Document ID: FDA-2016-N-2527-0001
Agency: fda
Document Type: Proposed Rule
Title: Tobacco Product Standard for N-Nitrosonornicotine Level in Finished Smokeless Tobacco Products
Posted Date: 2017-01-23T05:00Z

[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.

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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: http://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to http://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 http://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 http://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 http://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: http://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 http://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

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

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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.

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).
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    \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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    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

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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.
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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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 http://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 http://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 http://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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Sheet: The Delaney Paradox and Negligible Risk,'' January 1990.
205. National Research Council, ``Review of the Army's Technical 
Guides on Assessing and Managing Chemical Hazards to Deployed 
Personnel.'' Washington, DC: The National Academies Press, 2004, 
available at www.nap.edu/catalog/10974/html.
206. Stepanov, I., S.S. Hecht, S. Ramakrishnan, et al., ``Tobacco-
specific Nitrosamines in Smokeless Tobacco Products Marketed in 
India,'' International Journal of Cancer, 116(1):16-19, 2005.
207. Menzie Cura Associates, Inc., ``Estimating Risk to Cigarette 
Smokers From Smoke Constituents in Proposed `Testing and Reporting 
of Constituents of Cigarette Smoke' Regulations,'' August 1999. 
Prepared for: Massachusetts Tobacco Control Program, Boston, 
Massachusetts.
208. Fowles, J. and M. Bates, ``The Chemical Constituents in 
Cigarettes and Cigarette Smoke: Priorities for Harm Reduction,'' A 
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Assessment Principles to the Chemical Constituents of Cigarette 
Smoke,'' Tobacco Control, 12(4):424-430, 2003.
210. Watanabe, K.H., M.V. Djordjevic, S.D. Stellman, et al., 
``Incremental Lifetime Cancer Risks Computed for Benzo[a]pyrene and 
Two Tobacco-specific N-nitrosamines in Mainstream Cigarette Smoke 
Compared with Lung Cancer Risks Derived from Epidemiologic Data,'' 
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``Calculated Cancer Risks for Conventional and `Potentially Reduced 
Exposure Product' Cigarettes,'' Cancer Epidemiology Biomarkers & 
Prevention, 16(3):584-592, 2007.
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Salivary Cotinine Concentrations Among Smokeless Tobacco Users,'' 
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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 http://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 http://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