Tobacco Product Standard for N-Nitrosonornicotine Level in Finished Smokeless Tobacco Products, 8004-8053 [2017-01030]
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Federal Register / Vol. 82, No. 13 / Monday, January 23, 2017 / Proposed Rules
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Part 1132
[Docket No. FDA–2016–N–2527]
Tobacco Product Standard for NNitrosonornicotine Level in Finished
Smokeless Tobacco Products
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Proposed rule.
The Food and Drug
Administration (FDA) is proposing a
tobacco product standard that would
establish a limit of N-nitrosonornicotine
(NNN) in finished smokeless tobacco
products. FDA is taking this action
because NNN is a potent carcinogenic
agent found in smokeless tobacco
products and is a major contributor to
the elevated cancer risks associated with
smokeless tobacco use. Because
products with higher NNN levels pose
higher risks of cancer, FDA finds that
establishing a NNN limit in finished
smokeless tobacco products is
appropriate for the protection of the
public health.
DATES: Submit either electronic or
written comments on the proposed rule
by April 10, 2017. In accordance with
21 CFR 10.40(c), in finalizing this
rulemaking FDA will review and
consider all comments submitted before
the time for comment on this proposed
regulation has expired. If your comment
is submitted after the expiration of the
comment period, it will not be reviewed
and considered by FDA unless you
apply for, and receive, an extension of
the comment period pursuant to 21 CFR
10.40(b)(3). Submit comments on
information collection issues under the
Paperwork Reduction Act of 1995 (the
PRA) by February 22, 2017, (see the
‘‘Paperwork Reduction Act of 1995’’
section). See section VII of this
document for the proposed effective
date of a final ruled based on this
document.
SUMMARY:
ADDRESSES:
You may submit comments
as follows:
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Electronic Submissions
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following way:
• Federal eRulemaking Portal: https://
www.regulations.gov. Follow the
instructions for submitting comments.
Comments submitted electronically,
including attachments, to https://
www.regulations.gov will be posted to
the docket unchanged. Because your
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comment will be made public, you are
solely responsible for ensuring that your
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such as medical information, your or
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as a manufacturing process. Please note
that if you include your name, contact
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identifies you in the body of your
comments, that information will be
posted on https://www.regulations.gov.
• If you want to submit a comment
with confidential information that you
do not wish to be made available to the
public, submit the comment as a
written/paper submission and in the
manner detailed (see ‘‘Written/Paper
Submissions’’ and ‘‘Instructions’’).
Written/Paper Submissions
Submit written/paper submissions as
follows:
• Mail/Hand delivery/Courier (for
written/paper submissions): Division of
Dockets Management (HFA–305), Food
and Drug Administration, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.
• For written/paper comments
submitted to the Division of Dockets
Management, FDA will post your
comment, as well as any attachments,
except for information submitted,
marked and identified, as confidential,
if submitted as detailed in
‘‘Instructions.’’
Instructions: All submissions received
must include the Docket No. FDA–
2016–N–2527 for ‘‘Tobacco Product
Standard for N-nitrosonornicotine Level
in Finished Smokeless Tobacco
Products.’’ Received comments will be
placed in the docket and, except for
those submitted as ‘‘Confidential
Submissions,’’ publicly viewable at
https://www.regulations.gov or at the
Division of Dockets Management
between 9 a.m. and 4 p.m., Monday
through Friday.
• Confidential Submissions—To
submit a comment with confidential
information that you do not wish to be
made publicly available, submit your
comments only as a written/paper
submission. You should submit two
copies total. One copy will include the
information you claim to be confidential
with a heading or cover note that states
‘‘THIS DOCUMENT CONTAINS
CONFIDENTIAL INFORMATION.’’ The
Agency will review this copy, including
the claimed confidential information, in
its consideration of comments. The
second copy, which will have the
claimed confidential information
redacted/blacked out, will be available
for public viewing and posted on https://
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www.regulations.gov. Submit both
copies to the Division of Dockets
Management. If you do not wish your
name and contact information to be
made publicly available, you can
provide this information on the cover
sheet and not in the body of your
comments and you must identify this
information as ‘‘confidential.’’ Any
information marked as ‘‘confidential’’
will not be disclosed except in
accordance with 21 CFR 10.20 and other
applicable disclosure law. For more
information about FDA’s posting of
comments to public dockets, see 80 FR
56469, September 18, 2015, or access
the information at: https://www.fda.gov/
regulatoryinformation/dockets/
default.htm.
Docket: For access to the docket to
read background documents or the
electronic and written/paper comments
received, go to https://
www.regulations.gov and insert the
docket number, 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.
Submit comments on information
collection issues to the Office of
Management and Budget in the
following ways:
• Fax to the Office of Information and
Regulatory Affairs, OMB, Attn: FDA
Desk Officer, FAX: 202–395–7285, or
email to oira_submission@omb.eop.gov.
All comments should be identified with
the title, Tobacco Product Standard:
NNN Level in Finished Smokeless
Tobacco Products.
FOR FURTHER INFORMATION CONTACT: Beth
Buckler or Colleen Lee, Office of
Regulations, Center for Tobacco
Products (CTP), Food and Drug
Administration, Document Control
Center, Bldg. 71, Rm. G335, 10903 New
Hampshire Ave., Silver Spring, MD
20993–0002, 877–287–1373,
CTPRegulations@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Proposed Rule
B. Summary of the Major Provisions of the
Proposed Rule
C. Legal Authority
D. Costs and Benefits
II. Background Information
A. Purpose
B. Legal Authority
C. Additional Considerations and Requests
for Comment
III. Scope of Proposed Standard
A. Smokeless Tobacco Products
B. Current Prevalence and Initiation Rates
IV. Rationale for Developing a Standard for
NNN
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A. Smokeless Tobacco is Carcinogenic
B. NNN in Smokeless Tobacco Products is
Carcinogenic
C. NNN in Smokeless Tobacco Products
D. Basis for the NNN Limit in the Proposed
Standard
E. Information on Technical Achievability
F. Analytical Method
V. Standard is Appropriate for the Protection
of Public Health
A. Benefits to the Population as a Whole
B. The Likelihood That Existing Users of
Tobacco Products Will Stop Using Such
Products
C. The Likelihood That Non-Users Will
Start Using Tobacco Products
D. Conclusion
VI. Description of Proposed Regulation
A. General Provisions (Proposed Subpart
A)
B. Product Requirements (Proposed
Subpart B)
C. Labeling and Recordkeeping
Requirements (Proposed Subpart C)
VII. Proposed Effective Date
VIII. Incorporation by Reference
IX. Economic Analysis of Impacts
X. Analysis of Environmental Impact
XI. Paperwork Reduction Act of 1995
XII. Executive Order 13132
XIII. Executive Order 13175
XIV. References
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I. Executive Summary
A. Purpose of the Proposed Rule
FDA is proposing a tobacco product
standard that would establish a limit of
NNN in finished smokeless tobacco
products sold in the United States. NNN
is a potent carcinogenic agent found in
smokeless tobacco products and is a
major contributor to the elevated cancer
risks associated with smokeless tobacco
use. By FDA’s estimates, in the 20 years
following implementation of the
proposed product standard,
approximately 12,700 new cases of oral
cancer and approximately 2,200 oral
cancer deaths would be prevented in the
United States because of this rule.
Moreover, during that 20-year period,
FDA estimates that approximately
15,200 life years would be gained as a
result of the proposed standard. Because
oral cancer is associated with significant
health and economic impacts, we expect
positive public health benefits due to
prevention of new and fatal cancer
cases. For the reasons discussed in the
preamble of this rule, FDA finds that the
proposed standard would be
appropriate for the protection of the
public health.
B. Summary of the Major Provisions of
the Proposed Rule
This proposed rule would establish a
limit of NNN in finished smokeless
tobacco products. Under the proposed
rule, no person may manufacture,
distribute, sell, or offer for distribution
or sale within the United States a
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finished smokeless tobacco product that
is not in compliance with the product
standard. However, the proposed rule
would provide an exception for tobacco
retailers and distributors; we would not
consider tobacco retailers and
distributors to be in violation of part
1132 as it relates to the sale or
distribution of finished smokeless
tobacco products that exceed the
allowed NNN level if they meet certain
criteria set forth in the rule.
The proposed rule would require that
the mean level of NNN in any batch of
finished smokeless tobacco products not
exceed 1.0 microgram per gram (mg/g) of
tobacco (on a dry weight basis) at any
time through the product’s labeled
expiration date as determined by
specified product testing. The rule
would require that all finished
smokeless tobacco products have an
expiration date and provide that the
expiration date be no later than the final
date the manufacturer can demonstrate
that the NNN level in the finished
smokeless tobacco product conforms to
the limit when the product is stored
under its intended conditions (e.g.,
room temperature or refrigeration).
To ensure that products conform to
the product standard, the proposed rule
would establish requirements for testing
the products. Two types of testing
would be required for smokeless
tobacco products—stability testing and
batch testing. Stability testing would be
required to assess the stability of the
NNN level in the finished smokeless
tobacco products and to establish and
verify the product’s expiration date and
storage conditions. In addition, each
batch of finished smokeless tobacco
product would be required to be tested
to determine whether the products
conform to the proposed NNN level.
The proposed rule would also establish
the standard test method (to be
incorporated by reference) and
requirements for using an alternative
test method as well as the sampling
requirements for all testing.
The proposed rule would require that
the labels of finished smokeless tobacco
products contain a manufacturing code,
expiration date, and, if applicable,
storage conditions for the finished
smokeless tobacco product (such as
refrigeration). In addition, the proposed
rule would require manufacturers of
finished smokeless tobacco products to
establish and maintain certain records.
C. Legal Authority
This proposed rule is being issued
upon FDA’s authority to establish a
tobacco product standard under section
907 of the Federal Food, Drug, and
Cosmetic Act (the FD&C Act) (21 U.S.C.
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387g) including authority related to the
reduction of constituents or harmful
components in tobacco products under
section 907(a)(4)(A)(ii) and to the testing
of tobacco products under section
907(a)(4)(B)(ii) through (iv); FDA’s
authorities related to the sale and
distribution of tobacco products under
sections 907(a)(4)(B)(v) and 906(d);
FDA’s authority to require tobacco
product manufacturers to establish and
maintain records under section 909 of
the FD&C Act (21 U.S.C. 387i); FDA’s
authorities related to adulterated and
misbranded tobacco products under
sections 902 and 903 (21 U.S.C. 387b
and 387c); FDA’s authorities related to
prohibited acts under section 301 of the
FD&C Act (21 U.S.C. 331); and FDA’s
rulemaking and inspection authorities
under sections 701 and 704 of the FD&C
Act (21 U.S.C. 371 and 374).
D. Costs and Benefits
The costs of the proposed rule, when
finalized, will be due to affected entities
ensuring that the smokeless tobacco
products comply with the proposed
product standard. We have estimated
the annualized costs associated with the
proposed rule over 20 years to be
between $17.91 million and $42.72
million using a 3 percent discount rate,
with a primary value of $30.31 million,
and between $20.11 million and $50.57
million, with a primary value of $35.34
million using a 7 percent discount rate.
The primary estimate for the present
value of total quantified costs over 20
years is approximately $450.97 million
at a 3 percent discount rate and $374.36
million at a 7 percent discount rate.
NNN is a carcinogenic agent found in
smokeless tobacco products. As
described in the preamble of the
proposed rule, on the basis of the
available scientific evidence, FDA has
determined that NNN is the
predominant driver of excess oral
cancer risk among smokeless tobacco
users. We quantify benefits associated
with the proposed rule in the form of
reduced oral cancer morbidity and
mortality attributable to smokeless
tobacco. As described in section V.A.3
of the preamble of the proposed rule, we
also expect the standard to reduce the
risk of esophageal cancer, and it may
reduce the risks of other cancers such as
pancreatic, laryngeal, prostate, and lung
cancer. However, there is more limited
information to directly quantify these
health benefits. As such, we only
consider estimated reductions in oral
cancer as the quantified benefit of the
proposed product standard.
Most of the estimated benefits arise
from quality life-years gains gained from
reduced oral cancer mortality. The
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annualized value over 20 years of
quality adjusted life-years gained from
reduced oral cancer mortality ranges
from $228.66 million to $2.46 billion at
a 3 percent discount rate, with a
primary value of $858.46 million. Using
a 7 percent discount rate, the
annualized value of quality life-years
gained from averted deaths ranges from
$182.01 million to $1.96 billion, with a
primary value of $683.34 million. The
primary estimate of the present value of
mortality reductions quantified over 20
years is $12.77 billion at a 3 percent
discount rate and $7.24 billion at a 7
percent discount rate. The annualized
value over 20 years of quality adjusted
life-years gained from reduced oral
cancer mortality and morbidity ranges
from approximately $283.95 million to
$3.05 billion at a 3 percent discount
rate, with a primary value of $1.06
billion, and approximately $246.40
million to $2.65 billion, with a primary
value of $0.92 billion at a 7 percent
discount rate. The primary estimate of
the present value of total quantified
benefits over 20 years is approximately
$15.86 billion at a 3 percent discount
rate and $9.80 billion at a 7 percent
discount rate for reductions in oral
cancer alone. These values are likely an
underestimate of the benefits associated
with the proposed rule, as we do not
quantify reductions in mortality and
morbidity from cancers other than oral
cancer. Costs and benefits are
summarized in table 8 of the preamble
of the proposed rule.
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II. Background Information
A. Purpose
FDA is issuing this proposed rule to
address the harm caused by the toxicant
NNN in smokeless tobacco products.
When Congress enacted the Family
Smoking Prevention and Tobacco
Control Act (Tobacco Control Act) in
2009, it included the finding that ‘‘the
Food and Drug Administration is a
regulatory agency with the scientific
expertise to identify harmful substances
in products to which consumers are
exposed, [and] to design standards to
limit exposure to those substances’’
(section 2(44) of the Tobacco Control
Act).
Smokeless tobacco products,
including those currently marketed in
the United States, have been
demonstrated to cause certain types of
cancer. Several authoritative reviews
have been conducted on the
relationship between smokeless tobacco
use and cancer risk and have reached
similar conclusions (Refs. 1, 2, 3, 4). The
International Agency for Research on
Cancer (IARC) concluded in its 2007
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monograph ‘‘Smokeless Tobacco and
Some Tobacco-Specific Nitrosamines’’
that there is sufficient evidence in
humans to indicate that smokeless
tobacco is carcinogenic and that it
causes oral and pancreatic cancer (Ref.
1). IARC confirmed these findings of the
carcinogenicity of smokeless tobacco in
a 2012 review, concluding that there is
sufficient evidence in both humans and
experimental animal studies that
smokeless tobacco causes oral,
esophageal, and pancreatic cancer (Ref.
2). In addition, a 2014 report on
smokeless tobacco by the National
Cancer Institute (NCI) and Centers for
Disease Control and Prevention (CDC)
estimated that smokeless tobacco use is
responsible for approximately 1,600
new cases of oral cancer, 200 cases of
esophageal cancer, and 500 cases of
pancreatic cancer in the United States
each year (Ref. 4).
NNN 1 is a potent carcinogenic agent
found in smokeless tobacco products
and is a major contributor to the
elevated cancer risks associated with
smokeless tobacco use (see section IV,
Rationale for Developing a Standard for
NNN, of this document). NNN levels
vary substantially across subcategories
of smokeless tobacco products (e.g.,
moist snuff, chewing tobacco, dry snuff)
and within product subcategories (e.g.,
moist snuff) (Ref. 5, 10). International
comparisons of oral cancer rates and
smokeless tobacco products suggest that
products with higher NNN levels may
pose higher risks of cancer (Refs. 6,
100). FDA is using its authority to
propose a standard that would reduce
tobacco-related harms by establishing a
limit of NNN in smokeless tobacco
products sold in the United States (see
section V of this document).
FDA is proposing that the standard
would apply to finished smokeless
tobacco products. Although NNN is also
found in other tobacco products, this
rule focuses solely on NNN levels in
smokeless tobacco products, and not on
additional products. Different measures
are required to evaluate the contribution
to cancer of NNN among users of other
tobacco products, such as combustible
products like cigarettes and dissolvable
tobacco products that do not meet the
statutory definition of ‘‘smokeless
tobacco product.’’ For example,
additional factors, such as polycyclic
aromatic hydrocarbons (PAH),
aldehydes and other chemicals (Refs.
147, 106), contribute to the cancer
burden associated with combustible
1 Since 2012, manufacturers have been required
to test and report to FDA the levels of harmful and
potentially harmful constituents (HPHCs),
including NNN, in each tobacco product (section
904(A)(3) of the FD&C Act).
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products, which make the relationship
between NNN and cancer in these
products different from that in
smokeless tobacco products. With
regard to dissolvable tobacco products
that do not meet the statutory definition
of smokeless tobacco, different product
testing methods than the ones
developed and available for smokeless
tobacco, as described in this proposal,
may be necessary to evaluate NNN in
these products because they do not
consist of cut, ground, powdered or leaf
tobacco. Therefore, at this stage, FDA
has chosen to focus on smokeless
tobacco and has evaluated data relevant
to establishing an NNN limit in
smokeless tobacco products.
This proposed product standard
would require that the mean level of
NNN in any batch of finished smokeless
tobacco products not exceed 1.0 mg/g of
tobacco (on a dry weight basis) at any
time through the product’s labeled
expiration date as determined by testing
in compliance with § 1132.12 (proposed
§ 1132.10). FDA expects that, in the 20
years following implementation of the
proposed product standard,
approximately 12,700 new cases of oral
cancer and approximately 2,200 oral
cancer deaths would be prevented in the
United States because of this rule.
Moreover, during that 20-year period,
approximately 15,200 life years would
be gained in the United States as a result
of the proposed standard. We believe
that the main source of variability in the
estimated impacts would be different
assumptions about oral cancer relative
risks due to smokeless tobacco use.
Using alternate relative risk estimates
that are somewhat lower and higher
than our main estimate results in
approximately 7,300 to 24,000 new
cases of oral cancer prevented and 1,300
to 4,200 oral cancer deaths prevented
over the 20-year period. Because oral
cancer is associated with significant
health and economic impacts, we expect
positive public health benefits due to
prevention of new and fatal cancer
cases. These benefits are discussed in
detail in section V of this proposed rule.
Accordingly, based on the information
discussed in the following sections of
the preamble to this proposed rule, FDA
finds that the proposed standard would
be appropriate for the protection of the
public health.
B. Legal Authority
1. Product Standard
The Tobacco Control Act was enacted
on June 22, 2009, amending the FD&C
Act and providing FDA with the
authority to regulate tobacco products
(Pub. L. 111–31; 123 Stat. 1776). Among
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the authorities provided to FDA is the
authority to establish tobacco product
standards. To establish a tobacco
product standard, section 907(a)(3)(A)
and (B) of the FD&C Act (21 U.S.C.
387g(a)(3)(A) and (B)) requires that we
find that the standard is appropriate for
the protection of the public health,
taking into consideration scientific
evidence concerning:
• The risks and benefits of the
proposed standard to the population as
a whole, including users and nonusers
of tobacco products;
• The increased or decreased
likelihood that existing users of tobacco
products will stop using such products;
and
• The increased or decreased
likelihood that those who do not use
tobacco products will start using such
products.
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2. NNN Limit
Section 907 of the FD&C Act
authorizes FDA to promulgate tobacco
product standards that are appropriate
for the protection of the public health,
including provisions, where
appropriate, for the reduction or
elimination of constituents or harmful
components of tobacco products
(section 907(a)(4)(A)(ii) of the FD&C
Act). This proposed rule would limit the
level of NNN in finished smokeless
tobacco products. To ensure that
finished smokeless tobacco products
comply with the proposed NNN level,
FDA also is including provisions to
require that tobacco product
manufacturers test their products on a
sample basis (i.e., batch testing) using a
specified testing procedure for
conformance with the limit pursuant to
section 907(a)(4)(B)(ii) and (iv) of the
FD&C Act.
3. Sale and Distribution Restrictions
Section 907(a)(4)(B)(v) states that
product standards must, where
appropriate for the protection of public
health, include provisions requiring that
the sale and distribution of the tobacco
products be restricted but only to the
extent that the sale and distribution of
a tobacco product may be restricted
under section 906(d). Similar to section
907, section 906(d) of the FD&C Act
gives FDA authority to require
restrictions on the sale and distribution
of tobacco products by regulation if the
Agency determines that such regulation
would be appropriate for the protection
of the public health. The finding as to
whether a sales and distribution
regulation is appropriate for the
protection of the public health must be
determined with respect to the risks and
benefits to the population as a whole,
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including users and nonusers of the
tobacco products, and must take into
account:
• The increased or decreased
likelihood that existing users of tobacco
products will stop using such products;
and
• The increased or decreased
likelihood that those who do not use
tobacco products will start using such
products (see section 906(d)(1) of the
FD&C Act).
Under these authorities along with
section 701, which provides FDA with
the authority to ‘‘promulgate regulations
for the efficient enforcement of this
Act,’’ FDA is including provisions to
restrict the manufacture, sale, and
distribution of finished smokeless
tobacco products that are not in
compliance with this standard.
Specifically, FDA is proposing to
require that no person may
manufacture, distribute, sell, or offer for
distribution or sale within the United
States a finished smokeless tobacco
product that is not in compliance with
part 1132 (proposed § 1132.1(b)).
However, tobacco retailers and
distributors would not be considered in
violation of part 1132 as it relates to the
sale or distribution or offer for sale or
distribution of finished smokeless
tobacco products that exceed the NNN
level required in proposed § 1132.10 if
they: (1) Store and transport the finished
smokeless tobacco products according
to the package label, (2) do not sell or
distribute or offer for sale or distribution
finished smokeless tobacco products
past their expiration date, except to
return expired products to the
manufacturer, (3) do not conceal, alter
or remove the expiration date or storage
conditions on the package label, and (4)
do not sell or distribute or offer for sale
or distribution finished smokeless
tobacco products that are open or have
broken seals (proposed § 1132.1(c)).
FDA is proposing this exception for
tobacco retailers and distributors
because they are not in a position to
know or to confirm by testing whether
the smokeless tobacco products they are
selling or distributing or offering for sale
or distribution comply with the
proposed NNN level.
FDA is also proposing, under these
authorities, to require that the labels of
finished smokeless tobacco products
contain a manufacturing code,
expiration date, and, if applicable,
storage conditions for the finished
smokeless tobacco product (proposed
§ 1132.30). The labeling requirement for
storage conditions is also consistent
with FDA’s authority under section
907(a)(4)(C), which provides that a
product standard shall, where
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appropriate, require the use and
prescribe the format and content of
labeling for the proper use of the
tobacco product. These label
requirements would enable FDA to
determine whether a product on store
shelves purports to comply with the
standard, link the product to its
manufacturing history so that
compliance with the standard can be
verified, provide traceability of the
product in the event of a nonconforming
product investigation and corrective
action, and ensure that the product is
handled and stored under appropriate
conditions, in accordance with the
standard. In addition, the proposed
manufacturing code would serve as a
common identifier that will provide a
history of the manufacturing,
processing, packaging, labeling, holding,
and initial distribution of the tobacco
product from records maintained by the
smokeless tobacco product
manufacturer. The expiration date
would also inform retailers that the
manufacturer has not demonstrated
compliance with the standard beyond
the date after which the product should
not be sold to consumers.
Manufacturers would be responsible
for ensuring that finished smokeless
tobacco products contain labels with a
manufacturing code, expiration date,
and, if applicable, storage conditions
prior to sale and commercial
distribution. In addition, retailers and
distributors would be responsible for
not selling or distributing or offering for
sale or distribution finished smokeless
tobacco products that lack the required
labels, not concealing, altering, or
removing the expiration date or storage
conditions on the package label, not
selling or distributing or offering for sale
or distribution finished smokeless
tobacco products after their expiration
date (except to return expired product to
the manufacturer), not selling or
distributing or offering for sale or
distribution finished tobacco products
that are open or have broken seals, and,
if applicable, storing finished smokeless
tobacco product in accordance with the
package label.
Because these requirements would
assist FDA in enforcing the standard
and would ensure that manufacturers
and retailers are selling product that
complies with the standard, the Agency
has found all of these requirements to be
appropriate for the protection of the
public health consistent with sections
907(a)(4)(B)(v) and 906(d).
4. Testing Requirements
FDA’s proposed rule contains
provisions regarding testing
requirements under sections
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907(a)(4)(B) and 907(a)(4)(A)(iii) of the
FD&C Act to ensure that finished
smokeless tobacco products conform to
the requirements of the product
standard before they are distributed to
consumers and remain in conformance
until their expiration date. Section
907(a)(4)(B)(ii) provides that a product
standard must, where appropriate for
the protection of public health, include
‘‘provisions for the testing (on a sample
basis or, if necessary, on an individual
basis) of the tobacco product.’’ In
addition, section 907(a)(4)(B)(iv)
provides that, where appropriate for the
protection of public health, a product
standard must include provisions
requiring that the results of the tests of
the tobacco product required under
section 907(a)(4)(B)(ii) show that the
product is in conformity with the
portions of the standard for which the
tests were required.
Consistent with these statutory
provisions, proposed §§ 1132.12,
1132.14, 1132.16, and 1132.18 would
establish product testing and sampling
plan requirements. Proposed § 1132.12
would require two types of testing for
smokeless tobacco products—stability
testing and batch testing. Proposed
§ 1132.12(a) would require testing to
assess the stability of the NNN level in
finished smokeless tobacco products
and to establish and verify the product’s
expiration date and storage conditions
(either room temperature or
refrigeration). Proposed § 1132.12(b)
would require manufacturers to conduct
testing on each batch of finished
smokeless tobacco product to determine
whether the products conform to the
proposed NNN level. Proposed
§ 1132.12(c) would require the tobacco
product manufacturer to document all
testing. Proposed §§ 1132.14 and
1132.16 would establish the standard
and alternative test methods, while
§ 1132.18 would establish the sampling
requirements for all testing.
Section 907(a)(4)(A)(iii) states that
product standards must include
provisions that are appropriate for the
protection of the public health,
including provisions, where
appropriate, relating to any requirement
under subparagraph 907(a)(4)(B). As
discussed, FDA is proposing specific
testing requirements in §§ 1132.12,
1132.14, 1132.16, and 1132.18. To
support these proposed requirements,
proposed § 1132.22(b) would require
that if the mean of the representative
samples from any batch of a finished
smokeless tobacco product is
determined to be out of conformance
with the requirements of § 1132.10, or a
finished smokeless tobacco product’s
expiration date must be shortened due
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to the results of annual real-time
stability testing, or if FDA notifies a
tobacco product manufacturer that a
distributed finished smokeless tobacco
product does not conform to the
requirements of part 1132, the
manufacturer would have to conduct an
investigation to determine the scope of
the nonconformity and locations to
which nonconforming products have
been distributed. This proposed
requirement would ensure that any
reports of nonconforming products,
whether as a result of manufacturer
testing or otherwise, are examined and
investigated and that appropriate
measures are taken to ensure that
additional nonconforming product
batches are not distributed to consumers
and to prevent future nonconformity.
FDA finds that such provisions are
appropriate for the protection of the
public health and relate to requirements
under section 907(a)(4)(B) because they
will help to ensure that the finished
smokeless tobacco products are properly
tested and conform to the requirements
of the proposed product standard.
5. Recordkeeping
Section 909 of the FD&C Act
authorizes FDA to require tobacco
product manufacturers to establish and
maintain records, make reports, and
provide such information as the Agency
may by regulation reasonably require to
assure that a tobacco product is not
adulterated or misbranded and to
otherwise protect public health. In
addition, section 701(a) of the FD&C Act
authorizes FDA to promulgate
regulations for the efficient enforcement
of the FD&C Act. The recordkeeping
requirements would help FDA with the
efficient enforcement of the product
standard issued under the FD&C Act.
FDA is proposing to require that
manufacturers of smokeless tobacco
products maintain records regarding the
product testing (i.e., stability and batch
testing), including a full report of the
source data and results; all notifications
of an alternative test method and source
data for alternative test method
validation; all sampling plans and
reports; documentation that the persons
performing sampling have sufficient
education, training, and experience to
accomplish the assigned functions; all
identification, investigation,
segregation, and disposition procedures;
and all nonconforming product
investigations and rework (i.e., the
processing of nonconforming finished
smokeless tobacco products to meet the
requirements of part 1132).
FDA is also proposing to require
copies of all records be retained for a
period of not less than 4 years from the
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date of distribution of the finished
smokeless tobacco product that is the
subject of the record, except that certain
records relating to alternative test
methods would be required to be
retained for a period of not less than 4
years after the last date the method is
used. Retention of these records would
help ensure that finished smokeless
tobacco products are in conformance
with the proposed standard and are not
adulterated or misbranded.
C. Additional Considerations and
Requests for Comment
1. Section 907 of the FD&C Act
FDA is required by section 907 of the
FD&C Act to consider the following
information submitted in connection
with a proposed product standard:
• For a proposed product standard to
require the reduction or elimination of
an additive, constituent, or other
component of a tobacco product because
FDA has found that the additive,
constituent, or other component is or
may be harmful, scientific evidence
submitted that demonstrates that the
proposed standard will not reduce or
eliminate the risk of illness or injury
(section 907(a)(3)(B)(ii) of the FD&C
Act).
• Information submitted regarding the
technical achievability of compliance
with the standard (section 907(b)(1) of
the FD&C Act).
• All other information submitted,
including information concerning the
countervailing effects of the tobacco
product standard on the health of
adolescent tobacco users, adult tobacco
users, or nontobacco users, such as the
creation of a significant demand for
contraband or other tobacco products
that do not meet the requirements of
Chapter IX of the FD&C Act and the
significance of such demand (section
907(b)(2) of the FD&C Act).
As required by section 907(c)(2) of the
FD&C Act, FDA invites interested
persons to submit a draft or proposed
tobacco product standard for the
Agency’s consideration (section
907(c)(2)(B)) and information regarding
structuring the standard so as not to
advantage foreign-grown tobacco over
domestically grown tobacco (section
907(c)(2)(C)). In addition, FDA invites
the Secretary of Agriculture to provide
any information or analysis which the
Secretary of Agriculture believes is
relevant to the proposed tobacco
product standard (section 907(c)(2)(D) of
the FD&C Act).
FDA is requesting the documents and
information described in this section
with this proposed rule. Such
documents and information may be
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submitted in accordance with the
‘‘Instructions’’ included in the
preliminary information section of this
document.
Section 907(d)(5) of the FD&C Act
allows the Agency to refer a proposed
regulation for the establishment of a
tobacco product standard to the Tobacco
Products Scientific Advisory Committee
(TPSAC) at the Agency’s own initiative
or in response to a request for good
cause made before the expiration of the
comment period. If FDA opts to refer
this proposed regulation to TPSAC, the
Agency will publish a notice in the
Federal Register announcing the TPSAC
meeting to discuss this proposal.
2. Pathways to Market
To legally market a new tobacco
product in the United States, a tobacco
product manufacturer must receive
authorization from FDA permitting the
marketing of the new tobacco product
under one of three pathways for legally
marketing a new tobacco product: (1)
The manufacturer obtains an order
under section 910(c)(1)(A)(i) of the
FD&C Act (order after review of a
premarket tobacco application under
section 910(b)); (2) the manufacturer
obtains an order finding the new
product substantially equivalent to a
predicate tobacco product and in
compliance with the requirements of the
FD&C Act under section 910(a)(2)(A)(i)
(order after review of a substantial
equivalence (SE) report submitted under
section 905(j) of the FD&C Act); or (3)
the manufacturer makes a request under
21 CFR 1107.1, obtains an exemption
from the requirements related to
substantial equivalence (section
905(j)(3)(A)), and at least 90 days before
commercially marketing the product,
submits a report under section 905(j)
including the information required in
section 905(j)(1)(A)(ii) and (j)(1)(B).
A smokeless tobacco product that has
been modified to comply with the
product standard would be a ‘‘new
tobacco product’’ and subject to
premarket review. FDA believes that
changes made solely to bring a
smokeless tobacco product in
compliance with the proposed rule
would be appropriate for an SE
submission. We believe it is possible for
manufacturers to modify their product
so that it is both in compliance with the
proposed product standard and
substantially equivalent to an
appropriate predicate product (i.e.,
products that are grandfathered or SE).
FDA believes that manufacturers
would likely choose to comply with the
proposed standard in a manner that
makes the modified products eligible for
the SE pathway. For products that are
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eligible for an SE report, FDA is
considering whether a change to the
level of NNN in smokeless tobacco
products could be reviewed with the
submission of an SE report containing a
reduced, specific set of information that
focuses on the changes to the smokeless
tobacco where the SE report
demonstrates that the only
modifications made to the new product
were made to comply with the NNN
product standard and do not present
different questions of public health (e.g.,
significant increase in another harmful
or potentially harmful constituent
(HPHC)). As there may be multiple
modifications needed to comply with
the product standard, FDA requests
comments as to the type of
modifications that may allow a reduced
amount of information to proceed
through the SE pathway, and what types
of brief, specific supporting information
submitted as part of a substantial
equivalence application could
demonstrate that modifications made to
comply with this product standard do
not cause the new product to raise
different questions of public health.
III. Scope of Proposed Standard
Scientific evidence documents that
smokeless tobacco products cause
certain types of cancer (Refs. 1, 2, 3, 4).
As discussed in section IV of this
document, NNN is a potent carcinogenic
agent found in smokeless tobacco
products and is a major contributor to
the elevated cancer risks associated with
smokeless tobacco use (Refs. 7, 8, 1, 2).
FDA is issuing this proposed standard
to address the harm to smokeless
tobacco users caused by NNN by
establishing a limit for NNN in finished
smokeless tobacco products (see
proposed § 1132.10), thereby reducing
exposure to this harmful toxicant. NNN
levels vary substantially across
subcategories of smokeless tobacco
products (e.g., moist snuff, chewing
tobacco, dry snuff) and within product
subcategories (e.g., moist snuff) (Ref. 5).
Geographical comparisons show that
oral cancer rates among smokeless
tobacco users are higher in areas where
smokeless tobacco products have higher
NNN levels (Refs. 6, 100). Given this
geographic variation and the
toxicological evidence described in the
preamble of this rule, we expect that
lowering the level of NNN in smokeless
tobacco products in the United States
will lower the rate of oral cancers
among smokeless tobacco users. FDA
concludes that establishing a limit for
NNN in finished smokeless tobacco
products is appropriate for the
protection of the public health (see
section V of this document).
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8009
A. Smokeless Tobacco Products
The term ‘‘smokeless tobacco’’ covers
a wide range of tobacco products that
are used orally or nasally without
combustion (Ref. 1). Smokeless tobacco
is defined in section 900(18) of the
FD&C Act as ‘‘any tobacco product that
consists of cut, ground, powdered, or
leaf tobacco and that is intended to be
placed in the oral or nasal cavity.’’ This
includes moist snuff, snus, dry snuff,
chewing tobacco, and some
dissolvables. Some dissolvable tobacco
products do not meet the statutory
definition of ‘‘smokeless tobacco
product’’ because they do not contain
cut, ground, powdered, or leaf tobacco;
instead, these products contain nicotine
extracted from tobacco. Dissolvable
products that do not meet the statutory
definition of ‘‘smokeless tobacco
product’’ are not covered by this
proposed rule.
Moist snuff is the most popular type
of smokeless tobacco in the United
States (Refs. 4, 131). It is typically made
of fire-cured or air-cured tobacco that
has been finely ground or shredded and
fermented (Ref. 4). Moist snuff may
contain up to 60 percent moisture and
it is often flavored (e.g., wintergreen)
(Refs. 4, 10). It is sold as loose tobacco
or in sachets or small pouches (Ref. 1).
When loose moist snuff is used, a small
amount (e.g., a pinch or dip) is placed
and held between the lip or cheek and
gum and typically is held in the mouth
for at least 30 minutes (Refs. 1, 5).
Excess saliva may be spit out or
swallowed (Ref. 1). When pouched
moist snuff is used, a sachet or small
pouch containing the tobacco is placed
and held between the lip or cheek and
gum but it does not require spitting (Ref.
9).
Snus is a type of moist snuff and it
can have different characteristics
depending on where it is manufactured.
Swedish snus products generally have
much lower levels of tobacco-specific
nitrosamines (TSNAs) than smokeless
tobacco products found in the United
States (Refs. 5, 6, 10), and, therefore,
they were of particular interest in the
development of this proposed rule.
Swedish snus is commonly used in
Sweden but it is relatively new to the
U.S. market (Refs. 4, 11). It typically
consists of low-nitrosamine tobacco that
has been air-cured, moistened, ground,
and heat treated (Refs. 4, 12, 11).
Swedish snus may contain up to 50
percent moisture and some flavoring but
no added sugars (Refs. 13, 14, 11).
Swedish snus is sold as loose tobacco or
in sachets (Refs. 4, 12, 11). It is placed
between the cheek and gum and does
not require spitting (Refs. 1, 15).
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In Sweden, all snus manufacturers
must adhere to the requirements of the
Swedish Food Act. In addition, a
smokeless tobacco manufacturer
developed the GothiaTek voluntary
standard, which establishes limits for
the tobacco (e.g., low-nitrosamine raw
tobacco that has been air-cured or suncured) and other ingredients as well as
the manufacturing process (Refs. 11, 4).
The current GothiaTek standard for
NNN and 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone (NNK) (combined)
in snus is 0.95 mg/g wet weight 2
tobacco, which would be about 2 mg/g
(combined NNN and NNK) dry weight
tobacco (Refs. 13, 16). Swedish snus that
is made using the GothiaTek standard
tends to have lower levels of toxicants,
including NNN, than other smokeless
tobacco products in other countries (Ref.
4).
Swedish snus is usually refrigerated
by retailers to maintain its quality and
taste but refrigeration is not generally
required to maintain stability because
modern Swedish snus production
techniques achieve very low levels of
microbial activity and yield no new
nitrosamine formation even when held
at room temperature (Ref. 11). One of
the methods used to limit microbial
activity is pasteurization. In this
process, the leaf tobacco is ground and
subjected to heat treatment. The heating
is achieved by combining the tobacco
with water and salt, placed in closed
process blenders, and using steam to
achieve temperatures up to 80 to 100 °C
for several hours (Ref. 11).
In recent years, some U.S. tobacco
manufacturers began introducing snus
products (e.g., Marlboro Snus and
Camel Snus) in the United States (Ref.
17). Some of the early marketing of
these tobacco products emphasized the
Swedish origins of snus but there is
limited data available on whether the
chemical composition or manufacturing
processes of these products are
equivalent to Swedish snus (Refs. 4, 18,
19). Studies indicate that early versions
of these snus products would not
comply with the current GothiaTek
standard for NNN and NNK (i.e., 0.95
mg/g per wet weight combined) (Ref. 13).
From the limited information available,
snus manufactured in the United States
appears to consist of tobacco that has
been air-cured or sun-cured and is
pasteurized or heat treated (Refs. 20,
21). It may contain up to 34 percent
moisture and may contain some
flavoring, flavoring strip, and/or
2 The term ‘‘wet weight’’ refers to the weight of
tobacco as used by the consumer, while the term
‘‘dry weight’’ refers to the weight of tobacco after
the removal of water.
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sweeteners (Ref. 4, 56). It is generally
sold portioned in sachets or small
pouches (Ref. 4).
Unlike the relatively higher moisture
content of moist snuff, dry snuff usually
has a moisture content of less than 10
percent (Ref. 1). Dry snuff is a powdered
tobacco product that may be used orally
or nasally, although nasal use is rare in
the United States (Ref. 4). Typically dry
snuff is made with tobacco that has been
fire-cured, fermented, and finely ground
or pulverized into a powder (Refs. 1, 4).
A pinch or dip of dry snuff is typically
held between the cheek and gum (Ref.
1).
Chewing tobacco is sold as loose leaf,
plug, or twist. It is typically fire-cured
or air-cured tobacco that has been
fermented or aged (Refs. 4, 1). It may be
flavored and sweetened and then
processed into a plug, twist, or loose
leaf (Refs. 4, 1). Chewing tobacco may
be chewed or held in the mouth (i.e.,
dipped) (Ref. 5).
Dissolvable tobacco products that are
smokeless tobacco products are
generally made of finely ground tobacco
and sold as small lozenges, sticks
(toothpick), or strips (Refs. 4, 5). Such
dissolvable tobacco products may be
flavored and may have a moisture
content ranging from 1 to 20 percent,
depending on the product (Refs. 9, 22,
56). As the name suggests, a dissolvable
tobacco product is placed in the mouth
until it dissolves.
B. Current Prevalence and Initiation
Rates
In the United States, smokeless
tobacco products are predominately
used by men and high school age boys.
According to the 2014 National Survey
on Drug Use and Health, an estimated
8.7 million (3.3 percent) Americans
aged 12 and over were current (any use
in the past month) smokeless tobacco
users (chewing tobacco or snuff) in
2014, which is generally similar to the
percentage of smokeless tobacco users
estimated by this study for most years
from 2002 to 2013 (Ref. 23). An
estimated 6.4 percent of males over the
age of 12 were current smokeless
tobacco users, while only 0.3 percent of
females were current users (Ref. 24 at
tables 2.9B, 2.10B). Among adults, the
highest prevalence of current use of
smokeless tobacco was observed among
young adults aged 18 to 25 at 5.6
percent (Ref. 24 at 18). According to the
National Youth Tobacco Survey, in
2015, there were an estimated 1.1
million middle and high school
students that reported current (past 30
day) use of chewing tobacco, snuff or
dip, snus, or dissolvable tobacco
products (Ref. 25). The overall level of
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current smokeless tobacco product
usage was 6 percent among high school
students, and 1.8 percent among middle
school students (Ref. 25). Among youth,
the prevalence of smokeless tobacco use
varies by sex and race. In 2015, 10
percent of male high school students
reported current use of smokeless
tobacco, including snus and
dissolvables, compared with 1.8 percent
of female high school students (Ref. 25).
Among high school students, the
prevalence of current use of smokeless
tobacco, including snus and
dissolvables, was highest among nonHispanic White students (7.8 percent),
followed by Hispanic students (4.8
percent), and non-Hispanic Black
students (1.9 percent) (Ref. 25).
An estimated 1.0 million Americans
aged 12 or older used smokeless tobacco
for the first time in 2014 (Ref. 24 at table
4.5B). Nearly 75 percent of these new
initiates were male and about 42 percent
were under age 18 when they first used
a smokeless tobacco product (Ref. 24 at
tables 4.6B, 4.9A). The average age at
first use of smokeless tobacco among
recent initiates in 2014 was 19.0 years,
which was similar to the 2013 estimate
(Refs. 26, 24 at table 4.13B).
IV. Rationale for Developing a
Standard for NNN
A. Smokeless Tobacco is Carcinogenic
The scientific evidence demonstrates
that smokeless tobacco products cause
certain types of cancer, and that cancer
rates are higher in regions of the world
where smokeless tobacco products have
higher levels of NNN. In 1986, the
Surgeon General of the United States
released a report finding that ‘‘users of
smokeless tobacco products face a
strongly increased risk of oral cancer’’
(Ref. 27). In 2007, IARC classified
smokeless tobacco as carcinogenic to
humans (Group 1), concluding that
sufficient evidence in humans
demonstrate that smokeless tobacco
causes cancers of the oral cavity and
pancreas (Ref. 1). IARC confirmed these
findings of the carcinogenicity of
smokeless tobacco in a 2012 review,
concluding that there is sufficient
evidence in both humans and
experimental animal studies that
smokeless tobacco causes oral,
esophageal, and pancreatic cancer (Ref.
2). The Scientific Committee on
Emerging and Newly Identified Health
Risks (Ref. 3) was tasked by the
European Commission to evaluate the
cancer risks of smokeless tobacco
products, with particular attention to
moist snuff, which, in the European
Union is available only in Sweden, in
the form of snus. It concluded in its
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2008 review that smokeless tobacco
products cause esophageal and
pancreatic cancer in humans and that
studies in the United States demonstrate
an increased risk of oral cancer among
smokeless tobacco users, however, the
evidence for ‘‘users of Swedish moist
snuff (snus) is less clear’’ (Ref. 3). More
recently, the National Cancer Institute
(NCI), National Institutes of Health, in
coordination with the Centers for
Disease Control and Prevention (CDC)
8011
published a report on smokeless tobacco
use and health effects in 2014,
concluding that smokeless tobacco use
causes oral, esophageal, and pancreatic
cancer (Ref. 4).
TABLE 1—CONCLUSIONS OF AUTHORITATIVE REVIEWS ON SMOKELESS TOBACCO AND CANCER RISK
Authoritative body
Year
Conclusions
Surgeon General of the United
States.
International Agency for Research on
Cancer (IARC).
Scientific Committee on Emerging
and Newly Identified Health Risks
(SCENIHR).
1986
International Agency for Research on
Cancer (IARC).
National Cancer Institute (NCI) .........
2012
‘‘In summary, users of smokeless tobacco products face a strongly increased risk of oral cancer, particularly for the tissues that come in contact with the tobacco.’’
‘‘There is sufficient evidence in humans for the carcinogenicity of smokeless tobacco. Smokeless tobacco causes cancers of the oral cavity and pancreas.’’
‘‘STP [smokeless tobacco products] are carcinogenic to humans and the pancreas has been
identified as a main target organ. All STP cause localised oral lesions and a high risk for
development of oral cancer has been shown for various STP but the evidence for oral cancer in users of Swedish moist snuff (snus) is less clear.’’
‘‘There is sufficient evidence in humans for the carcinogenicity of smokeless tobacco. Smokeless tobacco causes cancers of the oral cavity, oesophagus and pancreas.’’
‘‘There is sufficient evidence that ST [smokeless tobacco] products cause addiction,
precancerous oral lesions, and cancer of the oral cavity, esophagus, and pancreas, and adverse reproductive and developmental effects including stillbirth, preterm birth, and low birth
weight.’’
2007
2008
2014
B. NNN in Smokeless Tobacco Products
is Carcinogenic
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Smokeless tobacco products contain
thousands of chemical constituents,
including carcinogens such as TSNAs
(Refs. 2, 1, 4). TSNAs are formed from
nitrosation, a chemical reaction between
tobacco alkaloids (nicotine, nornicotine,
anatabine, and anabasine) and
nitrosating agents such as nitrite (Refs.
28, 2). Because TSNAs are formed from
tobacco alkaloids, they are only found
in tobacco products (Ref. 28).
In smokeless tobacco, TSNAs are
present at a level capable of causing
cancer (Ref. 4). Of the five TSNAs
identified in tobacco products, NNN
and 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone (NNK) have been
classified by IARC as carcinogenic to
humans (Group 1) (Refs. 2, 4).3
The relatively high level of these
carcinogens has led the World Health
Organization (WHO) to call for limits on
these constituents in tobacco products
(Ref. 78). Tobacco science researchers
have also called for the reduction of
TSNAs in smokeless tobacco products
due to their potential impact on the
increased cancer risk associated with
smokeless tobacco use (Refs. 175, 176).
1. Evidence for NNN Carcinogenicity in
Animals
There is sufficient evidence to
indicate NNN may act as both a local
and systemic carcinogen in
experimental animals. Studies have
shown that NNN given by various routes
3 Section IV.D.3 explains why FDA is not
proposing a product standard for NNK levels in
smokeless tobacco at this time.
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of administration consistently causes
oral and esophageal tumors in rats, as
well as nasal cavity and tracheal tumors
across multiple species, with noted
route- and species-specific differences
(Refs. 7, 178, 148, 59, 94, 149 through
160). Rats are more likely to develop
tumors in the esophagus, oral and nasal
cavity following oral or subcutaneous
exposure to NNN (Refs. 7, 59, 94, 95,
148, 149) whereas mice develop tumors
in lung, forestomach, and to a limited
extent liver (Refs. 155, 156, 160). In
hamsters, tracheal tumors and nasal
cavity tumors are observed following
oral or intraperitoneal exposure to NNN
(Refs. 59, 151), with tracheal tumors
also observed following subcutaneous
exposure (Ref. 152). Studies in
experimental animals also demonstrate
that NNN can induce tumor formation
in a dose-dependent manner. For
example, in rats, a dose-dependent
formation of nasal cavity tumors has
been observed following subcutaneous
or oral exposure (via gastric instillation)
to NNN (Refs. 149, 161). In hamsters,
NNN stimulates tumors of the nasal
cavity, trachea and liver in a dosedependent manner following
subcutaneous exposure (Ref. 151).
Although a dose-dependent
relationship between oral and
esophageal tumor formation following
exposure to NNN has not been
extensively studied, chronic oral
exposure to NNN via drinking water
clearly identifies oral cavity and
esophageal tissues as the major targets
of tumorigenesis in animals (Refs. 7, 95).
As indicated previously, sites of tumor
formation following exposure to NNN
are not limited to oral and esophageal
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tissues. Studies in experimental animals
demonstrate oral exposure to NNN
stimulates tumor formation in other
tissues, such as nasal cavity, stomach,
lung and liver (Refs. 151, 155, 156, 161,
178, 179). However, the number of
tumors observed in oral and esophageal
tissues are often greater than the number
of tumors observed in other, non-target
tissues. For example, a greater number
of rats were reported to develop tumors
in the esophagus compared with the
lung following exposure to NNN in
liquid diet (Ref. 94). Another study
reported a similar trend, with
esophageal and oral tumors observed in
35 and 18 percent of rats exposed to
NNN via oral gavage, respectively,
whereas only 5 percent of exposed
animals developed lung tumors (Ref.
178). A more recent study by Balbo et
al. (Ref. 7) found that 100 percent of rats
treated orally with NNN in their
drinking water developed malignant
oral tumors. A high incidence of
esophageal tumors has been consistently
observed in rats following oral exposure
to NNN across studies, with 83 percent
of animals developing esophageal
tumors following exposure via liquid
diet (Ref. 94) and 60 to 100 percent of
animals developing esophageal tumors
following exposure via drinking water
(Refs. 148, 95, 59, 7).
The high incidence of tumor
formation in esophageal and oral tissue
observed in experimental animal studies
is consistent with what is known
regarding the metabolism of NNN and
subsequent DNA adduct formation in
target tissues. NNN is a genotoxic
carcinogen, it reacts with DNA and is
assumed to exhibit proportional
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responses at low doses (Refs. 168, 169).
The general understanding of the
mechanism of action (MOA) of NNNinduced carcinogenicity centers around
its metabolic activation. The metabolic
activation of NNN leads to the formation
of DNA and hemoglobin adducts and
subsequent mutagenicity, ultimately
resulting in cancer. NNN can be
metabolized by 2′-hydroxylation and 5′hydroxylation, with the 2′hydroxylation the more predominant
metabolic pathway (Ref. 8). The noted
DNA adducts formed from NNN are
POB–DNA via the 2′-hydroxylation
pathway (Refs. 172, 173, 177) and pypy-dI via the 5′-hydroxylation pathway
(Ref. 169). NNN has a chiral center at
the 2′-position and exists in 2
enantiomeric forms, (R)–NNN and (S)–
NNN, with (S)–NNN being the
predominant enantiomer in smokeless
tobacco products (Refs. 180, 181).
The MOA for NNN-induced
carcinogenicity is supported by the
pattern of mutagenesis and DNA adduct
formation in target tissues following oral
exposure to NNN in experimental
animals. For example, NNN was found
to be mutagenic in tongue, oral and
esophageal tissue in mice following oral
exposure via drinking water (Ref. 174).
Both POB–DNA and py-py-dI adducts
have been detected in the oral cavity,
esophageal mucosa, nasal cavity, liver
and lung of rats following exposure to
NNN via drinking water (Refs. 169
through 173). Additionally, dosedependent formation of POB–DNA
adducts has been observed in oral,
esophageal and nasal mucosa following
oral exposure to NNN (Ref. 170), as has
py-py-dI (Ref. 169). A greater number of
DNA adduct formation has been also
been observed in oral and esophageal
tissues compared with other sites,
consistent with previous findings of
increased tumor formation in oral and
esophageal tissues compared with other
sites (Refs. 94, 178). For example, POBadduct formation was greater in oral
cavity and esophageal mucosa
compared with lung or liver in rats
following oral exposure to (S)-NNN via
drinking water (Refs. 171, 172). These
findings are consistent with previous
reports of increased oral and esophageal
tumor formation as compared with other
tissues (Refs. 94, 178) and the reported
high incidence of oral and esophageal
tumors following oral exposure to NNN
in rats (Refs. 7, 95).
Recent evidence has demonstrated
target organ specificity for the
carcinogenic effects of NNN and NNK in
animals and in humans. As previously
discussed, NNN’s carcinogenic effects
have been documented in the
esophagus, nasal, and oral cavities when
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administered orally to animals (Refs. 7,
59, 95, 148), which provides some
degree of concordance with effects
observed at these sites in
epidemiological studies (Refs. 77, 96). In
contrast, NNK is known for being a
powerful systemic lung carcinogen.
NNK causes lung tumors in animals,
including mice, rats, and hamsters,
independent of the route of
administration (Refs. 8, 149, 162
through 167). Even when animals are
given NNK orally, a dose-dependent
formation of lung tumors is observed
(Refs. 164, 165, 166). Indeed, a recent
study found 100 percent of animals
receiving NNK via oral exposure
developed lung tumors (Ref. 167).
However, no oral cavity or esophageal
tumors have been reported in animals
exposed only to NNK (Ref. 8).
2. Evidence for NNN Carcinogenicity in
Humans
Although the data on NNN exposure
in humans is more limited, two recent
epidemiological studies have found
strong associations between NNN and
cancer risk among cigarette smokers,
providing evidence that increased
exposure to NNN through use of certain
tobacco products is associated with
greater risk of head, neck, and
esophageal cancer in tobacco users. In
one nested case-control study among
Chinese men, urinary levels of NNN in
smokers were significantly associated
with increased risk of developing
esophageal cancer, but not lung cancer,
after controlling urinary total NNAL
(used to measure NNK exposure),
smoking intensity and duration, alcohol
consumption, and urinary cotinine
(nicotine metabolite used to measure
nicotine exposure) (Ref. 77). In the same
cohort, total urinary NNAL was
independently and significantly
associated with increased risk of
developing lung cancer (Ref. 183),
whereas no association was observed
between urinary total NNAL and
esophageal cancer risk (Ref 77). In a
second case-control study, mean levels
of NNN were significantly higher in
cases diagnosed with head and neck
squamous cell carcinoma compared to
matched controls, although no
adjustment was made for potential
confounding factors (Ref. 96). Although
these studies were conducted among
smokers, they support the significant
role of NNN in cancer development in
humans and are highly relevant to
smokeless tobacco users, who have
comparable levels of exposure to NNN
and NNK as those of cigarette users
(Refs. 97, 72, 98, 99). Moreover, these
epidemiological findings support the
target organ specificity and cancer risk
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associated with exposure to NNN (oral
and esophageal) versus NNK (lung) that
are observed in experimental animals
(see section IV.B.1).
3. Geographic Differences in Cancer
Risks From Smokeless Tobacco Use
Although there is some heterogeneity
among particular study estimates,
research on the association between
smokeless tobacco use and oral cancer
risk generally has found significant
differences in risk by geographic region.
For the United States, Boffetta et al.
analyzed nine oral cancer risk estimates
from seven independent studies that
either adjusted for smoking or were
restricted to never smokers and found a
summary relative risk for smokeless
tobacco use of 2.6 (Ref. 100). Lee and
Hamling published a separate analysis
that generated an overall relative risk
estimate of 2.16 from all available U.S.
studies (Ref. 114). The authors also
generated estimates of never smoker oral
cancer relative risks (a relative risk of
3.33) for 5 studies and smoking-adjusted
oral cancer relative risks (a relative risk
of 1.65) for 12 studies for U.S. smokeless
tobacco users. Toombak, a smokeless
tobacco product commonly used in
Sudan, has been found to have a relative
risk for oral cancer of 3.9 (Refs. 104, 4),
while in India and Pakistan use of
smokeless tobacco products, including
pattiwala, naswar, khaini, and zarda,
was associated with relative risks for
oral cancer as high as 14 (Ref. 1 at table
71). In Scandinavia, increased oral
cancer risks were observed in some but
not all studies (Refs. 92, 188, 189, 191,
192).
The geographic variations in oral
cancer risks are believed to be due to
differences in product toxicant content
(Ref. 100). TSNA concentrations in
smokeless tobacco products vary by
product and region; NNN levels are
generally lowest in snus manufactured
in Sweden, while NNN levels in
smokeless tobacco products sold in the
United States are typically higher (Refs.
11, 13, 5, 10). Many smokeless tobacco
products sold elsewhere in the world,
including in India and Sudan, contain
even higher levels of NNN and other
carcinogens than those in the United
States (Refs. 206, 105). These analyses,
in addition to the toxicological evidence
demonstrating that NNN is a potent oral
cavity and esophageal carcinogen,
provide strong support for a relationship
between smokeless tobacco use, NNN
levels in these products, and oral cancer
risk by geographic region. Thus, FDA
believes that reducing NNN levels in
smokeless tobacco products would
reduce cancer risk.
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2. Factors That Influence NNN Levels
1. Formation of NNN in Smokeless
Tobacco Products
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C. NNN in Smokeless Tobacco Products
NNN levels in tobacco can vary
significantly from year to year, intrayear, and farm-to-farm (Ref. 34).
Although tobacco plants inherently
produce a small amount of NNN (Refs.
35, 1), a wide variety of factors can
affect the final levels of NNN found in
the finished tobacco product (Ref. 1).
These factors, which can either increase
or decrease NNN levels in smokeless
tobacco products, include the tobacco
type (e.g., dark air-cured tobacco, Bright
leaf tobacco, Burley tobacco), growing
conditions (e.g., geographic region,
climate, rainfall), curing techniques
(e.g., fire, flue, air, sun), production
process (e.g., additives), and storage
conditions (e.g., temperature, humidity,
duration) (Ref. 1). As discussed in
section IV.E, because there are many
factors that can influence the NNN level
in smokeless tobacco products, there
also are a number of options available
to manufacturers to reduce and control
NNN levels in order to meet the
requirements of this proposed standard.
NNN is formed either by the
nitrosation of nicotine with the loss of
a methyl group or by nitrosation of
nornicotine, primarily during the curing
of tobacco (Ref. 29). Nicotine is a
tertiary amine while nornicotine is a
secondary amine; the rate of nitrosation
of tertiary amines is slow compared to
the rate of nitrosation of secondary
amines (Ref. 30). As the concentration of
nicotine in smokeless tobacco products
is typically three orders of magnitude
larger than the TSNA concentration,
NNN formation does not have a
significant impact on product nicotine
levels (Refs. 5, 10).
The primary nitrosating agent is
nitrite (Ref. 31). Reduction of nitrate by
bacteria such as halotolerant
micrococci, Coryneforms, and
halophilic rods during the fermentation
process is the primary source of nitrite
in smokeless tobacco products (Ref. 34).
Nitrogen-rich fertilizer is also a source
of nitrate and, upon reduction, nitrite
(Ref. 41). Higher NNN levels are found
in tobacco crops fertilized with
nitrogen-rich fertilizers compared to
fertilizers with lower nitrogen content
(Refs. 42, 34). Tobacco and smokeless
tobacco products with low nitrite
concentrations have low levels of NNN,
while products high in nitrite contain
higher concentrations of NNN (Refs. 32,
31).
There is limited evidence to support
that an appreciable amount of NNN is
formed from nicotine or its metabolites
in humans (Refs. 193, 194). The reaction
of dietary precursors with nitrosating
agents supplied by the diet can result in
the endogenous formation of Nnitrosamines in humans (Refs. 195, 196,
197). The acidic environment in the
stomach creates favorable conditions for
nitrosation to occur (Ref. 198) and
nitrosation of nornicotine has been
observed in vitro under simulated
gastric conditions, whereas nitrosation
of nicotine has not been observed (Ref.
199). To date, there is not sufficient data
in humans to indicate any significant in
vivo NNN synthesis.
NNK is primarily formed through
nitrosation of nicotine during the later
stages of tobacco processing (i.e., curing
and fermentation) (Ref. 33). Similar to
NNN, the primary nitrosating agent is
nitrite and products with low nitrite
concentrations have low levels of NNK
while products with high nitrite
concentrations have high levels of NNK
(Refs. 32, 31).
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a. Tobacco Type
Studies have shown differences in
NNN levels prior to curing and
processing among different varieties of
tobacco. Higher NNN concentrations
have been found in Burley and dark
tobacco compared to flue-cured Bright
leaf tobacco (Ref. 36). Burley tobacco
also contains more NNN compared to
Virginia and Oriental types, whether
grown in the same or different
geographical locations (Ref. 37).
The use of selectively bred ‘‘low
converter’’ tobacco seed has been shown
to result in lower nornicotine (precursor
to NNN) levels in tobacco (Refs. 38, 39,
40). The amount of NNN in a tobacco
variety before curing or processing is
dependent on the amount of its
precursor nornicotine, which in turn is
dependent on the amount of its
precursor nicotine (Ref. 38). Nornicotine
is normally present at very low levels
compared to nicotine, but tobacco
plants, through a process called
‘‘conversion,’’ can convert some of their
nicotine to nornicotine (Ref. 39). Low
converter seeds come from plants
which, through selective breeding and
genetic engineering, have a lower
potential to convert nicotine to
nornicotine (Ref. 40).
b. Growing Conditions
• Climate. Weather is a significant
factor in NNN formation. Increased
rainfall, including more frequent intense
weather systems such as hurricanes,
correlate with higher levels of TSNAs
(Ref. 34). Specifically, wetter conditions
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8013
that increase relative humidity during
the growing season are more conducive
to increases in total TSNA formation.
• Fertilizer. Nitrogen rich fertilizer
can also have a profound effect on
nitrate and NNN levels found in tobacco
(Ref. 41). Higher NNN levels are found
in crops fertilized with nitrogen-rich
fertilizers compared to fertilizers with
lower nitrogen content (Refs. 42, 43, 34).
This is because, when nitrogen-rich
fertilizer is used during tobacco
growing, more nitrogen is incorporated
into the leaves of the tobacco in the
form of nitrate. As the tobacco leaves are
cured, the nitrate acts as a substrate for
microorganisms reducing the nitrate to
nitrite. The nitrite reacts with alkaloids
such as nicotine or nornicotine in the
tobacco during curing to form higher
levels of TSNAs such as NNN.
c. Curing Techniques
There are four main methods for
curing tobacco: Sun, air, flue, and fire
curing. Sun-cured tobacco is cured on
outdoor racks exposed to the sun while
air-cured tobacco is cured on racks in a
well-ventilated barn under ambient
temperatures (Ref. 4). Flue and fire
curing occur in artificially heated and
ventilated barns. Flue-cured tobacco is
cured on racks in a barn or other
enclosed structure with an external heat
source (e.g., heat exchanger, propane or
diesel heaters) so the tobacco isn’t
exposed to smoke (Refs. 34, 200). In
contrast, fire-cured tobacco is cured on
racks in a barn and exposed directly to
smoke from a wood fire (Ref. 201).
Curing can take from a few days to
several weeks depending on the curing
method (Ref. 44). The curing process not
only dries out and preserves the tobacco
but also imparts characteristic flavor.
During the curing process, the curing
method, humidity, air flow,
temperature, and the fuel used for
heating the tobacco influence the extent
to which the NNN level changes (Refs.
45, 46). Studies have shown that flue
and fire-curing tobacco results in higher
NNN levels than when the same tobacco
is air-cured (Refs. 47, 42, 1). In addition,
air-curing during periods of high
relative humidity produces tobacco with
higher amounts of TSNAs and nitrite
(Ref. 46). However, TSNAs in tobacco
were shown to be lower when cured by
reducing humidity by improving the air
circulation or by using an indirect
heating source to limit exposure to
smoke (Refs. 46, 48). Furthermore,
direct flue curing with liquid propane
gas leads to higher NNN levels than fire
curing or indirect flue curing (Ref. 49).
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d. Production Process
During production, microorganisms
(bacteria, fungi, and yeast) on tobacco
play a significant role in the generation
of nitrite and the subsequent formation
of TSNAs (Ref. 202). The
microorganisms can come from a variety
of sources including the soil and
surrounding environment, or unsanitary
manufacturing conditions (Ref. 12).
Fermentation is commonly used in
the production of U.S. smokeless
tobacco products. Fermentation imparts
flavor and contributes to higher nitrite
and NNN levels (Ref. 50). Reduction of
nitrate by bacteria during the
fermentation process is the primary
source of nitrite in smokeless tobacco
products (Ref. 34). The increased nitrite
concentration subsequently contributes
to the nitrosation of amino alkaloids and
the formation of NNN.
In contrast, certain processing
methods have been reported to help
limit the levels of NNN formed during
production. For example, using nonnitrate reducing bacteria during the
fermentation process (i.e., through
seeding or starter culture) can lower
NNN yields (Refs. 34, 51). Cleaning and
sanitizing all equipment used in the
processing and manufacturing of
smokeless tobacco products, including
the fermentation equipment, can lower
microorganisms on tobacco and lower
NNN yields (Ref. 34). In addition, using
closed process blenders at a high
temperature, adding bicarbonate and
carbonate salt solutions to control pH,
adding humectants, and pasteurization
or heat treatment can lower microbial
activity during production, leading to
lower NNN levels in smokeless tobacco
products (Ref. 11).
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e. Storage Conditions
Storage conditions (i.e., temperature
and humidity) and the duration of
storage have been shown to influence
NNN levels. Cured tobacco leaves and
finished smokeless tobacco products are
stored until they are processed or
consumed. Tobacco leaves are often
stored on farms for up to 3 months prior
to sale to tobacco product
manufacturers. Once sold, the tobacco
may be stored for another 18 months
before it is manufactured into a finished
product (Ref. 41).
Researchers have reported a 2-fold
increase in NNN levels in sun-cured
tobacco and a 3-fold increase in NNN
levels in Burley tobacco when stored at
ambient temperatures over a 1-year
period (Ref. 41). Further, studies have
shown that storage temperatures as low
as 27 °C can lead to increased NNN
formation in air-cured Burley tobacco,
and that the rate of increase becomes
greater as the temperature is increased
(Ref. 41). In addition, air-cured Burley
tobacco stored at higher temperature (24
°C v. 32 °C) and higher relative
humidity levels (70 v. 83 percent)
showed increases in both nitrite and
NNN levels (Ref. 52).
Similar to cured tobacco, high
temperature, high humidity, and
extended storage can cause levels of
NNN to increase in smokeless tobacco
products. As smokeless tobacco
products ‘‘age,’’ the water content can
change, leading to bacterial growth, and
the pH and nicotine content can
decrease, causing nitrosamine levels
such as NNN to rise (Ref. 11).
Studies have shown that NNN
increases in moist snuff and dry snuff
when stored at 24 °C for 24 days (Refs.
53, 54). Exposing moist and dry snuff to
ambient air, such as when a product is
opened and closed between dips, also
increases NNN concentrations (Ref. 53).
Similar to cured tobacco leaves, the
storage of moist snuff at low
temperatures (4 °C) reduces the increase
in NNN that was seen when the same
product is stored at ambient conditions
(Ref. 55).
Humidity levels during storage can
have an even greater influence than
temperature on NNN formation in
finished smokeless tobacco products.
Specifically, the NNN levels in moist
and dry snuff can be increased just by
raising the relative humidity during
storage from 22 to 50 percent (Ref. 54).
Moreover, the combined effects of
humidity and temperature are enhanced
in products with higher moisture
content (Ref. 54). Yet, storage conditions
do not have the same effect on all types
of smokeless tobacco. Studies on storage
of chewing tobacco did not show the
same increase in NNN as seen with
moist and dry snuff, which suggests that
some tobacco blends may be less prone
to producing nitrosamines during
storage (Refs. 53, 54). Furthermore,
although retailers are encouraged to
refrigerate Swedish snus to maintain
‘‘perceived product freshness,’’ the
product’s low bacterial activity may
stabilize the NNN level even when
stored at room temperature (Ref. 11).
3. Levels of NNN in U.S. Smokeless
Tobacco Products
The levels of NNN in smokeless
tobacco products on the U.S. market can
vary by several orders of magnitude, not
only among different subcategories of
products, but also among products in
the same subcategory (table 2, Refs. 5,
10, 56). After measuring NNN levels in
46 different smokeless tobacco products
available in the United States from 2006
and 2007, Borgerding et al. found NNN
levels ranged from below the limit of
quantification (0.02 mg/g) to 14.4 mg/g
per dry weight (Ref. 5). As shown in
table 2, the NNN levels within the class
of moist snuff and dry snuff ranged from
0.6 to 12.8 mg/g per dry weight and 5.91
to 12.0 mg/g per dry weight, respectively
(Ref. 5).
A more recent study by Ammann et
al. examined 34 products purchased in
the United States in 2015 (Ref. 10). In
line with the Borgerding study,
Ammann et al. found NNN levels
ranged from 0.64 to 12.0 mg/g per dry
weight (Ref. 10). The NNN levels for
moist snuff ranged from 1.0 to 9.5 mg/
g per dry weight while the NNN levels
for dry snuff ranged from 5.91 to 12.0
mg/g per dry weight (Ref. 10).
The range of NNN levels described in
these studies have been confirmed by
numerous other studies. Stepanov et al.
reported a similar range for moist snuff
(3.8 to 6.9 mg/g per dry weight) with dry
snuff ranging from 0.95 to 5.3 mg/g per
dry weight (Ref. 13). In a separate study,
Stepanov et al. reported a wide range of
NNN levels in 11 dissolvables that are
smokeless tobacco products (0.27 to 2.7
mg/g per dry weight) (Ref. 56). Finally,
Lawler et al. reported a wide range of
NNN levels in chewing tobacco (0.94 to
2.8 per wet weight which equates to 1.2
to 3.6 mg/g per dry weight) and in dry
snuff (6.1 to 31 mg/g per wet weight
which equates to 6.5 to 33 mg/g per dry
weight) (Ref. 20).
TABLE 2—NNN CONCENTRATION AND MARKET SHARE OF SMOKELESS TOBACCO PRODUCTS SOLD IN THE UNITED STATES
Mean 1 and range of NNN measured in μg/g dry weight (number of products)
Smokeless
tobacco product
Dissolvable .........................................
Chewing Tobacco (Loose leaf, plug,
chew).
Dry Snuff ............................................
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Market share 2
(%)
Stepanov et al., 2014
Borgerding et al., 2012
Amman et al., 2016
1.78; 0.27–2.66; (11) .........
............................................
............................................
2.21; 0.66–5.05; (8) ...........
............................................
2.24; 0.92–4.60; (8) ...........
<0.1
5.2
............................................
5.53; 0.81–14.42; (10) .......
7.50; 5.91–12.00; (4) .........
0.7
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TABLE 2—NNN CONCENTRATION AND MARKET SHARE OF SMOKELESS TOBACCO PRODUCTS SOLD IN THE UNITED
STATES—Continued
Mean 1 and range of NNN measured in μg/g dry weight (number of products)
Stepanov et al., 2014
Borgerding et al., 2012
Amman et al., 2016
Market share 2
(%)
............................................
............................................
............................................
3.76; 0.66–12.77; (28) .......
3.87 ....................................
3.69 ....................................
3.01; 0.64–9.50; (22) .........
3.36 ....................................
3.01 ....................................
94.1
........................
........................
Smokeless
tobacco product
Moist Snuff .........................................
Mean NNN across product categories
Market share adjusted mean across
product subcategories 3.
1 Mean values were determined by averaging the NNN concentrations across a smokeless tobacco product subcategory in each of the three
representative studies.
2 Market share data was based on 2015 retail scan data from Nielsen.
3 In order to calculate a market share adjusted mean the mean of each subcategory was multiplied by its representative market share (e.g.,
Chewing Tobacco [NNN] × .052). These values for each subcategory were then summed to estimate a market share weighted mean across all
smokeless tobacco product subcategories examined.
The range of the NNN levels in the
studies discussed in this subsection
suggest that there exists the potential to
reduce the levels of NNN in all
smokeless tobacco through
manipulation of starting materials and
curing processes, as well as careful
control of manufacturing and storage
practices.
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D. Basis for the NNN Limit in the
Proposed Standard
As discussed in section IV.B of this
document, the scientific evidence
supports that NNN is a potent
carcinogenic agent found in smokeless
tobacco products and that NNN in
smokeless tobacco products is a major
factor underlying oral and esophageal
cancers. The epidemiological evidence
indicates populations who use
smokeless tobacco products with lower
levels of NNN have lower cancer risks
(Refs. 4, 100, 101). Thus, it is
anticipated that reducing levels of NNN
in tobacco products in the United States
will reduce the incidence of oral and
esophageal cancers among smokeless
tobacco users.
Based on our assessment of the
evidence, we are proposing that the
mean level of NNN in any batch of
finished smokeless tobacco products not
exceed 1.0 mg/g of tobacco (on a dry
weight basis) at any time through the
product’s labeled expiration date as
determined by testing in compliance
with § 1132.12 (proposed § 1132.10). In
selecting the NNN limit in this proposed
standard, FDA took into consideration
the epidemiological evidence
demonstrating differences in observed
cancer risks between users of smokeless
tobacco products manufactured in the
United States and in Sweden, and the
technical achievability of the proposed
limit. To estimate the anticipated health
benefits of the proposed standard, FDA
modeled the estimated cancer risk
reduction determined by reducing NNN
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levels in smokeless tobacco products
from current levels.
As NNN appears to have a genotoxic
mode of action, FDA followed the U.S.
Environmental Protection Agency’s
(EPA’s) guidance for carcinogen risk
assessment and assumed a linear
relationship in the low-dose region of
the dose-response model (Ref. 203).
Using this model, the risk of cancer is
linearly reduced as exposure to NNN
approaches zero. While a limit of 0.0 mg/
g for NNN would maximize cancer risk
reduction to smokeless tobacco users,
there is limited information on NNN
levels lower than the proposed standard
and their technical achievability. We
note, however, that an NNN level of 1.0
mg/g of tobacco has been achieved in
some smokeless tobacco products sold
in the United States and is thus
achievable using current technology. As
discussed in section II.C of this
document, FDA may consider a lower
NNN level in the future. In addition,
FDA welcomes comments on the
technical achievability of complying
with the proposed standard in this rule.
FDA modelled NNN attributable
cancer risk to estimate the potential
benefits to public health. Specifically,
FDA modelled the effect an NNN
smokeless tobacco product standard
would have on reducing the cancer risk
to a population exposed to NNN
through use of smokeless products. This
analysis is described in detail in this
section.
FDA also considered the
epidemiological evidence demonstrating
differences in observed cancer risks
between users of smokeless tobacco
products manufactured in the United
States and in Sweden. We focused on
epidemiological evidence from Sweden
because Swedish smokeless tobacco
products tend to have lower levels of
NNN than other smokeless tobacco
products (Refs. 100, 114), which helps
inform our public health analysis of a
product standard limiting NNN. As
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discussed in section IV.B of this
document, epidemiological studies
demonstrate a lower risk of oral cancer
from the use of Swedish snus in Sweden
compared to other smokeless tobacco
products in other countries. It is
anticipated that the proposed product
standard of 1.0 mg/g dry weight would
bring the NNN level in U.S. smokeless
tobacco products in line with those of
Swedish snus.
With respect to risk reduction, FDA
assumed that changes in the growing
conditions and changes in product
curing and processing may be necessary
to achieve lower NNN levels in
smokeless tobacco products. As
discussed in section IV.E, it appears that
there are several options for achieving
the proposed NNN limit.
We note that FDA’s approach to
establishing the proposed limit differs
from that of other regulatory agencies,
such as the EPA and the U.S.
Occupational Safety and Health
Administration (OSHA), which set
regulatory exposure limits based upon a
risk level deemed to be ‘‘acceptable’’ or
‘‘negligible’’ (Refs. 204, 205 at appendix
B). FDA expects that although the
cancer risks posed by smokeless tobacco
products that meet the proposed
standard would be lowered, use of these
products would still pose increased
cancer risks, including increased oral
cancer risks, compared with not using
smokeless tobacco products. Thus, the
proposed product standard establishing
a limit for NNN in smokeless tobacco
products is not intended to
communicate that such levels are
‘‘acceptable’’ or ‘‘negligible’’ from a
public health perspective.
1. Excess Lifetime Cancer Risk of NNN
in U.S. Smokeless Tobacco Products
FDA estimated the excess lifetime
cancer risk (ELCR) for oral cancer
associated with the current NNN levels
in U.S. smokeless tobacco products and
compared it to an estimate of the ELCR
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lifetime cancer risk, the ELCR is a
unitless probability (e.g., 1 in 10,000
chance). The equation is based on the
U.S. Environmental Protection Agency
Risk Assessment Guidance (Ref. 57).
The key variables in the equation are:
(1) The level of NNN in the product (i.e.,
concentration in product as used); (2)
the amount of product (mass) used each
day; (3) the amount of NNN that leaves
the product during use (i.e., percent
extracted) and the amount of the
extracted NNN that is absorbed by the
body (i.e., absorption rate); (4) the length
of time the product is used over a
lifetime, which is determined by the
years of use (i.e., exposure duration)
over the lifetime (i.e., averaging time);
(5) body weight of the user; and (6) the
cancer slope factor (CSF), which is used
to represent the dose-response
relationship between NNN and cancer
incidence. As each of these variables is
associated with wide variability, we
attempted to derive average values to
estimate a population average ELCR.
Below we describe the assumptions that
are used in this analysis and the
justification for those assumptions.
Because of limitations in data,
particularly with regard to data
underlying the CSF, the ELCR
calculation is not used to assess
absolute cancer risk. Instead, the ELCR
is used to estimate the percent reduction
in cancer risk associated with
implementing an NNN limit for
smokeless tobacco products. FDA
welcomes public comments on
alternative assumptions that may affect
the ELCR estimate. Commenters should
provide explanations as to why the
alternative assumptions may lead to
more robust estimates of the ELCR
associated with this product standard.
C = Concentration of NNN in product as used
(mg/g wet weight)
IR = Intake rate (mg of wet (as used)) product
used per day (12 g/day; 2.5 g/day for
dissolvables)
AB = Absorption rate, how much of product
NNN is transferred to the user (60
percent)
EF = Exposure frequency (365 days/year)
ED = Exposure duration (60 years)
BW = Body weight in kg (70 kg)
AT = Averaging time (365 days/year; 78
years)
CSF = Cancer slope factor (1.4 mg/kg/day)
NNN is based upon tumor data from
hamsters orally exposed to NNN in
drinking water in a study conducted by
Hecht et al. (Ref. 59), which compared
a single dose scenario with a control
group. The CalEPA thus generated a
slope by drawing a line between the two
points (tumor rate at a single dose and
tumor rate in the control group). EPA’s
2005 Cancer Guidelines and subsequent
Benchmark Dose Guidance elaborate
extensively on the determination of the
point of departure (POD) for generating
a CSF (Refs. 203, 187). More
specifically, EPA recommends that the
starting point for subsequent
extrapolations and analyses be the
lowest dose adequately supported by
the data. However, in a single dose
study, without an understanding of the
shape of the exposure-response curve at
lower doses, there is potentially
significant bias in the derivation of the
CSF—leading to subsequent uncertainty
in the modeling of cancer risk. Thus, as
noted above, FDA’s ELCR calculation is
only used to estimate relative risk of
alternative exposure scenarios, not
absolute risk. FDA welcomes public
comment on whether there is a more
robust CSF available for NNN.
For the concentration of NNN in the
product, FDA used the Borgerding et al.
and Ammann et al. data (Refs. 5, 10) to
represent the range of levels of NNN in
current smokeless products, which
ranged from below the limit of
quantification (0.02 mg/g) to 14.4 mg/g
per dry weight. We chose these studies
because they are the most
comprehensive studies of NNN levels in
U.S. smokeless tobacco products and
the levels are similar to levels which
have been reported by other
investigators (see section IV.C.3). These
studies also reported the moisture
content of the smokeless tobacco
products, which FDA used to determine
the products wet weight NNN levels
(i.e., what a user would be exposed to).
This calculation involves taking the dry
weight NNN measurement and
accounting for the moisture found in the
product when used by consumers [NNN
mg/g dry weight] × [1-moisture content]
= [mg/g wet weight (as used)].
For the intake rate (mass of product
used each day), FDA chose an average
use assumption of 12 g of wet product
per day, every day based on an
experimental study in the United States
that indicated that the range of the most
common form of smokeless tobacco use,
moist snuff, is between 5.1 and 42.5 g/
day (Ref. 60), with an average use of 12
g/day (Ref. 60). This study is widely
cited for estimating average smokeless
tobacco use (Refs. 132, 212, 213). The 12
g/day assumed estimate is consistent
with studies that look at use in terms of
the number of tins (container holding
the smokeless tobacco product) of
tobacco consumed (Refs. 61 through 71).
These studies’ estimates ranged from 1.2
tins to 4.6 tins/week, with an average of
3.68 tins/week (0.53 tin/day. Based on
an average size of a tin of 1 ounce (or
slightly more than 28 g), we estimate
As defined by the EPA guidelines, the
cancer slope factor (CSF) is ‘‘an upper
bound (approximating a 95percent
confidence limit) on the increased
cancer risk from a lifetime exposure to
an agent. This estimate, usually
expressed in units of proportion (of a
population) affected per mg/kg/day, is
generally reserved for use in the lowdose region of the dose-response
relationship; that is, for exposures
corresponding to risks less than 1 in
100. This term is usually used to refer
to oral slope factors (i.e., slope factors
used for assessing ingestion exposure).’’
(Ref. 190).
For this ELCR assessment, FDA uses
the CSF for NNN generated by the
California Environmental Protection
Agency (CalEPA) in 1992 (Ref. 93).
Although this CSF has been used as the
basis for several published analyses
(Refs. 207, 208, 209, 74, 210, 211, 102),
it has significant limitations. The
CalEPA CSF of 1.4 (milligram per
kilogram per day (mg/kg/day))¥1 for
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Equation 1—ELCR Calculation
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under the proposed standard. We
calculated the ELCR with and without
the proposed product standard to
estimate the extent to which the
proposed standard can reduce the risk
of cancer among smokeless tobacco
users in the United States. Then FDA
used the resulting reduction in lifetime
cancer risk to estimate the potential
decrease in oral cancer cases as a result
of this rule.
Given the variability associated with
smokeless tobacco use (frequency,
quantity) and lack of data regarding the
dose-response relationship for NNN in
humans, FDA is using the ELCR
calculation to provide an understanding
of the relative, rather than absolute, risk
associated with different product classes
and the impact of the proposed product
standard on users of smokeless tobacco.
As demonstrated by Equation 1,
which FDA used to calculate the excess
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that the average amount of smokeless
tobacco product used is approximately
15 g/day [0.53 tin/day × 28 g/tin = 14.84
g/day], which suggests an assumption of
12 g/day is not unreasonable.
Conventional moist snuff constitutes
the overwhelming majority of the
smokeless tobacco market in the United
States (Ref. 131). The figure of 12 g/day
among moist snuff users does provide a
reasonable average estimate of what
most U.S. smokeless tobacco users of
most product subcategories consume on
a daily basis. However, FDA recognizes
that the amount of smokeless tobacco
used in a day varies by product. In
particular, some dissolvable smokeless
tobacco products weigh as little as onefifth or one-quarter as much (Ref. 56).
Therefore, 2.5 g/day was used for our
ELCR calculations for daily use of
dissolvable products based upon a usage
study by Krautter et al. (Ref. 15).
The extraction percentage, or fraction
of TSNAs removed from a smokeless
tobacco product while in use, has been
reported to range from 10 to 85 percent
(Refs. 58, 73, 74). Hecht et al. analyzed
extraction and direct absorption of
TSNAs in humans. A measured amount
of smokeless tobacco was inserted into
the oral cavity for 30 minutes. All saliva
was collected during use of the product
and three consecutive 24-hour urine
samples were analyzed. The amount of
TSNAs before and after use of the
smokeless tobacco product was
determined along with analysis of the
expectorated saliva and urine samples.
The individual subject data provided by
Hecht et al. yields a median extraction
of 60 percent (59 ± 23 percent) (Ref. 58).
Other studies also cite 60 percent as an
estimate of the amount of TSNAs
extracted from smokeless tobacco (Refs.
73, 74).
FDA assumed the absorption rate for
the average user to be 100 percent of the
extracted 60 percent of the
concentration of TSNAs found within a
given smokeless product. This
assumption is precautionary because it
assumes that the user is exposed to the
total amount of NNN extracted from the
product, even though some of the NNN
in saliva may be excreted without being
absorbed. Therefore, the absorption rate
used for the ELCR calculations is 60
percent (i.e., 100 percent absorption of
the 60 percent extracted NNN).
FDA used 60 years of product use as
the exposure duration for the ELCR
calculations assuming initiation at or
near 19 years of age (Ref. 23) and an
average life span of 78 years for the
general population (Ref. 75). We used 78
years because it is the recommended
value from the EPA (Ref. 75) to use
when calculating excess lifetime cancer
risk due to toxicant exposure in the
absence of specific data on the
population of interest (i.e., smokeless
tobacco users). Upon initiation, FDA
assumed daily use (365 days/year) of an
average mass of 12 g of wet product per
day. In addition, FDA used an average
adult body weight of 70 kg in the ELCR
calculations, which is consistent with
EPA practices (Ref. 57).
Table 3 shows the estimated ELCR
calculated by using the mean NNN
concentration of several different
categories of smokeless tobacco
products sold in the United States from
table 2, using Equation 1 and the
assumptions described in this section.
Given the assumed linear nature of the
CSF, use of products with lower NNN
levels has a lower ELCR while use of
products with higher NNN levels has
the highest ELCR. For example, use of
dissolvables with a mean level of NNN
of 1.6 mg/g (as used) has a very low
ELCR of 0.4 in 10,000, while use of dry
snuff with a level of NNN of 5.1–7.0 mg/
g (as used) has an ELCR of 5.6–7.6 in
10,000. The current market share
adjusted mean NNN level of all U.S.
smokeless tobacco products reported by
the Borgerding and Ammann studies is
1.7–1.8 mg/g wet weight (as used), the
use of which corresponds to an
estimated ELCR of 1.9–2.0 in 10,000.
TABLE 3—ESTIMATED ELCR FOR SUBCATEGORIES OF U.S. SMOKELESS TOBACCO PRODUCTS
ELCR
(expressed as ‘‘n’’ in 10,000)
Smokeless tobacco product
Stepanov et al.,
2014
Dissolvables .........................................................................................................
Dry Snuff ..............................................................................................................
Chewing Tobacco ................................................................................................
Moist Snuff ...........................................................................................................
Mean ELCR across product categories ..............................................................
Market share adjusted ELCR across product subcategories ..............................
Borgerding et al.,
2012
Ammann et al.,
2016
0.4
................................
................................
................................
................................
................................
................................
5.6
1.8
2.0
2.7
2.0
................................
7.6
2.0
1.8
2.6
1.9
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1 In order to calculate a market share adjusted mean ELCR, the mean of each subcategory was multiplied by its representative market share
(table 2). These values for each subcategory were then summed to estimate a market share weighted mean across all smokeless tobacco product subcategories examined.
Using the same assumptions as above
(Intake rate, NNN CSF), FDA estimated
the ELCR for use of smokeless tobacco
products with differing levels of NNN
(dry weight, e.g., 0.5, 1.0, 2.0 mg/g) and
how these levels would compare to the
current market estimates (table 4). FDA
first carried out a moisture correction on
the dry weight concentrations (0.5, 1.0,
and 2.0 mg/g dry weight) to determine an
‘‘as used’’ (wet weight) NNN
concentration. This estimation was
based upon the moisture concentrations
from the Ammann et al. study (Ref. 10),
and weighted by recent subcategory
market share data. As shown in table 4,
we estimate that, compared to the
current market, hypothetical marketwide NNN levels of 0.5, 1.0 and 2.0 mg/
g dry weight would reduce the ELCR by
83.2, 66.3 and 31.6 percent,
respectively.
TABLE 4—ELCR FOR HYPOTHETICAL MARKET-WIDE MEAN NNN LEVELS AND COMPARISON TO CURRENT MARKET ELCR
NNN
(μg/g, wet weight,
as used)
NNN
(μg/g dry weight)
0.5 ........................................................................................................................
1.0 ........................................................................................................................
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ELCR
(n in 10,000)
0.3
0.6
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0.32
0.64
23JAP2
% Reduction in
ELCR as compared
to current market 1
83.2
66.3
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TABLE 4—ELCR FOR HYPOTHETICAL MARKET-WIDE MEAN NNN LEVELS AND COMPARISON TO CURRENT MARKET
ELCR—Continued
NNN
(μg/g, wet weight,
as used)
NNN
(μg/g dry weight)
2.0 ........................................................................................................................
1
1.2
1.3
31.6
Percent reduction in ELCR compared to the market weighted mean ELCR value from Amman et al., 1.9 (table 3).
2. ELCR of NNN in Swedish Snus
As noted earlier, Swedish snus
generally has a lower NNN level than
other smokeless tobacco products sold
in the United States, and as discussed
in section IV.B.3, some epidemiological
studies demonstrate a lower risk of oral
cancer from the use of Swedish snus in
Scandinavia when compared to the use
of other smokeless tobacco products in
the United States (Refs. 100, 114).
Substituting the mean NNN level of 0.55
mg/g (wet weight) that is in Swedish
snus (Ref. 5), into Equation 1 yields an
ELCR of 0.59 in 10,000. As the proposed
product standard of 1 mg/g dry weight
for NNN would result in bringing U.S.
smokeless tobacco products in line with
NNN levels in Swedish snus, it is not
surprising that the ELCR for such a
hypothetical market-wide mean NNN
level (table 4) would be almost the same
as that estimated for Swedish snus.
Our analysis indicates that users of
smokeless tobacco products would have
their ELCR reduced by approximately
65 percent if the market adjusted mean
of NNN in smokeless tobacco products
was reduced from that of the current
market to 1.0 mg/g dry weight (table 4).
This value would approximate the ELCR
of the Swedish snus exposure scenario
which epidemiological data suggests has
a lower cancer risk.
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% Reduction in
ELCR as compared
to current market 1
ELCR
(n in 10,000)
3. Conclusion
Setting the proposed limit for NNN in
finished smokeless tobacco products
means that, on average, in a population
of daily users of smokeless tobacco
products, over their life time, there
would be an approximately 65 percent
reduction in ELCR, compared with
lifetime daily use of a population that
used smokeless tobacco products with
NNN levels at the current level. In
section V, we calculate the impact of an
estimated 65 percent reduction in
cancer risk on expected incidence of
oral cancer in the United States.
We note that FDA considered setting
a product standard for both NNN and
NNK. However, FDA is proposing a
product standard for only NNN at this
time because of the more limited data
available on the relationship between
NNK and smokeless tobacco-related
cancer risk. In particular, NNK is noted
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for its consistent systemic lung
carcinogenicity (Ref. 8). However, the
relationship between smokeless tobacco
use and lung cancer is a matter of
ongoing investigation and a definitive
association has not been established
(Refs. 3, 4).
NNN and NNK constitute potent
carcinogens in smokeless tobacco (Refs.
4, 78) and levels of these two TSNAs are
often correlated in smokeless tobacco
products (Refs. 5, 20). Because many
methods available to reduce NNN also
reduce NNK, there is some evidence
that a product standard that requires
lower NNN levels will potentially result
in lower NNK levels as well (Ref. 84).
A market survey of 16 snus brands
sold in Sweden in 1983, prior to the
adoption of the GothiaTek voluntary
quality control standard, showed
average NNN levels of 3.8 mg/g of
tobacco and average NNK levels of 0.8
mg/g of tobacco per wet weight (Ref. 84).
In 2002, after GothiaTek was adopted, a
market survey of 23 snus brands sold in
Sweden showed NNN levels decreased
to 0.49 mg/g of tobacco and NNK levels
decreased to 0.19 mg/g of tobacco per
wet weight (Ref. 84). More recent
analyses of constituents in smokeless
tobacco products manufactured in the
United States indicate that smokeless
tobacco brands that are lower in NNN
content are also lower in NNK (Refs. 5,
20). Additionally a study by Song et al.
(Ref. 6), examined the NNN and NNK
levels of conventional and low-TSNA
smokeless tobacco products on the U.S.
market. NNN:NNK ratios were 3.1 and
3.7 for the conventional and low-TSNA
varieties, respectively, which is in line
with results from previous studies (Refs.
5, 20). Accordingly, we anticipate a
potential reduction of NNK in
smokeless tobacco in response to the
proposed rule for NNN. We note that, in
2009, the WHO Study Group on
Tobacco Product Regulation
recommended a regulatory limit for
NNN and NNK (combined) of 2 mg/g dry
weight of tobacco (Ref. 78). Given the
ratio of NNN to NNK in smokeless
tobacco products, where the level of
NNN is generally greater than the level
of NNK, any smokeless tobacco product
that meets the proposed NNN standard
is likely to also meet the levels
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recommended by the WHO for NNN and
NNK.
E. Information on Technical
Achievability
Section 907(b)(1) of the Tobacco
Control Act requires FDA to consider
information submitted in connection
with a proposed product standard
regarding technical achievability of
compliance with the product standard.
FDA, therefore, invites public comment
addressing the technical achievability of
this proposed product standard, and
specifically requests submission of
evidence and data to support such
comments. FDA has also chosen to
consider available information regarding
technical achievability in developing
this proposed rule and it appears that
there are several options for achieving
the proposed NNN limit.
As described in more detail in section
IV.C.2, there are many factors that can
influence the level of NNN in smokeless
tobacco products. Accordingly, there are
a number of options available to
manufacturers to reduce and control
NNN levels in finished smokeless
tobacco products including, but not
limited to, the following:
• Using a type of tobacco with lower
concentrations of NNN (e.g., Bright
tobacco or low-converter types of Burley
tobacco);
• Using tobacco grown with limited
use of nitrogen-rich fertilizer on tobacco
crops;
• Using tobacco processed with a
different curing method (e.g., air curing
instead of flue curing the same tobacco)
or a modification of a currently used
curing method to minimize its effect on
NNN levels (e.g., reducing humidity
during curing by improving air
circulation);
• Using tobacco that had a
bacteriostatic, bactericidal, or heated
solution (25 to 55 ßC) applied to tobacco
leaves during the growing, harvesting,
or curing processes to reduce the
number of bacteria in the tobacco leaves
and thereby reduce the NNN level;
• Using a non-nitrate reducing
bacteria ‘‘starter culture’’ for the
fermentation process;
• Using cleaned and sanitized
equipment for processing and
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manufacturing smokeless tobacco
products;
• Adding humectants, sodium
chloride, or other additives to lower
water activity and reduce microbial
growth;
• Adding bicarbonate and carbonate
salt solutions to control pH;
• Pasteurization or heat treatment;
• Storing tobacco leaves and finished
smokeless tobacco products at lower
temperatures and relative humidity
levels; and
• Limiting the duration of storage.
For products that are already near the
proposed limit, one of these options
may be sufficient to bring the product
into compliance with the proposed
standard, while products which
currently have levels of NNN well above
the proposed limit may need to use a
combination of options. To the extent
that any change in the processing of
smokeless tobacco products (e.g.,
curing, fermentation) affects the
products flavor, FDA expects that
manufacturers would be able to adjust
the flavor profile of finished smokeless
tobacco products through minor
changes in flavor ingredients. This
proposed rule also could spur
innovation and development of
additional methods and technologies to
reduce NNN levels in smokeless tobacco
products.
The proposed rule does not prescribe
specific methods or processes for
meeting the proposed NNN level, so that
smokeless tobacco product
manufacturers would have flexibility in
identifying appropriate methods or
processes for reducing the NNN level in
their products. Because certain snus,
moist snuff, and chewing tobacco
already contain low NNN levels, FDA
expects that manufacturers of many of
those products may not need to make
any manufacturing changes to meet the
proposed NNN level (Refs. 5, 10, 56).
(Such manufacturers would remain
subject to the proposed standard,
including its testing, sampling, labeling,
and recordkeeping requirements.) Thus,
FDA expects some smokeless tobacco
products may require minimal changes
to the manufacturing process to meet
the proposed NNN level, while other
products may require extensive changes
to the manufacturing process to comply
with the proposed level (Ref. 56). A
smokeless tobacco product that has been
modified to comply with the product
standard would be a ‘‘new tobacco
product’’ and subject to premarket
review.
F. Analytical Method
To test for the NNN limit in this
product standard, FDA proposes that
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smokeless tobacco product
manufacturers use the validated method
that has been developed at FDA’s
Southeast Regional Laboratory (SRL) in
Atlanta, GA (Determination of Nnitrosonornicotine (NNN) in Smokeless
Tobacco and Tobacco Filler by HPLC–
MS/MS, LIB No. 4620, January 2017)
(Ref. 79). The results from the test
method demonstrate a high level of
specificity, accuracy, and precision in
measuring a range of NNN levels across
a variety of smokeless tobacco products.
Requiring that a single test method be
used would ensure that all of these
factors are met and would permit
comparison of test results among
finished smokeless tobacco products
and testing facilities. However, FDA is
proposing that other methods may be
used if they meet the requirements in
§ 1132.16 (Alternative test method).
Numerous methods have been
published that use either highperformance liquid chromatography/
mass spectrometry (LC–MS) or gas
chromatography (GC), combined with
thermal energy analyzer (TEA) detectors
to determine the content of NNN in
tobacco. The validated test method that
FDA is proposing to incorporate by
reference in § 1132.5(a) utilizes LC–MS
and has an analysis time of 8 minutes.
The method has a limit of quantification
of 0.4 mg/g of NNN, a linear range of 0.4
to 1.6 mg/g, and a method detection limit
of 0.1 mg/g. The method performance
parameters for the standard method for
NNN quantification in smokeless
tobacco products do not differ
significantly from the method
performance parameters of other
methods that are currently in use. This
method uses an extraction solvent of
100 milliMolar (mM) ammonium acetate
in high performance liquid
chromatography (HPLC) grade water
and a gradient of 5 to 50 percent of 5
mM ammonium acetate in 95 percent
acetonitrile at a 0.5 milliliter per minute
flow rate. Analysis is conducted after a
known amount of carbon-13-labeled
NNN is added to the tobacco, extracted
for 5 minutes with 100 mM ammonium
acetate at elevated temperature and
pressure, dried, and reconstituted in
methanol and ammonium acetate buffer.
The method includes the
determination of NNN levels as well as
moisture content, so the NNN level on
a dry weight basis can be calculated. In
this method, water levels are
determined according to International
Organization for Standardization (ISO)
standards ISO 6488:2004 and ISO
6488:2004/Cor 1:2008 or ISO
16632:2013. Validation of this method
was done using the smokeless tobacco
reference products for snus (CRP–1) and
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8019
for moist snuff (CRP–2), as well as the
University of Kentucky cigarette
reference product (3R4F cigarette
tobacco filler). Tobacco samples with
NNN levels expected to be higher than
4 mg/g tobacco were analyzed after
dilution because they were too
concentrated for analysis. This method
was proven to be applicable for tobacco
products with various moisture levels,
including cigarette tobacco filler, snus,
dry snuff, chewing tobacco, and moist
snuff.
HPLC is favored over gas
chromatography (GC) because it allows
for faster analysis and sample
preparation, although validated
methods exist for analysis of NNN well
below the level specified in § 1132.10 by
either LC or GC. Mass spectrometer
(MS) detection is favored over thermal
energy analyzer (TEA) detection because
of the possibility of using isotopicallylabeled NNN as an internal standard,
which controls for variation in sample
preparation. In addition,
instrumentation to perform LC–MS
analysis is more readily available than
for GC–TEA and, therefore,
manufacturers or analytical laboratories
wishing to establish this method
themselves will have better access to
equipment. The internal standard is
NNN that has been specially labeled
with isotopes of hydrogen and carbon,
deuterium or carbon-13, respectively.
The isotopic-labeling of the internal
NNN standard increases the mass of the
internal standard relative to naturally
occurring NNN, and the internal
standard appears as a distinct signal in
the mass spectrometer detector. Because
the analyst knows the quantity of
internal standard added to the tobacco
at the beginning of sample preparation,
the detector signal of the internal
standard can be used to quantify the
amount of natural NNN present in the
sample. The isotopically-labeled
internal standard is chemically identical
to NNN, so the internal standard used
for MS controls for all variations in
NNN levels that arise during sample
preparation and extraction. The
available scientific evidence suggests
that deuterated and carbon-13-labeled
internal standards are equally
acceptable for NNN analysis. Internal
standards used for TEA differ from
internal standards used for MS because
they are chemically different from NNN.
Therefore, slight differences may exist
between the yield of NNN and the yield
of the internal standard during the
extraction and sample preparation steps.
The limits of detection for NNN by MS
may be lower than limits of detection by
TEA. However, validated methods exist
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for analysis of NNN well below the level
specified in § 1132.10 by either MS or
TEA.
Over the years a variety of analytical
methods have been developed for the
detection of NNN in smokeless tobacco
products. For example, the Cooperation
Centre for Scientific Research Relative
to Tobacco (CORESTA) published
CORESTA 72, an LC–MS method for
determining NNN levels in smokeless
tobacco using a low calibration standard
of 0.015 mg/g of tobacco, extraction in
100 mM ammonium acetate, and a
deuterium-labeled NNN internal
standard (Ref. 80). CDC published an
LC–MS method for smokeless tobacco
with an extraction in ethyl acetate and
use of a carbon-13-labeled NNN internal
standard with an effective limit of
detection of 0.072 mg/g NNN and an 8
minute analysis time (Refs. 81, 82). The
Swedish National Food Administration
published an LC–MS method for
smokeless tobacco with extraction in
ethyl acetate, a limit of detection of
0.010 mg/g NNN, a 15 minute analysis
time, and quantification using an
external NNN standard (Refs. 83, 84).
British American Tobacco published an
LC–MS method for smokeless tobacco
with extraction in methanol, a
deuterium-labeled NNN internal
standard, and no published limit of
detection (Ref. 85).
The American Health Foundation
published several similar GC–TEA
methods for NNN in chewing tobacco
using extraction in a buffer containing
ascorbic acid, a 24 minute analysis time,
and confirmation by MS of the TEA
signal corresponding to NNN (Refs. 86,
87, 88). Health Canada published
Official Method T–309, which is a GC–
TEA method for NNN in tobacco using
extractions in a buffer of ascorbic acid
in dichloromethane, an internal
standard of N-nitrosopentyl-(3-picolyl)amine, a lowest calibration standard
corresponding to about 0.2 mg/g tobacco,
and a 35-minute analysis run time (Ref.
89).
Other approaches besides LC–MS and
GC–TEA have been explored to measure
NNN in tobacco filler. These methods
have included two ISO methods using
gas chromatography with
chemiluminescence detection (ISO
22303:2008 and ISO 22304:2008), an
American Health Foundation method
using HPLC with ultraviolet absorption
detection followed by confirmation of
the peak by MS (Ref. 90), and a Swedish
Match method using an NNN-specific
antibody in immunoassays (Ref. 91).
Although there are various methods to
test for NNN, only the CORESTA 72
method has been externally validated
via round-robin method validation
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studies in accordance with ISO 5725–2
(ISO 5725–2:1994) and only the SRL
method tests on a dry weight basis.
Thus, FDA concluded that levels of 1.0
mg/g or lower on a dry weight basis of
NNN in tobacco could be reliably
measured either by SRL’s method or by
optimizing existing common methods to
meet the requirements of § 1132.16
(Alternative test method).
V. Standard Is Appropriate for the
Protection of the Public Health
The Tobacco Control Act authorizes
FDA to adopt tobacco product standards
by regulation if it finds ‘‘that a tobacco
product standard is appropriate for the
protection of the public health’’ (section
907(a)(3)(A) of the FD&C Act). The
Notice of Proposed Rulemaking (NPRM)
for such a product standard must set
forth this finding with supporting
justification, which FDA is doing here
(section 907(c)(2)(A) of the FD&C Act).
In order to make this finding, FDA
must consider scientific evidence
concerning—
• The risks and benefits to the
population as a whole, including users
and nonusers of tobacco products, of the
proposed standard;
• The increased or decreased
likelihood that existing users of tobacco
products will stop using such products;
and
• The increased or decreased
likelihood that those who do not use
tobacco products will start using such
products. Section 907(a)(3)(B)(i) of the
FD&C Act.
As discussed in this section of the
document, FDA has considered
scientific evidence related to all three
factors. Based on these considerations,
we find that the proposed standard is
appropriate for the protection of public
health, because it will reduce the harm
associated with the use of smokeless
tobacco products and FDA does not
expect that the product standard will
increase the likelihood that non-users
will initiate tobacco or decrease the
likelihood that users will quit tobacco
use in a manner that would offset the
benefits of the reduced cancer risk.
A. Benefits to the Population as a Whole
As discussed in section IV, on the
basis of the best available scientific
evidence, FDA has determined that
NNN is the predominant driver of
excess oral cancer risk among smokeless
tobacco users. This determination is
based on multiple, consistent lines of
evidence. First, several authoritative
reviews have concluded smokeless
tobacco products, including those
currently marketed in the United States,
cause cancer (Refs. 1, 2, 3, 4). Second,
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NNN is a potent carcinogenic agent
found in smokeless tobacco and, along
with NNK, another TSNA, is labeled as
Group 1 (known human carcinogen) by
IARC (Refs. 1, 2). Third, substantial
recent evidence supports site-specific
concordance of the carcinogenic effects
of NNN in animal and human
epidemiologic studies. In particular,
oral and esophageal tissues have been
identified as targets for NNN-induced
carcinogenicity (Refs. 7, 95, 171, 172),
with observation of tumors in the oral
cavity and esophagus following oral
exposure to NNN in experimental
animals (Refs. 7, 59, 94, 95, 148, 178).
These animal studies suggest a degree of
concordance with effects observed at
these sites in epidemiologic studies
(Refs. 77, 96). Finally, several
authoritative reviews have observed
differences in the magnitude of cancer
risks due to smokeless tobacco use
across regions of the world, which have
been found to correlate highly with
variation in the levels of tobacco
specific nitrosamines in smokeless
products (Refs. 1, 4).
The proposed product standard is
intended to reduce tobacco-related
harms by requiring lower levels of NNN
(and likely also leading to
concomitantly lower NNK levels) in
smokeless tobacco products sold in the
United States. In this section, we
describe the expected benefits of the
proposed standard to the population as
a whole, including specifically the
benefits of reducing the number of new
cases of and deaths from oral cancer
attributable to smokeless tobacco.
In this section, FDA generates
estimates of the number of new cases
and fatal cases of oral cancer that would
be avoided over the 20 years following
implementation of the proposed product
standard. We estimate that
approximately 12,700 new cases of oral
cancer and approximately 2,200 oral
cancer deaths would be prevented in the
United States. Moreover, during that 20year period, approximately 15,200 life
years would be gained as a result of the
proposed standard. Because oral cancer
is associated with significant health and
economic impacts, we expect positive
public health benefits due to prevention
of new and fatal oral cancer cases. We
also expect that the proposed standard
would reduce the number of new and
fatal cases of esophageal cancer among
continuing smokeless tobacco users and
may reduce the risk of pancreatic cancer
as well.
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8021
published systematic review and metaanalysis of studies of oral cancer among
U.S. smokeless tobacco users (Ref. 100).
More specifically, as described in
section IV.C of this document, FDA
estimates, by comparing its calculation
of the ELCR using the NNN levels of
currently marketed U.S. smokeless
tobacco products to its calculation of the
hypothetical ELCR using the proposed
standard, that meeting the standard
would result in, on average, a 65 percent
reduction in the excess lifetime cancer
risk due to NNN among U.S. smokeless
tobacco users. Given the apparently
predominant role of nitrosamines in
smokeless tobacco cancer risk, we
assume that the 65 percent reduction
can be applied directly to the excess
oral cancer risks attributable to
smokeless tobacco in general. Public
comment is sought on the strength of
the assumptions underlying this
approach to estimate the anticipated
public health effects of the rule, and
whether alternative approaches may
exist. Commenters should provide
evidence supporting alternative
assumptions or approaches to
estimating likely reduction in incidence
of oral cancers associated with an
implementation of the proposed product
standard.
The analysis quantifies the estimated
public health impact of the proposed
product standard in terms of new and
fatal cases of oral cancer. Oral cancer is
used as the endpoint of interest because
of the established strong relationship
between smokeless tobacco use and oral
cancer risk, as well as the identification
of NNN as a known, potent oral
carcinogen. There are also a relatively
large number of published estimates of
oral cancer risk among U.S. smokeless
tobacco users.
As described in this section, we also
expect the standard to reduce the risk of
esophageal cancer and it may reduce the
risks of cancer at additional sites.
However, limited data are available to
permit direct quantification of this
health benefit (Ref. 100). As such, we
focus here on estimating the potential
benefits of the proposed product
standard in reducing the number of new
and fatal cases of oral cancer in the
United States.
We use the population attributable
risk formula introduced by Levin (Ref.
108) and subsequently used extensively
by the CDC in its Smoking-Attributable
Mortality, Morbidity, and Economic
Costs (SAMMEC) methodology for
modeling smoking-attributable mortality
(Ref. 109). Population attributable risk
(PAR) is calculated as the proportion of
cases of disease that are attributable to
the risk factor as:
where Pe is the prevalence of the
exposure and RR is the relative risk of
disease among the exposed compared
with the unexposed. The resulting
proportion is then multiplied by the
total number of cases of disease in the
population to estimate the number of
cases that are attributable to the risk
factor.
We first estimate smokeless tobaccoattributable oral cancer cases and deaths
for the United States in 2010. We use
this year because of the availability of
all relevant data inputs, including
smokeless tobacco use prevalence
estimates from the same data source
used in CDC’s SAMMEC method for
estimating cigarette smoking-
attributable mortality. Because the
National Survey on Drug Use and
Health reports that smokeless tobacco
use prevalence has been relatively
consistent among youth and adults in
recent years (Ref. 23), these estimates
also serve as a general measure of the
effects of smokeless tobacco use on oral
cancer in the United States in
subsequent years. We estimate the U.S.
prevalence of smokeless tobacco use
using 2010 National Health Interview
Survey data (Ref. 111). Current
smokeless tobacco use is defined as
reporting having used either chewing
tobacco or snuff at least 20 times in
one’s life and currently using that
product every day or some days. Ageand sex-specific prevalence of current
smokeless tobacco use is reported in
table 5, along with the number of new
and fatal oral cancer cases in the United
States in 2010. The latter were obtained
from United States Cancer Statistics
data available on CDC’s WONDER Web
site (Refs. 112, 182, 184, 185, 186).
Newly diagnosed (incident) oral cancer
cases and oral cancer deaths attributable
to use of smokeless tobacco products,
stratified by age group and sex, are also
reported in table 5. Oral cancer cases
attributable to smokeless tobacco
accounts for 3.4 percent of all newly
diagnosed oral cancer cases.
TABLE 5—PREVALENCE OF CURRENT SMOKELESS TOBACCO USE AND NUMBER OF NEWLY DIAGNOSED AND FATAL CASES
OF ORAL CANCER IN THE UNITED STATES, BY AGE GROUP AND SEX, U.S. 2010
Smokeless
tobacco use
prevalence 1
(%)
Newly
diagnosed
oral cancer
cases 2
Oral cancer
deaths 2
Attributable
oral cancer
cases
Males:
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Attributable
oral cancer
deaths
Attributable
fraction
(%)
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1. Estimated Impact of Proposed NNN
Standard on New and Fatal Oral
Cancers
The analysis in section IV.C suggests
that the estimated lifetime cancer risk
(ELCR) would drop by approximately 65
percent under the scenario where the
proposed product standard for
smokeless tobacco products was fully
implemented, and while assuming that
all other variables remained constant
(e.g., user habits). Thus, over time, FDA
expects implementation of the proposed
product standard to reduce the number
of incident cases (i.e., those new cases
of oral cancer that occur over time in the
smokeless tobacco user population) and
fatal cases of oral cancer by reducing the
concentrations of a potent oral
carcinogen in smokeless tobacco
products (Ref. 107). To estimate the
potential impact of the standard on
morbidity and mortality, we first model
the annual number of new cases and
deaths from oral cancer that are
attributable to smokeless tobacco use in
the United States. We then estimate the
number of these cases, both those new
cases that occur (incident cases) and
those that are fatal, that would be
prevented as a result of the proposed
standard by reducing the population
attributable risk by 65 percent. Relative
risk estimates used to model the
population attributable risk come from a
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TABLE 5—PREVALENCE OF CURRENT SMOKELESS TOBACCO USE AND NUMBER OF NEWLY DIAGNOSED AND FATAL CASES
OF ORAL CANCER IN THE UNITED STATES, BY AGE GROUP AND SEX, U.S. 2010—Continued
Smokeless
tobacco use
prevalence 1
(%)
35–64 years ......................................
65+ years ..........................................
Females:
35–64 years ......................................
65+ years ..........................................
1 Source
2 Source
Oral cancer
deaths 2
Attributable
oral cancer
cases
Attributable
oral cancer
deaths
Attributable
fraction
(%)
4.6
3.9
15,960
10,351
2,770
2,997
808
444
140
128
5.1
4.3
0.2
0.3
5,322
5,664
832
1,699
15
19
<10
<10
0.3
0.3
is the 2010 National Health Interview Survey conducted by the National Center for Health Statistics (Ref. 111).
is CDC WONDER, 2010 for cancers of the lip, oral cavity and pharynx (Ref. 112).
In calculating the population
attributable risk, FDA used summary
relative risks for the relationship
between smokeless tobacco use and oral
cancer risk derived from a meta-analysis
of epidemiology studies published by
Boffetta et al. in 2008 (Ref. 100).
Boffetta’s analysis, based on nine
relative risk estimates from seven
independent studies, generated a
summary relative risk of 2.6 (95 percent
confidence interval of 1.3–5.2) for oral
cancer associated with the use of
chewing tobacco or snuff in the United
States. The authors state that this metaanalysis included studies of smokeless
tobacco use among non-smokers or
among non-smokers and smokers with
adjustment for smoking. These risks
were used in estimates of the population
burden of smokeless tobacco use in the
United States, presented in a recent NCI
and CDC report on smokeless tobacco
use and global public health (Ref. 4).
One study notes that two of the
estimates included in Boffetta et al.’s
meta-analysis, from a study by
Stockwell and Lyman examining the
associations between smokeless tobacco
use and mouth/gum cancers and tongue
cancer, likely did not adjust for cigarette
smoking and consequently yielded
considerably larger risk estimates than
would have likely been observed with
adjustment (Refs. 103, 110). To
understand the sensitivity of the overall
results to this study, we replicated
Boffetta et al.’s summary relative risk
estimate (where relative risk was 2.6),
then re-analyzed the data omitting the
two estimates from Stockwell and
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Newly
diagnosed
oral cancer
cases 2
Lyman. The latter analysis yielded a
summary relative risk of 2.16 (with a 95
percent confidence interval of 1.08–
4.33). This value matched the overall
relative risk estimate from an
independent meta-analysis of the
relationship between smokeless tobacco
use and oral cancer risk in the United
States that was published in 2009 by
Lee and Hamling (i.e., a relative risk of
2.16; and a 95 percent confidence
interval of 1.55–3.02), although based
on different methods and a different set
of studies. In this analysis, we use the
relative risk of 2.16 as the summary
relative risk for oral cancer among
smokeless tobacco users as the relative
risk in 2010 (i.e., in the absence of the
proposed standard). Although we
believe this relative risk represents the
best available estimates based on the
research literature, it should be noted
that the accuracy and precision of
particular study estimates may be
somewhat limited due to sample size
and changes in study participants’
smokeless tobacco use and risk over
time.
Table 6 shows that an estimated 1,300
new cases of oral cancer in the United
States in 2010 were attributable to
smokeless tobacco use using this
summary relative risk. These estimates
are generally comparable to those
reported in the recent NCI and CDC
smokeless tobacco report (Ref. 4). The
majority of these cases occur among
men, which is consistent with low rates
of smokeless tobacco use among
women.
We use similar methods to estimate
the number of oral cancer deaths in the
United States in 2010 that were
attributable to smokeless tobacco use,
with the only difference being that we
use the number of oral cancer deaths
during this year, rather than new
diagnoses during the year, in the
population-attributable risk
calculations. We also estimate the life
years that were lost due to these oral
cancer deaths attributable to smokeless
tobacco use. We obtain the median ages
at death for those dying of oral cancer
by sex and age group (35–64 years and
65+ years) for the United States in 2010
(Ref. 112) and life expectancy estimates
by sex at these ages from life tables for
the United States in 2010 produced by
the National Center for Health Statistics
(Ref. 113). These life expectancy values
are then multiplied by the number of
attributable oral cancer deaths for each
group to estimate the number of life
years that were lost due to oral cancer.
In this case, all future life years lost due
to oral cancer deaths were assigned to
the year in which the death occurred.
Table 6 shows that an estimated 300
oral cancer deaths in the United States
in 2010 were attributable to smokeless
tobacco use. These deaths represent an
eventual loss of 4,900 life years.
Consistent with the data on new cases
and deaths from oral cancer shown in
table 5 and with the lower rates of
smokeless use among women, the
majority of attributable deaths and life
years lost occur among men.
TABLE 6—ESTIMATED ORAL CANCER CASES, DEATHS, AND CORRESPONDING LIFE YEARS LOST ATTRIBUTABLE TO
SMOKELESS TOBACCO USE, U.S. 2010
Life years lost due to
attributable oral cancer
deaths
Attributable oral
cancer deaths
Attributable new oral cancer cases
1,300 ........................................................................................................................................
300
4,900
Note: Smokeless tobacco attributable oral cancer cases and deaths are rounded to the nearest hundred and estimated from information presented in table 5 including the U.S. summary relative risk value reported by Boffetta et al. (Ref. 100), as revised by FDA.
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We also conducted a sensitivity
analysis using other oral cancer relative
risk estimates from the meta-analysis
conducted by Lee and Hamling (Ref.
114). Lee and Hamling’s analysis
generated estimates of never smoker oral
cancer relative risks (a relative risk of
3.33 and a 95 percent confidence
interval of 1.76–6.32) for 5 studies and
smoking-adjusted oral cancer relative
risks (a relative risk of 1.65 and a 95
percent confidence interval of 1.22–
2.25) for 12 studies for U.S. smokeless
tobacco users. Lee and Hamling
prioritized estimates for the population
of smokers and nonsmokers that
adjusted for smoking status over
estimates for never smokers in studies
that reported both types of estimates in
contrast to Boffetta et al., who did the
reverse. We did not use Lee and
Hamling’s never smoker relative risk in
the main analysis because the number of
studies that reported these risks is
limited and only two of these estimates
adjust for alcohol consumption. We also
did not use Lee and Hamling’s smokingadjusted relative risk in the main
analysis because smokeless tobacco
risks that control for smoking may overadjust if individuals who both smoke
and use smokeless tobacco are more
likely to smoke less or quit smoking
compared with exclusive smokers (Refs.
192, 92). These relative risks were used
to generate population-attributable risk
estimates with the other inputs used
above. Using these alternative relative
risks yields estimates of approximately
700 to 2,500 new oral cancer cases in
the United States that are attributable to
smokeless tobacco use per year.
Similarly, using these relative risks
yields estimates of attributable oral
cancer deaths ranging from
approximately 200 to 500 per year.
We then use similar methods to
project the effect of the proposed
product standard on oral cancer
attributable to smokeless tobacco use in
the United States over time. The
proposed standard would reduce the
levels of NNN in U.S. smokeless tobacco
products and is also expected to reduce
NNK levels. As described in this
section, the proposed standard is
predicted to eventually reduce excess
lifetime oral cancer risks among U.S.
smokeless tobacco users by 65 percent,
on average. This reduction in
population cancer risk would likely
occur over a period of time, given that
some smokeless tobacco users may still
develop oral cancer at the higher risk
level after implementation of the
proposed product standard due to
previous exposure to higher NNN levels
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in smokeless tobacco products. For the
purposes of generating projections, we
assume that any final rule on the
tobacco product standard for NNN
would become effective 3 years after the
date of publication of the final rule (see
section VII, Proposed Effective Date)
and that public health benefits would
begin to accrue once the standard is in
effect.
In estimating the health impact of the
proposed standard on smokeless
tobacco users, we begin with an oral
cancer relative risk for smokeless
tobacco users in the United States of
2.16 from FDA’s revised meta-analysis
of Boffetta et al. (Ref. 100). This relative
risk indicates an increase in oral cancer
risk of 116 percent among smokeless
tobacco users compared with never
users. We then reduce this value by 65
percent based on toxicological evidence
relating the estimated average reduction
in the dose of NNN to lifetime cancer
risk under the proposed standard. The
result is a reduction in the estimated
relative risk of oral cancer to 1.41 under
the proposed product standard. FDA
used the following calculation: (1 +
(2.16¥1) × (1¥0.65) = 1.41) for this
determination.
We use studies of relevant cancer
risks for former tobacco users by time
since cessation to provide information
about risk reductions over time after
reductions in toxicant exposure. Due to
limited data on the timing of cancer risk
reduction after smokeless tobacco
cessation, we applied estimates of
relative risks by time since cessation for
former cigarette smokers to approximate
the time it takes for excess cancer risk
to be eliminated after quitting smokeless
tobacco. Estimates from cigarette
smokers help inform our estimation of
the trajectory of oral cancer risk
reduction that could be expected as a
result of reducing regular exposure to
tobacco-related carcinogens. These
studies generally find higher risks for
oral cancer for former smokers during
the first 10 years after smoking cessation
compared to never smokers, but not
necessarily thereafter (Refs. 115, 2). We
therefore project that reductions in new
oral cancer cases attributable to
smokeless tobacco use would be fully
realized over a 10-year period after
manufacturers are in compliance with
the product standard, with the
reduction occurring in 10 percent
increments until the full benefit is
reached. We also assume that, in the
absence of the proposed standard, new
cancer cases attributable to smokeless
tobacco use in the United States would
remain constant over time, given that
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the National Survey on Drug Use and
Health data show that smokeless
tobacco use has remained relatively
consistent among youth and adults
since 2000 (Ref. 23). Using this
approach and the revised Boffetta
relative risk, we estimate that
approximately 12,700 new cases of oral
cancer would be prevented in the
United States in the 20 years following
implementation of the proposed product
standard (table 7), which represents a 50
percent reduction in estimated
smokeless-attributable oral cancer cases
over that time period. We use the same
approach to project the effect of the
proposed standard on oral cancer
deaths, once again assuming that
reductions in deaths would be realized
over a 10-year period but also assuming
that this reduction will begin 3 years
after implementation of the standard
due to previously existing or developing
cases of oral cancer. In this case, we
assign the life years gained due to
reductions in oral cancer deaths to the
years in which the additional life years
are actually lived. We estimate that
approximately 2,200 oral cancer deaths
would be prevented, and approximately
15,200 life years gained in the United
States in the 20 years following
implementation of the product standard
(table 7). This represents a 40 percent
reduction in estimated smokelessattributable oral cancer deaths as a
result of the product standard over a 20
year period.
We also conducted sensitivity
analyses of these projections with the
alternative summary relative risks from
Lee and Hamling. Using the smokingadjusted relative risk for oral cancer of
1.65 for U.S. smokeless tobacco users,
we obtain a cumulative reduction of
approximately 7,300 oral cancer cases
and 1,300 oral cancer deaths over a 20year period with the product standard.
With the never smoker relative risk of
3.33, we obtain a reduction of
approximately 24,000 oral cancer cases
and 4,200 oral cancer deaths during the
period.
We also examined possible impacts
from changes to input values in these
calculations. Specifically, we estimated
changes in the public health benefits
due to differences in smokeless tobacco
prevalence and the length of time in
which the full oral cancer risk reduction
will be observed among U.S. smokeless
tobacco users. These analyses are in the
Uncertainty and Sensitivity Analysis,
section II.G, of the Regulatory Impact
Analysis associated with this proposed
rule.
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TABLE 7—PROJECTED CUMULATIVE DIFFERENCE IN NEW ORAL CANCER CASES AND ORAL CANCER DEATHS ATTRIBUTABLE TO SMOKELESS TOBACCO USE IN THE U.S. AND CORRESPONDING LIFE YEARS GAINED DUE TO IMPLEMENTATION OF THE PROPOSED STANDARD
Cumulative
difference in
attributable cases
Years after full implementation of the standard
10 years ...............................................................................................................
20 years ...............................................................................................................
Cumulative
difference in
attributable deaths
4,500
12,700
500
2,200
Cumulative life
years gained
1,500
15,200
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Note: Estimates in the table are rounded to the nearest hundred.
2. Additional Public Health Benefits
From Reducing Oral Cancer
As a result of this proposed rule, we
estimate considerable public health
benefit to the United States resulting
from reduced risk of oral cancer among
smokeless tobacco users due to
reductions in NNN (and concomitant
reductions in NNK) levels in smokeless
tobacco. The public health impact of
oral cancer is estimated to be
considerable in size. In the United
States, about 65 percent of oral cancer
patients survive at least 5 years with
disease and those individuals who
survive oral cancer can face profound
challenges and reductions in quality of
life.
Oral cancer patients and survivors can
face major functional problems when
performing basic tasks of daily living
such as eating and talking. Treatment
procedures can result in disfigurement
or other serious cosmetic problems that
also adversely impact quality of life
(Ref. 116). Surgical treatments for head
and neck cancers have been found to be
associated with subsequent self-image
issues and social isolation that
increased with the level of
disfigurement (Ref. 117). Patients with
head and neck cancers also report high
levels of anxiety and depressive
symptoms (Ref. 116), and even longterm survivors report high levels of
psychological distress (Ref. 118).
In the United States in 2010,
approximately $3.63 billion annually
was spent on medical treatment and
followup care for all head and neck
cancers (Ref. 119), which includes
cancers of the oral cavity, pharynx,
larynx, nasal cavity, and salivary glands
(Ref. 120). The proposed standard will
benefit public health by preventing
thousands of new oral cancer cases and
deaths caused by smokeless tobacco use
over the next two decades.
3. Unquantified Potential Reductions in
Other Cancers
In addition to reducing the risk of oral
cancer, lower levels of NNN in
smokeless tobacco under the proposed
standard are expected to lower the risk
of esophageal cancer. Smokeless tobacco
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use has been identified as a cause of
esophageal cancer (Refs. 1, 2) and NNN
has been directly linked to esophageal
cancer in numerous animal studies (Ref.
8) and in an epidemiological study of
smokers (Ref. 77). However, limited data
are available, so the health benefit
cannot be directly quantified.
Pancreatic cancer has also been
identified as causally related to
smokeless tobacco use (Refs. 1, 2).
Lower levels of NNN (and potential
reductions in NNK) in U.S. smokeless
tobacco under the proposed standard
have the potential to reduce the
incidence of pancreatic cancer. Boffetta
et al. reported the relative risk of
pancreatic cancer from four studies of
U.S. smokeless tobacco users to be
elevated (i.e., a relative risk of 1.4),
although not statistically significant.
Yet, estimates of pancreatic cancer
relative risks have not consistently been
reported to be higher in U.S. smokeless
tobacco studies compared with
Scandinavian snus product studies
(Refs. 100, 114).
Lower levels of NNN in smokeless
tobacco may also reduce the incidence
of laryngeal and prostate cancers. Lee
and Hamling’s (Ref. 114) review found
U.S. smokeless tobacco use was
significantly associated with laryngeal
cancer in four studies including one
study that adjusted for cigarette
smoking. More recently, Zhou et al.
(Ref. 122) found that use of smokeless
tobacco for 10 or more years was
associated with elevated risk of
laryngeal cancer. Lee and Hamling (Ref.
114) also found a statistically significant
association between U.S. smokeless
tobacco use and prostate cancer.
Although NNN has not specifically been
linked with an increased risk of these
cancers, it is a potent carcinogen and
smokeless tobacco product use can
result in exposure throughout the
human body.
Given that U.S. smokeless products
contain high amounts of NNK, and NNK
is a recognized systemic lung
carcinogen (Ref. 8) in experimental
animals, potential reductions in NNK
levels in smokeless tobacco as a result
of the proposed NNN standard may lead
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to some reduction in lung cancer risk.
There is some evidence linking
smokeless tobacco use to lung cancer
(Ref. 121), although a definitive
association has not been established in
authoritative reviews (Refs. 3, 4).
B. The Likelihood That Existing Users of
Tobacco Products Will Stop Using Such
Products
Although data are lacking on
perceptions of smokeless tobacco
toxicants, including NNN, and
cessation, there is some evidence on
users’ motivations for quitting
smokeless tobacco. Some studies
suggest that concerns about developing
health problems are among the common
motives that smokeless tobacco users
provide for quitting (Refs. 123, 124).
These studies suggest that if the
proposed standard affects consumer
perceptions about the harms of
smokeless tobacco use, it may influence
their cessation motivations. Specifically,
if current smokeless tobacco users
interpret an NNN product standard to
mean the health risks from smokeless
tobacco use will be lower after the
standard is in effect, this might reduce
some users’ motivations to quit. It is
worth noting, however, that while the
magnitude of risk would be changed by
implementation of the proposed
standard, appreciable cancer risk would
remain. Accordingly, users would still
have a strong incentive to quit. FDA,
therefore, does not expect the proposed
product standard to appreciably
discourage cessation of smokeless
tobacco products in such a way as to
offset the beneficial public health
impact from reduced cancer risk.
Although data are lacking on
perceptions of smokeless tobacco
product toxicants, including NNN and
the effect of awareness on cessation
behaviors, prevalence of smokeless
tobacco use would need to increase
substantially in order to offset the
reduction in cancer risk expected as a
result of this rule. The magnitude of the
change needed can be estimated using
the population attributable risk
calculation presented in section V.A.1
of this document. The calculation
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includes the product of the excess
relative risk (RR–1) and the prevalence
of smokeless tobacco use. Therefore,
smokeless tobacco use prevalence
would need to nearly triple in order to
completely offset the expected
reduction in excess lifetime cancer risk
to the equivalent of approximately onethird of the baseline cancer risk.
While there is evidence that exposure
to media can lead to health behavior
changes (Refs. 126, 127), it is unclear
whether media coverage of this
proposed product standard would
promote sustained behavior change in
the form of increased or decreased
likelihood of smokeless tobacco
cessation.
Methods used to reduce NNN levels
as a result of this proposed rule may or
may not produce changes that affect the
sensory experiences of smokeless
tobacco use. Consumers’ sensory
experiences can in turn influence their
perceptions of product harms (Refs. 128,
129, 130), which can impact product
use. However, for moist snuff, which
constitutes the overwhelming majority
of the smokeless tobacco market in the
United States (Ref. 131), manufacturers
have already identified ways to reduce
nitrosamine content without negatively
impacting the taste or user experience
(see sections IV.C and IV.E of this
document). Smokeless tobacco products
are heavily flavored and the presence of
flavors is a significant driver of
consumer acceptance of these products
(Ref. 70). The proposed standard does
not prevent the addition of flavors to
offset any changes in the taste of the
product due to the methods used to
reduce NNN to meet the proposed
standard.
C. The Likelihood That Non-Users Will
Start Using Tobacco Products
The proposed product standard is not
expected to substantially increase, if at
all, the likelihood that those who do not
use smokeless tobacco will take up the
product. Public perception is that
smokeless tobacco use has some
potential harms (Refs. 76, 133, 134, 135,
136). At this time we are not aware of
direct scientific evidence demonstrating
that the proposed smokeless tobacco
product standard would influence
consumers’ perceptions of product
appeal, relative risk, and absolute risk,
or behaviors. Even if the proposed
standard were to result in some changes
to perceptions and behaviors, FDA
believes that they would not offset the
beneficial public health impact from
reduced cancer risk. As described in
this section, FDA estimates that the
prevalence of smokeless tobacco use
would have to nearly triple in order to
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offset the expected excess cancer risk
reduction due to the proposed rule.
Data are not available on consumers’
awareness and perceptions of NNN in
smokeless products, although a single
published study in a U.S. adult sample
of smokers and non-smokers found
awareness of and knowledge about NNN
in cigarette smoke was low, particularly
in comparison to other constituents
(Ref. 125). Although there is very low
awareness of NNN as a constituent, it is
possible that some non-users of
smokeless tobacco will be aware of the
proposed standard and interpret it to
mean that smokeless tobacco is less
harmful than other tobacco products
and this could, in turn, affect smokeless
tobacco initiation. Research suggests
that risk perceptions of tobacco use—
that is, judgments about its
harmfulness—can influence tobacco
initiation (Refs. 137, 138). However, if
the proposed standard were to result in
additional uptake of smokeless tobacco
use in the population, this could either
decrease or increase the expected health
benefits of the proposed standard. If
cigarette smokers who would not
otherwise quit smoking completely
switched to smokeless tobacco products
as a result of this standard, we would
expect additional reduction in risk to
these individual users. If cigarette
smokers became dual users of cigarettes
and smokeless tobacco products, this
could have varying impacts depending
on the extent to which such dual use led
to substantial reductions in cigarette
consumption or led to delayed cessation
of tobacco products altogether.
Conversely, the anticipated net
population health benefits of the
standard would be reduced if it led
substantial numbers of never or former
tobacco users to begin or resume using
smokeless tobacco products.
In the case that some adolescents and
young adults become aware that FDA is
taking steps to reduce the harmfulness
of smokeless tobacco products, FDA
expects that any impact on smokeless
tobacco initiation would be limited.
First, smokeless tobacco initiation
among youth has been shown to be
associated with social influences such
as actual or perceived peer use (Refs.
139, 140) to a greater extent than
perceptions of the long-term health
effects. Further, youth curiosity about
smokeless tobacco is lower than
curiosity about cigars or cigarettes (Ref.
141), suggesting that fewer adolescents
are at risk for future use, compared to
many other tobacco products. Thus, at
the population level, very few
adolescents are likely to be aware that
FDA is taking an action related to NNN
in smokeless tobacco products, and,
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even if there were some awareness,
given that the standard is related to
reducing long-term health effects, it is
unlikely to have an impact on youth
initiation.
It is possible that some former users
could potentially relapse back to
smokeless tobacco use due to
perceptions of lower risk. Although
specific data on relapse among
smokeless users is not available, there is
some data on relapse among smokers.
For example, predictors of relapse for
smokers who reported they had quit
between study waves were assessed in
one of the few studies assessing relapse
in the general population and not part
of a clinical trial. Neither the perceived
costs of smoking (such as thoughts
about the harms of smoking) nor
benefits of quitting (including health
benefits) were related to relapse (Ref.
142). However, nicotine dependence is
related to relapse among smokers (Refs.
143, 144); and because smokeless
tobacco products also deliver nicotine,
FDA expects that the same reason for
relapse would apply to former
smokeless tobacco users and that
changes to perceptions of costs and
benefits would have little effect on
relapse rates. Overall, the extent to
which the proposed standard may
influence behaviors of non-users and
former users is likely to be minimal
since health-related reasons are not
among the main drivers of smokeless
tobacco use initiation or relapse.
Finally, HHS plans to continue
developing and implementing public
education campaigns to help prevent
initiation of all tobacco products,
including smokeless tobacco.
D. Conclusion
NNN is a potent carcinogenic agent
found in smokeless tobacco and, along
with NNK, another TSNA, is a major
contributor to the elevated cancer risks
associated with smokeless tobacco use.
Oral and esophageal tissues have been
identified as targets for NNN-induced
carcinogenicity, when NNN was
administered orally in animal studies,
which indicates some concordance with
effects observed at these sites in
epidemiologic studies. NNN levels in
most smokeless tobacco manufactured
in the United States are higher than
NNN levels in smokeless tobacco
manufactured in Sweden. Oral cancer
risks in U.S. smokeless tobacco users are
elevated compared to the oral cancer
risks in Scandinavian users. The
proposed product standard is expected
to reduce tobacco-related harms by
reducing the levels of NNN in smokeless
tobacco products sold in the United
States, thereby reducing the risk of oral
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cancer in smokeless users. By our
estimates, in the 20 years following
implementation of the proposed product
standard, approximately 12,700 new
cases of oral cancer and approximately
2,200 oral cancer deaths would be
prevented in the United States.
Moreover, during that 20-year period,
approximately 15,200 life years would
be gained as a result of the proposed
standard. This represents a substantial
benefit to the public health. Because
oral cancer is associated with significant
impacts on health and quality of life, we
expect positive public health benefits
due to prevention of new and fatal
cancer cases. We also expect the
proposed product standard to reduce
the risk of esophageal cancer among
smokeless tobacco users, and it may
reduce the incidence of other cancer
types; however, there is limited data
available to directly quantify this health
benefit.
Based on currently available evidence
discussed previously, we do not
anticipate the proposed standard would
have behavioral impacts on smokeless
tobacco initiation, cessation, switching
to other products, or dual use in a way
that would offset the public health
benefits of the reduced cancer risk that
would result from the proposed
standard. Even if the proposed standard
were to result in some instances of
decreased smokeless tobacco cessation
or increased initiation among non-users
of tobacco, we would not expect the
magnitude of these effects to be
comparable to the public health benefits
of the proposed rule. As described in
this section, FDA estimates that the
prevalence of smokeless tobacco use
would have to nearly triple in order to
offset the excess cancer risk reduction
expected due to the proposed rule. In
addition, to the extent that cigarette
smokers who cannot or will not quit
smoking are motivated to switch
completely to smokeless tobacco due to
perceptions of lower risk, this complete
switching could result in additional
benefits to public health through
reduced risks to these individual users.
Accordingly, for the reasons
discussed in this section, we find that
the proposed standard is appropriate for
the protection of public health. It would
reduce the cancer risk posed by
smokeless tobacco products and FDA
does not expect that the product
standard would increase the likelihood
that non-users would initiate tobacco or
decrease the likelihood that users will
quit tobacco use. Even if the proposed
standard were to result in some
instances of decreased smokeless
tobacco cessation or increased initiation
among non-users of tobacco, we would
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not expect the magnitude of these
effects to offset the benefits of the
reduced cancer risk.
VI. Description of Proposed Regulation
A. General Provisions (Proposed
Subpart A)
1. Scope (Proposed § 1132.1)
Proposed § 1132.1 identifies the scope
of products that would be subject to this
NNN product standard. FDA intends for
this proposed standard to cover finished
smokeless tobacco products, which are
defined in proposed § 1132.3 (proposed
§ 1132.1(a)). This includes moist snuff,
snus, dry snuff, chewing tobacco, and
some dissolvables. Some dissolvable
tobacco products do not meet the
statutory definition of ‘‘smokeless
tobacco product’’ because they do not
contain cut, ground, powdered, or leaf
tobacco; instead, these products contain
nicotine extracted from tobacco.
Dissolvable products that do not meet
the statutory definition of ‘‘smokeless
tobacco product’’ are not covered by this
proposed rule. As previously noted, this
rule focuses on smokeless tobacco
products because different measures are
required to address NNN in other
tobacco products.
Proposed § 1132.1(b) states that no
person may manufacture, distribute,
sell, or offer for sale or distribution
within the United States a finished
smokeless tobacco product that is not in
compliance with this part. For example,
FDA would not consider finished
smokeless tobacco products to be in
compliance with this part if they exceed
the NNN level set forth in proposed
§ 1132.10, the package label does not
have a manufacturing code or expiration
date, or the package label has a
manufacturing code or expiration date
that has been altered, mutilated,
destroyed, obliterated, obstructed,
concealed, or removed in whole or in
part.
This provision is not intended to
restrict the manufacture of smokeless
tobacco products intended for export.
Consistent with section 801(e)(1) of the
FD&C Act, a tobacco product intended
for export shall not be deemed to be in
violation of section 907 or this product
standard, if it meets the criteria
enumerated in section 801(e)(1) of the
FD&C Act, including not being sold or
offered for sale in domestic commerce.
Proposed § 1132.1(c) explains that
tobacco retailers and distributors will
not be considered in violation of this
part as it relates to the sale or
distribution or offer for sale or
distribution of finished smokeless
tobacco products that exceed the NNN
level set forth in § 1132.10 if they: (1)
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Store and transport the finished
smokeless tobacco products according
to the package label, (2) do not sell or
distribute or offer for sale or distribution
finished smokeless tobacco products
past their expiration date, except to
return expired products to the
manufacturer, (3) do not conceal, alter,
or remove the expiration date or storage
conditions on the package label, and (4)
do not sell or distribute or offer for sale
or distribution finished smokeless
tobacco products that are open or have
broken seals.
FDA is proposing this exception for
tobacco retailers and distributors
because they cannot reasonably know or
confirm by testing whether the
smokeless tobacco products they are
selling or distributing or offering for sale
or distribution comply with the
proposed NNN level. Provided that the
tobacco retailers and distributors meet
the requirements set forth in proposed
§ 1132.1(c)(1) through (4), FDA will not
consider them to be in violation of part
1132 as it relates to the sale or
distribution or offer for sale or
distribution of products that exceed the
NNN level set forth in proposed
§ 1132.10.
We note that tobacco retailers and
distributors would need to meet all of
the requirements in proposed
§ 1132.1(c) in order to be considered in
compliance with this part as it relates to
the sale or distribution or offer for sale
or distribution of smokeless tobacco
products that exceed the NNN level set
forth in proposed § 1132.10. A retailer
or distributor who, for example, covers
the expiration date or storage conditions
with a sticker, changes the expiration
date, or scratches off the expiration date
or storage conditions on the package
label would not meet the requirements
in proposed § 1132.1(c)(3). Furthermore,
a retailer who sells finished smokeless
tobacco products that are open or have
broken seals would not meet the
requirements in proposed § 1132.1(c)(4),
because doing so could lead to changes
in the NNN level, especially if it is
exposed to heat or humidity.
2. Definitions (Proposed § 1132.3)
Proposed § 1132.3 provides the
definitions for the terms used in the
proposed rule. Several of these
definitions are included in the FD&C
Act or have been used in other
regulatory documents.
• Batch: FDA proposes to define
‘‘batch’’ as a specific identified amount
of a finished smokeless tobacco product
produced in a unit of time or quantity
and that is intended to have the same
characteristics. As stated in section
910(a)(3)(B) of the FD&C Act,
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characteristics means the ‘‘materials,
ingredients, design, composition,
heating source, or other features of a
tobacco product.’’
• Commercial distribution: FDA
proposes to define ‘‘commercial
distribution’’ as any distribution of a
finished smokeless tobacco product to
consumers or to another person through
sale or otherwise, but does not include
interplant transfers of a tobacco product
between registered establishments
within the same parent, subsidiary, and/
or affiliate company, nor does it include
providing a tobacco product for product
testing where such product is not made
available for consumption or resale.
• Finished smokeless tobacco
product: We propose to define ‘‘finished
smokeless tobacco product’’ as a
smokeless tobacco product including all
parts and components, packaged for
consumer use, but it would not include
a component, part, or accessory sold
without tobacco. A product that is
‘‘packaged for consumer use’’ would
have the package label on the product.
For example, a tin or can of loose snuff
or a pouch containing chewing tobacco,
with package labels, would meet this
definition.
• Manufacturing code: FDA proposes
to define ‘‘manufacturing code’’ as any
distinctive sequence or combination of
letters, numbers, or symbols that begins
with the manufacturing date in 2-digit
numerical values in the month, day,
year format (mmddyy) followed by the
batch number from which the
production batch can be identified. The
purpose of the manufacturing code is to
allow manufacturers and FDA to
identify the production batch of a
particular product that has been
released for commercial distribution.
This information would help determine
the product’s history (e.g., batch testing
records) and assist manufacturers and
FDA in the event of a nonconforming
product investigation and any corrective
actions that stem from the
nonconforming product investigation.
• Manufacturing date: We propose to
define ‘‘manufacturing date’’ as the
month, day, and year that a smokeless
tobacco product is packaged for
consumer use (i.e., when the package
label has been added to the product).
The manufacturing date is included in
the manufacturing code, which can be
used by the manufacturer and FDA to
help determine the product’s history
(e.g., batch testing history) in the event
of a nonconforming product
investigation.
• N-nitrosonornicotine (NNN): FDA
proposes to define ‘‘Nnitrosonornicotine’’ as a tobacco-
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specific nitrosamine (TSNA) with the
chemical formula C[9]H[11]N[3]O.
• New tobacco product: As defined in
section 910(a) of the FD&C Act, the term
‘‘new tobacco product’’ means: (1) Any
tobacco product (including those
products in test markets) that was not
commercially marketed in the United
States as of February 15, 2007; or (2) any
modification (including a change in
design, any component, any part, or any
constituent, including a smoke
constituent, or in the content, delivery
or form of nicotine, or any other
additive or ingredient) of a tobacco
product where the modified product
was commercially marketed in the
United States after February 15, 2007.
• Package: As defined in section
900(13) of the FD&C Act, the term
‘‘package’’ means a pack, box, carton, or
container of any kind or, if no other
container, any wrapping (including
cellophane) in which a tobacco product
is offered for sale, sold, or otherwise
distributed to consumers.
• Performance criteria: FDA proposes
to define ‘‘performance criteria’’ as the
validation requirements for the
acceptability of an analytical test
method, including accuracy, precision,
recovery, linearity, specificity, limit of
quantitation, limit of detection,
robustness, and range.
• Person: As defined in section 201(e)
of the FD&C Act, the term ‘‘person’’
includes an individual, partnership,
corporation, or association.
• Rework: We propose to define
‘‘rework’’ as the processing of
nonconforming finished smokeless
tobacco products to meet the
requirements of this part.
• Smokeless tobacco: As defined in
section 900(18) of the FD&C Act, the
term ‘‘smokeless tobacco’’ means any
tobacco product that consists of cut,
ground, powdered, or leaf tobacco and
that is intended to be placed in the oral
or nasal cavity. This includes moist
snuff, snus, dry snuff, chewing tobacco,
and some dissolvables. Some
dissolvable tobacco products do not
meet the statutory definition of
‘‘smokeless tobacco product’’ because
they do not contain cut, ground,
powdered, or leaf tobacco; instead, these
products contain nicotine extracted
from tobacco. Dissolvable products that
do not meet the statutory definition of
‘‘smokeless tobacco product’’ are not
covered by this proposed rule.
• Source data: FDA proposes to
define ‘‘source data’’ as all information
contained in original laboratory records
or exact copies of original records of
experimental findings, observations, or
other activities used for the creation,
reconstruction, and evaluation of a
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study or other laboratory work. Source
data includes any laboratory
worksheets, notebooks, correspondence,
notes, and other documentation
(regardless of capture medium) that are
the result of original observations and
activities of a laboratory study or other
laboratory work.
Source data could include protocols
and standard operating procedures,
information regarding calibration of
equipment used to measure or test
samples, test standards, and the
standard curves used to determine the
measure of the samples being tested or
of the accuracy and reliability of the
test. This type of information may be
needed to fully evaluate, for example,
whether the product meets the product
standard. In addition, if there are any
problems with the data, the
manufacturer and FDA would be able to
use the source data to reconstruct the
study or lab work, which could help
identify and correct any deviations. In
accordance with proposed § 1132.32,
source data records would have to be
maintained by the manufacturer.
• Tobacco product: As defined in
section 201(rr) of the FD&C Act, the
term ‘‘tobacco product’’ means any
product that is made or derived from
tobacco that is intended for human
consumption, including any
component, part, or accessory of a
tobacco product (except for raw
materials other than tobacco used in
manufacturing a component, part, or
accessory of a tobacco product). The
term ‘‘tobacco product’’ does not mean
an article that is a drug under section
201(g)(1), a device under section 201(h),
or a combination product described in
section 503(g) of the FD&C Act (21
U.S.C. 321(g)(1), 321(h), and 353(g)).
• Tobacco product manufacturer: As
defined in section 900(20) of the FD&C
Act, ‘‘tobacco product manufacturer’’
means any person, including a repacker
or relabeler, who manufactures,
fabricates, assembles, processes, or
labels a tobacco product or imports a
finished tobacco product for sale or
distribution in the United States.
• Tobacco-specific nitrosamine
(TSNA): We propose to define ‘‘tobaccospecific nitrosamine’’ to mean a
chemical compound formed through the
chemical reaction involving the
nitrosation of nicotine, nornicotine,
anabasine, or anatabine during the
growing, curing, processing, or storage
of tobacco.
• United States: As defined in section
900(22) of the FD&C Act, the term
‘‘United States’’ means the 50 states of
the United States of America and the
District of Columbia, the
Commonwealth of Puerto Rico, Guam,
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the Virgin Islands, American Samoa,
Wake Island, Midway Islands, Kingman
Reef, Johnston Atoll, the Northern
Mariana Islands, and any other trust
territory or possession of the United
States.
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3. Incorporation by Reference (Proposed
§ 1132.5)
Proposed § 1132.5 identifies the
materials that FDA proposes to
incorporate by reference in this part.
Information that is incorporated by
reference would have the same force
and effect as language explicitly stated
in the codified. Under the proposed
rule, a tobacco product manufacturer
would be required to follow procedures
and methods for testing as described in
any standards incorporated by
reference, unless the manufacturer
meets the requirements in § 1132.16 for
an alternative test method.
FDA is proposing to incorporate by
reference a validated method developed
by FDA’s SRL to be the standard test
method for NNN in smokeless tobacco
products (proposed §§ 1132.5(a) and
1132.14). As discussed in section IV.F of
this document, the results from the test
method demonstrate a high level of
specificity, accuracy, and precision in
measuring a range of NNN levels across
a variety of smokeless tobacco products.
If the proposed incorporation by
reference is approved by the Office of
the Federal Register and incorporated in
the final rule, interested parties would
be able to examine the incorporated
material at the National Archives and
Records Administration (NARA) and at
FDA’s Division of Dockets Management
(proposed § 1132.5(b)), and obtain
copies of the standard test method by
contacting FDA’s Center for Tobacco
Products at the addresses and/or Web
sites listed in proposed § 1132.5(b)(2).
If FDA subsequently determines that
a test method, which has been
incorporated by reference in a final rule,
should be replaced with another method
or updated, FDA will update the
regulation in accordance with the
Administrative Procedure Act (5 U.S.C.
553) and obtain approval of the change
to the incorporation by reference in
accordance with 1 CFR part 51.
Proposed § 1132.5(c) explains that if
tobacco manufacturers or testing
laboratories using these standards find
an inconsistency between a material
incorporated by reference in this part
and definitions or methods described by
FDA in proposed part 1132, the
definitions or methods in proposed part
1132 take precedence.
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B. Product Requirements (Proposed
Subpart B)
1. NNN Level (Proposed § 1132.10)
For the reasons discussed in section
IV of this document, FDA is proposing
that the mean level of NNN in any batch
of finished smokeless tobacco products
must not exceed 1.0 mg/g of tobacco (on
a dry weight basis) at any time through
the product’s labeled expiration date as
determined by testing in compliance
with § 1132.12. Under the proposed
rule, manufacturers would be required
to test their finished smokeless tobacco
products using the standard test method
in § 1132.14 or the alternative test
method in § 1132.16.
In proposing to set the limit in terms
of a batch mean, FDA has tentatively
determined that the mean value is more
appropriate than a limit applied to each
unit produced from the entire batch of
a product, given that the cancer risk is
due to long term and repeated exposure,
and given the variability of NNN in this
agricultural product. Although we
expect some degree of variability in
NNN to exist in smokeless tobacco
products, we recognize there may be
circumstances where there could be
wide ranges in the variability of NNN
for some smokeless tobacco products,
resulting in reduced consistency among
the units produced and reduced
predictability of compliance with a
standard requiring that each unit meet
a specific limit. FDA is requesting
scientific data that could be used to
determine the expected distribution of
individual results for samples for a perbatch mean limit of an NNN level of 1.0
mg/g of tobacco on a dry weight basis
(see proposed § 1132.10). FDA also
requests comment on the compliance
implications of the currently proposed
approach.
NNN-related cancer risk is due to long
term and repeated exposure to NNN.
Under the currently proposed approach,
as long as the mean of each batch
consistently conforms to the NNN level
of 1.0 mg/g of tobacco (on a dry weight
basis) in accordance with § 1132.10,
FDA expects that the long term impact
from an occasional exposure to a
product with slightly higher NNN level
will be offset by the exposure to slightly
lower levels. Therefore, any random
variation that may exist is not expected
to negatively impact the public health
benefit of the proposed standard, which
is based on reduction of excess lifetime
cancer risk.
FDA also is considering an alternative
approach that includes setting a
standard where the specified NNN level
of 1.0 mg/g of tobacco (on a dry weight
basis) would apply to all units produced
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from the entire batch, rather than to a
per-batch mean. This alternative
approach would thereby require the
manufacturer to ensure compliance of
each unit made from a batch despite
some expected random variation of the
NNN level between units. This could
further increase the public health
benefits of this product standard.
However, in instances where
manufacturers determined that some
units within a batch had levels of NNN
above the limit and others had levels
below the limit, this alternative
approach could add costs for
manufacturers (e.g., costs of rejecting or
reworking the batch) or require them to
manufacture product with NNN levels
lower than the NNN level of 1.0 mg/g of
tobacco (on a dry weight basis) in order
to minimize the risk of having to reject
a batch based on random variation. FDA
currently believes that this is not
necessary to achieve the public health
goals of the proposed standard, but
invites input on this point.
We invite comments on FDA’s
proposed approach and on the
alternative approach and their
implications for compliance with the
limit, and public health impact. We also
invite comments or information on
batch sampling methods or other
approaches manufacturers might use to
determine compliance with an absolute
limit on all units produced from a batch
given the expected variability of NNN in
relevant products.
2. Product Testing (Proposed § 1132.12)
Proposed § 1132.12 contains
provisions for the testing of smokeless
tobacco products. FDA is proposing to
require two types of testing—stability
testing and batch testing.
a. Stability testing. Proposed
§ 1132.12(a) would require each tobacco
product manufacturer to conduct testing
to assess the stability of the NNN level
in its finished smokeless tobacco
products. Given the variability of NNN
levels in current smokeless tobacco
products (see section IV.B.1 of this
document), stability testing would help
ensure that the NNN level in finished
smokeless tobacco products is being
properly monitored and controlled and
that it remains in conformance with the
proposed limit through the product’s
labeled expiration date. The initial
stability testing would establish the rate
of change of the NNN level for a product
and the annual stability testing would
identify any changes to the rate of
change of the NNN level in that product.
Manufacturers would be required to
use the results of stability testing to
establish and verify the product’s
expiration date and storage conditions
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(either room temperature or
refrigeration). Proposed § 1132.20 would
require all finished smokeless tobacco
products to have an expiration date
established by stability testing. This
date would have to be no later than the
final date the manufacturer can
demonstrate that the NNN level in the
finished smokeless tobacco product
conforms to § 1132.10 when the product
is stored under its intended conditions
(e.g., room temperature or refrigeration).
When conducting stability testing,
manufacturers would be required to use
either the standard test method in
§ 1132.14 or an alternative test method
that meets the requirements in § 1132.16
and samples would have to be selected
in accordance with the requirements set
forth in § 1132.18(a) and (c) (proposed
§ 1132.12(a)(1)).
Proposed § 1132.12(a)(2) would
require each manufacturer to establish
and maintain a written protocol for all
stability testing, that fully describes the
methodology used to determine the
stability of the NNN level, including the
test method used (the standard test
method in proposed § 1132.14 or an
alternative test method in accordance
with proposed § 1132.16), the sampling
plan and procedures required by
proposed § 1132.18(a) and (c), and the
storage conditions.
Proposed § 1132.12(a)(3) requires
initial real-time stability testing that
covers each finished smokeless tobacco
product. In certain circumstances, it
may not be necessary to conduct initial
real-time stability testing on a particular
product because the results from initial
real-time stability testing conducted on
another similar product apply. For
example, a manufacturer who
manufactures moist snuff in a tin and
moist snuff in a pouch would be
required to conduct initial real-time
stability testing on both products,
because the tin and the pouch could
have different impacts on the NNN level
and, thus, on the stability of the finished
products. In contrast, a manufacturer
who manufactures two finished
products, where the only difference
between them is a slight change in
flavor ingredients that does not affect
NNN levels, would only be required to
conduct initial real-time stability testing
on only one of the two products. The
results from that testing would apply to
both products and the testing would be
considered to cover both products.
Other examples of differences between
products that would not require
additional initial real-time stability
testing, if initial real time stability
testing has already been conducted on
one of the products, include slight
changes in acids, bases, or other pH
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modifiers with no resulting change in
final pH. This provision is intended to
reduce the burden on the manufacturer,
while ensuring that there is initial realtime stability data that applies to all
finished tobacco products, thus
preserving the goal of the requirement.
Manufacturers would be required to
use the results from initial stability
testing to establish an expiration date
and appropriate storage conditions
(either room temperature or
refrigeration) for the finished product.
We believe that room temperature or
refrigeration are the most likely storage
conditions for smokeless tobacco
products because most current
smokeless tobacco products are stored at
room temperature while some snus
products are refrigerated. FDA does not
expect that manufacturers would choose
to freeze their finished smokeless
tobacco products. The expiration date
and storage conditions would be
required to be displayed on the package
label in accordance with proposed
§ 1132.30.
For initial real-time stability testing,
FDA is proposing that, at a minimum,
samples be tested within 7 days of
manufacture to determine the starting
NNN level and at the expected
expiration date (proposed
§ 1132.12(a)(3)(i)). Testing the NNN
level at various time points is intended
to ensure that the NNN level in finished
smokeless tobacco will conform to
§ 1132.10 through the determined
expiration date under the intended
storage conditions. If the proposed
storage condition is room temperature,
samples for initial real-time stability
testing would have to be stored at 25 ±
2 degrees Celsius and 60 ± 5% relative
humidity (proposed
§ 1132.12(a)(3)(i)(A)) and, if the
proposed storage condition is
refrigeration, samples would have to be
stored at 5 ± 2 degrees Celsius (proposed
§ 1132.12(a)(3)(i)(B)).
FDA believes manufacturers will
likely choose to test at several
additional time points to determine the
rate of NNN change, if any. Testing of
additional time points could allow the
manufacturer to establish an acceptable
expiration date even if testing shows the
finished smokeless tobacco product
would exceed the level set forth in
§ 1132.10 at the expected expiration
date. For example, a manufacturer may
initially expect its product to have a
conforming NNN level for a period of 8
months, based on history of experience
with similar products. If instead of only
testing the product at 7 days and at 8
months, the manufacturer chooses to
test at 7 days, 6 months, and 8 months,
that manufacturer would still be able to
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establish an expiration date for its
product (at 6 months) if the testing
results showed that the product
conforms at 6 months but not at 8
months. Because NNN levels in the
product would only increase over time,
manufacturers would also be able to
choose a shorter expiration date if they
wish (Ref. 11). For instance, if stability
testing demonstrated the NNN level
remains in conformance with proposed
§ 1132.10 through at least 6 months, the
manufacturer could choose to use a 4month expiration date if the
manufacturer did not want the product
sold after that time period due to
freshness or taste changes.
FDA is proposing to allow
manufacturers to conduct accelerated
stability testing concurrently with initial
real-time stability testing to establish the
product’s expiration date and storage
conditions (proposed
§ 1132.12(a)(3)(ii)). The manufacturer
would be allowed to use an expiration
date of no longer than 1 year based on
initial accelerated stability testing.
Accelerated stability studies provide
preliminary information on NNN levels
over time and are of shorter duration
than long-term stability studies. By
allowing manufacturers to conduct
accelerated stability testing, FDA
intends to reduce the time required to
bring new products to market without
adversely impacting public health.
Proposed § 1132.12(a)(3)(iii) would
require that, at a minimum, samples for
initial accelerated stability testing be
tested at three time points within a 6month period. This testing paradigm is
similar to one used for stability testing
for drugs. We would require the first
time point be within 7 days of
manufacture and the last time point at
6 months after manufacture. Because it
may not always be possible to test
exactly 6 months after manufacture,
FDA notes that testing conducted within
the week prior to or the week after the
6 month date of manufacture would be
considered to meet this requirement. If
the proposed storage condition is room
temperature, samples for accelerated
stability testing would have to be stored
at 40 ± 2 degrees Celsius and 75 ± 5%
relative humidity (proposed
§ 1132.12(a)(3)(iii)(A)) and, if the
proposed storage condition is
refrigeration, samples would have to be
stored at 25 ± 2 degrees Celsius and 60
± 5% relative humidity (proposed
§ 1132.12(a)(3)(iii)(B)). Because higher
temperatures and humidity can increase
the biological activity, these conditions
will accelerate any increases in the NNN
level, thereby providing a prediction of
the stability of the NNN for a 12-month
period under normal conditions.
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Proposed § 1132.12(a)(3)(iv) would
require the manufacturer to use the
results of initial real-time stability
testing to establish an expiration date
and storage conditions if initial
accelerated stability testing shows the
NNN level in finished smokeless
tobacco products will not conform to
proposed § 1132.10. If the NNN levels
do not conform after 6 months of
accelerated testing conditions, then
there will be insufficient evidence to
project that NNN levels will conform
after 12 months of normal conditions.
Accordingly, this accelerated data may
not be used to forecast an expiration
date.
FDA is also proposing to require
manufacturers to conduct annual realtime stability testing on each finished
smokeless tobacco product to verify the
results of the initial stability testing and,
given the variability of NNN in tobacco,
to ensure that the established expiration
date and storage conditions remain
appropriate and don’t need to be
changed (proposed § 1132.12(a)(4)).
Accelerated stability testing would not
be permitted for annual stability testing.
We propose that accelerated stability
testing be permitted for initial stability
testing to reduce the time required to
bring new products to market without
adversely impacting public health.
However, accelerated testing is
unnecessary for annual stability testing
because these products would already
be on the market.
Proposed § 1132.12(a)(4)(i) would
generally require annual real-time
stability testing to begin within 12
months of the completion of initial
stability testing and then annually
thereafter, with no longer than 12
months between testing. When a
manufacturer has not conducted initial
real-time stability testing on a particular
smokeless tobacco product because it
has determined that the results from
initial real-time stability testing
conducted on another product apply,
annual stability testing would have to
begin when the product is first released
for commercial distribution and then
annually thereafter, with no longer than
12 months between testing (proposed
§ 1132.12(a)(4)(ii)). Samples for annual
real-time stability testing, at a
minimum, would have to be tested
within 7 days of manufacture to
determine the starting NNN level and at
the established expiration date
(proposed § 1132.12(a)(4)(iii)) to
determine the final NNN level and
provide assurance that the NNN level
conforms to the standard through the
expiration date. Also, similar to initial
real-time stability testing, the samples
would have to be stored at room
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temperature or refrigeration in
accordance with proposed
§ 1132.12(a)(4)(iii)(A) and (B).
FDA proposes that, if the results of
the most recent annual real-time
stability testing do not support the
finished smokeless tobacco product’s
previously established expiration date,
the manufacturer must use the results of
the most recent annual real-time
stability testing to establish a new
expiration date (proposed
§ 1132.12(a)(4)(iv)). After a new
expiration date has been established, the
package labels of all affected finished
smokeless tobacco products that have
not been released for commercial
distribution would be required to
display the new expiration date and
storage conditions in accordance with
proposed § 1132.30. Furthermore, if the
expiration date must be shortened, the
manufacturer would be required to
conduct, fully document, and maintain
records of an investigation to determine
why the results of the most recent
annual real-time stability testing do not
support the product’s previously
established expiration date (proposed
§ 1132.12(a)(4)(v) and (a)(2)).
b. Batch testing. FDA is proposing
that tobacco product manufacturers
conduct testing on each batch of
finished smokeless tobacco product to
ensure that the products conform with
proposed § 1132.10 prior to commercial
distribution (proposed § 1132.12(b)).
Testing each batch prior to its release
into commercial distribution provides
assurance to the manufacturer and FDA
that each batch conforms to the
proposed standard. Any problems with
the NNN level that may arise during
production (e.g., problems due to the
pasteurization equipment not heating
correctly) would be detected by batch
testing. In addition, finished product
that does not conform to the standard
would not be released for commercial
distribution.
The manufacturer would be required
to use either the standard test method in
proposed § 1132.14 or an alternative test
method that meets the requirements in
proposed § 1132.16 and samples would
have to be selected in accordance with
the requirements set forth in
§ 1132.18(b) and (c) (proposed
§ 1132.12(b)).
FDA expects tobacco product
manufacturers would use the results of
batch testing and annual stability testing
(proposed § 1132.12(a)) to inform their
determination that a batch of finished
smokeless tobacco product conforms to
the proposed NNN level (proposed
§ 1132.10) at the time of release for
commercial distribution and through
the expiration date. For example, since
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finished smokeless tobacco products
would have to conform with the
proposed NNN level at batch testing and
through their expiration date, the NNN
level at batch testing would have to be
low enough to ensure that the NNN
level remains compliant until the
expiration date. FDA believes that most
manufacturers will develop products
which have no, or minimal, changes in
NNN over time. However, that is not
required by this product standard. For
instance, if stability testing
demonstrates that the mean NNN level
in a batch increases by 0.2 mg/g of
tobacco on a dry weight basis over a 6
month expiration period, batch testing
that demonstrates the mean NNN level
is below 0.75 mg/g of tobacco on a dry
weight basis would be in conformance
because the mean NNN level of the
batch would be expected to remain
below 1.0 mg/g of tobacco on a dry
weight basis at least through the
expiration date of 6 months. We expect
that any changes in a rate of increase
would be observed and investigated
during annual stability testing.
c. Documentation of test results.
Proposed § 1132.12(c) would require the
tobacco product manufacturer to
maintain a full report of the source data
and results of all stability and batch
testing. This report would need to
include the full identification of the
smokeless tobacco product that is the
subject of the report, including the
product subcategory, brand, subbrand,
package size and quantity of product
(mass and, if portioned, count) and, for
portioned tobacco products, the size
(mass) of each portion. Subcategories of
smokeless tobacco products include, for
example, loose moist snuff, portioned
moist snuff, loose snus, portioned snus,
loose dry snuff, certain dissolvables,
loose chewing tobacco, and portioned
chewing tobacco.
In addition, the report would have to
include the following:
• NNN level of each sample tested;
• Mean NNN level and standard
deviation;
• The location, including facility
name and address, from which each
sample was pulled;
• The manufacturing code of each
sample tested or, for samples for initial
stability testing with no manufacturing
code, an identifying code created by the
manufacturer;
• The testing date and location,
including the testing facility name and
address;
• The test method and sampling
procedure used;
• All tobacco product reference
standard test results;
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• The names and qualifications of the
person(s) conducting the testing;
• The equipment used (including
documentation to show that the
equipment is appropriate for its
intended use and has been calibrated);
and
• For batch testing only, the criteria
used to make a decision to accept or
reject each batch and the decision made
with respect to each batch (e.g., accept,
reject) based on the results of the
product testing, including the NNN
level of the individual batch and the
results of the product’s stability testing.
For example, the criteria for accepting a
batch of product whose stability testing
demonstrates no change in the mean
NNN level would be a batch mean NNN
level less than or at 1.0 mg/g of tobacco,
while the acceptance criteria for a batch
of product whose stability testing
demonstrates an increase of 0.2 mg in
mean NNN level per gram of tobacco
over the expiration period would be a
batch mean NNN level at or below 0.8
mg/g of tobacco. The manufacturer
would also be required to keep records,
where applicable, of the decision made
and justification with respect to the
results of a nonconforming product
investigation required under proposed
§ 1132.22. For example, if a batch
initially tests out of compliance and a
nonconforming product investigation
finds the NNN levels were erroneously
high because of a malfunction of the
testing equipment, the manufacturer
could determine that the batch is
acceptable for release if the NNN levels
are in conformance after the equipment
has been fixed. The manufacturer would
be required to keep the records of the
decision made and the justification.
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3. Standard Test Method (Proposed
§ 1132.14)
Proposed § 1132.14 states that the
standard test method is the method
entitled ‘‘Determination of Nnitrosonornicotine (NNN) in Smokeless
Tobacco and Tobacco Filler by HPLC–
MS/MS,’’ that is incorporated by
reference in § 1132.5(a). The standard
test method is explained in further
detail in section IV.F, Analytical
Method. If FDA subsequently
determines that a test method, which
has been incorporated by reference in a
final rule, should be replaced with
another method or updated, FDA will
update the regulation in accordance
with the Administrative Procedure Act
(5 U.S.C. 553) and obtain approval of
the change to the incorporation by
reference in accordance with 1 CFR part
51.
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4. Alternative Test Method (Proposed
§ 1132.16)
If a tobacco product manufacturer
were to choose not to use the standard
test method in § 1132.14 to test each
batch, the manufacturer would be
required to use a validated alternative
test method that conforms to the
requirements of proposed § 1132.16.
The performance criteria of the
alternative test method would have to
meet or exceed the performance criteria
of the standard test method (proposed
§ 1132.16). FDA would consider the
following parameters to assess the
performance criteria of an alternative
test method: Accuracy, precision,
linearity, specificity, limit of
quantitation, limit of detection,
robustness, and range.
Proposed § 1132.16(a) would require
that, before using a validated alternative
test method, the manufacturer notify the
Director of the Office of Science for
FDA’s Center for Tobacco Products. By
requiring prior notification, we hope to
help manufacturers to avoid using a test
method that does not meet the
requirements in § 1132.16 and being
unable to release for commercial
distribution any product tested using
that method. Notification also allows
FDA to track what methods are being
used, by whom, and for what products.
This information can be used to inform
FDA inspectors regarding the use of an
alternative test method. In addition, if
any issues arise with regard to a specific
alternative test method, FDA would be
aware of other manufacturers who may
also be affected.
A manufacturer seeking to use a
validated alternative test method could
not begin to use this method until 60
calendar days after the date FDA
receives the notification regarding the
alternative test method. This would
allow time for FDA to review and act on
the notification. Smokeless tobacco
manufacturers would be informed of
FDA’s receipt of the notification through
the automated Document Control Center
process. A manufacturer may not begin
or continue using the alternative test
method if FDA notifies the
manufacturer that it has not been
demonstrated to meet the requirements
of § 1132.16.
The notification would have to
contain the information required by
proposed § 1132.16(b) and be in the
format discussed in proposed
§ 1132.16(d). Proposed § 1132.16(b)
provides the required contents for the
notification of use of an alternative test
method. The notification would be
required to include the following
information:
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• General information;
• A comprehensive index and table of
contents;
• Summary of the notification; and
• Complete description of the
method.
In addition, FDA may request
clarification and other relevant
information, if needed (proposed
§ 1132.16(c)).
The set of general information would
be submitted on the FDA-provided
form, a draft of which FDA is making
available as a reference for review and
comment (Ref. 145). The form would
include the following information:
• Date the manufacturer submitted
the notification to FDA;
• Identification of the submission as
a notification of an alternative test
method;
• Manufacturer’s name, address, and
contact information;
• Identification of and contact
information (including name, mailing
address, email address, and telephone
number) for an authorized
representative of the manufacturer
(which could be a U.S. agent for the
manufacturer);
• Identification of the subcategories
of finished smokeless tobacco products
(e.g., loose moist snuff, portioned moist
snuff, loose snus, portioned snus, loose
dry snuff, certain dissolvables, loose
chewing tobacco, portioned chewing
tobacco, or other) that can be analyzed
using the alternative test method; and
• The testing facility’s name and
address.
The summary section of the
notification would have to contain the
following information:
• Identification of the standard test
method for which the alternative test
method is being proposed;
• A concise description of the
performance criteria of the alternative
test method;
• A concise explanation regarding the
manufacturer’s rationale for proposing
to use the alternative test method; and
• A concise comparison of the
similarities and differences between the
alternative and standard test methods.
As stated in proposed § 1132.16(b)(4),
the manufacturer would be required to
provide a complete description of the
method with sufficient detail to enable
FDA to evaluate whether the
information demonstrates that the
alternative test method meets or exceeds
the performance criteria of the standard
test method set forth in § 1132.14. This
description would have to include a
complete explanation of the manner in
which the alternative test method is
proposed to deviate from the standard
test method in § 1132.14. The
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description would have to include an
explanation with scientific rationale and
supporting data, as well as a complete
copy of the testing protocol, to
demonstrate that the alternative method
meets or exceeds the performance
criteria established for the standard test
method. In proposed § 1132.16(b)(4)(ii)
and (c), the manufacturer also would
have to include any data and
information from other studies
comparing the alternative test method to
the standard test method and, if
requested by FDA, any other relevant
information needed to evaluate the
alternative test method (e.g., statistical
analysis comparing the alternative test
method to the standard test method,
proficiency test results, or evidence of
technical competence).
Proposed § 1132.16(d) provides the
format for a manufacturer’s notification
of use of an alternative test method.
First, the notification would have to be
submitted using the FDA-provided form
and all information would have to be
organized, legible, and written in the
English language. The comprehensive
index and table of contents (required by
proposed § 1132.16(b)) would provide
sufficient organization for the
document. FDA expects that the
manufacturer will submit this form
using the Agency’s electronic system.
The manufacturer’s notification and all
supporting information would be
required to be in an electronic format
that the Agency can process, review,
and archive. Current information about
electronic submission preparation (e.g.,
acceptable file formats, technical
specifications, data standards) and
transmission requirements may be
found on the FDA Web site.
FDA is proposing to require that
tobacco manufacturers use the
electronic format for the submission of
this information to facilitate our review
of the data submitted. Electronic
submission of information is consistent
with the Government Paperwork
Elimination Act (Pub. L. 105–277),
which requires that Federal Agencies
allow individuals or entities to submit
information or transact business with
the Agency electronically.
A smokeless tobacco manufacturer
that is not able to submit a notification
of use of an alternative test method in
an electronic format could submit a
written request to the Center for
Tobacco Products explaining in detail
why the company cannot submit the
notification in an electronic format and
requesting an alternative format (as
provided in proposed § 1132.16(d)(3)).
Proposed § 1132.16(d)(3) would
provide that, if a manufacturer cannot
submit a form electronically, the
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manufacturer may submit a request for
a waiver. A waiver would be granted
only if the use of electronic means is not
reasonable. If FDA grants the
manufacturer’s waiver request, the
Agency will provide information as to
how and where to submit the
notification and supporting
documentation in paper format.
If a manufacturer seeks a waiver, the
manufacturer must send a legible
written request in the English language
to the Document Control Center, with a
notation ‘‘ATTN: Office of Science,’’ to
the address included in our Web site at
www.fda.gov/TobaccoProducts. The
address can also be obtained by calling
1–877–CTP–2373 (1–877–287–1373).
The waiver request would have to
contain the following information: The
name and address of the tobacco
product manufacturer that wishes to
submit the notification; the name and
contact information of the
manufacturer’s authorized
representative (which could be a U.S.
agent for the manufacturer); and a
statement and rationale as to why the
creation and/or submission of
information in electronic format is not
reasonable (such statement must be
signed by the authorized representative
of the tobacco product manufacturer).
Proposed § 1132.16(e) clarifies the
applicability of an alternative test
method. An alternative test method
could be implemented only by the
tobacco product manufacturer who
submitted the notification and only with
respect to the subcategories of finished
smokeless tobacco products that were
the subject of the notification. We are
proposing this approach because an
alternative test method that is
appropriate for one subcategory of
smokeless tobacco product (e.g., moist
snuff) may not be generalizable to other
subcategories of smokeless products
(e.g., chewing tobacco). Also, because
some test methods may be proprietary
or may have been developed by the
manufacturer for a specific product,
FDA believes it is important for the
manufacturer to notify FDA and fully
describe the method they plan to use
and the products on which they intend
to use it.
Other manufacturers interested in
similar or identical alternative test
methods would have to submit their
own notification following the
procedures of proposed § 1132.16.
Therefore, if a manufacturer previously
submitted a notification of an
alternative test method and later sells
the company to another manufacturer,
the new manufacturer would have to
submit a notification if it wished to
continue using the alternative method.
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This would ensure that FDA is aware of
which manufacturers are using an
alternative test method. Similarly, if the
original notification pertains to one
subcategory of smokeless tobacco (e.g.,
moist snuff), and the manufacturer also
decides to use the method to test
another subcategory of product (e.g., dry
snuff), the manufacturer would have to
submit a new notification in accordance
with proposed § 1132.16. A new
notification would be needed because
an alternative test method may not be
suitable for testing of other product
subcategories and the test method
would need to be evaluated for them
before it can be used by the
manufacturer.
Proposed § 1132.16(f) indicates that
FDA will acknowledge the receipt of a
notification of an alternative test
method. If the applicant submits the
notification electronically, FDA will
acknowledge receipt electronically. This
provision also reiterates that there is a
waiting period before a smokeless
tobacco manufacturer may begin using
the alternative test method. A
manufacturer could start using an
alternative test method beginning 60
calendar days after FDA’s receipt of a
complete notification unless the Agency
notifies the manufacturer otherwise.
Proposed § 1132.16(f)(1) provides
that, if the notification is complete
when FDA receives it, the 60 calendar
day waiting period would begin on the
date the Agency receives the
notification. If the notification did not
contain all of the information required
by proposed § 1132.16(b) and was,
therefore, incomplete, FDA would not
accept the notification and would
inform the submitter (proposed
§ 1132.16(f)(2)). Upon notice from FDA
that the notification is incomplete, the
manufacturer may not supplement the
submission, but rather would be
required to submit a new notification
that includes all the information
required in proposed § 1132.16(b).
Providing all of the information in one
complete notification will facilitate
FDA’s review so that it can act
expeditiously on the notification. The
manufacturer would not be able to use
the alternative test method until the end
of the 60-day waiting period following
submission of the new, complete
notification, provided it has not
received an FDA notification informing
the submitter otherwise. If FDA informs
the manufacturer during the 60 calendar
day waiting period that the
manufacturer has not demonstrated that
the alternative test method meets or
exceeds the performance criteria of the
standard test method, the manufacturer
would be prohibited from implementing
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the alternative test method. If FDA
makes this determination after the 60
calendar day period has ended and the
manufacturer has already begun using
the procedure, the smokeless tobacco
manufacturer would have to
immediately cease using the alternative
test method upon receipt of FDA’s
notification.
Proposed § 1132.16(f)(4) explains that
acceptance of a notification does not
constitute a finding by the Agency that
an alternative test method meets or
exceeds the performance criteria of the
standard test method set forth in
§ 1132.14.
5. Sampling Plans and Procedures
(Proposed § 1132.18)
Proposed § 1132.18 would require
each smokeless tobacco manufacturer to
design and implement sampling plans
for stability testing and batch testing.
These sampling plans would be used in
conjunction with the product testing
required in proposed § 1132.12 (stability
testing and batch testing) and would
provide procedures for the manufacturer
to select samples to demonstrate
conformance with the proposed NNN
level.
Proposed § 1132.18(a) would require
each tobacco product manufacturer to
design and implement a sampling plan
or plans for all stability testing required
in proposed § 1132.12(a) based on a
valid statistical rationale to demonstrate
that the finished smokeless tobacco
product’s expiration date is appropriate
under the intended storage conditions.
One sampling plan could cover multiple
products (e.g., different flavors of the
same basic core tobacco blend and cut),
but multiple plans would be needed if
the products are sufficiently different
from one another in processing or
materials (e.g., one product is expected
to have a very stable NNN level,
whereas in another the NNN level
increases steadily over time).
The sampling plan would have to
ensure that samples taken are
representative and randomly selected.
Furthermore, to account for the
variability of NNN in the smokeless
tobacco products, the following factors
would have to be based on adequate
statistical criteria: The confidence
intervals, the level of necessary
precision, and the number of finished
products sampled. Finally, proposed
§ 1132.18(a) would require each
sampling plan to fully describe the
sampling methodology with scientific
rationale, incorporate all sources of
variability (including variability of the
analytic method and the NNN levels),
and describe the sample size needed
(including a full description of how the
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sample size is calculated) consistent
with the sampling design to achieve the
sampling objective.
Similarly, proposed § 1132.18(b)
would require each tobacco product
manufacturer to design and implement
a sampling plan or plans for all batch
testing required in § 1132.12(b) based on
a valid statistical rationale to ensure that
the finished smokeless tobacco product
consistently conforms to the NNN level
set forth in proposed § 1132.10. One
sampling plan could cover multiple
products (e.g., different flavors of the
same basic core tobacco blend and cut),
but multiple plans would be needed if
the products are sufficiently different
from one another in processing or
materials (e.g., one product is expected
to have a very stable NNN level,
whereas in another the NNN level
increases steadily over time).
The sampling plan would have to
ensure that the samples taken are
representative of an entire batch and are
randomly selected and collected from
each batch for testing. To account for
the variability of the NNN levels in the
finished smokeless tobacco products,
the following factors would have to be
based on adequate statistical criteria:
The confidence intervals, the level of
necessary precision, and the number of
finished products sampled. The
sampling plan would also have to take
into account the manufacturing quality
history of the manufacturer (e.g., batch
testing records and nonconforming
product investigations). For example, a
manufacturer who has a high number of
nonconforming product investigations
or high number of batch rejection
records may need to create a more
robust sampling plan because of their
history of producing nonconforming
products.
In addition, the sampling plan would
have to contain a full description of the
sampling methodology, with scientific
rationale, incorporate all sources of
variability (including variability of the
analytic method and the NNN levels
across batches), and describe the sample
size needed (including a full description
of how the sample size is calculated)
consistent with the sampling design to
achieve the sampling objective. Finally,
the sampling plan would also need to
fully describe the criteria the
manufacturer will use to make a
decision to accept or reject each batch.
For example, the criteria for accepting a
batch of a product would depend on the
results of the stability testing. If stability
testing demonstrates no change in mean
NNN level, the acceptance criteria could
be a batch mean NNN level less than or
at 1.0 mg/g of tobacco on a dry weight
basis. If the stability demonstrates an
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increase of 0.2 mg of mean NNN level
per gram of tobacco on a dry weight
basis over the expiration period, the
acceptance criteria would need to be a
batch mean NNN level below 0.8 mg/g of
tobacco on a dry weight basis. In those
cases, the batch of product is acceptable
because the manufacturer would expect
the batch mean NNN level to remain at
or below 1.0 mg/g of tobacco on a dry
weight basis through the expiration
date.
Proposed § 1132.18(c) would require
that samples be collected and examined
in accordance with certain procedures.
Under proposed § 1132.18(c)(1), test
samples for initial real-time and
accelerated stability testing would have
to consist of:
• Smokeless tobacco product that has
been manufactured using the same
production processes as products
manufactured for consumer use and
packaged in the identical package that
will be used for the finished smokeless
tobacco product, but it need not have
the product package label; or
• Finished smokeless tobacco product
as it is intended to be sold or distributed
to consumers.
This provision would allow flexibility
for the manufacturer to determine the
sample to be tested. It also recognizes
that, at this early stage, a manufacturer
may not want to or may not be able to
create package labels for new smokeless
tobacco products. For example, in
accordance with § 1132.30 a package
label would need to have the expiration
date for the product. Prior to completing
initial stability testing, the manufacturer
might not know what the appropriate
expiration date would be. Similarly, we
expect a manufacturer of a new
smokeless tobacco product would be
most likely to sample smokeless tobacco
that meets the requirements of
§ 1132.18(c)(1)(i) to minimize costs. In
contrast, we would expect a
manufacturer whose smokeless tobacco
products may already conform to the
proposed standard to test its finished
smokeless tobacco product
(§ 1132.18(c)(1)(ii)) rather than product
that has been manufactured specifically
for testing purposes.
Proposed § 1132.18(c)(2) would
require that test samples for annual realtime stability testing and batch testing
consist of the finished smokeless
tobacco product as it is intended to be
sold or distributed to consumers and not
of a separate production sample. This is
intended to ensure the samples tested
are representative of the product to be
sold or distributed to consumers.
Under proposed § 1132.18(c)(3), all
test samples would need to be stored
according to the intended storage
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conditions for the finished smokeless
tobacco product (either room
temperature or refrigeration), except that
test samples for initial accelerated
stability testing must be stored in
accordance with proposed
§ 1132.12(a)(3)(iii). The manufacturer
would have to include all of its
factories, stock rooms, warehouses, and
other locations containing finished
smokeless tobacco products in the
population to be sampled. Because a
batch may include product that is in the
warehouse and product that is in the
factory, or in a place between the
warehouse and factory, this would
ensure the sample is representative of
the entire population (batch) of finished
smokeless tobacco products packaged
for consumer use.
Proposed § 1132.18(c)(4) sets forth
when samples must be taken for testing.
Samples for stability testing would have
to be taken within 7 days of the
manufacturing date and tested in
accordance with proposed § 1132.12(a).
This would ensure the samples for
stability testing are tested as soon as
possible after manufacturing to establish
the starting NNN level. It also provides
sufficient time for the sample to be
shipped to a laboratory for testing.
Samples for batch testing would have to
be taken from each batch and tested
within 30 calendar days of the
manufacturing date.
The amount of material acquired
during sampling would have to be
sufficient for the test methods in
proposed §§ 1132.14 or 1132.16,
including any repeats that may be
necessary. For example, repeat tests
would be necessary if the test material
was damaged prior to or during the
analysis. Samples would have to be
randomly selected in accordance with
the applicable sampling plan and taken
within the same day. This would ensure
that there has not been any degradation
or change in part of the samples.
Proposed § 1132.18(c)(5) would
require that sampling be performed by
persons who have sufficient education,
training, and experience to accomplish
the assigned functions. This would
allow the manufacturer the flexibility to
determine the education, training, and
experience needed to perform this
function. For example, the manufacturer
may determine that a person has the
necessary education, training, and
experience for the position if they have
completed course work or training in
statistics, been trained by the
manufacturer on sampling procedures,
or have prior work experience.
Under proposed § 1132.18(c)(6), each
sample would have to be identified by
the following information:
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• Full identification of the smokeless
tobacco product sampled, including
product subcategory, brand, and
subbrand, package size and quantity of
the product (mass and, if portioned,
count) and, for portioned tobacco
products, the size (mass) of each
portion;
• Manufacturing code or, for samples
for initial stability testing with no
manufacturing code, an identifying code
created by the manufacturer;
• The date on which the sample was
taken;
• The sampling location (including
the address of the facility and specific
location within the facility where the
sample was taken);
• The name of the person(s) who
collected the sample; and
• The location where the sample will
be stored and tested (including the
facility name and address).
This information would be generated
at the time the samples are pulled for
testing.
The purpose of this information is to
fully identify each sample, including
what the product is, and when and
where it was taken. These records
would serve dual purposes. First, they
can be used to verify that a company is
following its sampling plan and the
procedures required under this part,
including the number of samples
pulled, when they are pulled, and the
locations from where they are pulled.
Second, these records can be used to
generate some of the information for the
report required under proposed
§ 1132.18(c)(9). The records also
document the start of sampling process.
Proposed § 1132.18(c)(7) provides
packing requirements for samples that
are sent for testing. Samples would have
to be packed securely to protect against
damage that might occur during
shipment to the testing facility,
including mechanical damage or severe
changes in humidity or temperature that
may affect the NNN level. The samples
would have to be sent to the testing
facility by the most expeditious means
in order to arrive no later than 3
calendar days after shipment. This is
intended to minimize the potential for
damage to or contamination of the
samples and would help to ensure that
the testing is completed within the
specified time periods. The smokeless
tobacco manufacturer would also have
to send, under separate cover, a list of
the samples (identified by the relevant
information required by proposed
§ 1132.18(c)(6)) included in each
shipment to the testing facility. This
would ensure the laboratory receives a
complete list of the samples to be tested.
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Proposed § 1132.18(c)(8) would
require that all the samples for a specific
stability or batch test be tested at the
same testing facility to ensure
consistency among the procedures used
and to protect against sample
degradation.
Proposed § 1132.18(c)(9) provides
sampling requirements for the testing
facility responsible for testing the
manufacturer’s samples. Once the
samples arrive at the testing facility, a
representative of the facility would have
to ensure that the samples are inspected,
accounted for, and stored under the
finished smokeless tobacco product’s
intended storage conditions (e.g., room
temperature or refrigeration) except that
test samples for initial accelerated
stability testing must be stored in
accordance with § 1132.12(a)(3)(iii). The
facility would then be responsible for
generating a report for the stability or
batch test that includes the following
information:
• Full identification of the smokeless
tobacco product sampled, including
product subcategory, brand, and
subbrand, package size and quantity of
the product (mass and, if portioned,
count) and, for portioned tobacco
products, the size(mass) of each portion;
• Manufacturing code or, for samples
for initial stability testing with no
manufacturing code, an identifying code
created by the manufacturer;
• The date when the samples were
taken from the batch, if available;
• Locations where samples were
drawn (including the address and
specific locations within any facilities
where the samples were taken), if
available;
• The number of test samples drawn;
and
• Complete records of the samples
received and tested, including the date
of receipt, the identifier of all persons
who tested the samples, and the test
results.
This information would be generated
once the samples arrive at the testing
facility. Unlike the information required
under proposed § 1132.18(c)(6), this
report would be an aggregate report for
all the samples taken from a batch. The
primary purpose of this information,
along with the information required by
proposed § 1132.18(c)(6), would be to
establish the chain of custody for the
samples from the time they were taken
up through their transfer to the testing
facility where they will be tested. The
smokeless tobacco manufacturer would
be required to maintain the sampling
information in accordance with
proposed § 1132.32. Thus, the
manufacturer would be responsible for
obtaining this information from the
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testing facility. FDA also expects that
this information would be integrated
into the records required by proposed
§ 1132.12(c) to provide information
across the batch.
Proposed § 1132.18(c)(10) explains
that the manufacturer would be required
to withhold from commercial
distribution each batch until it has been
sampled and tested, and the tobacco
product manufacturer has made a
decision to accept and release the batch.
The manufacturer would be required to
reject any nonconforming products as
discussed in proposed § 1132.22.
6. Expiration Date (Proposed § 1132.20)
Proposed § 1132.20 would require all
finished smokeless tobacco products to
have an expiration date established by
stability testing. The expiration date
would be required to be set no later than
the final date the manufacturer can
demonstrate the finished smokeless
tobacco product will not exceed the
NNN limit in proposed § 1132.10 when
stored under its intended conditions
(i.e., either room temperature or
refrigeration). FDA considered requiring
manufacturers to determine the time
point at which the NNN level exceeds
the limit. However, FDA rejected this
approach because manufacturers may
develop products with stable NNN
levels that do not exceed the NNN limit
for a prolonged period (e.g., 5 years) and
requiring manufacturers to conduct
stability testing for that entire period
would be unnecessary. FDA also
considered mandating a specific
expiration period (e.g., 6 months or 1
year) but determined this may be too
restrictive and stifle innovation.
Accordingly, FDA believes the proposed
approach would provide manufacturers
more flexibility in establishing an
expiration date that conforms to the
NNN level.
Requiring an expiration date that is
established by stability testing provides
assurance that the NNN level will
remain in conformance with the product
standard for the specified time period.
The expiration date also informs
retailers that the manufacturer has not
demonstrated compliance with the
product standard beyond that date and
the product cannot be sold to
consumers. The expiration date also
allows FDA inspectors to quickly
determine if products for sale in a retail
establishment purport to be in
conformance with the product standard.
7. Nonconforming Product (Proposed
§ 1132.22)
Proposed § 1132.22 would require
manufacturers to establish procedures
for handling nonconforming smokeless
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tobacco products. Proposed § 1132.22(a)
would require tobacco product
manufacturers to establish and maintain
procedures to identify, investigate,
segregate, and make disposition
decisions (i.e., acceptance, rejection, or
rework) about nonconforming finished
smokeless tobacco products to prevent
their release for commercial
distribution. FDA interprets ‘‘establish
and maintain’’ for purposes of proposed
§ 1132.22(a) to mean define, document
(in writing or electronically),
implement, follow, and, when
necessary, update. This section allows
manufacturers the flexibility to
determine how they will perform these
activities.
Proposed § 1132.22(b) would require
tobacco product manufacturers to
conduct an investigation if:
• The mean of the representative
samples from any batch of finished
smokeless tobacco product is
determined to be out of conformance
with the requirements of § 1132.10,
• A finished smokeless tobacco
product’s expiration date must be
shortened due to the results of annual
real-time stability testing, or
• FDA notifies the smokeless tobacco
manufacturer that a distributed finished
smokeless tobacco product does not
conform to the requirements of part
1132.
The purpose of a nonconforming
product investigation would be to
determine the extent and the cause, if
possible, of the nonconformity so that,
if identified early, the product is not
processed further or released for
commercial distribution. In addition, it
would help to prevent recurrence of the
nonconformity.
The manufacturer would be required
to conduct an investigation to determine
the extent of the nonconformity upon
identification of a nonconforming
product and, as applicable, the locations
where the nonconforming products have
been distributed. We expect the
manufacturer would be able to
determine the locations of the initial
consignees (e.g., wholesalers,
distributors, retailers) where the affected
products were shipped in the event a
corrective action needs to be taken. The
investigation would have to include an
examination of all relevant processes,
operations, records, complaints, any
corrective actions taken, and any other
relevant sources of information
concerning the nonconforming product.
For example, a manufacturer could
determine the extent of the
nonconformity by examining records
and in-process control records for any
batches, or portions of batches that have
been rejected during either in-process or
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finished inspection for failing to meet
any or all of the product’s
specifications. Furthermore, in the event
that a similar nonconforming product is
identified in a different batch, a
manufacturer’s investigation could
include any applicable information and
records from the previous
nonconforming product investigation
that are relevant to determining the
extent of nonconformity of the affected
batch.
The manufacturer would have to fully
document any investigation, including
any materials reviewed, name of the
person(s) making the disposition
decisions, justification for the
disposition decisions, results of
retesting, decisions with respect to
reworking, and followup results from
the investigation (e.g., corrective
actions). FDA may inspect these records
to verify the manufacturer has
adequately performed an investigation.
Proposed § 1132.22(c) would require
tobacco product manufacturers to reject
any batch of a finished smokeless
tobacco product if the mean of the
representative samples from the batch
does not meet the requirements of
§ 1132.10 unless a disposition decision
and justification to release the batch is
made after an investigation shows the
batch meets the requirements of part
1132. Manufacturers would not be able
to simply resample a batch until the
mean conforms with the proposed NNN
limit in § 1132.10 if a previous mean did
not meet the requirements of part 1132.
If the initial mean was not in
conformance, the manufacturer must
conduct a nonconforming product
investigation. If the manufacturer, for
instance, determines the NNN levels
were erroneously high because of a
malfunction of the testing equipment,
and the batch tests in conformance after
repair of the equipment, the
manufacturer could determine that the
batch is acceptable for release into
commercial distribution.
Proposed § 1132.22(d) would allow
smokeless tobacco manufacturers to
rework a batch of a nonconforming
finished smokeless tobacco product,
which does not conform to the
requirements of part 1132, to bring it
into conformance with all the
requirements of the part before it may be
released for commercial distribution.
However, FDA thinks it is unlikely that
a manufacturer would rework
nonconforming finished smokeless
tobacco product because this would
likely require removing the product
from its container and then mixing it
with smokeless tobacco product with
very low NNN levels to ensure that the
final product did not exceed the
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proposed NNN limit.4 We welcome
information and comments on this
provision.
C. Labeling and Recordkeeping
Requirements (Proposed Subpart C)
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1. Package Label Requirements
(Proposed § 1132.30)
Proposed § 1132.30 would require
that the package label of all finished
smokeless tobacco products include a
manufacturing code, expiration date,
and, if applicable, storage conditions.
FDA is proposing to require that the
labels of finished smokeless tobacco
products contain a manufacturing code,
expiration date, and, if applicable,
storage conditions for the finished
smokeless tobacco product (proposed
§ 1132.30) so that FDA can determine
whether a product on store shelves
purports to be in conformance with the
product standard and link the product
to records that substantiate its
conformance. These requirements
would also help ensure that the product
is handled and stored under appropriate
conditions so that the product remains
in compliance with the standard and
would help FDA verify that retailers are
storing products appropriately. The
information would be required to be
printed on or permanently affixed to the
package in a manner that assures it will
remain on the packaging or label
through the expected duration of use of
the product by the consumer. In
addition, it would have to appear
clearly, legibly, and indelibly in the
English language.
The purpose of the manufacturing
code is to allow manufacturers and FDA
to be able to link the product to a
specific batch that has been released for
commercial distribution, which would
be helpful in the event of a
nonconforming product investigation or
in the event that corrective or
preventive actions should be taken. The
manufacturing code could also help
determine the history of the
manufacturing, processing, packaging,
labeling, holding, and initial
distribution of the tobacco product from
records maintained by the smokeless
4 Based on comments provided by the Alcohol
and Tobacco Tax and Trade Bureau (TTB), we
understand that this process would likely constitute
the manufacture of tobacco products for purposes
of the Internal Revenue Code. Under the Internal
Revenue Code, the manufacture of tobacco products
requires a permit as a manufacturer of tobacco
products from TTB. As we understand TTB’s
permitting requirements, entities lacking a
manufacturing permit, including importers, may
not engage in manufacturing activities. We also
understand that certain provisions of the Internal
Revenue Code prohibit importers of tobacco
products from repackaging tobacco products after
such products are released from customs custody.
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tobacco product manufacturer. The
expiration date on the package label
would have to appear in two-digit
numerical values in the following
format: ‘‘Expires on month/day/year.’’
The expiration date informs retailers
that the manufacturer has not
demonstrated compliance with the
product standard beyond that date and
the product cannot be sold to
consumers. The expiration date also
allows FDA inspectors to quickly
determine if products for sale in a retail
establishment purport to be in
conformance with the product standard
and if retailers are selling expired
products.
Storage conditions would be required
to be on the label if the finished
smokeless tobacco product must be kept
in refrigerated storage to conform with
the product standard until the
expiration date (as determined by
stability testing) and the package label
would be required to bear the wording:
‘‘Keep Refrigerated.’’ However, no
wording would be required to be on the
package label if the product’s intended
storage condition is room temperature.
We note that proposed § 1132.1 states
that retailers and distributers would not
be in violation of part 1132 as it relates
to the sale or distribution or offer for
sale or distribution of smokeless tobacco
products that exceed the NNN limit if
they, among other things, store and
transport the finished tobacco product
according to the package label and do
not sell or distribute or offer for sale or
distribution finished smokeless tobacco
products past their expiration date.
Requiring package labels with an
expiration date and storage conditions
would allow retailers and distributers to
handle the product in accordance with
the manufacturer’s intent so the product
remains in conformance with the
product standard.
2. Recordkeeping Requirements
(Proposed § 1132.32)
Proposed § 1132.32 includes two
recordkeeping requirements. This
information is necessary for FDA to
ascertain and confirm that smokeless
tobacco products are in compliance
with the proposed standard.
First, proposed § 1132.32(a) would
require that each facility that
manufactures finished smokeless
tobacco products establish and maintain
records containing the following
information:
1. Full documentation of stability
testing protocols and the results of
initial and annual stability testing under
§ 1132.12(a), including all information
specified in § 1132.12(c).
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2. All investigations under
§ 1132.12(a)(4)(v).
3. The source data and results of batch
testing conducted to determine
conformance with § 1132.10, including
all information specified in § 1132.12(c).
4. All notifications of an alternative
test method and all related
correspondence under § 1132.16;
5. All source data for the alternative
test method validation;
6. All sampling plans and reports
under § 1132.18;
7. Documentation that the persons
performing sampling under § 1132.18
have sufficient education, training, and
experience to accomplish the assigned
functions;
8. All identification, investigation,
segregation, and disposition decision
procedures under § 1132.22(a); and
9. All nonconforming product
investigations and rework under
§ 1132.22(b) and (d).
Second, proposed § 1132.32(b)
provides certain specifications for these
records. The records would have to be
legible and written in English.
Documents that have been translated
from a foreign language into English
would have to be accompanied by the
foreign language version of the
document and a certification by the
manufacturer’s authorized
representative (which could be a U.S.
agent for the manufacturer) that the
English language translation is complete
and accurate. All records would be
required to be readily available for
inspection and copying or other means
of reproduction by FDA upon request
during an inspection.5 Requested
records that are maintained offsite
would have to be made available within
24 hours or, if that is not feasible, as
soon as possible before the close of the
inspection. While we expect that most
records can be made available to FDA
within 24 hours, we recognize that, in
some cases, additional time may be
needed to retrieve records from a third
party or archival storage. Records that
can be immediately retrieved from
another location, including by computer
or other electronic means, would meet
the requirement that the records be
readily available.
In addition, proposed § 1132.32(c)
would require that the records kept
under this part be retained for at least
4 years from the date of commercial
5 Several laws govern the confidentiality of
information submitted under sections 907 and 909
of the FD&C Act, including sections 301(j) and
906(c) of the FD&C Act (21 U.S.C. 331(j) and
387f(c)), the Trade Secrets Act (18 U.S.C. 1905), and
the Freedom of Information Act (FOIA) (5 U.S.C.
552), as well as FDA’s regulations in 21 CFR part
20.
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distribution of the finished smokeless
tobacco product that is the subject of the
record. However, for records relating to
alternative test methods under
§ 1132.16, the required 4-year retention
period would be for a period not less
than 4 years after the last date the
method that is the subject of the record
is used (e.g., 4 years from the last date
the manufacturer used an alternative
test method). FDA has selected 4 years
as a means to help ensure that the
records would be available for at least
one biennial FDA inspection under
sections 704 and 905(g) of the FD&C
Act.
FDA considered not requiring specific
recordkeeping requirements and,
instead, allowing the manufacturer to
determine recordkeeping needs but,
FDA believes that detailed
recordkeeping requirements are
necessary to confirm that the finished
smokeless tobacco products are in
compliance with the proposed standard.
For example, requiring manufacturers to
fully document their stability testing
protocols and test results will enable
FDA to confirm that the manufacturer’s
test method and protocols are adequate
to meet the requirements of part 1132.
In addition, requiring nonconforming
product records will help the
manufacturer and FDA determine the
extent of the nonconformity and, as
applicable, the locations where the
nonconforming products have been
distributed, in the event of a recall or
enforcement action (e.g., seizure).
VII. Proposed Effective Date
FDA proposes that any final rule on
the tobacco product standard for NNN
that may issue based on this proposal
become effective 3 years after the date
of publication of the final rule. FDA
believes this approach would allow
adequate time for developing any
necessary changes in technology to
achieve the NNN level, for any changes
made to manufacturers’ tobacco
purchasing choices and curing methods,
and for any preparation or changes
needed in facilities. In addition, FDA
believes that it will provide adequate
time for manufacturers to seek and
obtain marketing authorization from
FDA for their new tobacco products.
New tobacco products are subject to
enforcement if they are on the market
without FDA authorization.
Therefore, after the effective date of a
final rule for this proposed tobacco
product standard, no person would be
allowed to manufacture, distribute, sell,
or offer for sale or distribution within
the United States any finished
smokeless tobacco product that does not
comply with the rule. After the effective
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19:31 Jan 19, 2017
Jkt 241001
date of the final rule, manufacturers
would not be allowed to introduce into
domestic commerce any finished
smokeless tobacco product that does not
comply with the requirements of the
final rule, irrespective of the date of
manufacture. However, retailers would
be permitted to sell-off existing
inventory of noncompliant finished
smokeless tobacco products
manufactured before the effective date
for 60 days after the effective date of the
final rule. FDA notes that keeping
products with higher NNN levels on the
market for an extended period of time
after the effective date of the rule is not
in the interest of public health.
VIII. Incorporation by Reference
FDA is proposing to incorporate by
reference the test method entitled,
‘‘Determination of N-nitrosonornicotine
(NNN) in Smokeless Tobacco and
Tobacco Filler by HPLC–MS/MS,’’ LIB
No. 4620, January 2017 (Ref. 79). You
may obtain a free copy of the material
proposed to be incorporated from the
Docket at www.regulations.gov or from
the Food and Drug Administration,
Center for Tobacco Products, 10903
New Hampshire Ave., Silver Spring, MD
20993, 1–888–463–6332.
This is a technical document
developed by FDA specifically for use
in tobacco testing facilities. FDA
developed this test method for NNN in
order to streamline the testing process
and reduce testing costs. Other available
methods test for all TSNAs while this
test method is limited to NNN. As such
it is a highly specific method that
reduces testing costs while ensuring that
the results from the test method
demonstrate a high level of specificity,
accuracy, and precision in measuring a
range of NNN levels across a variety of
smokeless tobacco products.
This test method relies on several ISO
standards for determining moisture
content in tobacco and tobacco
products—ISO 6488:2004, ISO
6488:2004/Cor 1:2008, and ISO
16632:2013. FDA is not proposing to
incorporate these standards by
reference. You may purchase a copy of
the ISO standards from the International
Organization for Standardization, 1, ch.
de la Voie-Creuse, Case Postale 56, CH–
1211, Geneva 20, Switzerland, or from
the American National Standards
Institute, 1899 L Street NW., 11th Floor,
Washington, DC 20036, or on the
Internet at https://www.iso.org or
www.ansi.org. We note that these ISO
standards are relatively inexpensive
(about $50 each) and may already be
used by tobacco testing facilities.
For the reasons set forth in this
section, FDA considers the test method
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8037
proposed to be incorporated by
reference to be reasonably available and
usable by testing facilities (see 1 CFR
51.5(a) and 51.7).
IX. Economic Analysis of Impacts
We have examined the impacts of the
proposed 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 proposed
rule. We believe that this proposed rule
is an economically 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.
Because many smokeless tobacco
products may need to be reformulated,
and reformulation represents the main
driver of the costs of the rule, we
tentatively find that the proposed rule
would 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 proposing
‘‘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 proposed rule would
result in an expenditure in any year that
meets or exceeds this amount.
The proposed rule would establish a
product standard for all finished
smokeless tobacco products.
Specifically, the proposed rule would
require that all finished smokeless
tobacco products comply with a limit
for NNN in such products in order to be
marketed and distributed for sale in the
United States. This proposed product
standard would require that the mean
level of NNN in any batch of finished
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smokeless tobacco products not exceed
1.0 mg/g of tobacco (on a dry weight
basis) at any time through the product’s
labeled expiration date as determined
by product testing. The proposed
standard also includes requirements on
the sale and distribution of smokeless
tobacco products, product testing,
labeling, and recordkeeping.6
The costs of the proposed rule, when
finalized, will be due to affected entities
ensuring that the smokeless tobacco
products comply with the proposed
product standard. We have estimated
that the annualized costs associated
with the proposed rule over 20 years to
be between $17.91 million and $42.72
million using a 3 percent discount rate,
with a primary value of $30.31 million,
and between $20.11 million and $50.57
million, with a primary value of $35.34
million using a 7 percent discount rate.
The primary estimate for the present
value of total quantified costs over 20
years is approximately $450.97 million
at a 3 percent discount rate and $374.36
million at a 7 percent discount rate.
NNN is a carcinogenic agent found in
smokeless tobacco products. As
described in the preamble, on the basis
of the available scientific evidence, FDA
has determined that NNN is the
predominant driver of excess oral
cancer risk among smokeless tobacco
users.
We quantify benefits associated with
the proposed rule in the form of reduced
oral cancer morbidity and mortality
attributable to smokeless tobacco. As
described in section V.A.3 of the
preamble of the proposed rule, we also
expect the standard to reduce the risk of
esophageal cancer and it may reduce the
risks of other cancers such as
pancreatic, laryngeal, prostate, and lung
cancer. However, there is more limited
information to directly quantify these
health benefits. As such, we only
consider reductions in oral cancer as the
quantified benefit of the proposed
product standard.
Most of the estimated benefits arise
from quality life-years gains gained from
reduced oral cancer mortality. The
annualized value over 20 years of
quality adjusted life-years gained from
reduced oral cancer mortality ranges
from $228.66 million to $2.46 billion at
a 3 percent discount rate, with a
primary value of $858.46 million. Using
a 7 percent discount rate, the
annualized value of quality life-years
gained from averted deaths ranges from
$182.01 million to $1.96 billion, with a
primary value of $683.34 million. The
primary estimate of the present value of
mortality reductions quantified over 20
years is $12.77 billion at a 3 percent
discount rate and $7.24 billion at a 7
percent discount rate. The annualized
value over 20 years of quality adjusted
life-years gained from reduced oral
cancer mortality and morbidity ranges
from approximately $283.95 million to
$3.05 billion at a 3 percent discount
rate, with a primary value of $1.06
billion, and approximately $246.40
million to $2.65 billion, with a primary
value of $0.92 billion at a 7 percent
discount rate. The primary estimate of
the present value of total quantified
benefits over 20 years is approximately
$15.86 billion at a 3 percent discount
rate and $9.80 billion at a 7 percent
discount rate for reductions in oral
cancer alone. These values are likely an
underestimate of the benefits associated
with the proposed rule, as we do not
quantify reductions in mortality and
morbidity from cancers other than oral
cancer. Costs and benefits are
summarized in table 8.
The full analysis of economic impacts
is available in the docket for this
proposed rule (Ref. 146) and at https://
www.fda.gov/AboutFDA/Reports
ManualsForms/Reports/Economic
Analyses/default.htm.
TABLE 8—SUMMARY OF BENEFITS, COSTS AND DISTRIBUTIONAL EFFECTS OF PROPOSED RULE
Units
Category
Benefits:
Annualized Monetized millions/
year.
Annualized ...............................
Quantified ................................
Qualitative .......................................
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Costs:
Annualized ...............................
Monetized millions/year ...........
Annualized ...............................
Quantified ................................
Qualitative ...............................
Transfers:
Federal Annualized .................
Monetized $millions/year ................
Primary
estimate
Low
estimate
High
estimate
Discount
rate
(%)
Year
dollars
$246.40
$2,647.21
2015
7
20
$1,065.92
................
................
................
$ 283.95
................
................
................
$3,051.09
................
................
................
2015
................
................
................
3
7
3
................
20
20
20 years
................
$35.34
$30.31
................
................
................
$20.11
$17.91
................
................
................
$50.57
$42.72
................
................
................
2015
2015
................
................
................
7
3
7
3
................
20
20
20
20
................
.......................................................................................
.......................................................................................
.......................................................................................
.......................................................................................
.......................................................................................
................
................
................
................
................
................
7
................
20
3
................
20
.......................................................................................
7
20
.......................................................................................
................
6 The proposed product standard includes a
number of requirements in addition to the actual
NNN limit, including requirements related to
product testing, recordkeeping, and sale and
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20:18 Jan 19, 2017
Notes
$924.91
From:
Other Annualized ....................
Period
covered
(years)
Jkt 241001
................
To:
................
................
distribution restrictions. However, generally, this
analysis uses the term product standard as
shorthand for the NNN limit requirement. Similarly
when we discuss anticipated compliance status and
PO 00000
Most of the health benefits included in the totals
would be realized more than 20 years after publication of the final rule, but the risk reductions associated with these benefits occur during the 20-year
period beginning at publication of the final rule.
.......................................................................................
.......................................................................................
.......................................................................................
Potential cost savings from net life-time reduction in
medical care utilization; additional health benefits
from reduction in other toxicants correlated with
NNN; reduction in cancers, other than oral cancers
Frm 00036
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compliant versus noncompliant products, we
generally refer to compliance with the NNN limit
requirement.
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8039
TABLE 8—SUMMARY OF BENEFITS, COSTS AND DISTRIBUTIONAL EFFECTS OF PROPOSED RULE—Continued
Units
Category
Monetized $millions/year .........
Primary
estimate
Low
estimate
High
estimate
................
................
................
Year
dollars
................
From:
Effects
.........................................................
.........................................................
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XI. Paperwork Reduction Act of 1995
This proposed rule contains
information collection provisions that
are subject to review by the Office of
Management and Budget (OMB) under
the Paperwork Reduction Act of 1995
(44 U.S.C. 3501–3520). A description of
these provisions is given in the
Description section of this document
with an estimate of the annual
reporting, recordkeeping, and thirdparty disclosure burden. 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.
FDA invites comments on these
topics: (1) Whether the proposed
collection of information is necessary
for the proper performance of FDA’s
functions, including whether the
information will have practical utility;
(2) the accuracy of FDA’s estimate of the
burden of the proposed collection of
information, including the validity of
the methodology and assumptions used;
(3) ways to enhance the quality, utility,
and clarity of the information to be
collected; and (4) ways to minimize the
burden of the collection of information
20:18 Jan 19, 2017
3
Period
covered
(years)
20
Notes
.......................................................................................
To:
State, Local or Tribal Government: None estimated.
Small Business: The average cost per small entity is largest in Year 1 and range between $2.67 million and $7.97 million. Reformulation costs and stability testing represent the largest proportion of costs—up to 60 percent of average sales for entities with fewer than 50 employees and up to 13 percent of average sales for entities with 50–100 employees.
Wages: None estimated.
Growth: None estimated.
X. Analysis of Environmental Impact
The Agency has carefully considered
the potential environmental effects of
this action. 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. Under
FDA’s regulations implementing the
National Environmental Policy Act (21
CFR part 25), an action of this type
would require an environmental
assessment under 21 CFR 25.20.
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on respondents, including through the
use of automated collection techniques,
when appropriate, and other forms of
information technology.
Title: Tobacco Product Standard:
NNN Level in Finished Smokeless
Tobacco Products.
Description: FDA is proposing a
product standard to establish a limit of
NNN in finished smokeless tobacco
products sold in the United States.
Products with higher NNN levels pose
higher risks of cancer and FDA finds
that establishing a NNN limit in
finished smokeless tobacco products is
appropriate for the protection of the
public health. Proposed § 1132.10
would require that the mean level of
NNN in any batch of finished smokeless
tobacco products not exceed 1.0 mg/g of
tobacco (on a dry weight basis) at any
time through the product’s labeled
expiration date as determined by testing
in compliance with § 1132.12. Proposed
§§ 1132.12, 1132.14, 1132.16, and
1132.18 would establish product testing
and sampling plan requirements.
Proposed § 1132.12 would require two
types of testing for smokeless tobacco
products—stability testing and batch
testing. Proposed § 1132.12(a) would
require initial and annual stability
testing to assess the stability of the NNN
level in finished smokeless tobacco
products and to establish and verify the
product’s expiration date and storage
conditions (either room temperature or
refrigeration). Proposed § 1132.12(b)
would require manufacturers to conduct
batch testing on each batch of finished
smokeless tobacco product to determine
whether the products conform to the
proposed NNN limit. Proposed
§ 1132.12(c) would require the tobacco
product manufacturer to document all
testing.
Proposed §§ 1132.14 and 1132.16
would establish the standard and
alternative test methods. If a tobacco
product manufacturer were to choose
not to use the standard test method in
§ 1132.14 to test its smokeless tobacco
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products, the manufacturer would be
required to use a validated alternative
test method that conforms to the
requirements of proposed § 1132.16.
Proposed § 1132.16(a) would require
that, before using a validated alternative
test method, the manufacturer notify the
Center for Tobacco Products.
Proposed§ 1132.18 would establish
the sampling requirements for all
testing. These sampling requirements
would be used in conjunction with the
product testing required in proposed
§ 1132.12 (stability testing and batch
testing) and would provide procedures
for the manufacturer to select samples to
demonstrate conformance with the
proposed NNN limit.
Proposed § 1132.22 would require
tobacco product manufacturers to
establish and maintain procedures to
identify, investigate, segregate, and
make disposition decisions about
nonconforming finished smokeless
tobacco products in order to prevent
their release for commercial distribution
and to conduct investigations related to
nonconforming products.
Under proposed § 1132.30, the labels
of finished smokeless tobacco products
would be required to contain a
manufacturing code, expiration date,
and, if applicable, storage conditions for
the finished smokeless tobacco product.
The information would have to be
printed on or permanently affixed to the
package assuring that the label remains
intact through the expected duration of
use. It must appear clearly, legibly, and
indelibly in the English language. The
expiration date must appear on the
packaging in two-digit numerical
values. If the manufacturer determines
by stability testing that meets the
requirements in § 1132.12 that the
finished smokeless tobacco product
must be stored in a refrigerator, the
package label must state ‘‘Keep
Refrigerated.’’ The manufacturing code
would provide a history of the
manufacturing, processing, packaging,
labeling, holding, and initial
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distribution of the product from records
maintained by the tobacco product
manufacturer.
Proposed § 1132.32 would require
that tobacco product manufacturers
maintain records regarding the product
testing (i.e., stability and batch testing),
including protocols and a full report of
the source data and results; records
regarding investigations related to
shortening of expiration dates based on
results of annual stability testing; all
notifications of an alternative test
method and source data for alternative
test method validation; all sampling
plans and reports; documentation that
the persons performing sampling have
sufficient education, training, and
experience to accomplish the assigned
functions; all identification,
investigation, segregation, and
disposition procedures related to
nonconforming products; and all
nonconforming product investigations
and rework (i.e., the processing of
nonconforming finished smokeless
tobacco products to meet the
requirements of part 1132). FDA is also
proposing to require copies of all
records be retained for a period of not
less than 4 years from the date of
commercial distribution of the finished
smokeless tobacco product that is the
subject of the record, except that certain
records relating to alternative test
methods would be required to be
retained for a period of not less than 4
years after the last date the method is
used. FDA has selected 4 years as a
means to help ensure that the records
would be available for at least one
biennial FDA inspection under sections
704 and 905(g) of the FD&C Act.
Description of Respondents: The
provisions of this standard would apply
to finished smokeless tobacco products.
Finished smokeless tobacco product
means a smokeless tobacco product,
including all parts and components,
packaged for consumer use, except for
components, parts, or accessories sold
without tobacco. The respondents are
therefore manufacturers of smokeless
tobacco products.
FDA estimates the burden of this
collection of information as follows:
TABLE 9—ESTIMATED ANNUAL REPORTING BURDEN 1
Number of
respondents
21 CFR part
Number of
responses per
respondent
Average
burden per
response
Total annual
responses
Total hours
§ 1132.16 Alternative Test Method (FDA Form 3979) ........
§ 1132.16 Waiver from Electronic Submission ....................
23
2
1
1
23
2
20
.75
460
2
Total ..............................................................................
........................
........................
........................
........................
462
1
There are no capital costs or operating and maintenance costs associated with this collection of information.
The burden in the reporting chart corresponds to table 23 ‘‘Estimated Costs to Industry Associated with Notifications to FDA Regarding Use
of Alternative Testing Methods’’ in the RIA.
2
TABLE 10—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1
Number of
recordkeepers
Activity (units)
Number of
records per
recordkeeper
Total annual
records
Average
burden per
recordkeeping
Total hours
Change in process (Formulations) ......................................
Ingredient change (Formulations) ........................................
No change (Formulations) ...................................................
Labeling records, annual after year 1 (UPCs) .....................
Initial Stability Testing records (Manufacturers) ..................
Annual Stability Testing records (Manufacturers) ...............
Batch Testing (products) ......................................................
Batch Testing records (Manufacturers) ...............................
Procedures for nonconforming products and related investigations (Manufacturers) ..................................................
Notifications, alternate testing methods (Manufacturers) ....
68
28
60
1255
23
23
784
23
1
1
1
1
8
3
28
1
68
28
60
1255
184
69
21,952
23
8
8
4
2
4
4
4
4
544
224
240
2,510
736
276
87,808
92
23
23
1
2
23
46
4
0.75
92
35
Total 1 ............................................................................
........................
........................
........................
........................
92,557
1
There are no capital costs or operating and maintenance costs associated with this collection of information.
The burden in the recordkeeping chart corresponds to table 24 ‘‘Estimated Recordkeeping Costs to Industry’’ and table 13 ‘‘Estimated Number of Batch Tests’’ in the RIA.
2
TABLE 11—ESTIMATED ANNUAL THIRD-PARTY DISCLOSURE BURDEN 1
Number of
respondents
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Activity (units)
Number of
disclosures
per respondent
Total annual
disclosures
Average
burden per
disclosure
Total hours
Package Labeling Change Minor (UPCs) ...........................
Package Labeling Change Major (UPCs) ...........................
Initial Stability Testing (one time) (Products) .......................
Initial Stability Testing (recurring) (Products) ......................
Annual Stability Testing (Products) .....................................
Sampling Plans (Products) ..................................................
459
8
784
784
784
784
1
1
168
6.72
60.48
1
459
8
131,712
5,268
47,416
784
10
23
2
2
2
2
4,590
184
263,424
10,536
94,832
1,568
Total 1 ............................................................................
........................
........................
........................
........................
370,360
1
There are no capital costs or operating and maintenance costs associated with this collection of information.
The burden in the third-party disclosure chart corresponds to table 12 ‘‘Estimated Costs Associated with Proposed Stability Testing Requirements’’ and table 15 ‘‘Products with Expiration and Storage Information’’ in the RIA.
2
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FDA’s burden estimates are based on
the regulatory impact analysis, Agency
expertise, registration and listing data,
company revenue information from
Dunn & Bradstreet, and comparing to
other online sources in order to
categorize the entities and number of
products.
Table 9 describes the annual reporting
burden as a result of the requirements
proposed in § 1132.16 submitting a
notification of an alternative test
method and requesting a waiver from
electronic submission of such a
notification. FDA estimates that it will
receive 23 notifications for alternative
test methods using FDA Form 3979 (Ref.
145) for a total of 460 hours. Because
some of the manufacturers may
currently be conducting these reports,
the RIA anticipates that there would be
between 1 and 23 manufacturers
affected. For PRA purposes we have
used the high estimate of 23. FDA also
estimates that 2 respondents will submit
a waiver request from electronic
submission. Therefore, the total
estimated reporting burden for this
proposed rule is 462 hours.
Table 10 outlines the recordkeeping
requirements that are proposed in
§ 1132.32. We note that recordkeeping
time burden activities are derived from
the respective models (RTI
International, 2015a; RTI International,
2015a; RTI International, 2015(b). FDA
estimates recordkeeping time burden
related to product reformulation (change
in process, ingredient change, and no
change) to involve 156 formulations for
total of 1,008 hours. For recordkeeping
burden related to certain labeling
records, FDA estimates that after year
one 1,255 affected Universal Product
Code (UPC) records will be kept
annually for a total of 2,510 hours. The
number of UPCs subject to these
recordkeeping requirements is
determined by multiplying the number
of UPCs in each product category by the
percent of products with expiration date
information.
We estimate that batch testing will be
conducted for 784 products (21,952 tests
per year) for a total of 87,808 hours.
Proposed § 1132.32 requires records to
be maintained for stability and batch
tests. FDA estimates that 23
manufacturers will maintain records
related to initial stability testing, annual
stability testing, and batch testing for a
total of 1104 hours. Records are also
required to be maintained of procedures
for nonconforming products and related
investigations. We estimate that 23
manufacturers will maintain these
records for a total of 92 hours. Proposed
§ 1132.32 requires manufacturers to
maintain all notifications of an
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alternative test method. We estimate
that 23 manufacturers will maintain
these records for a total of 35 burden
hours. Therefore, the total estimated
recordkeeping hours are 92,557.
Table 11 represents third party
disclosures (package labeling) that a
respondent must display. This table also
covers the proposed stability testing that
must occur for the label. Labeling
burden is estimated by using data on the
number of active UPCs from Nielsen
Inc., and the estimated percentage of
products with expiration and storage
information come from FDA
Registration and Listing database (as of
March 1, 2016). To derive the number
of UPCs subject to a labeling change that
includes storage information, we
assume that only those products that are
currently refrigerated but for which we
did not find evidence that the labeling
exists would incur such labeling
change. Thus, we estimate that these
different products that would likely be
affected by labeling changes would
include up to 467 UPCs (derived by
assuming that each product would be
associated with one unique UPC).
Since all products already have either
an expiration date or a manufactured on
date, adding an expiration date or
storage conditions to labeling would be
considered a minor change if product
label redesign is not needed and major
if product label redesign is needed. FDA
believes that labeling changes associated
with adding storage information is
assumed to be ‘‘major’’ to incorporate
uncertainty regarding product label
redesign. We estimate that 459 affected
UPCs will undergo minor labeling
changes for a total of 4,590 hours.
Additionally, FDA estimates that 8
affected UPCs will undergo major
labeling changes regarding storage
information for a total of 184 hours.
Since establishing and verifying a
product’s expiration date and storage
conditions on a label requires actual
stability testing we categorize this
burden under third party disclosures.
For PRA purposes we have categorized
stability testing under third party
disclosures. For example, in accordance
with § 1132.30 a package label would
need to have the expiration date for the
product. Prior to completing initial
stability testing, the manufacturer might
not know what the appropriate
expiration date would be. Since the
testing will inform the label we believe
it is appropriate for the burden to fall
under this category. We estimate that
784 products would undergo initial
stability testing, and annual stability
testing each year thereafter. FDA
estimates that in year 1 there would be
131,712 initial tests for a total of
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263,424 hours. After the first year we
estimate that there would be 5,268
initial tests for a total of 10,536 hours.
After the initial testing we expect 47,416
annual tests per year for total of 94,832
hours.
FDA included sampling plans in the
third party disclosure chart because
each tobacco product manufacturer
would be required to demonstrate that
the finished smokeless tobacco
product’s expiration date (on the label)
is appropriate under the intended
storage conditions, and to do so the
manufacturer would conduct testing
pursuant to sampling plans. In
developing a sampling plan for NNN in
smokeless tobacco products a
manufacturer must take into account the
size of a batch, the variation of NNN in
their product, the margin of error
around their analytical techniques, and
any other variables they can justify as
pertinent to their calculation. While the
development of a sampling plan would
require some data analysis and
determination of assumptions, we
believe that the development of a
sampling plan could cover multiple
products. In addition once a sampling
plan had been developed we believe
that there would be significant
redundancy in the development of
subsequent plans which would reduce
the time needed to complete them.
Ultimately we have estimated that the
time for the development of a sampling
plan would average 2 hours per product
for a total of 1,568 hours. Therefore, the
total third party disclosure burden is
estimated to be 370,360 hours.
FDA estimates that the total burden
imposed by these proposed
requirements will be 463,379 hours (462
reporting, 92,557 recordkeeping, and
370,360 third party disclosures).
This proposed rule also refers to
previously approved collections of
information found in FDA regulations.
The collections of information in
section 905(j) of the FD&C Act
(substantial equivalence reports) have
been approved under OMB control
number 0910–0673.
To ensure that comments on
information collection are received,
OMB recommends that written
comments be faxed to the Office of
Information and Regulatory Affairs,
OMB (see ADDRESSES). All comments
should be identified with the title of the
information collection.
In compliance with the Paperwork
Reduction Act of 1995 (44 U.S.C.
3407(d)), the Agency has submitted the
information collection provisions of this
proposed rule to OMB for review. These
requirements will not be effective until
FDA obtains OMB approval. FDA will
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publish a notice concerning OMB
approval of these requirements in the
Federal Register.
XII. Executive Order 13132
FDA has analyzed this proposed rule
in accordance with the principles set
forth in Executive Order 13132. FDA
has determined that the proposed rule,
if finalized, would not contain policies
that would 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, the Agency tentatively
concludes that the proposed 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.
XIII. Executive Order 13175
FDA has analyzed this proposed rule
in accordance with the principles set
forth in Executive Order 13175. We
have tentatively concluded that the rule
does not contain policies that would
have a substantial direct effect on one or
more Indian tribes, on the relationship
between the Federal Government and
Indian tribes, or on the distribution of
power and responsibilities between the
Federal Government and Indian tribes.
The Agency solicits comments from
tribal officials on any potential impact
on Indian tribes from this proposed
action.
XIV. References
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The following references are on
display in the Division of Dockets
Management (see ADDRESSES) and are
available for viewing by interested
persons between 9 a.m. and 4 p.m.,
Monday through Friday; they are also
available electronically at https://
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.
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List of Subjects in 21 CFR Part 1132
Administrative practice and
procedure, Incorporation by reference,
Labeling, Smokeless tobacco, Tobacco
products.
Therefore, under the Federal Food,
Drug, and Cosmetic Act and under
authority delegated to the Commissioner
of Food and Drugs, it is proposed that
chapter I of title 21 of the Code of
Federal Regulations be amended by
adding part 1132 to subchapter K to
read as follows:
PART 1132—PRODUCT STANDARD:
DETERMINATION OF NNITROSONORNICOTINE (NNN) LEVEL
IN FINISHED SMOKELESS TOBACCO
PRODUCTS
Subpart A—General Provisions
1132.1 Scope.
1132.3 Definitions.
1132.5 Incorporation by reference.
Subpart B—Product Requirements
1132.10 NNN Level.
1132.12 Product testing.
1132.14 Standard test method.
1132.16 Alternative test method.
1132.18 Sampling plans and procedures.
1132.20 Expiration date.
1132.22 Nonconforming product.
Subpart C—Labeling and Recordkeeping
Requirements
1132.30 Package label requirements.
1132.32 Recordkeeping requirements.
Authority: 21 U.S.C. 331, 371, 374, 387b,
387c, 387f(d), 387g, 387i.
Subpart A—General Provisions
§ 1132.1
Scope.
(a) This part sets forth the
requirements for the maximum level of
N-nitrosonornicotine (NNN) in finished
smokeless tobacco products. The
provisions of this standard apply to
finished smokeless tobacco products as
defined in § 1132.3.
(b) No person may manufacture,
distribute, sell, or offer for sale or
distribution within the United States a
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finished smokeless tobacco product that
is not in compliance with this part.
(c) Tobacco retailers and distributors
will not be considered in violation of
this part as it relates to the sale or
distribution or offer for sale or
distribution of finished smokeless
tobacco products that exceed the NNN
level set forth in § 1132.10 if they:
(1) Store and transport the finished
smokeless tobacco products according
to the package label;
(2) Do not sell or distribute or offer for
sale or distribution finished smokeless
tobacco products past their expiration
date, except to return expired products
to the manufacturer;
(3) Do not conceal, alter, or remove
the expiration date or storage conditions
on the package label; and
(4) Do not sell or distribute or offer for
sale or distribution finished smokeless
tobacco products that are open or have
broken seals.
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§ 1132.3
Definitions.
For purposes of this part:
Batch means a specific identified
amount of a finished smokeless tobacco
product produced in a unit of time or
quantity and that is intended to have the
same characteristics.
Commercial distribution means any
distribution of a finished smokeless
tobacco product to consumers or to
another person through sale or
otherwise, but does not include
interplant transfers of a tobacco product
between registered establishments
within the same parent, subsidiary, and/
or affiliate company, nor does it include
providing a tobacco product for product
testing where such product is not made
available for consumption or resale.
Finished smokeless tobacco product
means a smokeless tobacco product,
including all parts and components,
packaged for consumer use, except for
components, parts, or accessories sold
without tobacco. An example of a
finished smokeless tobacco product is a
tin or can of loose snuff or a pouch
containing chewing tobacco.
Manufacturing code means any
distinctive sequence or combination of
letters, numbers, or symbols that begins
with the manufacturing date in 2-digit
numerical values in the month, day,
year format (mmddyy) followed by the
batch number from which the
production batch can be identified.
Manufacturing date means the month,
day, and year that a smokeless tobacco
product is packaged for consumer use
(i.e., when the package label has been
added to the product).
N-nitrosonornicotine (NNN) means a
tobacco-specific nitrosamine (TSNA)
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with the chemical formula
C[9]H[11]N[3]O.
New tobacco product means:
(1) Any tobacco product (including
those products in test markets) that was
not commercially marketed in the
United States as of February 15, 2007;
or
(2) Any modification (including a
change in design, any component, any
part, or any constituent, including a
smoke constituent, or in the content,
delivery or form of nicotine, or any
other additive or ingredient) of a
tobacco product where the modified
product was commercially marketed in
the United States after February 15,
2007.
Package means a pack, box, carton, or
container of any kind or, if no other
container, any wrapping (including
cellophane), in which a tobacco product
is offered for sale, sold, or otherwise
distributed to consumers.
Performance criteria means the
validation requirements for the
acceptability of an analytical test
method, including accuracy, precision,
recovery, linearity, specificity, limit of
quantitation, limit of detection,
robustness, and range.
Person includes an individual,
partnership, corporation, or association.
Rework means the processing of
nonconforming finished smokeless
tobacco products to meet the
requirements of this part.
Smokeless tobacco means any tobacco
product that consists of cut, ground,
powdered, or leaf tobacco and that is
intended to be placed in the oral or
nasal cavity.
Source data means all information
contained in original laboratory records
or exact copies of original records of
experimental findings, observations, or
other activities used for the creation,
reconstruction, and evaluation of a
study or other laboratory work. Source
data includes any laboratory
worksheets, notebooks, correspondence,
notes, and other documentation
(regardless of capture medium) that are
the result of original observations and
activities of a laboratory study or other
laboratory work.
Tobacco product, as stated in section
201(rr) of the Federal Food, Drug, and
Cosmetic Act in relevant part:
(1) Means any product made or
derived from tobacco that is intended
for human consumption, including any
component, part, or accessory of a
tobacco product (except for raw
materials other than tobacco used in
manufacturing a component, part, or
accessory of a tobacco product); and
(2) Does not mean an article that is a
drug defined in section 201(g)(1) of the
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Federal Food, Drug, and Cosmetic Act,
a device defined in section 201(h) of the
Federal Food, Drug, and Cosmetic Act,
or a combination product described in
section 503(g) of the Federal Food, Drug,
and Cosmetic Act.
Tobacco product manufacturer means
any person, including a repacker or
relabeler, who:
(1) Manufactures, fabricates,
assembles, processes, or labels a tobacco
product; or
(2) Imports a finished tobacco product
for sale or distribution in the United
States.
Tobacco-specific nitrosamine (TSNA)
means a chemical compound formed
through the chemical reaction involving
the nitrosation of nicotine, nornicotine,
anabasine, or anatabine during the
growing, curing, processing, or storage
of tobacco.
United States means the 50 States of
the United States of America and the
District of Columbia, the
Commonwealth of Puerto Rico, Guam,
the Virgin Islands, American Samoa,
Wake Island, Midway Islands, Kingman
Reef, Johnston Atoll, the Northern
Mariana Islands, and any other trust
territory or possession of the United
States.
§ 1132.5
Incorporation by reference.
(a) The Director of the Federal
Register approves this material for
incorporation by reference into this part
in accordance with 5 U.S.C. 552(a) and
1 CFR part 51. You may obtain a copy
of the material from the sources listed
below. You may inspect a copy at the
U.S. Food and Drug Administration,
Division of Dockets Management, 5630
Fishers Lane, Rm. 1061, Rockville, MD
20852 or 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.
(b) Center for Tobacco Products, U.S.
Food and Drug Administration, 10903
New Hampshire Ave., Silver Spring, MD
20993; 1–888–463–6332.
(1) ‘‘Determination of Nnitrosonornicotine (NNN) in Smokeless
Tobacco and Tobacco Filler by HPLC–
MS/MS,’’ LIB No. 4620, January 2017;
into § 1132.14. (Also available at https://
www.fda.gov/ScienceResearch/
FieldScience/ucm231463.htm.)
(2) [Reserved]
Subpart B—Product Requirements
§ 1132.10
NNN level.
The mean level of NNN in any batch
of finished smokeless tobacco product
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must not exceed 1.0 microgram per
gram (mg/g) of tobacco (on a dry weight
basis) at any time through the product’s
labeled expiration date as determined
by testing in compliance with § 1132.12.
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§ 1132.12
Product testing.
(a) Stability testing. Each tobacco
product manufacturer must conduct
testing to assess the stability of the NNN
level in its finished smokeless tobacco
products. The results of stability testing
must be used to establish and verify the
product’s expiration date and storage
conditions (either room temperature or
refrigeration).
(1) Test method. The manufacturer
must use either the standard test
method in § 1132.14 or an alternative
test method that meets the requirements
set forth in § 1132.16. Samples for
testing must be selected in accordance
with the requirements set forth in
§ 1132.18(a) and (c).
(2) Written protocol. Each
manufacturer must establish and
maintain a written protocol that
addresses all stability testing. The
protocol must fully describe the
methodology used to determine the
stability of the NNN level, including the
test method used (the standard test
method in § 1132.14 or an alternative
test method in accordance with
§ 1132.16), the sampling plan and
procedures required by § 1132.18(a) and
(c), and the storage conditions.
(3) Initial stability testing. A
manufacturer must conduct initial realtime stability testing that covers each
finished smokeless tobacco product and
use the results to establish an expiration
date and appropriate storage conditions
(either room temperature or
refrigeration) for the product. The
expiration date and storage conditions
must be displayed on the package label
in accordance with § 1132.30.
(i) For initial real-time stability
testing, at a minimum, samples must be
tested within 7 days of manufacture and
at the expected expiration date.
(A) If the proposed storage condition
is room temperature, samples for initial
real-time stability testing must be stored
at 25 ± 2 degrees Celsius and 60 ± 5%
relative humidity.
(B) If the proposed storage condition
is refrigeration, samples for initial realtime stability testing must be stored at
5 ± 2 degrees Celsius.
(ii) If initial real-time stability testing
is in progress but not yet complete, the
manufacturer may concurrently conduct
accelerated stability testing to establish
the product’s expiration date and
storage conditions. The manufacturer
may use an expiration date of no longer
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than 1 year based on initial accelerated
stability testing.
(iii) For initial accelerated stability
testing, at a minimum, samples must be
tested at three time points within a 6
month period. The first time point must
be within 7 days of manufacture and the
last time point at 6 months after
manufacture.
(A) If the proposed storage condition
is room temperature, samples for initial
accelerated stability testing must be
stored at 40 ± 2 degrees Celsius and 75
± 5% relative humidity.
(B) If the proposed storage condition
is refrigeration, samples for initial
accelerated stability testing must be
stored at 25 ± 2 degrees Celsius and 60
± 5% relative humidity.
(iv) If initial accelerated stability
testing shows the NNN level in the
finished smokeless tobacco products
will not conform to § 1132.10, the
manufacturer must establish an
expiration date and storage conditions,
as determined by the results of initial
real-time stability testing.
(4) Annual stability testing. A
manufacturer must conduct annual realtime stability testing on each finished
smokeless tobacco product to verify the
results of the initial stability testing and
to ensure that the expiration date and
storage conditions remain appropriate.
Accelerated stability testing may not be
used for annual stability testing.
(i) Except as provided in paragraph
(a)(4)(ii) of this section, annual real-time
stability testing must begin within 12
months of the completion of initial
stability testing and then annually
thereafter, with no longer than 12
months between testing.
(ii) When a manufacturer has not
conducted initial real-time stability
testing on a particular smokeless
tobacco product because it has
determined that the results from initial
real-time stability testing conducted on
another product apply, annual real-time
stability testing must begin when the
product is first released for commercial
distribution and then annually
thereafter, with no longer than 12
months between testing.
(iii) For annual real-time stability
testing, at a minimum, samples must be
tested within 7 days of manufacture and
at the established expiration date.
(A) If the intended storage condition
is room temperature, samples for annual
real-time stability testing must be stored
at 25 ± 2 degrees Celsius and 60% ± 5%
relative humidity.
(B) If the intended storage condition
is refrigeration, samples for annual realtime stability testing must be stored at
5 ± 2 degrees Celsius.
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(iv) If the results of the most recent
annual real-time stability testing do not
support the finished smokeless tobacco
product’s expiration date, the
manufacturer must use those results to
establish a new expiration date. After a
new expiration date has been
established, the package labels of all
affected finished smokeless tobacco
products that have not been released for
commercial distribution must display
the new expiration date and storage
conditions, in accordance with
§ 1132.30.
(v) If the finished smokeless tobacco
product’s expiration date must be
shortened due to the results of the
annual real-time stability testing, the
manufacturer must conduct an
investigation to determine why the
results of the most recent stability
testing do not support the product’s
previously established expiration date.
The investigation must be fully
documented and the records maintained
in accordance with § 1132.32.
(b) Batch testing. Tobacco product
manufacturers must conduct testing on
each batch of finished smokeless
tobacco product to ensure that the
products conform with § 1132.10. The
manufacturer must use either the
standard test method in § 1132.14 or an
alternative test method that meets the
requirements set forth in § 1132.16.
Samples for testing each batch to
determine if a product conforms with
§ 1132.10 must be selected in
accordance with the requirements set
forth in § 1132.18(b) and (c).
(c) Documentation of test results. A
full report of the source data and results
of all stability and batch testing must be
maintained by the tobacco product
manufacturer in accordance with
§ 1132.32, including the following:
(1) Full identification of the
smokeless tobacco product that is the
subject of the report, including product
subcategory, brand, subbrand, package
size and quantity of product (mass and,
if portioned, count) and, for portioned
tobacco products, the size (mass) of each
portion;
(2) NNN level of each sample tested;
(3) Mean NNN level and standard
deviation;
(4) The batch manufacturing date and
location, including facility name and
address;
(5) The location, including facility
name and address, from which each
sample was pulled;
(6) The manufacturing code of each
sample tested or, for samples for initial
stability testing with no manufacturing
code, an identifying code created by the
manufacturer;
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(7) The testing date and location,
including the testing facility name and
address;
(8) The test method and sampling
procedure used;
(9) All tobacco product reference
standard test results;
(10) The names and qualifications of
the person(s) conducting the testing;
(11) The equipment used (including
documentation to show that the
equipment is appropriate for its
intended use and has been calibrated);
and
(12) For batch testing only, the criteria
used to make a decision to accept or
reject each batch and the decision made
with respect to each batch (e.g., accept,
reject) based on the results of the
product testing, including, where
applicable, the NNN level of the
individual batch, the results of the
product’s stability testing, and the
decision made and justification with
respect to the results of a
nonconforming product investigation
under § 1132.22.
§ 1132.14
Standard test method.
(a) The standard test method for this
part is the method entitled
‘‘Determination of N-nitrosonornicotine
(NNN) in Smokeless Tobacco and
Tobacco Filler by HPLC–MS/MS,’’,
incorporated by reference in § 1132.5.
(b) In the event of an inconsistency
between a material incorporated by
reference and the definitions and
methods described in this part,
definitions and methods in this part will
apply.
mstockstill on DSK3G9T082PROD with PROPOSALS2
§ 1132.16
Alternative test method.
Tobacco product manufacturers may
use a validated alternative test method
in accordance with this section, only if
the alternative method meets or exceeds
the performance criteria of the standard
test method set forth in § 1132.14.
(a) Notice requirement. Tobacco
product manufacturers who intend to
use a validated alternative test method
to that listed in § 1132.14 for
determining conformance with
§ 1132.10 must notify the Director,
Office of Science, Center for Tobacco
Products, before beginning use of the
alternative test method. Manufacturers
may begin using the alternative test
method 60 calendar days after FDA
receives the notification as set forth in
paragraph (f) of this section unless FDA
notifies the manufacturer that the
alternative test method has not been
demonstrated to meet or exceed the
performance criteria of the standard test
method set forth in § 1132.14.
(b) Contents of notification of an
alternative test method. The
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manufacturer must include in the
notification of an alternative test
method the following information:
(1) General information. The
following information must be
submitted using the form that FDA
provides:
(i) The date the manufacturer
submitted the notification to FDA;
(ii) Identification of the submission as
a notification of an alternative test
method;
(iii) The manufacturer’s name,
address, and contact information;
(iv) Identification of and contact
information for an authorized
representative of the manufacturer
(which could be a U.S. agent for the
manufacturer), including name, address
(mailing and email), and telephone
number;
(v) Identification of the subcategories
of finished smokeless tobacco products
that can be analyzed using the
alternative test method; and
(vi) The testing facility’s name and
address.
(2) Index and table of contents. A
comprehensive index and table of
contents.
(3) Summary. The notification must
include a summary section that contains
the following information:
(i) Identification of the standard test
method for which the alternative test
method is being proposed;
(ii) A concise description of the
performance criteria of the alternative
test method;
(iii) A concise explanation of why the
manufacturer is proposing to use the
alternative test method; and
(iv) A concise comparison of the
similarities and differences between the
alternative test method and the standard
test method.
(4) Complete description. The
notification must describe the
alternative test method in sufficient
detail to enable FDA to evaluate
whether the information provided
demonstrates that the alternative test
method meets or exceeds the
performance criteria of the standard test
method set forth in § 1132.14. This
description must include:
(i) A complete description of the
manner in which the alternative test
method is proposed to deviate from the
standard test method and a complete
explanation, with scientific rationale
and supported by appropriate data,
including a complete copy of the testing
protocol, to demonstrate that the
alternative test method meets or exceeds
the performance criteria of the standard
test method set forth in § 1132.14; and
(ii) Any data and information from
other studies comparing the alternative
test method to the standard test method.
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(c) Relevant information. If requested
by FDA, the manufacturer must submit
any other relevant information needed
to evaluate the alternative test method.
(d) Format for notifications of an
alternative test method.
(1) General requirements. All
notifications must be submitted using
the form that FDA provides and must be
well-organized and legible, and written
in English.
(2) Electronic format requirement.
Except as provided in paragraph (d)(3)
of this section, notifications of an
alternative test method must be
submitted using the Agency’s electronic
system. The notification and all
supporting information must be in an
electronic format that the Agency can
process, review, and archive.
(3) Waivers from electronic format
requirement. If a notification cannot be
submitted electronically, a waiver may
be requested. Waivers will be granted
only if use of electronic means is not
reasonable for the tobacco product
manufacturer requesting the waiver. If
FDA grants the waiver request, FDA will
provide information on where to send
the notification in paper form. To
request a waiver, manufacturers must
send a written request that is legible and
in English to the Document Control
Center (ATTN: Office of Science) at the
address included on our Web site. The
written request must contain the
following information:
(i) The name and address of the
tobacco product manufacturer that
wishes to submit the notification, the
name of an authorized representative of
the manufacturer (which could be a U.S.
agent for the manufacturer), and their
contact information.
(ii) A statement that creation and/or
submission of information in electronic
format is not reasonable for the
manufacturer requesting the waiver, and
an explanation of why creation and/or
submission in electronic format is not
reasonable. This statement must be
signed by a person who is authorized to
make the declaration on behalf of the
tobacco product manufacturer.
(e) Applicability of an alternative test
method. An alternative test method may
be implemented only by the tobacco
product manufacturer that submitted
the notification and only with respect to
the subcategories of finished smokeless
tobacco products that were the subject
of the notification. Other manufacturers
interested in similar or identical
alternative test methods must submit
their own notifications following the
procedures of this section.
(f) Action on notifications. FDA will
acknowledge the receipt of a
notification of an alternative test
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method. Manufacturers may implement
an alternative test method beginning 60
calendar days after FDA receives the
notification of alternative test method
unless FDA notifies them otherwise.
(1) If a notification is complete when
received, the 60 calendar day period
begins on the date FDA receives the
notification.
(2) If any element required under
paragraph (b) of this section is missing
from a notification, FDA will not accept
the notification submission and will
inform the manufacturer.
(3) If FDA determines that an
alternative test method has not been
demonstrated to meet or exceed the
performance criteria of the standard test
method set forth in § 1132.14, FDA will
inform the submitter. If FDA informs the
submitter during the 60 calendar day
period, the submitter must not
implement the alternative test method.
If FDA determines that an alternative
test method does not comply with this
section after the 60 calendar day period,
FDA will provide a written
determination to the submitter and the
submitter must immediately cease using
the alternative test method.
(4) Acceptance of a notification
submission does not constitute a finding
by the Agency that the alternative test
method meets or exceeds the
performance criteria of the standard test
method set forth in § 1132.14.
mstockstill on DSK3G9T082PROD with PROPOSALS2
§ 1132.18
Sampling plans and procedures.
(a) Sampling plan for stability testing.
Each tobacco product manufacturer
must design and implement a sampling
plan or plans for all stability testing
required in § 1132.12(a) based on a valid
statistical rationale to demonstrate that
the finished smokeless tobacco
product’s expiration date is appropriate
under the intended storage conditions.
The sampling plan must ensure that
samples taken are representative and
randomly selected. To account for the
variability of the NNN in smokeless
tobacco products, the following factors
must be based on adequate statistical
criteria: The confidence intervals, the
level of necessary precision, and the
number of finished products sampled.
Each sampling plan must fully describe
the sampling methodology, with
scientific rationale, incorporate all
sources of variability (including
variability of the analytic method and
NNN levels), and describe the sample
size needed (including a full description
of how the sample size is calculated)
consistent with the sampling design to
achieve the sampling objective.
(b) Sampling plan for batch testing.
Each tobacco product manufacturer
must design and implement a sampling
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plan or plans for all batch testing
required in § 1132.12(b) based on a valid
statistical rationale to ensure that the
finished smokeless tobacco product
consistently conforms to the NNN level
set forth in § 1132.10. The sampling
plan must ensure that samples taken are
representative of an entire batch and are
randomly selected and collected from
each batch for testing. To account for
the variability of NNN in the finished
smokeless tobacco products, the
following factors must be based on
adequate statistical criteria: The
confidence intervals, the level of
necessary precision, and the number of
finished products sampled. The
sampling plan must take into account
the manufacturing quality history of the
manufacturer. Each sampling plan must
fully describe the sampling
methodology, with scientific rationale,
incorporate all sources of variability
(including variability of the analytic
method and the NNN levels), and
describe the sample size needed
(including a full description of how the
sample size is calculated) consistent
with the sampling design to achieve the
sampling objective. The sampling plan
must also fully describe the criteria the
manufacturer will use to make a
decision to accept or reject each batch.
(c) Sampling procedures. Test
samples must be collected and
examined in accordance with the
following procedures:
(1) Test samples for initial real-time
and accelerated stability testing are to
consist of:
(i) Smokeless tobacco product that has
been manufactured using the same
production processes as products
manufactured for consumer use and
packaged in the identical package that
will be used for the finished smokeless
tobacco product, but it need not have
the product package label; or
(ii) Finished smokeless tobacco
product as it is intended to be sold or
distributed to consumers.
(2) Test samples for annual real-time
stability testing and batch testing are to
consist of the finished smokeless
tobacco product as it is intended to be
sold or distributed to consumers and not
of a separate production sample.
(3) All test samples must be stored
according to the intended storage
conditions for the finished smokeless
tobacco product, except that test
samples for initial accelerated stability
testing must be stored in accordance
with § 1132.12(a)(3)(iii). A tobacco
product manufacturer must include all
of its factories, stock rooms,
warehouses, and other locations
containing finished smokeless tobacco
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8051
products in the population to be
sampled.
(4) Test samples for stability testing
must be taken within 7 days of the
manufacturing date and tested in
accordance with § 1132.12(a). Test
samples for batch testing must be taken
from each batch and tested within 30
calendar days of the manufacturing
date. The amount of material acquired
during sampling must be sufficient for
the test methods in §§ 1132.14 or
1132.16, including any repeats that may
be necessary (e.g., because test material
was damaged prior to or during
analysis). Samples must be randomly
selected in accordance with the
applicable sampling plan and the
samples must be taken within the same
day.
(5) Sampling must be performed by
persons who have sufficient education,
training, and experience to accomplish
the assigned functions.
(6) Each test sample must be
identified so that the following
information can be determined:
(i) Full identification of the smokeless
tobacco product sampled, including
product subcategory, brand, subbrand,
package size and quantity of product
(mass and, if portioned, count) and, for
portioned tobacco products, the size
(mass) of each portion;
(ii) The manufacturing code or, for
samples for initial stability testing with
no manufacturing code, an identifying
code created by the manufacturer;
(iii) The date on which the sample
was taken;
(iv) The sampling location (including
the address of the facility and specific
location within the facility where the
sample was taken);
(v) The name of the person(s) who
collected the sample; and
(vi) The location where the sample
will be stored and tested (including the
facility name and address).
(7) Samples sent for testing must be
packed securely with adequate
protection against damage (e.g.,
mechanical damage, severe changes in
humidity or temperature) and sent to
the testing facility by the most
expeditious means, arriving no later
than 3 calendar days after shipment. A
list of the samples in each shipment
must be sent to the testing facility under
separate cover.
(8) All samples for a specific stability
or batch test must be tested at the same
facility.
(9) Once test samples arrive at the
testing facility they must be inspected,
accounted for, and stored under the
finished smokeless tobacco product’s
intended storage conditions (e.g., room
temperature or refrigeration) except that
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test samples for initial accelerated
stability testing must be stored in
accordance with § 1132.12(a)(3)(iii), and
a report that includes the following
information must be generated for the
stability or batch test and be maintained
by the tobacco product manufacturer in
accordance with § 1132.32:
(i) Full identification of the smokeless
tobacco product, including product
subcategory, brand, subbrand, package
size and quantity of product (mass and,
if portioned, count) and, for portioned
tobacco products, the size (mass) of each
portion;
(ii) The manufacturing code or, for
samples for initial stability testing with
no manufacturing code, an identifying
code created by the manufacturer;
(iii) The date on which samples were
taken, if available;
(iv) The locations where samples were
drawn (including the address and
specific locations within any facilities
where samples were taken), if available;
(v) The number of test samples drawn;
(vi) Complete records of the samples
received and tested, including the date
of receipt, the identifier of all persons
who tested the samples, and the test
results.
(10) For batch testing only, each batch
must be withheld from commercial
distribution until it has been sampled
and tested, and a decision has been
made by the tobacco product
manufacturer that it may be released for
commercial distribution.
§ 1132.20
Expiration date.
All finished smokeless tobacco
products must have an expiration date
established by stability testing. The
expiration date must be set no later than
the final date the manufacturer can
demonstrate the finished smokeless
tobacco product conforms to § 1132.10
when stored under its intended
conditions (e.g., room temperature or
refrigeration).
mstockstill on DSK3G9T082PROD with PROPOSALS2
§ 1132.22
Nonconforming product.
(a) General requirements. Tobacco
product manufacturers must establish
and maintain procedures to identify,
investigate, segregate, and make
disposition decisions about
nonconforming finished smokeless
tobacco products in order to prevent
their release for commercial
distribution.
(b) Investigation. The tobacco product
manufacturer must conduct an
investigation to determine the extent of
the nonconformity and, as applicable,
the locations where the nonconforming
products have been distributed if the
mean of the representative samples from
any batch of finished smokeless tobacco
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product is determined to be out of
conformance with the requirements of
§ 1132.10, or a finished smokeless
tobacco product’s expiration date must
be shortened due to the results of
annual real-time stability testing, or if
FDA notifies a tobacco product
manufacturer that a distributed finished
smokeless tobacco product does not
conform to the requirements of this part.
The investigation must include, but is
not limited to, examination of all
relevant processes, operations, records,
complaints, any corrective actions
taken, and any other relevant sources of
information concerning the
nonconforming product. The
investigation must be fully documented,
including any materials reviewed, name
of the person(s) making the disposition
decisions, justification for the
disposition decisions, results of
retesting, decisions with respect to
reworking, and followup resulting from
the investigation.
(c) Rejection of nonconforming
product. Tobacco product
manufacturers must reject a batch of a
finished smokeless tobacco product if
the mean of the representative samples
from the batch does not conform to the
requirements of this part unless a
disposition decision and justification to
release the batch is made after an
investigation shows that the batch meets
the requirements of this part.
(d) Rework of nonconforming product.
If appropriate, a manufacturer may
rework a batch of a finished smokeless
tobacco product that does not conform
to the requirements of this part. The
reworked batch of finished smokeless
tobacco product must be determined to
conform to all the requirements of this
part with a disposition decision and
justification before it may be released
for commercial distribution.
Subpart C—Labeling and
Recordkeeping Requirements
§ 1132.30
Package label requirements.
The package of a finished smokeless
tobacco product must have a label that
includes the manufacturing code,
expiration date, and, if applicable,
storage conditions for the smokeless
tobacco product as follows:
(a) The information must be printed
on or permanently affixed to the
package in a manner that assures it will
remain on the packaging or label
through the expected duration of use of
the product by the consumer. It must
appear clearly, legibly, and indelibly in
the English language.
(b) The expiration date must appear
on the packaging in two-digit numerical
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values in the following format: ‘‘Expires
on month/day/year.’’
(c) If the manufacturer determines by
stability testing that meets the
requirements in § 1132.12 that the
finished smokeless tobacco product
must be stored in a refrigerator, the
package label must state ‘‘Keep
Refrigerated.’’
(d) It must be possible to determine
from the manufacturing code the history
of the manufacturing, processing,
packaging, labeling, holding, and initial
distribution of the product from records
maintained by the tobacco product
manufacturer.
§ 1132.32
Recordkeeping requirements.
(a) Each facility that manufactures
tobacco products subject to this part
must establish and maintain records of
the following information:
(1) Full documentation of stability
testing protocols and the results of
initial and annual stability testing under
§ 1132.12(a), including all information
specified in § 1132.12(c);
(2) All investigations under
§ 1132.12(a)(4)(v);
(3) The source data and results of
batch testing conducted to determine
conformance with § 1132.10, including
all information specified in § 1132.12(c);
(4) All notifications of an alternative
test method and all related
correspondence under § 1132.16;
(5) All source data for alternative test
method validation;
(6) All sampling plans and reports
under § 1132.18;
(7) Documentation that the persons
performing sampling under § 1132.18
have sufficient education, training, and
experience to accomplish the assigned
functions;
(8) All identification, investigation,
segregation, and disposition decision
procedures under § 1132.22(a); and
(9) All nonconforming product
investigations and rework under
§ 1132.22(b) and (d).
(b) The records must be legible and
written in English. Documents that have
been translated from a foreign language
into English must be accompanied by
the foreign language version of the
document and a certification by the
manufacturer’s authorized
representative (which could be a U.S.
agent for the manufacturer) that the
English language translation is complete
and accurate. All records must be
readily available for inspection and
copying or other means of reproduction
by FDA upon request during an
inspection. Requested records that are
maintained offsite must be made
available within 24 hours or, if that is
not feasible, as soon as possible before
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the close of the inspection. Records that
can be immediately retrieved from
another location, including by computer
or other electronic means, meet the
requirements of this paragraph.
(c) Copies of all records required
under this part must be retained for a
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period of not less than 4 years from the
date of commercial distribution of the
finished smokeless tobacco product that
is the subject of the record, or, for
records relating to alternative test
methods under § 1132.16, for a period of
not less than 4 years after the last date
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8053
the method that is the subject of the
record is used.
Dated: January 12, 2017.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2017–01030 Filed 1–19–17; 8:45 am]
BILLING CODE 4164–01–P
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]]>Agencies
[Federal Register Volume 82, Number 13 (Monday, January 23, 2017)]
[Proposed Rules]
[Pages 8004-8053]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-01030]
[[Page 8003]]
Vol. 82
Monday,
No. 13
January 23, 2017
Part IV
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Part 1132
Tobacco Product Standard for N-Nitrosonornicotine Level in Finished
Smokeless Tobacco Products; Proposed Rule
Federal Register / Vol. 82 , No. 13 / Monday, January 23, 2017 /
Proposed Rules
[[Page 8004]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 1132
[Docket No. FDA-2016-N-2527]
Tobacco Product Standard for N-Nitrosonornicotine Level in
Finished Smokeless Tobacco Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is proposing a tobacco
product standard that would establish a limit of N-nitrosonornicotine
(NNN) in finished smokeless tobacco products. FDA is taking this action
because NNN is a potent carcinogenic agent found in smokeless tobacco
products and is a major contributor to the elevated cancer risks
associated with smokeless tobacco use. Because products with higher NNN
levels pose higher risks of cancer, FDA finds that establishing a NNN
limit in finished smokeless tobacco products is appropriate for the
protection of the public health.
DATES: Submit either electronic or written comments on the proposed
rule by April 10, 2017. In accordance with 21 CFR 10.40(c), in
finalizing this rulemaking FDA will review and consider all comments
submitted before the time for comment on this proposed regulation has
expired. If your comment is submitted after the expiration of the
comment period, it will not be reviewed and considered by FDA unless
you apply for, and receive, an extension of the comment period pursuant
to 21 CFR 10.40(b)(3). Submit comments on information collection issues
under the Paperwork Reduction Act of 1995 (the PRA) by February 22,
2017, (see the ``Paperwork Reduction Act of 1995'' section). See
section VII of this document for the proposed effective date of a final
ruled based on this document.
ADDRESSES: You may submit comments as follows:
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand delivery/Courier (for written/paper
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Division of
Dockets Management, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2016-N-2527 for ``Tobacco Product Standard for N-nitrosonornicotine
Level in Finished Smokeless Tobacco Products.'' Received comments will
be placed in the docket and, except for those submitted as
``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Division of Dockets Management between 9
a.m. and 4 p.m., Monday through Friday.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Division of Dockets Management. If you do not
wish your name and contact information to be made publicly available,
you can provide this information on the cover sheet and not in the body
of your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.fda.gov/regulatoryinformation/dockets/default.htm.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, 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.
Submit comments on information collection issues to the Office of
Management and Budget in the following ways:
Fax to the Office of Information and Regulatory Affairs,
OMB, Attn: FDA Desk Officer, FAX: 202-395-7285, or email to
oira_submission@omb.eop.gov. All comments should be identified with the
title, Tobacco Product Standard: NNN Level in Finished Smokeless
Tobacco Products.
FOR FURTHER INFORMATION CONTACT: Beth Buckler or Colleen Lee, Office of
Regulations, Center for Tobacco Products (CTP), Food and Drug
Administration, Document Control Center, Bldg. 71, Rm. G335, 10903 New
Hampshire Ave., Silver Spring, MD 20993-0002, 877-287-1373,
CTPRegulations@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Proposed Rule
B. Summary of the Major Provisions of the Proposed Rule
C. Legal Authority
D. Costs and Benefits
II. Background Information
A. Purpose
B. Legal Authority
C. Additional Considerations and Requests for Comment
III. Scope of Proposed Standard
A. Smokeless Tobacco Products
B. Current Prevalence and Initiation Rates
IV. Rationale for Developing a Standard for NNN
[[Page 8005]]
A. Smokeless Tobacco is Carcinogenic
B. NNN in Smokeless Tobacco Products is Carcinogenic
C. NNN in Smokeless Tobacco Products
D. Basis for the NNN Limit in the Proposed Standard
E. Information on Technical Achievability
F. Analytical Method
V. Standard is Appropriate for the Protection of Public Health
A. Benefits to the Population as a Whole
B. The Likelihood That Existing Users of Tobacco Products Will
Stop Using Such Products
C. The Likelihood That Non-Users Will Start Using Tobacco
Products
D. Conclusion
VI. Description of Proposed Regulation
A. General Provisions (Proposed Subpart A)
B. Product Requirements (Proposed Subpart B)
C. Labeling and Recordkeeping Requirements (Proposed Subpart C)
VII. Proposed Effective Date
VIII. Incorporation by Reference
IX. Economic Analysis of Impacts
X. Analysis of Environmental Impact
XI. Paperwork Reduction Act of 1995
XII. Executive Order 13132
XIII. Executive Order 13175
XIV. References
I. Executive Summary
A. Purpose of the Proposed Rule
FDA is proposing a tobacco product standard that would establish a
limit of NNN in finished smokeless tobacco products sold in the United
States. NNN is a potent carcinogenic agent found in smokeless tobacco
products and is a major contributor to the elevated cancer risks
associated with smokeless tobacco use. By FDA's estimates, in the 20
years following implementation of the proposed product standard,
approximately 12,700 new cases of oral cancer and approximately 2,200
oral cancer deaths would be prevented in the United States because of
this rule. Moreover, during that 20-year period, FDA estimates that
approximately 15,200 life years would be gained as a result of the
proposed standard. Because oral cancer is associated with significant
health and economic impacts, we expect positive public health benefits
due to prevention of new and fatal cancer cases. For the reasons
discussed in the preamble of this rule, FDA finds that the proposed
standard would be appropriate for the protection of the public health.
B. Summary of the Major Provisions of the Proposed Rule
This proposed rule would establish a limit of NNN in finished
smokeless tobacco products. Under the proposed rule, no person may
manufacture, distribute, sell, or offer for distribution or sale within
the United States a finished smokeless tobacco product that is not in
compliance with the product standard. However, the proposed rule would
provide an exception for tobacco retailers and distributors; we would
not consider tobacco retailers and distributors to be in violation of
part 1132 as it relates to the sale or distribution of finished
smokeless tobacco products that exceed the allowed NNN level if they
meet certain criteria set forth in the rule.
The proposed rule would require that the mean level of NNN in any
batch of finished smokeless tobacco products not exceed 1.0 microgram
per gram ([mu]g/g) of tobacco (on a dry weight basis) at any time
through the product's labeled expiration date as determined by
specified product testing. The rule would require that all finished
smokeless tobacco products have an expiration date and provide that the
expiration date be no later than the final date the manufacturer can
demonstrate that the NNN level in the finished smokeless tobacco
product conforms to the limit when the product is stored under its
intended conditions (e.g., room temperature or refrigeration).
To ensure that products conform to the product standard, the
proposed rule would establish requirements for testing the products.
Two types of testing would be required for smokeless tobacco products--
stability testing and batch testing. Stability testing would be
required to assess the stability of the NNN level in the finished
smokeless tobacco products and to establish and verify the product's
expiration date and storage conditions. In addition, each batch of
finished smokeless tobacco product would be required to be tested to
determine whether the products conform to the proposed NNN level. The
proposed rule would also establish the standard test method (to be
incorporated by reference) and requirements for using an alternative
test method as well as the sampling requirements for all testing.
The proposed rule would require that the labels of finished
smokeless tobacco products contain a manufacturing code, expiration
date, and, if applicable, storage conditions for the finished smokeless
tobacco product (such as refrigeration). In addition, the proposed rule
would require manufacturers of finished smokeless tobacco products to
establish and maintain certain records.
C. Legal Authority
This proposed rule is being issued upon FDA's authority to
establish a tobacco product standard under section 907 of the Federal
Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 387g) including
authority related to the reduction of constituents or harmful
components in tobacco products under section 907(a)(4)(A)(ii) and to
the testing of tobacco products under section 907(a)(4)(B)(ii) through
(iv); FDA's authorities related to the sale and distribution of tobacco
products under sections 907(a)(4)(B)(v) and 906(d); FDA's authority to
require tobacco product manufacturers to establish and maintain records
under section 909 of the FD&C Act (21 U.S.C. 387i); FDA's authorities
related to adulterated and misbranded tobacco products under sections
902 and 903 (21 U.S.C. 387b and 387c); FDA's authorities related to
prohibited acts under section 301 of the FD&C Act (21 U.S.C. 331); and
FDA's rulemaking and inspection authorities under sections 701 and 704
of the FD&C Act (21 U.S.C. 371 and 374).
D. Costs and Benefits
The costs of the proposed rule, when finalized, will be due to
affected entities ensuring that the smokeless tobacco products comply
with the proposed product standard. We have estimated the annualized
costs associated with the proposed rule over 20 years to be between
$17.91 million and $42.72 million using a 3 percent discount rate, with
a primary value of $30.31 million, and between $20.11 million and
$50.57 million, with a primary value of $35.34 million using a 7
percent discount rate. The primary estimate for the present value of
total quantified costs over 20 years is approximately $450.97 million
at a 3 percent discount rate and $374.36 million at a 7 percent
discount rate.
NNN is a carcinogenic agent found in smokeless tobacco products. As
described in the preamble of the proposed rule, on the basis of the
available scientific evidence, FDA has determined that NNN is the
predominant driver of excess oral cancer risk among smokeless tobacco
users. We quantify benefits associated with the proposed rule in the
form of reduced oral cancer morbidity and mortality attributable to
smokeless tobacco. As described in section V.A.3 of the preamble of the
proposed rule, we also expect the standard to reduce the risk of
esophageal cancer, and it may reduce the risks of other cancers such as
pancreatic, laryngeal, prostate, and lung cancer. However, there is
more limited information to directly quantify these health benefits. As
such, we only consider estimated reductions in oral cancer as the
quantified benefit of the proposed product standard.
Most of the estimated benefits arise from quality life-years gains
gained from reduced oral cancer mortality. The
[[Page 8006]]
annualized value over 20 years of quality adjusted life-years gained
from reduced oral cancer mortality ranges from $228.66 million to $2.46
billion at a 3 percent discount rate, with a primary value of $858.46
million. Using a 7 percent discount rate, the annualized value of
quality life-years gained from averted deaths ranges from $182.01
million to $1.96 billion, with a primary value of $683.34 million. The
primary estimate of the present value of mortality reductions
quantified over 20 years is $12.77 billion at a 3 percent discount rate
and $7.24 billion at a 7 percent discount rate. The annualized value
over 20 years of quality adjusted life-years gained from reduced oral
cancer mortality and morbidity ranges from approximately $283.95
million to $3.05 billion at a 3 percent discount rate, with a primary
value of $1.06 billion, and approximately $246.40 million to $2.65
billion, with a primary value of $0.92 billion at a 7 percent discount
rate. The primary estimate of the present value of total quantified
benefits over 20 years is approximately $15.86 billion at a 3 percent
discount rate and $9.80 billion at a 7 percent discount rate for
reductions in oral cancer alone. These values are likely an
underestimate of the benefits associated with the proposed rule, as we
do not quantify reductions in mortality and morbidity from cancers
other than oral cancer. Costs and benefits are summarized in table 8 of
the preamble of the proposed rule.
II. Background Information
A. Purpose
FDA is issuing this proposed rule to address the harm caused by the
toxicant NNN in smokeless tobacco products. When Congress enacted the
Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act)
in 2009, it included the finding that ``the Food and Drug
Administration is a regulatory agency with the scientific expertise to
identify harmful substances in products to which consumers are exposed,
[and] to design standards to limit exposure to those substances''
(section 2(44) of the Tobacco Control Act).
Smokeless tobacco products, including those currently marketed in
the United States, have been demonstrated to cause certain types of
cancer. Several authoritative reviews have been conducted on the
relationship between smokeless tobacco use and cancer risk and have
reached similar conclusions (Refs. 1, 2, 3, 4). The International
Agency for Research on Cancer (IARC) concluded in its 2007 monograph
``Smokeless Tobacco and Some Tobacco-Specific Nitrosamines'' that there
is sufficient evidence in humans to indicate that smokeless tobacco is
carcinogenic and that it causes oral and pancreatic cancer (Ref. 1).
IARC confirmed these findings of the carcinogenicity of smokeless
tobacco in a 2012 review, concluding that there is sufficient evidence
in both humans and experimental animal studies that smokeless tobacco
causes oral, esophageal, and pancreatic cancer (Ref. 2). In addition, a
2014 report on smokeless tobacco by the National Cancer Institute (NCI)
and Centers for Disease Control and Prevention (CDC) estimated that
smokeless tobacco use is responsible for approximately 1,600 new cases
of oral cancer, 200 cases of esophageal cancer, and 500 cases of
pancreatic cancer in the United States each year (Ref. 4).
NNN \1\ is a potent carcinogenic agent found in smokeless tobacco
products and is a major contributor to the elevated cancer risks
associated with smokeless tobacco use (see section IV, Rationale for
Developing a Standard for NNN, of this document). NNN levels vary
substantially across subcategories of smokeless tobacco products (e.g.,
moist snuff, chewing tobacco, dry snuff) and within product
subcategories (e.g., moist snuff) (Ref. 5, 10). International
comparisons of oral cancer rates and smokeless tobacco products suggest
that products with higher NNN levels may pose higher risks of cancer
(Refs. 6, 100). FDA is using its authority to propose a standard that
would reduce tobacco-related harms by establishing a limit of NNN in
smokeless tobacco products sold in the United States (see section V of
this document).
---------------------------------------------------------------------------
\1\ Since 2012, manufacturers have been required to test and
report to FDA the levels of harmful and potentially harmful
constituents (HPHCs), including NNN, in each tobacco product
(section 904(A)(3) of the FD&C Act).
---------------------------------------------------------------------------
FDA is proposing that the standard would apply to finished
smokeless tobacco products. Although NNN is also found in other tobacco
products, this rule focuses solely on NNN levels in smokeless tobacco
products, and not on additional products. Different measures are
required to evaluate the contribution to cancer of NNN among users of
other tobacco products, such as combustible products like cigarettes
and dissolvable tobacco products that do not meet the statutory
definition of ``smokeless tobacco product.'' For example, additional
factors, such as polycyclic aromatic hydrocarbons (PAH), aldehydes and
other chemicals (Refs. 147, 106), contribute to the cancer burden
associated with combustible products, which make the relationship
between NNN and cancer in these products different from that in
smokeless tobacco products. With regard to dissolvable tobacco products
that do not meet the statutory definition of smokeless tobacco,
different product testing methods than the ones developed and available
for smokeless tobacco, as described in this proposal, may be necessary
to evaluate NNN in these products because they do not consist of cut,
ground, powdered or leaf tobacco. Therefore, at this stage, FDA has
chosen to focus on smokeless tobacco and has evaluated data relevant to
establishing an NNN limit in smokeless tobacco products.
This proposed product standard would require that the mean level of
NNN in any batch of finished smokeless tobacco products not exceed 1.0
[mu]g/g of tobacco (on a dry weight basis) at any time through the
product's labeled expiration date as determined by testing in
compliance with Sec. 1132.12 (proposed Sec. 1132.10). FDA expects
that, in the 20 years following implementation of the proposed product
standard, approximately 12,700 new cases of oral cancer and
approximately 2,200 oral cancer deaths would be prevented in the United
States because of this rule. Moreover, during that 20-year period,
approximately 15,200 life years would be gained in the United States as
a result of the proposed standard. We believe that the main source of
variability in the estimated impacts would be different assumptions
about oral cancer relative risks due to smokeless tobacco use. Using
alternate relative risk estimates that are somewhat lower and higher
than our main estimate results in approximately 7,300 to 24,000 new
cases of oral cancer prevented and 1,300 to 4,200 oral cancer deaths
prevented over the 20-year period. Because oral cancer is associated
with significant health and economic impacts, we expect positive public
health benefits due to prevention of new and fatal cancer cases. These
benefits are discussed in detail in section V of this proposed rule.
Accordingly, based on the information discussed in the following
sections of the preamble to this proposed rule, FDA finds that the
proposed standard would be appropriate for the protection of the public
health.
B. Legal Authority
1. Product Standard
The Tobacco Control Act was enacted on June 22, 2009, amending the
FD&C Act and providing FDA with the authority to regulate tobacco
products (Pub. L. 111-31; 123 Stat. 1776). Among
[[Page 8007]]
the authorities provided to FDA is the authority to establish tobacco
product standards. To establish a tobacco product standard, section
907(a)(3)(A) and (B) of the FD&C Act (21 U.S.C. 387g(a)(3)(A) and (B))
requires that we find that the standard is appropriate for the
protection of the public health, taking into consideration scientific
evidence concerning:
The risks and benefits of the proposed standard to the
population as a whole, including users and nonusers of tobacco
products;
The increased or decreased likelihood that existing users
of tobacco products will stop using such products; and
The increased or decreased likelihood that those who do
not use tobacco products will start using such products.
2. NNN Limit
Section 907 of the FD&C Act authorizes FDA to promulgate tobacco
product standards that are appropriate for the protection of the public
health, including provisions, where appropriate, for the reduction or
elimination of constituents or harmful components of tobacco products
(section 907(a)(4)(A)(ii) of the FD&C Act). This proposed rule would
limit the level of NNN in finished smokeless tobacco products. To
ensure that finished smokeless tobacco products comply with the
proposed NNN level, FDA also is including provisions to require that
tobacco product manufacturers test their products on a sample basis
(i.e., batch testing) using a specified testing procedure for
conformance with the limit pursuant to section 907(a)(4)(B)(ii) and
(iv) of the FD&C Act.
3. Sale and Distribution Restrictions
Section 907(a)(4)(B)(v) states that product standards must, where
appropriate for the protection of public health, include provisions
requiring that the sale and distribution of the tobacco products be
restricted but only to the extent that the sale and distribution of a
tobacco product may be restricted under section 906(d). Similar to
section 907, section 906(d) of the FD&C Act gives FDA authority to
require restrictions on the sale and distribution of tobacco products
by regulation if the Agency determines that such regulation would be
appropriate for the protection of the public health. The finding as to
whether a sales and distribution regulation is appropriate for the
protection of the public health must be determined with respect to the
risks and benefits to the population as a whole, including users and
nonusers of the tobacco products, and must take into account:
The increased or decreased likelihood that existing users
of tobacco products will stop using such products; and
The increased or decreased likelihood that those who do
not use tobacco products will start using such products (see section
906(d)(1) of the FD&C Act).
Under these authorities along with section 701, which provides FDA
with the authority to ``promulgate regulations for the efficient
enforcement of this Act,'' FDA is including provisions to restrict the
manufacture, sale, and distribution of finished smokeless tobacco
products that are not in compliance with this standard. Specifically,
FDA is proposing to require that no person may manufacture, distribute,
sell, or offer for distribution or sale within the United States a
finished smokeless tobacco product that is not in compliance with part
1132 (proposed Sec. 1132.1(b)). However, tobacco retailers and
distributors would not be considered in violation of part 1132 as it
relates to the sale or distribution or offer for sale or distribution
of finished smokeless tobacco products that exceed the NNN level
required in proposed Sec. 1132.10 if they: (1) Store and transport the
finished smokeless tobacco products according to the package label, (2)
do not sell or distribute or offer for sale or distribution finished
smokeless tobacco products past their expiration date, except to return
expired products to the manufacturer, (3) do not conceal, alter or
remove the expiration date or storage conditions on the package label,
and (4) do not sell or distribute or offer for sale or distribution
finished smokeless tobacco products that are open or have broken seals
(proposed Sec. 1132.1(c)). FDA is proposing this exception for tobacco
retailers and distributors because they are not in a position to know
or to confirm by testing whether the smokeless tobacco products they
are selling or distributing or offering for sale or distribution comply
with the proposed NNN level.
FDA is also proposing, under these authorities, to require that the
labels of finished smokeless tobacco products contain a manufacturing
code, expiration date, and, if applicable, storage conditions for the
finished smokeless tobacco product (proposed Sec. 1132.30). The
labeling requirement for storage conditions is also consistent with
FDA's authority under section 907(a)(4)(C), which provides that a
product standard shall, where appropriate, require the use and
prescribe the format and content of labeling for the proper use of the
tobacco product. These label requirements would enable FDA to determine
whether a product on store shelves purports to comply with the
standard, link the product to its manufacturing history so that
compliance with the standard can be verified, provide traceability of
the product in the event of a nonconforming product investigation and
corrective action, and ensure that the product is handled and stored
under appropriate conditions, in accordance with the standard. In
addition, the proposed manufacturing code would serve as a common
identifier that will provide a history of the manufacturing,
processing, packaging, labeling, holding, and initial distribution of
the tobacco product from records maintained by the smokeless tobacco
product manufacturer. The expiration date would also inform retailers
that the manufacturer has not demonstrated compliance with the standard
beyond the date after which the product should not be sold to
consumers.
Manufacturers would be responsible for ensuring that finished
smokeless tobacco products contain labels with a manufacturing code,
expiration date, and, if applicable, storage conditions prior to sale
and commercial distribution. In addition, retailers and distributors
would be responsible for not selling or distributing or offering for
sale or distribution finished smokeless tobacco products that lack the
required labels, not concealing, altering, or removing the expiration
date or storage conditions on the package label, not selling or
distributing or offering for sale or distribution finished smokeless
tobacco products after their expiration date (except to return expired
product to the manufacturer), not selling or distributing or offering
for sale or distribution finished tobacco products that are open or
have broken seals, and, if applicable, storing finished smokeless
tobacco product in accordance with the package label.
Because these requirements would assist FDA in enforcing the
standard and would ensure that manufacturers and retailers are selling
product that complies with the standard, the Agency has found all of
these requirements to be appropriate for the protection of the public
health consistent with sections 907(a)(4)(B)(v) and 906(d).
4. Testing Requirements
FDA's proposed rule contains provisions regarding testing
requirements under sections
[[Page 8008]]
907(a)(4)(B) and 907(a)(4)(A)(iii) of the FD&C Act to ensure that
finished smokeless tobacco products conform to the requirements of the
product standard before they are distributed to consumers and remain in
conformance until their expiration date. Section 907(a)(4)(B)(ii)
provides that a product standard must, where appropriate for the
protection of public health, include ``provisions for the testing (on a
sample basis or, if necessary, on an individual basis) of the tobacco
product.'' In addition, section 907(a)(4)(B)(iv) provides that, where
appropriate for the protection of public health, a product standard
must include provisions requiring that the results of the tests of the
tobacco product required under section 907(a)(4)(B)(ii) show that the
product is in conformity with the portions of the standard for which
the tests were required.
Consistent with these statutory provisions, proposed Sec. Sec.
1132.12, 1132.14, 1132.16, and 1132.18 would establish product testing
and sampling plan requirements. Proposed Sec. 1132.12 would require
two types of testing for smokeless tobacco products--stability testing
and batch testing. Proposed Sec. 1132.12(a) would require testing to
assess the stability of the NNN level in finished smokeless tobacco
products and to establish and verify the product's expiration date and
storage conditions (either room temperature or refrigeration). Proposed
Sec. 1132.12(b) would require manufacturers to conduct testing on each
batch of finished smokeless tobacco product to determine whether the
products conform to the proposed NNN level. Proposed Sec. 1132.12(c)
would require the tobacco product manufacturer to document all testing.
Proposed Sec. Sec. 1132.14 and 1132.16 would establish the standard
and alternative test methods, while Sec. 1132.18 would establish the
sampling requirements for all testing.
Section 907(a)(4)(A)(iii) states that product standards must
include provisions that are appropriate for the protection of the
public health, including provisions, where appropriate, relating to any
requirement under subparagraph 907(a)(4)(B). As discussed, FDA is
proposing specific testing requirements in Sec. Sec. 1132.12, 1132.14,
1132.16, and 1132.18. To support these proposed requirements, proposed
Sec. 1132.22(b) would require that if the mean of the representative
samples from any batch of a finished smokeless tobacco product is
determined to be out of conformance with the requirements of Sec.
1132.10, or a finished smokeless tobacco product's expiration date must
be shortened due to the results of annual real-time stability testing,
or if FDA notifies a tobacco product manufacturer that a distributed
finished smokeless tobacco product does not conform to the requirements
of part 1132, the manufacturer would have to conduct an investigation
to determine the scope of the nonconformity and locations to which
nonconforming products have been distributed. This proposed requirement
would ensure that any reports of nonconforming products, whether as a
result of manufacturer testing or otherwise, are examined and
investigated and that appropriate measures are taken to ensure that
additional nonconforming product batches are not distributed to
consumers and to prevent future nonconformity.
FDA finds that such provisions are appropriate for the protection
of the public health and relate to requirements under section
907(a)(4)(B) because they will help to ensure that the finished
smokeless tobacco products are properly tested and conform to the
requirements of the proposed product standard.
5. Recordkeeping
Section 909 of the FD&C Act authorizes FDA to require tobacco
product manufacturers to establish and maintain records, make reports,
and provide such information as the Agency may by regulation reasonably
require to assure that a tobacco product is not adulterated or
misbranded and to otherwise protect public health. In addition, section
701(a) of the FD&C Act authorizes FDA to promulgate regulations for the
efficient enforcement of the FD&C Act. The recordkeeping requirements
would help FDA with the efficient enforcement of the product standard
issued under the FD&C Act.
FDA is proposing to require that manufacturers of smokeless tobacco
products maintain records regarding the product testing (i.e.,
stability and batch testing), including a full report of the source
data and results; all notifications of an alternative test method and
source data for alternative test method validation; all sampling plans
and reports; documentation that the persons performing sampling have
sufficient education, training, and experience to accomplish the
assigned functions; all identification, investigation, segregation, and
disposition procedures; and all nonconforming product investigations
and rework (i.e., the processing of nonconforming finished smokeless
tobacco products to meet the requirements of part 1132).
FDA is also proposing to require copies of all records be retained
for a period of not less than 4 years from the date of distribution of
the finished smokeless tobacco product that is the subject of the
record, except that certain records relating to alternative test
methods would be required to be retained for a period of not less than
4 years after the last date the method is used. Retention of these
records would help ensure that finished smokeless tobacco products are
in conformance with the proposed standard and are not adulterated or
misbranded.
C. Additional Considerations and Requests for Comment
1. Section 907 of the FD&C Act
FDA is required by section 907 of the FD&C Act to consider the
following information submitted in connection with a proposed product
standard:
For a proposed product standard to require the reduction
or elimination of an additive, constituent, or other component of a
tobacco product because FDA has found that the additive, constituent,
or other component is or may be harmful, scientific evidence submitted
that demonstrates that the proposed standard will not reduce or
eliminate the risk of illness or injury (section 907(a)(3)(B)(ii) of
the FD&C Act).
Information submitted regarding the technical
achievability of compliance with the standard (section 907(b)(1) of the
FD&C Act).
All other information submitted, including information
concerning the countervailing effects of the tobacco product standard
on the health of adolescent tobacco users, adult tobacco users, or
nontobacco users, such as the creation of a significant demand for
contraband or other tobacco products that do not meet the requirements
of Chapter IX of the FD&C Act and the significance of such demand
(section 907(b)(2) of the FD&C Act).
As required by section 907(c)(2) of the FD&C Act, FDA invites
interested persons to submit a draft or proposed tobacco product
standard for the Agency's consideration (section 907(c)(2)(B)) and
information regarding structuring the standard so as not to advantage
foreign-grown tobacco over domestically grown tobacco (section
907(c)(2)(C)). In addition, FDA invites the Secretary of Agriculture to
provide any information or analysis which the Secretary of Agriculture
believes is relevant to the proposed tobacco product standard (section
907(c)(2)(D) of the FD&C Act).
FDA is requesting the documents and information described in this
section with this proposed rule. Such documents and information may be
[[Page 8009]]
submitted in accordance with the ``Instructions'' included in the
preliminary information section of this document.
Section 907(d)(5) of the FD&C Act allows the Agency to refer a
proposed regulation for the establishment of a tobacco product standard
to the Tobacco Products Scientific Advisory Committee (TPSAC) at the
Agency's own initiative or in response to a request for good cause made
before the expiration of the comment period. If FDA opts to refer this
proposed regulation to TPSAC, the Agency will publish a notice in the
Federal Register announcing the TPSAC meeting to discuss this proposal.
2. Pathways to Market
To legally market a new tobacco product in the United States, a
tobacco product manufacturer must receive authorization from FDA
permitting the marketing of the new tobacco product under one of three
pathways for legally marketing a new tobacco product: (1) The
manufacturer obtains an order under section 910(c)(1)(A)(i) of the FD&C
Act (order after review of a premarket tobacco application under
section 910(b)); (2) the manufacturer obtains an order finding the new
product substantially equivalent to a predicate tobacco product and in
compliance with the requirements of the FD&C Act under section
910(a)(2)(A)(i) (order after review of a substantial equivalence (SE)
report submitted under section 905(j) of the FD&C Act); or (3) the
manufacturer makes a request under 21 CFR 1107.1, obtains an exemption
from the requirements related to substantial equivalence (section
905(j)(3)(A)), and at least 90 days before commercially marketing the
product, submits a report under section 905(j) including the
information required in section 905(j)(1)(A)(ii) and (j)(1)(B).
A smokeless tobacco product that has been modified to comply with
the product standard would be a ``new tobacco product'' and subject to
premarket review. FDA believes that changes made solely to bring a
smokeless tobacco product in compliance with the proposed rule would be
appropriate for an SE submission. We believe it is possible for
manufacturers to modify their product so that it is both in compliance
with the proposed product standard and substantially equivalent to an
appropriate predicate product (i.e., products that are grandfathered or
SE).
FDA believes that manufacturers would likely choose to comply with
the proposed standard in a manner that makes the modified products
eligible for the SE pathway. For products that are eligible for an SE
report, FDA is considering whether a change to the level of NNN in
smokeless tobacco products could be reviewed with the submission of an
SE report containing a reduced, specific set of information that
focuses on the changes to the smokeless tobacco where the SE report
demonstrates that the only modifications made to the new product were
made to comply with the NNN product standard and do not present
different questions of public health (e.g., significant increase in
another harmful or potentially harmful constituent (HPHC)). As there
may be multiple modifications needed to comply with the product
standard, FDA requests comments as to the type of modifications that
may allow a reduced amount of information to proceed through the SE
pathway, and what types of brief, specific supporting information
submitted as part of a substantial equivalence application could
demonstrate that modifications made to comply with this product
standard do not cause the new product to raise different questions of
public health.
III. Scope of Proposed Standard
Scientific evidence documents that smokeless tobacco products cause
certain types of cancer (Refs. 1, 2, 3, 4). As discussed in section IV
of this document, NNN is a potent carcinogenic agent found in smokeless
tobacco products and is a major contributor to the elevated cancer
risks associated with smokeless tobacco use (Refs. 7, 8, 1, 2).
FDA is issuing this proposed standard to address the harm to
smokeless tobacco users caused by NNN by establishing a limit for NNN
in finished smokeless tobacco products (see proposed Sec. 1132.10),
thereby reducing exposure to this harmful toxicant. NNN levels vary
substantially across subcategories of smokeless tobacco products (e.g.,
moist snuff, chewing tobacco, dry snuff) and within product
subcategories (e.g., moist snuff) (Ref. 5). Geographical comparisons
show that oral cancer rates among smokeless tobacco users are higher in
areas where smokeless tobacco products have higher NNN levels (Refs. 6,
100). Given this geographic variation and the toxicological evidence
described in the preamble of this rule, we expect that lowering the
level of NNN in smokeless tobacco products in the United States will
lower the rate of oral cancers among smokeless tobacco users. FDA
concludes that establishing a limit for NNN in finished smokeless
tobacco products is appropriate for the protection of the public health
(see section V of this document).
A. Smokeless Tobacco Products
The term ``smokeless tobacco'' covers a wide range of tobacco
products that are used orally or nasally without combustion (Ref. 1).
Smokeless tobacco is defined in section 900(18) of the FD&C Act as
``any tobacco product that consists of cut, ground, powdered, or leaf
tobacco and that is intended to be placed in the oral or nasal
cavity.'' This includes moist snuff, snus, dry snuff, chewing tobacco,
and some dissolvables. Some dissolvable tobacco products do not meet
the statutory definition of ``smokeless tobacco product'' because they
do not contain cut, ground, powdered, or leaf tobacco; instead, these
products contain nicotine extracted from tobacco. Dissolvable products
that do not meet the statutory definition of ``smokeless tobacco
product'' are not covered by this proposed rule.
Moist snuff is the most popular type of smokeless tobacco in the
United States (Refs. 4, 131). It is typically made of fire-cured or
air-cured tobacco that has been finely ground or shredded and fermented
(Ref. 4). Moist snuff may contain up to 60 percent moisture and it is
often flavored (e.g., wintergreen) (Refs. 4, 10). It is sold as loose
tobacco or in sachets or small pouches (Ref. 1). When loose moist snuff
is used, a small amount (e.g., a pinch or dip) is placed and held
between the lip or cheek and gum and typically is held in the mouth for
at least 30 minutes (Refs. 1, 5). Excess saliva may be spit out or
swallowed (Ref. 1). When pouched moist snuff is used, a sachet or small
pouch containing the tobacco is placed and held between the lip or
cheek and gum but it does not require spitting (Ref. 9).
Snus is a type of moist snuff and it can have different
characteristics depending on where it is manufactured. Swedish snus
products generally have much lower levels of tobacco-specific
nitrosamines (TSNAs) than smokeless tobacco products found in the
United States (Refs. 5, 6, 10), and, therefore, they were of particular
interest in the development of this proposed rule.
Swedish snus is commonly used in Sweden but it is relatively new to
the U.S. market (Refs. 4, 11). It typically consists of low-nitrosamine
tobacco that has been air-cured, moistened, ground, and heat treated
(Refs. 4, 12, 11). Swedish snus may contain up to 50 percent moisture
and some flavoring but no added sugars (Refs. 13, 14, 11). Swedish snus
is sold as loose tobacco or in sachets (Refs. 4, 12, 11). It is placed
between the cheek and gum and does not require spitting (Refs. 1, 15).
[[Page 8010]]
In Sweden, all snus manufacturers must adhere to the requirements
of the Swedish Food Act. In addition, a smokeless tobacco manufacturer
developed the GothiaTek voluntary standard, which establishes limits
for the tobacco (e.g., low-nitrosamine raw tobacco that has been air-
cured or sun-cured) and other ingredients as well as the manufacturing
process (Refs. 11, 4). The current GothiaTek standard for NNN and 4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (combined) in snus
is 0.95 [mu]g/g wet weight \2\ tobacco, which would be about 2
[micro]g/g (combined NNN and NNK) dry weight tobacco (Refs. 13, 16).
Swedish snus that is made using the GothiaTek standard tends to have
lower levels of toxicants, including NNN, than other smokeless tobacco
products in other countries (Ref. 4).
---------------------------------------------------------------------------
\2\ The term ``wet weight'' refers to the weight of tobacco as
used by the consumer, while the term ``dry weight'' refers to the
weight of tobacco after the removal of water.
---------------------------------------------------------------------------
Swedish snus is usually refrigerated by retailers to maintain its
quality and taste but refrigeration is not generally required to
maintain stability because modern Swedish snus production techniques
achieve very low levels of microbial activity and yield no new
nitrosamine formation even when held at room temperature (Ref. 11). One
of the methods used to limit microbial activity is pasteurization. In
this process, the leaf tobacco is ground and subjected to heat
treatment. The heating is achieved by combining the tobacco with water
and salt, placed in closed process blenders, and using steam to achieve
temperatures up to 80 to 100 [deg]C for several hours (Ref. 11).
In recent years, some U.S. tobacco manufacturers began introducing
snus products (e.g., Marlboro Snus and Camel Snus) in the United States
(Ref. 17). Some of the early marketing of these tobacco products
emphasized the Swedish origins of snus but there is limited data
available on whether the chemical composition or manufacturing
processes of these products are equivalent to Swedish snus (Refs. 4,
18, 19). Studies indicate that early versions of these snus products
would not comply with the current GothiaTek standard for NNN and NNK
(i.e., 0.95 [mu]g/g per wet weight combined) (Ref. 13). From the
limited information available, snus manufactured in the United States
appears to consist of tobacco that has been air-cured or sun-cured and
is pasteurized or heat treated (Refs. 20, 21). It may contain up to 34
percent moisture and may contain some flavoring, flavoring strip, and/
or sweeteners (Ref. 4, 56). It is generally sold portioned in sachets
or small pouches (Ref. 4).
Unlike the relatively higher moisture content of moist snuff, dry
snuff usually has a moisture content of less than 10 percent (Ref. 1).
Dry snuff is a powdered tobacco product that may be used orally or
nasally, although nasal use is rare in the United States (Ref. 4).
Typically dry snuff is made with tobacco that has been fire-cured,
fermented, and finely ground or pulverized into a powder (Refs. 1, 4).
A pinch or dip of dry snuff is typically held between the cheek and gum
(Ref. 1).
Chewing tobacco is sold as loose leaf, plug, or twist. It is
typically fire-cured or air-cured tobacco that has been fermented or
aged (Refs. 4, 1). It may be flavored and sweetened and then processed
into a plug, twist, or loose leaf (Refs. 4, 1). Chewing tobacco may be
chewed or held in the mouth (i.e., dipped) (Ref. 5).
Dissolvable tobacco products that are smokeless tobacco products
are generally made of finely ground tobacco and sold as small lozenges,
sticks (toothpick), or strips (Refs. 4, 5). Such dissolvable tobacco
products may be flavored and may have a moisture content ranging from 1
to 20 percent, depending on the product (Refs. 9, 22, 56). As the name
suggests, a dissolvable tobacco product is placed in the mouth until it
dissolves.
B. Current Prevalence and Initiation Rates
In the United States, smokeless tobacco products are predominately
used by men and high school age boys. According to the 2014 National
Survey on Drug Use and Health, an estimated 8.7 million (3.3 percent)
Americans aged 12 and over were current (any use in the past month)
smokeless tobacco users (chewing tobacco or snuff) in 2014, which is
generally similar to the percentage of smokeless tobacco users
estimated by this study for most years from 2002 to 2013 (Ref. 23). An
estimated 6.4 percent of males over the age of 12 were current
smokeless tobacco users, while only 0.3 percent of females were current
users (Ref. 24 at tables 2.9B, 2.10B). Among adults, the highest
prevalence of current use of smokeless tobacco was observed among young
adults aged 18 to 25 at 5.6 percent (Ref. 24 at 18). According to the
National Youth Tobacco Survey, in 2015, there were an estimated 1.1
million middle and high school students that reported current (past 30
day) use of chewing tobacco, snuff or dip, snus, or dissolvable tobacco
products (Ref. 25). The overall level of current smokeless tobacco
product usage was 6 percent among high school students, and 1.8 percent
among middle school students (Ref. 25). Among youth, the prevalence of
smokeless tobacco use varies by sex and race. In 2015, 10 percent of
male high school students reported current use of smokeless tobacco,
including snus and dissolvables, compared with 1.8 percent of female
high school students (Ref. 25). Among high school students, the
prevalence of current use of smokeless tobacco, including snus and
dissolvables, was highest among non-Hispanic White students (7.8
percent), followed by Hispanic students (4.8 percent), and non-Hispanic
Black students (1.9 percent) (Ref. 25).
An estimated 1.0 million Americans aged 12 or older used smokeless
tobacco for the first time in 2014 (Ref. 24 at table 4.5B). Nearly 75
percent of these new initiates were male and about 42 percent were
under age 18 when they first used a smokeless tobacco product (Ref. 24
at tables 4.6B, 4.9A). The average age at first use of smokeless
tobacco among recent initiates in 2014 was 19.0 years, which was
similar to the 2013 estimate (Refs. 26, 24 at table 4.13B).
IV. Rationale for Developing a Standard for NNN
A. Smokeless Tobacco is Carcinogenic
The scientific evidence demonstrates that smokeless tobacco
products cause certain types of cancer, and that cancer rates are
higher in regions of the world where smokeless tobacco products have
higher levels of NNN. In 1986, the Surgeon General of the United States
released a report finding that ``users of smokeless tobacco products
face a strongly increased risk of oral cancer'' (Ref. 27). In 2007,
IARC classified smokeless tobacco as carcinogenic to humans (Group 1),
concluding that sufficient evidence in humans demonstrate that
smokeless tobacco causes cancers of the oral cavity and pancreas (Ref.
1). IARC confirmed these findings of the carcinogenicity of smokeless
tobacco in a 2012 review, concluding that there is sufficient evidence
in both humans and experimental animal studies that smokeless tobacco
causes oral, esophageal, and pancreatic cancer (Ref. 2). The Scientific
Committee on Emerging and Newly Identified Health Risks (Ref. 3) was
tasked by the European Commission to evaluate the cancer risks of
smokeless tobacco products, with particular attention to moist snuff,
which, in the European Union is available only in Sweden, in the form
of snus. It concluded in its
[[Page 8011]]
2008 review that smokeless tobacco products cause esophageal and
pancreatic cancer in humans and that studies in the United States
demonstrate an increased risk of oral cancer among smokeless tobacco
users, however, the evidence for ``users of Swedish moist snuff (snus)
is less clear'' (Ref. 3). More recently, the National Cancer Institute
(NCI), National Institutes of Health, in coordination with the Centers
for Disease Control and Prevention (CDC) published a report on
smokeless tobacco use and health effects in 2014, concluding that
smokeless tobacco use causes oral, esophageal, and pancreatic cancer
(Ref. 4).
Table 1--Conclusions of Authoritative Reviews on Smokeless Tobacco and
Cancer Risk
------------------------------------------------------------------------
Authoritative body Year Conclusions
------------------------------------------------------------------------
Surgeon General of the United 1986 ``In summary, users of
States. smokeless tobacco
products face a
strongly increased risk
of oral cancer,
particularly for the
tissues that come in
contact with the
tobacco.''
International Agency for Research 2007 ``There is sufficient
on Cancer (IARC). evidence in humans for
the carcinogenicity of
smokeless tobacco.
Smokeless tobacco
causes cancers of the
oral cavity and
pancreas.''
Scientific Committee on Emerging 2008 ``STP [smokeless tobacco
and Newly Identified Health Risks products] are
(SCENIHR). carcinogenic to humans
and the pancreas has
been identified as a
main target organ. All
STP cause localised
oral lesions and a high
risk for development of
oral cancer has been
shown for various STP
but the evidence for
oral cancer in users of
Swedish moist snuff
(snus) is less clear.''
International Agency for Research 2012 ``There is sufficient
on Cancer (IARC). evidence in humans for
the carcinogenicity of
smokeless tobacco.
Smokeless tobacco
causes cancers of the
oral cavity, oesophagus
and pancreas.''
National Cancer Institute (NCI).... 2014 ``There is sufficient
evidence that ST
[smokeless tobacco]
products cause
addiction, precancerous
oral lesions, and
cancer of the oral
cavity, esophagus, and
pancreas, and adverse
reproductive and
developmental effects
including stillbirth,
preterm birth, and low
birth weight.''
------------------------------------------------------------------------
B. NNN in Smokeless Tobacco Products is Carcinogenic
Smokeless tobacco products contain thousands of chemical
constituents, including carcinogens such as TSNAs (Refs. 2, 1, 4).
TSNAs are formed from nitrosation, a chemical reaction between tobacco
alkaloids (nicotine, nornicotine, anatabine, and anabasine) and
nitrosating agents such as nitrite (Refs. 28, 2). Because TSNAs are
formed from tobacco alkaloids, they are only found in tobacco products
(Ref. 28).
In smokeless tobacco, TSNAs are present at a level capable of
causing cancer (Ref. 4). Of the five TSNAs identified in tobacco
products, NNN and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)
have been classified by IARC as carcinogenic to humans (Group 1) (Refs.
2, 4).\3\
---------------------------------------------------------------------------
\3\ Section IV.D.3 explains why FDA is not proposing a product
standard for NNK levels in smokeless tobacco at this time.
---------------------------------------------------------------------------
The relatively high level of these carcinogens has led the World
Health Organization (WHO) to call for limits on these constituents in
tobacco products (Ref. 78). Tobacco science researchers have also
called for the reduction of TSNAs in smokeless tobacco products due to
their potential impact on the increased cancer risk associated with
smokeless tobacco use (Refs. 175, 176).
1. Evidence for NNN Carcinogenicity in Animals
There is sufficient evidence to indicate NNN may act as both a
local and systemic carcinogen in experimental animals. Studies have
shown that NNN given by various routes of administration consistently
causes oral and esophageal tumors in rats, as well as nasal cavity and
tracheal tumors across multiple species, with noted route- and species-
specific differences (Refs. 7, 178, 148, 59, 94, 149 through 160). Rats
are more likely to develop tumors in the esophagus, oral and nasal
cavity following oral or subcutaneous exposure to NNN (Refs. 7, 59, 94,
95, 148, 149) whereas mice develop tumors in lung, forestomach, and to
a limited extent liver (Refs. 155, 156, 160). In hamsters, tracheal
tumors and nasal cavity tumors are observed following oral or
intraperitoneal exposure to NNN (Refs. 59, 151), with tracheal tumors
also observed following subcutaneous exposure (Ref. 152). Studies in
experimental animals also demonstrate that NNN can induce tumor
formation in a dose-dependent manner. For example, in rats, a dose-
dependent formation of nasal cavity tumors has been observed following
subcutaneous or oral exposure (via gastric instillation) to NNN (Refs.
149, 161). In hamsters, NNN stimulates tumors of the nasal cavity,
trachea and liver in a dose-dependent manner following subcutaneous
exposure (Ref. 151).
Although a dose-dependent relationship between oral and esophageal
tumor formation following exposure to NNN has not been extensively
studied, chronic oral exposure to NNN via drinking water clearly
identifies oral cavity and esophageal tissues as the major targets of
tumorigenesis in animals (Refs. 7, 95). As indicated previously, sites
of tumor formation following exposure to NNN are not limited to oral
and esophageal tissues. Studies in experimental animals demonstrate
oral exposure to NNN stimulates tumor formation in other tissues, such
as nasal cavity, stomach, lung and liver (Refs. 151, 155, 156, 161,
178, 179). However, the number of tumors observed in oral and
esophageal tissues are often greater than the number of tumors observed
in other, non-target tissues. For example, a greater number of rats
were reported to develop tumors in the esophagus compared with the lung
following exposure to NNN in liquid diet (Ref. 94). Another study
reported a similar trend, with esophageal and oral tumors observed in
35 and 18 percent of rats exposed to NNN via oral gavage, respectively,
whereas only 5 percent of exposed animals developed lung tumors (Ref.
178). A more recent study by Balbo et al. (Ref. 7) found that 100
percent of rats treated orally with NNN in their drinking water
developed malignant oral tumors. A high incidence of esophageal tumors
has been consistently observed in rats following oral exposure to NNN
across studies, with 83 percent of animals developing esophageal tumors
following exposure via liquid diet (Ref. 94) and 60 to 100 percent of
animals developing esophageal tumors following exposure via drinking
water (Refs. 148, 95, 59, 7).
The high incidence of tumor formation in esophageal and oral tissue
observed in experimental animal studies is consistent with what is
known regarding the metabolism of NNN and subsequent DNA adduct
formation in target tissues. NNN is a genotoxic carcinogen, it reacts
with DNA and is assumed to exhibit proportional
[[Page 8012]]
responses at low doses (Refs. 168, 169). The general understanding of
the mechanism of action (MOA) of NNN-induced carcinogenicity centers
around its metabolic activation. The metabolic activation of NNN leads
to the formation of DNA and hemoglobin adducts and subsequent
mutagenicity, ultimately resulting in cancer. NNN can be metabolized by
2'-hydroxylation and 5'-hydroxylation, with the 2'-hydroxylation the
more predominant metabolic pathway (Ref. 8). The noted DNA adducts
formed from NNN are POB-DNA via the 2'-hydroxylation pathway (Refs.
172, 173, 177) and py-py-dI via the 5'-hydroxylation pathway (Ref.
169). NNN has a chiral center at the 2'-position and exists in 2
enantiomeric forms, (R)-NNN and (S)-NNN, with (S)-NNN being the
predominant enantiomer in smokeless tobacco products (Refs. 180, 181).
The MOA for NNN-induced carcinogenicity is supported by the pattern
of mutagenesis and DNA adduct formation in target tissues following
oral exposure to NNN in experimental animals. For example, NNN was
found to be mutagenic in tongue, oral and esophageal tissue in mice
following oral exposure via drinking water (Ref. 174). Both POB-DNA and
py-py-dI adducts have been detected in the oral cavity, esophageal
mucosa, nasal cavity, liver and lung of rats following exposure to NNN
via drinking water (Refs. 169 through 173). Additionally, dose-
dependent formation of POB-DNA adducts has been observed in oral,
esophageal and nasal mucosa following oral exposure to NNN (Ref. 170),
as has py-py-dI (Ref. 169). A greater number of DNA adduct formation
has been also been observed in oral and esophageal tissues compared
with other sites, consistent with previous findings of increased tumor
formation in oral and esophageal tissues compared with other sites
(Refs. 94, 178). For example, POB-adduct formation was greater in oral
cavity and esophageal mucosa compared with lung or liver in rats
following oral exposure to (S)-NNN via drinking water (Refs. 171, 172).
These findings are consistent with previous reports of increased oral
and esophageal tumor formation as compared with other tissues (Refs.
94, 178) and the reported high incidence of oral and esophageal tumors
following oral exposure to NNN in rats (Refs. 7, 95).
Recent evidence has demonstrated target organ specificity for the
carcinogenic effects of NNN and NNK in animals and in humans. As
previously discussed, NNN's carcinogenic effects have been documented
in the esophagus, nasal, and oral cavities when administered orally to
animals (Refs. 7, 59, 95, 148), which provides some degree of
concordance with effects observed at these sites in epidemiological
studies (Refs. 77, 96). In contrast, NNK is known for being a powerful
systemic lung carcinogen. NNK causes lung tumors in animals, including
mice, rats, and hamsters, independent of the route of administration
(Refs. 8, 149, 162 through 167). Even when animals are given NNK
orally, a dose-dependent formation of lung tumors is observed (Refs.
164, 165, 166). Indeed, a recent study found 100 percent of animals
receiving NNK via oral exposure developed lung tumors (Ref. 167).
However, no oral cavity or esophageal tumors have been reported in
animals exposed only to NNK (Ref. 8).
2. Evidence for NNN Carcinogenicity in Humans
Although the data on NNN exposure in humans is more limited, two
recent epidemiological studies have found strong associations between
NNN and cancer risk among cigarette smokers, providing evidence that
increased exposure to NNN through use of certain tobacco products is
associated with greater risk of head, neck, and esophageal cancer in
tobacco users. In one nested case-control study among Chinese men,
urinary levels of NNN in smokers were significantly associated with
increased risk of developing esophageal cancer, but not lung cancer,
after controlling urinary total NNAL (used to measure NNK exposure),
smoking intensity and duration, alcohol consumption, and urinary
cotinine (nicotine metabolite used to measure nicotine exposure) (Ref.
77). In the same cohort, total urinary NNAL was independently and
significantly associated with increased risk of developing lung cancer
(Ref. 183), whereas no association was observed between urinary total
NNAL and esophageal cancer risk (Ref 77). In a second case-control
study, mean levels of NNN were significantly higher in cases diagnosed
with head and neck squamous cell carcinoma compared to matched
controls, although no adjustment was made for potential confounding
factors (Ref. 96). Although these studies were conducted among smokers,
they support the significant role of NNN in cancer development in
humans and are highly relevant to smokeless tobacco users, who have
comparable levels of exposure to NNN and NNK as those of cigarette
users (Refs. 97, 72, 98, 99). Moreover, these epidemiological findings
support the target organ specificity and cancer risk associated with
exposure to NNN (oral and esophageal) versus NNK (lung) that are
observed in experimental animals (see section IV.B.1).
3. Geographic Differences in Cancer Risks From Smokeless Tobacco Use
Although there is some heterogeneity among particular study
estimates, research on the association between smokeless tobacco use
and oral cancer risk generally has found significant differences in
risk by geographic region. For the United States, Boffetta et al.
analyzed nine oral cancer risk estimates from seven independent studies
that either adjusted for smoking or were restricted to never smokers
and found a summary relative risk for smokeless tobacco use of 2.6
(Ref. 100). Lee and Hamling published a separate analysis that
generated an overall relative risk estimate of 2.16 from all available
U.S. studies (Ref. 114). The authors also generated estimates of never
smoker oral cancer relative risks (a relative risk of 3.33) for 5
studies and smoking-adjusted oral cancer relative risks (a relative
risk of 1.65) for 12 studies for U.S. smokeless tobacco users. Toombak,
a smokeless tobacco product commonly used in Sudan, has been found to
have a relative risk for oral cancer of 3.9 (Refs. 104, 4), while in
India and Pakistan use of smokeless tobacco products, including
pattiwala, naswar, khaini, and zarda, was associated with relative
risks for oral cancer as high as 14 (Ref. 1 at table 71). In
Scandinavia, increased oral cancer risks were observed in some but not
all studies (Refs. 92, 188, 189, 191, 192).
The geographic variations in oral cancer risks are believed to be
due to differences in product toxicant content (Ref. 100). TSNA
concentrations in smokeless tobacco products vary by product and
region; NNN levels are generally lowest in snus manufactured in Sweden,
while NNN levels in smokeless tobacco products sold in the United
States are typically higher (Refs. 11, 13, 5, 10). Many smokeless
tobacco products sold elsewhere in the world, including in India and
Sudan, contain even higher levels of NNN and other carcinogens than
those in the United States (Refs. 206, 105). These analyses, in
addition to the toxicological evidence demonstrating that NNN is a
potent oral cavity and esophageal carcinogen, provide strong support
for a relationship between smokeless tobacco use, NNN levels in these
products, and oral cancer risk by geographic region. Thus, FDA believes
that reducing NNN levels in smokeless tobacco products would reduce
cancer risk.
[[Page 8013]]
C. NNN in Smokeless Tobacco Products
1. Formation of NNN in Smokeless Tobacco Products
NNN is formed either by the nitrosation of nicotine with the loss
of a methyl group or by nitrosation of nornicotine, primarily during
the curing of tobacco (Ref. 29). Nicotine is a tertiary amine while
nornicotine is a secondary amine; the rate of nitrosation of tertiary
amines is slow compared to the rate of nitrosation of secondary amines
(Ref. 30). As the concentration of nicotine in smokeless tobacco
products is typically three orders of magnitude larger than the TSNA
concentration, NNN formation does not have a significant impact on
product nicotine levels (Refs. 5, 10).
The primary nitrosating agent is nitrite (Ref. 31). Reduction of
nitrate by bacteria such as halotolerant micrococci, Coryneforms, and
halophilic rods during the fermentation process is the primary source
of nitrite in smokeless tobacco products (Ref. 34). Nitrogen-rich
fertilizer is also a source of nitrate and, upon reduction, nitrite
(Ref. 41). Higher NNN levels are found in tobacco crops fertilized with
nitrogen-rich fertilizers compared to fertilizers with lower nitrogen
content (Refs. 42, 34). Tobacco and smokeless tobacco products with low
nitrite concentrations have low levels of NNN, while products high in
nitrite contain higher concentrations of NNN (Refs. 32, 31).
There is limited evidence to support that an appreciable amount of
NNN is formed from nicotine or its metabolites in humans (Refs. 193,
194). The reaction of dietary precursors with nitrosating agents
supplied by the diet can result in the endogenous formation of N-
nitrosamines in humans (Refs. 195, 196, 197). The acidic environment in
the stomach creates favorable conditions for nitrosation to occur (Ref.
198) and nitrosation of nornicotine has been observed in vitro under
simulated gastric conditions, whereas nitrosation of nicotine has not
been observed (Ref. 199). To date, there is not sufficient data in
humans to indicate any significant in vivo NNN synthesis.
NNK is primarily formed through nitrosation of nicotine during the
later stages of tobacco processing (i.e., curing and fermentation)
(Ref. 33). Similar to NNN, the primary nitrosating agent is nitrite and
products with low nitrite concentrations have low levels of NNK while
products with high nitrite concentrations have high levels of NNK
(Refs. 32, 31).
2. Factors That Influence NNN Levels
NNN levels in tobacco can vary significantly from year to year,
intra-year, and farm-to-farm (Ref. 34). Although tobacco plants
inherently produce a small amount of NNN (Refs. 35, 1), a wide variety
of factors can affect the final levels of NNN found in the finished
tobacco product (Ref. 1). These factors, which can either increase or
decrease NNN levels in smokeless tobacco products, include the tobacco
type (e.g., dark air-cured tobacco, Bright leaf tobacco, Burley
tobacco), growing conditions (e.g., geographic region, climate,
rainfall), curing techniques (e.g., fire, flue, air, sun), production
process (e.g., additives), and storage conditions (e.g., temperature,
humidity, duration) (Ref. 1). As discussed in section IV.E, because
there are many factors that can influence the NNN level in smokeless
tobacco products, there also are a number of options available to
manufacturers to reduce and control NNN levels in order to meet the
requirements of this proposed standard.
a. Tobacco Type
Studies have shown differences in NNN levels prior to curing and
processing among different varieties of tobacco. Higher NNN
concentrations have been found in Burley and dark tobacco compared to
flue-cured Bright leaf tobacco (Ref. 36). Burley tobacco also contains
more NNN compared to Virginia and Oriental types, whether grown in the
same or different geographical locations (Ref. 37).
The use of selectively bred ``low converter'' tobacco seed has been
shown to result in lower nornicotine (precursor to NNN) levels in
tobacco (Refs. 38, 39, 40). The amount of NNN in a tobacco variety
before curing or processing is dependent on the amount of its precursor
nornicotine, which in turn is dependent on the amount of its precursor
nicotine (Ref. 38). Nornicotine is normally present at very low levels
compared to nicotine, but tobacco plants, through a process called
``conversion,'' can convert some of their nicotine to nornicotine (Ref.
39). Low converter seeds come from plants which, through selective
breeding and genetic engineering, have a lower potential to convert
nicotine to nornicotine (Ref. 40).
b. Growing Conditions
Climate. Weather is a significant factor in NNN formation.
Increased rainfall, including more frequent intense weather systems
such as hurricanes, correlate with higher levels of TSNAs (Ref. 34).
Specifically, wetter conditions that increase relative humidity during
the growing season are more conducive to increases in total TSNA
formation.
Fertilizer. Nitrogen rich fertilizer can also have a
profound effect on nitrate and NNN levels found in tobacco (Ref. 41).
Higher NNN levels are found in crops fertilized with nitrogen-rich
fertilizers compared to fertilizers with lower nitrogen content (Refs.
42, 43, 34). This is because, when nitrogen-rich fertilizer is used
during tobacco growing, more nitrogen is incorporated into the leaves
of the tobacco in the form of nitrate. As the tobacco leaves are cured,
the nitrate acts as a substrate for microorganisms reducing the nitrate
to nitrite. The nitrite reacts with alkaloids such as nicotine or
nornicotine in the tobacco during curing to form higher levels of TSNAs
such as NNN.
c. Curing Techniques
There are four main methods for curing tobacco: Sun, air, flue, and
fire curing. Sun-cured tobacco is cured on outdoor racks exposed to the
sun while air-cured tobacco is cured on racks in a well-ventilated barn
under ambient temperatures (Ref. 4). Flue and fire curing occur in
artificially heated and ventilated barns. Flue-cured tobacco is cured
on racks in a barn or other enclosed structure with an external heat
source (e.g., heat exchanger, propane or diesel heaters) so the tobacco
isn't exposed to smoke (Refs. 34, 200). In contrast, fire-cured tobacco
is cured on racks in a barn and exposed directly to smoke from a wood
fire (Ref. 201). Curing can take from a few days to several weeks
depending on the curing method (Ref. 44). The curing process not only
dries out and preserves the tobacco but also imparts characteristic
flavor.
During the curing process, the curing method, humidity, air flow,
temperature, and the fuel used for heating the tobacco influence the
extent to which the NNN level changes (Refs. 45, 46). Studies have
shown that flue and fire-curing tobacco results in higher NNN levels
than when the same tobacco is air-cured (Refs. 47, 42, 1). In addition,
air-curing during periods of high relative humidity produces tobacco
with higher amounts of TSNAs and nitrite (Ref. 46). However, TSNAs in
tobacco were shown to be lower when cured by reducing humidity by
improving the air circulation or by using an indirect heating source to
limit exposure to smoke (Refs. 46, 48). Furthermore, direct flue curing
with liquid propane gas leads to higher NNN levels than fire curing or
indirect flue curing (Ref. 49).
[[Page 8014]]
d. Production Process
During production, microorganisms (bacteria, fungi, and yeast) on
tobacco play a significant role in the generation of nitrite and the
subsequent formation of TSNAs (Ref. 202). The microorganisms can come
from a variety of sources including the soil and surrounding
environment, or unsanitary manufacturing conditions (Ref. 12).
Fermentation is commonly used in the production of U.S. smokeless
tobacco products. Fermentation imparts flavor and contributes to higher
nitrite and NNN levels (Ref. 50). Reduction of nitrate by bacteria
during the fermentation process is the primary source of nitrite in
smokeless tobacco products (Ref. 34). The increased nitrite
concentration subsequently contributes to the nitrosation of amino
alkaloids and the formation of NNN.
In contrast, certain processing methods have been reported to help
limit the levels of NNN formed during production. For example, using
non-nitrate reducing bacteria during the fermentation process (i.e.,
through seeding or starter culture) can lower NNN yields (Refs. 34,
51). Cleaning and sanitizing all equipment used in the processing and
manufacturing of smokeless tobacco products, including the fermentation
equipment, can lower microorganisms on tobacco and lower NNN yields
(Ref. 34). In addition, using closed process blenders at a high
temperature, adding bicarbonate and carbonate salt solutions to control
pH, adding humectants, and pasteurization or heat treatment can lower
microbial activity during production, leading to lower NNN levels in
smokeless tobacco products (Ref. 11).
e. Storage Conditions
Storage conditions (i.e., temperature and humidity) and the
duration of storage have been shown to influence NNN levels. Cured
tobacco leaves and finished smokeless tobacco products are stored until
they are processed or consumed. Tobacco leaves are often stored on
farms for up to 3 months prior to sale to tobacco product
manufacturers. Once sold, the tobacco may be stored for another 18
months before it is manufactured into a finished product (Ref. 41).
Researchers have reported a 2-fold increase in NNN levels in sun-
cured tobacco and a 3-fold increase in NNN levels in Burley tobacco
when stored at ambient temperatures over a 1-year period (Ref. 41).
Further, studies have shown that storage temperatures as low as 27
[deg]C can lead to increased NNN formation in air-cured Burley tobacco,
and that the rate of increase becomes greater as the temperature is
increased (Ref. 41). In addition, air-cured Burley tobacco stored at
higher temperature (24 [deg]C v. 32 [deg]C) and higher relative
humidity levels (70 v. 83 percent) showed increases in both nitrite and
NNN levels (Ref. 52).
Similar to cured tobacco, high temperature, high humidity, and
extended storage can cause levels of NNN to increase in smokeless
tobacco products. As smokeless tobacco products ``age,'' the water
content can change, leading to bacterial growth, and the pH and
nicotine content can decrease, causing nitrosamine levels such as NNN
to rise (Ref. 11).
Studies have shown that NNN increases in moist snuff and dry snuff
when stored at 24 [deg]C for 24 days (Refs. 53, 54). Exposing moist and
dry snuff to ambient air, such as when a product is opened and closed
between dips, also increases NNN concentrations (Ref. 53). Similar to
cured tobacco leaves, the storage of moist snuff at low temperatures (4
[deg]C) reduces the increase in NNN that was seen when the same product
is stored at ambient conditions (Ref. 55).
Humidity levels during storage can have an even greater influence
than temperature on NNN formation in finished smokeless tobacco
products. Specifically, the NNN levels in moist and dry snuff can be
increased just by raising the relative humidity during storage from 22
to 50 percent (Ref. 54). Moreover, the combined effects of humidity and
temperature are enhanced in products with higher moisture content (Ref.
54). Yet, storage conditions do not have the same effect on all types
of smokeless tobacco. Studies on storage of chewing tobacco did not
show the same increase in NNN as seen with moist and dry snuff, which
suggests that some tobacco blends may be less prone to producing
nitrosamines during storage (Refs. 53, 54). Furthermore, although
retailers are encouraged to refrigerate Swedish snus to maintain
``perceived product freshness,'' the product's low bacterial activity
may stabilize the NNN level even when stored at room temperature (Ref.
11).
3. Levels of NNN in U.S. Smokeless Tobacco Products
The levels of NNN in smokeless tobacco products on the U.S. market
can vary by several orders of magnitude, not only among different
subcategories of products, but also among products in the same
subcategory (table 2, Refs. 5, 10, 56). After measuring NNN levels in
46 different smokeless tobacco products available in the United States
from 2006 and 2007, Borgerding et al. found NNN levels ranged from
below the limit of quantification (0.02 [mu]g/g) to 14.4 [mu]g/g per
dry weight (Ref. 5). As shown in table 2, the NNN levels within the
class of moist snuff and dry snuff ranged from 0.6 to 12.8 [mu]g/g per
dry weight and 5.91 to 12.0 [mu]g/g per dry weight, respectively (Ref.
5).
A more recent study by Ammann et al. examined 34 products purchased
in the United States in 2015 (Ref. 10). In line with the Borgerding
study, Ammann et al. found NNN levels ranged from 0.64 to 12.0 [mu]g/g
per dry weight (Ref. 10). The NNN levels for moist snuff ranged from
1.0 to 9.5 [mu]g/g per dry weight while the NNN levels for dry snuff
ranged from 5.91 to 12.0 [mu]g/g per dry weight (Ref. 10).
The range of NNN levels described in these studies have been
confirmed by numerous other studies. Stepanov et al. reported a similar
range for moist snuff (3.8 to 6.9 [micro]g/g per dry weight) with dry
snuff ranging from 0.95 to 5.3 [micro]g/g per dry weight (Ref. 13). In
a separate study, Stepanov et al. reported a wide range of NNN levels
in 11 dissolvables that are smokeless tobacco products (0.27 to 2.7
[micro]g/g per dry weight) (Ref. 56). Finally, Lawler et al. reported a
wide range of NNN levels in chewing tobacco (0.94 to 2.8 per wet weight
which equates to 1.2 to 3.6 [micro]g/g per dry weight) and in dry snuff
(6.1 to 31 [micro]g/g per wet weight which equates to 6.5 to 33
[micro]g/g per dry weight) (Ref. 20).
Table 2--NNN Concentration and Market Share of Smokeless Tobacco Products Sold in the United States
----------------------------------------------------------------------------------------------------------------
Mean[hairsp]\1\ and range of NNN measured in [mu]g/g dry
weight (number of products)
Smokeless tobacco product --------------------------------------------------------------- Market share
Stepanov et al., Borgerding et al., \2\ (%)
2014 2012 Amman et al., 2016
----------------------------------------------------------------------------------------------------------------
Dissolvable...................... 1.78; 0.27-2.66; ................... ................... <0.1
(11).
Chewing Tobacco (Loose leaf, ................... 2.21; 0.66-5.05; 2.24; 0.92-4.60; 5.2
plug, chew). (8). (8).
Dry Snuff........................ ................... 5.53; 0.81-14.42; 7.50; 5.91-12.00; 0.7
(10). (4).
[[Page 8015]]
Moist Snuff...................... ................... 3.76; 0.66-12.77; 3.01; 0.64-9.50; 94.1
(28). (22).
Mean NNN across product ................... 3.87............... 3.36............... ..............
categories.
Market share adjusted mean across ................... 3.69............... 3.01............... ..............
product subcategories \3\.
----------------------------------------------------------------------------------------------------------------
\1\ Mean values were determined by averaging the NNN concentrations across a smokeless tobacco product
subcategory in each of the three representative studies.
\2\ Market share data was based on 2015 retail scan data from Nielsen.
\3\ In order to calculate a market share adjusted mean the mean of each subcategory was multiplied by its
representative market share (e.g., Chewing Tobacco [NNN] x .052). These values for each subcategory were then
summed to estimate a market share weighted mean across all smokeless tobacco product subcategories examined.
The range of the NNN levels in the studies discussed in this
subsection suggest that there exists the potential to reduce the levels
of NNN in all smokeless tobacco through manipulation of starting
materials and curing processes, as well as careful control of
manufacturing and storage practices.
D. Basis for the NNN Limit in the Proposed Standard
As discussed in section IV.B of this document, the scientific
evidence supports that NNN is a potent carcinogenic agent found in
smokeless tobacco products and that NNN in smokeless tobacco products
is a major factor underlying oral and esophageal cancers. The
epidemiological evidence indicates populations who use smokeless
tobacco products with lower levels of NNN have lower cancer risks
(Refs. 4, 100, 101). Thus, it is anticipated that reducing levels of
NNN in tobacco products in the United States will reduce the incidence
of oral and esophageal cancers among smokeless tobacco users.
Based on our assessment of the evidence, we are proposing that the
mean level of NNN in any batch of finished smokeless tobacco products
not exceed 1.0 [micro]g/g of tobacco (on a dry weight basis) at any
time through the product's labeled expiration date as determined by
testing in compliance with Sec. 1132.12 (proposed Sec. 1132.10). In
selecting the NNN limit in this proposed standard, FDA took into
consideration the epidemiological evidence demonstrating differences in
observed cancer risks between users of smokeless tobacco products
manufactured in the United States and in Sweden, and the technical
achievability of the proposed limit. To estimate the anticipated health
benefits of the proposed standard, FDA modeled the estimated cancer
risk reduction determined by reducing NNN levels in smokeless tobacco
products from current levels.
As NNN appears to have a genotoxic mode of action, FDA followed the
U.S. Environmental Protection Agency's (EPA's) guidance for carcinogen
risk assessment and assumed a linear relationship in the low-dose
region of the dose-response model (Ref. 203). Using this model, the
risk of cancer is linearly reduced as exposure to NNN approaches zero.
While a limit of 0.0 [micro]g/g for NNN would maximize cancer risk
reduction to smokeless tobacco users, there is limited information on
NNN levels lower than the proposed standard and their technical
achievability. We note, however, that an NNN level of 1.0 [micro]g/g of
tobacco has been achieved in some smokeless tobacco products sold in
the United States and is thus achievable using current technology. As
discussed in section II.C of this document, FDA may consider a lower
NNN level in the future. In addition, FDA welcomes comments on the
technical achievability of complying with the proposed standard in this
rule.
FDA modelled NNN attributable cancer risk to estimate the potential
benefits to public health. Specifically, FDA modelled the effect an NNN
smokeless tobacco product standard would have on reducing the cancer
risk to a population exposed to NNN through use of smokeless products.
This analysis is described in detail in this section.
FDA also considered the epidemiological evidence demonstrating
differences in observed cancer risks between users of smokeless tobacco
products manufactured in the United States and in Sweden. We focused on
epidemiological evidence from Sweden because Swedish smokeless tobacco
products tend to have lower levels of NNN than other smokeless tobacco
products (Refs. 100, 114), which helps inform our public health
analysis of a product standard limiting NNN. As discussed in section
IV.B of this document, epidemiological studies demonstrate a lower risk
of oral cancer from the use of Swedish snus in Sweden compared to other
smokeless tobacco products in other countries. It is anticipated that
the proposed product standard of 1.0 [mu]g/g dry weight would bring the
NNN level in U.S. smokeless tobacco products in line with those of
Swedish snus.
With respect to risk reduction, FDA assumed that changes in the
growing conditions and changes in product curing and processing may be
necessary to achieve lower NNN levels in smokeless tobacco products. As
discussed in section IV.E, it appears that there are several options
for achieving the proposed NNN limit.
We note that FDA's approach to establishing the proposed limit
differs from that of other regulatory agencies, such as the EPA and the
U.S. Occupational Safety and Health Administration (OSHA), which set
regulatory exposure limits based upon a risk level deemed to be
``acceptable'' or ``negligible'' (Refs. 204, 205 at appendix B). FDA
expects that although the cancer risks posed by smokeless tobacco
products that meet the proposed standard would be lowered, use of these
products would still pose increased cancer risks, including increased
oral cancer risks, compared with not using smokeless tobacco products.
Thus, the proposed product standard establishing a limit for NNN in
smokeless tobacco products is not intended to communicate that such
levels are ``acceptable'' or ``negligible'' from a public health
perspective.
1. Excess Lifetime Cancer Risk of NNN in U.S. Smokeless Tobacco
Products
FDA estimated the excess lifetime cancer risk (ELCR) for oral
cancer associated with the current NNN levels in U.S. smokeless tobacco
products and compared it to an estimate of the ELCR
[[Page 8016]]
under the proposed standard. We calculated the ELCR with and without
the proposed product standard to estimate the extent to which the
proposed standard can reduce the risk of cancer among smokeless tobacco
users in the United States. Then FDA used the resulting reduction in
lifetime cancer risk to estimate the potential decrease in oral cancer
cases as a result of this rule.
Given the variability associated with smokeless tobacco use
(frequency, quantity) and lack of data regarding the dose-response
relationship for NNN in humans, FDA is using the ELCR calculation to
provide an understanding of the relative, rather than absolute, risk
associated with different product classes and the impact of the
proposed product standard on users of smokeless tobacco.
As demonstrated by Equation 1, which FDA used to calculate the
excess lifetime cancer risk, the ELCR is a unitless probability (e.g.,
1 in 10,000 chance). The equation is based on the U.S. Environmental
Protection Agency Risk Assessment Guidance (Ref. 57). The key variables
in the equation are: (1) The level of NNN in the product (i.e.,
concentration in product as used); (2) the amount of product (mass)
used each day; (3) the amount of NNN that leaves the product during use
(i.e., percent extracted) and the amount of the extracted NNN that is
absorbed by the body (i.e., absorption rate); (4) the length of time
the product is used over a lifetime, which is determined by the years
of use (i.e., exposure duration) over the lifetime (i.e., averaging
time); (5) body weight of the user; and (6) the cancer slope factor
(CSF), which is used to represent the dose-response relationship
between NNN and cancer incidence. As each of these variables is
associated with wide variability, we attempted to derive average values
to estimate a population average ELCR. Below we describe the
assumptions that are used in this analysis and the justification for
those assumptions. Because of limitations in data, particularly with
regard to data underlying the CSF, the ELCR calculation is not used to
assess absolute cancer risk. Instead, the ELCR is used to estimate the
percent reduction in cancer risk associated with implementing an NNN
limit for smokeless tobacco products. FDA welcomes public comments on
alternative assumptions that may affect the ELCR estimate. Commenters
should provide explanations as to why the alternative assumptions may
lead to more robust estimates of the ELCR associated with this product
standard.
Equation 1--ELCR Calculation
[GRAPHIC] [TIFF OMITTED] TP23JA17.000
C = Concentration of NNN in product as used ([micro]g/g wet weight)
IR = Intake rate (mg of wet (as used)) product used per day (12 g/
day; 2.5 g/day for dissolvables)
AB = Absorption rate, how much of product NNN is transferred to the
user (60 percent)
EF = Exposure frequency (365 days/year)
ED = Exposure duration (60 years)
BW = Body weight in kg (70 kg)
AT = Averaging time (365 days/year; 78 years)
CSF = Cancer slope factor (1.4 mg/kg/day)
As defined by the EPA guidelines, the cancer slope factor (CSF) is
``an upper bound (approximating a 95percent confidence limit) on the
increased cancer risk from a lifetime exposure to an agent. This
estimate, usually expressed in units of proportion (of a population)
affected per mg/kg/day, is generally reserved for use in the low-dose
region of the dose-response relationship; that is, for exposures
corresponding to risks less than 1 in 100. This term is usually used to
refer to oral slope factors (i.e., slope factors used for assessing
ingestion exposure).'' (Ref. 190).
For this ELCR assessment, FDA uses the CSF for NNN generated by the
California Environmental Protection Agency (CalEPA) in 1992 (Ref. 93).
Although this CSF has been used as the basis for several published
analyses (Refs. 207, 208, 209, 74, 210, 211, 102), it has significant
limitations. The CalEPA CSF of 1.4 (milligram per kilogram per day (mg/
kg/day))-\1\ for NNN is based upon tumor data from hamsters
orally exposed to NNN in drinking water in a study conducted by Hecht
et al. (Ref. 59), which compared a single dose scenario with a control
group. The CalEPA thus generated a slope by drawing a line between the
two points (tumor rate at a single dose and tumor rate in the control
group). EPA's 2005 Cancer Guidelines and subsequent Benchmark Dose
Guidance elaborate extensively on the determination of the point of
departure (POD) for generating a CSF (Refs. 203, 187). More
specifically, EPA recommends that the starting point for subsequent
extrapolations and analyses be the lowest dose adequately supported by
the data. However, in a single dose study, without an understanding of
the shape of the exposure-response curve at lower doses, there is
potentially significant bias in the derivation of the CSF--leading to
subsequent uncertainty in the modeling of cancer risk. Thus, as noted
above, FDA's ELCR calculation is only used to estimate relative risk of
alternative exposure scenarios, not absolute risk. FDA welcomes public
comment on whether there is a more robust CSF available for NNN.
For the concentration of NNN in the product, FDA used the
Borgerding et al. and Ammann et al. data (Refs. 5, 10) to represent the
range of levels of NNN in current smokeless products, which ranged from
below the limit of quantification (0.02 [mu]g/g) to 14.4 [mu]g/g per
dry weight. We chose these studies because they are the most
comprehensive studies of NNN levels in U.S. smokeless tobacco products
and the levels are similar to levels which have been reported by other
investigators (see section IV.C.3). These studies also reported the
moisture content of the smokeless tobacco products, which FDA used to
determine the products wet weight NNN levels (i.e., what a user would
be exposed to). This calculation involves taking the dry weight NNN
measurement and accounting for the moisture found in the product when
used by consumers [NNN [mu]g/g dry weight] x [1-moisture content] =
[[mu]g/g wet weight (as used)].
For the intake rate (mass of product used each day), FDA chose an
average use assumption of 12 g of wet product per day, every day based
on an experimental study in the United States that indicated that the
range of the most common form of smokeless tobacco use, moist snuff, is
between 5.1 and 42.5 g/day (Ref. 60), with an average use of 12 g/day
(Ref. 60). This study is widely cited for estimating average smokeless
tobacco use (Refs. 132, 212, 213). The 12 g/day assumed estimate is
consistent with studies that look at use in terms of the number of tins
(container holding the smokeless tobacco product) of tobacco consumed
(Refs. 61 through 71). These studies' estimates ranged from 1.2 tins to
4.6 tins/week, with an average of 3.68 tins/week (0.53 tin/day. Based
on an average size of a tin of 1 ounce (or slightly more than 28 g), we
estimate
[[Page 8017]]
that the average amount of smokeless tobacco product used is
approximately 15 g/day [0.53 tin/day x 28 g/tin = 14.84 g/day], which
suggests an assumption of 12 g/day is not unreasonable.
Conventional moist snuff constitutes the overwhelming majority of
the smokeless tobacco market in the United States (Ref. 131). The
figure of 12 g/day among moist snuff users does provide a reasonable
average estimate of what most U.S. smokeless tobacco users of most
product subcategories consume on a daily basis. However, FDA recognizes
that the amount of smokeless tobacco used in a day varies by product.
In particular, some dissolvable smokeless tobacco products weigh as
little as one-fifth or one-quarter as much (Ref. 56). Therefore, 2.5 g/
day was used for our ELCR calculations for daily use of dissolvable
products based upon a usage study by Krautter et al. (Ref. 15).
The extraction percentage, or fraction of TSNAs removed from a
smokeless tobacco product while in use, has been reported to range from
10 to 85 percent (Refs. 58, 73, 74). Hecht et al. analyzed extraction
and direct absorption of TSNAs in humans. A measured amount of
smokeless tobacco was inserted into the oral cavity for 30 minutes. All
saliva was collected during use of the product and three consecutive
24-hour urine samples were analyzed. The amount of TSNAs before and
after use of the smokeless tobacco product was determined along with
analysis of the expectorated saliva and urine samples. The individual
subject data provided by Hecht et al. yields a median extraction of 60
percent (59 23 percent) (Ref. 58). Other studies also cite
60 percent as an estimate of the amount of TSNAs extracted from
smokeless tobacco (Refs. 73, 74).
FDA assumed the absorption rate for the average user to be 100
percent of the extracted 60 percent of the concentration of TSNAs found
within a given smokeless product. This assumption is precautionary
because it assumes that the user is exposed to the total amount of NNN
extracted from the product, even though some of the NNN in saliva may
be excreted without being absorbed. Therefore, the absorption rate used
for the ELCR calculations is 60 percent (i.e., 100 percent absorption
of the 60 percent extracted NNN).
FDA used 60 years of product use as the exposure duration for the
ELCR calculations assuming initiation at or near 19 years of age (Ref.
23) and an average life span of 78 years for the general population
(Ref. 75). We used 78 years because it is the recommended value from
the EPA (Ref. 75) to use when calculating excess lifetime cancer risk
due to toxicant exposure in the absence of specific data on the
population of interest (i.e., smokeless tobacco users). Upon
initiation, FDA assumed daily use (365 days/year) of an average mass of
12 g of wet product per day. In addition, FDA used an average adult
body weight of 70 kg in the ELCR calculations, which is consistent with
EPA practices (Ref. 57).
Table 3 shows the estimated ELCR calculated by using the mean NNN
concentration of several different categories of smokeless tobacco
products sold in the United States from table 2, using Equation 1 and
the assumptions described in this section. Given the assumed linear
nature of the CSF, use of products with lower NNN levels has a lower
ELCR while use of products with higher NNN levels has the highest ELCR.
For example, use of dissolvables with a mean level of NNN of 1.6
[micro]g/g (as used) has a very low ELCR of 0.4 in 10,000, while use of
dry snuff with a level of NNN of 5.1-7.0 [micro]g/g (as used) has an
ELCR of 5.6-7.6 in 10,000. The current market share adjusted mean NNN
level of all U.S. smokeless tobacco products reported by the Borgerding
and Ammann studies is 1.7-1.8 [micro]g/g wet weight (as used), the use
of which corresponds to an estimated ELCR of 1.9-2.0 in 10,000.
Table 3--Estimated ELCR for Subcategories of U.S. Smokeless Tobacco Products
----------------------------------------------------------------------------------------------------------------
ELCR (expressed as ``n'' in 10,000)
-----------------------------------------------------------
Smokeless tobacco product Stepanov et al., Borgerding et al., Ammann et al.,
2014 2012 2016
----------------------------------------------------------------------------------------------------------------
Dissolvables........................................ 0.4 .................. ..................
Dry Snuff........................................... .................. 5.6 7.6
Chewing Tobacco..................................... .................. 1.8 2.0
Moist Snuff......................................... .................. 2.0 1.8
Mean ELCR across product categories................. .................. 2.7 2.6
Market share adjusted ELCR across product .................. 2.0 1.9
subcategories......................................
----------------------------------------------------------------------------------------------------------------
\1\ In order to calculate a market share adjusted mean ELCR, the mean of each subcategory was multiplied by its
representative market share (table 2). These values for each subcategory were then summed to estimate a market
share weighted mean across all smokeless tobacco product subcategories examined.
Using the same assumptions as above (Intake rate, NNN CSF), FDA
estimated the ELCR for use of smokeless tobacco products with differing
levels of NNN (dry weight, e.g., 0.5, 1.0, 2.0 [micro]g/g) and how
these levels would compare to the current market estimates (table 4).
FDA first carried out a moisture correction on the dry weight
concentrations (0.5, 1.0, and 2.0 [micro]g/g dry weight) to determine
an ``as used'' (wet weight) NNN concentration. This estimation was
based upon the moisture concentrations from the Ammann et al. study
(Ref. 10), and weighted by recent subcategory market share data. As
shown in table 4, we estimate that, compared to the current market,
hypothetical market-wide NNN levels of 0.5, 1.0 and 2.0 [mu]g/g dry
weight would reduce the ELCR by 83.2, 66.3 and 31.6 percent,
respectively.
Table 4--ELCR for Hypothetical Market-Wide Mean NNN Levels and Comparison to Current Market ELCR
----------------------------------------------------------------------------------------------------------------
% Reduction in
NNN ([micro]g/g, ELCR as compared
NNN ([micro]g/g dry weight) wet weight, as ELCR (n in 10,000) to current market
used) \1\
----------------------------------------------------------------------------------------------------------------
0.5................................................. 0.3 0.32 83.2
1.0................................................. 0.6 0.64 66.3
[[Page 8018]]
2.0................................................. 1.2 1.3 31.6
----------------------------------------------------------------------------------------------------------------
\1\ Percent reduction in ELCR compared to the market weighted mean ELCR value from Amman et al., 1.9 (table 3).
2. ELCR of NNN in Swedish Snus
As noted earlier, Swedish snus generally has a lower NNN level than
other smokeless tobacco products sold in the United States, and as
discussed in section IV.B.3, some epidemiological studies demonstrate a
lower risk of oral cancer from the use of Swedish snus in Scandinavia
when compared to the use of other smokeless tobacco products in the
United States (Refs. 100, 114). Substituting the mean NNN level of 0.55
[micro]g/g (wet weight) that is in Swedish snus (Ref. 5), into Equation
1 yields an ELCR of 0.59 in 10,000. As the proposed product standard of
1 [micro]g/g dry weight for NNN would result in bringing U.S. smokeless
tobacco products in line with NNN levels in Swedish snus, it is not
surprising that the ELCR for such a hypothetical market-wide mean NNN
level (table 4) would be almost the same as that estimated for Swedish
snus.
Our analysis indicates that users of smokeless tobacco products
would have their ELCR reduced by approximately 65 percent if the market
adjusted mean of NNN in smokeless tobacco products was reduced from
that of the current market to 1.0 [micro]g/g dry weight (table 4). This
value would approximate the ELCR of the Swedish snus exposure scenario
which epidemiological data suggests has a lower cancer risk.
3. Conclusion
Setting the proposed limit for NNN in finished smokeless tobacco
products means that, on average, in a population of daily users of
smokeless tobacco products, over their life time, there would be an
approximately 65 percent reduction in ELCR, compared with lifetime
daily use of a population that used smokeless tobacco products with NNN
levels at the current level. In section V, we calculate the impact of
an estimated 65 percent reduction in cancer risk on expected incidence
of oral cancer in the United States.
We note that FDA considered setting a product standard for both NNN
and NNK. However, FDA is proposing a product standard for only NNN at
this time because of the more limited data available on the
relationship between NNK and smokeless tobacco-related cancer risk. In
particular, NNK is noted for its consistent systemic lung
carcinogenicity (Ref. 8). However, the relationship between smokeless
tobacco use and lung cancer is a matter of ongoing investigation and a
definitive association has not been established (Refs. 3, 4).
NNN and NNK constitute potent carcinogens in smokeless tobacco
(Refs. 4, 78) and levels of these two TSNAs are often correlated in
smokeless tobacco products (Refs. 5, 20). Because many methods
available to reduce NNN also reduce NNK, there is some evidence that a
product standard that requires lower NNN levels will potentially result
in lower NNK levels as well (Ref. 84).
A market survey of 16 snus brands sold in Sweden in 1983, prior to
the adoption of the GothiaTek voluntary quality control standard,
showed average NNN levels of 3.8 [micro]g/g of tobacco and average NNK
levels of 0.8 [micro]g/g of tobacco per wet weight (Ref. 84). In 2002,
after GothiaTek was adopted, a market survey of 23 snus brands sold in
Sweden showed NNN levels decreased to 0.49 [micro]g/g of tobacco and
NNK levels decreased to 0.19 [micro]g/g of tobacco per wet weight (Ref.
84). More recent analyses of constituents in smokeless tobacco products
manufactured in the United States indicate that smokeless tobacco
brands that are lower in NNN content are also lower in NNK (Refs. 5,
20). Additionally a study by Song et al. (Ref. 6), examined the NNN and
NNK levels of conventional and low-TSNA smokeless tobacco products on
the U.S. market. NNN:NNK ratios were 3.1 and 3.7 for the conventional
and low-TSNA varieties, respectively, which is in line with results
from previous studies (Refs. 5, 20). Accordingly, we anticipate a
potential reduction of NNK in smokeless tobacco in response to the
proposed rule for NNN. We note that, in 2009, the WHO Study Group on
Tobacco Product Regulation recommended a regulatory limit for NNN and
NNK (combined) of 2 [micro]g/g dry weight of tobacco (Ref. 78). Given
the ratio of NNN to NNK in smokeless tobacco products, where the level
of NNN is generally greater than the level of NNK, any smokeless
tobacco product that meets the proposed NNN standard is likely to also
meet the levels recommended by the WHO for NNN and NNK.
E. Information on Technical Achievability
Section 907(b)(1) of the Tobacco Control Act requires FDA to
consider information submitted in connection with a proposed product
standard regarding technical achievability of compliance with the
product standard. FDA, therefore, invites public comment addressing the
technical achievability of this proposed product standard, and
specifically requests submission of evidence and data to support such
comments. FDA has also chosen to consider available information
regarding technical achievability in developing this proposed rule and
it appears that there are several options for achieving the proposed
NNN limit.
As described in more detail in section IV.C.2, there are many
factors that can influence the level of NNN in smokeless tobacco
products. Accordingly, there are a number of options available to
manufacturers to reduce and control NNN levels in finished smokeless
tobacco products including, but not limited to, the following:
Using a type of tobacco with lower concentrations of NNN
(e.g., Bright tobacco or low-converter types of Burley tobacco);
Using tobacco grown with limited use of nitrogen-rich
fertilizer on tobacco crops;
Using tobacco processed with a different curing method
(e.g., air curing instead of flue curing the same tobacco) or a
modification of a currently used curing method to minimize its effect
on NNN levels (e.g., reducing humidity during curing by improving air
circulation);
Using tobacco that had a bacteriostatic, bactericidal, or
heated solution (25 to 55 [ordm]C) applied to tobacco leaves during the
growing, harvesting, or curing processes to reduce the number of
bacteria in the tobacco leaves and thereby reduce the NNN level;
Using a non-nitrate reducing bacteria ``starter culture''
for the fermentation process;
Using cleaned and sanitized equipment for processing and
[[Page 8019]]
manufacturing smokeless tobacco products;
Adding humectants, sodium chloride, or other additives to
lower water activity and reduce microbial growth;
Adding bicarbonate and carbonate salt solutions to control
pH;
Pasteurization or heat treatment;
Storing tobacco leaves and finished smokeless tobacco
products at lower temperatures and relative humidity levels; and
Limiting the duration of storage.
For products that are already near the proposed limit, one of these
options may be sufficient to bring the product into compliance with the
proposed standard, while products which currently have levels of NNN
well above the proposed limit may need to use a combination of options.
To the extent that any change in the processing of smokeless tobacco
products (e.g., curing, fermentation) affects the products flavor, FDA
expects that manufacturers would be able to adjust the flavor profile
of finished smokeless tobacco products through minor changes in flavor
ingredients. This proposed rule also could spur innovation and
development of additional methods and technologies to reduce NNN levels
in smokeless tobacco products.
The proposed rule does not prescribe specific methods or processes
for meeting the proposed NNN level, so that smokeless tobacco product
manufacturers would have flexibility in identifying appropriate methods
or processes for reducing the NNN level in their products. Because
certain snus, moist snuff, and chewing tobacco already contain low NNN
levels, FDA expects that manufacturers of many of those products may
not need to make any manufacturing changes to meet the proposed NNN
level (Refs. 5, 10, 56). (Such manufacturers would remain subject to
the proposed standard, including its testing, sampling, labeling, and
recordkeeping requirements.) Thus, FDA expects some smokeless tobacco
products may require minimal changes to the manufacturing process to
meet the proposed NNN level, while other products may require extensive
changes to the manufacturing process to comply with the proposed level
(Ref. 56). A smokeless tobacco product that has been modified to comply
with the product standard would be a ``new tobacco product'' and
subject to premarket review.
F. Analytical Method
To test for the NNN limit in this product standard, FDA proposes
that smokeless tobacco product manufacturers use the validated method
that has been developed at FDA's Southeast Regional Laboratory (SRL) in
Atlanta, GA (Determination of N-nitrosonornicotine (NNN) in Smokeless
Tobacco and Tobacco Filler by HPLC-MS/MS, LIB No. 4620, January 2017)
(Ref. 79). The results from the test method demonstrate a high level of
specificity, accuracy, and precision in measuring a range of NNN levels
across a variety of smokeless tobacco products. Requiring that a single
test method be used would ensure that all of these factors are met and
would permit comparison of test results among finished smokeless
tobacco products and testing facilities. However, FDA is proposing that
other methods may be used if they meet the requirements in Sec.
1132.16 (Alternative test method).
Numerous methods have been published that use either high-
performance liquid chromatography/mass spectrometry (LC-MS) or gas
chromatography (GC), combined with thermal energy analyzer (TEA)
detectors to determine the content of NNN in tobacco. The validated
test method that FDA is proposing to incorporate by reference in Sec.
1132.5(a) utilizes LC-MS and has an analysis time of 8 minutes. The
method has a limit of quantification of 0.4 [micro]g/g of NNN, a linear
range of 0.4 to 1.6 [micro]g/g, and a method detection limit of 0.1
[micro]g/g. The method performance parameters for the standard method
for NNN quantification in smokeless tobacco products do not differ
significantly from the method performance parameters of other methods
that are currently in use. This method uses an extraction solvent of
100 milliMolar (mM) ammonium acetate in high performance liquid
chromatography (HPLC) grade water and a gradient of 5 to 50 percent of
5 mM ammonium acetate in 95 percent acetonitrile at a 0.5 milliliter
per minute flow rate. Analysis is conducted after a known amount of
carbon-13-labeled NNN is added to the tobacco, extracted for 5 minutes
with 100 mM ammonium acetate at elevated temperature and pressure,
dried, and reconstituted in methanol and ammonium acetate buffer.
The method includes the determination of NNN levels as well as
moisture content, so the NNN level on a dry weight basis can be
calculated. In this method, water levels are determined according to
International Organization for Standardization (ISO) standards ISO
6488:2004 and ISO 6488:2004/Cor 1:2008 or ISO 16632:2013. Validation of
this method was done using the smokeless tobacco reference products for
snus (CRP-1) and for moist snuff (CRP-2), as well as the University of
Kentucky cigarette reference product (3R4F cigarette tobacco filler).
Tobacco samples with NNN levels expected to be higher than 4 [micro]g/g
tobacco were analyzed after dilution because they were too concentrated
for analysis. This method was proven to be applicable for tobacco
products with various moisture levels, including cigarette tobacco
filler, snus, dry snuff, chewing tobacco, and moist snuff.
HPLC is favored over gas chromatography (GC) because it allows for
faster analysis and sample preparation, although validated methods
exist for analysis of NNN well below the level specified in Sec.
1132.10 by either LC or GC. Mass spectrometer (MS) detection is favored
over thermal energy analyzer (TEA) detection because of the possibility
of using isotopically-labeled NNN as an internal standard, which
controls for variation in sample preparation. In addition,
instrumentation to perform LC-MS analysis is more readily available
than for GC-TEA and, therefore, manufacturers or analytical
laboratories wishing to establish this method themselves will have
better access to equipment. The internal standard is NNN that has been
specially labeled with isotopes of hydrogen and carbon, deuterium or
carbon-13, respectively. The isotopic-labeling of the internal NNN
standard increases the mass of the internal standard relative to
naturally occurring NNN, and the internal standard appears as a
distinct signal in the mass spectrometer detector. Because the analyst
knows the quantity of internal standard added to the tobacco at the
beginning of sample preparation, the detector signal of the internal
standard can be used to quantify the amount of natural NNN present in
the sample. The isotopically-labeled internal standard is chemically
identical to NNN, so the internal standard used for MS controls for all
variations in NNN levels that arise during sample preparation and
extraction. The available scientific evidence suggests that deuterated
and carbon-13-labeled internal standards are equally acceptable for NNN
analysis. Internal standards used for TEA differ from internal
standards used for MS because they are chemically different from NNN.
Therefore, slight differences may exist between the yield of NNN and
the yield of the internal standard during the extraction and sample
preparation steps. The limits of detection for NNN by MS may be lower
than limits of detection by TEA. However, validated methods exist
[[Page 8020]]
for analysis of NNN well below the level specified in Sec. 1132.10 by
either MS or TEA.
Over the years a variety of analytical methods have been developed
for the detection of NNN in smokeless tobacco products. For example,
the Cooperation Centre for Scientific Research Relative to Tobacco
(CORESTA) published CORESTA 72, an LC-MS method for determining NNN
levels in smokeless tobacco using a low calibration standard of 0.015
[micro]g/g of tobacco, extraction in 100 mM ammonium acetate, and a
deuterium-labeled NNN internal standard (Ref. 80). CDC published an LC-
MS method for smokeless tobacco with an extraction in ethyl acetate and
use of a carbon-13-labeled NNN internal standard with an effective
limit of detection of 0.072 [micro]g/g NNN and an 8 minute analysis
time (Refs. 81, 82). The Swedish National Food Administration published
an LC-MS method for smokeless tobacco with extraction in ethyl acetate,
a limit of detection of 0.010 [micro]g/g NNN, a 15 minute analysis
time, and quantification using an external NNN standard (Refs. 83, 84).
British American Tobacco published an LC-MS method for smokeless
tobacco with extraction in methanol, a deuterium-labeled NNN internal
standard, and no published limit of detection (Ref. 85).
The American Health Foundation published several similar GC-TEA
methods for NNN in chewing tobacco using extraction in a buffer
containing ascorbic acid, a 24 minute analysis time, and confirmation
by MS of the TEA signal corresponding to NNN (Refs. 86, 87, 88). Health
Canada published Official Method T-309, which is a GC-TEA method for
NNN in tobacco using extractions in a buffer of ascorbic acid in
dichloromethane, an internal standard of N-nitrosopentyl-(3-picolyl)-
amine, a lowest calibration standard corresponding to about 0.2
[micro]g/g tobacco, and a 35-minute analysis run time (Ref. 89).
Other approaches besides LC-MS and GC-TEA have been explored to
measure NNN in tobacco filler. These methods have included two ISO
methods using gas chromatography with chemiluminescence detection (ISO
22303:2008 and ISO 22304:2008), an American Health Foundation method
using HPLC with ultraviolet absorption detection followed by
confirmation of the peak by MS (Ref. 90), and a Swedish Match method
using an NNN-specific antibody in immunoassays (Ref. 91).
Although there are various methods to test for NNN, only the
CORESTA 72 method has been externally validated via round-robin method
validation studies in accordance with ISO 5725-2 (ISO 5725-2:1994) and
only the SRL method tests on a dry weight basis. Thus, FDA concluded
that levels of 1.0 [micro]g/g or lower on a dry weight basis of NNN in
tobacco could be reliably measured either by SRL's method or by
optimizing existing common methods to meet the requirements of Sec.
1132.16 (Alternative test method).
V. Standard Is Appropriate for the Protection of the Public Health
The Tobacco Control Act authorizes FDA to adopt tobacco product
standards by regulation if it finds ``that a tobacco product standard
is appropriate for the protection of the public health'' (section
907(a)(3)(A) of the FD&C Act). The Notice of Proposed Rulemaking (NPRM)
for such a product standard must set forth this finding with supporting
justification, which FDA is doing here (section 907(c)(2)(A) of the
FD&C Act).
In order to make this finding, FDA must consider scientific
evidence concerning--
The risks and benefits to the population as a whole,
including users and nonusers of tobacco products, of the proposed
standard;
The increased or decreased likelihood that existing users
of tobacco products will stop using such products; and
The increased or decreased likelihood that those who do
not use tobacco products will start using such products. Section
907(a)(3)(B)(i) of the FD&C Act.
As discussed in this section of the document, FDA has considered
scientific evidence related to all three factors. Based on these
considerations, we find that the proposed standard is appropriate for
the protection of public health, because it will reduce the harm
associated with the use of smokeless tobacco products and FDA does not
expect that the product standard will increase the likelihood that non-
users will initiate tobacco or decrease the likelihood that users will
quit tobacco use in a manner that would offset the benefits of the
reduced cancer risk.
A. Benefits to the Population as a Whole
As discussed in section IV, on the basis of the best available
scientific evidence, FDA has determined that NNN is the predominant
driver of excess oral cancer risk among smokeless tobacco users. This
determination is based on multiple, consistent lines of evidence.
First, several authoritative reviews have concluded smokeless tobacco
products, including those currently marketed in the United States,
cause cancer (Refs. 1, 2, 3, 4). Second, NNN is a potent carcinogenic
agent found in smokeless tobacco and, along with NNK, another TSNA, is
labeled as Group 1 (known human carcinogen) by IARC (Refs. 1, 2).
Third, substantial recent evidence supports site-specific concordance
of the carcinogenic effects of NNN in animal and human epidemiologic
studies. In particular, oral and esophageal tissues have been
identified as targets for NNN-induced carcinogenicity (Refs. 7, 95,
171, 172), with observation of tumors in the oral cavity and esophagus
following oral exposure to NNN in experimental animals (Refs. 7, 59,
94, 95, 148, 178). These animal studies suggest a degree of concordance
with effects observed at these sites in epidemiologic studies (Refs.
77, 96). Finally, several authoritative reviews have observed
differences in the magnitude of cancer risks due to smokeless tobacco
use across regions of the world, which have been found to correlate
highly with variation in the levels of tobacco specific nitrosamines in
smokeless products (Refs. 1, 4).
The proposed product standard is intended to reduce tobacco-related
harms by requiring lower levels of NNN (and likely also leading to
concomitantly lower NNK levels) in smokeless tobacco products sold in
the United States. In this section, we describe the expected benefits
of the proposed standard to the population as a whole, including
specifically the benefits of reducing the number of new cases of and
deaths from oral cancer attributable to smokeless tobacco.
In this section, FDA generates estimates of the number of new cases
and fatal cases of oral cancer that would be avoided over the 20 years
following implementation of the proposed product standard. We estimate
that approximately 12,700 new cases of oral cancer and approximately
2,200 oral cancer deaths would be prevented in the United States.
Moreover, during that 20-year period, approximately 15,200 life years
would be gained as a result of the proposed standard. Because oral
cancer is associated with significant health and economic impacts, we
expect positive public health benefits due to prevention of new and
fatal oral cancer cases. We also expect that the proposed standard
would reduce the number of new and fatal cases of esophageal cancer
among continuing smokeless tobacco users and may reduce the risk of
pancreatic cancer as well.
[[Page 8021]]
1. Estimated Impact of Proposed NNN Standard on New and Fatal Oral
Cancers
The analysis in section IV.C suggests that the estimated lifetime
cancer risk (ELCR) would drop by approximately 65 percent under the
scenario where the proposed product standard for smokeless tobacco
products was fully implemented, and while assuming that all other
variables remained constant (e.g., user habits). Thus, over time, FDA
expects implementation of the proposed product standard to reduce the
number of incident cases (i.e., those new cases of oral cancer that
occur over time in the smokeless tobacco user population) and fatal
cases of oral cancer by reducing the concentrations of a potent oral
carcinogen in smokeless tobacco products (Ref. 107). To estimate the
potential impact of the standard on morbidity and mortality, we first
model the annual number of new cases and deaths from oral cancer that
are attributable to smokeless tobacco use in the United States. We then
estimate the number of these cases, both those new cases that occur
(incident cases) and those that are fatal, that would be prevented as a
result of the proposed standard by reducing the population attributable
risk by 65 percent. Relative risk estimates used to model the
population attributable risk come from a published systematic review
and meta-analysis of studies of oral cancer among U.S. smokeless
tobacco users (Ref. 100).
More specifically, as described in section IV.C of this document,
FDA estimates, by comparing its calculation of the ELCR using the NNN
levels of currently marketed U.S. smokeless tobacco products to its
calculation of the hypothetical ELCR using the proposed standard, that
meeting the standard would result in, on average, a 65 percent
reduction in the excess lifetime cancer risk due to NNN among U.S.
smokeless tobacco users. Given the apparently predominant role of
nitrosamines in smokeless tobacco cancer risk, we assume that the 65
percent reduction can be applied directly to the excess oral cancer
risks attributable to smokeless tobacco in general. Public comment is
sought on the strength of the assumptions underlying this approach to
estimate the anticipated public health effects of the rule, and whether
alternative approaches may exist. Commenters should provide evidence
supporting alternative assumptions or approaches to estimating likely
reduction in incidence of oral cancers associated with an
implementation of the proposed product standard.
The analysis quantifies the estimated public health impact of the
proposed product standard in terms of new and fatal cases of oral
cancer. Oral cancer is used as the endpoint of interest because of the
established strong relationship between smokeless tobacco use and oral
cancer risk, as well as the identification of NNN as a known, potent
oral carcinogen. There are also a relatively large number of published
estimates of oral cancer risk among U.S. smokeless tobacco users.
As described in this section, we also expect the standard to reduce
the risk of esophageal cancer and it may reduce the risks of cancer at
additional sites. However, limited data are available to permit direct
quantification of this health benefit (Ref. 100). As such, we focus
here on estimating the potential benefits of the proposed product
standard in reducing the number of new and fatal cases of oral cancer
in the United States.
We use the population attributable risk formula introduced by Levin
(Ref. 108) and subsequently used extensively by the CDC in its Smoking-
Attributable Mortality, Morbidity, and Economic Costs (SAMMEC)
methodology for modeling smoking-attributable mortality (Ref. 109).
Population attributable risk (PAR) is calculated as the proportion of
cases of disease that are attributable to the risk factor as:
[GRAPHIC] [TIFF OMITTED] TP23JA17.001
where Pe is the prevalence of the exposure and RR is the relative risk
of disease among the exposed compared with the unexposed. The resulting
proportion is then multiplied by the total number of cases of disease
in the population to estimate the number of cases that are attributable
to the risk factor.
We first estimate smokeless tobacco-attributable oral cancer cases
and deaths for the United States in 2010. We use this year because of
the availability of all relevant data inputs, including smokeless
tobacco use prevalence estimates from the same data source used in
CDC's SAMMEC method for estimating cigarette smoking-attributable
mortality. Because the National Survey on Drug Use and Health reports
that smokeless tobacco use prevalence has been relatively consistent
among youth and adults in recent years (Ref. 23), these estimates also
serve as a general measure of the effects of smokeless tobacco use on
oral cancer in the United States in subsequent years. We estimate the
U.S. prevalence of smokeless tobacco use using 2010 National Health
Interview Survey data (Ref. 111). Current smokeless tobacco use is
defined as reporting having used either chewing tobacco or snuff at
least 20 times in one's life and currently using that product every day
or some days. Age- and sex-specific prevalence of current smokeless
tobacco use is reported in table 5, along with the number of new and
fatal oral cancer cases in the United States in 2010. The latter were
obtained from United States Cancer Statistics data available on CDC's
WONDER Web site (Refs. 112, 182, 184, 185, 186). Newly diagnosed
(incident) oral cancer cases and oral cancer deaths attributable to use
of smokeless tobacco products, stratified by age group and sex, are
also reported in table 5. Oral cancer cases attributable to smokeless
tobacco accounts for 3.4 percent of all newly diagnosed oral cancer
cases.
Table 5--Prevalence of Current Smokeless Tobacco Use and Number of Newly Diagnosed and Fatal Cases of Oral Cancer in the United States, by Age Group and
Sex, U.S. 2010
--------------------------------------------------------------------------------------------------------------------------------------------------------
Smokeless Newly
tobacco use diagnosed oral Oral cancer Attributable Attributable Attributable
prevalence \1\ cancer cases deaths \2\ oral cancer oral cancer fraction (%)
(%) \2\ cases deaths
--------------------------------------------------------------------------------------------------------------------------------------------------------
Males:
[[Page 8022]]
35-64 years......................................... 4.6 15,960 2,770 808 140 5.1
65+ years........................................... 3.9 10,351 2,997 444 128 4.3
Females:
35-64 years......................................... 0.2 5,322 832 15 <10 0.3
65+ years........................................... 0.3 5,664 1,699 19 <10 0.3
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Source is the 2010 National Health Interview Survey conducted by the National Center for Health Statistics (Ref. 111).
\2\ Source is CDC WONDER, 2010 for cancers of the lip, oral cavity and pharynx (Ref. 112).
In calculating the population attributable risk, FDA used summary
relative risks for the relationship between smokeless tobacco use and
oral cancer risk derived from a meta-analysis of epidemiology studies
published by Boffetta et al. in 2008 (Ref. 100). Boffetta's analysis,
based on nine relative risk estimates from seven independent studies,
generated a summary relative risk of 2.6 (95 percent confidence
interval of 1.3-5.2) for oral cancer associated with the use of chewing
tobacco or snuff in the United States. The authors state that this
meta-analysis included studies of smokeless tobacco use among non-
smokers or among non-smokers and smokers with adjustment for smoking.
These risks were used in estimates of the population burden of
smokeless tobacco use in the United States, presented in a recent NCI
and CDC report on smokeless tobacco use and global public health (Ref.
4).
One study notes that two of the estimates included in Boffetta et
al.'s meta-analysis, from a study by Stockwell and Lyman examining the
associations between smokeless tobacco use and mouth/gum cancers and
tongue cancer, likely did not adjust for cigarette smoking and
consequently yielded considerably larger risk estimates than would have
likely been observed with adjustment (Refs. 103, 110). To understand
the sensitivity of the overall results to this study, we replicated
Boffetta et al.'s summary relative risk estimate (where relative risk
was 2.6), then re-analyzed the data omitting the two estimates from
Stockwell and Lyman. The latter analysis yielded a summary relative
risk of 2.16 (with a 95 percent confidence interval of 1.08-4.33). This
value matched the overall relative risk estimate from an independent
meta-analysis of the relationship between smokeless tobacco use and
oral cancer risk in the United States that was published in 2009 by Lee
and Hamling (i.e., a relative risk of 2.16; and a 95 percent confidence
interval of 1.55-3.02), although based on different methods and a
different set of studies. In this analysis, we use the relative risk of
2.16 as the summary relative risk for oral cancer among smokeless
tobacco users as the relative risk in 2010 (i.e., in the absence of the
proposed standard). Although we believe this relative risk represents
the best available estimates based on the research literature, it
should be noted that the accuracy and precision of particular study
estimates may be somewhat limited due to sample size and changes in
study participants' smokeless tobacco use and risk over time.
Table 6 shows that an estimated 1,300 new cases of oral cancer in
the United States in 2010 were attributable to smokeless tobacco use
using this summary relative risk. These estimates are generally
comparable to those reported in the recent NCI and CDC smokeless
tobacco report (Ref. 4). The majority of these cases occur among men,
which is consistent with low rates of smokeless tobacco use among
women.
We use similar methods to estimate the number of oral cancer deaths
in the United States in 2010 that were attributable to smokeless
tobacco use, with the only difference being that we use the number of
oral cancer deaths during this year, rather than new diagnoses during
the year, in the population-attributable risk calculations. We also
estimate the life years that were lost due to these oral cancer deaths
attributable to smokeless tobacco use. We obtain the median ages at
death for those dying of oral cancer by sex and age group (35-64 years
and 65+ years) for the United States in 2010 (Ref. 112) and life
expectancy estimates by sex at these ages from life tables for the
United States in 2010 produced by the National Center for Health
Statistics (Ref. 113). These life expectancy values are then multiplied
by the number of attributable oral cancer deaths for each group to
estimate the number of life years that were lost due to oral cancer. In
this case, all future life years lost due to oral cancer deaths were
assigned to the year in which the death occurred.
Table 6 shows that an estimated 300 oral cancer deaths in the
United States in 2010 were attributable to smokeless tobacco use. These
deaths represent an eventual loss of 4,900 life years. Consistent with
the data on new cases and deaths from oral cancer shown in table 5 and
with the lower rates of smokeless use among women, the majority of
attributable deaths and life years lost occur among men.
Table 6--Estimated Oral Cancer Cases, Deaths, and Corresponding Life Years Lost Attributable to Smokeless
Tobacco Use, U.S. 2010
----------------------------------------------------------------------------------------------------------------
Life years lost due to
Attributable new oral cancer cases Attributable oral attributable oral
cancer deaths cancer deaths
----------------------------------------------------------------------------------------------------------------
1,300......................................................... 300 4,900
----------------------------------------------------------------------------------------------------------------
Note: Smokeless tobacco attributable oral cancer cases and deaths are rounded to the nearest hundred and
estimated from information presented in table 5 including the U.S. summary relative risk value reported by
Boffetta et al. (Ref. 100), as revised by FDA.
[[Page 8023]]
We also conducted a sensitivity analysis using other oral cancer
relative risk estimates from the meta-analysis conducted by Lee and
Hamling (Ref. 114). Lee and Hamling's analysis generated estimates of
never smoker oral cancer relative risks (a relative risk of 3.33 and a
95 percent confidence interval of 1.76-6.32) for 5 studies and smoking-
adjusted oral cancer relative risks (a relative risk of 1.65 and a 95
percent confidence interval of 1.22-2.25) for 12 studies for U.S.
smokeless tobacco users. Lee and Hamling prioritized estimates for the
population of smokers and nonsmokers that adjusted for smoking status
over estimates for never smokers in studies that reported both types of
estimates in contrast to Boffetta et al., who did the reverse. We did
not use Lee and Hamling's never smoker relative risk in the main
analysis because the number of studies that reported these risks is
limited and only two of these estimates adjust for alcohol consumption.
We also did not use Lee and Hamling's smoking-adjusted relative risk in
the main analysis because smokeless tobacco risks that control for
smoking may over-adjust if individuals who both smoke and use smokeless
tobacco are more likely to smoke less or quit smoking compared with
exclusive smokers (Refs. 192, 92). These relative risks were used to
generate population-attributable risk estimates with the other inputs
used above. Using these alternative relative risks yields estimates of
approximately 700 to 2,500 new oral cancer cases in the United States
that are attributable to smokeless tobacco use per year. Similarly,
using these relative risks yields estimates of attributable oral cancer
deaths ranging from approximately 200 to 500 per year.
We then use similar methods to project the effect of the proposed
product standard on oral cancer attributable to smokeless tobacco use
in the United States over time. The proposed standard would reduce the
levels of NNN in U.S. smokeless tobacco products and is also expected
to reduce NNK levels. As described in this section, the proposed
standard is predicted to eventually reduce excess lifetime oral cancer
risks among U.S. smokeless tobacco users by 65 percent, on average.
This reduction in population cancer risk would likely occur over a
period of time, given that some smokeless tobacco users may still
develop oral cancer at the higher risk level after implementation of
the proposed product standard due to previous exposure to higher NNN
levels in smokeless tobacco products. For the purposes of generating
projections, we assume that any final rule on the tobacco product
standard for NNN would become effective 3 years after the date of
publication of the final rule (see section VII, Proposed Effective
Date) and that public health benefits would begin to accrue once the
standard is in effect.
In estimating the health impact of the proposed standard on
smokeless tobacco users, we begin with an oral cancer relative risk for
smokeless tobacco users in the United States of 2.16 from FDA's revised
meta-analysis of Boffetta et al. (Ref. 100). This relative risk
indicates an increase in oral cancer risk of 116 percent among
smokeless tobacco users compared with never users. We then reduce this
value by 65 percent based on toxicological evidence relating the
estimated average reduction in the dose of NNN to lifetime cancer risk
under the proposed standard. The result is a reduction in the estimated
relative risk of oral cancer to 1.41 under the proposed product
standard. FDA used the following calculation: (1 + (2.16-1) x (1-0.65)
= 1.41) for this determination.
We use studies of relevant cancer risks for former tobacco users by
time since cessation to provide information about risk reductions over
time after reductions in toxicant exposure. Due to limited data on the
timing of cancer risk reduction after smokeless tobacco cessation, we
applied estimates of relative risks by time since cessation for former
cigarette smokers to approximate the time it takes for excess cancer
risk to be eliminated after quitting smokeless tobacco. Estimates from
cigarette smokers help inform our estimation of the trajectory of oral
cancer risk reduction that could be expected as a result of reducing
regular exposure to tobacco-related carcinogens. These studies
generally find higher risks for oral cancer for former smokers during
the first 10 years after smoking cessation compared to never smokers,
but not necessarily thereafter (Refs. 115, 2). We therefore project
that reductions in new oral cancer cases attributable to smokeless
tobacco use would be fully realized over a 10-year period after
manufacturers are in compliance with the product standard, with the
reduction occurring in 10 percent increments until the full benefit is
reached. We also assume that, in the absence of the proposed standard,
new cancer cases attributable to smokeless tobacco use in the United
States would remain constant over time, given that the National Survey
on Drug Use and Health data show that smokeless tobacco use has
remained relatively consistent among youth and adults since 2000 (Ref.
23). Using this approach and the revised Boffetta relative risk, we
estimate that approximately 12,700 new cases of oral cancer would be
prevented in the United States in the 20 years following implementation
of the proposed product standard (table 7), which represents a 50
percent reduction in estimated smokeless-attributable oral cancer cases
over that time period. We use the same approach to project the effect
of the proposed standard on oral cancer deaths, once again assuming
that reductions in deaths would be realized over a 10-year period but
also assuming that this reduction will begin 3 years after
implementation of the standard due to previously existing or developing
cases of oral cancer. In this case, we assign the life years gained due
to reductions in oral cancer deaths to the years in which the
additional life years are actually lived. We estimate that
approximately 2,200 oral cancer deaths would be prevented, and
approximately 15,200 life years gained in the United States in the 20
years following implementation of the product standard (table 7). This
represents a 40 percent reduction in estimated smokeless-attributable
oral cancer deaths as a result of the product standard over a 20 year
period.
We also conducted sensitivity analyses of these projections with
the alternative summary relative risks from Lee and Hamling. Using the
smoking-adjusted relative risk for oral cancer of 1.65 for U.S.
smokeless tobacco users, we obtain a cumulative reduction of
approximately 7,300 oral cancer cases and 1,300 oral cancer deaths over
a 20-year period with the product standard. With the never smoker
relative risk of 3.33, we obtain a reduction of approximately 24,000
oral cancer cases and 4,200 oral cancer deaths during the period.
We also examined possible impacts from changes to input values in
these calculations. Specifically, we estimated changes in the public
health benefits due to differences in smokeless tobacco prevalence and
the length of time in which the full oral cancer risk reduction will be
observed among U.S. smokeless tobacco users. These analyses are in the
Uncertainty and Sensitivity Analysis, section II.G, of the Regulatory
Impact Analysis associated with this proposed rule.
[[Page 8024]]
Table 7--Projected Cumulative Difference in New Oral Cancer Cases and Oral Cancer Deaths Attributable to
Smokeless Tobacco Use in the U.S. and Corresponding Life Years Gained Due To Implementation of the Proposed
Standard
----------------------------------------------------------------------------------------------------------------
Cumulative
Cumulative difference in Cumulative life
Years after full implementation of the standard difference in attributable years gained
attributable cases deaths
----------------------------------------------------------------------------------------------------------------
10 years............................................ 4,500 500 1,500
20 years............................................ 12,700 2,200 15,200
----------------------------------------------------------------------------------------------------------------
Note: Estimates in the table are rounded to the nearest hundred.
2. Additional Public Health Benefits From Reducing Oral Cancer
As a result of this proposed rule, we estimate considerable public
health benefit to the United States resulting from reduced risk of oral
cancer among smokeless tobacco users due to reductions in NNN (and
concomitant reductions in NNK) levels in smokeless tobacco. The public
health impact of oral cancer is estimated to be considerable in size.
In the United States, about 65 percent of oral cancer patients survive
at least 5 years with disease and those individuals who survive oral
cancer can face profound challenges and reductions in quality of life.
Oral cancer patients and survivors can face major functional
problems when performing basic tasks of daily living such as eating and
talking. Treatment procedures can result in disfigurement or other
serious cosmetic problems that also adversely impact quality of life
(Ref. 116). Surgical treatments for head and neck cancers have been
found to be associated with subsequent self-image issues and social
isolation that increased with the level of disfigurement (Ref. 117).
Patients with head and neck cancers also report high levels of anxiety
and depressive symptoms (Ref. 116), and even long-term survivors report
high levels of psychological distress (Ref. 118).
In the United States in 2010, approximately $3.63 billion annually
was spent on medical treatment and followup care for all head and neck
cancers (Ref. 119), which includes cancers of the oral cavity, pharynx,
larynx, nasal cavity, and salivary glands (Ref. 120). The proposed
standard will benefit public health by preventing thousands of new oral
cancer cases and deaths caused by smokeless tobacco use over the next
two decades.
3. Unquantified Potential Reductions in Other Cancers
In addition to reducing the risk of oral cancer, lower levels of
NNN in smokeless tobacco under the proposed standard are expected to
lower the risk of esophageal cancer. Smokeless tobacco use has been
identified as a cause of esophageal cancer (Refs. 1, 2) and NNN has
been directly linked to esophageal cancer in numerous animal studies
(Ref. 8) and in an epidemiological study of smokers (Ref. 77). However,
limited data are available, so the health benefit cannot be directly
quantified.
Pancreatic cancer has also been identified as causally related to
smokeless tobacco use (Refs. 1, 2). Lower levels of NNN (and potential
reductions in NNK) in U.S. smokeless tobacco under the proposed
standard have the potential to reduce the incidence of pancreatic
cancer. Boffetta et al. reported the relative risk of pancreatic cancer
from four studies of U.S. smokeless tobacco users to be elevated (i.e.,
a relative risk of 1.4), although not statistically significant. Yet,
estimates of pancreatic cancer relative risks have not consistently
been reported to be higher in U.S. smokeless tobacco studies compared
with Scandinavian snus product studies (Refs. 100, 114).
Lower levels of NNN in smokeless tobacco may also reduce the
incidence of laryngeal and prostate cancers. Lee and Hamling's (Ref.
114) review found U.S. smokeless tobacco use was significantly
associated with laryngeal cancer in four studies including one study
that adjusted for cigarette smoking. More recently, Zhou et al. (Ref.
122) found that use of smokeless tobacco for 10 or more years was
associated with elevated risk of laryngeal cancer. Lee and Hamling
(Ref. 114) also found a statistically significant association between
U.S. smokeless tobacco use and prostate cancer. Although NNN has not
specifically been linked with an increased risk of these cancers, it is
a potent carcinogen and smokeless tobacco product use can result in
exposure throughout the human body.
Given that U.S. smokeless products contain high amounts of NNK, and
NNK is a recognized systemic lung carcinogen (Ref. 8) in experimental
animals, potential reductions in NNK levels in smokeless tobacco as a
result of the proposed NNN standard may lead to some reduction in lung
cancer risk. There is some evidence linking smokeless tobacco use to
lung cancer (Ref. 121), although a definitive association has not been
established in authoritative reviews (Refs. 3, 4).
B. The Likelihood That Existing Users of Tobacco Products Will Stop
Using Such Products
Although data are lacking on perceptions of smokeless tobacco
toxicants, including NNN, and cessation, there is some evidence on
users' motivations for quitting smokeless tobacco. Some studies suggest
that concerns about developing health problems are among the common
motives that smokeless tobacco users provide for quitting (Refs. 123,
124). These studies suggest that if the proposed standard affects
consumer perceptions about the harms of smokeless tobacco use, it may
influence their cessation motivations. Specifically, if current
smokeless tobacco users interpret an NNN product standard to mean the
health risks from smokeless tobacco use will be lower after the
standard is in effect, this might reduce some users' motivations to
quit. It is worth noting, however, that while the magnitude of risk
would be changed by implementation of the proposed standard,
appreciable cancer risk would remain. Accordingly, users would still
have a strong incentive to quit. FDA, therefore, does not expect the
proposed product standard to appreciably discourage cessation of
smokeless tobacco products in such a way as to offset the beneficial
public health impact from reduced cancer risk.
Although data are lacking on perceptions of smokeless tobacco
product toxicants, including NNN and the effect of awareness on
cessation behaviors, prevalence of smokeless tobacco use would need to
increase substantially in order to offset the reduction in cancer risk
expected as a result of this rule. The magnitude of the change needed
can be estimated using the population attributable risk calculation
presented in section V.A.1 of this document. The calculation
[[Page 8025]]
includes the product of the excess relative risk (RR-1) and the
prevalence of smokeless tobacco use. Therefore, smokeless tobacco use
prevalence would need to nearly triple in order to completely offset
the expected reduction in excess lifetime cancer risk to the equivalent
of approximately one-third of the baseline cancer risk.
While there is evidence that exposure to media can lead to health
behavior changes (Refs. 126, 127), it is unclear whether media coverage
of this proposed product standard would promote sustained behavior
change in the form of increased or decreased likelihood of smokeless
tobacco cessation.
Methods used to reduce NNN levels as a result of this proposed rule
may or may not produce changes that affect the sensory experiences of
smokeless tobacco use. Consumers' sensory experiences can in turn
influence their perceptions of product harms (Refs. 128, 129, 130),
which can impact product use. However, for moist snuff, which
constitutes the overwhelming majority of the smokeless tobacco market
in the United States (Ref. 131), manufacturers have already identified
ways to reduce nitrosamine content without negatively impacting the
taste or user experience (see sections IV.C and IV.E of this document).
Smokeless tobacco products are heavily flavored and the presence of
flavors is a significant driver of consumer acceptance of these
products (Ref. 70). The proposed standard does not prevent the addition
of flavors to offset any changes in the taste of the product due to the
methods used to reduce NNN to meet the proposed standard.
C. The Likelihood That Non-Users Will Start Using Tobacco Products
The proposed product standard is not expected to substantially
increase, if at all, the likelihood that those who do not use smokeless
tobacco will take up the product. Public perception is that smokeless
tobacco use has some potential harms (Refs. 76, 133, 134, 135, 136). At
this time we are not aware of direct scientific evidence demonstrating
that the proposed smokeless tobacco product standard would influence
consumers' perceptions of product appeal, relative risk, and absolute
risk, or behaviors. Even if the proposed standard were to result in
some changes to perceptions and behaviors, FDA believes that they would
not offset the beneficial public health impact from reduced cancer
risk. As described in this section, FDA estimates that the prevalence
of smokeless tobacco use would have to nearly triple in order to offset
the expected excess cancer risk reduction due to the proposed rule.
Data are not available on consumers' awareness and perceptions of
NNN in smokeless products, although a single published study in a U.S.
adult sample of smokers and non-smokers found awareness of and
knowledge about NNN in cigarette smoke was low, particularly in
comparison to other constituents (Ref. 125). Although there is very low
awareness of NNN as a constituent, it is possible that some non-users
of smokeless tobacco will be aware of the proposed standard and
interpret it to mean that smokeless tobacco is less harmful than other
tobacco products and this could, in turn, affect smokeless tobacco
initiation. Research suggests that risk perceptions of tobacco use--
that is, judgments about its harmfulness--can influence tobacco
initiation (Refs. 137, 138). However, if the proposed standard were to
result in additional uptake of smokeless tobacco use in the population,
this could either decrease or increase the expected health benefits of
the proposed standard. If cigarette smokers who would not otherwise
quit smoking completely switched to smokeless tobacco products as a
result of this standard, we would expect additional reduction in risk
to these individual users. If cigarette smokers became dual users of
cigarettes and smokeless tobacco products, this could have varying
impacts depending on the extent to which such dual use led to
substantial reductions in cigarette consumption or led to delayed
cessation of tobacco products altogether. Conversely, the anticipated
net population health benefits of the standard would be reduced if it
led substantial numbers of never or former tobacco users to begin or
resume using smokeless tobacco products.
In the case that some adolescents and young adults become aware
that FDA is taking steps to reduce the harmfulness of smokeless tobacco
products, FDA expects that any impact on smokeless tobacco initiation
would be limited. First, smokeless tobacco initiation among youth has
been shown to be associated with social influences such as actual or
perceived peer use (Refs. 139, 140) to a greater extent than
perceptions of the long-term health effects. Further, youth curiosity
about smokeless tobacco is lower than curiosity about cigars or
cigarettes (Ref. 141), suggesting that fewer adolescents are at risk
for future use, compared to many other tobacco products. Thus, at the
population level, very few adolescents are likely to be aware that FDA
is taking an action related to NNN in smokeless tobacco products, and,
even if there were some awareness, given that the standard is related
to reducing long-term health effects, it is unlikely to have an impact
on youth initiation.
It is possible that some former users could potentially relapse
back to smokeless tobacco use due to perceptions of lower risk.
Although specific data on relapse among smokeless users is not
available, there is some data on relapse among smokers. For example,
predictors of relapse for smokers who reported they had quit between
study waves were assessed in one of the few studies assessing relapse
in the general population and not part of a clinical trial. Neither the
perceived costs of smoking (such as thoughts about the harms of
smoking) nor benefits of quitting (including health benefits) were
related to relapse (Ref. 142). However, nicotine dependence is related
to relapse among smokers (Refs. 143, 144); and because smokeless
tobacco products also deliver nicotine, FDA expects that the same
reason for relapse would apply to former smokeless tobacco users and
that changes to perceptions of costs and benefits would have little
effect on relapse rates. Overall, the extent to which the proposed
standard may influence behaviors of non-users and former users is
likely to be minimal since health-related reasons are not among the
main drivers of smokeless tobacco use initiation or relapse. Finally,
HHS plans to continue developing and implementing public education
campaigns to help prevent initiation of all tobacco products, including
smokeless tobacco.
D. Conclusion
NNN is a potent carcinogenic agent found in smokeless tobacco and,
along with NNK, another TSNA, is a major contributor to the elevated
cancer risks associated with smokeless tobacco use. Oral and esophageal
tissues have been identified as targets for NNN-induced
carcinogenicity, when NNN was administered orally in animal studies,
which indicates some concordance with effects observed at these sites
in epidemiologic studies. NNN levels in most smokeless tobacco
manufactured in the United States are higher than NNN levels in
smokeless tobacco manufactured in Sweden. Oral cancer risks in U.S.
smokeless tobacco users are elevated compared to the oral cancer risks
in Scandinavian users. The proposed product standard is expected to
reduce tobacco-related harms by reducing the levels of NNN in smokeless
tobacco products sold in the United States, thereby reducing the risk
of oral
[[Page 8026]]
cancer in smokeless users. By our estimates, in the 20 years following
implementation of the proposed product standard, approximately 12,700
new cases of oral cancer and approximately 2,200 oral cancer deaths
would be prevented in the United States. Moreover, during that 20-year
period, approximately 15,200 life years would be gained as a result of
the proposed standard. This represents a substantial benefit to the
public health. Because oral cancer is associated with significant
impacts on health and quality of life, we expect positive public health
benefits due to prevention of new and fatal cancer cases. We also
expect the proposed product standard to reduce the risk of esophageal
cancer among smokeless tobacco users, and it may reduce the incidence
of other cancer types; however, there is limited data available to
directly quantify this health benefit.
Based on currently available evidence discussed previously, we do
not anticipate the proposed standard would have behavioral impacts on
smokeless tobacco initiation, cessation, switching to other products,
or dual use in a way that would offset the public health benefits of
the reduced cancer risk that would result from the proposed standard.
Even if the proposed standard were to result in some instances of
decreased smokeless tobacco cessation or increased initiation among
non-users of tobacco, we would not expect the magnitude of these
effects to be comparable to the public health benefits of the proposed
rule. As described in this section, FDA estimates that the prevalence
of smokeless tobacco use would have to nearly triple in order to offset
the excess cancer risk reduction expected due to the proposed rule. In
addition, to the extent that cigarette smokers who cannot or will not
quit smoking are motivated to switch completely to smokeless tobacco
due to perceptions of lower risk, this complete switching could result
in additional benefits to public health through reduced risks to these
individual users.
Accordingly, for the reasons discussed in this section, we find
that the proposed standard is appropriate for the protection of public
health. It would reduce the cancer risk posed by smokeless tobacco
products and FDA does not expect that the product standard would
increase the likelihood that non-users would initiate tobacco or
decrease the likelihood that users will quit tobacco use. Even if the
proposed standard were to result in some instances of decreased
smokeless tobacco cessation or increased initiation among non-users of
tobacco, we would not expect the magnitude of these effects to offset
the benefits of the reduced cancer risk.
VI. Description of Proposed Regulation
A. General Provisions (Proposed Subpart A)
1. Scope (Proposed Sec. 1132.1)
Proposed Sec. 1132.1 identifies the scope of products that would
be subject to this NNN product standard. FDA intends for this proposed
standard to cover finished smokeless tobacco products, which are
defined in proposed Sec. 1132.3 (proposed Sec. 1132.1(a)). This
includes moist snuff, snus, dry snuff, chewing tobacco, and some
dissolvables. Some dissolvable tobacco products do not meet the
statutory definition of ``smokeless tobacco product'' because they do
not contain cut, ground, powdered, or leaf tobacco; instead, these
products contain nicotine extracted from tobacco. Dissolvable products
that do not meet the statutory definition of ``smokeless tobacco
product'' are not covered by this proposed rule. As previously noted,
this rule focuses on smokeless tobacco products because different
measures are required to address NNN in other tobacco products.
Proposed Sec. 1132.1(b) states that no person may manufacture,
distribute, sell, or offer for sale or distribution within the United
States a finished smokeless tobacco product that is not in compliance
with this part. For example, FDA would not consider finished smokeless
tobacco products to be in compliance with this part if they exceed the
NNN level set forth in proposed Sec. 1132.10, the package label does
not have a manufacturing code or expiration date, or the package label
has a manufacturing code or expiration date that has been altered,
mutilated, destroyed, obliterated, obstructed, concealed, or removed in
whole or in part.
This provision is not intended to restrict the manufacture of
smokeless tobacco products intended for export. Consistent with section
801(e)(1) of the FD&C Act, a tobacco product intended for export shall
not be deemed to be in violation of section 907 or this product
standard, if it meets the criteria enumerated in section 801(e)(1) of
the FD&C Act, including not being sold or offered for sale in domestic
commerce.
Proposed Sec. 1132.1(c) explains that tobacco retailers and
distributors will not be considered in violation of this part as it
relates to the sale or distribution or offer for sale or distribution
of finished smokeless tobacco products that exceed the NNN level set
forth in Sec. 1132.10 if they: (1) Store and transport the finished
smokeless tobacco products according to the package label, (2) do not
sell or distribute or offer for sale or distribution finished smokeless
tobacco products past their expiration date, except to return expired
products to the manufacturer, (3) do not conceal, alter, or remove the
expiration date or storage conditions on the package label, and (4) do
not sell or distribute or offer for sale or distribution finished
smokeless tobacco products that are open or have broken seals.
FDA is proposing this exception for tobacco retailers and
distributors because they cannot reasonably know or confirm by testing
whether the smokeless tobacco products they are selling or distributing
or offering for sale or distribution comply with the proposed NNN
level. Provided that the tobacco retailers and distributors meet the
requirements set forth in proposed Sec. 1132.1(c)(1) through (4), FDA
will not consider them to be in violation of part 1132 as it relates to
the sale or distribution or offer for sale or distribution of products
that exceed the NNN level set forth in proposed Sec. 1132.10.
We note that tobacco retailers and distributors would need to meet
all of the requirements in proposed Sec. 1132.1(c) in order to be
considered in compliance with this part as it relates to the sale or
distribution or offer for sale or distribution of smokeless tobacco
products that exceed the NNN level set forth in proposed Sec. 1132.10.
A retailer or distributor who, for example, covers the expiration date
or storage conditions with a sticker, changes the expiration date, or
scratches off the expiration date or storage conditions on the package
label would not meet the requirements in proposed Sec. 1132.1(c)(3).
Furthermore, a retailer who sells finished smokeless tobacco products
that are open or have broken seals would not meet the requirements in
proposed Sec. 1132.1(c)(4), because doing so could lead to changes in
the NNN level, especially if it is exposed to heat or humidity.
2. Definitions (Proposed Sec. 1132.3)
Proposed Sec. 1132.3 provides the definitions for the terms used
in the proposed rule. Several of these definitions are included in the
FD&C Act or have been used in other regulatory documents.
Batch: FDA proposes to define ``batch'' as a specific
identified amount of a finished smokeless tobacco product produced in a
unit of time or quantity and that is intended to have the same
characteristics. As stated in section 910(a)(3)(B) of the FD&C Act,
[[Page 8027]]
characteristics means the ``materials, ingredients, design,
composition, heating source, or other features of a tobacco product.''
Commercial distribution: FDA proposes to define
``commercial distribution'' as any distribution of a finished smokeless
tobacco product to consumers or to another person through sale or
otherwise, but does not include interplant transfers of a tobacco
product between registered establishments within the same parent,
subsidiary, and/or affiliate company, nor does it include providing a
tobacco product for product testing where such product is not made
available for consumption or resale.
Finished smokeless tobacco product: We propose to define
``finished smokeless tobacco product'' as a smokeless tobacco product
including all parts and components, packaged for consumer use, but it
would not include a component, part, or accessory sold without tobacco.
A product that is ``packaged for consumer use'' would have the package
label on the product. For example, a tin or can of loose snuff or a
pouch containing chewing tobacco, with package labels, would meet this
definition.
Manufacturing code: FDA proposes to define ``manufacturing
code'' as any distinctive sequence or combination of letters, numbers,
or symbols that begins with the manufacturing date in 2-digit numerical
values in the month, day, year format (mmddyy) followed by the batch
number from which the production batch can be identified. The purpose
of the manufacturing code is to allow manufacturers and FDA to identify
the production batch of a particular product that has been released for
commercial distribution. This information would help determine the
product's history (e.g., batch testing records) and assist
manufacturers and FDA in the event of a nonconforming product
investigation and any corrective actions that stem from the
nonconforming product investigation.
Manufacturing date: We propose to define ``manufacturing
date'' as the month, day, and year that a smokeless tobacco product is
packaged for consumer use (i.e., when the package label has been added
to the product). The manufacturing date is included in the
manufacturing code, which can be used by the manufacturer and FDA to
help determine the product's history (e.g., batch testing history) in
the event of a nonconforming product investigation.
N-nitrosonornicotine (NNN): FDA proposes to define ``N-
nitrosonornicotine'' as a tobacco-specific nitrosamine (TSNA) with the
chemical formula C[9]H[11]N[3]O.
New tobacco product: As defined in section 910(a) of the
FD&C Act, the term ``new tobacco product'' means: (1) Any tobacco
product (including those products in test markets) that was not
commercially marketed in the United States as of February 15, 2007; or
(2) any modification (including a change in design, any component, any
part, or any constituent, including a smoke constituent, or in the
content, delivery or form of nicotine, or any other additive or
ingredient) of a tobacco product where the modified product was
commercially marketed in the United States after February 15, 2007.
Package: As defined in section 900(13) of the FD&C Act,
the term ``package'' means a pack, box, carton, or container of any
kind or, if no other container, any wrapping (including cellophane) in
which a tobacco product is offered for sale, sold, or otherwise
distributed to consumers.
Performance criteria: FDA proposes to define ``performance
criteria'' as the validation requirements for the acceptability of an
analytical test method, including accuracy, precision, recovery,
linearity, specificity, limit of quantitation, limit of detection,
robustness, and range.
Person: As defined in section 201(e) of the FD&C Act, the
term ``person'' includes an individual, partnership, corporation, or
association.
Rework: We propose to define ``rework'' as the processing
of nonconforming finished smokeless tobacco products to meet the
requirements of this part.
Smokeless tobacco: As defined in section 900(18) of the
FD&C Act, the term ``smokeless tobacco'' means any tobacco product that
consists of cut, ground, powdered, or leaf tobacco and that is intended
to be placed in the oral or nasal cavity. This includes moist snuff,
snus, dry snuff, chewing tobacco, and some dissolvables. Some
dissolvable tobacco products do not meet the statutory definition of
``smokeless tobacco product'' because they do not contain cut, ground,
powdered, or leaf tobacco; instead, these products contain nicotine
extracted from tobacco. Dissolvable products that do not meet the
statutory definition of ``smokeless tobacco product'' are not covered
by this proposed rule.
Source data: FDA proposes to define ``source data'' as all
information contained in original laboratory records or exact copies of
original records of experimental findings, observations, or other
activities used for the creation, reconstruction, and evaluation of a
study or other laboratory work. Source data includes any laboratory
worksheets, notebooks, correspondence, notes, and other documentation
(regardless of capture medium) that are the result of original
observations and activities of a laboratory study or other laboratory
work.
Source data could include protocols and standard operating
procedures, information regarding calibration of equipment used to
measure or test samples, test standards, and the standard curves used
to determine the measure of the samples being tested or of the accuracy
and reliability of the test. This type of information may be needed to
fully evaluate, for example, whether the product meets the product
standard. In addition, if there are any problems with the data, the
manufacturer and FDA would be able to use the source data to
reconstruct the study or lab work, which could help identify and
correct any deviations. In accordance with proposed Sec. 1132.32,
source data records would have to be maintained by the manufacturer.
Tobacco product: As defined in section 201(rr) of the FD&C
Act, the term ``tobacco product'' means any product that is made or
derived from tobacco that is intended for human consumption, including
any component, part, or accessory of a tobacco product (except for raw
materials other than tobacco used in manufacturing a component, part,
or accessory of a tobacco product). The term ``tobacco product'' does
not mean an article that is a drug under section 201(g)(1), a device
under section 201(h), or a combination product described in section
503(g) of the FD&C Act (21 U.S.C. 321(g)(1), 321(h), and 353(g)).
Tobacco product manufacturer: As defined in section
900(20) of the FD&C Act, ``tobacco product manufacturer'' means any
person, including a repacker or relabeler, who manufactures,
fabricates, assembles, processes, or labels a tobacco product or
imports a finished tobacco product for sale or distribution in the
United States.
Tobacco-specific nitrosamine (TSNA): We propose to define
``tobacco-specific nitrosamine'' to mean a chemical compound formed
through the chemical reaction involving the nitrosation of nicotine,
nornicotine, anabasine, or anatabine during the growing, curing,
processing, or storage of tobacco.
United States: As defined in section 900(22) of the FD&C
Act, the term ``United States'' means the 50 states of the United
States of America and the District of Columbia, the Commonwealth of
Puerto Rico, Guam,
[[Page 8028]]
the Virgin Islands, American Samoa, Wake Island, Midway Islands,
Kingman Reef, Johnston Atoll, the Northern Mariana Islands, and any
other trust territory or possession of the United States.
3. Incorporation by Reference (Proposed Sec. 1132.5)
Proposed Sec. 1132.5 identifies the materials that FDA proposes to
incorporate by reference in this part. Information that is incorporated
by reference would have the same force and effect as language
explicitly stated in the codified. Under the proposed rule, a tobacco
product manufacturer would be required to follow procedures and methods
for testing as described in any standards incorporated by reference,
unless the manufacturer meets the requirements in Sec. 1132.16 for an
alternative test method.
FDA is proposing to incorporate by reference a validated method
developed by FDA's SRL to be the standard test method for NNN in
smokeless tobacco products (proposed Sec. Sec. 1132.5(a) and 1132.14).
As discussed in section IV.F of this document, the results from the
test method demonstrate a high level of specificity, accuracy, and
precision in measuring a range of NNN levels across a variety of
smokeless tobacco products.
If the proposed incorporation by reference is approved by the
Office of the Federal Register and incorporated in the final rule,
interested parties would be able to examine the incorporated material
at the National Archives and Records Administration (NARA) and at FDA's
Division of Dockets Management (proposed Sec. 1132.5(b)), and obtain
copies of the standard test method by contacting FDA's Center for
Tobacco Products at the addresses and/or Web sites listed in proposed
Sec. 1132.5(b)(2).
If FDA subsequently determines that a test method, which has been
incorporated by reference in a final rule, should be replaced with
another method or updated, FDA will update the regulation in accordance
with the Administrative Procedure Act (5 U.S.C. 553) and obtain
approval of the change to the incorporation by reference in accordance
with 1 CFR part 51.
Proposed Sec. 1132.5(c) explains that if tobacco manufacturers or
testing laboratories using these standards find an inconsistency
between a material incorporated by reference in this part and
definitions or methods described by FDA in proposed part 1132, the
definitions or methods in proposed part 1132 take precedence.
B. Product Requirements (Proposed Subpart B)
1. NNN Level (Proposed Sec. 1132.10)
For the reasons discussed in section IV of this document, FDA is
proposing that the mean level of NNN in any batch of finished smokeless
tobacco products must not exceed 1.0 [micro]g/g of tobacco (on a dry
weight basis) at any time through the product's labeled expiration date
as determined by testing in compliance with Sec. 1132.12. Under the
proposed rule, manufacturers would be required to test their finished
smokeless tobacco products using the standard test method in Sec.
1132.14 or the alternative test method in Sec. 1132.16.
In proposing to set the limit in terms of a batch mean, FDA has
tentatively determined that the mean value is more appropriate than a
limit applied to each unit produced from the entire batch of a product,
given that the cancer risk is due to long term and repeated exposure,
and given the variability of NNN in this agricultural product. Although
we expect some degree of variability in NNN to exist in smokeless
tobacco products, we recognize there may be circumstances where there
could be wide ranges in the variability of NNN for some smokeless
tobacco products, resulting in reduced consistency among the units
produced and reduced predictability of compliance with a standard
requiring that each unit meet a specific limit. FDA is requesting
scientific data that could be used to determine the expected
distribution of individual results for samples for a per-batch mean
limit of an NNN level of 1.0 [micro]g/g of tobacco on a dry weight
basis (see proposed Sec. 1132.10). FDA also requests comment on the
compliance implications of the currently proposed approach.
NNN-related cancer risk is due to long term and repeated exposure
to NNN. Under the currently proposed approach, as long as the mean of
each batch consistently conforms to the NNN level of 1.0 [micro]g/g of
tobacco (on a dry weight basis) in accordance with Sec. 1132.10, FDA
expects that the long term impact from an occasional exposure to a
product with slightly higher NNN level will be offset by the exposure
to slightly lower levels. Therefore, any random variation that may
exist is not expected to negatively impact the public health benefit of
the proposed standard, which is based on reduction of excess lifetime
cancer risk.
FDA also is considering an alternative approach that includes
setting a standard where the specified NNN level of 1.0 [micro]g/g of
tobacco (on a dry weight basis) would apply to all units produced from
the entire batch, rather than to a per-batch mean. This alternative
approach would thereby require the manufacturer to ensure compliance of
each unit made from a batch despite some expected random variation of
the NNN level between units. This could further increase the public
health benefits of this product standard. However, in instances where
manufacturers determined that some units within a batch had levels of
NNN above the limit and others had levels below the limit, this
alternative approach could add costs for manufacturers (e.g., costs of
rejecting or reworking the batch) or require them to manufacture
product with NNN levels lower than the NNN level of 1.0 [micro]g/g of
tobacco (on a dry weight basis) in order to minimize the risk of having
to reject a batch based on random variation. FDA currently believes
that this is not necessary to achieve the public health goals of the
proposed standard, but invites input on this point.
We invite comments on FDA's proposed approach and on the
alternative approach and their implications for compliance with the
limit, and public health impact. We also invite comments or information
on batch sampling methods or other approaches manufacturers might use
to determine compliance with an absolute limit on all units produced
from a batch given the expected variability of NNN in relevant
products.
2. Product Testing (Proposed Sec. 1132.12)
Proposed Sec. 1132.12 contains provisions for the testing of
smokeless tobacco products. FDA is proposing to require two types of
testing--stability testing and batch testing.
a. Stability testing. Proposed Sec. 1132.12(a) would require each
tobacco product manufacturer to conduct testing to assess the stability
of the NNN level in its finished smokeless tobacco products. Given the
variability of NNN levels in current smokeless tobacco products (see
section IV.B.1 of this document), stability testing would help ensure
that the NNN level in finished smokeless tobacco products is being
properly monitored and controlled and that it remains in conformance
with the proposed limit through the product's labeled expiration date.
The initial stability testing would establish the rate of change of the
NNN level for a product and the annual stability testing would identify
any changes to the rate of change of the NNN level in that product.
Manufacturers would be required to use the results of stability
testing to establish and verify the product's expiration date and
storage conditions
[[Page 8029]]
(either room temperature or refrigeration). Proposed Sec. 1132.20
would require all finished smokeless tobacco products to have an
expiration date established by stability testing. This date would have
to be no later than the final date the manufacturer can demonstrate
that the NNN level in the finished smokeless tobacco product conforms
to Sec. 1132.10 when the product is stored under its intended
conditions (e.g., room temperature or refrigeration).
When conducting stability testing, manufacturers would be required
to use either the standard test method in Sec. 1132.14 or an
alternative test method that meets the requirements in Sec. 1132.16
and samples would have to be selected in accordance with the
requirements set forth in Sec. 1132.18(a) and (c) (proposed Sec.
1132.12(a)(1)).
Proposed Sec. 1132.12(a)(2) would require each manufacturer to
establish and maintain a written protocol for all stability testing,
that fully describes the methodology used to determine the stability of
the NNN level, including the test method used (the standard test method
in proposed Sec. 1132.14 or an alternative test method in accordance
with proposed Sec. 1132.16), the sampling plan and procedures required
by proposed Sec. 1132.18(a) and (c), and the storage conditions.
Proposed Sec. 1132.12(a)(3) requires initial real-time stability
testing that covers each finished smokeless tobacco product. In certain
circumstances, it may not be necessary to conduct initial real-time
stability testing on a particular product because the results from
initial real-time stability testing conducted on another similar
product apply. For example, a manufacturer who manufactures moist snuff
in a tin and moist snuff in a pouch would be required to conduct
initial real-time stability testing on both products, because the tin
and the pouch could have different impacts on the NNN level and, thus,
on the stability of the finished products. In contrast, a manufacturer
who manufactures two finished products, where the only difference
between them is a slight change in flavor ingredients that does not
affect NNN levels, would only be required to conduct initial real-time
stability testing on only one of the two products. The results from
that testing would apply to both products and the testing would be
considered to cover both products. Other examples of differences
between products that would not require additional initial real-time
stability testing, if initial real time stability testing has already
been conducted on one of the products, include slight changes in acids,
bases, or other pH modifiers with no resulting change in final pH. This
provision is intended to reduce the burden on the manufacturer, while
ensuring that there is initial real-time stability data that applies to
all finished tobacco products, thus preserving the goal of the
requirement.
Manufacturers would be required to use the results from initial
stability testing to establish an expiration date and appropriate
storage conditions (either room temperature or refrigeration) for the
finished product. We believe that room temperature or refrigeration are
the most likely storage conditions for smokeless tobacco products
because most current smokeless tobacco products are stored at room
temperature while some snus products are refrigerated. FDA does not
expect that manufacturers would choose to freeze their finished
smokeless tobacco products. The expiration date and storage conditions
would be required to be displayed on the package label in accordance
with proposed Sec. 1132.30.
For initial real-time stability testing, FDA is proposing that, at
a minimum, samples be tested within 7 days of manufacture to determine
the starting NNN level and at the expected expiration date (proposed
Sec. 1132.12(a)(3)(i)). Testing the NNN level at various time points
is intended to ensure that the NNN level in finished smokeless tobacco
will conform to Sec. 1132.10 through the determined expiration date
under the intended storage conditions. If the proposed storage
condition is room temperature, samples for initial real-time stability
testing would have to be stored at 25 2 degrees Celsius
and 60 5% relative humidity (proposed Sec.
1132.12(a)(3)(i)(A)) and, if the proposed storage condition is
refrigeration, samples would have to be stored at 5 2
degrees Celsius (proposed Sec. 1132.12(a)(3)(i)(B)).
FDA believes manufacturers will likely choose to test at several
additional time points to determine the rate of NNN change, if any.
Testing of additional time points could allow the manufacturer to
establish an acceptable expiration date even if testing shows the
finished smokeless tobacco product would exceed the level set forth in
Sec. 1132.10 at the expected expiration date. For example, a
manufacturer may initially expect its product to have a conforming NNN
level for a period of 8 months, based on history of experience with
similar products. If instead of only testing the product at 7 days and
at 8 months, the manufacturer chooses to test at 7 days, 6 months, and
8 months, that manufacturer would still be able to establish an
expiration date for its product (at 6 months) if the testing results
showed that the product conforms at 6 months but not at 8 months.
Because NNN levels in the product would only increase over time,
manufacturers would also be able to choose a shorter expiration date if
they wish (Ref. 11). For instance, if stability testing demonstrated
the NNN level remains in conformance with proposed Sec. 1132.10
through at least 6 months, the manufacturer could choose to use a 4-
month expiration date if the manufacturer did not want the product sold
after that time period due to freshness or taste changes.
FDA is proposing to allow manufacturers to conduct accelerated
stability testing concurrently with initial real-time stability testing
to establish the product's expiration date and storage conditions
(proposed Sec. 1132.12(a)(3)(ii)). The manufacturer would be allowed
to use an expiration date of no longer than 1 year based on initial
accelerated stability testing. Accelerated stability studies provide
preliminary information on NNN levels over time and are of shorter
duration than long-term stability studies. By allowing manufacturers to
conduct accelerated stability testing, FDA intends to reduce the time
required to bring new products to market without adversely impacting
public health.
Proposed Sec. 1132.12(a)(3)(iii) would require that, at a minimum,
samples for initial accelerated stability testing be tested at three
time points within a 6-month period. This testing paradigm is similar
to one used for stability testing for drugs. We would require the first
time point be within 7 days of manufacture and the last time point at 6
months after manufacture. Because it may not always be possible to test
exactly 6 months after manufacture, FDA notes that testing conducted
within the week prior to or the week after the 6 month date of
manufacture would be considered to meet this requirement. If the
proposed storage condition is room temperature, samples for accelerated
stability testing would have to be stored at 40 2 degrees
Celsius and 75 5% relative humidity (proposed Sec.
1132.12(a)(3)(iii)(A)) and, if the proposed storage condition is
refrigeration, samples would have to be stored at 25 2
degrees Celsius and 60 5% relative humidity (proposed
Sec. 1132.12(a)(3)(iii)(B)). Because higher temperatures and humidity
can increase the biological activity, these conditions will accelerate
any increases in the NNN level, thereby providing a prediction of the
stability of the NNN for a 12-month period under normal conditions.
[[Page 8030]]
Proposed Sec. 1132.12(a)(3)(iv) would require the manufacturer to
use the results of initial real-time stability testing to establish an
expiration date and storage conditions if initial accelerated stability
testing shows the NNN level in finished smokeless tobacco products will
not conform to proposed Sec. 1132.10. If the NNN levels do not conform
after 6 months of accelerated testing conditions, then there will be
insufficient evidence to project that NNN levels will conform after 12
months of normal conditions. Accordingly, this accelerated data may not
be used to forecast an expiration date.
FDA is also proposing to require manufacturers to conduct annual
real-time stability testing on each finished smokeless tobacco product
to verify the results of the initial stability testing and, given the
variability of NNN in tobacco, to ensure that the established
expiration date and storage conditions remain appropriate and don't
need to be changed (proposed Sec. 1132.12(a)(4)). Accelerated
stability testing would not be permitted for annual stability testing.
We propose that accelerated stability testing be permitted for initial
stability testing to reduce the time required to bring new products to
market without adversely impacting public health. However, accelerated
testing is unnecessary for annual stability testing because these
products would already be on the market.
Proposed Sec. 1132.12(a)(4)(i) would generally require annual
real-time stability testing to begin within 12 months of the completion
of initial stability testing and then annually thereafter, with no
longer than 12 months between testing. When a manufacturer has not
conducted initial real-time stability testing on a particular smokeless
tobacco product because it has determined that the results from initial
real-time stability testing conducted on another product apply, annual
stability testing would have to begin when the product is first
released for commercial distribution and then annually thereafter, with
no longer than 12 months between testing (proposed Sec.
1132.12(a)(4)(ii)). Samples for annual real-time stability testing, at
a minimum, would have to be tested within 7 days of manufacture to
determine the starting NNN level and at the established expiration date
(proposed Sec. 1132.12(a)(4)(iii)) to determine the final NNN level
and provide assurance that the NNN level conforms to the standard
through the expiration date. Also, similar to initial real-time
stability testing, the samples would have to be stored at room
temperature or refrigeration in accordance with proposed Sec.
1132.12(a)(4)(iii)(A) and (B).
FDA proposes that, if the results of the most recent annual real-
time stability testing do not support the finished smokeless tobacco
product's previously established expiration date, the manufacturer must
use the results of the most recent annual real-time stability testing
to establish a new expiration date (proposed Sec. 1132.12(a)(4)(iv)).
After a new expiration date has been established, the package labels of
all affected finished smokeless tobacco products that have not been
released for commercial distribution would be required to display the
new expiration date and storage conditions in accordance with proposed
Sec. 1132.30. Furthermore, if the expiration date must be shortened,
the manufacturer would be required to conduct, fully document, and
maintain records of an investigation to determine why the results of
the most recent annual real-time stability testing do not support the
product's previously established expiration date (proposed Sec.
1132.12(a)(4)(v) and (a)(2)).
b. Batch testing. FDA is proposing that tobacco product
manufacturers conduct testing on each batch of finished smokeless
tobacco product to ensure that the products conform with proposed Sec.
1132.10 prior to commercial distribution (proposed Sec. 1132.12(b)).
Testing each batch prior to its release into commercial distribution
provides assurance to the manufacturer and FDA that each batch conforms
to the proposed standard. Any problems with the NNN level that may
arise during production (e.g., problems due to the pasteurization
equipment not heating correctly) would be detected by batch testing. In
addition, finished product that does not conform to the standard would
not be released for commercial distribution.
The manufacturer would be required to use either the standard test
method in proposed Sec. 1132.14 or an alternative test method that
meets the requirements in proposed Sec. 1132.16 and samples would have
to be selected in accordance with the requirements set forth in Sec.
1132.18(b) and (c) (proposed Sec. 1132.12(b)).
FDA expects tobacco product manufacturers would use the results of
batch testing and annual stability testing (proposed Sec. 1132.12(a))
to inform their determination that a batch of finished smokeless
tobacco product conforms to the proposed NNN level (proposed Sec.
1132.10) at the time of release for commercial distribution and through
the expiration date. For example, since finished smokeless tobacco
products would have to conform with the proposed NNN level at batch
testing and through their expiration date, the NNN level at batch
testing would have to be low enough to ensure that the NNN level
remains compliant until the expiration date. FDA believes that most
manufacturers will develop products which have no, or minimal, changes
in NNN over time. However, that is not required by this product
standard. For instance, if stability testing demonstrates that the mean
NNN level in a batch increases by 0.2 [micro]g/g of tobacco on a dry
weight basis over a 6 month expiration period, batch testing that
demonstrates the mean NNN level is below 0.75 [micro]g/g of tobacco on
a dry weight basis would be in conformance because the mean NNN level
of the batch would be expected to remain below 1.0 [micro]g/g of
tobacco on a dry weight basis at least through the expiration date of 6
months. We expect that any changes in a rate of increase would be
observed and investigated during annual stability testing.
c. Documentation of test results. Proposed Sec. 1132.12(c) would
require the tobacco product manufacturer to maintain a full report of
the source data and results of all stability and batch testing. This
report would need to include the full identification of the smokeless
tobacco product that is the subject of the report, including the
product subcategory, brand, subbrand, package size and quantity of
product (mass and, if portioned, count) and, for portioned tobacco
products, the size (mass) of each portion. Subcategories of smokeless
tobacco products include, for example, loose moist snuff, portioned
moist snuff, loose snus, portioned snus, loose dry snuff, certain
dissolvables, loose chewing tobacco, and portioned chewing tobacco.
In addition, the report would have to include the following:
NNN level of each sample tested;
Mean NNN level and standard deviation;
The location, including facility name and address, from
which each sample was pulled;
The manufacturing code of each sample tested or, for
samples for initial stability testing with no manufacturing code, an
identifying code created by the manufacturer;
The testing date and location, including the testing
facility name and address;
The test method and sampling procedure used;
All tobacco product reference standard test results;
[[Page 8031]]
The names and qualifications of the person(s) conducting
the testing;
The equipment used (including documentation to show that
the equipment is appropriate for its intended use and has been
calibrated); and
For batch testing only, the criteria used to make a
decision to accept or reject each batch and the decision made with
respect to each batch (e.g., accept, reject) based on the results of
the product testing, including the NNN level of the individual batch
and the results of the product's stability testing. For example, the
criteria for accepting a batch of product whose stability testing
demonstrates no change in the mean NNN level would be a batch mean NNN
level less than or at 1.0 [micro]g/g of tobacco, while the acceptance
criteria for a batch of product whose stability testing demonstrates an
increase of 0.2 [micro]g in mean NNN level per gram of tobacco over the
expiration period would be a batch mean NNN level at or below 0.8
[micro]g/g of tobacco. The manufacturer would also be required to keep
records, where applicable, of the decision made and justification with
respect to the results of a nonconforming product investigation
required under proposed Sec. 1132.22. For example, if a batch
initially tests out of compliance and a nonconforming product
investigation finds the NNN levels were erroneously high because of a
malfunction of the testing equipment, the manufacturer could determine
that the batch is acceptable for release if the NNN levels are in
conformance after the equipment has been fixed. The manufacturer would
be required to keep the records of the decision made and the
justification.
3. Standard Test Method (Proposed Sec. 1132.14)
Proposed Sec. 1132.14 states that the standard test method is the
method entitled ``Determination of N-nitrosonornicotine (NNN) in
Smokeless Tobacco and Tobacco Filler by HPLC-MS/MS,'' that is
incorporated by reference in Sec. 1132.5(a). The standard test method
is explained in further detail in section IV.F, Analytical Method. If
FDA subsequently determines that a test method, which has been
incorporated by reference in a final rule, should be replaced with
another method or updated, FDA will update the regulation in accordance
with the Administrative Procedure Act (5 U.S.C. 553) and obtain
approval of the change to the incorporation by reference in accordance
with 1 CFR part 51.
4. Alternative Test Method (Proposed Sec. 1132.16)
If a tobacco product manufacturer were to choose not to use the
standard test method in Sec. 1132.14 to test each batch, the
manufacturer would be required to use a validated alternative test
method that conforms to the requirements of proposed Sec. 1132.16. The
performance criteria of the alternative test method would have to meet
or exceed the performance criteria of the standard test method
(proposed Sec. 1132.16). FDA would consider the following parameters
to assess the performance criteria of an alternative test method:
Accuracy, precision, linearity, specificity, limit of quantitation,
limit of detection, robustness, and range.
Proposed Sec. 1132.16(a) would require that, before using a
validated alternative test method, the manufacturer notify the Director
of the Office of Science for FDA's Center for Tobacco Products. By
requiring prior notification, we hope to help manufacturers to avoid
using a test method that does not meet the requirements in Sec.
1132.16 and being unable to release for commercial distribution any
product tested using that method. Notification also allows FDA to track
what methods are being used, by whom, and for what products. This
information can be used to inform FDA inspectors regarding the use of
an alternative test method. In addition, if any issues arise with
regard to a specific alternative test method, FDA would be aware of
other manufacturers who may also be affected.
A manufacturer seeking to use a validated alternative test method
could not begin to use this method until 60 calendar days after the
date FDA receives the notification regarding the alternative test
method. This would allow time for FDA to review and act on the
notification. Smokeless tobacco manufacturers would be informed of
FDA's receipt of the notification through the automated Document
Control Center process. A manufacturer may not begin or continue using
the alternative test method if FDA notifies the manufacturer that it
has not been demonstrated to meet the requirements of Sec. 1132.16.
The notification would have to contain the information required by
proposed Sec. 1132.16(b) and be in the format discussed in proposed
Sec. 1132.16(d). Proposed Sec. 1132.16(b) provides the required
contents for the notification of use of an alternative test method. The
notification would be required to include the following information:
General information;
A comprehensive index and table of contents;
Summary of the notification; and
Complete description of the method.
In addition, FDA may request clarification and other relevant
information, if needed (proposed Sec. 1132.16(c)).
The set of general information would be submitted on the FDA-
provided form, a draft of which FDA is making available as a reference
for review and comment (Ref. 145). The form would include the following
information:
Date the manufacturer submitted the notification to FDA;
Identification of the submission as a notification of an
alternative test method;
Manufacturer's name, address, and contact information;
Identification of and contact information (including name,
mailing address, email address, and telephone number) for an authorized
representative of the manufacturer (which could be a U.S. agent for the
manufacturer);
Identification of the subcategories of finished smokeless
tobacco products (e.g., loose moist snuff, portioned moist snuff, loose
snus, portioned snus, loose dry snuff, certain dissolvables, loose
chewing tobacco, portioned chewing tobacco, or other) that can be
analyzed using the alternative test method; and
The testing facility's name and address.
The summary section of the notification would have to contain the
following information:
Identification of the standard test method for which the
alternative test method is being proposed;
A concise description of the performance criteria of the
alternative test method;
A concise explanation regarding the manufacturer's
rationale for proposing to use the alternative test method; and
A concise comparison of the similarities and differences
between the alternative and standard test methods.
As stated in proposed Sec. 1132.16(b)(4), the manufacturer would
be required to provide a complete description of the method with
sufficient detail to enable FDA to evaluate whether the information
demonstrates that the alternative test method meets or exceeds the
performance criteria of the standard test method set forth in Sec.
1132.14. This description would have to include a complete explanation
of the manner in which the alternative test method is proposed to
deviate from the standard test method in Sec. 1132.14. The
[[Page 8032]]
description would have to include an explanation with scientific
rationale and supporting data, as well as a complete copy of the
testing protocol, to demonstrate that the alternative method meets or
exceeds the performance criteria established for the standard test
method. In proposed Sec. 1132.16(b)(4)(ii) and (c), the manufacturer
also would have to include any data and information from other studies
comparing the alternative test method to the standard test method and,
if requested by FDA, any other relevant information needed to evaluate
the alternative test method (e.g., statistical analysis comparing the
alternative test method to the standard test method, proficiency test
results, or evidence of technical competence).
Proposed Sec. 1132.16(d) provides the format for a manufacturer's
notification of use of an alternative test method. First, the
notification would have to be submitted using the FDA-provided form and
all information would have to be organized, legible, and written in the
English language. The comprehensive index and table of contents
(required by proposed Sec. 1132.16(b)) would provide sufficient
organization for the document. FDA expects that the manufacturer will
submit this form using the Agency's electronic system. The
manufacturer's notification and all supporting information would be
required to be in an electronic format that the Agency can process,
review, and archive. Current information about electronic submission
preparation (e.g., acceptable file formats, technical specifications,
data standards) and transmission requirements may be found on the FDA
Web site.
FDA is proposing to require that tobacco manufacturers use the
electronic format for the submission of this information to facilitate
our review of the data submitted. Electronic submission of information
is consistent with the Government Paperwork Elimination Act (Pub. L.
105-277), which requires that Federal Agencies allow individuals or
entities to submit information or transact business with the Agency
electronically.
A smokeless tobacco manufacturer that is not able to submit a
notification of use of an alternative test method in an electronic
format could submit a written request to the Center for Tobacco
Products explaining in detail why the company cannot submit the
notification in an electronic format and requesting an alternative
format (as provided in proposed Sec. 1132.16(d)(3)).
Proposed Sec. 1132.16(d)(3) would provide that, if a manufacturer
cannot submit a form electronically, the manufacturer may submit a
request for a waiver. A waiver would be granted only if the use of
electronic means is not reasonable. If FDA grants the manufacturer's
waiver request, the Agency will provide information as to how and where
to submit the notification and supporting documentation in paper
format.
If a manufacturer seeks a waiver, the manufacturer must send a
legible written request in the English language to the Document Control
Center, with a notation ``ATTN: Office of Science,'' to the address
included in our Web site at www.fda.gov/TobaccoProducts. The address
can also be obtained by calling 1-877-CTP-2373 (1-877-287-1373). The
waiver request would have to contain the following information: The
name and address of the tobacco product manufacturer that wishes to
submit the notification; the name and contact information of the
manufacturer's authorized representative (which could be a U.S. agent
for the manufacturer); and a statement and rationale as to why the
creation and/or submission of information in electronic format is not
reasonable (such statement must be signed by the authorized
representative of the tobacco product manufacturer).
Proposed Sec. 1132.16(e) clarifies the applicability of an
alternative test method. An alternative test method could be
implemented only by the tobacco product manufacturer who submitted the
notification and only with respect to the subcategories of finished
smokeless tobacco products that were the subject of the notification.
We are proposing this approach because an alternative test method that
is appropriate for one subcategory of smokeless tobacco product (e.g.,
moist snuff) may not be generalizable to other subcategories of
smokeless products (e.g., chewing tobacco). Also, because some test
methods may be proprietary or may have been developed by the
manufacturer for a specific product, FDA believes it is important for
the manufacturer to notify FDA and fully describe the method they plan
to use and the products on which they intend to use it.
Other manufacturers interested in similar or identical alternative
test methods would have to submit their own notification following the
procedures of proposed Sec. 1132.16. Therefore, if a manufacturer
previously submitted a notification of an alternative test method and
later sells the company to another manufacturer, the new manufacturer
would have to submit a notification if it wished to continue using the
alternative method. This would ensure that FDA is aware of which
manufacturers are using an alternative test method. Similarly, if the
original notification pertains to one subcategory of smokeless tobacco
(e.g., moist snuff), and the manufacturer also decides to use the
method to test another subcategory of product (e.g., dry snuff), the
manufacturer would have to submit a new notification in accordance with
proposed Sec. 1132.16. A new notification would be needed because an
alternative test method may not be suitable for testing of other
product subcategories and the test method would need to be evaluated
for them before it can be used by the manufacturer.
Proposed Sec. 1132.16(f) indicates that FDA will acknowledge the
receipt of a notification of an alternative test method. If the
applicant submits the notification electronically, FDA will acknowledge
receipt electronically. This provision also reiterates that there is a
waiting period before a smokeless tobacco manufacturer may begin using
the alternative test method. A manufacturer could start using an
alternative test method beginning 60 calendar days after FDA's receipt
of a complete notification unless the Agency notifies the manufacturer
otherwise.
Proposed Sec. 1132.16(f)(1) provides that, if the notification is
complete when FDA receives it, the 60 calendar day waiting period would
begin on the date the Agency receives the notification. If the
notification did not contain all of the information required by
proposed Sec. 1132.16(b) and was, therefore, incomplete, FDA would not
accept the notification and would inform the submitter (proposed Sec.
1132.16(f)(2)). Upon notice from FDA that the notification is
incomplete, the manufacturer may not supplement the submission, but
rather would be required to submit a new notification that includes all
the information required in proposed Sec. 1132.16(b). Providing all of
the information in one complete notification will facilitate FDA's
review so that it can act expeditiously on the notification. The
manufacturer would not be able to use the alternative test method until
the end of the 60-day waiting period following submission of the new,
complete notification, provided it has not received an FDA notification
informing the submitter otherwise. If FDA informs the manufacturer
during the 60 calendar day waiting period that the manufacturer has not
demonstrated that the alternative test method meets or exceeds the
performance criteria of the standard test method, the manufacturer
would be prohibited from implementing
[[Page 8033]]
the alternative test method. If FDA makes this determination after the
60 calendar day period has ended and the manufacturer has already begun
using the procedure, the smokeless tobacco manufacturer would have to
immediately cease using the alternative test method upon receipt of
FDA's notification.
Proposed Sec. 1132.16(f)(4) explains that acceptance of a
notification does not constitute a finding by the Agency that an
alternative test method meets or exceeds the performance criteria of
the standard test method set forth in Sec. 1132.14.
5. Sampling Plans and Procedures (Proposed Sec. 1132.18)
Proposed Sec. 1132.18 would require each smokeless tobacco
manufacturer to design and implement sampling plans for stability
testing and batch testing. These sampling plans would be used in
conjunction with the product testing required in proposed Sec. 1132.12
(stability testing and batch testing) and would provide procedures for
the manufacturer to select samples to demonstrate conformance with the
proposed NNN level.
Proposed Sec. 1132.18(a) would require each tobacco product
manufacturer to design and implement a sampling plan or plans for all
stability testing required in proposed Sec. 1132.12(a) based on a
valid statistical rationale to demonstrate that the finished smokeless
tobacco product's expiration date is appropriate under the intended
storage conditions. One sampling plan could cover multiple products
(e.g., different flavors of the same basic core tobacco blend and cut),
but multiple plans would be needed if the products are sufficiently
different from one another in processing or materials (e.g., one
product is expected to have a very stable NNN level, whereas in another
the NNN level increases steadily over time).
The sampling plan would have to ensure that samples taken are
representative and randomly selected. Furthermore, to account for the
variability of NNN in the smokeless tobacco products, the following
factors would have to be based on adequate statistical criteria: The
confidence intervals, the level of necessary precision, and the number
of finished products sampled. Finally, proposed Sec. 1132.18(a) would
require each sampling plan to fully describe the sampling methodology
with scientific rationale, incorporate all sources of variability
(including variability of the analytic method and the NNN levels), and
describe the sample size needed (including a full description of how
the sample size is calculated) consistent with the sampling design to
achieve the sampling objective.
Similarly, proposed Sec. 1132.18(b) would require each tobacco
product manufacturer to design and implement a sampling plan or plans
for all batch testing required in Sec. 1132.12(b) based on a valid
statistical rationale to ensure that the finished smokeless tobacco
product consistently conforms to the NNN level set forth in proposed
Sec. 1132.10. One sampling plan could cover multiple products (e.g.,
different flavors of the same basic core tobacco blend and cut), but
multiple plans would be needed if the products are sufficiently
different from one another in processing or materials (e.g., one
product is expected to have a very stable NNN level, whereas in another
the NNN level increases steadily over time).
The sampling plan would have to ensure that the samples taken are
representative of an entire batch and are randomly selected and
collected from each batch for testing. To account for the variability
of the NNN levels in the finished smokeless tobacco products, the
following factors would have to be based on adequate statistical
criteria: The confidence intervals, the level of necessary precision,
and the number of finished products sampled. The sampling plan would
also have to take into account the manufacturing quality history of the
manufacturer (e.g., batch testing records and nonconforming product
investigations). For example, a manufacturer who has a high number of
nonconforming product investigations or high number of batch rejection
records may need to create a more robust sampling plan because of their
history of producing nonconforming products.
In addition, the sampling plan would have to contain a full
description of the sampling methodology, with scientific rationale,
incorporate all sources of variability (including variability of the
analytic method and the NNN levels across batches), and describe the
sample size needed (including a full description of how the sample size
is calculated) consistent with the sampling design to achieve the
sampling objective. Finally, the sampling plan would also need to fully
describe the criteria the manufacturer will use to make a decision to
accept or reject each batch. For example, the criteria for accepting a
batch of a product would depend on the results of the stability
testing. If stability testing demonstrates no change in mean NNN level,
the acceptance criteria could be a batch mean NNN level less than or at
1.0 [micro]g/g of tobacco on a dry weight basis. If the stability
demonstrates an increase of 0.2 [micro]g of mean NNN level per gram of
tobacco on a dry weight basis over the expiration period, the
acceptance criteria would need to be a batch mean NNN level below 0.8
[micro]g/g of tobacco on a dry weight basis. In those cases, the batch
of product is acceptable because the manufacturer would expect the
batch mean NNN level to remain at or below 1.0 [micro]g/g of tobacco on
a dry weight basis through the expiration date.
Proposed Sec. 1132.18(c) would require that samples be collected
and examined in accordance with certain procedures.
Under proposed Sec. 1132.18(c)(1), test samples for initial real-
time and accelerated stability testing would have to consist of:
Smokeless tobacco product that has been manufactured using
the same production processes as products manufactured for consumer use
and packaged in the identical package that will be used for the
finished smokeless tobacco product, but it need not have the product
package label; or
Finished smokeless tobacco product as it is intended to be
sold or distributed to consumers.
This provision would allow flexibility for the manufacturer to
determine the sample to be tested. It also recognizes that, at this
early stage, a manufacturer may not want to or may not be able to
create package labels for new smokeless tobacco products. For example,
in accordance with Sec. 1132.30 a package label would need to have the
expiration date for the product. Prior to completing initial stability
testing, the manufacturer might not know what the appropriate
expiration date would be. Similarly, we expect a manufacturer of a new
smokeless tobacco product would be most likely to sample smokeless
tobacco that meets the requirements of Sec. 1132.18(c)(1)(i) to
minimize costs. In contrast, we would expect a manufacturer whose
smokeless tobacco products may already conform to the proposed standard
to test its finished smokeless tobacco product (Sec.
1132.18(c)(1)(ii)) rather than product that has been manufactured
specifically for testing purposes.
Proposed Sec. 1132.18(c)(2) would require that test samples for
annual real-time stability testing and batch testing consist of the
finished smokeless tobacco product as it is intended to be sold or
distributed to consumers and not of a separate production sample. This
is intended to ensure the samples tested are representative of the
product to be sold or distributed to consumers.
Under proposed Sec. 1132.18(c)(3), all test samples would need to
be stored according to the intended storage
[[Page 8034]]
conditions for the finished smokeless tobacco product (either room
temperature or refrigeration), except that test samples for initial
accelerated stability testing must be stored in accordance with
proposed Sec. 1132.12(a)(3)(iii). The manufacturer would have to
include all of its factories, stock rooms, warehouses, and other
locations containing finished smokeless tobacco products in the
population to be sampled. Because a batch may include product that is
in the warehouse and product that is in the factory, or in a place
between the warehouse and factory, this would ensure the sample is
representative of the entire population (batch) of finished smokeless
tobacco products packaged for consumer use.
Proposed Sec. 1132.18(c)(4) sets forth when samples must be taken
for testing. Samples for stability testing would have to be taken
within 7 days of the manufacturing date and tested in accordance with
proposed Sec. 1132.12(a). This would ensure the samples for stability
testing are tested as soon as possible after manufacturing to establish
the starting NNN level. It also provides sufficient time for the sample
to be shipped to a laboratory for testing. Samples for batch testing
would have to be taken from each batch and tested within 30 calendar
days of the manufacturing date.
The amount of material acquired during sampling would have to be
sufficient for the test methods in proposed Sec. Sec. 1132.14 or
1132.16, including any repeats that may be necessary. For example,
repeat tests would be necessary if the test material was damaged prior
to or during the analysis. Samples would have to be randomly selected
in accordance with the applicable sampling plan and taken within the
same day. This would ensure that there has not been any degradation or
change in part of the samples.
Proposed Sec. 1132.18(c)(5) would require that sampling be
performed by persons who have sufficient education, training, and
experience to accomplish the assigned functions. This would allow the
manufacturer the flexibility to determine the education, training, and
experience needed to perform this function. For example, the
manufacturer may determine that a person has the necessary education,
training, and experience for the position if they have completed course
work or training in statistics, been trained by the manufacturer on
sampling procedures, or have prior work experience.
Under proposed Sec. 1132.18(c)(6), each sample would have to be
identified by the following information:
Full identification of the smokeless tobacco product
sampled, including product subcategory, brand, and subbrand, package
size and quantity of the product (mass and, if portioned, count) and,
for portioned tobacco products, the size (mass) of each portion;
Manufacturing code or, for samples for initial stability
testing with no manufacturing code, an identifying code created by the
manufacturer;
The date on which the sample was taken;
The sampling location (including the address of the
facility and specific location within the facility where the sample was
taken);
The name of the person(s) who collected the sample; and
The location where the sample will be stored and tested
(including the facility name and address).
This information would be generated at the time the samples are
pulled for testing.
The purpose of this information is to fully identify each sample,
including what the product is, and when and where it was taken. These
records would serve dual purposes. First, they can be used to verify
that a company is following its sampling plan and the procedures
required under this part, including the number of samples pulled, when
they are pulled, and the locations from where they are pulled. Second,
these records can be used to generate some of the information for the
report required under proposed Sec. 1132.18(c)(9). The records also
document the start of sampling process.
Proposed Sec. 1132.18(c)(7) provides packing requirements for
samples that are sent for testing. Samples would have to be packed
securely to protect against damage that might occur during shipment to
the testing facility, including mechanical damage or severe changes in
humidity or temperature that may affect the NNN level. The samples
would have to be sent to the testing facility by the most expeditious
means in order to arrive no later than 3 calendar days after shipment.
This is intended to minimize the potential for damage to or
contamination of the samples and would help to ensure that the testing
is completed within the specified time periods. The smokeless tobacco
manufacturer would also have to send, under separate cover, a list of
the samples (identified by the relevant information required by
proposed Sec. 1132.18(c)(6)) included in each shipment to the testing
facility. This would ensure the laboratory receives a complete list of
the samples to be tested.
Proposed Sec. 1132.18(c)(8) would require that all the samples for
a specific stability or batch test be tested at the same testing
facility to ensure consistency among the procedures used and to protect
against sample degradation.
Proposed Sec. 1132.18(c)(9) provides sampling requirements for the
testing facility responsible for testing the manufacturer's samples.
Once the samples arrive at the testing facility, a representative of
the facility would have to ensure that the samples are inspected,
accounted for, and stored under the finished smokeless tobacco
product's intended storage conditions (e.g., room temperature or
refrigeration) except that test samples for initial accelerated
stability testing must be stored in accordance with Sec.
1132.12(a)(3)(iii). The facility would then be responsible for
generating a report for the stability or batch test that includes the
following information:
Full identification of the smokeless tobacco product
sampled, including product subcategory, brand, and subbrand, package
size and quantity of the product (mass and, if portioned, count) and,
for portioned tobacco products, the size(mass) of each portion;
Manufacturing code or, for samples for initial stability
testing with no manufacturing code, an identifying code created by the
manufacturer;
The date when the samples were taken from the batch, if
available;
Locations where samples were drawn (including the address
and specific locations within any facilities where the samples were
taken), if available;
The number of test samples drawn; and
Complete records of the samples received and tested,
including the date of receipt, the identifier of all persons who tested
the samples, and the test results.
This information would be generated once the samples arrive at the
testing facility. Unlike the information required under proposed Sec.
1132.18(c)(6), this report would be an aggregate report for all the
samples taken from a batch. The primary purpose of this information,
along with the information required by proposed Sec. 1132.18(c)(6),
would be to establish the chain of custody for the samples from the
time they were taken up through their transfer to the testing facility
where they will be tested. The smokeless tobacco manufacturer would be
required to maintain the sampling information in accordance with
proposed Sec. 1132.32. Thus, the manufacturer would be responsible for
obtaining this information from the
[[Page 8035]]
testing facility. FDA also expects that this information would be
integrated into the records required by proposed Sec. 1132.12(c) to
provide information across the batch.
Proposed Sec. 1132.18(c)(10) explains that the manufacturer would
be required to withhold from commercial distribution each batch until
it has been sampled and tested, and the tobacco product manufacturer
has made a decision to accept and release the batch. The manufacturer
would be required to reject any nonconforming products as discussed in
proposed Sec. 1132.22.
6. Expiration Date (Proposed Sec. 1132.20)
Proposed Sec. 1132.20 would require all finished smokeless tobacco
products to have an expiration date established by stability testing.
The expiration date would be required to be set no later than the final
date the manufacturer can demonstrate the finished smokeless tobacco
product will not exceed the NNN limit in proposed Sec. 1132.10 when
stored under its intended conditions (i.e., either room temperature or
refrigeration). FDA considered requiring manufacturers to determine the
time point at which the NNN level exceeds the limit. However, FDA
rejected this approach because manufacturers may develop products with
stable NNN levels that do not exceed the NNN limit for a prolonged
period (e.g., 5 years) and requiring manufacturers to conduct stability
testing for that entire period would be unnecessary. FDA also
considered mandating a specific expiration period (e.g., 6 months or 1
year) but determined this may be too restrictive and stifle innovation.
Accordingly, FDA believes the proposed approach would provide
manufacturers more flexibility in establishing an expiration date that
conforms to the NNN level.
Requiring an expiration date that is established by stability
testing provides assurance that the NNN level will remain in
conformance with the product standard for the specified time period.
The expiration date also informs retailers that the manufacturer has
not demonstrated compliance with the product standard beyond that date
and the product cannot be sold to consumers. The expiration date also
allows FDA inspectors to quickly determine if products for sale in a
retail establishment purport to be in conformance with the product
standard.
7. Nonconforming Product (Proposed Sec. 1132.22)
Proposed Sec. 1132.22 would require manufacturers to establish
procedures for handling nonconforming smokeless tobacco products.
Proposed Sec. 1132.22(a) would require tobacco product manufacturers
to establish and maintain procedures to identify, investigate,
segregate, and make disposition decisions (i.e., acceptance, rejection,
or rework) about nonconforming finished smokeless tobacco products to
prevent their release for commercial distribution. FDA interprets
``establish and maintain'' for purposes of proposed Sec. 1132.22(a) to
mean define, document (in writing or electronically), implement,
follow, and, when necessary, update. This section allows manufacturers
the flexibility to determine how they will perform these activities.
Proposed Sec. 1132.22(b) would require tobacco product
manufacturers to conduct an investigation if:
The mean of the representative samples from any batch of
finished smokeless tobacco product is determined to be out of
conformance with the requirements of Sec. 1132.10,
A finished smokeless tobacco product's expiration date
must be shortened due to the results of annual real-time stability
testing, or
FDA notifies the smokeless tobacco manufacturer that a
distributed finished smokeless tobacco product does not conform to the
requirements of part 1132.
The purpose of a nonconforming product investigation would be to
determine the extent and the cause, if possible, of the nonconformity
so that, if identified early, the product is not processed further or
released for commercial distribution. In addition, it would help to
prevent recurrence of the nonconformity.
The manufacturer would be required to conduct an investigation to
determine the extent of the nonconformity upon identification of a
nonconforming product and, as applicable, the locations where the
nonconforming products have been distributed. We expect the
manufacturer would be able to determine the locations of the initial
consignees (e.g., wholesalers, distributors, retailers) where the
affected products were shipped in the event a corrective action needs
to be taken. The investigation would have to include an examination of
all relevant processes, operations, records, complaints, any corrective
actions taken, and any other relevant sources of information concerning
the nonconforming product. For example, a manufacturer could determine
the extent of the nonconformity by examining records and in-process
control records for any batches, or portions of batches that have been
rejected during either in-process or finished inspection for failing to
meet any or all of the product's specifications. Furthermore, in the
event that a similar nonconforming product is identified in a different
batch, a manufacturer's investigation could include any applicable
information and records from the previous nonconforming product
investigation that are relevant to determining the extent of
nonconformity of the affected batch.
The manufacturer would have to fully document any investigation,
including any materials reviewed, name of the person(s) making the
disposition decisions, justification for the disposition decisions,
results of retesting, decisions with respect to reworking, and followup
results from the investigation (e.g., corrective actions). FDA may
inspect these records to verify the manufacturer has adequately
performed an investigation.
Proposed Sec. 1132.22(c) would require tobacco product
manufacturers to reject any batch of a finished smokeless tobacco
product if the mean of the representative samples from the batch does
not meet the requirements of Sec. 1132.10 unless a disposition
decision and justification to release the batch is made after an
investigation shows the batch meets the requirements of part 1132.
Manufacturers would not be able to simply resample a batch until the
mean conforms with the proposed NNN limit in Sec. 1132.10 if a
previous mean did not meet the requirements of part 1132. If the
initial mean was not in conformance, the manufacturer must conduct a
nonconforming product investigation. If the manufacturer, for instance,
determines the NNN levels were erroneously high because of a
malfunction of the testing equipment, and the batch tests in
conformance after repair of the equipment, the manufacturer could
determine that the batch is acceptable for release into commercial
distribution.
Proposed Sec. 1132.22(d) would allow smokeless tobacco
manufacturers to rework a batch of a nonconforming finished smokeless
tobacco product, which does not conform to the requirements of part
1132, to bring it into conformance with all the requirements of the
part before it may be released for commercial distribution. However,
FDA thinks it is unlikely that a manufacturer would rework
nonconforming finished smokeless tobacco product because this would
likely require removing the product from its container and then mixing
it with smokeless tobacco product with very low NNN levels to ensure
that the final product did not exceed the
[[Page 8036]]
proposed NNN limit.\4\ We welcome information and comments on this
provision.
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\4\ Based on comments provided by the Alcohol and Tobacco Tax
and Trade Bureau (TTB), we understand that this process would likely
constitute the manufacture of tobacco products for purposes of the
Internal Revenue Code. Under the Internal Revenue Code, the
manufacture of tobacco products requires a permit as a manufacturer
of tobacco products from TTB. As we understand TTB's permitting
requirements, entities lacking a manufacturing permit, including
importers, may not engage in manufacturing activities. We also
understand that certain provisions of the Internal Revenue Code
prohibit importers of tobacco products from repackaging tobacco
products after such products are released from customs custody.
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C. Labeling and Recordkeeping Requirements (Proposed Subpart C)
1. Package Label Requirements (Proposed Sec. 1132.30)
Proposed Sec. 1132.30 would require that the package label of all
finished smokeless tobacco products include a manufacturing code,
expiration date, and, if applicable, storage conditions. FDA is
proposing to require that the labels of finished smokeless tobacco
products contain a manufacturing code, expiration date, and, if
applicable, storage conditions for the finished smokeless tobacco
product (proposed Sec. 1132.30) so that FDA can determine whether a
product on store shelves purports to be in conformance with the product
standard and link the product to records that substantiate its
conformance. These requirements would also help ensure that the product
is handled and stored under appropriate conditions so that the product
remains in compliance with the standard and would help FDA verify that
retailers are storing products appropriately. The information would be
required to be printed on or permanently affixed to the package in a
manner that assures it will remain on the packaging or label through
the expected duration of use of the product by the consumer. In
addition, it would have to appear clearly, legibly, and indelibly in
the English language.
The purpose of the manufacturing code is to allow manufacturers and
FDA to be able to link the product to a specific batch that has been
released for commercial distribution, which would be helpful in the
event of a nonconforming product investigation or in the event that
corrective or preventive actions should be taken. The manufacturing
code could also help determine the history of the manufacturing,
processing, packaging, labeling, holding, and initial distribution of
the tobacco product from records maintained by the smokeless tobacco
product manufacturer. The expiration date on the package label would
have to appear in two-digit numerical values in the following format:
``Expires on month/day/year.'' The expiration date informs retailers
that the manufacturer has not demonstrated compliance with the product
standard beyond that date and the product cannot be sold to consumers.
The expiration date also allows FDA inspectors to quickly determine if
products for sale in a retail establishment purport to be in
conformance with the product standard and if retailers are selling
expired products.
Storage conditions would be required to be on the label if the
finished smokeless tobacco product must be kept in refrigerated storage
to conform with the product standard until the expiration date (as
determined by stability testing) and the package label would be
required to bear the wording: ``Keep Refrigerated.'' However, no
wording would be required to be on the package label if the product's
intended storage condition is room temperature. We note that proposed
Sec. 1132.1 states that retailers and distributers would not be in
violation of part 1132 as it relates to the sale or distribution or
offer for sale or distribution of smokeless tobacco products that
exceed the NNN limit if they, among other things, store and transport
the finished tobacco product according to the package label and do not
sell or distribute or offer for sale or distribution finished smokeless
tobacco products past their expiration date. Requiring package labels
with an expiration date and storage conditions would allow retailers
and distributers to handle the product in accordance with the
manufacturer's intent so the product remains in conformance with the
product standard.
2. Recordkeeping Requirements (Proposed Sec. 1132.32)
Proposed Sec. 1132.32 includes two recordkeeping requirements.
This information is necessary for FDA to ascertain and confirm that
smokeless tobacco products are in compliance with the proposed
standard.
First, proposed Sec. 1132.32(a) would require that each facility
that manufactures finished smokeless tobacco products establish and
maintain records containing the following information:
1. Full documentation of stability testing protocols and the
results of initial and annual stability testing under Sec. 1132.12(a),
including all information specified in Sec. 1132.12(c).
2. All investigations under Sec. 1132.12(a)(4)(v).
3. The source data and results of batch testing conducted to
determine conformance with Sec. 1132.10, including all information
specified in Sec. 1132.12(c).
4. All notifications of an alternative test method and all related
correspondence under Sec. 1132.16;
5. All source data for the alternative test method validation;
6. All sampling plans and reports under Sec. 1132.18;
7. Documentation that the persons performing sampling under Sec.
1132.18 have sufficient education, training, and experience to
accomplish the assigned functions;
8. All identification, investigation, segregation, and disposition
decision procedures under Sec. 1132.22(a); and
9. All nonconforming product investigations and rework under Sec.
1132.22(b) and (d).
Second, proposed Sec. 1132.32(b) provides certain specifications
for these records. The records would have to be legible and written in
English. Documents that have been translated from a foreign language
into English would have to be accompanied by the foreign language
version of the document and a certification by the manufacturer's
authorized representative (which could be a U.S. agent for the
manufacturer) that the English language translation is complete and
accurate. All records would be required to be readily available for
inspection and copying or other means of reproduction by FDA upon
request during an inspection.\5\ Requested records that are maintained
offsite would have to be made available within 24 hours or, if that is
not feasible, as soon as possible before the close of the inspection.
While we expect that most records can be made available to FDA within
24 hours, we recognize that, in some cases, additional time may be
needed to retrieve records from a third party or archival storage.
Records that can be immediately retrieved from another location,
including by computer or other electronic means, would meet the
requirement that the records be readily available.
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\5\ Several laws govern the confidentiality of information
submitted under sections 907 and 909 of the FD&C Act, including
sections 301(j) and 906(c) of the FD&C Act (21 U.S.C. 331(j) and
387f(c)), the Trade Secrets Act (18 U.S.C. 1905), and the Freedom of
Information Act (FOIA) (5 U.S.C. 552), as well as FDA's regulations
in 21 CFR part 20.
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In addition, proposed Sec. 1132.32(c) would require that the
records kept under this part be retained for at least 4 years from the
date of commercial
[[Page 8037]]
distribution of the finished smokeless tobacco product that is the
subject of the record. However, for records relating to alternative
test methods under Sec. 1132.16, the required 4-year retention period
would be for a period not less than 4 years after the last date the
method that is the subject of the record is used (e.g., 4 years from
the last date the manufacturer used an alternative test method). FDA
has selected 4 years as a means to help ensure that the records would
be available for at least one biennial FDA inspection under sections
704 and 905(g) of the FD&C Act.
FDA considered not requiring specific recordkeeping requirements
and, instead, allowing the manufacturer to determine recordkeeping
needs but, FDA believes that detailed recordkeeping requirements are
necessary to confirm that the finished smokeless tobacco products are
in compliance with the proposed standard. For example, requiring
manufacturers to fully document their stability testing protocols and
test results will enable FDA to confirm that the manufacturer's test
method and protocols are adequate to meet the requirements of part
1132. In addition, requiring nonconforming product records will help
the manufacturer and FDA determine the extent of the nonconformity and,
as applicable, the locations where the nonconforming products have been
distributed, in the event of a recall or enforcement action (e.g.,
seizure).
VII. Proposed Effective Date
FDA proposes that any final rule on the tobacco product standard
for NNN that may issue based on this proposal become effective 3 years
after the date of publication of the final rule. FDA believes this
approach would allow adequate time for developing any necessary changes
in technology to achieve the NNN level, for any changes made to
manufacturers' tobacco purchasing choices and curing methods, and for
any preparation or changes needed in facilities. In addition, FDA
believes that it will provide adequate time for manufacturers to seek
and obtain marketing authorization from FDA for their new tobacco
products. New tobacco products are subject to enforcement if they are
on the market without FDA authorization.
Therefore, after the effective date of a final rule for this
proposed tobacco product standard, no person would be allowed to
manufacture, distribute, sell, or offer for sale or distribution within
the United States any finished smokeless tobacco product that does not
comply with the rule. After the effective date of the final rule,
manufacturers would not be allowed to introduce into domestic commerce
any finished smokeless tobacco product that does not comply with the
requirements of the final rule, irrespective of the date of
manufacture. However, retailers would be permitted to sell-off existing
inventory of noncompliant finished smokeless tobacco products
manufactured before the effective date for 60 days after the effective
date of the final rule. FDA notes that keeping products with higher NNN
levels on the market for an extended period of time after the effective
date of the rule is not in the interest of public health.
VIII. Incorporation by Reference
FDA is proposing to incorporate by reference the test method
entitled, ``Determination of N-nitrosonornicotine (NNN) in Smokeless
Tobacco and Tobacco Filler by HPLC-MS/MS,'' LIB No. 4620, January 2017
(Ref. 79). You may obtain a free copy of the material proposed to be
incorporated from the Docket at www.regulations.gov or from the Food
and Drug Administration, Center for Tobacco Products, 10903 New
Hampshire Ave., Silver Spring, MD 20993, 1-888-463-6332.
This is a technical document developed by FDA specifically for use
in tobacco testing facilities. FDA developed this test method for NNN
in order to streamline the testing process and reduce testing costs.
Other available methods test for all TSNAs while this test method is
limited to NNN. As such it is a highly specific method that reduces
testing costs while ensuring that the results from the test method
demonstrate a high level of specificity, accuracy, and precision in
measuring a range of NNN levels across a variety of smokeless tobacco
products.
This test method relies on several ISO standards for determining
moisture content in tobacco and tobacco products--ISO 6488:2004, ISO
6488:2004/Cor 1:2008, and ISO 16632:2013. FDA is not proposing to
incorporate these standards by reference. You may purchase a copy of
the ISO standards from the International Organization for
Standardization, 1, ch. de la Voie-Creuse, Case Postale 56, CH-1211,
Geneva 20, Switzerland, or from the American National Standards
Institute, 1899 L Street NW., 11th Floor, Washington, DC 20036, or on
the Internet at https://www.iso.org or www.ansi.org. We note that these
ISO standards are relatively inexpensive (about $50 each) and may
already be used by tobacco testing facilities.
For the reasons set forth in this section, FDA considers the test
method proposed to be incorporated by reference to be reasonably
available and usable by testing facilities (see 1 CFR 51.5(a) and
51.7).
IX. Economic Analysis of Impacts
We have examined the impacts of the proposed 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 proposed rule. We believe that this
proposed rule is an economically 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. Because many smokeless tobacco products may need to be
reformulated, and reformulation represents the main driver of the costs
of the rule, we tentatively find that the proposed rule would 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 proposing ``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 proposed rule would
result in an expenditure in any year that meets or exceeds this amount.
The proposed rule would establish a product standard for all
finished smokeless tobacco products. Specifically, the proposed rule
would require that all finished smokeless tobacco products comply with
a limit for NNN in such products in order to be marketed and
distributed for sale in the United States. This proposed product
standard would require that the mean level of NNN in any batch of
finished
[[Page 8038]]
smokeless tobacco products not exceed 1.0 [micro]g/g of tobacco (on a
dry weight basis) at any time through the product's labeled expiration
date as determined by product testing. The proposed standard also
includes requirements on the sale and distribution of smokeless tobacco
products, product testing, labeling, and recordkeeping.\6\
---------------------------------------------------------------------------
\6\ The proposed product standard includes a number of
requirements in addition to the actual NNN limit, including
requirements related to product testing, recordkeeping, and sale and
distribution restrictions. However, generally, this analysis uses
the term product standard as shorthand for the NNN limit
requirement. Similarly when we discuss anticipated compliance status
and compliant versus noncompliant products, we generally refer to
compliance with the NNN limit requirement.
---------------------------------------------------------------------------
The costs of the proposed rule, when finalized, will be due to
affected entities ensuring that the smokeless tobacco products comply
with the proposed product standard. We have estimated that the
annualized costs associated with the proposed rule over 20 years to be
between $17.91 million and $42.72 million using a 3 percent discount
rate, with a primary value of $30.31 million, and between $20.11
million and $50.57 million, with a primary value of $35.34 million
using a 7 percent discount rate. The primary estimate for the present
value of total quantified costs over 20 years is approximately $450.97
million at a 3 percent discount rate and $374.36 million at a 7 percent
discount rate.
NNN is a carcinogenic agent found in smokeless tobacco products. As
described in the preamble, on the basis of the available scientific
evidence, FDA has determined that NNN is the predominant driver of
excess oral cancer risk among smokeless tobacco users.
We quantify benefits associated with the proposed rule in the form
of reduced oral cancer morbidity and mortality attributable to
smokeless tobacco. As described in section V.A.3 of the preamble of the
proposed rule, we also expect the standard to reduce the risk of
esophageal cancer and it may reduce the risks of other cancers such as
pancreatic, laryngeal, prostate, and lung cancer. However, there is
more limited information to directly quantify these health benefits. As
such, we only consider reductions in oral cancer as the quantified
benefit of the proposed product standard.
Most of the estimated benefits arise from quality life-years gains
gained from reduced oral cancer mortality. The annualized value over 20
years of quality adjusted life-years gained from reduced oral cancer
mortality ranges from $228.66 million to $2.46 billion at a 3 percent
discount rate, with a primary value of $858.46 million. Using a 7
percent discount rate, the annualized value of quality life-years
gained from averted deaths ranges from $182.01 million to $1.96
billion, with a primary value of $683.34 million. The primary estimate
of the present value of mortality reductions quantified over 20 years
is $12.77 billion at a 3 percent discount rate and $7.24 billion at a 7
percent discount rate. The annualized value over 20 years of quality
adjusted life-years gained from reduced oral cancer mortality and
morbidity ranges from approximately $283.95 million to $3.05 billion at
a 3 percent discount rate, with a primary value of $1.06 billion, and
approximately $246.40 million to $2.65 billion, with a primary value of
$0.92 billion at a 7 percent discount rate. The primary estimate of the
present value of total quantified benefits over 20 years is
approximately $15.86 billion at a 3 percent discount rate and $9.80
billion at a 7 percent discount rate for reductions in oral cancer
alone. These values are likely an underestimate of the benefits
associated with the proposed rule, as we do not quantify reductions in
mortality and morbidity from cancers other than oral cancer. Costs and
benefits are summarized in table 8.
The full analysis of economic impacts is available in the docket
for this proposed rule (Ref. 146) and at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
Table 8--Summary of Benefits, Costs and Distributional Effects of Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
---------------------------------
Category Primary Low High Period Notes
estimate estimate estimate Year Discount covered
dollars rate (%) (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized millions/year............... $924.91 $246.40 $2,647.21 2015 7 20 Most of the health benefits
included in the totals would
be realized more than 20 years
after publication of the final
rule, but the risk reductions
associated with these benefits
occur during the 20-year
period beginning at
publication of the final rule.
$1,065.92 $ 283.95 $3,051.09 2015 3 20 ...............................
Annualized....................................... ......... ......... ......... ......... 7 20 ...............................
Quantified....................................... ......... ......... ......... ......... 3 20 years ...............................
Qualitative.......................................... ......... ......... ......... ......... ......... ......... Potential cost savings from net
life-time reduction in medical
care utilization; additional
health benefits from reduction
in other toxicants correlated
with NNN; reduction in
cancers, other than oral
cancers
Costs:
Annualized....................................... $35.34 $20.11 $50.57 2015 7 20 ...............................
Monetized millions/year.......................... $30.31 $17.91 $42.72 2015 3 20 ...............................
Annualized....................................... ......... ......... ......... ......... 7 20 ...............................
Quantified....................................... ......... ......... ......... ......... 3 20 ...............................
Qualitative...................................... ......... ......... ......... ......... ......... ......... ...............................
Transfers:
Federal Annualized............................... ......... ......... ......... 7 20 .........
Monetized $millions/year............................. ......... ......... ......... ......... 3 20 ...............................
--------------------------------------------------------------------------------------------------------------------------------------------------------
From:
To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Other Annualized................................. ......... ......... ......... ......... 7 20 ...............................
[[Page 8039]]
Monetized $millions/year......................... ......... ......... ......... ......... 3 20 ...............................
--------------------------------------------------------------------------------------------------------------------------------------------------------
From:
To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects State, Local or Tribal Government: None estimated.
Small Business: The average cost per small entity is largest in Year 1 and range between $2.67
million and $7.97 million. Reformulation costs and stability testing represent the largest
proportion of costs--up to 60 percent of average sales for entities with fewer than 50 employees
and up to 13 percent of average sales for entities with 50-100 employees.
Wages: None estimated.
Growth: None estimated.
--------------------------------------------------------------------------------------------------------------------------------------------------------
X. Analysis of Environmental Impact
The Agency has carefully considered the potential environmental
effects of this action. 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. Under FDA's regulations implementing the National
Environmental Policy Act (21 CFR part 25), an action of this type would
require an environmental assessment under 21 CFR 25.20.
XI. Paperwork Reduction Act of 1995
This proposed rule contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). A
description of these provisions is given in the Description section of
this document with an estimate of the annual reporting, recordkeeping,
and third-party disclosure burden. 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.
FDA invites comments on these topics: (1) Whether the proposed
collection of information is necessary for the proper performance of
FDA's functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
Title: Tobacco Product Standard: NNN Level in Finished Smokeless
Tobacco Products.
Description: FDA is proposing a product standard to establish a
limit of NNN in finished smokeless tobacco products sold in the United
States. Products with higher NNN levels pose higher risks of cancer and
FDA finds that establishing a NNN limit in finished smokeless tobacco
products is appropriate for the protection of the public health.
Proposed Sec. 1132.10 would require that the mean level of NNN in any
batch of finished smokeless tobacco products not exceed 1.0 [micro]g/g
of tobacco (on a dry weight basis) at any time through the product's
labeled expiration date as determined by testing in compliance with
Sec. 1132.12. Proposed Sec. Sec. 1132.12, 1132.14, 1132.16, and
1132.18 would establish product testing and sampling plan requirements.
Proposed Sec. 1132.12 would require two types of testing for smokeless
tobacco products--stability testing and batch testing. Proposed Sec.
1132.12(a) would require initial and annual stability testing to assess
the stability of the NNN level in finished smokeless tobacco products
and to establish and verify the product's expiration date and storage
conditions (either room temperature or refrigeration). Proposed Sec.
1132.12(b) would require manufacturers to conduct batch testing on each
batch of finished smokeless tobacco product to determine whether the
products conform to the proposed NNN limit. Proposed Sec. 1132.12(c)
would require the tobacco product manufacturer to document all testing.
Proposed Sec. Sec. 1132.14 and 1132.16 would establish the
standard and alternative test methods. If a tobacco product
manufacturer were to choose not to use the standard test method in
Sec. 1132.14 to test its smokeless tobacco products, the manufacturer
would be required to use a validated alternative test method that
conforms to the requirements of proposed Sec. 1132.16. Proposed Sec.
1132.16(a) would require that, before using a validated alternative
test method, the manufacturer notify the Center for Tobacco Products.
ProposedSec. 1132.18 would establish the sampling requirements for
all testing. These sampling requirements would be used in conjunction
with the product testing required in proposed Sec. 1132.12 (stability
testing and batch testing) and would provide procedures for the
manufacturer to select samples to demonstrate conformance with the
proposed NNN limit.
Proposed Sec. 1132.22 would require tobacco product manufacturers
to establish and maintain procedures to identify, investigate,
segregate, and make disposition decisions about nonconforming finished
smokeless tobacco products in order to prevent their release for
commercial distribution and to conduct investigations related to
nonconforming products.
Under proposed Sec. 1132.30, the labels of finished smokeless
tobacco products would be required to contain a manufacturing code,
expiration date, and, if applicable, storage conditions for the
finished smokeless tobacco product. The information would have to be
printed on or permanently affixed to the package assuring that the
label remains intact through the expected duration of use. It must
appear clearly, legibly, and indelibly in the English language. The
expiration date must appear on the packaging in two-digit numerical
values. If the manufacturer determines by stability testing that meets
the requirements in Sec. 1132.12 that the finished smokeless tobacco
product must be stored in a refrigerator, the package label must state
``Keep Refrigerated.'' The manufacturing code would provide a history
of the manufacturing, processing, packaging, labeling, holding, and
initial
[[Page 8040]]
distribution of the product from records maintained by the tobacco
product manufacturer.
Proposed Sec. 1132.32 would require that tobacco product
manufacturers maintain records regarding the product testing (i.e.,
stability and batch testing), including protocols and a full report of
the source data and results; records regarding investigations related
to shortening of expiration dates based on results of annual stability
testing; all notifications of an alternative test method and source
data for alternative test method validation; all sampling plans and
reports; documentation that the persons performing sampling have
sufficient education, training, and experience to accomplish the
assigned functions; all identification, investigation, segregation, and
disposition procedures related to nonconforming products; and all
nonconforming product investigations and rework (i.e., the processing
of nonconforming finished smokeless tobacco products to meet the
requirements of part 1132). FDA is also proposing to require copies of
all records be retained for a period of not less than 4 years from the
date of commercial distribution of the finished smokeless tobacco
product that is the subject of the record, except that certain records
relating to alternative test methods would be required to be retained
for a period of not less than 4 years after the last date the method is
used. FDA has selected 4 years as a means to help ensure that the
records would be available for at least one biennial FDA inspection
under sections 704 and 905(g) of the FD&C Act.
Description of Respondents: The provisions of this standard would
apply to finished smokeless tobacco products. Finished smokeless
tobacco product means a smokeless tobacco product, including all parts
and components, packaged for consumer use, except for components,
parts, or accessories sold without tobacco. The respondents are
therefore manufacturers of smokeless tobacco products.
FDA estimates the burden of this collection of information as
follows:
Table 9--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of
21 CFR part Number of responses per Total annual Average burden Total hours
respondents respondent responses per response
----------------------------------------------------------------------------------------------------------------
Sec. 1132.16 Alternative Test 23 1 23 20 460
Method (FDA Form 3979).........
Sec. 1132.16 Waiver from 2 1 2 .75 2
Electronic Submission..........
-------------------------------------------------------------------------------
Total....................... .............. .............. .............. .............. 462
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
\2\ The burden in the reporting chart corresponds to table 23 ``Estimated Costs to Industry Associated with
Notifications to FDA Regarding Use of Alternative Testing Methods'' in the RIA.
Table 10--Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of Average burden
Activity (units) Number of records per Total annual per Total hours
recordkeepers recordkeeper records recordkeeping
----------------------------------------------------------------------------------------------------------------
Change in process (Formulations) 68 1 68 8 544
Ingredient change (Formulations) 28 1 28 8 224
No change (Formulations)........ 60 1 60 4 240
Labeling records, annual after 1255 1 1255 2 2,510
year 1 (UPCs)..................
Initial Stability Testing 23 8 184 4 736
records (Manufacturers)........
Annual Stability Testing records 23 3 69 4 276
(Manufacturers)................
Batch Testing (products)........ 784 28 21,952 4 87,808
Batch Testing records 23 1 23 4 92
(Manufacturers)................
Procedures for nonconforming 23 1 23 4 92
products and related
investigations (Manufacturers).
Notifications, alternate testing 23 2 46 0.75 35
methods (Manufacturers)........
-------------------------------------------------------------------------------
Total \1\................... .............. .............. .............. .............. 92,557
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
\2\ The burden in the recordkeeping chart corresponds to table 24 ``Estimated Recordkeeping Costs to Industry''
and table 13 ``Estimated Number of Batch Tests'' in the RIA.
Table 11--Estimated Annual Third-Party Disclosure Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of
Activity (units) Number of disclosures Total annual Average burden Total hours
respondents per respondent disclosures per disclosure
----------------------------------------------------------------------------------------------------------------
Package Labeling Change Minor 459 1 459 10 4,590
(UPCs).........................
Package Labeling Change Major 8 1 8 23 184
(UPCs).........................
Initial Stability Testing (one 784 168 131,712 2 263,424
time) (Products)...............
Initial Stability Testing 784 6.72 5,268 2 10,536
(recurring) (Products).........
Annual Stability Testing 784 60.48 47,416 2 94,832
(Products).....................
Sampling Plans (Products)....... 784 1 784 2 1,568
-------------------------------------------------------------------------------
Total \1\................... .............. .............. .............. .............. 370,360
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
\2\ The burden in the third-party disclosure chart corresponds to table 12 ``Estimated Costs Associated with
Proposed Stability Testing Requirements'' and table 15 ``Products with Expiration and Storage Information'' in
the RIA.
[[Page 8041]]
FDA's burden estimates are based on the regulatory impact analysis,
Agency expertise, registration and listing data, company revenue
information from Dunn & Bradstreet, and comparing to other online
sources in order to categorize the entities and number of products.
Table 9 describes the annual reporting burden as a result of the
requirements proposed in Sec. 1132.16 submitting a notification of an
alternative test method and requesting a waiver from electronic
submission of such a notification. FDA estimates that it will receive
23 notifications for alternative test methods using FDA Form 3979 (Ref.
145) for a total of 460 hours. Because some of the manufacturers may
currently be conducting these reports, the RIA anticipates that there
would be between 1 and 23 manufacturers affected. For PRA purposes we
have used the high estimate of 23. FDA also estimates that 2
respondents will submit a waiver request from electronic submission.
Therefore, the total estimated reporting burden for this proposed rule
is 462 hours.
Table 10 outlines the recordkeeping requirements that are proposed
in Sec. 1132.32. We note that recordkeeping time burden activities are
derived from the respective models (RTI International, 2015a; RTI
International, 2015a; RTI International, 2015(b). FDA estimates
recordkeeping time burden related to product reformulation (change in
process, ingredient change, and no change) to involve 156 formulations
for total of 1,008 hours. For recordkeeping burden related to certain
labeling records, FDA estimates that after year one 1,255 affected
Universal Product Code (UPC) records will be kept annually for a total
of 2,510 hours. The number of UPCs subject to these recordkeeping
requirements is determined by multiplying the number of UPCs in each
product category by the percent of products with expiration date
information.
We estimate that batch testing will be conducted for 784 products
(21,952 tests per year) for a total of 87,808 hours. Proposed Sec.
1132.32 requires records to be maintained for stability and batch
tests. FDA estimates that 23 manufacturers will maintain records
related to initial stability testing, annual stability testing, and
batch testing for a total of 1104 hours. Records are also required to
be maintained of procedures for nonconforming products and related
investigations. We estimate that 23 manufacturers will maintain these
records for a total of 92 hours. Proposed Sec. 1132.32 requires
manufacturers to maintain all notifications of an alternative test
method. We estimate that 23 manufacturers will maintain these records
for a total of 35 burden hours. Therefore, the total estimated
recordkeeping hours are 92,557.
Table 11 represents third party disclosures (package labeling) that
a respondent must display. This table also covers the proposed
stability testing that must occur for the label. Labeling burden is
estimated by using data on the number of active UPCs from Nielsen Inc.,
and the estimated percentage of products with expiration and storage
information come from FDA Registration and Listing database (as of
March 1, 2016). To derive the number of UPCs subject to a labeling
change that includes storage information, we assume that only those
products that are currently refrigerated but for which we did not find
evidence that the labeling exists would incur such labeling change.
Thus, we estimate that these different products that would likely be
affected by labeling changes would include up to 467 UPCs (derived by
assuming that each product would be associated with one unique UPC).
Since all products already have either an expiration date or a
manufactured on date, adding an expiration date or storage conditions
to labeling would be considered a minor change if product label
redesign is not needed and major if product label redesign is needed.
FDA believes that labeling changes associated with adding storage
information is assumed to be ``major'' to incorporate uncertainty
regarding product label redesign. We estimate that 459 affected UPCs
will undergo minor labeling changes for a total of 4,590 hours.
Additionally, FDA estimates that 8 affected UPCs will undergo major
labeling changes regarding storage information for a total of 184
hours.
Since establishing and verifying a product's expiration date and
storage conditions on a label requires actual stability testing we
categorize this burden under third party disclosures. For PRA purposes
we have categorized stability testing under third party disclosures.
For example, in accordance with Sec. 1132.30 a package label would
need to have the expiration date for the product. Prior to completing
initial stability testing, the manufacturer might not know what the
appropriate expiration date would be. Since the testing will inform the
label we believe it is appropriate for the burden to fall under this
category. We estimate that 784 products would undergo initial stability
testing, and annual stability testing each year thereafter. FDA
estimates that in year 1 there would be 131,712 initial tests for a
total of 263,424 hours. After the first year we estimate that there
would be 5,268 initial tests for a total of 10,536 hours. After the
initial testing we expect 47,416 annual tests per year for total of
94,832 hours.
FDA included sampling plans in the third party disclosure chart
because each tobacco product manufacturer would be required to
demonstrate that the finished smokeless tobacco product's expiration
date (on the label) is appropriate under the intended storage
conditions, and to do so the manufacturer would conduct testing
pursuant to sampling plans. In developing a sampling plan for NNN in
smokeless tobacco products a manufacturer must take into account the
size of a batch, the variation of NNN in their product, the margin of
error around their analytical techniques, and any other variables they
can justify as pertinent to their calculation. While the development of
a sampling plan would require some data analysis and determination of
assumptions, we believe that the development of a sampling plan could
cover multiple products. In addition once a sampling plan had been
developed we believe that there would be significant redundancy in the
development of subsequent plans which would reduce the time needed to
complete them. Ultimately we have estimated that the time for the
development of a sampling plan would average 2 hours per product for a
total of 1,568 hours. Therefore, the total third party disclosure
burden is estimated to be 370,360 hours.
FDA estimates that the total burden imposed by these proposed
requirements will be 463,379 hours (462 reporting, 92,557
recordkeeping, and 370,360 third party disclosures).
This proposed rule also refers to previously approved collections
of information found in FDA regulations. The collections of information
in section 905(j) of the FD&C Act (substantial equivalence reports)
have been approved under OMB control number 0910-0673.
To ensure that comments on information collection are received, OMB
recommends that written comments be faxed to the Office of Information
and Regulatory Affairs, OMB (see ADDRESSES). All comments should be
identified with the title of the information collection.
In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3407(d)), the Agency has submitted the information collection
provisions of this proposed rule to OMB for review. These requirements
will not be effective until FDA obtains OMB approval. FDA will
[[Page 8042]]
publish a notice concerning OMB approval of these requirements in the
Federal Register.
XII. Executive Order 13132
FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule, if finalized, would not contain policies that would
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, the Agency tentatively concludes that the proposed 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.
XIII. Executive Order 13175
FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13175. We have tentatively
concluded that the rule does not contain policies that would have a
substantial direct effect on one or more Indian tribes, on the
relationship between the Federal Government and Indian tribes, or on
the distribution of power and responsibilities between the Federal
Government and Indian tribes. The Agency solicits comments from tribal
officials on any potential impact on Indian tribes from this proposed
action.
XIV. References
The following references are on display in the Division of Dockets
Management (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at https://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. International Agency for Research on Cancer, ``Smokeless
Tobacco and Some Tobacco-specific N-nitrosamines,'' IARC Monographs
on the Evaluation of Carcinogenic Risks to Humans, 89, 2007,
available at https://monographs.iarc.fr/ENG/Monographs/vol89/mono89.pdf.
2. International Agency for Research on Cancer, ``Personal Habits
and Indoor Combustions: A Review of Human Carcinogens,'' IARC
Monographs on the Evaluation of Carcinogenic Risks to Humans,
100(e), 2012, available at https://monographs.iarc.fr/ENG/Monographs/vol100E/mono100E.pdf.
3. European Commission, Scientific Committee on Emerging and Newly
Identified Health Risks, ``Health Effects of Smokeless Tobacco
Products,'' 2008.
4. National Cancer Institute, Centers for Disease Control and
Prevention, U.S. Department of Health and Human Services,
``Smokeless Tobacco and Public Health: A Global Perspective,'' 2014,
available at https://cancercontrol.cancer.gov/brp/tcrb/global-perspective/SmokelessTobaccoAndPublicHealth.pdf.
5. Borgerding, M.F., J.A. Bodnar, G.M. Curtin, et al., ``The
Chemical Composition of Smokeless Tobacco: A Survey of Products Sold
in the United States in 2006 and 2007,'' Regulatory Toxicology and
Pharmacology, 64(3):367-387, 2012.
6. Song, M., C. Marian, T.M. Brasky, et al., ``Chemical and
Toxicological Characteristics of Conventional and Low-TSNA Moist
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List of Subjects in 21 CFR Part 1132
Administrative practice and procedure, Incorporation by reference,
Labeling, Smokeless tobacco, Tobacco products.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that chapter I of title 21 of the Code of Federal Regulations
be amended by adding part 1132 to subchapter K to read as follows:
PART 1132--PRODUCT STANDARD: DETERMINATION OF N-NITROSONORNICOTINE
(NNN) LEVEL IN FINISHED SMOKELESS TOBACCO PRODUCTS
Subpart A--General Provisions
1132.1 Scope.
1132.3 Definitions.
1132.5 Incorporation by reference.
Subpart B--Product Requirements
1132.10 NNN Level.
1132.12 Product testing.
1132.14 Standard test method.
1132.16 Alternative test method.
1132.18 Sampling plans and procedures.
1132.20 Expiration date.
1132.22 Nonconforming product.
Subpart C--Labeling and Recordkeeping Requirements
1132.30 Package label requirements.
1132.32 Recordkeeping requirements.
Authority: 21 U.S.C. 331, 371, 374, 387b, 387c, 387f(d), 387g,
387i.
Subpart A--General Provisions
Sec. 1132.1 Scope.
(a) This part sets forth the requirements for the maximum level of
N-nitrosonornicotine (NNN) in finished smokeless tobacco products. The
provisions of this standard apply to finished smokeless tobacco
products as defined in Sec. 1132.3.
(b) No person may manufacture, distribute, sell, or offer for sale
or distribution within the United States a
[[Page 8048]]
finished smokeless tobacco product that is not in compliance with this
part.
(c) Tobacco retailers and distributors will not be considered in
violation of this part as it relates to the sale or distribution or
offer for sale or distribution of finished smokeless tobacco products
that exceed the NNN level set forth in Sec. 1132.10 if they:
(1) Store and transport the finished smokeless tobacco products
according to the package label;
(2) Do not sell or distribute or offer for sale or distribution
finished smokeless tobacco products past their expiration date, except
to return expired products to the manufacturer;
(3) Do not conceal, alter, or remove the expiration date or storage
conditions on the package label; and
(4) Do not sell or distribute or offer for sale or distribution
finished smokeless tobacco products that are open or have broken seals.
Sec. 1132.3 Definitions.
For purposes of this part:
Batch means a specific identified amount of a finished smokeless
tobacco product produced in a unit of time or quantity and that is
intended to have the same characteristics.
Commercial distribution means any distribution of a finished
smokeless tobacco product to consumers or to another person through
sale or otherwise, but does not include interplant transfers of a
tobacco product between registered establishments within the same
parent, subsidiary, and/or affiliate company, nor does it include
providing a tobacco product for product testing where such product is
not made available for consumption or resale.
Finished smokeless tobacco product means a smokeless tobacco
product, including all parts and components, packaged for consumer use,
except for components, parts, or accessories sold without tobacco. An
example of a finished smokeless tobacco product is a tin or can of
loose snuff or a pouch containing chewing tobacco.
Manufacturing code means any distinctive sequence or combination of
letters, numbers, or symbols that begins with the manufacturing date in
2-digit numerical values in the month, day, year format (mmddyy)
followed by the batch number from which the production batch can be
identified.
Manufacturing date means the month, day, and year that a smokeless
tobacco product is packaged for consumer use (i.e., when the package
label has been added to the product).
N-nitrosonornicotine (NNN) means a tobacco-specific nitrosamine
(TSNA) with the chemical formula C[9]H[11]N[3]O.
New tobacco product means:
(1) Any tobacco product (including those products in test markets)
that was not commercially marketed in the United States as of February
15, 2007; or
(2) Any modification (including a change in design, any component,
any part, or any constituent, including a smoke constituent, or in the
content, delivery or form of nicotine, or any other additive or
ingredient) of a tobacco product where the modified product was
commercially marketed in the United States after February 15, 2007.
Package means a pack, box, carton, or container of any kind or, if
no other container, any wrapping (including cellophane), in which a
tobacco product is offered for sale, sold, or otherwise distributed to
consumers.
Performance criteria means the validation requirements for the
acceptability of an analytical test method, including accuracy,
precision, recovery, linearity, specificity, limit of quantitation,
limit of detection, robustness, and range.
Person includes an individual, partnership, corporation, or
association.
Rework means the processing of nonconforming finished smokeless
tobacco products to meet the requirements of this part.
Smokeless tobacco means any tobacco product that consists of cut,
ground, powdered, or leaf tobacco and that is intended to be placed in
the oral or nasal cavity.
Source data means all information contained in original laboratory
records or exact copies of original records of experimental findings,
observations, or other activities used for the creation,
reconstruction, and evaluation of a study or other laboratory work.
Source data includes any laboratory worksheets, notebooks,
correspondence, notes, and other documentation (regardless of capture
medium) that are the result of original observations and activities of
a laboratory study or other laboratory work.
Tobacco product, as stated in section 201(rr) of the Federal Food,
Drug, and Cosmetic Act in relevant part:
(1) Means any product made or derived from tobacco that is intended
for human consumption, including any component, part, or accessory of a
tobacco product (except for raw materials other than tobacco used in
manufacturing a component, part, or accessory of a tobacco product);
and
(2) Does not mean an article that is a drug defined in section
201(g)(1) of the Federal Food, Drug, and Cosmetic Act, a device defined
in section 201(h) of the Federal Food, Drug, and Cosmetic Act, or a
combination product described in section 503(g) of the Federal Food,
Drug, and Cosmetic Act.
Tobacco product manufacturer means any person, including a repacker
or relabeler, who:
(1) Manufactures, fabricates, assembles, processes, or labels a
tobacco product; or
(2) Imports a finished tobacco product for sale or distribution in
the United States.
Tobacco-specific nitrosamine (TSNA) means a chemical compound
formed through the chemical reaction involving the nitrosation of
nicotine, nornicotine, anabasine, or anatabine during the growing,
curing, processing, or storage of tobacco.
United States means the 50 States of the United States of America
and the District of Columbia, the Commonwealth of Puerto Rico, Guam,
the Virgin Islands, American Samoa, Wake Island, Midway Islands,
Kingman Reef, Johnston Atoll, the Northern Mariana Islands, and any
other trust territory or possession of the United States.
Sec. 1132.5 Incorporation by reference.
(a) The Director of the Federal Register approves this material for
incorporation by reference into this part in accordance with 5 U.S.C.
552(a) and 1 CFR part 51. You may obtain a copy of the material from
the sources listed below. You may inspect a copy at the U.S. Food and
Drug Administration, Division of Dockets Management, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852 or 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.
(b) Center for Tobacco Products, U.S. Food and Drug Administration,
10903 New Hampshire Ave., Silver Spring, MD 20993; 1-888-463-6332.
(1) ``Determination of N-nitrosonornicotine (NNN) in Smokeless
Tobacco and Tobacco Filler by HPLC-MS/MS,'' LIB No. 4620, January 2017;
into Sec. 1132.14. (Also available at https://www.fda.gov/ScienceResearch/FieldScience/ucm231463.htm.)
(2) [Reserved]
Subpart B--Product Requirements
Sec. 1132.10 NNN level.
The mean level of NNN in any batch of finished smokeless tobacco
product
[[Page 8049]]
must not exceed 1.0 microgram per gram ([micro]g/g) of tobacco (on a
dry weight basis) at any time through the product's labeled expiration
date as determined by testing in compliance with Sec. 1132.12.
Sec. 1132.12 Product testing.
(a) Stability testing. Each tobacco product manufacturer must
conduct testing to assess the stability of the NNN level in its
finished smokeless tobacco products. The results of stability testing
must be used to establish and verify the product's expiration date and
storage conditions (either room temperature or refrigeration).
(1) Test method. The manufacturer must use either the standard test
method in Sec. 1132.14 or an alternative test method that meets the
requirements set forth in Sec. 1132.16. Samples for testing must be
selected in accordance with the requirements set forth in Sec.
1132.18(a) and (c).
(2) Written protocol. Each manufacturer must establish and maintain
a written protocol that addresses all stability testing. The protocol
must fully describe the methodology used to determine the stability of
the NNN level, including the test method used (the standard test method
in Sec. 1132.14 or an alternative test method in accordance with Sec.
1132.16), the sampling plan and procedures required by Sec. 1132.18(a)
and (c), and the storage conditions.
(3) Initial stability testing. A manufacturer must conduct initial
real-time stability testing that covers each finished smokeless tobacco
product and use the results to establish an expiration date and
appropriate storage conditions (either room temperature or
refrigeration) for the product. The expiration date and storage
conditions must be displayed on the package label in accordance with
Sec. 1132.30.
(i) For initial real-time stability testing, at a minimum, samples
must be tested within 7 days of manufacture and at the expected
expiration date.
(A) If the proposed storage condition is room temperature, samples
for initial real-time stability testing must be stored at 25 2 degrees Celsius and 60 5% relative humidity.
(B) If the proposed storage condition is refrigeration, samples for
initial real-time stability testing must be stored at 5 2
degrees Celsius.
(ii) If initial real-time stability testing is in progress but not
yet complete, the manufacturer may concurrently conduct accelerated
stability testing to establish the product's expiration date and
storage conditions. The manufacturer may use an expiration date of no
longer than 1 year based on initial accelerated stability testing.
(iii) For initial accelerated stability testing, at a minimum,
samples must be tested at three time points within a 6 month period.
The first time point must be within 7 days of manufacture and the last
time point at 6 months after manufacture.
(A) If the proposed storage condition is room temperature, samples
for initial accelerated stability testing must be stored at 40 2 degrees Celsius and 75 5% relative humidity.
(B) If the proposed storage condition is refrigeration, samples for
initial accelerated stability testing must be stored at 25
2 degrees Celsius and 60 5% relative humidity.
(iv) If initial accelerated stability testing shows the NNN level
in the finished smokeless tobacco products will not conform to Sec.
1132.10, the manufacturer must establish an expiration date and storage
conditions, as determined by the results of initial real-time stability
testing.
(4) Annual stability testing. A manufacturer must conduct annual
real-time stability testing on each finished smokeless tobacco product
to verify the results of the initial stability testing and to ensure
that the expiration date and storage conditions remain appropriate.
Accelerated stability testing may not be used for annual stability
testing.
(i) Except as provided in paragraph (a)(4)(ii) of this section,
annual real-time stability testing must begin within 12 months of the
completion of initial stability testing and then annually thereafter,
with no longer than 12 months between testing.
(ii) When a manufacturer has not conducted initial real-time
stability testing on a particular smokeless tobacco product because it
has determined that the results from initial real-time stability
testing conducted on another product apply, annual real-time stability
testing must begin when the product is first released for commercial
distribution and then annually thereafter, with no longer than 12
months between testing.
(iii) For annual real-time stability testing, at a minimum, samples
must be tested within 7 days of manufacture and at the established
expiration date.
(A) If the intended storage condition is room temperature, samples
for annual real-time stability testing must be stored at 25 2 degrees Celsius and 60% 5% relative humidity.
(B) If the intended storage condition is refrigeration, samples for
annual real-time stability testing must be stored at 5 2
degrees Celsius.
(iv) If the results of the most recent annual real-time stability
testing do not support the finished smokeless tobacco product's
expiration date, the manufacturer must use those results to establish a
new expiration date. After a new expiration date has been established,
the package labels of all affected finished smokeless tobacco products
that have not been released for commercial distribution must display
the new expiration date and storage conditions, in accordance with
Sec. 1132.30.
(v) If the finished smokeless tobacco product's expiration date
must be shortened due to the results of the annual real-time stability
testing, the manufacturer must conduct an investigation to determine
why the results of the most recent stability testing do not support the
product's previously established expiration date. The investigation
must be fully documented and the records maintained in accordance with
Sec. 1132.32.
(b) Batch testing. Tobacco product manufacturers must conduct
testing on each batch of finished smokeless tobacco product to ensure
that the products conform with Sec. 1132.10. The manufacturer must use
either the standard test method in Sec. 1132.14 or an alternative test
method that meets the requirements set forth in Sec. 1132.16. Samples
for testing each batch to determine if a product conforms with Sec.
1132.10 must be selected in accordance with the requirements set forth
in Sec. 1132.18(b) and (c).
(c) Documentation of test results. A full report of the source data
and results of all stability and batch testing must be maintained by
the tobacco product manufacturer in accordance with Sec. 1132.32,
including the following:
(1) Full identification of the smokeless tobacco product that is
the subject of the report, including product subcategory, brand,
subbrand, package size and quantity of product (mass and, if portioned,
count) and, for portioned tobacco products, the size (mass) of each
portion;
(2) NNN level of each sample tested;
(3) Mean NNN level and standard deviation;
(4) The batch manufacturing date and location, including facility
name and address;
(5) The location, including facility name and address, from which
each sample was pulled;
(6) The manufacturing code of each sample tested or, for samples
for initial stability testing with no manufacturing code, an
identifying code created by the manufacturer;
[[Page 8050]]
(7) The testing date and location, including the testing facility
name and address;
(8) The test method and sampling procedure used;
(9) All tobacco product reference standard test results;
(10) The names and qualifications of the person(s) conducting the
testing;
(11) The equipment used (including documentation to show that the
equipment is appropriate for its intended use and has been calibrated);
and
(12) For batch testing only, the criteria used to make a decision
to accept or reject each batch and the decision made with respect to
each batch (e.g., accept, reject) based on the results of the product
testing, including, where applicable, the NNN level of the individual
batch, the results of the product's stability testing, and the decision
made and justification with respect to the results of a nonconforming
product investigation under Sec. 1132.22.
Sec. 1132.14 Standard test method.
(a) The standard test method for this part is the method entitled
``Determination of N-nitrosonornicotine (NNN) in Smokeless Tobacco and
Tobacco Filler by HPLC-MS/MS,'', incorporated by reference in Sec.
1132.5.
(b) In the event of an inconsistency between a material
incorporated by reference and the definitions and methods described in
this part, definitions and methods in this part will apply.
Sec. 1132.16 Alternative test method.
Tobacco product manufacturers may use a validated alternative test
method in accordance with this section, only if the alternative method
meets or exceeds the performance criteria of the standard test method
set forth in Sec. 1132.14.
(a) Notice requirement. Tobacco product manufacturers who intend to
use a validated alternative test method to that listed in Sec. 1132.14
for determining conformance with Sec. 1132.10 must notify the
Director, Office of Science, Center for Tobacco Products, before
beginning use of the alternative test method. Manufacturers may begin
using the alternative test method 60 calendar days after FDA receives
the notification as set forth in paragraph (f) of this section unless
FDA notifies the manufacturer that the alternative test method has not
been demonstrated to meet or exceed the performance criteria of the
standard test method set forth in Sec. 1132.14.
(b) Contents of notification of an alternative test method. The
manufacturer must include in the notification of an alternative test
method the following information:
(1) General information. The following information must be
submitted using the form that FDA provides:
(i) The date the manufacturer submitted the notification to FDA;
(ii) Identification of the submission as a notification of an
alternative test method;
(iii) The manufacturer's name, address, and contact information;
(iv) Identification of and contact information for an authorized
representative of the manufacturer (which could be a U.S. agent for the
manufacturer), including name, address (mailing and email), and
telephone number;
(v) Identification of the subcategories of finished smokeless
tobacco products that can be analyzed using the alternative test
method; and
(vi) The testing facility's name and address.
(2) Index and table of contents. A comprehensive index and table of
contents.
(3) Summary. The notification must include a summary section that
contains the following information:
(i) Identification of the standard test method for which the
alternative test method is being proposed;
(ii) A concise description of the performance criteria of the
alternative test method;
(iii) A concise explanation of why the manufacturer is proposing to
use the alternative test method; and
(iv) A concise comparison of the similarities and differences
between the alternative test method and the standard test method.
(4) Complete description. The notification must describe the
alternative test method in sufficient detail to enable FDA to evaluate
whether the information provided demonstrates that the alternative test
method meets or exceeds the performance criteria of the standard test
method set forth in Sec. 1132.14. This description must include:
(i) A complete description of the manner in which the alternative
test method is proposed to deviate from the standard test method and a
complete explanation, with scientific rationale and supported by
appropriate data, including a complete copy of the testing protocol, to
demonstrate that the alternative test method meets or exceeds the
performance criteria of the standard test method set forth in Sec.
1132.14; and
(ii) Any data and information from other studies comparing the
alternative test method to the standard test method.
(c) Relevant information. If requested by FDA, the manufacturer
must submit any other relevant information needed to evaluate the
alternative test method.
(d) Format for notifications of an alternative test method.
(1) General requirements. All notifications must be submitted using
the form that FDA provides and must be well-organized and legible, and
written in English.
(2) Electronic format requirement. Except as provided in paragraph
(d)(3) of this section, notifications of an alternative test method
must be submitted using the Agency's electronic system. The
notification and all supporting information must be in an electronic
format that the Agency can process, review, and archive.
(3) Waivers from electronic format requirement. If a notification
cannot be submitted electronically, a waiver may be requested. Waivers
will be granted only if use of electronic means is not reasonable for
the tobacco product manufacturer requesting the waiver. If FDA grants
the waiver request, FDA will provide information on where to send the
notification in paper form. To request a waiver, manufacturers must
send a written request that is legible and in English to the Document
Control Center (ATTN: Office of Science) at the address included on our
Web site. The written request must contain the following information:
(i) The name and address of the tobacco product manufacturer that
wishes to submit the notification, the name of an authorized
representative of the manufacturer (which could be a U.S. agent for the
manufacturer), and their contact information.
(ii) A statement that creation and/or submission of information in
electronic format is not reasonable for the manufacturer requesting the
waiver, and an explanation of why creation and/or submission in
electronic format is not reasonable. This statement must be signed by a
person who is authorized to make the declaration on behalf of the
tobacco product manufacturer.
(e) Applicability of an alternative test method. An alternative
test method may be implemented only by the tobacco product manufacturer
that submitted the notification and only with respect to the
subcategories of finished smokeless tobacco products that were the
subject of the notification. Other manufacturers interested in similar
or identical alternative test methods must submit their own
notifications following the procedures of this section.
(f) Action on notifications. FDA will acknowledge the receipt of a
notification of an alternative test
[[Page 8051]]
method. Manufacturers may implement an alternative test method
beginning 60 calendar days after FDA receives the notification of
alternative test method unless FDA notifies them otherwise.
(1) If a notification is complete when received, the 60 calendar
day period begins on the date FDA receives the notification.
(2) If any element required under paragraph (b) of this section is
missing from a notification, FDA will not accept the notification
submission and will inform the manufacturer.
(3) If FDA determines that an alternative test method has not been
demonstrated to meet or exceed the performance criteria of the standard
test method set forth in Sec. 1132.14, FDA will inform the submitter.
If FDA informs the submitter during the 60 calendar day period, the
submitter must not implement the alternative test method. If FDA
determines that an alternative test method does not comply with this
section after the 60 calendar day period, FDA will provide a written
determination to the submitter and the submitter must immediately cease
using the alternative test method.
(4) Acceptance of a notification submission does not constitute a
finding by the Agency that the alternative test method meets or exceeds
the performance criteria of the standard test method set forth in Sec.
1132.14.
Sec. 1132.18 Sampling plans and procedures.
(a) Sampling plan for stability testing. Each tobacco product
manufacturer must design and implement a sampling plan or plans for all
stability testing required in Sec. 1132.12(a) based on a valid
statistical rationale to demonstrate that the finished smokeless
tobacco product's expiration date is appropriate under the intended
storage conditions. The sampling plan must ensure that samples taken
are representative and randomly selected. To account for the
variability of the NNN in smokeless tobacco products, the following
factors must be based on adequate statistical criteria: The confidence
intervals, the level of necessary precision, and the number of finished
products sampled. Each sampling plan must fully describe the sampling
methodology, with scientific rationale, incorporate all sources of
variability (including variability of the analytic method and NNN
levels), and describe the sample size needed (including a full
description of how the sample size is calculated) consistent with the
sampling design to achieve the sampling objective.
(b) Sampling plan for batch testing. Each tobacco product
manufacturer must design and implement a sampling plan or plans for all
batch testing required in Sec. 1132.12(b) based on a valid statistical
rationale to ensure that the finished smokeless tobacco product
consistently conforms to the NNN level set forth in Sec. 1132.10. The
sampling plan must ensure that samples taken are representative of an
entire batch and are randomly selected and collected from each batch
for testing. To account for the variability of NNN in the finished
smokeless tobacco products, the following factors must be based on
adequate statistical criteria: The confidence intervals, the level of
necessary precision, and the number of finished products sampled. The
sampling plan must take into account the manufacturing quality history
of the manufacturer. Each sampling plan must fully describe the
sampling methodology, with scientific rationale, incorporate all
sources of variability (including variability of the analytic method
and the NNN levels), and describe the sample size needed (including a
full description of how the sample size is calculated) consistent with
the sampling design to achieve the sampling objective. The sampling
plan must also fully describe the criteria the manufacturer will use to
make a decision to accept or reject each batch.
(c) Sampling procedures. Test samples must be collected and
examined in accordance with the following procedures:
(1) Test samples for initial real-time and accelerated stability
testing are to consist of:
(i) Smokeless tobacco product that has been manufactured using the
same production processes as products manufactured for consumer use and
packaged in the identical package that will be used for the finished
smokeless tobacco product, but it need not have the product package
label; or
(ii) Finished smokeless tobacco product as it is intended to be
sold or distributed to consumers.
(2) Test samples for annual real-time stability testing and batch
testing are to consist of the finished smokeless tobacco product as it
is intended to be sold or distributed to consumers and not of a
separate production sample.
(3) All test samples must be stored according to the intended
storage conditions for the finished smokeless tobacco product, except
that test samples for initial accelerated stability testing must be
stored in accordance with Sec. 1132.12(a)(3)(iii). A tobacco product
manufacturer must include all of its factories, stock rooms,
warehouses, and other locations containing finished smokeless tobacco
products in the population to be sampled.
(4) Test samples for stability testing must be taken within 7 days
of the manufacturing date and tested in accordance with Sec.
1132.12(a). Test samples for batch testing must be taken from each
batch and tested within 30 calendar days of the manufacturing date. The
amount of material acquired during sampling must be sufficient for the
test methods in Sec. Sec. 1132.14 or 1132.16, including any repeats
that may be necessary (e.g., because test material was damaged prior to
or during analysis). Samples must be randomly selected in accordance
with the applicable sampling plan and the samples must be taken within
the same day.
(5) Sampling must be performed by persons who have sufficient
education, training, and experience to accomplish the assigned
functions.
(6) Each test sample must be identified so that the following
information can be determined:
(i) Full identification of the smokeless tobacco product sampled,
including product subcategory, brand, subbrand, package size and
quantity of product (mass and, if portioned, count) and, for portioned
tobacco products, the size (mass) of each portion;
(ii) The manufacturing code or, for samples for initial stability
testing with no manufacturing code, an identifying code created by the
manufacturer;
(iii) The date on which the sample was taken;
(iv) The sampling location (including the address of the facility
and specific location within the facility where the sample was taken);
(v) The name of the person(s) who collected the sample; and
(vi) The location where the sample will be stored and tested
(including the facility name and address).
(7) Samples sent for testing must be packed securely with adequate
protection against damage (e.g., mechanical damage, severe changes in
humidity or temperature) and sent to the testing facility by the most
expeditious means, arriving no later than 3 calendar days after
shipment. A list of the samples in each shipment must be sent to the
testing facility under separate cover.
(8) All samples for a specific stability or batch test must be
tested at the same facility.
(9) Once test samples arrive at the testing facility they must be
inspected, accounted for, and stored under the finished smokeless
tobacco product's intended storage conditions (e.g., room temperature
or refrigeration) except that
[[Page 8052]]
test samples for initial accelerated stability testing must be stored
in accordance with Sec. 1132.12(a)(3)(iii), and a report that includes
the following information must be generated for the stability or batch
test and be maintained by the tobacco product manufacturer in
accordance with Sec. 1132.32:
(i) Full identification of the smokeless tobacco product, including
product subcategory, brand, subbrand, package size and quantity of
product (mass and, if portioned, count) and, for portioned tobacco
products, the size (mass) of each portion;
(ii) The manufacturing code or, for samples for initial stability
testing with no manufacturing code, an identifying code created by the
manufacturer;
(iii) The date on which samples were taken, if available;
(iv) The locations where samples were drawn (including the address
and specific locations within any facilities where samples were taken),
if available;
(v) The number of test samples drawn;
(vi) Complete records of the samples received and tested, including
the date of receipt, the identifier of all persons who tested the
samples, and the test results.
(10) For batch testing only, each batch must be withheld from
commercial distribution until it has been sampled and tested, and a
decision has been made by the tobacco product manufacturer that it may
be released for commercial distribution.
Sec. 1132.20 Expiration date.
All finished smokeless tobacco products must have an expiration
date established by stability testing. The expiration date must be set
no later than the final date the manufacturer can demonstrate the
finished smokeless tobacco product conforms to Sec. 1132.10 when
stored under its intended conditions (e.g., room temperature or
refrigeration).
Sec. 1132.22 Nonconforming product.
(a) General requirements. Tobacco product manufacturers must
establish and maintain procedures to identify, investigate, segregate,
and make disposition decisions about nonconforming finished smokeless
tobacco products in order to prevent their release for commercial
distribution.
(b) Investigation. The tobacco product manufacturer must conduct an
investigation to determine the extent of the nonconformity and, as
applicable, the locations where the nonconforming products have been
distributed if the mean of the representative samples from any batch of
finished smokeless tobacco product is determined to be out of
conformance with the requirements of Sec. 1132.10, or a finished
smokeless tobacco product's expiration date must be shortened due to
the results of annual real-time stability testing, or if FDA notifies a
tobacco product manufacturer that a distributed finished smokeless
tobacco product does not conform to the requirements of this part. The
investigation must include, but is not limited to, examination of all
relevant processes, operations, records, complaints, any corrective
actions taken, and any other relevant sources of information concerning
the nonconforming product. The investigation must be fully documented,
including any materials reviewed, name of the person(s) making the
disposition decisions, justification for the disposition decisions,
results of retesting, decisions with respect to reworking, and followup
resulting from the investigation.
(c) Rejection of nonconforming product. Tobacco product
manufacturers must reject a batch of a finished smokeless tobacco
product if the mean of the representative samples from the batch does
not conform to the requirements of this part unless a disposition
decision and justification to release the batch is made after an
investigation shows that the batch meets the requirements of this part.
(d) Rework of nonconforming product. If appropriate, a manufacturer
may rework a batch of a finished smokeless tobacco product that does
not conform to the requirements of this part. The reworked batch of
finished smokeless tobacco product must be determined to conform to all
the requirements of this part with a disposition decision and
justification before it may be released for commercial distribution.
Subpart C--Labeling and Recordkeeping Requirements
Sec. 1132.30 Package label requirements.
The package of a finished smokeless tobacco product must have a
label that includes the manufacturing code, expiration date, and, if
applicable, storage conditions for the smokeless tobacco product as
follows:
(a) The information must be printed on or permanently affixed to
the package in a manner that assures it will remain on the packaging or
label through the expected duration of use of the product by the
consumer. It must appear clearly, legibly, and indelibly in the English
language.
(b) The expiration date must appear on the packaging in two-digit
numerical values in the following format: ``Expires on month/day/
year.''
(c) If the manufacturer determines by stability testing that meets
the requirements in Sec. 1132.12 that the finished smokeless tobacco
product must be stored in a refrigerator, the package label must state
``Keep Refrigerated.''
(d) It must be possible to determine from the manufacturing code
the history of the manufacturing, processing, packaging, labeling,
holding, and initial distribution of the product from records
maintained by the tobacco product manufacturer.
Sec. 1132.32 Recordkeeping requirements.
(a) Each facility that manufactures tobacco products subject to
this part must establish and maintain records of the following
information:
(1) Full documentation of stability testing protocols and the
results of initial and annual stability testing under Sec. 1132.12(a),
including all information specified in Sec. 1132.12(c);
(2) All investigations under Sec. 1132.12(a)(4)(v);
(3) The source data and results of batch testing conducted to
determine conformance with Sec. 1132.10, including all information
specified in Sec. 1132.12(c);
(4) All notifications of an alternative test method and all related
correspondence under Sec. 1132.16;
(5) All source data for alternative test method validation;
(6) All sampling plans and reports under Sec. 1132.18;
(7) Documentation that the persons performing sampling under Sec.
1132.18 have sufficient education, training, and experience to
accomplish the assigned functions;
(8) All identification, investigation, segregation, and disposition
decision procedures under Sec. 1132.22(a); and
(9) All nonconforming product investigations and rework under Sec.
1132.22(b) and (d).
(b) The records must be legible and written in English. Documents
that have been translated from a foreign language into English must be
accompanied by the foreign language version of the document and a
certification by the manufacturer's authorized representative (which
could be a U.S. agent for the manufacturer) that the English language
translation is complete and accurate. All records must be readily
available for inspection and copying or other means of reproduction by
FDA upon request during an inspection. Requested records that are
maintained offsite must be made available within 24 hours or, if that
is not feasible, as soon as possible before
[[Page 8053]]
the close of the inspection. Records that can be immediately retrieved
from another location, including by computer or other electronic means,
meet the requirements of this paragraph.
(c) Copies of all records required under this part must be retained
for a period of not less than 4 years from the date of commercial
distribution of the finished smokeless tobacco product that is the
subject of the record, or, for records relating to alternative test
methods under Sec. 1132.16, for a period of not less than 4 years
after the last date the method that is the subject of the record is
used.
Dated: January 12, 2017.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2017-01030 Filed 1-19-17; 8:45 am]
BILLING CODE 4164-01-P
