, not
the substance itself.
• Deleted reference to parts 182 and 582. If FDA affirms GRAS status, the affirmation regulation would
appear in part 184 or 186.
Include statutory language from section 201(s) of the
FD&C Act to clarify that GRAS affirmation applies to
the intended conditions of use of a substance, not
the substance itself.
• See Response 41.
• Conforming change in light of the deletion of the
GRAS affirmation petition process.
• Include statutory language from section 201(s) of the
FD&C Act to clarify that GRAS affirmation applies to
the intended conditions of use of a substance, not
the substance itself.
Editorial change. Although data is a type of ‘‘information,’’ it is simpler and clearer to say ‘‘data and information.’’
Replace variations of ‘‘determine’’ and ‘‘determination’’
with ‘‘conclude’’ and ‘‘conclusion’’.
See Response 41.
• Replace ‘‘exempt’’ with ‘‘not subject to: ...................
• Replace ‘‘claim’’ with ‘‘view’’ ........................................
See Response 42.
In the definition of ‘‘notifier,’’ add a parenthetical with
examples of what we mean by ‘‘person’’ (e.g., an individual, partnership, corporation, association, or
other legal entity).
Replace the proposed phrase ‘‘applicable conditions of
use’’ with ‘‘intended conditions of use’’.
Replace ‘‘The direct human food ingredients listed in
this part have been reviewed by the Food and Drug
Administration and determined to be generally recognized as safe (GRAS) for the purposes and conditions prescribed’’ with ‘‘The direct human food ingredients listed in this part have been reviewed by the
Food and Drug Administration and affirmed to be
generally recognized as safe (GRAS) for the purposes and under the conditions prescribed’’.
Clarification by including text from the definition of
‘‘person’’ in § 10.3.
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Clarifying change to use the statutory term ‘‘intended’’
in place of ‘‘applicable’’.
Clarify that the GRAS status of the uses of substances
listed in part 184 has been affirmed by FDA, either
on FDA’s initiative or in response to a GRAS affirmation petition.
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Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations
55041
TABLE 29—PRINCIPAL EDITORIAL, CLARIFYING, AND CONFORMING CHANGES—Continued
Designation in the
regulatory text
(§ )
§ 184.1(b)(1) .........................
§ 186.1(a) .............................
§ 186.1(b)(1) .........................
§ 570.3(f) ..............................
§ 570.3(k) .............................
§ 570.3 .................................
§ 570.30(c) ...........................
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§ 570.30(d) ...........................
§ 570.30(i) ............................
570.225(c)(4), 570.225(c)(5),
570.230(c), 570.235,
570.240, 570.245.
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Revision
Explanation
• Replace ‘‘shall independently establish’’ with ‘‘shall
have a basis to conclude’’.
• Remove the last sentence, i.e., ‘‘Persons seeking
FDA approval of an independent determination that a
use of an ingredient is GRAS may submit a GRAS
petition in accordance with 170.35 of this chapter.’’.
Replace ‘‘The indirect human food ingredients listed in
this part have been reviewed by the Food and Drug
Administration and determined to be generally recognized as safe (GRAS)’’ with ‘‘The indirect human
food ingredients listed in this part have been reviewed by the Food and Drug Administration and affirmed to be generally recognized as safe (GRAS)’’.
• Replace ‘‘shall independently establish’’ with ‘‘shall
have a basis to conclude’’.
• Remove the last sentence, i.e., ‘‘Persons seeking
FDA approval of an independent determination that a
use of an ingredient is GRAS may submit a GRAS
petition in accordance with 170.35 of this chapter.’’.
• Add ‘‘of the species to which the substance is intended to be fed’’ in describing the animals consuming the substance.
• Delete ‘‘in the United States’’ ......................................
• Add ‘‘(and, for food-producing animals fed with such
substance, also means a substantial history of consumption by humans consuming human foods derived from those food-producing animals) prior to
January 1, 1958.
• Conforming change to reflect ‘‘conclusions’’ of GRAS
status.
• Conforming change in light of the deletion of the
GRAS affirmation petition process.
Replace ‘‘General recognition of safety shall be determined in accordance with § 570.30’’ with ‘‘General
recognition of safety shall be in accordance with
§ 570.30’’.
Define ‘‘food-producing animal’’ to mean an animal
used to produce human food.
Replace ‘‘General recognition of safety through experience based on common use in food prior to January
1, 1958, may be determined without the quantity or
quality of scientific procedures required for approval
of a food additive regulation’’ with ‘‘General recognition of safety through experience based on common
use in food prior to January 1, 1958, may be
achieved without the quantity or quality of scientific
procedures required for approval of a food additive’’.
• Replace ‘‘ingredients listed as GRAS in part 582 of
this chapter’’ with ‘‘ingredients listed as GRAS in part
582 of this chapter or affirmed as GRAS in part 584
of this chapter’’.
• Replace ‘‘without specific inclusion in part 582 of this
chapter’’ with ‘‘without specific inclusion in part 582
or part 584 of this chapter’’.
Replace ‘‘Any use of such and ingredient’’ with ‘‘Any
use of such an ingredient’’.
Replace ‘‘food’’ with ‘‘animal food’’ .................................
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Clarify that the GRAS status of the uses of substances
listed in part 186 has been affirmed by FDA, either
on FDA’s initiative or in response to a GRAS affirmation petition.
Conforming change in light of the deletion of the GRAS
affirmation petition process.
Changes to
• Conform with revisions to § 570.30(a) and (c)
• Conform with the corresponding definition for human
food in § 170.3(f), which does not specify ‘‘in the
United States.’’
• Clarify that substantial history of consumption should
be demonstrated by the same animal species as the
species intended to be fed to conform with the submission requirements in part 5 of a GRAS notice
when the basis for the conclusion of GRAS status is
through experience based on common use in food
(§ 570.245).
• Clarify that substantial history of consumption for
food-producing animals also should be demonstrated
by a substantial history of consumption by humans
consuming human foods derived from those foodproducing animals prior to January 1, 1958 to conform with the submission requirements in part 5 of a
GRAS notice.
Conforming change. The GRAS notification procedure
does not use the term ‘‘determine.’’
Clarify the meaning of this term for the purpose of part
570, subpart E in light of provisions that address the
safety of a substance for humans consuming human
food derived from an animal used to produce human
food.
• Conforming change. The GRAS notification procedure does not use the term ‘‘determine.’’
• Clarify that FDA approves a food additive, not a
‘‘food additive regulation’’.
Clarify that the provisions apply regardless of whether
an ingredient is listed as GRAS in part 582 or affirmed as GRAS in part 584.
Editorial correction of ‘‘and’’ to ‘‘an’’.
Clarification for part 570.
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Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations
XXVII. Economic Analysis of Impacts
We have examined the impacts of the
final rule under Executive Order 12866,
Executive Order 13563, the Regulatory
Flexibility Act (5 U.S.C. 601–612), and
the Unfunded Mandates Reform Act of
1995 (Pub. L. 104–4). Executive Orders
12866 and 13563 direct us to assess all
costs and benefits of available regulatory
alternatives and, when regulation is
necessary, to select regulatory
approaches that maximize net benefits
(including potential economic,
environmental, public health and safety,
and other advantages; distributive
impacts; and equity). We have
developed a comprehensive Economic
Analysis of Impacts that assesses the
impacts of the final rule. We believe that
this final rule is not a significant
regulatory action as defined by
Executive Order 12866.
The Regulatory Flexibility Act
requires us to analyze regulatory options
that would minimize any significant
impact of a rule on small entities. The
final rule replaces the voluntary GRAS
affirmation petition process with a
voluntary GRAS notification procedure.
Similar to the petition process, we
expect that profit-maximizing firms will
only submit the GRAS notice when the
private benefits equal or exceed the
costs of the GRAS notice, regardless of
the size of the firm. Because small firms
face the same voluntary business
decision as large firms, we certify that
the final rule will not have a significant
economic impact on a substantial
number of small entities.
The Unfunded Mandates Reform Act
of 1995 (section 202(a)) requires us to
prepare a written statement, which
includes an assessment of anticipated
costs and benefits, before issuing ‘‘any
rule that includes any Federal mandate
that may result in the expenditure by
State, local, and tribal governments, in
the aggregate, or by the private sector, of
$100,000,000 or more (adjusted
annually for inflation) in any one year.’’
The current threshold after adjustment
for inflation is $146 million, using the
most current (2015) Implicit Price
Deflator for the Gross Domestic Product.
This final rule will not result in an
expenditure in any year that meets or
exceeds this amount.
The final rule will eliminate the
petition process to affirm a substance is
GRAS and replace the petition process
with a GRAS notification procedure.
The level of effort required by a firm to
reach a conclusion that a substance is
GRAS for its intended use remains
unchanged by the final rule. However,
the rule will require that firms submit
some additional information to support
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their conclusion with their notices.
Although uncertain, we estimate that
notifiers will spend between 5 more
hours and 20 more hours to prepare and
submit each notice. We estimate that
this will cost notifiers less than $0.1
million each year.
For all affected notifiers, we expect
that they will spend time reading and
understanding the requirements of the
final rule and revising standard
operating procedures for preparing and
submitting GRAS notices. We estimate
that it will take from 20 hours to 80
hours for notifiers to perform this
action. Firms with outstanding GRAS
affirmation petitions may choose to
submit GRAS notices and incorporate
the information included in their
petition. To account for the additional
effort by these firms, we include the
one-time cost to prepare and submit a
GRAS notice for all outstanding
petitions. We estimate that notifiers will
spend between 170 and 190 hours to
submit GRAS notices for each
outstanding petition. The total one-time
costs of the final rule range from $0.8
million to $2.7 million.
We estimate that over 10 years with
a 7 percent discount rate, the present
value of the total costs of the final rule
range from $0.9 million to $3.3 million;
with a 3 percent discount rate, the
present value of the total costs range
from $0.9 million to $3.4 million. The
annualized costs of the rule range from
$0.1 million to $0.4 million with a 7
percent discount rate and range from
$0.1 million to $0.5 million with a 3
percent discount rate.
We do not quantify the benefits of the
final rule. However, based on the
differences in review time between the
GRAS petition process and the GRAS
notification procedure, we anticipate
that industry will benefit from the more
speedy notification procedure. For
example, we have filed more than 600
GRAS notices for human food
substances since 1998. During this time,
it took an average of 200 days for us to
respond to 588 GRAS notices; it took an
average of 7.9 years to complete 24
previous GRAS affirmation petitions.
We began to accept GRAS notices for
animal food substances in 2010 and we
have filed 18 GRAS notices for animal
food substances since that time. It took
an average of 294 days for us to respond
to 12 GRAS notices with a ‘‘no
questions letter’’ or ‘‘insufficient basis
letter’’; it took an average of 4.9 years to
respond to the three previous GRAS
affirmation petitions. With the GRAS
notification procedure, we can complete
our evaluation within the timelines
specified in the final rule.
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The Economic Analysis of Impacts of
the final rule performed in accordance
with Executive Order 12866, Executive
Order 13563, the Regulatory Flexibility
Act, and the Unfunded Mandates
Reform Act (Ref. 51) is available at
https://www.regulations.gov under the
docket number for this final rule and at
https://www.fda.gov/AboutFDA/
ReportsManualsForms/Reports/
EconomicAnalyses/default.htm.
XXVIII. Analysis of Environmental
Impact
We have carefully considered the
potential environmental effects of this
action. We have concluded under 21
CFR 25.30(h) that this action is of a type
that does not individually or
cumulatively have a significant effect on
the human environment. Therefore,
neither an environmental assessment
nor an environmental impact statement
is required.
XXIX. Paperwork Reduction Act of
1995
This final rule contains information
collection provisions that are subject to
review by OMB under the PRA (44
U.S.C. 3501–3520). The title,
description, and respondent description
of the information collection provisions
are shown in the following paragraphs
with an estimate of the one-time and
annual reporting burdens. Included in
the estimate is the time for reviewing
instructions, searching existing data
sources, gathering and maintaining the
data needed, and completing and
reviewing each collection of
information.
Title: Substances Generally
Recognized as Safe Notification
Procedure (21 CFR parts 170 and 570)
(OMB Control No. 0910–0342)—
Revision.
Description: The FD&C Act requires
that all food additives (as defined by
section 201(s)) be approved by FDA
before they are marketed (sections
402(a)(2)(C) and 409 of the FD&C Act).
Section 201(s) of the FD&C Act excludes
from the definition of a food additive a
substance ‘‘generally recognized, among
experts qualified by scientific training
and experience to evaluate its safety, as
having been adequately shown through
scientific procedures (or, in the case of
a substance used in food prior to
January 1, 1958, through either
scientific procedures or experience
based on common use in food) to be safe
under the conditions of its intended
use.’’ This final rule amends our
regulations in parts 170 and 570 and
revises the information collection
provisions regarding the notification
procedures for GRAS substances. The
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Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations
regulations implement the GRAS
provision of section 201(s) of the FD&C
Act in part 170 and part 570 for human
food and animal food, respectively.
Description of Respondents:
Respondents to the collection of
information are manufacturers of
substances used in human food and
animal food. We estimate there are 480
such respondents. As estimated in the
Final Regulatory Impact Analysis (Ref.
51), approximately 340 to 460 notifiers
(for human food) and approximately 10
to 20 notifiers (for animal food) will be
affected by the final rule. The Final
Regulatory Impact Analysis reflects an
overall increase in respondents to the
program and we have therefore adjusted
our respondent numbers accordingly.
As discussed in section II.B of the
preamble to this final rule, previously
manufacturers were invited to submit
notices of their independent GRAS
determinations for review under the
framework of the proposed rule during
the period between issuance of the
proposed rule and any final rule based
on the proposed rule. The proposed
regulations provided a standard format
for the voluntary submission of a notice.
To date, the GRAS program has been
administered under these proposed
procedures. Comments regarding the
information collection topics solicited
in the proposed rule and subsequent
2010 notice are discussed in the
preamble in sections IV, VII, and X
55043
through XVIII. While none of the
comments suggested we modify the
estimated annual burden associated
with the information collection, we
have revised the underlying notification
procedures and, consequently, have
revised the underlying information
collection provisions consistent with
the final rule.
Specifically the final rule establishes
a voluntary administrative procedure for
notifying FDA about a conclusion that a
substance is GRAS under the conditions
of its intended use in human food or
animal food. The final rule explains that
a GRAS notice must include the
following seven parts:
TABLE 30—INFORMATION TO BE INCLUDED IN EACH PART OF A GRAS NOTICE
Part No.
Information to be included
Part 1 ..............................................
Part 2 ..............................................
Signed statements and a certification.
The identity, method of manufacture, specifications, and physical or technical effect of the notified substance.
Dietary exposure to the notified substance.
Self-limiting levels of use in circumstances where the amount of the notified substance that can be added
to human food or animal food is limited because the food containing levels of the notified substance
above a particular level would become unpalatable or technologically impractical.
The history of consumption of the substance for food use by a significant number of consumers (or animals in the case of animal food) prior to January 1, 1958, if a conclusion of GRAS status is based on
common use of the substance in food prior to 1958.
A narrative that provides the basis for the notifier’s conclusion of GRAS status, including why the scientific
data, information, methods, and principles described in the notice provide a basis for the conclusion that
the notified substance is generally recognized, among qualified experts, to be safe under the conditions
of its intended use.
A list of the generally available data, information, and methods the notifier cites in the GRAS notice.
Part 3 ..............................................
Part 4 ..............................................
Part 5 ..............................................
Part 6 ..............................................
Part 7 ..............................................
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The information submitted to us in a
GRAS notice is necessary to allow us to
administer efficiently the FD&C Act’s
various provisions that apply to the use
of substances added to food, specifically
with regard to whether a substance is
GRAS under the conditions of its
intended use or is a food additive
subject to premarket review. We will
use the information collected through
the GRAS notification procedure to
complete our evaluation within the
timelines specified in the final rule.
One-Time Reporting Burden
Table 31 shows the estimated onetime reporting burden associated with
the final rule. We expect that all
respondents to the information
collection will spend time reading and
understanding the requirements of the
final rule and revising standard
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operating procedures for preparing and
submitting GRAS notices. As noted, we
estimate that approximately 340 to 460
notifiers (for human food) and
approximately 10 to 20 notifiers (for
animal food) will be affected by the final
rule. We use the upper-bound estimates
of 460 and 20 respondents as shown in
rows 1 and 2. We estimate that it will
take from 20 to 80 hours for respondents
to perform this action. We use the
upper-bound estimate of 80 hours as
shown in rows 1 and 2. Of the 480
affected respondents, some will have
outstanding GRAS petitions. Firms with
outstanding GRAS petitions regarding
substances intended for use in human
food may choose to submit GRAS
notices and incorporate the information
included in their petition. As estimated
in the Final Regulatory Impact Analysis
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(Ref. 51), up to 45 petitions (for human
food) will be submitted as GRAS notices
and incorporated. We use the upperbound estimate of 45 as shown in row
3. To account for the additional effort by
these firms, we include the one-time
burden to prepare and submit a GRAS
notice for all outstanding petitions.
Because there are no outstanding GRAS
petitions regarding substances intended
for use in animal food, we do not
account for any burden for the
submission of a GRAS notice that
incorporates a GRAS petition regarding
a substance intended for use in animal
food. We estimate that respondents will
spend between 170 and 190 hours to
submit GRAS notices for each
outstanding petition and have used,
therefore, an average estimate of 185
hours as shown in row 3.
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Federal Register / Vol. 81, No. 159 / Wednesday, August 17, 2016 / Rules and Regulations
TABLE 31—ESTIMATED ONE-TIME REPORTING BURDEN 1
Number of
respondents
Activity/21 CFR section
Notifier’s review of final rule and revision of procedures for
preparing and submitting GRAS notices for human food,
170.210 through 170.270. ................................................
Notifier’s review of final rule and revision of procedures for
preparing and submitting GRAS notices for animal food,
570.210 through 570.270 .................................................
Prepare and submit GRAS notice for an outstanding
GRAS petition, 170.285 ...................................................
Total ..............................................................................
1 There
Number of
responses per
respondent
Total annual
responses
Average
burden per
response
Total hours
460
1
460
80
36,800
20
1
20
80
1,600
45
1
45
185
8,325
........................
........................
........................
........................
46,725
are no capital costs or operating and maintenance costs associated with this collection of information.
Recurring Reporting Burden
Table 32 shows the estimated
recurring annual reporting burden
associated with the final rule. As
previously discussed, the final rule
replaces the petition process with a
GRAS notification procedure. The level
of effort required by a firm to reach a
conclusion that a substance is GRAS for
its intended use remains unchanged by
the final rule. However, the final rule
requires that firms submit some
additional information to support the
conclusions found within their notices.
The additional information might
include an amendment (§§ 170.260 and
570.260); a supplement (§§ 170.280 and
570.280); a request for FDA to cease to
evaluate a GRAS notice (§§ 170.260 and
570.260); an incorporation into a GRAS
notice (§§ 170.215 and 570.215); and,
information required when the intended
conditions of use of a notified substance
includes use in a product subject to
regulation by FSIS, including
authorization to us to share any trade
secrets with FSIS (§ 170.270). Because
the amount of additional information
may vary, we estimate that respondents
will spend between 155 and 170 hours
to prepare and submit each notice.
Using the upper-bound figure of 170
hours, we therefore estimate that the 50
notifiers for human food and 25
notifiers for animal food will expend
12,750 hours annually as shown,
respectively, in rows 1 and 2.
TABLE 32—ESTIMATED ANNUAL REPORTING BURDEN 1
Number of
respondents
Activity/21 CFR section
GRAS notification
through 170.270
GRAS notification
through 570.270
procedure for human food, 170.210
...............................................................
procedure for animal food, 570.210
...............................................................
Total ..............................................................................
1 There
Total annual
responses
Average
burden per
response
Total hours
50
1
50
170
8,500
25
1
25
170
4,250
........................
........................
........................
........................
12,750
are no capital costs or operating and maintenance costs associated with this collection of information.
Recordkeeping
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Number of
responses per
respondent
The final rule does not contain
recordkeeping requirements. We believe
that documentation used by
respondents in support of a conclusion
of GRAS status is information that is
collected and retained as a part of usual
and customary business practices for a
firm engaged in the manufacture of
substances used in human food and
animal food. We have, therefore, not
provided an estimate for these activities
(5 CFR 1320.3(b)(2)).
This final rule also refers to other
currently approved collections of
information found in our regulations.
These collections of information are
subject to review by OMB under the
PRA. The collections of information in
21 CFR 25.32(i) are approved under
OMB control number 0910–0541. The
collections of information in 21 CFR
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10.33 are approved under OMB control
number 0910–0191.
The information collection provisions
of this final rule have been submitted to
OMB for review as required by section
3507(d) of the PRA. Before the effective
date of this final rule, FDA will publish
a notice in the Federal Register
announcing OMB’s decision to approve,
modify, or disapprove the information
collection provisions in this final rule.
An Agency may not conduct or sponsor,
and a person is not required to respond
to, a collection of information unless it
displays a currently valid OMB control
number.
XXX. Federalism
We have analyzed this final rule in
accordance with the principles set forth
in Executive Order 13132. FDA has
determined that the rule does not
contain policies that have substantial
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direct effects on the States, on the
relationship between the National
Government and the States, or on the
distribution of power and
responsibilities among the various
levels of government. Accordingly, we
have concluded that the rule does not
contain policies that have federalism
implications as defined in the Executive
order and, consequently, a federalism
summary impact statement is not
required.
XXXI. References
The following references are on
display in the Division of Dockets
Management (HFA–305), Food and Drug
Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852, and are
available for viewing by interested
persons between 9 a.m. and 4 p.m.,
Monday through Friday; they also are
available electronically at https://
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www.regulations.gov. FDA has verified
the Web site addresses, as of the date
this document publishes in the Federal
Register, but Web sites are subject to
change over time.
1. House Report No. 2284, July 28, 1958. See
Reference 1 to the proposed rule.
2. Price, J.M., C.G. Biava, B.L. Oser, et al.,
‘‘Bladder Tumors in Rats Fed
Cyclohexylamine or High Doses of a
Mixture of Cyclamate and Saccharin,’’
Science, 167:1131–1132, 1970. See
Reference 2 to the proposed rule.
3. New York Times, p. 22, October 31, 1969.
See Reference 3 to the proposed rule.
4. United States Government Accountability
Office, ‘‘Report to Congressional
Requestors on Food Safety: FDA Should
Strengthen Its Oversight of Food
Ingredients Determined to Be Generally
Recognized as Safe (GRAS),’’ Report No.
GAO–10–246, (https://www.gao.gov/
new.items/d10246.pdf), February 2010.
Accessed and printed on May 3, 2010.
See Reference 2 to the 2010 notice.
5. FDA, ‘‘Draft Guidance for Industry:
Assessing the Effects of Significant
Manufacturing Process Changes,
Including Emerging Technologies, on the
Safety and Regulatory Status of Food
Ingredients and Food Contact
Substances, Including Food Ingredients
that Are Color Additives,’’ (https://
www.regulations.gov in Docket No.
FDA–2011–D–0490), 2012. Accessed and
printed on February 19, 2016.
6. FDA, ‘‘Guidance for Industry: Assessing
the Effects of Significant Manufacturing
Process Changes, Including Emerging
Technologies, on the Safety and
Regulatory Status of Food Ingredients
and Food Contact Substances, Including
Food Ingredients that Are Color
Additives,’’ (https://www.fda.gov/Food/
GuidanceRegulation/Guidance
DocumentsRegulatoryInformation/
ucm300661.htm), 2014. Accessed and
printed on January 15, 2016.
7. FDA, ‘‘Draft Guidance for Industry:
Considering Whether an FDA-Regulated
Product Involves the Application of
Nanotechnology,’’ (https://
www.regulations.gov in Docket No.
FDA–2010–D–0530), 2011. Accessed and
printed on February 19, 2016.
8. FDA, ‘‘Guidance for Industry: Considering
Whether an FDA-Regulated Product
Involves the Application of
Nanotechnology,’’ (https://www.fda.gov/
RegulatoryInformation/Guidances/
ucm257698.htm), 2014. Accessed and
printed on January 15, 2016.
9. The Pew Charitable Trusts, ‘‘Fixing the
Oversight of Chemicals Added to Our
Food,’’ (https://www.pewtrusts.org/∼/
media/legacy/uploadedfiles/phg/
content_level_pages/reports/food
additivescapstonereportpdf.pdf), 2013.
Accessed and printed on February 19,
2016.
10. Letter dated November 17, 2010, from
Joann M. Givens of FDA to Mr. Tim
Baggs, Charge Beverages Corporation,
(https://www.fda.gov/iceci/enforcement
actions/warningletters/2010/
VerDate Sep<11>2014
17:25 Aug 16, 2016
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ucm233990.htm). Accessed and printed
on January 31, 2016.
11. Letter dated November 17, 2010, from
Joann M. Givens of FDA to Rhonda
Kallman of New Century Brewing
Company, (https://www.fda.gov/iceci/
enforcementactions/warningletters/2010/
ucm234028.htm). Accessed and printed
on January 31, 2016.
12. Letter dated November 17, 2010, from
Joann M. Givens of FDA to Jaisen
Freeman, Chris Hunter, and Jeff Wright
of Phusion Projects, (https://www.fda.gov/
iceci/enforcementactions/warningletters/
2010/ucm234023.htm). Accessed and
printed on January 31, 2016.
13. Letter dated November 17, 2010, from
Joann M. Givens of FDA to Michael
Michail of United Brands Company,
(https://www.fda.gov/iceci/enforcement
actions/warningletters/2010/
ucm234002.htm). Accessed and printed
on January 31, 2016.
14. TTB, Industry Circular 2010–8, (https://
www.ttb.gov/industry_circulars/archives/
2010/10–08.html), 2010. Accessed and
printed on January 21, 2016.
15. The National Academies of Sciences,
Health and Medicine Division, ‘‘Caffeine
in Food and Dietary Supplements:
Examining Safety—Workshop
Summary,’’ (https://www.national
academies.org/hmd/Reports/2014/
Caffeine-in-Food-and-DietarySupplements-Examining-Safety.aspx),
2014. Accessed and printed on May 27,
2016.
16. Memorandum of Meeting Held on
December 11, 2014, between
Representatives of FDA and
Representatives of the Caffeine Technical
Working Group on the American
Beverage Association (ABA) Caffeine
Technical Working Group (CTWG)
Research Plans.
17. International Life Sciences Institute (ILSI
North America), ‘‘Caffeine Working
Group,’’ (https://ilsina.org/our-work/foodsafety/caffeine/), 2015. Accessed and
printed on June 8, 2016.
18. Experience With GRAS Notices Under the
1997 Proposed Rule, Memorandum
Dated November 4, 2010, from Linda S.
Kahl of FDA to Docket No. FDA–1997–
N–0020. See Reference 1 to the 2010
notice.
19. ‘‘Substances that Are Generally
Recognized as Safe (GRAS); Updated
Experience With GRAS Notices,’’
Memorandum Dated June 1, 2016, from
Paulette M. Gaynor of FDA to Docket No.
FDA–1997–N–0020.
20. ‘‘Experience With GRAS Notices Under
CVM’s Interim Pilot Program,’’
Memorandum Dated June 10, 2016, from
David Edwards of FDA to Docket No.
FDA–1997–N–0020.
21. Memorandum for the Heads of Executive
Departments and Agencies, Dated June 1,
1998, Signed by President William J.
Clinton, (https://www.plainlanguage.gov/
whatisPL/govmandates/memo.cfm).
Accessed and printed on July 14, 2008.
See Reference 3 to the 2010 notice.
22. eRulemaking Program, ‘‘Improving
Electronic Dockets on Regulations.gov
PO 00000
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55045
and the Federal Docket Management
System: Best Practices for Federal
Agencies,’’ (https://www.regulations.gov/
docs/FactSheet_eRulemaking_Best_
Practices.pdf), 2010. Accessed and
printed on January 15, 2016.
23. Dictionary.com. Dictionary.com
Unabridged. Random House, Inc. (https://
dictionary.reference.com/browse/
corroborate), 2016. Accessed and printed
on February 23, 2016.
24. Food and Agriculture Organization of the
United Nations and the World Health
Organization, ‘‘Chapter 6, Dietary
Exposure Assessment of Chemicals in
Food’’ in Environmental Health Criteria
240. Principles and Methods for the Risk
Assessment of Chemicals in Food,
(https://apps.who.int/iris/bitstream/
10665/44065/9/WHO_EHC_240_9_eng_
Chapter6.pdf), 2009. Accessed and
printed on February 13, 2006.
25. FDA, ‘‘Guidance for Industry: Estimating
Dietary Intake of Substances in Food,’’
(https://www.fda.gov/Food/Guidance
Regulation/GuidanceDocuments
RegulatoryInformation/ucm074725.htm),
2006. Accessed and printed on January
15, 2016.
26. Renwick, A.G., ‘‘The Use of a Sweetener
Substitution Method to Predict Dietary
Exposures for the Intense Sweetener
Rebaudioside A.,’’ Food and Chemical
Toxicology, 46:S61–S69, 2008.
27. Mitchell, D.C., C.A. Knight, J.
Hockenberry, et al., ‘‘Beverage Caffeine
Intakes in the U.S.,’’ Food and Chemical
Toxicology, 63:136–142, 2014.
28. Fulgoni, V.L., D.R. Keast, and H.R.
Lieberman, ‘‘Trends in Intake and
Sources of Caffeine in the Diets of US
Adults: 2001–2010,’’ The American
Journal of Clinical Nutrition, 101:1081–
1087, 2015.
29. Branum, A.M., L.M. Rossen, and K.C.
Schoendorf, ‘‘Trends in Caffeine Intake
Among U.S. Children and Adolescents,’’
Pediatrics, 133(3):386–393, 2014.
30. Food and Agriculture Organization and
World Health Organization, ‘‘Joint FAO/
WHO Expert Consultation on
Biotechnology and Food Safety,’’ (ftp://
ftp.fao.org/es/esn/food/
biotechnology.pdf), 1996. See Reference
6 to the proposed rule.
31. FDA, ‘‘Guidance for Industry:
Recommendations for Submission of
Chemical and Technological Data for
Direct Food Additive Petitions,’’ (https://
www.fda.gov/Food/GuidanceRegulation/
GuidanceDocumentsRegulatory
Information/ucm124917.htm), 2009.
Accessed and printed on January 15,
2016.
32. FDA, ‘‘Guidance for Industry:
Microbiological Considerations for
Antimicrobial Food Additive
Submissions,’’ (https://www.fda.gov/
Food/GuidanceRegulation/Guidance
DocumentsRegulatoryInformation/
ucm230417.htm), 2008. Accessed and
printed on January 15, 2016.
33. FDA, ‘‘Guidance for Industry: Enzyme
Preparations: Recommendations for
Submission of Chemical and
Technological Data for Food Additive
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Petitions and GRAS Notices,’’ (https://
www.fda.gov/Food/GuidanceRegulation/
GuidanceDocumentsRegulatory
Information/IngredientsAdditives
GRASPackaging/ucm217685.htm), 2010.
Accessed and printed on January 15,
2016.
34. FDA, ‘‘Guidance for Industry: Summary
Table of Recommended Toxicological
Testing for Additives Used in Food,’’
(https://www.fda.gov/Food/Guidance
Regulation/GuidanceDocuments
RegulatoryInformation/ucm054658.htm),
2006. Accessed and printed on January
15, 2016.
35. FDA, ‘‘Guidance for Industry and Other
Stakeholders: Toxicological Principles
for the Safety Assessment of Food
Ingredients. Redbook 2000,’’ (https://
www.fda.gov/Food/GuidanceRegulation/
GuidanceDocumentsRegulatory
Information/IngredientsAdditives
GRASPackaging/ucm2006826.htm),
2007. Accessed and printed on January
15, 2016.
36. 225–00–2000 ‘‘Amendment 1:
Memorandum of Understanding Between
the United States Department of
Agriculture Food Safety Inspection
Service and the United States
Department of Health and Human
Services Food and Drug Administration,
(https://www.fda.gov/AboutFDA/
PartnershipsCollaborations/
MemorandaofUnderstandingMOUs/
DomesticMOUs/ucm441552.htm), 2000.
Accessed and printed on November 25,
2015.
37. FDA, ‘‘Guidance for Industry: Providing
Regulatory Submissions in Electronic or
Paper Format to the Office of Food
Additive Safety; Draft Guidance,’’
(https://www.fda.gov/Food/Guidance
Regulation/GuidanceDocuments
RegulatoryInformation/Ingredients
AdditivesGRASPackaging/
ucm2021277.htm), 2010. Accessed and
printed on January 15, 2016.
38. Form FDA 3667. ‘‘Generally Recognized
As Safe (GRAS) Notice,’’ (https://
www.fda.gov/downloads/AboutFDA/
ReportsManualsForms/Forms/
UCM350015.pdf), 2016. Accessed and
printed on June 1, 2016.
39. Form FDA 3480. ‘‘Food Contact
Substance: Notification for New Use,
Pre-Notification Consultation, Food
Master File’’, (https://www.fda.gov/
downloads/AboutFDA/ReportsManuals
Forms/Forms/UCM076880.pdf), 2016.
Accessed and printed on June 1, 2016.
40. Form FDA 3537. ‘‘DHHS/FDA Food
Facility Registration,’’ (https://
www.fda.gov/downloads/aboutfda/
reportsmanualsforms/forms/
ucm071977.pdf), 2014. Accessed and
printed on January 15, 2016.
41. FSIS, ‘‘Contact Us,’’ (https://
www.fsis.usda.gov/wps/portal/
informational/contactus). Accessed and
printed on January 28, 2016.
42. Pariza, M.W. and M. Cook, ‘‘Determining
the Safety of Enzymes Used in Animal
Feed,’’ Regulatory Toxicology and
Pharmacology, 56:332–342, 2010.
43. Olempska-Beer Z.S., R.I Merker, M.D.
Ditto, and M.J. DiNovi, ‘‘Food-Processing
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Enzymes From Recombinant
Microorganisms—A Review,’’ Regulatory
Toxicology and Pharmacology,
45(2):144–158, 2006.
44. ‘‘Guidance for Industry: Use of
Nanomaterials in Food for Animals (#
220),’’ (https://www.fda.gov/downloads/
AnimalVeterinary/GuidanceCompliance
Enforcement/GuidanceforIndustry/
UCM401508.pdf), 2015. Accessed and
printed on January 15, 2016.
45. ‘‘GRAS Notices, Search Results, Common
Use in Food,’’ 2016.
46. GRAS Notice Inventory, (https://
www.fda.gov/Food/IngredientsPackaging
Labeling/GRAS/NoticeInventory/
default.htm), 2016. Accessed and printed
on January 15, 2016.
47. Current Animal Food GRAS Notices
Inventory, (https://www.fda.gov/Animal
Veterinary/Products/AnimalFoodFeeds/
GenerallyRecognizedasSafeGRAS
Notifications/ucm243845.htm), 2016.
Accessed and printed on February 23,
2016.
48. FDA, List of Pending GRAS Affirmation
Petitions as of December 31, 2015.
49. FDA, ‘‘Guidance for Industry: Frequently
Asked Questions About GRAS,’’ (https://
www.fda.gov/Food/GuidanceRegulation/
GuidanceDocumentsRegulatory
Information/IngredientsAdditivesGRAS
Packaging/ucm061846.htm), 2004.
Accessed and printed on October 13,
2010. See Reference 6 to the 2010 notice.
50. FDA, Memorandum of Telephone
Conference Held on May 19, 1998,
between Linda S. Kahl and Gloria
Overholser of FDA and Carlton Kempter
and Jonathan Fleuchaus, U.S.
Environmental Protection Agency.
51. FDA, ‘‘Substances Generally Recognized
as Safe Final Rule: Final Regulatory
Impact Analysis, Final Regulatory
Flexibility Analysis, Final Unfunded
Mandates Reform Act Analysis,’’ 2016.
52. FDA, ‘‘Compliance Policy Guide CPG
Sec. 665.100 Common or Usual Names
for Animal Feed Ingredients,’’ (https://
www.fda.gov/iceci/compliancemanuals/
compliancepolicyguidancemanual/
ucm074687.htm), 1995. Accessed and
printed on January 7, 2016.
53. Selle, P.H. and V. Ravindran, ‘‘Microbial
Phytase in Poultry Nutrition,’’ Animal
Feed Science and Technology, 135:1–41,
2007.
54. Hatten., L.F., D.R. Ingram., and S.T.
Pittman, ‘‘Effect of Phytase on
Production Parameters and Nutrient
Availability in Broilers and Laying Hens:
A Review,’’ The Journal of Applied
Poultry Research, 10(3):274–278, 2001.
55. Angel, C.R., W. Saylor, S.L. Vieira, and
N. Ward, ‘‘Effects of a Monocomponent
Protease on Performance and Protein
Utilization in 7- to 22-Day-Old Broiler
Chickens,’’ Poultry Science, 90:2281–
2286, 2011.
56. FDA, ‘‘Guidance for Industry:
Recommendations for Preparation and
Submission of Animal Food Additive
Petitions (# 221),’’ (https://www.fda.gov/
downloads/AnimalVeterinary/Guidance
ComplianceEnforcement/Guidancefor
Industry/UCM367746.pdf), 2015.
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Fmt 4701
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Accessed and printed on January 15,
2016.
57. National Research Council, ‘‘General
Considerations in Determining Safety of
Animal Dietary Supplements,’’ in Safety
of Dietary Supplements for Horses, Dogs,
and Cats, Washington, DC, Chapter 9,
pp. 169–175, The National Academies
Press, 2009.
58. FDA, ‘‘Compliance Policy Guide CPG
Sec. 527.400. Whole Milk, Lowfat Milk,
Skim Milk—Aflatoxin M1,’’ (https://
www.fda.gov/iceci/compliancemanuals/
compliancepolicyguidancemanual/
ucm074482.htm), 2005. Accessed and
printed on January 15, 2016.
List of Subjects
21 CFR Part 20
Confidential business information,
Courts, Freedom of information,
Government employees.
21 CFR Part 25
Environmental impact statements,
Foreign relations, Reporting and
recordkeeping requirements.
21 CFR Part 170
Administrative practice and
procedure, Food additives, Reporting
and recordkeeping requirements.
21 CFR Part 184
Food additives.
21 CFR Part 186
Food additives, Food packaging.
21 CFR Part 570
Animal feeds, Animal foods, Food
additives.
Therefore, under the Federal Food,
Drug, and Cosmetic Act and under
authority delegated to the Commissioner
of Food and Drugs, 21 CFR chapter I is
amended as follows:
PART 20—PUBLIC INFORMATION
1. The authority citation for part 20
continues to read as follows:
■
Authority: 5 U.S.C. 552; 18 U.S.C. 1905;
19 U.S.C. 2531–2582; 21 U.S.C. 321–393,
1401–1403; 42 U.S.C. 241, 242, 242a, 242l,
242n, 243, 262, 263, 263b–263n, 264, 265,
300u–300u–5, 300aa–1.
2. In § 20.100, add paragraph (c)(46) to
read as follows:
■
§ 20.100 Applicability; cross-reference to
other regulations.
*
*
*
*
*
(c) * * *
(46) Generally recognized as safe
(GRAS) notices, in part 170, subpart E
and part 570, subpart E of this chapter.
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PART 25—ENVIRONMENTAL IMPACT
CONSIDERATIONS
3. The authority citation for part 25
continues to read as follows:
■
Authority: 21 U.S.C. 321–393; 42 U.S.C.
262, 263b–264; 42 U.S.C. 4321, 4332; 40 CFR
parts 1500–1508; E.O. 11514, 35 FR 4247, 3
CFR, 1971 Comp., p. 531–533 as amended by
E.O. 11991, 42 FR 26967, 3 CFR, 1978 Comp.,
p. 123–124 and E.O. 12114, 44 FR 1957, 3
CFR, 1980 Comp., p. 356–360.
4. In § 25.20, revise paragraph (k) to
read as follows:
■
§ 25.20 Actions requiring preparation of an
environmental assessment.
*
*
*
*
*
(k) Establishment or amendment of a
regulation for a food substance as GRAS
under the conditions of its intended use
for humans or animals under parts 182,
184, 186, 582, or 584 of this chapter, or
establishment or amendment of a
regulation for a prior-sanctioned food
ingredient, as defined in §§ 170.3(l) and
181.5(a) of this chapter, unless
categorically excluded in § 25.32(f), (i),
(j), (k), or (r).
*
*
*
*
*
■ 5. In § 25.32, revise paragraphs (f), (i),
(j), (k), and (r) to read as follows:
§ 25.32 Foods, food additives, and color
additives.
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*
*
*
*
*
(f) Establishment or amendment of a
regulation for a food substance as GRAS
under the conditions of its intended use
for humans or animals under parts 182,
184, 186, 582, or 584 of this chapter,
and establishment or amendment of a
regulation for a prior-sanctioned food
ingredient, as defined in §§ 170.3(l) and
181.5(a) of this chapter, if the substance
or food ingredient is already marketed
in the United States for the proposed
use.
*
*
*
*
*
(i) Approval of a food additive
petition, establishment or amendment of
a regulation for a food substance as
GRAS under the conditions of its
intended use for humans or animals
under parts 182, 184, 186, 582, or 584
of this chapter, the granting of a request
for exemption from regulation as a food
additive under § 170.39 of this chapter,
or allowing a notification submitted
under 21 U.S.C. 348(h) to become
effective, when the substance is present
in finished food-packaging material at
not greater than 5 percent-by-weight and
is expected to remain with finished
food-packaging material through use by
consumers or when the substance is a
component of a coating of a finished
food-packaging material.
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(j) Approval of a food additive
petition, establishment or amendment of
a regulation for a food substance as
GRAS under the conditions of its
intended use for humans or animals
under parts 182, 184, 186, 582, or 584
of this chapter, the granting of a request
for exemption from regulation as a food
additive under § 170.39 of this chapter,
or allowing a notification submitted
under 21 U.S.C. 348(h) to become
effective, when the substance is to be
used as a component of a food-contact
surface of permanent or semipermanent
equipment or of another food-contact
article intended for repeated use.
(k) Approval of a food additive
petition or color additive petition,
establishment or amendment of a
regulation for a food substance as GRAS
under the conditions of its intended use
for humans or animals under parts 182,
184, 186, 582, or 584 of this chapter, or
allowing a notification submitted under
21 U.S.C. 348(h) to become effective, for
substances added directly to food that
are intended to remain in food through
ingestion by consumers and that are not
intended to replace macronutrients in
food.
*
*
*
*
*
(r) Approval of a food additive
petition or color additive petition,
establishment or amendment of a
regulation for a food substance as GRAS
under the conditions of its intended use
for humans or animals under parts 182,
184, 186, 582, or 584 of this chapter, or
allowing a notification submitted under
21 U.S.C. 348(h) to become effective for
a substance that occurs naturally in the
environment, when the action does not
alter significantly the concentration or
distribution of the substance, its
metabolites, or degradation products in
the environment.
PART 170—FOOD ADDITIVES
6. The authority citation for part 170
continues to read as follows:
■
Authority: 21 U.S.C. 321, 341, 342, 346a,
348, 371.
7. In § 170.3, revise paragraph (h), the
first sentence of paragraph (i), and
paragraph (k), to read as follows:
■
§ 170.3
Definitions.
*
*
*
*
*
(h) Scientific procedures include the
application of scientific data (including,
as appropriate, data from human,
animal, analytical, or other scientific
studies), information, and methods,
whether published or unpublished, as
well as the application of scientific
principles, appropriate to establish the
PO 00000
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55047
safety of a substance under the
conditions of its intended use.
(i) Safe or safety means that there is
a reasonable certainty in the minds of
competent scientists that the substance
is not harmful under the conditions of
its intended use. * * *
*
*
*
*
*
(k) General recognition of safety shall
be in accordance with § 170.30.
*
*
*
*
*
■ 8. Amend § 170.30 as follows:
■ a. Revise the last sentence of
paragraph (a);
■ b. Revise paragraph (b).
■ c. Revise the the first sentence of
paragraph (c)(1) and revise paragraph
(c)(2);
■ d. Remove ‘‘§ 186.1’’ and add in its
place ‘‘part 186’’ wherever it appears in
paragraph (d);
■ e. Revise paragraph (e);
■ f. Remove and reserve paragraph (f);
■ g. Remove ‘‘§ 186.1’’ and add in its
place ‘‘part 186’’ in paragraphs (h)
introductory text, (h)(1), (i), (j), and (k);
and
■ h. Revise the last sentence of
paragraph (l).
The revisions read as follows:
§ 170.30 Eligibility for classification as
generally recognized as safe (GRAS).
(a) * * * General recognition of safety
requires common knowledge throughout
the scientific community knowledgeable
about the safety of substances directly or
indirectly added to food that there is
reasonable certainty that the substance
is not harmful under the conditions of
its intended use (see § 170.3(i)).
(b) General recognition of safety based
upon scientific procedures shall require
the same quantity and quality of
scientific evidence as is required to
obtain approval of a food additive.
General recognition of safety through
scientific procedures shall be based
upon the application of generally
available and accepted scientific data,
information, or methods, which
ordinarily are published, as well as the
application of scientific principles, and
may be corroborated by the application
of unpublished scientific data,
information, or methods.
(c)(1) General recognition of safety
through experience based on common
use in food prior to January 1, 1958,
may be achieved without the quantity or
quality of scientific procedures required
for approval of a food additive. * * *
(2) A substance used in food prior to
January 1, 1958, may be generally
recognized as safe through experience
based on its common use in food when
that use occurred exclusively or
primarily outside of the United States if
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the information about the experience
establishes that the substance is safe
under the conditions of its intended use
within the meaning of section 201(u) of
the Federal Food, Drug, and Cosmetic
Act (see also § 170.3(i)). Common use in
food prior to January 1, 1958, that
occurred outside of the United States
shall be documented by published or
other information and shall be
corroborated by information from a
second, independent source that
confirms the history and circumstances
of use of the substance. The information
used to document and to corroborate the
history and circumstances of use of the
substance must be generally available;
that is, it must be widely available in
the country in which the history of use
has occurred and readily available to
interested qualified experts in the
United States. A person who concludes
that a use of a substance is GRAS
through experience based on its
common use in food outside of the
United States should notify FDA of that
view in accordance with subpart E of
this part.
*
*
*
*
*
(e) Food ingredients were listed as
GRAS in part 182 of this chapter during
1958–1962 without a detailed scientific
review of all available data and
information relating to their safety.
Beginning in 1969, the Food and Drug
Administration has undertaken a
systematic review of the status of all
ingredients used in food based on the
view that they are GRAS under the
conditions of their intended use or
subject to a prior sanction. All
affirmations of GRAS status or
determinations of food additive status or
prior sanction status pursuant to this
review shall be handled pursuant to
§§ 170.35, 170.38, and 180.1 of this
chapter. Affirmation of GRAS status
shall be announced in part 184 or part
186 of this chapter.
*
*
*
*
*
(l) * * * Any change to the GRAS
status of a food ingredient in parts 182,
184, or 186 of this chapter shall be
accomplished pursuant to § 170.38.
■ 9. In § 170.35, revise paragraphs (a),
(b)(1), (3), and (4), and remove
paragraph (c) to read as follows:
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§ 170.35 Affirmation of generally
recognized as safe (GRAS) status.
(a) The Commissioner, on his own
initiative, may affirm that a substance
that directly or indirectly becomes a
component of food is GRAS under the
conditions of its intended use.
(b)(1) If the Commissioner proposes
on his own initiative that a substance is
entitled to affirmation as GRAS under
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the conditions of its intended use, he
will place all of the data and
information on which he relies on
public file in the office of the Division
of Dockets Management and will
publish in the Federal Register a notice
giving the name of the substance, its
proposed uses, and any limitations
proposed for purposes other than safety.
*
*
*
*
*
(3) The Commissioner will evaluate
all comments received. If he concludes
that there is convincing evidence that
the substance is GRAS under the
conditions of its intended use as
described in § 170.30, he will publish a
notice in the Federal Register listing the
GRAS conditions of use of the substance
in part 184 or part 186 of this chapter,
as appropriate.
(4) If, after evaluation of the
comments, the Commissioner concludes
that there is a lack of convincing
evidence that a substance is GRAS
under the conditions of its intended use
and that it should be considered a food
additive subject to section 409 of the
Federal Food, Drug, and Cosmetic Act,
he shall publish a notice thereof in the
Federal Register in accordance with
§ 170.38.
■ 10. In § 170.38, revise paragraph (a) to
read as follows:
§ 170.38
status.
Determination of food additive
(a) The Commissioner may, in
accordance with § 170.35(b)(4), publish
a notice in the Federal Register
determining that a substance is not
GRAS under the conditions of its
intended use and is a food additive
subject to section 409 of the Federal
Food, Drug, and Cosmetic Act.
*
*
*
*
*
■ 11. Add subpart E, consisting of
§§ 170.203 through 170.285, to read as
follows:
Subpart E—Generally Recognized as
Safe (GRAS) Notice
Sec.
170.203 Definitions.
170.205 Opportunity to submit a GRAS
notice.
170.210 How to send your GRAS notice to
FDA.
170.215 Incorporation into a GRAS notice.
170.220 General requirements applicable to
a GRAS notice.
170.225 Part 1 of a GRAS notice: Signed
statements and certification.
170.230 Part 2 of a GRAS notice: Identity,
method of manufacture, specifications,
and physical or technical effect.
170.235 Part 3 of a GRAS notice: Dietary
exposure.
170.240 Part 4 of a GRAS notice: Selflimiting levels of use.
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170.245 Part 5 of a GRAS notice:
Experience based on common use in
food before 1958.
170.250 Part 6 of a GRAS notice: Narrative.
170.255 Part 7 of a GRAS notice: List of
supporting data and information in your
GRAS notice.
170.260 Steps you may take before FDA
responds to your GRAS notice.
170.265 What FDA will do with a GRAS
notice.
170.270 Procedures that apply when the
intended conditions of use of a notified
substance include use in a product or
products subject to regulation by the
Food Safety and Inspection Service
(FSIS) of the United States Department of
Agriculture.
170.275 Public disclosure of a GRAS
notice.
170.280 Submission of a supplement.
170.285 Disposition of pending GRAS
affirmation petitions.
Subpart E—Generally Recognized as
Safe (GRAS) Notice
§ 170.203
Definitions.
The definitions and interpretations of
terms in § 170.3 apply to such terms
when used in this subpart. The
following definitions also apply:
Amendment means any data and
information that you submit regarding a
filed GRAS notice before we respond to
your notice by letter in accordance with
§ 170.265(b)(1) or cease to evaluate your
notice in accordance with
§ 170.265(b)(3).
GRAS means generally recognized as
safe.
GRAS notice means a submission that
informs us of your view that a substance
is not subject to the premarket approval
requirements of the Federal Food, Drug,
and Cosmetic Act based on your
conclusion that the substance is GRAS
under the conditions of its intended use
in accordance with § 170.30.
Notified substance means the
substance that is the subject of your
GRAS notice.
Notifier means the person (e.g., an
individual, partnership, corporation,
association, or other legal entity) who is
responsible for the GRAS notice, even if
another person (such as an attorney,
agent, or qualified expert) prepares or
submits the notice or provides an
opinion about the basis for a conclusion
of GRAS status.
Qualified expert means an individual
who is qualified by scientific training
and experience to evaluate the safety of
substances under the conditions of their
intended use in food.
Supplement means any data and
information that you submit regarding a
filed GRAS notice after we respond to
your notice by letter in accordance with
§ 170.265(b)(1) or cease to evaluate your
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notice in accordance with
§ 170.265(b)(3).
We, our, and us refer to the United
States Food and Drug Administration
(FDA).
You and your refer to a notifier.
§ 170.205
notice.
Opportunity to submit a GRAS
Any person may notify FDA of a view
that a substance is not subject to the
premarket approval requirements of
section 409 of the Federal Food, Drug,
and Cosmetic Act based on that person’s
conclusion that the substance is GRAS
under the conditions of its intended use.
§ 170.210
to FDA.
How to send your GRAS notice
(a) Send your GRAS notice to the
Office of Food Additive Safety (HFS–
200), Center for Food Safety and
Applied Nutrition, Food and Drug
Administration, 5001 Campus Drive,
College Park, MD 20740.
(b) When you submit your GRAS
notice, you may do so either in an
electronic format that is accessible for
our evaluation or on paper. If you send
your GRAS notice on paper, a single
paper copy is sufficient.
§ 170.215
notice.
Incorporation into a GRAS
You may incorporate into your GRAS
notice either specifically identified data
and information that you previously
submitted to the Center for Food Safety
and Applied Nutrition (CFSAN), or
specifically identified publicly available
data and information submitted by
another party, when such data and
information remain in CFSAN’s records,
such as data and information contained
in a previous GRAS notice or a food
additive petition.
§ 170.220 General requirements applicable
to a GRAS notice.
mstockstill on DSK3G9T082PROD with RULES2
(a) A GRAS notice has seven parts as
required by §§ 170.225 through 170.255.
You must submit the data and
information specified in each of these
parts on separate pages or sets of pages.
(b) You must include each of the
seven parts in your GRAS notice. If you
do not include a part, you must include
with your GRAS notice an explanation
of why that part does not apply to your
GRAS notice.
§ 170.225 Part 1 of a GRAS notice: Signed
statements and certification.
(a) Part 1 of your GRAS notice must
be dated and signed by a responsible
official of your organization, or by your
attorney or agent.
(b) Except as required by paragraph
(c)(8) of this section, you must not
include any information that is trade
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secret or confidential commercial
information in Part 1 of your GRAS
notice.
(c) In Part 1 of your GRAS notice, you
must:
(1) Inform us that you are submitting
a GRAS notice in accordance with this
subpart;
(2) Provide the name and address of
your organization;
(3) Provide the name of the notified
substance, using an appropriately
descriptive term;
(4) Describe the intended conditions
of use of the notified substance,
including the foods in which the
substance will be used, the levels of use
in such foods, and the purposes for
which the substance will be used,
including, when appropriate, a
description of a subpopulation expected
to consume the notified substance;
(5) Inform us of the statutory basis for
your conclusion of GRAS status (i.e.,
through scientific procedures in
accordance with § 170.30(a) and (b) or
through experience based on common
use in food in accordance with
§ 170.30(a) and (c));
(6) State your view that the notified
substance is not subject to the premarket
approval requirements of the Federal
Food, Drug, and Cosmetic Act based on
your conclusion that the notified
substance is GRAS under the conditions
of its intended use;
(7) State that, if we ask to see the data
and information that are the basis for
your conclusion of GRAS status, either
during or after our evaluation of your
notice, you will:
(i) Agree to make the data and
information available to us; and
(ii) Agree to both of the following
procedures for making the data and
information available to us:
(A) Upon our request, you will allow
us to review and copy the data and
information during customary business
hours at the address you specify for
where these data and information will
be available to us; and
(B) Upon our request, you will
provide us with a complete copy of the
data and information either in an
electronic format that is accessible for
our evaluation or on paper;
(8) State your view as to whether any
of the data and information in Parts 2
through 7 of your GRAS notice are
exempt from disclosure under the
Freedom of Information Act, 5 U.S.C.
552 (e.g., as trade secret or as
commercial or financial information
that is privileged or confidential).
(9) Certify that, to the best of your
knowledge, your GRAS notice is a
complete, representative, and balanced
submission that includes unfavorable
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55049
information, as well as favorable
information, known to you and
pertinent to the evaluation of the safety
and GRAS status of the use of the
substance;
(10) State both the name and position
or title of the person who signs the
GRAS notice; and
(11) When applicable, state as
required by § 170.270 whether you:
(i) Authorize us to send any trade
secrets to the Food Safety and
Inspection Service (FSIS) of the U.S.
Department of Agriculture; or
(ii) Ask us to exclude any trade
secrets from the copy of the GRAS
notice that we will send to FSIS.
§ 170.230 Part 2 of a GRAS notice: Identity,
method of manufacture, specifications, and
physical or technical effect.
In Part 2 of your GRAS notice, you
must include:
(a) Scientific data and information
that identifies the notified substance.
(1) Examples of appropriate data and
information include the chemical name,
applicable registry numbers (such as a
Chemical Abstracts Service (CAS)
registry number or an Enzyme
Commission (EC) number), empirical
formula, structural formula, quantitative
composition, and characteristic
properties.
(2) When the source of a notified
substance is a biological material, you
must include data and information
sufficient to identify:
(i) The taxonomic source (e.g., genus,
species) including, as applicable, data
and information at the sub-species level
(e.g., variety, strain);
(ii) The part of any plant or animal
used as the source; and
(iii) Any known toxicants that could
be in the source;
(b) A description of the method of
manufacture of the notified substance in
sufficient detail to evaluate the safety of
the notified substance as manufactured;
(c) Specifications for food-grade
material; and
(d) When necessary to demonstrate
safety, relevant data and information
bearing on the physical or other
technical effect the notified substance is
intended to produce, including the
quantity of the notified substance
required to produce such effect.
§ 170.235 Part 3 of a GRAS notice: Dietary
exposure.
In part 3 of your GRAS notice, you
must provide data and information
about dietary exposure (i.e., the amount
of relevant substances that consumers
are likely to eat or drink as part of a total
diet), regardless of whether your
conclusion of GRAS status is through
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scientific procedures or through
experience based on common use in
food, as follows:
(a) You must provide an estimate of
dietary exposure to the notified
substance that includes exposure from
its intended use and all sources in the
diet; and
(b) When applicable, you must
provide an estimate of dietary exposure
to any other substance that is expected
to be formed in or on food because of
the use of the notified substance (e.g.,
hydrolytic products or reaction
products);
(c) When applicable, you must
provide an estimate of dietary exposure
to any other substance that is present
with the notified substance either
naturally or due to its manufacture (e.g.,
contaminants or by-products);
(d) You must describe the source of
any food consumption data that you use
to estimate dietary exposure in
accordance with paragraphs (a) through
(c) of this section; and
(e) You must explain any assumptions
you made to estimate dietary exposure
in accordance with paragraphs (a)
through (c) of this section.
§ 170.240 Part 4 of a GRAS notice: Selflimiting levels of use.
In circumstances where the amount of
the notified substance that can be added
to food is limited because food
containing levels of the notified
substance above a particular level
would become unpalatable or
technologically impractical, in Part 4 of
your GRAS notice you must include
data and information on such selflimiting levels of use.
§ 170.245 Part 5 of a GRAS notice:
Experience based on common use in food
before 1958.
If the statutory basis for your
conclusion of GRAS status is through
experience based on common use in
food, in Part 5 of your GRAS notice you
must include evidence of a substantial
history of consumption of the notified
substance for food use by a significant
number of consumers prior to January 1,
1958.
mstockstill on DSK3G9T082PROD with RULES2
§ 170.250 Part 6 of a GRAS notice:
Narrative.
In Part 6 of your GRAS notice, you
must include a narrative that provides
the basis for your conclusion of GRAS
status, in which:
(a)(1) You must explain why the data
and information in your notice provide
a basis for your view that the notified
substance is safe under the conditions of
its intended use. In your explanation,
you must address the safety of the
notified substance, considering all
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dietary sources and taking into account
any chemically or pharmacologically
related substances in such diet;
(2) In your explanation, you must
identify what specific data and
information that you discuss in
accordance with paragraph (a)(1) of this
section are generally available, and what
specific data and information that you
discuss in accordance with paragraph
(a)(1) of this section are not generally
available, by providing citations to the
list of data and information that you
include in Part 7 of your GRAS notice
in accordance with § 170.255;
(b) You must explain how the
generally available data and information
that you rely on to establish safety in
accordance with paragraph (a) of this
section provide a basis for your
conclusion that the notified substance is
generally recognized, among qualified
experts, to be safe under the conditions
of its intended use;
(c) You must either:
(1) Identify, discuss, and place in
context, data and information that are,
or may appear to be, inconsistent with
your conclusion of GRAS status,
regardless of whether those data and
information are generally available; or
(2) State that you have reviewed the
available data and information and are
not aware of any data and information
that are, or may appear to be,
inconsistent with your conclusion of
GRAS status;
(d) If you view any of the data and
information in your notice as exempt
from disclosure under the Freedom of
Information Act, you must identify the
specific data and information; and
(e) For non-public, safety-related data
and information considered in reaching
a conclusion of GRAS status, you must
explain how there could be a basis for
a conclusion of GRAS status if qualified
experts do not have access to such data
and information.
§ 170.255 Part 7 of a GRAS notice: List of
supporting data and information in your
GRAS notice.
(a) In part 7 of your GRAS notice, you
must include a list of all of the data and
information that you discuss in Part 6 of
your GRAS notice to provide a basis for
your view that the notified substance is
safe under the conditions of its intended
use as described in accordance with
§ 170.250(a)(1).
(b) You must specify which data and
information that you list in accordance
with paragraph (a) of this section are
generally available, and which data and
information are not generally available.
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§ 170.260 Steps you may take before FDA
responds to your GRAS notice.
(a) You may submit a timely
amendment to your filed GRAS notice,
to update your GRAS notice or in
response to a question from us, before
we respond to your notice by letter in
accordance with § 170.265(b)(1) or cease
to evaluate your notice in accordance
with § 170.265(b)(3).
(b) At any time before we respond to
your GRAS notice in accordance with
§ 170.265(b)(1), you may request in
writing that we cease to evaluate your
GRAS notice. Your request does not
preclude you from submitting a future
GRAS notice in accordance with this
subpart with respect to the notified
substance.
§ 170.265
notice.
What FDA will do with a GRAS
(a)(1) We will conduct an initial
evaluation of your submission to
determine whether to file it as a GRAS
notice for evaluation of your view that
the notified substance is GRAS under
the conditions of its intended use.
(2) If we file your submission as a
GRAS notice, we will send you a letter
that informs you of the date of filing.
(3) If we do not file your submission
as a GRAS notice, we will send you a
letter that informs you of that fact and
provides our reasons for not filing the
submission as a GRAS notice.
(4) We will consider any timely
amendment that you submit to a filed
GRAS notice, to update your GRAS
notice or in response to a question from
us, before we respond to you by letter
in accordance with paragraph (b)(1) of
this section, if we deem that doing so is
feasible within the timeframes
established in paragraph (b) of this
section. If we deem that considering
your amendment is not feasible within
the timeframes established in paragraph
(b) of this section or if we have granted
your request to cease to evaluate your
notice, we will inform you that we are
not considering your amendment.
(b)(1) Within 180 days of filing, we
will respond to you by letter based on
our evaluation of your notice. We may
extend the 180 day timeframe by 90
days on an as needed basis.
(2) If we extend the timeframe, we
will inform you in writing of the
extension as soon as practicable but no
later than within 180 days of filing.
(3) If you ask us to cease to evaluate
your GRAS notice in accordance with
§ 170.260(b), we will send you a letter
informing you of our decision regarding
your request.
(c) If circumstances warrant, we will
send you a subsequent letter about the
notice.
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§ 170.270 Procedures that apply when the
intended conditions of use of a notified
substance include use in a product or
products subject to regulation by the Food
Safety and Inspection Service (FSIS) of the
United States Department of Agriculture.
If the intended conditions of use of
the notified substance include use in a
product or products subject to
regulation by FSIS under statutes that it
administers:
(a) When applicable, you must
include in your GRAS notice a
statement as to whether you:
(1) Authorize us to send any trade
secrets to FSIS; or
(2) Ask us to exclude any trade secrets
from the copy of the GRAS notice that
we will send to FSIS.
(b)(1) We will forward a copy of a
GRAS notice or relevant portions
thereof to FSIS;
(2) We will exclude any trade secrets
unless you have authorized us to do so
in accordance with paragraph (a)(1) of
this section; and
(c) We will ask FSIS to advise
whether the intended conditions of use
comply with applicable statutes and
regulations, or, if not, whether the use
of the substance would be permitted in
products under FSIS’ jurisdiction under
specified conditions or restrictions.
(d) As appropriate, we will inform
you of the advice we receive from FSIS
in the letter we send you in accordance
with § 170.265(b)(1).
mstockstill on DSK3G9T082PROD with RULES2
§ 170.275
notice.
from public disclosure in accordance
with part 20 of this chapter.
§ 170.280
If circumstances warrant, you may
submit a supplement to a filed GRAS
notice after we respond to your notice
by letter in accordance with
§ 170.265(b)(1) or cease to evaluate your
notice in accordance with
§ 170.265(b)(3).
§ 170.285 Disposition of pending GRAS
affirmation petitions.
Because the procedure to submit a
GRAS notice is replacing the former
process to submit a GRAS affirmation
petition, the following will happen to a
filed GRAS affirmation petition that is
pending on October 17, 2016.
(a) On October 17, 2016, we will close
the docket for any GRAS affirmation
petition that is still pending as of
October 17, 2016.
(b) Any person who submitted a
GRAS affirmation petition described in
this section may submit a GRAS notice
as described in this subpart and request
that we incorporate the GRAS
affirmation petition as described in
§ 170.215.
PART 184—DIRECT FOOD
SUBSTANCES AFFIRMED AS
GENERALLY RECOGNIZED AS SAFE
12. The authority citation for part 184
continues to read as follows:
■
Public disclosure of a GRAS
Authority: 21 U.S.C. 321, 342, 348, 371.
(a) The data and information in a
GRAS notice (including data and
information submitted in any
amendment or supplement to your
GRAS notice or incorporated into your
GRAS notice) are:
(1) Considered a mandatory, rather
than voluntary, submission for purposes
of their status under the Freedom of
Information Act and our public
information requirements in part 20 of
this chapter; and
(2) Available for public disclosure in
accordance with part 20 of this chapter
as of the date that we receive your
GRAS notice.
(b) We will make the following
readily accessible to the public:
(1) A list of filed GRAS notices,
including the information described in
§ 170.225(c)(2) through (c)(5);
(2) The text of any letter that we issue
under § 170.265(b)(1) or (c); and
(3) The text of any letter that we issue
under § 170.265(b)(3) if we grant your
request that we cease to evaluate your
notice.
(c) We will disclose all remaining data
and information that are not exempt
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Submission of a supplement.
13. In § 184.1, revise the first sentence
of paragraph (a), and revise the fifth
sentence and remove the last sentence
of paragraph (b)(1) to read as follows.
■
§ 184.1 Substances added directly to
human food affirmed as generally
recognized as safe (GRAS).
(a) The direct human food ingredients
listed in this part have been reviewed by
the Food and Drug Administration and
affirmed to be generally recognized as
safe (GRAS) for the purposes and under
the conditions prescribed. * * *
(b) * * *
(1) * * * In such a case, a
manufacturer may not rely on the
regulation as authorizing that use but
shall have a basis to conclude that that
use is GRAS or shall use the ingredient
in accordance with a food additive
regulation. * * *
*
*
*
*
*
PART 186—INDIRECT FOOD
SUBSTANCES AFFIRMED AS
GENERALLY RECOGNIZED AS SAFE
14. The authority citation for part 186
continues to read as follows:
■
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Authority: 21 U.S.C. 321, 342, 348, 371.
15. In § 186.1, revise the first sentence
of paragraph (a), and revise the fifth
sentence and remove the last sentence
of paragraph (b)(1) to read as follows.
■
§ 186.1 Substances added indirectly to
human food affirmed as generally
recognized as safe (GRAS).
(a) The indirect human food
ingredients listed in this part have been
reviewed by the Food and Drug
Administration and affirmed to be
generally recognized as safe (GRAS) for
the purposes and under the conditions
prescribed, providing they comply with
the purity specifications listed in this
part or, in the absence of purity
specifications, are of a purity suitable
for their intended use in accordance
with § 170.30(h)(1) of this chapter.
* * *
(b) * * *
(1) * * * In such a case, a
manufacturer may not rely on the
regulation as authorizing that use but
shall have a basis to conclude that the
use is GRAS or shall use the ingredient
in accordance with a food additive
regulation. * * *
*
*
*
*
*
PART 570—FOOD ADDITIVES
16. The authority citation for part 570
continues to read as follows:
■
Authority: 21 U.S.C. 321, 341, 342, 346a,
348, 371.
17. In § 570.3, revise paragraphs (f),
(h), the first sentence of (i), and (k), and
add paragraph (n) to read as follows:
■
§ 570.3
Definitions.
*
*
*
*
*
(f) Common use in food means a
substantial history of consumption of a
substance by a significant number of
animals of the species to which the
substance is intended to be fed (and, for
food-producing animals fed with such
substance, also means a substantial
history of consumption by humans
consuming human foods derived from
those food-producing animals), prior to
January 1, 1958.
*
*
*
*
*
(h) Scientific procedures include the
application of scientific data (including,
as appropriate, data from human,
animal, analytical, or other scientific
studies), information, and methods,
whether published or unpublished, as
well as the application of scientific
principles, appropriate to establish the
safety of a substance under the
conditions of its intended use.
(i) Safe or safety means that there is
a reasonable certainty in the minds of
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competent scientists that the substance
is not harmful under the conditions of
its intended use. * * *
*
*
*
*
*
(k) General recognition of safety shall
be in accordance with § 570.30.
*
*
*
*
*
(n) Food-producing animal means an
animal used to produce human food.
■ 18. In § 570.30, revise the last
sentence of paragraph; (a); revise
paragraphs (b) through (d); and revise
the last sentence in paragraph (i) to read
as follows:
mstockstill on DSK3G9T082PROD with RULES2
§ 570.30 Eligibility for classification as
generally recognized as safe (GRAS).
(a) * * * General recognition of safety
requires common knowledge throughout
the scientific community knowledgeable
about the safety of substances directly or
indirectly added to food that there is
reasonable certainty that the substance
is not harmful to either the target animal
or to humans consuming human food
derived from food-producing animals
under the conditions of its intended use
(see § 570.3(i)).
(b) General recognition of safety based
upon scientific procedures shall require
the same quantity and quality of
scientific evidence as is required to
obtain approval of a food additive.
General recognition of safety through
scientific procedures shall address
safety for both the target animal and for
humans consuming human food derived
from food-producing animals and shall
be based upon the application of
generally available and accepted
scientific data, information, or methods,
which ordinarily are published, as well
as the application of scientific
principles, and may be corroborated by
the application of unpublished
scientific data, information, or methods.
(c)(1) General recognition of safety
through experience based on common
use in food prior to January 1, 1958,
shall address safety for both the target
animal and for humans consuming
human food derived from foodproducing animals and may be achieved
without the quantity or quality of
scientific procedures required for
approval of a food additive. General
recognition of safety through experience
based on common use in food prior to
January 1, 1958, shall be based solely on
food use of the substance in the same
animal species prior to January 1, 1958,
and shall ordinarily be based upon
generally available data and
information. An ingredient not in
common use in food prior to January 1,
1958, may achieve general recognition
of safety only through scientific
procedures.
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(2) A substance used in food prior to
January 1, 1958, may be generally
recognized as safe through experience
based on its common use in food when
that use occurred exclusively or
primarily outside of the United States if
the information about the experience
establishes that the substance is safe
under the conditions of its intended use
within the meaning of section 201(u) of
the Federal Food, Drug, and Cosmetic
Act (see also § 570.3(i)) for both the
target animal and for humans
consuming human food derived from
food-producing animals. Common use
in food prior to January 1, 1958, that
occurred outside of the United States
shall be documented by published or
other information and shall be
corroborated by information from a
second, independent source that
confirms the history and circumstances
of use of the substance. The information
used to document and to corroborate the
history and circumstances of use of the
substance must be generally available;
that is, it must be widely available in
the country in which the history of use
has occurred and readily available to
interested qualified experts in the
United States. A person who concludes
that a use of a substance is GRAS
through experience based on its
common use in food outside of the
United States should notify FDA of that
view in accordance with subpart E of
this part.
(d) The food ingredients listed as
GRAS in part 582 of this chapter or
affirmed as GRAS in part 584 of this
chapter do not include all substances
that are generally recognized as safe for
their intended use in food. Because of
the large number of substances the
intended use of which results or may
reasonably be expected to result,
directly or indirectly, in their becoming
a component or otherwise affecting the
characteristics of food, it is
impracticable to list all such substances
that are GRAS. A food ingredient of
natural biological origin that has been
widely consumed for its nutrient
properties in the United States prior to
January 1, 1958, without known
detrimental effects, which is subject
only to conventional processing as
practiced prior to January 1, 1958, and
for which no known safety hazard
exists, will ordinarily be regarded as
GRAS without specific inclusion in part
582 or part 584 of this chapter.
*
*
*
*
*
(i) * * * Any use of such an
ingredient not in full compliance with
each such established limitation shall
require a food additive regulation.
*
*
*
*
*
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19. In § 570.35, revise paragraphs (a),
(b)(1), (3), and (4), and remove
paragraph (c) to read as follows:
■
§ 570.35 Affirmation of generally
recognized as safe (GRAS) status.
(a) The Commissioner, on his own
initiative, may affirm that a substance
that directly or indirectly becomes a
component of food is GRAS under the
conditions of its intended use.
(b)(1) If the Commissioner proposes
on his own initiative that a substance is
entitled to affirmation as GRAS under
the conditions of its intended use, he
will place all of the data and
information on which he relies on
public file in the office of the Division
of Dockets Management and will
publish in the Federal Register a notice
giving the name of the substance, its
proposed uses, and any limitations
proposed for purposes other than safety.
*
*
*
*
*
(3) The Commissioner will evaluate
all comments received. If he concludes
that there is convincing evidence that
the substance is GRAS under the
conditions of its intended use as
described in § 570.30, he will publish a
notice in the Federal Register listing the
GRAS conditions of use in this
subchapter E.
(4) If, after evaluation of the
comments, the Commissioner concludes
that there is a lack of convincing
evidence that the substance is GRAS
under the conditions of its intended use
and that it should be considered a food
additive subject to section 409 of the
Federal Food, Drug, and Cosmetic Act,
he shall publish a notice thereof in the
Federal Register in accordance with
§ 570.38.
■ 20. In § 570.38, revise paragraph (a) to
read as follows:
§ 570.38
status.
Determination of food additive
(a) The Commissioner may, in
accordance with § 570.35(b)(4), publish
a notice in the Federal Register
determining that a substance is not
GRAS under the conditions of its
intended use and is a food additive
subject to section 409 of the Federal
Food, Drug, and Cosmetic Act.
*
*
*
*
*
■ 21. Add and reserve subparts C and D.
■ 22. Add subpart E, consisting of
§§ 570.203 through 570.280, to read as
follows:
Subpart E—Generally Recognized as
Safe (GRAS) Notice
Sec.
570.203 Definitions.
570.205 Opportunity to submit a GRAS
notice.
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570.210 How to send your GRAS notice to
FDA.
570.215 Incorporation into a GRAS notice.
570.220 General requirements applicable to
a GRAS notice.
570.225 Part 1 of a GRAS notice: Signed
statements and certification.
570.230 Part 2 of a GRAS notice: Identity,
method of manufacture, specifications,
and physical or technical effect.
570.235 Part 3 of a GRAS notice: Target
animal and human exposures.
570.240 Part 4 of a GRAS notice: Selflimiting levels of use.
570.245 Part 5 of a GRAS notice:
Experience based on common use in
food before 1958.
570.250 Part 6 of a GRAS notice: Narrative.
570.255 Part 7 of a GRAS notice: List of
supporting data and information in your
GRAS notice.
570.260 Steps you may take before FDA
responds to your GRAS notice.
570.265 What FDA will do with a GRAS
notice.
570.275 Public disclosure of a GRAS
notice.
570.280 Submission of a supplement.
Subpart E—Generally Recognized as
Safe (GRAS) Notice
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§ 570.203
Definitions.
The definitions and interpretations of
terms in § 570.3 apply to such terms
when used in this subpart. The
following definitions also apply:
Amendment means any data and
information that you submit regarding a
filed GRAS notice before we respond to
your notice by letter in accordance with
§ 570.265(b)(1) or cease to evaluate your
notice in accordance with
§ 570.265(b)(3).
GRAS means generally recognized as
safe.
GRAS notice means a submission that
informs us of your view that a substance
is not subject to the premarket approval
requirements of the Federal Food, Drug,
and Cosmetic Act based on your
conclusion that the substance is GRAS
under the conditions of its intended use
in accordance with § 570.30.
Notified substance means the
substance that is the subject of your
GRAS notice.
Notifier means the person (e.g., an
individual, partnership, corporation,
association, or other legal entity) who is
responsible for the GRAS notice, even if
another person (such as an attorney,
agent, or qualified expert) prepares or
submits the notice or provides an
opinion about the basis for a conclusion
of GRAS status.
Qualified expert means an individual
who is qualified by scientific training
and experience to evaluate the safety of
substances under the conditions of their
intended use in animal food.
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Supplement means any data and
information that you submit regarding a
filed GRAS notice after we respond to
your notice by letter in accordance with
§ 570.265(b)(1) or cease to evaluate your
notice in accordance with
§ 570.265(b)(3).
We, our, and us refer to the United
States Food and Drug Administration
(FDA).
You and your refer to a notifier.
§ 570.205
notice.
Opportunity to submit a GRAS
Any person may notify FDA of a view
that a substance is not subject to the
premarket approval requirements of
section 409 of the Federal Food, Drug,
and Cosmetic Act based on that person’s
conclusion that the substance is GRAS
under the conditions of its intended use.
§ 570.210
to FDA.
How to send your GRAS notice
(a) Send your GRAS notice to the
Division of Animal Feeds (HFV–220),
Center for Veterinary Medicine, Food
and Drug Administration, 7519 Standish
Pl., Rockville, MD 20855.
(b) When you submit your GRAS
notice, you may do so either in an
electronic format that is accessible for
our evaluation or on paper. If you send
your GRAS notice on paper, a single
paper copy is sufficient.
§ 570.215
notice.
Incorporation into a GRAS
You may incorporate into your GRAS
notice either specifically identified data
and information that you previously
submitted to the Center for Veterinary
Medicine (CVM), or specifically
identified publicly available data and
information submitted by another party,
when such data and information remain
in CVM’s records, such as data and
information contained in a previous
GRAS notice or a food additive petition.
§ 570.220 General requirements applicable
to a GRAS notice.
(a) A GRAS notice has seven parts as
required by §§ 570.225 through 570.255.
You must submit the data and
information specified in each of these
parts on separate pages or sets of pages.
(b) You must include each of the
seven parts in your GRAS notice. If you
do not include a part, you must include
with your GRAS notice an explanation
of why that part does not apply to your
GRAS notice.
§ 570.225 Part 1 of a GRAS notice: Signed
statements and certification.
(a) Part 1 of your GRAS notice must
be dated and signed by a responsible
official of your organization, or by your
attorney or agent.
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(b) Except as required by paragraph
(c)(8) of this section, you must not
include any information that is trade
secret or confidential commercial
information in Part 1 of your GRAS
notice.
(c) In Part 1 of your GRAS notice, you
must:
(1) Inform us that you are submitting
a GRAS notice in accordance with this
subpart;
(2) Provide the name and address of
your organization;
(3) Provide the name of the notified
substance, using an appropriately
descriptive term;
(4) Describe the intended conditions
of use of the notified substance,
including stating whether the substance
will be added to food (including
drinking water) for animals in which the
substance will be used; identifying the
foods to which it will be added, the
levels of use in such foods, and the
animal species for which these foods are
intended (including, when appropriate,
a description of a subpopulation
expected to consume the notified
substance); and the purposes for which
the substance will be used;
(5) Inform us of the statutory basis for
your conclusion of GRAS status (i.e.,
through scientific procedures in
accordance with § 570.30(a) and (b) or
through experience based on common
use in animal food in accordance with
§ 570.30(a) and (c));
(6) State your view that the notified
substance is not subject to the premarket
approval requirements of the Federal
Food, Drug, and Cosmetic Act based on
your conclusion that the notified
substance is GRAS under the conditions
of its intended use;
(7) State that, if we ask to see the data
and information that are the basis for
your conclusion of GRAS status, either
during or after our evaluation of your
notice, you will:
(i) Agree to make the data and
information available to us; and
(ii) Agree to both of the following
procedures for making the data and
information available to us:
(A) Upon our request, you will allow
us to review and copy the data and
information during customary business
hours at the address you specify for
where these data and information will
be available to us; and
(B) Upon our request, you will
provide us with a complete copy of the
data and information either in an
electronic format that is accessible for
our evaluation or on paper;
(8) State your view as to whether any
of the data and information in Parts 2
through 7 of your GRAS notice are
exempt from disclosure under the
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Freedom of Information Act, 5 U.S.C.
552 (e.g., as trade secret or as
commercial or financial information
that is privileged or confidential);
(9) Certify that, to the best of your
knowledge, the GRAS notice is a
complete, representative, and balanced
submission that includes unfavorable
information, as well as favorable
information, known to you and
pertinent to the evaluation of the safety
and GRAS status of the use of the
substance; and
(10) State both the name and the
position or title of the person who signs
the GRAS notice.
§ 570.230 Part 2 of a GRAS notice: Identity,
method of manufacture, specifications, and
physical or technical effect.
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In Part 2 of your GRAS notice, you
must include:
(a) Scientific data and information
that identifies the notified substance.
(1) Examples of appropriate data and
information include the chemical name,
applicable registry numbers (such as a
Chemical Abstracts Service (CAS)
registry number or an Enzyme
Commission (EC) number), empirical
formula, structural formula, quantitative
composition, and characteristic
properties.
(2) When the source of a notified
substance is a biological material, you
must include data and information
sufficient to identify:
(i) The taxonomic source (e.g., genus,
species), including as applicable data
and information at the sub-species level
(e.g., variety, strain);
(ii) The part of any plant or animal
used as the source; and
(iii) Any known toxicants that could
be in the source;
(b) A description of the method of
manufacture of the notified substance in
sufficient detail to evaluate the safety of
the notified substance as manufactured;
(c) Specifications for material that is
of appropriate grade for use in animal
food; and
(d) When necessary to demonstrate
safety, relevant data and information
bearing on the physical or other
technical effect the notified substance is
intended to produce, including the
quantity of the notified substance
required to produce such effect.
§ 570.235 Part 3 of a GRAS notice: Target
animal and human exposures.
In part 3 of your GRAS notice, you
must provide data and information
about exposure to the target animal and
to humans consuming human food
derived from food-producing animals,
regardless of whether your conclusion
of GRAS status is through scientific
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procedures or through experience based
on common use in food, as follows:
(a) For exposure to the target animal,
you must provide:
(1) The amount of the notified
substance that different target animal
species are likely to consume in the
animal food (including drinking water)
as part of the animal’s total diet,
including the intended use and all other
sources in the total diet; and
(2) When applicable, the amount of
any other substance that is expected to
be formed in or on food because of the
use of the notified substance (e.g.,
hydrolytic products or reaction
products);
(3) When applicable, the amount of
any other substance that is present with
the notified substance either naturally
or due to its manufacture (e.g.,
contaminants or by-products);
(4) The data and information you rely
on to establish the amount of the
notified substance and the amounts of
any other substance in accordance with
paragraphs (a)(1) through (a)(3) of this
section that different target animal
species are likely to consume in the
animal food (including drinking water)
as part of the animal’s total diet; and
(b) When the intended use is in food
for food-producing animals, you must
provide:
(1) The potential quantities of any
residues that humans may be exposed to
in edible animal tissues, including:
(i) Residues of the notified substance;
(ii) Residues of any other substance
that is expected to be formed in or on
the animal food because of the use of
the notified substance; and
(iii) Residues from any other
substance that is present with the
notified substance whether naturally,
due to its manufacture (e.g.,
contaminants or by-products), or
produced as a metabolite in edible
animal tissues when the notified
substance is consumed by a foodproducing animal; and
(2) The data and information you rely
on to establish, in accordance with
paragraph (b)(1) of this section, the
potential quantities of any residues that
humans may be exposed to in edible
animal tissues.
§ 570.240 Part 4 of a GRAS notice: Selflimiting levels of use.
In circumstances where the amount of
the notified substance that can be added
to animal food is limited because animal
food containing levels of the notified
substance above a particular level
would become unpalatable or
technologically impractical, in Part 4 of
your GRAS notice you must include
data and information on such selflimiting levels of use.
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§ 570.245 Part 5 of a GRAS notice:
Experience based on common use in food
before 1958.
If the statutory basis for your
conclusion of GRAS status is through
experience based on common use in
animal food, in Part 5 of your GRAS
notice you must include evidence of a
substantial history of consumption of
the notified substance for food use by a
significant number of animals of the
species to which the substance is
intended to be fed prior to January 1,
1958, and evidence of a substantial
history of consumption by humans
consuming human foods derived from
food-producing animals prior to January
1, 1958.
§ 570.250 Part 6 of a GRAS notice:
Narrative.
In Part 6 of your GRAS notice, you
must include a narrative that provides
the basis for your conclusion of GRAS
status, in which:
(a)(1) You must explain why the data
and information in your notice provide
a basis for your view that the notified
substance is safe under the conditions of
its intended use for both the target
animal and for humans consuming
human food derived from foodproducing animals. In your explanation,
you must address the safety of the
notified substance, considering all
animal food (including drinking water)
as part of the animal’s total diet, taking
into account any chemically or
pharmacologically related substances in
such diet. In your explanation, you must
also address the safety of the notified
substance in regard to human exposure,
considering all dietary sources and
taking into account any chemically or
pharmacologically related substances;
(2) In your explanation, you must
identify what specific data and
information that you discuss in
accordance with paragraph (a)(1) of this
section are generally available, and what
specific data and information that you
discuss in accordance with paragraph
(a)(1) of this section are not generally
available, by providing citations to the
list of data and information that you
include in Part 7 of your GRAS notice
in accordance with § 570.255;
(b) You must explain how the
generally available data and information
that you rely on to establish safety in
accordance with paragraph (a) of this
section provide a basis for your
conclusion that the notified substance is
generally recognized, among qualified
experts, to be safe under the conditions
of its intended use for both the target
animal and for humans consuming
human food derived from foodproducing animals;
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(c) You must either:
(1) Identify, discuss, and place in
context, data and information that are,
or may appear to be, inconsistent with
your conclusion of GRAS status,
regardless of whether those data and
information are generally available; or
(2) State that you have reviewed the
available data and information and are
not aware of any data and information
that are, or may appear to be,
inconsistent with your conclusion of
GRAS status;
(d) If you view any of the data and
information in your notice as exempt
from disclosure under the Freedom of
Information Act, you must identify the
specific data and information; and
(e) For non-public, safety-related data
and information considered in reaching
a conclusion of GRAS status, you must
explain how there could be a basis for
a conclusion of GRAS status if qualified
experts do not have access to such data
and information.
§ 570.255 Part 7 of a GRAS notice: List of
supporting data and information in your
GRAS notice.
(a) In part 7 of your GRAS notice, you
must include a list of all of the data and
information that you discuss in Part 6 of
your GRAS notice to provide a basis for
your view that the notified substance is
safe under the conditions of its intended
use as described in accordance with
§ 570.250(a)(1).
(b) You must specify which data and
information that you list in accordance
with paragraph (a) of this section are
generally available, and which data and
information are not generally available.
§ 570.260 Steps you may take before FDA
responds to your GRAS notice.
mstockstill on DSK3G9T082PROD with RULES2
(a) You may submit a timely
amendment to your filed GRAS notice,
to update your GRAS notice or in
response to a question from us, before
we respond to your notice by letter in
accordance with § 570.265(b)(1) or cease
to evaluate your notice in accordance
with § 570.265(b)(3).
(b) At any time before we respond to
your notice by letter in accordance with
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§ 570.265(b)(1), you may request in
writing that we cease to evaluate your
GRAS notice. Your request does not
preclude you from submitting a future
GRAS notice in accordance with this
subpart with respect to the notified
substance.
§ 570.265
notice.
What FDA will do with a GRAS
(a)(1) We will conduct an initial
evaluation of your submission to
determine whether to file it as a GRAS
notice for evaluation of your view that
the notified substance is GRAS under
the conditions of its intended use.
(2) If we file your submission as a
GRAS notice, we will send you a letter
that informs you of the date of filing.
(3) If we do not file your submission
as a GRAS notice, we will send you a
letter that informs you of that fact and
provide our reasons for not filing the
submission as a GRAS notice.
(4) We will consider any timely
amendment that you submit to a filed
GRAS notice, to update your GRAS
notice or in response to a question from
us, before we respond to you by letter
in accordance with paragraph (b)(1) of
this section, if we deem that doing so is
feasible within the timeframes
established in paragraph (b) of this
section. If we deem that considering
your amendment is not feasible within
the timeframes established in paragraph
(b) of this section or if we have granted
your request to cease to evaluate your
notice, we will inform you that we are
not considering your amendment.
(b)(1) Within 180 days of filing, we
will respond to you by letter based on
our evaluation of your notice. We may
extend the 180 day timeframe by 90
days on an as needed basis.
(2) If we extend the timeframe, we
will inform you in writing of the
extension as soon as practicable but no
later than within 180 days of filing.
(3) If you ask us to cease to evaluate
your GRAS notice in accordance with
§ 570.260(b), we will send you a letter
informing you of our decision regarding
your request.
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(c) If circumstances warrant, we will
send you a subsequent letter about the
notice.
§ 570.275
notice.
Public disclosure of a GRAS
(a) The data and information in a
GRAS notice (including data and
information submitted in any
amendment or supplement to your
GRAS notice, or incorporated into your
GRAS notice) are:
(1) Considered a mandatory, rather
than voluntary, submission for purposes
of their status under the Freedom of
Information Act and our public
information requirements in part 20 of
this chapter; and
(2) Available for public disclosure in
accordance with part 20 of this chapter
as of the date that we receive your
GRAS notice.
(b) We will make the following
readily accessible to the public:
(1) A list of filed GRAS notices,
including the information described in
§ 570.225(c)(2) through (c)(5);
(2) The text of any letter that we issue
under § 570.265(b)(1) or (c); and
(3) The text of any letter that we issue
under § 570.265(b)(3) if we grant your
request that we cease to evaluate your
notice.
(c) We will disclose all remaining data
and information that are not exempt
from public disclosure in accordance
with part 20 of this chapter.
§ 570.280
Submission of a supplement.
If circumstances warrant, you may
submit a supplement to a filed GRAS
notice after we respond to your notice
by letter in accordance with
§ 570.265(b)(1) or cease to evaluate your
notice in accordance with
§ 570.265(b)(3).
Dated: August 8, 2016.
Jeremy Sharp,
Deputy Commissioner for Policy, Planning,
Legislation and Analysis.
[FR Doc. 2016–19164 Filed 8–12–16; 11:15 am]
BILLING CODE 4164–01–P
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Agencies
[Federal Register Volume 81, Number 159 (Wednesday, August 17, 2016)]
[Rules and Regulations]
[Pages 54959-55055]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-19164]
[[Page 54959]]
Vol. 81
Wednesday,
No. 159
August 17, 2016
Part III
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 20, 25, 170, et al.
Substances Generally Recognized as Safe; Final Rule
Federal Register / Vol. 81 , No. 159 / Wednesday, August 17, 2016 /
Rules and Regulations
[[Page 54960]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 20, 25, 170, 184, 186, and 570
[Docket No. FDA-1997-N-0020 (formerly 97N-0103)]
RIN 0910-AH15
Substances Generally Recognized as Safe
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA or we) is issuing a
final rule that amends and clarifies the criteria in our regulations
for when the use of a substance in food for humans or animals is not
subject to the premarket approval requirements of the Federal Food,
Drug, and Cosmetic Act (the FD&C Act) because the substance is
generally recognized as safe (GRAS) under the conditions of its
intended use. We also are amending our regulations to replace the
voluntary GRAS affirmation petition process with a voluntary
notification procedure under which any person may notify us of a
conclusion that a substance is GRAS under the conditions of its
intended use. The clarified criteria for GRAS status should help
stakeholders draw more informed conclusions about whether the intended
conditions of use of a substance in food for humans or animals complies
with the FD&C Act, and the notification procedure will enable
stakeholders to be aware of whether we have questioned the basis of a
conclusion of GRAS status.
DATES: This rule is effective October 17, 2016. Submit comments on
information collection issues under the Paperwork Reduction Act of 1995
by October 17, 2016 (see section XXIX, the ``Paperwork Reduction Act of
1995'' section of this document).
ADDRESSES: To ensure that comments on the information collection are
received, the Office of Management and Budget (OMB) recommends that
written comments be faxed to the Office of Information and Regulatory
Affairs, OMB, Attn: FDA Desk Officer, FAX: 202-395-7285, or emailed to
oira_submission@omb.eop.gov. All comments should be identified with the
OMB control number 0910-0342 and titled ``Substances Generally
Recognized as Safe.'' Also include the FDA docket number found in
brackets in the heading of this document.
FOR FURTHER INFORMATION CONTACT: Regarding substances that would be
used in human food: Paulette M. Gaynor, Center for Food Safety and
Applied Nutrition (HFS-255), Food and Drug Administration, 5001 Campus
Drive, College Park, MD 20740, 240-402-1192. Regarding substances that
would be used in animal food: Geoffrey K. Wong, Center for Veterinary
Medicine (HFV-224), Food and Drug Administration, 7519 Standish Pl.,
Rockville, MD 20855, 240-402-5838.
SUPPLEMENTARY INFORMATION:
Table of Contents
Executive Summary
Purpose and Coverage of the Rule
Summary of the Major Provisions of the Rule
Costs and Benefits
I. Introduction
A. History of FDA's Approach to the GRAS Provision of the FD&C
Act
B. Report by the Government Accountability Office and How We Are
Addressing Its Recommendations
C. Issues Regarding the Legal and Regulatory Framework for
Substances Added to Food
D. Recent FDA Actions Related to GRAS Criteria
E. Moving Forward Under This Final Rule
II. Background
A. The Proposed Rule
B. Interim Pilot Program
C. 2010 Report of the Government Accountability Office
D. 2010 Notice Reopening the Comment Period
E. Public Comments
F. Applicability of Discussions in This Document to Both the
Human Food Regulations and the Animal Food Regulations
G. Use of Pronouns in This Document
H. Summary of Principal Changes to the Proposed Notification
Procedure
III. Legal Authority
IV. General Comments on the Proposed Rule
V. Comments on the Definition of Scientific Procedures
VI. Comments on the Criteria for Eligibility for Classification as
GRAS
A. General Criteria for Eligibility for Classification as GRAS
B. Criteria for Eligibility for Classification as GRAS Through
Scientific Procedures
C. Criteria for Eligibility for Classification as GRAS Through
Experience Based on Common Use in Food
D. Other Comments on the Criteria for Eligibility for
Classification as GRAS
E. GRAS Status of Certain Food Substances
VII. Comments on the Substitution of a GRAS Notification Procedure
for the GRAS Affirmation Petition Process
A. Affirmation on the Initiative of the Commissioner
B. Deletion of the GRAS Affirmation Petition Process
C. General Comments on the Proposed GRAS Notification Procedure
D. Comments on Certain Terms Used in the Proposed Regulatory
Text
E. Comments on the Use of ``Plain Language'' in the Regulatory
Text
VIII. Definitions Applicable to a GRAS Notice
A. Definitions We Described in the 2010 Notice
B. Definition of ``GRAS Notice''
C. Other Terms We Are Defining in the Rule
IX. Opportunity to Submit a GRAS Notice
X. Comments on Administrative Procedures for Submission of a GRAS
Notice
A. How to Send a GRAS Notice to FDA
B. Option for Submission of Electronic or Paper Copies of a GRAS
Notice
C. Incorporation into a GRAS Notice
XI. General Requirements Applicable to a GRAS Notice
XII. Comments on Part 1 of a GRAS Notice: Signed Statements and
Certification
A. Exclusion of Trade Secret and Confidential Commercial
Information From the Signed Statements
B. Name of the Notified Substance, Using an Appropriately
Descriptive Term
C. Intended Conditions of Use of the Notified Substance
D. Statutory Basis for the Conclusion of GRAS Status
E. Agreement to Make Data and Information Available Upon Request
F. Statements and Any Applicable Explanation Regarding Data and
Information That a Notifier Views as Exempt From Disclosure Under
FOIA
G. Certification Statement
H. Person Signing Part 1 of the GRAS Notice
I. Authorization for FDA to Send Trade Secret Information to
FSIS
XIII. Comments on Part 2 of a GRAS Notice: Identity, Method of
Manufacture, Specifications, and Physical or Technical Effect
A. Scientific Information About the Identity of a Notified
Substance
B. Method of Manufacture
C. Specifications for the Notified Substance
D. Data and Information Bearing on the Physical or Other
Technical Effect of the Notified Substance
XIV. Comments on Part 3 of a GRAS Notice: Dietary Exposure
XV. Comments on Part 4 of a GRAS Notice: Self-Limiting Levels of Use
XVI. Comments on Part 5 of a GRAS Notice: Common Use in Food Before
1958
XVII. Comments on Parts 6 and 7 of a GRAS Notice: Narrative and List
of Supporting Data and Information
XVIII. Comments on Steps a Notifier May Take Before We Respond to a
GRAS Notice
A. Communicating With a Notifier Before We Respond to a GRAS
Notice
B. Submitting an Amendment
C. Notifier's Request That We Cease To Evaluate a GRAS Notice
XIX. Comments on What We Will Do With a GRAS Notice
A. Filing Decision
B. Our Response to a GRAS Notice
C. Additional Correspondence as Circumstances Warrant
D. Procedures If a Notifier Disagrees With Our Response
[[Page 54961]]
XX. Coordinating Our Evaluation of a GRAS Notice With FSIS
XXI. Comments on Public Disclosure of a GRAS Notice
A. Data and Information in a GRAS Notice Are Available for
Public Disclosure on the Date That We Receive It
B. We Will Make a List of Filed GRAS Notices and Our Responses
to GRAS Notices Readily Accessible
C. Public Disclosure of a GRAS Notice Is in Accordance With Our
Public Information Regulations in Part 20
XXII. Submission of a Supplement
XXIII. Comments on the Administrative Process for Pending GRAS
Affirmation Petitions
XXIV. Other Comments
A. GRAS Panels and Conflict of Interest
B. Guidance on Documenting Conclusions of GRAS Status
C. Compliance With Other FDA Regulations
D. Impact on Other Federal Agencies
E. Impact on International Trade
F. Audits
G. Lack of an Environmental Assessment
H. Substances Affirmed as GRAS With Specific Limitations
XXV. Comments on Substances Intended for Use in Animal Food
A. Issues in the 2010 Notice Specific to Animal Food
B. Criteria for Eligibility for Classification as GRAS for a
Substance Intended for Use in Animal Food (Sec. 570.30)
C. Part 1 of a GRAS Notice for a Substance Intended for Use in
Animal Food: Name of the Notified Substance (Sec. 570.225(c)(3))
D. Part 1 of a GRAS Notice for a Substance Intended for Use in
Animal Food: Intended Conditions of Use (Sec. 570.225(c)(4))
E. Part 2 of a GRAS Notice for a Substance Intended for Use in
Animal Food: Data and Information Bearing on the Physical or Other
Technical Effect of the Notified Substance (Sec. 570.230(d))
F. Part 3 of a GRAS Notice for a Substance Intended for Use in
Animal Food: Target Animal and Human Exposures (Sec. 570.235)
G. Data and Information in a GRAS Notice About Safety for the
Target Animal (Sec. 570.250)
H. Data and Information in a GRAS Notice About the Safety for
Humans Consuming Human Food Derived From a Food-Producing Animal
(Sec. Sec. 570.235 and 570.250)
I. Filing Decision, Opportunity for a Notifier to Submit an
Amendment, and Asking Us to Cease to Evaluate a GRAS Notice for a
Substance Intended for Use in Animal Food (Sec. Sec. 570.260 and
570.265)
J. Opportunity for a Notifier to Submit a Supplement to a GRAS
Notice for a Substance Intended for Use in Animal Food (Sec.
570.280)
K. GRAS Affirmation Petitions for Substances Used in Animal Food
XXVI. Editorial, Clarifying, and Conforming Amendments
XXVII. Economic Analysis of Impacts
XXVIII. Analysis of Environmental Impact
XXIX. Paperwork Reduction Act of 1995
XXX. Federalism
XXXI. References
Executive Summary
Purpose and Coverage of the Rule
Although we have premarket review authority over food additives, a
food manufacturer can intentionally add a substance to human food or
animal food without our premarket review or approval if the substance
is generally recognized, among qualified experts, to be safe under the
conditions of its intended use (GRAS). Since the 1970s, we have had
regulations clarifying the statutory provision for eligibility for
classification as GRAS. We also have had regulations governing a
procedure for any person to voluntarily submit to us a petition asking
us to affirm the GRAS status of a substance under the conditions of its
intended use, and for us to engage in an intensive rulemaking process
in response to that petition. Experience has shown that our regulations
need further clarification to help stakeholders understand when a
substance is eligible for classification as GRAS in human food or
animal food under the conditions of its intended use. Experience also
has shown that streamlining our evaluation of conclusions of GRAS
status will enable us to evaluate more, and higher priority,
substances. We are issuing this final rule to amend and clarify the
criteria in our regulations for when a substance is GRAS under the
conditions of its intended use in human food or animal food, and to
replace the voluntary administrative procedure for petitioning us to
affirm the GRAS status of a use of a substance in human food or animal
food with a voluntary administrative procedure for notifying us about a
conclusion that a substance is GRAS under the conditions of its
intended use in human food or animal food.
Summary of the Major Provisions of the Rule
The final rule clarifies the criteria for the use of a substance to
be eligible for classification as GRAS and establishes a new
administrative procedure for any person to notify us of the basis for a
conclusion that a substance is GRAS under the conditions of its
intended use. With respect to criteria for eligibility for
classification as GRAS, in the final rule we clarify that:
A substance cannot be classified as GRAS under the
conditions of its intended use if the available data and information do
not satisfy the safety standard for a food additive under the FD&C Act;
General recognition of safety requires common knowledge,
throughout the expert scientific community knowledgeable about the
safety of substances directly or indirectly added to food, that there
is a reasonable certainty that the substance is not harmful under the
conditions of its intended use;
``Common knowledge'' can be based on either ``scientific
procedures'' or on experience based on common use of a substance in
food prior to January 1, 1958; and
General recognition of safety through scientific
procedures must be based upon the application of generally available
and accepted scientific data, information, or methods, which ordinarily
are published, as well as the application of scientific principles, and
may be corroborated by the application of unpublished scientific data,
information, or methods.
With respect to the procedure for submitting a GRAS notice, we
provide:
Definitions for certain terms, including amendment, GRAS
notice, notified substance, notifier, qualified expert, supplement, we/
our/us, and you/your;
A clear statement of the opportunity for any person to
submit a GRAS notice;
Information on available formats (electronic and paper)
and where to send a GRAS notice;
What data and other information may be incorporated into a
GRAS notice;
General provisions applicable to a GRAS notice;
Specific information you must provide in your GRAS notice,
including:
[cir] Signed statements and a certification (Part 1);
[cir] The identity, method of manufacture, specifications, and
physical or technical effect of the notified substance (Part 2);
[cir] Dietary exposure (Part 3);
[cir] Self-limiting levels of use, in circumstances where the
amount of the notified substance that can be added to human food or
animal food is limited because the food containing levels of the
notified substance above a particular level would become unpalatable or
technologically impractical (Part 4);
[cir] The history of consumption of the substance for food use by a
significant number of consumers (or animals in the case of animal food)
prior to January 1, 1958, if a conclusion of GRAS status is based on
common use of the substance in food prior to 1958 (Part 5);
[cir] A narrative that provides the basis for your conclusion of
GRAS status, including why the scientific data, information, methods,
and principles
[[Page 54962]]
described in the notice provide a basis for your conclusion that the
notified substance is generally recognized, among qualified experts, to
be safe under the conditions of its intended use (Part 6); and
[cir] A list of the data and information that you discuss in the
narrative of your GRAS notice, specifying which of these data and
information are generally available, and which of these data and
information are not generally available (Part 7); and
Process for you to submit an amendment to your GRAS
notice; and
Process for you to request that we cease to evaluate your
GRAS notice.
With respect to our administration of a GRAS notice, we specify:
Information about how we will file a GRAS notice, respond
to it, and send subsequent correspondence about it;
Our commitment to respond within 180 days of filing of a
GRAS notice, with a potential to extend our response timeframe by
another 90 days;
Our procedures in the event the intended conditions of use
of the notified substance include use in a product subject to
regulation by the Food Safety and Inspection Service (FSIS) of the U.S.
Department of Agriculture (USDA); and
Provisions governing the public disclosure of a GRAS
notice, including the actions we take to make some information
regarding a GRAS notice readily accessible to the public.
As of the effective date of the final rule, we will close the
docket for any pending GRAS affirmation petition. The petitioner may
incorporate the applicable petition into a new GRAS notice.
Costs and Benefits
The final rule eliminates the petition process to affirm that a
substance is GRAS under the conditions of its intended use and replaces
that petition process with a GRAS notification procedure. We estimate
that over 10 years with a 7 percent discount rate, the present value of
the total costs of the final rule range from $0.9 million to $3.3
million; with a 3 percent discount rate, the present value of the total
costs range from $0.9 million to $3.4 million. The annualized costs of
the rule range from $0.1 million to $0.4 million with a 7 percent
discount rate and range from $0.1 million to $0.5 million with a 3
percent discount rate. We do not quantify the benefits of the final
rule, but assume that firms will only participate in the GRAS
notification procedure when they expect to receive a non-negative
private benefit. The GRAS notification procedure will allow us to
complete our evaluation within the timelines specified in the final
rule. The following table includes a summary of the benefits and costs
of the final rule.
Summary of Benefits and Costs of the Final Rule
----------------------------------------------------------------------------------------------------------------
Total annualized Total annualized
Present value of Present value of costs over 10 costs over 10
Total benefits total costs with 7 total costs with 3 years with 7 years with 3
percent discount percent discount percent discount percent discount
rate ($ mil) rate ($ mil) rate ($ mil) rate ($ mil)
----------------------------------------------------------------------------------------------------------------
Not estimated................... $0.9 to $3.3...... $0.9 to $3.4...... $0.1 to $0.4...... $0.1 to $0.5.
----------------------------------------------------------------------------------------------------------------
Table of Abbreviations and Acronyms
------------------------------------------------------------------------
Abbreviation/acronym What it means
------------------------------------------------------------------------
1958 amendment............................ 1958 Food Additives
Amendment to the Federal
Food, Drug, and Cosmetic
Act.
AAFCO..................................... Association of American Feed
Control Officials.
Affected petitioner....................... Any person who had submitted
a pending petition.
BATF...................................... Bureau of Alcohol, Tobacco,
and Firearms.
CFSAN..................................... Center for Food Safety and
Applied Nutrition.
CVM....................................... Center for Veterinary
Medicine.
EPA....................................... U.S. Environmental
Protection Agency.
FDA....................................... U.S. Food and Drug
Administration.
FDAMA..................................... 1997 Food and Drug
Administration
Modernization Act.
FD&C Act.................................. Federal Food, Drug, and
Cosmetic Act.
FOIA...................................... Freedom of Information Act.
FSIS...................................... Food Safety and Inspection
Service of the U.S.
Department of Agriculture.
GAO....................................... Government Accountability
Office.
GRAS...................................... Generally Recognized as
Safe.
JECFA..................................... Joint Expert Committee on
Food Additives.
MOU....................................... Memorandum of Understanding.
N/A....................................... Not Applicable.
OMB....................................... Office of Management and
Budget.
Pdf....................................... Portable document format.
Pending petition.......................... A filed GRAS affirmation
petition that is pending on
the date that the petition
process is replaced with a
notification procedure.
PHO....................................... Partially hydrogenated oil.
PRA....................................... Paperwork Reduction Act.
TTB....................................... Alcohol and Tobacco Tax and
Trade Bureau.
USDA...................................... U.S. Department of
Agriculture.
------------------------------------------------------------------------
I. Introduction
A. History of FDA's Approach to the GRAS Provision of the FD&C Act
In 1958, in response to public concern about the increased use of
chemicals in foods and food processing and with the support of the food
industry, Congress enacted the Food Additives Amendment (the 1958
amendment) to the FD&C Act. The basic thrust of the 1958 amendment was
to require that, before a substance could be used in food, its sponsor
demonstrate the safety of the substance to FDA, and that we establish a
regulation prescribing the conditions under which the substance may be
safely used. The 1958 amendment
[[Page 54963]]
defined the terms ``food additive'' (21 U.S.C. 321(s)) and ``unsafe
food additive'' (21 U.S.C. 348(a)), established a premarket approval
process for food additives (21 U.S.C. 348(b) through (g)), and amended
the food adulteration provisions of the FD&C Act to deem adulterated
any food that is, or bears or contains, any food additive that is
unsafe within the meaning of 21 U.S.C. 348 (see 21 U.S.C.
342(a)(2)(C)).
Congress recognized that, under this scheme, the safety of a food
additive could not be established with absolute certainty, and thus
provided for a science-based safety standard that requires sponsors of
food additives to demonstrate to a reasonable certainty that no harm
will result from the intended use of an additive (Ref. 1). We have
incorporated this safety standard into our regulations for food
additives and GRAS substances (Sec. 170.3(i)) (21 CFR 170.3(i)). (We
note that although this rule addresses substances intended for use in
animal food as well as substances intended for use in human food, in
this introduction we describe the history of the our GRAS regulations
from the perspective of human food only.) If we find an additive to be
safe, based ordinarily on data submitted by the sponsor to us in a food
additive petition, we promulgate a regulation specifying the conditions
under which the additive may be safely used.
In enacting the 1958 amendment, Congress recognized that many
substances intentionally added to food would not require a formal
premarket review by FDA to assure their safety, either because their
safety had been established by a long history of use in food or by
virtue of the nature of the substance, its customary or projected
conditions of use, and the information generally available to
scientists about the substance. Congress thus adopted, in section
201(s) of the FD&C Act (21 U.S.C. 321(s)), a two-step definition of
``food additive.'' The first step broadly includes any substance, the
intended use of which results or may reasonably be expected to result,
directly or indirectly, in its becoming a component or otherwise
affecting the characteristics of food. The second step, however,
excludes from the definition of ``food additive'' substances that are
generally recognized, among experts qualified by scientific training
and experience to evaluate their safety (``qualified experts''), as
having been adequately shown through scientific procedures (or, in the
case of a substance used in food prior to January 1, 1958, through
either scientific procedures or through experience based on common use
in food) to be safe under the conditions of their intended use.
Importantly, under section 201(s) of the FD&C Act, it is the use of a
substance, rather than the substance itself, that is eligible for GRAS
status. It is on the basis of the GRAS provision within the food
additive definition that many substances (such as vinegar, vegetable
oil, baking powder, and many spices, flavors, gums, and preservatives)
are lawfully marketed today without a food additive regulation. Under
the 1958 amendment, a substance that is GRAS for a particular use may
be marketed for that use without our review and approval. However, when
a use of a substance does not qualify for GRAS status or other
exceptions provided under section 201(s) of the FD&C Act, that use of
the substance is a food additive use subject to the premarket approval
mandated by the FD&C Act. In such circumstances, we can take
enforcement action to stop distribution of the food substance and foods
containing it on the grounds that such foods are or contain an unlawful
food additive.
Shortly after passage of the 1958 amendment, we clarified the
regulatory status of a multitude of food substances that were used in
food prior to 1958 and amended our regulations to include a list of
food substances that, when used for the purposes indicated and in
accordance with good manufacturing practice, are GRAS. This list was
incorporated into our regulations as Sec. 121.101(d) (21 CFR
121.101(d)) (now part 182 (21 CFR part 182)) (24 FR 9368; November 20,
1959). As part of that rulemaking, however, we acknowledged that it
would be impracticable to list all substances that are GRAS for their
intended use (Sec. 121.101(a); current Sec. 182.1(a)).
Section 121.101(d) became commonly referred to as ``the GRAS
list.'' We added other categories of substances (e.g., spices,
seasonings, and flavorings) to the GRAS list in subsequent rulemakings
(25 FR 404, January 19, 1960; and 26 FR 3991, May 9, 1961).
Many substances that were considered GRAS by the food industry were
not included in our GRAS list. Under the 1958 amendment, a substance
that is GRAS under the conditions of its intended use may be marketed
for that use without Agency review and approval. Nonetheless, as a
practical matter, manufacturers who concluded on their own initiative
that use of a substance qualified for GRAS status frequently decided to
obtain our opinion on whether their conclusion was justified. Many
manufacturers wrote to us and requested an ``opinion letter,'' in which
Agency officials would render an informal opinion on the GRAS status of
use of a substance. Although convenient and expedient, these opinion
letters were often available only to the requestor. Moreover, these
opinion letters were not binding on us even at the time they were
issued and letters issued before April 9, 1970, were in fact revoked
(21 CFR 170.6; 35 FR 5810; April 9, 1970).
In 1969 (34 FR 17063; October 21, 1969), we deleted various
cyclamate salts, a family of nonnutritive sweeteners, from the GRAS
list because they were implicated in the formation of bladder tumors in
rats (Ref. 2). In response to the concerns raised by the new
information on cyclamates, then-President Nixon directed us to
reexamine the safety of GRAS substances (Ref. 3), and we announced that
we were conducting a comprehensive study of substances presumed to be
GRAS (35 FR 18623; December 8, 1970). The purpose of the study was to
evaluate, by contemporary standards, the available safety information
regarding substances presumed to be GRAS and to promulgate each item in
a new (i.e., affirmed) GRAS list, a food additive regulation, or an
interim food additive regulation pending completion of additional
studies.
In the notice announcing the comprehensive review of presumed GRAS
substances, we proposed criteria that could be used to establish
whether these substances should be listed as GRAS, become the subject
of a food additive regulation, or be listed in an interim food additive
regulation pending completion of additional studies (35 FR 18623).
These criteria were incorporated into our regulations as Sec. 121.3
(precursor of current Sec. 170.30) (36 FR 12093; June 25, 1971).
We made a second announcement that we were conducting a study of
presumed GRAS substances (36 FR 20546; October 23, 1971) and
subsequently instituted a rulemaking to establish procedures that we
could use, on our own initiative, to affirm the GRAS status of
substances that were the subject of that review and were found to
satisfy the criteria established in Sec. 121.3 (proposed rule, 37 FR
6207, March 25, 1972; final rule, 37 FR 25705, December 2, 1972). These
procedures were subsequently codified at Sec. 170.35(a) and (b).
Because the GRAS review did not cover all GRAS substances (e.g., it did
not cover many substances that were marketed based on a manufacturer's
independent conclusion of GRAS status), that rulemaking included a
mechanism (the GRAS affirmation petition process; Sec. 170.35(c))
whereby
[[Page 54964]]
an individual could petition us to review the GRAS status of substances
not being considered as part of our GRAS review. We codified our
affirmations of GRAS status in current parts 184 and 186 (21 CFR parts
184 and 186).
In 1974, we proposed to clarify the criteria for GRAS status, the
differences between GRAS status and food additive status, and the
procedures being used to conduct the current review of food substances
(39 FR 34194; September 23, 1974). The final regulations based on this
proposal amended Sec. 121.3 (now Sec. 170.30) to distinguish a
conclusion of GRAS status through scientific procedures (Sec.
170.30(b)) from a conclusion of GRAS status through experience based on
common use in food (Sec. 170.30(c)) (41 FR 53600; December 7, 1976).
Those final regulations also established definitions for ``common use
in food'' (now Sec. 170.3(f)) and ``scientific procedures'' (now Sec.
170.3(h)). We subsequently added criteria (Sec. 170.30(c)(2)) for the
determination of GRAS status through experience based on common use in
food when that use occurred exclusively or primarily outside of the
United States (53 FR 16544; May 10, 1988).
To the extent that a person elected to submit a GRAS affirmation
petition, the GRAS affirmation process could facilitate awareness, by
us as well as the domestic and international food industry, of
independent conclusions of GRAS status. However, the GRAS affirmation
petition process involved the resource-intensive rulemaking process. In
the Federal Register of April 17, 1997 (62 FR 18938; the proposed
rule), we proposed to: (1) Clarify the criteria for eligibility for
classification as GRAS; and (2) replace the GRAS affirmation petition
process with a notification procedure whereby any person may notify us
of a conclusion that a particular use of a substance is GRAS. We
explained that we would evaluate whether the notice provides a
sufficient basis for a GRAS conclusion and whether information in the
notice or otherwise available to us raises issues that lead us to
question whether use of the substance is GRAS. We would respond to the
notifier in writing and could advise the notifier that we had
identified a problem with the notice. Although information in a notice
would be publicly available consistent with the Freedom of Information
Act (FOIA), we would make readily accessible to the public a basic
description the notified substance, the conditions of its intended use,
and the statutory basis for GRAS status (i.e., through scientific
procedures or through experience based on common use in food), as well
as our response to the notice. In 2010, we reopened the comment period
for the proposed rule to update comments and to solicit comment on
specific issues (75 FR 81536, December 28, 2010; the 2010 notice). (See
section II.D for additional information about this reopening of the
comment period).
In the proposed rule, we invited interested persons to notify us
about their conclusions of GRAS status as described in the proposed
rule (62 FR 18938 at 18954; the ``Interim Pilot program''). Our Center
for Food Safety and Applied Nutrition (CFSAN) filed its first GRAS
notice in 1998 and has filed 614 GRAS notices as of December 31, 2015.
Our Center for Veterinary Medicine (CVM) established its Interim Pilot
program more recently (75 FR 31800, June 4, 2010) and filed its first
GRAS notice in December 2010. As of December 31, 2015, CVM has filed 18
GRAS notices.
B. Report by the Government Accountability Office and How We Are
Addressing Its Recommendations
From 2008 to 2010, the Government Accountability Office (GAO)
conducted a study related to ingredients used in human food on the
basis of the GRAS provision in section 201(s) of the FD&C Act. In 2010,
GAO issued a report (Ref. 4; the GAO report) that included a number of
recommendations for FDA. For example, the GAO report recommended that
we finalize the proposed rule to establish a notification program for
GRAS substances, strive to minimize the potential for conflict of
interest on ``GRAS panels,'' issue guidance on how to document GRAS
conclusions, and obtain more information about the use of engineered
nanomaterials. (As we note in section VI.B, this document uses the term
``GRAS panel'' to mean a panel of individuals convened for the purpose
of evaluating whether the available scientific data, information, and
methods establish that a substance is safe under the conditions of its
intended use in food.) Consistent with the recommendations in the GAO
report, this document finalizes the GRAS notification procedure as
requested by GAO. It also announces our intent to issue guidance in the
near future to: (1) Provide recommendations regarding the use of a
``GRAS panel,'' including the potential for conflict of interest; and
(2) remind the food industry that the same standards apply to a
conclusion of GRAS status regardless of whether the conclusion is
submitted to us as a GRAS notice or is not submitted to us. (See
Response 125, Response 128, and Response 129).
In 2012, we made available a draft guidance entitled ``Draft
Guidance for Industry: Assessing the Effects of Significant
Manufacturing Process Changes, Including Emerging Technologies, on the
Safety and Regulatory Status of Food Ingredients and Food Contact
Substances, Including Food Ingredients That Are Color Additives'' (Ref.
5) (77 FR 24722, April 25, 2012). We finalized this guidance in 2014
(Ref. 6) (79 FR 36533, June 27, 2014). The guidance includes
recommendations for assessing the effect of a significant manufacturing
process change (including the use of nanotechnology) on the safety and
regulatory status of substances used in human food, including those
that are GRAS. In this guidance, we stated that, at present, for
nanotechnology applications in food substances, there are questions
related to the technical evidence of safety as well as the general
recognition of that safety, that are likely to be sufficient to warrant
formal premarket review and approval by FDA, rather than to satisfy
criteria for GRAS status. In addition, in 2011, we made available a
draft guidance entitled ``Considering Whether an FDA-Regulated Product
Involves the Application of Nanotechnology'' (Ref. 7) (76 FR 34715,
June 14, 2011). We finalized this guidance in 2014 (Ref. 8) (June 27,
2014, 79 FR 36534), which describes our thinking on determining whether
FDA-regulated products involve the application of nanotechnology.
C. Issues Regarding the Legal and Regulatory Framework for Substances
Added to Food
The GAO report discussed issues fundamental to the legal and
regulatory framework for our oversight of the safety of substances
added to food, such as the voluntary nature of the GRAS affirmation
petition process and the proposed GRAS notification procedure. In light
of these issues, the GAO report recommended that we ask any company
evaluating whether a substance is GRAS under the conditions of its
intended use to provide us with basic information about any conclusion
of GRAS status (Ref. 4). Some comments to this rulemaking raise similar
issues. For example, some comments address the voluntary nature of the
GRAS notification procedure or assert that we have implied legal
authority to require that companies notify us of a conclusion of GRAS
status (see Comment 1 and Comment 28). Some comments ask us to require
companies to maintain active
[[Page 54965]]
and accurate listings for all GRAS substances, not just those that are
the subject of a GRAS regulation or a GRAS notice, in a public database
(see Comment 3). Some comments ask us to require certain postmarket
submissions of exposure and safety data related to all GRAS substances,
to require submissions for conclusions of GRAS status that predate the
final rule, and to require any notifier who ``withdraws'' a GRAS notice
or receives an ``insufficient basis letter'' to notify us about any use
of that substance (see Comment 30). One comment asks us to exclude uses
of ``novel'' substances from consideration for eligibility for
classification as GRAS (see Comment 19).
Some comments discuss an industry practice of convening a ``GRAS
panel'' of ``qualified experts'' to provide an opinion on whether a
company's evaluation of the available data and information support a
conclusion that a substance is safe under the conditions of its
intended use, and express concern that such a ``GRAS panel'' may base
its opinion partly on confidential data and information that are
provided to the GRAS panel, but not provided to us in a submitted GRAS
notice (see Comment 10 through Comment 14, Comment 69, and Comment 78).
Some comments express concern that the GRAS notification procedure
would be viewed as a ``fast-track'' option that would tempt a company
that should submit a food additive petition to submit a GRAS notice
instead (see Comment 32). A published critique of the GRAS notification
procedure (Ref. 9) likewise expresses concern that industry is simply
using the GRAS notification procedure as an alternative to the food
additive petition process, contrasting the number of food additive
petitions filed in recent years with the number of GRAS notices filed
in recent years. This report also expresses concern that there are an
indeterminate--but not insignificant--number of industry conclusions of
GRAS status that are not the subject of a GRAS notice to FDA.
In this document, we respond to such comments in the context of our
proposed revisions to the criteria for eligibility for classification
as GRAS and our proposal to replace one voluntary administrative
procedure, i.e., the GRAS affirmation petition process, with a
different voluntary administrative procedure, i.e., the GRAS
notification procedure. (See Response 1, Response 3, Response 10
through Response 14, Response 19, Response 28, Response 30, Response
32, Response 69, and Response 78). As we discuss in Response 28, the
broader issues raised by these comments about the legal and regulatory
framework for our oversight of the safety of substances added to food
are outside the scope of this rulemaking. Thus, this final rule does
not address the possibility that we might enhance our oversight through
additional rulemaking or other actions based on our current legal
authority. Nonetheless, we will continue to consider the broader issues
raised by these comments and take further action as appropriate under
our existing authority through future rulemaking. Importantly, however,
this final rule does establish uniform criteria for describing the
basis for a conclusion that a substance is GRAS under the conditions of
its intended use, and those uniform criteria apply to all conclusions
of GRAS status, not just conclusions of GRAS status that are submitted
to us as a GRAS notice. As discussed in Response 129, we are issuing a
guidance directed to any person who evaluates whether the available
data and information regarding the safety of a substance under the
conditions of its intended use satisfy GRAS criteria. The purpose of
the guidance is to: (1) Remind such persons of their responsibilities
under the FD&C Act regarding a conclusion of GRAS status, regardless of
whether the conclusion of GRAS status is submitted to us as a GRAS
notice; and (2) refer such persons to key resources, such as those
discussed in Response 128, for evaluating the safety of the substance
under the conditions of its intended use and for evaluating whether the
available data and information regarding safety satisfy the criteria
for eligibility for classification as GRAS in Sec. 170.30.
D. Recent FDA Actions Related to GRAS Criteria
In the following paragraphs, we describe two examples of steps we
have taken to address concerns about the safety of certain substances
marketed under the GRAS provision. The first example is partially
hydrogenated oils (PHOs), which are the primary dietary source of
industrially produced trans fatty acids, or trans fat. The second
example is certain uses of caffeine.
Although we had not listed the most commonly used PHOs in either
part 182 or part 184, they had been used in food for many years based
on conclusions of GRAS status by industry. In a notice published in the
Federal Register of November 8, 2013 (78 FR 67169), we described new
scientific evidence and the findings of expert scientific panels
regarding trans fat and requested comments and scientific data and
information on our tentative determination that PHOs are not GRAS for
any use in food based on current scientific evidence establishing the
health risks associated with the consumption of trans fat. In the
Federal Register of June 17, 2015 (80 FR 34650), we issued a
declaratory order announcing our final determination that there is no
longer a consensus among qualified experts that PHOs are GRAS for any
use in human food.
The GRAS list in part 182 includes the use of caffeine in cola-type
beverages at a maximum level of 0.02 percent (Sec. 182.1180). In 2010,
we issued four warning letters regarding the use of caffeine under
markedly different conditions of use than the use listed in Sec.
182.1180, i.e., the use of caffeine as an added ingredient in alcoholic
beverages (Ref. 10 through Ref. 13). In our letters, we stated that,
based on the publicly available literature, a number of qualified
experts have concerns about the safety of caffeinated alcoholic
beverages. We described these concerns, citing published literature. We
further stated that FDA is not aware of data or other information to
establish the safety of caffeine as used in these products. We
therefore informed the companies who were marketing these caffeinated
alcoholic beverages that caffeine, as used in the companies' products,
is an unsafe food additive, and therefore the products are adulterated
under section 402(a)(2)(C) of the FD&C Act (21 U.S.C. 342(a)(2)(C)).
(The Alcohol and Tobacco Tax and Trade Bureau (TTB) also notified the
four companies that if we deem their caffeinated alcohol beverage
products adulterated under the FD&C Act, TTB would consider them to be
mislabeled under the Federal Alcohol Administration Act, making it a
violation for industry members to sell or ship the products in
interstate or foreign commerce (Ref. 14).) The companies subsequently
ceased distribution of these products.
In recent years, other food and beverage products containing
caffeine as an added substance have been introduced into the
marketplace, including so-called ``energy drinks'' that are frequently
marketed for their stimulant properties. When there are new uses of an
added food substance without FDA's premarket engagement, presumably
because a manufacturer has concluded that such a use is GRAS, we must
react to the new uses after they emerge. In such cases, it can be
challenging for FDA to accurately assess consumption patterns and
intake levels and to determine whether those new uses are safe and
lawful in light of all of the available safety data. FDA has engaged
with the National Academies of Science (Ref. 15), trade associations,
and other industry representatives, some of
[[Page 54966]]
whom are conducting a systematic review on the health effects
associated with the consumption of caffeine (Ref. 16 and Ref. 17).
E. Moving Forward Under This Final Rule
We believe that our filing of more than 600 GRAS notices for
substances used in human food is evidence that the substitution of a
GRAS notification procedure for the GRAS affirmation petition process
has benefits for consumers, FDA, the regulated industry, and other
stakeholders. We have increased our awareness of the composition of the
nation's food supply and the dietary exposure to GRAS substances, which
helps us to ensure the safe use of substances added to food. The
ongoing submission of GRAS notices provides evidence that our response
to a GRAS notice can support the marketing of a food substance by the
regulated industry. Notified substances include substances that are
intended to address food safety problems (e.g., antimicrobial
substances and substances intended to reduce acrylamide formation) and
public health issues (e.g., substances that would reduce levels of
sodium chloride in food). In addition, the letters we issue responding
to GRAS notices demonstrate that we inform notifiers of any scientific
or regulatory issues that call into question a notifier's conclusion of
GRAS status, and stakeholders have ready access to those letters. As
discussed in Response 81, we intend to increase the transparency of our
response letters when a notifier asks us to cease to evaluate a GRAS
notice.
In the years since we published the proposed rule, we have taken
important public health actions with respect to substances used in food
on the basis of the GRAS provision of the FD&C Act. For example, we
recently announced an initiative to establish voluntary short-term and
long-term goals for sodium reduction in a variety of identified
categories of foods to address the excessive intake of sodium in the
current population and promote improvements in public health (81 FR
35363, June 2, 2016). In addition, we recently held a public meeting in
which we invited public comment on what should be included, changed, or
even excluded from our guidance entitled ``Guidance for Industry and
Other Stakeholders: Toxicological Principles for the Safety Assessment
of Food Ingredients'' (79 FR 64603, October 30, 2014); that guidance is
intended to help interested parties understand our expectations
regarding how to determine which toxicity studies are appropriate and
regarding the design, conduct, and reporting of the results of toxicity
studies and applies to assessing the safety of GRAS substances. As
discussed in section I.D, we also have taken key postmarket actions
such as issuing a declaratory order announcing our final determination
that there is no longer a consensus among qualified experts that PHOs
are GRAS for any use in human food, as well as issuing warning letters
regarding the use of caffeine as an added ingredient in alcoholic
beverages.
For reasons such as those discussed in this section, and after
fully considering comments submitted to this rulemaking, this rule
announces that we are replacing the former GRAS affirmation petition
process with a GRAS notification procedure.
We strongly encourage any company considering the addition of a
substance to any food on the basis of a conclusion of GRAS status to
contact us and follow the available procedures for FDA oversight of
such decisions. As we move forward to implement the GRAS notification
procedure that is the subject of this rulemaking, we intend to continue
to closely monitor and assess the ramifications of the use of
substances without food additive approval or evaluation by FDA through
the GRAS notification procedure. We intend to take action as
appropriate, such as we did in the case of PHOs and caffeinated
alcoholic beverages, particularly when the available data and
information raise a safety concern about the use of a substance.
We advise any company that intends to market a food substance on
the basis of an independent conclusion of GRAS status (i.e., a
conclusion of GRAS status that would remain with the proponent of the
conclusion rather than be submitted to us as a GRAS notice) to
carefully consider whether this use fully satisfies the criteria for
eligibility for classification as GRAS and to carefully review the
discussions in this document relevant to those criteria. Fundamental to
all conclusions of GRAS status is the criterion that general
recognition of safety requires common knowledge throughout the
scientific community knowledgeable about the safety of substances
directly or indirectly added to food that there is reasonable certainty
that the substance is not harmful under the conditions of its intended
use (see Sec. 170.30(a)). In addition, the criteria for eligibility
for classification as GRAS through scientific procedures require that
general recognition of safety through scientific procedures be based
upon the application of generally available and accepted scientific
data, information, or methods, which ordinarily are published, as well
as the application of scientific principles (Sec. 170.30(b)). Although
general recognition of safety through scientific procedures may be
corroborated by the application of unpublished scientific data,
information, or methods (Sec. 170.30(b)), to satisfy GRAS criteria
qualified experts must be able to conclude that the substance is not
harmful under the conditions of its intended use without access to
``corroborative'' information (see, e.g., Response 9). For example, as
discussed in Response 69 there could be no basis for a conclusion of
GRAS status if trade secret information (or other non-public
information) is necessary for qualified experts to reach a conclusion
that the notified substance is safe under the conditions of its
intended use.
We also advise any company who intends to market a food substance
on the basis of an independent GRAS conclusion that relies, in whole or
in part, on the opinion of a specially convened ``GRAS panel'' to
carefully review the discussions in this document regarding whether and
how the opinion of a GRAS panel can support an independent conclusion
of GRAS status. For example, as discussed in Response 10 and Response
11 whether a published ``GRAS panel'' opinion that discusses data and
information that are available to the members of the GRAS panel, but
not generally available to qualified experts, could support an
independent conclusion of GRAS status would depend on factors such as
whether that publication includes details similar to details that would
be included in a publication in the primary scientific literature; the
subject matter expertise of the members of the GRAS panel; and whether
the members of the GRAS panel would be considered representative of
experts qualified by scientific training and experience to evaluate the
safety of the substance under the conditions of its intended use. For
example, a published GRAS panel opinion that includes a very general
statement that a study was conducted and reported no adverse findings
would not suffice to make the study ``generally available'' as required
by the criteria for eligibility for classification as GRAS and would
merely be a generally available opinion about data and information that
are not generally available. As another example, a ``GRAS panel''
opinion published by scientists without expertise appropriate to
address the applicable safety questions could not provide evidence that
the conclusions in the publication are ``generally
[[Page 54967]]
accepted.'' Unless both criteria, i.e., ``generally available'' as well
as ``generally accepted'', are satisfied, there would be no basis for a
conclusion of GRAS status.
II. Background
A. The Proposed Rule
We proposed to: (1) Clarify the criteria for eligibility for
classification as GRAS; and (2) replace the GRAS affirmation petition
process with a notification procedure through which any interested
person may notify us of a determination that a particular use of a
substance is GRAS (62 FR 18938). In the proposed rule, we:
Discussed the 1958 amendment, including judicial decisions
bearing on GRAS criteria and the burden on the proponent of a
conclusion of GRAS status to show that there is a consensus of expert
opinion regarding the safety of the use of the substance (62 FR 18938
at 18939);
Described the history of our approach to the GRAS
provision, including: (1) A GRAS list, first established in 1959, in
which we clarified the regulatory status of a multitude of food
substances that were used in food prior to 1958; (2) opinion letters in
which Agency officials rendered an informal, non-binding opinion on the
GRAS status of a use of a substance; (3) an FDA-initiated GRAS review
to evaluate the available safety information regarding substances
presumed to be GRAS; and (4) GRAS criteria and the GRAS affirmation
petition process (62 FR 18938 at 18939 to 18940);
Discussed ``elements of the GRAS standard,'' in which we
distinguished the ``technical element'' of the GRAS standard (i.e.,
safety) from the ``common knowledge element'' of the GRAS standard
(i.e., general recognition) (62 FR 18938 at 18940 to 18941);
Proposed the submission requirements for the GRAS
notification procedure, including: (1) A ``GRAS exemption claim,'' in
which a notifier would take responsibility for a GRAS determination;
(2) information about the identity of the notified substance; (3)
information about any self-limiting levels of use; and (4) a
comprehensive discussion of the basis for the GRAS determination
(proposed Sec. Sec. 170.36 (c) and 570.36(c));
Proposed what we would do when we received a GRAS notice,
including: (1) Acknowledge receipt of the GRAS notice; (2) evaluate
whether the notice provides a sufficient basis for a GRAS determination
and respond to the notifier in writing; (3) make readily accessible to
the public the notice's ``GRAS exemption claim'' and our response to
the notice; and (4) disclose other releasable information in a notice
in accordance with our regulations, in part 20 (21 CFR part 20),
implementing the FOIA (proposed Sec. Sec. 170.36 (d) through (f) and
570.36(d) through (f)); and
Proposed to: (1) Convert any GRAS affirmation petition
that was pending on the effective date of the rule establishing the
notification procedure to a GRAS notice; and (2) require the petitioner
to submit an amendment to the converted petition to satisfy the
procedural requirements of the GRAS notification procedure (proposed
Sec. Sec. 170.36(g) and 570.36(g)).
We requested comments on the proposed rule by July 16, 1997.
B. Interim Pilot Program
In the proposed rule, we invited interested persons who determine
that a use of a substance is GRAS to notify us of those determinations
as described in the proposed rule (62 FR 18938 at 18954). We explained
that we would administer the notices as described in the proposed rule
(i.e., we would acknowledge receipt of the notice, respond in writing
to the notifier, and make publicly accessible a copy of all ``GRAS
exemption claims'' and our response). Although we would make a good
faith effort to respond within the proposed 90-day timeframe, we would
not be bound by such a timeframe. We stated that we would determine
whether our experience in administering such notices suggests
modifications to the proposed procedure.
CFSAN received its first GRAS notice in 1998. CFSAN wrote a
memorandum documenting its experience in evaluating GRAS notices during
the period 1998-2009 (Ref. 18, ``CFSAN's 2010 experience document'')
and added that memorandum to the docket for this rulemaking in 2010.
Unless we say otherwise, the discussions in this document referring to
FDA's experience during the Interim Pilot program refer to CFSAN's
experience.
During the Interim Pilot program, CFSAN's response to a GRAS notice
fell into three categories as shown in table 1 in this document. We
refer to these categories of response throughout this document. Table 1
in CFSAN's 2010 experience document shows the category of response for
CFSAN's GRAS notices that came to closure by December 31, 2009. CFSAN
has now written an updated memorandum showing the category of response
for CFSAN's GRAS notices that came to closure by December 31, 2015
(Ref. 19).
Table 1--Categories of Letters Responding to a GRAS Notice During the
Interim Pilot Program
------------------------------------------------------------------------
Category of response letter Typical text of the response
------------------------------------------------------------------------
``No questions letter''........... Based on the information provided by
the notifier, as well as other
information available to FDA, the
Agency has no questions at this
time regarding the notifier's
conclusion that the notified
substance is GRAS under the
intended conditions of use. The
Agency has not, however, made its
own determination regarding the
GRAS status of the subject use of
the notified substance. As always,
it is the continuing responsibility
of the notifier to ensure that food
ingredients that the firm markets
are safe, and are otherwise in
compliance with all applicable
legal and regulatory requirements.
``Insufficient basis letter''..... FDA has evaluated the information
that the notifier discusses in its
GRAS notice as well as other data
and information that are available
to us. The notice does not provide
a sufficient basis for a
determination that the notified
substance is GRAS under the
conditions of its intended use.
``Cease to evaluate letter''...... In correspondence dated [month, day,
year], you asked that we cease to
evaluate your notice. We ceased to
evaluate your GRAS notice,
effective the date we received your
correspondence.
------------------------------------------------------------------------
In this document, we frequently cite CFSAN's experience during the
Interim Pilot program when responding to comments asking us to clarify
how we intend to administer various provisions of the rule, as well as
state our intent to continue the applicable practice in the future,
because this experience is relevant to our administration of the GRAS
notification program. Nonetheless, we intend to adapt our practices,
consistent with the provisions of this rule, as circumstances warrant
and as necessary to administer the GRAS notification program consistent
[[Page 54968]]
with appropriate public health policy, current scientific information,
our available resources, and the scientific and regulatory issues
raised by specific GRAS notices. For example, as discussed in Response
92 we intend to continue to include standard language such as that
shown in table 1 in responding to GRAS notices. However, this language
may evolve over time.
CVM established its Interim Pilot program in June, 2010 (75 FR
31800, Docket No. FDA-2010-N-0215) and filed its first GRAS notice in
December 2010. CVM did not have any experience to document as of 2010
and, thus, had not written its own experience document at that time. As
of December 31, 2015, CVM had responded to 18 GRAS notices, and has now
documented its experience with those 18 GRAS notices with respect to
some comments specifically directed to the GRAS notification procedure
administered by CVM (Ref. 20; ``CVM's experience document''). We
discuss CVM's experience with GRAS notices submitted for substances
intended for use in animal food in section XXV.
We are ending both the CFSAN Interim Pilot program announced in the
proposed rule, and the CVM pilot program announced in Docket No. FDA-
2010-N-0215, as of October 17, 2016. On that date, the final rule
becomes effective and will govern the GRAS notification procedure.
C. 2010 Report of the Government Accountability Office
As noted in section I.B, from 2008 to 2010 GAO conducted a study
related to ingredients used in human food on the basis of the GRAS
provision of section 201(s) of the FD&C Act. In 2010, GAO issued a
report (Ref. 4) that included a number of recommendations for FDA. We
responded to the GAO's recommendations, and that response is also
included in the GAO report.
D. 2010 Notice Reopening the Comment Period
As noted in section I.A, we reopened the comment period for the
proposed rule to update comments (75 FR 81536). We did so because of
the length of time that had elapsed since publication of the proposed
rule and because we had identified a number of issues within the scope
of the proposed rule that may require further clarification based on
CFSAN's experience with GRAS notices during the Interim Pilot program,
comments we received on the proposed rule, and GAO's recommendations
(75 FR 81536 at 81537). These issues related to the proposed revisions
to the criteria for eligibility for classification as GRAS (Issue 1),
the proposed establishment of a notification procedure (Issues 2
through 16), and the effect of the proposed notification procedure on
existing GRAS affirmation petitions (Issue 17). Accordingly, we
requested comments, by March 28, 2011, on the entire proposed rule as
well as on the specific issues identified in the 2010 notice.
In Issue 2 in the 2010 notice, we explained our reasons for
tentatively concluding that the terms ``conclude'' and ``conclusion''
would be more appropriate in lieu of ``determine'' and
``determination'' and requested comment on these terms. In the
remainder of this document, we generally use the terms ``conclude'' and
``conclusion'' in lieu of ``determine'' and ``determination'' except
when we are describing provisions of the proposed rule (see Response
41).
E. Public Comments
We received submissions, each containing one or more comments, from
diverse members of the public, including manufacturers; trade
organizations; consulting firms; law firms; public advocacy groups;
non-profit organizations; individuals; a Federal Agency; and other
organizations. In the remainder of this document, we describe these
comments, respond to them, and explain any revisions we made to the
proposed rule.
Some comments address issues that are outside the scope of this
rule. For example, some comments ask us to add a new definition to part
170, to define the term ``harm'' that is used in our current definition
of ``safe'' or ``safety'' (Sec. 170.3(e)(i)) (where ``safe'' or
``safety'' means that there is a reasonable certainty in the minds of
competent scientists that the substance is not harmful under the
intended conditions of use). We did not propose to add a definition of
the term ``harm'' or ask for comment on whether we should do so, and
adding a new definition in the final rule for a term that is used in
the definition of ``safe'' and ``safety'' would broadly affect our
regulations for food additives and GRAS substances without opportunity
for public comment. As another example, one comment asks us to prepare
an alphabetical index of food additive and GRAS regulations and cites
the alphabetical list in our Investigations Operations Manual as
evidence that it is feasible to develop such a list. Regardless of
whether it is feasible to develop such a list, doing so is not within
the scope of our proposal to establish a notification procedure for
uses of substances that are not listed in our regulations. We do not
discuss such comments in this document.
F. Applicability of Discussions in This Document to Both the Human Food
Regulations and the Animal Food Regulations
To simplify the discussion in this document, in general we refer to
provisions of the proposed rule and the 2010 notice from the
perspective of the regulations that would be established in part 170.
Unless we say otherwise, however, the issues discussed also apply to
the corresponding provisions for part 570. Any reference to CFSAN
documents (such as guidance documents) is specific to CFSAN. See
section XXV for a discussion of comments and issues specifically
directed to substances used in animal food.
G. Use of Pronouns in This Document
In this document, terms such as ``we,'' ``our,'' and ``us'' refer
to FDA. The regulatory text of the final rule for the GRAS notification
procedure specifies that the terms ``you'' and ``your'' refer to a
notifier (i.e., a person who is responsible for a GRAS notice). To
simplify the discussion in this document, in general we use pronouns
such as ``you'' and ``your'' to refer to a notifier, even though some
persons who read this document may not be notifiers.
H. Summary of Principal Changes to the Proposed Notification Procedure
In table 2, we briefly describe the principal changes to the GRAS
notification procedure in the final rule compared to the proposed rule.
In the remainder of this document, we discuss each of these changes in
more detail, including our response to comments relevant to these
changes. See table 28 for principal changes that are specific to the
GRAS notification procedure for substances used in animal food in part
570.
[[Page 54969]]
Table 2--Summary of Principal Changes to the Proposed Notification
Procedure
------------------------------------------------------------------------
Proposed rule Final rule
------------------------------------------------------------------------
Would not define any terms............. Defines the terms
``amendment,'' ``GRAS,''
``GRAS notice,'' ``notified
substance,'' ``notifier,''
``qualified expert,''
``supplement,'' ``we, our, and
us,'' and ``you and your.''
Referred to a ``GRAS determination''... Refers to a ``GRAS conclusion''
or ``conclusion of GRAS
status.''
Referred to the statutory GRAS Refers to the statutory GRAS
provision as an ``exemption''. provision as an ``exclusion.''
Would not use ``Plain Language'' Uses ``Plain Language''
techniques as outlined in a techniques such as pronouns
Presidential Memorandum dated June 1, and short regulatory sections.
1998 (Ref. 21) and in ``Improving
Electronic Dockets on Regulations.gov
and the Federal Docket Management
System: Best Practices for Federal
Agencies'' (Ref. 22).
Was silent on whether you could Expressly provides for you to
incorporate into your GRAS notice incorporate into your GRAS
specifically identified data and notice specifically identified
information previously submitted to data and information
CFSAN or CVM. previously submitted to CFSAN
or CVM.
Would not specify individual parts of a Specifies the seven parts of a
GRAS notice. GRAS notice.
Would require three paper copies of a Provides that you may submit a
GRAS notice. GRAS notice either in
electronic format that is
accessible for our evaluation
or on paper. If you send your
GRAS notice on paper, a single
paper copy is sufficient.
Referred to dated and signed statements Refers to dated and signed
in a GRAS notice as a ``claim''. statements in a GRAS notice as
``signed statements.''
Assumed that a notice will not contain Specifies that you must not
any information that is protected from include any information that
public disclosure under the FOIA. is trade secret or
confidential commercial
information in certain
sections of the signed
statements in your GRAS
notice, but does not otherwise
prohibit the submission of
information that is protected
from public disclosure under
the FOIA.
Would require that you inform us of the Requires that you provide an
``common or usual name'' of the ``appropriately descriptive
notified substance. term'' for the notified
substance.
Would not require that you state your Requires that you state your
view as to whether any data and view as to whether any of the
information in your GRAS notice are data and information in your
exempt from disclosure under the FOIA. GRAS notice are exempt from
disclosure under the FOIA
(e.g., as trade secret or as
commercial or financial
information that is privileged
or confidential).
Would not expressly require a signed Expressly requires a signed
certification regarding the certification that to the best
representative and balanced nature of of your knowledge, your GRAS
the GRAS notice. notice is a complete,
representative, and balanced
submission that includes
unfavorable information, as
well as favorable information,
known to you and pertinent to
the evaluation of the safety
and GRAS status of the use of
the substance.
For a notified substance of natural For a notified substance of
biological origin, would require natural biological origin,
source information such as genus and requires source information
species. that includes applicable data
and information at the sub-
species level (e.g., variety,
strain) in addition to genus
and species.
Would require the method of manufacture Requires a description of the
(excluding any trade secrets). method of manufacture of the
notified substance in
sufficient detail to evaluate
the safety of the notified
substance as manufactured; you
may include trade secret
information.
Would not expressly require relevant When necessary to demonstrate
data and information bearing on the safety, expressly requires
physical or other technical effect the relevant data and information
notified substance is intended to bearing on the physical or
produce. other technical effect the
notified substance is intended
to produce, including the
quantity of the notified
substance required to produce
such effect.
Would require consideration of dietary Separates the statutory
exposure as part of a comprehensive language of section
discussion of the data and information 409(c)(5)(A) and (B) of the
that you rely on to establish safety, FD&C Act into two distinct
using the statutory language of parts of the GRAS notice: (1)
section 409(c)(5)(A) and (B) of the Part 3, which addresses how
FD&C Act. much of the notified substance
consumers would eat as part of
the total diet (including
exposure from its intended use
and all sources in the diet),
as well as how much consumers
would eat of other substances
(e.g., contaminants or by-
products); and (2) Part 6,
which requires that you
address, in your narrative,
the safety of the notified
substance, considering all
dietary sources and taking
into account any chemically or
pharmacologically related
substances in such diet.
Would require a ``comprehensive Requires a narrative (Part 6 of
discussion'' of, and citations to, a GRAS notice) and a list of
generally available and accepted supporting data and
scientific data, information, methods, information (Part 7 of a GRAS
or principles that you rely on to notice).
establish safety.
Would not require consideration of Expressly requires
dietary exposure as part of a consideration of dietary
comprehensive discussion of the data exposure, regardless of
and information that you rely on to whether your conclusion of
establish safety for a conclusion of GRAS status is through
GRAS status through experience based scientific procedures or
on common use in food. through experience based on
common use in food.
Would require a comprehensive Requires that you either: (1)
discussion of any reports of Identify, discuss, and place
investigations or other information in context, data and
that may appear to be inconsistent information that are, or may
with the GRAS determination. appear to be, inconsistent
with your conclusion of GRAS
status; or (2) state that you
have reviewed the available
data and information and are
not aware of any data and
information that are, or may
appear to be, inconsistent
with your conclusion of GRAS
status.
Would not require that you identify If you view any of the data and
data and information that you view as information in your notice as
exempt from disclosure under the FOIA. exempt from disclosure under
the FOIA, requires that you
identify the specific data and
information.
[[Page 54970]]
Would not require that you explain how Requires that you explain how
there could be a basis for a there could be a basis for a
conclusion of GRAS status if qualified conclusion of GRAS status if
experts generally do not have access qualified experts generally do
to non-public, safety-related data and not have access to non-public,
information. safety-related data and
information.
Would require that the comprehensive Uses the term ``generally
discussion include the basis for recognized'' rather than the
concluding that there is consensus term ``consensus.''
among qualified experts that there is
reasonable certainty that the
substance is not harmful under the
intended conditions of use.
Was silent on whether you could submit Expressly provides for you to
an amendment to a GRAS notice. submit a timely ``amendment''
to a GRAS notice before we
respond to your GRAS notice or
cease to evaluate your GRAS
notice.
Considered that it was implicit that Expressly provides that you may
you could ask us to cease to evaluate ask us to cease to evaluate
a GRAS notice. your GRAS notice, and
expressly provides that we
will inform you of our
decision regarding your
request.
We would acknowledge receipt of a GRAS We will conduct an initial
notice within 30 days of receipt. evaluation of your submission
to determine whether to file
it as a GRAS notice for
evaluation of your view that
the notified substance is GRAS
under the conditions of its
intended use. If we file your
submission as a GRAS notice,
we will send you a letter that
informs you of the date of
filing. If we do not file your
submission as a GRAS notice,
we will send you a letter that
informs you of that fact and
provides our reasons for not
filing the submission as a
GRAS notice.
We would respond to you in writing Within 180 days of filing, we
within 90 days of receipt of the will respond to you by letter
notice. based on our evaluation of
your notice. We may extend the
180 day timeframe by 90 days
on an as needed basis. If we
extend the timeframe, we will
inform you of the extension as
soon as practicable but no
later than within 180 days of
filing.
Was silent on procedures that apply Specifies procedures that apply
when the intended conditions of use of when the intended conditions
a notified substance include use in a of use of a notified substance
product or products subject to in human food include use in a
regulation by USDA's FSIS. product or products subject to
regulation by USDA's FSIS.
We noted that, although the decision to The regulatory text of the
submit a GRAS notice would be final rule specifies that the
voluntary, the provisions governing data and information in a GRAS
the GRAS notification procedure, notice are considered a
including the information to be mandatory, rather than
submitted, would be mandatory. voluntary, submission for
purposes of its status under
the FOIA and our public
information requirements in
part 20.
Was silent on whether you could submit Expressly provides for you to
additional information to a GRAS submit a ``supplement'' to a
notice after we respond to it. GRAS notice after we respond
to your GRAS notice or cease
to evaluate it.
Would presumptively convert any filed, On the effective date of the
pending GRAS affirmation petition to a rule, we will close the docket
notice on the effective date of the for any GRAS affirmation
rule. If we did not receive an petition that is still
amendment from the petitioner within pending. Any person who
90 days of the effective date of the submitted a GRAS affirmation
rule, with information and statements petition that is closed may
analogous to those in the proposed submit a GRAS notice and
``GRAS exemption claim,'' we would request that we incorporate
consider the converted petition to be the GRAS affirmation petition.
inadequate as a notice and would send
the petitioner a letter to that
effect..
------------------------------------------------------------------------
III. Legal Authority
We are amending our regulations in 21 CFR parts 170 and 570 to
replace the voluntary GRAS affirmation petition process with a
voluntary GRAS notification procedure and to clarify when the intended
conditions of use of a substance are eligible for classification as
GRAS under our authority in sections 201, 402, 409, and 701 of the FD&C
Act (21 U.S.C. 321, 342, 348, and 371). Section 701(a) of the FD&C Act
authorizes the Secretary of the Department of Health and Human Services
(the Secretary) to issue regulations for the efficient administration
of the FD&C Act; under section 1003(d) of the FD&C Act (21 U.S.C.
393(d)), the Secretary is responsible for executing the FD&C Act,
including section 701(a), through the Commissioner of Food and Drugs.
The FD&C Act requires that all food additives (as defined by section
201(s) of the FD&C Act) be approved by FDA before they are marketed
(sections 402(a)(2)(C) and 409 of the FD&C Act). Section 201(s)
excludes from the definition of a food additive a substance generally
recognized, among experts qualified by scientific training and
experience to evaluate its safety, as having been adequately shown
through scientific procedures (or, in the case of a substance used in
food prior to January 1, 1958, through either scientific procedures or
experience based on common use in food) to be safe under the conditions
of its intended use.
These regulations will help FDA administer efficiently the FD&C
Act's various provisions that apply to the use of substances added to
food, specifically on the question of whether a substance is GRAS under
the conditions of its intended use or is a food additive subject to
FDA's premarket review. These regulations provide clarification of the
GRAS criteria and provide a more efficient procedure.
As an error, the authority citation that we listed for the proposed
amendments to part 570 did not include an existing authority citation,
i.e., section 408 of the FD&C Act (21 U.S.C. 346a). Nothing in the
proposed rule would alter the citation to section 408. Therefore, the
authority citation for 21 CFR part 570 continues to include section
408.
As an error, the authority citation that we listed for the proposed
amendments to part 170 stated that we were revising the authority
citation. Nothing in the proposed rule would alter the authority
citation for part 170. Therefore, the authority citation for 21 CFR
part 170 states that the authority citation ``continues to read''
rather than ``is revised to read.''
(Comment 1) Some comments state that the proposed rule violates the
1958 amendment because FDA would not be
[[Page 54971]]
fulfilling its statutory duty to oversee food additives, and,
therefore, FDA's interpretation of the GRAS provision is arbitrary and
capricious. The comments state that the proposed rule violates the 1958
amendment because it would not require companies to notify FDA of a
conclusion that the use of a substance is GRAS. One comment states that
without mandatory submissions FDA lacks a ``comprehensive catalog'' of
such substances and their dietary exposure, and therefore cannot
``police the border between food additives and GRAS substances'' and
that FDA and food manufacturers do not have access to accurate exposure
data and cannot assess the cumulative effect of similar substances. The
comment further states that because the proposed rule ``establishes no
real oversight over the safety of GRAS substances'' it violates the
1958 amendment.
(Response 1) We disagree that the voluntary nature of the GRAS
notification procedure violates the 1958 amendment. The FD&C Act
provides for premarket review by FDA of a food additive, and excludes
from this review any substance that is generally recognized, among
qualified experts, to be safe under the conditions of its intended use.
Although the FD&C Act specifically provides for our review of food
additives, it is silent with respect to industry submissions to us on
the use of GRAS substances. To administer the provisions of the FD&C
Act with respect to the use of GRAS substances, we are retaining the
voluntary nature of the GRAS administrative procedure. This rule
replaces one longstanding voluntary administrative procedure with a
different voluntary administrative procedure.
IV. General Comments on the Proposed Rule
(Comment 2) One comment states that the rule does not give
consumers an opportunity to participate in the process before a
substance is used in food. Another comment asserts that the lack of an
opportunity for public comment or participation is a ``major flaw'' in
the rule.
(Response 2) We disagree that the GRAS notification procedure does
not allow for public participation. We proactively disclose to the
public information about each GRAS notice that we have filed for
evaluation, including the name and address of the notifier; the name of
the notified substance; the intended conditions of use of the notified
substance; and the statutory basis for the conclusion of GRAS status
(i.e., through scientific procedures or through experience based on
common use in food). In the past, outside parties who have accessed
this information have made us aware of dissenting views about whether
available data and information support a conclusion that a notified
substance is safe under the conditions of its intended use (see
sections III.C.2, III.E, and III.I.1 in CFSAN's 2010 experience
document) (Ref. 18). We continue to welcome substantive information
from stakeholders regarding the safety of a notified substance. We
advise stakeholders who wish to provide us with such substantive
information to submit it to the same address where a notifier would
send a GRAS notice and ask us to add it to the administrative file for
the applicable GRAS notice. This administrative file is maintained by
the responsible Center (i.e., CFSAN or CVM). We would consider the
submitted information, along with other information that is available
to us, on a case-by-case basis.
(Comment 3) One comment asks us to require companies to maintain
active and accurate registrations for GRAS substances in a public
database.
(Response 3) We decline this request. This comment is suggesting a
process not within our regulatory framework and does not provide a
legal basis whereby we could require companies to maintain
registrations in a public database for substances that are used in food
on the basis of the GRAS provision in section 201(s) of the FD&C Act.
We note, however, that the final rule provides a framework for making
the GRAS notices, and our responses to these notices, available to the
public.
(Comment 4) One comment asks us to specify whether the notified
substance would be for human or animal consumption. Another comment
notes that specifying whether the notified substance is intended for
human or animal consumption is important because food for humans is not
necessarily appropriate for animals and vice versa.
(Response 4) We agree with these comments. This rule establishes
requirements for a GRAS notice about the intended use of a notified
substance in human food in part 170 and establishes separate
requirements for a GRAS notice about the intended use of a notified
substance in animal food in part 570. Regardless of whether the
notified substance would be used in human food or in animal food, the
notifier must specify the intended conditions of use (see Sec. Sec.
170.225(c)(4) and 570.225(c)(4)). As discussed in Response 90, we
include the intended conditions of use in our publicly available
letters responding to GRAS notices.
(Comment 5) One comment notes that the experience highlighted in
CFSAN's experience document (Ref. 18) can provide valuable learning
that can be of benefit to CVM and asks CFSAN and CVM to strive for
harmonization of their requirements and policies in all areas, so the
process is not more stringent for one industry than the other.
(Response 5) We agree that CFSAN and CVM can learn from each
other's experience with the implementation of the GRAS notification
procedure and that procedural and scientific requirements should be
consistent as much as is feasible and appropriate. As noted in section
II.B, CVM has now documented its experience with 18 GRAS notices with
respect to some comments specifically directed to the GRAS notification
procedure administered by CVM (Ref. 20).
(Comment 6) One comment urges CFSAN and CVM to put forth similar
training and resources for staff assigned to evaluate GRAS notices to
decrease the time necessary to complete the evaluation of a GRAS
notice.
(Response 6) We staff, equip, and train our employees consistent
with our priorities and budgets, which are specific to each Center. As
a practical matter, our current organizational framework, in which
CFSAN and CVM are both components of the Office of Foods and Veterinary
Medicine, promotes interactions between staff in the two Centers.
V. Comments on the Definition of Scientific Procedures
We proposed to amend the definition of ``scientific procedures'' to
specify that scientific procedures include scientific data (such as
human, animal, analytical, or other scientific studies), information,
methods, and principles, whether published or unpublished, appropriate
to establish the safety of a substance. In the 2010 notice, we
described comments relevant to this proposed amendment, including
comments that support it and a comment that objected to it because,
under the proposed amendment, an ``unpublished principle'' could
inappropriately be considered a sufficient scientific procedure for
demonstrating the safety of a food substance. We also noted that we had
reviewed our use of the term ``study'' in the proposed companion change
to the definition of scientific procedures and explained our view that,
to be a ``procedure,'' data, information, methods, or principles would
need to be acquired or applied. We stated that we were considering
whether to revise the
[[Page 54972]]
definition of scientific procedures in Sec. 170.3(h) to include the
application of scientific data (including, as appropriate, data from
human, animal, analytical, and other scientific studies), information,
and methods, whether published or unpublished, as well as the
application of scientific principles, appropriate to establish the
safety of a substance (see Issue 1, 75 FR 81536 at 81537-81538). We
requested comment on this issue.
Several comments support the proposed amendment to the definition
of scientific procedures as described in the proposed rule, with the
potential modifications described in the 2010 notice, because the
revised definition would more accurately reflect the state of
contemporary science than the definition it would replace. Some
comments express the view that specifying that it is ``the
application'' of unpublished scientific data, information, or methods
that would corroborate GRAS status would make it clear that a
submission to us regarding a conclusion of GRAS status may include
discussions of unpublished studies. In the following paragraphs, we
discuss comments that suggest additional changes to the definition of
``scientific procedures.'' After considering these comments, we are
finalizing the definition of scientific procedures as proposed, with
the modifications described in the 2010 notice and with editorial
changes as shown in table 29.
(Comment 7) One comment that supports the potential modifications
to the definition of ``scientific procedures'' as described in the 2010
notice asks us to incorporate an additional clarification that
``scientific principles appropriate to establishing the safety of a
substance'' encompass consideration of both the data supporting the
safety of the substance and the probable dietary exposure.
(Response 7) To the extent that the comment means that ``scientific
procedures'' (rather than ``scientific principles'') encompass
consideration of both the data supporting the safety of the substance
and the probable dietary exposure, we agree. However, it is not
necessary to revise the definition of scientific procedures to make
that clear. The definition of ``scientific procedures'' already
specifies the application of data from human, animal, analytical, or
other scientific studies, and the definition of ``safe'' or ``safety''
in Sec. 170.3(i) includes probable dietary exposure as a factor that
must be considered in determining safety.
As discussed in the 2010 notice, ``principle'' can be defined as a
fundamental cause or basis of something; a primary element, force, or
law determining a particular result; or a fundamental truth or
proposition on which others depend. Thus, a principle is a different
genre than data, information, and methods. Therefore, although we agree
that ``scientific procedures'' encompass consideration of both the data
supporting the safety of the substance and the probable dietary
exposure, we disagree that the data supporting the safety of the
substance and the probable dietary exposure are ``scientific
principles.''
VI. Comments on the Criteria for Eligibility for Classification as GRAS
Section 170.30 specifies three types of criteria for eligibility
for classification as GRAS: (1) General criteria; (2) criteria for
classification as GRAS through scientific procedures; and (3) criteria
for classification as GRAS through experience based on common use in
food. We proposed to amend all three criteria to: (1) Clarify that the
safety standard for a GRAS substance is identical to the safety
standard for a food additive; (2) clarify the types of technical
evidence of safety that could form the basis for classification as GRAS
through scientific procedures, and clarify the role of publication in
establishing general recognition of safety through scientific
procedures; and (3) make conforming changes to the criteria for
eligibility for classification as GRAS through experience based on
common use in food. We proposed these amendments in association with
our concurrent proposal to replace the GRAS affirmation petition
process with a GRAS notification procedure. In the 2010 notice, we
stated that we were considering an additional revision to correspond
with the revision to the definition of scientific procedures (see
section V in this document and Issue 1, 75 FR 81536 at 81537-81538 in
the 2010 notice).
In the following sections, we discuss comments that disagree with
one or more aspects of our proposal to amend the criteria for
eligibility for classification as GRAS, with the potential
modifications described in the 2010 notice (see, e.g., Comment 9 and
Comment 13); ask us to clarify how we will interpret the revised
criteria or offer suggestions for how we should interpret the revised
criteria (see, e.g., Comment 12, Comment 16, Comment 17, and Comment
18); or suggest one or more changes to the revised criteria (see, e.g.,
Comment 10, Comment 19, and Comment 20). After considering these
comments, we are establishing the criteria for eligibility for
classification as GRAS for use of a substance in human food as
proposed, with the modification we described in the 2010 notice and
with editorial, clarifying, and conforming changes as shown in table
29. See section XXV.B for a description of additional changes we made
to the criteria for eligibility for classification as GRAS for use of a
substance in animal food.
A. General Criteria for Eligibility for Classification as GRAS
We proposed to revise the final sentence of Sec. 170.30(a) to
specify that general recognition of safety requires common knowledge
throughout the scientific community knowledgeable about the safety of
substances directly or indirectly added to food that there is
reasonable certainty that the substance is not harmful under the
intended conditions of use. As discussed in the proposed rule, we
proposed this revision to clarify that the safety standard for a GRAS
substance is identical to the safety standard for food additives (see
Sec. 170.3(i)) and that a GRAS substance is neither more safe, nor
less safe, than an approved food additive (62 FR 18938 at 18942). We
received no comments that disagreed with this proposed revision and are
finalizing Sec. 170.30(a) as proposed with conforming changes as shown
in table 29.
See section XXV.B regarding revisions to the general criteria for
eligibility for classification as GRAS for a substance used in animal
food.
B. Criteria for Eligibility for Classification as GRAS Through
Scientific Procedures
We proposed to amend the criteria for eligibility for
classification as GRAS through scientific procedures to: (1) Require
that the data and information for general recognition of safety be
``generally available and accepted,'' and (2) broaden the types of
acceptable data and information by replacing ``studies'' with ``data,
information, methods, or principles.'' In the 2010 notice, we stated
that we were considering whether to revise these criteria with respect
to the types of acceptable data and information to include ``the
application'' of generally available and accepted scientific data,
information, or methods, as well as ``the application'' of scientific
principles'' (see section V in this document and Issue 1, 75 FR 81536
at 81537-81538 in the 2010 notice).
See section XXV.B regarding revisions to the criteria for
eligibility for classification as GRAS through scientific procedures
for a substance used in animal food.
[[Page 54973]]
(Comment 8) One comment asserts that the criterion for the
generally available data or information establishing safety to
ordinarily be published is artificial. Other comments point out that
information that is not published can nonetheless be considered
``generally available.'' Some comments object to the proposed amendment
to the criteria for eligibility for classification as GRAS through
scientific procedures and assert that it would de-emphasize or
eliminate the existing criterion for peer-reviewed studies.
(Response 8) Regardless of whether the data and information are
published or unpublished, under the revised criteria a GRAS conclusion
must be based on data and information that are generally available and
accepted, and as such, are publicly available. As we stated in the
proposed rule, the common knowledge element of the GRAS standard
precludes a GRAS conclusion if the data and information (e.g., as
evaluated by a ``GRAS panel'') are only available in files that are not
publicly accessible, such as in confidential industry files (62 FR
18938 at 18943). We disagree that the criterion for the generally
available data or information establishing safety to ordinarily be
published is artificial. Publication in a peer-reviewed scientific
journal is the usual mechanism to establish that scientific information
is generally available, provided that the journal is representative of
scientific publications accessed by the expert scientific community (62
FR 18938 at 18943). Nonetheless, the revised criteria provide
flexibility for supporting a conclusion of GRAS status through the
application of scientific data, information, or methods that are
generally available through a mechanism other than publication in a
peer-reviewed scientific journal, such as publication in a textbook and
other sources of technical literature. One example of another source of
technical literature is the Joint Expert Committee on Food Additives
(JECFA, a joint committee of the Food and Agriculture Organization/
World Health Organization). We note, however, that the mere fact that
data and information are published or otherwise publicly available does
not satisfy the criteria for general recognition of safety. Regardless
of the mechanism of making data and information generally available to
qualified experts, it must be plausible that qualified experts would be
accessing those data and information using that mechanism. For example,
scientists who routinely access peer-reviewed journals in electronic
form on the Internet may avoid Internet ``publications'' about a
scientific topic when the ``publication'' is not associated with a
reputable scientific institution.
We have not changed our position on the importance of peer review.
The basis for GRAS status continues to be the application of generally
available scientific data, information, and methods, which ordinarily
are published (and, thus, are subject to peer review as part of the
scientific publication process for most journals). We continue to
believe that whether scientific data, information, and methods have
been peer reviewed before publication in a scientific journal that is
representative of scientific publications accessed by the expert
scientific community is a factor that bears on the objectivity and
scientific merit of study, and is a variable we consider in determining
whether experts accept the report of a scientific investigation as a
credible report and whether there is general knowledge of the
scientific investigation.
CFSAN's 2010 experience document (Ref. 18) provides factual
information on how CFSAN already has interpreted the criteria for
eligibility for classification of GRAS status through scientific
procedures for GRAS notices CFSAN received during the Interim Pilot
program (see section III.A.1 of CFSAN's 2010 experience document), and
we intend to continue this approach in the future. In most cases, a
submitted GRAS notice described a mixture of information published in
peer-reviewed journals, information (such as in textbooks) that was
generally available in a form other than a peer-reviewed journal, and
unpublished information. As shown in table 1 in CFSAN's 2016 experience
document, CFSAN had no questions about GRAS status based on this
mixture of information in approximately 81 percent of the GRAS notices
CFSAN evaluated between 1998 and 2015 (Ref. 19). Importantly, CFSAN's
evaluation of the basis for a conclusion that a use of a food substance
is GRAS in addition to being safe was a case-by-case evaluation. As
discussed in section III.A.4 of CFSAN's 2010 experience document, in
some cases it was CFSAN's view that the available data and information
were sufficient to demonstrate safety, but not GRAS status, and CFSAN
established a food additive regulation for the use of the substance in
response to a food additive petition for that use (Ref. 18).
(Comment 9) Some comments state that all available relevant data,
including unpublished data, should be used in evaluating GRAS status.
Some of these comments cited the placement of the word ``ordinarily''
in the criteria for classification as GRAS through scientific
procedures as support for this interpretation. Several comments urge us
to interpret, in a flexible manner, the proposed criteria for the
scientific data, information, methods or principles that establish
safety to be ``generally available and accepted'' and ``ordinarily . .
. published.''
(Response 9) We agree that all relevant data should be used in
evaluating GRAS status, including unpublished data. However, regardless
of whether data and information are published or unpublished, a GRAS
conclusion based on scientific procedures must be based on data and
information that are generally available and accepted, and as such, are
publicly available (see Response 8). The GRAS criteria for scientific
procedures, as established in 1976, state that the applicable data and
information are ``ordinarily'' published and may be ``corroborated'' by
unpublished data and information, and this rule retains these criteria.
The common meaning of ``corroborate'' is to make more certain or
confirm (Ref. 23). Although unpublished data and information can
confirm a conclusion of GRAS status, to satisfy GRAS criteria qualified
experts must be able to conclude that the substance is not harmful
under the conditions of its intended use without access to
``corroborative'' information (see Sec. 170.30(a)). Under this rule, a
notifier is required to explain how there could be a basis for a
conclusion of GRAS status if qualified experts do not have access to
non-public safety-related data and information considered in reaching a
conclusion of GRAS status (see Sec. 170.250(e)).
Whether data and information are corroborative of safety, rather
than establish safety, depends on what those data and information are
and how they relate to the safety assessment, not just whether they are
published or otherwise publicly available. Whereas unpublished data and
information that have a bearing on a safety conclusion, and therefore
could help confirm a safety conclusion based on other data and
information, in general, can only be considered as corroborative in the
context of a GRAS conclusion, published data and information may be
either the basis for a safety conclusion or corroborative of a safety
conclusion, depending on the nature of the data and information. For
example, a published 90-day toxicology study could be the basis for a
safety conclusion, but a preliminary toxicology study conducted
primarily for the purpose of selecting
[[Page 54974]]
the doses to be used in that 90-day toxicology study is unlikely to be
the basis for a safety conclusion, regardless of whether that
preliminary toxicology study is published.
See also the discussion in Response 58 regarding the requirement
for you to submit a signed statement certifying that, to the best of
your knowledge, your GRAS notice is a complete, representative, and
balanced submission that includes unfavorable information, as well as
favorable information, known to you and pertinent to the evaluation of
the safety and GRAS status of the use of the substance (Sec.
170.225(c)(9)). See also the discussion in section XVII regarding the
requirement for your narrative to identify, and place in context, data
and information that are, or may appear to be, inconsistent with your
conclusion of GRAS status, regardless of whether those data and
information are generally available (Sec. 170.250(c)).
(Comment 10) One comment asks us to explicitly acknowledge
publication of information in the secondary scientific literature as a
mechanism to satisfy the standard for general availability.
(Response 10) We decline this request. In general, the secondary
scientific literature includes publications (such as review articles,
textbooks, and compendia) which disseminate the views of scientists who
are critically evaluating a primary body of data and information
already published in peer-reviewed scientific journals that are
representative of scientific publications accessed by the expert
scientific community (i.e., the primary scientific literature). Whether
a publication in the secondary scientific literature satisfies the
criteria for GRAS status through scientific procedures is a case-by-
case determination that depends on the circumstances. See section
III.A.1 of CFSAN's 2010 experience document (Ref. 18) for examples of
how CFSAN considered publications in the secondary scientific
literature during the Interim Pilot program. When the underlying data
being reviewed in the secondary scientific literature are themselves
generally available, a publication in the secondary scientific
literature can provide evidence that the data and information discussed
in the publication are generally accepted as well as generally
available. If a publication in the secondary scientific literature
discusses data and information that are available to the authors, but
not previously published in the primary scientific literature, whether
that publication could satisfy the ``generally available'' aspect of
the criteria for eligibility for GRAS status through scientific
procedures would depend on the nature and extent of the discussion in
the publication. For example, a very general statement that a study was
conducted and reported no adverse findings would not suffice to make
the study ``generally available''; instead, such a statement would
merely be a generally available opinion about data and information, in
that study, that are not generally available. Such a publication may
satisfy the ``generally accepted'' aspect of the criteria for GRAS
status through scientific procedures for that study, but would be
insufficient, by itself, to satisfy the ``generally available'' aspect
of those criteria. However, a comprehensive description in the
secondary scientific literature of a previously unpublished study,
including details similar to details that would be included in a
publication in the primary scientific literature, may suffice to make
the study published in the secondary scientific literature ``generally
available.'' In such circumstances, the publication in the secondary
scientific literature may be able to satisfy both the ``generally
available'' and ``generally accepted'' aspects of the criteria for
eligibility for GRAS status through scientific procedures for certain
data and information.
(Comment 11) One comment asks us to recognize that publication of
an opinion of a specially convened ``expert panel'' would satisfy the
standard for general availability because, in the comment's view,
review by such a panel would be equivalent to, or exceed, peer review.
(By ``expert panel,'' we assume that the comment is referring to a
``GRAS panel'', i.e., a panel of individuals convened for the purpose
of evaluating whether the available scientific data, information, and
methods establish that a substance is safe under the conditions of its
intended use in food. See the discussion in section III.A.1 of CFSAN's
2010 experience document (Ref. 18).)
(Response 11) We would consider publication of an opinion of a
specially convened ``GRAS panel'' to be part of the secondary
scientific literature as discussed in Response 10. As with any
publication in the secondary scientific literature, when the underlying
data being reviewed in a published ``GRAS panel'' opinion are
themselves generally available, a published ``GRAS panel'' opinion
could provide evidence that the data and information discussed in the
publication are generally accepted, depending on factors such as the
subject matter expertise of the members of the GRAS panel and whether
the members of the GRAS panel would be considered representative of
experts qualified by scientific training and experience to evaluate the
safety of the substance under the conditions of its intended use. For
example, a ``GRAS panel'' opinion published by scientists without
expertise appropriate to address the applicable safety questions could
not provide evidence that the conclusions in the publication are
``generally accepted.''
If a published ``GRAS panel'' opinion discusses data and
information that are available to the members of the GRAS panel, but
not generally available to qualified experts, whether that publication
could satisfy the ``generally available'' aspect of the criteria for
eligibility for GRAS status through scientific procedures would depend
on the nature and extent of the discussion in the publication (see
Response 10). Unless both criteria, i.e., ``generally available'' and
``generally accepted'', are satisfied, there would be no basis for a
conclusion of GRAS status based on a published ``GRAS panel'' opinion.
(Comment 12) One comment states that all available relevant data,
including unpublished data, should be used in evaluating GRAS status,
as long as any unpublished data are generated by appropriate and valid
scientific methods as judged and reviewed by an external qualified GRAS
panel and are accessible to FDA for review.
(Response 12) We agree that all available relevant data should be
used in evaluating whether a use of a substance in food is GRAS through
scientific procedures. By ``all relevant data,'' we mean data that
support a conclusion of GRAS status as well as data that are
inconsistent with a conclusion of GRAS status, not just whether the
data are published. (See Sec. Sec. 170.225(c)(9) and 170.250(c) and
the discussion in Response 58, Response 69, and Response 78.) We also
agree that it is appropriate for unpublished data to be generated by
valid scientific methods and to be accessible to FDA for review (e.g.,
when such data are cited in a submission to FDA). In addition, we have
acknowledged the practice of convening an external ``GRAS panel'' to
evaluate whether the available scientific data, information, and
methods demonstrate that a substance is safe under the conditions of
its intended use in food (see section III.A.1 of CFSAN's 2010
experience document) (Ref. 18). However, we disagree that information
that is not generally available to qualified experts could be used as
evidence for a GRAS conclusion merely because a GRAS panel has reviewed
it. Such information would need to be considered, but generally would
only be
[[Page 54975]]
corroborative of safety. (See Response 9 and Response 11.)
(Comment 13) One comment asserts that the proposed rule treats the
findings of GRAS panels as equivalent to determinations by
authoritative bodies and peer reviewed published articles.
(Response 13) We disagree. In the proposed rule, we noted that the
basis for concluding there is expert consensus about the safety of a
substance under the conditions of its intended use may be quite varied,
and described common mechanisms that have been used to do so. We stated
that these common mechanisms included publication in the primary, peer-
reviewed scientific literature; publication in the secondary scientific
literature; documentation of the opinion of an ``expert panel'' that is
specifically convened for this purpose; and the opinion or
recommendation of an authoritative body such as the National Academy of
Sciences or the Committee on Nutrition of the American Academy of
Pediatrics on a broad or specific issue that is related to a conclusion
of GRAS status (62 FR 18938 at 18940-18941). We also stated that there
could be a basis to conclude that there is expert consensus that the
published results of a particular safety study (i.e., the primary
scientific literature) establish the safety of a substance for its
intended use if the study raises no safety questions that experts would
need to interpret and resolve (62 FR 18938 at 18943). In addition,
technical literature from JECFA can provide evidence that generally
available safety data and information are generally accepted (see
section III.A.1 of CFSAN's 2010 experience document (Ref. 18)).
However, acknowledging that the opinion of an ``expert panel''
(which we now refer to as a ``GRAS panel'') has been used to provide
evidence that safety data and information are generally accepted does
not mean that these mechanisms are ``equivalent.'' Whether the findings
of a GRAS panel, a determination by an authoritative body, or a peer-
reviewed scientific study provide sufficient evidence that safety data
and information are generally accepted would depend on the specific
findings of the GRAS panel, the specific determination by the
authoritative body, and the data and information in the peer-reviewed
scientific study rather than on the classification of the mechanism for
providing evidence that safety data and information are generally
accepted.
(Comment 14) One comment asks us to develop and publish guidelines
regarding specific duties that would be expected of any GRAS panel.
This comment suggests that such guidelines could include
recommendations for: (1) Number of panel members; (2) measures of
``general acceptance,'' such as a majority (rather than unanimous)
opinion and the impact of a dissenting opinion; and (3) the content of
a letter from a GRAS panel.
(Response 14) See Response 125. We intend to issue for public
comment a draft guidance to address GRAS panels.
(Comment 15) Some comments assert it can be difficult to publish
data and information that do not raise an issue of concern.
(Response 15) We infer this comment to refer primarily to
toxicology studies. Toxicology studies are designed to provide
information about potential adverse effects from exposure to a
substance and any dose-response relationship. Although studies that
fail to identity any adverse effects may be difficult to publish, some
scientific journals report the findings of such studies. (See section
III.A.1 of CFSAN's 2010 experience document (Ref. 18)).
(Comment 16) One comment asks us to require that both toxicology
and exposure data be published because a safety assessment for the use
of a substance in food requires consideration of both.
(Response 16) We agree that a safety assessment for the use of a
substance in food requires consideration of both safety information
(such as toxicology studies) and dietary exposure (i.e., the amount of
the substance that consumers are likely to eat or drink). Toxicology
data are ordinarily published.
A premarket exposure assessment typically would be calculated by
applying generally available and accepted methods to two types of data
and information: (1) Generally available and accepted data about food
consumption; and (2) specific food categories, and levels of use in
those food categories, projected by the sponsor of a food additive
petition or by the proponent of GRAS status (Ref. 24 and Ref. 25).
Using generally available and accepted data about food consumption, a
qualified expert who has access to the specific food categories and
associated levels of use intended by the proponent of GRAS status can
calculate an estimated dietary exposure. When the proponent of GRAS
status submits a GRAS notice, the proponent must: (1) Provide data and
information about dietary exposure (see Sec. 170.235); and (2) include
a narrative that addresses the safety of the notified substance,
considering all dietary sources (see Sec. 170.250). Those calculations
and discussions included in the GRAS notice are subject to the public
disclosure provisions of this rule (see Sec. 170.275) and, thus, would
be available to the expert scientific community. However, when the
proponent of GRAS status does not submit a GRAS notice, the expert
scientific community that does not have access to the specific food
categories and associated levels of use would not be able to calculate
an estimated dietary exposure. When the available data and information
suggest that the specific food categories and associated levels of use
must be carefully chosen to keep consumption of the substance in a safe
range (e.g., when fortifying food with certain vitamins), the expert
scientific community that does not have access to the specific food
categories and associated levels of use would not be able to reach a
conclusion about whether the substance is safe under the conditions of
its intended use, and GRAS criteria would not be satisfied.
After market entry of the substance, it may be appropriate to re-
assess dietary exposure. For example, dietary exposure may need to be
reassessed when a key assumption in the methodology is changed; as
dietary consumption patterns change; when there is an unresolved
question about consumer intake; when there is a small margin of
exposure; or when other new information becomes available. As with a
premarket exposure assessment, a postmarket exposure assessment
typically would be calculated by applying generally available and
accepted methods to two types of data and information: (1) Generally
available and accepted data about food consumption; and (2) specific
food categories, and levels of use in those food categories. In some
cases, postmarket exposure assessments have been published so that the
expert scientific community has access to them. For example, exposure
assessments have been published for some sweeteners using relative
sweetness as the basis of the estimate (Ref. 26). As another example,
estimates of dietary exposure to caffeine have been published to
address consumer intake and patterns of use (Ref. 27 through Ref. 29).
However, as with a premarket exposure assessment, when a postmarket
exposure assessment is not publicly available, the expert scientific
community that does not have access to the specific food categories and
associated levels of use would not be able to reach a conclusion about
whether the substance is safe under the conditions of its intended use
when the available data and information suggest
[[Page 54976]]
that the specific food categories and associated levels of use must be
carefully chosen to keep consumption of the substance in a safe range.
(Comment 17) One comment asks us to recognize that published
literature does not need to address a specific substance, but could
involve publications on a class of substances or a related substance to
support a conclusion that the use of a substance is GRAS through
scientific procedures.
(Response 17) We agree that published information for a specific
substance is not always necessary to support a conclusion that the use
of a substance is GRAS through scientific procedures. For example,
there may be situations where the safety of the use of the substance in
food can be demonstrated by relevant published information on a
closely, structurally related compound. In such cases, the analysis
leading to the conclusion of GRAS status should explain how the
information on the closely, structurally related compound is relevant
to the safety assessment of the substance being evaluated. In other
cases, there may a body of information published in the primary or
secondary literature about a class of substances, which reflect
generally available and accepted data and information that can be
called to bear on the safety assessment of a specific substance. For
example, generally available metabolism information about commonly
consumed components of food, such as carbohydrates, lipids, and
proteins, could support a conclusion that a specific substance is GRAS
under the conditions of its intended use.
To help ensure that the data are, in fact, relevant to the safety
assessment of the substance being evaluated, we strongly encourage any
person who intends to rely on data and information regarding a class of
substances, or a specific substance related to the substance that would
be added to food, to submit any conclusion of GRAS status to FDA via
the GRAS notification procedure.
(Comment 18) One comment states that the use of an approved food
additive can, through the passage of time, become GRAS as the substance
becomes widely used and as information about the substance becomes
publicly available.
(Response 18) We disagree that widespread use of an approved food
additive as time passes has any bearing on the eligibility of this use
for classification as GRAS. Eligibility for classification as GRAS
through scientific procedures would depend on the status of the
information--as generally available and generally accepted--rather than
on the amount of time that a food additive has been used in food.
However, in general, much of the data submitted for our review of a
food additive contains unpublished data and trade secret or
confidential information that is neither published nor otherwise
generally available. Although the safety data are available for public
disclosure under 21 CFR 171.1(h)(1), they typically are based on
unpublished studies sponsored by the petitioner.
See also the discussion in Response 19 regarding the impact of the
passage of time and the discussion in Response 79 that the qualified
experts who evaluate the basis for a conclusion that the notified
substance is safe under the conditions of its intended use must not
exclusively be ``FDA's experts.''
(Comment 19) One comment asks us to exclude uses of ``novel''
substances from consideration for eligibility for classification as
GRAS. The comment asserts that novel or newly discovered uses of
substances that are the subject of a conclusion of GRAS status are in
conflict with the original intent of the 1958 amendment and the plain
meaning of ``generally recognized,'' because there is no history of
safe use for these substances. The comment also states that similar
``general recognition'' provisions for new drugs are not interpreted to
allow industry-made safety determinations for new or novel drugs.
(Response 19) We do not have a regulatory definition for a
``novel'' substance. As a general matter, section 201(s) of the FD&C
Act provides two alternatives for general recognition of safety--
through scientific procedures, or through experience based on common
use in food. Section 201(s) does not limit eligibility, or otherwise
exclude, the use of a substance from classification as GRAS through
scientific procedures if there is no history of use. Likewise, section
201(s) does not limit eligibility, or otherwise exclude, the use of a
substance from classification as GRAS through scientific procedures
based on other criteria, such as whether a substance or its use in food
is ``novel'' or ``newly discovered.'' Unlike the definition of a ``new
drug'' in section 201(p) of the FD&C Act, section 201(s) does not
require that a food ingredient be used ``to a material extent or for a
material time under such conditions'' before it can become GRAS.
Rather, the criteria for eligibility for classification as GRAS depend
on whether generally available and accepted data and information
establish that the substance is safe under the conditions of its
intended use.
However, a conclusion of GRAS status must be based on common
knowledge throughout the scientific community knowledgeable about the
safety of substances added to food that there is reasonable certainty
that the substance is not harmful under the conditions of its intended
use (Sec. 170.30(a)), and a substance cannot be considered GRAS when
its characteristics are known to only a few experts (Final rule
establishing GRAS criteria, 41 FR 53600, December 7, 1976). In
addition, the passage of time is relevant in an evaluation of whether a
substance is GRAS under the conditions of its intended use. In our 1974
proposed rule on general recognition of safety and prior sanctions for
food ingredients, we acknowledged that there would be at least some gap
between the gathering of the scientific knowledge necessary to provide
the toxicological underpinning for general recognition of safety and
the dissemination to and assimilation by the scientific community of
this material that is necessary for general recognition of safety to
exist.'' (39 FR 34194 at 34194, September 23, 1974). More recently, the
discussions in sections III.A.4 and IV.K of CFSAN's 2010 experience
document (Ref. 18) show our approach to the time gap between the
publication of safety data and the use of the published safety data to
support a conclusion of GRAS status during the Interim Pilot program.
See also Response 67 regarding nanotechnology applications in food
substances.
(Comment 20) One comment asserts that we must define the extent of
agreement needed to establish a consensus among qualified experts, and
that we must exclude from eligibility for classification as GRAS any
substance whose safety has been called into question by expert
authorities or authoritative entities within the scientific community.
(Response 20) The proponent of a GRAS conclusion for a food
substance must demonstrate that the conditions of use of the substance
satisfy the definition of ``safe'' in our regulations (i.e., that there
is reasonable certainty that the substance is not harmful under the
conditions of its intended use (see Sec. 170.3(i)). The proponent of
GRAS status also must demonstrate that there is common knowledge about
this safety throughout the knowledgeable scientific community (Sec.
170.30(a)). Although courts have established that general recognition
of safety requires a consensus of expert opinion regarding the safety
of the use of the substance, (see, e.g., United States v. Western
[[Page 54977]]
Serum Co., Inc., 666 F.2d 335, 338 (9th Cir. 1982) (citing Weinberger
v. Hynson, Westcott & Dunning, 412 U.S. 609, 629-32 (1973)), we
disagree that we must define the extent of agreement needed to
establish such a consensus. Courts have established that general
recognition of safety does not require unanimous agreement. See, e.g.,
United States v. Articles of Drug * * * 5,906 Boxes, 745 F.2d 105, 119
n. 22 (1st Cir. 1984); United States v. Articles of Food and Drug
(Coli-Trol 80), 518 F.2d 743, 746 (5th Cir. 1975) (``What is required
is not unanimous recognition but general recognition''). Importantly,
general recognition of safety does not exist if there is a genuine
dispute among qualified experts that the use of a substance is safe.
See, e.g., Premo Pharmaceutical Laboratories v. United States, 629 F.2d
795, 803-4 (2nd Cir. 1980) (``genuine dispute among qualified experts''
precludes finding of general recognition, and no general recognition
existed as a matter of law where there was a ``sharp difference'' of
expert opinion); United States v. Article of Food * * * Coco Rico, 752
F.2d 11, 15 n 6 (1st Cir. 1985) (substance was not GRAS as a matter of
law based on existence of ``genuine dispute among qualified experts''
regarding safety of use). For discussions of additional judicial
decisions bearing on the criteria for eligibility for classification as
GRAS, see the notice of declaratory order providing our final
determination regarding partially hydrogenated oils (80 FR 34650).
A conclusion of GRAS status must be based on the totality of the
publicly available and corroborative evidence about the safety of the
substance under the conditions of its intended use, including both
favorable and potentially unfavorable information. Thus, reports of
expert authorities or authoritative entities within the scientific
community may indicate that there is no general recognition of safety
when the reports call into question the safety of a substance for use
in food. However, we disagree that the outcome of an evaluation of such
information can be predetermined as suggested by the comments.
Regardless of whether particular scientific data and information lead
experts to conclude that a substance is safe under the conditions of
its intended use, or raise questions about the safety of the substance
under the conditions of its intended use, the evaluation of whether a
use of a substance in food is safe, and whether safety is generally
recognized, is a case-by-case evaluation. For example, data and
information that lead expert authorities or authoritative entities
within the scientific community to raise a concern about the safety of
the substance under the conditions of its intended use in food would
have reduced significance if the concern was related to a contaminant
in the substance and scientifically valid data and information supplied
by the proponent of GRAS status provide evidence that an improved
method of manufacture eliminates that contaminant.
See also Response 77, in which we explain that we proposed to
provide the judicial interpretation of section 201(s) of the FD&C Act
in the requirement for the comprehensive discussion of the notifier's
basis for a conclusion of GRAS status to provide more context to
notifiers than merely repeating the statutory language. However, as
discussed in Response 77, we have decided to use the statutory language
(i.e., ``generally recognized'') rather than the proposed term
``consensus'' in the submission requirements for a GRAS notice to
mirror the GRAS criteria in Sec. 170.30, which continue to use the
statutory language rather than the consensus standard applied by the
courts in applying the statutory language to specific situations.
(Comment 21) In the proposed rule, we asked for comment on the
potential for a conclusion of GRAS status through scientific procedures
to be based in part on the ``substantial equivalence'' of the
applicable substance to a substance that is GRAS through experience
based on common use in food. One comment agrees with the view,
expressed in a 1996 JECFA Report (Ref. 30) and reported in the proposed
rule (62 FR 18938 at 18944), that ``substantial equivalence'' embodies
the concept that if a new food component is found to be substantially
equivalent to an existing food component, the food component could be
considered to be as safe as the existing food component, after taking
into account any processing that the food component may undergo as well
as the intended use and the intake by the population. Several comments
assert that the concept of substantial equivalence, although useful, is
nonetheless ambiguous. One comment asks us to clearly state our
interpretation of this concept in the final rule.
(Response 21) We have decided not to include the term ``substantial
equivalence'' in the regulatory text of this rule, because whether, and
to what extent, similarity between two substances could support a
conclusion of GRAS status depends on too many situation-specific
variables. As discussed in section IV.N of CFSAN's 2010 experience
document, GRAS notices filed during the Interim Pilot program that
relied on the concept of ``substantial equivalence'' generally
addressed alternative sources of enzymes already used in food (Ref.
18). Most of these notices both emphasized the similarities of the new
enzyme preparations to existing enzyme preparations and explained the
differences between the new enzyme preparation and currently used
enzyme preparations. However, none of these GRAS notices relied solely
on the concept of ``substantial equivalence.'' Instead, these notices
also described other applicable data and information, such as data and
information about the biological source of the enzyme preparation; the
method of manufacture of the enzyme preparation; constituents of the
enzyme preparation that derive from the source organism or the
manufacturing process; the technical effect of the enzyme preparation;
dietary exposure to the enzyme preparation; specifications for the
enzyme preparation; and applicable safety studies.
C. Criteria for Eligibility for Classification as GRAS Through
Experience Based on Common Use in Food
We proposed to amend the criteria for eligibility for
classification as GRAS through experience based on common use in food
(Sec. 170.30(c)(2)) to state that persons who claim that use of a
substance is GRAS through experience based on its common use in food
outside of the United States should notify FDA of that claim in
accordance with the GRAS notification procedure. We received no
comments that disagreed with this proposed amendment and are finalizing
it as proposed, with conforming changes as shown in table 29.
See section XXV.B regarding revisions to the criteria for
eligibility for classification as GRAS through experience based on
common use in food for a substance used in animal food.
D. Other Comments on the Criteria for Eligibility for Classification as
GRAS
(Comment 22) One comment asserts that the proposed rule would add
unnecessary complexity to continued use of substances currently
presumed to be GRAS. This comment also asserts that the proposed rule
would remove the ``pre-1958 exemption'' and, as a result, would place
an unnecessary burden on food producers and processors with respect to
substances
[[Page 54978]]
that are the subject of previous conclusions of GRAS status.
(Response 22) These comments are unclear. By ``pre-1958 exemption''
these comments could mean a conclusion of GRAS status through
experience based on common use in food, which requires common use in
food before January 1, 1958. Alternatively, these comments could be
referring to the statutory exception from the definition of ``food
additive'' for a substance that is the subject of a prior sanction
within the meaning of section 201(s)(4) of the FD&C Act and part 181
(21 CFR part 181). Either way, nothing in this rule would affect a
lawful use of a food substance that is GRAS based on common use in food
prior to January 1, 1958 or that is the subject of a prior sanction.
This rule does not remove GRAS status based on common use in food prior
to January 1, 1958. Likewise, the lawful use of a substance listed in
part 181 as being the subject of a prior sanction is not affected by
this rule.
However, any person who relies on a conclusion of GRAS status
through experience based on common use in food prior to 1958 or on a
prior sanction within the meaning of section 201(s)(4) of the FD&C Act
needs to consider whether the conditions of use associated with the
applicable substance, such as the foods in which the substance would be
used and the levels of use of the substance, are within the scope of
these statutory provisions. As discussed in section I.D, in 2010 we
issued warning letters informing four companies marketing caffeinated
alcoholic beverages that caffeine, as used in the companies' products,
is an unsafe food additive, and therefore the products are adulterated
under section 402(a)(2)(C) of the FD&C Act, and the companies
subsequently ceased distribution of these products. Thus, we advise any
manufacturer or distributor to carefully consider whether there is
adequate support for concluding that a substance is GRAS under the
conditions of its intended use and to submit a GRAS notice to us if it
intends to manufacture or distribute a food product containing a
substance that has been used in food as a GRAS substance under
conditions of use different from those in the manufacturer's or
distributor's product.
In addition, new data and information may call into question the
safety of a substance used in food as a GRAS substance, whether the
basis for a conclusion of GRAS status is through experience based on
common use in food or through scientific procedures. As discussed in
section I.A, in 1969 we deleted various cyclamate salts from the GRAS
list because they were implicated in the formation of bladder tumors in
rats; as discussed in section I.D, we recently issued a declaratory
order making a final determination that there is no longer a consensus
among qualified experts that PHOs are GRAS for any use in human food
(80 FR 34650).
(Comment 23) One comment asks us to require minimum safety or
short-term toxicology studies for all conclusions of GRAS status,
regardless of whether the conclusion is through scientific procedures
or through experience based on common use in food before 1958. This
comment explains that such studies could corroborate safety when GRAS
status is based on common use on food, e.g., by taking into account any
impact of the manufacturing process on food safety.
(Response 23) We decline this request. We agree that the method of
manufacture can impact safety, regardless of whether GRAS status is
through experience based on common use on food or through scientific
procedures. See, e.g., our guidance entitled ``Assessing the Effects of
Significant Manufacturing Process Changes, Including Emerging
Technologies, on the Safety and Regulatory Status of Food Ingredients
and Food Contact Substances, Including Food Ingredients that Are Color
Additives'' (Ref. 6). The rule requires submission of a description of
the method of manufacture in sufficient detail to evaluate the safety
of the notified substance as manufactured, regardless of whether the
basis for the conclusion of GRAS status is through scientific
procedures or through experience based on common use in food (see Sec.
170.230(b)). If the method of manufacture has changed over time, a new
evaluation of GRAS status based on scientific procedures may be
warranted. We advise any manufacturer of a substance that is used in
food based on a conclusion of GRAS status to carefully consider the
impact of its method of manufacture on the safety of the substance
before introducing the substance into commerce.
We disagree that the rule must require minimum safety or short-term
toxicology studies for all conclusions of GRAS status because the kinds
of data and information needed to demonstrate safety (or that could be
used to corroborate safety) will vary based on the substance and its
intended use. A conclusion of GRAS status based on scientific
procedures must be based on the same quantity and quality of scientific
evidence as is required to obtain approval of a food additive (Sec.
170.30(b)). We have issued guidance on the types of data and
information in support of a food additive petition, and these types of
data and information would be useful in the evaluation of the safety of
a substance when the proponent of the substance seeks to demonstrate
that the substance is GRAS under the conditions of its intended use
(see Response 37 and Response 66).
For a safety assessment of a chemical, the specific types of data
and information generally follow from the chemical structure and
estimated dietary exposure of the substance. For example, chemistry
data, including manufacturing information, as well as information
sufficient to estimate exposure, are necessary to consider in arriving
at a conclusion of GRAS status. Whether toxicological studies are
necessary to demonstrate safety depends on the properties of the
substance such as the presence or absence of chemical alerts, physical
properties, and physiological fate of the substance. For example, well
understood and accepted metabolism information about a substance that
is a component of commonly consumed foods (such as vegetables or
fruits) may provide sufficient safety information to arrive at a
conclusion of GRAS status at a specified level of the use of that
substance in food. As discussed in section III.A.2 of CFSAN's 2010
experience document, during the Interim Pilot program it was CFSAN's
view that toxicological studies were not necessary to evaluate the
safety of substances such as carrot fiber and dried orange pulp (Ref.
18). Likewise, for simple substances (such as minerals and their salts)
that are readily dissociated to components that have long been viewed
as GRAS (e.g., by a listing in part 182 or by a GRAS affirmation
regulation in part 184), toxicological studies would likely not be
necessary. As discussed in section III.A.2 of CFSAN's 2010 experience
document, during the Interim Pilot program it was CFSAN's view that
toxicological studies were not necessary to evaluate the safety of
substances such as potassium bisulfate and seaweed-derived calcium
(with calcium carbonate as the major component) (Ref. 18).
For a safety assessment of a substance produced from a
microorganism, the specific types of data and information generally
follow from the identity of the microorganism and how the substance is
produced from that microorganism in addition to the substance itself.
For example, the safety of a substance produced from a microorganism
generally considers generally available microbiological data and
information about the potential toxigenicity and
[[Page 54979]]
pathogenicity of the microorganism. Whether toxicological studies would
be necessary to demonstrate the safety of the substance as manufactured
would depend on what the substance is and its intended use in food.
E. GRAS Status of Certain Food Substances
We proposed to remove Sec. 170.30(f), which expresses our intent
to review the GRAS status of certain food substances. We received no
comments that disagreed with our proposal to remove Sec. 170.30(f) and
are removing it as proposed.
VII. Comments on the Substitution of a GRAS Notification Procedure for
the GRAS Affirmation
Petition Process
Our regulations specify procedures for us to affirm the GRAS status
of the use of a food substance, whether on our own initiative (Sec.
170.35(a) and (b)) or on the petition of an interested person (Sec.
170.35(c)). We proposed to eliminate the GRAS affirmation petition
process in Sec. 170.35(c) and replace it with a GRAS notification
procedure (proposed Sec. 170.36) in which any person may notify us of
a claim that a particular use of a substance is exempt from the
statutory premarket approval requirements based on the notifier's
determination that such use is GRAS. Under the proposed notification
procedure, we would evaluate whether the submitted notice provides a
sufficient basis for a GRAS determination and whether information in
the notice or otherwise available to us raises issues that lead us to
question whether use of the substance is GRAS. We also proposed to
presumptively convert any filed GRAS affirmation petition that is
pending on the date that the petition process is replaced with a
notification procedure (``pending petition'') to a GRAS notice and
provide an opportunity for the person who had submitted a pending
petition (``affected petitioner'') to amend the petition to meet the
requirements for a GRAS notice.
In the 2010 notice, we discussed several issues broadly applicable
to the proposed substitution of a GRAS notification procedure for the
GRAS affirmation petition process (see table 3).
Table 3--Issues in the 2010 Notice Broadly Applicable to the Proposed
Substitution of a GRAS Notification Procedure for the GRAS Affirmation
Petition Process
------------------------------------------------------------------------
Description of
Issue No. our request for Reference
comment
------------------------------------------------------------------------
N/A....... Our intent to use 75 FR 81536 at 81537.
``Plain
Language'' tools
such as pronouns
in the final
rule.
2......... Our reasons for 75 FR 81536 at 81538.
tentatively
concluding that
the terms
``conclude'' and
``conclusion''
would be more
appropriate in
lieu of
``determine''
and
``determination'
'.
17........ Alternative 75 FR 81536 at 81542-81543.
approach to
administering
pending GRAS
affirmation
petitions.
------------------------------------------------------------------------
Several comments support the proposed replacement of the GRAS
affirmation petition process with a GRAS notification procedure. For
example, several comments support the expectation we expressed in the
proposed rule (62 FR 18938 at 18941) that the substitution of a GRAS
notification procedure for the GRAS affirmation petition process would
result in our increased awareness of the composition of the nation's
food supply and the cumulative dietary exposure to GRAS substances.
Most of these comments agree that such increased awareness could be an
advantage of the notification procedure if manufacturers view our
response to a GRAS notice as an incentive to participate in the
program. Many comments that support the proposed replacement of the
GRAS affirmation petition process with a GRAS notification procedure
nonetheless raise questions about how we would administer the pending
GRAS affirmation petitions. We discuss those comments in section XXIII.
In the following sections, we discuss comments that disagree with
one or more aspects of our proposal to replace the GRAS affirmation
petition process with a GRAS notification procedure (see, e.g., Comment
24, Comment 25, and Comment 32); ask us to clarify how we generally
will administer the proposed GRAS notification procedure (see, e.g.,
Comment 31); or suggest one or more general changes to the proposed
GRAS notification procedure (see, e.g., Comment 27, Comment 28, Comment
30, Comment 31, and Comment 36). After considering these comments, we
are replacing the GRAS affirmation petition process with a GRAS
notification procedure, using the terms ``conclude'' and ``conclusion''
as described in the 2010 notice. As noted in the 2010 notice, the final
rule uses Plain Language tools such as pronouns.
To improve clarity and readability we used another Plain Language
tool, i.e., the use of short regulatory sections that have limited
subparagraph designations. To do so we redesignated the single proposed
section (i.e., proposed Sec. 170.36) into several distinct, short
sections of regulatory text in a newly established subpart E (GRAS
Notice), with editorial changes associated with the new structure of
the redesignated regulations. See table 4 for the section numbers and
titles of the regulatory text in subpart E. Many provisions of the
regulatory text in subpart E use singular nouns when discussing the
intended use of the notified substance, e.g., the definition of ``GRAS
notice'' means a submission that informs us of your view that a
specified use of a substance is not subject to the premarket approval
requirements of the FD&C Act based on your conclusion that such use is
GRAS. The singular term ``use'' is employed for a simple and consistent
presentation in the regulatory text and does not mean, for example,
that you are limited to notifying us about a single use of the notified
substance.
We also are establishing in new subpart E the process we described
in the 2010 notice for administering pending GRAS affirmation
petitions. Finally, we made editorial, clarifying, and conforming
changes as shown in table 29. Because the editorial changes associated
with the redesignation of the notification procedure in subpart E are
extensive, we do not list them in table 29.
A. Affirmation on the Initiative of the Commissioner
We proposed to amend current Sec. 170.35(a) to clarify that the
Commissioner would affirm the GRAS status of a use of a substance,
rather than the substance itself, and to include a grammatical change
to place Sec. 170.35(a) in the singular. The single
[[Page 54980]]
comment that expressly addressed this proposed amendment concurred with
us on this point and we are finalizing it as proposed.
We also proposed to amend current Sec. 170.35(a) to remove the
provision that we may review the GRAS status of a substance added to
food in response to a petition from an interested party. Under current
Sec. 170.35, such a petition would be submitted in accordance with the
provisions of the GRAS affirmation petition process established in
current Sec. 170.35(c). We are deleting this provision as proposed.
The comments we received relevant to our proposed deletion of the
petition-related provision in Sec. 170.35(a) are directed to our
proposed deletion of the GRAS affirmation petition process in current
Sec. 170.35(c), and we discuss those comments in section VII.B.
B. Deletion of the GRAS Affirmation Petition Process
We proposed to eliminate the GRAS affirmation petition process in
current Sec. 170.35(c).
(Comment 24) Several comments oppose our proposal to eliminate the
GRAS affirmation petition process. In general, these comments assert
that we should provide manufacturers the option of seeking GRAS
affirmation even though we would be establishing a new notification
procedure. The comments assert that such an option is essential to
support the marketing of a product in certain situations, such as when
recognition of GRAS status is needed by international standard-setting
bodies.
(Response 24) We acknowledge that a regulation listing the use of a
substance in food could provide some support for marketing a product in
certain situations, but disagree that we should retain the GRAS
affirmation petition process. We note that CFSAN filed more than 600
GRAS notices during the time period 1998 through 2015 (Ref. 19), for an
average of approximately 34 GRAS notices per year, including 69 GRAS
notices filed during 2014 and 51 GRAS notices filed during 2015. By
contrast, during that time CFSAN finalized six GRAS affirmation
regulations. We believe that the ongoing submission of GRAS notices is
evidence that our response to a GRAS notice can support the marketing
of a food substance.
(Comment 25) Some comments assert that the proposed GRAS
notification procedure would be less protective of food safety than the
GRAS affirmation petition process it would replace. Some comments
assert that our role in ensuring the safety of food ingredients is best
carried out by a review of the data supporting the safety of the
ingredient and that the public should also have access to these data.
These comments also assert that the GRAS affirmation petition process,
in which we conduct a review of supporting data, provides an incentive
to manufacturers to fully research each substance and that removing
this incentive would compromise safety. Other comments assert that the
GRAS notification procedure would be less thorough than the GRAS
affirmation petition process. One comment states that consumers are
concerned about the safety and wholesomeness of substances added to
food and criticizes the proposed rule as not being ``rigorous enough''
and as not creating a ``meaningful process for adequately reviewing the
safety of substances used in human and animal food.''
(Response 25) We disagree that the notification procedure is less
protective of food safety than the affirmation petition process. In the
proposed rule, we stated that our response to a GRAS notice would not
be equivalent to an agency affirmation of GRAS status because we would
neither receive nor review the detailed data and information that
support the GRAS determination (62 FR 18938 at 18951). These comments
may have misinterpreted that statement to mean that we would not
conduct a substantive evaluation of the summary information that we
receive in a GRAS notice. This is not the case. CFSAN's 2010 experience
document (Ref. 18) demonstrates that we have conducted a substantive
evaluation of the GRAS notices that we received during the Interim
Pilot program. For example, section III.C.1 of CFSAN's 2010 experience
document describes examples of situations in which we contacted a
notifier to request clarification about data and information in the
notice. CFSAN's 2010 experience document also demonstrates that during
the period 1998-2009 CFSAN had questions about 21 percent of GRAS
notices, such that CFSAN either responded to the notifier that the
submitted GRAS notice did not provide a basis for a conclusion of GRAS
status or the notifier asked us to cease to evaluate the GRAS notice
(see section III.B of CFSAN's 2010 experience document). Furthermore,
we believe that the GRAS notification procedure provides us with
greater flexibility to respond to safety concerns that may arise about
a substance that is the subject of a GRAS notice, compared to a
substance that is the subject of a GRAS affirmation regulation, which
would require rulemaking to revoke.
We acknowledge that the term (i.e., ``evaluate'') we use to
describe our actions when we receive a GRAS notice is different from
the term (i.e., ``review'') we use to describe our actions when we
receive a petition (whether a food or color additive petition or a GRAS
affirmation petition). We decided to use a different term because, as
already noted, the data and information we will receive in a GRAS
notice (i.e., summary data and discussions) are different from the data
and information we receive in a petition (which generally includes the
underlying data from studies described in the petition).
As discussed in Response 120, we currently make a hyperlink to an
electronic copy of each GRAS notice accessible from our Internet site
and, thus, the public has access to each GRAS notice. We also make our
response to each GRAS notice accessible from our Internet site (see
Sec. 170.275(b), Response 115, and Response 116). We acknowledge that
supporting data and information that are provided to us in the form of
a petition can provide the public with ready access to such data and
information (e.g., through a FOIA request), but disagree that
substitution of the GRAS notification procedure for the GRAS
affirmation petition process has a fundamental impact on the public's
access to supporting data and information, because a conclusion of GRAS
status must be based on generally available data and information. Under
the notification procedure, the publicly accessible GRAS notice both
summarizes the available data and information and provides a list of
publicly available data and information (see Sec. Sec. 170.250 and
170.255). Under the GRAS affirmation petition process, we placed a copy
of each publication provided by the petitioner to support a conclusion
of GRAS status in the public docket for that petition, but our current
practice with respect to copyrighted publications is to refer the
public to the primary records (see Sec. 20.51, Referral to primary
source of records).
We cannot say whether a petition process would provide an incentive
for a manufacturer to more fully research the safety of a substance
before sending a GRAS notice to us. However, we advise a manufacturer
who intends to submit a GRAS notice to expect a substantive evaluation
of that GRAS notice by us. Likewise, we advise a manufacturer who
reaches a conclusion that a substance is GRAS under the conditions of
its intended use, but does not submit a GRAS notice to us, that when a
substance is not GRAS under
[[Page 54981]]
the conditions of its intended use (or is not otherwise excepted from
the definition of ``food additive'' in section 201(s) of the FD&C Act),
that use of the substance is a food additive use subject to our
premarket review as mandated by the FD&C Act. In such circumstances, we
can take various actions, including issuing a warning letter (which we
make public on our Web site) to companies that manufacture or
distribute the food additive and/or food containing the food additive;
issuing a public alert; taking enforcement action to stop distribution
of the food substance and foods containing it on the grounds that such
foods are or contain an unlawful food additive; and issuing a
declaratory order determining that the substance is not GRAS under the
conditions of its intended use and is a food additive subject to
section 409 of the FD&C Act. For example, as already discussed in
section I.D, we recently issued a declaratory order making a final
determination that there is no longer a consensus among qualified
experts that PHOs are GRAS for any use in human food (80 FR 34650). As
another example discussed in section I.D, we have issued warning
letters informing four companies marketing caffeinated alcoholic
beverages that caffeine, as used in the companies' products, is an
unsafe food additive, and therefore the products are adulterated under
section 402(a)(2)(C) of the FD&C Act (Ref. 10 through Ref. 13), and the
companies subsequently ceased distribution of these products. Thus, we
advise any manufacturer or distributor to carefully consider whether
there is adequate support for concluding that a substance is GRAS under
the conditions of its intended use and to submit its conclusion of GRAS
status to us in the form of a GRAS notice.
(Comment 26) A few comments express skepticism that the
substitution of a GRAS notification procedure for the GRAS affirmation
petition process would result in our increased awareness of the
composition of the nation's food supply and the cumulative dietary
exposure to GRAS substances. These comments assert that the proposed
notification procedure offered a risk (i.e., the risk of a publicly
available ``insufficient basis letter'') without the potential benefit
that was available under the petition process (i.e., a regulation
affirming GRAS status). These comments predict that, unless we modify
the proposed rule substantially, we likely would have less awareness of
GRAS substances under the notification procedure than we currently have
under the GRAS affirmation petition process.
One comment asserts that the notification procedure would in no
manner be equivalent to the GRAS affirmation petition process, and the
substitution of a notification procedure for a petition process would
be anything but neutral. This comment asserts that the proposed
substitution of a notification process for the affirmation process
would actually reduce the incentive for producers to notify FDA,
because notification would invite regulatory scrutiny without requiring
FDA to attest to a conclusion of GRAS status.
(Response 26) We disagree that the notification procedure we are
establishing in this rule will reduce the incentive for producers to
notify us. As already noted in Response 24, CFSAN has filed more than
600 GRAS notices between 1998 and 2015, for an average of approximately
34 GRAS notices per year. In contrast, as discussed in section IV.L of
CFSAN's 2010 experience document (Ref. 18), between 1987 and 1996 CFSAN
received a total of fewer than 100 GRAS affirmation petitions, with an
average of approximately 8 GRAS affirmation petitions per year. These
data support the expectation we expressed in the proposed rule that the
substitution of a GRAS notification procedure for the GRAS affirmation
petition process would result in our increased awareness of the
composition of the nation's food supply and the cumulative dietary
exposure to GRAS substances.
The comments that predict that we would need to modify the final
rule substantially to achieve increased awareness of the nation's food
supply did not suggest specific modifications for this purpose.
However, this document discusses the changes we have made to the
proposed notification procedure as a result of comments, described in
this document and the 2010 notice, that raised specific issues and
concerns regarding the proposed notification procedure. For example,
the final rule defines the term ``amendment'' (Sec. 170.203) and
expressly provides that a notifier may submit a timely amendment to
address our questions (Sec. 170.260(a)). As another example, the final
rule expressly provides that a notifier may ask us to cease to evaluate
a GRAS notice (Sec. 170.260(b)). In addition, see Response 80
regarding our willingness to engage with a notifier to clarify
particular aspects of the notice and Response 96 and Response 97
regarding comments that raise concerns about a publicly available
insufficient basis letter. For a summary of the principal changes to
the notification procedure in this final rule relative to the proposed
rule, see table 2.
(Comment 27) One comment asks us to require the submission of a
GRAS affirmation petition on a random basis for 20 percent of the GRAS
notices we receive. This comment states that such a requirement would
be essential in light of our concurrent proposal to broaden the types
of safety information that could support GRAS status in the criteria
for eligibility for classification as GRAS through scientific
procedures. The comment refers to this procedure as a ``verification
audit'' and describes a ``verification audit'' as a detailed evaluation
of the scientific data and other technical information. The comment
asks that the final rule give FDA such ``verification authority'' and
asserts that such a verification system would give consumers greater
confidence that the new notification system was not just a system of
deregulation.
(Response 27) We decline this request. Both the GRAS notification
procedure and the GRAS affirmation petition process that it is
replacing are voluntary procedures and, thus, the comment's position
that we could require a GRAS affirmation petition--on a random or any
other basis--is incorrect. Moreover, we disagree that the revised
criteria for eligibility for GRAS status through scientific procedures
have any bearing on whether we should evaluate a conclusion of GRAS
status through a notification procedure or a petition process. The
revised criteria reflect the nature of substances being added to food,
and the fact that the quantity and quality of scientific evidence
required to demonstrate safety vary considerably depending upon the
estimated dietary exposure to the substance and the chemical, physical,
and physiological properties of the substance. See Response 23.
C. General Comments on the Proposed GRAS Notification Procedure
(Comment 28) Some comments ask us to require that companies notify
us of a conclusion of GRAS status and assert that we have implied legal
authority to require such notification. These comments express concern
that potentially dangerous substances could enter the food supply
without our knowledge or supervision. Other comments emphasize that the
GRAS notification procedure should remain voluntary and assert that we
lack express statutory authority to require companies to submit GRAS
notices.
(Response 28) We agree that we lack express statutory authority to
require
[[Page 54982]]
companies to submit GRAS notices. In creating the premarket approval
requirement for food additives in the 1958 amendment, Congress excluded
a substance that is GRAS under the conditions of its intended use from
the definition of food additive. The creation of this GRAS provision
reflected Congress' determination that many substances intentionally
added to food for a specific use do not need premarket review by FDA to
ensure their safety, either because their safety has been established
by a long history of use in food, or because their safety has been
established by information that is generally available to and accepted
by qualified experts, regarding the intended conditions of use of a
substance in food. Subsequently, in 1997, the Food and Drug
Administration Modernization Act (FDAMA) amended section 409 of the
FD&C Act to require the establishment of a mandatory food contact
notification program for human food. By contrast, Congress has not
amended section 409 of the FD&C Act to require the establishment of a
premarket GRAS notification procedure--either voluntary or mandatory.
We did not propose to require the submission to FDA of notices
concerning all conclusions of GRAS status. We recognize that some
comments suggest that such a requirement might be within our legal
authority, even if not expressly required by the FD&C Act. We will
consider these comments and our experience under this final rule in
evaluating what, if any, further action is needed with respect to
ensuring the safety of the food supply. However, mandating submission
of GRAS notices would need to be done in a separate rulemaking to
ensure adequate notice and comment.
(Comment 29) One comment notes that the proposed rule did not
specifically ask members of the food industry to notify us of all
conclusions of GRAS status. This comment suggests that the final rule
include such a request, explaining that such a provision would help us
to achieve our goal of increasing our awareness of substances added to
food.
(Response 29) We view our establishment of the GRAS notification
procedure in this final rule, as well as our announcement of the
Interim Pilot program in the proposed rule, as an invitation to
industry to submit GRAS notices to us for evaluation. See also Sec.
170.205, entitled ``Opportunity to submit a GRAS notice.'' The ongoing
submission of GRAS notices during the Interim Pilot program
demonstrates that the food industry is actively submitting GRAS
notices. As already noted in Response 26, we believe that our filing of
more than 600 GRAS notices for substances used in human food is
evidence that we have increased our awareness of the composition of the
nation's food supply and the dietary exposure to GRAS substances.
(Comment 30) Some comments ask us to require certain postmarket
submissions of exposure and safety data related to all GRAS substances,
to require submissions for conclusions of GRAS status that predate the
final rule, and to require any notifier who ``withdraws'' a GRAS notice
or receives an ``insufficient basis letter'' to notify us about any use
of that substance.
(Response 30) We decline this request for the same reasons that we
discuss in Response 28. See also the discussions in Response 25 and
Response 35 regarding the responsibility of a manufacturer to ensure
that a substance added to food complies with the FD&C Act, and the
potential that we may disagree with a conclusion of GRAS status and
take regulatory action against use of the food substance when we do so.
(Comment 31) Some comments ask us to clarify all the information we
expect to be submitted in a GRAS notice. One comment states its
opposition for the proposed GRAS notification procedure, but also
states that if we implement such a program we should establish the
framework and criteria for the voluntary submission of GRAS notices.
Another comment asks us to include core requirements in the final rule.
Another comment asks us to provide more explicit instructions
concerning the level of detail necessary within the required elements
of a GRAS notice.
(Response 31) Subpart E of part 170 (subpart E) establishes a
comprehensive framework for the submission of GRAS notices, describing
in detail ``core requirements'' such as the seven distinct parts of a
GRAS notice. Subpart E also includes provisions that will govern what
we will do when we receive a GRAS notice, as well as provisions that
will govern disclosure of a GRAS notice. Section 170.30 establishes the
revised criteria for eligibility for classification of the food use of
a substance as GRAS.
(Comment 32) One comment expresses concern that the proposed GRAS
notification procedure would be viewed as a ``fast-track'' option that
would tempt a company that should submit a food additive petition to
submit a GRAS notice instead.
(Response 32) We recognize that there is a possibility that some
manufacturers of food ingredients may decide that they do not need to
submit a food additive petition because they have concluded that the
substance is GRAS under the conditions of its intended use; this
possibility exists regardless of how we structure the GRAS notification
procedure. However, a manufacturer's decision that a food additive
petition is not required must be based on the extent to which the
manufacturer has information both that the intended conditions of use
of a substance in food are ``safe,'' and that there is ``general
recognition'' of that safety. In this rule, we clarify the criteria
(Sec. 170.30) that govern when the intended conditions of use of a
substance in food are more properly the subject of a food additive
petition than a GRAS notice.
The record of our actions during the Interim Pilot program
demonstrates that we will, when appropriate, issue an ``insufficient
basis letter'' or a ``cease to evaluate letter'' signaling that a
petition to obtain a regulation is more appropriate than a GRAS notice.
As described in sections III.A.4 and III.N.2 of CFSAN's 2010 experience
document (Ref. 18), in several cases during the Interim Pilot program
the outcome of CFSAN's review of a GRAS notice was the notifier's
subsequent submission of a food additive petition.
(Comment 33) One comment expresses the opinion that a GRAS notice
could be an appropriate mechanism to inform us of a view that an
additional use of an approved food additive is GRAS.
(Response 33) We agree, provided that the available data and
information demonstrate that the criteria for GRAS status are
satisfied. Whether an additional use of a food additive is GRAS depends
on both whether that additional use is safe and on whether the safety
of that additional use is generally recognized by qualified experts. To
support a conclusion of GRAS status for the additional use of the
substance, there must be evidence that qualified experts generally (not
solely FDA experts who conducted a premarket review of a food additive
petition) have evaluated generally available data and information about
the intended conditions of use of the substance, and reached agreement
that those generally available data and information establish the
safety of the additional use of the substance. During the Interim Pilot
program, CFSAN received several GRAS notices informing CFSAN of a
conclusion that an additional use of an approved food additive is GRAS.
As discussed in section III.A.4 of CFSAN's 2010 experience document
(Ref. 18), CFSAN's response to these GRAS notices has been a case-by-
case response
[[Page 54983]]
that depends on the circumstances. In several cases, CFSAN had no
questions about the notifier's conclusion of GRAS status for an
additional use of a food additive; in one case, the GRAS notice did not
support GRAS status for the additional use of the food additive, and
the notifier subsequently submitted a food additive petition for the
additional use of the substance.
(Comment 34) One comment suggests that the GRAS notification
procedure would shift the burden of proof to FDA to demonstrate that a
use of a substance is not safe or not GRAS after the substance is
already on the market.
(Response 34) We disagree. Under the FD&C Act, the burden of
supporting a conclusion that a substance is GRAS under the conditions
of its intended use is on the proponent of this conclusion. United
States v. An Article of Food, 752 F.2d 11, 15 (1st Cir. P.R. 1985).
This burden of proof remains after the substance is on the market
regardless of whether the proponent asks FDA to evaluate that GRAS
conclusion, and our rule does not change this. By establishing a
process for the submission of GRAS notices for FDA to review, our rule
encourages firms to seek our evaluation of their conclusions, before
they introduce the substance into the market.
(Comment 35) A few comments note that a notifier who markets a food
substance before we issue our letter responding to the notice runs the
risk that we may disagree with the conclusion of GRAS status. One
comment expresses concern that we would take regulatory action to
remove the substance from the food supply rather than discuss our
concerns with the notifier.
(Response 35) The comments are correct that a notifier who markets
a food substance before we issue our letter based on our evaluation of
the notice runs the risk that we may disagree with the conclusion of
GRAS status. (We note that a manufacturer who markets a food substance
without submitting a GRAS notice runs a similar risk.) However, we make
every effort to evaluate the data and information submitted on a timely
basis, and in this rule we commit to responding to a GRAS notice within
180 days after filing the notice, with the option to extend an
additional 90 days as needed. Because a substance that is GRAS under
the conditions of its intended use is not subject to premarket review
as a food additive under the FD&C Act, a notifier could decide to
introduce the substance into the market without waiting for the letter;
we could subsequently determine that the substance is an unapproved
food additive, and we may take action to remove the substance from the
food supply.
See also the discussion in Response 80. Our experience during the
Interim Pilot program demonstrates that we are willing to contact a
notifier to clarify particular aspects of a GRAS notice. As also
discussed in Response 80, under the final rule, we intend to contact a
notifier when we identify a safety concern. However, whether the
purpose of the contact is to provide an opportunity to address that
concern (e.g., in an amendment or in a newly submitted GRAS notice), or
to alert the notifier to our concerns while we prepare an
``insufficient basis letter,'' has been, and will continue to be, a
matter committed to our discretion depending on the totality of the
circumstances.
(Comment 36) One comment suggests that we ask notifiers who
previously received a ``no questions letter'' under the Interim Pilot
program to review their prior submissions and align them with the
requirements of the final rule.
(Response 36) We decline this suggestion. The final rule does not
pose any substantially different data requirements than did the Interim
Pilot program in terms of data quality and quantity to support the
conclusion of GRAS status. We do not anticipate, as a general matter,
the need to ask previous notifiers who received a ``no questions
letter'' to provide any supplemental information. However, if we become
aware of data or information that questions the GRAS status of the use
of a substance that has been the subject of a ``no questions letter,''
we may send the notifier a subsequent letter advising the notifier of
those questions (see Sec. 170.265(c)). Because we would make the
subsequent letter readily accessible to the public (see Sec.
170.275(b)(2)), other stakeholders would have ready access to those
questions.
(Comment 37) One comment states that GRAS ``determinations'' must
be evaluated based on adequate science and recommends that GRAS
``determinations'' comply with our guidance on food additive testing.
(Response 37) We agree that safe use(s) of a substance must be
supported by adequate science. We do have extensive guidance on food
additive testing (Ref. 31 through Ref. 35), and we agree that this
guidance on food additive testing can be useful in the evaluation of
the safety of a substance when the proponent of the substance seeks to
demonstrate that the substance is GRAS under the conditions of its
intended use. As discussed in Response 128, as resources allow we
intend to re-visit these scientific guidance documents to determine
whether and how to modify them to clarify that our guidance on
evaluating the safety of a food substance generally applies regardless
of whether the substance would be used in food as a food additive or as
a GRAS substance.
Recently, we issued a notice (79 FR 64603, October 30, 2014)
announcing a public meeting, and requesting comments, on our intent to
update our guidance entitled ``Guidance for Industry and Other
Stakeholders: Toxicological Principles for the Safety Assessment of
Food Ingredients'' (Ref. 35; commonly referred to as our ``Redbook'').
In that notice, we reiterated that general recognition of safety based
upon scientific procedures requires the same quantity and quality of
evidence as is required to approve a food additive. We also asked for
comment on how we should balance the desire for transparency and
consistency in risk assessment, as described in the Redbook, with the
goal of flexibility in applying the most appropriate analysis for
specific contexts.
(Comment 38) One comment states that the resource-intensive
petition process would be reserved for ingredients not eligible to meet
GRAS criteria, or those which pose questions necessitating indepth
review by FDA scientists, even though the safety standard for GRAS
ingredients and food additives is the same.
(Response 38) The comment is correct that a food additive petition
would be required for an ingredient that is not eligible for
classification as GRAS and is not otherwise excepted from the statutory
definition of a food additive. We agree that indepth review of the
safety of a substance under the conditions of its intended use in food
by FDA scientists is necessary when there is no basis for a conclusion
that the intended conditions of use have GRAS status. However, see
Response 25. Our evaluation of a GRAS notice is a substantive
evaluation even though we respond to a GRAS notice by letter rather
than by establishing a regulation.
(Comment 39) One comment asserts that we tentatively concluded that
the proposed notification procedure would allow us to direct our
resources to the more significant questions about GRAS status, without
further explaining what these ``more significant questions'' are. This
comment further asserts that the obvious conclusion is that we will
simply reduce the Federal layer of oversight in the interests of
efficiency and in doing so ignore the history of food law, which has
repeatedly shown
[[Page 54984]]
that the public suffers when FDA declines to regulate.
(Response 39) See the actions we describe in section I.D, on PHOs
and caffeinated alcoholic beverages, for examples of what we mean by
``more significant questions.'' We disagree that directing our
resources in such a manner reduces our oversight; on the contrary, such
actions demonstrate that we will take appropriate steps to address
concerns about the safety of substances marketed under the GRAS
provision of the FD&C Act. The comment provides no basis for its
assertion that the notification procedure ignores the history of food
law or that the public will suffer.
(Comment 40) One comment points out that our response to a GRAS
notice addresses the question of whether a particular use of a notified
substance is GRAS, without limiting that question to production of that
food substance by a specific manufacturer (e.g., the notifier who
submitted the GRAS notice). This comment asks us to require that any
other food producer who uses the substance in food on the basis of a
GRAS conclusion submitted to FDA in a GRAS notice meet all requirements
and specifications in the submitted GRAS notice, including use of the
same source for the production of the food substance.
(Response 40) The comment is correct that our response to a GRAS
notice would not limit a food producer other than the notifier from
relying on the submitted GRAS notice, and our response to that GRAS
notice, when that food producer concludes that a substance is GRAS
under the conditions of its intended use in food. The method of
manufacture (including any source specified for the production of the
notified substance) and specifications identified in a GRAS notice are
relevant to both the identity of the substance and its safety for use
in food. We advise any food producer who relies on a GRAS notice
submitted by another person to carefully consider whether its
production process, and/or the intended conditions of use of the
notified substance, fall within the parameters, such as method of
manufacture (including a specified source) and specifications,
addressed by the submitted GRAS notice. We recently issued guidance to
help food producers to do so. See our guidance entitled ``Assessing the
Effects of Significant Manufacturing Process Changes, Including
Emerging Technologies, on the Safety and Regulatory Status of Food
Ingredients and Food Contact Substances, Including Food Ingredients
that Are Color Additives'' (Ref. 6).
D. Comments on Certain Terms Used in the Proposed Regulatory Text
1. Replacing the Terms ``Determine'' and ``Determination'' With the
Terms ``Conclude'' and ``Conclusion''
In the 2010 notice, we explained our reasons for tentatively
concluding that the terms ``conclude'' and ``conclusion'' would be more
appropriate in lieu of ``determine'' and ``determination'' and
requested comment on these terms (see Issue 2, 75 FR 81536 at 81538).
(Comment 41) Many comments support replacing the terms
``determine'' and ``determination'' with the terms ``conclude'' and
``conclusion.'' One comment disagrees with changing the terms
``determine'' and ``determination.'' This comment asserts that the
terms ``determine'' and ``determination'' are more appropriate because
a determination is made based on the sum of the total assembled data
and conclusions. This comment also disagrees with changing the terms
because individuals who already are involved in the GRAS notification
procedure as a result of the Interim Pilot program are already familiar
with the terms and meanings of ``determine'' and ``determination.''
One comment observes that the terms ``determined'' and
``determination'' are used in Sec. 170.30 of our regulations within
the context of establishing GRAS status. This comment asks us to
clarify how we would apply the terms ``determined,'' ``determination,''
``conclude,'' and ``conclusion'' and whether we would limit how some
terms apply depending on whether a substance is the subject of a GRAS
notice. This comment expresses concern that such a distinction in terms
could lead to a misperception that a substance that is the subject of a
GRAS notice has a more authoritative and/or superior legal standing
than a substance that does not.
(Response 41) We are replacing the term ``determination'' with
``conclusion,'' and referring to a ``conclusion of GRAS status'' rather
than to a ``GRAS determination,'' throughout the regulatory text for
the GRAS notification procedure. We recognize that notifiers involved
with the GRAS notification procedure may be more familiar with the
terms ``determine'' and ``determination.'' Nevertheless, we believe
that as notifiers gain more experience with the GRAS notification
procedure set forth in this final rule, notifiers will adjust to using
``concludes'' and ``conclusion.''
We are making conforming changes to current regulations regarding
the use of GRAS substances in food to no longer use the terms
``determine'' and ``determination'' (see the changes to Sec. Sec.
170.3(k), 170.30(c)(1), and 170.30(e) in table 29). We are making these
conforming changes to clarify that there would be no distinction
between a conclusion of GRAS status submitted to us as a GRAS notice
and a conclusion of GRAS status that remains with its proponent as an
independent conclusion (formerly referred to as a ``self-
determination'') of GRAS status.
2. The Terms ``Exempt,'' ``Exemption,'' and ``Claim''
Several provisions in the proposed rule would use terms such as
``exempt,'' ``exemption,'' and ``claim.''
(Comment 42) Several comments object to some terms used in the
proposed procedure for submitting a GRAS notice. Some comments object
to proposed title for the GRAS notification procedure, i.e., ``Notice
of a claim for exemption based on a GRAS determination.'' Most of these
comments also object to our characterization of one of the proposed
provisions (proposed Sec. 170.36(c)(1)) as a ``GRAS exemption claim.''
In general, these comments assert that nothing in the FD&C Act or in
the legislative history of the FD&C Act supports designation of GRAS
status as an ``exemption.'' In addition, several comments object to our
use of the term ``claim'' in various proposed provisions because our
use of this term implies that we have legal authority to deny a claim
or that GRAS status is not operative unless a claim is filed.
(Response 42) We have made the following editorial changes
throughout the regulatory text to no longer use terms such as
``exempt,'' ``exemption,'' and ``claim.'' First, we replaced the term
``exempt'' with the phrase ``not subject to.'' Section 201(s) of the
FD&C Act provides that a substance that is GRAS under the conditions of
its intended use is not within the definition of food additive. Whether
the statutory GRAS provision in section 201(s) is an ``exemption,'' or,
is an ``exclusion,'' is not essential to this rulemaking and, thus, we
need not include any variations of the term ``exempt'' in the final
rule. Second, we replaced the term ``claim'' (when used as a noun) with
the term ``view.'' In the past, we have used the term ``view'' when
describing a statement or assertion that a use of a substance is GRAS
(see, e.g., 62 FR 36749, July 9, 1997). Finally, we simplified the
title of the regulatory text to ``Generally Recognized as Safe (GRAS)
Notice.''
[[Page 54985]]
E. Comments on the Use of ``Plain Language'' in the Regulatory Text
In the 2010 notice, we noted our intent to use ``Plain Language''
tools such as pronouns in the final rule (75 FR 81536 at 81537). The
use of ``Plain Language'' tools in government writing, now called
``plain writing,'' is consistent with the government-wide initiative to
promote transparency, public participation, and collaboration
throughout the Federal Government's programs and activities as set out
in ``Improving Electronic Dockets on Regulations.gov and the Federal
Docket Management System: Best Practices for Federal Agencies'' (Ref.
22).
(Comment 43) One comment recommends that we use Plain Language
throughout the regulatory text to foster greater understanding about
the regulatory requirements and expectations for the notification
procedure, leading to a more effective program.
(Response 43) We have used ``Plain Language'' tools (such as short
sections and the use of pronouns) throughout the regulatory text of
subpart E, which establishes the requirements for the GRAS notification
procedure. See table 4 for the section numbers and titles of the
redesignated regulatory text in subpart E.
Table 4--Redesignation of the GRAS Notification Procedure in Subpart E
------------------------------------------------------------------------
Section Title
------------------------------------------------------------------------
170.203.................. Definitions.
170.205.................. Opportunity to submit a GRAS notice.
170.210.................. How to send your GRAS notice to FDA.
170.215.................. Incorporation into a GRAS notice.
170.220.................. General requirements applicable to a GRAS
notice.
170.225.................. Part 1 of a GRAS notice: Signed statements
and certification.
170.230.................. Part 2 of a GRAS notice: Identity, method of
manufacture, specifications, and physical or
technical effect.
170.235.................. Part 3 of a GRAS notice: Dietary exposure.
170.240.................. Part 4 of a GRAS notice: Self-limiting levels
of use.
170.245.................. Part 5 of a GRAS notice: Experience based on
common use in food before 1958.
170.250.................. Part 6 of a GRAS notice: Narrative.
170.255.................. Part 7 of a GRAS notice: List of supporting
data and information in your GRAS notice.
170.260.................. Steps you may take before FDA responds to
your GRAS notice.
170.265.................. What FDA will do with a GRAS notice.
170.270.................. Procedures that apply when the intended
conditions of use of a notified substance
include use in a product or products subject
to regulation by FSIS.
170.275.................. Public disclosure of a GRAS notice.
170.280.................. Submission of a supplement.
170.285.................. Disposition of pending GRAS affirmation
petitions.
------------------------------------------------------------------------
VIII. Definitions Applicable to a GRAS Notice
A. Definitions We Described in the 2010 Notice
In the 2010 notice, we requested comment on definitions for the
terms ``amendment,'' ``notified substance,'' ``notifier,'' ``qualified
expert,'' and ``supplement'' (see Issue 3, 75 FR 81536 at 81538). We
received several comments that generally support adding definitions for
these terms, and we are establishing a section in the regulatory text
of subpart E to define these and other terms (see Sec. 170.203).
B. Definition of ``GRAS Notice''
(Comment 44) Some comments express concern about the potential for
confusion between the proposed GRAS notification procedure and another
FDA ``notification program'', i.e., the premarket notification program
for food contact substances (in part 170, subpart D) that we
established under FDAMA. These comments assert that this confusion can
lead to uncertainty about the nature of the proposed GRAS notification
procedure, such as with respect to market ``exclusivity'' for the
notified substance. One comment states that the terms ``GRAS notice''
and ``GRAS notification'' appear to be used interchangeably in the 2010
notice and asks whether it is our intention to use ``notice,''
``notification,'' or both terms with regard to the proposed procedure
for submission of a conclusion of GRAS status for a use of a food
substance.
Another comment notes that the proposed rule to establish a GRAS
notification procedure was followed soon thereafter by the rulemaking
to establish the premarket notification program for food contact
substances as authorized by FDAMA (the FCN program; proposed rule 65 FR
43269, July 13, 2000; final rule 67 FR 35724, May 21, 2002). This
comment asserts that although the proposed GRAS notification procedure
and the established FCN program are distinct, industry reasonably
relied on the close temporal proximity of the 1997 proposed rule to
establish a GRAS ``notification'' procedure, and the rulemaking to
establish the FCN program, as contemporaneous guidance for the meaning
of the term ``notification'' under FDAMA. Because the FCN program
provides market ``exclusivity'' for the food contact substance, the
comment asserts that it is understandable why regulated industry would
think that submitting a GRAS notice likewise implies ``exclusivity''
for the substance. The comment notes that FDA is not responsible for
misinterpretations made by industry, but asks us to recognize this lack
of transparency and clarity and remedy it in a fair and equitable
manner.
(Response 44) In the proposed rule and in this final rule, we use
the term ``notice'' as a noun to refer to the submission that you send
to us and we use the term ``notification'' as an adjective, e.g., to
modify the noun ``procedure.'' In contrast, the FCN program uses the
term ``notification'' as a noun in addition to using the term as an
adjective, consistent with FDAMA's use of the term as a noun. We
continue to use the term ``notification'' as an adjective (e.g., GRAS
notification procedure) in this preamble discussion of the requirements
for submitting a GRAS notice. However, in the regulatory text we only
use the term ``notice,'' and we have added a definition of the term
``GRAS notice'' to the regulatory text (see Sec. 170.203).
The ``exclusivity'' within the FCN program is provided by section
409(h)(2)(C) of the FD&C Act. See also our implementing regulation at
[[Page 54986]]
Sec. 170.100(a), which provides that a FCN is effective for the food
contact substance manufactured or prepared by the manufacturer or
supplier identified in the FCN submission. There is no similar
provision in the FD&C Act or our regulations providing exclusivity for
a substance that is used in food based on a conclusion that the
substance is GRAS under the conditions of its intended use.
C. Other Terms We Are Defining in the Rule
We are defining the abbreviation ``GRAS'' to mean ``generally
recognized as safe'' so that we can use that abbreviation throughout
the regulatory text without defining it in each section where it
appears. To clarify how pronouns apply in the regulatory text, we also
are specifying in the definition section that ``you'' and ``your''
refer to a notifier, and that ``we,'' ``our,'' and ``us'' refer to FDA.
IX. Opportunity To Submit a GRAS Notice
We proposed to provide that any person may notify FDA of a claim
that a particular use of a substance is exempt from the statutory
premarket approval requirements based on the notifier's determination
that such use is generally recognized as safe (GRAS) (proposed Sec.
170.36(a)). We are establishing this statement of an opportunity to
submit a GRAS notice in Sec. 170.205, with the editorial changes
described in Response 41 and Response 42.
X. Comments on Administrative Procedures for Submission of a GRAS
Notice
We proposed that a notice of a ``GRAS exemption claim'' be
submitted in triplicate to a specified address (proposed Sec.
170.36(b)). We also asked for comment on whether it would be
appropriate to require or recommend that the submission include an
electronic copy in addition to the three paper copies (62 FR 18938 at
18946) or, at a minimum, an electronic copy of the proposed ``GRAS
exemption claim'' (proposed Sec. 170.36(c)(1); final Sec. 170.225
(part 1 of a GRAS notice).
In the 2010 notice, we described comments asking us to permit a
notifier to reference a previously submitted GRAS notice to support a
view that an additional use of the applicable substance is GRAS. We
also discussed a coordinated evaluation process with FSIS when the use
of a notified substance includes use in products subject to regulation
by FSIS. (Note that the discussion in the 2010 notice referred to a
``coordinated review process.'' As discussed in Response 25, we are
using the term ``evaluation'' rather than ``review'' in connection with
GRAS notices. In addition, in a Memorandum of Understanding (MOU)
between FDA and FSIS (Ref. 36), we specify that we will inform the
notifier in writing that the notice will also be ``evaluated'' by FSIS
to determine the suitability of the use of the substance in the
production of meat, poultry, or egg products. Given the discussion in
Response 25 and the terms of the MOU with FSIS, in this document, we
use the term ``coordinated evaluation'' rather than ``coordinated
review.'') We asked for comment relevant to these administrative
procedures (see table 5).
Table 5--Issues in the 2010 Notice Relevant to Procedures for
Administering a GRAS Notice
------------------------------------------------------------------------
Description of
Issue No. our request for Reference
comment
------------------------------------------------------------------------
4......... Whether the final 75 FR 81536 at 81538.
rule should
include a
provision to
expressly permit
a notifier to
incorporate into
a GRAS notice
data and
information that
were previously
submitted by the
notifier, or
public data and
information
submitted by
another party,
when such data
and information
remain in our
files.
13........ Whether a 75 FR 81536 at 81541-81542.
notifier who
submits a GRAS
notice for such
a substance
should provide
an additional
paper copy or an
electronic copy
of the GRAS
notice that we
could send to
FSIS.
------------------------------------------------------------------------
Several comments support the administrative procedures that we
proposed or described in the 2010 notice. For example, several comments
support adding a provision to allow a notifier to incorporate
information into a GRAS notice, including data and information
previously submitted by the notifier and public data and information
submitted by another party, because such a provision would be
practical, promote administrative efficiency, or reduce paper. In the
following sections, we discuss comments that disagree with one or more
aspects of the administrative procedures that we proposed or described
as potential modifications in the 2010 notice (see, e.g., Comment 45);
ask us to clarify these administrative procedures (see, e.g., Comment
48 and Comment 49); or suggest one or more changes to these
administrative procedures (see, e.g., Comment 47). After considering
these comments, we are providing that you may submit a GRAS notice
either in electronic format that is accessible for our evaluation or on
paper; for paper submissions, a single paper copy of a GRAS notice is
sufficient.
We also are finalizing a provision to allow for incorporation into
a GRAS notice of data and information as described in the 2010 notice,
with clarification that the referenced data and information must be
specifically identified. As discussed in the 2010 notice, the provision
specifies that incorporation into a GRAS notice applies only when data
and information remain in our files. We do not retain records
indefinitely; rather, records may be retired to a Federal Records
Center and subsequently disposed of in accordance with our Records
Control Schedule.
A. How To Send a GRAS Notice to FDA
We proposed to specify in the regulatory text the address where you
would send a GRAS notice. We are finalizing this administrative
provision with updates to reflect the current mailing address and the
editorial changes described in Response 42. See the regulatory text in
Sec. 170.210(a).
(Comment 45) One comment asserts that a single GRAS notice to
either CFSAN or CVM should suffice to inform both Centers of a
conclusion of GRAS status.
(Response 45) We disagree. Our regulations directed to human food
are established in subchapter B of 21 CFR (i.e., Food For Human
Consumption, parts 100-199), whereas our regulations directed to animal
food are established in subchapter E of 21 CFR (i.e., Animal Drugs,
Feeds, And Related Products, parts 500-599). We have separately
established requirements applicable to GRAS substances for use in human
food in subchapter B of 21 CFR (e.g., in parts 170, 182, 184, and 186)
and requirements applicable to GRAS substances for use in animal food
in subchapter E of 21 CFR (e.g., in parts 570, 582, and 584). We also
had separately established requirements for the GRAS affirmation
petition process
[[Page 54987]]
(which the GRAS notification procedure is replacing) for substances for
use in human food in subchapter B of 21 CFR (i.e., in Sec. 170.35(c))
and requirements applicable to the GRAS affirmation petition process
for substances for use in animal food in subchapter E of 21 CFR (i.e.,
in Sec. 570.35(c)). We address food substances separately for human
use and for animal use because the safety evaluation of a food
substance relates to the conditions of its intended use, and the
conditions of use of a substance in human food can raise different
safety questions than the conditions of use of that same substance in
animal food. For example, a substance containing copper can be safely
used in human food and in food for many animal species, but even small
amounts of copper can be toxic to sheep. As another example, FDA has
affirmed that several uses of propylene glycol in human food are GRAS
(Sec. 184.1666), but propylene glycol is known to be toxic to cats and
FDA has prohibited its use in cat food (see Sec. 589.1001). Therefore,
the final rule establishes separate (albeit parallel) requirements for
submission of a GRAS notice to CFSAN for the use of a substance in
human food and for submission of a GRAS notice to CVM for the use of a
substance in animal food.
B. Option for Submission of Electronic or Paper Copies of a GRAS Notice
(Comment 46) Most of the comments that responded to our request for
comment on the submission of an electronic copy of a GRAS notice
encourage us to recommend, but not require, submission of an electronic
copy, explaining that an electronic copy would make our administration
of the notification procedure more efficient. However, one comment
notes that electronic technology may not be universally available. As
discussed in Comment 47, another comment expresses concern about
protection for confidential information in an electronic copy. One
comment suggests that if we use an electronic means to make GRAS
notices readily accessible to the public, then we should require that
the submission include an electronic copy. Comments that address Issue
13 support requiring the notifier to provide an additional paper copy
that we would send to FSIS as part of this procedure.
(Response 46) We agree that an electronic copy will make our
administration of the GRAS notification procedure more efficient. For
example, an electronic copy generated from a word processing format
generally is searchable without the need for Optical Character
Recognition techniques, but an electronic copy generated by scanning a
paper document into ``Portable Document Format'' (``pdf'') requires
Optical Character Recognition before it can be searched electronically.
Furthermore, the Government Paperwork Elimination Act of 1998 (Pub. L.
105-277, Title XVII) requires Federal agencies to give persons who
correspond with these agencies the option of doing so electronically
when practicable as a substitute for paper, and to use electronic
authentication (electronic signature) methods to verify the identity of
the sender and the integrity of the electronic content. We acknowledge
that technology may not be available to every notifier and, thus, the
final rule does not require the submission of an electronic copy.
Instead, the final rule provides that when you submit your GRAS notice,
you may do so either in electronic format that is accessible for our
evaluation or on paper (see Sec. 170.210(b)). Because you have an
option to submit a GRAS notice either electronically or on paper, an
electronic copy will essentially replace the need for a paper copy. In
2010, CFSAN issued draft guidance for how to transmit a submission,
including a GRAS notice, in electronic format (Ref. 37).
We used electronic means to make submitted GRAS notices accessible
to the public during the Interim Pilot program, and intend to continue
to do so under the final rule. However, we decline the request to
require that the submission include an electronic copy solely because
we are doing so. We acknowledge that an electronic copy will improve
the efficiency with which we make GRAS notices available to the public
(see the public disclosure provisions of this rule in Sec. 170.275).
However, during the Interim Pilot program we made an electronic copy of
a submitted GRAS notice available on the Internet by scanning the paper
GRAS notice to create an electronic pdf document, and we intend to
continue to do so when you submit a GRAS notice on paper under the
final rule.
We have decided that a single copy of a GRAS notice that is
submitted on paper is acceptable (rather than the three copies that we
proposed to require) and have specified that a single paper copy is
sufficient in the regulatory text (Sec. 170.210(b)). We proposed to
require three copies of a submitted GRAS notice to make it easier to
provide a paper copy of the GRAS notice to all members of our staff who
will evaluate the GRAS notice. However, in practice during the Interim
Pilot program we developed internal procedures in which we scan a GRAS
notice submitted on paper to create an electronic pdf version of the
GRAS notice, and we make the electronic pdf document available to all
staff who will evaluate the GRAS notice. This procedure has reduced the
resources needed to distribute the GRAS notice to our staff, and we
intend to continue to use this procedure when we receive a GRAS notice
on paper. When we coordinate our evaluation of a GRAS notice with FSIS,
we send an electronic copy to FSIS and, thus, an additional paper copy
for use by FSIS is not necessary.
(Comment 47) One comment expresses concern about the security of
confidential information in an electronic submission. This comment asks
us to allow a notifier to edit an electronic copy to remove
confidential information and present that information only in the paper
copy. Another comment asks us to provide the same protections that
would apply to confidential information in written records to
confidential information in electronic records.
(Response 47) We decline the request to allow you to edit an
electronic copy of your GRAS notice such that the electronic copy would
differ from the paper copy. If you have concerns about the security of
confidential information in an electronic submission, you have the
option to send the GRAS notice on paper (see Response 46). The
protections applicable to confidential information are the same
regardless of whether the information is in written or electronic form
(see part 20, ``Public Information''). In particular, under Sec.
20.20(e), ``Policy on disclosure of Food and Drug Administration
records,'' the term ``record'' (as well as any other term used in Sec.
20.20 in reference to information) includes any information that would
be an agency record maintained by the Agency in any format, including
an electronic format.
In addition, the final rule requires you to state in writing your
view as to whether any of the data and information in your GRAS notice
are exempt from disclosure under FOIA (e.g., as trade secret or as
commercial or financial information that is privileged or confidential)
(see Sec. 170.225(c)(8)). The final rule also requires that if you
view any of the data and information in your GRAS notice as exempt from
disclosure under FOIA, you must identify the specific data and
information (Sec. 170.250(d)). Together, these provisions will give us
notice as to whether we will need to evaluate specific data and
information under the FOIA and take steps to protect applicable data
and information from public disclosure.
[[Page 54988]]
C. Incorporation Into a GRAS Notice
(Comment 48) One comment supports adding a provision to allow a
notifier to incorporate data and information into a GRAS notice as long
as the notifier has explicit first-hand knowledge of the referenced
files. Other comments address the limitation, discussed in the 2010
notice, that data and information that are submitted by a person other
than the notifier must be public, noting that it would be difficult to
prevent the use of public information by others or that incorporating
such data and information into a GRAS notice would be consistent with
the criteria for general recognition of safety.
(Response 48) A notifier must have sufficient knowledge of data and
information submitted by another party to be able to identify the
specific data and information that would be incorporated into a GRAS
notice. To make this clear, the provision we are adding to the rule to
allow for incorporation of data and information into a GRAS notice
requires that such data and information be specifically identified. For
example, we expect you to provide a specific file number (e.g., for a
GRAS notice or a food additive petition) that contains the referenced
data and information, and to identify the specific data and information
in that file (rather than to broadly incorporate into a GRAS notice the
entire file without explaining which data and information to
incorporate). Although you may also incorporate into a GRAS notice a
``food master file'' (provided that you specifically identify both the
file number and the data and information in that file that you are
asking us to incorporate into a GRAS notice), the regulatory text does
not include ``food master file'' as an example of the type of file that
you may reference because we do not have a regulatory definition for
``food master file.'' See the discussion of ``food master file'' in
Response 49.
A notifier also must have sufficient knowledge of data and
information submitted by another party to be able to discuss these data
and information in the narrative that is required in part 6 of a GRAS
notice (see Sec. 170.250). This narrative must explain the basis for
the notifier's view that the notified substance is safe under the
conditions of its intended use and that GRAS criteria--for both general
availability and general acceptance--are satisfied. In other words, a
GRAS notice must present the independent conclusions of the notifier
regarding the basis for GRAS status, even if the data and information
on which the notifier relies were submitted by another person.
Consistent with the discussion in the 2010 notice, the provision we
are adding to allow for incorporation of data and information into a
GRAS notice specifies that data and information submitted by another
party must be ``public.'' By ``public,'' we mean data and information
that we have provided (or would provide) in response to a request under
the FOIA, or that are otherwise publicly available (e.g., in a docket).
Consistent with the views expressed in the comments, we see no reason
to preclude you from referring us to such public information when we
already have such information in our files, provided that you identify
the specific data and information and the file(s) containing these data
and information. We would not, for example, search our files to look
for the referenced data and information. However, if you intend to
incorporate into a GRAS notice data and information that were submitted
by another party, and that you believe to be public information, we
recommend that you explain the basis for your view that the data and
information are public. If we need to evaluate the status of the data
and information under the FOIA (e.g., because the data and information
have not previously been disclosed to the public), we may decline to
file the GRAS notice until we have evaluated the status of the
referenced data and information under the FOIA. Doing so would be
appropriate in light of the perspective of the comments, as discussed
in the 2010 notice, that the process of incorporation would be
administratively efficient (75 FR 81536 at 81538) and the limited time
(i.e., 180 days) that we have to respond after we file a submission as
a GRAS notice (see Sec. 170.265(b)). A notifier who intends to
incorporate data and information that we must evaluate under the FOIA
before we determine whether the data and information can be disclosed
under the FOIA may find it advantageous to request those data and
information under our public information procedures (see part 20), and
then either include the data and information we disclose in response to
that request in the submitted GRAS notice, or refer us to
administrative information identifying the completed FOIA request when
asking us to incorporate the data and information into a GRAS notice.
(Comment 49) One comment states its presumption that a ``food
master file'' is not available for public viewing, referring to a
``long-standing center policy'' that such files are confidential. This
comment asks us to continue to provide that a ``food master file'' be a
confidential repository for proprietary data, such as utility and
manufacturing information.
(Response 49) We establish a ``food master file'' for a variety of
reasons. For example, a person who submits a food additive petition may
need us to evaluate data and information regarding a substance that the
petitioner purchases from another party for use in the manufacture of
the food additive. The petitioner may ask the manufacturer of that
substance to provide the applicable data and information to us, and we
then place the submitted data and information in a food master file.
Although some or all of the data in such a food master file may be
exempt from public disclosure (e.g., as trade secret information or
confidential commercial information), a determination of whether
specific data and information in a food master file is exempt from
public disclosure is based on the status of the data and information
under FOIA rather than on the type of file in which we place the data
and information. We do not limit the type of data and information that
may be included in a food master file to proprietary data and
information.
See also Sec. 170.215 and Response 48. Data and information
submitted by a party other than a notifier must be public information.
If you previously submitted a food master file to us, and you view the
data and information in your food master file as proprietary, you must
explain in part 6 of your GRAS notice how GRAS criteria are satisfied
(see Sec. 170.250(e)).
XI. General Requirements Applicable to a GRAS Notice
The final rule specifies two general provisions applicable to a
GRAS notice (see Sec. 170.220). As discussed in Response 43, we have
redesignated the single proposed section (i.e., proposed Sec. 170.36)
into several distinct, short sections of regulatory text in a newly
established subpart E (GRAS Notice). The first general provision
specifies that a GRAS notice has seven parts, refers the user to the
regulatory text for each of these parts, and specifies that you must
submit the information specified in each of these parts on separate
pages or sets of pages (Sec. 170.220 (a)). Submitting the information
on separate pages or sets of pages is consistent both with the guidance
we developed for preparation of a GRAS notice in electronic format
(Ref. 37) and with long-standing requirements for other regulatory
submissions, such as a food additive petition (see Sec. 171.1(f)) and
a health claim petition (see Sec. 101.70(g)).
[[Page 54989]]
The second general provision specifies that you must include each
of the seven parts; if a part is not included, you must include an
explanation of why that part does not apply to your GRAS notice (Sec.
170.220 (b)). We added this provision because some parts of a GRAS
notice (e.g., Part 4 (self-limiting levels of use) and Part 5
(experience based on common use in food before 1958)) would not apply
to most GRAS notices. Specifying that Parts 4 and 5 do not apply to a
particular GRAS notice will make it clear that a notifier is aware of
the requirements of those parts and has acknowledged that they do not
apply.
XII. Comments on Part 1 of a GRAS Notice: Signed Statements and
Certification
We proposed that a GRAS notice must include a dated and signed
claim that a particular use of a substance is exempt from the premarket
approval requirements of the FD&C Act because the notifier has
determined that such use is GRAS. The proposed ``GRAS exemption claim''
would include: (1) The name and address of the notifier; (2) the common
or usual name of the notified substance; (3) the applicable conditions
of use of the notified substance, including the foods in which the
substance is to be used, levels of use in such foods, and the purposes
for which the substance is used, including, when appropriate, a
description of the population expected to consume the substance; (4)
the basis for the GRAS determination (i.e., through scientific
procedures or through experience based on common use in food); and (5)
a statement that the data and information that are the basis for the
notifier's GRAS determination are available for our review and copying
at reasonable times at a specific address set out in the notice or will
be sent to us upon request (proposed Sec. 170.36(c)(1)). In the 2010
notice, we requested comment on several issues relevant to the proposed
``GRAS exemption claim'' (see table 6).
As discussed in Response 42, we have made editorial changes
throughout the rule to replace the term ``exempt'' with the phrase
``not subject to'' and to replace the term ``claim'' (when used as a
noun) with the term ``view.'' In light of these editorial changes, in
the remainder of this section we generally use the term ``proposed
signed statements'' (rather than ``GRAS exemption claim'') when
referring to the provisions that we had proposed to include in proposed
Sec. 170.36(c)(1)).
Table 6--Issues in the 2010 Notice Regarding the Proposed Signed
Statements in a GRAS Notice
------------------------------------------------------------------------
Description of
Issue No. our request for Reference
comment
------------------------------------------------------------------------
6a........ How to best 75 FR 81536 at 81539.
ensure that the
identity and
authority of the
person who is
signing the GRAS
notice is made
clear.
6b........ Whether to 75 FR 81536 at 81539.
require that a
notifier submit
a statement that
to the best of
his knowledge,
the GRAS notice
is a
representative
and balanced
submission that
includes
unfavorable
information, as
well as
favorable
information,
known to him and
pertinent to the
evaluation of
the safety of
the substance.
6b........ Whether to 75 FR 81536 at 81539.
require a
notifier to
certify to the
statement
(described in
Issue 6a)
regarding the
representative
and balanced
nature of the
GRAS notice.
7......... Whether to 75 FR 81536 at 81539.
require that the
GRAS notice
include the name
of the notified
substance, using
an appropriately
descriptive
term, instead of
the ``common or
usual name'' of
the notified
substance.
8......... Whether to 75 FR 81536 at 81539.
explicitly
require that the
information
submitted in the
``GRAS exemption
claim'' exclude
non-public
information.
9b *...... Whether to 75 FR 81536 at 81540.
require that a
notifier who
identifies one
or more trade
secret(s) in the
GRAS notice
explain why it
is trade secret
information and
how qualified
experts could
conclude that
the intended use
of the notified
substance is
safe without
access to the
trade secret(s).
9c *...... Whether to 75 FR 81536 at 81540.
require that a
notifier who
identifies
confidential
commercial or
financial
information in
the GRAS notice
explain why it
is confidential
commercial or
financial
information and
how qualified
experts could
conclude that
the intended use
of the notified
substance is
safe without
access to such
information.
13........ Whether to make 75 FR 81536 at 81541-81542.
our coordinated
evaluation
process with
FSIS explicit in
the final rule.
------------------------------------------------------------------------
* In the 2010 notice, Issues 9b and 9c asked how qualified experts could
conclude that the intended use of the notified substance is ``GRAS''
rather than ``safe.'' However, the qualified experts evaluate safety
rather than GRAS status; the person who is responsible for the
conclusion of GRAS status considers the view of the qualified experts
on safety in reaching the conclusion that GRAS criteria are satisfied.
In the remainder of this document, we describe Issues 9b and 9c with
respect to whether qualified experts could conclude that the intended
use of the substance is ``safe'' rather than ``GRAS.''
In general, comments directed to the proposed signed statements
agree that we should modify the provisions as discussed in Issues 6a,
6b, 7, 8, 9a, 9b, 9c, and 13 in the 2010 notice. In the following
sections, we discuss comments that address the issues discussed in the
2010 notice (see, e.g., Comment 50, Comment 51, Comment 57, Comment 58,
and Comment 59); address provisions of the proposed signed statements
that we did not discuss in the 2010 notice (see, e.g., Comment 53); ask
us to clarify how we will interpret the provisions of the proposed
signed statements and potential modifications (see, e.g., Comment 54
and Comment 55); or suggest one or more changes to the proposed signed
statements and potential modifications (see, e.g., Comment 52, Comment
56, and Comment 59). After considering these comments, we are
establishing requirements for Part 1 of a GRAS notice to include
certain signed statements and a certification as shown in table 7, with
editorial, clarifying, and conforming changes as shown in table 29.
(See Sec. 170.225.) Table 7 identifies changes we made relative to the
proposed rule or the description in the 2010 notice other than the
editorial, clarifying, and conforming changes shown in table 29 and the
additional editorial changes associated with the redesignation of
proposed Sec. 170.36(c)(1) as Sec. 170.225.
We did not receive comments disagreeing with the proposed
requirement for a GRAS notice to: (1) Be dated and signed by a
responsible official of your organization, or by your attorney or
agent; (2) provide your name and address; and (3) provide the
applicable conditions of use of the notified substance. Therefore, we
are establishing those requirements in the rule (see Sec.
170.225(c)(1), (2), and (4)).
[[Page 54990]]
See Comment 42 for our discussion of comments on the terms used in
final Sec. 170.225(c)(6), in which you inform us of your view that the
notified substance is not subject to the premarket approval
requirements of the FD&C Act based on your conclusion that the
substance is GRAS under the conditions of its intended use; see
Response 42 for the editorial changes we made in response to those
comments.
Table 7--Final Requirements for Signed Statements and a Certification in Part 1 of a GRAS Notice
----------------------------------------------------------------------------------------------------------------
Revisions (other
than editorial,
Proposed Issue No. in Description. Part 1 clarifying, and
Final designation in the designation in the the 2010 of your GRAS conforming changes)
regulatory text (Sec. ) regulatory text notice notice: relative to the
(Sec. ) proposed rule or
the 2010 notice
----------------------------------------------------------------------------------------------------------------
170.225(a)....................... 170.36(c)(1)....... N/A Must be dated and N/A.
signed by a
responsible
official of your
organization, or
by your attorney
or agent.
170.225(b)....................... N/A................ 8 Must not include Makes an exception
any information for Sec.
that is trade 170.225(c)(8),
secret or which requires you
confidential to state your view
commercial as to whether any
information. of the data and
information in
Parts 2 through 7
of your GRAS
notice are exempt
from disclosure
under the FOIA.
170.225(c)(1).................... N/A................ N/A Informs us that you N/A.
are submitting a
GRAS notice in
accordance with
subpart E.
170.225(c)(2).................... 170.36(c)(1)(i).... N/A Provides the name N/A.
and address of
your organization.
170.225(c)(3).................... 170.36(c)(1)(ii)... 7 Provides the name N/A.
of the notified
substance, using
an appropriately
descriptive term.
170.225(c)(4).................... 170.36(c)(1)(iii).. N/A Describes the Uses the term
intended ``subpopulation''
conditions of use rather than
of the notified ``population''.
substance,
including the
foods in which the
substance will be
used, the levels
of use in such
foods, and the
purposes for which
the substance will
be used,
including, when
appropriate, a
description of a
subpopulation
expected to
consume the
substance.
170.225(c)(5).................... 170.36(c)(1)(iv)... N/A Informs us of the Specifies
statutory basis that a conclusion
for your of GRAS status
conclusion of GRAS through scientific
status (i.e., procedures is in
through scientific accordance with
procedures or both Sec.
through experience 170.30(a) and (b).
based on common Specifies
use in food). that a conclusion
of GRAS status
through experience
based on common
use in food is in
accordance with
both Sec.
170.30(a) and (c).
170.225(c)(6).................... 170.36(c)(1)....... 2 States your view See Response 42.
that the notified
substance is not
subject to the
premarket approval
requirements of
the FD&C Act based
on your conclusion
that the substance
is GRAS under the
conditions of its
intended use.
170.225(c)(7).................... 170.36(c)(1)(v).... N/A States your You agree to a
agreements procedure in which
regarding making we can access data
data and and information
information ``during customary
available to us business hours''
upon our request. rather than ``at
reasonable
times''.
170.225(c)(8).................... N/A................ 9 States your view as N/A.
to whether any of
the data and
information in
Parts 2 through 7
of your GRAS
notice are exempt
from disclosure
under the FOIA.
170.225(c)(9).................... 170.36(c)(4)....... 6b Certifies that, to Specifies that your
the best of your GRAS notice is
knowledge, your ``complete'' in
GRAS notice is a addition to
complete, ``representative''
representative, and ``balanced''.
and balanced
submission that
includes
unfavorable
information, as
well as favorable
information, known
to you and
pertinent to the
evaluation of the
safety and GRAS
status of the use
of the substance.
170.225(c)(10)................... 170.36(c)(1)....... 6a States both the N/A.
name and position
or title of the
person who signs
the GRAS notice.
[[Page 54991]]
170.225(c)(11)................... N/A................ 13 When applicable, We added a
states whether statement
you: (1) Authorize communicating how
us to send any you want us to
trade secrets to handle trade
FSIS; or (2) ask secret information
us to exclude any in a copy of a
trade secrets from GRAS notice that
the copy of the we send to FSIS.
GRAS notice that
we will send to
FSIS.
----------------------------------------------------------------------------------------------------------------
A. Exclusion of Trade Secret and Confidential Commercial Information
From the Signed Statements
(Comment 50) Several comments support a provision specifying that
information submitted in the signed statements exclude non-public
information. One of these comments states that the information in the
signed statements should be publicly disclosed because public
disclosure is critical to the continued success of the GRAS program,
and that for the use of a substance to be ``generally recognized as
safe'' the data and research supporting a conclusion of GRAS status
must be available for public view. Other comments disagree that non-
public information should be excluded from the signed statements and
assert that the final rule should allow for the submission of limited
amounts of non-public information at the discretion of the notifier or
when necessary to clarify the safety of the notified substance for the
purposes of our evaluation. These comments emphasize we should take
care to remove such non-public information from any public disclosure
or, or at a minimum, discuss or clear our intent to disclose non-public
information with the notifier before disclosing it.
(Response 50) Some of these comments appear to misinterpret the
reach of our request for comment in Issue 8 in the 2010 notice. We
narrowly directed Issue 8 to the signed statements that would provide
the name and address of the notifier; the name of the notified
substance; the applicable conditions of use of the notified substance;
the statutory basis for the conclusion of GRAS status; and agreement to
make the data and information that are the basis for the notifier's
conclusion of GRAS status available for our review and copying. The
signed statements provide administrative information rather than safety
information and, as discussed in the 2010 notice, we extract notice-
specific information from the signed statements for the purpose of
informing the public about GRAS notices that we are evaluating.
However, some comments seem to be addressing the issue of whether other
sections of a GRAS notice (e.g., Part 2 of a GRAS notice (in which a
notifier describes the method of manufacture of the notified substance)
and Part 6 of a GRAS notice (in which a notifier discusses the safety
of the notified substance)) can include non-public information.
Consistent with our request for comment in Issue 8, the final rule
specifies that a notifier must not include any information that is
trade secret or confidential commercial information in Part 1 of a GRAS
notice, except in the statement in Sec. 170.225(c)(8) (see Sec.
170.225(b) and the discussion of Sec. 170.225(c)(8) in Response 57).
This provision does not preclude a notifier from including non-public
information in other parts of a GRAS notice. However, if a notifier
views any submitted data and information as exempt from disclosure
under the FOIA then that notifier must identify the specific data and
information, and explain how there could be a basis for a conclusion of
GRAS status if qualified experts generally do not have access to those
data and information (see Sec. 170.250(d) and (e)). Section 170.250(d)
and (e) is consistent with the criteria for eligibility for
classification as GRAS, because: (1) The criteria provide that general
recognition of safety may be corroborated by unpublished information;
and (2) the notifier has a burden to explain how GRAS criteria are
satisfied given that certain data and information in the GRAS notice
are trade secret or confidential commercial information.
See section XIII.B for a discussion of comments regarding including
non-public information in part 2 of a GRAS notice (particularly with
respect to the method of manufacture). Regarding whether we would
``clear our intent'' to disclose non-public information with the
notifier before disclosing it, see Response 70. Regarding how we treat
non-public information in a GRAS notice, see section XXI regarding the
provisions of the final rule regarding public disclosure of information
in a GRAS notice. Under Sec. 170.275(c), we will disclose information
that is not exempt from public disclosure in accordance with part 20.
B. Name of the Notified Substance, Using an Appropriately Descriptive
Term
(Comment 51) Some comments agree that the signed statements should
identify the name of the notified substance using an ``appropriately
descriptive term'' instead of the ``common or usual name,'' and also
agree with our statement in the 2010 notice that the ``appropriately
descriptive term'' may be the same as the common or usual name of the
substance in some circumstances (75 FR 81536 at 81539). One comment
disagrees and asks us to continue to specify that the signed statements
in a GRAS notice identify the name of the notified substance using the
common or usual name of the notified substance. This comment recommends
that a notifier work with us to establish the common or usual name of
the notified substance if the common or usual name is not known or well
defined. This comment also asks us to include the common or usual name
of the notified substance in any ``no questions letter'' from us to
make the common our usual name clear to the public. A few comments
support requiring that the signed statements include both the common or
usual name of the notified substance, as well as an appropriately
descriptive term for the notified substance. One comment asks us to
continue the practice, described in the 2010 notice (75 FR 81536 at
81539), of reminding notifiers that our response to a GRAS notice
should not be considered an endorsement for any given term for the
purpose of complying with the labeling provisions of the FD&C Act.
[[Page 54992]]
(Response 51) The final rule requires that you provide the name of
the notified substance, using an appropriately descriptive term, in
Part 1 of your GRAS notice (Sec. 170.225(c)(3)). The appropriately
descriptive term may be the same as the common or usual name of the
substance under our labeling regulations (see 21 CFR 102.5). We decline
the request to use resources that we are directing to the evaluation of
the safety and regulatory status of food substances under sections 201
and 409 of the FD&C Act to also address the labeling requirements of
the FD&C Act given the limited time (i.e., 180 days) that we have to
respond (see Sec. 170.265(b)). You may consult with our staff in
operating divisions that address the labeling requirements of the FD&C
Act, currently CFSAN's Office of Nutrition and Food Labeling (for human
food); however, doing so would be a separate process from the GRAS
notification procedure. (See section XXV.C for contact information for
CVM.)
C. Intended Conditions of Use of the Notified Substance
We did not receive comments disagreeing with the proposed
requirement for the signed statements in a GRAS notice to include the
applicable conditions of use of the notified substance, including the
foods in which the substance is to be used, levels of use in such
foods, and the purposes for which the substance is used, including,
when appropriate, a description of the population expected to consume
the substance, and we are establishing this requirement in the final
rule (see Sec. 170.225(c)(4)). As noted in table 29, the final rule
refers to the ``intended conditions of use'' rather than the
``applicable conditions of use'' for consistency with other provisions
in the rule. The final rule also uses the term ``subpopulation'' rather
than ``population'' to provide more context about when it would be
appropriate to specify the expected consumers of a food. Most foods are
broadly available to all consumers; a few are more specifically
targeted to particular subpopulations, such as persons with specific
dietary needs (such as persons on liquid diets or persons with
conditions like phenylketonuria), infants consuming infant formula, and
persons seeking alternatives to commonly used food ingredients (such as
persons on a gluten-free diet).
D. Statutory Basis for the Conclusion of GRAS Status
(Comment 52) Some comments ask us to modify the rule to provide
that the statutory basis for a conclusion of GRAS status may be through
scientific procedures, through experience based on common use in food,
or through both scientific procedures and experience based on common
use in food. These comments assert that many conclusions of GRAS status
are based on both statutory criteria.
(Response 52) We disagree that this modification is needed. The
final rule does not prevent you from basing your conclusion of GRAS
status on both statutory criteria. Importantly, if you assert that your
conclusion of GRAS status is based on both statutory criteria, you must
fully support each conclusion and address all requirements of the rule
regarding each conclusion; partial support for each of the two
statutory criteria for a conclusion of GRAS status is not adequate. You
could not, for example, assert that a substance is GRAS under the
conditions of its intended use through scientific procedures, but
``fill in data gaps'' by also asserting that the substance was commonly
used in food before 1958. Likewise, you could not assert that a
substance is GRAS under the conditions of its intended use through
experience based on common use in food if you cannot provide evidence
of a substantial history of consumption of the notified substance for
food use by a significant number of consumers prior to January 1, 1958.
These comments highlight the importance of fully supporting a
conclusion of GRAS status through each of the statutory criteria.
Because the general criteria in Sec. 170.30(a), as well as the
specific criteria in Sec. 170.30(b) or (c), must be satisfied to
support a conclusion of GRAS status, the final rule specifies that a
conclusion of GRAS status through scientific procedures is in
accordance with both Sec. 170.30(a) and (b) and that a conclusion of
GRAS status through experience based on common use in food is in
accordance with both Sec. 170.30(a) and (c).
E. Agreement To Make Data and Information Available Upon Request
(Comment 53) Some comments recommend that there be a means for us
to request non-public information if we deem it necessary for our
evaluation of the intended conditions of use of the notified substance,
provided that the information can be considered as confidential and
protected from disclosure.
(Response 53) These comments appear to misinterpret the reach of
the proposed requirement to agree to provide us access to data and
information that a notifier relies on to support a conclusion of GRAS
status. Some of the data and information that we may ask to see during
our evaluation of a GRAS notice may be ``public'' data and information
in that it would be data and information that we would provide in
response to a request under the FOIA (see Response 48), even though it
may not have been disseminated to the public (e.g., in the scientific
literature or on the Internet (e.g., when a science-based organization
uses the Internet to disseminate scientific or technical information or
recommendations)). If we receive data and information that are non-
public, such data and information would be protected from public
disclosure in accordance with part 20.
(Comment 54) One comment states that the phrase ``at reasonable
times'' refers not only to hours of a day, but also to a reasonable
amount of time following the submission of a GRAS notice. This comment
recommends that ``several years (for example, five years)'' after
submission of a GRAS notice would be a reasonable time for notifiers to
retain such data and information in their active files.
(Response 54) By ``at reasonable times,'' we meant the time of day
that we would have access to data and information you retained but did
not include in your GRAS notice. To clarify that the requirement
relates to the time of day rather than to the timeframe for retaining
the data and information, the final rule specifies that you agree to a
procedure in which we can access data and information ``during
customary business hours'' rather than ``at reasonable times.''
As previously discussed (62 FR 18938 at 18951), we may, at some
point after our response to a GRAS notice, receive additional
information about a notified substance that raises questions about the
safety of that substance. To address this possibility, the rule
specifies that we will send you a subsequent letter about your GRAS
notice if circumstances warrant (see Sec. 170.265(c)). Although the
rule does not specify any timeframe to retain the data and information
that support your conclusion of GRAS status, preservation of the data
and information that are the basis for the conclusion of GRAS status
represents prudent practice for those who claim an exclusion from a
statutory requirement regardless of whether the person subsequently
notifies us (62 FR 18938 at 18947).
(Comment 55) One comment asks us to clarify that electronic records
are acceptable for documenting the data and information that support a
conclusion of GRAS status.
[[Page 54993]]
(Response 55) Electronic records are acceptable for documenting the
data and information that support a conclusion of GRAS status. If we
ask you to send us such data and information for a notified substance
that would be used in human food, we recommend that you do so by
following the instructions in CFSAN's guidance entitled ``Guidance for
Industry: Providing Regulatory Submissions in Electronic or Paper
Format to the Office of Food Additive Safety'' (Ref. 37), which
includes instructions for making an electronic submission through our
Electronic Submission Gateway, as well as on media that we can access
on our network computers. CFSAN's procedures for making an electronic
submission through our Electronic Submission Gateway use a form that
CFSAN developed for a GRAS notice when a substance would be used in
human food (i.e., Form FDA 3667) (Ref. 38). Form FDA 3667 prompts a
notifier to include certain elements of a GRAS notice in a standard
format. The form, and elements that would be prepared as attachments to
the form, may be submitted in electronic format via the Electronic
Submissions Gateway, as electronic files on physical media, or in paper
format. At this time, we cannot accept media such as thumb drives,
which can present a security risk.
(Comment 56) One comment asks us to develop criteria for the
required documentation underlying industry conclusions of GRAS status.
(Response 56) We are not establishing criteria in the rule for the
documentation a notifier would have regarding a conclusion of GRAS
status. Regardless of whether a person who concludes that a use of a
food substance is GRAS notifies us, the applicable documentation would
address the safety of the substance as described in the definition of
``safe'' or ``safety'' (see Sec. 170.3(i)); as applicable, the
definition of ``common use in food'' (see Sec. 170.3(f) and/or the
definition of ``scientific procedures'' (Sec. 170.3(h)); and the
criteria for general recognition of safety (see Sec. 170.30)).
F. Statements and Any Applicable Explanation Regarding Data and
Information That a Notifier Views as Exempt From Disclosure Under FOIA
In Issue 9 in the 2010 notice (75 FR 81536 at 81539-81540), we
discussed three issues regarding confidential data and information that
are included in a GRAS notice. See table 8. Most of the comments that
address Issue 9 address Issue 9a, particularly with respect to how we
would protect trade secret or confidential commercial information from
public disclosure. See sections XIII.B and XXI.C for a discussion of
those comments, and our response to those comments. In the following
paragraphs, we discuss comments on Issues 9b and 9c, and respond to
those comments.
Table 8--Issues in the 2010 Notice Regarding Confidential Data and
Information in a GRAS Notice
------------------------------------------------------------------------
Description of
Issue No. our request for Reference
comment
------------------------------------------------------------------------
9a........ Whether the final 75 FR 81536 at 81539-81540.
rule should
stipulate that
the method of
manufacture
exclude any
trade secrets,
as we proposed.
9b........ Whether to 75 FR 81536 at 81539-81540.
require that a
notifier who
identifies one
or more trade
secret(s), as
defined in Sec.
20.61(a), in
the GRAS notice
explain why it
is trade secret
information and
how qualified
experts could
conclude that
the intended use
of the notified
substance is
safe without
access to the
trade secret(s).
9c........ Whether to 75 FR 81536 at 81539-81540.
require that a
notifier who
identifies
confidential
commercial or
financial
information, as
defined in Sec.
20.61(b), in
the GRAS notice
explain why it
is confidential
commercial or
financial
information and
how qualified
experts could
conclude that
the intended use
of the notified
substance is
safe without
access to such
information.
------------------------------------------------------------------------
(Comment 57) One comment supports the recommendation we made in the
proposed rule for a notifier who considers that certain information in
a submission should not be available for public disclosure to identify
as confidential the relevant portions of the submission for our
consideration (62 FR 18938 at 18952). Those comments that address
Issues 9b and 9c agree with the outcome of our discussion, in the 2010
notice, that we should require that a notifier who identifies a trade
secret or confidential commercial information explain why it is a trade
secret or confidential commercial information and how qualified experts
can conclude that the use of a substance is safe without access to the
trade secret or confidential commercial information.
(Response 57) The final rule requires a notifier to state his view
as to whether any of the data and information in Parts 2 through 7 of a
GRAS notice are exempt from disclosure under the FOIA (e.g., as trade
secret or as commercial or financial information that is privileged or
confidential) (Sec. 170.225(c)(8)). Requiring this statement in Part 1
of a GRAS notice will give us notice as to whether we will need to
evaluate specific data and information under the FOIA and take steps to
protect applicable data and information from public disclosure. See
also Sec. 170.250(d), which requires that Part 6 of a GRAS notice (a
narrative) identify specific data and information that a notifier views
as exempt from disclosure under the FOIA. Whereas Part 1 of a GRAS
notice only requires that the signed statements in a GRAS notice state
the notifier's view as to whether any of the data and information in
Parts 2 through 7 of a GRAS notice are exempt from disclosure under the
FOIA, in Part 6 of a GRAS notice the notifier would specifically
identify the applicable data and information.
During the Interim Pilot program, we sometimes received a
curriculum vitae (e.g., of a GRAS panel member) containing personal
privacy information that we needed to redact before we could make the
GRAS notice available to the public. The rule does not require that a
notifier submit such information, and redaction of unnecessary privacy
information takes resources that we would otherwise use to evaluate the
GRAS notice. We ask that notifiers exclude personal privacy information
from a GRAS notice whenever possible. If a notifier does include such
information, in Part 1 of a GRAS notice the notifier should state his
view that the GRAS notice contains personal privacy information. In
Part 6 of a GRAS notice, the notifier should identify the personal
privacy information.
G. Certification Statement
(Comment 58) Several comments support a requirement for a GRAS
notice to include a certification statement similar to the
certification statement that had been required in a GRAS affirmation
petition. One
[[Page 54994]]
comment agrees that the notifier should submit a statement that the
notice is a representative and balanced submission, but does not agree
that the notifier needs to certify the statement.
(Response 58) The final rule requires a certification statement as
described in the 2010 notice, with one modification (see Sec.
170.225(c)(9)). We added that the statement certify that the GRAS
notices is ``complete'' in addition to ``representative'' and
``balanced,'' to emphasize your responsibility to identify, discuss,
and place in context, data and information that are, or may appear to
be, inconsistent with a conclusion of GRAS status, regardless of
whether those data and information are generally available (see the
requirements of the narrative in Part 6 of a GRAS notice (Sec.
170.250, in particular Sec. 170.250(c))). The certification is
appropriate and necessary to underscore your legal responsibility for
the conclusion of GRAS status. As discussed in the 2010 notice, the
specific text of the certification statement that you must include in a
GRAS notice is consistent with the specific text of the certification
statement in the GRAS affirmation petition process that the
notification procedure is replacing. The use of certification
statements has become routine in other submissions to FDA for food
programs (see, e.g., the certification statement in Part V of Form FDA
3480 (for a food contact notification submission) (Ref. 39); and the
certification statement in Section 13 of Form FDA 3537 (for
registration of a food facility) (Ref. 40)).
By ``complete,'' we also mean that your GRAS notice identifies, and
places in context, unpublished data and information that you believe
corroborate GRAS status. For example, if you conduct six toxicology
studies, but only publish three of the studies, it may be that you
consider the remaining three studies to be corroborative of safety. As
an example, it may be that you were dissatisfied with the study design
of one study, repeated that study with an improved study design, and
published the study with the improved study design. If you consider
that the findings of the unpublished studies corroborate safety, even
if they do not establish it, a ``complete, representative, and
balanced'' submission would briefly describe the unpublished studies.
In addition, we expect that you would describe, and place in context,
unpublished data and information if you consider that the findings of
the unpublished data and information warrant sharing with any ``GRAS
panel'' that you convene. See also the discussion in Response 69 and
Response 78.
(Comment 59) One comment asks us to specify that the statement
include the date the statement was certified.
(Response 59) The rule requires that Part 1 of a GRAS notice be
dated and signed by a responsible official of your organization, or by
your attorney or agent (see Sec. 170.225(a)). The certification
statement is included in Part 1 of the GRAS notice; it is not necessary
to date each statement included in Part 1.
H. Person Signing Part 1 of the GRAS Notice
(Comment 60) Several comments support a provision to require a GRAS
notice to clearly identify the person signing the GRAS notice, such as
by printing or stating the name and the title of the person signing the
GRAS notice.
(Response 60) The final rule requires you to state both the name
and position or title of the person who signs the GRAS notice (see
Sec. 170.225(c)(10)).
I. Authorization for FDA To Send Trade Secret Information to FSIS
In the 2010 notice, we described some of the terms of a MOU,
between FDA and USDA's FSIS, that provides for a coordinated evaluation
process with FSIS when the intended conditions of use of a notified
substance include use in a product or products subject to regulation by
USDA under statutes that it administers (75 FR 81536 at 81541-81542);
in 2015 we amended that MOU to include more details about the
procedures FDA and FSIS will follow to do so (Ref. 36). We also asked
for comment on whether to make our coordinated evaluation process with
FSIS explicit in the final rule (see Issue 13, 75 FR 81536 at 81541-
81542).
In accordance with our public information regulations in Sec.
20.85 (Disclosure to other Federal government departments and
agencies), we can share confidential commercial information with
another Federal agency pursuant to a written agreement that the record
will not be further disclosed. The amended MOU between FDA and USDA's
FSIS now provides for FDA to share with FSIS confidential commercial
information in a submission such as a GRAS notice (Ref. 36). We
generally cannot share trade secret information with other Federal
agencies under section 301(j) of the FD&C Act (21 U.S.C. 331(j)), and
therefore we would need your authorization to share this information
with FSIS. For efficiency in administering the coordinated evaluation
of a GRAS notice with FSIS, we have added a requirement for a notifier
who submits a GRAS notice that we would send to FSIS to include in part
1 of the GRAS notice a statement as to whether the notifier: (1)
Authorizes us to send any trade secrets to FSIS; or (2) asks us to
exclude any trade secrets from the copy of the GRAS notice that we will
send to FSIS (see Sec. 170.225(c)(11)). Under the provisions that make
the coordinated evaluation of a GRAS notice with FSIS explicit, we will
exclude any trade secrets unless you have authorized us to send trade
secret information to FSIS (see Sec. 170.270). These provisions will
enable us, with your authorization, to share a GRAS notice that
includes trade secret information with FSIS without first redacting the
GRAS notice to remove the trade secret information and, thus, will
reduce the time it takes for us to provide FSIS with a copy of the GRAS
notice. These provisions also will clarify your expectations regarding
whether we should share trade secret information with FSIS and, thus,
require us to redact the trade secret information from the copy we send
to FSIS when consistent with your express wishes.
Note that our rule establishing the requirements of the GRAS
notification procedure does not specify the data and information that
FSIS will need to evaluate whether the intended use of the notified
substance complies with applicable statutes and regulations, or, if
not, whether the use of the substance would be permitted in products
under FSIS jurisdiction under specified conditions or restrictions. We
recommend that you contact the appropriate staff at FSIS regarding the
data and information that FSIS will need you to provide. FSIS provides
contact information for its programs on its Web site (Ref. 41).
XIII. Comments on Part 2 of a GRAS Notice: Identity, Method of
Manufacture, Specifications, and Physical or Technical Effect
We proposed to require that a GRAS notice include detailed
information about the identity of the notified substance, including, as
applicable, its chemical name, Chemical Abstracts Service (CAS)
Registry Number, Enzyme Commission number, empirical formula,
structural formula, quantitative composition, method of manufacture
(excluding any trade secrets and including, for a substance of natural
biological origin, source information such as genus and species),
characteristic properties, any content of potential human toxicants,
and specifications for food-grade material (proposed Sec.
170.36(c)(2)). In the 2010 notice, we requested comment on
[[Page 54995]]
several issues relevant to the proposed requirements for detailed
information about the identity of the notified substance (see table 9).
Table 9--Issues in the 2010 Notice Regarding the Proposed Requirements
for Detailed Information About the Identity of the Notified Substance
------------------------------------------------------------------------
Description of
Issue No. our request for Reference
comment
------------------------------------------------------------------------
9a........ Whether the final 75 FR 81536 at 81539-81540.
rule should
continue to
stipulate that
the method of
manufacture
exclude any
trade secrets,
as proposed.
10a....... What scientific 75 FR 81536 at 81540.
information
would be
sufficient to
identify the
biological
source.
10b....... Whether to 75 FR 81536 at 81540.
require that
information
about the
identity of the
notified
substance
specify any
known toxicants
that could be in
the source.
10c....... Whether the final 75 FR 81536 at 81540.
rule should
address, as part
of identity,
particle size
and other
chemical and
physical
properties that
may be used to
characterize
engineered
materials.
------------------------------------------------------------------------
Some comments support the proposed requirements, with the potential
modifications described in the 2010 notice, without change. For
example, most of the comments that address the issue of scientific
information sufficient to identify a biological source support
requiring both taxonomic information and the part of any animal or
plant used as a source. As another example, several comments that
address the issue of scientific information sufficient to identify a
biological source support requiring that this information specify
toxicants that could be in the source.
Most of the comments regarding our proposal to require that a GRAS
notice include detailed information about the identity of the notified
substance address the issues discussed in 2010 notice. In the following
sections, we discuss these and other comments. After considering these
comments, we are establishing requirements for Part 2 of a GRAS notice
to include information about the identity, method of manufacture,
specifications, and physical or technical effect of the notified
substance as shown in table 10, with editorial, clarifying, and
conforming changes as shown in table 29. (See Sec. 170.230). Table 10
identifies changes we made relative to the proposed rule or the
description in the 2010 notice other than the editorial, clarifying,
and conforming changes shown in table 29 and the additional editorial
changes associated with the redesignation of proposed Sec.
170.36(c)(2) as Sec. 170.230.
Table 10--Final Requirements for Detailed Information in Part 2 of a GRAS Notice About the Identity of a
Notified Substance
----------------------------------------------------------------------------------------------------------------
Revisions (other
than editorial,
Proposed Issue No. in Description. Part 2 clarifying, and
Final designation in the designation in the the 2010 of your GRAS conforming changes)
regulatory text (Sec. ) regulatory text notice notice: relative to the
(Sec. ) proposed rule or
the 2010 notice
----------------------------------------------------------------------------------------------------------------
170.230(a)(1).................... 170.36(c)(2)....... N/A Must include N/A.
scientific data
and information
that identifies
the notified
substance.
170.230(a)(1).................... 170.36(c)(2)....... 10a Must include data Must
and information provide taxonomic
sufficient to information at the
identify a sub-species level
biological source (e.g., variety,
of a notified strain) in
substance. addition to genus
and species.
Must
specify the part
of any plant or
animal used as the
source.
170.230(a)(2).................... 170.36(c)(2)....... 10b Must include data N/A.
and information
sufficient to
identify any known
toxicants that
could be in the
source.
170.230(b)....................... 170.36(c)(2)....... 9a Must include the No longer
method of requires that the
manufacture of the method of
notified substance manufacture
in sufficient exclude any trade
detail to evaluate secrets.
the safety of the Requires
notified substance ``sufficient
as manufactured. detail to evaluate
the safety of the
notified substance
as manufactured''
rather than
``detailed
information.''
170.230(c)....................... 170.36(c)(2)....... N/A Must include N/A.
specifications for
food-grade
material.
170.230(d)....................... N/A................ N/A When necessary to New requirement
demonstrate based on comments
safety, must that addressed
include relevant experience during
data and CVM's Interim
information Pilot program (see
bearing on the section XXV.E).
physical or other
technical effect
the notified
substance is
intended to
produce, including
the quantity of
the notified
substance required
to produce such
effect.
----------------------------------------------------------------------------------------------------------------
[[Page 54996]]
A. Scientific Information About the Identity of a Notified Substance
1. Scientific Information Sufficient To Identify a Biological Source
(Comment 61) One comment asserts that the scientific information,
beyond the standard taxonomic information, that is sufficient to
identify a biological source for a notified substance should be
determined on a case-by-case basis consistent with established practice
and publicly available guidance. Another comment asserts that
identifying the source organism by the genus and species (without
additional information such as strain or variety) is sufficient when
the notified substance is an enzyme preparation produced by a
microorganism. However, this comment also asserts that if safety
concerns for a specific genus and species have been addressed (i.e., by
genetic modification to remove a characteristic of concern) for a
specific strain within that species then information about the strain
would be appropriate. This comment emphasizes that the description of
the source of a biological material should be based on the safety of
that source and consider all relevant information related to safety.
(Response 61) The information, beyond the standard taxonomic
information, that we discussed in the 2010 notice is consistent with
established practice (see section III.J.1 of CFSAN's 2010 experience
document (Ref. 18)) and the final rule specifies that when the source
of a notified substance is a biological material, your GRAS notice must
include both taxonomic information (e.g., genus, species), including as
applicable data and information at the sub-species level (e.g.,
variety, strain) and the part of any plant or animal used as the source
(see Sec. 170.230(a)(2)). We agree that the specific scientific
information, beyond the standard taxonomic information, that is
sufficient to identify a biological source is determined on a case-by-
case basis, and section III.J.1 of CFSAN's 2010 experience document
demonstrates that the specific scientific information included in a
GRAS notice to describe a biological source varied on a case-by-case
basis. For example, when the notified substance was derived from a
microorganism, the notifier specified a particular strain or subspecies
or stated the strain was a nontoxigenic and nonpathogenic strain; when
the notified substance was derived from a plant, the notifier
identified the specific part(s) of the plant used as the starting
material, such as fruit, seeds or seed husks, expressed oil, flowers,
roots, leaves, pulp, wood, or bark. However, we disagree that we should
use guidance, rather than the regulatory text of this rule, to describe
the types of data and information that are necessary to sufficiently
identify the biological source because the types of information we are
specifying are necessary--rather than merely recommended--information.
For example, data and information at the sub-species level (e.g.,
variety, strain) is necessary for source microorganisms because so many
microorganisms (e.g., Escherichia coli and Saccharomyces cerevisiae)
have multiple strains, and although some strains are both non-toxigenic
and non-pathogenic, others are not. For example, there are several
pathogenic strains of Saccharomyces cerevisiae, even though
nonpathogenic strains are commonly used in food and in the production
of enzyme preparations. As another example, both Aspergillus oryzae and
Aspergillus niger naturally produce mycotoxins, but strains that do not
produce mycotoxins have been developed and are used for production of
enzyme preparations. In addition, for phage production some host
strains have been pathogens (e.g., Listeria monocytogenes) and produce
toxins. Likewise, data and information about the part of a plant used
as a source is necessary because some plants that have edible parts
also secrete toxins in non-edible parts. For example, the leaf stalks
(petioles) of rhubarb (Rheum rhaponticum) are edible, but the leaves
contain notable quantities of oxalic acid. As another example, the
leaves and stems of tomato (Solanum lycopersicum) contain solanine.
We agree that the description of a biological source should be
based on the safety of that source and consider all relevant
information related to safety. The regulatory text requires taxonomic
information beyond genus and species, such as variety or strain, ``when
applicable'' for a source microorganism such as those used to produce
enzyme preparations. Examples of when information such as variety or
strain would be applicable are those microbial sources, such as some
fungi, for which there are multiple strains or subspecies that have
different properties with respect to the ability to produce toxins,
antibiotics, or other substances that are not suitable for use in food.
(Comment 62) One comment asks us to specify that information
identifying a substance derived from a biological source must include
the breed of animal or plant.
(Response 62) During the Interim Pilot program we did not evaluate
any GRAS notices in which the breed of an animal or plant source was a
taxonomic descriptor necessary to sufficiently identify that animal or
plant source. Therefore, although breed may be an appropriate taxonomic
descriptor in some circumstances, the circumstances are rare enough
that we have not seen it as necessary information in more than 15
years. Therefore, we are not specifying it as an example of applicable
taxonomic information in the rule. In a specific circumstance where
breed is necessary to adequately identify a particular animal or plant
source, and you do not specify the breed, we intend to ask you to amend
your GRAS notice to identify the breed.
(Comment 63) One comment asks us to address substances produced
from microorganisms, particularly bioengineered microorganisms. This
comment explains that the development of a production microorganism
through bioengineering is, for the most part, highly confidential and
cannot be disclosed publicly. In addition, the production microorganism
often is modified on an ongoing basis, e.g., to improve yield. This
comment asks us to specify the point at which subsequent modification
of a production microorganism would trigger submission of a new GRAS
notice and notes that in some cases subsequent modification of a
production organism could be incorporated into the original GRAS notice
by ``amendment'' or by reference. This comment also asserts that
submission of a new GRAS notice should not be needed in the case of
safe strain lineage as described in the scientific literature (Ref.
42).
Another comment asks us to specify that information identifying a
substance derived from a biological source must specify whether the
plant or animal is genetically engineered or cloned.
(Response 63) We recommend that notifiers consult our guidance
entitled ``Assessing the Effects of Significant Manufacturing Process
Changes, Including Emerging Technologies, on the Safety and Regulatory
Status of Food Ingredients and Food Contact Substances, Including Food
Ingredients that Are Color Additives'' (Ref. 6). That guidance lists a
change in the source microorganism (including a change in strain) used
for a food substance derived from fermentation of a microorganism as an
example of a significant manufacturing process change. Whenever there
has been a significant manufacturing process change for a food
substance that is the subject of a previous conclusion of GRAS status,
the guidance recommends that the manufacturer consider whether the GRAS
status of the use of the food substance would be affected; consult
[[Page 54997]]
with us regarding the conclusions about the impact of the significant
manufacturing change on the safety and regulatory status of the use of
the food substance; and make an appropriate regulatory submission to us
as circumstances warrant. In the specific circumstance of a production
microorganism that is modified on an ongoing basis, a modification that
results in a new strain would no longer fall within the description of
the source, which must include information at the sub-species level
(see Sec. 170.230(a)(2)(i)). If a notifier concludes that a
modification that results in a new strain has no impact on the
conclusion of GRAS status, one approach could be to submit a supplement
to the GRAS notice. Doing so would be consistent with CFSAN's 2010
experience during the Interim Pilot program. See section IV.J of
CFSAN's 2010 experience document (Ref. 18), in which CFSAN discusses a
GRAS notice in which a notifier consulted with CFSAN about mechanisms
to inform CFSAN about its conclusion that additional uses of the
notified substance are also GRAS. The notifier supplemented its
original GRAS notice with a letter informing CFSAN of the additional
conclusion of GRAS status and CFSAN issued a second ``no questions
letter'' to the notifier as additional correspondence.
We decline the request to require that information identifying a
substance derived from a biological source specify whether the plant or
animal is ``genetically engineered'' or ``cloned.'' We consider that
the more general requirement to identify a biological source at the
sub-species level is adequate to identify the source. In practice
during the Interim Pilot program, notifiers routinely informed us about
the use of such techniques in describing production microorganisms,
particularly for GRAS notices about the intended conditions of use of
enzyme preparations. (See, e.g., the list of enzyme preparations in
section IV.N of CFSAN's 2010 experience document (Ref. 18).) The source
microorganisms for several of the listed enzyme preparations were
developed using bioengineering techniques.
When confidential data and information about the development of a
production microorganism through bioengineering are necessary to
provide evidence that a notified substance produced from that
production organism is safe under the conditions of its intended use,
the use of the notified substance would not satisfy GRAS criteria. See
the discussion in Response 69, where we explain that it may be possible
to explain that confidential information (whether included in a GRAS
notice, or provided privately to a GRAS panel) is corroborative of
safety, rather than necessary to demonstrate safety, if, for example,
the method of manufacture included in a GRAS notice meets the
requirements of the rule to provide sufficient detail to evaluate the
safety of the notified substance as manufactured. Alternatively, the
notifier could describe the development of the production microorganism
in sufficient detail to address any safety issues associated with use
of that production microorganism. For enzyme preparations that would be
used in human food, we recommend that notifiers consult our guidance
entitled ``Guidance for Industry: Enzyme Preparations: Recommendations
for Submission of Chemical and Technological Data for Food Additive
Petitions and GRAS Notices'' (Ref. 33), and ``Food-Processing Enzymes
From Recombinant Microorganisms--A Review'' (Ref. 43), for details
about our recommendations for safety information regarding enzyme
preparations derived from bioengineered microorganisms.
2. Potential Toxicants in the Source of the Notified Substance
(Comment 64) One comment agrees that a review of known toxicants
that could be produced by the biological source of a notified substance
should be part of the safety review, but recommends that the depth of
the review be addressed on a case-by-case basis and be tailored to the
substance and the source of the substance. This comment asserts that it
would be difficult and impractical to define a method for this review
or to define the specific toxicants that are required to be reviewed
for each particular substance.
(Response 64) We agree that the safety review should be tailored to
the substance and its source because of the diversity of toxicants that
could be in the biological source. It is your responsibility to
determine how to conduct the safety review; the rule does not prescribe
any method for this review or any specific toxicants that must be
reviewed for a particular substance or source. In some cases (e.g.,
when it is well established in the scientific community that a source
is non-toxigenic), citations to publicly available information about a
biological source may be sufficient to address the safety of the
notified substance with respect to potential toxicants in the source.
In other cases (e.g., when a source is known to be toxigenic), the
information about the toxigenic source would lead you to a discussion,
in the narrative required in Part 6 of a GRAS notice, of how the method
of manufacture and specifications for the notified substance lead you
to conclude that the notified substance as manufactured is safe and
that the criteria for general recognition are satisfied.
(Comment 65) One comment refers to a statement we made, in the 2010
notice, that we have found that information about substances known to
be toxicants is relevant regardless of the state of the science
regarding the specific toxicity of the substance to humans (75 FR 81536
at 81540). This comment asserts that specifying that the identity of
the notified substance include any known toxicants that could be in the
source does not fully address whether the toxicants cause a safety
concern. Another comment states that the ``GRAS process'' should
contain a safety/risk assessment for known toxicants, not just identify
the toxicants.
(Response 65) We agree that a GRAS notice must address the safety
concerns associated with toxicants known to be in a biological source,
not just identify the toxicants. See the requirements for a GRAS notice
to include the method of manufacture of the notified substance (Sec.
170.230(b)), specifications for food-grade material (Sec. 170.230(c)),
and a narrative explaining why the data and information in a GRAS
notice provide a basis for the notifier's view that the notified
substance is safe under the conditions of its intended use (Sec.
170.250).
(Comment 66) One comment recommends using our guidance entitled
``Recommendations for Submission of Chemical and Technological Data for
Direct Food Additive Petitions'' (Ref. 31) as a more ``holistic''
approach to addressing potential safety concerns regarding known
toxicants in a biological source, because the guidance describes how to
use the manufacturing process to control, reduce, or concentrate
toxicant levels and explains the importance of establishing limits for
any known natural toxicants in or on food additives derived from a
natural source. The comment asserts that this guidance should apply to
GRAS substances as well as food additives because general recognition
of safety through scientific procedures requires the same quantity and
quality of evidence as is required to establish a food additive
regulation for the use of the substance, and therefore the information
about the identity of the substance should be consistent with the
requirements for food additives. This comment notes that section III.A
of ``Recommendations for Submission of Chemical and Technological Data
for
[[Page 54998]]
Direct Food Additive Petitions'' clearly outlines the information
needed for ``allowing the unequivocal identification and
characterization of the food additive'' and that the principles in
specific sections in section III.A of the guidance apply to GRAS
substances even though they are written to specifically address food
additives.
(Response 66) We agree that many of the recommendations in our
guidance entitled ``Recommendations for Submission of Chemical and
Technological Data for Direct Food Additive Petitions'' (Ref. 31) could
be useful to a person who assesses whether a substance is GRAS under
the conditions of its intended use. As the comment points out, the
guidance currently is structured to address the specific requirements
in Sec. 171.1 (particularly Sec. 171.1(c)) for food additive
petitions. Consistent with available resources, we will consider
revising that guidance to clarify how its recommendations apply to an
evaluation of whether a substance is GRAS under the conditions of its
intended use.
3. Particle Size
In the 2010 notice, we noted that substances that have a small
particle size often have chemical, physical, or biological properties
that are different from those of their larger counterparts (75 FR 81536
at 81540). We requested comment on whether the final rule should
address, as part of identity, particle size and other chemical and
physical properties that may be used to characterize engineered
materials (see table 9).
(Comment 67) Some comments recommend that a GRAS notice discuss
particle size only if it is relevant to the safety or effectiveness of
the notified substance. One comment recommends that the rule not
address particle size, at least until this area is better understood.
Another comment asks us to clarify what we mean by the term ``small
particle size'' if we include that term in the rule.
One comment asks us to require information about particle size and
other physical/chemical properties that may be used to characterize
engineered materials. This comment asserts that nanoparticles are not
simply smaller versions of materials; instead nanoparticles are
specifically engineered to create new properties and behaviors that
give products certain attributes and highly reactive nanoparticles can
exhibit a toxic reaction with their environments, including the cells
of living organisms. This comment also notes that the U.S.
Environmental Protection Agency (EPA) has already made case-by-case
rulings on the safety of certain nanoparticles.
Several comments assert that any requirement for a GRAS notice to
address particle size and other chemical or physical properties should
apply only to engineered nanomaterials, and that it is not typically
necessary to address such properties for non-engineered materials. One
comment asserts that engineered nanomaterials could never be eligible
for classification as GRAS because they either are new materials with
unfamiliar properties or represent a significant new use of a material.
(Response 67) The final rule requires that a GRAS notice include
scientific information that identifies the notified substance, and
includes ``characteristic properties'' in a list of examples of
appropriate information that a notifier would include. We agree that
data and information about particle size, and any chemical and physical
properties attributable to small particle size, are appropriate for
engineered nanomaterials; a GRAS notice about an engineered
nanomaterial likely would not provide an adequate basis for a
conclusion of GRAS status without such information. We also agree that
data and information about particle size may not be relevant for non-
engineered materials and, thus, we are including the broad example of
``characteristic properties'' in the final rule without adding the
narrow example of ``particle size'' (see Sec. 170.230(a)(1)).
We note that we have several guidances applicable to significant
manufacturing changes in food, including nanotechnology (Ref. 6; Ref.
8; and Ref. 44). Our guidance entitled ``Guidance for Industry:
Assessing the Effects of Significant Manufacturing Process Changes,
Including Emerging Technologies, on the Safety and Regulatory Status of
Food Ingredients and Food Contact Substances, Including Food
Ingredients that are Color Additives'' (Ref. 6) states: ``At present,
for nanotechnology applications in food substances, there are questions
related to the technical evidence of safety as well as the general
recognition of that safety, that are likely to be sufficient to warrant
formal premarket review and approval by FDA, rather than to satisfy
criteria for GRAS status.'' However, that guidance reflects the
generally available data and information at present, and we disagree
that data and information supporting the safety of engineered
nanomaterials could never satisfy GRAS criteria. Whether the generally
available data and information supporting the safety of the intended
conditions of use of any substance--including an engineered
nanomaterial--satisfy GRAS criteria is a case-by-case conclusion that
depends on whether the generally available data and information support
a conclusion that the substance is generally recognized, among
qualified experts, to be safe under the conditions of its intended use.
Section 201(s) of the FD&C Act does not limit the eligibility of a
substance for classification as GRAS based on factors such as its
characteristic properties.
4. Other Comments About the Identity of the Notified Substance
(Comment 68) One comment asserts that the criteria used to conclude
that a particular substance is GRAS, including details regarding
biological source, known toxicants, particle size, etc., should be
based on what qualified experts determine to be necessary.
(Response 68) We disagree that the role of qualified experts in a
conclusion of GRAS status means that the requirements for a GRAS notice
should be silent on the types of data and information that generally
apply to any conclusion of GRAS status--in this case, data and
information regarding the identity of the substance. In the narrative
required by part 6 of a GRAS notice, a notifier must explain why the
data and information in the notice provide a basis for the notifier's
view that the notified substance is safe under the conditions of its
intended use (Sec. 170.250(a)(1)); identify what specific data and
information that the notifier discusses to support his view that the
notified substance is safe under the conditions of its intended use are
generally available, and what specific data and information that the
notifier discusses are not generally available (Sec. 170.250(a)(2));
and explain how the generally available data and information that a
notifier relies on to establish safety provide a basis for the
notifier's conclusion that the notified substance is generally
recognized, among qualified experts, to be safe under the conditions of
its intended use (Sec. 170.250(b)). The narrative is the appropriate
mechanism for a notifier to explain how the view of qualified experts
supports his view that the notified substance is GRAS under the
conditions of its intended use.
B. Method of Manufacture
(Comment 69) Several comments address Issue 9a, i.e., whether the
final rule should continue to stipulate that the method of manufacture
exclude any trade secrets, as proposed. Some of these comments support
stipulating that the method of manufacture exclude any trade secrets.
The stated reasons varied.
[[Page 54999]]
For example, some comments state that in the past experience of
notifiers, it is generally possible to include sufficient information
on the manufacturing process without disclosing trade secrets. One
comment states that transparency, by both FDA and industry, and the use
of publicly available information is critical to the continued success
of the GRAS notification procedure. One comment states that the common
knowledge element of the GRAS standard inherently limits the submission
of confidential information and/or trade secrets by the notifier to
substantiate a conclusion of GRAS status.
Other comments point to the proposed requirement that a GRAS notice
include ``detailed information about the . . . method of manufacture
(excluding any trade secrets . . .)'' and question whether a method of
manufacture that excludes trade secrets can be sufficiently detailed to
meet the requirements of a GRAS notice. One comment recommends that we
clarify the rule by requiring that the notice include appropriate
information on the method of manufacture, sufficient to conduct an
adequate safety review, so that confidential information would not be
submitted when a very general and non-confidential description
suffices.
Several comments acknowledge that there may be situations where
trade secret information is necessary to complete the description of
the method of manufacture and recommend that the final rule provide
flexibility for a notifier to provide trade secret information when
appropriate (e.g., to help us evaluate the GRAS notice), and for FDA to
protect trade secrets or other confidential information in a GRAS
notice from public disclosure, just as we would in the case of
submissions such as food additive petitions. To promote clarity and
transparency, some of these comments recommend revising the rule to
require that a notifier who includes trade secret information explain
why the information is trade secret and why the trade secret
information has a corroborative role in the safety assessment. Some
comments emphasize that a notifier who submits trade secret information
must mark the information as non-public. Other comments assert that
information identified as trade secret or confidential information
should only be allowed if the information is not critical to a
conclusion of GRAS status.
One comment suggests that a notifier could provide trade secret
information to a GRAS panel for review on a confidential basis because
deliberations of the panel would not necessarily be subject to public
disclosure. One comment notes that supporting information can be
valuable to a GRAS panel and allowing submission of confidential
information in a GRAS notice could inform FDA of the full range of
information taken into consideration by a GRAS panel.
Some comments cite our regulations for new drugs, premarket
notification for medical devices, and premarket approval of medical
devices as evidence that our regulations implementing FOIA specifically
regard methods of manufacture as confidential and urge us to adopt a
similar approach for GRAS notices.
See also Comment 57.
(Response 69) See table 11, and the regulatory text in Sec. Sec.
170.230(b), 170.225(c)(8), 170.250(d), and 170.250(e), for a series of
changes we made to the rule to address these comments about the method
of manufacture included in a GRAS notice, including comments about
trade secret information associated with the method of manufacture.
Although the changes in Parts 1 and 6 of a GRAS notice broadly apply to
any non-public information, in this response we focus on how these
provisions apply to trade secret information that you may include in
the description of the method of manufacture. Collectively, these
changes: (1) Emphasize that the description of the method of
manufacture must be in sufficient detail to evaluate the safety of the
notified substance as manufactured, without stipulating that the method
of manufacture exclude any trade secrets (Sec. 170.230(b)); (2)
require the notifier to include a signed statement with his view as to
whether the method of manufacture includes trade secret information
(Sec. 170.225(c)(8)); (3) require the notifier to identify any trade
secret information in the method of manufacture (Sec. 170.250(d)); and
(4) require the notifier to explain how there could be a basis for a
conclusion of GRAS status if qualified experts do not have access to
trade secret information that the notifier considered in concluding
that the substance is safe under the conditions of its intended use
(Sec. 170.250(e)). See also Response 57, Response 78, and section
XVII.
Table 11--Requirements That Apply When a Notifier Includes Trade Secret or Other Non-Public Information in a
GRAS Notice
----------------------------------------------------------------------------------------------------------------
Proposed designation
Final designation in the in the regulatory Description Revision
regulatory text (Sec. ) text (Sec. )
----------------------------------------------------------------------------------------------------------------
170.230(b)........................ 170.36(c)(2)......... In Part 2 of your GRAS We replaced
notice, you must include ``detailed'' with
a description of the ``sufficient detail to
method of manufacture in evaluate the safety of
sufficient detail to the notified substance
evaluate the safety of as manufactured''.
the notified substance as We no longer
manufactured. stipulate that the
description of the
method of manufacture
must exclude trade
secret information.
170.225(c)(8)..................... N/A.................. In Part 1 of your GRAS Requires a notifier who
notice, you must state includes information
your view as to whether that the notifier views
any of the data and as non-public
information in Parts 2 information to make FDA
through 7 of your GRAS aware of that view. See
notice are exempt from Response 57.
disclosure under the FOIA
(e.g., as trade secret or
as commercial or
financial information
that is privileged or
confidential).
170.250(d)........................ N/A.................. In Part 6 of your GRAS Requires a notifier who
notice (the narrative), includes information
if you view any of the that the notifier views
data and information in as non-public
your notice as exempt information to identify
from disclosure under the the non-public
FOIA, you must identify information. See section
the specific data and XVII.
information.
[[Page 55000]]
170.250(e)........................ In Part 6 of your GRAS Requires a notifier to
notice (the narrative), place non-public
you must explain how information in the
there could be a basis context of a conclusion
for a conclusion of GRAS of GRAS status. See
status if qualified section XVII.
experts generally do not
have access to non-
public, safety-related
data and information.
170.275(c)........................ 170.36(f)(1)......... We will disclose all Uses active voice to
remaining data and emphasize that we will
information that are not apply the protections
exempt from public from public disclosure
disclosure in accordance under the FOIA to non-
with part 20. public information
included in a GRAS
notice.
----------------------------------------------------------------------------------------------------------------
This rule establishes requirements for the information that a
notifier submits to FDA in a GRAS notice. GRAS criteria require that
any conclusion of GRAS status be based on common knowledge (see Sec.
170.30(a)) and, thus, there could be no basis for a conclusion of GRAS
status if trade secret information (or other non-public information) is
necessary for qualified experts to reach a conclusion that the notified
substance is safe under the conditions of its intended use. In the
particular case of a conclusion of GRAS status through scientific
procedures, GRAS criteria require that the conclusion of GRAS status be
based on data, information, and methods that are generally available
(see Sec. 170.30(b)). Non-public information may be used to
corroborate safety but cannot be used to establish safety; as discussed
in Response 9, qualified experts must be able to conclude that the
substance is not harmful under the conditions of its intended use
without access to ``corroborative'' information (see Sec. 170.30(a)).
We believe that it will be rare for a GRAS notice to include trade
secret information. Likewise, we expect it will be rare that trade
secret information would warrant sharing with members of a GRAS panel,
because a notifier must write a non-confidential description of the
method of manufacture to include in the GRAS notice and could share
this non-confidential description, rather than trade secret
information, with the GRAS panel. If the GRAS panel had questions about
that description of the method of manufacture, we expect that the
notifier would revise the description to address those questions rather
than provide the GRAS panel with trade secret information to address
those questions. If, however, a notifier does provide the GRAS panel
with trade secret information, we agree that the notifier should inform
us of the full range of information taken into consideration by the
GRAS panel, consistent with the signed statement that the GRAS notice
is a complete, representative, and balanced submission (see Response 58
and Sec. 170.225(c)(9)). The notifier could do so either by including
in his GRAS notice a non-confidential description of the trade secret
information that was shared, or by providing the trade secret
information shared with a GRAS panel. Importantly, the notifier would
be required to explain how there could be a basis for a conclusion of
GRAS status if qualified experts generally do not have access to non-
public, safety related data and information (see Response 78 and Sec.
170.250(e)). If the public description of the method of manufacture
that a notifier includes in a GRAS notice cannot provide sufficient
detail to evaluate the safety of the notified substance as
manufactured, there could be no basis to support a conclusion of GRAS
status. However, if that public description meets the requirements of
the rule to provide sufficient detail to evaluate the safety of the
notified substance as manufactured (see Sec. 170.230(b)), it may be
possible to explain that trade secret information that a GRAS panel
evaluated is corroborative of safety rather than necessary to
demonstrate safety.
Under Sec. 20.61, trade secrets and commercial or financial
information which is privileged or confidential are exempt from public
disclosure. Under Sec. Sec. 20.100(c)(7) and 171.1(h)(2)(i),
manufacturing methods or processes, including quality control
procedures, are exempt from public disclosure unless they have been
previously disclosed to the public (as defined in Sec. 20.81) or they
relate to a product or ingredient that has been abandoned. If a
notifier believes that all information about the method of manufacture
should be non-public, it is unlikely that the notifier has a basis to
conclude that the notified substance is GRAS under the conditions of
its intended use. The use of the substance would be a food additive use
and, if the notifier submits a food additive petition for that use, our
regulations governing a food additive petition would protect the
information from public disclosure, as do our regulations for new
drugs, premarket notification for medical devices, and premarket
approval of medical devices.
(Comment 70) Several comments express concern about the possibility
that we would determine that information a notifier identifies as a
trade secret or as confidential commercial information is available for
public disclosure. One comment asserts that if we choose to allow the
submission of confidential information in a GRAS notice, we should not
be the party who determines whether information should be publicly
disclosed. Another comment asks us to provide an opportunity for a
notifier to make a ``cease to evaluate'' request before we disclose
confidential information.
One comment asks us to allow the submission of limited confidential
information to supplement (or corroborate) the publicly available
information in a GRAS notice, such as by providing sufficient
information in a GRAS notice to support a conclusion of GRAS status but
also including additional, corroborating information in a food master
file. The comment explains that the public GRAS notice would be
complete and sufficient to form a conclusion of GRAS status, but we
would have access to additional, confidential information that would
ensure that we are informed of new manufacturing or technological
developments. This comment points out that we have for many years
employed food, drug, and medical device master files for the submission
of confidential information.
[[Page 55001]]
(Response 70) We disagree that we should not be the party who
determines whether information should be publicly disclosed. Under our
public information regulations in part 20, we have the responsibility
to determine whether information should be publicly disclosed,
regardless of whether a person who submits the information has marked
it as non-public. Marking records submitted to us as confidential, or
with any other similar term, raises no obligation by FDA to regard such
records as confidential, to return them to the person who has submitted
them, to withhold them from disclosure to the public, or to advise the
person submitting them when a request for their public disclosure is
received or when they are in fact disclosed (see Sec. 20.27). We also
disagree that providing an opportunity for a notifier to ask us to
cease to evaluate a GRAS notice would impact the public disclosure of
data and information that do not satisfy the criteria in part 20 for
exemption from disclosure; under Sec. 20.29 a GRAS notice is available
for public disclosure in accordance with part 20.
Data and information submitted to us are available for public
disclosure based on the nature of the data and information, not the
name of the file where we store the data and information. Thus, asking
us to store data and information that you view as confidential in a
specific type of file, such as a ``food master file,'' would not
automatically protect the information from public disclosure.
Furthermore, in Part 6 of your GRAS notice you would be required to
explain how there could be a basis for a conclusion of GRAS status if
qualified experts generally do not have access to the confidential data
and information in the separate file. We also would expect that you
provide a statement in Part 1 of your GRAS notice with your view that
the additional data and information in the separate file are exempt
from disclosure under the FOIA (see Sec. 170.225(c)(8)). Because part
20 already provides protection of non-public information from
disclosure, and because your GRAS notice would need to both acknowledge
the data and information in the separate file and explain how there
could be a basis for a conclusion of GRAS status if qualified experts
generally do not have access to these data and information, we consider
it administratively inefficient to maintain the data and information
submitted in support of a conclusion of GRAS status in two separate
files, and we may decide to decline to file a GRAS notice that is
accompanied by a separate file containing data and information that you
view as non-public.
(Comment 71) Some comments assert that many manufacturers will
choose not to notify us of a conclusion of GRAS status because they
expect that we will determine that all information submitted in a GRAS
notice is available for public disclosure in most circumstances.
(Response 71) Our experience during the Interim Pilot program does
not support the assertions in these comments. As noted in Response 24
and Response 26, CFSAN has filed more than 600 GRAS notices between
1998 and 2015, for an average of approximately 34 GRAS notices per
year.
(Comment 72) One comment states that commercial and financial
information are not relevant to the determination of safety of a
notified substance.
(Response 72) Confidential commercial information may on occasion
be used to corroborate safety. One example is an article that has been
accepted for publication, but has not yet been published. This article
would likely be considered confidential until it is published, but it
could be used to corroborate other published information.
C. Specifications for the Notified Substance
We received no comments that disagreed with our proposed
requirement for a GRAS notice to include specifications for food-grade
material and we are finalizing it as proposed for a substance used in
human food. See table 29 for an editorial change we made to the
regulatory text for specifications for a substance used in animal food.
D. Data and Information Bearing on the Physical or Other Technical
Effect of the Notified Substance
As discussed in section XXV.E, several comments discuss their
experience with CVM's practice, during the Interim Pilot program, of
asking a notifier to provide data or information demonstrating the
effectiveness, or utility, of the notified substance. After considering
these comments, we have added a requirement for Part 2 of a GRAS notice
to include relevant data and information bearing on the physical or
other technical effect the notified substance is intended to produce,
including the quantity of the notified substance required to produce
such effect, when necessary to demonstrate safety (see Sec. 170.230(d)
and Response 144). Data and information bearing on the physical or
other technical effect the notified substance is intended to produce
are only necessary when they bear on safety. This relationship to
safety is consistent with the requirements of the FD&C Act for a
petition to establish the safety of a food additive (see section
409(b)(2)(C) of the FD&C Act). An example of when such data and
information would be relevant to safety is when the intended use of the
notified substance is as an antimicrobial agent. For example, an
antimicrobial agent may change the microbiological profile of food such
that it suppresses one group of pathogenic microorganisms while
allowing others to proliferate, thereby creating a potential health
problem (Ref. 32).
XIV. Comments on Part 3 of a GRAS Notice: Dietary Exposure
We proposed that a notice regarding a conclusion of GRAS status
through scientific procedures include a comprehensive discussion of,
and citations to, generally available and accepted scientific data,
information, methods, or principles that the notifier relies on to
establish safety, including a consideration of the probable consumption
of the substance and the probable consumption of any substance formed
in or on food because of its use and the cumulative effect of the
substance in the diet, taking into account any chemically or
pharmacologically related substances in such diet (proposed Sec.
170.36(c)(4)(i)(A)). In the 2010 notice, we requested comment on
several issues relevant to the proposed requirements for a
comprehensive discussion that considers the probable consumption of the
substance and the probable consumption of any substance formed in or on
food because of its use and the cumulative effect of the substance in
the diet, and noted that the simple term ``dietary exposure'' could be
used in place of the statutory language (i.e., derived from section
409(c)(5) of the FD&C Act) we used in the proposed rule (see table 12).
See table 27 for issues in the 2010 notice regarding dietary exposure
when a notified substance would be added to animal food.
[[Page 55002]]
Table 12--Issues in the 2010 Notice Regarding Dietary Exposure When a
Notified Substance Would Be Added to Human Food
------------------------------------------------------------------------
Description of our request for
Issue No. comment Reference
------------------------------------------------------------------------
11a............ Whether the final rule should 75 FR 81536 at 81540-
continue to restate the 81541.
statutory language of section
409(c)(5) of the FD&C Act or
whether this provision should
be stated more clearly, for
example, by requiring
information about dietary
exposure (i.e., the amount of
the notified substance that
consumers are likely to eat or
drink as part of a total diet).
11b............ Whether a GRAS notice should be 75 FR 81536 at 81540-
required to include 81541.
information about dietary
exposure to contemporary
consumers regardless of
whether the determination of
GRAS status is through
scientific procedures or
through experience based on
common use in food.
------------------------------------------------------------------------
In the following sections, we discuss comments on the proposed
requirements applicable to dietary exposure and the issues discussed in
the 2010 notice. After considering these comments, we are establishing
requirements for Part 3 of a GRAS notice as shown in table 13, with
editorial, clarifying, and conforming changes as shown in table 29.
(See Sec. 170.235). Table 13 identifies changes we made relative to
the proposed rule or the description in the 2010 notice other than the
editorial, clarifying, and conforming changes shown in table 29 and the
additional editorial changes associated with the redesignation of some
of the regulatory text of proposed Sec. 170.36(c)(4)(i)(A) as Sec.
170.235.
Table 13--Final Requirements for Data and Information About Dietary Exposure in Part 3 of a GRAS Notice
----------------------------------------------------------------------------------------------------------------
Revisions (other
than editorial,
Proposed Issue No. in clarifying, and
Final designation in the designation in the the 2010 Description conforming changes)
regulatory text (Sec. ) regulatory text notice relative to the
(Sec. ) proposed rule or
the 2010 notice
----------------------------------------------------------------------------------------------------------------
170.235.......................... 170.36(c)(4)(i)(A). 11a In Part 3 of your Uses the
11b GRAS Notice, you term ``dietary
must provide data exposure'' and
and information describes it as
about dietary meaning ``the
exposure (i.e., amount of relevant
the amount of substances that
relevant consumers are
substances that likely to eat or
consumers are drink as part of a
likely to eat or total diet.''
drink as part of a Requires
total diet), data and
regardless of information about
whether your dietary exposure
conclusion of GRAS regardless of
status is through whether your
scientific conclusion of GRAS
procedures or status is through
through experience scientific
based on common procedures or
use in food. through experience
based on common
use in food.
170.235(a)....................... 170.36(c)(4)(i)(A). 11a In Part 3 of your Uses the term
GRAS Notice, you ``dietary
must provide data exposure.''
and information
about dietary
exposure to the
notified substance
that includes
exposure from its
intended use and
all sources in the
diet.
170.235(b)....................... 170.36(c)(4)(i)(A). 11a When applicable, in Uses the
Part 3 of your term ``dietary
GRAS Notice you exposure.''
must provide data Gives
and information examples of
about dietary substances that
exposure to any could be formed in
other substance or on food because
that is expected of the use of the
to be formed in or notified
on food because of substance.
the use of the
notified substance
(e.g., hydrolytic
products or
reaction products).
170.235(c)....................... 170.36(c)(4)(i)(A), 11a When applicable, in Requires an
170.36(c)(2). Part 3 of your estimate of
GRAS Notice you dietary exposure
must provide data to substances such
and information as contaminants
about dietary and by-products as
exposure to any a means to
other substance establish
that is present specifications for
with the notified applicable
substance either contaminants and
naturally or due by-products.
to its manufacture
(e.g.,
contaminants or by-
products).
170.235(d)....................... 170.36(c)(4)(i)(A). 11a In Part 3 of your Specifies a
GRAS notice, you necessary aspect
must describe the of the proposed
source of any food ``comprehensive
consumption data discussion'' of
that you use to scientific data,
estimate dietary information, and
exposure. methods.
170.235(e)....................... 170.36(c)(4)(i)(A). 11a In Part 3 of your Specifies a
GRAS notice, you necessary aspect
must explain any of the proposed
assumptions you ``comprehensive
made to estimate discussion'' of
dietary exposure. scientific data,
information, and
methods.
[[Page 55003]]
170.250(a)(1).................... 170.36(c)(4)(i)(A). N/A In Part 6 of your N/A.
GRAS notice, you
must explain why
the data and
information in
your notice
provide a basis
for your view that
the notified
substance is safe
under the
conditions of its
intended use,
considering all
dietary sources
and taking into
account any
chemically or
pharmacologically
related substances
in such diet.
----------------------------------------------------------------------------------------------------------------
See section XXV.F for a discussion of comments on the issues listed
in table 27 regarding dietary exposure when a notified substance would
be added to animal food and for changes we made to the regulatory text
regarding dietary exposure when a notified substance would be added to
animal food.
(Comment 73) Some comments support retaining the statutory language
derived from section 409(c)(5) of the FD&C Act when stating the
requirement for a comprehensive discussion in a GRAS notice that
considers dietary exposure. One of these comments states that the
proposed statutory language regarding dietary exposure is consistent
with the criteria for general recognition of safety through scientific
procedures, which requires the same quantity and quality of scientific
evidence necessary for a food additive petition. Other comments support
revising the proposed requirement as a means of clarifying that the
comprehensive discussion in a GRAS notice must consider dietary
exposure.
(Response 73) We agree that: (1) The requirements of the rule
regarding what a notifier must include in a GRAS notice regarding
dietary exposure must be clear; and (2) the statutory language of
section 409(c)(5)(A) of the FD&C Act is consistent with the criteria
for general recognition of safety through scientific procedures, which
requires the same quantity and quality of scientific evidence necessary
for a food additive petition. To meet both of these goals, the final
rule requires information about dietary exposure (i.e., the amount of
relevant substances that consumers are likely to eat or drink as part
of a total diet), as we suggested in the 2010 notice, but also retains
the detailed statutory direction as proposed (see Sec. 170.235(a)
through (c), Sec. 170.250(a)(1), and table 13). In addition to
requiring an estimate of dietary exposure to the notified substance
(Sec. 170.235(a)), the rule requires, when applicable, that a notifier
provide data and information about dietary exposure to any other
substance that is expected to be formed in or on food because of the
use of the notified substance (e.g., hydrolytic products or reaction
products) (Sec. 170.235(b)). Example of such substances are benzoates
(which react with ascorbic acid (such as in beverages) to form benzene)
and sulfur dioxide (which reacts irreversibly with thiamine, such that
we have prescribed limitations on the use of sulfur dioxide in some
food products (see Sec. 182.3862)). The rule also requires, when
applicable, that a notifier provide data and information about dietary
exposure to any other substance that is present with the notified
substance either naturally or due to its manufacture (e.g.,
contaminants or by-products). An estimate of dietary exposure to
substances such as contaminants and by-products is necessary to
establish specifications for applicable contaminants and by-products
(see Sec. 170.230(c), which requires that a GRAS notice include
specifications for food-grade material). See also Response 75.
(Comment 74) One comment asks us to allow for a reasonable
methodology that does not overestimate dietary exposure in the extreme.
(Response 74) The rule neither prescribes the methodology you would
use to estimate dietary exposure nor requires that you overestimate
dietary exposure. Consistent with the proposed requirement for the
consideration of dietary exposure to be a ``comprehensive discussion,''
the rule requires you to describe the source of any food consumption
data that you use to estimate dietary exposure and any assumptions you
made to estimate dietary exposure; such information is necessary for
the estimates of dietary exposure to be scientifically sound and
provides an opportunity for you to explain why the methodology you used
is reasonable (see Sec. 170.235(d) and (e) and table 13). Our guidance
entitled ``Estimating Dietary Intake of Substances in Food'' provides
general recommendations for calculating and submitting estimates of
dietary intake to support the documentation of the safety of substances
introduced into food either intentionally to accomplish a technical
effect, adventitiously as a component of an added substance, or
inadvertently through contamination resulting from processing (Ref.
25).
(Comment 75) One comment emphasizes that the requirement for
consideration of dietary exposure must discuss the potential cumulative
effect of the notified substance.
(Response 75) We agree. We are specifying that the narrative
included in Part 6 of a GRAS notice must address the safety of the
notified substance, considering all dietary sources and taking into
account any chemically or pharmacologically related substances in such
diet (see Sec. 170.250(a)(1)).
(Comment 76) Some comments support requiring that a GRAS notice
include information about dietary exposure to contemporary consumers
when the conclusion of GRAS status is through experience based on
common use in food prior to 1958, e.g., because dietary exposure to
contemporary consumers serves as a baseline for future studies/
assessment. Other comments do not support such a requirement and assert
that it is not critical to update the exposure data if consumption of
the GRAS substance was already widespread before 1958, or that
information about dietary exposure to contemporary consumers would only
be necessary if the exposure has significantly changed since 1958.
One comment questions the value of requiring information about
contemporary dietary intake of an ingredient that is GRAS through
experience based on common use in foods. This comment asserts that the
[[Page 55004]]
FD&C Act deems an ingredient to be GRAS if it was commonly used in
foods prior to January 1, 1958, and that FDA has long recognized that a
conclusion of GRAS status through experience based on common use in
food may be made without the quantity or quality of scientific
procedures required for establishment of a food additive regulation.
This comment asserts that there is no requirement for a GRAS ingredient
to be consumed at the same use level as in 1958 and that imposition of
such a new requirement may be impracticable, e.g., because there may
not be any databases that would allow for the calculation of dietary
exposures prior to 1958. This comment also asserts that in many
instances there may be insufficient information to establish an
acceptable daily intake (ADI) for the ingredient because studies that
can be used to calculate ADIs may not be available for many of these
ingredients, and that without information about the ADI it would be
difficult to imagine the relevance of the estimated daily intake, which
would be calculated through dietary exposure.
Another comment asserts that Sec. Sec. 170.30(c) and 170.3(f)
clearly provide that for a substance to be GRAS through experience
based on common use in food there must be a substantial history of
consumption of the substance in food by a significant number of people
prior to 1958 and that the requirements for information about
consumption data in a GRAS notice should be consistent with those
regulatory provisions. This comment also asserts that requiring
information about dietary exposure to contemporary consumers would
represent an additional regulatory burden that would not impact the
original conclusion of GRAS status through experience based on common
use in food if there are no safety concerns when the notified substance
is used in accordance with the intended conditions of use.
(Response 76) We are requiring that a notifier provide data and
information about dietary exposure, regardless of whether the
conclusion of GRAS status is through scientific procedures or through
experience based on common use in food (see Sec. 170.235). The FD&C
Act and our regulations do not provide that a substance is necessarily
GRAS under the conditions of its intended use merely because it was
commonly used in food prior to 1958. Rather, the FD&C Act provides that
such a substance must be generally recognized, among experts qualified
by scientific training and experience to evaluate its safety, through
experience based on common use in food, to be safe under the conditions
of its intended use. Under both the FD&C Act and the definition of
``safe'' in our regulations, relevant factors must be considered,
including the ``probable consumption of the substance and of any
substance formed in or on food because of its use'' (see section
409(c)(5)(A) of the FD&C Act and Sec. 170.3(i)(1)). We recognize that
a conclusion of GRAS status through experience based on common use in
food does not require the same quantity or quality of scientific
information required for establishment of a food additive regulation;
however, this means that a conclusion of GRAS status through experience
based on common use in food is not necessarily supported by the same
testing data as would be required to support establishment of a food
additive regulation. See, for example, the 1976 final rule establishing
GRAS criteria, which provides, ``for those substances that were widely
used before 1958, under the terms of the statute FDA must consider
available data and may not prohibit use of a substance merely because
tests that would be required for new food additives have not been
performed.'' (41 FR 53600, December 7, 1976). Like a conclusion of GRAS
status based on scientific procedures, a conclusion of GRAS status
through experience based on common use in food requires that the
substance be ``safe,'' as defined in 21 CFR 170.3(i), under the
conditions of its intended use.
The rule requires that a notifier provide evidence of substantial
history of consumption of the substance for food use by a significant
number of consumers prior to January 1, 1958, but does not require an
estimate of dietary exposure prior to 1958 (see Sec. 170.245). The
rule requires that the narrative in Part 6 of a GRAS notice explain why
the data and information in the notice provide a basis for the
notifier's view that the notified substance is safe under the
conditions of its intended use, considering all dietary sources and
taking into account any chemically or pharmacologically related
substances in such diet (Sec. 170.250(a)); to do so, the notifier must
consider the estimated dietary exposure (which this comment refers to
as ``estimated daily intake''). However, the rule does not specify that
a notifier must determine an ``acceptable daily intake'' as part of the
narrative.
XV. Comments on Part 4 of a GRAS Notice: Self-Limiting Levels of Use
We proposed that a GRAS notice must include information on any
self-limiting levels of use (proposed Sec. 170.36(c)(3)). We did not
receive comments disagreeing with this proposed requirement. Therefore,
we are establishing a requirement for you to include in Part 4 of your
GRAS notice data and information on self-limiting levels of use in
circumstances where the amount of the notified substance that can be
added to food is limited because food containing levels of the notified
substance above a particular level would become unpalatable or
technologically impractical (see Sec. 170.240). We included an
explanation of the circumstances in which the level of use is self-
limiting for clarity.
XVI. Comments on Part 5 of a GRAS Notice: Common Use in Food Before
1958
We proposed that a GRAS notice include a comprehensive discussion
of, and citations to, generally available data and information that the
notifier relies on to establish safety, including evidence of a
substantial history of consumption of the substance by a significant
number of consumers, for a conclusion of GRAS status through experience
based on common use in food (proposed Sec. 170.36(c)(4)(ii)(A)).
During the Interim Pilot program, we received fewer than a dozen GRAS
notices where the statutory basis was through experience based on
common use in food (Ref. 45).
We did not receive comments disagreeing with this proposed
requirement and we are establishing a requirement for you to include in
Part 5 of your GRAS notice evidence of a substantial history of
consumption of the notified substance for food use by a significant
number of consumers prior to January 1, 1958 if the statutory basis for
your conclusion of GRAS status is through experience based on common
use in food (see Sec. 170.245). See table 29 for conforming changes
for a substance used in animal food.
XVII. Comments on Parts 6 and 7 of a GRAS Notice: Narrative and List of
Supporting Data and Information
We proposed that a GRAS notice must include a detailed summary of
the basis for the notifier's determination that a particular use of the
notified substance is exempt from the premarket approval requirements
of the FD&C Act because such use is GRAS (proposed Sec. 170.36(c)(4)).
Regardless of whether the conclusion of GRAS status was based on
scientific procedures or through experience based on common use in
food, we proposed to require: (1) A comprehensive discussion of, and
citations to, generally available and accepted scientific data and
information that the notifier relies on to establish
[[Page 55005]]
safety (proposed Sec. 170.36(c)(4)(i)(A) and 170.36(c)(4)(ii)(A)); (2)
a comprehensive discussion of any reports of investigations or other
information that may appear to be inconsistent with the GRAS
determination (proposed Sec. 170.36(c)(4)(i)(B) and (c)(4)(ii)(B));
and (3) the basis for concluding, in light of the data and information
in the GRAS notice, that there is consensus among experts qualified by
scientific training and experience to evaluate the safety of substances
added to food that there is reasonable certainty that the substance is
not harmful under the intended conditions of use (proposed Sec.
170.36(c)(4)(i)(C) and (c)(4)(ii)(C)). When the conclusion of GRAS
status is based on scientific procedures, we also proposed that the
discussion of generally available and accepted information that the
notifier relies on to establish safety include methods and principles,
and include a consideration of the probable consumption of the
substance and the probable consumption of any substance formed in or on
food because of its use and the cumulative effect of the substance in
the diet, taking into account any chemically or pharmacologically
related substances in such diet (proposed Sec. 170.36(c)(4)(i)(A)).
In the 2010 notice, we requested comment on issues relevant to the
applicability of confidential data and information to a conclusion that
a substance is GRAS under the conditions of its intended use (see table
14).
Table 14--Issues in the 2010 Notice Regarding the Applicability of
Confidential Data and Information to a Conclusion of GRAS Status
------------------------------------------------------------------------
Description of
Issue No. our request for Reference
comment
------------------------------------------------------------------------
9b........ Whether to 75 FR 81536 at 81539-81540.
require that a
notifier who
identifies one
or more trade
secret(s), as
defined in Sec.
20.61(a), in
the GRAS notice
explain why it
is trade secret
information and
how qualified
experts could
conclude that
the intended use
of the notified
substance is
safe without
access to the
trade secret(s).
9c........ Whether to 75 FR 81536 at 81539-81540.
require that a
notifier who
identifies
confidential
commercial or
financial
information, as
defined in Sec.
20.61(b), in
the GRAS notice
explain why it
is confidential
commercial or
financial
information and
how qualified
experts could
conclude that
the intended use
of the notified
substance is
safe without
access to such
information.
------------------------------------------------------------------------
In the following paragraphs, we discuss comments on the proposed
requirements applicable to a detailed summary of the basis for the
notifier's conclusion of GRAS status and the issues discussed in the
2010 notice. After considering these comments, we are establishing
requirements for Part 6 of a GRAS notice to include a narrative as
shown in table 15, and for Part 7 of a GRAS notice to include a list of
supporting data and information as shown in table 16, with editorial,
clarifying, and conforming changes as shown in table 29. (See
Sec. Sec. 170.250 and 170.255.)
Table 15 and table 16 identify changes we made relative to the
proposed rule or the description in the 2010 notice other than the
editorial, clarifying, and conforming changes shown in table 29 and the
additional editorial changes associated with the redesignation of
proposed Sec. 170.36(c)(4) as Sec. Sec. 170.250 and 170.255.
Table 15--Final Requirements for a Narrative in Part 6 of a GRAS Notice
----------------------------------------------------------------------------------------------------------------
Revisions (other
than editorial,
Proposed Issue No. in Description. Part 6 clarifying, and
Final designation in the designation in the the 2010 of your GRAS conforming changes)
regulatory text (Sec. ) regulatory text notice notice: relative to the
(Sec. ) proposed rule or
the 2010 notice
----------------------------------------------------------------------------------------------------------------
170.250.......................... 170.36(c)(4)....... N/A You must include a N/A.
narrative that
provides the basis
for your
conclusion of GRAS
status.
170.250(a)(1).................... 170.36(c)(4)....... N/A You must explain N/A.
why the data and
information in
your notice
provide a basis
for your view that
the notified
substance is safe
under the
conditions of its
intended use,
considering all
dietary sources
and taking into
account any
chemically or
pharmacologically
related substances
in such diet.
170.250(a)(2).................... 170.36(c)(4)....... 9a, 9b, and 9c You must identify Requires that your
what specific data narrative clarify
and information the status of all
are generally data and
available, and information that
what specific data you rely on to
and information establish safety.
are not generally
available, by
providing
citations to the
list of data and
information that
you include in
Part 7 of your
GRAS notice.
[[Page 55006]]
170.250(b)....................... 170.36(c)(4)....... N/A You must explain Uses the term
how the generally ``generally
available data and recognized''
information that rather than the
you rely on to term
establish safety ``consensus.''
provide a basis
for your
conclusion that
the notified
substance is
generally
recognized, among
qualified experts,
to be safe under
the conditions of
its intended use.
170.250(c)....................... 170.36(c)(4)....... 6b You must either: When applicable,
(1) Identify, requires an
discuss, and place affirmative
in context, data statement that you
and information have reviewed the
that are, or may available data and
appear to be, information and
inconsistent with are not aware of
your conclusion of any data and
GRAS status, information that
regardless of are, or may appear
whether those data to be,
and information inconsistent with
are generally your conclusion of
available; or GRAS status.
(2) State that you
have reviewed the
available data and
information and
are not aware of
any data and
information that
are, or may appear
to be,
inconsistent with
your conclusion of
GRAS status..
170.250(d)....................... N/A................ 9b and 9c In Part 6 of your N/A.
GRAS notice (the
narrative), if you
view any of the
data and
information in
your notice as
exempt from
disclosure under
the FOIA, you must
identify the
specific data and
information.
170.250(e)....................... N/A................ 9b and 9c In Part 6 of your Your explanation
GRAS notice (the must address all
narrative), you non-public safety-
must explain how related data and
there could be a information, not
basis for a just confidential
conclusion of GRAS data and
status if information
qualified experts included in your
generally do not GRAS notice.
have access non-
public, safety-
related data and
information.
----------------------------------------------------------------------------------------------------------------
Table 16--Final Requirements for a List of Supporting Data and Information in Part 7 of a GRAS Notice
----------------------------------------------------------------------------------------------------------------
Revisions (other
than editorial,
Proposed Issue No. in Description. Part 7 clarifying, and
Final designation in the designation in the the 2010 of your GRAS conforming changes)
regulatory text (Sec. ) regulatory text notice notice: relative to the
(Sec. ) proposed rule or
the 2010 notice
----------------------------------------------------------------------------------------------------------------
170.255(a)....................... 9a, 9b, and 9c You must include a Clarifies that the
170.36(c)(4)(i)(A). list of all of the list includes all
data and data and
170.36(c)(4)(ii)(A information that information, not
). you discuss in just generally
part 6 of your available data and
GRAS notice to information.
provide a basis
for your view that
the notified
substance is safe
under the
conditions of its
intended use.
170.255(b)....................... 9a, 9b, and 9c The data and Requires that you
170.36(c)(4)(i)(A). information that characterize each
you list must item in your list
170.36(c)(4)(ii)(A specify which data as to whether it
). and information is generally
are generally available.
available, and
which data and
information are
not generally
available.
----------------------------------------------------------------------------------------------------------------
In the requirements for Parts 6 and 7 of the final rule, we made
changes to require that the narrative in Part 6 of your GRAS notice,
and the accompanying list of supporting data and information in Part 7
of your GRAS notice, clarify the status of all data and information
that you rely on to establish safety as to whether it is generally
available (see Sec. Sec. 170.250(a)(2) and 170.255, table 15, and
table 16). We made these changes relative to the proposed requirements
for a detailed summary and comprehensive discussion for consistency
with: (1) The criteria for eligibility for classification as GRAS
through scientific procedures (which provide that a conclusion of GRAS
status may be corroborated by the application of unpublished scientific
data, information, or methods (see Sec. 170.30(b), Response 8, and
Response 12)); and (2) the provisions of the rule that allow you to
include data and information that are not generally available (see
Sec. 170.230(b) (which no longer stipulates that the method of
manufacture must exclude trade secret), Sec. 170.225(c)(8), Response
57 and Response 69).
In the requirements for Part 6 of a GRAS notice, we also made a
change to require that your narrative either: (1) Identify, discuss,
and place in context, data and information that are, or may appear to
be, inconsistent with your
[[Page 55007]]
conclusion of GRAS status, regardless of whether those data and
information are generally available; or (2) state that you have
reviewed the available data and information and are not aware of any
data and information that are, or may appear to be, inconsistent with
your conclusion of GRAS status. See Sec. 170.250(c) and table 15. We
made this change relative to the proposed requirement for a
comprehensive discussion of any reports of investigations or other
information that may appear to be inconsistent with a conclusion of
GRAS status to emphasize your responsibility to seek out such reports
and information, as we do during our evaluation of a GRAS notice. See
also Sec. 170.225(c)(9) and Response 58, in which we discuss the
requirements for a statement certifying that the GRAS notice is
``complete'' in addition to ``representative'' and ``balanced,'' to
emphasize your responsibility to identify, discuss, and place in
context, data and information that are, or may appear to be,
inconsistent with a conclusion of GRAS status. Under Sec. Sec.
170.225(c)(9) and 170.250(c), we expect you to describe unpublished
reports of investigations or other information that may appear to be
inconsistent with a conclusion of GRAS status, not just published
reports. If we identify relevant information that was not discussed in
the GRAS notice, we may question the credibility of the certification
statements in the GRAS notice and respond with an ``insufficient basis
letter.'' As noted in Response 58, the use of certification statements
has become routine in other submissions to FDA for food programs, and
the certification statements in Form FDA 3480 (for a food contact
notification submission) (Ref. 39) and in Form FDA 3537 (for
registration of a food facility) (Ref. 40) remind the submitter of
criminal penalties under 18 U.S.C. 1001 for a materially false,
fictitious, or fraudulent statement to the U.S. Government. Now that
certification statements will be required in a GRAS notice, we intend
to modify the form that we make available for the submission of a GRAS
notice (i.e., Form FDA 3667 (Ref. 38)) to likewise remind any person
who submits a GRAS notice of the applicability of criminal penalties
for a materially false, fictitious, or fraudulent statement to the U.S.
Government.
See also Response 78. We also expect you to describe unpublished
data and information that you consider to be corroborative of safety
(e.g., if you consider that the unpublished data and information
warrant sharing with any ``GRAS panel'' that you convene).
(Comment 77) One comment asserts that the proposed requirement for
a GRAS notice to include the basis for concluding that there is
consensus among qualified experts about the safety of the substance
misstates the statutory standard for general recognition in section
201(s) of the FD&C Act. This comment asserts that the term
``consensus'' denotes complete or near unanimity, whereas the standard
of general recognition requires that qualified experts predominantly,
but not unanimously, accept the safety of the substance. Although the
comment acknowledges that the proposed rule stated that the term
``consensus'' does not imply unanimity (62 FR 18938 at 18941), the
comment argues that the example used in our explanation, about whether
a single published report questioning the safety of use of a substance
in food would preclude general recognition, wrongly implied that
general recognition requires near unanimity (62 FR 18938 at 18941). The
comment asks us to revise the rule by replacing the term ``consensus,''
which does not appear in the statute, with the phrase ``general
recognition,'' which derives from the statute itself.
(Response 77) As discussed in the proposed rule (62 FR 18938 at
18939), our interpretation that general recognition requires consensus
is consistent with the case law on the general recognition standard.
See United States v. Western Serum Co., Inc., 666 F.2d 335, 338 (9th
Cir. 1982); United States v. Articles of Drug...Promise Toothpaste, 624
F.Supp. 776, 778 (N.D. Ill. 1985), aff'd 826 F.2d 564 (7th Cir. 1987);
United States v. Articles of Drug...Hormonin, 498 F.Supp.2d 424, 435
(D.N.J. 1980). See also the discussion of the consensus standard in
Response 20.
We proposed to provide our interpretation of section 201(s) of the
FD&C Act in the requirement for Part 6 of a GRAS notice to provide more
context to notifiers than merely repeating the statutory language. We
disagree with the comment's assertion that the example we described in
the proposed rule requires ``near unanimity''; CFSAN's experience
during the Interim Pilot program demonstrates that CFSAN's
``insufficient basis letters'' did not apply a standard of ``near
unanimity'' when evaluating the notifier's basis for a conclusion of
GRAS status (see section III.A.3 of CFSAN's 2010 experience document
(Ref. 18)).
However, we have decided to use the statutory language (i.e.,
``generally recognized'') rather than the proposed term ``consensus''
because the revised GRAS criteria that we are establishing in Sec.
170.30 continue to use the statutory language rather than the consensus
standard applied by the courts in applying the statutory language to
specific situations. Using the statutory language in both the GRAS
criteria and the requirement for the submission of a narrative in a
GRAS notice will emphasize your burden to explain how the data and
information in the notice regarding the safety of the notified
substance under the conditions of its intended use satisfy the GRAS
criteria.
See also Response 128, in which we respond to comments recommending
that we clarify that the same standards apply to a conclusion of GRAS
status regardless of whether the conclusion is submitted to us as a
GRAS notice or is not submitted to us. As noted in Response 128, we
believe that the provisions of the GRAS notification procedure will be
a useful resource to any person who intends to use a substance in food
based on a conclusion of GRAS status, regardless of whether the
conclusion of GRAS status is submitted to us in a GRAS notice. In
developing any recommendations (e.g., in guidance) that would broadly
apply to any conclusion of GRAS status, it is simpler to consistently
use the same regulatory text in both the GRAS criteria and the
submission requirements for a GRAS notice.
(Comment 78) One comment notes that industry has various options
for handling confidential information. For example, confidential
agreements are commonly used instruments to help maintain the
confidentiality of proprietary trade secret information, and therefore
qualified experts on GRAS panels can have access to such information if
it is necessary for a conclusion of GRAS status. The comment asks us to
require that notifiers indicate whether qualified experts (such as on
the notifier's GRAS panel) had access to trade secrets when they
concluded that the substance is safe under the conditions of its
intended use.
(Response 78) The rule establishes no requirements specific to a
GRAS panel. However, we agree that it is appropriate for a notifier to
indicate whether qualified experts (such as on the notifier's GRAS
panel) who reviewed the data and information supporting safety had
access to safety-related trade secrets in reaching a conclusion that
the notified substance is safe under the conditions of its intended
use. Therefore, we are requiring that a notifier explain how there
could be a basis for a conclusion of GRAS status if
[[Page 55008]]
qualified experts generally do not have access to non-public safety-
related data and information (see Sec. 170.250(e)). This requirement
applies to all non-public safety-related data and information, not just
trade secret information, and is not limited to non-public safety-
related data and information that are included in the notice. As
requested by the comment, this requirement would apply if the notifier
provided non-public safety-related information to outside experts (such
as on a GRAS panel). As already discussed, if a GRAS panel considers
non-public safety-related information that a notifier does not include
in a GRAS notice, we also expect the notifier to inform us that the
GRAS panel had access to such information, consistent with the
notifier's signed statement that the GRAS notice is a complete,
representative, and balanced submission (see Sec. 170.225(c)(9)) (see
Response 58 and Response 69).
See also table 11 and table 15. The rule also requires that a
notifier state his view as to whether any of the data and information
in Parts 2 through 7 of a GRAS notice are exempt from disclosure under
the FOIA (see Sec. 170.225(c)(8)) and identify what specific data and
information in the notice are generally available, and what specific
data and information in the notice are not generally available (see
Sec. 170.250(a)(2) and (d)). Collectively, the requirements in
Sec. Sec. 170.225(c)(8) and (9) and 170.250(a)(2), (d), and (e)
address the underlying issue in the comment's request, i.e., that there
must be a basis for a conclusion of GRAS status if some safety-related
data and information that a notifier assesses in his deliberations are
non-public (e.g., trade secret information or otherwise are
confidential information), regardless of whether the notifier shares
such information with a GRAS panel. If a GRAS notice does not provide a
basis for a conclusion that the notified substance is safe under the
conditions of its intended use without access to such information, we
would respond to the notice with an ``insufficient basis letter.'' If
we respond with a ``no questions letter,'' and later determine that the
GRAS notice was not ``complete'' (e.g., because it did not describe
unpublished reports of investigations that are, or may appear to be,
inconsistent with the conclusion of GRAS status), we may send the
notifier a subsequent letter regarding the omission; such a letter
would be readily accessible to the public (Sec. Sec. 170.265(c) and
170.275(b)(2)).
(Comment 79) One comment suggests that if the qualified experts are
FDA reviewers, an option might be for the notifier to submit a
``sanitized'' version of the GRAS notice, excluding non-public
information, together with a separate appendix to the GRAS notice where
the notifier would include relevant trade secrets or confidential
information needed to support the conclusion of GRAS status.
Alternatively, we could require that a notifier submit two versions of
the submission: (1) A sanitized version that excludes non-public
information; and (2) a more detailed version including the confidential
information. The comment states that these options would both allow our
reviewers access to the information and facilitate the process of
promptly making GRAS notices available for public disclosure.
(Response 79) In enacting the GRAS provision, Congress clearly
contemplated a process of concluding that a food substance is GRAS
under the conditions of its intended use as an alternative to
submission of a food additive petition to FDA and establishment of a
regulation prescribing the conditions under which the substance may be
safely used. It follows that the qualified experts who evaluate the
basis for a conclusion that the notified substance is safe under the
conditions of its intended use must not exclusively be ``FDA's
experts'' (such as our scientific staff who evaluate GRAS notices). The
suggestion of this comment that a notifier could rely exclusively on
evaluation by FDA experts to support his view that there is a basis for
concluding that there is consensus among ``qualified experts'' is
inconsistent with the GRAS provision in section 201(s) of the FD&C Act,
which requires general recognition among qualified experts. See also
the discussion in Response 70, in which we explain our reasons for why
we may decide to decline to file a GRAS notice that is accompanied by a
separate file containing data and information that you view as non-
public.
XVIII. Comments on Steps a Notifier May Take Before We Respond to a
GRAS Notice
In the 2010 notice, we described comments regarding steps you may
take before we respond to your GRAS notice (see table 17). As noted in
section VIII.A, we are establishing a definition for ``amendment'' in
the rule (see Sec. 170.203). In the following paragraphs, we discuss
additional comments regarding the issues in table 17. Some of these
comments agree that the rule should have such a provision. Other
comments ask us to clarify how such a provision would operate in
practice (see, e.g., Comment 82) or suggest one or more changes to the
provision as we described it in the 2010 notice (see, e.g., Comment 80,
Comment 81, and Comment 83). After considering these comments, we are
establishing two provisions regarding steps you may take before we
complete our evaluation of a GRAS notice. The first provision specifies
that you may submit a timely amendment to your filed GRAS notice, to
update your GRAS notice or in response to a question from us, before we
respond to your notice by letter (see the regulatory text of Sec.
170.260(a)). The second provision specifies that you may ask us to
cease to evaluate your GRAS notice as described in the 2010 notice,
with clarifications as a result of comments (see the regulatory text of
Sec. 170.260(b)). One clarification is that such a request does not
preclude you from submitting a future GRAS notice with respect to the
notified substance. A second clarification is that we will send you a
letter informing you of our decision regarding your request (see the
regulatory text of Sec. 170.265(b)(3)).
Table 17--Issues in the 2010 Notice Regarding Steps You May Take Before
We Respond to Your GRAS Notice
------------------------------------------------------------------------
Description of
Issue No. our request for Reference
comment
------------------------------------------------------------------------
3a........ Whether to define 75 FR 81536 at 81538.
``amendment'' to
mean any data or
other
information that
you submit
regarding a
filed GRAS
notice before we
respond to the
notice.
5......... Whether the final 75 FR 81536 at 81538-81539.
rule should
explicitly
provide that you
may request in
writing that we
cease to
evaluate your
GRAS notice at
any time during
our evaluation
of that GRAS
notice.
------------------------------------------------------------------------
[[Page 55009]]
See section XXV.I for a discussion of comments regarding steps you
may take before we respond to your GRAS notice for a substance used in
animal food, and for our response to those comments.
A. Communicating With a Notifier Before We Respond to a GRAS Notice
(Comment 80) Several comments note that the proposed rule did not
say that we would contact a notifier, before we issue our publicly
available response, to provide preliminary feedback regarding our
evaluation of a GRAS notice. One of these comments asks us to include a
provision specifying that we may communicate with the notifier about
any aspect of a notice while the notice is pending. Some comments
express concern that a letter listing answerable and nonsubstantive
questions about a GRAS notice could cause confusion and
misunderstanding in the marketplace, particularly if additional
information, clarification, or amendment would address our concerns.
(Response 80) We decline the request to include a provision
specifying that we may communicate with you about any aspect of a
notice while your notice is pending. As discussed in section III.C.1 of
CFSAN's 2010 experience document (Ref. 18), during the Interim Pilot
program CFSAN contacted several notifiers to request clarification
about data and information in the notice under the framework of
existing regulations governing meetings and correspondence (Sec.
10.65(g)). It is not necessary to duplicate the existing procedures in
Sec. 10.65(g) in the requirements for the GRAS notification procedure.
We infer that this comment is specifically asking us to require
that we contact you to provide preliminary feedback before we respond
to your GRAS notice with an ``insufficient basis letter.'' As discussed
in section III.C.1 of CFSAN's 2010 experience document (Ref. 18), our
experience during the Interim Pilot program demonstrates that we are
willing to engage in a dialog with a notifier to clarify particular
aspects of a GRAS notice. As discussed in section IV.H.4 of CFSAN's
2010 experience document (Ref. 18), our experience during the Interim
Pilot program also demonstrates that we do not issue an ``insufficient
basis letter'' with ``nonsubstantive questions.'' Although we have
issued ``insufficient basis letters'' due to an overall poor quality of
a submission, to conserve resources our practices have evolved so that
we generally do not file such submissions as GRAS notices (see section
XIX.A regarding filing decisions and section III.K of CFSAN's 2010
experience document (Ref. 18)). Although we expect to contact you when
we have questions, whether we intend to provide you with an opportunity
to submit an amendment to a GRAS notice before responding to the notice
has been, and will continue to be, a matter committed to our
discretion.
In the following paragraphs, we discuss some key factors we intend
to consider regarding the purpose of our contact with you regarding
your GRAS notice, particularly with respect to whether we intend to
provide you with an opportunity to submit an amendment to a GRAS
notice. These factors are: (1) Whether our questions can be addressed
by a timely, clarifying amendment; (2) whether our evaluation
identifies a safety concern; and (3) whether we question whether GRAS
criteria are satisfied, even if our evaluation does not identify a
safety concern. See also the discussion in Response 85 regarding
factors that could lead us to decline to file a submission as a GRAS
notice, rather than to file it for our evaluation of your view that the
notified substance is GRAS under the conditions of its intended use and
issue an ``insufficient basis letter.''
We agree that an ``insufficient basis letter'' listing answerable
questions about a GRAS notice could cause confusion and
misunderstanding in the marketplace, particularly if additional
information, clarification, or amendment would address our concerns.
Section III.C.1 of CFSAN's 2010 experience document provides examples
of circumstances where CFSAN contacted a notifier and expected that the
information exchanged between CFSAN and the notifier would clarify,
rather than substantively amend, the original notice. We intend to
continue contacting notifiers in such circumstances. By ``clarify,
rather than substantively amend,'' we mean that the amendment would add
or modify specific sections in the notice, not that the clarifying
information would necessarily be nonsubstantive in nature. For example,
as discussed in Response 96 during the Interim Pilot program we
contacted notifiers when the notice contained insufficient information
about dietary exposure and when the notice contained insufficient
information to adequately identify the substance. We did so because it
is efficient, for us as well as the notifier, to bring a GRAS notice to
closure with a ``no questions letter'' when it is likely that a timely,
clarifying amendment would resolve our questions. For example, it is
more efficient for us to bring a GRAS notice to closure while our
reviewers are already immersed in the substantive evaluation of the
notice, rather than to issue an ``insufficient basis letter'' and begin
the evaluation process anew when the notifier addresses the questions
in a new GRAS notice. See section XVIII.B for a discussion of what we
mean by a ``timely'' amendment.
If we file your submission as a GRAS notice and our evaluation of
the available data and information identifies a safety concern, the
purpose of our contact with you would depend on whether the safety
concern could be addressed by a timely, clarifying amendment. For
example, in some cases the available data and information may support
safety only under modified conditions of use relative to the conditions
of use described in your GRAS notice, and our contact with you would
focus on your opportunity to address the safety concern through a
timely amendment specifying modified conditions of use. However, if we
believe that the safety concern could not be addressed through a
timely, clarifying amendment or by re-submission of a new GRAS notice
(e.g., after studies are conducted to address the safety concern), we
likely would contact you to make you aware of our concerns and then
issue an ``insufficient basis letter'' that clearly and fully
articulates our reasons for that safety concern, including the full
context of the risk to human or animal health.
If we file your submission as a GRAS notice and find that your
narrative does not support a conclusion of GRAS status, even if the
available data and information support your view that the notified
substance is safe under the conditions of its intended use (e.g.,
because data and information that are necessary to establish safety are
not generally available), the purpose of our contact with you would
focus on your opportunity to address the regulatory status of the
notified substance. For example, it may be possible for you to submit a
new GRAS notice after publishing applicable data and information and
allowing sufficient time to allow the expert scientific community to
access the published information. Alternatively, it may be more
appropriate for you to consider the notified substance as a food
additive under the conditions of its intended use, and to make a
premarket submission such as a food additive petition. For examples of
circumstances leading to the options for addressing questions about the
regulatory status of the substance when we have not identified a safety
concern, see section III.A.4 of CFSAN's 2010 experience document (Ref.
18). Any letter we issue would
[[Page 55010]]
include our view of the regulatory status of the substance at the time
that we issued the letter, based on the generally available data and
information at that time.
B. Submitting an Amendment
Comments support adding a provision to clarify that you may submit
an amendment to your GRAS notice and, thus, we are establishing a
provision specifying that you may submit a timely amendment to your
filed GRAS notice (Sec. 170.260(a)). In some cases, you would submit
such an amendment after we contact you to discuss our questions about
your GRAS notice. (See the discussion in Response 80 regarding
contacting a notifier.) In other cases, you may conclude that it is
appropriate to submit an amendment to update your GRAS notice on your
own initiative, e.g., if new data and information about the notified
substance under the conditions of its intended use become available
after we file your submission as a GRAS notice. Depending on the
circumstances, you could then decide to explain your view that the new
data and information do not alter the basis for your conclusion of GRAS
status; alternatively, you could decide to ask us to cease to evaluate
your GRAS notice while you evaluate the impact of the new data and
information on the GRAS status of the notified substance under the
conditions of its intended use (see Sec. 170.260(b)).
By timely, we mean that you submit your amendment in a timeframe
that provides us with sufficient time to evaluate it before we respond
to your GRAS notice. Given that the rule requires us to end our
evaluation and respond to your GRAS notice within 180 days, with an
extension of up to an additional 90 days on an as needed basis Sec.
170.265(b)(1)), we reserve the right to not consider your amendment if
you submit it so late in our evaluation that it would impact our
ability to respond within our established timeframes. Therefore, as a
companion provision, the rule also provides that we will consider any
timely amendment that you submit to a filed GRAS notice, to update your
GRAS notice or in response to a question from us, before we respond to
you by letter based on our evaluation of your notice if we deem that
doing so is feasible within the established timeframes (see Sec.
170.265(a)(4)). If we deem that considering your amendment is not
feasible within the established timeframes, we will inform you that we
are not considering your amendment.
See also the discussion in Response 101, which emphasizes that the
role of an amendment is to clarify questions that we have about your
conclusion of GRAS status rather than to substantively amend the GRAS
notice.
C. Notifier's Request That We Cease To Evaluate a GRAS Notice
(Comment 81) Some comments ask us to make public the reason for a
notifier's request that we cease to evaluate a notice. One comment asks
that any new information, or questions about the scientific consensus
about whether a substance is safe, be made clear to the public as well
as FDA. Another comment expresses concern that companies ask FDA to
cease evaluations of their GRAS notices with ``alarming frequency.''
(Response 81) We are establishing a provision specifying that a
notifier may ask us to cease to evaluate his GRAS notice (see Sec.
170.260(b)). As a companion provision, we are specifying that if a
notifier asks us to cease to evaluate a GRAS notice, we will send the
notifier a letter informing the notifier of our decision regarding that
request (see Sec. 170.265(b)(3)). As discussed in section III.E of
CFSAN's 2010 experience document (Ref. 18), during the Interim Pilot
program CFSAN's ``cease to evaluate letters'' generally repeated any
reason specified in a request letter, but may not have otherwise
described the reasons underlying the request. If a notified substance
is marketed even though we issue a ``cease to evaluate letter,'' there
could be confusion about the GRAS status of the notified substance even
when the conditions of use in the marketplace differ from the notified
use that was the subject of the ``cease to evaluate letter.'' For
example, a notifier could ask us to cease to evaluate a GRAS notice
because we identified a safety concern about the specified use level of
the notified substance in food products, and then decide to market the
substance at a lower use level than the level specified in the GRAS
notice, where we would no longer have that concern. In addition, as
discussed in the proposed rule we proposed to make all response letters
readily accessible to the public because such a system will properly
underscore a notifier's acceptance of responsibility for the conclusion
of GRAS status, and a GRAS notice that is submitted to us is a public
notice (62 FR 18938 at 18953). A ``cease to evaluate letter'' signals
that a submitted GRAS notice does not provide an adequate basis for a
conclusion that the notified substance is GRAS under the conditions of
its intended use, even though we do not issue an ``insufficient basis
letter.'' Given the public nature of a GRAS notice, it is appropriate
for the reasons leading to a ``cease to evaluate letter'' to also be
public. Therefore, as of October 17, 2016, we intend to change this
practice and increase transparency by describing the reasons leading to
any ``cease to evaluate letter.''
Table 1 in CFSAN's 2010 experience document (Ref. 18) shows that
approximately 16 percent of GRAS notices that CFSAN responded to during
the 12-year period spanning 1998 through 2009 came to closure when the
notifier asked us to cease to evaluate a GRAS notice. Table 1 in
CFSAN's 2010 experience document also shows that CFSAN issued equal
numbers of ``cease to evaluate letters'' and ``insufficient basis
letters'' during the years 1998 through 2002 (i.e., 16 ``cease to
evaluate letters'' and 16 ``insufficient basis letters''). However,
during the years 2003 through 2009 CFSAN issued 31 ``cease to evaluate
letters,'' but no ``insufficient basis letters.'' In addition, table 1
in CFSAN's 2016 experience document (Ref. 19) shows that during the
years 2010 through 2015 CFSAN issued 48 ``cease to evaluate letters''
but only one ``insufficient basis letter.'' We acknowledge that there
has been a distinct shift between the ratio of the number of ``cease to
evaluate letters'' compared to the number of ``insufficient basis
letters'' issued during the years 1998 through 2002 and the
corresponding ratio for letters issued during the years 2003 through
2015. We consider that the data in the experience document demonstrate
an evolving practice in which CFSAN has declined to file some
submissions as GRAS notices when the notice lacks much of the required
data and information necessary for us to evaluate a notifier's view
that the notified substance is GRAS under the conditions of its
intended use (see Response 85). In addition, such a frequency
demonstrates that CFSAN has been willing to contact notifiers with
questions about a conclusion that the notified substance is GRAS under
the conditions of its intended use. As discussed in Response 80, when
our questions cannot be addressed by a timely amendment, contacting the
notifier provides the notifier an opportunity to re-submit a new GRAS
notice or other regulatory submission (such as a food additive
petition) that addresses our questions.
As discussed in section III.E of CFSAN's 2010 experience document
(Ref. 18), in many cases a notifier who received a ``cease to evaluate
letter'' resubmitted a new GRAS notice, and CFSAN responded with a ``no
questions letter.'' For many GRAS notices, the
[[Page 55011]]
questions we raised and discussed with the notifier clearly addressed
issues other than a fundamental safety concern. For example, some of
the letters that CFSAN lists in section III.E of its 2010 experience
document provide reasons such as preparing a new notice that will not
contain any confidential business information and that will clarify
that the statutory basis for the conclusion of GRAS status is through
scientific procedures; needing to revise an estimate of dietary
exposure; and clarifying and providing additional information for a new
notice. However, CFSAN only made these reasons transparent to the
public because the notifier chose to provide these reasons in his
request that we cease to evaluate the GRAS notice. In other
circumstances, the public had no way to know what the issue was until
we responded to the resubmitted notice. We intend to continue to
contact a notifier to discuss our questions, and provide an opportunity
for the notifier to ask us to cease to evaluate the GRAS notice (e.g.,
so that the notifier can submit a new GRAS notice that addresses the
issues). However, we also intend to briefly describe these issues in a
``cease to evaluate letter'' that follows that contact. As CFSAN did
during the Interim Pilot program, we intend to consider any reasons a
notifier provides for the request, and to include those reasons in our
``cease to evaluate letter.'' If, however, we conclude that a
notifier's explanation does not adequately describe the reasons leading
to a ``cease to evaluate'' request, we intend to explain the reasons
for ceasing to evaluate the notice from our point of view. Doing so
will both ensure clear communication about the reasons and make the
reasons transparent to the public.
As discussed in Response 80, if we identify a safety concern and
believe that the safety concern could not be addressed through a
timely, clarifying amendment, by re-submitting a new GRAS notice, or by
submitting another premarket submission (such as a food additive
petition), we likely would issue an ``insufficient basis letter'' even
though we would have contacted the notifier to discuss our concerns.
Asking us to cease to evaluate a GRAS notice does not guarantee
that we will honor that request. Depending on the circumstances, we may
decide to decline the request and instead respond with an
``insufficient basis letter''; depending on the time remaining between
when we receive the request and the timeframes by which we must respond
to the GRAS notice, we may either send the notifier a separate letter
declining the request, or note in the ``insufficient basis letter''
that we had declined the request. See the discussion in section III.C.1
of CFSAN's 2010 experience document (Ref. 18) for an example of a
situation in which CFSAN responded with an ``insufficient basis
letter'' after a notifier asked CFSAN to cease to evaluate its GRAS
notice, submitted a new GRAS notice, and asked CFSAN to cease to
evaluate the second submitted GRAS notice.
(Comment 82) One comment asks us to clarify that a notifier's
request that we cease to evaluate a GRAS notice would be without
prejudice for future submissions.
(Response 82) The final provision specifies that your request that
we cease to evaluate a GRAS notice does not preclude you from
submitting a future GRAS notice with respect to the notified substance.
(Comment 83) One comment asks us to specify that, if feasible, the
files could be returned to the notifier at the notifier's expense.
(Response 83) We decline this request. As discussed in the 2010
notice (75 FR 81536 at 81538-81539), our current regulations regarding
public information stipulate that no person may withdraw records
submitted to FDA (see Sec. 20.29), and those regulations will apply to
any GRAS notice that we receive. To make this clear, the provision we
are establishing in the final rule provides an opportunity for you to
ask us to ``cease to evaluate'' a GRAS notice rather than ``withdraw''
a GRAS notice.
(Comment 84) Some comments ask us to specify that if a notifier
requests that we cease to evaluate a submitted GRAS notice, such
notices will remain in our files and will be available for public
disclosure.
(Response 84) See Sec. 20.29 and the discussion of Issue 5 in the
2010 notice (75 FR 81536 at 81538-81539). If a notifier asks us to
cease to evaluate a submitted GRAS notice, the notice will remain in
our files and will be available for public disclosure in accordance
with part 20. It is not necessary to repeat the provisions of Sec.
20.29 in the GRAS notification procedure.
XIX. Comments on What We Will Do With a GRAS Notice
We proposed that: (1) We would acknowledge receipt of a notice,
within 30 days of receipt, by informing the notifier in writing of the
date on which the notice was received (proposed Sec. 170.36(d)); (2)
we would respond to the notifier in writing within 90 days of receipt
of the notice (proposed Sec. 170.36(e)); and (3) a copy of any
subsequent letter that we issued regarding a GRAS notice would be
readily accessible for public review and copying (proposed Sec.
170.36(f)(2)(iii)). In the 2010 notice, we asked for comment on issues
relating to what we will do with a GRAS notice as shown in table 18.
Table 18--Issues in the 2010 Notice Regarding What We Will Do With a
GRAS Notice
------------------------------------------------------------------------
Description of
Issue No. our request for Reference
comment
------------------------------------------------------------------------
12........ Whether we should 75 FR 81536 at 81541.
make explicit
the process by
which we make a
filing decision,
including the
factors we would
use to determine
whether to file
a submission as
a GRAS notice.
14........ Whether we should 75 FR 81536 at 81542.
retain a set
timeframe for us
to respond to a
GRAS notice,
and, if so,
whether it
should be 90
days or another
timeframe.
------------------------------------------------------------------------
In the following sections, we discuss comments on what we will do
when we receive a GRAS notice. After considering these comments, we are
establishing requirements in Sec. 170.265 for what we will do when we
receive a GRAS notice as shown in table 19, with editorial, clarifying,
and conforming changes as shown in table 29. Table 19 identifies
changes we made relative to the proposed rule or the description in the
2010 notice other than the editorial, clarifying, and conforming
changes shown in table 29 and the additional editorial changes
associated with the redesignation of proposed Sec. 170.36(d), (e), and
(f)(2)(iii) as Sec. 170.265. See section XXV.I for a discussion of
comments specific to a filing decision for a substance used in animal
food.
[[Page 55012]]
Table 19--Final Requirements for What FDA Will Do With a GRAS Notice
----------------------------------------------------------------------------------------------------------------
Revisions (other
than editorial,
Proposed Issue No. in clarifying, and
Final designation in the designation in the the 2010 Description conforming changes)
regulatory text (Sec. ) regulatory text notice relative to the
(Sec. ) proposed rule or
the 2010 notice
----------------------------------------------------------------------------------------------------------------
170.265(a)(1).................... N/A................ 12 We will conduct an N/A.
initial evaluation
of your submission
to determine
whether to file it
as a GRAS notice
for evaluation of
your view that the
notified substance
is GRAS under the
conditions of its
intended use.
170.265(a)(2).................... 170.36(d).......... 12 If we file your N/A.
submission as a
GRAS notice, we
will send you a
letter that
informs you of the
date of filing.
170.265(a)(3).................... N/A................ 12 If we do not file Clarifies that we
your submission as would inform you
a GRAS notice, we by letter if we do
will send you a not file your
letter that submission as a
informs you of GRAS notice.
that fact and
provides our
reasons.
170.265(a)(4).................... N/A................ 3a We will consider Clarifies that we
any timely will only consider
amendment that you an amendment if we
submit to a filed deem that doing so
GRAS notice, to is feasible within
update your GRAS the established
notice or in timeframes.
response to a
question from us,
before we respond
to you by letter
based on our
evaluation of your
notice if we deem
that doing so is
feasible within
the established
timeframes. If we
deem that
considering your
amendment is not
feasible within
the established
timeframes, or if
we have granted
your request to
cease to evaluate
your notice, we
will inform you
that we are not
considering your
amendment.
170.265(b)(1).................... 170.36(e).......... 14 Within 180 days of Specifies
filing, we will that the timeframe
respond to you by for our response
letter based on is 180 days,
our evaluation of rather than 90
your notice. We days.
may extend the 180 Provides
day timeframe by for an extension
90 days on an as of our evaluation
needed basis. by 90 days on an
as needed basis.
170.265(b)(2).................... N/A................ 14 If we extend the Provides that we
timeframe, we will will inform you if
inform you of the we extend the
change in writing timeframe for our
as soon as response.
practicable but no
later than within
180 days of filing.
170.265(b)(3).................... N/A................ 5 If you ask us to Companion change in
cease to evaluate light of new
your GRAS notice, regulatory text
we will send you a (in Sec.
letter informing 170.260(b))
you of our expressly
decision regarding providing that you
your request. may ask us to
cease to evaluate
your GRAS notice.
170.265(c)....................... 170.36(f)(2)(iii).. N/A If circumstances Clarifies that we
warrant, we will may send a
send you a subsequent letter,
subsequent letter in addition to
about the notice. specifying under
the public
disclosure
provisions of the
rule that such a
letter would be
readily available
to the public (see
Sec.
170.275(b)(2)).
----------------------------------------------------------------------------------------------------------------
A. Filing Decision
(Comment 85) One comment asks for greater refinement, clarity, and
transparency when we decline to file a GRAS notice. Some comments ask
us to communicate any questions or concerns that could be quickly
addressed upon submission of a GRAS notice. Another comment asks us to
use specific criteria for a ``decline to file'' determination when
format and general categories are adequate. Another comment states that
an explicit process for how we will make a filing decision need not be
detailed ``in the public domain'' even though it would be beneficial to
the notifier.
Another comment asks us to specify the criteria that we use to
decide to provide verbal feedback to a notifier (e.g., by telephone)
rather than send the notifier a letter informing the notifier that we
have declined to file a submission as a GRAS notice. This comment
expresses concern that our refusal to explain the problem in a letter
could be interpreted to mean that we have safety concerns. This comment
asserts that a process in which we neither provide specific guidance,
nor provide written feedback, when we decline to file a submission as a
GRAS notice would both discourage voluntary submissions of GRAS
conclusions from industry and conflict with GAO's recommendations (in
their 2010 report) that we should take steps to increase our awareness
of independent conclusions of GRAS status.
(Response 85) These comments raise a number of issues regarding the
importance of a written communication from us to a notifier when we
decline to file a submission as a GRAS notice, including transparency
and the potential that lack of a written explanation for why we
declined to file
[[Page 55013]]
a submission as a GRAS notice could lead to suppositions, such as
whether we have safety concerns. To address these issues, the final
rule provides that if we do not file a submission as a GRAS notice, we
will send the notifier a letter that informs the notifier of that fact
and provides our reasons for not filing the submission as a GRAS notice
(see Sec. 170.265(a)(3)). We would not place that letter ``in the
public domain'' by including it in our publicly available Inventory of
GRAS Notices, because the submission had not been filed as a GRAS
notice and, thus, there would be no entry where we would place the
letter. However, whether the letter would be releasable in response to
a FOIA request would be a case-by-case determination based on the
contents of the letter and the provisions of part 20.
We are not specifying in the regulatory text the factors that could
lead us to decline to file a submission as a GRAS notice, because the
factors that apply to a particular GRAS notice may be very specific to
that notice. Importantly, a GRAS notice presents an opportunity for a
notifier to inform us about a conclusion of GRAS status rather than an
opportunity for a notifier to test a hypothesis that there is a
sufficient basis to reach a conclusion of GRAS status. If our initial
evaluation of a submission demonstrates that it lacks much of the
required data and information necessary for us to evaluate the
notifier's view that the notified substance is GRAS under the
conditions of its intended use, our current practice is to decline to
file it as a GRAS notice (see Sec. 170.265(a)(3)). By declining to
file a submission as a GRAS notice, we would both conserve our own
resources and provide the notifier an opportunity to submit a new GRAS
notice, that contains appropriate data and information and an adequate
narrative, rather than move forward knowing that an amendment necessary
for us to evaluate the notifier's view that the notified substance is
GRAS under the conditions of its intended use would be so substantive
as to make the original submission largely irrelevant. For additional
examples of factors we have considered in determining whether to file a
submission as a GRAS notice, see the examples we provided in the 2010
notice (75 FR 81536 at 81541), the discussion of filing decisions in
section III.K of CFSAN's 2010 experience document (Ref. 18), Response
48, and Response 70. As discussed in Response 152, CVM intends to
consider the same factors that CFSAN considers regarding whether to
file a submission as a GRAS notice.
(Comment 86) In the 2010 notice, we explained that we may decide to
respond to a submission as general correspondence, rather than file it
as a GRAS notice, if the subject of the submission is: (1) Already
authorized for use under our regulations; or (2) a mixture of
substances that are already authorized for use under our regulations.
One comment asks us to clarify how we would determine that the use of a
substance is authorized for use under our regulations, with respect to
the similarity of factors such as: (1) The substance; (2) the intended
conditions of use of the substance, including food categories and use
levels; and (3) the manufacturing process.
(Response 86) We decline this request because it is overly broad.
We do not have a ``formula'' that would apply in all circumstances.
Just as the factors that apply to a particular GRAS notice may be very
specific to that notice, the factors that would apply in determining
whether the intended conditions of use of a notified substance are
already authorized by our regulations may be very specific to that
substance. However, with regard to similarities in the manufacturing
process, we likely would apply the same factors that we have advised
industry to apply when assessing the effects of significant
manufacturing process changes on the safety and regulatory status of
food ingredients (Ref. 6).
We note that we also may decide to respond to a submission as
general correspondence, after communicating with the submitter as
appropriate, rather than file it for evaluation as a GRAS notice, if
the subject of the submission is: (1) Already the subject of a GRAS
notice, and we have responded to that GRAS notice with a ``no questions
letter''; or (2) a mixture of substances that already are the subject
of GRAS notices, and we have responded to those GRAS notices with ``no
questions letters.'' In contrast to the statutory provisions for the
FCN program (section 409(h) of the FD&C Act), there is no provision in
the FD&C Act providing exclusivity for a notifier for the use of a
substance on the basis that it is GRAS under the conditions of its
intended use.
(Comment 87) One comment asks us to conduct a preliminary
evaluation of a GRAS notice to determine whether the notice appears to
be inadequate because the intended conditions of use of the notified
substance raise ``general policy'' issues.
(Response 87) It is not clear what the comment means by ``general
policy'' issues. However, we note that we would not file a submission
as a GRAS notice if the intended conditions of use of the notified
substance are not eligible for classification as GRAS because, for
example, the intended conditions of use are excepted from the
definition of ``food additive'' in section 201(s) of the FD&C Act (and
thus, from the GRAS provision included in that definition of ``food
additive''). See, for example, the exception for a color additive in
section 201(s)(3) of the FD&C Act, for a dietary ingredient intended
for use in a dietary supplement in section 201(s)(6) of the FD&C Act,
and for a new animal drug in section 201(s)(5) of the FD&C Act.
(Comment 88) Some comments ask us to contact the notifier when our
initial evaluation of a GRAS notice raises questions, and provide the
notifier with an opportunity to withdraw the notice without prejudice
before we begin a substantive evaluation of the notice.
(Response 88) We agree that our decision to not file a submission
as a GRAS notice would be without prejudice to a future submission of a
GRAS notice for the notified substance. However, see Response 70,
Response 112, and the discussion in the 2010 notice at 75 FR 81536 at
81539. Just as a filed GRAS notice is available for public disclosure
subject to the procedures established in part 20, a submission that you
send to us is a record that is available for public disclosure subject
to the procedures established in part 20, regardless of whether we file
that submission as a GRAS notice. Thus, you cannot ``withdraw'' a
submission from our files after you send it to us.
(Comment 89) One comment asks whether ``substantial equivalence''
considerations are linked to ``decline to file'' decisions or play a
dominant role in ``decline to file'' decisions. This comment also asks
us to issue a letter to the notifier explaining the basis for a
``decline to file'' decision if ``substantial equivalence'' is the
reason.
(Response 89) As discussed in section IV.N of CFSAN's 2010
experience document (Ref. 18), several GRAS notices filed during the
Interim Pilot program relied, in part, on the concept of ``substantial
equivalence''; in each of the listed examples CFSAN had no questions
about the notifier's conclusion of GRAS status. As discussed in
Response 21, whether, and to what extent, similarity between two
substances could support a conclusion of GRAS status depends on many
situation-specific variables. Thus, it would be the complete evaluation
process, rather than the initial evaluation that we conduct as part of
a filing decision, that would determine whether a GRAS notice that
relies on the concept of ``substantial equivalence''
[[Page 55014]]
provides a basis for a conclusion of GRAS status. As discussed in
Response 85, the final rule provides that if we do not file a
submission as a GRAS notice, we will send the notifier a letter that
informs the notifier of that fact and provide our reasons for not
filing the submission as a GRAS notice (see Sec. 170.265(a)(3)); if
problems with a notifier's use of the concept of ``substantial
equivalence'' play a role in our decision to not file a submission as a
GRAS notice, we intend to say so.
B. Our Response to a GRAS Notice
1. Administrative Content of Our Response to a GRAS Notice
(Comment 90) Several comments address the administrative content of
a letter that responds to a GRAS notice. In general, these comments ask
us to include the following items in the response letter: (1) Name and
address of the notifier; (2) the date of our receipt of the notice; (3)
the common or usual name of the notified substance; and (4) the
applicable conditions of use of the notified substance. One comment
states that use of a standard format and language in our letters would
be administratively efficient.
(Response 90) We agree that a standard format and language in our
letters would be administratively efficient and that the administrative
features suggested by these comments are appropriate to include in our
response letter. During the Interim Pilot program, we both developed a
standard format and language for our response letters and included the
administrative features suggested by these comments (see section
III.H.1 of CFSAN's 2010 experience document (Ref. 18)). We intend to
continue incorporating these features in letters issued under the final
rule. However, as discussed in Response 51, the final rule requires
that you provide the name of the notified substance, using an
appropriately descriptive term, rather than the ``common or usual
name'' of the notified substance (see Sec. 170.225(c)(3)). Therefore,
CFSAN's response letters will include an appropriately descriptive term
for the notified substance provided in a GRAS notice submitted to
CFSAN. See section XXV.C regarding the name of the notified substance
provided in a GRAS notice submitted to CVM.
2. Substantive Content of Our Response to a GRAS Notice
(Comment 91) Several comments note that the proposed rule did not
specify what we would say in a letter responding to a GRAS notice and
ask us to include in the final rule the specific language for the
response letter, particularly when we do not raise any questions about
the notifier's conclusion of GRAS status. Some comments assert that a
notifier who invests resources in a GRAS notice deserves a response
that is standardized and predictable and will not change as personnel
changes occur.
(Response 91) See table 1. During the Interim Pilot program we
developed three categories of response letter: (1) ``No questions
letter''; (2) ``insufficient basis letter''; and (3) ``cease to
evaluate letter.'' As discussed in sections IV.H.1 through IV.H.7 of
CFSAN's 2010 experience document (Ref. 18), these letters include some
standard information that is consistent across those letters, such as
opening and closing paragraphs using a standard format, and
administrative information (e.g., the date of our receipt of the GRAS
notice). They also include unique features that depend upon the
circumstances, such as labeling issues and whether the use of the
substance could require a color additive listing. The content of the
three categories of response letter has evolved over time, and may
continue to evolve. In addition, it is possible that in the future a
response to a GRAS notice may not fit squarely within one of the
current categories of response letter. Therefore, the final rule
continues to specify that we will respond to a GRAS notice but does not
specify any detail about the nature of the response.
(Comment 92) Several comments address the content of a ``no
questions letter.'' These comments ask that a ``no questions letter''
be clear and definitive, provide clear assurance that we recognize the
GRAS status of the substance under the conditions of its intended use,
have some regulatory significance, and be as affirmative as possible.
Some of these comments note that our statements in the proposed rule
(62 FR 18938 at 18950) indicated that we would evaluate a GRAS notice
to determine whether there is a sufficient basis for the notifier's
conclusion of GRAS status and suggest that our response to a GRAS
notice could reflect those statements. Comments also suggest the
following specific statements that could be included in a ``no
questions letter'':
``FDA at this time does not question your determination
that the notified use(s) of this substance is (are) Generally
Recognized as Safe.''
``The Agency finds that there is substantial evidence
supporting both the safety of the intended uses of the substance and
the fact that this safety is generally known and accepted by qualified
experts.''
``The notice provides a sufficient basis for the
notifier's determination that the substance is GRAS for its intended
use.''
(Response 92) See table 1 for the typical text of a ``no questions
letter'' that we issued during the Interim Pilot program. At this time,
we intend to continue including such text in our ``no questions
letters.'' We agree that the regulatory significance of a ``no
questions letter'' should be clear. As shown in table 1, during the
Interim Pilot program a typical ``no questions letter'' made clear
that: (1) It is the information that is provided by the notifier that
forms the basis for our response, and that the notifier (rather than
FDA) is responsible for the conclusion of GRAS status; and (2) our
response must be considered in context based on the knowledge and
information available to us at a point in time, because scientific
knowledge and information about a particular ingredient can evolve and
sometimes change over time.
The typical text of a ``no questions letter'' issued during the
Interim Pilot program is similar to the specific suggestion of one
comment (i.e., FDA at this time does not question your determination
that the notified use of this substance is GRAS), except that under the
final rule we will use the term ``conclusion'' rather than
``determination.'' We disagree that a ``no questions letter'' should
state that we ``find'' that there is substantial evidence supporting
both the safety of the intended conditions of use of the notified
substance and the fact that this safety is generally known and accepted
by qualified experts; a GRAS notice reflects the conclusion of the
notifier, not a finding by FDA. Likewise, we disagree that a ``no
questions letter'' should state that a notice ``provides a sufficient
basis'' for the notifier's conclusion that the notified substance is
GRAS under the conditions of its intended use; the phrase ``providing a
sufficient basis'' would imply that we are taking responsibility for
the notifier's conclusion of GRAS status.
As discussed in Response 41, we are replacing the term
``determination'' with ``conclusion,'' and referring to a ``conclusion
of GRAS status'' rather than to a ``GRAS determination,'' throughout
the regulatory text for the GRAS notification procedure. We intend to
modify the typical text of our response letters to refer to the
``notifier's conclusion'' (rather than the ``notifier's
determination'') in letters issued under the final rule (see table 20).
We also
[[Page 55015]]
intend to specify that we have not affirmed the GRAS status of the
notified substance under the conditions of its intended use, rather
than to specify that we have not made our own determination. However,
as noted in section II.B, we intend to adapt our practices, consistent
with the provisions of this rule, as circumstances warrant and as
necessary to administer the GRAS notification program consistent with
appropriate public health policy, current scientific information, our
available resources, and the scientific and regulatory issues raised by
specific GRAS notices. Thus, the text shown in table 20 is for
illustrative purposes only and could evolve over time.
Table 20--Categories of Letters Responding to a GRAS Notice Under the
Final Rule
------------------------------------------------------------------------
Typical text of for a response as
Category of response letter modified to incorporate terms used
in the rule
------------------------------------------------------------------------
``No questions letter''........... Based on the information provided by
the notifier, as well as other
information available to FDA, the
Agency has no questions at this
time regarding the notifier's
conclusion that the notified
substance is GRAS under the
conditions of its intended use. By
this letter, however, the Agency
has not affirmed the GRAS status of
the notified substance under the
conditions of its intended use in
accordance with 21 CFR 170.35. As
always, it is the continuing
responsibility of the notifier to
ensure that food ingredients that
the firm markets are safe, and are
otherwise in compliance with all
applicable legal and regulatory
requirements.
``Insufficient basis letter''..... FDA has evaluated the data and
information in the GRAS notice as
well as other available
information. The notice does not
provide a sufficient basis for a
conclusion that the notified
substance is GRAS under the
conditions of its intended use.
``Cease to evaluate letter''...... In correspondence dated [month, day,
year], you asked that we cease to
evaluate your GRAS notice. We
ceased to evaluate your GRAS
notice, effective the date we
received your correspondence.
------------------------------------------------------------------------
(Comment 93) One comment suggests that a written response need not
assess the quality of the submission but rather could acknowledge
whether the notice was complete in addressing all key issues.
(Response 93) We disagree that we could acknowledge whether a
notice is ``complete'' without assessing the quality of the submission.
Providing a basis for whether the data and information regarding the
safety of a substance under the conditions of its intended use satisfy
GRAS criteria is not a matter of whether there is ``something behind
each tab.'' It would not be appropriate, for example, for us to
acknowledge that a GRAS notice is ``complete'' because it included the
narrative required by Part 6 of a GRAS notice without assessing the
adequacy of the narrative. Whether a notice is ``complete'' in
addressing all key issues depends on the nature and quality of the
submitted data and information.
(Comment 94) Some comments ask that a ``no questions letter''
qualify that we have not affirmed that the intended conditions of use
of the notified substance are GRAS. Other comments ask that a ``no
questions letter'' qualify that we have not conducted a substantive
review.
(Response 94) We agree that a ``no questions letter'' should be
clear that we have not affirmed that the substance is GRAS under the
conditions of its intended use. See table 20.
However, we disagree that a ``no questions letter'' should state
that we did not conduct a substantive review of the GRAS notice. See
Response 25. Our evaluation of a GRAS notice is a substantive
evaluation of the notifier's basis for concluding that the intended
conditions of use of the notified substance are safe and the criteria
for GRAS status are satisfied. In addition, as circumstances warrant,
we evaluate information that is not included in the notice but is
otherwise available to us (see section IV.G of CFSAN's 2010 experience
document (Ref. 18)).
(Comment 95) Some comments ask that a ``no questions letter''
include a positive statement that we have not identified a problem with
the notice because finished food producers have been reluctant to use a
substance without such documentation. These comments both assert that
the only alternative available to manufacturers whose customers require
such a positive statement would be to seek food additive approval for
an ingredient and maintain that such approval is unnecessary from a
legal perspective.
(Response 95) Consistent with the request of these comments, we
intend to continue including a statement that we ``have no questions at
this time'' (see table 1 and table 20). Whether a manufacturer's
customer requires a regulation prescribing the conditions under which a
substance may be safely used in food, when there is a basis for
concluding that the substance is GRAS under the conditions of its
intended use, is a business matter between the manufacturer and the
customer. If the manufacturer submits a food additive petition and we
find, based on the data and information submitted in the petition, that
the intended conditions of use of the substance are safe, we would
issue a regulation prescribing the conditions under which the food
additive may be safely used.
(Comment 96) Several comments address the specific content of an
``insufficient basis letter'' and ask us to be specific about any
deficiencies that we identify in the notice. Some comments assert that
an ``insufficient basis letter'' must clearly distinguish between
deficiencies that relate to safety and those that relate to a technical
matter, such as the level of the substance that is needed to accomplish
the intended technical effect. One comment asks us to include in the
final rule guidelines that articulate clear standards for issues that
are of sufficient magnitude to result in an ``insufficient basis
letter.''
(Response 96) We agree that we should be specific about identified
problems and distinguish between circumstances that lead to an
insufficient basis letter. Our experience during the Interim Pilot
program demonstrates that we have done so, and we intend to continue
this practice under the final rule. For example, as discussed in
sections IV.H.4 and IV.H.7 of CFSAN's 2010 experience document (Ref.
18), we have issued an insufficient basis letter in cases where health
effects seen in toxicological or clinical studies were not adequately
explained or because the notice did not describe adequate toxicological
studies; when the notice contained insufficient information about
dietary exposure; when the notice contained insufficient information to
adequately identify the substance; when the notice contained
insufficient information to satisfy the standard for demonstration of
GRAS status through experience based on common use in food; and as a
result of the regulatory framework associated with the substance. To
date, we have not issued an insufficient basis letter solely as a
result of insufficient
[[Page 55016]]
evidence regarding the level of the substance that is needed to
accomplish the intended technical effect. However, CVM's experience
document demonstrates that CVM has included lack of information
regarding the intended technical effect as one of several reasons
leading to an insufficient basis letter (Ref. 20). Some ``no questions
letters'' issued by CFSAN have discussed the level of the substance
that is needed to accomplish the intended technical effect, e.g., when
CFSAN informed a notifier who received a ``no questions letter'' that
FSIS needed information regarding the lowest level necessary for the
substance to achieve its intended effect in meat, meat food product, or
poultry product (see section III.L of CFSAN's 2010 experience document
(Ref. 18)).
Our experience during the Interim Pilot program demonstrates that
whether a notice provides a sufficient basis for a conclusion of GRAS
status is a case-by-case evaluation and that the circumstances vary.
Therefore, we decline the request to specify standards for issues that
are of sufficient magnitude to result in an ``insufficient basis
letter.'' See sections IV.H.4 and IV.H.7 of CFSAN's 2010 experience
document (Ref. 18) for information on specific GRAS notices that
received an ``insufficient basis letter'' from CFSAN, and table 1 in
CVM's experience document (Ref. 20) for information on GRAS notices
that received an ``insufficient basis letter'' from CVM. Our letters
responding to each of these GRAS notices describe the problems in more
detail and are available on CFSAN's Web site (Ref. 46) and CVM's Web
site (Ref. 47).
(Comment 97) Some comments ask that an ``insufficient basis
letter'' include a qualifying statement that we have not conducted a
substantive review and have not concluded that the intended conditions
of use of the notified substance are not GRAS. These comments assert
that a response that does not include such a statement could have the
practical effect of challenging the use of a substance in the absence
of a threshold determination that the notified use is not GRAS.
(Response 97) We disagree that an ``insufficient basis letter''
should state that we did not conduct a substantive review of the GRAS
notice. See Response 25 and Response 94. Our evaluation of a GRAS
notice is a substantive evaluation.
The typical text of an ``insufficient basis letter'' specified that
``the notice does not provide a sufficient basis'' for a determination
that the notified substance is GRAS under the conditions of its
intended use (see table 1), and we intend to continue including such
text in letters issued under the final rule, modified to refer to a
``conclusion'' of GRAS status rather than a ``determination'' of GRAS
status (see table 20). This typical text addresses the adequacy of the
notice rather than the regulatory status of the substance; consistent
with the request of these comments, this text does not specify that we
have concluded that the intended conditions of use of the notified
substance are ``not GRAS.'' In several cases during the Interim Pilot
program, a notifier who received an ``insufficient basis letter''
submitted a second GRAS notice and received a ``no questions letter''
in response to the second GRAS notice (see sections III.D and IV.K of
the experience document (Ref. 18)). In these examples, CFSAN's response
to the notifier's first GRAS notice made clear that the submitted
notice did not provide a basis for a conclusion of GRAS status, but
CFSAN had no questions about the basis for GRAS status provided by the
second notice.
3. Our Consideration of a Timely Amendment
As discussed in section XVIII.B, the rule provides that you may
submit a timely amendment to your filed GRAS notice to update your GRAS
notice or in response to a question from us (Sec. 170.260(a)). As a
companion provision, the rule also provides that we will consider any
timely amendment that you submit to a filed GRAS notice, to update your
GRAS notice or in response to a question from us, before we respond to
your notice based on our evaluation of your notice if we deem that
doing so is feasible within the established timeframes (see Sec.
170.265(a)(4)). If we deem that considering your amendment is not
feasible within the established timeframes, we will inform you that we
are not considering your amendment (see Sec. 170.265(a)(4)). We also
will inform you that we are not considering your amendment if we have
granted your request to cease to evaluate your notice (i.e., if we send
you a ``cease to evaluate letter''). See Sec. 170.265(b)) and Response
98 for the timeframe established in this rule for our response to your
GRAS notice.
4. Timeframe for Our Response to a GRAS Notice
(Comment 98) Several comments support retaining the proposed 90-day
timeframe. According to these comments, a 90-day timeframe would
provide an incentive for a manufacturer to submit a GRAS notice. One
comment asserts that we should be held accountable to the proposed 90-
day timeframe, whereas another comment suggests that the proposed 90-
day timeframe provide a benchmark at which we should make the notifier
aware of the current status of our evaluation of the notice even if we
have not had sufficient time to completely review the safety of the
notified substance.
One comment that asks us to retain the proposed 90-day timeframe
stresses that we should have flexibility to take additional time as
needed. Another comment agrees that it would be appropriate for us to
extend the evaluation period, provided we do so only in limited
instances.
One comment asserts that the requirements of the GRAS notification
procedure are similar to the requirements of the GRAS affirmation
petition process and questions whether we could respond to a GRAS
notice within 90 days because we did not respond to a GRAS petition in
such a short timeframe. One comment that stresses the importance of
retaining a set evaluation timeframe suggests that the timeframe be 90-
180 days based on CFSAN's experience during the Interim Pilot program,
and opposes a timeframe greater than 180 days. Other comments support a
180-day timeframe because it would be realistic and reasonable, would
be sufficient to resolve all of the issues raised by a GRAS notice with
procedural fairness, and could be consistent and fair across both CFSAN
and CVM.
(Response 98) We are establishing a timeframe of 180 days from the
date of filing for our response to a GRAS notice. We also are providing
that we may extend the 180-day response timeframe by 90 days on an as
needed basis; if we do so, we will inform you of the extension in
writing as soon as practicable but no later than within 180 days of
filing. (See the regulatory text of Sec. 170.265(b)(1) and (2)). We
agree that the 180-day timeframe is realistic and reasonable, would be
sufficient to resolve all of the issues raised by a GRAS notice with
procedural fairness in most cases, and could be consistent and fair
across both CFSAN and CVM.
We disagree that we should establish a 90-day timeframe merely
because we had proposed this timeframe before we gained experience with
evaluating GRAS notices. As shown in section III.M of CFSAN's 2010
experience document, less than 12 percent of the response letters CFSAN
issued as of December 31, 2009, were sent within the proposed 90-day
timeframe (Ref.
[[Page 55017]]
18). Importantly, section III.M of CFSAN's 2010 experience document
also shows that in many cases a dialog between FDA and a notifier about
scientific issues associated with a GRAS notice, with an ensuing
amendment from the notifier, played a role in the timeframe for CFSAN's
response to a GRAS notice. As discussed in the 2010 notice, several
comments ask us to allow a notifier to address questions we have about
a GRAS notice by submitting an amendment to the notice (see Issue 3a,
75 FR 81536 at 81538), and the final rule expressly provides that you
may submit an amendment to a filed GRAS notice before we respond to the
notice (see Sec. 170.260(a)). Although we are including flexibility to
take additional time as needed, our goal is to do so in only limited
instances, such as when the intended conditions of use of the notified
substance raise complex scientific issues.
We have no basis to judge whether a 90-day timeframe, but not a
180-day timeframe, would provide an incentive to a manufacturer to
submit a GRAS notice. However, as noted in Response 24 CFSAN filed more
than 600 GRAS notices during the time period 1998 through 2015,
including 69 GRAS notices filed during 2014 and 51 GRAS notices filed
during 2015, even though CFSAN rarely responded to a GRAS notice within
90 days. We believe that the ongoing submission of GRAS notices is
evidence that the 180-day timeframe that is consistent with our
experience during the Interim Pilot program is not a disincentive to a
manufacturer.
We note that the procedural requirements of the GRAS notification
procedure are very different from the procedural requirements of the
GRAS affirmation petition process in that we respond to a GRAS notice
by letter whereas we respond to a GRAS affirmation petition through
rulemaking. As previously discussed (62 FR 18938 at 18941), the
resource-intensive rulemaking process includes: (1) Publishing a filing
notice in the Federal Register; (2) requesting comment on the
petitioned request; (3) conducting a comprehensive review of the
petition's data and information and comments received to the filing
notice to determine whether the evidence establishes that the
petitioned use of the substance is GRAS; (4) drafting a detailed
explanation of why the use is GRAS (as opposed to simply being safe);
and (5) publishing that explanation in the Federal Register. Therefore,
we disagree with the perspective of one comment that our experience in
responding to a GRAS affirmation petition should have any bearing on
the determination of an appropriate timeframe for our response to a
GRAS notice.
(Comment 99) One comment expresses concern that a 90-day timeframe
would be unrealistic unless we allocate additional resources to the
program. This comment asks us to consider a process similar to the
process for the FCN program, where there is a fixed review period
during which we can ``object to'' a submitted notification. If we do
not object within the review period or do not request an extension to
the review period, a notification submitted to the FCN program is
considered effective.
(Response 99) We decline this request. We disagree that the GRAS
notification procedure should be modeled after the FCN program. Unlike
the GRAS notification procedure, the FCN program is a mandatory process
for food contact substances under section 409(h) of the FD&C Act.
Furthermore, the statute provides that the FCN program shall not
operate unless it has certain appropriated funds. See section
409(h)(5)(A)(i) of the FD&C Act and Sec. 170.104(c)(3). There are no
similar statutory requirements applicable to our evaluation of the
basis for a conclusion of GRAS status.
(Comment 100) One comment asserts that we should respond to a GRAS
notice within 90 days unless we identify a problem that warrants dialog
with the notifier and an ensuing amendment.
(Response 100) We disagree. The suggestion of this comment could
lead to the unintended consequence of seeking unnecessary amendments
merely to stay within an established timeframe. We believe it is more
appropriate to establish a single timeframe that would broadly apply to
all GRAS notices, with the potential to extend the timeframe on an as
needed basis.
(Comment 101) One comment asks us to stop the ``review clock'' when
we inform a notifier that we have questions about a notice and then
restart the ``review clock'' upon receipt of an amendment that answers
our questions.
(Response 101) We decline this request. We acknowledge that there
could be an advantage to such a process, because stopping the review
clock would reduce the time pressures on our staff. However, the role
of an amendment is to clarify questions that we have about your
conclusion of GRAS status rather than to substantively amend the GRAS
notice. A process in which we stop and start a review clock implies
that the timeframe for you to submit an amendment could be so long as
to significantly impact our ability to respond within an established
timeframe. Rather than a process in which we stop and start a review
clock on a particular GRAS notice, we have provided that you may ask us
to cease to evaluate a GRAS notice when your preparation of an
amendment would impact our ability to respond within 180 days.
5. Responding to a GRAS Notice in All Circumstances
In the proposed rule, we noted that the GRAS notification procedure
could be structured so that we respond only when we question the GRAS
status of the intended use of the substance and requested comment on
whether we should, in all cases, provide a notifier with a letter at
the conclusion of our evaluation of a notice (62 FR 18938 at 18951).
(Comment 102) Several comments agree with our discussion in the
proposed rule that a written response from us would give manufacturers
an incentive to notify us of their conclusions of GRAS status; these
comments recommend that we respond in writing in all circumstances.
Other comments suggest that we limit our response to circumstances in
which we identify a problem with a notice because such a limitation
would make it easier for us to respond within the proposed 90-day
timeframe. One comment expresses concern that a written response could
create a misperception that we had undertaken an independent review of
the data described in the GRAS notice; to prevent this misperception,
this comment suggests that we respond in writing only if we find a
problem with the notice.
(Response 102) We acknowledge that limiting our response to
circumstances in which we identify a problem with a notice would reduce
the number of letters that we write. However, we believe that it is
important to publicly document our evaluation of the GRAS notice in
light of all the comments submitted to this rulemaking. (See, e.g.,
Comment 25 and the comments we discuss in section VII.C). In addition,
in our experience it is the process of evaluating a submission and
reaching a decision about whether the notice provides a basis for a
conclusion of GRAS status, rather than the process of drafting and
issuing a letter, that requires the most time.
We acknowledge the potential that a ``no questions letter'' could
be misinterpreted, e.g., to mean that FDA, rather than the notifier,
had reached a conclusion of GRAS status. To mitigate the potential for
such misinterpretation, the typical text of our response letters
[[Page 55018]]
issued during the Interim Pilot program referred to the notifier's
determination and stated that we have not made our own determination
regarding the GRAS status of the subject use of the notified substance
(see table 1). We intend to continue including such typical text in
letters issued under the final rule, modified as shown in table 20.
(Comment 103) One comment suggests that we respond in writing only
at the notifier's request.
(Response 103) We decline this suggestion, which is contrary to
emphasis that the rule places on the notifier's acceptance of
responsibility for a conclusion of GRAS status (see the discussion at
62 FR 18938 at 18953).
(Comment 104) One comment asserts that a letter acknowledging
receipt of a GRAS notice would constitute a form of response. Another
comment suggests that a letter acknowledging receipt of a GRAS notice
state whether the notice meets the listed requirements for a GRAS
notice, eliminating the need for a second letter responding to the
notice when we complete our evaluation. This comment asserts that a
second letter would be unnecessary for two reasons. First, the notifier
has accepted full responsibility for the conclusion of GRAS status and
does not require premarket approval from us. Second, under the terms of
the rule a notifier must agree to make all data and information
available to us.
(Response 104) The final rule provides that we will inform you of
the date on which we filed your notice rather than the date on which we
received it, as we had proposed. We disagree that a letter informing
you of the date of filing in any way responds to a GRAS notice or
should state whether the notice meets the listed requirements for a
GRAS notice. As discussed in Response 93, we cannot acknowledge whether
a notice ``meets the listed requirements'' without assessing the
quality of the submission, which we do during the evaluation that
follows filing the submission as a GRAS notice.
We acknowledge that submitting a GRAS notice means that a notifier
has accepted full responsibility for the conclusion of GRAS status. We
also acknowledge that the use of a GRAS substance is not subject to our
premarket review. However, we disagree that a relevant factor in
determining whether we should respond to a notifier is the notifier's
agreement to make all data and information available to us if we
question whether the notice provides an adequate basis for a conclusion
of GRAS status. A GRAS notice presents an opportunity for you to inform
us about your conclusion of GRAS status rather than an opportunity for
you to test a hypothesis that there is a sufficient basis to reach a
conclusion of GRAS status.
(Comment 105) One comment suggests that we issue a written response
only when we have reached a conclusion regarding safety.
(Response 105) This comment may have misunderstood the proposed
notification procedure. Under the notification procedure, you analyze
the available data and information and reach a conclusion about whether
the notified substance is safe under the conditions of its intended use
and whether there is a basis to conclude that the criteria for GRAS
status are satisfied. We evaluate your conclusions regarding the
available data and information. During the Interim Pilot program, the
typical text of a ``no questions letter'' stated that we had not
reached our own determination regarding the GRAS status of the notified
substance under the conditions of its intended use (see table 1).
To the extent that the comment is suggesting that we issue an
``insufficient basis letter'' when the problem with the notice relates
to safety, but not to general recognition, we disagree. It would be
inconsistent with the legal basis of the GRAS standard for us to only
focus on safety, and we did not do so during the Interim Pilot program.
(See section III.A.3 of CFSAN's 2010 experience document (Ref. 18),
where CFSAN identifies ``insufficient basis letters'' in which CFSAN
had questions about whether there was general recognition of safety.)
C. Additional Correspondence as Circumstances Warrant
(Comment 106) One comment expresses the view that a ``no questions
letter'' should not affect our ability to change our position if
additional information indicates that the use of the substance raises
any safety concerns.
(Response 106) We agree, and the final rule expressly provides that
we will send the notifier a subsequent letter about the notice if
circumstances warrant (see Sec. 170.265(c)). The circumstances may not
relate to safety. As discussed in section IV.J of CFSAN's 2010
experience document (Ref. 18), as of December 31, 2009, none of the
subsequent letters CFSAN issued during the Interim Pilot program
reflected a change in CFSAN's position and several addressed issues
other than the safety of the use of the substance. For example, CFSAN
issued subsequent letters that: (1) Clarified the intended conditions
of use; (2) clarified that the term CFSAN used to refer to the notified
substance for the purpose of the letter should not be considered an
endorsement of that term for the purpose of declaring the substance in
the ingredient statement of food products; (3) clarified FSIS' position
regarding the use of the notified substance in meat, meat food product
or poultry product; and (4) corrected a mistake in the original
response. CFSAN also sent a subsequent letter as an administratively
efficient mechanism of responding to a notifier who provided CFSAN with
information supporting a conclusion that an additional use of the
notified substance satisfied GRAS criteria.
In addition, CFSAN has issued a subsequent letter when CFSAN's
first letter was an ``insufficient basis letter'' rather than a ``no
questions letter.'' For example, CFSAN did so when a notifier who
received an ``insufficient basis letter'' submitted a new GRAS notice
that did not address the questions CFSAN raised in the ``insufficient
basis letter.'' CFSAN also did so when a notifier who received an
``insufficient basis letter'' submitted a supplement to its original
GRAS notice rather than submit a new GRAS notice. See section IV.J of
CFSAN's 2010 experience document (Ref. 18).
D. Procedures if a Notifier Disagrees With Our Response
In the proposed rule, we explained that there are existing
processes that we considered would be appropriate for a notifier to use
to engage us if the notifier disagreed with our response (see 62 FR
18938 at 18952 and table 21). We also noted that any person with
concerns about our response to a GRAS notice may contact our Office of
the Chief Mediator and Ombudsman; that office works on resolving issues
and conflicts that arise in any FDA component.
Table 21--Existing Procedures in Our Regulations That Can Apply if a
Notifier Disagrees With Our Response to a GRAS Notice
------------------------------------------------------------------------
Regulatory section (Sec. ) Description
------------------------------------------------------------------------
10.25............................. Initiation of administrative
proceedings.
10.33............................. Administrative reconsideration of
action.
10.65............................. Meetings and correspondence.
10.75............................. Internal agency review of decisions.
------------------------------------------------------------------------
(Comment 107) Several comments express concern that the processes
discussed in the proposed rule would be
[[Page 55019]]
available only after we sent, and made readily accessible to the
public, an ``insufficient basis letter.'' Other comments express
concern about the practical effect of an ``insufficient basis letter''
on the notifier's ability to market a notified substance while the
notifier is seeking review of our evaluation. Some comments ask that
our letter be ``stayed'' until any problems that we identified in our
response to the notice are resolved under such a process.
(Response 107) We acknowledge the concerns expressed in these
comments but are making no changes to the rule to address these
concerns. One of the underpinnings of the GRAS notification procedure
is that making our response readily accessible to the public will
properly underscore your responsibility for the conclusion of GRAS
status (62 FR 18938 at 18953). As discussed in Response 104, a GRAS
notice presents an opportunity for you to inform us about your
conclusion of GRAS status rather than for you to test a hypothesis that
there is a sufficient basis to reach a conclusion of GRAS status. If we
send you an ``insufficient basis letter,'' we advise you to carefully
consider whether marketing the notified substance would be lawful.
``Staying'' an ``insufficient basis letter'' informing you that there
may not be a legal basis to market the notified substance, e.g., so
that you could market the substance while you are working to resolve
the issues that led us to send you an ``insufficient basis letter'',
would not change the legal status of the notified substance.
(Comment 108) Several comments assert that the processes we had
identified in the proposed rule are cumbersome and do not provide
manufacturers with a clear framework or timeline for responding to our
questions or concerns. In general, these comments ask us to include in
the final rule a prompt, fair, and effective process that would be
specific to the GRAS notification procedure. A few comments suggest
that such an appeal mechanism also apply to subsequent correspondence
from us about a GRAS notice.
Some comments provide specific suggestions for how an appeals
mechanism specific to the GRAS notification procedure could work, e.g.,
by specifying that a notifier may submit additional data and
information for our evaluation, or by providing for an independent
advisory committee or an FDA-certified third-party review organization
to review the matter and issue an opinion. Some comments suggest that
an appeals mechanism specify appeal steps and stressed the importance
of timeframes for decisions by our officials.
(Response 108) We decline the request to include in the final rule
an appeals process that would be specific to the GRAS notification
procedure. We agree that the process to contact us about a response to
a GRAS notice should be clear. However, we disagree that the existing
procedures are unclear, because our regulations fully describe these
procedures (Sec. Sec. 10.25, 10.33, 10.65, and 10.75). We acknowledge
that the listed procedures do not provide a clear timeline and that
some of the listed procedures (e.g., Sec. Sec. 10.25 and 10.33) are
more cumbersome than others (such as requesting a meeting under Sec.
10.65 or requesting internal Agency review of a decision under Sec.
10.75). In practice during the Interim Pilot program, several notifiers
who received an ``insufficient basis letter'' took steps to resolve our
questions and subsequently submitted a new GRAS notice or a food
additive petition (see the discussion in section III.K of CFSAN's 2010
experience document (Ref. 18)). Given the variety of circumstances that
could lead to an ``insufficient basis letter,'' we believe that taking
steps to resolve our questions, and submitting a new GRAS notice or a
food additive petition, can be an efficient mechanism for you to use in
lieu of the procedures we discussed in the proposed rule. Doing so
would be consistent with the suggestion of some comments that an
appeals mechanism specific to the GRAS notification procedure could
include submission of additional data and information for our
evaluation, except that the data and information would be submitted in
a new GRAS notice rather than be an ``appeal'' to the GRAS notice that
received an ``insufficient basis letter.''
We do not have an FDA-certified third-party review organization
that could review the matter and issue an opinion. We disagree that
convening an independent advisory committee would be appropriate as an
additional, routine mechanism to appeal an ``insufficient basis
letter.'' Under our regulations in part 14 governing advisory
committees, it would be FDA--not a notifier--who decided to convene a
meeting of our Food Advisory Committee about the use of a substance in
food. We would have little basis to convene a meeting of our Food
Advisory Committee as part of an appeal to an ``insufficient basis
letter'' unless the notifier had first used one or more of the
procedures listed in table 21.
XX. Coordinating Our Evaluation of a GRAS Notice With FSIS
In the 2010 notice, we described some of the terms of a MOU,
between FDA and USDA's FSIS, that provides for a coordinated evaluation
process with FSIS when the intended conditions of use of a notified
substance include use in a product or products subject to regulation by
USDA under statutes that it administers (75 FR 81536 at 81541-81542).
We also asked for comment on whether to make our coordinated evaluation
process with FSIS explicit in the final rule (see Issue 13, 75 FR 81536
at 81541-81542). In 2015, we amended that MOU to include more details
about the procedures FDA and FSIS will follow to do so (Ref. 36).
(Comment 109) Comments support coordinating our evaluation of GRAS
notices with FSIS and including the procedure for this coordination in
the final rule. Comments also support requiring the notifier to provide
an additional paper copy that we would send to FSIS as part of this
procedure.
(Response 109) The final rule includes procedures for coordinating
our evaluation of a GRAS notice with FSIS when the use of the notified
substance includes use in a product or products subject to regulation
by FSIS under statutes that it administers. (See Sec. 170.270). If you
send your GRAS notice on paper, a single paper copy is sufficient; we
would send FSIS an electronic copy. (See Sec. 170.210(b) and Response
46). Under Sec. 170.270(d), we will inform you of the advice we
receive from FSIS in the letter we send you in accordance with Sec.
170.265(b)(1), as appropriate. By ``as appropriate,'' we mean that in
most circumstances we do not intend to provide advice from FSIS about
the use of the notified substance when we respond with an
``insufficient basis letter,'' because doing so has the potential to
create confusion about the regulatory status of a use of the notified
substance in products subject to regulation by FSIS. Likewise, we do
not intend to provide advice from FSIS about the use of the notified
substance when we respond with a ``cease to evaluate letter'' and,
thus, the procedure described in Sec. 170.270(d) does not specify that
we will inform you of the advice we receive from FSIS in a letter we
send you in accordance with Sec. 170.265(b)(3).
As we noted in section XII.I, this rule does not specify the data
and information that FSIS will need to evaluate whether the intended
use of the notified substance complies with applicable statutes and
regulations, or, if not, whether the use of the substance
[[Page 55020]]
would be permitted in products under FSIS jurisdiction under specified
conditions or restrictions. We recommend that you contact the
appropriate staff at FSIS regarding the data and information that FSIS
will need you to provide. FSIS provides contact information for its
programs on its Web site (Ref. 41).
(Comment 110) One comment agrees that the evaluation of a GRAS
notice should be coordinated between FDA and FSIS when ``animal
products'' are involved. This comment notes that FSIS does not
currently review the use of a substance intended for use in animal food
and recommends that CVM be involved in the safety review process of the
notice if the notice involves a substance to be used in animal food.
(Response 110) This comment appears to have misunderstood the
purpose of the coordinated evaluation process that we discussed in the
2010 notice. That process applies to the use of a substance in human
food products, such as meat and poultry products, that are subject to
regulation by USDA and would be evaluated by CFSAN; it does not apply
to the use of a substance in animal food. FSIS, under the statutes it
administers, does not evaluate a substance intended for use in animal
food and, thus, the process would not apply to a GRAS notice received
by CVM. See also Response 45.
XXI. Comments on Public Disclosure of a GRAS Notice
We proposed that a ``GRAS exemption claim'' would be immediately
available for public disclosure on the date the notice is received. All
remaining data and information in the notice would be available for
public disclosure, in accordance with part 20, on the date the notice
is received (proposed Sec. 170.36(f)(1)). We also proposed that the
following information would be readily accessible for public review and
copying: (1) A copy of the ``GRAS exemption claim'' (proposed Sec.
170.36(f)(2)(i)); (2) a copy of our response letter (proposed Sec.
170.36(f)(2)(ii)); and (3) a copy of any subsequent letter we issued
regarding the notice (proposed Sec. 170.36(f)(2)(iii)). In the 2010
notice, we noted that although the decision to submit a GRAS notice
would be voluntary, the provisions governing the GRAS notification
procedure, including the information to be submitted, would be
mandatory (75 FR 81536 at 81540).
In the final rule, you include the signed statements that we
proposed be in a ``GRAS exemption claim'' in Part 1 of your GRAS
notice, and we no longer use the term ``GRAS exemption claim'' (see
Response 42). As discussed in Response 50, the final rule stipulates
that you must not include any information that is trade secret or
confidential commercial information in Part 1 of your GRAS notice (see
Sec. 170.225(b)).
In the following sections, we discuss comments on the proposed
requirements for public disclosure of a GRAS notice. After considering
these comments, we are establishing requirements applicable to the
public disclosure of a GRAS notice as shown in table 22, with
editorial, clarifying, and conforming changes as shown in table 29.
(See Sec. 170.275.) Table 22 identifies changes we made relative to
the proposed rule or the description in the 2010 notice other than the
editorial, clarifying, and conforming changes shown in table 29 and the
additional editorial changes associated with the redesignation of
proposed Sec. 170.36(f) as Sec. 170.275.
Table 22--Final Requirements Applicable to Public Disclosure of a GRAS Notice
----------------------------------------------------------------------------------------------------------------
Revisions (other
than editorial,
Proposed Issue No. in clarifying, and
Final designation in the designation in the the 2010 Description conforming changes)
regulatory text (Sec. ) regulatory text notice relative to the
(Sec. ) proposed rule or
the 2010 notice
----------------------------------------------------------------------------------------------------------------
170.275(a)(1).................... N/A................ N/A The data and Clarify that a
information in a notice is
GRAS notice considered a
(including data mandatory, rather
and information than voluntary,
submitted in any submission for
amendment or purposes of their
supplement to your status under the
GRAS notice or FOIA and part 20.
incorporated into
your GRAS notice)
are considered a
mandatory, rather
than voluntary,
submission for
purposes of its
status under the
FOIA and part 20.
170.275(a)(2).................... 170.36(f)(1)....... N/A The data and Clarify that part
information in a 20 applies to
GRAS notice amendments and
(including data supplements as
and information well as to the
submitted in any GRAS notice as
amendment or originally
supplement to your submitted.
GRAS notice or
incorporated into
your GRAS notice)
are available for
public disclosure
in accordance with
part 20 as of the
date that we
receive your GRAS
notice.
170.275(b)(1).................... 170.36(f)(2)(i).... N/A We will make Clarifies that the
readily accessible list of
to the public a submissions that
list of filed GRAS we make publicly
notices, including available are
the information those that we have
described in the ``filed'' as GRAS
signed statements notices.
you include in
Sec.
170.225(c)(2)
through (c)(5).
170.275(b)(2).................... 170.36(f)(2)(ii)... N/A We will make N/A.
readily accessible
to the public the
text of any letter
that we issue
under Sec.
170.265(b)(1) or
(3) (e.g., a ``no
questions letter''
or an
``insufficient
basis letter'');
or under Sec.
170.265(c) (a
``subsequent
letter'').
170.275(b)(3).................... 170.36(f)(2)(ii)... N/A We will make Clarify that the
readily accessible provisions in
to the public the which we make
text of any letter certain letters
that we issue readily accessible
under Sec. to the public
170.265(b)(3) apply to a ``cease
(e.g., a ``cease to evaluate
to evaluate letter''.
letter'').
[[Page 55021]]
170.275(c)....................... 170.36(f)(2)(iii).. N/A We will disclose N/A.
public information
in accordance with
part 20.
----------------------------------------------------------------------------------------------------------------
A. Data and Information in a GRAS Notice Are Available for Public
Disclosure on the Date That We Receive It
(Comment 111) One comment asserts that the releasability of the
contents of a GRAS notice should be governed by Sec. 20.111 (data and
information submitted voluntarily to us) because the FD&C Act does not
require submission of a GRAS notice. The comment asserts that Sec.
20.111 would affect the releasability of the content of a GRAS notice
in three ways. First, while a GRAS notice is pending, Sec. 20.111
would protect from disclosure safety data or information about an
ingredient under development. Second, Sec. 20.111 would permanently
protect from disclosure any data or information relating to
manufacturing, production or sales, or formulas. Third, Sec. 20.111
would establish that a notifier has the right to request that we
evaluate the notifier's position that specific data or information in a
GRAS notice are protected from disclosure because these data or
information fall within the exemption in Sec. 20.61 for trade secrets
and commercial or financial information, which is privileged or
confidential.
(Response 111) We disagree that the provisions of Sec. 20.111
apply to a GRAS notice. Although your decision to submit a GRAS notice
is voluntary, the information included in your GRAS notice is required.
To make that clear, the final rule stipulates that the data and
information in a GRAS notice (including data and information submitted
in any amendment or supplement to your GRAS notice or incorporated into
your GRAS notice) are considered a mandatory, rather than voluntary,
submission for purposes of its status under the FOIA and part 20 (see
Sec. 170.275(a)(1)).
We agree that a notifier has a right to request that we evaluate
the notifier's position that specific data or information in a GRAS
notice are protected from disclosure because these data or information
fall within the exemption in Sec. 20.61 for trade secrets and
confidential commercial information. See Sec. 170.225(c)(8), which
requires that you state your view as to whether any of the data and
information in Parts 2 through 7 of your GRAS notice are exempt from
disclosure under the FOIA.
(Comment 112) Several comments assert that a GRAS notice should not
be publicly available until after we have completed our evaluation.
These comments also assert that a delay in disclosure, coupled with an
opportunity for a notifier to amend the notice, would: (1) Avoid the
release of information that we deemed to be inadequate or incomplete;
and (2) avoid release of a notice that was withdrawn if coupled with an
opportunity for a notifier to withdraw a notice.
(Response 112) We disagree that we should refrain from disclosing
the existence of a GRAS notice, or the contents of a GRAS notice, until
after we have completed our evaluation. As previously discussed,
immediate disclosure of a GRAS notice underscores a notifier's
responsibility for a conclusion of GRAS status (62 FR 18938 at 18953).
As discussed in Response 2, immediate disclosure of a GRAS notice also
provides an opportunity for outside parties to make us aware of
dissenting views about whether the available data and information
support a conclusion that the notified substance is safe under the
conditions of its intended use, and we did receive information from
outside parties during the Interim Pilot program. Continuing to provide
an opportunity for public participation is consistent with our
substitution of the GRAS notification procedure for the former GRAS
affirmation petition process, in which there was a public comment
period.
As discussed in Response 83, our current regulations regarding
public information stipulate that no person may withdraw records
submitted to FDA (see Sec. 20.29), and those regulations will apply to
a GRAS notice that you to ask us to ``cease to evaluate.''
(Comment 113) One comment asks us to make a GRAS notice available
for public disclosure only after we accept the submission for review.
Some comments contrast our proposal for immediate disclosure of a GRAS
notice with the provisions of: (1) The GRAS affirmation petition
process, in which a GRAS affirmation petition is disclosed only after
the petition has been accepted for filing (former Sec. 170.35(c)(2));
and (2) the health claim petition process, in which a health claim
petition becomes available for public disclosure only after it is filed
and a health claim petition that is denied without filing is not
available for disclosure (21 CFR 101.70(j)).
(Response 113) The final rule continues to specify that the data
and information in a GRAS notice are available for public disclosure as
of the date of receipt (see Sec. 170.275(a)(2)). The former GRAS
affirmation petition process did not specify when a submitted GRAS
affirmation petition would be available for public disclosure. Instead,
the former GRAS affirmation petition process merely specified that we
would place the petition on public file in the office of the Division
of Dockets Management and publish a notice of filing in the Federal
Register within 30 days after the date of filing. In addition, we
disagree that the public disclosure provisions in Sec. 101.70(j)
applicable to the health claim petition process should apply to the
GRAS notification procedure. Those provisions derive directly from the
statutory provisions that direct the health claim program (section
403(r)(4)(A)(i) of the FD&C Act (21 U.S.C. 343(r)(4)(A)(i))).
Under Sec. 20.103, with few exceptions all correspondence from
members of the public, organization or company officials, or other
persons, is available for public disclosure at the time that we receive
it unless a different time for such disclosure is specified in other
rules established or cross-referenced in part 20. As noted in Comment
86 and Response 86, we may decide to file and respond to a submission
as general correspondence, rather than as a GRAS notice, in certain
circumstances; if we do so, the data and information in the submission
would be available as of the date of receipt. Retaining date of receipt
as the timeframe for when a submission you transmit as a GRAS notice is
available for public disclosure is both consistent with Sec. 20.103
and a practical approach to a situation in which we receive a FOIA
request for a GRAS
[[Page 55022]]
submission before we have determined whether to file the submission as
a GRAS notice. As a practical matter, we believe that such situations
will be rare, and that in most cases a GRAS submission will be
disclosed after we have determined whether to file it and evaluate it
as a GRAS notice, or to file it and respond to it as general
correspondence.
(Comment 114) Some comments disagree with the assumption we stated
in the proposed rule (62 FR 18938 at 18952) that submission of a GRAS
notice would not reflect the notifier's plans about the timing or the
use of the substance in a marketed product, because a GRAS substance
may be marketed without prior approval.
(Response 114) We acknowledge that immediate disclosure of a GRAS
notice could, in certain circumstances, provide information about the
timing of market entry. However, when the data and information
regarding the safety of the substance under the conditions of its
intended use satisfy GRAS criteria, neither the law nor this rulemaking
would prevent you from marketing a substance before submitting a GRAS
notice or during our evaluation of that notice.
B. We Will Make a List of Filed GRAS Notices and Our Responses to GRAS
Notices Readily Accessible
(Comment 115) Several comments address our stated intention to
maintain an inventory of GRAS notices that we receive, our response,
and any subsequent relevant correspondence. (See the discussion at 68
FR 18938 at 18953.) Some of these comments agree with the discussion in
the proposed rule that an inventory of GRAS notices should be an
adjunct to the proposed rule rather than be included in the regulatory
text. Other comments disagree and ask us to include the creation and
availability of the inventory in the regulatory text. These comments
assert that a provision that merely states that the inventory exists
and is available for public review would address the concern that we
identified in the proposed rule about the need to maintain flexibility
regarding our administration of the inventory.
(Response 115) The final rule specifies that we will make the
following readily accessible to the public: (1) A list of filed GRAS
notices, including the information described in certain of the signed
statements that are included in Part 1 of a GRAS notice (i.e., Sec.
170.225(c)(2) through (c)(5)); and (2) The text of any letter that we
issue under Sec. 170.265(b)(1) (our response to a GRAS notice based on
our evaluation of the notice), Sec. 170.265(b)(3) (a letter if we
grant a request that we cease to evaluate a GRAS notice), or Sec.
170.265(c) (a subsequent letter that we send about a GRAS notice). (See
Sec. 170.275(b).) We are not specifying that the mechanism for us to
do so is through an ``Inventory'' because the procedure we used to make
this information readily accessible to the public evolved over time
during the Interim Pilot program, and may continue to evolve (see
section III.I.1 in CFSAN's 2010 experience document (Ref. 18)).
(Comment 116) In the proposed rule, we stated our intention to
initially maintain a paper version of an inventory at our Dockets
Management Branch (now Division of Dockets Management) and asked for
comment on making an inventory available through electronic means such
as the Internet (62 FR 18938 at 18953). Comments support maintaining an
inventory in paper format, electronic format, or both formats so that
all members of the public could have ready access to such information
regarding GRAS notices. Some comments point out that electronic access
would be particularly important to the international food industry.
Some comments support the Division of Dockets Management as the best
location for an inventory maintained in paper format.
(Response 116) As discussed in section III.I.1 in CFSAN's 2010
experience document (Ref. 18), the procedure we used to make this
information readily accessible to the public evolved over time during
the Interim Pilot program. It began as a paper file (first maintained
at the Division of Dockets Management, and then maintained in the
public reading room of our Freedom of Information Staff), and evolved
into its current electronic format on our Internet site (Ref. 46). We
intend to continue using the Internet as the principal means to make
the inventory readily accessible because doing so is an efficient and
effective mechanism to disseminate information to anyone who has access
to the Internet. The inventory on the Internet can be accessed and
printed from computers in the public reading room at Division of
Dockets Management, as well as from computers located at businesses, at
homes, and at public locations such as libraries and Internet cafes. If
a person either does not have access to the Internet or chooses not to
access the inventory through the Internet, that person can request each
GRAS notice, and each letter listed in Sec. 170.265(b)(1) or (3) or
(c), under the FOIA. It is no longer practical for us to maintain a
paper file at the Division of Dockets Management, because all new
information sent to the Division of Dockets Management is maintained
electronically; paper submissions are scanned to electronic form.
(Comment 117) One comment that addresses the discussion in the 2010
notice about the reasons that may lead us to decline to file a
submission as a GRAS notice, such as when the use is covered by an
existing regulation, asks us to include those submissions in the GRAS
inventory so there will be no confusion as to the status of the
ingredient.
(Response 117) We decline this request. The purpose of the
inventory of GRAS notices is to provide a list of all the GRAS notices
that we have filed and evaluated, not to interpret the uses listed in
our regulations or, as discussed in Response 86, covered by an existing
GRAS notice.
(Comment 118) A few comments suggest that a publicly available
inventory of GRAS notices could suffice to document that certain
notices raised no significant issues.
(Response 118) We agree that a publicly available inventory of GRAS
notices can document which notices result in a ``no questions letter,
e.g., by prominently listing the category of our response. The
Inventory of GRAS Notices developed during the Interim Pilot program
prominently classifies each response letter as ``no questions,''
``insufficient basis,'' and ``cease to evaluate'' (Ref. 46). However,
we disagree that merely displaying the category of our response,
without providing the full text of a letter that places that category
of response in context, is appropriate, regardless of whether the
response to the GRAS notice is ``no questions,'' ``insufficient
basis,'' or ``cease to evaluate.'' For example, even when we answer
``FDA has no questions,'' our response letter highlights key safety
considerations, such as the importance of ensuring that the method of
manufacture removes potential contaminants.
(Comment 119) One comment asks us to provide ``public notice'' of
all GRAS notices and the information provided therein. Another comment
asks us to make the ``GRAS exemption claim'' readily accessible to the
public by publishing information that would be in the publicly
accessible file in the Federal Register in addition to placing the
``GRAS exemption claim'' in a readily accessible file. This comment
states that doing so would provide the public with access to as much
information as possible about what substances would be used in food on
the basis of the GRAS provision if FDA is
[[Page 55023]]
going to ``forgo its role'' in the evaluation of the safety of GRAS
substances. This comment also asks us to publish the receipt of the
notice and all of our subsequent responses to the notice in the Federal
Register.
Another comment asks us to publish semi-annually, either in a
Federal Register notice or by regulation, a list of GRAS notices that
receive a ``no questions letter'' in addition to posting the Inventory
of GRAS notices on our Web site. This comment explains that questions
are sometimes raised--especially from outside the United States--about
the regulatory status of a substance used in food on the basis of the
GRAS provision unless that use of the substance is either incorporated
into the CFR or otherwise officially published. This comment asserts
that periodic publications in the Federal Register would assist in
addressing this concern.
(Response 119) By specifying that we will make a list of filed GRAS
notices readily accessible (currently, through the inventory on the
Internet), the rule requires us to actively disclose those GRAS
notices. There is a gap between the date on which we receive a GRAS
notice and the date on which we add it to the inventory, e.g., CFSAN
currently updates its inventory on an approximately monthly basis.
However, in practice during the Interim Pilot program there was ample
public notice of the receipt of the GRAS notice before CFSAN responded
to it (see the discussion of the timeframe for CFSAN's response in
section III.M of CFSAN's 2010 experience document (Ref. 18)). In
addition, the rule provides that we may send a subsequent letter about
the GRAS notice if circumstances warrant; such circumstances could
include data and information, received from a member of the public,
after we responded to the GRAS notice.
We decline the requests to provide public notice through an
announcement in the Federal Register. Publishing an announcement in the
Federal Register requires an expenditure of our resources (including
time and cost of publication) that would be inconsistent with our goal
of using our resources efficiently and effectively. Even if we
conserved resources by publishing such a notice only on a semi-annual
basis, we disagree that ``officially publishing'' a list of GRAS
notices that receive a ``no questions letter'' in the Federal Register
would address concerns, in the domestic or international community,
about the regulatory status of the use of a substance when that use is
not listed in our regulations. It is the Code of Federal Regulations,
not the Federal Register, that is the official repository of our
regulations listing authorized uses of food substances.
We disagree that we are forgoing our role in the evaluation of the
safety of substances used in food on the basis of the GRAS provision.
See Response 25.
(Comment 120) One comment asks us to place the entire GRAS notice,
rather than only the proposed ``GRAS exemption claim,'' in a readily
accessible paper file, e.g., at the Division of Dockets Management. In
the comment's view, a simple provision that a notifier submit one
additional paper copy would mitigate our concerns about the
administrative inefficiency of maintaining duplicate files at both the
center and Agency levels. Another comment asks us to make the entire
notice readily accessible in electronic form.
(Response 120) We currently make a hyperlink to an electronic copy
of each GRAS notice accessible from within the entry for that GRAS
notice in the inventory, after appropriate redaction (e.g., of privacy
information, copyrighted material, and any data and information that
are exempt from public disclosure) (Ref. 18, footnote 3). As a
practical matter, placing paper files on public display requires space,
which is finite, and our Division of Dockets Management scans paper
submissions into electronic format.
C. Public Disclosure of a GRAS Notice Is in Accordance With Our Public
Information Regulations in Part 20
(Comment 121) One comment agrees that information submitted under
the proposed ``GRAS exemption claim'' should exclude from public
disclosure the non-public confidential information with the exception
of safety data.
(Response 121) This comment appears to have misinterpreted the
proposed provisions regarding submission of non-public information and
how the public disclosure provisions of this rule apply to non-public
information. The proposed ``GRAS exemption claim'' is the precursor of
Part 1 of a GRAS notice (which we are establishing in Sec. 170.225).
The rule specifies that you must not include any information that is
trade secret or confidential commercial information in Part 1 of your
GRAS notice, except in the statement of your view as to whether any of
the data and information in Parts 2 through 7 of your GRAS notice are
exempt from disclosure under the FOIA. Part 1 of a GRAS notice includes
signed statements and a certification, not ``safety data.'' The
``safety data'' would be included in Parts 2 through 7 of the GRAS
notice. Consistent with the view of this comment, the rule provides
that those data and information are available for public disclosure
upon receipt (see Sec. 170.275(a)(2)). See also Response 50.
(Comment 122) Some comments ask us to alert the notifier, and grant
the notifier an option to withdraw the notice, in order to protect
information designated as confidential from disclosure.
(Response 122) We decline this request. A person who submits a
record to us may not withdraw that record from our files (Sec. 20.29).
Rather, the procedures that govern the release of information that a
notifier identifies as confidential in a GRAS notice are established in
Sec. Sec. 20.61 and 20.27. Under Sec. 20.61(d), a person who submits
records to us may designate part or all of the information in such
records as exempt from disclosure under exemption 4 of FOIA. However,
under Sec. 20.27 marking records submitted to us as confidential, or
with any other similar term, raises no obligation by FDA to regard such
records as confidential, to return them to the person who has submitted
them, to withhold them from disclosure to the public, or to advise the
person submitting them when a request for their public disclosure is
received or when they are in fact disclosed.
XXII. Submission of a Supplement
The rule provides that you may submit a supplement to a GRAS notice
after we respond to your notice based on our evaluation of your notice
or cease to evaluate your notice (Sec. 170.280). However, if our
response to your GRAS notice raises questions about your conclusion
that the notified substance is GRAS under the conditions of its
intended use, the appropriate mechanism for you to address those
questions would be to submit a new GRAS notice or other regulatory
submission (such as a food additive petition) rather than to submit a
supplement. See section III.C.2 of CFSAN's 2010 experience document for
examples of supplements that CFSAN received during the Interim Pilot
program (Ref. 18).
XXIII. Comments on the Administrative Process for Pending GRAS
Affirmation Petitions
We proposed that any pending petitions would be presumptively
converted to a GRAS notice on the date the final rule becomes effective
(proposed Sec. 170.36(g)(1)). An affected petitioner would have an
opportunity to amend the converted petition to meet the requirements of
the GRAS notification procedure by submitting a
[[Page 55024]]
``GRAS exemption claim'' (proposed Sec. 170.36(g)(2)). A GRAS
affirmation petition that is converted to a notice and that the
affected petitioner amends would be reviewed and administered according
to the provisions of the GRAS notification procedure; the date of
receipt of the amendment would be the date of receipt of the notice
(proposed Sec. 170.36(g)(3)(i)). After 90 days from the date of
publication of the final rule, we would inform any affected petitioner
who had not amended an applicable petition that the converted petition
is inadequate as a GRAS notice.
In the 2010 notice, we requested comments on three issues related
to the pending petitions as shown in table 23. Although the 2010 notice
classified all of these issues as ``Issue 17,'' for presentation
purposes in this document we classify the three issues as 17a, 17b, and
17c.
Table 23--Issues in the 2010 Notice Regarding Pending GRAS Affirmation
Petitions
------------------------------------------------------------------------
Description of
Issue No. our request for Reference
comment
------------------------------------------------------------------------
17a....... How to reduce the 75 FR 81536 at 81542-81543.
impact on
affected
petitioners
while retaining
the principle
that we will not
devote resources
to pending
petitions.
17b....... Whether an 75 FR 81536 at 81542-81543.
outcome of
``withdrawal
without
prejudice''
instead of
``insufficient
basis'' would be
more appropriate
when an affected
petitioner
simply chooses
not to have the
pending petition
considered under
the GRAS
notification
procedure.
17c....... Whether an 75 FR 81536 at 81542-81543.
affected
petitioner could
request that we
incorporate into
a GRAS notice a
withdrawn GRAS
affirmation
petition into a
GRAS notice, and
if so, if any
requirements of
the GRAS
notification
procedure should
be waived.
------------------------------------------------------------------------
In the following paragraphs, we discuss comments regarding the
disposition of pending petitions in light of the deletion of the GRAS
affirmation petition process. After considering these comments, we are
establishing provisions for the pending petitions as shown in table 24,
with editorial, clarifying, and conforming changes as shown in table
29. (See Sec. 170.285.) Table 24 identifies changes we made relative
to the proposed rule or the description in the 2010 notice other than
the editorial, clarifying, and conforming changes shown in table 29 and
the additional editorial changes associated with the redesignation of
proposed Sec. 170.36(g) as Sec. 170.285.
Table 24--Final Requirements for Disposition of Pending GRAS Affirmation Petitions
----------------------------------------------------------------------------------------------------------------
Revisions (other
than editorial,
Proposed Issue No. in clarifying, and
Final designation in the designation in the the 2010 Description conforming changes)
regulatory text (Sec. ) regulatory text notice relative to the
(Sec. ) proposed rule or
the 2010 notice
----------------------------------------------------------------------------------------------------------------
170.285(a)....................... 170.36(g)(1)....... 17a and 17b On the effective We administratively
date of the rule, close the docket
we will close the for the GRAS
docket for any affirmation
GRAS affirmation petition
petition that is rulemaking rather
still pending as than convert the
of that date. pending petition
to a GRAS notice.
170.285(b)....................... 170.36(g)(2)....... 17c Any person who The affected
submitted a GRAS petitioner submits
affirmation a GRAS notice
petition that is rather than an
pending as of the amendment to a
date of the final ``converted
rule may submit a petition''.
GRAS notice and
request that we
incorporate the
GRAS affirmation
petition.
N/A.............................. 170.36(g)(3)(i).... N/A N/A................ No longer specifies
the procedures for
FDA's evaluation
of a former
pending petition.
N/A.............................. 170.36(g)(3)(ii)... 17a and 17b N/A................ No longer treats a
pending petition
that is not
evaluated as a
GRAS notice as
having an
insufficient basis
to support GRAS
status.
----------------------------------------------------------------------------------------------------------------
(Comment 123) Some comments to the proposed rule support our
proposal to convert pending GRAS affirmation petitions to GRAS notices
on the effective date of the rule. However, as discussed in the 2010
notice, many comments to the proposed rule object to our proposal for
administering the pending petitions as being fundamentally unfair,
because an affected petitioner had invested considerable time and
resources in the petition process and should not be penalized by our
adoption of a new GRAS notification procedure. Some of these comments
state that, in most cases, FDA also had dedicated significant resources
to the review of these petitions and, in some cases, had even arranged
for an additional third party to review the substance that was the
subject of the petition. These comments suggest options such as
``grandfathering'' pending petitions, i.e., completing the rulemaking
process for them, particularly if we had completed our scientific
review with no outstanding questions. Some comments ask us to provide
an affected petitioner 180 days, rather than 90 days, to amend the
converted petition to satisfy the requirements of the GRAS notification
procedure. One of these comments argues that there need not be any
urgency in closing the applicable files because many of these petitions
had been pending for years, and the subjects of the petitions had been
marketed during those years.
Some comments to the proposed rule assert that more resources would
be needed to review a petition that is converted to a GRAS notice than
would be needed to complete the review of each pending petition and
issue a
[[Page 55025]]
regulation. One comment suggests that it would be simpler and more
efficient administratively to allow an affected petitioner an option to
update a GRAS affirmation petition to include additional conditions of
use or new specifications than to require separate GRAS notices for
such changes.
Other comments ask us to clarify the procedures we would use to
convert a GRAS affirmation petition to a GRAS notice as well as
procedures for amending a petition that was converted to a GRAS notice
through an additional submission. Some comments assert that we should
not require an affected petitioner to submit such an amendment because
all of the pertinent information would already be included in the
petition and argue that technical adherence to the format of a GRAS
notice should not take precedence over administrative efficiency and
common sense. Other comments express concern that it was not clear that
the proposed additional submission (proposed Sec. 170.36(g)(2)) was in
fact a skeleton notice that primarily would cross-reference the
original GRAS affirmation petition.
Some comments to the 2010 notice suggest that a pending petition
could be ``withdrawn without prejudice'' or ``suspended'' so that it
would no longer require FDA resources to review it. Other comments to
the 2010 notice express the view that a simple letter of conversion
should be adequate, but that if an affected petitioner chose not do so
then the outcome of the converted petition would more appropriately be
described as ``withdrawn without prejudice'' rather than
``insufficient'' as a GRAS notice. Other comments to the 2010 notice
continue to express the view that we should ``grandfather'' a pending
petition. One of these comments asserts that failure to grandfather
those affirmation petitions where FDA had completed its review and no
outstanding scientific issues exist would be unfair because the GRAS
notification procedure results in a lower level of authoritativeness
than the GRAS affirmation petition process, and the affected
petitioners had invested considerable time and resources in the
petition process. This comment also notes that after we published the
proposed rule we continued to review GRAS affirmation petitions and
completed the process for six GRAS affirmation petitions before
discontinuing further activity in 1999. Comments that address Issue 17c
recommend that an affected petitioner be allowed to incorporate
information from a ``withdrawn'' GRAS affirmation petition into a GRAS
notice.
We received no comments asking us to waive any of the requirements
of the notification procedure.
(Response 123) We have revised the proposed provisions regarding
the disposition of pending petitions in light of the concern of the
comments that the proposed process was unfair to affected petitioners.
The final rule provides that on the effective date of the rule, we will
close the docket for any GRAS affirmation petition that is still
pending as of that date (Sec. 170.285(a)). Any person who submitted a
GRAS affirmation petition that is pending as of the date of the final
rule may submit a GRAS notice and request that we incorporate the GRAS
affirmation petition (Sec. 170.285(b)). We are closing the docket for
the petition by operation of law because the process that would be
necessary to bring a petition to closure (i.e., Sec. 170.35(c)) no
longer exists. We decided to close the docket for the petition, rather
than classify the petition as withdrawn without prejudice, for two
reasons. First, closing the docket is an administrative option that is
open to us, whereas in our petition processes withdrawing a petition is
an option that falls to the petitioner (see, e.g., Sec. 171.1(j) for
withdrawal of a food additive petition without prejudice). Second,
``withdrawal without prejudice'' generally means ``without prejudice to
a future filing,'' and ``future filing'' refers to the same type of
filing; however, we have eliminated the GRAS affirmation petition
process and, thus, an affected petitioner could not submit another GRAS
affirmation petition.
Closing the docket is neutral with respect to a conclusion by an
affected petitioner that the petitioned substance is GRAS under the
conditions of its intended use, because closing the docket does not
result in a publicly available ``insufficient basis letter.'' To
clarify that closing the petition is without prejudice to eligibility
for classification of the use of the substance as GRAS, the final rule
specifically provides that an affected petitioner may incorporate the
former GRAS affirmation petition into a GRAS notice. Given the passage
of time since the pending petitions were submitted, it is likely that
some of the data and information in the petition would need to be
updated. In addition, the affected petitioner would need to follow all
format requirements for a GRAS notice, including the narrative required
in Part 6 of a GRAS notice.
We acknowledge that our response to a GRAS notice does not have the
same level of ``authoritativeness'' as a listing in our regulations.
However, some of the comments that objected to the proposal to convert
a pending petition to a GRAS notice assert that the substances that are
the subject of the pending petitions have been marketed for years;
clearly, these affected petitioners are able to market the substance
without a listing in our regulations.
We agree that it is appropriate to extend the timeframe for an
affected petitioner to take action with respect to a pending petition.
Under final Sec. 170.285(b), there is no limit on the timeframe for an
affected petitioner to submit a GRAS notice that incorporates a GRAS
affirmation petition.
We decline the request to ``grandfather'' any pending petitions. We
simply do not have sufficient resources to devote to the rulemaking
process that is required for GRAS affirmation, regardless of whether we
already have completed our scientific review. For example, even if we
have completed our scientific review, the Administrative Procedures Act
(5 U.S.C. 553) requires that we consider relevant data, views, or
arguments submitted to us by interested persons and that we publish a
concise general statement of the basis and purpose of the regulation.
In addition, Executive Order 12866 requires that we assess the costs
and benefits of available regulatory alternatives when we conduct
rulemaking, and the Regulatory Flexibility Act (5 U.S.C. 601-612)
requires that we consider alternatives that would minimize the economic
impact of our regulations on small entities. Thus, to complete the
rulemaking associated with the GRAS affirmation petition process, we
require significant resources beyond those associated with scientific
review. Even if we did ``grandfather'' a pending petition, it is highly
unlikely that we would be able to devote resources to this voluntary
process in light of competing programs that are required by statute.
For example, the resources that could be directed to the GRAS
affirmation petition process must be considered together with the
resources that are required to administer the food and color additive
petition processes and the premarket notification process for food
contact substances, which are required programs under sections 409 and
721 of the FD&C Act.
For the reasons discussed in the previous paragraph, we disagree
that we would have needed more resources to review a petition that is
converted to a GRAS notice than to complete the review of each pending
petition and issue a regulation. We also disagree that it would be
simpler and more efficient administratively to allow an affected
[[Page 55026]]
petitioner an option to update a GRAS affirmation petition. As
discussed in CFSAN's 2016 experience document (Ref. 19), during the 10-
year period extending from 1990 through 1999, CFSAN completed the
rulemaking process for 24 GRAS affirmation petitions, with an average
elapsed time of approximately 7.9 years (median elapsed time
approximately 6.9 years). In contrast, under the final rule we will
respond to a GRAS notice in 180 days, with an option to extend the
timeframe by an additional 90 days (see Response 98).
As of August 17, 2016 there are 45 pending GRAS affirmation
petitions. We intend to contact each affected petitioner to inform the
petitioner that: (1) We are closing the affected docket as of October
17, 2016; and (2) the petitioner may submit a GRAS notice that
incorporates the former GRAS affirmation petition.
(Comment 124) One comment asks us to issue a regulation, to be
included in part 184, that lists the pending petitions. The comment
also asks us to include a statement that the lack of an affirmation
regulation does not indicate that FDA disagrees with the affected
petitioner's GRAS determination.
(Response 124) We decline this request. Our regulations in part 184
represent our own conclusions regarding the GRAS status of a listed
substance under the conditions of its intended use. It is inappropriate
for our regulations to become a catalog of circumstances where we have
not reached our own conclusion regarding GRAS status.
However, under final Sec. 170.275(b), we will make a list of filed
GRAS notices readily accessible to the public. The inventory of GRAS
notices that currently makes this list available includes a link to
information about each listed GRAS notice. When the GRAS notice was
originally submitted as a GRAS affirmation petition, we have included
the petition number. We intend to continue this practice under the
final rule.
We also have placed a list of the pending petitions that we are
closing in the docket for this rule (Ref. 48).
XXIV. Other Comments
A. GRAS Panels and Conflict of Interest
In the 2010 notice, we explained that the GAO report noted that we
have not issued any conflict of interest guidance that companies can
use to help ensure that the members of their expert panels are
independent (75 FR 81536 at 81542). The GAO report recommended that we
develop a strategy to minimize the potential for conflicts of interest,
including taking steps such as issuing guidance for companies on
conflict of interest and requiring information in GRAS notices
regarding expert panelists' independence. In the 2010 notice, we
requested comments on three issues related to GAO's recommendation
regarding conflict of interest as shown in table 25. Although the 2010
notice classified all of these issues as ``Issue 15,'' for presentation
purposes in this document we classify the three issues as 15a, 15b, and
15c.
Table 25--Issues in the 2010 Notice Regarding Guidance on Conflict of
Interest
------------------------------------------------------------------------
Description of
Issue No. our request for Reference
comment
------------------------------------------------------------------------
15a....... Whether companies 75 FR 81536 at 81542.
would find it
useful to have
guidance on
potential
conflicts of
interest of GRAS
expert panelists.
15b....... If guidance on 75 FR 81536 at 81542.
potential
conflicts of
interest of GRAS
expert panelists
would be useful,
what companies
currently do to
mitigate such a
conflict.
15c....... Whether to 75 FR 81536 at 81542.
require that
GRAS notices
include
information
regarding expert
panelists'
independence.
------------------------------------------------------------------------
(Comment 125) Most of the comments that addressed Issues 15a and
15b ask us to provide guidance regarding potential conflicts of
interest of GRAS panel members. One of these comments provided an
example of a draft guidance for our consideration. Other comments
provide criteria that they ask us to consider in the guidance. One
comment asks us to provide an opportunity for industry, academia, and
the public to comment on our proposed course of action for the topic of
conflict of interest.
One comment asserts that there is no need for guidance regarding
potential conflicts of interest of GRAS panel members because industry
is aware of the importance of disclosing and addressing potential
conflicts of interest and often has Standard Operating Procedures
delineating rules for disclosure.
(Response 125) We have decided to issue guidance regarding conflict
of interest. We will do so as Level 1 guidance within the framework of
our good guidance practices regulation (see Sec. 10.115(c) and (g)).
Under that framework, we prepare a draft of Level 1 guidance and then:
(1) Publish a notice in the Federal Register announcing that the draft
guidance document is available; (2) post the draft guidance document on
the Internet and make it available in hard copy; and (3) invite public
comment on the draft guidance document. After providing an opportunity
for public comment on a Level 1 guidance document, FDA will: (1) Review
any comments received and prepare the final version of the guidance
document that incorporates suggested changes, when appropriate; (2)
publish a notice in the Federal Register announcing that the guidance
document is available; (3) post the guidance document on the Internet
and make it available in hard copy; and (4) implement the guidance
document. We will consider the recommendations and draft guidance
submitted in the comments to this rule in developing our draft guidance
for public comment.
We acknowledge that some members of industry are aware of the
importance of disclosing and addressing potential conflicts of
interest. However, we disagree that this awareness means that we should
not issue a guidance regarding conflict of interest. A guidance from us
on conflict of interest could promote consistency in addressing
conflict of interest by different companies.
(Comment 126) One comment notes that an external GRAS panel is not
required for a conclusion of GRAS status when the conclusion is
supported by peer-reviewed literature or a ``long history of safe
use.'' (By ``long history of safe use,'' we assume that the comment is
referring to the provision that GRAS criteria may be satisfied through
experience based on common use in food prior to January 1, 1958. See
Sec. 170.30(a) and (c)).
(Response 126) We agree that an external GRAS panel is not required
for a conclusion of GRAS status. As we previously noted, convening a
GRAS panel has historically been a way to provide evidence that
generally available data and information are
[[Page 55027]]
generally accepted by the expert scientific community, but convening a
GRAS panel is not the only way to provide such evidence (62 FR 18938 at
18943).
(Comment 127) Some comments address Issue 15c and recommend that a
notifier include information on independence of the panel members in a
submitted GRAS notice.
(Response 127) The rule neither requires that a notifier convene a
GRAS panel nor establishes any other requirements applicable to a GRAS
panel. Therefore, we are addressing issues regarding a GRAS panel in
guidance rather than in the regulation. See also Comment 14 and
Response 14.
B. Guidance on Documenting Conclusions of GRAS Status
In the 2010 notice, we explained that the GAO report recommended
that we issue guidance on how to document a conclusion of GRAS status
(75 FR 81536 at 81542). We noted that there is guidance in the preamble
to the proposed rule and in our guidance for industry entitled
``Frequently Asked Questions About GRAS'' (Ref. 49). We requested
comments on two issues related to guidance on documenting a conclusion
of GRAS status as shown in table 26. Although the 2010 notice
classified both of these issues as ``Issue 16,'' for presentation
purposes in this document we classify the two issues as 16a and 16b.
Table 26--Issues in the 2010 Notice Regarding Guidance on Documenting
GRAS Conclusions
------------------------------------------------------------------------
Description of
Issue No. our request for Reference
comment
------------------------------------------------------------------------
16a....... Whether there is 75 FR 81536 at 81542.
a need to
clarify that our
guidance
applying to GRAS
submissions also
applies to a
GRAS conclusion
that is not
submitted to us
in the form of a
GRAS notice.
16b....... Whether there is 75 FR 81536 at 81542.
a need for us to
develop further
guidance on
documenting a
GRAS conclusion
when the GRAS
conclusion is
not submitted to
us as a GRAS
notice.
------------------------------------------------------------------------
(Comment 128) Most of the comments that addressed Issue 16a
recommend that we clarify that the same standards apply to a conclusion
of GRAS status regardless of whether the conclusion is submitted to us
as a GRAS notice or is not submitted to us.
(Response 128) To reach a conclusion of GRAS status, the proponent
of GRAS status must: (1) Establish that the substance is safe under the
conditions of its intended use within the meaning of section 409(c)(5)
of the FD&C Act and our implementing regulation in Sec. 170.3(i); and
(2) establish that the safety of the substance under the conditions of
its intended use is generally recognized within the meaning of section
201(s) of the FD&C Act and our regulations in Sec. 170.30 governing
the eligibility for classification as GRAS. See the discussion in
section I.C of the proposed rule of the elements of the GRAS standard,
where we described the evaluation of safety as the ``technical
element'' of the GRAS standard and the evaluation of general
recognition as the ``common knowledge element'' of the GRAS standard.
In considering whether GRAS criteria are satisfied because the
available data and information demonstrate that the use of a substance
is safe and the safety is generally recognized, we do not distinguish
between a conclusion of GRAS status submitted to us as a GRAS notice
and an independent conclusion of GRAS status that remains with the
proponent. As discussed in Response 41, in this rulemaking we made
conforming changes to current regulations regarding the use of GRAS
substances in food, and our affirmation of GRAS status on our own
initiative, to emphasize that point (see the changes to Sec. Sec.
170.3(i) and (k), 170.30(c), 170.30(e), and 170.35(a) and (b) in table
29). As already noted in section I.E of this document, we advise any
company that intends to market a food substance on the basis of an
independent conclusion of GRAS status to carefully consider whether
this use fully satisfies the criteria for eligibility for
classification as GRAS and to carefully review the discussions in this
document relevant to those criteria, such as the discussion in Response
9 regarding the role of corroborative data and information, the
discussions in Response 10 and Response 11 regarding the limitations of
a published report of a GRAS panel, and the discussion in Response 69
regarding the ramifications of providing trade secret information (or
other non-public information) to a GRAS panel.
Our 2004 guidance entitled ``Frequently Asked Questions About
GRAS'' generally applies to a conclusion of GRAS status regardless of
whether that conclusion of GRAS status is submitted to us as a GRAS
notice. Exceptions include current questions specific to the
notification procedure as it operated during the Interim Pilot program,
such as ``Where do I send my GRAS notice? '' We are modifying that
guidance to update it in light of the publication of this rule.
We believe that the provisions of the GRAS notification procedure
in part 170, subpart E will be a useful resource to any person who
intends to use a substance in food based on a conclusion of GRAS
status, regardless of whether the conclusion of GRAS status is
submitted to us in a GRAS notice or is an independent GRAS conclusion
that is not submitted to us. For example, the requirements in Part 3 of
a GRAS notice make clear that a conclusion of GRAS status requires
consideration of dietary exposure. Likewise, the requirements in Part 6
of a GRAS notice demonstrate the importance of a complete and balanced
evaluation of all applicable data and information, including data and
information that are, or may appear to be, inconsistent with a
conclusion of GRAS status. Therefore, we recommend that any person who
intends to use a substance in food based on a conclusion of GRAS
status, but does not intend to submit a GRAS notice to us, use the
provisions of part 170, subpart E as guidance. We also recommend that
such persons organize the data and information that support an
independent conclusion of GRAS status according to the organization
presented by Parts 1 through 7 of a GRAS notice. Doing so would
facilitate our evaluation of that independent conclusion of GRAS status
if circumstances warrant, e.g., if we have cause to question the
independent conclusion of GRAS status. Because we make information
about GRAS notices readily accessible to the public, we also recommend
that you make the basis for your independent GRAS conclusion publicly
available (e.g., by making publicly available a document analogous to
the narrative of a GRAS notice, a report of a GRAS panel (if you
convene a GRAS panel), or both a narrative and a report of a GRAS
panel).
General recognition of safety based upon scientific procedures
requires the same quantity and quality of scientific evidence as is
required to obtain
[[Page 55028]]
approval of a food additive regulation for the ingredient (Sec.
170.30(b)). We address scientific issues associated with demonstrating
the safety of a food substance in a series of guidance documents on our
Internet (Ref. 6, Ref. 25, and Ref. 32 through Ref. 35). Currently,
some of these scientific guidance documents are expressly directed to
evaluation of the safety of food additives. For example, in Response 66
we noted that our guidance entitled ``Recommendations for Submission of
Chemical and Technological Data for Direct Food Additive Petitions''
(Ref. 31) currently is structured to address the specific requirements
of a food additive petition, even though many of the recommendations in
that guidance could nonetheless be useful to any person who evaluates
whether a substance is GRAS under the conditions of its intended use.
As resources allow, we intend to re-visit these scientific guidance
documents to determine whether and how to modify them to clarify that
our guidance on evaluating the safety of a food substance generally
applies regardless of whether the substance would be used in food as a
food additive or as a GRAS substance. Regardless of any implication, in
the title or text of these guidance documents, that the subject of the
document applies to a food additive, we recommend that you consider
that the scientific recommendations in these guidance documents may
also apply to substances that would be used in food on the basis of a
GRAS conclusion.
Some scientific guidance documents already do make clear that they
apply regardless of the regulatory status of a substance (e.g., as a
food additive, color additive, food contact substance, or GRAS
substance) (Ref. 6). In addition, as discussed in Response 37, we
recently issued a notice announcing a public meeting, and requesting
comments, on our intent to update our guidance entitled ``Guidance for
Industry and Other Stakeholders: Toxicological Principles for the
Safety Assessment of Food Ingredients'' (79 FR 64603), and reiterated
that general recognition of safety based upon scientific procedures
requires the same quantity and quality of evidence as is required to
approve a food additive.
(Comment 129) Some comments support issuing additional guidance on
documenting a conclusion of GRAS status, particularly for a GRAS
conclusion that is not submitted to us. One comment asserts that there
is no need for us to develop additional guidance on documenting a
conclusion of GRAS status that is not submitted to us. One comment
agrees with the recommendation in the GAO report that we take steps to
ensure that companies maintain proper documentation to support a
conclusion of GRAS status.
(Response 129) We agree that companies should maintain proper
documentation to support a conclusion of GRAS status. As we discussed
in the proposed rule (62 FR 18938 at 18947), any person who concludes
that a substance is GRAS under the conditions of its intended use
should have assembled and evaluated the evidence that forms the basis
of that conclusion, regardless of whether the person subsequently
notifies us. Preserving the applicable data and information represents
prudent practice for those who assert that the statutory premarket
review requirements do not apply to the use of a substance in food.
To emphasize the importance of maintaining the data and information
that support an independent conclusion of GRAS status, we are issuing a
guidance directed to any person who evaluates whether the available
data and information regarding the safety of a substance under the
conditions of its intended use satisfy GRAS criteria. The purpose of
the guidance is to: (1) Remind such persons of their responsibilities
under the FD&C Act regarding a conclusion of GRAS status, regardless of
whether the conclusion of GRAS status is submitted to us as a GRAS
notice; and (2) refer such persons to key resources, such as those
discussed in Response 128, for evaluating the safety of the substance
under the conditions of its intended use and for evaluating whether the
available data and information regarding safety satisfy the criteria
for eligibility for classification as GRAS in Sec. 170.30. We believe
that such guidance is appropriate in light of the recommendations of
the GAO report.
C. Compliance With Other FDA Regulations
We proposed that a GRAS notice would not constitute compliance with
the requirements for a health claim petition in Sec. 101.14(b)(3)(ii)
or for a new infant formula submission in Sec. 106.120(b)(6)(ii). We
specified that any person who submits a health claim petition, or who
submits a new infant formula submission, must comply in full with the
requirements of the applicable program (proposed Sec. 170.36(a)(2)).
(Comment 130) Several comments object to the perceived implication
that a GRAS notice could never be used to support a health claim
petition or a new infant formula submission. In general, the comments
maintain we should consider, on a case-by-case basis, whether a
particular GRAS notice is sufficient to comply with the requirements of
the applicable program rather than categorically disallow a GRAS notice
as a means for satisfying the requirements of the applicable program.
(Response 130) We are not including this proposed provision in the
final rule because it is not necessary to do so. Any person who submits
a health claim petition, or who submits a new infant formula
submission, must comply in full with the requirements of the applicable
program whether this rule says so or not. An FDA office that evaluates
a health claim petition or a new infant formula submission will take
into account our response to a GRAS notice when evaluating the health
claim petition or new infant formula submission. In practice during the
Interim Pilot program, an FDA office evaluated a health claim petition
or a new infant formula submission for several substances that were the
subject of a previously submitted GRAS notice. In each case, FDA's
evaluation of the health claim petition or new infant formula
submission had an outcome that was consistent with our response to that
GRAS notice (see section IV.A of CFSAN's 2010 experience document (Ref.
18)).
D. Impact on Other Federal Agencies
In our discussion in the proposed rule of the proposed procedures
for making information about GRAS notices readily accessible to the
public, we stated our belief that there would be considerable interest,
from a broad segment of the public, including other Federal agencies,
in notices received under the proposed notification procedure (62 FR
18938 at 18952). We also stated our expectation that such groups will
likely want to know whether we are aware that a substance is being used
in food on the basis of the GRAS provision and whether we have advised
a notifier that we have identified a problem with the notice.
(Comment 131) The Bureau of Alcohol, Tobacco and Firearms (BATF)
(in the U.S. Department of the Treasury (now TTB) submitted a comment
stating that it has no major problem with our proposal to replace the
GRAS affirmation petition process with a notification procedure, but
that there are two ways in which the proposed rule would impact TTB.
First, TTB's wine regulations in 27 CFR 24.250 (Application for use of
new treating material or process) require that a proprietor who wishes
to use a new
[[Page 55029]]
wine treating material submit to TTB an application that includes
documentary evidence of FDA's approval of the material under the
conditions of its intended use. If we issue a final rule to establish a
GRAS notification procedure, TTB would need to amend this requirement
to state that TTB needs either evidence of FDA approval or evidence
that FDA has been notified of a conclusion of GRAS status and has no
questions about that conclusion.
Second, certain alcoholic beverage products require formula
approval by TTB due to the ingredients (such as colors, flavors, herbs,
and spices) in the products. Currently, TTB requires that these
ingredients be approved by FDA before TTB approves the formula. If we
issue a final rule to establish a GRAS notification procedure, TTB
would still check the ingredients in these formulas before approving
the formula, but could accept evidence that FDA has been notified of a
conclusion of GRAS status and has no questions about that conclusion.
TTB asks us to include the conditions of use in our response to a
GRAS notice so that TTB would know the parameters that FDA evaluated in
considering the GRAS notice (i.e., the foods and beverages and the
amounts in those foods and beverages). TTB also asks us to publish and
update a list of GRAS notices on a frequent basis, and to include the
conditions of use that FDA evaluated in this list.
(Response 131) The provisions of this rule are consistent with
TTB's requests. The rule specifies that we will make a list of filed
GRAS notices, including the information described in Sec.
170.225(c)(2) through (c)(5), readily accessible to the public (see
Sec. 170.275(b)(1)). The information the rule specifies will be
readily accessible includes the intended conditions of use of the
notified substance, including the foods in which the substance will be
used, the levels of use in such foods, and the purpose(s) for which the
substance will be used (see Sec. 170.225(c)(4)). The response letters
that we issued during the Interim Pilot program described the
conditions of use of the notified substance, and we intend to continue
describing the conditions of use of the notified substance in letters
issued under the final rule.
(Comment 132) Some comments assert that our affirmation of GRAS
status established a clear standard that was needed by other Federal
agencies to carry out their own regulatory responsibilities. The
comments cite BATF (now TTB), FSIS (in USDA), and EPA as examples of
such Federal agencies. In general, these comments maintain that the
applicable Federal agency must be able to accept our response to a GRAS
notice in lieu of a regulation affirming GRAS status. One comment notes
that the proposed rule did not explicitly address the impact of the
proposed rule on other Federal agencies and urges us to consult with
the cited Federal agencies prior to issuing the final rule.
(Response 132) None of the Federal agencies cited by these comments
have advised us that the absence of a regulation affirming GRAS status
for the use of a food substance would preclude the applicable Agency
from carrying out its statutory responsibilities. As discussed in the
following paragraphs, we have interacted with each of these agencies as
requested.
TTB. As discussed in section IV.B of CFSAN's 2010 experience
document (Ref. 18), during the Interim Pilot program CFSAN received and
filed several GRAS notices for substances intended for use in alcoholic
beverage products. These notices demonstrate that manufacturers of
alcoholic beverage products are aware of the GRAS notification
procedure and are using GRAS notices as a means to satisfy TTB's
regulations. As also discussed in section IV.B of CFSAN's 2010
experience document (Ref. 18), on September 29, 2005, representatives
of TTB met with representatives of CFSAN in the offices of CFSAN's
Office of Food Additive Safety. At that meeting, representatives of
CFSAN described the GRAS notification procedure that was operating
under the framework of the proposed rule. CFSAN provided a copy of
TTB's comments to these representatives, and none of TTB's
representatives expressed any concern about the operation of the
program.
FSIS. As discussed in section III.L of CFSAN's 2010 experience
document (Ref. 18), during the period 1998 through 2009 more than 25
percent of GRAS notices filed by CFSAN described use of the notified
substance in meat, meat food products, or poultry products. During
CFSAN's review of these GRAS notices, CFSAN consulted with FSIS
regarding the use of the applicable substance. FSIS provided feedback
to CFSAN about the use of the notified substance in products regulated
by FSIS and requested that CFSAN provide this feedback to the notifier.
In 2000, FDA and FSIS formalized this process of inter-agency
consultation in a MOU (65 FR 33330, May 23, 2000). Subsequently, FDA
and FSIS have amended the MOU to include simultaneous evaluation of
substances subject to regulation by USDA under the Egg Products
Inspection Act (21 U.S.C. 1033(a)(2)) (Ref. 36). The final rule
includes the procedures CFSAN will use when coordinating its evaluation
of a GRAS notice with FSIS (see Sec. 170.270).
EPA. CFSAN has discussed the concerns raised by these comments with
representatives from EPA (Ref. 50). The representatives from EPA
deferred to CFSAN regarding the appropriate process for voluntary
interaction between us and the regulated industry with respect to GRAS
substances.
E. Impact on International Trade
In the proposed rule, we requested comment on whether the proposed
substitution of a GRAS notification procedure for the GRAS affirmation
petition process would have any impact on international trade (62 FR
18938 at 18955).
(Comment 133) Comments that responded to this request for comment
express the view that whether the proposed substitution of a GRAS
notification procedure for the GRAS affirmation petition process would
have a positive, neutral, or negative impact on international trade
would depend on the nature of our response to a GRAS notice,
particularly when we do not question the notifier's basis for a
conclusion of GRAS status. The comments explain that the proposed rule
could have a positive or neutral impact on international trade if our
response is clear and definitive, provides regulatory significance, and
is as affirmative as possible, but could have a negative impact on
international trade if our response is neutral or vague. One comment
expresses the opinion that any impact on international trade would be
minimal because JECFA frequently assesses uses of a food ingredient,
and foreign regulatory agencies frequently reach a decision to allow
uses of a food ingredient, before we complete our rulemaking under the
GRAS affirmation petition process.
(Response 133) The ``no questions letters'' we issued during the
Interim Pilot program make clear that the notifier (rather than FDA) is
responsible for the conclusion of GRAS status, and place our statement
that we have no questions about the notifier's conclusion of GRAS
status in the contexts of both time and the available data and
information (see table 1). These features of the ``no questions
letters'' make the letters clear and definitive and provide regulatory
significance (i.e., regulatory status), and we intend to retain these
features in letters we issue under the final rule. Moreover, the fact
that many GRAS notices were submitted by foreign firms demonstrates
that foreign firms see value in submitting GRAS notices to us (Ref.
51).
[[Page 55030]]
Under the final rule, we will respond to a GRAS notice within 180
days after we file a submission as a GRAS notice, with an option to
extend the timeframe by an additional 90 days as needed (see Sec.
170.265(b)(1)). As discussed in Response 123, during the ten year
period extending from 1990 through 1999, we completed the rulemaking
process for 24 GRAS affirmation petitions, with an average elapsed time
of approximately 7.9 years (median elapsed time approximately 6.9
years). Thus, we believe that the GRAS notification procedure will come
to closure more quickly than the GRAS affirmation petition process.
F. Audits
In the proposed rule, we stated that it would be prudent for us
monitor compliance with the essence of the statutory requirements for
GRAS status (i.e., that there is common knowledge among qualified
experts that there is reasonable certainty that the substance is not
harmful under the conditions of its intended use) and announced that we
intended to conduct random audits of data and information maintained by
the notifier (62 FR 18938 at 18947). In addition, because the proposed
substitution of a GRAS notification procedure for the GRAS affirmation
petition process would allow us to direct our resources to priority
questions about GRAS status, we might conduct an audit on a broad issue
or class of products if the issue or use of a class of products raises
important public health issues.
(Comment 134) One comment asks us to renew our commitment to random
auditing to ensure that companies maintain proper recordkeeping
practices.
(Response 134) As discussed in section IV.C of CFSAN's 2010
experience document (Ref. 18), during the Interim Pilot program, CFSAN
did not conduct any random audits of data and information maintained by
the notifier. However, CFSAN did not hesitate to ask a notifier to
provide certain data or information as an amendment to a GRAS notice.
(See also the discussion in section III.C.1 of CFSAN's 2010 experience
document regarding amendments to GRAS notices.) In essence, CFSAN used
its resources to seek access to data and information on a priority,
rather than a random, basis. At this time, we intend to continue
directing our resources on a priority basis under the final rule.
(Comment 135) One comment asks us to provide a notifier with the
option of converting a GRAS notice to a GRAS affirmation petition if we
audit the data supporting a GRAS notice.
(Response 135) As discussed in Response 24 and Response 123, we
have eliminated the former GRAS affirmation petition process.
Therefore, the administrative process requested by these comments is no
longer operative.
(Comment 136) One comment asks us to incorporate two procedures to
avoid any uncertainty regarding the results of the audit. First, the
comment asks us to provide the notifier with a letter confirming that
the audit is completed and we have no basis to question the conclusion
of GRAS status if that is the outcome of our audit. Second, the comment
asks us to apply any appeal mechanism specified by the rule to
circumstances in which we question a conclusion of GRAS status based on
an audit.
(Response 136) We decline these requests. If we have no questions
about the notifier's conclusion of GRAS status, we would respond with a
``no questions letter'' based on our evaluation of the entire GRAS
notice, not based solely on the results of an audit of the data and
information maintained by the notifier to support the notifier's GRAS
notice. As discussed in Response 108, the rule does not include an
appeals process that would be specific to the GRAS notification
procedure.
(Comment 137) One comment suggests that our audit examine the same
``quantum of evidence'' as we would review to affirm GRAS status, and
asserts that a strong statement of confidence, if not outright
affirmation, would be appropriate after successful completion of this
type of an indepth review.
(Response 137) The purpose of the audit would be to verify that a
notifier maintains the data and information specified in the notice,
not to conduct a full scientific evaluation of those data and
information (62 FR 18938 at 18947). Therefore, we decline the request
to examine the same ``quantum of evidence'' as we would review to
affirm GRAS status. Because the purpose of an audit would be to verify
compliance with the statutory requirements for GRAS criteria, we
disagree our response to a GRAS notice following a favorable audit
should result in a ``strong statement of confidence'' rather than a
``no questions letter.'' However, we intend that our response letter
would mention any audit that we conduct before responding to a GRAS
notice.
G. Lack of an Environmental Assessment
(Comment 138) One comment suggests that a GRAS notice is ideal in
circumstances where our evaluation of an environmental assessment,
which is required for a food additive petition, precludes timely action
by us on a petition.
(Response 138) We advise potential notifiers that the lack of a
requirement to submit an environmental component (e.g., an
environmental assessment) with a GRAS notice does not eliminate a
notifier's responsibility to comply with applicable Federal, State,
tribal, and local law or requirements regarding protection of the
environment.
H. Substances Affirmed as GRAS With Specific Limitations
(Comment 139) One comment asks us to ``modernize the standard'' in
Sec. 184.1(b)(2) to allow expedited review under the notification
program of new uses of substances affirmed as GRAS under Sec.
184.1(b)(2). (Section 184.1(b)(2) specifies that if an ingredient is
affirmed as GRAS with specific limitation(s), it shall be used in food
only within such limitation(s), including the category of food(s), the
functional use(s) of the ingredient, and the level(s) of use, and any
use of such an ingredient not in full compliance with each such
established limitation shall require a food additive regulation.)
(Response 139) We decline the request to amend Sec. 184.1(b)
beyond the editorial, clarifying, and conforming changes listed in
table 29. The comment provides no basis for us to do so. As discussed
during the rulemaking to establish Sec. 184.1(b)(2) (41 CFR 53600 at
53601, December 7, 1976), that regulation does not require that a
subsequent use be covered by a food additive regulation even though it
may be GRAS. As an alternative to a food additive regulation, the
regulation affirming a substance as GRAS with specific limitations on
the conditions of use may be amended to cover additional uses that have
become GRAS. Importantly, both mechanisms (i.e., food additive
regulation and GRAS affirmation regulation) require rulemaking, and the
appropriate mechanism for a manufacturer to lawfully use a substance
outside the limitations established in a regulation affirming specific
uses of the substance as GRAS with specific limitations is to submit a
petition to us. A manufacturer may submit a food additive petition
asking us to conduct rulemaking that results in a food additive
regulation; alternatively, now that the GRAS affirmation petition
process is no longer operative, the manufacturer may submit a citizen
petition in accordance with Sec. 10.30 asking us to conduct rulemaking
that amends the regulation affirming a
[[Page 55031]]
substance as GRAS with specific limitations on the conditions of use.
(See also Ref. 4.58 to CFSAN's 2010 experience document).
See section III.N.2 of CFSAN's 2010 experience document (Ref. 18)
for a discussion of a GRAS affirmation petition to amend a specific
regulation that affirmed a substance as GRAS with specific limitations
on the conditions of use; we converted that GRAS affirmation petition
to a food additive petition and authorized the additional conditions of
use in a food additive regulation. We advise persons who wish to
petition us to provide for additional uses of substances that have been
affirmed as GRAS with specific limitations that under Sec. 10.30(e) we
may advise that we are denying the request to initiate rulemaking to
amend the GRAS affirmation regulation, but note that we could
accommodate the request to conduct rulemaking through the food additive
petition process.
XXV. Comments on Substances Intended for Use in Animal Food
A. Issues in the 2010 Notice Specific to Animal Food
In the 2010 notice, we discussed several issues associated with the
requirements for a GRAS notice for an intended use in animal food to
consider dietary exposure (see table 27). Although we discussed these
issues in a section entitled ``Dietary exposure,'' these issues broadly
applied to several provisions of the rule (see, e.g., Sec. Sec.
570.30, 570.225(c)(4), 570.235, 570.245, and 570.250). In the following
sections, we discuss how comments on these issues, and associated
conforming changes, lead to specific revisions to the regulatory text.
See table 28 for the principal changes specific to the proposed animal
food rule other than the editorial, clarifying, and conforming changes
shown in table 29 and the additional editorial changes associated with
the redesignation of the proposed notification procedure (proposed
Sec. 570.36) as part 570, subpart E. Table 28 does not include those
changes that we made to the proposed requirements when we made an
analogous change to the human food regulations in part 170.
Table 27--Issues in the 2010 Notice Specific to Animal Food
------------------------------------------------------------------------
Description of
Issue No. our request for Reference
comment
------------------------------------------------------------------------
11c....... Whether it is 75 FR 81536 at 81541.
necessary to
clarify that the
GRAS
notification
procedure is
applicable to
substances used
in both food and
drinking water
of animals and,
if so, whether
it would be
necessary to
clarify this in
the provisions
of the proposed
notification
procedure.
11d....... Whether it is 75 FR 81536 at 81541.
necessary to
clarify proposed
Sec.
570.36(c)(1)(iii
) to explicitly
require
submission of
information
about the animal
species expected
to consume the
substance.
11e....... Whether it is 75 FR 81536 at 81541.
necessary to
clarify
applicable
sections of the
proposed rule to
explicitly
require, for
substances
intended for use
in the food of
an animal used
to produce human
food, the
submission of
information
about both
target animal
and human safety.
------------------------------------------------------------------------
Table 28--Summary of Principal Changes Specific to the Proposed Animal
Food Rule
------------------------------------------------------------------------
Regulatory section in the final
rule Change
------------------------------------------------------------------------
Sec. 570.30(a), (b), and (c).... Specify that general recognition of
safety is based on data and
information that addresses safety
for both the target animal and for
humans consuming human food derived
from food-producing animals.
Sec. 570.225(c)(4).............. Requires you to describe the
intended conditions of use of a
notified substance in animal food
by specifying the levels of use in
foods or drinking water.
Sec. 570.235.................... In part 3 of your GRAS notice, you
must provide data and information
about exposure to the target animal
and to humans consuming human food
derived from food-producing
animals.
Sec. 570.250(a) and (b)......... You must explain how the generally
available data and information in
your notice provide a basis for
your view that the notified
substance is generally recognized
as safe, among qualified experts,
under the conditions of its
intended use for both the target
animal and for humans consuming
human food derived from food-
producing animals.
------------------------------------------------------------------------
B. Criteria for Eligibility for Classification as GRAS for a Substance
Intended for Use in Animal Food (Sec. 570.30)
(Comment 140) Comments that address Issue 11e agree that data and
information in a GRAS notice must be sufficient to address safety for
both the target animal and for humans consuming human food derived from
food-producing animals (see Comment 150 and Comment 151).
(Response 140) We have modified several provisions of the GRAS
notification procedure to specify how the notifier must provide data
and information to address the safety of the notified substance under
the conditions of its intended use for both the target animal and for
humans consuming human food derived from food-producing animals (see
Sec. Sec. 570.225(c)(4), 570.235, 570.245, and 570.250). To clarify
that the submission requirements reflect the GRAS criteria for the use
of a substance in animal food, we also have modified Sec. 570.30(a),
(b), and (c) to specify that general recognition of safety is based on
data and information that addresses safety for both the target animal
and for humans consuming human food derived from food-producing
animals. See the regulatory text of Sec. 570.30. See also Response 141
regarding the definition of common use in food in Sec. 570.3(f).
(Comment 141) One comment notes that the proposed human food
regulations, but not the proposed animal food regulations, include
specific criteria for eligibility for classification as GRAS through
experience based on common use in food prior to 1958 when that use
occurred exclusively or primarily outside the United States (see Sec.
170.30(c)(2)). This comment asks us to maintain parallel criteria for
eligibility for classification as GRAS through experience based on
common use in food in the human food regulations and the animal food
regulations by amending Sec. 570.30(c) of the animal food regulations
to include a provision analogous to Sec. 170.30(c)(2).
(Response 141) We are amending Sec. 570.30(c) to include a
provision analogous to Sec. 170.30(c)(2). See the regulatory text of
Sec. 570.30(c)(1) and (2). For consistency with the clarifying
[[Page 55032]]
amendment to the general criteria in Sec. 570.30(a), we also are
revising Sec. 570.30(c) to clarify that general recognition of safety
through experience based on common use in food shall address safety for
both the target animal and for humans consuming human food derived from
food-producing animals. For consistency with the clarifying amendment
to the general criteria in Sec. 570.30(a), we also are revising the
definition of common use in food to mean a substantial history of
consumption of a substance by a significant number of animals of the
species to which the substance is intended to be fed (and, for food-
producing animals fed with such substance, also means a substantial
history of consumption by humans consuming human foods derived from
those food-producing animals), prior to January 1, 1958 (see Sec.
570.3(f) and table 29).
C. Part 1 of a GRAS Notice for a Substance Intended for Use in Animal
Food: Name of the Notified Substance (Sec. 570.225(c)(3))
As shown in table 6, in the 2010 notice we asked for comment on
whether to require that the GRAS notice include the name of the
notified substance, using an appropriately descriptive term, instead of
the ``common or usual name'' of the notified substance (Issue 7). The
final rule requires that Part 1 of a GRAS notice for an intended use of
a notified substance in animal food include the name of the notified
substance, using an appropriately descriptive term (Sec.
570.225(c)(3)). The appropriately descriptive term may be the same as
the common or usual name of the substance. You may consult with CVM's
staff in operating divisions that address the labeling requirements of
the FD&C Act, currently CVM's Division of Animal Feeds, regarding any
common or usual name for a substance used in animal food. In addition,
for substances used in animal food, the Association of American Feed
Control Officials (AAFCO) annually publishes its Official Publication,
a handbook which contains, among other things, Official Feed Terms,
which define many of the terms commonly used in the animal food
manufacturing industry. It also contains Official and Tentative
Definitions of Feed Ingredients, a set of definitions for ingredients
commonly used in animal food. Under CVM's Compliance Policy Guide CPG
665.100 (Common or Usual Names for Animal Feed Ingredients), the
definitions, as they appear in the AAFCO Official Publication, are
generally regarded as constituting the common or usual name for animal
food ingredients, including pet food (Ref. 52).
D. Part 1 of a GRAS Notice for a Substance Intended for Use in Animal
Food: Intended Conditions of Use (Sec. 570.225(c)(4))
(Comment 142) One comment asks us to require that a notifier
specify whether the intended use of the notified substance is in food
or in drinking water. Another comment asks CVM to accept the
anticipated consumption levels by animals that are based upon general
formulation principles that consider the availability of contemporary
feedstuffs.
(Response 142) The final requirements for Part 1 of a GRAS notice
require you to describe the intended conditions of use of a notified
substance in animal food by stating whether the substance will be added
to food (including drinking water) for animals in which the substance
will be used, and by identifying the foods to which it will be added
and the levels of use in such foods (see Sec. 570.225(c)(4)). In
describing the levels of use of the notified substance, you may base
the levels of use upon general formulation principles that consider the
availability of contemporary feedstuffs. See also Response 148
regarding the calculation of target animal exposure.
(Comment 143) Some comments ask us to specifically require
submission of information about the animal species expected to consume
the substance. One comment states that specifying the target animal is
as important as specifying whether the substance would be consumed by
humans in human food derived from the animal. Another comment suggests
that requiring submission of information about the animal that would
consume the substance would avoid the unnecessary delays associated
with CVM's questions that result in an amendment to the notice with
information about the animal species expected to consume the substance.
(Response 143) The final requirements for Part 1 of a GRAS notice
require you to describe the intended conditions of use of a notified
substance in animal food, including the animal species for which the
foods are intended. In addition, the final requirements for Part 1 of a
GRAS notice specify that in describing the intended conditions of use
of a notified substance in animal food, you must, when appropriate,
describe any ``subpopulation'' expected to consume the notified
substance; the life stage of an animal is an example of what we mean by
``subpopulation.'' The physical, physiologic, and absorption/
distribution/metabolism/elimination characteristics of a given animal
species may vary based on life stages within the same animal species. A
substance that is safe for use in an animal species at one stage of
life may not be safe for use in the same animal species at a different
stage of life. See also Response 51.
E. Part 2 of a GRAS Notice for a Substance Intended for Use in Animal
Food: Data and Information Bearing on the Physical or Other Technical
Effect of the Notified Substance (Sec. 570.230(d))
(Comment 144) Several comments discuss CVM's practice, during the
Interim Pilot program, of asking a notifier to provide data or
information demonstrating the effectiveness, or utility, of the
substance. Some comments ask us to limit the notification procedure to
the information necessary to conduct an appropriate safety assessment,
without submission of additional data and information to demonstrate
the technical effect of the substance within animal food in cases where
the technical effect has no impact on safety. Some comments agree that
the intended conditions of use of the notified substance in animal food
must be described and supported in the notice, but assert that the need
for utility data generated from target animal feeding studies is
inappropriate and unnecessary because the pivotal issue is whether the
ingredient is safe to feed to animals.
(Response 144) We have added a requirement for Part 2 of a GRAS
notice to include relevant data and information bearing on the physical
or other technical effect the notified substance is intended to
produce, including the quantity of the notified substance required to
produce such effect, when necessary to demonstrate safety (see Sec.
570.230(d)). We agree that data and information bearing on the physical
or other technical effect the notified substance is intended to produce
are only necessary when they bear on safety. This relationship to
safety is consistent with the requirements of the FD&C Act for a
petition to establish the safety of a food additive (see section
409(b)(2)(C) of the FD&C Act).
The physical or other technical effects of substances added to
animal food fall into two main categories: (1) Substances fed for a
nutritive effect in the animal (e.g., providing one or more nutrients
or other nutritive effect); and (2) substances that have technical
effects in the food (e.g., anti-caking agents, binders, emulsifiers,
enzymes, mixing
[[Page 55033]]
aids, preservatives, processing aids, stabilizers, and substances added
for aroma, flavor, or other technical effects) rather than nutritive
effects in the animal. As discussed in the following paragraphs, a
substance added for either a nutritive effect or for a technical effect
in animal food can have an impact on safety for the target animal.
Nutritive effect in the animal. Data and information bearing on the
nutritive effect of a substance may be necessary to demonstrate safety
because animals (e.g., food-producing animals, companion animals)
typically are fed the same diet formula for long periods of their life.
These diets are formulated to supply all of the animal's daily nutrient
needs for a specific life stage (e.g., growth, reproduction, adult
maintenance). The diet must provide appropriate amounts of all
nutrients the animal requires in a form that the animal can use and
consume daily; otherwise, a nutrient deficiency or toxicity can result,
causing adverse effects to animal health, including poor growth,
excessive weight loss, organ system failures, and death. Under these
constraints of how animals are fed, a substance intended to provide one
or more nutrients becomes unsafe if the nutrients are, in fact, not
provided in a form usable by the animals consuming the diet.
The typical approach to support the nutritive effect of a substance
intended for use in animal food is to combine generally available and
accepted data and information about the general function of the
substance with animal feeding studies demonstrating that the substance
acts as intended. When an appropriate animal feeding study (i.e., an
animal feeding study that is relevant, properly designed, and well-
controlled) is already generally available (e.g., in the peer-reviewed
scientific literature), it can be possible to support the nutritive
effect of a substance without conducting a new study. If an appropriate
animal feeding study is not already generally available, an animal
feeding study specifically conducted to support the nutritive effect
would ordinarily be published and, as discussed in Response 19, there
would be a time gap between the publication of the study and the use of
the published study to support a conclusion of GRAS status. (As
discussed in Response 9, unpublished studies can be used to
corroboratively support the intended nutritive effect of the substance
under the conditions of its intended use.) In addition, for any animal
feeding study a factor to be considered is whether data and information
obtained from a feeding study conducted in one animal species (or in
one stage of life of an animal species) can be used to support safety
in another animal species (or in a different stage of life in the same
animal species). See Response 145 for a discussion of when data and
information that are obtained from an animal study and bear on the
nutritive effect of a substance could be extrapolated from one animal
species to another animal species, or to a different stage of life of
the same animal species. In the following paragraphs, we provide
examples of when data and information bearing on the nutritive effect
of a substance intended for use in animal food could be established
through the use of generally available and accepted data and
information, or likely would need to be established through an animal
feeding study that specifically supports the nutritive effect of the
substance under the conditions of its intended use.
For some types of substances, generally available and accepted data
and information about the function of a substance may be adequate to
support the nutritive effect of the substance without also relying on
an animal feeding study. For example, generally available and accepted
data and information about the function of fat and carbohydrates as
sources of dietary energy often can be used for substances providing
fat intended as a source of dietary energy (rather than as a source of
essential fatty acids) and for substances providing carbohydrates
intended as a source of dietary energy. Likewise, generally available
and accepted data and information about the nutritive content of human
food can provide support for the nutritive effect of unsalable human
food products (such as bruised produce) being collected for animal food
use for their nutritional content rather than entering landfills or
being incinerated.
For other types of substances, an animal feeding study (whether
previously published or newly conducted) is the norm to support the
nutritive effect of the substance. For example, for an ingredient that
is intended to supply an essential mineral (such as phosphorus or
zinc), generally available data and information can provide support
that the mineral is an essential nutrient for the animal, but the
bioavailability of the mineral in the ingredient that would be added to
animal food generally needs to be determined in an animal feeding study
conducted with that specific ingredient, because data regarding the
amount of the mineral that is added to the feed in the ingredient (or
that can be detected analytically in the feed or in the ingredient)
would not provide evidence that the mineral is in a form that is
available to the animal. However, for an ingredient that is intended to
provide an essential amino acid, the need for an animal feeding study
can depend on the form and composition of the ingredient. For example,
it can be possible to rely on published literature to establish that a
crystalline amino acid will be bioavailable to an animal (and, thus,
functional). However, if a complex matrix, such as a biomass composed
of microbial cells or a processed oilseed meal, is intended to be a
source of amino acids, an animal feeding study generally would be
needed to provide evidence that the bioavailability of the amino acids
has not been adversely impacted by the other substances present in the
complex matrix.
Technical effect in the food (rather than nutritive effect in the
animal). As with a substance intended to provide a nutritive effect in
the animal, data and information bearing on a substance's technical
effect in the food (e.g., substances such as anti-caking agents,
binders, emulsifiers, enzymes, mixing aids, preservatives, processing
aids, stabilizers, and substances added for aroma, flavor or other
technical effects) may be necessary to demonstrate safety because of
the physical form and properties of animal diets. Although generally
available and accepted data and information can provide evidence of a
technical effect in the food, it is common for studies to be conducted
with the animal food to demonstrate the intended technical effect.
Depending on the intended technical effect, an animal feeding study
(whether previously published or newly conducted) may be also needed to
demonstrate the intended technical effect of the substance. In the
following paragraphs, we provide examples of when animal feeding
studies may be needed to support the intended technical effect of the
substance. We also provide examples of when an intended technical
effect in animal food could be established through the use of generally
available and accepted data and information about the technical effect
and the studies conducted with the intended animal food matrix. As with
a substance intended to provide a nutritive effect in the animal, when
an appropriate study, which may be an animal feeding study, is already
generally available (e.g., in the peer-reviewed scientific literature),
it can be possible to support the technical effect of a substance in
the food without conducting a new study. If an appropriate study is not
already generally available, a study conducted
[[Page 55034]]
to support the technical effect in the food would ordinarily be
published and, as discussed in Response 19, there would be a time gap
between the publication of the study and the use of the published study
to support a conclusion of GRAS status.
Enzymes are often added to animal food to alter the bioavailability
of nutrients already in the food. For example, it is well known that
the enzyme phytase increases the bioavailability to animals of the
phosphorus present in grain (Ref. 53), and substances that provide
phytase activity are often added to diets for poultry and swine.
Poultry and swine diets are typically formulated with the minimal
amount of phosphorus. If the phytase enzyme does not carry out the
effect of improving phosphorus availability to the animal as intended,
the consequence will be a diet that is deficient in phosphorus and
therefore results in adverse impacts on animal health in the form of
decreased growth, increased orthopedic disease (e.g., rickets), and
suffering animals (Ref. 54). As another example, protease enzymes can
be added to an animal food to affect the digestibility of proteins in
the food (Ref. 55). Both animal feeding studies and stability studies
(to assess the stability of the enzyme in the food and, thus, its
ability to perform its intended technical effect) are the norm when
enzymes are added to animal food. However, when the function of an
enzyme in animal food is well known, it is also common to use generally
available and accepted data and information about the function of the
enzyme in combination with animal feeding studies and stability studies
to support the function of the enzyme (see section IV in CVM's
experience document (Ref. 20)).
Substances such as binders, lubricants, and pelleting agents are
added to animal food that will be fed as pellets. In some cases, such
substances are added to ensure that the pellet retains its desired form
and that the individual ingredients remain agglomerated, making it more
difficult for an animal to select only those ingredients it prefers. In
aquaculture foods, such substances are added to prevent the pellet from
dissolving or prevent the nutrients from leaching out of the pellet.
Depending on the circumstances, either technical effect studies
conducted with the animal food, or generally available and accepted
data and information about the function of the substance, can be used
to support the intended technical effect, such as that of a binder,
lubricant, or pelleting agent, etc., when added to animal food.
Flavors are added to animal food for certain species, generally for
specific life stages of that species. For example, flavors can be added
to animal food intended for consumption by piglets being transitioned
from a milk-based diet to a commercial growth diet to increase
consumption of the commercial growth diet. Flavors also are added to
commercial animal food intended for aquaculture to attract newly
hatched fish (fish fry) to the commercial food when the commercial food
does not resemble the food that fish fry would consume in nature. If
the fish fry are not attracted to the commercial food, the fish fry can
starve to death. Animal feeding studies are the norm to support the
function of the substance as a flavor when added to animal food.
Substances such as emulsifiers and stabilizers are added to animal
food to ensure that an animal consumes all of the ingredients in the
correct proportions in order to meet its nutritional needs.
Inconsistent nutrient content and delivery of a diet to the animal can
cause either nutrient deficiency diseases, or toxicities. For example,
liquid cattle foods are often available to the animal at all times and
cattle simply lick the feeding device to obtain the food. If the
minerals present in the liquid fall out of suspension and settle to the
bottom, the first animals to access the feeder will consume lower
nutrient levels than expected, while those animals that access the
feeder later and consume the bottommost material may be at risk of
toxicity due to higher nutrient levels. For dry ingredients, the
ingredients in the formulated diet must be uniformly dispersed and
mixed, remain mixed during handling, and be physically stable as a
formulated animal diet is moved through augers and conveyors, and
transported in bulk in trucks, which can result in the loss of
nutrients through sifting or ``unmixing.'' These effects are assessed
on the diet itself through appropriate studies.
(Comment 145) One comment asks us to accept reasonable arguments as
to the worst-case exposures (inclusion levels) if the substance or
class of substances has well-established use patterns rather than
require utility data to support the intended nutritional effect. This
comment also asks us to be flexible when utility data are warranted to
support an entirely new use in animal feeds when utility data from one
representative species would be sufficient to address utility in the
target animal.
(Response 145) When animal feeding studies are necessary to provide
data and information bearing on the nutritive effects of a substance
intended for use in animal food, the potential to extrapolate from the
conclusions of a feeding study conducted in one animal species to
another animal species depends on the similarities of their digestive
systems, physiology, and diets. For example, when a bioavailability
study for selenium present in selenium yeast is conducted in cattle
(which have a fermentative digestive tract), it can be possible to
extrapolate the conclusions of that bioavailability study to other
animal species that have fermentative digestive tracts. However, when a
bioavailability study for copper is conducted in a ruminant animal
species, it may not be appropriate to extrapolate the conclusions of
that bioavailability study to sheep, even though sheep are ruminants,
because sheep physiology is such that sheep are much more sensitive to
copper toxicity than other ruminant species. In addition, when a
bioavailability study for a nutrient is conducted in animals other than
fish, it may not be possible to extrapolate the conclusions of that
bioavailability study to aquaculture-fed fish, because aquaculture
diets that are consumed in the water present special challenges,
particularly for slow-feeding or bottom-feeding aquaculture species,
where the diet pellet must retain its form and nutrient content until
the pellet is consumed. For example, it is possible for nutrients that
are soluble in water to dissolve out of the pellet before consumption,
preventing the aquaculture animal from accessing all the required
nutrients.
See Response 144 for a discussion of circumstances where generally
available and accepted data and information can be used to provide
evidence bearing on the nutritive effects of a substance intended for
use in animal food (e.g., for substances providing fat intended as a
source of dietary energy, for substances providing carbohydrates
intended as a source of dietary energy, for unsalable human food
products, and when a crystalline amino acid is added to animal food).
See also Response 150 for additional discussion of limitations on the
use of generally available and accepted data and information, such as a
weight of evidence approach, for the extrapolation of available data
and information from an animal species other than the target animal.
Regardless of whether the intended use of the notified substance is
to provide nutritive value or technical effect, any person who
concludes that the available data and information regarding the safety
of a notified substance under the conditions of its intended use
satisfy GRAS criteria must
[[Page 55035]]
have a basis for the conclusion of GRAS status, irrespective of whether
that person notifies us of that conclusion in a GRAS notice. If you
submit your conclusion of GRAS status to FDA, you must explain how the
data and information in your GRAS notice provide the basis for your
conclusion, e.g., in Part 2 of the GRAS notice (where you would
describe the applicable data and information), in the narrative in Part
6 of your GRAS notice, or in both Parts 2 and 6 of your GRAS notice. We
would then evaluate whether the data, information, and narrative in
your GRAS notice support your conclusion. When data and information
bearing on the physical or other technical effect of the notified
substance are necessary to support safety, we could conclude that a
GRAS notice that does not discuss such data and information is
incomplete, and either contact a notifier to request an amendment
discussing such data and information, or issue an insufficient basis
letter.
(Comment 146) One comment asserts that a requirement for proof of
utility, with subsequent publication of utility data, is unnecessary,
and that a requirement for utility data to be documented by means of a
peer-reviewed publication would burden the industry with additional
cost, not only to conduct the studies but also to prepare the
manuscript and have it accepted for publication. This comment also
asserts that finding a journal willing to publish such germane studies
may be challenging because the manuscript may be viewed as serving the
manufacturer's interest rather than providing any new scientific
information. As alternatives to publication of a target animal feeding
study, this comment suggests means such as documenting the chemical
nature of the substance in relation to same (or similar) substance with
ample public information, and placing unpublished studies conducted by
the notifier in the context of published literature about the use of
the substance or related substances. This comment also asserts that CVM
and industry resources could be better utilized to demonstrate the
safety of the intended use of the substance with a focus on
establishing the worst-case exposure and relating it to available
safety information to establish a margin of safety.
(Response 146) See Response 15, in which we respond to comments
asserting it can be difficult to publish data and information that do
not raise an issue of concern. Consistent with CFSAN's experience
during the Interim Pilot program, we believe that some journals
directed to food safety would be willing to publish data and
information bearing on the physical or other technical effect the
notified substance is intended to produce when those data and
information are necessary to demonstrate safety (see section III.A.1 of
CFSAN's 2010 experience document (Ref. 18)).
See also Response 144 for a discussion of circumstances where
generally available and accepted data and information can be used to
provide evidence bearing on the nutritive effects of a substance
intended for use in animal food. There may be situations where
sufficient generally available and accepted data and information on
exposure to the substance or class of substances can satisfy GRAS
criteria without publication of specific data and information bearing
on the physical or other technical effect the notified substance is
intended to produce. For example, as discussed in section IV of CVM's
experience document during the Interim Pilot program CVM responded with
a ``no questions letter'' when the use of published information for
technical effects such as nutrient, enzyme, and component of a defoamer
was used, in whole or in part, to support such technical effects (Ref.
20). As discussed in Response 12, GRAS status may be corroborated by
unpublished scientific data, information, or methods, and there may be
some unpublished scientific data, information, or methods regarding the
safety of a use of a food substance. As discussed in Response 8, the
criteria for GRAS status through scientific procedures provide for the
application of ``generally available and accepted'' scientific data,
information, or methods, which ``ordinarily'' are published and, thus,
provide flexibility for supporting a conclusion of GRAS status through
the application of scientific data, information, or methods that are
generally available through a mechanism other than publication in a
peer-reviewed scientific journal.
See the discussion in Response 150 regarding the evaluation of
safety studies, including the applicability of worst-case exposure on a
case-by-case basis.
F. Part 3 of a GRAS Notice for a Substance Intended for Use in Animal
Food: Target Animal and Human Exposures (Sec. 570.235)
1. Substances Intended for Use in Food or Drinking Water for Animals
(Comment 147) Comments that address Issue 11c support clarifying
that the GRAS notification procedure is applicable to substances used
in both food and drinking water of animals.
(Response 147) The final requirements for Part 3 of a GRAS notice
specify that ``animal food'' includes ``drinking water.'' See also
Response 142.
2. Data and Information About the Dietary Exposure for the Target
Animal
(Comment 148) One comment states that exposure information can
usually be obtained from published data sources and that if a worst-
case exposure cannot be established without new data, then data for one
representative animal species are sufficient, especially if the
selected species represents a worst-case scenario. As an example, the
comment suggests that data from one representative poultry species
would be sufficient to address the conditions of use of a notified
substance intended for poultry. As noted in Comment 142, another
comment asks CVM to accept the anticipated consumption levels by
animals that are based upon general formulation principles that
consider the availability of contemporary feedstuffs.
(Response 148) See the regulatory text of Sec. 570.235(a) for the
requirements for what you must provide in Part 3 of a GRAS notice
regarding exposure to the target animal. The regulatory text addressing
the types of exposure to the target animal parallels the regulatory
text for dietary exposure to a notified substance in the human food
regulations (see Sec. 170.235). As noted in Response 142, you may base
the levels of use upon general formulation principles that consider the
availability of contemporary feedstuffs. We agree that exposure
information may be available from published data sources. If exposure
cannot be established without new data, then data for one
representative animal species may be sufficient if the selected species
represents a worst-case scenario.
(Comment 149) One comment asks that any restatement of the
regulatory text regarding dietary exposure consider how to use the word
``consumer,'' because ``consumers'' are humans for the purpose of part
170 but are ``animals'' for the purpose of part 570.
(Response 149) To reduce the potential for confusion, the final
requirements for part 3 of a GRAS notice for a substance intended for
use in animal food do not use the term ``consumer.''
G. Data and Information in a GRAS Notice About Safety for the Target
Animal (Sec. 570.250)
(Comment 150) Comments that address Issue 11e agree that data and
information in a GRAS notice must be
[[Page 55036]]
sufficient to address safety for the target animal. However, most of
these comments express concern about the standard for demonstrating
safety to the target animal, specifically whether safety must be
established through feeding studies specific to the target animal or
could be extrapolated from data and information regarding species other
than the target animal. Although one comment asserts that a notifier
must submit evidence that the substance is safe for all the species in
question if a substance is expected to be consumed by different animal
species, other comments emphasize that safety could be established
through either feeding studies in the target animal or through
extrapolation of data obtained from species other than the target
animal. Some comments suggest that the rule require a clear and concise
written explanation of how studies in non-target species relate to the
target animal rather than require safety data in the target animal
species.
One comment disagrees that the GRAS notification procedure should
establish any absolute requirement for data addressing safety for the
target species. This comment asserts that CVM should not require
species-specific data for all substances and species covered by the
intended use of the notified substance because recognized scientific
procedures, such as a weight of evidence approach, allow for the
extrapolation of data and that these types of scientific procedures can
be applied to notified substances. This comment also asserts that a CVM
requirement for safety data in the target animal, rather than a written
explanation of how studies in non-target species relate to the target
animal, cannot be scientifically justified and will put the animal feed
industry at a disadvantage for obtaining recognition of new GRAS
substances, and that the additional cost and time will stifle
innovation and reduce growth in the U.S. feed industry and animal
agriculture.
(Response 150) Whether species-specific data and information (such
as feeding studies) are necessary to satisfy GRAS criteria depends on
the intended use of the notified substance. We recognize that there may
be situations where scientific procedures, such as a weight of evidence
approach, allow for the extrapolation of available data and information
from an animal species other than the target animal. For example, CVM
had no questions regarding an enzyme preparation intended for use in
food for turkeys, broiler chickens, and laying hens, when the feeding
studies used to support target animal safety were conducted only on
broiler chickens (Ref. 20). In such cases, you would explain the
relevance of the available data to the target species in the narrative
required in Part 6 of a GRAS notice rather than describe species-
specific data and information.
However, extrapolating data from one animal species to another is
not always appropriate because a substance that is safe for use in one
animal species may not be safe for use in another species or in the
same species at a different stage of life. For example, a substance
that is safe for use in a species that is a ruminant animal (e.g.,
cattle) may not be safe for use in a species considered a monogastric
animal (e.g., swine) because of the difference in their digestive
systems and different nutrient requirements. For example, in ruminant
animals, non-protein nitrogen compounds (e.g., urea and biuret) release
ammonia, which is then metabolized by rumen microorganisms into
microbial proteins. These microbial proteins are a useful source of
protein to ruminant animals. However, in monogastric animals, the
liberated ammonia from non-protein nitrogen compounds is absorbed
directly by the animal, resulting in adverse toxicological events, and
possibly death. Even within the same species of animal, or for
different species in the same class of animals (e.g., chicken, duck,
turkey), extrapolating safety data may not be appropriate. For example,
a substance that is safe for laying hens may not be safe for use in
broilers because of the different nutrient requirements, such as the
higher calcium level in a laying hen diet (which is intended to meet
the nutrient demand for egg production). If that high level of calcium
is consumed by broiler chickens, the potential calcification of soft
tissue such as that of kidneys could become detrimental to the broiler
chickens. Likewise, a substance that is safe for chickens may not be
safe for ducks or turkeys because the nutrient requirements for
different species of poultry vary widely. Feeding a diet intended for
one species of poultry to another species could cause nutrient
imbalances, deficiencies, or excesses, which could have adverse
consequences ranging from loss of production to damages to tissues and
organs and even to death. When extrapolating data and information from
another animal species is not appropriate, in Part 6 of your GRAS
notice you would discuss data and information developed specifically
for the target animal, or for the stage of life in the same animal
species, rather than explain how you extrapolated available data and
information from an animal species other than the target animal, or how
you extrapolated available data and information from the same animal
species to a different life stage of that animal species.
Any person who concludes that the available data and information
regarding the safety of a notified substance under the conditions of
its intended use satisfy GRAS criteria must have a basis for the
conclusion of GRAS status, regardless of whether that person notifies
us of that conclusion in a GRAS notice. A resource that may help
determine when it could be appropriate to extrapolate species-specific
data and information from one animal species to another animal species
is our guidance entitled ``Guidance for Industry: Recommendations for
Preparation and Submission of Animal Food Additive Petitions'' (# 221)
(June 2015) (Ref. 56). Section G.2 of that guidance (on target animal
safety) recommends that target animal safety studies be conducted using
the life stage and animal species for which the food additive will be
marketed. In cases where the food additive is intended for multiple
animal species or life stages, the food additive should be tested in
the most sensitive life stage and/or species. The guidance recommends
using current scientific literature to identify the most sensitive life
stage and/or species. As with guidance documents prepared by CFSAN,
CVM's scientific recommendations in a guidance directed to food
additives can be applied to the evaluation of whether a substance is
GRAS under the conditions of its intended use (see Response 66).
Another resource is a book entitled ``Safety of Dietary Supplements
for Horses, Dogs, and Cats'' by the National Research Council (Ref.
57), which identifies five factors to consider when selecting
appropriate surrogates for horses, dogs and cats. In addition, it
advises considering nutritional, metabolic, pharmacokinetic, and
natural dietary patterns when selecting appropriate animal model
species. Although the material is directed to only three target
animals, some aspects of its approach can be generalized.
If you submit your conclusion of GRAS status to FDA, you must
explain how the data and information in your GRAS notice provide the
basis for your conclusion; we would then evaluate whether the data,
information, and narrative in your GRAS notice support your conclusion.
[[Page 55037]]
H. Data and Information in a GRAS Notice About the Safety for Humans
Consuming Human Food Derived From a Food-Producing Animal (Sec. Sec.
570.235 and 570.250)
(Comment 151) Some comments support clarifying the rule to
explicitly require the submission of information about safety for both
the target animal and for humans consuming human food derived from
food-producing animals. One comment states that the safety and
wholesomeness of food given to animals that eventually end up in human
food must be held to the same standard as for a substance intended for
use in human food. Another comment asks us to specify that the
submission of data and information about both target animal and human
safety is required when such data and information are developed for
food-producing animals.
One comment states that it is the responsibility of the notifier to
determine the extent of the safety assessment of a substance intended
for use in the food of a food-producing animal. This comment asserts
that there is no need to set explicit standards for addressing both
target animal and human food safety in applicable sections of the rule,
because whether new data, such as tissue residue data, would be
warranted would be determined through application of general scientific
principles from the fields of animal nutrition and metabolism.
Another comment asserts that neither human feeding studies nor
tissue residue accumulation data should be required when available
scientific information can be used to draw conclusions using a weight
of the evidence approach, as CFSAN does for human food substances. This
comment asserts that CVM must clarify what data need to be provided
regarding safety for humans consuming human food derived from food-
producing animals before industry could agree to the requirement.
(Response 151) We are clarifying the requirement to address safety
for humans consuming human food derived from food-producing animals in
Parts 3 and 6 of a GRAS notice.
In the requirements for Part 3 of a GRAS notice for a substance
intended for use in animal food, we have modified the title of the
regulatory text to specify that Part 3 addresses exposures to both the
target animal and to humans consuming human food derived from food-
producing animals (see Sec. 570.235). When the intended use of the
notified substance is in food for food-producing animals, you must
provide: (1) The potential quantities of any residues that humans may
be exposed to in edible animal tissues; and (2) the data and
information you rely on to establish the potential quantities of such
residues (see Sec. 570.235(b)). These requirements parallel the
requirements for target animal exposure, but are directed to the
quantity of potential residues of the notified substance, and of any
other substance that is expected to be formed in or on the animal food
because of the use of the notified substance, and those residues from
any other substances present with the notified substance, whether
naturally, due to its manufacture (e.g., contaminants or by-products),
or produced as a metabolite in edible animal tissues when the notified
substance is consumed by a food-producing animal. It is well
established that substances consumed by food-producing animals, and
substances such as metabolites produced by a food-producing animal, can
accumulate in edible animal tissues and have an adverse impact on
public health. For example, aflatoxin M1 is a metabolite of aflatoxin
B1 that is produced during normal biological processes of animals
ingesting the toxin (e.g., from food contaminated with aflatoxin B1)
and has been shown to cause liver cancer in certain animals (Ref. 58).
As another example, there can be human food safety concerns about the
level of selenium in animal tissues when food-producing animals consume
large amounts of a substance that contains selenium in their diets.
We agree that the specific data and information that are necessary
to determine the safety for humans consuming human food derived from a
food-producing animal would be determined through the application of
general scientific principles from the fields of animal nutrition and
metabolism and that it is the notifier's responsibility to determine
what those specific data and information are. Therefore, we have
modified the requirements for the narrative in Part 6 of a GRAS notice
to clarify that the narrative must address the safety for both the
target animal and for humans consuming human food derived from food-
producing animals (see Sec. 570.250(a)(1) and (b)).
I. Filing Decision, Opportunity for a Notifier To Submit an Amendment,
and Asking Us To Cease To Evaluate a GRAS Notice for a Substance
Intended for Use in Animal Food (Sec. Sec. 570.260 and 570.265)
(Comment 152) Some comments express concern about differences in
how CFSAN and CVM administered GRAS notices during the Interim Pilot
program. Some comments describe CFSAN's practice of using conference
calls to obtain a clarification or additional information, with a
reasonable period of time for the notifier to provide the clarification
or additional information. These comments assert that CVM's practice is
different from CFSAN's practice because CVM does not contact a notifier
to discuss CVM's questions after a submission has been accepted for
filing. One comment asserts that CVM has informally indicated that once
a GRAS notice is accepted for filing, there will be no further
communication with the notifier and the GRAS notice will be judged
solely on what was accepted for filing. This comment further asserts
that such a process is unreasonable because the error or omission may
be trivial and/or easily remedied. This comment also asserts that
allowing informal contacts (including telephone, email, and fax) to
address minor issues would be consistent with how FDA has handled a
wide range of submissions that require review. Another comment asserts
that CVM's practice of not contacting the notifier is a major concern
for the industry and that CVM's reviewers may have questions that could
be easily answered by the notifier, if contacted.
Some comments ask CVM to engage in the same informal practice as
CFSAN, with respect to contacting the notifier and allowing remedial
action, if such action may be completed in a reasonable period of time.
Some comments ask the Centers to establish a uniform system of contact
and communication after a submission (and/or agreeing to evaluate an
amendment to a GRAS notice) to prevent delays or other inefficiencies
over issues that could easily be clarified and resolved. Some comments
note that uniformity between CFSAN and CVM in the submission and
handling of requests to cease to evaluate a GRAS notice is of great
importance in maintaining transparency and efficiency in the GRAS
notification procedure.
(Response 152) The regulatory text governing what CVM will do with
a GRAS notice (Sec. 570.265) is the same as the regulatory text
governing what CFSAN will do with a GRAS notice (Sec. 170.265). In
addition, the regulatory text that provides for a notifier who submits
a GRAS notice to CVM to submit a timely amendment to a filed GRAS
notice, and to ask us to cease to evaluate a GRAS notice (Sec.
570.260), is the same as the regulatory text that provides for a
notifier who submits a GRAS notice to CFSAN to submit a timely
amendment to a filed GRAS
[[Page 55038]]
notice, and to ask us to cease to evaluate a GRAS notice (Sec.
170.260).
We disagree that CVM did not contact notifiers during the Interim
Pilot program. As shown in table 1 in CVM's experience document (Ref.
20), CVM contacted the notifier regarding 9 of 18 GRAS notices during
its evaluation process. CVM issued ``no questions letters'' to seven of
these nine notices after the notifiers provided clarifying amendments.
Moving forward under the final rule, CVM intends to consider the
same factors that CFSAN considers regarding whether to file a
submission as a GRAS notice (see Response 85), the purpose of
contacting a notifier (including whether to provide an opportunity for
a notifier to ask us to cease to evaluate a GRAS notice) (see Response
80), and the transparency of the reasons for a ``cease to evaluate
letter'' (see Response 81). Because our factors regarding the purpose
of contacting a notifier, and the provisions that provide an
opportunity for a notifier to submit an amendment, consider whether an
amendment is (or could be) timely, the final rule does, as requested by
the comments, consider whether an amendment could be prepared and
submitted in a reasonable period of time. Importantly, as discussed in
Response 101, the role of an amendment is to clarify questions that we
have about your conclusion of GRAS status, rather than to substantively
amend the notice. Whether we will evaluate an amendment to a GRAS
notice before responding to the notice is a matter that we will
consider on a case-by-case basis.
J. Opportunity for a Notifier To Submit a Supplement to a GRAS Notice
for a Substance Intended for Use in Animal Food (Sec. 570.280)
(Comment 153) One comment asks CVM to adopt CFSAN's approach of
allowing a notifier to submit information to a GRAS notice after FDA
responds to the notice.
(Response 153) The rule provides that, if circumstances warrant, a
notifier who submits a GRAS notice to CVM may submit a supplement to a
filed GRAS notice after we respond to your notice by letter or cease to
evaluate your notice (Sec. 570.280). As discussed in section VI of
CVM's experience document (Ref. 20), as of December 31, 2015, CVM had
not received any supplements to a GRAS notice.
K. GRAS Affirmation Petitions for Substances Used in Animal Food
CVM has no pending GRAS affirmation petitions and, thus, the final
animal food regulations do not include provisions for the disposition
of pending GRAS affirmation petitions for substances used in animal
food.
XXVI. Editorial, Clarifying, and Conforming Amendments
The revised regulatory text includes several changes that we have
made to make the requirements more clear and improve readability. The
revised regulatory text also includes several conforming changes that
we have made when a change to one provision affects other provisions.
We summarize the principal editorial and conforming changes in table
29.
Table 29--Principal Editorial, Clarifying, and Conforming Changes
------------------------------------------------------------------------
Designation in the
regulatory text (Sec. ) Revision Explanation
------------------------------------------------------------------------
Sec. 20.100(c)(46)........ Add new paragraph Conforming change in
(c)(46) to clarify light of the new
applicability of GRAS notification
Sec. 20.100 (the procedures
handling of FDA established in Sec.
records upon a Sec. 170.36 and
request for public 570.36.
disclosure) to GRAS
notices in Sec.
Sec. 170.36(h)
and 570.36(h).
Sec. 25.20(k)............. Replace Conforming
``Affirmation of a change in light of
food substance as the deletion of the
GRAS for humans or GRAS affirmation
animals, on FDA's petition process.
initiative or in Correct the
response to a list of applicable
petition, under categorical
parts 182, 184, exclusions that
186, or 582 of this apply to include
chapter'' with the categorical
``Establishment or exclusions listed
amendment of a in Sec. 25.32(i)
regulation for a and (j).
food substance as
GRAS under the
conditions of its
intended use for
humans or animals
under parts 182,
184, 186, 582, or
584 of this
chapter''.
Replace
``unless
categorically
excluded in Sec.
25.32(f), (k), or
(r)'' with ``unless
categorically
excluded in Sec.
25.32(f), (i), (j),
(k), or (r)''.
Sec. 25.32(f)............. Replace Clarify
``Affirmation of a that GRAS
food substance as affirmation applies
GRAS for humans or to the intended
animals on FDA's conditions of use
initiative or in of a substance, not
response to a the substance
petition, under itself.
parts 182, 184, Conforming
186, or 582 of this change in light of
chapter'' with the deletion of the
``Establishment or GRAS affirmation
amendment of a petition process.
regulation for a
food substance as
GRAS under the
conditions of its
intended use for
humans or animals
under parts 182,
184, 186, 582, or
584 of this
chapter''.
Sec. 25.32 (i), (j), (k), Replace ``or GRAS Clarify
and (r). affirmation that GRAS
petition'' with affirmation applies
``establishment or to the intended
amendment of a conditions of use
regulation for a of a substance, not
food substance as the substance
GRAS under the itself.
conditions of its Conforming
intended use for change in light of
humans or animals the deletion of the
under parts 182, GRAS affirmation
184, 186, 582, or petition process.
584 of this
chapter''.
Sec. 170.3(h), Sec. Specify Clarify
570.3(h). ``data from human, that the four
animal, analytical, listed types of
or other scientific studies (human,
studies'' rather animal, analytical,
than ``data from and other) do not
human, animal, necessarily apply
analytical, and in all
other scientific circumstances.
studies''.
Replace Include
``appropriate to statutory language
establish the from section 201(s)
safety of a of the FD&C Act to
substance'' with clarify that GRAS
``appropriate to status applies to
establish the the intended
safety of a conditions of use
substance under the of a substance, not
conditions of its the substance
intended use''. itself.
[[Page 55039]]
170.3(i).................... In the definition of Conforming change to
``safe'' or consistently use
``safety,'' replace the exact statutory
``under the language in section
intended conditions 201(s) ``under the
of use'' with conditions of its
``under the intended use''
conditions of its rather than
intended use''. variations (such as
under the intended
conditions of use).
Sec. 170.3(k)............. Replace ``General Conforming change.
recognition of See Response 41.
safety shall be
determined in
accordance with
170.30'' with
``General
recognition of
safety shall be in
accordance with
Sec. 170.30''.
Throughout Sec. 170.30.... Replace ``Sec. Correction to
186.1'' with ``part clarify that the
186''. provision applies
to all of part 186,
not just Sec.
186.1.
Sec. 170.30(a)............ Replace the proposed Conforming change to
regulatory text consistently use
``there is the exact statutory
reasonable language in section
certainty that the 201(s) ``under the
substance is not conditions of its
harmful under the intended use''
intended conditions rather than
of use'' with variations (such as
``there is under the intended
reasonable conditions of use).
certainty that the
substance is not
harmful under the
conditions of its
intended use''.
Sec. 170.30(b), Sec. Replace ``General Clarify
570.30(b). recognition of that FDA approves a
safety based upon food additive, not
scientific a ``food additive
procedures shall regulation''.
require the same Clarify
quantity and that the same
quality of quantity and
scientific evidence quality of
as is required to scientific evidence
obtain approval of is required
a food additive regardless of
regulation for the whether the
ingredient'' with substance is
``General intended for use as
recognition of an ``ingredient''.
safety based upon
scientific
procedures shall
require the same
quantity and
quality of
scientific evidence
as is required to
obtain approval of
a food additive''.
Sec. 170.30(c)(1), Sec. Replace ``General Conforming
570.30(c)(1). recognition of change. See
safety through Response 41.
experience based on Clarify
common use in food that FDA approves a
prior to January 1, food additive, not
1958, may be a ``food additive
determined without regulation''.
the quantity or
quality of
scientific
procedures required
for approval of a
food additive
regulation'' with
``General
recognition of
safety through
experience based on
common use in food
prior to January 1,
1958, may be
achieved without
the quantity or
quality of
scientific
procedures required
for approval of a
food additive''.
Sec. 170.30(c)(2)......... Replace Conforming
``if the change to
information about consistently use
the experience the exact statutory
establishes that language in section
the use of the 201(s) ``under the
substance is safe conditions of its
within the meaning intended use''
of the act (see rather than
Sec. 170.3(i))'' variations (such as
with ``if the ``the use of the
information about substance'').
the experience Clarify
establishes that that the applicable
the substance is section of the FD&C
safe under the Act is section
conditions of its 201(u). Section
intended use within 170.3(i) is in our
the meaning of regulations, not in
section 201(u) of the FD&C Act.
the Federal Food, Editorial
Drug, and Cosmetic change to include
Act (see also Sec. the full name of
170.3(i))''. the statute.
Replace Editorial
``in this country'' change to be
with ``in the specific that
United States''. ``this country''
means ``the United
States''.
170.30(c)(2), 170.38(a), Replace ``the act'' Editorial. It is now
570.38(a). with ``the Federal our practice to
Food, Drug, and include the full
Cosmetic Act'' in name of this
any provision that statute when we
we otherwise refer to it.
revised.
Sec. 170.30(e)............ Replace See
``Beginning in Response 41.
1969, the Food and Include
Drug Administration statutory language
has undertaken a from section 201(s)
systematic review of the FD&C Act to
of the status of clarify that GRAS
all ingredients status applies to
used in food on the the intended
determination that conditions of use
they are GRAS or of a substance, not
subject to a prior the substance
sanction'' with itself.
``Beginning in Clarify
1969, the Food and that GRAS status
Drug Administration pursuant to parts
has undertaken a 184 and 186 is
systematic review affirmed by FDA.
of the status of
all ingredients
used in food based
on the view that
they are GRAS under
the conditions of
their intended use
or subject to a
prior sanction''.
Replace
``All
determinations of
GRAS status or food
additive status or
prior sanction
status pursuant to
this review shall
be handled pursuant
to Sec. Sec.
170.35, 170.38, and
180.1 of this
chapter.
Affirmation of GRAS
status shall be
announced in part
184 or Sec. 186.1
of this chapter''
with ``All
affirmations of
GRAS status or
determinations of
food additive
status or prior
sanction status
pursuant to this
review shall be
handled pursuant to
Sec. Sec.
170.35, 170.38, and
180.1 of this
chapter.
Affirmation of GRAS
status shall be
announced in part
184 or part 186 of
this chapter''.
[[Page 55040]]
Sec. 170.30(l)............ Replace ``Any change Clarify the
in part 182, part applicability of
184, or Sec. the requirement.
186.1 of this
chapter shall be
accomplished
pursuant to Sec.
170.38'' with ``Any
change to the GRAS
status of a food
ingredient in part
182, part 184, or
part 186 of this
chapter shall be
accomplished
pursuant to Sec.
170.38''.
Sec. 170.35(a), Sec. Replace ``may affirm Editorial
570.35(a). the GRAS status of change to use the
substances'' with singular.
``may affirm that a Include
substance that statutory language
directly or from section 201(s)
indirectly becomes of the FD&C Act to
a component of food clarify that GRAS
is GRAS under the affirmation applies
conditions of its to the intended
intended use''. conditions of use
of a substance, not
the substance
itself.
Sec. 170.35(b)(1), Sec. Replace ``If the Include statutory
570.35(b)(1). Commissioner language from
proposes on his own section 201(s) of
initiative that a the FD&C Act to
substance is clarify that GRAS
entitled to affirmation applies
affirmation as to the intended
GRAS'' with ``If conditions of use
the Commissioner of a substance, not
proposes on his own the substance
initiative that a itself.
substance is
entitled to
affirmation as GRAS
under the
conditions of its
intended use''.
Sec. 170.35(b)(3), Sec. Replace Include
570.35(b)(3). ``convincing statutory language
evidence that the from section 201(s)
substance is GRAS'' of the FD&C Act to
with ``convincing clarify that GRAS
evidence that the affirmation applies
substance is GRAS to the intended
under the conditions of use
conditions of its of a substance, not
intended use''. the substance
Replace itself.
``listing the Deleted
substance as GRAS reference to parts
in part 182, part 182 and 582. If FDA
184, or part 186 of affirms GRAS
this chapter'' with status, the
``listing the GRAS affirmation
conditions of use regulation would
of the substance in appear in part 184
part 184 or part or 186.
186 of this
chapter''.
Sec. 170.35(b)(4), Sec. Replace ``there is a Include statutory
570.35(b)(4). lack of convincing language from
evidence that the section 201(s) of
substance is GRAS'' the FD&C Act to
with ``there is a clarify that GRAS
lack of convincing affirmation applies
evidence that the to the intended
substance is GRAS conditions of use
under the of a substance, not
conditions of its the substance
intended use''. itself.
Sec. 170.38(a), Sec. Replace See
570.38(a). ``may, in Response 41.
accordance with Conforming
Sec. 170.35(b)(4) change in light of
or (c)(5), publish the deletion of the
a notice in the GRAS affirmation
Federal Register petition process.
determining that a Include
substance is not statutory language
GRAS'' with ``may, from section 201(s)
in accordance with of the FD&C Act to
Sec. clarify that GRAS
170.35(b)(4), affirmation applies
publish a notice in to the intended
the Federal conditions of use
Register of a substance, not
determining that a the substance
substance is not itself.
GRAS under the
conditions of its
intended use''.
Replace
``may, in
accordance with
Sec. 570.35(b)(4)
or (c)(5), publish
a notice in the
Federal Register
determining that a
substance is not
GRAS'' with ``may,
in accordance with
Sec.
570.35(b)(4),
publish a notice in
the Federal
Register
determining that a
substance is not
GRAS under the
conditions of its
intended use''.
Throughout part Replace variations Editorial change.
170, subpart E. of ``data or other Although data is a
Throughout part information'' with type of
570, subpart E. ``data and ``information,'' it
information''. is simpler and
clearer to say
``data and
information.''
Throughout part Replace variations See Response 41.
170, subpart E. of ``determine''
Throughout part and
570, subpart E. ``determination''
with ``conclude''
and ``conclusion''.
Throughout part Replace See Response 42.
170, subpart E. ``exempt'' with
Throughout part ``not subject to:.
570, subpart E. Replace
``claim'' with
``view''.
Sec. 170.203, Sec. In the definition of Clarification by
570.203. ``notifier,'' add a including text from
parenthetical with the definition of
examples of what we ``person'' in Sec.
mean by ``person'' 10.3.
(e.g., an
individual,
partnership,
corporation,
association, or
other legal entity).
Sec. 170.225(c)(4)........ Replace the proposed Clarifying change to
phrase ``applicable use the statutory
conditions of use'' term ``intended''
with ``intended in place of
conditions of use''. ``applicable''.
Sec. 184.1(a)............. Replace ``The direct Clarify that the
human food GRAS status of the
ingredients listed uses of substances
in this part have listed in part 184
been reviewed by has been affirmed
the Food and Drug by FDA, either on
Administration and FDA's initiative or
determined to be in response to a
generally GRAS affirmation
recognized as safe petition.
(GRAS) for the
purposes and
conditions
prescribed'' with
``The direct human
food ingredients
listed in this part
have been reviewed
by the Food and
Drug Administration
and affirmed to be
generally
recognized as safe
(GRAS) for the
purposes and under
the conditions
prescribed''.
[[Page 55041]]
Sec. 184.1(b)(1).......... Replace Conforming
``shall change to reflect
independently ``conclusions'' of
establish'' with GRAS status.
``shall have a Conforming
basis to conclude''. change in light of
Remove the the deletion of the
last sentence, GRAS affirmation
i.e., ``Persons petition process.
seeking FDA
approval of an
independent
determination that
a use of an
ingredient is GRAS
may submit a GRAS
petition in
accordance with
170.35 of this
chapter.''.
Sec. 186.1(a)............. Replace ``The Clarify that the
indirect human food GRAS status of the
ingredients listed uses of substances
in this part have listed in part 186
been reviewed by has been affirmed
the Food and Drug by FDA, either on
Administration and FDA's initiative or
determined to be in response to a
generally GRAS affirmation
recognized as safe petition.
(GRAS)'' with ``The
indirect human food
ingredients listed
in this part have
been reviewed by
the Food and Drug
Administration and
affirmed to be
generally
recognized as safe
(GRAS)''.
Sec. 186.1(b)(1).......... Replace Conforming change in
``shall light of the
independently deletion of the
establish'' with GRAS affirmation
``shall have a petition process.
basis to conclude''.
Remove the
last sentence,
i.e., ``Persons
seeking FDA
approval of an
independent
determination that
a use of an
ingredient is GRAS
may submit a GRAS
petition in
accordance with
170.35 of this
chapter.''.
Sec. 570.3(f)............. Add ``of Changes to
the species to Conform
which the substance with revisions to
is intended to be Sec. 570.30(a)
fed'' in describing and (c)
the animals Conform
consuming the with the
substance. corresponding
Delete ``in definition for
the United States''. human food in Sec.
Add ``(and, 170.3(f), which
for food-producing does not specify
animals fed with ``in the United
such substance, States.''
also means a Clarify
substantial history that substantial
of consumption by history of
humans consuming consumption should
human foods derived be demonstrated by
from those food- the same animal
producing animals) species as the
prior to January 1, species intended to
1958. be fed to conform
with the submission
requirements in
part 5 of a GRAS
notice when the
basis for the
conclusion of GRAS
status is through
experience based on
common use in food
(Sec. 570.245).
Clarify
that substantial
history of
consumption for
food-producing
animals also should
be demonstrated by
a substantial
history of
consumption by
humans consuming
human foods derived
from those food-
producing animals
prior to January 1,
1958 to conform
with the submission
requirements in
part 5 of a GRAS
notice.
Sec. 570.3(k)............. Replace ``General Conforming change.
recognition of The GRAS
safety shall be notification
determined in procedure does not
accordance with use the term
Sec. 570.30'' ``determine.''
with ``General
recognition of
safety shall be in
accordance with
Sec. 570.30''.
Sec. 570.3................ Define ``food- Clarify the meaning
producing animal'' of this term for
to mean an animal the purpose of part
used to produce 570, subpart E in
human food. light of provisions
that address the
safety of a
substance for
humans consuming
human food derived
from an animal used
to produce human
food.
Sec. 570.30(c)............ Replace ``General Conforming
recognition of change. The GRAS
safety through notification
experience based on procedure does not
common use in food use the term
prior to January 1, ``determine.''
1958, may be Clarify
determined without that FDA approves a
the quantity or food additive, not
quality of a ``food additive
scientific regulation''.
procedures required
for approval of a
food additive
regulation'' with
``General
recognition of
safety through
experience based on
common use in food
prior to January 1,
1958, may be
achieved without
the quantity or
quality of
scientific
procedures required
for approval of a
food additive''.
Sec. 570.30(d)............ Replace Clarify that the
``ingredients provisions apply
listed as GRAS in regardless of
part 582 of this whether an
chapter'' with ingredient is
``ingredients listed as GRAS in
listed as GRAS in part 582 or
part 582 of this affirmed as GRAS in
chapter or affirmed part 584.
as GRAS in part 584
of this chapter''.
Replace
``without specific
inclusion in part
582 of this
chapter'' with
``without specific
inclusion in part
582 or part 584 of
this chapter''.
Sec. 570.30(i)............ Replace ``Any use of Editorial correction
such and of ``and'' to
ingredient'' with ``an''.
``Any use of such
an ingredient''.
570.225(c)(4), Replace ``food'' Clarification for
570.225(c)(5), 570.230(c), with ``animal part 570.
570.235, 570.240, 570.245. food''.
------------------------------------------------------------------------
[[Page 55042]]
XXVII. Economic Analysis of Impacts
We have examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct us to assess all costs
and benefits of available regulatory alternatives and, when regulation
is necessary, to select regulatory approaches that maximize net
benefits (including potential economic, environmental, public health
and safety, and other advantages; distributive impacts; and equity). We
have developed a comprehensive Economic Analysis of Impacts that
assesses the impacts of the final rule. We believe that this final rule
is not a significant regulatory action as defined by Executive Order
12866.
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. The final rule replaces the voluntary GRAS affirmation
petition process with a voluntary GRAS notification procedure. Similar
to the petition process, we expect that profit-maximizing firms will
only submit the GRAS notice when the private benefits equal or exceed
the costs of the GRAS notice, regardless of the size of the firm.
Because small firms face the same voluntary business decision as large
firms, we certify that the final rule will not have a significant
economic impact on a substantial number of small entities.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before issuing ``any rule that includes
any Federal mandate that may result in the expenditure by State, local,
and tribal governments, in the aggregate, or by the private sector, of
$100,000,000 or more (adjusted annually for inflation) in any one
year.'' The current threshold after adjustment for inflation is $146
million, using the most current (2015) Implicit Price Deflator for the
Gross Domestic Product. This final rule will not result in an
expenditure in any year that meets or exceeds this amount.
The final rule will eliminate the petition process to affirm a
substance is GRAS and replace the petition process with a GRAS
notification procedure. The level of effort required by a firm to reach
a conclusion that a substance is GRAS for its intended use remains
unchanged by the final rule. However, the rule will require that firms
submit some additional information to support their conclusion with
their notices. Although uncertain, we estimate that notifiers will
spend between 5 more hours and 20 more hours to prepare and submit each
notice. We estimate that this will cost notifiers less than $0.1
million each year.
For all affected notifiers, we expect that they will spend time
reading and understanding the requirements of the final rule and
revising standard operating procedures for preparing and submitting
GRAS notices. We estimate that it will take from 20 hours to 80 hours
for notifiers to perform this action. Firms with outstanding GRAS
affirmation petitions may choose to submit GRAS notices and incorporate
the information included in their petition. To account for the
additional effort by these firms, we include the one-time cost to
prepare and submit a GRAS notice for all outstanding petitions. We
estimate that notifiers will spend between 170 and 190 hours to submit
GRAS notices for each outstanding petition. The total one-time costs of
the final rule range from $0.8 million to $2.7 million.
We estimate that over 10 years with a 7 percent discount rate, the
present value of the total costs of the final rule range from $0.9
million to $3.3 million; with a 3 percent discount rate, the present
value of the total costs range from $0.9 million to $3.4 million. The
annualized costs of the rule range from $0.1 million to $0.4 million
with a 7 percent discount rate and range from $0.1 million to $0.5
million with a 3 percent discount rate.
We do not quantify the benefits of the final rule. However, based
on the differences in review time between the GRAS petition process and
the GRAS notification procedure, we anticipate that industry will
benefit from the more speedy notification procedure. For example, we
have filed more than 600 GRAS notices for human food substances since
1998. During this time, it took an average of 200 days for us to
respond to 588 GRAS notices; it took an average of 7.9 years to
complete 24 previous GRAS affirmation petitions. We began to accept
GRAS notices for animal food substances in 2010 and we have filed 18
GRAS notices for animal food substances since that time. It took an
average of 294 days for us to respond to 12 GRAS notices with a ``no
questions letter'' or ``insufficient basis letter''; it took an average
of 4.9 years to respond to the three previous GRAS affirmation
petitions. With the GRAS notification procedure, we can complete our
evaluation within the timelines specified in the final rule.
The Economic Analysis of Impacts of the final rule performed in
accordance with Executive Order 12866, Executive Order 13563, the
Regulatory Flexibility Act, and the Unfunded Mandates Reform Act (Ref.
51) is available at https://www.regulations.gov under the docket number
for this final rule and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
XXVIII. Analysis of Environmental Impact
We have carefully considered the potential environmental effects of
this action. We have concluded under 21 CFR 25.30(h) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
XXIX. Paperwork Reduction Act of 1995
This final rule contains information collection provisions that are
subject to review by OMB under the PRA (44 U.S.C. 3501-3520). The
title, description, and respondent description of the information
collection provisions are shown in the following paragraphs with an
estimate of the one-time and annual reporting burdens. Included in the
estimate is the time for reviewing instructions, searching existing
data sources, gathering and maintaining the data needed, and completing
and reviewing each collection of information.
Title: Substances Generally Recognized as Safe Notification
Procedure (21 CFR parts 170 and 570) (OMB Control No. 0910-0342)--
Revision.
Description: The FD&C Act requires that all food additives (as
defined by section 201(s)) be approved by FDA before they are marketed
(sections 402(a)(2)(C) and 409 of the FD&C Act). Section 201(s) of the
FD&C Act excludes from the definition of a food additive a substance
``generally recognized, among experts qualified by scientific training
and experience to evaluate its safety, as having been adequately shown
through scientific procedures (or, in the case of a substance used in
food prior to January 1, 1958, through either scientific procedures or
experience based on common use in food) to be safe under the conditions
of its intended use.'' This final rule amends our regulations in parts
170 and 570 and revises the information collection provisions regarding
the notification procedures for GRAS substances. The
[[Page 55043]]
regulations implement the GRAS provision of section 201(s) of the FD&C
Act in part 170 and part 570 for human food and animal food,
respectively.
Description of Respondents: Respondents to the collection of
information are manufacturers of substances used in human food and
animal food. We estimate there are 480 such respondents. As estimated
in the Final Regulatory Impact Analysis (Ref. 51), approximately 340 to
460 notifiers (for human food) and approximately 10 to 20 notifiers
(for animal food) will be affected by the final rule. The Final
Regulatory Impact Analysis reflects an overall increase in respondents
to the program and we have therefore adjusted our respondent numbers
accordingly.
As discussed in section II.B of the preamble to this final rule,
previously manufacturers were invited to submit notices of their
independent GRAS determinations for review under the framework of the
proposed rule during the period between issuance of the proposed rule
and any final rule based on the proposed rule. The proposed regulations
provided a standard format for the voluntary submission of a notice. To
date, the GRAS program has been administered under these proposed
procedures. Comments regarding the information collection topics
solicited in the proposed rule and subsequent 2010 notice are discussed
in the preamble in sections IV, VII, and X through XVIII. While none of
the comments suggested we modify the estimated annual burden associated
with the information collection, we have revised the underlying
notification procedures and, consequently, have revised the underlying
information collection provisions consistent with the final rule.
Specifically the final rule establishes a voluntary administrative
procedure for notifying FDA about a conclusion that a substance is GRAS
under the conditions of its intended use in human food or animal food.
The final rule explains that a GRAS notice must include the following
seven parts:
Table 30--Information To Be Included in Each Part of a GRAS Notice
------------------------------------------------------------------------
Part No. Information to be included
------------------------------------------------------------------------
Part 1............................ Signed statements and a
certification.
Part 2............................ The identity, method of manufacture,
specifications, and physical or
technical effect of the notified
substance.
Part 3............................ Dietary exposure to the notified
substance.
Part 4............................ Self-limiting levels of use in
circumstances where the amount of
the notified substance that can be
added to human food or animal food
is limited because the food
containing levels of the notified
substance above a particular level
would become unpalatable or
technologically impractical.
Part 5............................ The history of consumption of the
substance for food use by a
significant number of consumers (or
animals in the case of animal food)
prior to January 1, 1958, if a
conclusion of GRAS status is based
on common use of the substance in
food prior to 1958.
Part 6............................ A narrative that provides the basis
for the notifier's conclusion of
GRAS status, including why the
scientific data, information,
methods, and principles described
in the notice provide a basis for
the conclusion that the notified
substance is generally recognized,
among qualified experts, to be safe
under the conditions of its
intended use.
Part 7............................ A list of the generally available
data, information, and methods the
notifier cites in the GRAS notice.
------------------------------------------------------------------------
The information submitted to us in a GRAS notice is necessary to
allow us to administer efficiently the FD&C Act's various provisions
that apply to the use of substances added to food, specifically with
regard to whether a substance is GRAS under the conditions of its
intended use or is a food additive subject to premarket review. We will
use the information collected through the GRAS notification procedure
to complete our evaluation within the timelines specified in the final
rule.
One-Time Reporting Burden
Table 31 shows the estimated one-time reporting burden associated
with the final rule. We expect that all respondents to the information
collection will spend time reading and understanding the requirements
of the final rule and revising standard operating procedures for
preparing and submitting GRAS notices. As noted, we estimate that
approximately 340 to 460 notifiers (for human food) and approximately
10 to 20 notifiers (for animal food) will be affected by the final
rule. We use the upper-bound estimates of 460 and 20 respondents as
shown in rows 1 and 2. We estimate that it will take from 20 to 80
hours for respondents to perform this action. We use the upper-bound
estimate of 80 hours as shown in rows 1 and 2. Of the 480 affected
respondents, some will have outstanding GRAS petitions. Firms with
outstanding GRAS petitions regarding substances intended for use in
human food may choose to submit GRAS notices and incorporate the
information included in their petition. As estimated in the Final
Regulatory Impact Analysis (Ref. 51), up to 45 petitions (for human
food) will be submitted as GRAS notices and incorporated. We use the
upper-bound estimate of 45 as shown in row 3. To account for the
additional effort by these firms, we include the one-time burden to
prepare and submit a GRAS notice for all outstanding petitions. Because
there are no outstanding GRAS petitions regarding substances intended
for use in animal food, we do not account for any burden for the
submission of a GRAS notice that incorporates a GRAS petition regarding
a substance intended for use in animal food. We estimate that
respondents will spend between 170 and 190 hours to submit GRAS notices
for each outstanding petition and have used, therefore, an average
estimate of 185 hours as shown in row 3.
[[Page 55044]]
Table 31--Estimated One-Time Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of
Activity/21 CFR section Number of responses per Total annual Average burden Total hours
respondents respondent responses per response
----------------------------------------------------------------------------------------------------------------
Notifier's review of final rule 460 1 460 80 36,800
and revision of procedures for
preparing and submitting GRAS
notices for human food, 170.210
through 170.270................
Notifier's review of final rule 20 1 20 80 1,600
and revision of procedures for
preparing and submitting GRAS
notices for animal food,
570.210 through 570.270........
Prepare and submit GRAS notice 45 1 45 185 8,325
for an outstanding GRAS
petition, 170.285..............
-------------------------------------------------------------------------------
Total....................... .............. .............. .............. .............. 46,725
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Recurring Reporting Burden
Table 32 shows the estimated recurring annual reporting burden
associated with the final rule. As previously discussed, the final rule
replaces the petition process with a GRAS notification procedure. The
level of effort required by a firm to reach a conclusion that a
substance is GRAS for its intended use remains unchanged by the final
rule. However, the final rule requires that firms submit some
additional information to support the conclusions found within their
notices. The additional information might include an amendment
(Sec. Sec. 170.260 and 570.260); a supplement (Sec. Sec. 170.280 and
570.280); a request for FDA to cease to evaluate a GRAS notice
(Sec. Sec. 170.260 and 570.260); an incorporation into a GRAS notice
(Sec. Sec. 170.215 and 570.215); and, information required when the
intended conditions of use of a notified substance includes use in a
product subject to regulation by FSIS, including authorization to us to
share any trade secrets with FSIS (Sec. 170.270). Because the amount
of additional information may vary, we estimate that respondents will
spend between 155 and 170 hours to prepare and submit each notice.
Using the upper-bound figure of 170 hours, we therefore estimate that
the 50 notifiers for human food and 25 notifiers for animal food will
expend 12,750 hours annually as shown, respectively, in rows 1 and 2.
Table 32--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of
Activity/21 CFR section Number of responses per Total annual Average burden Total hours
respondents respondent responses per response
----------------------------------------------------------------------------------------------------------------
GRAS notification procedure for 50 1 50 170 8,500
human food, 170.210 through
170.270........................
GRAS notification procedure for 25 1 25 170 4,250
animal food, 570.210 through
570.270........................
-------------------------------------------------------------------------------
Total....................... .............. .............. .............. .............. 12,750
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
Recordkeeping
The final rule does not contain recordkeeping requirements. We
believe that documentation used by respondents in support of a
conclusion of GRAS status is information that is collected and retained
as a part of usual and customary business practices for a firm engaged
in the manufacture of substances used in human food and animal food. We
have, therefore, not provided an estimate for these activities (5 CFR
1320.3(b)(2)).
This final rule also refers to other currently approved collections
of information found in our regulations. These collections of
information are subject to review by OMB under the PRA. The collections
of information in 21 CFR 25.32(i) are approved under OMB control number
0910-0541. The collections of information in 21 CFR 10.33 are approved
under OMB control number 0910-0191.
The information collection provisions of this final rule have been
submitted to OMB for review as required by section 3507(d) of the PRA.
Before the effective date of this final rule, FDA will publish a notice
in the Federal Register announcing OMB's decision to approve, modify,
or disapprove the information collection provisions in this final rule.
An Agency may not conduct or sponsor, and a person is not required to
respond to, a collection of information unless it displays a currently
valid OMB control number.
XXX. Federalism
We have analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that have substantial direct effects on the
States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, we have concluded that the
rule does not contain policies that have federalism implications as
defined in the Executive order and, consequently, a federalism summary
impact statement is not required.
XXXI. References
The following references are on display in the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, and are available for viewing by
interested persons between 9 a.m. and 4 p.m., Monday through Friday;
they also are available electronically at https://
[[Page 55045]]
www.regulations.gov. FDA has verified the Web site addresses, as of the
date this document publishes in the Federal Register, but Web sites are
subject to change over time.
1. House Report No. 2284, July 28, 1958. See Reference 1 to the
proposed rule.
2. Price, J.M., C.G. Biava, B.L. Oser, et al., ``Bladder Tumors in
Rats Fed Cyclohexylamine or High Doses of a Mixture of Cyclamate and
Saccharin,'' Science, 167:1131-1132, 1970. See Reference 2 to the
proposed rule.
3. New York Times, p. 22, October 31, 1969. See Reference 3 to the
proposed rule.
4. United States Government Accountability Office, ``Report to
Congressional Requestors on Food Safety: FDA Should Strengthen Its
Oversight of Food Ingredients Determined to Be Generally Recognized
as Safe (GRAS),'' Report No. GAO-10-246, (https://www.gao.gov/new.items/d10246.pdf), February 2010. Accessed and printed on May 3,
2010. See Reference 2 to the 2010 notice.
5. FDA, ``Draft Guidance for Industry: Assessing the Effects of
Significant Manufacturing Process Changes, Including Emerging
Technologies, on the Safety and Regulatory Status of Food
Ingredients and Food Contact Substances, Including Food Ingredients
that Are Color Additives,'' (https://www.regulations.gov in Docket
No. FDA-2011-D-0490), 2012. Accessed and printed on February 19,
2016.
6. FDA, ``Guidance for Industry: Assessing the Effects of
Significant Manufacturing Process Changes, Including Emerging
Technologies, on the Safety and Regulatory Status of Food
Ingredients and Food Contact Substances, Including Food Ingredients
that Are Color Additives,'' (https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm300661.htm), 2014. Accessed and printed on January 15, 2016.
7. FDA, ``Draft Guidance for Industry: Considering Whether an FDA-
Regulated Product Involves the Application of Nanotechnology,''
(https://www.regulations.gov in Docket No. FDA-2010-D-0530), 2011.
Accessed and printed on February 19, 2016.
8. FDA, ``Guidance for Industry: Considering Whether an FDA-
Regulated Product Involves the Application of Nanotechnology,''
(https://www.fda.gov/RegulatoryInformation/Guidances/ucm257698.htm),
2014. Accessed and printed on January 15, 2016.
9. The Pew Charitable Trusts, ``Fixing the Oversight of Chemicals
Added to Our Food,'' (https://www.pewtrusts.org/~/media/legacy/
uploadedfiles/phg/content_level_pages/reports/
foodadditivescapstonereportpdf.pdf), 2013. Accessed and printed on
February 19, 2016.
10. Letter dated November 17, 2010, from Joann M. Givens of FDA to
Mr. Tim Baggs, Charge Beverages Corporation, (https://www.fda.gov/iceci/enforcementactions/warningletters/2010/ucm233990.htm).
Accessed and printed on January 31, 2016.
11. Letter dated November 17, 2010, from Joann M. Givens of FDA to
Rhonda Kallman of New Century Brewing Company, (https://www.fda.gov/iceci/enforcementactions/warningletters/2010/ucm234028.htm).
Accessed and printed on January 31, 2016.
12. Letter dated November 17, 2010, from Joann M. Givens of FDA to
Jaisen Freeman, Chris Hunter, and Jeff Wright of Phusion Projects,
(https://www.fda.gov/iceci/enforcementactions/warningletters/2010/ucm234023.htm). Accessed and printed on January 31, 2016.
13. Letter dated November 17, 2010, from Joann M. Givens of FDA to
Michael Michail of United Brands Company, (https://www.fda.gov/iceci/enforcementactions/warningletters/2010/ucm234002.htm). Accessed and
printed on January 31, 2016.
14. TTB, Industry Circular 2010-8, (https://www.ttb.gov/industry_circulars/archives/2010/10-08.html), 2010. Accessed and
printed on January 21, 2016.
15. The National Academies of Sciences, Health and Medicine
Division, ``Caffeine in Food and Dietary Supplements: Examining
Safety--Workshop Summary,'' (https://www.nationalacademies.org/hmd/Reports/2014/Caffeine-in-Food-and-Dietary-Supplements-Examining-Safety.aspx), 2014. Accessed and printed on May 27, 2016.
16. Memorandum of Meeting Held on December 11, 2014, between
Representatives of FDA and Representatives of the Caffeine Technical
Working Group on the American Beverage Association (ABA) Caffeine
Technical Working Group (CTWG) Research Plans.
17. International Life Sciences Institute (ILSI North America),
``Caffeine Working Group,'' (https://ilsina.org/our-work/food-safety/caffeine/), 2015. Accessed and printed on June 8, 2016.
18. Experience With GRAS Notices Under the 1997 Proposed Rule,
Memorandum Dated November 4, 2010, from Linda S. Kahl of FDA to
Docket No. FDA-1997-N-0020. See Reference 1 to the 2010 notice.
19. ``Substances that Are Generally Recognized as Safe (GRAS);
Updated Experience With GRAS Notices,'' Memorandum Dated June 1,
2016, from Paulette M. Gaynor of FDA to Docket No. FDA-1997-N-0020.
20. ``Experience With GRAS Notices Under CVM's Interim Pilot
Program,'' Memorandum Dated June 10, 2016, from David Edwards of FDA
to Docket No. FDA-1997-N-0020.
21. Memorandum for the Heads of Executive Departments and Agencies,
Dated June 1, 1998, Signed by President William J. Clinton, (https://www.plainlanguage.gov/whatisPL/govmandates/memo.cfm). Accessed and
printed on July 14, 2008. See Reference 3 to the 2010 notice.
22. eRulemaking Program, ``Improving Electronic Dockets on
Regulations.gov and the Federal Docket Management System: Best
Practices for Federal Agencies,'' (https://www.regulations.gov/docs/FactSheet_eRulemaking_Best_Practices.pdf), 2010. Accessed and
printed on January 15, 2016.
23. Dictionary.com. Dictionary.com Unabridged. Random House, Inc.
(https://dictionary.reference.com/browse/corroborate), 2016. Accessed
and printed on February 23, 2016.
24. Food and Agriculture Organization of the United Nations and the
World Health Organization, ``Chapter 6, Dietary Exposure Assessment
of Chemicals in Food'' in Environmental Health Criteria 240.
Principles and Methods for the Risk Assessment of Chemicals in Food,
(https://apps.who.int/iris/bitstream/10665/44065/9/WHO_EHC_240_9_eng_Chapter6.pdf), 2009. Accessed and printed on
February 13, 2006.
25. FDA, ``Guidance for Industry: Estimating Dietary Intake of
Substances in Food,'' (https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm074725.htm), 2006.
Accessed and printed on January 15, 2016.
26. Renwick, A.G., ``The Use of a Sweetener Substitution Method to
Predict Dietary Exposures for the Intense Sweetener Rebaudioside
A.,'' Food and Chemical Toxicology, 46:S61-S69, 2008.
27. Mitchell, D.C., C.A. Knight, J. Hockenberry, et al., ``Beverage
Caffeine Intakes in the U.S.,'' Food and Chemical Toxicology,
63:136-142, 2014.
28. Fulgoni, V.L., D.R. Keast, and H.R. Lieberman, ``Trends in
Intake and Sources of Caffeine in the Diets of US Adults: 2001-
2010,'' The American Journal of Clinical Nutrition, 101:1081-1087,
2015.
29. Branum, A.M., L.M. Rossen, and K.C. Schoendorf, ``Trends in
Caffeine Intake Among U.S. Children and Adolescents,'' Pediatrics,
133(3):386-393, 2014.
30. Food and Agriculture Organization and World Health Organization,
``Joint FAO/WHO Expert Consultation on Biotechnology and Food
Safety,'' (ftp://ftp.fao.org/es/esn/food/biotechnology.pdf), 1996.
See Reference 6 to the proposed rule.
31. FDA, ``Guidance for Industry: Recommendations for Submission of
Chemical and Technological Data for Direct Food Additive
Petitions,'' (https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm124917.htm), 2009.
Accessed and printed on January 15, 2016.
32. FDA, ``Guidance for Industry: Microbiological Considerations for
Antimicrobial Food Additive Submissions,'' (https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm230417.htm), 2008. Accessed and printed on January 15, 2016.
33. FDA, ``Guidance for Industry: Enzyme Preparations:
Recommendations for Submission of Chemical and Technological Data
for Food Additive
[[Page 55046]]
Petitions and GRAS Notices,'' (https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/IngredientsAdditivesGRASPackaging/ucm217685.htm), 2010. Accessed and
printed on January 15, 2016.
34. FDA, ``Guidance for Industry: Summary Table of Recommended
Toxicological Testing for Additives Used in Food,'' (https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm054658.htm), 2006.
Accessed and printed on January 15, 2016.
35. FDA, ``Guidance for Industry and Other Stakeholders:
Toxicological Principles for the Safety Assessment of Food
Ingredients. Redbook 2000,'' (https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/IngredientsAdditivesGRASPackaging/ucm2006826.htm), 2007. Accessed
and printed on January 15, 2016.
36. 225-00-2000 ``Amendment 1: Memorandum of Understanding Between
the United States Department of Agriculture Food Safety Inspection
Service and the United States Department of Health and Human
Services Food and Drug Administration, (https://www.fda.gov/AboutFDA/PartnershipsCollaborations/MemorandaofUnderstandingMOUs/DomesticMOUs/ucm441552.htm), 2000. Accessed and printed on November
25, 2015.
37. FDA, ``Guidance for Industry: Providing Regulatory Submissions
in Electronic or Paper Format to the Office of Food Additive Safety;
Draft Guidance,'' (https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/IngredientsAdditivesGRASPackaging/ucm2021277.htm), 2010. Accessed
and printed on January 15, 2016.
38. Form FDA 3667. ``Generally Recognized As Safe (GRAS) Notice,''
(https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM350015.pdf), 2016. Accessed and printed on June 1, 2016.
39. Form FDA 3480. ``Food Contact Substance: Notification for New
Use, Pre-Notification Consultation, Food Master File'', (https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM076880.pdf), 2016. Accessed and printed on June 1, 2016.
40. Form FDA 3537. ``DHHS/FDA Food Facility Registration,'' (https://www.fda.gov/downloads/aboutfda/reportsmanualsforms/forms/ucm071977.pdf), 2014. Accessed and printed on January 15, 2016.
41. FSIS, ``Contact Us,'' (https://www.fsis.usda.gov/wps/portal/informational/contactus). Accessed and printed on January 28, 2016.
42. Pariza, M.W. and M. Cook, ``Determining the Safety of Enzymes
Used in Animal Feed,'' Regulatory Toxicology and Pharmacology,
56:332-342, 2010.
43. Olempska-Beer Z.S., R.I Merker, M.D. Ditto, and M.J. DiNovi,
``Food-Processing Enzymes From Recombinant Microorganisms--A
Review,'' Regulatory Toxicology and Pharmacology, 45(2):144-158,
2006.
44. ``Guidance for Industry: Use of Nanomaterials in Food for
Animals (# 220),'' (https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM401508.pdf),
2015. Accessed and printed on January 15, 2016.
45. ``GRAS Notices, Search Results, Common Use in Food,'' 2016.
46. GRAS Notice Inventory, (https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/default.htm),
2016. Accessed and printed on January 15, 2016.
47. Current Animal Food GRAS Notices Inventory, (https://www.fda.gov/AnimalVeterinary/Products/AnimalFoodFeeds/GenerallyRecognizedasSafeGRASNotifications/ucm243845.htm), 2016.
Accessed and printed on February 23, 2016.
48. FDA, List of Pending GRAS Affirmation Petitions as of December
31, 2015.
49. FDA, ``Guidance for Industry: Frequently Asked Questions About
GRAS,'' (https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/IngredientsAdditivesGRASPackaging/ucm061846.htm), 2004. Accessed and
printed on October 13, 2010. See Reference 6 to the 2010 notice.
50. FDA, Memorandum of Telephone Conference Held on May 19, 1998,
between Linda S. Kahl and Gloria Overholser of FDA and Carlton
Kempter and Jonathan Fleuchaus, U.S. Environmental Protection
Agency.
51. FDA, ``Substances Generally Recognized as Safe Final Rule: Final
Regulatory Impact Analysis, Final Regulatory Flexibility Analysis,
Final Unfunded Mandates Reform Act Analysis,'' 2016.
52. FDA, ``Compliance Policy Guide CPG Sec. 665.100 Common or Usual
Names for Animal Feed Ingredients,'' (https://www.fda.gov/iceci/compliancemanuals/compliancepolicyguidancemanual/ucm074687.htm),
1995. Accessed and printed on January 7, 2016.
53. Selle, P.H. and V. Ravindran, ``Microbial Phytase in Poultry
Nutrition,'' Animal Feed Science and Technology, 135:1-41, 2007.
54. Hatten., L.F., D.R. Ingram., and S.T. Pittman, ``Effect of
Phytase on Production Parameters and Nutrient Availability in
Broilers and Laying Hens: A Review,'' The Journal of Applied Poultry
Research, 10(3):274-278, 2001.
55. Angel, C.R., W. Saylor, S.L. Vieira, and N. Ward, ``Effects of a
Monocomponent Protease on Performance and Protein Utilization in 7-
to 22-Day-Old Broiler Chickens,'' Poultry Science, 90:2281-2286,
2011.
56. FDA, ``Guidance for Industry: Recommendations for Preparation
and Submission of Animal Food Additive Petitions (# 221),'' (https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM367746.pdf),
2015. Accessed and printed on January 15, 2016.
57. National Research Council, ``General Considerations in
Determining Safety of Animal Dietary Supplements,'' in Safety of
Dietary Supplements for Horses, Dogs, and Cats, Washington, DC,
Chapter 9, pp. 169-175, The National Academies Press, 2009.
58. FDA, ``Compliance Policy Guide CPG Sec. 527.400. Whole Milk,
Lowfat Milk, Skim Milk--Aflatoxin M1,'' (https://www.fda.gov/iceci/compliancemanuals/compliancepolicyguidancemanual/ucm074482.htm),
2005. Accessed and printed on January 15, 2016.
List of Subjects
21 CFR Part 20
Confidential business information, Courts, Freedom of information,
Government employees.
21 CFR Part 25
Environmental impact statements, Foreign relations, Reporting and
recordkeeping requirements.
21 CFR Part 170
Administrative practice and procedure, Food additives, Reporting
and recordkeeping requirements.
21 CFR Part 184
Food additives.
21 CFR Part 186
Food additives, Food packaging.
21 CFR Part 570
Animal feeds, Animal foods, Food additives.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR
chapter I is amended as follows:
PART 20--PUBLIC INFORMATION
0
1. The authority citation for part 20 continues to read as follows:
Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531-2582;
21 U.S.C. 321-393, 1401-1403; 42 U.S.C. 241, 242, 242a, 242l, 242n,
243, 262, 263, 263b-263n, 264, 265, 300u-300u-5, 300aa-1.
0
2. In Sec. 20.100, add paragraph (c)(46) to read as follows:
Sec. 20.100 Applicability; cross-reference to other regulations.
* * * * *
(c) * * *
(46) Generally recognized as safe (GRAS) notices, in part 170,
subpart E and part 570, subpart E of this chapter.
[[Page 55047]]
PART 25--ENVIRONMENTAL IMPACT CONSIDERATIONS
0
3. The authority citation for part 25 continues to read as follows:
Authority: 21 U.S.C. 321-393; 42 U.S.C. 262, 263b-264; 42
U.S.C. 4321, 4332; 40 CFR parts 1500-1508; E.O. 11514, 35 FR 4247, 3
CFR, 1971 Comp., p. 531-533 as amended by E.O. 11991, 42 FR 26967, 3
CFR, 1978 Comp., p. 123-124 and E.O. 12114, 44 FR 1957, 3 CFR, 1980
Comp., p. 356-360.
0
4. In Sec. 25.20, revise paragraph (k) to read as follows:
Sec. 25.20 Actions requiring preparation of an environmental
assessment.
* * * * *
(k) Establishment or amendment of a regulation for a food substance
as GRAS under the conditions of its intended use for humans or animals
under parts 182, 184, 186, 582, or 584 of this chapter, or
establishment or amendment of a regulation for a prior-sanctioned food
ingredient, as defined in Sec. Sec. 170.3(l) and 181.5(a) of this
chapter, unless categorically excluded in Sec. 25.32(f), (i), (j),
(k), or (r).
* * * * *
0
5. In Sec. 25.32, revise paragraphs (f), (i), (j), (k), and (r) to
read as follows:
Sec. 25.32 Foods, food additives, and color additives.
* * * * *
(f) Establishment or amendment of a regulation for a food substance
as GRAS under the conditions of its intended use for humans or animals
under parts 182, 184, 186, 582, or 584 of this chapter, and
establishment or amendment of a regulation for a prior-sanctioned food
ingredient, as defined in Sec. Sec. 170.3(l) and 181.5(a) of this
chapter, if the substance or food ingredient is already marketed in the
United States for the proposed use.
* * * * *
(i) Approval of a food additive petition, establishment or
amendment of a regulation for a food substance as GRAS under the
conditions of its intended use for humans or animals under parts 182,
184, 186, 582, or 584 of this chapter, the granting of a request for
exemption from regulation as a food additive under Sec. 170.39 of this
chapter, or allowing a notification submitted under 21 U.S.C. 348(h) to
become effective, when the substance is present in finished food-
packaging material at not greater than 5 percent-by-weight and is
expected to remain with finished food-packaging material through use by
consumers or when the substance is a component of a coating of a
finished food-packaging material.
(j) Approval of a food additive petition, establishment or
amendment of a regulation for a food substance as GRAS under the
conditions of its intended use for humans or animals under parts 182,
184, 186, 582, or 584 of this chapter, the granting of a request for
exemption from regulation as a food additive under Sec. 170.39 of this
chapter, or allowing a notification submitted under 21 U.S.C. 348(h) to
become effective, when the substance is to be used as a component of a
food-contact surface of permanent or semipermanent equipment or of
another food-contact article intended for repeated use.
(k) Approval of a food additive petition or color additive
petition, establishment or amendment of a regulation for a food
substance as GRAS under the conditions of its intended use for humans
or animals under parts 182, 184, 186, 582, or 584 of this chapter, or
allowing a notification submitted under 21 U.S.C. 348(h) to become
effective, for substances added directly to food that are intended to
remain in food through ingestion by consumers and that are not intended
to replace macronutrients in food.
* * * * *
(r) Approval of a food additive petition or color additive
petition, establishment or amendment of a regulation for a food
substance as GRAS under the conditions of its intended use for humans
or animals under parts 182, 184, 186, 582, or 584 of this chapter, or
allowing a notification submitted under 21 U.S.C. 348(h) to become
effective for a substance that occurs naturally in the environment,
when the action does not alter significantly the concentration or
distribution of the substance, its metabolites, or degradation products
in the environment.
PART 170--FOOD ADDITIVES
0
6. The authority citation for part 170 continues to read as follows:
Authority: 21 U.S.C. 321, 341, 342, 346a, 348, 371.
0
7. In Sec. 170.3, revise paragraph (h), the first sentence of
paragraph (i), and paragraph (k), to read as follows:
Sec. 170.3 Definitions.
* * * * *
(h) Scientific procedures include the application of scientific
data (including, as appropriate, data from human, animal, analytical,
or other scientific studies), information, and methods, whether
published or unpublished, as well as the application of scientific
principles, appropriate to establish the safety of a substance under
the conditions of its intended use.
(i) Safe or safety means that there is a reasonable certainty in
the minds of competent scientists that the substance is not harmful
under the conditions of its intended use. * * *
* * * * *
(k) General recognition of safety shall be in accordance with Sec.
170.30.
* * * * *
0
8. Amend Sec. 170.30 as follows:
0
a. Revise the last sentence of paragraph (a);
0
b. Revise paragraph (b).
0
c. Revise the the first sentence of paragraph (c)(1) and revise
paragraph (c)(2);
0
d. Remove ``Sec. 186.1'' and add in its place ``part 186'' wherever it
appears in paragraph (d);
0
e. Revise paragraph (e);
0
f. Remove and reserve paragraph (f);
0
g. Remove ``Sec. 186.1'' and add in its place ``part 186'' in
paragraphs (h) introductory text, (h)(1), (i), (j), and (k); and
0
h. Revise the last sentence of paragraph (l).
The revisions read as follows:
Sec. 170.30 Eligibility for classification as generally recognized
as safe (GRAS).
(a) * * * General recognition of safety requires common knowledge
throughout the scientific community knowledgeable about the safety of
substances directly or indirectly added to food that there is
reasonable certainty that the substance is not harmful under the
conditions of its intended use (see Sec. 170.3(i)).
(b) General recognition of safety based upon scientific procedures
shall require the same quantity and quality of scientific evidence as
is required to obtain approval of a food additive. General recognition
of safety through scientific procedures shall be based upon the
application of generally available and accepted scientific data,
information, or methods, which ordinarily are published, as well as the
application of scientific principles, and may be corroborated by the
application of unpublished scientific data, information, or methods.
(c)(1) General recognition of safety through experience based on
common use in food prior to January 1, 1958, may be achieved without
the quantity or quality of scientific procedures required for approval
of a food additive. * * *
(2) A substance used in food prior to January 1, 1958, may be
generally recognized as safe through experience based on its common use
in food when that use occurred exclusively or primarily outside of the
United States if
[[Page 55048]]
the information about the experience establishes that the substance is
safe under the conditions of its intended use within the meaning of
section 201(u) of the Federal Food, Drug, and Cosmetic Act (see also
Sec. 170.3(i)). Common use in food prior to January 1, 1958, that
occurred outside of the United States shall be documented by published
or other information and shall be corroborated by information from a
second, independent source that confirms the history and circumstances
of use of the substance. The information used to document and to
corroborate the history and circumstances of use of the substance must
be generally available; that is, it must be widely available in the
country in which the history of use has occurred and readily available
to interested qualified experts in the United States. A person who
concludes that a use of a substance is GRAS through experience based on
its common use in food outside of the United States should notify FDA
of that view in accordance with subpart E of this part.
* * * * *
(e) Food ingredients were listed as GRAS in part 182 of this
chapter during 1958-1962 without a detailed scientific review of all
available data and information relating to their safety. Beginning in
1969, the Food and Drug Administration has undertaken a systematic
review of the status of all ingredients used in food based on the view
that they are GRAS under the conditions of their intended use or
subject to a prior sanction. All affirmations of GRAS status or
determinations of food additive status or prior sanction status
pursuant to this review shall be handled pursuant to Sec. Sec. 170.35,
170.38, and 180.1 of this chapter. Affirmation of GRAS status shall be
announced in part 184 or part 186 of this chapter.
* * * * *
(l) * * * Any change to the GRAS status of a food ingredient in
parts 182, 184, or 186 of this chapter shall be accomplished pursuant
to Sec. 170.38.
0
9. In Sec. 170.35, revise paragraphs (a), (b)(1), (3), and (4), and
remove paragraph (c) to read as follows:
Sec. 170.35 Affirmation of generally recognized as safe (GRAS)
status.
(a) The Commissioner, on his own initiative, may affirm that a
substance that directly or indirectly becomes a component of food is
GRAS under the conditions of its intended use.
(b)(1) If the Commissioner proposes on his own initiative that a
substance is entitled to affirmation as GRAS under the conditions of
its intended use, he will place all of the data and information on
which he relies on public file in the office of the Division of Dockets
Management and will publish in the Federal Register a notice giving the
name of the substance, its proposed uses, and any limitations proposed
for purposes other than safety.
* * * * *
(3) The Commissioner will evaluate all comments received. If he
concludes that there is convincing evidence that the substance is GRAS
under the conditions of its intended use as described in Sec. 170.30,
he will publish a notice in the Federal Register listing the GRAS
conditions of use of the substance in part 184 or part 186 of this
chapter, as appropriate.
(4) If, after evaluation of the comments, the Commissioner
concludes that there is a lack of convincing evidence that a substance
is GRAS under the conditions of its intended use and that it should be
considered a food additive subject to section 409 of the Federal Food,
Drug, and Cosmetic Act, he shall publish a notice thereof in the
Federal Register in accordance with Sec. 170.38.
0
10. In Sec. 170.38, revise paragraph (a) to read as follows:
Sec. 170.38 Determination of food additive status.
(a) The Commissioner may, in accordance with Sec. 170.35(b)(4),
publish a notice in the Federal Register determining that a substance
is not GRAS under the conditions of its intended use and is a food
additive subject to section 409 of the Federal Food, Drug, and Cosmetic
Act.
* * * * *
0
11. Add subpart E, consisting of Sec. Sec. 170.203 through 170.285, to
read as follows:
Subpart E--Generally Recognized as Safe (GRAS) Notice
Sec.
170.203 Definitions.
170.205 Opportunity to submit a GRAS notice.
170.210 How to send your GRAS notice to FDA.
170.215 Incorporation into a GRAS notice.
170.220 General requirements applicable to a GRAS notice.
170.225 Part 1 of a GRAS notice: Signed statements and
certification.
170.230 Part 2 of a GRAS notice: Identity, method of manufacture,
specifications, and physical or technical effect.
170.235 Part 3 of a GRAS notice: Dietary exposure.
170.240 Part 4 of a GRAS notice: Self-limiting levels of use.
170.245 Part 5 of a GRAS notice: Experience based on common use in
food before 1958.
170.250 Part 6 of a GRAS notice: Narrative.
170.255 Part 7 of a GRAS notice: List of supporting data and
information in your GRAS notice.
170.260 Steps you may take before FDA responds to your GRAS notice.
170.265 What FDA will do with a GRAS notice.
170.270 Procedures that apply when the intended conditions of use of
a notified substance include use in a product or products subject to
regulation by the Food Safety and Inspection Service (FSIS) of the
United States Department of Agriculture.
170.275 Public disclosure of a GRAS notice.
170.280 Submission of a supplement.
170.285 Disposition of pending GRAS affirmation petitions.
Subpart E--Generally Recognized as Safe (GRAS) Notice
Sec. 170.203 Definitions.
The definitions and interpretations of terms in Sec. 170.3 apply
to such terms when used in this subpart. The following definitions also
apply:
Amendment means any data and information that you submit regarding
a filed GRAS notice before we respond to your notice by letter in
accordance with Sec. 170.265(b)(1) or cease to evaluate your notice in
accordance with Sec. 170.265(b)(3).
GRAS means generally recognized as safe.
GRAS notice means a submission that informs us of your view that a
substance is not subject to the premarket approval requirements of the
Federal Food, Drug, and Cosmetic Act based on your conclusion that the
substance is GRAS under the conditions of its intended use in
accordance with Sec. 170.30.
Notified substance means the substance that is the subject of your
GRAS notice.
Notifier means the person (e.g., an individual, partnership,
corporation, association, or other legal entity) who is responsible for
the GRAS notice, even if another person (such as an attorney, agent, or
qualified expert) prepares or submits the notice or provides an opinion
about the basis for a conclusion of GRAS status.
Qualified expert means an individual who is qualified by scientific
training and experience to evaluate the safety of substances under the
conditions of their intended use in food.
Supplement means any data and information that you submit regarding
a filed GRAS notice after we respond to your notice by letter in
accordance with Sec. 170.265(b)(1) or cease to evaluate your
[[Page 55049]]
notice in accordance with Sec. 170.265(b)(3).
We, our, and us refer to the United States Food and Drug
Administration (FDA).
You and your refer to a notifier.
Sec. 170.205 Opportunity to submit a GRAS notice.
Any person may notify FDA of a view that a substance is not subject
to the premarket approval requirements of section 409 of the Federal
Food, Drug, and Cosmetic Act based on that person's conclusion that the
substance is GRAS under the conditions of its intended use.
Sec. 170.210 How to send your GRAS notice to FDA.
(a) Send your GRAS notice to the Office of Food Additive Safety
(HFS-200), Center for Food Safety and Applied Nutrition, Food and Drug
Administration, 5001 Campus Drive, College Park, MD 20740.
(b) When you submit your GRAS notice, you may do so either in an
electronic format that is accessible for our evaluation or on paper. If
you send your GRAS notice on paper, a single paper copy is sufficient.
Sec. 170.215 Incorporation into a GRAS notice.
You may incorporate into your GRAS notice either specifically
identified data and information that you previously submitted to the
Center for Food Safety and Applied Nutrition (CFSAN), or specifically
identified publicly available data and information submitted by another
party, when such data and information remain in CFSAN's records, such
as data and information contained in a previous GRAS notice or a food
additive petition.
Sec. 170.220 General requirements applicable to a GRAS notice.
(a) A GRAS notice has seven parts as required by Sec. Sec. 170.225
through 170.255. You must submit the data and information specified in
each of these parts on separate pages or sets of pages.
(b) You must include each of the seven parts in your GRAS notice.
If you do not include a part, you must include with your GRAS notice an
explanation of why that part does not apply to your GRAS notice.
Sec. 170.225 Part 1 of a GRAS notice: Signed statements and
certification.
(a) Part 1 of your GRAS notice must be dated and signed by a
responsible official of your organization, or by your attorney or
agent.
(b) Except as required by paragraph (c)(8) of this section, you
must not include any information that is trade secret or confidential
commercial information in Part 1 of your GRAS notice.
(c) In Part 1 of your GRAS notice, you must:
(1) Inform us that you are submitting a GRAS notice in accordance
with this subpart;
(2) Provide the name and address of your organization;
(3) Provide the name of the notified substance, using an
appropriately descriptive term;
(4) Describe the intended conditions of use of the notified
substance, including the foods in which the substance will be used, the
levels of use in such foods, and the purposes for which the substance
will be used, including, when appropriate, a description of a
subpopulation expected to consume the notified substance;
(5) Inform us of the statutory basis for your conclusion of GRAS
status (i.e., through scientific procedures in accordance with Sec.
170.30(a) and (b) or through experience based on common use in food in
accordance with Sec. 170.30(a) and (c));
(6) State your view that the notified substance is not subject to
the premarket approval requirements of the Federal Food, Drug, and
Cosmetic Act based on your conclusion that the notified substance is
GRAS under the conditions of its intended use;
(7) State that, if we ask to see the data and information that are
the basis for your conclusion of GRAS status, either during or after
our evaluation of your notice, you will:
(i) Agree to make the data and information available to us; and
(ii) Agree to both of the following procedures for making the data
and information available to us:
(A) Upon our request, you will allow us to review and copy the data
and information during customary business hours at the address you
specify for where these data and information will be available to us;
and
(B) Upon our request, you will provide us with a complete copy of
the data and information either in an electronic format that is
accessible for our evaluation or on paper;
(8) State your view as to whether any of the data and information
in Parts 2 through 7 of your GRAS notice are exempt from disclosure
under the Freedom of Information Act, 5 U.S.C. 552 (e.g., as trade
secret or as commercial or financial information that is privileged or
confidential).
(9) Certify that, to the best of your knowledge, your GRAS notice
is a complete, representative, and balanced submission that includes
unfavorable information, as well as favorable information, known to you
and pertinent to the evaluation of the safety and GRAS status of the
use of the substance;
(10) State both the name and position or title of the person who
signs the GRAS notice; and
(11) When applicable, state as required by Sec. 170.270 whether
you:
(i) Authorize us to send any trade secrets to the Food Safety and
Inspection Service (FSIS) of the U.S. Department of Agriculture; or
(ii) Ask us to exclude any trade secrets from the copy of the GRAS
notice that we will send to FSIS.
Sec. 170.230 Part 2 of a GRAS notice: Identity, method of
manufacture, specifications, and physical or technical effect.
In Part 2 of your GRAS notice, you must include:
(a) Scientific data and information that identifies the notified
substance.
(1) Examples of appropriate data and information include the
chemical name, applicable registry numbers (such as a Chemical
Abstracts Service (CAS) registry number or an Enzyme Commission (EC)
number), empirical formula, structural formula, quantitative
composition, and characteristic properties.
(2) When the source of a notified substance is a biological
material, you must include data and information sufficient to identify:
(i) The taxonomic source (e.g., genus, species) including, as
applicable, data and information at the sub-species level (e.g.,
variety, strain);
(ii) The part of any plant or animal used as the source; and
(iii) Any known toxicants that could be in the source;
(b) A description of the method of manufacture of the notified
substance in sufficient detail to evaluate the safety of the notified
substance as manufactured;
(c) Specifications for food-grade material; and
(d) When necessary to demonstrate safety, relevant data and
information bearing on the physical or other technical effect the
notified substance is intended to produce, including the quantity of
the notified substance required to produce such effect.
Sec. 170.235 Part 3 of a GRAS notice: Dietary exposure.
In part 3 of your GRAS notice, you must provide data and
information about dietary exposure (i.e., the amount of relevant
substances that consumers are likely to eat or drink as part of a total
diet), regardless of whether your conclusion of GRAS status is through
[[Page 55050]]
scientific procedures or through experience based on common use in
food, as follows:
(a) You must provide an estimate of dietary exposure to the
notified substance that includes exposure from its intended use and all
sources in the diet; and
(b) When applicable, you must provide an estimate of dietary
exposure to any other substance that is expected to be formed in or on
food because of the use of the notified substance (e.g., hydrolytic
products or reaction products);
(c) When applicable, you must provide an estimate of dietary
exposure to any other substance that is present with the notified
substance either naturally or due to its manufacture (e.g.,
contaminants or by-products);
(d) You must describe the source of any food consumption data that
you use to estimate dietary exposure in accordance with paragraphs (a)
through (c) of this section; and
(e) You must explain any assumptions you made to estimate dietary
exposure in accordance with paragraphs (a) through (c) of this section.
Sec. 170.240 Part 4 of a GRAS notice: Self-limiting levels of use.
In circumstances where the amount of the notified substance that
can be added to food is limited because food containing levels of the
notified substance above a particular level would become unpalatable or
technologically impractical, in Part 4 of your GRAS notice you must
include data and information on such self-limiting levels of use.
Sec. 170.245 Part 5 of a GRAS notice: Experience based on common use
in food before 1958.
If the statutory basis for your conclusion of GRAS status is
through experience based on common use in food, in Part 5 of your GRAS
notice you must include evidence of a substantial history of
consumption of the notified substance for food use by a significant
number of consumers prior to January 1, 1958.
Sec. 170.250 Part 6 of a GRAS notice: Narrative.
In Part 6 of your GRAS notice, you must include a narrative that
provides the basis for your conclusion of GRAS status, in which:
(a)(1) You must explain why the data and information in your notice
provide a basis for your view that the notified substance is safe under
the conditions of its intended use. In your explanation, you must
address the safety of the notified substance, considering all dietary
sources and taking into account any chemically or pharmacologically
related substances in such diet;
(2) In your explanation, you must identify what specific data and
information that you discuss in accordance with paragraph (a)(1) of
this section are generally available, and what specific data and
information that you discuss in accordance with paragraph (a)(1) of
this section are not generally available, by providing citations to the
list of data and information that you include in Part 7 of your GRAS
notice in accordance with Sec. 170.255;
(b) You must explain how the generally available data and
information that you rely on to establish safety in accordance with
paragraph (a) of this section provide a basis for your conclusion that
the notified substance is generally recognized, among qualified
experts, to be safe under the conditions of its intended use;
(c) You must either:
(1) Identify, discuss, and place in context, data and information
that are, or may appear to be, inconsistent with your conclusion of
GRAS status, regardless of whether those data and information are
generally available; or
(2) State that you have reviewed the available data and information
and are not aware of any data and information that are, or may appear
to be, inconsistent with your conclusion of GRAS status;
(d) If you view any of the data and information in your notice as
exempt from disclosure under the Freedom of Information Act, you must
identify the specific data and information; and
(e) For non-public, safety-related data and information considered
in reaching a conclusion of GRAS status, you must explain how there
could be a basis for a conclusion of GRAS status if qualified experts
do not have access to such data and information.
Sec. 170.255 Part 7 of a GRAS notice: List of supporting data and
information in your GRAS notice.
(a) In part 7 of your GRAS notice, you must include a list of all
of the data and information that you discuss in Part 6 of your GRAS
notice to provide a basis for your view that the notified substance is
safe under the conditions of its intended use as described in
accordance with Sec. 170.250(a)(1).
(b) You must specify which data and information that you list in
accordance with paragraph (a) of this section are generally available,
and which data and information are not generally available.
Sec. 170.260 Steps you may take before FDA responds to your GRAS
notice.
(a) You may submit a timely amendment to your filed GRAS notice, to
update your GRAS notice or in response to a question from us, before we
respond to your notice by letter in accordance with Sec. 170.265(b)(1)
or cease to evaluate your notice in accordance with Sec.
170.265(b)(3).
(b) At any time before we respond to your GRAS notice in accordance
with Sec. 170.265(b)(1), you may request in writing that we cease to
evaluate your GRAS notice. Your request does not preclude you from
submitting a future GRAS notice in accordance with this subpart with
respect to the notified substance.
Sec. 170.265 What FDA will do with a GRAS notice.
(a)(1) We will conduct an initial evaluation of your submission to
determine whether to file it as a GRAS notice for evaluation of your
view that the notified substance is GRAS under the conditions of its
intended use.
(2) If we file your submission as a GRAS notice, we will send you a
letter that informs you of the date of filing.
(3) If we do not file your submission as a GRAS notice, we will
send you a letter that informs you of that fact and provides our
reasons for not filing the submission as a GRAS notice.
(4) We will consider any timely amendment that you submit to a
filed GRAS notice, to update your GRAS notice or in response to a
question from us, before we respond to you by letter in accordance with
paragraph (b)(1) of this section, if we deem that doing so is feasible
within the timeframes established in paragraph (b) of this section. If
we deem that considering your amendment is not feasible within the
timeframes established in paragraph (b) of this section or if we have
granted your request to cease to evaluate your notice, we will inform
you that we are not considering your amendment.
(b)(1) Within 180 days of filing, we will respond to you by letter
based on our evaluation of your notice. We may extend the 180 day
timeframe by 90 days on an as needed basis.
(2) If we extend the timeframe, we will inform you in writing of
the extension as soon as practicable but no later than within 180 days
of filing.
(3) If you ask us to cease to evaluate your GRAS notice in
accordance with Sec. 170.260(b), we will send you a letter informing
you of our decision regarding your request.
(c) If circumstances warrant, we will send you a subsequent letter
about the notice.
[[Page 55051]]
Sec. 170.270 Procedures that apply when the intended conditions of
use of a notified substance include use in a product or products
subject to regulation by the Food Safety and Inspection Service (FSIS)
of the United States Department of Agriculture.
If the intended conditions of use of the notified substance include
use in a product or products subject to regulation by FSIS under
statutes that it administers:
(a) When applicable, you must include in your GRAS notice a
statement as to whether you:
(1) Authorize us to send any trade secrets to FSIS; or
(2) Ask us to exclude any trade secrets from the copy of the GRAS
notice that we will send to FSIS.
(b)(1) We will forward a copy of a GRAS notice or relevant portions
thereof to FSIS;
(2) We will exclude any trade secrets unless you have authorized us
to do so in accordance with paragraph (a)(1) of this section; and
(c) We will ask FSIS to advise whether the intended conditions of
use comply with applicable statutes and regulations, or, if not,
whether the use of the substance would be permitted in products under
FSIS' jurisdiction under specified conditions or restrictions.
(d) As appropriate, we will inform you of the advice we receive
from FSIS in the letter we send you in accordance with Sec.
170.265(b)(1).
Sec. 170.275 Public disclosure of a GRAS notice.
(a) The data and information in a GRAS notice (including data and
information submitted in any amendment or supplement to your GRAS
notice or incorporated into your GRAS notice) are:
(1) Considered a mandatory, rather than voluntary, submission for
purposes of their status under the Freedom of Information Act and our
public information requirements in part 20 of this chapter; and
(2) Available for public disclosure in accordance with part 20 of
this chapter as of the date that we receive your GRAS notice.
(b) We will make the following readily accessible to the public:
(1) A list of filed GRAS notices, including the information
described in Sec. 170.225(c)(2) through (c)(5);
(2) The text of any letter that we issue under Sec. 170.265(b)(1)
or (c); and
(3) The text of any letter that we issue under Sec. 170.265(b)(3)
if we grant your request that we cease to evaluate your notice.
(c) We will disclose all remaining data and information that are
not exempt from public disclosure in accordance with part 20 of this
chapter.
Sec. 170.280 Submission of a supplement.
If circumstances warrant, you may submit a supplement to a filed
GRAS notice after we respond to your notice by letter in accordance
with Sec. 170.265(b)(1) or cease to evaluate your notice in accordance
with Sec. 170.265(b)(3).
Sec. 170.285 Disposition of pending GRAS affirmation petitions.
Because the procedure to submit a GRAS notice is replacing the
former process to submit a GRAS affirmation petition, the following
will happen to a filed GRAS affirmation petition that is pending on
October 17, 2016.
(a) On October 17, 2016, we will close the docket for any GRAS
affirmation petition that is still pending as of October 17, 2016.
(b) Any person who submitted a GRAS affirmation petition described
in this section may submit a GRAS notice as described in this subpart
and request that we incorporate the GRAS affirmation petition as
described in Sec. 170.215.
PART 184--DIRECT FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED
AS SAFE
0
12. The authority citation for part 184 continues to read as follows:
Authority: 21 U.S.C. 321, 342, 348, 371.
0
13. In Sec. 184.1, revise the first sentence of paragraph (a), and
revise the fifth sentence and remove the last sentence of paragraph
(b)(1) to read as follows.
Sec. 184.1 Substances added directly to human food affirmed as
generally recognized as safe (GRAS).
(a) The direct human food ingredients listed in this part have been
reviewed by the Food and Drug Administration and affirmed to be
generally recognized as safe (GRAS) for the purposes and under the
conditions prescribed. * * *
(b) * * *
(1) * * * In such a case, a manufacturer may not rely on the
regulation as authorizing that use but shall have a basis to conclude
that that use is GRAS or shall use the ingredient in accordance with a
food additive regulation. * * *
* * * * *
PART 186--INDIRECT FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED
AS SAFE
0
14. The authority citation for part 186 continues to read as follows:
Authority: 21 U.S.C. 321, 342, 348, 371.
0
15. In Sec. 186.1, revise the first sentence of paragraph (a), and
revise the fifth sentence and remove the last sentence of paragraph
(b)(1) to read as follows.
Sec. 186.1 Substances added indirectly to human food affirmed as
generally recognized as safe (GRAS).
(a) The indirect human food ingredients listed in this part have
been reviewed by the Food and Drug Administration and affirmed to be
generally recognized as safe (GRAS) for the purposes and under the
conditions prescribed, providing they comply with the purity
specifications listed in this part or, in the absence of purity
specifications, are of a purity suitable for their intended use in
accordance with Sec. 170.30(h)(1) of this chapter. * * *
(b) * * *
(1) * * * In such a case, a manufacturer may not rely on the
regulation as authorizing that use but shall have a basis to conclude
that the use is GRAS or shall use the ingredient in accordance with a
food additive regulation. * * *
* * * * *
PART 570--FOOD ADDITIVES
0
16. The authority citation for part 570 continues to read as follows:
Authority: 21 U.S.C. 321, 341, 342, 346a, 348, 371.
0
17. In Sec. 570.3, revise paragraphs (f), (h), the first sentence of
(i), and (k), and add paragraph (n) to read as follows:
Sec. 570.3 Definitions.
* * * * *
(f) Common use in food means a substantial history of consumption
of a substance by a significant number of animals of the species to
which the substance is intended to be fed (and, for food-producing
animals fed with such substance, also means a substantial history of
consumption by humans consuming human foods derived from those food-
producing animals), prior to January 1, 1958.
* * * * *
(h) Scientific procedures include the application of scientific
data (including, as appropriate, data from human, animal, analytical,
or other scientific studies), information, and methods, whether
published or unpublished, as well as the application of scientific
principles, appropriate to establish the safety of a substance under
the conditions of its intended use.
(i) Safe or safety means that there is a reasonable certainty in
the minds of
[[Page 55052]]
competent scientists that the substance is not harmful under the
conditions of its intended use. * * *
* * * * *
(k) General recognition of safety shall be in accordance with Sec.
570.30.
* * * * *
(n) Food-producing animal means an animal used to produce human
food.
0
18. In Sec. 570.30, revise the last sentence of paragraph; (a); revise
paragraphs (b) through (d); and revise the last sentence in paragraph
(i) to read as follows:
Sec. 570.30 Eligibility for classification as generally recognized
as safe (GRAS).
(a) * * * General recognition of safety requires common knowledge
throughout the scientific community knowledgeable about the safety of
substances directly or indirectly added to food that there is
reasonable certainty that the substance is not harmful to either the
target animal or to humans consuming human food derived from food-
producing animals under the conditions of its intended use (see Sec.
570.3(i)).
(b) General recognition of safety based upon scientific procedures
shall require the same quantity and quality of scientific evidence as
is required to obtain approval of a food additive. General recognition
of safety through scientific procedures shall address safety for both
the target animal and for humans consuming human food derived from
food-producing animals and shall be based upon the application of
generally available and accepted scientific data, information, or
methods, which ordinarily are published, as well as the application of
scientific principles, and may be corroborated by the application of
unpublished scientific data, information, or methods.
(c)(1) General recognition of safety through experience based on
common use in food prior to January 1, 1958, shall address safety for
both the target animal and for humans consuming human food derived from
food-producing animals and may be achieved without the quantity or
quality of scientific procedures required for approval of a food
additive. General recognition of safety through experience based on
common use in food prior to January 1, 1958, shall be based solely on
food use of the substance in the same animal species prior to January
1, 1958, and shall ordinarily be based upon generally available data
and information. An ingredient not in common use in food prior to
January 1, 1958, may achieve general recognition of safety only through
scientific procedures.
(2) A substance used in food prior to January 1, 1958, may be
generally recognized as safe through experience based on its common use
in food when that use occurred exclusively or primarily outside of the
United States if the information about the experience establishes that
the substance is safe under the conditions of its intended use within
the meaning of section 201(u) of the Federal Food, Drug, and Cosmetic
Act (see also Sec. 570.3(i)) for both the target animal and for humans
consuming human food derived from food-producing animals. Common use in
food prior to January 1, 1958, that occurred outside of the United
States shall be documented by published or other information and shall
be corroborated by information from a second, independent source that
confirms the history and circumstances of use of the substance. The
information used to document and to corroborate the history and
circumstances of use of the substance must be generally available; that
is, it must be widely available in the country in which the history of
use has occurred and readily available to interested qualified experts
in the United States. A person who concludes that a use of a substance
is GRAS through experience based on its common use in food outside of
the United States should notify FDA of that view in accordance with
subpart E of this part.
(d) The food ingredients listed as GRAS in part 582 of this chapter
or affirmed as GRAS in part 584 of this chapter do not include all
substances that are generally recognized as safe for their intended use
in food. Because of the large number of substances the intended use of
which results or may reasonably be expected to result, directly or
indirectly, in their becoming a component or otherwise affecting the
characteristics of food, it is impracticable to list all such
substances that are GRAS. A food ingredient of natural biological
origin that has been widely consumed for its nutrient properties in the
United States prior to January 1, 1958, without known detrimental
effects, which is subject only to conventional processing as practiced
prior to January 1, 1958, and for which no known safety hazard exists,
will ordinarily be regarded as GRAS without specific inclusion in part
582 or part 584 of this chapter.
* * * * *
(i) * * * Any use of such an ingredient not in full compliance with
each such established limitation shall require a food additive
regulation.
* * * * *
0
19. In Sec. 570.35, revise paragraphs (a), (b)(1), (3), and (4), and
remove paragraph (c) to read as follows:
Sec. 570.35 Affirmation of generally recognized as safe (GRAS)
status.
(a) The Commissioner, on his own initiative, may affirm that a
substance that directly or indirectly becomes a component of food is
GRAS under the conditions of its intended use.
(b)(1) If the Commissioner proposes on his own initiative that a
substance is entitled to affirmation as GRAS under the conditions of
its intended use, he will place all of the data and information on
which he relies on public file in the office of the Division of Dockets
Management and will publish in the Federal Register a notice giving the
name of the substance, its proposed uses, and any limitations proposed
for purposes other than safety.
* * * * *
(3) The Commissioner will evaluate all comments received. If he
concludes that there is convincing evidence that the substance is GRAS
under the conditions of its intended use as described in Sec. 570.30,
he will publish a notice in the Federal Register listing the GRAS
conditions of use in this subchapter E.
(4) If, after evaluation of the comments, the Commissioner
concludes that there is a lack of convincing evidence that the
substance is GRAS under the conditions of its intended use and that it
should be considered a food additive subject to section 409 of the
Federal Food, Drug, and Cosmetic Act, he shall publish a notice thereof
in the Federal Register in accordance with Sec. 570.38.
0
20. In Sec. 570.38, revise paragraph (a) to read as follows:
Sec. 570.38 Determination of food additive status.
(a) The Commissioner may, in accordance with Sec. 570.35(b)(4),
publish a notice in the Federal Register determining that a substance
is not GRAS under the conditions of its intended use and is a food
additive subject to section 409 of the Federal Food, Drug, and Cosmetic
Act.
* * * * *
0
21. Add and reserve subparts C and D.
0
22. Add subpart E, consisting of Sec. Sec. 570.203 through 570.280, to
read as follows:
Subpart E--Generally Recognized as Safe (GRAS) Notice
Sec.
570.203 Definitions.
570.205 Opportunity to submit a GRAS notice.
[[Page 55053]]
570.210 How to send your GRAS notice to FDA.
570.215 Incorporation into a GRAS notice.
570.220 General requirements applicable to a GRAS notice.
570.225 Part 1 of a GRAS notice: Signed statements and
certification.
570.230 Part 2 of a GRAS notice: Identity, method of manufacture,
specifications, and physical or technical effect.
570.235 Part 3 of a GRAS notice: Target animal and human exposures.
570.240 Part 4 of a GRAS notice: Self-limiting levels of use.
570.245 Part 5 of a GRAS notice: Experience based on common use in
food before 1958.
570.250 Part 6 of a GRAS notice: Narrative.
570.255 Part 7 of a GRAS notice: List of supporting data and
information in your GRAS notice.
570.260 Steps you may take before FDA responds to your GRAS notice.
570.265 What FDA will do with a GRAS notice.
570.275 Public disclosure of a GRAS notice.
570.280 Submission of a supplement.
Subpart E--Generally Recognized as Safe (GRAS) Notice
Sec. 570.203 Definitions.
The definitions and interpretations of terms in Sec. 570.3 apply
to such terms when used in this subpart. The following definitions also
apply:
Amendment means any data and information that you submit regarding
a filed GRAS notice before we respond to your notice by letter in
accordance with Sec. 570.265(b)(1) or cease to evaluate your notice in
accordance with Sec. 570.265(b)(3).
GRAS means generally recognized as safe.
GRAS notice means a submission that informs us of your view that a
substance is not subject to the premarket approval requirements of the
Federal Food, Drug, and Cosmetic Act based on your conclusion that the
substance is GRAS under the conditions of its intended use in
accordance with Sec. 570.30.
Notified substance means the substance that is the subject of your
GRAS notice.
Notifier means the person (e.g., an individual, partnership,
corporation, association, or other legal entity) who is responsible for
the GRAS notice, even if another person (such as an attorney, agent, or
qualified expert) prepares or submits the notice or provides an opinion
about the basis for a conclusion of GRAS status.
Qualified expert means an individual who is qualified by scientific
training and experience to evaluate the safety of substances under the
conditions of their intended use in animal food.
Supplement means any data and information that you submit regarding
a filed GRAS notice after we respond to your notice by letter in
accordance with Sec. 570.265(b)(1) or cease to evaluate your notice in
accordance with Sec. 570.265(b)(3).
We, our, and us refer to the United States Food and Drug
Administration (FDA).
You and your refer to a notifier.
Sec. 570.205 Opportunity to submit a GRAS notice.
Any person may notify FDA of a view that a substance is not subject
to the premarket approval requirements of section 409 of the Federal
Food, Drug, and Cosmetic Act based on that person's conclusion that the
substance is GRAS under the conditions of its intended use.
Sec. 570.210 How to send your GRAS notice to FDA.
(a) Send your GRAS notice to the Division of Animal Feeds (HFV-
220), Center for Veterinary Medicine, Food and Drug Administration,
7519 Standish Pl., Rockville, MD 20855.
(b) When you submit your GRAS notice, you may do so either in an
electronic format that is accessible for our evaluation or on paper. If
you send your GRAS notice on paper, a single paper copy is sufficient.
Sec. 570.215 Incorporation into a GRAS notice.
You may incorporate into your GRAS notice either specifically
identified data and information that you previously submitted to the
Center for Veterinary Medicine (CVM), or specifically identified
publicly available data and information submitted by another party,
when such data and information remain in CVM's records, such as data
and information contained in a previous GRAS notice or a food additive
petition.
Sec. 570.220 General requirements applicable to a GRAS notice.
(a) A GRAS notice has seven parts as required by Sec. Sec. 570.225
through 570.255. You must submit the data and information specified in
each of these parts on separate pages or sets of pages.
(b) You must include each of the seven parts in your GRAS notice.
If you do not include a part, you must include with your GRAS notice an
explanation of why that part does not apply to your GRAS notice.
Sec. 570.225 Part 1 of a GRAS notice: Signed statements and
certification.
(a) Part 1 of your GRAS notice must be dated and signed by a
responsible official of your organization, or by your attorney or
agent.
(b) Except as required by paragraph (c)(8) of this section, you
must not include any information that is trade secret or confidential
commercial information in Part 1 of your GRAS notice.
(c) In Part 1 of your GRAS notice, you must:
(1) Inform us that you are submitting a GRAS notice in accordance
with this subpart;
(2) Provide the name and address of your organization;
(3) Provide the name of the notified substance, using an
appropriately descriptive term;
(4) Describe the intended conditions of use of the notified
substance, including stating whether the substance will be added to
food (including drinking water) for animals in which the substance will
be used; identifying the foods to which it will be added, the levels of
use in such foods, and the animal species for which these foods are
intended (including, when appropriate, a description of a subpopulation
expected to consume the notified substance); and the purposes for which
the substance will be used;
(5) Inform us of the statutory basis for your conclusion of GRAS
status (i.e., through scientific procedures in accordance with Sec.
570.30(a) and (b) or through experience based on common use in animal
food in accordance with Sec. 570.30(a) and (c));
(6) State your view that the notified substance is not subject to
the premarket approval requirements of the Federal Food, Drug, and
Cosmetic Act based on your conclusion that the notified substance is
GRAS under the conditions of its intended use;
(7) State that, if we ask to see the data and information that are
the basis for your conclusion of GRAS status, either during or after
our evaluation of your notice, you will:
(i) Agree to make the data and information available to us; and
(ii) Agree to both of the following procedures for making the data
and information available to us:
(A) Upon our request, you will allow us to review and copy the data
and information during customary business hours at the address you
specify for where these data and information will be available to us;
and
(B) Upon our request, you will provide us with a complete copy of
the data and information either in an electronic format that is
accessible for our evaluation or on paper;
(8) State your view as to whether any of the data and information
in Parts 2 through 7 of your GRAS notice are exempt from disclosure
under the
[[Page 55054]]
Freedom of Information Act, 5 U.S.C. 552 (e.g., as trade secret or as
commercial or financial information that is privileged or
confidential);
(9) Certify that, to the best of your knowledge, the GRAS notice is
a complete, representative, and balanced submission that includes
unfavorable information, as well as favorable information, known to you
and pertinent to the evaluation of the safety and GRAS status of the
use of the substance; and
(10) State both the name and the position or title of the person
who signs the GRAS notice.
Sec. 570.230 Part 2 of a GRAS notice: Identity, method of
manufacture, specifications, and physical or technical effect.
In Part 2 of your GRAS notice, you must include:
(a) Scientific data and information that identifies the notified
substance.
(1) Examples of appropriate data and information include the
chemical name, applicable registry numbers (such as a Chemical
Abstracts Service (CAS) registry number or an Enzyme Commission (EC)
number), empirical formula, structural formula, quantitative
composition, and characteristic properties.
(2) When the source of a notified substance is a biological
material, you must include data and information sufficient to identify:
(i) The taxonomic source (e.g., genus, species), including as
applicable data and information at the sub-species level (e.g.,
variety, strain);
(ii) The part of any plant or animal used as the source; and
(iii) Any known toxicants that could be in the source;
(b) A description of the method of manufacture of the notified
substance in sufficient detail to evaluate the safety of the notified
substance as manufactured;
(c) Specifications for material that is of appropriate grade for
use in animal food; and
(d) When necessary to demonstrate safety, relevant data and
information bearing on the physical or other technical effect the
notified substance is intended to produce, including the quantity of
the notified substance required to produce such effect.
Sec. 570.235 Part 3 of a GRAS notice: Target animal and human
exposures.
In part 3 of your GRAS notice, you must provide data and
information about exposure to the target animal and to humans consuming
human food derived from food-producing animals, regardless of whether
your conclusion of GRAS status is through scientific procedures or
through experience based on common use in food, as follows:
(a) For exposure to the target animal, you must provide:
(1) The amount of the notified substance that different target
animal species are likely to consume in the animal food (including
drinking water) as part of the animal's total diet, including the
intended use and all other sources in the total diet; and
(2) When applicable, the amount of any other substance that is
expected to be formed in or on food because of the use of the notified
substance (e.g., hydrolytic products or reaction products);
(3) When applicable, the amount of any other substance that is
present with the notified substance either naturally or due to its
manufacture (e.g., contaminants or by-products);
(4) The data and information you rely on to establish the amount of
the notified substance and the amounts of any other substance in
accordance with paragraphs (a)(1) through (a)(3) of this section that
different target animal species are likely to consume in the animal
food (including drinking water) as part of the animal's total diet; and
(b) When the intended use is in food for food-producing animals,
you must provide:
(1) The potential quantities of any residues that humans may be
exposed to in edible animal tissues, including:
(i) Residues of the notified substance;
(ii) Residues of any other substance that is expected to be formed
in or on the animal food because of the use of the notified substance;
and
(iii) Residues from any other substance that is present with the
notified substance whether naturally, due to its manufacture (e.g.,
contaminants or by-products), or produced as a metabolite in edible
animal tissues when the notified substance is consumed by a food-
producing animal; and
(2) The data and information you rely on to establish, in
accordance with paragraph (b)(1) of this section, the potential
quantities of any residues that humans may be exposed to in edible
animal tissues.
Sec. 570.240 Part 4 of a GRAS notice: Self-limiting levels of use.
In circumstances where the amount of the notified substance that
can be added to animal food is limited because animal food containing
levels of the notified substance above a particular level would become
unpalatable or technologically impractical, in Part 4 of your GRAS
notice you must include data and information on such self-limiting
levels of use.
Sec. 570.245 Part 5 of a GRAS notice: Experience based on common use
in food before 1958.
If the statutory basis for your conclusion of GRAS status is
through experience based on common use in animal food, in Part 5 of
your GRAS notice you must include evidence of a substantial history of
consumption of the notified substance for food use by a significant
number of animals of the species to which the substance is intended to
be fed prior to January 1, 1958, and evidence of a substantial history
of consumption by humans consuming human foods derived from food-
producing animals prior to January 1, 1958.
Sec. 570.250 Part 6 of a GRAS notice: Narrative.
In Part 6 of your GRAS notice, you must include a narrative that
provides the basis for your conclusion of GRAS status, in which:
(a)(1) You must explain why the data and information in your notice
provide a basis for your view that the notified substance is safe under
the conditions of its intended use for both the target animal and for
humans consuming human food derived from food-producing animals. In
your explanation, you must address the safety of the notified
substance, considering all animal food (including drinking water) as
part of the animal's total diet, taking into account any chemically or
pharmacologically related substances in such diet. In your explanation,
you must also address the safety of the notified substance in regard to
human exposure, considering all dietary sources and taking into account
any chemically or pharmacologically related substances;
(2) In your explanation, you must identify what specific data and
information that you discuss in accordance with paragraph (a)(1) of
this section are generally available, and what specific data and
information that you discuss in accordance with paragraph (a)(1) of
this section are not generally available, by providing citations to the
list of data and information that you include in Part 7 of your GRAS
notice in accordance with Sec. 570.255;
(b) You must explain how the generally available data and
information that you rely on to establish safety in accordance with
paragraph (a) of this section provide a basis for your conclusion that
the notified substance is generally recognized, among qualified
experts, to be safe under the conditions of its intended use for both
the target animal and for humans consuming human food derived from
food-producing animals;
[[Page 55055]]
(c) You must either:
(1) Identify, discuss, and place in context, data and information
that are, or may appear to be, inconsistent with your conclusion of
GRAS status, regardless of whether those data and information are
generally available; or
(2) State that you have reviewed the available data and information
and are not aware of any data and information that are, or may appear
to be, inconsistent with your conclusion of GRAS status;
(d) If you view any of the data and information in your notice as
exempt from disclosure under the Freedom of Information Act, you must
identify the specific data and information; and
(e) For non-public, safety-related data and information considered
in reaching a conclusion of GRAS status, you must explain how there
could be a basis for a conclusion of GRAS status if qualified experts
do not have access to such data and information.
Sec. 570.255 Part 7 of a GRAS notice: List of supporting data and
information in your GRAS notice.
(a) In part 7 of your GRAS notice, you must include a list of all
of the data and information that you discuss in Part 6 of your GRAS
notice to provide a basis for your view that the notified substance is
safe under the conditions of its intended use as described in
accordance with Sec. 570.250(a)(1).
(b) You must specify which data and information that you list in
accordance with paragraph (a) of this section are generally available,
and which data and information are not generally available.
Sec. 570.260 Steps you may take before FDA responds to your GRAS
notice.
(a) You may submit a timely amendment to your filed GRAS notice, to
update your GRAS notice or in response to a question from us, before we
respond to your notice by letter in accordance with Sec. 570.265(b)(1)
or cease to evaluate your notice in accordance with Sec.
570.265(b)(3).
(b) At any time before we respond to your notice by letter in
accordance with Sec. 570.265(b)(1), you may request in writing that we
cease to evaluate your GRAS notice. Your request does not preclude you
from submitting a future GRAS notice in accordance with this subpart
with respect to the notified substance.
Sec. 570.265 What FDA will do with a GRAS notice.
(a)(1) We will conduct an initial evaluation of your submission to
determine whether to file it as a GRAS notice for evaluation of your
view that the notified substance is GRAS under the conditions of its
intended use.
(2) If we file your submission as a GRAS notice, we will send you a
letter that informs you of the date of filing.
(3) If we do not file your submission as a GRAS notice, we will
send you a letter that informs you of that fact and provide our reasons
for not filing the submission as a GRAS notice.
(4) We will consider any timely amendment that you submit to a
filed GRAS notice, to update your GRAS notice or in response to a
question from us, before we respond to you by letter in accordance with
paragraph (b)(1) of this section, if we deem that doing so is feasible
within the timeframes established in paragraph (b) of this section. If
we deem that considering your amendment is not feasible within the
timeframes established in paragraph (b) of this section or if we have
granted your request to cease to evaluate your notice, we will inform
you that we are not considering your amendment.
(b)(1) Within 180 days of filing, we will respond to you by letter
based on our evaluation of your notice. We may extend the 180 day
timeframe by 90 days on an as needed basis.
(2) If we extend the timeframe, we will inform you in writing of
the extension as soon as practicable but no later than within 180 days
of filing.
(3) If you ask us to cease to evaluate your GRAS notice in
accordance with Sec. 570.260(b), we will send you a letter informing
you of our decision regarding your request.
(c) If circumstances warrant, we will send you a subsequent letter
about the notice.
Sec. 570.275 Public disclosure of a GRAS notice.
(a) The data and information in a GRAS notice (including data and
information submitted in any amendment or supplement to your GRAS
notice, or incorporated into your GRAS notice) are:
(1) Considered a mandatory, rather than voluntary, submission for
purposes of their status under the Freedom of Information Act and our
public information requirements in part 20 of this chapter; and
(2) Available for public disclosure in accordance with part 20 of
this chapter as of the date that we receive your GRAS notice.
(b) We will make the following readily accessible to the public:
(1) A list of filed GRAS notices, including the information
described in Sec. 570.225(c)(2) through (c)(5);
(2) The text of any letter that we issue under Sec. 570.265(b)(1)
or (c); and
(3) The text of any letter that we issue under Sec. 570.265(b)(3)
if we grant your request that we cease to evaluate your notice.
(c) We will disclose all remaining data and information that are
not exempt from public disclosure in accordance with part 20 of this
chapter.
Sec. 570.280 Submission of a supplement.
If circumstances warrant, you may submit a supplement to a filed
GRAS notice after we respond to your notice by letter in accordance
with Sec. 570.265(b)(1) or cease to evaluate your notice in accordance
with Sec. 570.265(b)(3).
Dated: August 8, 2016.
Jeremy Sharp,
Deputy Commissioner for Policy, Planning, Legislation and Analysis.
[FR Doc. 2016-19164 Filed 8-12-16; 11:15 am]
BILLING CODE 4164-01-P