# Tobacco Product Standard for N-Nitrosonornicotine Level in Finished Smokeless Tobacco Products

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URL: https://www.frixlaw.com/law-library/documents/fr%3A2017-01030

## Record

- **Collection:** Federal Register
- **Document type:** Proposed Rule
- **Published:** January 23, 2017
- **Citation:** 82 FR 8004

## Text

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 1132
[Docket No. FDA-2016-N-2527]
Tobacco Product Standard for N-Nitrosonornicotine Level in Finished Smokeless Tobacco Products

AGENCY:

Food and Drug Administration, HHS.

ACTION:

Proposed rule.

SUMMARY:

The Food and Drug Administration (FDA) is proposing a tobacco product standard that would establish a limit of N-nitrosonornicotine (NNN) in finished smokeless tobacco products. FDA is taking this action because NNN is a potent carcinogenic agent found in smokeless tobacco products and is a major contributor to the elevated cancer risks associated with smokeless tobacco use. Because products with higher NNN levels pose higher risks of cancer, FDA finds that establishing a NNN limit in finished smokeless tobacco products is appropriate for the protection of the public health.

DATES:

Submit either electronic or written comments on the proposed rule by April 10, 2017. In accordance with 21 CFR 10.40(c), in finalizing this rulemaking FDA will review and consider all comments submitted before the time for comment on this proposed regulation has expired. If your comment is submitted after the expiration of the comment period, it will not be reviewed and considered by FDA unless you apply for, and receive, an extension of the comment period pursuant to 21 CFR 10.40(b)(3). Submit comments on information collection issues under the Paperwork Reduction Act of 1995 (the PRA) by February 22, 2017, (see the “Paperwork Reduction Act of 1995” section). See section VII of this document for the proposed effective date of a final ruled based on this document.

ADDRESSES:

You may submit comments as follows:

Electronic Submissions

Submit electronic comments in the following way:

•
Federal eRulemaking Portal: 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

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 (μg/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

annualized value over 20 years of quality adjusted life-years gained from reduced oral cancer mortality ranges from $228.66 million to $2.46 billion at a 3 percent discount rate, with a primary value of $858.46 million. Using a 7 percent discount rate, the annualized value of quality life-years gained from averted deaths ranges from $182.01 million to $1.96 billion, with a primary value of $683.34 million. The primary estimate of the present value of mortality reductions quantified over 20 years is $12.77 billion at a 3 percent discount rate and $7.24 billion at a 7 percent discount rate. The annualized value over 20 years of quality adjusted life-years gained from reduced oral cancer mortality and morbidity ranges from approximately $283.95 million to $3.05 billion at a 3 percent discount rate, with a primary value of $1.06 billion, and approximately $246.40 million to $2.65 billion, with a primary value of $0.92 billion at a 7 percent discount rate. The primary estimate of the present value of total quantified benefits over 20 years is approximately $15.86 billion at a 3 percent discount rate and $9.80 billion at a 7 percent discount rate for reductions in oral cancer alone. These values are likely an underestimate of the benefits associated with the proposed rule, as we do not quantify reductions in mortality and morbidity from cancers other than oral cancer. Costs and benefits are summarized in table 8 of the preamble of the proposed rule.

II. Background Information

A. Purpose

FDA is issuing this proposed rule to address the harm caused by the toxicant NNN in smokeless tobacco products. When Congress enacted the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) in 2009, it included the finding that “the Food and Drug Administration is a regulatory agency with the scientific expertise to identify harmful substances in products to which consumers are exposed, [and] to design standards to limit exposure to those substances” (section 2(44) of the Tobacco Control Act).

Smokeless tobacco products, including those currently marketed in the United States, have been demonstrated to cause certain types of cancer. Several authoritative reviews have been conducted on the relationship between smokeless tobacco use and cancer risk and have reached similar conclusions (Refs. 1, 2, 3, 4). The International Agency for Research on Cancer (IARC) concluded in its 2007 monograph “Smokeless Tobacco and Some Tobacco-Specific Nitrosamines” that there is sufficient evidence in humans to indicate that smokeless tobacco is carcinogenic and that it causes oral and pancreatic cancer (Ref. 1). IARC confirmed these findings of the carcinogenicity of smokeless tobacco in a 2012 review, concluding that there is sufficient evidence in both humans and experimental animal studies that smokeless tobacco causes oral, esophageal, and pancreatic cancer (Ref. 2). In addition, a 2014 report on smokeless tobacco by the National Cancer Institute (NCI) and Centers for Disease Control and Prevention (CDC) estimated that smokeless tobacco use is responsible for approximately 1,600 new cases of oral cancer, 200 cases of esophageal cancer, and 500 cases of pancreatic cancer in the United States each year (Ref. 4).

NNN
1

is a potent carcinogenic agent found in smokeless tobacco products and is a major contributor to the elevated cancer risks associated with smokeless tobacco use (see section IV, Rationale for Developing a Standard for NNN, of this document). NNN levels vary substantially across subcategories of smokeless tobacco products (
e.g.,
moist snuff, chewing tobacco, dry snuff) and within product subcategories (
e.g.,
moist snuff) (Ref. 5, 10). International comparisons of oral cancer rates and smokeless tobacco products suggest that products with higher NNN levels may pose higher risks of cancer (Refs. 6, 100). FDA is using its authority to propose a standard that would reduce tobacco-related harms by establishing a limit of NNN in smokeless tobacco products sold in the United States (see section V of this document).

1
Since 2012, manufacturers have been required to test and report to FDA the levels of harmful and potentially harmful constituents (HPHCs), including NNN, in each tobacco product (section 904(A)(3) of the FD&C Act).

FDA is proposing that the standard would apply to finished smokeless tobacco products. Although NNN is also found in other tobacco products, this rule focuses solely on NNN levels in smokeless tobacco products, and not on additional products. Different measures are required to evaluate the contribution to cancer of NNN among users of other tobacco products, such as combustible products like cigarettes and dissolvable tobacco products that do not meet the statutory definition of “smokeless tobacco product.” For example, additional factors, such as polycyclic aromatic hydrocarbons (PAH), aldehydes and other chemicals (Refs. 147, 106), contribute to the cancer burden associated with combustible products, which make the relationship between NNN and cancer in these products different from that in smokeless tobacco products. With regard to dissolvable tobacco products that do not meet the statutory definition of smokeless tobacco, different product testing methods than the ones developed and available for smokeless tobacco, as described in this proposal, may be necessary to evaluate NNN in these products because they do not consist of cut, ground, powdered or leaf tobacco. Therefore, at this stage, FDA has chosen to focus on smokeless tobacco and has evaluated data relevant to establishing an NNN limit in smokeless tobacco products.

This proposed product standard would require that the mean level of NNN in any batch of finished smokeless tobacco products not exceed 1.0 μg/g of tobacco (on a dry weight basis) at any time through the product's labeled expiration date as determined by testing in compliance with § 1132.12 (proposed § 1132.10). FDA expects that, in the 20 years following implementation of the proposed product standard, approximately 12,700 new cases of oral cancer and approximately 2,200 oral cancer deaths would be prevented in the United States because of this rule. Moreover, during that 20-year period, approximately 15,200 life years would be gained in the United States as a result of the proposed standard. We believe that the main source of variability in the estimated impacts would be different assumptions about oral cancer relative risks due to smokeless tobacco use. Using alternate relative risk estimates that are somewhat lower and higher than our main estimate results in approximately 7,300 to 24,000 new cases of oral cancer prevented and 1,300 to 4,200 oral cancer deaths prevented over the 20-year period. Because oral cancer is associated with significant health and economic impacts, we expect positive public health benefits due to prevention of new and fatal cancer cases. These benefits are discussed in detail in section V of this proposed rule. Accordingly, based on the information discussed in the following sections of the preamble to this proposed rule, FDA finds that the proposed standard would be appropriate for the protection of the public health.

B. Legal Authority

1. Product Standard

The Tobacco Control Act was enacted on June 22, 2009, amending the FD&C Act and providing FDA with the authority to regulate tobacco products (Pub. L. 111-31; 123 Stat. 1776). Among

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 § 1132.1(b)). However, tobacco retailers and distributors would not be considered in violation of part 1132 as it relates to the sale or distribution or offer for sale or distribution of finished smokeless tobacco products that exceed the NNN level required in proposed § 1132.10 if they: (1) Store and transport the finished smokeless tobacco products according to the package label, (2) do not sell or distribute or offer for sale or distribution finished smokeless tobacco products past their expiration date, except to return expired products to the manufacturer, (3) do not conceal, alter or remove the expiration date or storage conditions on the package label, and (4) do not sell or distribute or offer for sale or distribution finished smokeless tobacco products that are open or have broken seals (proposed § 1132.1(c)). FDA is proposing this exception for tobacco retailers and distributors because they are not in a position to know or to confirm by testing whether the smokeless tobacco products they are selling or distributing or offering for sale or distribution comply with the proposed NNN level.

FDA is also proposing, under these authorities, to require that the labels of finished smokeless tobacco products contain a manufacturing code, expiration date, and, if applicable, storage conditions for the finished smokeless tobacco product (proposed § 1132.30). The labeling requirement for storage conditions is also consistent with FDA's authority under section 907(a)(4)(C), which provides that a product standard shall, where 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

907(a)(4)(B) and 907(a)(4)(A)(iii) of the FD&C Act to ensure that finished smokeless tobacco products conform to the requirements of the product standard before they are distributed to consumers and remain in conformance until their expiration date. Section 907(a)(4)(B)(ii) provides that a product standard must, where appropriate for the protection of public health, include “provisions for the testing (on a sample basis or, if necessary, on an individual basis) of the tobacco product.” In addition, section 907(a)(4)(B)(iv) provides that, where appropriate for the protection of public health, a product standard must include provisions requiring that the results of the tests of the tobacco product required under section 907(a)(4)(B)(ii) show that the product is in conformity with the portions of the standard for which the tests were required.

Consistent with these statutory provisions, proposed §§ 1132.12, 1132.14, 1132.16, and 1132.18 would establish product testing and sampling plan requirements. Proposed § 1132.12 would require two types of testing for smokeless tobacco products—stability testing and batch testing. Proposed § 1132.12(a) would require testing to assess the stability of the NNN level in finished smokeless tobacco products and to establish and verify the product's expiration date and storage conditions (either room temperature or refrigeration). Proposed § 1132.12(b) would require manufacturers to conduct testing on each batch of finished smokeless tobacco product to determine whether the products conform to the proposed NNN level. Proposed § 1132.12(c) would require the tobacco product manufacturer to document all testing. Proposed §§ 1132.14 and 1132.16 would establish the standard and alternative test methods, while § 1132.18 would establish the sampling requirements for all testing.

Section 907(a)(4)(A)(iii) states that product standards must include provisions that are appropriate for the protection of the public health, including provisions, where appropriate, relating to any requirement under subparagraph 907(a)(4)(B). As discussed, FDA is proposing specific testing requirements in §§ 1132.12, 1132.14, 1132.16, and 1132.18. To support these proposed requirements, proposed § 1132.22(b) would require that if the mean of the representative samples from any batch of a finished smokeless tobacco product is determined to be out of conformance with the requirements of § 1132.10, or a finished smokeless tobacco product's expiration date must be shortened due 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

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 § 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).

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 μg/g wet weight
2

tobacco, which would be about 2 µg/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 °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 μg/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

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 States
1986
“In summary, users of smokeless tobacco products face a strongly increased risk of oral cancer, particularly for the tissues that come in contact with the tobacco.”

International Agency for Research on Cancer (IARC)
2007
“There is sufficient evidence in humans for the carcinogenicity of smokeless tobacco. Smokeless tobacco causes cancers of the oral cavity and pancreas.”

Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR)
2008
“STP [smokeless tobacco products] are carcinogenic to humans and the pancreas has been identified as a main target organ. All STP cause localised oral lesions and a high risk for development of oral cancer has been shown for various STP but the evidence for oral cancer in users of Swedish moist snuff (snus) is less clear.”

International Agency for Research on Cancer (IARC)
2012
“There is sufficient 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

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.

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).

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 °C can lead to increased NNN formation in air-cured Burley tobacco, and that the rate of increase becomes greater as the temperature is increased (Ref. 41). In addition, air-cured Burley tobacco stored at higher temperature (24 °C v. 32 °C) and higher relative humidity levels (70 v. 83 percent) showed increases in both nitrite and NNN levels (Ref. 52).

Similar to cured tobacco, high temperature, high humidity, and extended storage can cause levels of NNN to increase in smokeless tobacco products. As smokeless tobacco products “age,” the water content can change, leading to bacterial growth, and the pH and nicotine content can decrease, causing nitrosamine levels such as NNN to rise (Ref. 11).

Studies have shown that NNN increases in moist snuff and dry snuff when stored at 24 °C for 24 days (Refs. 53, 54). Exposing moist and dry snuff to ambient air, such as when a product is opened and closed between dips, also increases NNN concentrations (Ref. 53). Similar to cured tobacco leaves, the storage of moist snuff at low temperatures (4 °C) reduces the increase in NNN that was seen when the same product is stored at ambient conditions (Ref. 55).

Humidity levels during storage can have an even greater influence than temperature on NNN formation in finished smokeless tobacco products. Specifically, the NNN levels in moist and dry snuff can be increased just by raising the relative humidity during storage from 22 to 50 percent (Ref. 54). Moreover, the combined effects of humidity and temperature are enhanced in products with higher moisture content (Ref. 54). Yet, storage conditions do not have the same effect on all types of smokeless tobacco. Studies on storage of chewing tobacco did not show the same increase in NNN as seen with moist and dry snuff, which suggests that some tobacco blends may be less prone to producing nitrosamines during storage (Refs. 53, 54). Furthermore, although retailers are encouraged to refrigerate Swedish snus to maintain “perceived product freshness,” the product's low bacterial activity may stabilize the NNN level even when stored at room temperature (Ref. 11).

3. Levels of NNN in U.S. Smokeless Tobacco Products

The levels of NNN in smokeless tobacco products on the U.S. market can vary by several orders of magnitude, not only among different subcategories of products, but also among products in the same subcategory (table 2, Refs. 5, 10, 56). After measuring NNN levels in 46 different smokeless tobacco products available in the United States from 2006 and 2007, Borgerding et al. found NNN levels ranged from below the limit of quantification (0.02 μg/g) to 14.4 μg/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 μg/g per dry weight and 5.91 to 12.0 μg/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 μg/g per dry weight (Ref. 10). The NNN levels for moist snuff ranged from 1.0 to 9.5 μg/g per dry weight while the NNN levels for dry snuff ranged from 5.91 to 12.0 μg/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 µg/g per dry weight) with dry snuff ranging from 0.95 to 5.3 µg/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 µg/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 µg/g per dry weight) and in dry snuff (6.1 to 31 µg/g per wet weight which equates to 6.5 to 33 µg/g per dry weight) (Ref. 20).

Table 2—NNN Concentration and Market Share of Smokeless Tobacco Products Sold in the United States

Smokeless
tobacco product

Mean
1
and range of NNN measured in μg/g dry weight (number of products)

Stepanov et al., 2014
Borgerding et al., 2012
Amman et al., 2016

Market share
2
(%)

Dissolvable
1.78; 0.27-2.66; (11)

<0.1

Chewing Tobacco (Loose leaf, plug, chew)

2.21; 0.66-5.05; (8)
2.24; 0.92-4.60; (8)
5.2

Dry Snuff

5.53; 0.81-14.42; (10)
7.50; 5.91-12.00; (4)
0.7

Moist Snuff

3.76; 0.66-12.77; (28)
3.01; 0.64-9.50; (22)
94.1

Mean NNN across product categories

3.87
3.36

Market share adjusted mean across product subcategories
3

3.69
3.01

1
Mean values were determined by averaging the NNN concentrations across a smokeless tobacco product subcategory in each of the three representative studies.

2
Market share data was based on 2015 retail scan data from Nielsen.

3
In order to calculate a market share adjusted mean the mean of each subcategory was multiplied by its representative market share (
e.g.,
Chewing Tobacco [NNN] × .052). These values for each subcategory were then summed to estimate a market share weighted mean across all smokeless tobacco product subcategories examined.

The range of the NNN levels in the studies discussed in this subsection suggest that there exists the potential to reduce the levels of NNN in all smokeless tobacco through manipulation of starting materials and curing processes, as well as careful control of manufacturing and storage practices.

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 µg/g of tobacco (on a dry weight basis) at any time through the product's labeled expiration date as determined by testing in compliance with § 1132.12 (proposed § 1132.10). In selecting the NNN limit in this proposed standard, FDA took into consideration the epidemiological evidence demonstrating differences in observed cancer risks between users of smokeless tobacco products manufactured in the United States and in Sweden, and the technical achievability of the proposed limit. To estimate the anticipated health benefits of the proposed standard, FDA modeled the estimated cancer risk reduction determined by reducing NNN 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 µg/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 µg/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 μg/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

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

EP23JA17.000

C = Concentration of NNN in product as used (µg/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 μg/g) to 14.4 μg/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 μg/g dry weight] × [1-moisture content] = [μg/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

that the average amount of smokeless tobacco product used is approximately 15 g/day [0.53 tin/day × 28 g/tin = 14.84 g/day], which suggests an assumption of 12 g/day is not unreasonable.

Conventional moist snuff constitutes the overwhelming majority of the smokeless tobacco market in the United States (Ref. 131). The figure of 12 g/day among moist snuff users does provide a reasonable average estimate of what most U.S. smokeless tobacco users of most product subcategories consume on a daily basis. However, FDA recognizes that the amount of smokeless tobacco used in a day varies by product. In particular, some dissolvable smokeless tobacco products weigh as little as 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 µg/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 µg/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 µg/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

Smokeless tobacco product

ELCR
(expressed as “n” in 10,000)

Stepanov et al.,
2014

Borgerding et al.,
2012

Ammann et al.,
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 subcategories

2.0
1.9

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 µg/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 µg/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 μg/g dry weight would reduce the ELCR by 83.2, 66.3 and 31.6 percent, respectively.

Table 4—ELCR for Hypothetical Market-Wide Mean NNN Levels and Comparison to Current Market ELCR

NNN
(µg/g dry weight)

NNN
(µg/g, wet weight, as used)

ELCR
(n in 10,000)

% Reduction in
ELCR as compared

to current market
1

0.5
0.3
0.32
83.2

1.0
0.6
0.64
66.3

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 µg/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 µg/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 µg/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 µg/g of tobacco and average NNK levels of 0.8 µg/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 µg/g of tobacco and NNK levels decreased to 0.19 µg/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 µg/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 ºC) 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

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 § 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 § 1132.5(a) utilizes LC-MS and has an analysis time of 8 minutes. The method has a limit of quantification of 0.4 µg/g of NNN, a linear range of 0.4 to 1.6 µg/g, and a method detection limit of 0.1 µg/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 µg/g tobacco were analyzed after dilution because they were too concentrated for analysis. This method was proven to be applicable for tobacco products with various moisture levels, including cigarette tobacco filler, snus, dry snuff, chewing tobacco, and moist snuff.

HPLC is favored over gas chromatography (GC) because it allows for faster analysis and sample preparation, although validated methods exist for analysis of NNN well below the level specified in § 1132.10 by either LC or GC. Mass spectrometer (MS) detection is favored over thermal energy analyzer (TEA) detection because of the possibility of using 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

for analysis of NNN well below the level specified in § 1132.10 by either MS or TEA.

Over the years a variety of analytical methods have been developed for the detection of NNN in smokeless tobacco products. For example, the Cooperation Centre for Scientific Research Relative to Tobacco (CORESTA) published CORESTA 72, an LC-MS method for determining NNN levels in smokeless tobacco using a low calibration standard of 0.015 µg/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 µg/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 µg/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 µg/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 µg/g or lower on a dry weight basis of NNN in tobacco could be reliably measured either by SRL's method or by optimizing existing common methods to meet the requirements of § 1132.16 (Alternative test method).

V. Standard Is Appropriate for the Protection of the Public Health

The Tobacco Control Act authorizes FDA to adopt tobacco product standards by regulation if it finds “that a tobacco product standard is appropriate for the protection of the public health” (section 907(a)(3)(A) of the FD&C Act). The Notice of Proposed Rulemaking (NPRM) for such a product standard must set forth this finding with supporting justification, which FDA is doing here (section 907(c)(2)(A) of the FD&C Act).

In order to make this finding, FDA must consider scientific evidence concerning—

• The risks and benefits to the population as a whole, including users and nonusers of tobacco products, of the proposed standard;

• The increased or decreased likelihood that existing users of tobacco products will stop using such products; and

• The increased or decreased likelihood that those who do not use tobacco products will start using such products. Section 907(a)(3)(B)(i) of the FD&C Act.

As discussed in this section of the document, FDA has considered scientific evidence related to all three factors. Based on these considerations, we find that the proposed standard is appropriate for the protection of public health, because it will reduce the harm associated with the use of smokeless tobacco products and FDA does not expect that the product standard will increase the likelihood that non-users will initiate tobacco or decrease the likelihood that users will quit tobacco use in a manner that would offset the benefits of the reduced cancer risk.

A. Benefits to the Population as a Whole

As discussed in section IV, on the basis of the best available scientific evidence, FDA has determined that NNN is the predominant driver of excess oral cancer risk among smokeless tobacco users. This determination is based on multiple, consistent lines of evidence. First, several authoritative reviews have concluded smokeless tobacco products, including those currently marketed in the United States, cause cancer (Refs. 1, 2, 3, 4). Second, 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.

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

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Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A2017-01030. Public record. Not legal advice.