Food Additives Permitted For Direct Addition to Food for Human Consumption; Glycerides and Polyglycides, 12618-12621 [06-2354]
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12618
Federal Register / Vol. 71, No. 48 / Monday, March 13, 2006 / Rules and Regulations
17676, April 10, 1998), and by adding
a new airworthiness directive (AD),
Amendment 39–14510, to read as
follows:
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
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2006–06–02 Eurocopter France:
Amendment 39–14510. Docket No.
FAA–2005–23159; Directorate Identifier
2005–SW–10–AD. Supersedes AD 98–
08–14, Amendment 39–10463, Docket
No. 97–SW–21–AD.
Applicability: Model SA–365N, SA365N1,
AS–365N2, and SA–366G1 helicopters with
a main gearbox (MGB) suspension diagonal
cross-member (diagonal cross-member), part
number (P/N) 365A38–3023–20, –21, –22,
–23, or –24, installed, certificated in any
category.
Compliance: Required as indicated, unless
accomplished previously.
To prevent failure of the diagonal crossmember, pivoting of the MGB, severe
vibrations, and subsequent forced landing, do
the following:
(a) For Model SA–365N and SA–365N1
helicopters, before accumulating 15,000
operating cycles; and for Model AS–365N2
and SA–366G1 helicopters, before
accumulating 11,000 operating cycles:
(1) Inspect the diagonal cross-member for
a crack in the area of the center borehole. Use
a borescope with a 90-degree drive, a video
assembly with optical fiber illumination, or
any other appropriate device that allows you
to visually inspect the center area of the part.
(2) Repeat the inspection required by
paragraph (a)(1) of this AD at intervals not to
exceed 250 operating cycles or 50 hours timein-service, whichever occurs first.
Note 1: ‘‘Operating cycles’’ are defined in
the Airworthiness Limitations Section of the
Master Servicing Recommendations.
(b) If a crack is found as a result of the
inspections required by this AD, before
further flight, replace the diagonal crossmember with an airworthy diagonal crossmember.
(c) To request a different method of
compliance or a different compliance time
for this AD, follow the procedures in 14 CFR
39.19. Contact the Rotorcraft Directorate,
FAA, ATTN: Gary Roach, Aviation Safety
Engineer, Regulations and Guidance Group,
Fort Worth, Texas 76193–0111, telephone
(817) 222–5130, fax (817) 222–5961, for
information about previously approved
alternative methods of compliance.
(d) This amendment becomes effective on
April 17, 2006.
Note 2: The subject of this AD is addressed
in Direction Generale De L-Aviation Civile
(France) AD 1997–093–041(A) R2, dated June
25, 2003, and 2003–241(A), dated June 25,
2003.
Issued in Fort Worth, Texas, on March 1,
2006.
David A. Downey,
Manager, Rotorcraft Directorate, Aircraft
Certification Service.
[FR Doc. 06–2358 Filed 3–10–06; 8:45 am]
BILLING CODE 4910–13–P
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21 CFR Part 172
[Docket No. 1991F–0457] (formerly Docket
No. 91F–0457)
Food Additives Permitted For Direct
Addition to Food for Human
Consumption; Glycerides and
Polyglycides
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Final rule.
SUMMARY: The Food and Drug
Administration (FDA) is amending the
food additive regulations to provide for
the safe use of a mixture of glycerides
and polyethylene glycol mono- and diesters of fatty acids of hydrogenated
vegetable oils as an excipient in dietary
supplement tablets, capsules, and liquid
formulations that are intended for
ingestion in daily quantities measured
in drops or similar small units of
measure. This action is in response to a
petition filed by Gattefosse Corp.
DATES: This rule is effective March 13,
2006. Submit written or electronic
objections and requests for a hearing by
April 12, 2006. See section VII of this
document for information on the filing
of objections. The Director of the Office
of the Federal Register approves the
incorporation by reference of certain
publications in accordance with 5
U.S.C. 552(a) and 1 CFR part 51 as of
March 13, 2006.
ADDRESSES: You may submit comments,
identified by Docket No. 1991F–0457,
by any of the following methods:
Electronic Submissions
Submit electronic comments in the
following ways:
• Federal eRulemaking Portal: https://
www.regulations.gov. Follow the
instructions for submitting comments.
• Agency Web site: https://
www.fda.gov/dockets/ecomments.
Follow the instructions for submitting
comments on the agency Web site.
Written Submissions
Submit written submissions in the
following ways:
• FAX: 301–827–6870.
• Mail/Hand delivery/Courier [For
paper, disk, or CD–ROM submissions]:
Division of Dockets Management (HFA–
305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville,
MD 20852.
To ensure more timely processing of
comments, FDA is no longer accepting
comments submitted to the agency by email. FDA encourages you to continue
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to submit electronic comments by using
the Federal eRulemaking Portal or the
agency Web site, as described in the
Electronic Submissions portion of this
paragraph.
Instructions: All submissions received
must include the agency name and
Docket No(s). and Regulatory
Information Number (RIN) (if a RIN
number has been assigned) for this
rulemaking. All comments received may
be posted without change to https://
www.fda.gov/ohrms/dockets/
default.htm, including any personal
information provided. For additional
information on submitting comments,
see the ‘‘Objections’’ heading of the
SUPPLEMENTARY INFORMATION section of
this document.
Docket: For access to the docket to
read background documents or
comments received, go to https://
www.fda.gov/ohrms/dockets/
default.htm and insert the docket
number(s), found in brackets in the
heading of this document, into the
‘‘Search’’ box and follow the prompts
and/or go to the Division of Dockets
Management, 5630 Fishers Lane, rm.
1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT:
Raphael A. Davy, Center for Food Safety
and Applied Nutrition (HFS–265), Food
and Drug Administration, 5100 Paint
Branch Pkwy., College Park, MD 20740,
301–436–1272.
SUPPLEMENTARY INFORMATION:
I. Background
In a notice published in the Federal
Register of December 19, 1991 (56 FR
65907), FDA announced that a food
additive petition (FAP 9A4155) had
been filed by Parexel International
Corp., One Alewife Place, Cambridge,
MA 02140 on behalf of Gattefosse S.A.,
Saint-Priest, France. The petition
proposed to amend the food additive
regulations to provide for the safe use of
a mixture of glycerides and
polyethylene glycol esters of fatty acids
of vegetable origin as an excipient in
vitamin tablets and liquid formulations.
Subsequently, in a letter dated January
7, 1998, the petitioner informed the
agency that the petition was being
amended by narrowing the polyethylene
glycol esters (commonly known as
polyglycides) to one class of
compounds, namely, the polyethylene
glycol esters of fatty acids from
hydrogenated vegetable oils. Further,
under an e-mail dated October 5, 2005,
the petitioner later clarified that the
additive was intended for use as an
excipient in all dietary supplement
tablets, capsules, and liquid
formulations that are intended for
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Federal Register / Vol. 71, No. 48 / Monday, March 13, 2006 / Rules and Regulations
ingestion in daily quantities measured
in drops or similar small units of
measure.
In evaluating the safety of the
petitioned substance, FDA has reviewed
the safety of the additive (glycerides and
polyglycides mixture) and the chemical
impurities that may be present in the
additive as a result of the manufacturing
process. The mono-, di-, and triglycerides component of the additive
are commonly found in food. In
addition, mono-, and di-glycerides are
affirmed as generally recognized as safe
(GRAS) for use in food (§ 184.1505 (21
CFR 184.1505)). The ‘‘polyglycides,’’
consist of mono- and di-esters of
polyethylene glycol, made using fatty
acids derived from hydrogenated oils of
vegetable origin. Although the additive
itself (glycerides and polyglycides
mixture) has not been shown to cause
cancer, it may contain minute amounts
of carcinogenic residues resulting from
the manufacture of the polyethylene
glycol. In particular, the additive may
contain traces of 1,4-dioxane and
ethylene oxide, which have been shown
to cause cancer in test animals.
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II. Determination of Safety
Under the general safety standard in
section 409 of the Federal Food, Drug,
and Cosmetic Act (the act) (21 U.S.C.
348), a food additive cannot be
approved for a particular use unless a
fair evaluation of the data available to
FDA establishes that the additive is safe
for that use. FDA’s food additive
regulations (21 CFR 170.3(i)) define safe
as ‘‘a reasonable certainty in the minds
of competent scientists that the
substance is not harmful under the
intended conditions of use.’’
The food additives anticancer, or
Delaney, clause of the act (section
409(c)(3)(A)) provides that no food
additive shall be deemed safe if it is
found to induce cancer when ingested
by man or animal, or if it is found, after
tests which are appropriate for the
evaluation of the safety of food
additives, to induce cancer in man or
animal. Importantly, however, the
Delaney clause applies to the additive
itself and not to impurities in the
additive. That is, where an additive
itself has not been shown to cause
cancer, but contains a carcinogenic
impurity, the additive is evaluated
properly under the general safety
standard using risk assessment
procedures to determine whether there
is a reasonable certainty that no harm
will result from the intended use of the
additive (Scott v. FDA, 728 F.2d 322
(6th Cir. 1984)).
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III. Safety of the Petitioned Use of the
Additive
FDA estimates that the petitioned use
of the additive as an excipient in dietary
supplement tablets, capsules, and liquid
formulations that are intended for
ingestion in daily quantities measured
in drops or similar small units of
measure will result in an estimated
average daily intake of no more than 720
milligrams per person per day (mg/p/d)
of polyglycides, based on the
consumption of 2 dietary supplement
doses per day and assuming that the
polyglycide portion comprises 75
percent of the total excipient in the dose
(Ref. 1). Although the filing notice
specifically referenced vitamin tablets
and liquid formulations only, this
estimate considered use of the additive
in all dietary supplement tablets,
capsules, and liquid formulations that
are intended for ingestion in daily
quantities measured in drops or similar
small units of measure, due to the
petitioner’s clarification of the
additive’s intended use. The estimate is
conservative as it assumes that all
dietary supplements would be
formulated with the additive. This
estimate does not include the daily
intake of the glycerides because
glycerides are GRAS for use with no
limit other than current good
manufacturing practice (§ 184.1505).
Based on the available toxicological
data on this new food additive mixture,
and considering the cumulative
exposure of the components of the
mixture from the use of other
ingredients, the agency concludes that
the estimated dietary exposure to
polyglycides resulting from the
petitioned use of this additive is well
within an acceptable margin of safety.
FDA has evaluated the safety of this
additive under the general safety
standard, considering all available
toxicological data and using risk
assessment procedures to estimate the
upper-bound limit of lifetime human
risk presented by 1,4-dioxane and
ethylene oxide, the carcinogenic
chemicals that may be present as
impurities in the additive. The risk
evaluation of 1,4-dioxane and ethylene
oxide has two aspects: (1) Assessment of
exposure to the impurities from the
petitioned use of the additive and (2)
extrapolation of the risk observed in the
animal bioassays to the conditions of
exposure to humans.
A. 1,4-Dioxane
FDA has estimated the exposure to
1,4-dioxane from the petitioned use of
the additive as an excipient in dietary
supplement tablets, capsules, and liquid
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formulations that are intended for
ingestion in daily quantities measured
in drops or similar small units of
measure to be 800 nanograms per
person per day (ng/p/d) (Ref. 1). This
estimate is conservative as it was based
on the assumptions that the additive
(glycerides and polyglycides mixture)
would be the sole excipient in all
dietary supplement tablets, capsules,
and liquid formulations that are
intended for ingestion in daily
quantities measured in drops or similar
small units of measure, and that the
additive would be used in all dietary
supplement tablets, capsules, and liquid
formulations that are intended for
ingestion in daily quantities measured
in drops or similar small units of
measure at a maximum practical 80
percent use level.
The agency used data from a
carcinogenesis bioassay on 1,4-dioxane,
conducted by the National Cancer
Institute, to estimate the upper-bound
limit of lifetime human risk from
exposure to this chemical resulting from
the petitioned use of the additive. The
results of the bioassay on 1,4-dioxane
demonstrated that the material was
carcinogenic for female rats under the
conditions of the study. The authors
reported that the test material caused
significantly increased incidence of
squamous cell carcinomas and
hepatocellular tumors in female rats.
Based on the agency’s estimate that
exposure to 1,4-dioxane will not exceed
800 ng/p/d, FDA estimates that the
upper-bound limit of lifetime human
risk from exposure to 1,4-dioxane
resulting from the petitioned use of the
subject additive is 2.8 x 10-8 or 28 in 1
billion. Because of the numerous
conservative assumptions used in
calculating the exposure estimate, the
actual lifetime-averaged individual
exposure to 1,4-dioxane is likely to be
substantially less than the estimated
exposure, and therefore, the probable
lifetime human risk is also likely to be
substantially less than the estimated
upper-bound limit of lifetime human
risk. Thus, the agency concludes that
there is a reasonable certainty that no
harm from exposure to 1,4-dioxane
would result from the petitioned use of
the additive.
B. Ethylene Oxide
FDA has estimated the exposure to
ethylene oxide from the petitioned use
of the additive as an excipient in dietary
supplement tablets, capsules, and liquid
formulations that are intended for
ingestion in daily quantities measured
in drops or similar small units of
measure to be 80 ng/p/d, using the same
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Federal Register / Vol. 71, No. 48 / Monday, March 13, 2006 / Rules and Regulations
additive exposure assumptions
described above for 1,4-dioxane (Ref. 1).
The agency used data from a
carcinogenesis bioassay on ethylene
oxide conducted by the Institute of
Hygiene, University of Mainz, Germany,
to estimate the upper-bound limit of
lifetime human risk from exposure to
ethylene oxide resulting from the
petitioned use of the additive. The
authors reported that the test material
caused significantly increased incidence
of squamous cell carcinomas of the
forestomach and carcinomas in situ of
the glandular stomach in female rats.
Based on the agency’s estimate that
exposure to ethylene oxide will not
exceed 80 ng/p/d, FDA estimates that
the upper-bound limit of lifetime
human risk from exposure to ethylene
oxide resulting from the petitioned use
of the subject additive is 15 x 10-8 or 150
in 1 billion. Because of the numerous
conservative assumptions used in
calculating the exposure estimate, the
actual lifetime-averaged individual
exposure to ethylene oxide is likely to
be substantially less than the estimated
exposure, and therefore, the probable
lifetime human risk is also likely to be
substantially less than the estimated
upper-bound limit of lifetime human
risk. Therefore, FDA concludes that
there is reasonable certainty that no
harm from exposure to ethylene oxide
would result from the petitioned use of
the additive.
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C. Need for Specifications
Because 1,4-dioxane and ethylene
oxide are animal carcinogens and
because the additive is intended to be
ingested in its entirety, the agency has
concluded that specifications are
necessary to ensure that safe levels of
1,4-dioxane and ethylene oxide
impurities in the petitioned food
additive are maintained in future
batches. Thus, the agency is including
in this regulation a specification limit of
not greater than 10 parts per million
(ppm) for 1,4-dioxane and not greater
than 1 ppm for ethylene oxide. We are
also including in this regulation
specifications for total ester content,
acid value, hydroxyl value, and lead in
order to ensure that the product in the
marketplace reflects the identity and
purity of the material evaluated (Ref. 2).
IV. Conclusion
FDA has evaluated data in the
petition and other relevant material.
Based on this information, the agency
concludes that the proposed use of the
food additive as an excipient in dietary
supplement tablets, capsules, and liquid
formulations that are intended for
ingestion in daily quantities measured
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in drops or similar small units of
measure is safe. Therefore, the
regulations in 21 CFR part 172 should
be amended as set forth in this
document.
In accordance with § 171.1(h) (21 CFR
171.1(h)), the petition and the
documents that FDA considered and
relied upon in reaching its decision to
approve the petition are available for
inspection at the Center for Food Safety
and Applied Nutrition by appointment
with the information contact person (see
FOR FURTHER INFORMATION CONTACT). As
provided in § 171.1(h), the agency will
delete from the documents any
materials that are not available for
public disclosure before making the
documents available for inspection.
V. Environmental Impact
The agency has carefully considered
the potential environmental effects of
this final rule. FDA has concluded that
the action will not have a significant
impact on the human environment, and
that an environmental impact statement
is not required. The agency’s finding of
no significant impact and the evidence
supporting that finding, contained in an
environmental assessment, may be seen
in the Division of Dockets Management
(see ADDRESSES) between 9 a.m. and 4
p.m., Monday through Friday.
VI. Paperwork Reduction Act of 1995
This final rule contains no collection
of information. Therefore, clearance by
the Office of Management and Budget
under the Paperwork Reduction Act of
1995 is not required.
VII. Objections
Any person who will be adversely
affected by this regulation may file with
the Division of Dockets Management
(see ADDRESSES) written or electronic
objections. Each objection shall be
separately numbered, and each
numbered objection shall specify with
particularity the provisions of the
regulation to which objection is made
and the grounds for the objection. Each
numbered objection on which a hearing
is requested shall specifically so state.
Failure to request a hearing for any
particular objection shall constitute a
waiver of the right to a hearing on that
objection. Each numbered objection for
which a hearing is requested shall
include a detailed description and
analysis of the specific factual
information intended to be presented in
support of the objection in the event
that a hearing is held. Failure to include
such a description and analysis for any
particular objection shall constitute a
waiver of the right to a hearing on the
objection. Three copies of all documents
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are to be submitted and are to be
identified with the docket number
found in brackets in the heading of this
document. Any objections received in
response to the regulation may be seen
in the Division of Dockets Management
between 9 a.m. and 4 p.m., Monday
through Friday.
VIII. References
The following references have been
placed on display in the Division of
Dockets Management and may be seen
by interested persons between 9 a.m.
and 4 p.m., Monday through Friday.
1. Memorandum dated January 22,
2004, from the Division of Biotech and
GRAS Notice Review to Division of
Petition Review, ‘‘FAP 9A4155:
Gattefosse Corp. Polyglycides From
Hydrogenated Vegetable Oils. Revised
Estimate of Exposure for 1,4-Dioxane
and Ethylene Oxide.’’
2. Memorandum dated October 30,
1998, from Chemistry Review Branch to
the Division of Product Policy, ‘‘FAP
9A4155: (MATS Milestone 2.3)
American Clinical Research
Consultants, Inc., on behalf of Gattefosse
S.A. Polyglycides for use as Tablet
Excipients. Submission of 1–7–98.’’
List of Subjects in 21 CFR Part 172
Food additives, Incorporation by
reference, Reporting and recordkeeping
requirements.
I Therefore, under the Federal Food,
Drug, and Cosmetic Act and under
authority delegated to the Commissioner
of Food and Drugs, 21 CFR part 172 is
amended as follows:
PART 172—FOOD ADDITIVES
PERMITTED FOR DIRECT ADDITION
TO FOOD FOR HUMAN
CONSUMPTION
1. The authority citation for 21 CFR
part 172 continues to read as follows:
I
Authority: 21 U.S.C. 321, 341, 342, 348,
371, 379e.
2. Section 172.736 is added to subpart
H to read as follows:
I
§ 172.736 Glycerides and polyglycides of
hydrogenated vegetable oils.
The food additive glycerides and
polyglycides of hydrogenated vegetable
oils may be safely used in food in
accordance with the following
prescribed conditions:
(a) The additive is manufactured by
heating a mixture of hydrogenated oils
of vegetable origin and polyethylene
glycol in the presence of an alkaline
catalyst followed by neutralization with
any acid that is approved or is generally
recognized as safe for this use to yield
the finished product.
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(b) The additive consists of a mixture
of mono-, di- and tri-glycerides and
polyethylene glycol mono- and di-esters
of fatty acids (polyglycides) of
hydrogenated vegetable oils and meets
the following specifications:
(1) Total ester content, greater than 90
percent as determined by a method
entitled ‘‘Determination of Esterified
Glycerides and Polyoxyethylene
Glycols,’’ approved November 16, 2001,
printed by Gattefosse S.A.S., and
incorporated by reference. The Director
of the Office of the Federal Register
approves this incorporation by reference
in accordance with 5 U.S.C. 552(a) and
1 CFR part 51. You may obtain a copy
from the Office of Food Additive Safety,
5100 Paint Branch Pkwy., College Park,
MD 20740 or you may examine a copy
at the Center for Food Safety and
Applied Nutrition’s Library, Food and
Drug Administration, 5100 Paint Branch
Pkwy., College Park, MD 20740, or at
the National Archives and Records
Administration (NARA). For
information on the availability of this
material at NARA, call 202–741–6030,
or go to https://www.archives.gov/
federal_register/
code_of_federal_regulations/
ibr_locations.html.
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(2) Acid value, not greater than 2, and
hydroxyl value, not greater than 56 as
determined by the methods entitled
‘‘Acid Value,’’ p. 934 and ‘‘Hydroxyl
Value,’’ p. 936, respectively, in the Food
Chemicals Codex, 5th ed., effective
January 1, 2004, and incorporated by
reference in accordance with 5 U.S.C.
552(a) and 1 CFR part 51. Copies are
available from the National Academies
Press, 500 Fifth St. NW., Washington,
DC 20055 (Internet address https://
www.nap.edu), or may be examined at
the Center for Food Safety and Applied
Nutrition’s Library, 5100 Paint Branch
Pkwy., College Park, MD 20740, or at
the National Archives and Records
Administration (NARA). For
information on the availability of this
material at NARA, call 202–741–6030,
or go to https://www.archives.gov/
federal_register/
code_of_federal_regulations/
ibr_locations.html.
(3) Lead, not greater than 0.1 mg/kg as
determined by the American Oil
Chemists’ Society (A.O.C.S.) method Ca
18c–91, ‘‘Determination of Lead by
Direct Graphite Furnace Atomic
Absorption Spectrophotometry,’’
updated 1995, and incorporated by
reference in accordance with 5 U.S.C.
552(a) and 1 CFR part 51. Copies are
available from American Oil Chemists’
Society, P. O. Box 3489, Champaign, IL
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61826–3489, or may be examined in the
library at the Center for Food Safety and
Applied Nutrition, 5100 Paint Branch
Pkwy., College Park, MD 20740, or at
the National Archives and Records
Administration (NARA). For
information on the availability of this
material at NARA, call 202–741–6030,
or go to https://www.archives.gov/
federal_register/
code_of_federal_regulations/
ibr_locations.html.
(4) 1,4-Dioxane, not greater than 10
milligrams per kilogram (mg/kg), and
ethylene oxide, not greater than 1 mg/
kg, as determined by a gas
chromatographic method entitled
‘‘Determination of Ethylene Oxide and
1,4-Dioxane by Headspace Gas
Chromatography,’’ approved November
5, 1998, printed by Gattefosse S.A.S.,
and incorporated by reference in
accordance with 5 U.S.C. 552(a) and 1
CFR part 51; see paragraph (b)(1) of this
section for availability of the
incorporation by reference.
(c) The additive is used or intended
for use as an excipient in dietary
supplement tablets, capsules, and liquid
formulations that are intended for
ingestion in daily quantities measured
in drops or similar small units of
measure.
Dated: March 2, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 06–2354 Filed 3–10–06; 8:45 am]
BILLING CODE 4160–01–S
DEPARTMENT OF HOMELAND
SECURITY
Coast Guard
33 CFR Part 117
[CGD01–06–006]
RIN 1625–AA09
Drawbridge Operation Regulations;
Jamaica Bay and Connecting
Waterways, New York City, NY
Coast Guard, DHS.
Temporary final rule.
AGENCY:
ACTION:
SUMMARY: The Coast Guard has
temporarily changed the regulation
governing the operation of the New
York City Highway Bridge (Belt
Parkway), at mile 0.8, across Mill Basin,
at New York City, New York. This
temporary final rule allows the bridge
owner to open only one of the two
moveable spans for the passage of vessel
traffic from March 8, 2006 through
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September 7, 2006. This rule is
necessary to facilitate bridge deck
replacement.
DATES: This temporary rule is effective
from March 8, 2006 through September
7, 2006.
ADDRESSES: Comments and material
received from the public, as well as
documents indicated in this preamble as
being available in the docket, are part of
docket [CGD01–06–006] and are
available for inspection or copying at
the First Coast Guard District, Bridge
Branch Office, 408 Atlantic Avenue,
Boston, Massachusetts, 02110, between
7 a.m. and 3 p.m., Monday through
Friday, except Federal holidays.
FOR FURTHER INFORMATION CONTACT: Ms.
Judy Leung-Yee, Project Officer, First
Coast Guard District, (212) 668–7195.
SUPPLEMENTARY INFORMATION:
Regulatory Information
On January 30, 2006, we published a
notice of proposed rulemaking (NPRM)
entitled ‘‘Drawbridge Operation
Regulations’’; Jamaica Bay and
Connecting Waterways, New York, in
the Federal Register (71 FR 4852). We
received no comments in response to
the notice of proposed rulemaking. No
public hearing was requested and none
was held.
Under 5 U.S.C. 553(d)(3), the Coast
Guard finds that good cause exists for
making this rule effective less than 30
days after publication in the Federal
Register.
Making this rule effective in less than
30 days after publication in the Federal
Register will allow this rule to become
effective in time for the March 8, 2006,
deck replacement construction start
date.
The deck replacement for the New
York City Highway Bridge is vital
necessary work that must be performed
without delay as a result of deterioration
of the existing bridge deck which could
fail if not replaced with all due speed.
In order to assure the continued safe
and reliable operation of the bridge,
construction work should begin on
schedule on March 8, 2006.
Background and Purpose
The New York City Highway Bridge
(Belt Parkway), has a vertical clearance
of 34 feet at mean high water and 39 feet
at mean low water in the closed
position. The existing regulations are
listed at 33 CFR 117.795(b).
The owner of the bridge, New York
City Department of Transportation
(NYCDOT), requested a temporary
change to the drawbridge operation
regulations to facilitate the replacement
of the bridge roadway deck.
E:\FR\FM\13MRR1.SGM
13MRR1
]]>Agencies
[Federal Register Volume 71, Number 48 (Monday, March 13, 2006)]
[Rules and Regulations]
[Pages 12618-12621]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 06-2354]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 172
[Docket No. 1991F-0457] (formerly Docket No. 91F-0457)
Food Additives Permitted For Direct Addition to Food for Human
Consumption; Glycerides and Polyglycides
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the food
additive regulations to provide for the safe use of a mixture of
glycerides and polyethylene glycol mono- and di-esters of fatty acids
of hydrogenated vegetable oils as an excipient in dietary supplement
tablets, capsules, and liquid formulations that are intended for
ingestion in daily quantities measured in drops or similar small units
of measure. This action is in response to a petition filed by
Gattefosse Corp.
DATES: This rule is effective March 13, 2006. Submit written or
electronic objections and requests for a hearing by April 12, 2006. See
section VII of this document for information on the filing of
objections. The Director of the Office of the Federal Register approves
the incorporation by reference of certain publications in accordance
with 5 U.S.C. 552(a) and 1 CFR part 51 as of March 13, 2006.
ADDRESSES: You may submit comments, identified by Docket No. 1991F-
0457, by any of the following methods:
Electronic Submissions
Submit electronic comments in the following ways:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: https://www.fda.gov/dockets/ecomments.
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
Submit written submissions in the following ways:
FAX: 301-827-6870.
Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions]: Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
To ensure more timely processing of comments, FDA is no longer
accepting comments submitted to the agency by e-mail. FDA encourages
you to continue to submit electronic comments by using the Federal
eRulemaking Portal or the agency Web site, as described in the
Electronic Submissions portion of this paragraph.
Instructions: All submissions received must include the agency name
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN
number has been assigned) for this rulemaking. All comments received
may be posted without change to https://www.fda.gov/ohrms/dockets/
default.htm, including any personal information provided. For
additional information on submitting comments, see the ``Objections''
heading of the SUPPLEMENTARY INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to https://www.fda.gov/ohrms/dockets/default.htm
and insert the docket number(s), found in brackets in the heading of
this document, into the ``Search'' box and follow the prompts and/or go
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Raphael A. Davy, Center for Food
Safety and Applied Nutrition (HFS-265), Food and Drug Administration,
5100 Paint Branch Pkwy., College Park, MD 20740, 301-436-1272.
SUPPLEMENTARY INFORMATION:
I. Background
In a notice published in the Federal Register of December 19, 1991
(56 FR 65907), FDA announced that a food additive petition (FAP 9A4155)
had been filed by Parexel International Corp., One Alewife Place,
Cambridge, MA 02140 on behalf of Gattefosse S.A., Saint-Priest, France.
The petition proposed to amend the food additive regulations to provide
for the safe use of a mixture of glycerides and polyethylene glycol
esters of fatty acids of vegetable origin as an excipient in vitamin
tablets and liquid formulations. Subsequently, in a letter dated
January 7, 1998, the petitioner informed the agency that the petition
was being amended by narrowing the polyethylene glycol esters (commonly
known as polyglycides) to one class of compounds, namely, the
polyethylene glycol esters of fatty acids from hydrogenated vegetable
oils. Further, under an e-mail dated October 5, 2005, the petitioner
later clarified that the additive was intended for use as an excipient
in all dietary supplement tablets, capsules, and liquid formulations
that are intended for
[[Page 12619]]
ingestion in daily quantities measured in drops or similar small units
of measure.
In evaluating the safety of the petitioned substance, FDA has
reviewed the safety of the additive (glycerides and polyglycides
mixture) and the chemical impurities that may be present in the
additive as a result of the manufacturing process. The mono-, di-, and
tri-glycerides component of the additive are commonly found in food. In
addition, mono-, and di-glycerides are affirmed as generally recognized
as safe (GRAS) for use in food (Sec. 184.1505 (21 CFR 184.1505)). The
``polyglycides,'' consist of mono- and di-esters of polyethylene
glycol, made using fatty acids derived from hydrogenated oils of
vegetable origin. Although the additive itself (glycerides and
polyglycides mixture) has not been shown to cause cancer, it may
contain minute amounts of carcinogenic residues resulting from the
manufacture of the polyethylene glycol. In particular, the additive may
contain traces of 1,4-dioxane and ethylene oxide, which have been shown
to cause cancer in test animals.
II. Determination of Safety
Under the general safety standard in section 409 of the Federal
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 348), a food additive
cannot be approved for a particular use unless a fair evaluation of the
data available to FDA establishes that the additive is safe for that
use. FDA's food additive regulations (21 CFR 170.3(i)) define safe as
``a reasonable certainty in the minds of competent scientists that the
substance is not harmful under the intended conditions of use.''
The food additives anticancer, or Delaney, clause of the act
(section 409(c)(3)(A)) provides that no food additive shall be deemed
safe if it is found to induce cancer when ingested by man or animal, or
if it is found, after tests which are appropriate for the evaluation of
the safety of food additives, to induce cancer in man or animal.
Importantly, however, the Delaney clause applies to the additive itself
and not to impurities in the additive. That is, where an additive
itself has not been shown to cause cancer, but contains a carcinogenic
impurity, the additive is evaluated properly under the general safety
standard using risk assessment procedures to determine whether there is
a reasonable certainty that no harm will result from the intended use
of the additive (Scott v. FDA, 728 F.2d 322 (6th Cir. 1984)).
III. Safety of the Petitioned Use of the Additive
FDA estimates that the petitioned use of the additive as an
excipient in dietary supplement tablets, capsules, and liquid
formulations that are intended for ingestion in daily quantities
measured in drops or similar small units of measure will result in an
estimated average daily intake of no more than 720 milligrams per
person per day (mg/p/d) of polyglycides, based on the consumption of 2
dietary supplement doses per day and assuming that the polyglycide
portion comprises 75 percent of the total excipient in the dose (Ref.
1). Although the filing notice specifically referenced vitamin tablets
and liquid formulations only, this estimate considered use of the
additive in all dietary supplement tablets, capsules, and liquid
formulations that are intended for ingestion in daily quantities
measured in drops or similar small units of measure, due to the
petitioner's clarification of the additive's intended use. The estimate
is conservative as it assumes that all dietary supplements would be
formulated with the additive. This estimate does not include the daily
intake of the glycerides because glycerides are GRAS for use with no
limit other than current good manufacturing practice (Sec. 184.1505).
Based on the available toxicological data on this new food additive
mixture, and considering the cumulative exposure of the components of
the mixture from the use of other ingredients, the agency concludes
that the estimated dietary exposure to polyglycides resulting from the
petitioned use of this additive is well within an acceptable margin of
safety.
FDA has evaluated the safety of this additive under the general
safety standard, considering all available toxicological data and using
risk assessment procedures to estimate the upper-bound limit of
lifetime human risk presented by 1,4-dioxane and ethylene oxide, the
carcinogenic chemicals that may be present as impurities in the
additive. The risk evaluation of 1,4-dioxane and ethylene oxide has two
aspects: (1) Assessment of exposure to the impurities from the
petitioned use of the additive and (2) extrapolation of the risk
observed in the animal bioassays to the conditions of exposure to
humans.
A. 1,4-Dioxane
FDA has estimated the exposure to 1,4-dioxane from the petitioned
use of the additive as an excipient in dietary supplement tablets,
capsules, and liquid formulations that are intended for ingestion in
daily quantities measured in drops or similar small units of measure to
be 800 nanograms per person per day (ng/p/d) (Ref. 1). This estimate is
conservative as it was based on the assumptions that the additive
(glycerides and polyglycides mixture) would be the sole excipient in
all dietary supplement tablets, capsules, and liquid formulations that
are intended for ingestion in daily quantities measured in drops or
similar small units of measure, and that the additive would be used in
all dietary supplement tablets, capsules, and liquid formulations that
are intended for ingestion in daily quantities measured in drops or
similar small units of measure at a maximum practical 80 percent use
level.
The agency used data from a carcinogenesis bioassay on 1,4-dioxane,
conducted by the National Cancer Institute, to estimate the upper-bound
limit of lifetime human risk from exposure to this chemical resulting
from the petitioned use of the additive. The results of the bioassay on
1,4-dioxane demonstrated that the material was carcinogenic for female
rats under the conditions of the study. The authors reported that the
test material caused significantly increased incidence of squamous cell
carcinomas and hepatocellular tumors in female rats.
Based on the agency's estimate that exposure to 1,4-dioxane will
not exceed 800 ng/p/d, FDA estimates that the upper-bound limit of
lifetime human risk from exposure to 1,4-dioxane resulting from the
petitioned use of the subject additive is 2.8 x 10-8 or 28 in 1
billion. Because of the numerous conservative assumptions used in
calculating the exposure estimate, the actual lifetime-averaged
individual exposure to 1,4-dioxane is likely to be substantially less
than the estimated exposure, and therefore, the probable lifetime human
risk is also likely to be substantially less than the estimated upper-
bound limit of lifetime human risk. Thus, the agency concludes that
there is a reasonable certainty that no harm from exposure to 1,4-
dioxane would result from the petitioned use of the additive.
B. Ethylene Oxide
FDA has estimated the exposure to ethylene oxide from the
petitioned use of the additive as an excipient in dietary supplement
tablets, capsules, and liquid formulations that are intended for
ingestion in daily quantities measured in drops or similar small units
of measure to be 80 ng/p/d, using the same
[[Page 12620]]
additive exposure assumptions described above for 1,4-dioxane (Ref. 1).
The agency used data from a carcinogenesis bioassay on ethylene
oxide conducted by the Institute of Hygiene, University of Mainz,
Germany, to estimate the upper-bound limit of lifetime human risk from
exposure to ethylene oxide resulting from the petitioned use of the
additive. The authors reported that the test material caused
significantly increased incidence of squamous cell carcinomas of the
forestomach and carcinomas in situ of the glandular stomach in female
rats.
Based on the agency's estimate that exposure to ethylene oxide will
not exceed 80 ng/p/d, FDA estimates that the upper-bound limit of
lifetime human risk from exposure to ethylene oxide resulting from the
petitioned use of the subject additive is 15 x 10-8 or 150 in 1
billion. Because of the numerous conservative assumptions used in
calculating the exposure estimate, the actual lifetime-averaged
individual exposure to ethylene oxide is likely to be substantially
less than the estimated exposure, and therefore, the probable lifetime
human risk is also likely to be substantially less than the estimated
upper-bound limit of lifetime human risk. Therefore, FDA concludes that
there is reasonable certainty that no harm from exposure to ethylene
oxide would result from the petitioned use of the additive.
C. Need for Specifications
Because 1,4-dioxane and ethylene oxide are animal carcinogens and
because the additive is intended to be ingested in its entirety, the
agency has concluded that specifications are necessary to ensure that
safe levels of 1,4-dioxane and ethylene oxide impurities in the
petitioned food additive are maintained in future batches. Thus, the
agency is including in this regulation a specification limit of not
greater than 10 parts per million (ppm) for 1,4-dioxane and not greater
than 1 ppm for ethylene oxide. We are also including in this regulation
specifications for total ester content, acid value, hydroxyl value, and
lead in order to ensure that the product in the marketplace reflects
the identity and purity of the material evaluated (Ref. 2).
IV. Conclusion
FDA has evaluated data in the petition and other relevant material.
Based on this information, the agency concludes that the proposed use
of the food additive as an excipient in dietary supplement tablets,
capsules, and liquid formulations that are intended for ingestion in
daily quantities measured in drops or similar small units of measure is
safe. Therefore, the regulations in 21 CFR part 172 should be amended
as set forth in this document.
In accordance with Sec. 171.1(h) (21 CFR 171.1(h)), the petition
and the documents that FDA considered and relied upon in reaching its
decision to approve the petition are available for inspection at the
Center for Food Safety and Applied Nutrition by appointment with the
information contact person (see FOR FURTHER INFORMATION CONTACT). As
provided in Sec. 171.1(h), the agency will delete from the documents
any materials that are not available for public disclosure before
making the documents available for inspection.
V. Environmental Impact
The agency has carefully considered the potential environmental
effects of this final rule. FDA has concluded that the action will not
have a significant impact on the human environment, and that an
environmental impact statement is not required. The agency's finding of
no significant impact and the evidence supporting that finding,
contained in an environmental assessment, may be seen in the Division
of Dockets Management (see ADDRESSES) between 9 a.m. and 4 p.m., Monday
through Friday.
VI. Paperwork Reduction Act of 1995
This final rule contains no collection of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.
VII. Objections
Any person who will be adversely affected by this regulation may
file with the Division of Dockets Management (see ADDRESSES) written or
electronic objections. Each objection shall be separately numbered, and
each numbered objection shall specify with particularity the provisions
of the regulation to which objection is made and the grounds for the
objection. Each numbered objection on which a hearing is requested
shall specifically so state. Failure to request a hearing for any
particular objection shall constitute a waiver of the right to a
hearing on that objection. Each numbered objection for which a hearing
is requested shall include a detailed description and analysis of the
specific factual information intended to be presented in support of the
objection in the event that a hearing is held. Failure to include such
a description and analysis for any particular objection shall
constitute a waiver of the right to a hearing on the objection. Three
copies of all documents are to be submitted and are to be identified
with the docket number found in brackets in the heading of this
document. Any objections received in response to the regulation may be
seen in the Division of Dockets Management between 9 a.m. and 4 p.m.,
Monday through Friday.
VIII. References
The following references have been placed on display in the
Division of Dockets Management and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Memorandum dated January 22, 2004, from the Division of Biotech
and GRAS Notice Review to Division of Petition Review, ``FAP 9A4155:
Gattefosse Corp. Polyglycides From Hydrogenated Vegetable Oils. Revised
Estimate of Exposure for 1,4-Dioxane and Ethylene Oxide.''
2. Memorandum dated October 30, 1998, from Chemistry Review Branch
to the Division of Product Policy, ``FAP 9A4155: (MATS Milestone 2.3)
American Clinical Research Consultants, Inc., on behalf of Gattefosse
S.A. Polyglycides for use as Tablet Excipients. Submission of 1-7-98.''
List of Subjects in 21 CFR Part 172
Food additives, Incorporation by reference, Reporting and
recordkeeping requirements.
0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
172 is amended as follows:
PART 172--FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR
HUMAN CONSUMPTION
0
1. The authority citation for 21 CFR part 172 continues to read as
follows:
Authority: 21 U.S.C. 321, 341, 342, 348, 371, 379e.
0
2. Section 172.736 is added to subpart H to read as follows:
Sec. 172.736 Glycerides and polyglycides of hydrogenated vegetable
oils.
The food additive glycerides and polyglycides of hydrogenated
vegetable oils may be safely used in food in accordance with the
following prescribed conditions:
(a) The additive is manufactured by heating a mixture of
hydrogenated oils of vegetable origin and polyethylene glycol in the
presence of an alkaline catalyst followed by neutralization with any
acid that is approved or is generally recognized as safe for this use
to yield the finished product.
[[Page 12621]]
(b) The additive consists of a mixture of mono-, di- and tri-
glycerides and polyethylene glycol mono- and di-esters of fatty acids
(polyglycides) of hydrogenated vegetable oils and meets the following
specifications:
(1) Total ester content, greater than 90 percent as determined by a
method entitled ``Determination of Esterified Glycerides and
Polyoxyethylene Glycols,'' approved November 16, 2001, printed by
Gattefosse S.A.S., and incorporated by reference. The Director of the
Office of the Federal Register approves this incorporation by reference
in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain a
copy from the Office of Food Additive Safety, 5100 Paint Branch Pkwy.,
College Park, MD 20740 or you may examine a copy at the Center for Food
Safety and Applied Nutrition's Library, Food and Drug Administration,
5100 Paint Branch Pkwy., College Park, MD 20740, or at the National
Archives and Records Administration (NARA). For information on the
availability of this material at NARA, call 202-741-6030, or go to
https://www.archives.gov/federal_register/code_of_federal_
regulations/ibr_locations.html.
(2) Acid value, not greater than 2, and hydroxyl value, not greater
than 56 as determined by the methods entitled ``Acid Value,'' p. 934
and ``Hydroxyl Value,'' p. 936, respectively, in the Food Chemicals
Codex, 5th ed., effective January 1, 2004, and incorporated by
reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies
are available from the National Academies Press, 500 Fifth St. NW.,
Washington, DC 20055 (Internet address https://www.nap.edu), or may be
examined at the Center for Food Safety and Applied Nutrition's Library,
5100 Paint Branch Pkwy., College Park, MD 20740, or at the National
Archives and Records Administration (NARA). For information on the
availability of this material at NARA, call 202-741-6030, or go to
https://www.archives.gov/federal_register/code_of_federal_
regulations/ibr_locations.html.
(3) Lead, not greater than 0.1 mg/kg as determined by the American
Oil Chemists' Society (A.O.C.S.) method Ca 18c-91, ``Determination of
Lead by Direct Graphite Furnace Atomic Absorption Spectrophotometry,''
updated 1995, and incorporated by reference in accordance with 5 U.S.C.
552(a) and 1 CFR part 51. Copies are available from American Oil
Chemists' Society, P. O. Box 3489, Champaign, IL 61826-3489, or may be
examined in the library at the Center for Food Safety and Applied
Nutrition, 5100 Paint Branch Pkwy., College Park, MD 20740, or at the
National Archives and Records Administration (NARA). For information on
the availability of this material at NARA, call 202-741-6030, or go to
https://www.archives.gov/federal_register/code_of_federal_
regulations/ibr_locations.html.
(4) 1,4-Dioxane, not greater than 10 milligrams per kilogram (mg/
kg), and ethylene oxide, not greater than 1 mg/kg, as determined by a
gas chromatographic method entitled ``Determination of Ethylene Oxide
and 1,4-Dioxane by Headspace Gas Chromatography,'' approved November 5,
1998, printed by Gattefosse S.A.S., and incorporated by reference in
accordance with 5 U.S.C. 552(a) and 1 CFR part 51; see paragraph (b)(1)
of this section for availability of the incorporation by reference.
(c) The additive is used or intended for use as an excipient in
dietary supplement tablets, capsules, and liquid formulations that are
intended for ingestion in daily quantities measured in drops or similar
small units of measure.
Dated: March 2, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 06-2354 Filed 3-10-06; 8:45 am]
BILLING CODE 4160-01-S
