8004 Federal Register / Vol. 82, No. 13 / Monday, January 23, 2017 / Proposed Rules

DEPARTMENT OF HEALTH AND comment will be made public, you are www.regulations.gov. Submit both HUMAN SERVICES solely responsible for ensuring that your copies to the Division of Dockets comment does not include any Management. If you do not wish your Food and Drug Administration confidential information that you or a name and contact information to be third party may not wish to be posted, made publicly available, you can 21 CFR Part 1132 such as medical information, your or provide this information on the cover [Docket No. FDA–2016–N–2527] anyone else’s Social Security number, or sheet and not in the body of your confidential business information, such comments and you must identify this Tobacco Product Standard for N- as a manufacturing process. Please note information as ‘‘confidential.’’ Any Nitrosonornicotine Level in Finished that if you include your name, contact information marked as ‘‘confidential’’ Smokeless Tobacco Products information, or other information that will not be disclosed except in identifies you in the body of your accordance with 21 CFR 10.20 and other AGENCY: Food and Drug Administration, comments, that information will be applicable disclosure law. For more HHS. posted on http://www.regulations.gov. information about FDA’s posting of • ACTION: Proposed rule. If you want to submit a comment comments to public dockets, see 80 FR with confidential information that you 56469, September 18, 2015, or access SUMMARY: The Food and Drug do not wish to be made available to the the information at: http://www.fda.gov/ Administration (FDA) is proposing a public, submit the comment as a regulatoryinformation/dockets/ tobacco product standard that would written/paper submission and in the default.htm. establish a limit of N-nitrosonornicotine manner detailed (see ‘‘Written/Paper Docket: For access to the docket to (NNN) in finished smokeless tobacco Submissions’’ and ‘‘Instructions’’). read background documents or the products. FDA is taking this action Written/Paper Submissions electronic and written/paper comments because NNN is a potent carcinogenic received, go to http:// agent found in smokeless tobacco Submit written/paper submissions as www.regulations.gov and insert the products and is a major contributor to follows: docket number, found in brackets in the • Mail/Hand delivery/Courier (for the elevated cancer risks associated with heading of this document, into the written/paper submissions): Division of smokeless tobacco use. Because ‘‘Search’’ box and follow the prompts Dockets Management (HFA–305), Food products with higher NNN levels pose and/or go to the Division of Dockets and Drug Administration, 5630 Fishers higher risks of cancer, FDA finds that Management, 5630 Fishers Lane, Rm. establishing a NNN limit in finished Lane, Rm. 1061, Rockville, MD 20852. • For written/paper comments 1061, Rockville, MD 20852. smokeless tobacco products is Submit comments on information submitted to the Division of Dockets appropriate for the protection of the collection issues to the Office of Management, FDA will post your public health. Management and Budget in the comment, as well as any attachments, DATES: Submit either electronic or following ways: except for information submitted, written comments on the proposed rule • Fax to the Office of Information and marked and identified, as confidential, by April 10, 2017. In accordance with Regulatory Affairs, OMB, Attn: FDA if submitted as detailed in 21 CFR 10.40(c), in finalizing this Desk Officer, FAX: 202–395–7285, or ‘‘Instructions.’’ email to [email protected]. rulemaking FDA will review and Instructions: All submissions received All comments should be identified with consider all comments submitted before must include the Docket No. FDA– the title, Tobacco Product Standard: the time for comment on this proposed 2016–N–2527 for ‘‘Tobacco Product NNN Level in Finished Smokeless regulation has expired. If your comment Standard for N-nitrosonornicotine Level Tobacco Products. is submitted after the expiration of the in Finished Smokeless Tobacco comment period, it will not be reviewed Products.’’ Received comments will be FOR FURTHER INFORMATION CONTACT: Beth and considered by FDA unless you placed in the docket and, except for Buckler or Colleen Lee, Office of apply for, and receive, an extension of those submitted as ‘‘Confidential Regulations, Center for Tobacco the comment period pursuant to 21 CFR Submissions,’’ publicly viewable at Products (CTP), Food and Drug 10.40(b)(3). Submit comments on http://www.regulations.gov or at the Administration, Document Control information collection issues under the Division of Dockets Management Center, Bldg. 71, Rm. G335, 10903 New Paperwork Reduction Act of 1995 (the between 9 a.m. and 4 p.m., Monday Hampshire Ave., Silver Spring, MD PRA) by February 22, 2017, (see the through Friday. 20993–0002, 877–287–1373, ‘‘Paperwork Reduction Act of 1995’’ • Confidential Submissions—To [email protected]. section). See section VII of this submit a comment with confidential SUPPLEMENTARY INFORMATION: document for the proposed effective information that you do not wish to be Table of Contents date of a final ruled based on this made publicly available, submit your document. comments only as a written/paper I. Executive Summary submission. You should submit two A. Purpose of the Proposed Rule ADDRESSES: You may submit comments B. Summary of the Major Provisions of the as follows: copies total. One copy will include the Proposed Rule information you claim to be confidential Electronic Submissions C. Legal Authority with a heading or cover note that states D. Costs and Benefits Submit electronic comments in the ‘‘THIS DOCUMENT CONTAINS II. Background Information following way: CONFIDENTIAL INFORMATION.’’ The A. Purpose • Federal eRulemaking Portal: http:// Agency will review this copy, including B. Legal Authority www.regulations.gov. Follow the the claimed confidential information, in C. Additional Considerations and Requests instructions for submitting comments. its consideration of comments. The for Comment III. Scope of Proposed Standard Comments submitted electronically, second copy, which will have the A. Smokeless Tobacco Products including attachments, to http:// claimed confidential information B. Current Prevalence and Initiation Rates www.regulations.gov will be posted to redacted/blacked out, will be available IV. Rationale for Developing a Standard for the docket unchanged. Because your for public viewing and posted on http:// NNN

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A. Smokeless Tobacco is Carcinogenic finished smokeless tobacco product that 387g) including authority related to the B. NNN in Smokeless Tobacco Products is is not in compliance with the product reduction of constituents or harmful Carcinogenic standard. However, the proposed rule components in tobacco products under C. NNN in Smokeless Tobacco Products would provide an exception for tobacco section 907(a)(4)(A)(ii) and to the testing D. Basis for the NNN Limit in the Proposed Standard retailers and distributors; we would not of tobacco products under section E. Information on Technical Achievability consider tobacco retailers and 907(a)(4)(B)(ii) through (iv); FDA’s F. Analytical Method distributors to be in violation of part authorities related to the sale and V. Standard is Appropriate for the Protection 1132 as it relates to the sale or distribution of tobacco products under of Public Health distribution of finished smokeless sections 907(a)(4)(B)(v) and 906(d); A. Benefits to the Population as a Whole tobacco products that exceed the FDA’s authority to require tobacco B. The Likelihood That Existing Users of allowed NNN level if they meet certain product manufacturers to establish and Tobacco Products Will Stop Using Such criteria set forth in the rule. maintain records under section 909 of Products C. The Likelihood That Non-Users Will The proposed rule would require that the FD&C Act (21 U.S.C. 387i); FDA’s Start Using Tobacco Products the mean level of NNN in any batch of authorities related to adulterated and D. Conclusion finished smokeless tobacco products not misbranded tobacco products under VI. Description of Proposed Regulation exceed 1.0 microgram per gram (mg/g) of sections 902 and 903 (21 U.S.C. 387b A. General Provisions (Proposed Subpart tobacco (on a dry weight basis) at any and 387c); FDA’s authorities related to A) time through the product’s labeled prohibited acts under section 301 of the B. Product Requirements (Proposed expiration date as determined by FD&C Act (21 U.S.C. 331); and FDA’s Subpart B) specified product testing. The rule rulemaking and inspection authorities C. Labeling and Recordkeeping Requirements (Proposed Subpart C) would require that all finished under sections 701 and 704 of the FD&C VII. Proposed Effective Date smokeless tobacco products have an Act (21 U.S.C. 371 and 374). expiration date and provide that the VIII. Incorporation by Reference D. Costs and Benefits IX. Economic Analysis of Impacts expiration date be no later than the final X. Analysis of Environmental Impact date the manufacturer can demonstrate The costs of the proposed rule, when XI. Paperwork Reduction Act of 1995 that the NNN level in the finished finalized, will be due to affected entities XII. Executive Order 13132 smokeless tobacco product conforms to ensuring that the smokeless tobacco XIII. Executive Order 13175 the limit when the product is stored products comply with the proposed XIV. References under its intended conditions (e.g., product standard. We have estimated I. Executive Summary room temperature or refrigeration). the annualized costs associated with the To ensure that products conform to proposed rule over 20 years to be A. Purpose of the Proposed Rule the product standard, the proposed rule between $17.91 million and $42.72 FDA is proposing a tobacco product would establish requirements for testing million using a 3 percent discount rate, standard that would establish a limit of the products. Two types of testing with a primary value of $30.31 million, NNN in finished smokeless tobacco would be required for smokeless and between $20.11 million and $50.57 products sold in the United States. NNN tobacco products—stability testing and million, with a primary value of $35.34 is a potent carcinogenic agent found in batch testing. Stability testing would be million using a 7 percent discount rate. smokeless tobacco products and is a required to assess the stability of the The primary estimate for the present major contributor to the elevated cancer NNN level in the finished smokeless value of total quantified costs over 20 risks associated with smokeless tobacco tobacco products and to establish and years is approximately $450.97 million use. By FDA’s estimates, in the 20 years verify the product’s expiration date and at a 3 percent discount rate and $374.36 following implementation of the storage conditions. In addition, each million at a 7 percent discount rate. proposed product standard, batch of finished smokeless tobacco NNN is a carcinogenic agent found in approximately 12,700 new cases of oral product would be required to be tested smokeless tobacco products. As cancer and approximately 2,200 oral to determine whether the products described in the preamble of the cancer deaths would be prevented in the conform to the proposed NNN level. proposed rule, on the basis of the United States because of this rule. The proposed rule would also establish available scientific evidence, FDA has Moreover, during that 20-year period, the standard test method (to be determined that NNN is the FDA estimates that approximately incorporated by reference) and predominant driver of excess oral 15,200 life years would be gained as a requirements for using an alternative cancer risk among smokeless tobacco result of the proposed standard. Because test method as well as the sampling users. We quantify benefits associated oral cancer is associated with significant requirements for all testing. with the proposed rule in the form of health and economic impacts, we expect The proposed rule would require that reduced oral cancer morbidity and positive public health benefits due to the labels of finished smokeless tobacco mortality attributable to smokeless prevention of new and fatal cancer products contain a manufacturing code, tobacco. As described in section V.A.3 cases. For the reasons discussed in the expiration date, and, if applicable, of the preamble of the proposed rule, we preamble of this rule, FDA finds that the storage conditions for the finished also expect the standard to reduce the proposed standard would be smokeless tobacco product (such as risk of esophageal cancer, and it may appropriate for the protection of the refrigeration). In addition, the proposed reduce the risks of other cancers such as public health. rule would require manufacturers of pancreatic, laryngeal, prostate, and lung finished smokeless tobacco products to cancer. However, there is more limited B. Summary of the Major Provisions of establish and maintain certain records. information to directly quantify these the Proposed Rule health benefits. As such, we only This proposed rule would establish a C. Legal Authority consider estimated reductions in oral limit of NNN in finished smokeless This proposed rule is being issued cancer as the quantified benefit of the tobacco products. Under the proposed upon FDA’s authority to establish a proposed product standard. rule, no person may manufacture, tobacco product standard under section Most of the estimated benefits arise distribute, sell, or offer for distribution 907 of the Federal Food, Drug, and from quality life-years gains gained from or sale within the United States a Cosmetic Act (the FD&C Act) (21 U.S.C. reduced oral cancer mortality. The

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annualized value over 20 years of monograph ‘‘Smokeless Tobacco and products, which make the relationship quality adjusted life-years gained from Some Tobacco-Specific Nitrosamines’’ between NNN and cancer in these reduced oral cancer mortality ranges that there is sufficient evidence in products different from that in from $228.66 million to $2.46 billion at humans to indicate that smokeless smokeless tobacco products. With a 3 percent discount rate, with a tobacco is carcinogenic and that it regard to dissolvable tobacco products primary value of $858.46 million. Using causes oral and pancreatic cancer (Ref. that do not meet the statutory definition a 7 percent discount rate, the 1). IARC confirmed these findings of the of smokeless tobacco, different product annualized value of quality life-years carcinogenicity of smokeless tobacco in testing methods than the ones gained from averted deaths ranges from a 2012 review, concluding that there is developed and available for smokeless $182.01 million to $1.96 billion, with a sufficient evidence in both humans and tobacco, as described in this proposal, primary value of $683.34 million. The experimental animal studies that may be necessary to evaluate NNN in primary estimate of the present value of smokeless tobacco causes oral, these products because they do not mortality reductions quantified over 20 esophageal, and pancreatic cancer (Ref. consist of cut, ground, powdered or leaf years is $12.77 billion at a 3 percent 2). In addition, a 2014 report on tobacco. Therefore, at this stage, FDA discount rate and $7.24 billion at a 7 smokeless tobacco by the National has chosen to focus on smokeless percent discount rate. The annualized Cancer Institute (NCI) and Centers for tobacco and has evaluated data relevant value over 20 years of quality adjusted Disease Control and Prevention (CDC) to establishing an NNN limit in life-years gained from reduced oral estimated that smokeless tobacco use is smokeless tobacco products. cancer mortality and morbidity ranges responsible for approximately 1,600 This proposed product standard from approximately $283.95 million to new cases of oral cancer, 200 cases of would require that the mean level of $3.05 billion at a 3 percent discount esophageal cancer, and 500 cases of NNN in any batch of finished smokeless rate, with a primary value of $1.06 pancreatic cancer in the United States tobacco products not exceed 1.0 mg/g of billion, and approximately $246.40 each year (Ref. 4). tobacco (on a dry weight basis) at any 1 million to $2.65 billion, with a primary NNN is a potent carcinogenic agent time through the product’s labeled value of $0.92 billion at a 7 percent found in smokeless tobacco products expiration date as determined by testing discount rate. The primary estimate of and is a major contributor to the in compliance with § 1132.12 (proposed the present value of total quantified elevated cancer risks associated with § 1132.10). FDA expects that, in the 20 benefits over 20 years is approximately smokeless tobacco use (see section IV, years following implementation of the $15.86 billion at a 3 percent discount Rationale for Developing a Standard for proposed product standard, rate and $9.80 billion at a 7 percent NNN, of this document). NNN levels approximately 12,700 new cases of oral discount rate for reductions in oral vary substantially across subcategories cancer and approximately 2,200 oral cancer alone. These values are likely an of smokeless tobacco products (e.g., cancer deaths would be prevented in the underestimate of the benefits associated moist snuff, chewing tobacco, dry snuff) United States because of this rule. with the proposed rule, as we do not and within product subcategories (e.g., Moreover, during that 20-year period, quantify reductions in mortality and moist snuff) (Ref. 5, 10). International approximately 15,200 life years would morbidity from cancers other than oral comparisons of oral cancer rates and be gained in the United States as a result cancer. Costs and benefits are smokeless tobacco products suggest that of the proposed standard. We believe summarized in table 8 of the preamble products with higher NNN levels may that the main source of variability in the of the proposed rule. pose higher risks of cancer (Refs. 6, estimated impacts would be different 100). FDA is using its authority to assumptions about oral cancer relative II. Background Information propose a standard that would reduce risks due to smokeless tobacco use. A. Purpose tobacco-related harms by establishing a Using alternate relative risk estimates limit of NNN in smokeless tobacco that are somewhat lower and higher FDA is issuing this proposed rule to products sold in the United States (see address the harm caused by the toxicant than our main estimate results in section V of this document). approximately 7,300 to 24,000 new NNN in smokeless tobacco products. FDA is proposing that the standard cases of oral cancer prevented and 1,300 When Congress enacted the Family would apply to finished smokeless to 4,200 oral cancer deaths prevented Smoking Prevention and Tobacco tobacco products. Although NNN is also over the 20-year period. Because oral Control Act (Tobacco Control Act) in found in other tobacco products, this cancer is associated with significant 2009, it included the finding that ‘‘the rule focuses solely on NNN levels in Food and Drug Administration is a smokeless tobacco products, and not on health and economic impacts, we expect regulatory agency with the scientific additional products. Different measures positive public health benefits due to expertise to identify harmful substances are required to evaluate the contribution prevention of new and fatal cancer in products to which consumers are to cancer of NNN among users of other cases. These benefits are discussed in exposed, [and] to design standards to tobacco products, such as combustible detail in section V of this proposed rule. limit exposure to those substances’’ products like cigarettes and dissolvable Accordingly, based on the information (section 2(44) of the Tobacco Control tobacco products that do not meet the discussed in the following sections of Act). statutory definition of ‘‘smokeless the preamble to this proposed rule, FDA Smokeless tobacco products, tobacco product.’’ For example, finds that the proposed standard would including those currently marketed in additional factors, such as polycyclic be appropriate for the protection of the the United States, have been aromatic hydrocarbons (PAH), public health. demonstrated to cause certain types of aldehydes and other chemicals (Refs. B. Legal Authority cancer. Several authoritative reviews 147, 106), contribute to the cancer have been conducted on the burden associated with combustible 1. Product Standard relationship between smokeless tobacco The Tobacco Control Act was enacted use and cancer risk and have reached 1 Since 2012, manufacturers have been required on June 22, 2009, amending the FD&C similar conclusions (Refs. 1, 2, 3, 4). The to test and report to FDA the levels of harmful and Act and providing FDA with the potentially harmful constituents (HPHCs), International Agency for Research on including NNN, in each tobacco product (section authority to regulate tobacco products Cancer (IARC) concluded in its 2007 904(A)(3) of the FD&C Act). (Pub. L. 111–31; 123 Stat. 1776). Among

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the authorities provided to FDA is the including users and nonusers of the appropriate, require the use and authority to establish tobacco product tobacco products, and must take into prescribe the format and content of standards. To establish a tobacco account: labeling for the proper use of the product standard, section 907(a)(3)(A) • The increased or decreased tobacco product. These label and (B) of the FD&C Act (21 U.S.C. likelihood that existing users of tobacco requirements would enable FDA to 387g(a)(3)(A) and (B)) requires that we products will stop using such products; determine whether a product on store find that the standard is appropriate for and shelves purports to comply with the the protection of the public health, • The increased or decreased standard, link the product to its taking into consideration scientific likelihood that those who do not use manufacturing history so that evidence concerning: tobacco products will start using such compliance with the standard can be • The risks and benefits of the products (see section 906(d)(1) of the verified, provide traceability of the proposed standard to the population as FD&C Act). product in the event of a nonconforming a whole, including users and nonusers Under these authorities along with product investigation and corrective of tobacco products; section 701, which provides FDA with action, and ensure that the product is • The increased or decreased the authority to ‘‘promulgate regulations handled and stored under appropriate likelihood that existing users of tobacco for the efficient enforcement of this conditions, in accordance with the products will stop using such products; Act,’’ FDA is including provisions to standard. In addition, the proposed and restrict the manufacture, sale, and manufacturing code would serve as a • The increased or decreased distribution of finished smokeless common identifier that will provide a likelihood that those who do not use tobacco products that are not in history of the manufacturing, tobacco products will start using such compliance with this standard. processing, packaging, labeling, holding, products. Specifically, FDA is proposing to and initial distribution of the tobacco require that no person may 2. NNN Limit product from records maintained by the manufacture, distribute, sell, or offer for smokeless tobacco product Section 907 of the FD&C Act distribution or sale within the United manufacturer. The expiration date authorizes FDA to promulgate tobacco States a finished smokeless tobacco would also inform retailers that the product standards that are appropriate product that is not in compliance with manufacturer has not demonstrated for the protection of the public health, part 1132 (proposed § 1132.1(b)). compliance with the standard beyond including provisions, where However, tobacco retailers and the date after which the product should appropriate, for the reduction or distributors would not be considered in not be sold to consumers. elimination of constituents or harmful violation of part 1132 as it relates to the Manufacturers would be responsible components of tobacco products sale or distribution or offer for sale or for ensuring that finished smokeless (section 907(a)(4)(A)(ii) of the FD&C distribution of finished smokeless tobacco products contain labels with a Act). This proposed rule would limit the tobacco products that exceed the NNN manufacturing code, expiration date, level of NNN in finished smokeless level required in proposed § 1132.10 if and, if applicable, storage conditions tobacco products. To ensure that they: (1) Store and transport the finished prior to sale and commercial finished smokeless tobacco products smokeless tobacco products according distribution. In addition, retailers and comply with the proposed NNN level, to the package label, (2) do not sell or distributors would be responsible for FDA also is including provisions to distribute or offer for sale or distribution not selling or distributing or offering for require that tobacco product finished smokeless tobacco products sale or distribution finished smokeless manufacturers test their products on a past their expiration date, except to tobacco products that lack the required sample basis (i.e., batch testing) using a return expired products to the labels, not concealing, altering, or specified testing procedure for manufacturer, (3) do not conceal, alter removing the expiration date or storage conformance with the limit pursuant to or remove the expiration date or storage conditions on the package label, not section 907(a)(4)(B)(ii) and (iv) of the conditions on the package label, and (4) selling or distributing or offering for sale FD&C Act. do not sell or distribute or offer for sale or distribution finished smokeless or distribution finished smokeless 3. Sale and Distribution Restrictions tobacco products after their expiration tobacco products that are open or have date (except to return expired product to Section 907(a)(4)(B)(v) states that broken seals (proposed § 1132.1(c)). the manufacturer), not selling or product standards must, where FDA is proposing this exception for distributing or offering for sale or appropriate for the protection of public tobacco retailers and distributors distribution finished tobacco products health, include provisions requiring that because they are not in a position to that are open or have broken seals, and, the sale and distribution of the tobacco know or to confirm by testing whether if applicable, storing finished smokeless products be restricted but only to the the smokeless tobacco products they are tobacco product in accordance with the extent that the sale and distribution of selling or distributing or offering for sale package label. a tobacco product may be restricted or distribution comply with the Because these requirements would under section 906(d). Similar to section proposed NNN level. assist FDA in enforcing the standard 907, section 906(d) of the FD&C Act FDA is also proposing, under these and would ensure that manufacturers gives FDA authority to require authorities, to require that the labels of and retailers are selling product that restrictions on the sale and distribution finished smokeless tobacco products complies with the standard, the Agency of tobacco products by regulation if the contain a manufacturing code, has found all of these requirements to be Agency determines that such regulation expiration date, and, if applicable, appropriate for the protection of the would be appropriate for the protection storage conditions for the finished public health consistent with sections of the public health. The finding as to smokeless tobacco product (proposed 907(a)(4)(B)(v) and 906(d). whether a sales and distribution § 1132.30). The labeling requirement for regulation is appropriate for the storage conditions is also consistent 4. Testing Requirements protection of the public health must be with FDA’s authority under section FDA’s proposed rule contains determined with respect to the risks and 907(a)(4)(C), which provides that a provisions regarding testing benefits to the population as a whole, product standard shall, where requirements under sections

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907(a)(4)(B) and 907(a)(4)(A)(iii) of the to the results of annual real-time date of distribution of the finished FD&C Act to ensure that finished stability testing, or if FDA notifies a smokeless tobacco product that is the smokeless tobacco products conform to tobacco product manufacturer that a subject of the record, except that certain the requirements of the product distributed finished smokeless tobacco records relating to alternative test standard before they are distributed to product does not conform to the methods would be required to be consumers and remain in conformance requirements of part 1132, the retained for a period of not less than 4 until their expiration date. Section manufacturer would have to conduct an years after the last date the method is 907(a)(4)(B)(ii) provides that a product investigation to determine the scope of used. Retention of these records would standard must, where appropriate for the nonconformity and locations to help ensure that finished smokeless the protection of public health, include which nonconforming products have tobacco products are in conformance ‘‘provisions for the testing (on a sample been distributed. This proposed with the proposed standard and are not basis or, if necessary, on an individual requirement would ensure that any adulterated or misbranded. basis) of the tobacco product.’’ In reports of nonconforming products, addition, section 907(a)(4)(B)(iv) whether as a result of manufacturer C. Additional Considerations and provides that, where appropriate for the testing or otherwise, are examined and Requests for Comment protection of public health, a product investigated and that appropriate 1. Section 907 of the FD&C Act standard must include provisions measures are taken to ensure that FDA is required by section 907 of the requiring that the results of the tests of additional nonconforming product FD&C Act to consider the following the tobacco product required under batches are not distributed to consumers information submitted in connection section 907(a)(4)(B)(ii) show that the and to prevent future nonconformity. product is in conformity with the FDA finds that such provisions are with a proposed product standard: • For a proposed product standard to portions of the standard for which the appropriate for the protection of the require the reduction or elimination of tests were required. public health and relate to requirements Consistent with these statutory under section 907(a)(4)(B) because they an additive, constituent, or other provisions, proposed §§ 1132.12, will help to ensure that the finished component of a tobacco product because 1132.14, 1132.16, and 1132.18 would smokeless tobacco products are properly FDA has found that the additive, establish product testing and sampling tested and conform to the requirements constituent, or other component is or plan requirements. Proposed § 1132.12 of the proposed product standard. may be harmful, scientific evidence would require two types of testing for submitted that demonstrates that the 5. Recordkeeping smokeless tobacco products—stability proposed standard will not reduce or testing and batch testing. Proposed Section 909 of the FD&C Act eliminate the risk of illness or injury § 1132.12(a) would require testing to authorizes FDA to require tobacco (section 907(a)(3)(B)(ii) of the FD&C product manufacturers to establish and Act). assess the stability of the NNN level in • finished smokeless tobacco products maintain records, make reports, and Information submitted regarding the and to establish and verify the product’s provide such information as the Agency technical achievability of compliance expiration date and storage conditions may by regulation reasonably require to with the standard (section 907(b)(1) of (either room temperature or assure that a tobacco product is not the FD&C Act). • refrigeration). Proposed § 1132.12(b) adulterated or misbranded and to All other information submitted, would require manufacturers to conduct otherwise protect public health. In including information concerning the testing on each batch of finished addition, section 701(a) of the FD&C Act countervailing effects of the tobacco smokeless tobacco product to determine authorizes FDA to promulgate product standard on the health of whether the products conform to the regulations for the efficient enforcement adolescent tobacco users, adult tobacco proposed NNN level. Proposed of the FD&C Act. The recordkeeping users, or nontobacco users, such as the § 1132.12(c) would require the tobacco requirements would help FDA with the creation of a significant demand for product manufacturer to document all efficient enforcement of the product contraband or other tobacco products testing. Proposed §§ 1132.14 and standard issued under the FD&C Act. that do not meet the requirements of 1132.16 would establish the standard FDA is proposing to require that Chapter IX of the FD&C Act and the and alternative test methods, while manufacturers of smokeless tobacco significance of such demand (section § 1132.18 would establish the sampling products maintain records regarding the 907(b)(2) of the FD&C Act). requirements for all testing. product testing (i.e., stability and batch As required by section 907(c)(2) of the Section 907(a)(4)(A)(iii) states that testing), including a full report of the FD&C Act, FDA invites interested product standards must include source data and results; all notifications persons to submit a draft or proposed provisions that are appropriate for the of an alternative test method and source tobacco product standard for the protection of the public health, data for alternative test method Agency’s consideration (section including provisions, where validation; all sampling plans and 907(c)(2)(B)) and information regarding appropriate, relating to any requirement reports; documentation that the persons structuring the standard so as not to under subparagraph 907(a)(4)(B). As performing sampling have sufficient advantage foreign-grown tobacco over discussed, FDA is proposing specific education, training, and experience to domestically grown tobacco (section testing requirements in §§ 1132.12, accomplish the assigned functions; all 907(c)(2)(C)). In addition, FDA invites 1132.14, 1132.16, and 1132.18. To identification, investigation, the Secretary of Agriculture to provide support these proposed requirements, segregation, and disposition procedures; any information or analysis which the proposed § 1132.22(b) would require and all nonconforming product Secretary of Agriculture believes is that if the mean of the representative investigations and rework (i.e., the relevant to the proposed tobacco samples from any batch of a finished processing of nonconforming finished product standard (section 907(c)(2)(D) of smokeless tobacco product is smokeless tobacco products to meet the the FD&C Act). determined to be out of conformance requirements of part 1132). FDA is requesting the documents and with the requirements of § 1132.10, or a FDA is also proposing to require information described in this section finished smokeless tobacco product’s copies of all records be retained for a with this proposed rule. Such expiration date must be shortened due period of not less than 4 years from the documents and information may be

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submitted in accordance with the eligible for an SE report, FDA is A. Smokeless Tobacco Products ‘‘Instructions’’ included in the considering whether a change to the The term ‘‘smokeless tobacco’’ covers preliminary information section of this level of NNN in smokeless tobacco a wide range of tobacco products that document. products could be reviewed with the are used orally or nasally without Section 907(d)(5) of the FD&C Act submission of an SE report containing a combustion (Ref. 1). Smokeless tobacco allows the Agency to refer a proposed reduced, specific set of information that is defined in section 900(18) of the regulation for the establishment of a focuses on the changes to the smokeless FD&C Act as ‘‘any tobacco product that tobacco product standard to the Tobacco tobacco where the SE report consists of cut, ground, powdered, or Products Scientific Advisory Committee demonstrates that the only leaf tobacco and that is intended to be (TPSAC) at the Agency’s own initiative modifications made to the new product placed in the oral or nasal cavity.’’ This or in response to a request for good were made to comply with the NNN includes moist snuff, snus, dry snuff, cause made before the expiration of the product standard and do not present chewing tobacco, and some comment period. If FDA opts to refer different questions of public health (e.g., dissolvables. Some dissolvable tobacco this proposed regulation to TPSAC, the significant increase in another harmful products do not meet the statutory Agency will publish a notice in the or potentially harmful constituent definition of ‘‘smokeless tobacco Federal Register announcing the TPSAC (HPHC)). As there may be multiple product’’ because they do not contain meeting to discuss this proposal. modifications needed to comply with cut, ground, powdered, or leaf tobacco; the product standard, FDA requests 2. Pathways to Market instead, these products contain nicotine comments as to the type of extracted from tobacco. Dissolvable To legally market a new tobacco modifications that may allow a reduced products that do not meet the statutory product in the United States, a tobacco amount of information to proceed product manufacturer must receive through the SE pathway, and what types definition of ‘‘smokeless tobacco authorization from FDA permitting the of brief, specific supporting information product’’ are not covered by this marketing of the new tobacco product submitted as part of a substantial proposed rule. Moist snuff is the most popular type under one of three pathways for legally equivalence application could of smokeless tobacco in the United marketing a new tobacco product: (1) demonstrate that modifications made to The manufacturer obtains an order comply with this product standard do States (Refs. 4, 131). It is typically made under section 910(c)(1)(A)(i) of the not cause the new product to raise of fire-cured or air-cured tobacco that FD&C Act (order after review of a different questions of public health. has been finely ground or shredded and premarket tobacco application under fermented (Ref. 4). Moist snuff may section 910(b)); (2) the manufacturer III. Scope of Proposed Standard contain up to 60 percent moisture and obtains an order finding the new Scientific evidence documents that it is often flavored (e.g., wintergreen) product substantially equivalent to a smokeless tobacco products cause (Refs. 4, 10). It is sold as loose tobacco predicate tobacco product and in certain types of cancer (Refs. 1, 2, 3, 4). or in sachets or small pouches (Ref. 1). compliance with the requirements of the As discussed in section IV of this When loose moist snuff is used, a small FD&C Act under section 910(a)(2)(A)(i) document, NNN is a potent carcinogenic amount (e.g., a pinch or dip) is placed (order after review of a substantial agent found in smokeless tobacco and held between the lip or cheek and equivalence (SE) report submitted under products and is a major contributor to gum and typically is held in the mouth section 905(j) of the FD&C Act); or (3) the elevated cancer risks associated with for at least 30 minutes (Refs. 1, 5). the manufacturer makes a request under smokeless tobacco use (Refs. 7, 8, 1, 2). Excess saliva may be spit out or 21 CFR 1107.1, obtains an exemption FDA is issuing this proposed standard swallowed (Ref. 1). When pouched from the requirements related to to address the harm to smokeless moist snuff is used, a sachet or small substantial equivalence (section tobacco users caused by NNN by pouch containing the tobacco is placed 905(j)(3)(A)), and at least 90 days before establishing a limit for NNN in finished and held between the lip or cheek and commercially marketing the product, smokeless tobacco products (see gum but it does not require spitting (Ref. submits a report under section 905(j) proposed § 1132.10), thereby reducing 9). including the information required in exposure to this harmful toxicant. NNN Snus is a type of moist snuff and it section 905(j)(1)(A)(ii) and (j)(1)(B). levels vary substantially across can have different characteristics A smokeless tobacco product that has subcategories of smokeless tobacco depending on where it is manufactured. been modified to comply with the products (e.g., moist snuff, chewing Swedish snus products generally have product standard would be a ‘‘new tobacco, dry snuff) and within product much lower levels of tobacco-specific tobacco product’’ and subject to subcategories (e.g., moist snuff) (Ref. 5). nitrosamines (TSNAs) than smokeless premarket review. FDA believes that Geographical comparisons show that tobacco products found in the United changes made solely to bring a oral cancer rates among smokeless States (Refs. 5, 6, 10), and, therefore, smokeless tobacco product in tobacco users are higher in areas where they were of particular interest in the compliance with the proposed rule smokeless tobacco products have higher development of this proposed rule. would be appropriate for an SE NNN levels (Refs. 6, 100). Given this Swedish snus is commonly used in submission. We believe it is possible for geographic variation and the Sweden but it is relatively new to the manufacturers to modify their product toxicological evidence described in the U.S. market (Refs. 4, 11). It typically so that it is both in compliance with the preamble of this rule, we expect that consists of low-nitrosamine tobacco that proposed product standard and lowering the level of NNN in smokeless has been air-cured, moistened, ground, substantially equivalent to an tobacco products in the United States and heat treated (Refs. 4, 12, 11). appropriate predicate product (i.e., will lower the rate of oral cancers Swedish snus may contain up to 50 products that are grandfathered or SE). among smokeless tobacco users. FDA percent moisture and some flavoring but FDA believes that manufacturers concludes that establishing a limit for no added sugars (Refs. 13, 14, 11). would likely choose to comply with the NNN in finished smokeless tobacco Swedish snus is sold as loose tobacco or proposed standard in a manner that products is appropriate for the in sachets (Refs. 4, 12, 11). It is placed makes the modified products eligible for protection of the public health (see between the cheek and gum and does the SE pathway. For products that are section V of this document). not require spitting (Refs. 1, 15).

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In Sweden, all snus manufacturers sweeteners (Ref. 4, 56). It is generally current smokeless tobacco product must adhere to the requirements of the sold portioned in sachets or small usage was 6 percent among high school Swedish Food Act. In addition, a pouches (Ref. 4). students, and 1.8 percent among middle smokeless tobacco manufacturer Unlike the relatively higher moisture school students (Ref. 25). Among youth, developed the GothiaTek voluntary content of moist snuff, dry snuff usually the prevalence of smokeless tobacco use standard, which establishes limits for has a moisture content of less than 10 varies by sex and race. In 2015, 10 the tobacco (e.g., low-nitrosamine raw percent (Ref. 1). Dry snuff is a powdered percent of male high school students tobacco that has been air-cured or sun- tobacco product that may be used orally reported current use of smokeless cured) and other ingredients as well as or nasally, although nasal use is rare in tobacco, including snus and the manufacturing process (Refs. 11, 4). the United States (Ref. 4). Typically dry dissolvables, compared with 1.8 percent The current GothiaTek standard for snuff is made with tobacco that has been of female high school students (Ref. 25). NNN and 4-(methylnitrosamino)-1-(3- fire-cured, fermented, and finely ground Among high school students, the pyridyl)-1-butanone (NNK) (combined) or pulverized into a powder (Refs. 1, 4). prevalence of current use of smokeless in snus is 0.95 mg/g wet weight 2 A pinch or dip of dry snuff is typically tobacco, including snus and tobacco, which would be about 2 mg/g held between the cheek and gum (Ref. dissolvables, was highest among non- (combined NNN and NNK) dry weight 1). Hispanic White students (7.8 percent), tobacco (Refs. 13, 16). Swedish snus that Chewing tobacco is sold as loose leaf, followed by Hispanic students (4.8 is made using the GothiaTek standard plug, or twist. It is typically fire-cured percent), and non-Hispanic Black tends to have lower levels of toxicants, or air-cured tobacco that has been students (1.9 percent) (Ref. 25). including NNN, than other smokeless fermented or aged (Refs. 4, 1). It may be An estimated 1.0 million Americans tobacco products in other countries (Ref. flavored and sweetened and then aged 12 or older used smokeless tobacco 4). processed into a plug, twist, or loose for the first time in 2014 (Ref. 24 at table Swedish snus is usually refrigerated leaf (Refs. 4, 1). Chewing tobacco may 4.5B). Nearly 75 percent of these new by retailers to maintain its quality and be chewed or held in the mouth (i.e., initiates were male and about 42 percent taste but refrigeration is not generally dipped) (Ref. 5). were under age 18 when they first used required to maintain stability because Dissolvable tobacco products that are a smokeless tobacco product (Ref. 24 at modern Swedish snus production smokeless tobacco products are tables 4.6B, 4.9A). The average age at techniques achieve very low levels of generally made of finely ground tobacco first use of smokeless tobacco among microbial activity and yield no new and sold as small lozenges, sticks recent initiates in 2014 was 19.0 years, nitrosamine formation even when held (toothpick), or strips (Refs. 4, 5). Such which was similar to the 2013 estimate at room temperature (Ref. 11). One of dissolvable tobacco products may be (Refs. 26, 24 at table 4.13B). the methods used to limit microbial flavored and may have a moisture content ranging from 1 to 20 percent, IV. Rationale for Developing a activity is pasteurization. In this depending on the product (Refs. 9, 22, Standard for NNN process, the leaf tobacco is ground and 56). As the name suggests, a dissolvable subjected to heat treatment. The heating A. Smokeless Tobacco is Carcinogenic tobacco product is placed in the mouth is achieved by combining the tobacco until it dissolves. The scientific evidence demonstrates with water and salt, placed in closed that smokeless tobacco products cause process blenders, and using steam to B. Current Prevalence and Initiation certain types of cancer, and that cancer ° achieve temperatures up to 80 to 100 C Rates rates are higher in regions of the world for several hours (Ref. 11). In the United States, smokeless where smokeless tobacco products have In recent years, some U.S. tobacco tobacco products are predominately higher levels of NNN. In 1986, the manufacturers began introducing snus used by men and high school age boys. Surgeon General of the United States products (e.g., Marlboro Snus and According to the 2014 National Survey released a report finding that ‘‘users of Camel Snus) in the United States (Ref. on Drug Use and Health, an estimated smokeless tobacco products face a 17). Some of the early marketing of 8.7 million (3.3 percent) Americans strongly increased risk of oral cancer’’ these tobacco products emphasized the aged 12 and over were current (any use (Ref. 27). In 2007, IARC classified Swedish origins of snus but there is in the past month) smokeless tobacco smokeless tobacco as carcinogenic to limited data available on whether the users (chewing tobacco or snuff) in humans (Group 1), concluding that chemical composition or manufacturing 2014, which is generally similar to the sufficient evidence in humans processes of these products are percentage of smokeless tobacco users demonstrate that smokeless tobacco equivalent to Swedish snus (Refs. 4, 18, estimated by this study for most years causes cancers of the oral cavity and 19). Studies indicate that early versions from 2002 to 2013 (Ref. 23). An pancreas (Ref. 1). IARC confirmed these of these snus products would not estimated 6.4 percent of males over the findings of the carcinogenicity of comply with the current GothiaTek age of 12 were current smokeless smokeless tobacco in a 2012 review, standard for NNN and NNK (i.e., 0.95 tobacco users, while only 0.3 percent of concluding that there is sufficient mg/g per wet weight combined) (Ref. 13). females were current users (Ref. 24 at evidence in both humans and From the limited information available, tables 2.9B, 2.10B). Among adults, the experimental animal studies that snus manufactured in the United States highest prevalence of current use of smokeless tobacco causes oral, appears to consist of tobacco that has smokeless tobacco was observed among esophageal, and pancreatic cancer (Ref. been air-cured or sun-cured and is young adults aged 18 to 25 at 5.6 2). The Scientific Committee on pasteurized or heat treated (Refs. 20, percent (Ref. 24 at 18). According to the Emerging and Newly Identified Health 21). It may contain up to 34 percent National Youth Tobacco Survey, in Risks (Ref. 3) was tasked by the moisture and may contain some 2015, there were an estimated 1.1 European Commission to evaluate the flavoring, flavoring strip, and/or million middle and high school cancer risks of smokeless tobacco students that reported current (past 30 products, with particular attention to 2 The term ‘‘wet weight’’ refers to the weight of moist snuff, which, in the European tobacco as used by the consumer, while the term day) use of chewing tobacco, snuff or ‘‘dry weight’’ refers to the weight of tobacco after dip, snus, or dissolvable tobacco Union is available only in Sweden, in the removal of water. products (Ref. 25). The overall level of the form of snus. It concluded in its

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2008 review that smokeless tobacco evidence for ‘‘users of Swedish moist published a report on smokeless tobacco products cause esophageal and snuff (snus) is less clear’’ (Ref. 3). More use and health effects in 2014, pancreatic cancer in humans and that recently, the National Cancer Institute concluding that smokeless tobacco use studies in the United States demonstrate (NCI), National Institutes of Health, in causes oral, esophageal, and pancreatic an increased risk of oral cancer among coordination with the Centers for cancer (Ref. 4). smokeless tobacco users, however, the Disease Control and Prevention (CDC)

TABLE 1—CONCLUSIONS OF AUTHORITATIVE REVIEWS ON SMOKELESS TOBACCO AND CANCER RISK

Authoritative body Year Conclusions

Surgeon General of the United 1986 ‘‘In summary, users of smokeless tobacco products face a strongly increased risk of oral can- States. cer, particularly for the tissues that come in contact with the tobacco.’’ International Agency for Research on 2007 ‘‘There is sufficient evidence in humans for the carcinogenicity of smokeless tobacco. Smoke- Cancer (IARC). less tobacco causes cancers of the oral cavity and pancreas.’’ Scientific Committee on Emerging 2008 ‘‘STP [smokeless tobacco products] are carcinogenic to humans and the pancreas has been and Newly Identified Health Risks identified as a main target organ. All STP cause localised oral lesions and a high risk for (SCENIHR). development of oral cancer has been shown for various STP but the evidence for oral can- cer in users of Swedish moist snuff (snus) is less clear.’’ International Agency for Research on 2012 ‘‘There is sufficient evidence in humans for the carcinogenicity of smokeless tobacco. Smoke- Cancer (IARC). less 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 ad- verse reproductive and developmental effects including stillbirth, preterm birth, and low birth weight.’’

B. NNN in Smokeless Tobacco Products of administration consistently causes tissues. Studies in experimental animals is Carcinogenic oral and esophageal tumors in rats, as demonstrate oral exposure to NNN Smokeless tobacco products contain well as nasal cavity and tracheal tumors stimulates tumor formation in other thousands of chemical constituents, across multiple species, with noted tissues, such as nasal cavity, stomach, including carcinogens such as TSNAs route- and species-specific differences lung and liver (Refs. 151, 155, 156, 161, (Refs. 2, 1, 4). TSNAs are formed from (Refs. 7, 178, 148, 59, 94, 149 through 178, 179). However, the number of nitrosation, a chemical reaction between 160). Rats are more likely to develop tumors observed in oral and esophageal tumors in the esophagus, oral and nasal tissues are often greater than the number tobacco alkaloids (nicotine, nornicotine, cavity following oral or subcutaneous of tumors observed in other, non-target anatabine, and anabasine) and exposure to NNN (Refs. 7, 59, 94, 95, tissues. For example, a greater number nitrosating agents such as nitrite (Refs. 148, 149) whereas mice develop tumors of rats were reported to develop tumors 28, 2). Because TSNAs are formed from in lung, forestomach, and to a limited in the esophagus compared with the tobacco alkaloids, they are only found extent liver (Refs. 155, 156, 160). In lung following exposure to NNN in in tobacco products (Ref. 28). hamsters, tracheal tumors and nasal liquid diet (Ref. 94). Another study In smokeless tobacco, TSNAs are cavity tumors are observed following reported a similar trend, with present at a level capable of causing oral or intraperitoneal exposure to NNN esophageal and oral tumors observed in cancer (Ref. 4). Of the five TSNAs (Refs. 59, 151), with tracheal tumors 35 and 18 percent of rats exposed to identified in tobacco products, NNN also observed following subcutaneous NNN via oral gavage, respectively, and 4-(methylnitrosamino)-1-(3- exposure (Ref. 152). Studies in whereas only 5 percent of exposed pyridyl)-1-butanone (NNK) have been experimental animals also demonstrate animals developed lung tumors (Ref. classified by IARC as carcinogenic to that NNN can induce tumor formation 178). A more recent study by Balbo et humans (Group 1) (Refs. 2, 4).3 in a dose-dependent manner. For al. (Ref. 7) found that 100 percent of rats The relatively high level of these example, in rats, a dose-dependent treated orally with NNN in their carcinogens has led the World Health formation of nasal cavity tumors has drinking water developed malignant Organization (WHO) to call for limits on been observed following subcutaneous oral tumors. A high incidence of these constituents in tobacco products or oral exposure (via gastric instillation) esophageal tumors has been consistently (Ref. 78). Tobacco science researchers to NNN (Refs. 149, 161). In hamsters, observed in rats following oral exposure have also called for the reduction of NNN stimulates tumors of the nasal to NNN across studies, with 83 percent TSNAs in smokeless tobacco products cavity, trachea and liver in a dose- of animals developing esophageal due to their potential impact on the dependent manner following tumors following exposure via liquid increased cancer risk associated with subcutaneous exposure (Ref. 151). diet (Ref. 94) and 60 to 100 percent of smokeless tobacco use (Refs. 175, 176). Although a dose-dependent animals developing esophageal tumors 1. Evidence for NNN Carcinogenicity in relationship between oral and following exposure via drinking water Animals esophageal tumor formation following (Refs. 148, 95, 59, 7). exposure to NNN has not been The high incidence of tumor There is sufficient evidence to extensively studied, chronic oral formation in esophageal and oral tissue indicate NNN may act as both a local exposure to NNN via drinking water observed in experimental animal studies and systemic carcinogen in clearly identifies oral cavity and is consistent with what is known experimental animals. Studies have esophageal tissues as the major targets regarding the metabolism of NNN and shown that NNN given by various routes of tumorigenesis in animals (Refs. 7, 95). subsequent DNA adduct formation in 3 Section IV.D.3 explains why FDA is not As indicated previously, sites of tumor target tissues. NNN is a genotoxic proposing a product standard for NNK levels in formation following exposure to NNN carcinogen, it reacts with DNA and is smokeless tobacco at this time. are not limited to oral and esophageal assumed to exhibit proportional

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responses at low doses (Refs. 168, 169). administered orally to animals (Refs. 7, associated with exposure to NNN (oral The general understanding of the 59, 95, 148), which provides some and esophageal) versus NNK (lung) that mechanism of action (MOA) of NNN- degree of concordance with effects are observed in experimental animals induced carcinogenicity centers around observed at these sites in (see section IV.B.1). its metabolic activation. The metabolic epidemiological studies (Refs. 77, 96). In 3. Geographic Differences in Cancer activation of NNN leads to the formation contrast, NNK is known for being a of DNA and hemoglobin adducts and powerful systemic lung carcinogen. Risks From Smokeless Tobacco Use subsequent mutagenicity, ultimately NNK causes lung tumors in animals, Although there is some heterogeneity resulting in cancer. NNN can be including mice, rats, and hamsters, among particular study estimates, metabolized by 2′-hydroxylation and 5′- independent of the route of research on the association between hydroxylation, with the 2′- administration (Refs. 8, 149, 162 smokeless tobacco use and oral cancer hydroxylation the more predominant through 167). Even when animals are risk generally has found significant metabolic pathway (Ref. 8). The noted given NNK orally, a dose-dependent differences in risk by geographic region. DNA adducts formed from NNN are formation of lung tumors is observed For the United States, Boffetta et al. POB–DNA via the 2′-hydroxylation (Refs. 164, 165, 166). Indeed, a recent analyzed nine oral cancer risk estimates pathway (Refs. 172, 173, 177) and py- study found 100 percent of animals from seven independent studies that py-dI via the 5′-hydroxylation pathway receiving NNK via oral exposure either adjusted for smoking or were (Ref. 169). NNN has a chiral center at developed lung tumors (Ref. 167). restricted to never smokers and found a ′ the 2 -position and exists in 2 However, no oral cavity or esophageal summary relative risk for smokeless enantiomeric forms, (R)–NNN and (S)– tumors have been reported in animals tobacco use of 2.6 (Ref. 100). Lee and NNN, with (S)–NNN being the exposed only to NNK (Ref. 8). Hamling published a separate analysis predominant enantiomer in smokeless 2. Evidence for NNN Carcinogenicity in that generated an overall relative risk tobacco products (Refs. 180, 181). Humans estimate of 2.16 from all available U.S. The MOA for NNN-induced studies (Ref. 114). The authors also Although the data on NNN exposure carcinogenicity is supported by the generated estimates of never smoker oral in humans is more limited, two recent pattern of mutagenesis and DNA adduct cancer relative risks (a relative risk of epidemiological studies have found formation in target tissues following oral 3.33) for 5 studies and smoking-adjusted strong associations between NNN and exposure to NNN in experimental oral cancer relative risks (a relative risk cancer risk among cigarette smokers, animals. For example, NNN was found of 1.65) for 12 studies for U.S. smokeless providing evidence that increased to be mutagenic in tongue, oral and tobacco users. Toombak, a smokeless exposure to NNN through use of certain esophageal tissue in mice following oral tobacco product commonly used in tobacco products is associated with exposure via drinking water (Ref. 174). Sudan, has been found to have a relative greater risk of head, neck, and Both POB–DNA and py-py-dI adducts risk for oral cancer of 3.9 (Refs. 104, 4), esophageal cancer in tobacco users. In have been detected in the oral cavity, while in India and Pakistan use of esophageal mucosa, nasal cavity, liver one nested case-control study among smokeless tobacco products, including and lung of rats following exposure to Chinese men, urinary levels of NNN in pattiwala, naswar, khaini, and zarda, NNN via drinking water (Refs. 169 smokers were significantly associated was associated with relative risks for through 173). Additionally, dose- with increased risk of developing oral cancer as high as 14 (Ref. 1 at table dependent formation of POB–DNA esophageal cancer, but not lung cancer, 71). In Scandinavia, increased oral adducts has been observed in oral, after controlling urinary total NNAL cancer risks were observed in some but esophageal and nasal mucosa following (used to measure NNK exposure), not all studies (Refs. 92, 188, 189, 191, oral exposure to NNN (Ref. 170), as has smoking intensity and duration, alcohol 192). py-py-dI (Ref. 169). A greater number of consumption, and urinary cotinine DNA adduct formation has been also (nicotine metabolite used to measure The geographic variations in oral been observed in oral and esophageal nicotine exposure) (Ref. 77). In the same cancer risks are believed to be due to tissues compared with other sites, cohort, total urinary NNAL was differences in product toxicant content consistent with previous findings of independently and significantly (Ref. 100). TSNA concentrations in increased tumor formation in oral and associated with increased risk of smokeless tobacco products vary by esophageal tissues compared with other developing lung cancer (Ref. 183), product and region; NNN levels are sites (Refs. 94, 178). For example, POB- whereas no association was observed generally lowest in snus manufactured adduct formation was greater in oral between urinary total NNAL and in Sweden, while NNN levels in cavity and esophageal mucosa esophageal cancer risk (Ref 77). In a smokeless tobacco products sold in the compared with lung or liver in rats second case-control study, mean levels United States are typically higher (Refs. following oral exposure to (S)-NNN via of NNN were significantly higher in 11, 13, 5, 10). Many smokeless tobacco drinking water (Refs. 171, 172). These cases diagnosed with head and neck products sold elsewhere in the world, findings are consistent with previous squamous cell carcinoma compared to including in India and Sudan, contain reports of increased oral and esophageal matched controls, although no even higher levels of NNN and other tumor formation as compared with other adjustment was made for potential carcinogens than those in the United tissues (Refs. 94, 178) and the reported confounding factors (Ref. 96). Although States (Refs. 206, 105). These analyses, high incidence of oral and esophageal these studies were conducted among in addition to the toxicological evidence tumors following oral exposure to NNN smokers, they support the significant demonstrating that NNN is a potent oral in rats (Refs. 7, 95). role of NNN in cancer development in cavity and esophageal carcinogen, Recent evidence has demonstrated humans and are highly relevant to provide strong support for a relationship target organ specificity for the smokeless tobacco users, who have between smokeless tobacco use, NNN carcinogenic effects of NNN and NNK in comparable levels of exposure to NNN levels in these products, and oral cancer animals and in humans. As previously and NNK as those of cigarette users risk by geographic region. Thus, FDA discussed, NNN’s carcinogenic effects (Refs. 97, 72, 98, 99). Moreover, these believes that reducing NNN levels in have been documented in the epidemiological findings support the smokeless tobacco products would esophagus, nasal, and oral cavities when target organ specificity and cancer risk reduce cancer risk.

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C. NNN in Smokeless Tobacco Products 2. Factors That Influence NNN Levels that increase relative humidity during the growing season are more conducive 1. Formation of NNN in Smokeless NNN levels in tobacco can vary to increases in total TSNA formation. Tobacco Products significantly from year to year, intra- year, and farm-to-farm (Ref. 34). • Fertilizer. Nitrogen rich fertilizer NNN is formed either by the Although tobacco plants inherently can also have a profound effect on nitrosation of nicotine with the loss of produce a small amount of NNN (Refs. nitrate and NNN levels found in tobacco a methyl group or by nitrosation of 35, 1), a wide variety of factors can (Ref. 41). Higher NNN levels are found nornicotine, primarily during the curing affect the final levels of NNN found in in crops fertilized with nitrogen-rich of tobacco (Ref. 29). Nicotine is a the finished tobacco product (Ref. 1). fertilizers compared to fertilizers with tertiary amine while nornicotine is a These factors, which can either increase lower nitrogen content (Refs. 42, 43, 34). secondary amine; the rate of nitrosation or decrease NNN levels in smokeless This is because, when nitrogen-rich of tertiary amines is slow compared to tobacco products, include the tobacco fertilizer is used during tobacco the rate of nitrosation of secondary type (e.g., dark air-cured tobacco, Bright growing, more nitrogen is incorporated amines (Ref. 30). As the concentration of leaf tobacco, Burley tobacco), growing into the leaves of the tobacco in the nicotine in smokeless tobacco products conditions (e.g., geographic region, form of nitrate. As the tobacco leaves are is typically three orders of magnitude climate, rainfall), curing techniques cured, the nitrate acts as a substrate for larger than the TSNA concentration, (e.g., fire, flue, air, sun), production microorganisms reducing the nitrate to NNN formation does not have a process (e.g., additives), and storage nitrite. The nitrite reacts with alkaloids significant impact on product nicotine conditions (e.g., temperature, humidity, such as nicotine or nornicotine in the levels (Refs. 5, 10). duration) (Ref. 1). As discussed in tobacco during curing to form higher The primary nitrosating agent is section IV.E, because there are many levels of TSNAs such as NNN. nitrite (Ref. 31). Reduction of nitrate by factors that can influence the NNN level bacteria such as halotolerant in smokeless tobacco products, there c. Curing Techniques micrococci, Coryneforms, and also are a number of options available There are four main methods for halophilic rods during the fermentation to manufacturers to reduce and control curing tobacco: Sun, air, flue, and fire process is the primary source of nitrite NNN levels in order to meet the curing. Sun-cured tobacco is cured on in smokeless tobacco products (Ref. 34). requirements of this proposed standard. outdoor racks exposed to the sun while Nitrogen-rich fertilizer is also a source a. Tobacco Type of nitrate and, upon reduction, nitrite air-cured tobacco is cured on racks in a (Ref. 41). Higher NNN levels are found Studies have shown differences in well-ventilated barn under ambient in tobacco crops fertilized with NNN levels prior to curing and temperatures (Ref. 4). Flue and fire nitrogen-rich fertilizers compared to processing among different varieties of curing occur in artificially heated and fertilizers with lower nitrogen content tobacco. Higher NNN concentrations ventilated barns. Flue-cured tobacco is (Refs. 42, 34). Tobacco and smokeless have been found in Burley and dark cured on racks in a barn or other tobacco products with low nitrite tobacco compared to flue-cured Bright enclosed structure with an external heat concentrations have low levels of NNN, leaf tobacco (Ref. 36). Burley tobacco source (e.g., heat exchanger, propane or while products high in nitrite contain also contains more NNN compared to diesel heaters) so the tobacco isn’t higher concentrations of NNN (Refs. 32, Virginia and Oriental types, whether exposed to smoke (Refs. 34, 200). In 31). grown in the same or different contrast, fire-cured tobacco is cured on geographical locations (Ref. 37). racks in a barn and exposed directly to There is limited evidence to support The use of selectively bred ‘‘low smoke from a wood fire (Ref. 201). that an appreciable amount of NNN is converter’’ tobacco seed has been shown Curing can take from a few days to formed from nicotine or its metabolites to result in lower nornicotine (precursor several weeks depending on the curing in humans (Refs. 193, 194). The reaction to NNN) levels in tobacco (Refs. 38, 39, method (Ref. 44). The curing process not of dietary precursors with nitrosating 40). The amount of NNN in a tobacco agents supplied by the diet can result in only dries out and preserves the tobacco variety before curing or processing is but also imparts characteristic flavor. the endogenous formation of N- dependent on the amount of its During the curing process, the curing nitrosamines in humans (Refs. 195, 196, precursor nornicotine, which in turn is method, humidity, air flow, 197). The acidic environment in the dependent on the amount of its temperature, and the fuel used for stomach creates favorable conditions for precursor nicotine (Ref. 38). Nornicotine heating the tobacco influence the extent nitrosation to occur (Ref. 198) and is normally present at very low levels nitrosation of nornicotine has been compared to nicotine, but tobacco to which the NNN level changes (Refs. observed in vitro under simulated plants, through a process called 45, 46). Studies have shown that flue gastric conditions, whereas nitrosation ‘‘conversion,’’ can convert some of their and fire-curing tobacco results in higher of nicotine has not been observed (Ref. nicotine to nornicotine (Ref. 39). Low NNN levels than when the same tobacco 199). To date, there is not sufficient data converter seeds come from plants is air-cured (Refs. 47, 42, 1). In addition, in humans to indicate any significant in which, through selective breeding and air-curing during periods of high vivo NNN synthesis. genetic engineering, have a lower relative humidity produces tobacco with NNK is primarily formed through potential to convert nicotine to higher amounts of TSNAs and nitrite nitrosation of nicotine during the later nornicotine (Ref. 40). (Ref. 46). However, TSNAs in tobacco stages of tobacco processing (i.e., curing were shown to be lower when cured by and fermentation) (Ref. 33). Similar to b. Growing Conditions reducing humidity by improving the air NNN, the primary nitrosating agent is • Climate. Weather is a significant circulation or by using an indirect nitrite and products with low nitrite factor in NNN formation. Increased heating source to limit exposure to concentrations have low levels of NNK rainfall, including more frequent intense smoke (Refs. 46, 48). Furthermore, while products with high nitrite weather systems such as hurricanes, direct flue curing with liquid propane concentrations have high levels of NNK correlate with higher levels of TSNAs gas leads to higher NNN levels than fire (Refs. 32, 31). (Ref. 34). Specifically, wetter conditions curing or indirect flue curing (Ref. 49).

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d. Production Process Researchers have reported a 2-fold storage (Refs. 53, 54). Furthermore, During production, microorganisms increase in NNN levels in sun-cured although retailers are encouraged to (bacteria, fungi, and yeast) on tobacco tobacco and a 3-fold increase in NNN refrigerate Swedish snus to maintain play a significant role in the generation levels in Burley tobacco when stored at ‘‘perceived product freshness,’’ the of nitrite and the subsequent formation ambient temperatures over a 1-year product’s low bacterial activity may of TSNAs (Ref. 202). The period (Ref. 41). Further, studies have stabilize the NNN level even when shown that storage temperatures as low stored at room temperature (Ref. 11). microorganisms can come from a variety ° of sources including the soil and as 27 C can lead to increased NNN formation in air-cured Burley tobacco, 3. Levels of NNN in U.S. Smokeless surrounding environment, or unsanitary Tobacco Products manufacturing conditions (Ref. 12). and that the rate of increase becomes greater as the temperature is increased Fermentation is commonly used in The levels of NNN in smokeless (Ref. 41). In addition, air-cured Burley the production of U.S. smokeless tobacco products on the U.S. market can tobacco products. Fermentation imparts tobacco stored at higher temperature (24 °C v. 32 °C) and higher relative vary by several orders of magnitude, not flavor and contributes to higher nitrite only among different subcategories of and NNN levels (Ref. 50). Reduction of humidity levels (70 v. 83 percent) showed increases in both nitrite and products, but also among products in nitrate by bacteria during the the same subcategory (table 2, Refs. 5, fermentation process is the primary NNN levels (Ref. 52). Similar to cured tobacco, high 10, 56). After measuring NNN levels in source of nitrite in smokeless tobacco 46 different smokeless tobacco products products (Ref. 34). The increased nitrite temperature, high humidity, and extended storage can cause levels of available in the United States from 2006 concentration subsequently contributes and 2007, Borgerding et al. found NNN to the nitrosation of amino alkaloids and NNN to increase in smokeless tobacco products. As smokeless tobacco levels ranged from below the limit of the formation of NNN. m m In contrast, certain processing products ‘‘age,’’ the water content can quantification (0.02 g/g) to 14.4 g/g methods have been reported to help change, leading to bacterial growth, and per dry weight (Ref. 5). As shown in limit the levels of NNN formed during the pH and nicotine content can table 2, the NNN levels within the class production. For example, using non- decrease, causing nitrosamine levels of moist snuff and dry snuff ranged from nitrate reducing bacteria during the such as NNN to rise (Ref. 11). 0.6 to 12.8 mg/g per dry weight and 5.91 fermentation process (i.e., through Studies have shown that NNN to 12.0 mg/g per dry weight, respectively increases in moist snuff and dry snuff (Ref. 5). seeding or starter culture) can lower ° NNN yields (Refs. 34, 51). Cleaning and when stored at 24 C for 24 days (Refs. A more recent study by Ammann et sanitizing all equipment used in the 53, 54). Exposing moist and dry snuff to al. examined 34 products purchased in processing and manufacturing of ambient air, such as when a product is the United States in 2015 (Ref. 10). In smokeless tobacco products, including opened and closed between dips, also line with the Borgerding study, the fermentation equipment, can lower increases NNN concentrations (Ref. 53). Ammann et al. found NNN levels microorganisms on tobacco and lower Similar to cured tobacco leaves, the ranged from 0.64 to 12.0 mg/g per dry NNN yields (Ref. 34). In addition, using storage of moist snuff at low ° weight (Ref. 10). The NNN levels for closed process blenders at a high temperatures (4 C) reduces the increase moist snuff ranged from 1.0 to 9.5 mg/ temperature, adding bicarbonate and in NNN that was seen when the same g per dry weight while the NNN levels carbonate salt solutions to control pH, product is stored at ambient conditions for dry snuff ranged from 5.91 to 12.0 adding humectants, and pasteurization (Ref. 55). mg/g per dry weight (Ref. 10). or heat treatment can lower microbial Humidity levels during storage can The range of NNN levels described in activity during production, leading to have an even greater influence than lower NNN levels in smokeless tobacco temperature on NNN formation in these studies have been confirmed by products (Ref. 11). finished smokeless tobacco products. numerous other studies. Stepanov et al. Specifically, the NNN levels in moist reported a similar range for moist snuff e. Storage Conditions and dry snuff can be increased just by (3.8 to 6.9 mg/g per dry weight) with dry Storage conditions (i.e., temperature raising the relative humidity during snuff ranging from 0.95 to 5.3 mg/g per and humidity) and the duration of storage from 22 to 50 percent (Ref. 54). dry weight (Ref. 13). In a separate study, storage have been shown to influence Moreover, the combined effects of Stepanov et al. reported a wide range of NNN levels. Cured tobacco leaves and humidity and temperature are enhanced NNN levels in 11 dissolvables that are finished smokeless tobacco products are in products with higher moisture smokeless tobacco products (0.27 to 2.7 stored until they are processed or content (Ref. 54). Yet, storage conditions mg/g per dry weight) (Ref. 56). Finally, consumed. Tobacco leaves are often do not have the same effect on all types Lawler et al. reported a wide range of stored on farms for up to 3 months prior of smokeless tobacco. Studies on storage NNN levels in chewing tobacco (0.94 to to sale to tobacco product of chewing tobacco did not show the 2.8 per wet weight which equates to 1.2 manufacturers. Once sold, the tobacco same increase in NNN as seen with to 3.6 mg/g per dry weight) and in dry may be stored for another 18 months moist and dry snuff, which suggests that snuff (6.1 to 31 mg/g per wet weight before it is manufactured into a finished some tobacco blends may be less prone which equates to 6.5 to 33 mg/g per dry product (Ref. 41). to producing nitrosamines during weight) (Ref. 20).

TABLE 2—NNN CONCENTRATION AND MARKET SHARE OF SMOKELESS TOBACCO PRODUCTS SOLD IN THE UNITED STATES

Mean1 and range of NNN measured in μg/g dry weight (number of products) Smokeless Market share 2 tobacco product Stepanov et al., 2014 Borgerding et al., 2012 Amman et al., 2016 (%)

Dissolvable ...... 1.78; 0.27–2.66; (11) ...... <0.1 Chewing Tobacco (Loose leaf, plug, ...... 2.21; 0.66–5.05; (8) ...... 2.24; 0.92–4.60; (8) ...... 5.2 chew). Dry Snuff ...... 5.53; 0.81–14.42; (10) ...... 7.50; 5.91–12.00; (4) ...... 0.7

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TABLE 2—NNN CONCENTRATION AND MARKET SHARE OF SMOKELESS TOBACCO PRODUCTS SOLD IN THE UNITED STATES—Continued

Mean1 and range of NNN measured in μg/g dry weight (number of products) Smokeless Market share 2 tobacco product Stepanov et al., 2014 Borgerding et al., 2012 Amman et al., 2016 (%)

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 ...... 3.69 ...... 3.01 ...... product subcategories 3. 1 Mean values were determined by averaging the NNN concentrations across a smokeless tobacco product subcategory in each of the three representative studies. 2 Market share data was based on 2015 retail scan data from Nielsen. 3 In order to calculate a market share adjusted mean the mean of each subcategory was multiplied by its representative market share (e.g., Chewing Tobacco [NNN] × .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 levels in smokeless tobacco products discussed in section IV.B of this studies discussed in this subsection from current levels. document, epidemiological studies suggest that there exists the potential to As NNN appears to have a genotoxic demonstrate a lower risk of oral cancer reduce the levels of NNN in all mode of action, FDA followed the U.S. from the use of Swedish snus in Sweden smokeless tobacco through Environmental Protection Agency’s compared to other smokeless tobacco manipulation of starting materials and (EPA’s) guidance for carcinogen risk products in other countries. It is curing processes, as well as careful assessment and assumed a linear anticipated that the proposed product control of manufacturing and storage relationship in the low-dose region of standard of 1.0 mg/g dry weight would practices. the dose-response model (Ref. 203). bring the NNN level in U.S. smokeless Using this model, the risk of cancer is tobacco products in line with those of D. Basis for the NNN Limit in the linearly reduced as exposure to NNN Swedish snus. Proposed Standard approaches zero. While a limit of 0.0 mg/ With respect to risk reduction, FDA As discussed in section IV.B of this g for NNN would maximize cancer risk assumed that changes in the growing reduction to smokeless tobacco users, document, the scientific evidence conditions and changes in product there is limited information on NNN supports that NNN is a potent curing and processing may be necessary levels lower than the proposed standard carcinogenic agent found in smokeless to achieve lower NNN levels in and their technical achievability. We smokeless tobacco products. As tobacco products and that NNN in note, however, that an NNN level of 1.0 discussed in section IV.E, it appears that smokeless tobacco products is a major mg/g of tobacco has been achieved in there are several options for achieving factor underlying oral and esophageal some smokeless tobacco products sold the proposed NNN limit. cancers. The epidemiological evidence in the United States and is thus We note that FDA’s approach to indicates populations who use achievable using current technology. As establishing the proposed limit differs smokeless tobacco products with lower discussed in section II.C of this from that of other regulatory agencies, levels of NNN have lower cancer risks document, FDA may consider a lower such as the EPA and the U.S. (Refs. 4, 100, 101). Thus, it is NNN level in the future. In addition, Occupational Safety and Health anticipated that reducing levels of NNN FDA welcomes comments on the Administration (OSHA), which set in tobacco products in the United States technical achievability of complying regulatory exposure limits based upon a will reduce the incidence of oral and with the proposed standard in this rule. risk level deemed to be ‘‘acceptable’’ or esophageal cancers among smokeless FDA modelled NNN attributable ‘‘negligible’’ (Refs. 204, 205 at appendix tobacco users. cancer risk to estimate the potential B). FDA expects that although the Based on our assessment of the benefits to public health. Specifically, cancer risks posed by smokeless tobacco evidence, we are proposing that the FDA modelled the effect an NNN products that meet the proposed mean level of NNN in any batch of smokeless tobacco product standard standard would be lowered, use of these finished smokeless tobacco products not would have on reducing the cancer risk products would still pose increased exceed 1.0 mg/g of tobacco (on a dry to a population exposed to NNN cancer risks, including increased oral weight basis) at any time through the through use of smokeless products. This cancer risks, compared with not using product’s labeled expiration date as analysis is described in detail in this smokeless tobacco products. Thus, the determined by testing in compliance section. proposed product standard establishing with § 1132.12 (proposed § 1132.10). In FDA also considered the a limit for NNN in smokeless tobacco selecting the NNN limit in this proposed epidemiological evidence demonstrating products is not intended to standard, FDA took into consideration differences in observed cancer risks communicate that such levels are the epidemiological evidence between users of smokeless tobacco ‘‘acceptable’’ or ‘‘negligible’’ from a demonstrating differences in observed products manufactured in the United public health perspective. cancer risks between users of smokeless States and in Sweden. We focused on tobacco products manufactured in the epidemiological evidence from Sweden 1. Excess Lifetime Cancer Risk of NNN United States and in Sweden, and the because Swedish smokeless tobacco in U.S. Smokeless Tobacco Products technical achievability of the proposed products tend to have lower levels of FDA estimated the excess lifetime limit. To estimate the anticipated health NNN than other smokeless tobacco cancer risk (ELCR) for oral cancer benefits of the proposed standard, FDA products (Refs. 100, 114), which helps associated with the current NNN levels modeled the estimated cancer risk inform our public health analysis of a in U.S. smokeless tobacco products and reduction determined by reducing NNN product standard limiting NNN. As compared it to an estimate of the ELCR

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under the proposed standard. We lifetime cancer risk, the ELCR is a associated with wide variability, we calculated the ELCR with and without unitless probability (e.g., 1 in 10,000 attempted to derive average values to the proposed product standard to chance). The equation is based on the estimate a population average ELCR. estimate the extent to which the U.S. Environmental Protection Agency Below we describe the assumptions that proposed standard can reduce the risk Risk Assessment Guidance (Ref. 57). are used in this analysis and the of cancer among smokeless tobacco The key variables in the equation are: justification for those assumptions. users in the United States. Then FDA (1) The level of NNN in the product (i.e., Because of limitations in data, used the resulting reduction in lifetime concentration in product as used); (2) particularly with regard to data cancer risk to estimate the potential the amount of product (mass) used each underlying the CSF, the ELCR decrease in oral cancer cases as a result day; (3) the amount of NNN that leaves calculation is not used to assess of this rule. the product during use (i.e., percent absolute cancer risk. Instead, the ELCR Given the variability associated with extracted) and the amount of the is used to estimate the percent reduction smokeless tobacco use (frequency, extracted NNN that is absorbed by the in cancer risk associated with quantity) and lack of data regarding the body (i.e., absorption rate); (4) the length implementing an NNN limit for dose-response relationship for NNN in of time the product is used over a smokeless tobacco products. FDA humans, FDA is using the ELCR lifetime, which is determined by the welcomes public comments on calculation to provide an understanding years of use (i.e., exposure duration) alternative assumptions that may affect of the relative, rather than absolute, risk over the lifetime (i.e., averaging time); the ELCR estimate. Commenters should associated with different product classes (5) body weight of the user; and (6) the provide explanations as to why the and the impact of the proposed product cancer slope factor (CSF), which is used alternative assumptions may lead to more robust estimates of the ELCR standard on users of smokeless tobacco. to represent the dose-response associated with this product standard. As demonstrated by Equation 1, relationship between NNN and cancer which FDA used to calculate the excess incidence. As each of these variables is Equation 1—ELCR Calculation

C = Concentration of NNN in product as used NNN is based upon tumor data from because they are the most (mg/g wet weight) hamsters orally exposed to NNN in comprehensive studies of NNN levels in IR = Intake rate (mg of wet (as used)) product drinking water in a study conducted by U.S. smokeless tobacco products and used per day (12 g/day; 2.5 g/day for Hecht et al. (Ref. 59), which compared the levels are similar to levels which dissolvables) AB = Absorption rate, how much of product a single dose scenario with a control have been reported by other NNN is transferred to the user (60 group. The CalEPA thus generated a investigators (see section IV.C.3). These percent) slope by drawing a line between the two studies also reported the moisture EF = Exposure frequency (365 days/year) points (tumor rate at a single dose and content of the smokeless tobacco ED = Exposure duration (60 years) tumor rate in the control group). EPA’s products, which FDA used to determine BW = Body weight in kg (70 kg) 2005 Cancer Guidelines and subsequent the products wet weight NNN levels AT = Averaging time (365 days/year; 78 Benchmark Dose Guidance elaborate (i.e., what a user would be exposed to). years) extensively on the determination of the This calculation involves taking the dry CSF = Cancer slope factor (1.4 mg/kg/day) point of departure (POD) for generating weight NNN measurement and As defined by the EPA guidelines, the a CSF (Refs. 203, 187). More accounting for the moisture found in the cancer slope factor (CSF) is ‘‘an upper specifically, EPA recommends that the product when used by consumers [NNN bound (approximating a 95percent starting point for subsequent mg/g dry weight] × [1-moisture content] confidence limit) on the increased extrapolations and analyses be the = [mg/g wet weight (as used)]. cancer risk from a lifetime exposure to lowest dose adequately supported by For the intake rate (mass of product an agent. This estimate, usually the data. However, in a single dose used each day), FDA chose an average expressed in units of proportion (of a study, without an understanding of the use assumption of 12 g of wet product population) affected per mg/kg/day, is shape of the exposure-response curve at per day, every day based on an generally reserved for use in the low- lower doses, there is potentially experimental study in the United States dose region of the dose-response significant bias in the derivation of the that indicated that the range of the most relationship; that is, for exposures CSF—leading to subsequent uncertainty common form of smokeless tobacco use, corresponding to risks less than 1 in in the modeling of cancer risk. Thus, as moist snuff, is between 5.1 and 42.5 g/ 100. This term is usually used to refer noted above, FDA’s ELCR calculation is day (Ref. 60), with an average use of 12 to oral slope factors (i.e., slope factors only used to estimate relative risk of g/day (Ref. 60). This study is widely used for assessing ingestion exposure).’’ alternative exposure scenarios, not cited for estimating average smokeless (Ref. 190). absolute risk. FDA welcomes public tobacco use (Refs. 132, 212, 213). The 12 For this ELCR assessment, FDA uses comment on whether there is a more g/day assumed estimate is consistent the CSF for NNN generated by the robust CSF available for NNN. with studies that look at use in terms of California Environmental Protection For the concentration of NNN in the the number of tins (container holding Agency (CalEPA) in 1992 (Ref. 93). product, FDA used the Borgerding et al. the smokeless tobacco product) of Although this CSF has been used as the and Ammann et al. data (Refs. 5, 10) to tobacco consumed (Refs. 61 through 71). basis for several published analyses represent the range of levels of NNN in These studies’ estimates ranged from 1.2 (Refs. 207, 208, 209, 74, 210, 211, 102), current smokeless products, which tins to 4.6 tins/week, with an average of it has significant limitations. The ranged from below the limit of 3.68 tins/week (0.53 tin/day. Based on CalEPA CSF of 1.4 (milligram per quantification (0.02 mg/g) to 14.4 mg/g an average size of a tin of 1 ounce (or kilogram per day (mg/kg/day))¥1 for per dry weight. We chose these studies slightly more than 28 g), we estimate

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that the average amount of smokeless TSNAs before and after use of the absence of specific data on the tobacco product used is approximately smokeless tobacco product was population of interest (i.e., smokeless 15 g/day [0.53 tin/day × 28 g/tin = 14.84 determined along with analysis of the tobacco users). Upon initiation, FDA g/day], which suggests an assumption of expectorated saliva and urine samples. assumed daily use (365 days/year) of an 12 g/day is not unreasonable. The individual subject data provided by average mass of 12 g of wet product per Conventional moist snuff constitutes Hecht et al. yields a median extraction day. In addition, FDA used an average ± the overwhelming majority of the of 60 percent (59 23 percent) (Ref. 58). adult body weight of 70 kg in the ELCR smokeless tobacco market in the United Other studies also cite 60 percent as an calculations, which is consistent with States (Ref. 131). The figure of 12 g/day estimate of the amount of TSNAs EPA practices (Ref. 57). among moist snuff users does provide a extracted from smokeless tobacco (Refs. reasonable average estimate of what 73, 74). Table 3 shows the estimated ELCR most U.S. smokeless tobacco users of FDA assumed the absorption rate for calculated by using the mean NNN most product subcategories consume on the average user to be 100 percent of the concentration of several different a daily basis. However, FDA recognizes extracted 60 percent of the categories of smokeless tobacco that the amount of smokeless tobacco concentration of TSNAs found within a products sold in the United States from used in a day varies by product. In given smokeless product. This table 2, using Equation 1 and the particular, some dissolvable smokeless assumption is precautionary because it assumptions described in this section. tobacco products weigh as little as one- assumes that the user is exposed to the Given the assumed linear nature of the fifth or one-quarter as much (Ref. 56). total amount of NNN extracted from the CSF, use of products with lower NNN Therefore, 2.5 g/day was used for our product, even though some of the NNN levels has a lower ELCR while use of ELCR calculations for daily use of in saliva may be excreted without being products with higher NNN levels has dissolvable products based upon a usage absorbed. Therefore, the absorption rate the highest ELCR. For example, use of study by Krautter et al. (Ref. 15). used for the ELCR calculations is 60 dissolvables with a mean level of NNN The extraction percentage, or fraction percent (i.e., 100 percent absorption of of 1.6 mg/g (as used) has a very low of TSNAs removed from a smokeless the 60 percent extracted NNN). tobacco product while in use, has been FDA used 60 years of product use as ELCR of 0.4 in 10,000, while use of dry reported to range from 10 to 85 percent the exposure duration for the ELCR snuff with a level of NNN of 5.1–7.0 mg/ (Refs. 58, 73, 74). Hecht et al. analyzed calculations assuming initiation at or g (as used) has an ELCR of 5.6–7.6 in extraction and direct absorption of near 19 years of age (Ref. 23) and an 10,000. The current market share TSNAs in humans. A measured amount average life span of 78 years for the adjusted mean NNN level of all U.S. of smokeless tobacco was inserted into general population (Ref. 75). We used 78 smokeless tobacco products reported by the oral cavity for 30 minutes. All saliva years because it is the recommended the Borgerding and Ammann studies is was collected during use of the product value from the EPA (Ref. 75) to use 1.7–1.8 mg/g wet weight (as used), the and three consecutive 24-hour urine when calculating excess lifetime cancer use of which corresponds to an samples were analyzed. The amount of risk due to toxicant exposure in the estimated ELCR of 1.9–2.0 in 10,000.

TABLE 3—ESTIMATED ELCR FOR SUBCATEGORIES OF U.S. SMOKELESS TOBACCO PRODUCTS

ELCR (expressed as ‘‘n’’ in 10,000) Smokeless tobacco product Stepanov et al., Borgerding et al., Ammann et al., 2014 2012 2016

Dissolvables ...... 0.4 ...... Dry Snuff ...... 5.6 7.6 Chewing Tobacco ...... 1.8 2.0 Moist Snuff ...... 2.0 1.8 Mean ELCR across product categories ...... 2.7 2.6 Market share adjusted ELCR across product 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 prod- uct subcategories examined.

Using the same assumptions as above the dry weight concentrations (0.5, 1.0, we estimate that, compared to the (Intake rate, NNN CSF), FDA estimated and 2.0 mg/g dry weight) to determine an current market, hypothetical market- the ELCR for use of smokeless tobacco ‘‘as used’’ (wet weight) NNN wide NNN levels of 0.5, 1.0 and 2.0 mg/ products with differing levels of NNN concentration. This estimation was g dry weight would reduce the ELCR by (dry weight, e.g., 0.5, 1.0, 2.0 mg/g) and based upon the moisture concentrations 83.2, 66.3 and 31.6 percent, how these levels would compare to the from the Ammann et al. study (Ref. 10), respectively. current market estimates (table 4). FDA and weighted by recent subcategory first carried out a moisture correction on market share data. As shown in table 4,

TABLE 4—ELCR FOR HYPOTHETICAL MARKET-WIDE MEAN NNN LEVELS AND COMPARISON TO CURRENT MARKET ELCR

NNN % Reduction in NNN μ ELCR (μg/g dry weight) ( g/g, wet weight, (n in 10,000) ELCR as compared as used) to current market 1

0.5 ...... 0.3 0.32 83.2 1.0 ...... 0.6 0.64 66.3

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TABLE 4—ELCR FOR HYPOTHETICAL MARKET-WIDE MEAN NNN LEVELS AND COMPARISON TO CURRENT MARKET ELCR—Continued

NNN % Reduction in NNN μ ELCR (μg/g dry weight) ( g/g, wet weight, (n in 10,000) ELCR as compared as used) to current market 1

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 for its consistent systemic lung recommended by the WHO for NNN and As noted earlier, Swedish snus carcinogenicity (Ref. 8). However, the NNK. relationship between smokeless tobacco generally has a lower NNN level than E. Information on Technical use and lung cancer is a matter of other smokeless tobacco products sold Achievability in the United States, and as discussed ongoing investigation and a definitive in section IV.B.3, some epidemiological association has not been established Section 907(b)(1) of the Tobacco studies demonstrate a lower risk of oral (Refs. 3, 4). Control Act requires FDA to consider cancer from the use of Swedish snus in NNN and NNK constitute potent information submitted in connection Scandinavia when compared to the use carcinogens in smokeless tobacco (Refs. with a proposed product standard of other smokeless tobacco products in 4, 78) and levels of these two TSNAs are regarding technical achievability of the United States (Refs. 100, 114). often correlated in smokeless tobacco compliance with the product standard. Substituting the mean NNN level of 0.55 products (Refs. 5, 20). Because many FDA, therefore, invites public comment mg/g (wet weight) that is in Swedish methods available to reduce NNN also addressing the technical achievability of snus (Ref. 5), into Equation 1 yields an reduce NNK, there is some evidence this proposed product standard, and ELCR of 0.59 in 10,000. As the proposed that a product standard that requires specifically requests submission of product standard of 1 mg/g dry weight lower NNN levels will potentially result evidence and data to support such for NNN would result in bringing U.S. in lower NNK levels as well (Ref. 84). comments. FDA has also chosen to A market survey of 16 snus brands smokeless tobacco products in line with consider available information regarding sold in Sweden in 1983, prior to the NNN levels in Swedish snus, it is not technical achievability in developing adoption of the GothiaTek voluntary surprising that the ELCR for such a this proposed rule and it appears that quality control standard, showed hypothetical market-wide mean NNN there are several options for achieving average NNN levels of 3.8 mg/g of level (table 4) would be almost the same the proposed NNN limit. tobacco and average NNK levels of 0.8 as that estimated for Swedish snus. As described in more detail in section Our analysis indicates that users of mg/g of tobacco per wet weight (Ref. 84). IV.C.2, there are many factors that can smokeless tobacco products would have In 2002, after GothiaTek was adopted, a influence the level of NNN in smokeless their ELCR reduced by approximately market survey of 23 snus brands sold in tobacco products. Accordingly, there are 65 percent if the market adjusted mean Sweden showed NNN levels decreased a number of options available to of NNN in smokeless tobacco products to 0.49 mg/g of tobacco and NNK levels manufacturers to reduce and control was reduced from that of the current decreased to 0.19 mg/g of tobacco per NNN levels in finished smokeless market to 1.0 mg/g dry weight (table 4). wet weight (Ref. 84). More recent tobacco products including, but not This value would approximate the ELCR analyses of constituents in smokeless limited to, the following: of the Swedish snus exposure scenario tobacco products manufactured in the • Using a type of tobacco with lower which epidemiological data suggests has United States indicate that smokeless concentrations of NNN (e.g., Bright a lower cancer risk. tobacco brands that are lower in NNN tobacco or low-converter types of Burley content are also lower in NNK (Refs. 5, tobacco); 3. Conclusion 20). Additionally a study by Song et al. • Using tobacco grown with limited Setting the proposed limit for NNN in (Ref. 6), examined the NNN and NNK use of nitrogen-rich fertilizer on tobacco finished smokeless tobacco products levels of conventional and low-TSNA crops; means that, on average, in a population smokeless tobacco products on the U.S. • Using tobacco processed with a of daily users of smokeless tobacco market. NNN:NNK ratios were 3.1 and different curing method (e.g., air curing products, over their life time, there 3.7 for the conventional and low-TSNA instead of flue curing the same tobacco) would be an approximately 65 percent varieties, respectively, which is in line or a modification of a currently used reduction in ELCR, compared with with results from previous studies (Refs. curing method to minimize its effect on lifetime daily use of a population that 5, 20). Accordingly, we anticipate a NNN levels (e.g., reducing humidity used smokeless tobacco products with potential reduction of NNK in during curing by improving air NNN levels at the current level. In smokeless tobacco in response to the circulation); section V, we calculate the impact of an proposed rule for NNN. We note that, in • Using tobacco that had a estimated 65 percent reduction in 2009, the WHO Study Group on bacteriostatic, bactericidal, or heated cancer risk on expected incidence of Tobacco Product Regulation solution (25 to 55 ßC) applied to tobacco oral cancer in the United States. recommended a regulatory limit for leaves during the growing, harvesting, We note that FDA considered setting NNN and NNK (combined) of 2 mg/g dry or curing processes to reduce the a product standard for both NNN and weight of tobacco (Ref. 78). Given the number of bacteria in the tobacco leaves NNK. However, FDA is proposing a ratio of NNN to NNK in smokeless and thereby reduce the NNN level; product standard for only NNN at this tobacco products, where the level of • Using a non-nitrate reducing time because of the more limited data NNN is generally greater than the level bacteria ‘‘starter culture’’ for the available on the relationship between of NNK, any smokeless tobacco product fermentation process; NNK and smokeless tobacco-related that meets the proposed NNN standard • Using cleaned and sanitized cancer risk. In particular, NNK is noted is likely to also meet the levels equipment for processing and

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manufacturing smokeless tobacco smokeless tobacco product for moist snuff (CRP–2), as well as the products; manufacturers use the validated method University of Kentucky cigarette • Adding humectants, sodium that has been developed at FDA’s reference product (3R4F cigarette chloride, or other additives to lower Southeast Regional Laboratory (SRL) in tobacco filler). Tobacco samples with water activity and reduce microbial Atlanta, GA (Determination of N- NNN levels expected to be higher than growth; nitrosonornicotine (NNN) in Smokeless 4 mg/g tobacco were analyzed after • Adding bicarbonate and carbonate Tobacco and Tobacco Filler by HPLC– dilution because they were too salt solutions to control pH; MS/MS, LIB No. 4620, January 2017) concentrated for analysis. This method • Pasteurization or heat treatment; (Ref. 79). The results from the test • was proven to be applicable for tobacco Storing tobacco leaves and finished method demonstrate a high level of products with various moisture levels, smokeless tobacco products at lower specificity, accuracy, and precision in including cigarette tobacco filler, snus, temperatures and relative humidity measuring a range of NNN levels across dry snuff, chewing tobacco, and moist levels; and a variety of smokeless tobacco products. snuff. • Limiting the duration of storage. Requiring that a single test method be HPLC is favored over gas For products that are already near the used would ensure that all of these proposed limit, one of these options chromatography (GC) because it allows factors are met and would permit for faster analysis and sample may be sufficient to bring the product comparison of test results among into compliance with the proposed preparation, although validated finished smokeless tobacco products methods exist for analysis of NNN well standard, while products which and testing facilities. However, FDA is currently have levels of NNN well above below the level specified in § 1132.10 by proposing that other methods may be either LC or GC. Mass spectrometer the proposed limit may need to use a used if they meet the requirements in combination of options. To the extent (MS) detection is favored over thermal § 1132.16 (Alternative test method). energy analyzer (TEA) detection because that any change in the processing of Numerous methods have been of the possibility of using isotopically- smokeless tobacco products (e.g., published that use either high- labeled NNN as an internal standard, curing, fermentation) affects the performance liquid chromatography/ which controls for variation in sample products flavor, FDA expects that mass spectrometry (LC–MS) or gas preparation. In addition, manufacturers would be able to adjust chromatography (GC), combined with instrumentation to perform LC–MS the flavor profile of finished smokeless thermal energy analyzer (TEA) detectors analysis is more readily available than tobacco products through minor to determine the content of NNN in changes in flavor ingredients. This tobacco. The validated test method that for GC–TEA and, therefore, proposed rule also could spur FDA is proposing to incorporate by manufacturers or analytical laboratories innovation and development of reference in § 1132.5(a) utilizes LC–MS wishing to establish this method additional methods and technologies to and has an analysis time of 8 minutes. themselves will have better access to reduce NNN levels in smokeless tobacco The method has a limit of quantification equipment. The internal standard is products. of 0.4 mg/g of NNN, a linear range of 0.4 NNN that has been specially labeled The proposed rule does not prescribe to 1.6 mg/g, and a method detection limit with isotopes of hydrogen and carbon, specific methods or processes for of 0.1 mg/g. The method performance deuterium or carbon-13, respectively. meeting the proposed NNN level, so that parameters for the standard method for The isotopic-labeling of the internal smokeless tobacco product NNN quantification in smokeless NNN standard increases the mass of the manufacturers would have flexibility in tobacco products do not differ internal standard relative to naturally identifying appropriate methods or significantly from the method occurring NNN, and the internal processes for reducing the NNN level in performance parameters of other standard appears as a distinct signal in their products. Because certain snus, methods that are currently in use. This the mass spectrometer detector. Because moist snuff, and chewing tobacco method uses an extraction solvent of the analyst knows the quantity of already contain low NNN levels, FDA 100 milliMolar (mM) ammonium acetate internal standard added to the tobacco expects that manufacturers of many of in high performance liquid at the beginning of sample preparation, those products may not need to make chromatography (HPLC) grade water the detector signal of the internal any manufacturing changes to meet the and a gradient of 5 to 50 percent of 5 standard can be used to quantify the proposed NNN level (Refs. 5, 10, 56). mM ammonium acetate in 95 percent amount of natural NNN present in the (Such manufacturers would remain acetonitrile at a 0.5 milliliter per minute sample. The isotopically-labeled subject to the proposed standard, flow rate. Analysis is conducted after a internal standard is chemically identical including its testing, sampling, labeling, known amount of carbon-13-labeled to NNN, so the internal standard used and recordkeeping requirements.) Thus, NNN is added to the tobacco, extracted for MS controls for all variations in FDA expects some smokeless tobacco for 5 minutes with 100 mM ammonium NNN levels that arise during sample products may require minimal changes acetate at elevated temperature and preparation and extraction. The to the manufacturing process to meet pressure, dried, and reconstituted in available scientific evidence suggests the proposed NNN level, while other methanol and ammonium acetate buffer. that deuterated and carbon-13-labeled products may require extensive changes The method includes the internal standards are equally to the manufacturing process to comply determination of NNN levels as well as acceptable for NNN analysis. Internal with the proposed level (Ref. 56). A moisture content, so the NNN level on standards used for TEA differ from smokeless tobacco product that has been a dry weight basis can be calculated. In internal standards used for MS because modified to comply with the product this method, water levels are they are chemically different from NNN. standard would be a ‘‘new tobacco determined according to International Therefore, slight differences may exist product’’ and subject to premarket Organization for Standardization (ISO) between the yield of NNN and the yield review. standards ISO 6488:2004 and ISO of the internal standard during the 6488:2004/Cor 1:2008 or ISO extraction and sample preparation steps. F. Analytical Method 16632:2013. Validation of this method The limits of detection for NNN by MS To test for the NNN limit in this was done using the smokeless tobacco may be lower than limits of detection by product standard, FDA proposes that reference products for snus (CRP–1) and TEA. However, validated methods exist

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for analysis of NNN well below the level studies in accordance with ISO 5725–2 NNN is a potent carcinogenic agent specified in § 1132.10 by either MS or (ISO 5725–2:1994) and only the SRL found in smokeless tobacco and, along TEA. method tests on a dry weight basis. with NNK, another TSNA, is labeled as Over the years a variety of analytical Thus, FDA concluded that levels of 1.0 Group 1 (known human carcinogen) by methods have been developed for the mg/g or lower on a dry weight basis of IARC (Refs. 1, 2). Third, substantial detection of NNN in smokeless tobacco NNN in tobacco could be reliably recent evidence supports site-specific products. For example, the Cooperation measured either by SRL’s method or by concordance of the carcinogenic effects Centre for Scientific Research Relative optimizing existing common methods to of NNN in animal and human to Tobacco (CORESTA) published meet the requirements of § 1132.16 epidemiologic studies. In particular, CORESTA 72, an LC–MS method for (Alternative test method). oral and esophageal tissues have been determining NNN levels in smokeless tobacco using a low calibration standard V. Standard Is Appropriate for the identified as targets for NNN-induced of 0.015 mg/g of tobacco, extraction in Protection of the Public Health carcinogenicity (Refs. 7, 95, 171, 172), 100 mM ammonium acetate, and a The Tobacco Control Act authorizes with observation of tumors in the oral deuterium-labeled NNN internal FDA to adopt tobacco product standards cavity and esophagus following oral standard (Ref. 80). CDC published an by regulation if it finds ‘‘that a tobacco exposure to NNN in experimental LC–MS method for smokeless tobacco product standard is appropriate for the animals (Refs. 7, 59, 94, 95, 148, 178). with an extraction in ethyl acetate and protection of the public health’’ (section These animal studies suggest a degree of use of a carbon-13-labeled NNN internal 907(a)(3)(A) of the FD&C Act). The concordance with effects observed at standard with an effective limit of Notice of Proposed Rulemaking (NPRM) these sites in epidemiologic studies detection of 0.072 mg/g NNN and an 8 for such a product standard must set (Refs. 77, 96). Finally, several minute analysis time (Refs. 81, 82). The forth this finding with supporting authoritative reviews have observed Swedish National Food Administration justification, which FDA is doing here differences in the magnitude of cancer published an LC–MS method for (section 907(c)(2)(A) of the FD&C Act). risks due to smokeless tobacco use smokeless tobacco with extraction in In order to make this finding, FDA across regions of the world, which have ethyl acetate, a limit of detection of must consider scientific evidence been found to correlate highly with 0.010 mg/g NNN, a 15 minute analysis concerning— • variation in the levels of tobacco time, and quantification using an The risks and benefits to the specific nitrosamines in smokeless external NNN standard (Refs. 83, 84). population as a whole, including users products (Refs. 1, 4). British American Tobacco published an and nonusers of tobacco products, of the LC–MS method for smokeless tobacco proposed standard; The proposed product standard is with extraction in methanol, a • The increased or decreased intended to reduce tobacco-related deuterium-labeled NNN internal likelihood that existing users of tobacco harms by requiring lower levels of NNN standard, and no published limit of products will stop using such products; (and likely also leading to detection (Ref. 85). and concomitantly lower NNK levels) in The American Health Foundation • The increased or decreased smokeless tobacco products sold in the published several similar GC–TEA likelihood that those who do not use United States. In this section, we methods for NNN in chewing tobacco tobacco products will start using such describe the expected benefits of the using extraction in a buffer containing products. Section 907(a)(3)(B)(i) of the proposed standard to the population as ascorbic acid, a 24 minute analysis time, FD&C Act. a whole, including specifically the and confirmation by MS of the TEA As discussed in this section of the benefits of reducing the number of new document, FDA has considered signal corresponding to NNN (Refs. 86, cases of and deaths from oral cancer scientific evidence related to all three 87, 88). Health Canada published attributable to smokeless tobacco. Official Method T–309, which is a GC– factors. Based on these considerations, TEA method for NNN in tobacco using we find that the proposed standard is In this section, FDA generates extractions in a buffer of ascorbic acid appropriate for the protection of public estimates of the number of new cases in dichloromethane, an internal health, because it will reduce the harm and fatal cases of oral cancer that would standard of N-nitrosopentyl-(3-picolyl)- associated with the use of smokeless be avoided over the 20 years following amine, a lowest calibration standard tobacco products and FDA does not implementation of the proposed product corresponding to about 0.2 mg/g tobacco, expect that the product standard will standard. We estimate that and a 35-minute analysis run time (Ref. increase the likelihood that non-users approximately 12,700 new cases of oral 89). will initiate tobacco or decrease the cancer and approximately 2,200 oral Other approaches besides LC–MS and likelihood that users will quit tobacco cancer deaths would be prevented in the GC–TEA have been explored to measure use in a manner that would offset the United States. Moreover, during that 20- NNN in tobacco filler. These methods benefits of the reduced cancer risk. year period, approximately 15,200 life have included two ISO methods using A. Benefits to the Population as a Whole years would be gained as a result of the gas chromatography with proposed standard. Because oral cancer chemiluminescence detection (ISO As discussed in section IV, on the is associated with significant health and 22303:2008 and ISO 22304:2008), an basis of the best available scientific economic impacts, we expect positive American Health Foundation method evidence, FDA has determined that public health benefits due to prevention using HPLC with ultraviolet absorption NNN is the predominant driver of detection followed by confirmation of excess oral cancer risk among smokeless of new and fatal oral cancer cases. We the peak by MS (Ref. 90), and a Swedish tobacco users. This determination is also expect that the proposed standard Match method using an NNN-specific based on multiple, consistent lines of would reduce the number of new and antibody in immunoassays (Ref. 91). evidence. First, several authoritative fatal cases of esophageal cancer among Although there are various methods to reviews have concluded smokeless continuing smokeless tobacco users and test for NNN, only the CORESTA 72 tobacco products, including those may reduce the risk of pancreatic cancer method has been externally validated currently marketed in the United States, as well. via round-robin method validation cause cancer (Refs. 1, 2, 3, 4). Second,

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1. Estimated Impact of Proposed NNN published systematic review and meta- product standard in terms of new and Standard on New and Fatal Oral analysis of studies of oral cancer among fatal cases of oral cancer. Oral cancer is Cancers U.S. smokeless tobacco users (Ref. 100). used as the endpoint of interest because The analysis in section IV.C suggests More specifically, as described in of the established strong relationship that the estimated lifetime cancer risk section IV.C of this document, FDA between smokeless tobacco use and oral (ELCR) would drop by approximately 65 estimates, by comparing its calculation cancer risk, as well as the identification percent under the scenario where the of the ELCR using the NNN levels of of NNN as a known, potent oral proposed product standard for currently marketed U.S. smokeless carcinogen. There are also a relatively smokeless tobacco products was fully tobacco products to its calculation of the large number of published estimates of implemented, and while assuming that hypothetical ELCR using the proposed oral cancer risk among U.S. smokeless all other variables remained constant standard, that meeting the standard tobacco users. would result in, on average, a 65 percent (e.g., user habits). Thus, over time, FDA As described in this section, we also reduction in the excess lifetime cancer expects implementation of the proposed expect the standard to reduce the risk of risk due to NNN among U.S. smokeless product standard to reduce the number esophageal cancer and it may reduce the tobacco users. Given the apparently of incident cases (i.e., those new cases risks of cancer at additional sites. predominant role of nitrosamines in of oral cancer that occur over time in the However, limited data are available to smokeless tobacco cancer risk, we smokeless tobacco user population) and permit direct quantification of this assume that the 65 percent reduction fatal cases of oral cancer by reducing the health benefit (Ref. 100). As such, we can be applied directly to the excess concentrations of a potent oral focus here on estimating the potential oral cancer risks attributable to carcinogen in smokeless tobacco benefits of the proposed product products (Ref. 107). To estimate the smokeless tobacco in general. Public standard in reducing the number of new potential impact of the standard on comment is sought on the strength of and fatal cases of oral cancer in the morbidity and mortality, we first model the assumptions underlying this United States. the annual number of new cases and approach to estimate the anticipated deaths from oral cancer that are public health effects of the rule, and We use the population attributable attributable to smokeless tobacco use in whether alternative approaches may risk formula introduced by Levin (Ref. the United States. We then estimate the exist. Commenters should provide 108) and subsequently used extensively number of these cases, both those new evidence supporting alternative by the CDC in its Smoking-Attributable cases that occur (incident cases) and assumptions or approaches to Mortality, Morbidity, and Economic those that are fatal, that would be estimating likely reduction in incidence Costs (SAMMEC) methodology for prevented as a result of the proposed of oral cancers associated with an modeling smoking-attributable mortality standard by reducing the population implementation of the proposed product (Ref. 109). Population attributable risk attributable risk by 65 percent. Relative standard. (PAR) is calculated as the proportion of risk estimates used to model the The analysis quantifies the estimated cases of disease that are attributable to population attributable risk come from a public health impact of the proposed the risk factor as:

where Pe is the prevalence of the attributable mortality. Because the product every day or some days. Age- exposure and RR is the relative risk of National Survey on Drug Use and and sex-specific prevalence of current disease among the exposed compared Health reports that smokeless tobacco smokeless tobacco use is reported in with the unexposed. The resulting use prevalence has been relatively table 5, along with the number of new proportion is then multiplied by the consistent among youth and adults in and fatal oral cancer cases in the United total number of cases of disease in the recent years (Ref. 23), these estimates States in 2010. The latter were obtained population to estimate the number of also serve as a general measure of the from United States Cancer Statistics cases that are attributable to the risk effects of smokeless tobacco use on oral data available on CDC’s WONDER Web factor. cancer in the United States in site (Refs. 112, 182, 184, 185, 186). We first estimate smokeless tobacco- subsequent years. We estimate the U.S. Newly diagnosed (incident) oral cancer attributable oral cancer cases and deaths for the United States in 2010. We use prevalence of smokeless tobacco use cases and oral cancer deaths attributable this year because of the availability of using 2010 National Health Interview to use of smokeless tobacco products, all relevant data inputs, including Survey data (Ref. 111). Current stratified by age group and sex, are also smokeless tobacco use prevalence smokeless tobacco use is defined as reported in table 5. Oral cancer cases estimates from the same data source reporting having used either chewing attributable to smokeless tobacco used in CDC’s SAMMEC method for tobacco or snuff at least 20 times in accounts for 3.4 percent of all newly estimating cigarette smoking- one’s life and currently using that diagnosed oral cancer cases.

TABLE 5—PREVALENCE OF CURRENT SMOKELESS TOBACCO USE AND NUMBER OF NEWLY DIAGNOSED AND FATAL CASES OF ORAL CANCER IN THE UNITED STATES, BY AGE GROUP AND SEX, U.S. 2010

Smokeless Newly tobacco use diagnosed Oral cancer Attributable Attributable Attributable 1 2 oral cancer oral cancer fraction prevalence oral cancer deaths cases deaths (%) (%) cases 2

Males:

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TABLE 5—PREVALENCE OF CURRENT SMOKELESS TOBACCO USE AND NUMBER OF NEWLY DIAGNOSED AND FATAL CASES OF ORAL CANCER IN THE UNITED STATES, BY AGE GROUP AND SEX, U.S. 2010—Continued

Smokeless Newly Attributable Attributable Attributable tobacco use diagnosed Oral cancer 1 2 oral cancer oral cancer fraction prevalence oral cancer deaths cases deaths (%) (%) cases 2

35–64 years ...... 4.6 15,960 2,770 808 140 5.1 65+ years ...... 3.9 10,351 2,997 444 128 4.3 Females: 35–64 years ...... 0.2 5,322 832 15 <10 0.3 65+ years ...... 0.3 5,664 1,699 19 <10 0.3 1 Source is the 2010 National Health Interview Survey conducted by the National Center for Health Statistics (Ref. 111). 2 Source is CDC WONDER, 2010 for cancers of the lip, oral cavity and pharynx (Ref. 112).

In calculating the population Lyman. The latter analysis yielded a We use similar methods to estimate attributable risk, FDA used summary summary relative risk of 2.16 (with a 95 the number of oral cancer deaths in the relative risks for the relationship percent confidence interval of 1.08– United States in 2010 that were between smokeless tobacco use and oral 4.33). This value matched the overall attributable to smokeless tobacco use, cancer risk derived from a meta-analysis relative risk estimate from an with the only difference being that we of epidemiology studies published by independent meta-analysis of the use the number of oral cancer deaths Boffetta et al. in 2008 (Ref. 100). relationship between smokeless tobacco during this year, rather than new Boffetta’s analysis, based on nine use and oral cancer risk in the United diagnoses during the year, in the relative risk estimates from seven States that was published in 2009 by population-attributable risk independent studies, generated a Lee and Hamling (i.e., a relative risk of calculations. We also estimate the life summary relative risk of 2.6 (95 percent 2.16; and a 95 percent confidence years that were lost due to these oral confidence interval of 1.3–5.2) for oral interval of 1.55–3.02), although based cancer associated with the use of cancer deaths attributable to smokeless on different methods and a different set tobacco use. We obtain the median ages chewing tobacco or snuff in the United of studies. In this analysis, we use the States. The authors state that this meta- at death for those dying of oral cancer relative risk of 2.16 as the summary by sex and age group (35–64 years and analysis included studies of smokeless relative risk for oral cancer among 65+ years) for the United States in 2010 tobacco use among non-smokers or smokeless tobacco users as the relative (Ref. 112) and life expectancy estimates among non-smokers and smokers with risk in 2010 (i.e., in the absence of the by sex at these ages from life tables for adjustment for smoking. These risks proposed standard). Although we the United States in 2010 produced by were used in estimates of the population believe this relative risk represents the the National Center for Health Statistics burden of smokeless tobacco use in the best available estimates based on the United States, presented in a recent NCI research literature, it should be noted (Ref. 113). These life expectancy values and CDC report on smokeless tobacco that the accuracy and precision of are then multiplied by the number of use and global public health (Ref. 4). particular study estimates may be attributable oral cancer deaths for each One study notes that two of the group to estimate the number of life estimates included in Boffetta et al.’s somewhat limited due to sample size and changes in study participants’ years that were lost due to oral cancer. meta-analysis, from a study by In this case, all future life years lost due Stockwell and Lyman examining the smokeless tobacco use and risk over time. to oral cancer deaths were assigned to associations between smokeless tobacco the year in which the death occurred. use and mouth/gum cancers and tongue Table 6 shows that an estimated 1,300 cancer, likely did not adjust for cigarette new cases of oral cancer in the United Table 6 shows that an estimated 300 smoking and consequently yielded States in 2010 were attributable to oral cancer deaths in the United States considerably larger risk estimates than smokeless tobacco use using this in 2010 were attributable to smokeless would have likely been observed with summary relative risk. These estimates tobacco use. These deaths represent an adjustment (Refs. 103, 110). To are generally comparable to those eventual loss of 4,900 life years. understand the sensitivity of the overall reported in the recent NCI and CDC Consistent with the data on new cases results to this study, we replicated smokeless tobacco report (Ref. 4). The and deaths from oral cancer shown in Boffetta et al.’s summary relative risk majority of these cases occur among table 5 and with the lower rates of estimate (where relative risk was 2.6), men, which is consistent with low rates smokeless use among women, the then re-analyzed the data omitting the of smokeless tobacco use among majority of attributable deaths and life two estimates from Stockwell and women. years lost occur among men.

TABLE 6—ESTIMATED ORAL CANCER CASES, DEATHS, AND CORRESPONDING LIFE YEARS LOST ATTRIBUTABLE TO SMOKELESS TOBACCO USE, U.S. 2010

Life years lost due to Attributable new oral cancer cases Attributable oral attributable oral cancer cancer deaths deaths

1,300 ...... 300 4,900 Note: Smokeless tobacco attributable oral cancer cases and deaths are rounded to the nearest hundred and estimated from information pre- sented in table 5 including the U.S. summary relative risk value reported by Boffetta et al. (Ref. 100), as revised by FDA.

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We also conducted a sensitivity in smokeless tobacco products. For the the National Survey on Drug Use and analysis using other oral cancer relative purposes of generating projections, we Health data show that smokeless risk estimates from the meta-analysis assume that any final rule on the tobacco use has remained relatively conducted by Lee and Hamling (Ref. tobacco product standard for NNN consistent among youth and adults 114). Lee and Hamling’s analysis would become effective 3 years after the since 2000 (Ref. 23). Using this generated estimates of never smoker oral date of publication of the final rule (see approach and the revised Boffetta cancer relative risks (a relative risk of section VII, Proposed Effective Date) relative risk, we estimate that 3.33 and a 95 percent confidence and that public health benefits would approximately 12,700 new cases of oral interval of 1.76–6.32) for 5 studies and begin to accrue once the standard is in cancer would be prevented in the smoking-adjusted oral cancer relative effect. United States in the 20 years following risks (a relative risk of 1.65 and a 95 In estimating the health impact of the implementation of the proposed product percent confidence interval of 1.22– proposed standard on smokeless standard (table 7), which represents a 50 2.25) for 12 studies for U.S. smokeless tobacco users, we begin with an oral percent reduction in estimated tobacco users. Lee and Hamling cancer relative risk for smokeless smokeless-attributable oral cancer cases prioritized estimates for the population tobacco users in the United States of over that time period. We use the same of smokers and nonsmokers that 2.16 from FDA’s revised meta-analysis approach to project the effect of the adjusted for smoking status over of Boffetta et al. (Ref. 100). This relative proposed standard on oral cancer estimates for never smokers in studies risk indicates an increase in oral cancer deaths, once again assuming that that reported both types of estimates in risk of 116 percent among smokeless reductions in deaths would be realized contrast to Boffetta et al., who did the tobacco users compared with never over a 10-year period but also assuming reverse. We did not use Lee and users. We then reduce this value by 65 that this reduction will begin 3 years Hamling’s never smoker relative risk in percent based on toxicological evidence after implementation of the standard the main analysis because the number of relating the estimated average reduction due to previously existing or developing studies that reported these risks is in the dose of NNN to lifetime cancer cases of oral cancer. In this case, we limited and only two of these estimates risk under the proposed standard. The assign the life years gained due to adjust for alcohol consumption. We also result is a reduction in the estimated reductions in oral cancer deaths to the did not use Lee and Hamling’s smoking- relative risk of oral cancer to 1.41 under years in which the additional life years adjusted relative risk in the main the proposed product standard. FDA are actually lived. We estimate that analysis because smokeless tobacco used the following calculation: (1 + approximately 2,200 oral cancer deaths ¥ × ¥ risks that control for smoking may over- (2.16 1) (1 0.65) = 1.41) for this would be prevented, and approximately adjust if individuals who both smoke determination. 15,200 life years gained in the United and use smokeless tobacco are more We use studies of relevant cancer States in the 20 years following likely to smoke less or quit smoking risks for former tobacco users by time implementation of the product standard compared with exclusive smokers (Refs. since cessation to provide information (table 7). This represents a 40 percent 192, 92). These relative risks were used about risk reductions over time after reduction in estimated smokeless- to generate population-attributable risk reductions in toxicant exposure. Due to attributable oral cancer deaths as a estimates with the other inputs used limited data on the timing of cancer risk result of the product standard over a 20 above. Using these alternative relative reduction after smokeless tobacco year period. risks yields estimates of approximately cessation, we applied estimates of 700 to 2,500 new oral cancer cases in relative risks by time since cessation for We also conducted sensitivity the United States that are attributable to former cigarette smokers to approximate analyses of these projections with the smokeless tobacco use per year. the time it takes for excess cancer risk alternative summary relative risks from Similarly, using these relative risks to be eliminated after quitting smokeless Lee and Hamling. Using the smoking- yields estimates of attributable oral tobacco. Estimates from cigarette adjusted relative risk for oral cancer of cancer deaths ranging from smokers help inform our estimation of 1.65 for U.S. smokeless tobacco users, approximately 200 to 500 per year. the trajectory of oral cancer risk we obtain a cumulative reduction of We then use similar methods to reduction that could be expected as a approximately 7,300 oral cancer cases project the effect of the proposed result of reducing regular exposure to and 1,300 oral cancer deaths over a 20- product standard on oral cancer tobacco-related carcinogens. These year period with the product standard. attributable to smokeless tobacco use in studies generally find higher risks for With the never smoker relative risk of the United States over time. The oral cancer for former smokers during 3.33, we obtain a reduction of proposed standard would reduce the the first 10 years after smoking cessation approximately 24,000 oral cancer cases levels of NNN in U.S. smokeless tobacco compared to never smokers, but not and 4,200 oral cancer deaths during the products and is also expected to reduce necessarily thereafter (Refs. 115, 2). We period. NNK levels. As described in this therefore project that reductions in new We also examined possible impacts section, the proposed standard is oral cancer cases attributable to from changes to input values in these predicted to eventually reduce excess smokeless tobacco use would be fully calculations. Specifically, we estimated lifetime oral cancer risks among U.S. realized over a 10-year period after changes in the public health benefits smokeless tobacco users by 65 percent, manufacturers are in compliance with due to differences in smokeless tobacco on average. This reduction in the product standard, with the prevalence and the length of time in population cancer risk would likely reduction occurring in 10 percent which the full oral cancer risk reduction occur over a period of time, given that increments until the full benefit is will be observed among U.S. smokeless some smokeless tobacco users may still reached. We also assume that, in the tobacco users. These analyses are in the develop oral cancer at the higher risk absence of the proposed standard, new Uncertainty and Sensitivity Analysis, level after implementation of the cancer cases attributable to smokeless section II.G, of the Regulatory Impact proposed product standard due to tobacco use in the United States would Analysis associated with this proposed previous exposure to higher NNN levels remain constant over time, given that rule.

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TABLE 7—PROJECTED CUMULATIVE DIFFERENCE IN NEW ORAL CANCER CASES AND ORAL CANCER DEATHS ATTRIB- UTABLE TO SMOKELESS TOBACCO USE IN THE U.S. AND CORRESPONDING LIFE YEARS GAINED DUE TO IMPLEMENTA- TION OF THE PROPOSED STANDARD

Cumulative Cumulative Years after full implementation of the standard difference in difference in Cumulative life attributable cases attributable deaths years gained

10 years ...... 4,500 500 1,500 20 years ...... 12,700 2,200 15,200 Note: Estimates in the table are rounded to the nearest hundred.

2. Additional Public Health Benefits use has been identified as a cause of to some reduction in lung cancer risk. From Reducing Oral Cancer esophageal cancer (Refs. 1, 2) and NNN There is some evidence linking As a result of this proposed rule, we has been directly linked to esophageal smokeless tobacco use to lung cancer estimate considerable public health cancer in numerous animal studies (Ref. (Ref. 121), although a definitive benefit to the United States resulting 8) and in an epidemiological study of association has not been established in from reduced risk of oral cancer among smokers (Ref. 77). However, limited data authoritative reviews (Refs. 3, 4). are available, so the health benefit smokeless tobacco users due to B. The Likelihood That Existing Users of reductions in NNN (and concomitant cannot be directly quantified. Pancreatic cancer has also been Tobacco Products Will Stop Using Such reductions in NNK) levels in smokeless Products tobacco. The public health impact of identified as causally related to Although data are lacking on oral cancer is estimated to be smokeless tobacco use (Refs. 1, 2). perceptions of smokeless tobacco considerable in size. In the United Lower levels of NNN (and potential toxicants, including NNN, and States, about 65 percent of oral cancer reductions in NNK) in U.S. smokeless cessation, there is some evidence on patients survive at least 5 years with tobacco under the proposed standard users’ motivations for quitting disease and those individuals who have the potential to reduce the smokeless tobacco. Some studies survive oral cancer can face profound incidence of pancreatic cancer. Boffetta suggest that concerns about developing challenges and reductions in quality of et al. reported the relative risk of health problems are among the common life. pancreatic cancer from four studies of Oral cancer patients and survivors can U.S. smokeless tobacco users to be motives that smokeless tobacco users face major functional problems when elevated (i.e., a relative risk of 1.4), provide for quitting (Refs. 123, 124). performing basic tasks of daily living although not statistically significant. These studies suggest that if the such as eating and talking. Treatment Yet, estimates of pancreatic cancer proposed standard affects consumer procedures can result in disfigurement relative risks have not consistently been perceptions about the harms of or other serious cosmetic problems that reported to be higher in U.S. smokeless smokeless tobacco use, it may influence also adversely impact quality of life tobacco studies compared with their cessation motivations. Specifically, (Ref. 116). Surgical treatments for head Scandinavian snus product studies if current smokeless tobacco users and neck cancers have been found to be (Refs. 100, 114). interpret an NNN product standard to associated with subsequent self-image Lower levels of NNN in smokeless mean the health risks from smokeless issues and social isolation that tobacco may also reduce the incidence tobacco use will be lower after the increased with the level of of laryngeal and prostate cancers. Lee standard is in effect, this might reduce disfigurement (Ref. 117). Patients with and Hamling’s (Ref. 114) review found some users’ motivations to quit. It is head and neck cancers also report high U.S. smokeless tobacco use was worth noting, however, that while the levels of anxiety and depressive significantly associated with laryngeal magnitude of risk would be changed by symptoms (Ref. 116), and even long- cancer in four studies including one implementation of the proposed term survivors report high levels of study that adjusted for cigarette standard, appreciable cancer risk would psychological distress (Ref. 118). smoking. More recently, Zhou et al. remain. Accordingly, users would still In the United States in 2010, (Ref. 122) found that use of smokeless have a strong incentive to quit. FDA, approximately $3.63 billion annually tobacco for 10 or more years was therefore, does not expect the proposed was spent on medical treatment and associated with elevated risk of product standard to appreciably followup care for all head and neck laryngeal cancer. Lee and Hamling (Ref. discourage cessation of smokeless cancers (Ref. 119), which includes 114) also found a statistically significant tobacco products in such a way as to cancers of the oral cavity, pharynx, association between U.S. smokeless offset the beneficial public health larynx, nasal cavity, and salivary glands tobacco use and prostate cancer. impact from reduced cancer risk. (Ref. 120). The proposed standard will Although NNN has not specifically been Although data are lacking on benefit public health by preventing linked with an increased risk of these perceptions of smokeless tobacco thousands of new oral cancer cases and cancers, it is a potent carcinogen and product toxicants, including NNN and deaths caused by smokeless tobacco use smokeless tobacco product use can the effect of awareness on cessation over the next two decades. result in exposure throughout the behaviors, prevalence of smokeless human body. tobacco use would need to increase 3. Unquantified Potential Reductions in Given that U.S. smokeless products substantially in order to offset the Other Cancers contain high amounts of NNK, and NNK reduction in cancer risk expected as a In addition to reducing the risk of oral is a recognized systemic lung result of this rule. The magnitude of the cancer, lower levels of NNN in carcinogen (Ref. 8) in experimental change needed can be estimated using smokeless tobacco under the proposed animals, potential reductions in NNK the population attributable risk standard are expected to lower the risk levels in smokeless tobacco as a result calculation presented in section V.A.1 of esophageal cancer. Smokeless tobacco of the proposed NNN standard may lead of this document. The calculation

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includes the product of the excess offset the expected excess cancer risk even if there were some awareness, relative risk (RR–1) and the prevalence reduction due to the proposed rule. given that the standard is related to of smokeless tobacco use. Therefore, Data are not available on consumers’ reducing long-term health effects, it is smokeless tobacco use prevalence awareness and perceptions of NNN in unlikely to have an impact on youth would need to nearly triple in order to smokeless products, although a single initiation. completely offset the expected published study in a U.S. adult sample It is possible that some former users reduction in excess lifetime cancer risk of smokers and non-smokers found could potentially relapse back to to the equivalent of approximately one- awareness of and knowledge about NNN smokeless tobacco use due to third of the baseline cancer risk. in cigarette smoke was low, particularly perceptions of lower risk. Although While there is evidence that exposure in comparison to other constituents specific data on relapse among to media can lead to health behavior (Ref. 125). Although there is very low smokeless users is not available, there is changes (Refs. 126, 127), it is unclear awareness of NNN as a constituent, it is some data on relapse among smokers. whether media coverage of this possible that some non-users of For example, predictors of relapse for proposed product standard would smokeless tobacco will be aware of the smokers who reported they had quit promote sustained behavior change in proposed standard and interpret it to between study waves were assessed in the form of increased or decreased mean that smokeless tobacco is less one of the few studies assessing relapse likelihood of smokeless tobacco harmful than other tobacco products in the general population and not part cessation. and this could, in turn, affect smokeless of a clinical trial. Neither the perceived Methods used to reduce NNN levels tobacco initiation. Research suggests costs of smoking (such as thoughts as a result of this proposed rule may or that risk perceptions of tobacco use— about the harms of smoking) nor may not produce changes that affect the that is, judgments about its benefits of quitting (including health sensory experiences of smokeless harmfulness—can influence tobacco benefits) were related to relapse (Ref. tobacco use. Consumers’ sensory initiation (Refs. 137, 138). However, if 142). However, nicotine dependence is experiences can in turn influence their the proposed standard were to result in related to relapse among smokers (Refs. perceptions of product harms (Refs. 128, additional uptake of smokeless tobacco 143, 144); and because smokeless 129, 130), which can impact product use in the population, this could either tobacco products also deliver nicotine, use. However, for moist snuff, which decrease or increase the expected health FDA expects that the same reason for constitutes the overwhelming majority benefits of the proposed standard. If relapse would apply to former of the smokeless tobacco market in the cigarette smokers who would not smokeless tobacco users and that United States (Ref. 131), manufacturers otherwise quit smoking completely changes to perceptions of costs and have already identified ways to reduce switched to smokeless tobacco products benefits would have little effect on nitrosamine content without negatively as a result of this standard, we would relapse rates. Overall, the extent to impacting the taste or user experience expect additional reduction in risk to which the proposed standard may (see sections IV.C and IV.E of this these individual users. If cigarette influence behaviors of non-users and document). Smokeless tobacco products smokers became dual users of cigarettes former users is likely to be minimal are heavily flavored and the presence of and smokeless tobacco products, this since health-related reasons are not flavors is a significant driver of could have varying impacts depending among the main drivers of smokeless consumer acceptance of these products on the extent to which such dual use led tobacco use initiation or relapse. (Ref. 70). The proposed standard does to substantial reductions in cigarette Finally, HHS plans to continue not prevent the addition of flavors to consumption or led to delayed cessation developing and implementing public offset any changes in the taste of the of tobacco products altogether. education campaigns to help prevent product due to the methods used to Conversely, the anticipated net initiation of all tobacco products, reduce NNN to meet the proposed population health benefits of the including smokeless tobacco. standard. standard would be reduced if it led D. Conclusion substantial numbers of never or former C. The Likelihood That Non-Users Will NNN is a potent carcinogenic agent Start Using Tobacco Products tobacco users to begin or resume using smokeless tobacco products. found in smokeless tobacco and, along The proposed product standard is not In the case that some adolescents and with NNK, another TSNA, is a major expected to substantially increase, if at young adults become aware that FDA is contributor to the elevated cancer risks all, the likelihood that those who do not taking steps to reduce the harmfulness associated with smokeless tobacco use. use smokeless tobacco will take up the of smokeless tobacco products, FDA Oral and esophageal tissues have been product. Public perception is that expects that any impact on smokeless identified as targets for NNN-induced smokeless tobacco use has some tobacco initiation would be limited. carcinogenicity, when NNN was potential harms (Refs. 76, 133, 134, 135, First, smokeless tobacco initiation administered orally in animal studies, 136). At this time we are not aware of among youth has been shown to be which indicates some concordance with direct scientific evidence demonstrating associated with social influences such effects observed at these sites in that the proposed smokeless tobacco as actual or perceived peer use (Refs. epidemiologic studies. NNN levels in product standard would influence 139, 140) to a greater extent than most smokeless tobacco manufactured consumers’ perceptions of product perceptions of the long-term health in the United States are higher than appeal, relative risk, and absolute risk, effects. Further, youth curiosity about NNN levels in smokeless tobacco or behaviors. Even if the proposed smokeless tobacco is lower than manufactured in Sweden. Oral cancer standard were to result in some changes curiosity about cigars or cigarettes (Ref. risks in U.S. smokeless tobacco users are to perceptions and behaviors, FDA 141), suggesting that fewer adolescents elevated compared to the oral cancer believes that they would not offset the are at risk for future use, compared to risks in Scandinavian users. The beneficial public health impact from many other tobacco products. Thus, at proposed product standard is expected reduced cancer risk. As described in the population level, very few to reduce tobacco-related harms by this section, FDA estimates that the adolescents are likely to be aware that reducing the levels of NNN in smokeless prevalence of smokeless tobacco use FDA is taking an action related to NNN tobacco products sold in the United would have to nearly triple in order to in smokeless tobacco products, and, States, thereby reducing the risk of oral

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cancer in smokeless users. By our not expect the magnitude of these Store and transport the finished estimates, in the 20 years following effects to offset the benefits of the smokeless tobacco products according implementation of the proposed product reduced cancer risk. to the package label, (2) do not sell or standard, approximately 12,700 new distribute or offer for sale or distribution VI. Description of Proposed Regulation cases of oral cancer and approximately finished smokeless tobacco products 2,200 oral cancer deaths would be A. General Provisions (Proposed past their expiration date, except to prevented in the United States. Subpart A) return expired products to the Moreover, during that 20-year period, manufacturer, (3) do not conceal, alter, 1. Scope (Proposed § 1132.1) approximately 15,200 life years would or remove the expiration date or storage be gained as a result of the proposed Proposed § 1132.1 identifies the scope conditions on the package label, and (4) standard. This represents a substantial of products that would be subject to this do not sell or distribute or offer for sale benefit to the public health. Because NNN product standard. FDA intends for or distribution finished smokeless oral cancer is associated with significant this proposed standard to cover finished tobacco products that are open or have impacts on health and quality of life, we smokeless tobacco products, which are broken seals. expect positive public health benefits defined in proposed § 1132.3 (proposed FDA is proposing this exception for due to prevention of new and fatal § 1132.1(a)). This includes moist snuff, tobacco retailers and distributors cancer cases. We also expect the snus, dry snuff, chewing tobacco, and because they cannot reasonably know or proposed product standard to reduce some dissolvables. Some dissolvable confirm by testing whether the the risk of esophageal cancer among tobacco products do not meet the smokeless tobacco products they are smokeless tobacco users, and it may statutory definition of ‘‘smokeless selling or distributing or offering for sale reduce the incidence of other cancer tobacco product’’ because they do not or distribution comply with the types; however, there is limited data contain cut, ground, powdered, or leaf proposed NNN level. Provided that the available to directly quantify this health tobacco; instead, these products contain tobacco retailers and distributors meet benefit. nicotine extracted from tobacco. the requirements set forth in proposed Based on currently available evidence Dissolvable products that do not meet § 1132.1(c)(1) through (4), FDA will not discussed previously, we do not the statutory definition of ‘‘smokeless consider them to be in violation of part anticipate the proposed standard would tobacco product’’ are not covered by this 1132 as it relates to the sale or have behavioral impacts on smokeless proposed rule. As previously noted, this distribution or offer for sale or tobacco initiation, cessation, switching rule focuses on smokeless tobacco distribution of products that exceed the to other products, or dual use in a way products because different measures are NNN level set forth in proposed that would offset the public health required to address NNN in other § 1132.10. benefits of the reduced cancer risk that tobacco products. We note that tobacco retailers and would result from the proposed Proposed § 1132.1(b) states that no distributors would need to meet all of standard. Even if the proposed standard person may manufacture, distribute, the requirements in proposed were to result in some instances of sell, or offer for sale or distribution § 1132.1(c) in order to be considered in decreased smokeless tobacco cessation within the United States a finished compliance with this part as it relates to or increased initiation among non-users smokeless tobacco product that is not in the sale or distribution or offer for sale of tobacco, we would not expect the compliance with this part. For example, or distribution of smokeless tobacco magnitude of these effects to be FDA would not consider finished products that exceed the NNN level set comparable to the public health benefits smokeless tobacco products to be in forth in proposed § 1132.10. A retailer of the proposed rule. As described in compliance with this part if they exceed or distributor who, for example, covers this section, FDA estimates that the the NNN level set forth in proposed the expiration date or storage conditions prevalence of smokeless tobacco use § 1132.10, the package label does not with a sticker, changes the expiration would have to nearly triple in order to have a manufacturing code or expiration date, or scratches off the expiration date offset the excess cancer risk reduction date, or the package label has a or storage conditions on the package expected due to the proposed rule. In manufacturing code or expiration date label would not meet the requirements addition, to the extent that cigarette that has been altered, mutilated, in proposed § 1132.1(c)(3). Furthermore, smokers who cannot or will not quit destroyed, obliterated, obstructed, a retailer who sells finished smokeless smoking are motivated to switch concealed, or removed in whole or in tobacco products that are open or have completely to smokeless tobacco due to part. broken seals would not meet the perceptions of lower risk, this complete This provision is not intended to requirements in proposed § 1132.1(c)(4), switching could result in additional restrict the manufacture of smokeless because doing so could lead to changes benefits to public health through tobacco products intended for export. in the NNN level, especially if it is reduced risks to these individual users. Consistent with section 801(e)(1) of the exposed to heat or humidity. Accordingly, for the reasons FD&C Act, a tobacco product intended discussed in this section, we find that for export shall not be deemed to be in 2. Definitions (Proposed § 1132.3) the proposed standard is appropriate for violation of section 907 or this product Proposed § 1132.3 provides the the protection of public health. It would standard, if it meets the criteria definitions for the terms used in the reduce the cancer risk posed by enumerated in section 801(e)(1) of the proposed rule. Several of these smokeless tobacco products and FDA FD&C Act, including not being sold or definitions are included in the FD&C does not expect that the product offered for sale in domestic commerce. Act or have been used in other standard would increase the likelihood Proposed § 1132.1(c) explains that regulatory documents. that non-users would initiate tobacco or tobacco retailers and distributors will • Batch: FDA proposes to define decrease the likelihood that users will not be considered in violation of this ‘‘batch’’ as a specific identified amount quit tobacco use. Even if the proposed part as it relates to the sale or of a finished smokeless tobacco product standard were to result in some distribution or offer for sale or produced in a unit of time or quantity instances of decreased smokeless distribution of finished smokeless and that is intended to have the same tobacco cessation or increased initiation tobacco products that exceed the NNN characteristics. As stated in section among non-users of tobacco, we would level set forth in § 1132.10 if they: (1) 910(a)(3)(B) of the FD&C Act,

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characteristics means the ‘‘materials, specific nitrosamine (TSNA) with the study or other laboratory work. Source ingredients, design, composition, chemical formula C[9]H[11]N[3]O. data includes any laboratory heating source, or other features of a • New tobacco product: As defined in worksheets, notebooks, correspondence, tobacco product.’’ section 910(a) of the FD&C Act, the term notes, and other documentation • Commercial distribution: FDA ‘‘new tobacco product’’ means: (1) Any (regardless of capture medium) that are proposes to define ‘‘commercial tobacco product (including those the result of original observations and distribution’’ as any distribution of a products in test markets) that was not activities of a laboratory study or other finished smokeless tobacco product to commercially marketed in the United laboratory work. consumers or to another person through States as of February 15, 2007; or (2) any Source data could include protocols sale or otherwise, but does not include modification (including a change in and standard operating procedures, interplant transfers of a tobacco product design, any component, any part, or any information regarding calibration of between registered establishments constituent, including a smoke equipment used to measure or test within the same parent, subsidiary, and/ constituent, or in the content, delivery samples, test standards, and the or affiliate company, nor does it include or form of nicotine, or any other standard curves used to determine the providing a tobacco product for product additive or ingredient) of a tobacco measure of the samples being tested or testing where such product is not made product where the modified product of the accuracy and reliability of the available for consumption or resale. was commercially marketed in the test. This type of information may be • United States after February 15, 2007. needed to fully evaluate, for example, Finished smokeless tobacco • product: We propose to define ‘‘finished Package: As defined in section whether the product meets the product smokeless tobacco product’’ as a 900(13) of the FD&C Act, the term standard. In addition, if there are any smokeless tobacco product including all ‘‘package’’ means a pack, box, carton, or problems with the data, the parts and components, packaged for container of any kind or, if no other manufacturer and FDA would be able to consumer use, but it would not include container, any wrapping (including use the source data to reconstruct the cellophane) in which a tobacco product a component, part, or accessory sold study or lab work, which could help is offered for sale, sold, or otherwise without tobacco. A product that is identify and correct any deviations. In distributed to consumers. ‘‘packaged for consumer use’’ would accordance with proposed § 1132.32, • Performance criteria: FDA proposes source data records would have to be have the package label on the product. to define ‘‘performance criteria’’ as the For example, a tin or can of loose snuff maintained by the manufacturer. validation requirements for the • Tobacco product: As defined in or a pouch containing chewing tobacco, acceptability of an analytical test section 201(rr) of the FD&C Act, the with package labels, would meet this method, including accuracy, precision, term ‘‘tobacco product’’ means any definition. • recovery, linearity, specificity, limit of product that is made or derived from Manufacturing code: FDA proposes quantitation, limit of detection, tobacco that is intended for human to define ‘‘manufacturing code’’ as any robustness, and range. consumption, including any distinctive sequence or combination of • Person: As defined in section 201(e) component, part, or accessory of a letters, numbers, or symbols that begins of the FD&C Act, the term ‘‘person’’ tobacco product (except for raw with the manufacturing date in 2-digit includes an individual, partnership, materials other than tobacco used in numerical values in the month, day, corporation, or association. manufacturing a component, part, or year format (mmddyy) followed by the • Rework: We propose to define accessory of a tobacco product). The batch number from which the ‘‘rework’’ as the processing of term ‘‘tobacco product’’ does not mean production batch can be identified. The nonconforming finished smokeless an article that is a drug under section purpose of the manufacturing code is to tobacco products to meet the 201(g)(1), a device under section 201(h), allow manufacturers and FDA to requirements of this part. or a combination product described in identify the production batch of a • Smokeless tobacco: As defined in section 503(g) of the FD&C Act (21 particular product that has been section 900(18) of the FD&C Act, the U.S.C. 321(g)(1), 321(h), and 353(g)). released for commercial distribution. term ‘‘smokeless tobacco’’ means any • Tobacco product manufacturer: As This information would help determine tobacco product that consists of cut, defined in section 900(20) of the FD&C the product’s history (e.g., batch testing ground, powdered, or leaf tobacco and Act, ‘‘tobacco product manufacturer’’ records) and assist manufacturers and that is intended to be placed in the oral means any person, including a repacker FDA in the event of a nonconforming or nasal cavity. This includes moist or relabeler, who manufactures, product investigation and any corrective snuff, snus, dry snuff, chewing tobacco, fabricates, assembles, processes, or actions that stem from the and some dissolvables. Some labels a tobacco product or imports a nonconforming product investigation. dissolvable tobacco products do not finished tobacco product for sale or • Manufacturing date: We propose to meet the statutory definition of distribution in the United States. define ‘‘manufacturing date’’ as the ‘‘smokeless tobacco product’’ because • Tobacco-specific nitrosamine month, day, and year that a smokeless they do not contain cut, ground, (TSNA): We propose to define ‘‘tobacco- tobacco product is packaged for powdered, or leaf tobacco; instead, these specific nitrosamine’’ to mean a consumer use (i.e., when the package products contain nicotine extracted chemical compound formed through the label has been added to the product). from tobacco. Dissolvable products that chemical reaction involving the The manufacturing date is included in do not meet the statutory definition of nitrosation of nicotine, nornicotine, the manufacturing code, which can be ‘‘smokeless tobacco product’’ are not anabasine, or anatabine during the used by the manufacturer and FDA to covered by this proposed rule. growing, curing, processing, or storage help determine the product’s history • Source data: FDA proposes to of tobacco. (e.g., batch testing history) in the event define ‘‘source data’’ as all information • United States: As defined in section of a nonconforming product contained in original laboratory records 900(22) of the FD&C Act, the term investigation. or exact copies of original records of ‘‘United States’’ means the 50 states of • N-nitrosonornicotine (NNN): FDA experimental findings, observations, or the United States of America and the proposes to define ‘‘N- other activities used for the creation, District of Columbia, the nitrosonornicotine’’ as a tobacco- reconstruction, and evaluation of a Commonwealth of Puerto Rico, Guam,

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the Virgin Islands, American Samoa, B. Product Requirements (Proposed from the entire batch, rather than to a Wake Island, Midway Islands, Kingman Subpart B) per-batch mean. This alternative approach would thereby require the Reef, Johnston Atoll, the Northern 1. NNN Level (Proposed § 1132.10) Mariana Islands, and any other trust manufacturer to ensure compliance of territory or possession of the United For the reasons discussed in section each unit made from a batch despite States. IV of this document, FDA is proposing some expected random variation of the that the mean level of NNN in any batch NNN level between units. This could 3. Incorporation by Reference (Proposed of finished smokeless tobacco products further increase the public health § 1132.5) must not exceed 1.0 mg/g of tobacco (on benefits of this product standard. a dry weight basis) at any time through However, in instances where Proposed § 1132.5 identifies the the product’s labeled expiration date as manufacturers determined that some materials that FDA proposes to determined by testing in compliance units within a batch had levels of NNN incorporate by reference in this part. with § 1132.12. Under the proposed above the limit and others had levels Information that is incorporated by rule, manufacturers would be required below the limit, this alternative reference would have the same force to test their finished smokeless tobacco approach could add costs for and effect as language explicitly stated products using the standard test method manufacturers (e.g., costs of rejecting or in the codified. Under the proposed in § 1132.14 or the alternative test reworking the batch) or require them to rule, a tobacco product manufacturer method in § 1132.16. manufacture product with NNN levels would be required to follow procedures In proposing to set the limit in terms lower than the NNN level of 1.0 mg/g of and methods for testing as described in of a batch mean, FDA has tentatively tobacco (on a dry weight basis) in order any standards incorporated by determined that the mean value is more to minimize the risk of having to reject reference, unless the manufacturer appropriate than a limit applied to each a batch based on random variation. FDA meets the requirements in § 1132.16 for unit produced from the entire batch of currently believes that this is not an alternative test method. a product, given that the cancer risk is necessary to achieve the public health FDA is proposing to incorporate by due to long term and repeated exposure, goals of the proposed standard, but reference a validated method developed and given the variability of NNN in this invites input on this point. by FDA’s SRL to be the standard test agricultural product. Although we We invite comments on FDA’s method for NNN in smokeless tobacco expect some degree of variability in proposed approach and on the products (proposed §§ 1132.5(a) and NNN to exist in smokeless tobacco alternative approach and their 1132.14). As discussed in section IV.F of products, we recognize there may be implications for compliance with the circumstances where there could be this document, the results from the test limit, and public health impact. We also wide ranges in the variability of NNN method demonstrate a high level of invite comments or information on for some smokeless tobacco products, specificity, accuracy, and precision in batch sampling methods or other resulting in reduced consistency among measuring a range of NNN levels across approaches manufacturers might use to the units produced and reduced a variety of smokeless tobacco products. determine compliance with an absolute predictability of compliance with a limit on all units produced from a batch If the proposed incorporation by standard requiring that each unit meet given the expected variability of NNN in reference is approved by the Office of a specific limit. FDA is requesting relevant products. the Federal Register and incorporated in scientific data that could be used to the final rule, interested parties would determine the expected distribution of 2. Product Testing (Proposed § 1132.12) be able to examine the incorporated individual results for samples for a per- Proposed § 1132.12 contains material at the National Archives and batch mean limit of an NNN level of 1.0 provisions for the testing of smokeless Records Administration (NARA) and at mg/g of tobacco on a dry weight basis tobacco products. FDA is proposing to FDA’s Division of Dockets Management (see proposed § 1132.10). FDA also require two types of testing—stability (proposed § 1132.5(b)), and obtain requests comment on the compliance testing and batch testing. copies of the standard test method by implications of the currently proposed a. Stability testing. Proposed contacting FDA’s Center for Tobacco approach. § 1132.12(a) would require each tobacco Products at the addresses and/or Web NNN-related cancer risk is due to long product manufacturer to conduct testing sites listed in proposed § 1132.5(b)(2). term and repeated exposure to NNN. to assess the stability of the NNN level If FDA subsequently determines that Under the currently proposed approach, in its finished smokeless tobacco a test method, which has been as long as the mean of each batch products. Given the variability of NNN consistently conforms to the NNN level levels in current smokeless tobacco incorporated by reference in a final rule, of 1.0 mg/g of tobacco (on a dry weight products (see section IV.B.1 of this should be replaced with another method basis) in accordance with § 1132.10, document), stability testing would help or updated, FDA will update the FDA expects that the long term impact ensure that the NNN level in finished regulation in accordance with the from an occasional exposure to a smokeless tobacco products is being Administrative Procedure Act (5 U.S.C. product with slightly higher NNN level properly monitored and controlled and 553) and obtain approval of the change will be offset by the exposure to slightly that it remains in conformance with the to the incorporation by reference in lower levels. Therefore, any random proposed limit through the product’s accordance with 1 CFR part 51. variation that may exist is not expected labeled expiration date. The initial Proposed § 1132.5(c) explains that if to negatively impact the public health stability testing would establish the rate tobacco manufacturers or testing benefit of the proposed standard, which of change of the NNN level for a product laboratories using these standards find is based on reduction of excess lifetime and the annual stability testing would an inconsistency between a material cancer risk. identify any changes to the rate of incorporated by reference in this part FDA also is considering an alternative change of the NNN level in that product. and definitions or methods described by approach that includes setting a Manufacturers would be required to FDA in proposed part 1132, the standard where the specified NNN level use the results of stability testing to definitions or methods in proposed part of 1.0 mg/g of tobacco (on a dry weight establish and verify the product’s 1132 take precedence. basis) would apply to all units produced expiration date and storage conditions

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(either room temperature or modifiers with no resulting change in establish an expiration date for its refrigeration). Proposed § 1132.20 would final pH. This provision is intended to product (at 6 months) if the testing require all finished smokeless tobacco reduce the burden on the manufacturer, results showed that the product products to have an expiration date while ensuring that there is initial real- conforms at 6 months but not at 8 established by stability testing. This time stability data that applies to all months. Because NNN levels in the date would have to be no later than the finished tobacco products, thus product would only increase over time, final date the manufacturer can preserving the goal of the requirement. manufacturers would also be able to demonstrate that the NNN level in the Manufacturers would be required to choose a shorter expiration date if they finished smokeless tobacco product use the results from initial stability wish (Ref. 11). For instance, if stability conforms to § 1132.10 when the product testing to establish an expiration date testing demonstrated the NNN level is stored under its intended conditions and appropriate storage conditions remains in conformance with proposed (e.g., room temperature or refrigeration). (either room temperature or § 1132.10 through at least 6 months, the When conducting stability testing, refrigeration) for the finished product. manufacturer could choose to use a 4- manufacturers would be required to use We believe that room temperature or month expiration date if the either the standard test method in refrigeration are the most likely storage manufacturer did not want the product § 1132.14 or an alternative test method conditions for smokeless tobacco sold after that time period due to that meets the requirements in § 1132.16 products because most current freshness or taste changes. and samples would have to be selected smokeless tobacco products are stored at FDA is proposing to allow in accordance with the requirements set room temperature while some snus manufacturers to conduct accelerated forth in § 1132.18(a) and (c) (proposed products are refrigerated. FDA does not stability testing concurrently with initial § 1132.12(a)(1)). expect that manufacturers would choose real-time stability testing to establish the Proposed § 1132.12(a)(2) would to freeze their finished smokeless product’s expiration date and storage require each manufacturer to establish tobacco products. The expiration date conditions (proposed and maintain a written protocol for all and storage conditions would be § 1132.12(a)(3)(ii)). The manufacturer stability testing, that fully describes the required to be displayed on the package would be allowed to use an expiration methodology used to determine the label in accordance with proposed date of no longer than 1 year based on stability of the NNN level, including the § 1132.30. initial accelerated stability testing. test method used (the standard test For initial real-time stability testing, Accelerated stability studies provide method in proposed § 1132.14 or an FDA is proposing that, at a minimum, preliminary information on NNN levels alternative test method in accordance samples be tested within 7 days of over time and are of shorter duration with proposed § 1132.16), the sampling manufacture to determine the starting than long-term stability studies. By plan and procedures required by NNN level and at the expected allowing manufacturers to conduct proposed § 1132.18(a) and (c), and the expiration date (proposed accelerated stability testing, FDA storage conditions. § 1132.12(a)(3)(i)). Testing the NNN intends to reduce the time required to Proposed § 1132.12(a)(3) requires level at various time points is intended bring new products to market without initial real-time stability testing that to ensure that the NNN level in finished adversely impacting public health. covers each finished smokeless tobacco smokeless tobacco will conform to Proposed § 1132.12(a)(3)(iii) would product. In certain circumstances, it § 1132.10 through the determined require that, at a minimum, samples for may not be necessary to conduct initial expiration date under the intended initial accelerated stability testing be real-time stability testing on a particular storage conditions. If the proposed tested at three time points within a 6- product because the results from initial storage condition is room temperature, month period. This testing paradigm is real-time stability testing conducted on samples for initial real-time stability similar to one used for stability testing another similar product apply. For testing would have to be stored at 25 ± for drugs. We would require the first example, a manufacturer who 2 degrees Celsius and 60 ± 5% relative time point be within 7 days of manufactures moist snuff in a tin and humidity (proposed manufacture and the last time point at moist snuff in a pouch would be § 1132.12(a)(3)(i)(A)) and, if the 6 months after manufacture. Because it required to conduct initial real-time proposed storage condition is may not always be possible to test stability testing on both products, refrigeration, samples would have to be exactly 6 months after manufacture, because the tin and the pouch could stored at 5 ± 2 degrees Celsius (proposed FDA notes that testing conducted within have different impacts on the NNN level § 1132.12(a)(3)(i)(B)). the week prior to or the week after the and, thus, on the stability of the finished FDA believes manufacturers will 6 month date of manufacture would be products. In contrast, a manufacturer likely choose to test at several considered to meet this requirement. If who manufactures two finished additional time points to determine the the proposed storage condition is room products, where the only difference rate of NNN change, if any. Testing of temperature, samples for accelerated between them is a slight change in additional time points could allow the stability testing would have to be stored flavor ingredients that does not affect manufacturer to establish an acceptable at 40 ± 2 degrees Celsius and 75 ± 5% NNN levels, would only be required to expiration date even if testing shows the relative humidity (proposed conduct initial real-time stability testing finished smokeless tobacco product § 1132.12(a)(3)(iii)(A)) and, if the on only one of the two products. The would exceed the level set forth in proposed storage condition is results from that testing would apply to § 1132.10 at the expected expiration refrigeration, samples would have to be both products and the testing would be date. For example, a manufacturer may stored at 25 ± 2 degrees Celsius and 60 considered to cover both products. initially expect its product to have a ± 5% relative humidity (proposed Other examples of differences between conforming NNN level for a period of 8 § 1132.12(a)(3)(iii)(B)). Because higher products that would not require months, based on history of experience temperatures and humidity can increase additional initial real-time stability with similar products. If instead of only the biological activity, these conditions testing, if initial real time stability testing the product at 7 days and at 8 will accelerate any increases in the NNN testing has already been conducted on months, the manufacturer chooses to level, thereby providing a prediction of one of the products, include slight test at 7 days, 6 months, and 8 months, the stability of the NNN for a 12-month changes in acids, bases, or other pH that manufacturer would still be able to period under normal conditions.

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Proposed § 1132.12(a)(3)(iv) would temperature or refrigeration in finished smokeless tobacco products require the manufacturer to use the accordance with proposed would have to conform with the results of initial real-time stability § 1132.12(a)(4)(iii)(A) and (B). proposed NNN level at batch testing and testing to establish an expiration date FDA proposes that, if the results of through their expiration date, the NNN and storage conditions if initial the most recent annual real-time level at batch testing would have to be accelerated stability testing shows the stability testing do not support the low enough to ensure that the NNN NNN level in finished smokeless finished smokeless tobacco product’s level remains compliant until the tobacco products will not conform to previously established expiration date, expiration date. FDA believes that most proposed § 1132.10. If the NNN levels the manufacturer must use the results of manufacturers will develop products do not conform after 6 months of the most recent annual real-time which have no, or minimal, changes in accelerated testing conditions, then stability testing to establish a new NNN over time. However, that is not there will be insufficient evidence to expiration date (proposed required by this product standard. For project that NNN levels will conform § 1132.12(a)(4)(iv)). After a new instance, if stability testing after 12 months of normal conditions. expiration date has been established, the demonstrates that the mean NNN level Accordingly, this accelerated data may package labels of all affected finished in a batch increases by 0.2 mg/g of not be used to forecast an expiration smokeless tobacco products that have tobacco on a dry weight basis over a 6 date. not been released for commercial month expiration period, batch testing FDA is also proposing to require distribution would be required to that demonstrates the mean NNN level manufacturers to conduct annual real- display the new expiration date and is below 0.75 mg/g of tobacco on a dry time stability testing on each finished storage conditions in accordance with weight basis would be in conformance smokeless tobacco product to verify the proposed § 1132.30. Furthermore, if the because the mean NNN level of the results of the initial stability testing and, expiration date must be shortened, the batch would be expected to remain given the variability of NNN in tobacco, manufacturer would be required to below 1.0 mg/g of tobacco on a dry to ensure that the established expiration conduct, fully document, and maintain weight basis at least through the date and storage conditions remain records of an investigation to determine expiration date of 6 months. We expect appropriate and don’t need to be why the results of the most recent that any changes in a rate of increase changed (proposed § 1132.12(a)(4)). annual real-time stability testing do not would be observed and investigated Accelerated stability testing would not support the product’s previously during annual stability testing. be permitted for annual stability testing. established expiration date (proposed c. Documentation of test results. We propose that accelerated stability § 1132.12(a)(4)(v) and (a)(2)). Proposed § 1132.12(c) would require the b. Batch testing. FDA is proposing testing be permitted for initial stability tobacco product manufacturer to that tobacco product manufacturers testing to reduce the time required to maintain a full report of the source data conduct testing on each batch of bring new products to market without and results of all stability and batch finished smokeless tobacco product to adversely impacting public health. testing. This report would need to ensure that the products conform with However, accelerated testing is include the full identification of the proposed § 1132.10 prior to commercial unnecessary for annual stability testing smokeless tobacco product that is the because these products would already distribution (proposed § 1132.12(b)). subject of the report, including the be on the market. Testing each batch prior to its release product subcategory, brand, subbrand, Proposed § 1132.12(a)(4)(i) would into commercial distribution provides generally require annual real-time assurance to the manufacturer and FDA package size and quantity of product stability testing to begin within 12 that each batch conforms to the (mass and, if portioned, count) and, for months of the completion of initial proposed standard. Any problems with portioned tobacco products, the size stability testing and then annually the NNN level that may arise during (mass) of each portion. Subcategories of thereafter, with no longer than 12 production (e.g., problems due to the smokeless tobacco products include, for months between testing. When a pasteurization equipment not heating example, loose moist snuff, portioned manufacturer has not conducted initial correctly) would be detected by batch moist snuff, loose snus, portioned snus, real-time stability testing on a particular testing. In addition, finished product loose dry snuff, certain dissolvables, smokeless tobacco product because it that does not conform to the standard loose chewing tobacco, and portioned has determined that the results from would not be released for commercial chewing tobacco. initial real-time stability testing distribution. In addition, the report would have to conducted on another product apply, The manufacturer would be required include the following: • annual stability testing would have to to use either the standard test method in NNN level of each sample tested; • begin when the product is first released proposed § 1132.14 or an alternative test Mean NNN level and standard for commercial distribution and then method that meets the requirements in deviation; annually thereafter, with no longer than proposed § 1132.16 and samples would • The location, including facility 12 months between testing (proposed have to be selected in accordance with name and address, from which each § 1132.12(a)(4)(ii)). Samples for annual the requirements set forth in sample was pulled; real-time stability testing, at a § 1132.18(b) and (c) (proposed • The manufacturing code of each minimum, would have to be tested § 1132.12(b)). sample tested or, for samples for initial within 7 days of manufacture to FDA expects tobacco product stability testing with no manufacturing determine the starting NNN level and at manufacturers would use the results of code, an identifying code created by the the established expiration date batch testing and annual stability testing manufacturer; (proposed § 1132.12(a)(4)(iii)) to (proposed § 1132.12(a)) to inform their • The testing date and location, determine the final NNN level and determination that a batch of finished including the testing facility name and provide assurance that the NNN level smokeless tobacco product conforms to address; conforms to the standard through the the proposed NNN level (proposed • The test method and sampling expiration date. Also, similar to initial § 1132.10) at the time of release for procedure used; real-time stability testing, the samples commercial distribution and through • All tobacco product reference would have to be stored at room the expiration date. For example, since standard test results;

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• The names and qualifications of the 4. Alternative Test Method (Proposed • General information; person(s) conducting the testing; § 1132.16) • A comprehensive index and table of • The equipment used (including If a tobacco product manufacturer contents; • Summary of the notification; and documentation to show that the were to choose not to use the standard • Complete description of the equipment is appropriate for its test method in § 1132.14 to test each method. intended use and has been calibrated); batch, the manufacturer would be In addition, FDA may request and required to use a validated alternative clarification and other relevant • For batch testing only, the criteria test method that conforms to the information, if needed (proposed used to make a decision to accept or requirements of proposed § 1132.16. § 1132.16(c)). reject each batch and the decision made The performance criteria of the The set of general information would with respect to each batch (e.g., accept, alternative test method would have to be submitted on the FDA-provided reject) based on the results of the meet or exceed the performance criteria form, a draft of which FDA is making product testing, including the NNN of the standard test method (proposed available as a reference for review and level of the individual batch and the § 1132.16). FDA would consider the comment (Ref. 145). The form would results of the product’s stability testing. following parameters to assess the include the following information: For example, the criteria for accepting a performance criteria of an alternative • Date the manufacturer submitted batch of product whose stability testing test method: Accuracy, precision, the notification to FDA; demonstrates no change in the mean linearity, specificity, limit of • Identification of the submission as quantitation, limit of detection, NNN level would be a batch mean NNN a notification of an alternative test robustness, and range. level less than or at 1.0 mg/g of tobacco, method; Proposed § 1132.16(a) would require • while the acceptance criteria for a batch Manufacturer’s name, address, and that, before using a validated alternative of product whose stability testing contact information; test method, the manufacturer notify the • demonstrates an increase of 0.2 mg in Identification of and contact Director of the Office of Science for information (including name, mailing mean NNN level per gram of tobacco FDA’s Center for Tobacco Products. By over the expiration period would be a address, email address, and telephone requiring prior notification, we hope to number) for an authorized batch mean NNN level at or below 0.8 help manufacturers to avoid using a test mg/g of tobacco. The manufacturer representative of the manufacturer method that does not meet the (which could be a U.S. agent for the would also be required to keep records, requirements in § 1132.16 and being where applicable, of the decision made manufacturer); unable to release for commercial • Identification of the subcategories and justification with respect to the distribution any product tested using results of a nonconforming product of finished smokeless tobacco products that method. Notification also allows (e.g., loose moist snuff, portioned moist investigation required under proposed FDA to track what methods are being § 1132.22. For example, if a batch snuff, loose snus, portioned snus, loose used, by whom, and for what products. dry snuff, certain dissolvables, loose initially tests out of compliance and a This information can be used to inform nonconforming product investigation chewing tobacco, portioned chewing FDA inspectors regarding the use of an tobacco, or other) that can be analyzed finds the NNN levels were erroneously alternative test method. In addition, if high because of a malfunction of the using the alternative test method; and any issues arise with regard to a specific • The testing facility’s name and testing equipment, the manufacturer alternative test method, FDA would be address. could determine that the batch is aware of other manufacturers who may The summary section of the acceptable for release if the NNN levels also be affected. notification would have to contain the are in conformance after the equipment A manufacturer seeking to use a following information: has been fixed. The manufacturer would validated alternative test method could • Identification of the standard test be required to keep the records of the not begin to use this method until 60 method for which the alternative test decision made and the justification. calendar days after the date FDA method is being proposed; 3. Standard Test Method (Proposed receives the notification regarding the • A concise description of the § 1132.14) alternative test method. This would performance criteria of the alternative allow time for FDA to review and act on test method; Proposed § 1132.14 states that the the notification. Smokeless tobacco • A concise explanation regarding the standard test method is the method manufacturers would be informed of manufacturer’s rationale for proposing entitled ‘‘Determination of N- FDA’s receipt of the notification through to use the alternative test method; and nitrosonornicotine (NNN) in Smokeless the automated Document Control Center • A concise comparison of the Tobacco and Tobacco Filler by HPLC– process. A manufacturer may not begin similarities and differences between the MS/MS,’’ that is incorporated by or continue using the alternative test alternative and standard test methods. reference in § 1132.5(a). The standard method if FDA notifies the As stated in proposed § 1132.16(b)(4), test method is explained in further manufacturer that it has not been the manufacturer would be required to detail in section IV.F, Analytical demonstrated to meet the requirements provide a complete description of the Method. If FDA subsequently of § 1132.16. method with sufficient detail to enable determines that a test method, which The notification would have to FDA to evaluate whether the has been incorporated by reference in a contain the information required by information demonstrates that the final rule, should be replaced with proposed § 1132.16(b) and be in the alternative test method meets or exceeds another method or updated, FDA will format discussed in proposed the performance criteria of the standard update the regulation in accordance § 1132.16(d). Proposed § 1132.16(b) test method set forth in § 1132.14. This with the Administrative Procedure Act provides the required contents for the description would have to include a (5 U.S.C. 553) and obtain approval of notification of use of an alternative test complete explanation of the manner in the change to the incorporation by method. The notification would be which the alternative test method is reference in accordance with 1 CFR part required to include the following proposed to deviate from the standard 51. information: test method in § 1132.14. The

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description would have to include an manufacturer may submit a request for This would ensure that FDA is aware of explanation with scientific rationale and a waiver. A waiver would be granted which manufacturers are using an supporting data, as well as a complete only if the use of electronic means is not alternative test method. Similarly, if the copy of the testing protocol, to reasonable. If FDA grants the original notification pertains to one demonstrate that the alternative method manufacturer’s waiver request, the subcategory of smokeless tobacco (e.g., meets or exceeds the performance Agency will provide information as to moist snuff), and the manufacturer also criteria established for the standard test how and where to submit the decides to use the method to test method. In proposed § 1132.16(b)(4)(ii) notification and supporting another subcategory of product (e.g., dry and (c), the manufacturer also would documentation in paper format. snuff), the manufacturer would have to have to include any data and If a manufacturer seeks a waiver, the submit a new notification in accordance information from other studies manufacturer must send a legible with proposed § 1132.16. A new comparing the alternative test method to written request in the English language notification would be needed because the standard test method and, if to the Document Control Center, with a an alternative test method may not be requested by FDA, any other relevant notation ‘‘ATTN: Office of Science,’’ to suitable for testing of other product information needed to evaluate the the address included in our Web site at subcategories and the test method alternative test method (e.g., statistical www.fda.gov/TobaccoProducts. The would need to be evaluated for them analysis comparing the alternative test address can also be obtained by calling before it can be used by the method to the standard test method, 1–877–CTP–2373 (1–877–287–1373). manufacturer. proficiency test results, or evidence of The waiver request would have to Proposed § 1132.16(f) indicates that technical competence). contain the following information: The FDA will acknowledge the receipt of a Proposed § 1132.16(d) provides the name and address of the tobacco notification of an alternative test format for a manufacturer’s notification product manufacturer that wishes to method. If the applicant submits the of use of an alternative test method. submit the notification; the name and notification electronically, FDA will First, the notification would have to be contact information of the acknowledge receipt electronically. This submitted using the FDA-provided form manufacturer’s authorized provision also reiterates that there is a and all information would have to be representative (which could be a U.S. waiting period before a smokeless organized, legible, and written in the agent for the manufacturer); and a tobacco manufacturer may begin using English language. The comprehensive statement and rationale as to why the the alternative test method. A index and table of contents (required by creation and/or submission of manufacturer could start using an proposed § 1132.16(b)) would provide information in electronic format is not alternative test method beginning 60 sufficient organization for the reasonable (such statement must be calendar days after FDA’s receipt of a document. FDA expects that the signed by the authorized representative complete notification unless the Agency manufacturer will submit this form of the tobacco product manufacturer). notifies the manufacturer otherwise. using the Agency’s electronic system. Proposed § 1132.16(e) clarifies the Proposed § 1132.16(f)(1) provides The manufacturer’s notification and all applicability of an alternative test that, if the notification is complete supporting information would be method. An alternative test method when FDA receives it, the 60 calendar required to be in an electronic format could be implemented only by the day waiting period would begin on the that the Agency can process, review, tobacco product manufacturer who date the Agency receives the and archive. Current information about submitted the notification and only with notification. If the notification did not electronic submission preparation (e.g., respect to the subcategories of finished contain all of the information required acceptable file formats, technical smokeless tobacco products that were by proposed § 1132.16(b) and was, specifications, data standards) and the subject of the notification. We are therefore, incomplete, FDA would not transmission requirements may be proposing this approach because an accept the notification and would found on the FDA Web site. alternative test method that is inform the submitter (proposed FDA is proposing to require that appropriate for one subcategory of § 1132.16(f)(2)). Upon notice from FDA tobacco manufacturers use the smokeless tobacco product (e.g., moist that the notification is incomplete, the electronic format for the submission of snuff) may not be generalizable to other manufacturer may not supplement the this information to facilitate our review subcategories of smokeless products submission, but rather would be of the data submitted. Electronic (e.g., chewing tobacco). Also, because required to submit a new notification submission of information is consistent some test methods may be proprietary that includes all the information with the Government Paperwork or may have been developed by the required in proposed § 1132.16(b). Elimination Act (Pub. L. 105–277), manufacturer for a specific product, Providing all of the information in one which requires that Federal Agencies FDA believes it is important for the complete notification will facilitate allow individuals or entities to submit manufacturer to notify FDA and fully FDA’s review so that it can act information or transact business with describe the method they plan to use expeditiously on the notification. The the Agency electronically. and the products on which they intend manufacturer would not be able to use A smokeless tobacco manufacturer to use it. the alternative test method until the end that is not able to submit a notification Other manufacturers interested in of the 60-day waiting period following of use of an alternative test method in similar or identical alternative test submission of the new, complete an electronic format could submit a methods would have to submit their notification, provided it has not written request to the Center for own notification following the received an FDA notification informing Tobacco Products explaining in detail procedures of proposed § 1132.16. the submitter otherwise. If FDA informs why the company cannot submit the Therefore, if a manufacturer previously the manufacturer during the 60 calendar notification in an electronic format and submitted a notification of an day waiting period that the requesting an alternative format (as alternative test method and later sells manufacturer has not demonstrated that provided in proposed § 1132.16(d)(3)). the company to another manufacturer, the alternative test method meets or Proposed § 1132.16(d)(3) would the new manufacturer would have to exceeds the performance criteria of the provide that, if a manufacturer cannot submit a notification if it wished to standard test method, the manufacturer submit a form electronically, the continue using the alternative method. would be prohibited from implementing

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the alternative test method. If FDA sample size is calculated) consistent increase of 0.2 mg of mean NNN level makes this determination after the 60 with the sampling design to achieve the per gram of tobacco on a dry weight calendar day period has ended and the sampling objective. basis over the expiration period, the manufacturer has already begun using Similarly, proposed § 1132.18(b) acceptance criteria would need to be a the procedure, the smokeless tobacco would require each tobacco product batch mean NNN level below 0.8 mg/g of manufacturer would have to manufacturer to design and implement tobacco on a dry weight basis. In those immediately cease using the alternative a sampling plan or plans for all batch cases, the batch of product is acceptable test method upon receipt of FDA’s testing required in § 1132.12(b) based on because the manufacturer would expect notification. a valid statistical rationale to ensure that the batch mean NNN level to remain at Proposed § 1132.16(f)(4) explains that the finished smokeless tobacco product or below 1.0 mg/g of tobacco on a dry acceptance of a notification does not consistently conforms to the NNN level weight basis through the expiration constitute a finding by the Agency that set forth in proposed § 1132.10. One date. an alternative test method meets or sampling plan could cover multiple Proposed § 1132.18(c) would require exceeds the performance criteria of the products (e.g., different flavors of the that samples be collected and examined standard test method set forth in same basic core tobacco blend and cut), in accordance with certain procedures. § 1132.14. but multiple plans would be needed if Under proposed § 1132.18(c)(1), test the products are sufficiently different samples for initial real-time and 5. Sampling Plans and Procedures from one another in processing or accelerated stability testing would have (Proposed § 1132.18) materials (e.g., one product is expected to consist of: Proposed § 1132.18 would require to have a very stable NNN level, • Smokeless tobacco product that has each smokeless tobacco manufacturer to whereas in another the NNN level been manufactured using the same design and implement sampling plans increases steadily over time). production processes as products for stability testing and batch testing. The sampling plan would have to manufactured for consumer use and These sampling plans would be used in ensure that the samples taken are packaged in the identical package that conjunction with the product testing representative of an entire batch and are will be used for the finished smokeless required in proposed § 1132.12 (stability randomly selected and collected from tobacco product, but it need not have testing and batch testing) and would each batch for testing. To account for the product package label; or provide procedures for the manufacturer the variability of the NNN levels in the • Finished smokeless tobacco product to select samples to demonstrate finished smokeless tobacco products, as it is intended to be sold or distributed conformance with the proposed NNN the following factors would have to be to consumers. level. based on adequate statistical criteria: This provision would allow flexibility Proposed § 1132.18(a) would require The confidence intervals, the level of for the manufacturer to determine the each tobacco product manufacturer to necessary precision, and the number of sample to be tested. It also recognizes design and implement a sampling plan finished products sampled. The that, at this early stage, a manufacturer or plans for all stability testing required sampling plan would also have to take may not want to or may not be able to in proposed § 1132.12(a) based on a into account the manufacturing quality create package labels for new smokeless valid statistical rationale to demonstrate history of the manufacturer (e.g., batch tobacco products. For example, in that the finished smokeless tobacco testing records and nonconforming accordance with § 1132.30 a package product’s expiration date is appropriate product investigations). For example, a label would need to have the expiration under the intended storage conditions. manufacturer who has a high number of date for the product. Prior to completing One sampling plan could cover multiple nonconforming product investigations initial stability testing, the manufacturer products (e.g., different flavors of the or high number of batch rejection might not know what the appropriate same basic core tobacco blend and cut), records may need to create a more expiration date would be. Similarly, we but multiple plans would be needed if robust sampling plan because of their expect a manufacturer of a new the products are sufficiently different history of producing nonconforming smokeless tobacco product would be from one another in processing or products. most likely to sample smokeless tobacco materials (e.g., one product is expected In addition, the sampling plan would that meets the requirements of to have a very stable NNN level, have to contain a full description of the § 1132.18(c)(1)(i) to minimize costs. In whereas in another the NNN level sampling methodology, with scientific contrast, we would expect a increases steadily over time). rationale, incorporate all sources of manufacturer whose smokeless tobacco The sampling plan would have to variability (including variability of the products may already conform to the ensure that samples taken are analytic method and the NNN levels proposed standard to test its finished representative and randomly selected. across batches), and describe the sample smokeless tobacco product Furthermore, to account for the size needed (including a full description (§ 1132.18(c)(1)(ii)) rather than product variability of NNN in the smokeless of how the sample size is calculated) that has been manufactured specifically tobacco products, the following factors consistent with the sampling design to for testing purposes. would have to be based on adequate achieve the sampling objective. Finally, Proposed § 1132.18(c)(2) would statistical criteria: The confidence the sampling plan would also need to require that test samples for annual real- intervals, the level of necessary fully describe the criteria the time stability testing and batch testing precision, and the number of finished manufacturer will use to make a consist of the finished smokeless products sampled. Finally, proposed decision to accept or reject each batch. tobacco product as it is intended to be § 1132.18(a) would require each For example, the criteria for accepting a sold or distributed to consumers and not sampling plan to fully describe the batch of a product would depend on the of a separate production sample. This is sampling methodology with scientific results of the stability testing. If stability intended to ensure the samples tested rationale, incorporate all sources of testing demonstrates no change in mean are representative of the product to be variability (including variability of the NNN level, the acceptance criteria could sold or distributed to consumers. analytic method and the NNN levels), be a batch mean NNN level less than or Under proposed § 1132.18(c)(3), all and describe the sample size needed at 1.0 mg/g of tobacco on a dry weight test samples would need to be stored (including a full description of how the basis. If the stability demonstrates an according to the intended storage

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conditions for the finished smokeless • Full identification of the smokeless Proposed § 1132.18(c)(8) would tobacco product (either room tobacco product sampled, including require that all the samples for a specific temperature or refrigeration), except that product subcategory, brand, and stability or batch test be tested at the test samples for initial accelerated subbrand, package size and quantity of same testing facility to ensure stability testing must be stored in the product (mass and, if portioned, consistency among the procedures used accordance with proposed count) and, for portioned tobacco and to protect against sample § 1132.12(a)(3)(iii). The manufacturer products, the size (mass) of each degradation. would have to include all of its portion; Proposed § 1132.18(c)(9) provides factories, stock rooms, warehouses, and • Manufacturing code or, for samples sampling requirements for the testing other locations containing finished for initial stability testing with no facility responsible for testing the smokeless tobacco products in the manufacturing code, an identifying code manufacturer’s samples. Once the population to be sampled. Because a created by the manufacturer; samples arrive at the testing facility, a batch may include product that is in the • The date on which the sample was representative of the facility would have warehouse and product that is in the taken; to ensure that the samples are inspected, factory, or in a place between the • The sampling location (including accounted for, and stored under the warehouse and factory, this would the address of the facility and specific finished smokeless tobacco product’s ensure the sample is representative of location within the facility where the intended storage conditions (e.g., room the entire population (batch) of finished sample was taken); temperature or refrigeration) except that smokeless tobacco products packaged • The name of the person(s) who test samples for initial accelerated for consumer use. collected the sample; and stability testing must be stored in Proposed § 1132.18(c)(4) sets forth • The location where the sample will accordance with § 1132.12(a)(3)(iii). The when samples must be taken for testing. be stored and tested (including the facility would then be responsible for Samples for stability testing would have facility name and address). generating a report for the stability or to be taken within 7 days of the This information would be generated batch test that includes the following manufacturing date and tested in at the time the samples are pulled for information: accordance with proposed § 1132.12(a). • Full identification of the smokeless testing. This would ensure the samples for tobacco product sampled, including The purpose of this information is to stability testing are tested as soon as product subcategory, brand, and fully identify each sample, including possible after manufacturing to establish subbrand, package size and quantity of what the product is, and when and the starting NNN level. It also provides the product (mass and, if portioned, where it was taken. These records sufficient time for the sample to be count) and, for portioned tobacco would serve dual purposes. First, they shipped to a laboratory for testing. products, the size(mass) of each portion; Samples for batch testing would have to can be used to verify that a company is • Manufacturing code or, for samples be taken from each batch and tested following its sampling plan and the for initial stability testing with no within 30 calendar days of the procedures required under this part, manufacturing code, an identifying code manufacturing date. including the number of samples created by the manufacturer; The amount of material acquired pulled, when they are pulled, and the • The date when the samples were during sampling would have to be locations from where they are pulled. taken from the batch, if available; sufficient for the test methods in Second, these records can be used to • Locations where samples were proposed §§ 1132.14 or 1132.16, generate some of the information for the drawn (including the address and including any repeats that may be report required under proposed specific locations within any facilities necessary. For example, repeat tests § 1132.18(c)(9). The records also where the samples were taken), if would be necessary if the test material document the start of sampling process. available; was damaged prior to or during the Proposed § 1132.18(c)(7) provides • The number of test samples drawn; analysis. Samples would have to be packing requirements for samples that and randomly selected in accordance with are sent for testing. Samples would have • Complete records of the samples the applicable sampling plan and taken to be packed securely to protect against received and tested, including the date within the same day. This would ensure damage that might occur during of receipt, the identifier of all persons that there has not been any degradation shipment to the testing facility, who tested the samples, and the test or change in part of the samples. including mechanical damage or severe results. Proposed § 1132.18(c)(5) would changes in humidity or temperature that This information would be generated require that sampling be performed by may affect the NNN level. The samples once the samples arrive at the testing persons who have sufficient education, would have to be sent to the testing facility. Unlike the information required training, and experience to accomplish facility by the most expeditious means under proposed § 1132.18(c)(6), this the assigned functions. This would in order to arrive no later than 3 report would be an aggregate report for allow the manufacturer the flexibility to calendar days after shipment. This is all the samples taken from a batch. The determine the education, training, and intended to minimize the potential for primary purpose of this information, experience needed to perform this damage to or contamination of the along with the information required by function. For example, the manufacturer samples and would help to ensure that proposed § 1132.18(c)(6), would be to may determine that a person has the the testing is completed within the establish the chain of custody for the necessary education, training, and specified time periods. The smokeless samples from the time they were taken experience for the position if they have tobacco manufacturer would also have up through their transfer to the testing completed course work or training in to send, under separate cover, a list of facility where they will be tested. The statistics, been trained by the the samples (identified by the relevant smokeless tobacco manufacturer would manufacturer on sampling procedures, information required by proposed be required to maintain the sampling or have prior work experience. § 1132.18(c)(6)) included in each information in accordance with Under proposed § 1132.18(c)(6), each shipment to the testing facility. This proposed § 1132.32. Thus, the sample would have to be identified by would ensure the laboratory receives a manufacturer would be responsible for the following information: complete list of the samples to be tested. obtaining this information from the

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testing facility. FDA also expects that tobacco products. Proposed § 1132.22(a) finished inspection for failing to meet this information would be integrated would require tobacco product any or all of the product’s into the records required by proposed manufacturers to establish and maintain specifications. Furthermore, in the event § 1132.12(c) to provide information procedures to identify, investigate, that a similar nonconforming product is across the batch. segregate, and make disposition identified in a different batch, a Proposed § 1132.18(c)(10) explains decisions (i.e., acceptance, rejection, or manufacturer’s investigation could that the manufacturer would be required rework) about nonconforming finished include any applicable information and to withhold from commercial smokeless tobacco products to prevent records from the previous distribution each batch until it has been their release for commercial nonconforming product investigation sampled and tested, and the tobacco distribution. FDA interprets ‘‘establish that are relevant to determining the product manufacturer has made a and maintain’’ for purposes of proposed extent of nonconformity of the affected decision to accept and release the batch. § 1132.22(a) to mean define, document batch. The manufacturer would be required to (in writing or electronically), The manufacturer would have to fully reject any nonconforming products as implement, follow, and, when document any investigation, including discussed in proposed § 1132.22. necessary, update. This section allows any materials reviewed, name of the person(s) making the disposition 6. Expiration Date (Proposed § 1132.20) manufacturers the flexibility to determine how they will perform these decisions, justification for the Proposed § 1132.20 would require all activities. disposition decisions, results of finished smokeless tobacco products to Proposed § 1132.22(b) would require retesting, decisions with respect to have an expiration date established by tobacco product manufacturers to reworking, and followup results from stability testing. The expiration date conduct an investigation if: the investigation (e.g., corrective would be required to be set no later than • The mean of the representative actions). FDA may inspect these records the final date the manufacturer can samples from any batch of finished to verify the manufacturer has demonstrate the finished smokeless smokeless tobacco product is adequately performed an investigation. tobacco product will not exceed the determined to be out of conformance Proposed § 1132.22(c) would require NNN limit in proposed § 1132.10 when with the requirements of § 1132.10, tobacco product manufacturers to reject stored under its intended conditions • A finished smokeless tobacco any batch of a finished smokeless (i.e., either room temperature or product’s expiration date must be tobacco product if the mean of the refrigeration). FDA considered requiring shortened due to the results of annual representative samples from the batch manufacturers to determine the time real-time stability testing, or does not meet the requirements of point at which the NNN level exceeds • FDA notifies the smokeless tobacco § 1132.10 unless a disposition decision the limit. However, FDA rejected this manufacturer that a distributed finished and justification to release the batch is approach because manufacturers may smokeless tobacco product does not made after an investigation shows the develop products with stable NNN conform to the requirements of part batch meets the requirements of part levels that do not exceed the NNN limit 1132. 1132. Manufacturers would not be able for a prolonged period (e.g., 5 years) and The purpose of a nonconforming to simply resample a batch until the requiring manufacturers to conduct product investigation would be to mean conforms with the proposed NNN stability testing for that entire period determine the extent and the cause, if limit in § 1132.10 if a previous mean did would be unnecessary. FDA also possible, of the nonconformity so that, not meet the requirements of part 1132. considered mandating a specific if identified early, the product is not If the initial mean was not in expiration period (e.g., 6 months or 1 processed further or released for conformance, the manufacturer must year) but determined this may be too commercial distribution. In addition, it conduct a nonconforming product restrictive and stifle innovation. would help to prevent recurrence of the investigation. If the manufacturer, for Accordingly, FDA believes the proposed nonconformity. instance, determines the NNN levels approach would provide manufacturers The manufacturer would be required were erroneously high because of a more flexibility in establishing an to conduct an investigation to determine malfunction of the testing equipment, expiration date that conforms to the the extent of the nonconformity upon and the batch tests in conformance after NNN level. identification of a nonconforming repair of the equipment, the Requiring an expiration date that is product and, as applicable, the locations manufacturer could determine that the established by stability testing provides where the nonconforming products have batch is acceptable for release into assurance that the NNN level will been distributed. We expect the commercial distribution. remain in conformance with the product manufacturer would be able to Proposed § 1132.22(d) would allow standard for the specified time period. determine the locations of the initial smokeless tobacco manufacturers to The expiration date also informs consignees (e.g., wholesalers, rework a batch of a nonconforming retailers that the manufacturer has not distributors, retailers) where the affected finished smokeless tobacco product, demonstrated compliance with the products were shipped in the event a which does not conform to the product standard beyond that date and corrective action needs to be taken. The requirements of part 1132, to bring it the product cannot be sold to investigation would have to include an into conformance with all the consumers. The expiration date also examination of all relevant processes, requirements of the part before it may be allows FDA inspectors to quickly operations, records, complaints, any released for commercial distribution. determine if products for sale in a retail corrective actions taken, and any other However, FDA thinks it is unlikely that establishment purport to be in relevant sources of information a manufacturer would rework conformance with the product standard. concerning the nonconforming product. nonconforming finished smokeless For example, a manufacturer could tobacco product because this would 7. Nonconforming Product (Proposed determine the extent of the likely require removing the product § 1132.22) nonconformity by examining records from its container and then mixing it Proposed § 1132.22 would require and in-process control records for any with smokeless tobacco product with manufacturers to establish procedures batches, or portions of batches that have very low NNN levels to ensure that the for handling nonconforming smokeless been rejected during either in-process or final product did not exceed the

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proposed NNN limit.4 We welcome tobacco product manufacturer. The 2. All investigations under information and comments on this expiration date on the package label § 1132.12(a)(4)(v). provision. would have to appear in two-digit 3. The source data and results of batch numerical values in the following testing conducted to determine C. Labeling and Recordkeeping format: ‘‘Expires on month/day/year.’’ conformance with § 1132.10, including Requirements (Proposed Subpart C) The expiration date informs retailers all information specified in § 1132.12(c). 1. Package Label Requirements that the manufacturer has not 4. All notifications of an alternative (Proposed § 1132.30) demonstrated compliance with the test method and all related Proposed § 1132.30 would require product standard beyond that date and correspondence under § 1132.16; that the package label of all finished the product cannot be sold to 5. All source data for the alternative smokeless tobacco products include a consumers. The expiration date also test method validation; manufacturing code, expiration date, allows FDA inspectors to quickly 6. All sampling plans and reports and, if applicable, storage conditions. determine if products for sale in a retail under § 1132.18; FDA is proposing to require that the establishment purport to be in 7. Documentation that the persons labels of finished smokeless tobacco conformance with the product standard performing sampling under § 1132.18 products contain a manufacturing code, and if retailers are selling expired have sufficient education, training, and expiration date, and, if applicable, products. experience to accomplish the assigned storage conditions for the finished Storage conditions would be required functions; smokeless tobacco product (proposed to be on the label if the finished 8. All identification, investigation, § 1132.30) so that FDA can determine smokeless tobacco product must be kept segregation, and disposition decision whether a product on store shelves in refrigerated storage to conform with procedures under § 1132.22(a); and purports to be in conformance with the the product standard until the 9. All nonconforming product product standard and link the product expiration date (as determined by investigations and rework under to records that substantiate its stability testing) and the package label § 1132.22(b) and (d). Second, proposed § 1132.32(b) conformance. These requirements would be required to bear the wording: provides certain specifications for these would also help ensure that the product ‘‘Keep Refrigerated.’’ However, no records. The records would have to be is handled and stored under appropriate wording would be required to be on the legible and written in English. conditions so that the product remains package label if the product’s intended Documents that have been translated in compliance with the standard and storage condition is room temperature. from a foreign language into English would help FDA verify that retailers are We note that proposed § 1132.1 states would have to be accompanied by the storing products appropriately. The that retailers and distributers would not foreign language version of the information would be required to be be in violation of part 1132 as it relates document and a certification by the printed on or permanently affixed to the to the sale or distribution or offer for manufacturer’s authorized package in a manner that assures it will sale or distribution of smokeless tobacco representative (which could be a U.S. remain on the packaging or label products that exceed the NNN limit if agent for the manufacturer) that the through the expected duration of use of they, among other things, store and English language translation is complete the product by the consumer. In transport the finished tobacco product and accurate. All records would be addition, it would have to appear according to the package label and do required to be readily available for clearly, legibly, and indelibly in the not sell or distribute or offer for sale or inspection and copying or other means English language. distribution finished smokeless tobacco The purpose of the manufacturing products past their expiration date. of reproduction by FDA upon request 5 code is to allow manufacturers and FDA Requiring package labels with an during an inspection. Requested to be able to link the product to a expiration date and storage conditions records that are maintained offsite specific batch that has been released for would allow retailers and distributers to would have to be made available within commercial distribution, which would handle the product in accordance with 24 hours or, if that is not feasible, as be helpful in the event of a the manufacturer’s intent so the product soon as possible before the close of the nonconforming product investigation or remains in conformance with the inspection. While we expect that most in the event that corrective or product standard. records can be made available to FDA preventive actions should be taken. The within 24 hours, we recognize that, in 2. Recordkeeping Requirements manufacturing code could also help some cases, additional time may be (Proposed § 1132.32) determine the history of the needed to retrieve records from a third manufacturing, processing, packaging, Proposed § 1132.32 includes two party or archival storage. Records that labeling, holding, and initial recordkeeping requirements. This can be immediately retrieved from distribution of the tobacco product from information is necessary for FDA to another location, including by computer records maintained by the smokeless ascertain and confirm that smokeless or other electronic means, would meet tobacco products are in compliance the requirement that the records be 4 Based on comments provided by the Alcohol with the proposed standard. readily available. In addition, proposed § 1132.32(c) and Tobacco Tax and Trade Bureau (TTB), we First, proposed § 1132.32(a) would understand that this process would likely constitute would require that the records kept require that each facility that the manufacture of tobacco products for purposes under this part be retained for at least manufactures finished smokeless of the Internal Revenue Code. Under the Internal 4 years from the date of commercial Revenue Code, the manufacture of tobacco products tobacco products establish and maintain requires a permit as a manufacturer of tobacco records containing the following products from TTB. As we understand TTB’s 5 Several laws govern the confidentiality of permitting requirements, entities lacking a information: information submitted under sections 907 and 909 manufacturing permit, including importers, may 1. Full documentation of stability of the FD&C Act, including sections 301(j) and not engage in manufacturing activities. We also testing protocols and the results of 906(c) of the FD&C Act (21 U.S.C. 331(j) and understand that certain provisions of the Internal initial and annual stability testing under 387f(c)), the Trade Secrets Act (18 U.S.C. 1905), and Revenue Code prohibit importers of tobacco the Freedom of Information Act (FOIA) (5 U.S.C. products from repackaging tobacco products after § 1132.12(a), including all information 552), as well as FDA’s regulations in 21 CFR part such products are released from customs custody. specified in § 1132.12(c). 20.

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distribution of the finished smokeless date of the final rule, manufacturers proposed to be incorporated by tobacco product that is the subject of the would not be allowed to introduce into reference to be reasonably available and record. However, for records relating to domestic commerce any finished usable by testing facilities (see 1 CFR alternative test methods under smokeless tobacco product that does not 51.5(a) and 51.7). § 1132.16, the required 4-year retention comply with the requirements of the IX. Economic Analysis of Impacts period would be for a period not less final rule, irrespective of the date of than 4 years after the last date the manufacture. However, retailers would We have examined the impacts of the method that is the subject of the record be permitted to sell-off existing proposed rule under Executive Order is used (e.g., 4 years from the last date inventory of noncompliant finished 12866, Executive Order 13563, the the manufacturer used an alternative smokeless tobacco products Regulatory Flexibility Act (5 U.S.C. test method). FDA has selected 4 years manufactured before the effective date 601–612), and the Unfunded Mandates as a means to help ensure that the for 60 days after the effective date of the Reform Act of 1995 (Pub. L. 104–4). records would be available for at least final rule. FDA notes that keeping Executive Orders 12866 and 13563 one biennial FDA inspection under products with higher NNN levels on the direct us to assess all costs and benefits sections 704 and 905(g) of the FD&C market for an extended period of time of available regulatory alternatives and, Act. after the effective date of the rule is not when regulation is necessary, to select FDA considered not requiring specific in the interest of public health. regulatory approaches that maximize recordkeeping requirements and, net benefits (including potential instead, allowing the manufacturer to VIII. Incorporation by Reference economic, environmental, public health determine recordkeeping needs but, FDA is proposing to incorporate by and safety, and other advantages; FDA believes that detailed reference the test method entitled, distributive impacts; and equity). We recordkeeping requirements are ‘‘Determination of N-nitrosonornicotine have developed a comprehensive necessary to confirm that the finished (NNN) in Smokeless Tobacco and Economic Analysis of Impacts that smokeless tobacco products are in Tobacco Filler by HPLC–MS/MS,’’ LIB assesses the impacts of the proposed compliance with the proposed standard. No. 4620, January 2017 (Ref. 79). You rule. We believe that this proposed rule For example, requiring manufacturers to may obtain a free copy of the material is an economically significant regulatory fully document their stability testing proposed to be incorporated from the action as defined by Executive Order protocols and test results will enable Docket at www.regulations.gov or from 12866. FDA to confirm that the manufacturer’s the Food and Drug Administration, The Regulatory Flexibility Act test method and protocols are adequate Center for Tobacco Products, 10903 requires us to analyze regulatory options to meet the requirements of part 1132. New Hampshire Ave., Silver Spring, MD that would minimize any significant In addition, requiring nonconforming 20993, 1–888–463–6332. impact of a rule on small entities. product records will help the This is a technical document Because many smokeless tobacco manufacturer and FDA determine the developed by FDA specifically for use products may need to be reformulated, extent of the nonconformity and, as in tobacco testing facilities. FDA and reformulation represents the main applicable, the locations where the developed this test method for NNN in driver of the costs of the rule, we nonconforming products have been order to streamline the testing process tentatively find that the proposed rule distributed, in the event of a recall or and reduce testing costs. Other available would have a significant economic enforcement action (e.g., seizure). methods test for all TSNAs while this impact on a substantial number of small test method is limited to NNN. As such entities. VII. Proposed Effective Date it is a highly specific method that The Unfunded Mandates Reform Act FDA proposes that any final rule on reduces testing costs while ensuring that of 1995 (section 202(a)) requires us to the tobacco product standard for NNN the results from the test method prepare a written statement, which that may issue based on this proposal demonstrate a high level of specificity, includes an assessment of anticipated become effective 3 years after the date accuracy, and precision in measuring a costs and benefits, before proposing of publication of the final rule. FDA range of NNN levels across a variety of ‘‘any rule that includes any Federal believes this approach would allow smokeless tobacco products. mandate that may result in the adequate time for developing any This test method relies on several ISO expenditure by State, local, and tribal necessary changes in technology to standards for determining moisture governments, in the aggregate, or by the achieve the NNN level, for any changes content in tobacco and tobacco private sector, of $100,000,000 or more made to manufacturers’ tobacco products—ISO 6488:2004, ISO (adjusted annually for inflation) in any purchasing choices and curing methods, 6488:2004/Cor 1:2008, and ISO one year.’’ The current threshold after and for any preparation or changes 16632:2013. FDA is not proposing to adjustment for inflation is $146 million, needed in facilities. In addition, FDA incorporate these standards by using the most current (2015) Implicit believes that it will provide adequate reference. You may purchase a copy of Price Deflator for the Gross Domestic time for manufacturers to seek and the ISO standards from the International Product. This proposed rule would obtain marketing authorization from Organization for Standardization, 1, ch. result in an expenditure in any year that FDA for their new tobacco products. de la Voie-Creuse, Case Postale 56, CH– meets or exceeds this amount. New tobacco products are subject to 1211, Geneva 20, Switzerland, or from The proposed rule would establish a enforcement if they are on the market the American National Standards product standard for all finished without FDA authorization. Institute, 1899 L Street NW., 11th Floor, smokeless tobacco products. Therefore, after the effective date of a Washington, DC 20036, or on the Specifically, the proposed rule would final rule for this proposed tobacco Internet at http://www.iso.org or require that all finished smokeless product standard, no person would be www.ansi.org. We note that these ISO tobacco products comply with a limit allowed to manufacture, distribute, sell, standards are relatively inexpensive for NNN in such products in order to be or offer for sale or distribution within (about $50 each) and may already be marketed and distributed for sale in the the United States any finished used by tobacco testing facilities. United States. This proposed product smokeless tobacco product that does not For the reasons set forth in this standard would require that the mean comply with the rule. After the effective section, FDA considers the test method level of NNN in any batch of finished

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smokeless tobacco products not exceed cancer risk among smokeless tobacco mortality reductions quantified over 20 1.0 mg/g of tobacco (on a dry weight users. years is $12.77 billion at a 3 percent basis) at any time through the product’s We quantify benefits associated with discount rate and $7.24 billion at a 7 labeled expiration date as determined the proposed rule in the form of reduced percent discount rate. The annualized by product testing. The proposed oral cancer morbidity and mortality value over 20 years of quality adjusted standard also includes requirements on attributable to smokeless tobacco. As life-years gained from reduced oral the sale and distribution of smokeless described in section V.A.3 of the cancer mortality and morbidity ranges tobacco products, product testing, preamble of the proposed rule, we also from approximately $283.95 million to labeling, and recordkeeping.6 expect the standard to reduce the risk of $3.05 billion at a 3 percent discount The costs of the proposed rule, when esophageal cancer and it may reduce the rate, with a primary value of $1.06 finalized, will be due to affected entities risks of other cancers such as billion, and approximately $246.40 ensuring that the smokeless tobacco pancreatic, laryngeal, prostate, and lung million to $2.65 billion, with a primary products comply with the proposed cancer. However, there is more limited value of $0.92 billion at a 7 percent product standard. We have estimated information to directly quantify these discount rate. The primary estimate of that the annualized costs associated health benefits. As such, we only the present value of total quantified with the proposed rule over 20 years to consider reductions in oral cancer as the benefits over 20 years is approximately be between $17.91 million and $42.72 quantified benefit of the proposed $15.86 billion at a 3 percent discount million using a 3 percent discount rate, product standard. rate and $9.80 billion at a 7 percent with a primary value of $30.31 million, Most of the estimated benefits arise discount rate for reductions in oral and between $20.11 million and $50.57 from quality life-years gains gained from cancer alone. These values are likely an million, with a primary value of $35.34 reduced oral cancer mortality. The underestimate of the benefits associated million using a 7 percent discount rate. annualized value over 20 years of with the proposed rule, as we do not The primary estimate for the present quality adjusted life-years gained from quantify reductions in mortality and value of total quantified costs over 20 reduced oral cancer mortality ranges morbidity from cancers other than oral years is approximately $450.97 million from $228.66 million to $2.46 billion at cancer. Costs and benefits are at a 3 percent discount rate and $374.36 a 3 percent discount rate, with a summarized in table 8. million at a 7 percent discount rate. primary value of $858.46 million. Using NNN is a carcinogenic agent found in a 7 percent discount rate, the The full analysis of economic impacts smokeless tobacco products. As annualized value of quality life-years is available in the docket for this described in the preamble, on the basis gained from averted deaths ranges from proposed rule (Ref. 146) and at http:// of the available scientific evidence, FDA $182.01 million to $1.96 billion, with a www.fda.gov/AboutFDA/Reports has determined that NNN is the primary value of $683.34 million. The ManualsForms/Reports/Economic predominant driver of excess oral primary estimate of the present value of Analyses/default.htm. TABLE 8—SUMMARY OF BENEFITS, COSTS AND DISTRIBUTIONAL EFFECTS OF PROPOSED RULE

Units Category Primary Low High Discount Period Notes estimate estimate estimate Year rate covered dollars (%) (years)

Benefits: Annualized Monetized millions/ $924.91 $246.40 $2,647.21 2015 7 20 Most of the health benefits included in the totals year. would be realized more than 20 years after publica- tion of the final rule, but the risk reductions associ- ated with these benefits occur during the 20-year period beginning at publication of the final rule. $1,065.92 $ 283.95 $3,051.09 2015 3 20 ...... Annualized ...... 7 20 ...... Quantified ...... 3 20 years ...... Qualitative ...... Potential cost savings from net life-time reduction in medical care utilization; additional health benefits from reduction in other toxicants correlated with NNN; reduction in cancers, other than oral cancers Costs: Annualized ...... $35.34 $20.11 $50.57 2015 7 20 ...... Monetized millions/year ...... $30.31 $17.91 $42.72 2015 3 20 ...... Annualized ...... 7 20 ...... Quantified ...... 3 20 ...... Qualitative ...... Transfers: Federal Annualized ...... 7 20 ...... Monetized $millions/year ...... 3 20 ......

From: To:

Other Annualized ...... 7 20 ......

6 The proposed product standard includes a distribution restrictions. However, generally, this compliant versus noncompliant products, we number of requirements in addition to the actual analysis uses the term product standard as generally refer to compliance with the NNN limit NNN limit, including requirements related to shorthand for the NNN limit requirement. Similarly requirement. product testing, recordkeeping, and sale and when we discuss anticipated compliance status and

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TABLE 8—SUMMARY OF BENEFITS, COSTS AND DISTRIBUTIONAL EFFECTS OF PROPOSED RULE—Continued

Units Category Primary Low High Discount Period Notes estimate estimate estimate Year rate covered dollars (%) (years)

Monetized $millions/year ...... 3 20 ......

From: To:

Effects State, Local or Tribal Government: None estimated. Small Business: The average cost per small entity is largest in Year 1 and range between $2.67 million and $7.97 million. Re- formulation costs and stability testing represent the largest proportion of costs—up to 60 percent of average sales for enti- ties with fewer than 50 employees and up to 13 percent of average sales for entities with 50–100 employees...... Wages: None estimated...... Growth: None estimated.

X. Analysis of Environmental Impact on respondents, including through the products, the manufacturer would be The Agency has carefully considered use of automated collection techniques, required to use a validated alternative the potential environmental effects of when appropriate, and other forms of test method that conforms to the this action. FDA has concluded that the information technology. requirements of proposed § 1132.16. action will not have a significant impact Title: Tobacco Product Standard: Proposed § 1132.16(a) would require on the human environment, and that an NNN Level in Finished Smokeless that, before using a validated alternative environmental impact statement is not Tobacco Products. test method, the manufacturer notify the required. The Agency’s finding of no Description: FDA is proposing a Center for Tobacco Products. significant impact and the evidence product standard to establish a limit of Proposed§ 1132.18 would establish supporting that finding, contained in an NNN in finished smokeless tobacco the sampling requirements for all environmental assessment, may be seen products sold in the United States. testing. These sampling requirements in the Division of Dockets Management Products with higher NNN levels pose would be used in conjunction with the (see ADDRESSES) between 9 a.m. and 4 higher risks of cancer and FDA finds product testing required in proposed p.m., Monday through Friday. Under that establishing a NNN limit in § 1132.12 (stability testing and batch FDA’s regulations implementing the finished smokeless tobacco products is testing) and would provide procedures National Environmental Policy Act (21 appropriate for the protection of the for the manufacturer to select samples to CFR part 25), an action of this type public health. Proposed § 1132.10 demonstrate conformance with the would require an environmental would require that the mean level of proposed NNN limit. assessment under 21 CFR 25.20. NNN in any batch of finished smokeless Proposed § 1132.22 would require tobacco products not exceed 1.0 mg/g of tobacco product manufacturers to XI. Paperwork Reduction Act of 1995 tobacco (on a dry weight basis) at any establish and maintain procedures to This proposed rule contains time through the product’s labeled identify, investigate, segregate, and information collection provisions that expiration date as determined by testing make disposition decisions about are subject to review by the Office of in compliance with § 1132.12. Proposed nonconforming finished smokeless Management and Budget (OMB) under §§ 1132.12, 1132.14, 1132.16, and tobacco products in order to prevent the Paperwork Reduction Act of 1995 1132.18 would establish product testing their release for commercial distribution (44 U.S.C. 3501–3520). A description of and sampling plan requirements. and to conduct investigations related to these provisions is given in the Proposed § 1132.12 would require two nonconforming products. Description section of this document types of testing for smokeless tobacco Under proposed § 1132.30, the labels with an estimate of the annual products—stability testing and batch of finished smokeless tobacco products reporting, recordkeeping, and third- testing. Proposed § 1132.12(a) would would be required to contain a party disclosure burden. Included in the require initial and annual stability manufacturing code, expiration date, estimate is the time for reviewing testing to assess the stability of the NNN and, if applicable, storage conditions for instructions, searching existing data level in finished smokeless tobacco the finished smokeless tobacco product. sources, gathering and maintaining the products and to establish and verify the The information would have to be data needed, and completing and product’s expiration date and storage printed on or permanently affixed to the reviewing each collection of conditions (either room temperature or package assuring that the label remains information. refrigeration). Proposed § 1132.12(b) intact through the expected duration of FDA invites comments on these would require manufacturers to conduct use. It must appear clearly, legibly, and topics: (1) Whether the proposed batch testing on each batch of finished indelibly in the English language. The collection of information is necessary smokeless tobacco product to determine expiration date must appear on the for the proper performance of FDA’s whether the products conform to the packaging in two-digit numerical functions, including whether the proposed NNN limit. Proposed values. If the manufacturer determines information will have practical utility; § 1132.12(c) would require the tobacco by stability testing that meets the (2) the accuracy of FDA’s estimate of the product manufacturer to document all requirements in § 1132.12 that the burden of the proposed collection of testing. finished smokeless tobacco product information, including the validity of Proposed §§ 1132.14 and 1132.16 must be stored in a refrigerator, the the methodology and assumptions used; would establish the standard and package label must state ‘‘Keep (3) ways to enhance the quality, utility, alternative test methods. If a tobacco Refrigerated.’’ The manufacturing code and clarity of the information to be product manufacturer were to choose would provide a history of the collected; and (4) ways to minimize the not to use the standard test method in manufacturing, processing, packaging, burden of the collection of information § 1132.14 to test its smokeless tobacco labeling, holding, and initial

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distribution of the product from records functions; all identification, used. FDA has selected 4 years as a maintained by the tobacco product investigation, segregation, and means to help ensure that the records manufacturer. disposition procedures related to would be available for at least one Proposed § 1132.32 would require nonconforming products; and all biennial FDA inspection under sections that tobacco product manufacturers nonconforming product investigations 704 and 905(g) of the FD&C Act. maintain records regarding the product and rework (i.e., the processing of Description of Respondents: The testing (i.e., stability and batch testing), nonconforming finished smokeless provisions of this standard would apply including protocols and a full report of tobacco products to meet the to finished smokeless tobacco products. the source data and results; records requirements of part 1132). FDA is also Finished smokeless tobacco product regarding investigations related to proposing to require copies of all means a smokeless tobacco product, shortening of expiration dates based on records be retained for a period of not results of annual stability testing; all less than 4 years from the date of including all parts and components, notifications of an alternative test commercial distribution of the finished packaged for consumer use, except for method and source data for alternative smokeless tobacco product that is the components, parts, or accessories sold test method validation; all sampling subject of the record, except that certain without tobacco. The respondents are plans and reports; documentation that records relating to alternative test therefore manufacturers of smokeless the persons performing sampling have methods would be required to be tobacco products. sufficient education, training, and retained for a period of not less than 4 FDA estimates the burden of this experience to accomplish the assigned years after the last date the method is collection of information as follows:

TABLE 9—ESTIMATED ANNUAL REPORTING BURDEN 1

Number of Average 21 CFR part Number of responses per Total annual burden per Total hours respondents respondent responses response

§ 1132.16 Alternative Test Method (FDA Form 3979) ...... 23 1 23 20 460 § 1132.16 Waiver from Electronic Submission ...... 2 1 2 .75 2 Total ...... 462 1 There are no capital costs or operating and maintenance costs associated with this collection of information. 2 The burden in the reporting chart corresponds to table 23 ‘‘Estimated Costs to Industry Associated with Notifications to FDA Regarding Use of Alternative Testing Methods’’ in the RIA.

TABLE 10—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1

Number of Average Activity (units) Number of records per Total annual burden per Total hours recordkeepers recordkeeper records recordkeeping

Change in process (Formulations) ...... 68 1 68 8 544 Ingredient change (Formulations) ...... 28 1 28 8 224 No change (Formulations) ...... 60 1 60 4 240 Labeling records, annual after year 1 (UPCs) ...... 1255 1 1255 2 2,510 Initial Stability Testing records (Manufacturers) ...... 23 8 184 4 736 Annual Stability Testing records (Manufacturers) ...... 23 3 69 4 276 Batch Testing (products) ...... 784 28 21,952 4 87,808 Batch Testing records (Manufacturers) ...... 23 1 23 4 92 Procedures for nonconforming products and related inves- tigations (Manufacturers)...... 23 1 23 4 92 Notifications, alternate testing methods (Manufacturers) .... 23 2 46 0.75 35 Total 1 ...... 92,557 1 There are no capital costs or operating and maintenance costs associated with this collection of information. 2 The burden in the recordkeeping chart corresponds to table 24 ‘‘Estimated Recordkeeping Costs to Industry’’ and table 13 ‘‘Estimated Num- ber of Batch Tests’’ in the RIA.

TABLE 11—ESTIMATED ANNUAL THIRD-PARTY DISCLOSURE BURDEN 1

Number of Number of disclosures Total annual Average Activity (units) respondents per respond- disclosures burden per Total hours ent disclosure

Package Labeling Change Minor (UPCs) ...... 459 1 459 10 4,590 Package Labeling Change Major (UPCs) ...... 8 1 8 23 184 Initial Stability Testing (one time) (Products) ...... 784 168 131,712 2 263,424 Initial Stability Testing (recurring) (Products) ...... 784 6.72 5,268 2 10,536 Annual Stability Testing (Products) ...... 784 60.48 47,416 2 94,832 Sampling Plans (Products) ...... 784 1 784 2 1,568 Total 1 ...... 370,360 1 There are no capital costs or operating and maintenance costs associated with this collection of information. 2 The burden in the third-party disclosure chart corresponds to table 12 ‘‘Estimated Costs Associated with Proposed Stability Testing Require- ments’’ and table 15 ‘‘Products with Expiration and Storage Information’’ in the RIA.

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FDA’s burden estimates are based on alternative test method. We estimate 263,424 hours. After the first year we the regulatory impact analysis, Agency that 23 manufacturers will maintain estimate that there would be 5,268 expertise, registration and listing data, these records for a total of 35 burden initial tests for a total of 10,536 hours. company revenue information from hours. Therefore, the total estimated After the initial testing we expect 47,416 Dunn & Bradstreet, and comparing to recordkeeping hours are 92,557. annual tests per year for total of 94,832 other online sources in order to Table 11 represents third party hours. categorize the entities and number of disclosures (package labeling) that a FDA included sampling plans in the products. respondent must display. This table also third party disclosure chart because Table 9 describes the annual reporting covers the proposed stability testing that each tobacco product manufacturer burden as a result of the requirements must occur for the label. Labeling would be required to demonstrate that proposed in § 1132.16 submitting a burden is estimated by using data on the the finished smokeless tobacco notification of an alternative test number of active UPCs from Nielsen product’s expiration date (on the label) method and requesting a waiver from Inc., and the estimated percentage of is appropriate under the intended electronic submission of such a products with expiration and storage storage conditions, and to do so the notification. FDA estimates that it will information come from FDA manufacturer would conduct testing receive 23 notifications for alternative Registration and Listing database (as of pursuant to sampling plans. In test methods using FDA Form 3979 (Ref. March 1, 2016). To derive the number developing a sampling plan for NNN in 145) for a total of 460 hours. Because of UPCs subject to a labeling change that smokeless tobacco products a some of the manufacturers may includes storage information, we manufacturer must take into account the currently be conducting these reports, assume that only those products that are size of a batch, the variation of NNN in the RIA anticipates that there would be currently refrigerated but for which we their product, the margin of error between 1 and 23 manufacturers did not find evidence that the labeling around their analytical techniques, and affected. For PRA purposes we have exists would incur such labeling any other variables they can justify as used the high estimate of 23. FDA also change. Thus, we estimate that these pertinent to their calculation. While the estimates that 2 respondents will submit different products that would likely be development of a sampling plan would a waiver request from electronic affected by labeling changes would require some data analysis and submission. Therefore, the total include up to 467 UPCs (derived by determination of assumptions, we estimated reporting burden for this assuming that each product would be believe that the development of a proposed rule is 462 hours. associated with one unique UPC). sampling plan could cover multiple Table 10 outlines the recordkeeping Since all products already have either products. In addition once a sampling requirements that are proposed in an expiration date or a manufactured on plan had been developed we believe § 1132.32. We note that recordkeeping date, adding an expiration date or that there would be significant time burden activities are derived from storage conditions to labeling would be redundancy in the development of the respective models (RTI considered a minor change if product subsequent plans which would reduce International, 2015a; RTI International, label redesign is not needed and major the time needed to complete them. 2015a; RTI International, 2015(b). FDA if product label redesign is needed. FDA Ultimately we have estimated that the estimates recordkeeping time burden believes that labeling changes associated time for the development of a sampling related to product reformulation (change with adding storage information is plan would average 2 hours per product in process, ingredient change, and no assumed to be ‘‘major’’ to incorporate for a total of 1,568 hours. Therefore, the change) to involve 156 formulations for uncertainty regarding product label total third party disclosure burden is total of 1,008 hours. For recordkeeping redesign. We estimate that 459 affected estimated to be 370,360 hours. burden related to certain labeling UPCs will undergo minor labeling FDA estimates that the total burden records, FDA estimates that after year changes for a total of 4,590 hours. imposed by these proposed one 1,255 affected Universal Product Additionally, FDA estimates that 8 requirements will be 463,379 hours (462 Code (UPC) records will be kept affected UPCs will undergo major reporting, 92,557 recordkeeping, and annually for a total of 2,510 hours. The labeling changes regarding storage 370,360 third party disclosures). number of UPCs subject to these information for a total of 184 hours. This proposed rule also refers to recordkeeping requirements is Since establishing and verifying a previously approved collections of determined by multiplying the number product’s expiration date and storage information found in FDA regulations. of UPCs in each product category by the conditions on a label requires actual The collections of information in percent of products with expiration date stability testing we categorize this section 905(j) of the FD&C Act information. burden under third party disclosures. (substantial equivalence reports) have We estimate that batch testing will be For PRA purposes we have categorized been approved under OMB control conducted for 784 products (21,952 tests stability testing under third party number 0910–0673. per year) for a total of 87,808 hours. disclosures. For example, in accordance To ensure that comments on Proposed § 1132.32 requires records to with § 1132.30 a package label would information collection are received, be maintained for stability and batch need to have the expiration date for the OMB recommends that written tests. FDA estimates that 23 product. Prior to completing initial comments be faxed to the Office of manufacturers will maintain records stability testing, the manufacturer might Information and Regulatory Affairs, related to initial stability testing, annual not know what the appropriate OMB (see ADDRESSES). All comments stability testing, and batch testing for a expiration date would be. Since the should be identified with the title of the total of 1104 hours. Records are also testing will inform the label we believe information collection. required to be maintained of procedures it is appropriate for the burden to fall In compliance with the Paperwork for nonconforming products and related under this category. We estimate that Reduction Act of 1995 (44 U.S.C. investigations. We estimate that 23 784 products would undergo initial 3407(d)), the Agency has submitted the manufacturers will maintain these stability testing, and annual stability information collection provisions of this records for a total of 92 hours. Proposed testing each year thereafter. FDA proposed rule to OMB for review. These § 1132.32 requires manufacturers to estimates that in year 1 there would be requirements will not be effective until maintain all notifications of an 131,712 initial tests for a total of FDA obtains OMB approval. FDA will

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publish a notice concerning OMB 3. European Commission, Scientific Tobacco Products in Four U.S. Cities,’’ approval of these requirements in the Committee on Emerging and Newly Nicotine &Tobacco Research, 12(1):69– Federal Register. Identified Health Risks, ‘‘Health Effects 72, 2010. of Smokeless Tobacco Products,’’ 2008. 18. Bahreinifar, S., N.M. Sheon, and P.M. XII. Executive Order 13132 4. National Cancer Institute, Centers for Ling, ‘‘Is Snus the Same as Dip? Disease Control and Prevention, U.S. Smokers’ Perceptions of New Smokeless FDA has analyzed this proposed rule Department of Health and Human Tobacco Advertising,’’ Tobacco Control, in accordance with the principles set Services, ‘‘Smokeless Tobacco and 22(2):84–90, 2013. forth in Executive Order 13132. FDA Public Health: A Global Perspective,’’ 19. Foulds, J. and H. Furberg, ‘‘Is Low- has determined that the proposed rule, 2014, available at http:// Nicotine Marlboro Snus Really Snus?’’ if finalized, would not contain policies cancercontrol.cancer.gov/brp/tcrb/ Harm Reduction Journal, 5:9, 2008. that would have substantial direct global-perspective/ 20. Lawler, T.S., S.B. Stanfill, L. Zhang, et al., SmokelessTobaccoAndPublicHealth.pdf. ‘‘Chemical Characterization of Domestic effects on the States, on the relationship 5. Borgerding, M.F., J.A. Bodnar, G.M. Curtin, Oral Tobacco Products: Total Nicotine, between the National Government and et al., ‘‘The Chemical Composition of pH, Unprotonated Nicotine and Tobacco- the States, or on the distribution of Smokeless Tobacco: A Survey of specific N-nitrosamines,’’ Food and power and responsibilities among the Products Sold in the United States in Chemical Toxicology, 57:380–386, 2013. various levels of government. 2006 and 2007,’’ Regulatory Toxicology 21. Savage, L., ‘‘Experts Fear Swedish Snus Accordingly, the Agency tentatively and Pharmacology, 64(3):367–387, 2012. Sales in the U.S. Could Thwart Anti- concludes that the proposed rule does 6. Song, M., C. Marian, T.M. Brasky, et al., tobacco Measures,’’ Journal of the not contain policies that have ‘‘Chemical and Toxicological National Cancer Institute, 99(18):1358– Characteristics of Conventional and Low- 1359, 1365, 2007. federalism implications as defined in TSNA Moist Snuff Tobacco Products,’’ 22. Belushkin, M., G. Jaccard, and A. the Executive order and, consequently, Toxicology Letters, 245:68–77, 2016. Kondylis, ‘‘Considerations for a federalism summary impact statement 7. Balbo, S., S. James-Yi, C.S. Johnson, et al., Comparative Tobacco Product is not required. ‘‘(S)-N′-nitrosonornicotine, a Constituent Assessments Based on Smoke of Smokeless Tobacco, is a Powerful Oral Constituent Yields,’’ Regulatory XIII. Executive Order 13175 Cavity Carcinogen in Rats,’’ Toxicology and Pharmacology, FDA has analyzed this proposed rule Carcinogenesis, 34(9):2178–2183, 2013. 73(1):105–113, 2015. in accordance with the principles set 8. Hecht, S.S., ‘‘Biochemistry, Biology, and 23. Substance Abuse and Mental Health Carcinogenicity of Tobacco-specific N- Services Administration, ‘‘Behavioral forth in Executive Order 13175. We nitrosamines,’’ Chemical Research in Health Trends in the United States: have tentatively concluded that the rule Toxicology, 11(6):559–603, 1998. Results from the 2014 National Survey does not contain policies that would 9. Stepanov, I., L. Biener, A. Knezevich, et on Drug Use and Health,’’ 2015, available have a substantial direct effect on one or al., ‘‘Monitoring Tobacco-specific N- at http://www.samhsa.gov/data/sites/ more Indian tribes, on the relationship nitrosamines and Nicotine in Novel default/files/NSDUH-FRR1-2014/ between the Federal Government and Marlboro and Camel Smokeless Tobacco NSDUH-FRR1-2014.htm. Indian tribes, or on the distribution of Products: Findings From Round 1 of the 24. Substance Abuse and Mental Health power and responsibilities between the New Product Watch,’’ Nicotine & Services Administration, ‘‘Results From Federal Government and Indian tribes. Tobacco Research, 14(3):274–281, 2012. the 2014 National Survey on Drug Use 10. Ammann, J.R., K.S. Lovejoy, M.J. Walters, and Health: Detailed Tables,’’ 2015, The Agency solicits comments from et al., ‘‘A Survey of N′-nitrosonornicotine available at http://www.samhsa.gov/ tribal officials on any potential impact (NNN) and Total Water Content in Select data/sites/default/files/NSDUH- on Indian tribes from this proposed Smokeless Tobacco Products Purchased DetTabs2014/NSDUH-DetTabs2014.htm. action. in the United States in 2015,’’ Journal of 25. Centers for Disease Control and Agricultural and Food Chemistry, Prevention, ‘‘Tobacco Use Among XIV. References 64(21):4400–4406, 2016. Middle and High School Students— The following references are on 11. Rutqvist, L.E., M. Curvall, T. Hassler, et United States 2011–2015,’’ Morbidity ® display in the Division of Dockets al., ‘‘Swedish Snus and the GothiaTek and Mortality Weekly Report, Standard,’’ Harm Reduction Journal, 65(14):361–367, April 15, 2016, available ADDRESSES Management (see ) and are 8:11, 2011. at http://www.cdc.gov/mmwr/volumes/ available for viewing by interested 12. Foulds, J., L. Ramstrom, M. Burke, et al., 65/wr/mm6514a1.htm. persons between 9 a.m. and 4 p.m., ‘‘Effect of Smokeless Tobacco (Snus) on 26. Substance Abuse and Mental Health Monday through Friday; they are also Smoking and Public Health in Sweden,’’ Services Administration, ‘‘Results From available electronically at http:// Tobacco Control, 12:349–359, 2003. the 2013 National Survey on Drug Use www.regulations.gov. FDA has verified 13. Stepanov, I., J. Jensen, D. Hatsukami, et and Health,’’ 2014. the Web site addresses, as of the date al., ‘‘New and Traditional Smokeless 27. U.S. Department of Health and Human this document publishes in the Federal Tobacco: Comparison of Toxicant and Services, ‘‘The Health Consequences of Register, but Web sites are subject to Carcinogen Levels,’’ Nicotine & Tobacco Using Smokeless Tobacco,’’ A Report of Research, 10(12):1773–1782, 2008. the Advisory Committee to the Surgeon change over time. 14. McNeill, A., R. Bedi, S. Islam, et al., General, 1986. 1. International Agency for Research on ‘‘Levels of Toxins in Oral Tobacco 28. World Health Organization, ‘‘The Cancer, ‘‘Smokeless Tobacco and Some Products in the UK,’’ Tobacco Control, Scientific Basis of Tobacco Product Tobacco-specific N-nitrosamines,’’ IARC 15(1):64–67, 2006. Regulation,’’ Third Report of a WHO Monographs on the Evaluation of 15. Krautter, G.P., P.X. Chen, and M.F. Study Group, WHO Technical Report Carcinogenic Risks to Humans, 89, 2007, Borgerding, ‘‘Consumption Patterns and Series 955, 2009. available at http://monographs.iarc.fr/ENG/ Biomarkers of Exposure in Cigarette 29. Fisher, S., B. Spiegelhalder, J. Eisenbarth, Monographs/vol89/mono89.pdf. Smokers Switched to Snus, Various et al., ‘‘Investigations on the Origin of 2. International Agency for Research on Dissolvable Products, Dual Use, or Tobacco-specific Nitrosamines in Cancer, ‘‘Personal Habits and Indoor Tobacco Abstinence,’’ Regulatory Mainstream Smoke of Cigarettes,’’ Combustions: A Review of Human Toxicology and Pharmacology, Carcinogenesis, 11(5):723–730, 1990. Carcinogens,’’ IARC Monographs on the 71(2):186–197, 2015. 30. Brunnemann, K.D., B. Prokopczyk, M.V. Evaluation of Carcinogenic Risks to 16. Swedish Match, ‘‘Gothiatek® Limits for Djordjevic, et al., ‘‘Formation and Humans, 100(e), 2012, available at Undesired Components,’’ March 7, 2016. Analysis of Tobacco-specific N- http://monographs.iarc.fr/ENG/ 17. Rogers, J.D., L. Biener, and P.I. Clark, nitrosamines,’’ Critical Reviews in Monographs/vol100E/mono100E.pdf. ‘‘Test Marketing of New Smokeless Toxicology, 26(2):121–137, 1996.

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31. Hoffmann, D., M.V. Djordjevic, J. Fan, et 43. Hecht, S.S., C.B. Chen, M. Dong, et al., nitrosamines and Nicotine in Novel al., ‘‘Five Leading U.S. Commercial ‘‘Chemical Studies on Tobacco Smoke,’’ Smokeless Tobacco Products: Findings Brands of Moist Snuff in 1994: Beitra¨ ge zur Tabakforschung from Round II of the New Product Assessment of Carcinogenic N- International, 9(11), 1977. Watch,’’ Nicotine & Tobacco Research, nitrosamines,’’ Journal of National 44. Geiss, O. and D. Kotzias, ‘‘Tobacco, 16(8):1070–1078, 2014. Cancer Institute, 87(24):1862–1869, Cigarettes and Cigarette Smoke, An 57. U.S. Environmental Protection Agency, 1995. Overview,’’ Institute for Health and ‘‘Risk Assessment Guidance for 32. Burton, H.R., L.P. Bush, and M.V. Consumer Protection, European Superfund,’’ 1989, available at https:// Djordjevic, ‘‘Influence of Temperature Commission Joint Research Centre, 2007. www.epa.gov/risk/risk-assessment- and Humidity on the Accumulation of 45. Bush, L.P., M. Cui, H. Shi, et al., guidance-superfund-rags-part. Tobacco Specific Nitrosamines in Stored ‘‘Formation of Tobacco-specific 58. Hecht S.S., S.G. Carmella, Stepanov, I., et Burley Tobacco,’’ Journal of Agricultural Nitrosamines in Air-Cured Tobacco,’’ al., ‘‘Metabolism of the Tobacco-specific and Food Chemistry, 37:1372–1377, Recent Advances in Tobacco Science, Carcinogen 4-(Methylnitrosamino)-1-(3- 1989. 27:23–46, 2001. Pyridyl)-1-Butanone to Its Biomarker 33. Spiegelhalder, B. and S. Fischer, 46. Staaf, M., S. Back, A. Wiernik, et al., Total NNAL in Smokeless Tobacco ‘‘Formation of Tobacco-specific ‘‘Formation of Tobacco-specific Users,’’ Cancer Epidemiology, Nitrosamines,’’ Critical Reviews in Nitrosamines (TSNA) During Air-curing: Biomarkers & Prevention, 17(3): 732– Toxicology, 21(4):241, 1991. Conditions and Control,’’ Beitra¨ ge zur 735, 2008. 34. Fisher, M.T., C.B. Bennett, A. Hayes, et Tabakforschung International, 59. Hecht, S.S., R. Young, and Y. Maeura, al., ‘‘Sources of and Technical 21(6):321–330, 2005. ‘‘Comparative Carcinogenicity in F344 Approaches for the Abatement of 47. Andersen, R.A., P.D. Fleming, H.R. Rats and Syrian Golden Hamsters of N′- Tobacco Specific Nitrosamine Formation Burton, et al., ‘‘Levels of Alkaloids and nitrosonornicotine and N’- in Moist Smokeless Tobacco Products,’’ Their Derivatives in Air- and Fire-cured nitrosonornicotine-1–N-oxide,’’ Cancer Food and Chemical Toxicology, 50(3– KY 171 Dark Tobacco During Prolonged Letters, 20(3):333–340, 1983. 4):942–948, 2012. Storage: Effects of Temperature and 60. Hatsukami, D.K., R.M. Keenan, and D.J. 35. Brunnemann, K.D., S.S. Hecht, and D. Moisture,’’ Tobacco International, Anton, ‘‘Topographical Features of Hoffmann, ‘‘N-nitrosamines: 192(10):49–55, 1990. Smokeless Tobacco Use,’’ Environmental Occurrence, in vivo 48. Morin, A., A. Porter, A. Ratavicius, et al., Psychopharmacology, 96(3):428–429, Formation and Metabolism,’’ Journal of ‘‘Evolution of Tobacco Specific 1988. Toxicology: Clinical Toxicology, 19(6– Nitrosamines and Microbial Populations 61. Ary, D.V., E. Lichtenstein, and H.H. 7):661–688, 1982. During Flue-Curing of Tobacco Under Severson, ‘‘Smokeless Tobacco Use Direct and Indirect Heating,’’ Beitra¨ ge 36. Burton, H.R., N.K. Dye, and L.P. Bush, Among Male Adolescents: Patterns, zur Tabakforschung International, ‘‘Relationship Between Tobacco-specific Correlates, Predictors, and the Use of 21(1):40–46, 2004. Nitrosamines and Nitrite from Different Other Drugs,’’ Preventive Medicine, 49. Nestor, T.B., J.S. Gentry, D.M. Peele et al., Air-Cured Tobacco Varieties,’’ Journal of 16(3):385–401, 1987. ‘‘Role of Oxides of Nitrogen in Tobacco- 62. Andersson, G. and T. Axell, ‘‘Clinical Agricultural and Food Chemistry, 42(9), specific Nitrosamine Formation in Flue- Appearance of Lesions Associated with 2007–2011, 1994. cured Tobacco,’’ Beitra¨ ge zur the Use of Loose and Portion-bag Packed 37. Fischer, S., B. Spiegelhalder, and R. Tabakforschung International, Preussmann, ‘‘Preformed Tobacco- 20(7):467–475, 2003. Swedish Moist Snuff: A Comparative specific Nitrosamines—Role of Nitrate 50. Rodu, B. and C. Jansson, ‘‘Smokeless Study,’’ Journal of Oral Pathology & and Influence of Tobacco Type,’’ Tobacco and Oral Cancer: A Review of Medicine, 18(1):2–7, 1989. Carcinogenesis, 10(8):1511–1517, 1989. the Risks and Determinants,’’ Critical 63. Digard, H., G. Errington, A. Richter, et al., 38. De Roton, C., A. Wiernik, I. Wahlberg, et Reviews in Oral Biology and Medicine, ‘‘Patterns and Behaviors of Snus al., ‘‘Factors Influencing the Formation 15(50):252–263, 2004. Consumption in Sweden,’’ Nicotine & of Tobacco-specific Nitrosamines in 51. Parsons, L.L., M.S. Smith, J.L. Hamilton, Tobacco Research, 11(10):1175–1181, French Air-Cured Tobaccos in Trials and et al., ‘‘Nitrate Reduction During Curing 2009. at the Farm Level,’’ Beitra¨ ge zur and Processing of Burley Tobacco,’’ 64. Hatsukami, D.K., D. Anton, A. Callies, et Tabakforschung International, 21(6): Tobacco Science, 30:100–103, 1986. al., ‘‘Situational Factors and Patterns 305–320, 2005. 52. Burton, H.R., G.H. Childs, R.A. Andersen, Associated With Smokeless Tobacco 39. Siminszky, B., L. Gavilano, S. Bowen, et et al., ‘‘Changes in Chemical Use,’’ Journal of Behavioral Medicine, al., ‘‘Conversion of Nicotine to Composition of Burley Tobacco During 14(4):383–396, 1991. Nornicotine in Nicotiana Tabacum is Senescence and Curing .3. Tobacco- 65. Boyle, R.G., M.A. Gerend, C.B. Peterson, Mediated by CYP82E4, a Cytochrome specific Nitrosamines,’’ Journal of et al., ‘‘Use of Smokeless Tobacco by P450 Monooxygenase,’’ Proceedings of Agricultural and Food Chemistry, Young Adult Females,’’ Journal of the National Academy of Sciences of the 37(2):426–430, 1989. Substance Abuse, 10(1):19–25, 1998. United States of America, 53. Andersen, R.A., H.R. Burton, P.D. 66. Lemmonds, C.A., S.S. Hecht, J.A. Jensen, 102(41):14919–14924, 2005. Fleming, et al., ‘‘Effect of Storage et al., ‘‘Smokeless Tobacco Topography 40. Gavilano, L.B., N.P. Coleman, L.E. Conditions on Nitrosated, Acylated, and and Toxin Exposure,’’ Nicotine & Burnley, et al., ‘‘Genetic Engineering of Oxidized Pyridine Alkaloid Derivatives Tobacco Research, 7(3):469–474, 2005. Nicotiana Tabacum for Reduced in Smokeless Tobacco Products,’’ Cancer 67. Ferketich, A.K., A.G. Wee, J. Shultz, et al., Nornicotine Content,’’ Journal of Research, 49(21):5895–5900, 1989. ‘‘Smokeless Tobacco Use and Salivary Agricultural and Food Chemistry, 54. Andersen, R.A., P.D. Fleming, H.R. Cotinine Concentration,’’ Addictive 54(24):9071–9078, 2006. Burton, et al., ‘‘Nitrosated, Acylated, and Behaviors, 32(12):2953–2962, 2007. 41. Shi, H., R. Wang, L.P. Bush, et al., Oxidized Pyridine Alkaloids During 68. Hatsukami, D.K., J.O. Ebbert, R.M. Feuer, ‘‘Changes in TSNA Contents During Storage of Smokeless Tobaccos: Effects of et al., ‘‘Changing Smokeless Tobacco Tobacco Storage and the Effect of Moisture, Temperature, and Their Products New Tobacco-delivery Temperature and Nitrate Level on TSNA Interactions,’’ Journal of Agricultural Systems,’’ American Journal of Formation,’’ Journal of Agricultural and Food Chemistry, 39(7):1280–1287, 1991. Preventive Medicine, 33(6 Suppl): S368– Food Chemistry, 61(47):11588–11594, 55. Djordjevic, M.V., J. Fan, L.P. Bush, et al., S378, 2007. 2013. ‘‘Effects of Storage Conditions on Levels 69. Caraway, J.W. and P.X. Chen, 42. Chamberlain, W.J. and O.T. Chortyk, of Tobacco-specific N-nitrosamines and ‘‘Assessment of Mouth-level Exposure to ‘‘Effects of Curing and Fertilization on N-nitrosamino Acids in U.S. Moist Tobacco Constituents in U.S. Snus Nitrosamine Formation in Bright and Snuff,’’ Journal of Agricultural and Food Consumers,’’ Nicotine & Tobacco Burley Tobacco,’’ Beitra¨ ge zur Chemistry, 41(10):1790–1794, 1993. Research, 15(3):670–677, 2013. Tabakforschung International, 15(2):87– 56. Stepanov, I., L. Biener, K. Yershova, et al., 70. Oliver, A.J., J.A. Jensen, R.I. Vogel, et al., 92, 1992. ‘‘Monitoring Tobacco-specific N- ‘‘Flavored and Nonflavored Smokeless

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Tobacco Products: Rate, Pattern of Use, Chromatography A, 1008(2):135–143, Tobacco Users: Results From 1999 to and Effects,’’ Nicotine & Tobacco 2003. 2012 National Health and Nutrition Research, 15(1):88–92, 2013. 84. Osterdahl, B., C. Jansson, and A. Paccou, Examination Survey Data,’’ Cancer 71. Jitnarin, N., W.S.C. Poston, C.K. Haddock, ‘‘Decreased Levels of Tobacco-specific N- Epidemiology, Biomarkers & Prevention, et al., ‘‘Tobacco Use Pattern Among a nitrosamines in Moist Snuff on the 24(12):1829–1837, 2015. National Firefighter Cohort,’’ Nicotine & Swedish Market,’’ Journal of Agricultural 98. Hecht, S.S., S.G. Carmella, SE. Murphy, Tobacco Research, 17(1):66–73, 2015. and Food Chemistry, 52(16):5085–5088, et al., ‘‘Similar Exposure to a Tobacco- 72. Hecht, S.S., S.G. Carmella, A. Edmonds, 2004. specific Carcinogen in Smokeless et al., ‘‘Exposure to Nicotine and a 85. Digard, H., N. Gale, G. Errington, et al., Tobacco Users and Cigarette Smokers,’’ Tobacco-specific Carcinogen Increase ‘‘Multi-analyte Approach for Cancer Epidemiology, Biomarkers & with Duration of Use of Smokeless Determining the Extraction of Tobacco Prevention, 16(8):1567–1572, 2007. Tobacco,’’ Tobacco Control, 17(2):128– Constituents From Pouched Snus by 99. Stepanov, I., and S.S. Hecht, ‘‘Tobacco 131, 2008. Consumers During Use,’’ Chemistry Specific Nitrosamines and Their 73. Nilsson, R., ‘‘A Qualitative and Central Journal, 7:55, 2013. Pyridine-N-glucoronides in the Urine of Quantitative Risk Assessment of Snuff 86. Adams, J.D., K.D. Brunnemann, and D. Smokers and Smokeless Tobacco Users,’’ Dipping,’’ Regulatory Toxicology and Hoffmann, ‘‘Chemical Studies on Cancer Epidemiology, Biomarkers & Pharmacology, 28(1):1–16, 1998. Tobacco Smoke,’’ Journal of Prevention, 14(4), 885–891, 2005. 74. Ayo-Yusuf, O.A. and G.N. Connolly, Chromatography A, 256(2):347–351, 100. Boffetta, P., S.S Hecht, N. Gray, et al., ‘‘Applying Toxicological Risk 1983. ‘‘Smokeless Tobacco and Cancer,’’ Assessment Principles to Constituents of 87. Brunnemann, K.D., L. Genoble, and D. Lancet Oncology, 9(9):822, 2008. Smokeless Tobacco Products: Hoffmann, ‘‘Identification and Analysis 101. Pednekar, M.S., P.C. Gupta, B.B. Yeole, Implications for Product Regulation,’’ of a New Tobacco-specific N- et al., ‘‘Association of Tobacco Habits, Tobacco Control, 20(1):53–57, 2011. nitrosamine, 4-(Methylnitrosamino)-4-(3- Including Bidi Smoking, With Overall 75. U.S. Environmental Protection Agency, Pyridyl)-1-Butanol,’’ Carcinogenesis, and Site-specific Cancer Incidence: ‘‘Exposure Factors Handbook,’’ Chapter 8(3):465–469, 1987. Results From the Mumbai Cohort 18, 2011, available at http:// 88. Djordjevic, M.V., K.D. Brunnemann, and Study,’’ Cancer Causes and Control, ofmpub.epa.gov/eims/ D. Hoffmann, ‘‘Identification and 22(6):859–868, 2011. eimscomm.getfile?p_download_ Analysis of a Nicotine-Derived N- 102. Haussmann, H., ‘‘Use of Hazard Indices id=526181. nitrosamino Acid and Other Nitrosamino for a Theoretical Evaluation of Cigarette 76. Berg, C.J., E. Stratton, G.L. Schauer, et al., Acids in Tobacco,’’ Carcinogenesis, Smoke Composition,’’ Chemical ‘‘Perceived Harm, Addictiveness, and 10(9):1725–1731, 1989. Research in Toxicology, 25(4):794–810, Social Acceptability of Tobacco Products 89. Health Canada, ‘‘Official Method T–309: 2012. and Marijuana Among Young Adults: Determination of Nitrosamines in Whole 103. Lee, P.N. and J. Hamling, ‘‘The Relation Marijuana, Hookah, and Electronic Tobacco,’’ 1999. Between Smokeless Tobacco and Cancer Cigarettes Win,’’ Substance Use and 90. Hecht, S.S., R.M. Ornaf, and D. in Northern Europe and North America. Misuse, 50(1): 79–89, 2015. Hoffmann, ‘‘Determination of N′- A Commentary on Differences Between 77. Yuan, J.M., A.D. Knezevich, R. Wang, et nitrosonornicotine in Tobacco by High the Conclusions Researched by Two al., ‘‘Urinary Levels of the Tobacco- Speed Liquid Chromatography,’’ Recent Reviews,’’ BMC Cancer, 9:256, specific Carcinogen N′- Analytical Chemistry, 47(12):2046–2048, 2009. nitrosonornicotine and its Glucuronide 1975. 104. Idris, A.M., H. Ahmed, and M. Malik, are Strongly Associated with Esophageal 91. Brown, M.C., D.V. Onisk, J.W. Stave, et ‘‘Toombak Dipping and Cancer of the Cancer Risk in Smokers,’’ al., ‘‘Tobacco-specific Nitrosamine Oral Cavity in the Sudan: A Case-Control Carcinogenesis, 32(9):1366–1371, 2011. Detection Assays and Reagents,’’ U.S. Study,’’ International Journal of Cancer, 78. World Health Organization, ‘‘The Patent Application No. 20050043515 A1, 63(4):477–480, 1995. Scientific Basis of Tobacco Product 2005. 105. Idris, A.M., J. Nair, H. Ohshima, et al., Regulation 2nd Report,’’ 2008. 92. Roosaar, A., A.L. Johansson, G. ‘‘Unusually High Levels of Carcinogenic 79. U.S. Food and Drug Administration, Sandborgh-Englund, et al., ‘‘Cancer and Tobacco-specific Nitrosamines in Sudan ‘‘Determination of N-nitrosonornicotine Mortality Among Users and Nonusers of Snuff (Toombak),’’ Carcinogenesis, (NNN) in Smokeless Tobacco and Snus,’’ International Journal of Cancer, 12(6):1115–1118, 1991. Tobacco Filler by HPLC–MS/MS,’’ LIB 123(1):168–173, 2008. 106. U.S. Department of Health and Human No. 4620, January 2017, available at 93. California Environmental Protection Services, ‘‘How Tobacco Smoke Causes http://www.fda.gov/ScienceResearch/ Agency, ‘‘Expedited Cancer Potency Disease—The Biology and Behavioral FieldScience/ucm231463.htm. Values and Proposed Regulatory Levels Basis for Smoking-Attributable Disease: 80. CORESTA, ‘‘Recommended Method No for Certain Proposition 65 Carcinogens,’’ A Report of the Surgeon General,’’ 72: Determination of Tobacco-specific 1992. Chapter 3, 2010, available at https:// Nitrosamines in Smokeless Tobacco 94. Castonguay, A., A. Rivenson, N. Trushin, www.ncbi.nlm.nih.gov/books/NBK53017/ Products by LC–MS/MS.’’ 2016. et al., ‘‘Effects of Chronic Ethanol . 81. Wu, W., D. Ashley, and C. Watson, Consumption on the Metabolism and 107. Hecht, S.S., I. Stepanov, and S. ‘‘Simultaneous Determination of Five Carcinogenicity of N′-nitrosonornicotine Carmella, ‘‘Exposure and Metabolic Tobacco-specific Nitrosamines in in F344 Rats,’’ Cancer Research, Activation Biomarkers of Carcinogenic Mainstream Cigarette Smoke by Isotope 44(6):2285–2290, 1984. Tobacco-specific Nitrosamines,’’ Dilution Liquid Chromatography/ 95. Stoner, G.D. C. Adams, L.A. Kresty, et al., Accounts of Chemical Research, Electrospray Ionization Tandem Mass ‘‘Inhibition of N′-nitrosonornicotine- 49(1):106–114, 2016. Spectrometry,’’ Analytical Chemistry, induced Esophageal Tumorigenesis by 3- 108. Levin, M.L., ‘‘The Occurrence of Lung 75(18):4827–4832, 2003. phenylpropyl isothiocyanate,’’ Cancer in Man,’’ Acta: Unio 82. Richter, P., K. Hodge, S. Stanfill, et al., Carcinogenesis, 19(12):2139–2143, 1998. Internationalis Contra Cancrum, ‘‘Surveillance of Moist Snuff: Total 96. Khariwala, S.S., S.G. Carmella, I. 9(3):531–541, 1953. Nicotine, Moisture, pH, Un-ionized Stepanov, et al., ‘‘Elevated Levels of 1- 109. U.S. Department of Health and Human Nicotine, and Tobacco-specific hydroxypyrene and N′- Services, ‘‘The Health Consequences of Nitrosamines,’’ Nicotine & Tobacco nitrosonornicotine in Smokers with Smoking—50 Years of Progress: A Report Research, 10(11):1645–1652, 2008. Head and Neck Cancer: A Matched of the Surgeon General,’’ Chapter 12, 83. Jansson, C., A. Paccou, and B. O¨ sterdahl, Control Study,’’ Head & Neck, 2014, available at https:// ‘‘Analysis of Tobacco-specific N- 35(8):1096–1100, 2013. www.surgeongeneral.gov/library/reports/ nitrosamines in Snuff by Ethyl Acetate 97. Rostron, B.L., C.M. Chang, D.M. van 50-years-of-progress/index.html. Extraction and Liquid Chromatography— Bemmel, et al., ‘‘Nicotine and Toxicant 110. Stockwell, H.G. and Lyman, G.H, tandem Mass Spectrometry,’’ Journal of Exposure Among U.S. Smokeless ‘‘Impact of Smoking and Smokeless

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Tobacco on the Risk of Cancer of the Behavior of Former and Current or Smokeless Tobacco Among U.S. High Head and Neck,’’ Head & Neck Surgery, Smokeless Tobacco Users,’’ Journal of School Seniors,’’ Nicotine & Tobacco 9(2):104–110, 1986. American College of Health, 46(3):133– Research, 9(11):1191–1196, 2007. 111. Centers for Disease Control and 138, 1997. 137. Krosnick, J.A, L. Chang, S.J. Sherman, et Prevention, ‘‘2010 National Health 125. Hall, M.G., K.M. Ribisl, and N. Brewer, al., ‘‘The Effects of Beliefs About the Interview Survey,’’ 2011, available at ‘‘Smokers’ and Nonsmokers’ Beliefs Health Consequences of Cigarette http://www.cdc.gov/nchs/nhis/nhis_ About Harmful Tobacco Constituents: Smoking on Smoking Onset,’’ Journal of 2010_data_release.htm. Accessed on Implications for FDA Communication Communication, 56(S1):S18–S37, 2006. April 11, 2016. Efforts,’’ Nicotine & Tobacco Research, 138. Song, A.V., H.E.R. Morrell, J.L. Cornell, 112. United States Cancer and Cancer 16(3):343–350, 2014. et al., ‘‘Perceptions of Smoking-related Mortality Statistics: 1999–2013, 126. Yanovitzky, I. and C.L. Blitz, ‘‘Effect of Risks and Benefits as Predictors of WONDER Online Database. United Media Coverage and Physician Advice Adolescent Smoking Initiation,’’ States Department of Health and Human on Utilization of Breast Cancer Screening American Journal of Public Health, Services, Centers for Disease Control and by Women 40 Years and Older,’’ Journal 99(3):487–492, 2009. Prevention and National Cancer of Health Communication, 5(2):117–134, 139. Boyle, R.G., A.J. Claxton, and J.L. Institute; 2016, available at http:// 2000. Forster, ‘‘The Role of Social Influences wonder.cdc.gov/cancer.html. Accessed 127. Cram, P., A. Fendrick, J. Inadomi, et al., and Tobacco Availability on Adolescent on April 11, 2016. ‘‘The Impact of a Celebrity Promotional Smokeless Tobacco Use,’’ Journal of 113. Centers for Disease Control and Campaign on the Use of Colon Cancer Adolescent Health, 20(4):279–285, 1997. Prevention, National Vital Statistic Screening—The Katie Couric Effect,’’ 140. Nemeth, J.M., S.T. Liu, E.G. Klein, et al., Report, U.S. Life Tables 2010, available Archives of Internal Medicine, ‘‘Factors Influencing Smokeless Tobacco at http://www.cdc.gov/nchs/data/nvsr/ 163(13):1601–1605, 2003. Use in Rural Ohio Appalachia,’’ Journal _ nvsr63/nvsr63 07. 128. Johnson, SE., C. Choiniere, G. Tessman, of Community Health, 37(6):1208–1217, 114. Lee, P.N. and J. Hamling, ‘‘Systematic et al., ‘‘How Do Young Adult Consumers 2012. Review of the Relation Between Evaluate and Compare the Harmfulness 141. Portnoy, D.B., C.C. Wu, C. Tworek, et al., Smokeless Tobacco and Cancer in of Cigarettes and Smokeless Tobacco? A ‘‘Youth Curiosity about Cigarettes, Europe and North America,’’ BMC Focus Group Study,’’ In B. Apelberg Smokeless Tobacco, and Cigars: Medicine, 7:36, 2009. (Chr.), Youth and Young Adult Use and Prevalence and Associations with 115. International Agency for Research on Risk Perception of Tobacco Products: Advertising,’’ American Journal of Cancer, ‘‘Tobacco Control: Reversal of Research to Inform FDA Regulations, Preventive Medicine, 47(2 Suppl 1):S76– Risk After Quitting Smoking,’’ IARC 2013, Symposium conducted at the S86, 2014. Handbooks of Cancer Prevention, 2007. annual meeting of the Society for 142. Herd, N., R. Borland, and A. Hyland, 116. Chandu, A., A.C.H. Smith, and S.N. Research on Nicotine and Tobacco ‘‘Predictors of Smoking Relapse by Rogers, ‘‘Health-related Quality of Life in (SRNT), Boston, MA. Duration of Abstinence: Findings From Oral Cancer: A Review,’’ Journal of Oral 129. Loewenstein, G., ‘‘Out of Control: the International Tobacco Control (ITC) and Maxillofacial Surgery, 64(3):495– Visceral Influences on Behavior,’’ Four Country Survey,’’ Addiction, 502, 2006. Organizational Behavior and Human 104(12):2088–2099, 2009. 117. Gamba, A. M. Romano, I.M. Grosso, et Decision Processes, 65(3):272–292, 1996. 143. Ockene, J.K., K.M. Emmons, R.J. al., ‘‘Psychosocial Adjustment of Patients Mermelstein, et al., ‘‘Relapse and Surgically Treated for Head and Neck 130. Mutti, S., D. Hammond, R. Borland, et Cancer,’’ Head & Neck, 14(3):218–223, al., ‘‘Beyond Light and Mild: Cigarette Maintenance Issues for Smoking 1992. Brand Descriptors and Perceptions of Cessation,’’ Health Psychology, 19(1, 118. Bjordal, K. and S. Kaasa, ‘‘Psychological Risk in the International Tobacco Control Suppl):17–31, 2000. Distress in Head and Neck Cancer (ITC) Four Country Survey,’’ Addiction, 144. Killen, J.D. and S.P. Fortmann, ‘‘Craving Patients 7–11 Years After Curative 106(6):1166–1175, 2011. is Associated with Smoking Relapse: Treatment,’’ British Journal of Cancer, 131. Delnevo, C.D., O.A. Wackowski, D.P. Findings From Three Prospective 71(3):592–597, 1995. Giovenco, et al., ‘‘Examining Market Studies,’’ Experimental and Clinical 119. National Cancer Institute, ‘‘Cancer Trends in the United States Smokeless Psychopharmacology, 5(2):137–142, Prevalence and Cost of Care Projections,’’ Tobacco Use: 2005–2011,’’ Tobacco 1997. 2015, available at http:// Control, 23(2):107–112, 2014. 145. Draft FDA Form 3979 (Alternative Test costprojections.cancer.gov/graph.php. 132. Alpert, H.R., H. Koh, and G.N. Connolly, Method Notification). Accessed on April 11, 2016. ‘‘Free Nicotine Content and Strategic 146. Food and Drug Administration, 120. National Cancer Institute, ‘‘A Snapshot Marketing of Moist Snuff Tobacco Preliminary Regulatory Impact Analysis; of Head and Neck Cancer,’’ 2014, Products in the United States: 2000– Initial Regulatory Flexibility Analysis; available at http://www.cancer.gov/ 2006,’’ Tobacco Control, 17(5):332–338, Unfunded Mandates Reform Act research/progress/snapshots/head-and- 2008. Analysis; Tobacco Product Standard for neck. Accessed on April 11, 2016. 133. O’Connor, R.J., A. McNeill, R. Borland, N-nitrosonornicotine Level in Finished 121. Henley, S.J., M.J. Thun, C. Connell, et et al., ‘‘Smokers’ Beliefs About the Smokeless Tobacco Products; Proposed al., ‘‘Two Large Prospective Studies of Relative Safety of Other Tobacco Rule. Mortality Among Men Who Use Snuff or Products: Findings From the ITC 147. Hoffmann, D. and S.S. Hecht, Chewing Tobacco (United States),’’ Collaboration,’’ Nicotine & Tobacco ‘‘Advances in Tobacco Carcinogenesis,’’ Cancer Causes and Control, 16(4):347– Research, 9(10):1033–1042, 2007. Handbook of Experimental 358, 2005. 134. Borland, R., J. Cooper, A. McNeill, et al., Pharmacology, 63–102, 1990. 122. Zhou, J., D.S Michaud, S.M Langevin, et ‘‘Trends in Beliefs About the 148. Hoffmann, D., R. Raineri, S.S. Hecht, et al., ‘‘Smokeless Tobacco and Risk of Harmfulness and Use of Stop-smoking al., ‘‘A Study of Tobacco Carcinogenesis. Head and Neck Cancer: Evidence From Medications and Smokeless Tobacco XIV. Effects of N′-nitrosonornicotine and a Case-control Study in New England,’’ Products Among Cigarettes Smokers: N′-nitrosonanabasine in Rats,’’ Journal of International Journal of Cancer, Findings From the ITC Four-country the National Cancer Institute, 55(4):977– 132(8):1911–1917, 2013. Survey,’’ Harm Reduction Journal, 8, 981, 1975. 123. Agaku, I., A.O Akinyele, and U. 2011. 149. Hoffmann D., A. Rivenson, S. Amin, et Omaduvie, ‘‘Evaluation of Factors 135. Smith, S.Y., B. Curbow, and F.A. al., ‘‘Dose-response Study of the Influencing Intention To Quit Smokeless Stillman, ‘‘Harm Perception of Nicotine Carcinogenicity of Tobacco-specific N- and Cigarette Tobacco Use Among Products in College Freshmen,’’ Nicotine nitrosamines in F344 Rats,’’ Journal of Nigerian Adolescents,’’ Nigerian Medical & Tobacco Research, 9(9): 977–982, Cancer Research and Clinical Journal, 53(1):31–36, 2012. 2007. Oncology,’’ 108(1):81–86, 1984. 124. Chakravorty, B. and S. Chakravorty, 136. Tomar, S.L. and D.K. Hatsukami, 150. Prokopczyk, B., A. Rivenson, and D. ‘‘Cessation Related Perceptions and ‘‘Perceived Risk of Harm From Cigarettes Hoffmann, ‘‘A Study of Betel Quid

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Carcinogenesis. IX. Comparative 162. Chung, F.L., G. Kelloff, V. Steele, et al., Chemical Research in Toxicology, Carcinogenicity of 3- ‘‘Chemopreventive Efficacy of Arylalkyl 22(5):949–956, 2009. (methylnitrosamino)propionitrile and 4- Isothiocyanates and N-acetylcysteine for 173. Lao, Y., N. Yu, F. Kassie, et al., (methylnitrosamino)-1-(3-pyridyl)-1- Lung Tumorigenesis in Fischer Rats,’’ ‘‘Analysis of Pyridyloxobutyl DNA butanone upon Local Application to Cancer Research, 56(4):772–778, 1996. Adducts in F344 Rats Chronically Mouse Skin and Rat Oral Mucosa,’’ 163. Boorman, G.A., R. Hailey, S. Grumbein, Treated with (R)- and (S)-N′- Cancer Letters, 60(2):153–157, 1991. et al., ‘‘Toxicology and Carcinogenesis nitrosonornicotine,’’ Chemical Research 151. McCoy, G.D., S.S. Hecht, S. Katayama, Studies of Ozone and 4-(N- in Toxicology, 20(2):246–256, 2007. et al., ‘‘Differential Effect of Chronic nitrosomethylamino)-1-(-3-pyridyl)-1- 174. von Pressentin, M.M., W. Kosinska, and Ethanol Consumption on the butanone in Fischer-344/N Rats,’’ J.B. Guttenplan, ‘‘Mutagenesis Induced Carcinogenicity of N-nitrosopyrrolidine Toxicologic Patholology, 22(5): 545–554, by Oral Carcinogens in lacZ Mouse and N′-nitrosonornicotine in Male Syrian 1994. (MutaMouse) Tongue and Other Oral Golden Hamsters,’’ Cancer Research, 164. Rivenson, A., D. Hoffmann, B. Tissues,’’ Carcinogenesis, 20(11):2167– 41(7):2849–2854, 1981. Prokopczyk, et al., ‘‘Induction of Lung 2170, 1999. 152. Hilfrich, J., S.S. Hecht, and D. and Exocrine Pancreas Tumors in F344 175. Hatsukami, D., I. Stepanov, H. Severson, Hoffmann, ‘‘A Study of Tobacco Rats by Tobacco-specific and Areca- et al., ‘‘Evidence Supporting Product Carcinogenesis. XV. Effects of N′- derived N-nitrosamines,’’ Cancer Standards for Carcinogens in Smokeless nitrosonornicotine and N′- Research, 48(23):6912–6917, 1988. Tobacco Products,’’ Cancer Prevention nitrosoanabasine in Syrian Golden 165. Hecht, S.S., N. Trushin, J. Rigotty, et al., Research, 8(1):20–26, 2015. Hamsters,’’ Cancer Letters, 2(3):169–175, ‘‘Complete Inhibition of 4- 176. Hecht, S.S., I. Stepanov, and D. 1977. (methylnitrosamino)-1-(3-pyridyl)-1- Hatsukami, ‘‘Major Tobacco Companies 153. Koppang, N., A. Rivenson, A. Reith, et butanone induced Rat Lung Have Technology to Reduce Carcinogen al., ‘‘A Study of Tobacco Carcinogenesis Tumorigenesis and Favorable Levels But Do Not Apply It to Popular ′ XLVIII. Carcinogenicity of N - Modification of Biomarkers by Phenethyl Smokeless Tobacco Products,’’ Tobacco nitrosonornicotine in Mink (Mustela Isothiocyanate,’’ Cancer Epidemiology, Control, 20(6):443, 2011. vison),’’ Carcinogenesis, 13(11):1957– 177. McIntee, E.J. and S.S. Hecht, Biomarkers & Prevention, 5(8):645–652, ′ 1960, 1992. 1996. ‘‘Metabolism of N -nitrosonornicotine 154. Koppang, N., A. Rivenson, H.K. Dahle, 166. Hoffmann, D., A. Rivenson, R. Abbi, et Enantiomers by Cultured Rat Esophagus et al., ‘‘A Study of Tobacco al., ‘‘A Study of Tobacco Carcinogenesis: and In Vivo in Rats,’’ Chemical Research Carcinogenesis, LIII: Carcinogenicity of in Toxicology, 13(3):192–199, 2000. ′ Effect of the Fat Content of the Diet on N -nitrosonornicotine (NNN) and 4- the Carcinogenic Activity of 4- 178. Nachiappan, V., S.I. Mufti, A. (methylnitrosamino)-1-(3-pyridyl)-1- Chakravarti, et al., ‘‘Lipid Peroxidation (methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) in Mink (Mustela and Ethanol-related Tumor Promotion in butanone in F344 Rats,’’ Cancer vison),’’ Cancer Letters, 111(1–2):167– Fischer-344 Rats Treated With Tobacco- Research, 53(12):2758–2761, 1993. 171, 1997. specific Nitrosamines,’’ Alcohol and 167. Balbo, S., C.S. Johnson, R.C. Kovi, et al., 155. Padma, P.R., V.S. Lalitha, A.J. Amonkar, Alcoholism, 29(5):565–574, 1994. ‘‘Carcinogenicity and DNA Adduct et al., ‘‘Anticarcinogenic Effect of Betel 179. Singer, G.M. and H.W. Taylor, Formation of 4-(methylnitrosamino)-1-(3- Leaf Extract Against Tobacco ‘‘Carcinogenicity of N′nitrosonornicotine Carcinogens,’’ Cancer Letters, 45(3):195– pyridyl)-1-butanone and Enantiomers of in Sprague Dawley Rats,’’ Journal of the 202, 1989. its Metabolite 4-(methylnitrosamino)-1- National Cancer Institute, 57(6):1275– 156. Padma, P.R., V.S. Lalitha, A.J. Amonkar, (3-pyridyl)-1-butanol in F-344 Rats,’’ 1276, 1976. et al., ‘‘Carcinogenicity Studies on the Carcinogenesis, 35(12): 2798–2806, 2014. 180. Carmella, S.G., E.J. McIntee, M. Chen, et two Tobacco-specific N-nitrosamines, N′- 168. Pool-Zobel, B.L., R.G. Klein, U.M. al, ‘‘Enantiomeric Composition of N′- nitrosonornicotine and 4- Liegibel, et al., ‘‘Systemic Genotoxic nitrosonornicotine and N′- (methylnitrosamino)-1-(3-pyridyl)-1- Effects of Tobacco-related Nitrosamines nitrosoanatabine in tobacco,’’ butanone,’’ Carcinogenesis, 10(11):1997– Following Oral and Inhalational Carcinogenesis, 21(4):839–43, 2000. 2002, 1989. Administration to Sprague-Dawley 181. Stepanov, I., K. Yershova, S. Carmella, 157. Hecht, S.S., C.B. Chen, R.M. Ornaf, et Rats,’’ Clinical Investigation, 70(3– et al., ‘‘Levels of (S)-N′- al., ‘‘Chemical Studies on Tobacco 4):299–306, 1992. nitrosonornicotine in U.S. Tobacco Smoke LVI. Tobacco Specific 169. Zarth, A.T., P. Upadhyaya, J. Yang, et Products,’’ Nicotine & Tobacco Research, Nitrosamines: Origins, Carcinogenicity al., ‘‘DNA Adduct Formation from 15(7):1305–10, 2013. ′ and Metabolism,’’ IARC Scientific Metabolic 5 -Hydroxylation of the 182. United States Cancer Statistics (USCS). ′ Publications, (19):395–413, 1978. Tobacco-specific Carcinogen N - United States Department of Health and 158. Hecht, S.S. and D. Hoffmann, ‘‘Tobacco- nitrosonornicotine in Human Enzyme Human Services, Centers for Disease specific Nitrosamines, an Important Systems and in Rats,’’ Chemical Control and Prevention; 2016, available Group of Carcinogens in Tobacco and Research in Toxicology, 29(3):380–389, at https://www.cdc.gov/cancer/npcr/ Tobacco Smoke,’’ Carcinogenesis, 2016. uscs/technical_notes/contributors/. 9(6):875–884, 1988. 170. Yang, J., P.W. Villalta, P. Upadhyaya, et 183. Yuan, J.M., W.P. Koh, S.E. Murphy, et 159. Peterson, L.A. and S.S. Hecht, ‘‘06- al., ‘‘Analysis of 06-[4-(3-Pyridyl)-4- al., ‘‘Urinary Levels of Tobacco-specific Methylguanine is a Critical Determinant oxobut-1-yl]-2′-deoxyguanosine and Nitrosamine Metabolites in Relation to of 4-(methylnitrosamino)-1-(3-pyridyl)-1- Other DNA Adducts in Rats Treated with Lung Cancer Development in Two butanone Tumorigenesis in A/J Mouse Enantiomeric or Racemic N′- Prospective Cohorts of Cigarette Lung,’’ Cancer Research, 51(20): 5557– nitrosonornicotine,’’ Chemical Research Smokers,’’ Cancer Research, 69(7):2990– 5564, 1991. in Toxicology, 29(1):87–95, 2016. 2995, 2009. 160. Castonguay, A., D. Lin, G.D. Stoner, et 171. Zhao, L., S. Balbo, M. Wang, et al., 184. National Program of Cancer Registries. al., ‘‘Comparative Carcinogenicity in A/ ‘‘Quantitation of Pyridyloxobutyl-DNA United States Department of Health and J Mice and Metabolism by Cultured Adducts in Tissues of Rats Treated Human Services, Centers for Disease Mouse Peripheral Lung of N′- Chronically with (R)- or (S)-N′- Control and Prevention; 2016, available nitrosonornicotine, 4- nitrosonornicotine (NNN) in a at https://www.cdc.gov/cancer/npcr/. (methylnitrosamino)-1-(3-pyridyl)-1- Carcinogenicity Study,’’ Chemical 185. Surveillance, Epidemiology, and End butanone and their Analogues,’’ Cancer Research in Toxicology, 26(10):1526– Results Program. United States Research, 43(3):1223–1229, 1983. 1535, 2013. Department of Health and Human 161. Griciute, L., M. Castegnaro, J.C. Bereziat, 172. Zhang, S., M. Wang, P.W. Villalta, et al., Services, National Institutes of Health, et al., ‘‘Influence of Ethyl Alcohol on the ‘‘Quantitation of Pyridyloxobutyl DNA National Cancer Institute; 2016, available Carcinogenic Activity of N- Adducts in Nasal and Oral Mucosa of at https://seer.cancer.gov/. nitrosonornicotine,’’ Cancer Letters, Rats Treated Chronically with 186. National Vital Statistics System. United 31(3):267–275, 1986. Enantiomers of N′-nitrosonornicotine,’’ States Department of Health and Human

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Services, Centers for Disease Control and Vivo Occurrence,’’ Toxicology and Toxicology and Pharmacology, Prevention; 2016, available at https:// Applied Pharmacology, 31(3):325–351, 55(2):123–133, 2009. www.cdc.gov/cancer/npcr/uscs/ 1975. 211. Pankow, J.F., K.H. Watanabe, P.L. technical_notes/contributors/nvss.htm. 199. Tricker, A.R., R. Haubner, B. Toccalino, et al., ‘‘Calculated Cancer 187. U.S. Environmental Protection Agency, Spiegelhalder, et al., ‘‘The Occurrence of Risks for Conventional and ‘Potentially ‘‘Guidelines for Carcinogen Risk Tobacco-specific Nitrosamines in Oral Reduced Exposure Product’ Cigarettes,’’ Assessment,’’ 2012, available at https:// Tobacco Products and Their Potential Cancer Epidemiology Biomarkers & www.epa.gov/sites/production/files/ Formation under Simulated Gastric Prevention, 16(3):584–592, 2007. 2015-01/documents/benchmark_dose_ Conditions,’’ Food Chemistry and 212. Boyle, R.G., J. Jensen, D.K. Hatsukami, guidance.pdf. Toxicology, 26(10):861–865, 1988. et al., ‘‘Measuring Dependence In 188. Lewin, F., S.E. Norell, H. Johansson, et 200. Peedin, G.F. ‘‘Production Practices: Smokeless Tobacco Users,’’ Addictive al., ‘‘Smoking Tobacco, Oral Snuff, and Flue-cured Tobacco’’ Tobacco: Behaviors, 20(4):443–450, 1995. Alcohol in the Etiology of Squamous Cell Production, Chemistry, and Technology, 213. Mushtaq, N., L.A. Beebe, and S.K. Carcinoma of the Head and Neck: A 104–142, 1999. Vesely, ‘‘Determinants of Salivary Population-Based Case-Referent Study in 201. Miller, R.D. and D.J. Fowlkes, ‘‘Dark Cotinine Concentrations Among Sweden,’’ Cancer, 82:1367–1375, 1998. Fire-cured Tobacco,’’ Tobacco: Smokeless Tobacco Users,’’ Nicotine & 189. Schildt, B.B., M. Eriksson, L. Hardell, et Production, Chemistry, and Technology, Tobacco Research, 14(10): 1229–1234, al., ‘‘Oral Snuff, Smoking Habits, and 164–182, 1999. 2012. Alcohol Consumption in Relation to Oral 202. Wiernik, A., A. Christakopoulos, L. Cancer in a Swedish Case-Control Johansson, et al., ‘‘Effect of Air-curing on List of Subjects in 21 CFR Part 1132 Study,’’ International Journal of Cancer, the Chemical Composition of Tobacco,’’ Administrative practice and 77:341–346, 1998. Recent Advances in Tobacco Science, procedure, Incorporation by reference, 190. Definition of ‘‘cancer slope factor’’ from 21:39–80, 1995. Labeling, Smokeless tobacco, Tobacco the U.S. Environmental Protection 203. U.S. Environmental Protection Agency, products. Agency’s Thesaurus of Terms Used in ‘‘Guidelines for Carcinogen Risk Microbial Risk Assessment available at Assessment,’’ 2005, available at https:// Therefore, under the Federal Food, https://ofmpub.epa.gov/sor_internet/ www.epa.gov/sites/production/files/ Drug, and Cosmetic Act and under registry/termreg/searchandretrieve/ 2013–09/documents/cancer_guidelines_ authority delegated to the Commissioner glossariesandkeywordlists/search.do? final_3-25-05.pdf. of Food and Drugs, it is proposed that details=&vocabName=MRA%20 204. U.S. Environmental Protection Agency, chapter I of title 21 of the Code of Thesaurus (type in ‘‘cancer slope ‘‘Environmental Fact Sheet: The Delaney Federal Regulations be amended by factor’’). Paradox and Negligible Risk,’’ January adding part 1132 to subchapter K to 1990. 191. Boffetta, P., B. Aagnes, E. Weiderpass, et read as follows: al., ‘‘Smokeless Tobacco Use and Risk of 205. National Research Council, ‘‘Review of Cancer of the Pancreas and Other the Army’s Technical Guides on PART 1132—PRODUCT STANDARD: Organs,’’ International Journal of Cancer, Assessing and Managing Chemical 114:992–995, 2005. Hazards to Deployed Personnel.’’ DETERMINATION OF N- 192. Luo, J., W. Ye, K. Zendehdel, et al., Washington, DC: The National NITROSONORNICOTINE (NNN) LEVEL ‘‘Oral Use of Swedish Moist Snuff (Snus) Academies Press, 2004, available at IN FINISHED SMOKELESS TOBACCO and Risk of Cancer of the Mouth, Lung, www.nap.edu/catalog/10974/html. PRODUCTS and Pancreas in Male Construction 206. Stepanov, I., S.S. Hecht, S. Workers: A Retrospective Cohort Study,’’ Ramakrishnan, et al., ‘‘Tobacco-specific Subpart A—General Provisions Lancet, 369:2015–2020, 2007. Nitrosamines in Smokeless Tobacco 1132.1 Scope. 193. Ziebarth, D., B. Spiegelhalder and H. Products Marketed in India,’’ 1132.3 Definitions. Bartsch, ‘‘N-nitrosation of Medicinal International Journal of Cancer, 1132.5 Incorporation by reference. Drugs Catalysed by Bacteria from Human 116(1):16–19, 2005. Subpart B—Product Requirements Saliva and Gastro-intestinal Tract, 207. Menzie Cura Associates, Inc., including Helicobacter Pylori,’’ ‘‘Estimating Risk to Cigarette Smokers 1132.10 NNN Level. Carcinogenesis, 18(2):383–389, 1997. From Smoke Constituents in Proposed 1132.12 Product testing. 194. Knezevich, A., J. Muzic, D.K. ‘Testing and Reporting of Constituents of 1132.14 Standard test method. Hatsukami, et al., ‘‘Nornicotine Cigarette Smoke’ Regulations,’’ August 1132.16 Alternative test method. Nitrosation in Saliva and its Relation to 1999. Prepared for: Massachusetts 1132.18 Sampling plans and procedures. Endogenous Synthesis of N′- Tobacco Control Program, Boston, 1132.20 Expiration date. nitrosonornicotine in Humans,’’ Nicotine Massachusetts. 1132.22 Nonconforming product. & Tobacco Research, 15(2):591–595, 208. Fowles, J. and M. Bates, ‘‘The Chemical Subpart C—Labeling and Recordkeeping 2013. Constituents in Cigarettes and Cigarette Requirements 195. Bartsch, H., H. Ohshima, B. Pignatelli, Smoke: Priorities for Harm Reduction,’’ et al., ‘‘Human Exposure to Endogenous A Report to the New Zealand Ministry of 1132.30 Package label requirements. N-nitroso Compounds: Quantitative Health, March 2000, available at http:// 1132.32 Recordkeeping requirements. Estimates in Subjects at High Risk for www.health.govt.nz/publication/ Authority: 21 U.S.C. 331, 371, 374, 387b, Cancer of the Oral Cavity, Oesophagus, chemical-constituents-cigarettes-and- 387c, 387f(d), 387g, 387i. Stomach and Urinary Bladder,’’ Cancer cigarette-smoke-priorities-harm- Surveys, 8(2):335–362, 1989. reduction. Subpart A—General Provisions 196. Marletta, M.A., ‘‘Mammalian Synthesis 209. Fowles, J. and E. Dybling, ‘‘Application of Nitrite, Nitrate, Nitric Oxide, and N- of Toxicological Risk Assessment § 1132.1 Scope. nitrosating Agents,’’ Chemical Research Principles to the Chemical Constituents (a) This part sets forth the in Toxicology, 1(5):249–257, 1988. of Cigarette Smoke,’’ Tobacco Control, requirements for the maximum level of 197. Mirvish, S.S., ‘‘Role of N-nitroso 12(4):424–430, 2003. N-nitrosonornicotine (NNN) in finished compounds (NOC) and N-nitrosation in 210. Watanabe, K.H., M.V. Djordjevic, S.D. smokeless tobacco products. The Etiology of Gastric, Esophageal, Stellman, et al., ‘‘Incremental Lifetime Nasopharyngeal and Bladder Cancer and Cancer Risks Computed for provisions of this standard apply to Contribution to Cancer of Known Benzo[a]pyrene and Two Tobacco- finished smokeless tobacco products as Exposures to NOC,’’ Cancer Letters, specific N-nitrosamines in Mainstream defined in § 1132.3. 93(1):17–48, 1995. Cigarette Smoke Compared with Lung (b) No person may manufacture, 198. Mirvish, S.S., ‘‘Formation of N-nitroso Cancer Risks Derived from distribute, sell, or offer for sale or compounds: Chemistry, Kinetics, and In Epidemiologic Data,’’ Regulatory distribution within the United States a

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finished smokeless tobacco product that with the chemical formula Federal Food, Drug, and Cosmetic Act, is not in compliance with this part. C[9]H[11]N[3]O. a device defined in section 201(h) of the (c) Tobacco retailers and distributors New tobacco product means: Federal Food, Drug, and Cosmetic Act, will not be considered in violation of (1) Any tobacco product (including or a combination product described in this part as it relates to the sale or those products in test markets) that was section 503(g) of the Federal Food, Drug, distribution or offer for sale or not commercially marketed in the and Cosmetic Act. distribution of finished smokeless United States as of February 15, 2007; Tobacco product manufacturer means tobacco products that exceed the NNN or any person, including a repacker or level set forth in § 1132.10 if they: (2) Any modification (including a relabeler, who: (1) Store and transport the finished change in design, any component, any (1) Manufactures, fabricates, smokeless tobacco products according part, or any constituent, including a assembles, processes, or labels a tobacco to the package label; smoke constituent, or in the content, product; or (2) Do not sell or distribute or offer for delivery or form of nicotine, or any (2) Imports a finished tobacco product sale or distribution finished smokeless other additive or ingredient) of a for sale or distribution in the United tobacco products past their expiration tobacco product where the modified States. date, except to return expired products product was commercially marketed in Tobacco-specific nitrosamine (TSNA) to the manufacturer; the United States after February 15, means a chemical compound formed (3) Do not conceal, alter, or remove 2007. through the chemical reaction involving the expiration date or storage conditions Package means a pack, box, carton, or the nitrosation of nicotine, nornicotine, on the package label; and container of any kind or, if no other anabasine, or anatabine during the container, any wrapping (including (4) Do not sell or distribute or offer for growing, curing, processing, or storage cellophane), in which a tobacco product sale or distribution finished smokeless of tobacco. is offered for sale, sold, or otherwise tobacco products that are open or have United States means the 50 States of distributed to consumers. broken seals. the United States of America and the Performance criteria means the District of Columbia, the § 1132.3 Definitions. validation requirements for the Commonwealth of Puerto Rico, Guam, For purposes of this part: acceptability of an analytical test the Virgin Islands, American Samoa, Batch means a specific identified method, including accuracy, precision, Wake Island, Midway Islands, Kingman amount of a finished smokeless tobacco recovery, linearity, specificity, limit of Reef, Johnston Atoll, the Northern product produced in a unit of time or quantitation, limit of detection, Mariana Islands, and any other trust quantity and that is intended to have the robustness, and range. territory or possession of the United Person includes an individual, same characteristics. States. partnership, corporation, or association. Commercial distribution means any Rework means the processing of § 1132.5 Incorporation by reference. distribution of a finished smokeless nonconforming finished smokeless tobacco product to consumers or to (a) The Director of the Federal tobacco products to meet the Register approves this material for another person through sale or requirements of this part. otherwise, but does not include incorporation by reference into this part Smokeless tobacco means any tobacco in accordance with 5 U.S.C. 552(a) and interplant transfers of a tobacco product product that consists of cut, ground, between registered establishments 1 CFR part 51. You may obtain a copy powdered, or leaf tobacco and that is of the material from the sources listed within the same parent, subsidiary, and/ intended to be placed in the oral or or affiliate company, nor does it include below. You may inspect a copy at the nasal cavity. U.S. Food and Drug Administration, providing a tobacco product for product Source data means all information testing where such product is not made Division of Dockets Management, 5630 contained in original laboratory records Fishers Lane, Rm. 1061, Rockville, MD available for consumption or resale. or exact copies of original records of Finished smokeless tobacco product 20852 or the National Archives and experimental findings, observations, or Records Administration (NARA). For means a smokeless tobacco product, other activities used for the creation, including all parts and components, information on the availability of this reconstruction, and evaluation of a material at NARA, call 202–741–6030, packaged for consumer use, except for study or other laboratory work. Source components, parts, or accessories sold or go to http://www.archives.gov/ data includes any laboratory federal_register/code_of_federal_ without tobacco. An example of a worksheets, notebooks, correspondence, _ finished smokeless tobacco product is a regulations/ibr locations.html. notes, and other documentation (b) Center for Tobacco Products, U.S. tin or can of loose snuff or a pouch (regardless of capture medium) that are containing chewing tobacco. Food and Drug Administration, 10903 the result of original observations and New Hampshire Ave., Silver Spring, MD Manufacturing code means any activities of a laboratory study or other 20993; 1–888–463–6332. distinctive sequence or combination of laboratory work. (1) ‘‘Determination of N- letters, numbers, or symbols that begins Tobacco product, as stated in section nitrosonornicotine (NNN) in Smokeless with the manufacturing date in 2-digit 201(rr) of the Federal Food, Drug, and Tobacco and Tobacco Filler by HPLC– numerical values in the month, day, Cosmetic Act in relevant part: MS/MS,’’ LIB No. 4620, January 2017; year format (mmddyy) followed by the (1) Means any product made or into § 1132.14. (Also available at http:// batch number from which the derived from tobacco that is intended www.fda.gov/ScienceResearch/ production batch can be identified. for human consumption, including any FieldScience/ucm231463.htm.) Manufacturing date means the month, component, part, or accessory of a (2) [Reserved] day, and year that a smokeless tobacco tobacco product (except for raw product is packaged for consumer use materials other than tobacco used in Subpart B—Product Requirements (i.e., when the package label has been manufacturing a component, part, or added to the product). accessory of a tobacco product); and § 1132.10 NNN level. N-nitrosonornicotine (NNN) means a (2) Does not mean an article that is a The mean level of NNN in any batch tobacco-specific nitrosamine (TSNA) drug defined in section 201(g)(1) of the of finished smokeless tobacco product

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must not exceed 1.0 microgram per than 1 year based on initial accelerated (iv) If the results of the most recent gram (mg/g) of tobacco (on a dry weight stability testing. annual real-time stability testing do not basis) at any time through the product’s (iii) For initial accelerated stability support the finished smokeless tobacco labeled expiration date as determined testing, at a minimum, samples must be product’s expiration date, the by testing in compliance with § 1132.12. tested at three time points within a 6 manufacturer must use those results to month period. The first time point must establish a new expiration date. After a § 1132.12 Product testing. be within 7 days of manufacture and the new expiration date has been (a) Stability testing. Each tobacco last time point at 6 months after established, the package labels of all product manufacturer must conduct manufacture. affected finished smokeless tobacco testing to assess the stability of the NNN (A) If the proposed storage condition products that have not been released for level in its finished smokeless tobacco is room temperature, samples for initial commercial distribution must display products. The results of stability testing accelerated stability testing must be the new expiration date and storage must be used to establish and verify the stored at 40 ± 2 degrees Celsius and 75 conditions, in accordance with product’s expiration date and storage ± 5% relative humidity. § 1132.30. conditions (either room temperature or (B) If the proposed storage condition (v) If the finished smokeless tobacco refrigeration). is refrigeration, samples for initial product’s expiration date must be (1) Test method. The manufacturer accelerated stability testing must be shortened due to the results of the must use either the standard test stored at 25 ± 2 degrees Celsius and 60 annual real-time stability testing, the method in § 1132.14 or an alternative ± 5% relative humidity. manufacturer must conduct an test method that meets the requirements (iv) If initial accelerated stability investigation to determine why the set forth in § 1132.16. Samples for testing shows the NNN level in the results of the most recent stability testing must be selected in accordance finished smokeless tobacco products testing do not support the product’s with the requirements set forth in will not conform to § 1132.10, the previously established expiration date. § 1132.18(a) and (c). manufacturer must establish an The investigation must be fully (2) Written protocol. Each expiration date and storage conditions, documented and the records maintained manufacturer must establish and as determined by the results of initial in accordance with § 1132.32. maintain a written protocol that real-time stability testing. (b) Batch testing. Tobacco product addresses all stability testing. The (4) Annual stability testing. A manufacturers must conduct testing on protocol must fully describe the manufacturer must conduct annual real- each batch of finished smokeless methodology used to determine the time stability testing on each finished tobacco product to ensure that the stability of the NNN level, including the smokeless tobacco product to verify the products conform with § 1132.10. The test method used (the standard test results of the initial stability testing and manufacturer must use either the method in § 1132.14 or an alternative to ensure that the expiration date and standard test method in § 1132.14 or an test method in accordance with storage conditions remain appropriate. alternative test method that meets the § 1132.16), the sampling plan and Accelerated stability testing may not be requirements set forth in § 1132.16. procedures required by § 1132.18(a) and used for annual stability testing. Samples for testing each batch to (c), and the storage conditions. (i) Except as provided in paragraph determine if a product conforms with (3) Initial stability testing. A (a)(4)(ii) of this section, annual real-time § 1132.10 must be selected in manufacturer must conduct initial real- stability testing must begin within 12 accordance with the requirements set time stability testing that covers each months of the completion of initial forth in § 1132.18(b) and (c). finished smokeless tobacco product and stability testing and then annually (c) Documentation of test results. A use the results to establish an expiration thereafter, with no longer than 12 full report of the source data and results date and appropriate storage conditions months between testing. of all stability and batch testing must be (either room temperature or (ii) When a manufacturer has not maintained by the tobacco product refrigeration) for the product. The conducted initial real-time stability manufacturer in accordance with expiration date and storage conditions testing on a particular smokeless § 1132.32, including the following: must be displayed on the package label tobacco product because it has (1) Full identification of the in accordance with § 1132.30. determined that the results from initial smokeless tobacco product that is the (i) For initial real-time stability real-time stability testing conducted on subject of the report, including product testing, at a minimum, samples must be another product apply, annual real-time subcategory, brand, subbrand, package tested within 7 days of manufacture and stability testing must begin when the size and quantity of product (mass and, at the expected expiration date. product is first released for commercial if portioned, count) and, for portioned (A) If the proposed storage condition distribution and then annually tobacco products, the size (mass) of each is room temperature, samples for initial thereafter, with no longer than 12 portion; real-time stability testing must be stored months between testing. (2) NNN level of each sample tested; at 25 ± 2 degrees Celsius and 60 ± 5% (iii) For annual real-time stability (3) Mean NNN level and standard relative humidity. testing, at a minimum, samples must be deviation; (B) If the proposed storage condition tested within 7 days of manufacture and (4) The batch manufacturing date and is refrigeration, samples for initial real- at the established expiration date. location, including facility name and time stability testing must be stored at (A) If the intended storage condition address; 5 ± 2 degrees Celsius. is room temperature, samples for annual (5) The location, including facility (ii) If initial real-time stability testing real-time stability testing must be stored name and address, from which each is in progress but not yet complete, the at 25 ± 2 degrees Celsius and 60% ± 5% sample was pulled; manufacturer may concurrently conduct relative humidity. (6) The manufacturing code of each accelerated stability testing to establish (B) If the intended storage condition sample tested or, for samples for initial the product’s expiration date and is refrigeration, samples for annual real- stability testing with no manufacturing storage conditions. The manufacturer time stability testing must be stored at code, an identifying code created by the may use an expiration date of no longer 5 ± 2 degrees Celsius. manufacturer;

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(7) The testing date and location, manufacturer must include in the (c) Relevant information. If requested including the testing facility name and notification of an alternative test by FDA, the manufacturer must submit address; method the following information: any other relevant information needed (8) The test method and sampling (1) General information. The to evaluate the alternative test method. procedure used; following information must be (d) Format for notifications of an (9) All tobacco product reference submitted using the form that FDA alternative test method. standard test results; provides: (1) General requirements. All (10) The names and qualifications of (i) The date the manufacturer notifications must be submitted using the person(s) conducting the testing; submitted the notification to FDA; the form that FDA provides and must be (11) The equipment used (including (ii) Identification of the submission as well-organized and legible, and written documentation to show that the a notification of an alternative test in English. equipment is appropriate for its method; (2) Electronic format requirement. intended use and has been calibrated); (iii) The manufacturer’s name, Except as provided in paragraph (d)(3) and address, and contact information; of this section, notifications of an (12) For batch testing only, the criteria (iv) Identification of and contact alternative test method must be used to make a decision to accept or information for an authorized submitted using the Agency’s electronic reject each batch and the decision made representative of the manufacturer system. The notification and all with respect to each batch (e.g., accept, (which could be a U.S. agent for the supporting information must be in an reject) based on the results of the manufacturer), including name, address electronic format that the Agency can product testing, including, where (mailing and email), and telephone process, review, and archive. applicable, the NNN level of the number; (3) Waivers from electronic format individual batch, the results of the (v) Identification of the subcategories requirement. If a notification cannot be product’s stability testing, and the of finished smokeless tobacco products submitted electronically, a waiver may that can be analyzed using the decision made and justification with be requested. Waivers will be granted alternative test method; and respect to the results of a only if use of electronic means is not (vi) The testing facility’s name and reasonable for the tobacco product nonconforming product investigation address. under § 1132.22. manufacturer requesting the waiver. If (2) Index and table of contents. A FDA grants the waiver request, FDA will § 1132.14 Standard test method. comprehensive index and table of provide information on where to send (a) The standard test method for this contents. the notification in paper form. To (3) Summary. The notification must part is the method entitled request a waiver, manufacturers must include a summary section that contains ‘‘Determination of N-nitrosonornicotine send a written request that is legible and the following information: in English to the Document Control (NNN) in Smokeless Tobacco and (i) Identification of the standard test Tobacco Filler by HPLC–MS/MS,’’, method for which the alternative test Center (ATTN: Office of Science) at the incorporated by reference in § 1132.5. method is being proposed; address included on our Web site. The (b) In the event of an inconsistency (ii) A concise description of the written request must contain the between a material incorporated by performance criteria of the alternative following information: reference and the definitions and test method; (i) The name and address of the methods described in this part, (iii) A concise explanation of why the tobacco product manufacturer that definitions and methods in this part will manufacturer is proposing to use the wishes to submit the notification, the apply. alternative test method; and name of an authorized representative of the manufacturer (which could be a U.S. § 1132.16 Alternative test method. (iv) A concise comparison of the similarities and differences between the agent for the manufacturer), and their Tobacco product manufacturers may alternative test method and the standard contact information. use a validated alternative test method test method. (ii) A statement that creation and/or in accordance with this section, only if (4) Complete description. The submission of information in electronic the alternative method meets or exceeds notification must describe the format is not reasonable for the the performance criteria of the standard alternative test method in sufficient manufacturer requesting the waiver, and test method set forth in § 1132.14. detail to enable FDA to evaluate an explanation of why creation and/or (a) Notice requirement. Tobacco whether the information provided submission in electronic format is not product manufacturers who intend to demonstrates that the alternative test reasonable. This statement must be use a validated alternative test method method meets or exceeds the signed by a person who is authorized to to that listed in § 1132.14 for performance criteria of the standard test make the declaration on behalf of the determining conformance with method set forth in § 1132.14. This tobacco product manufacturer. § 1132.10 must notify the Director, description must include: (e) Applicability of an alternative test Office of Science, Center for Tobacco (i) A complete description of the method. An alternative test method may Products, before beginning use of the manner in which the alternative test be implemented only by the tobacco alternative test method. Manufacturers method is proposed to deviate from the product manufacturer that submitted may begin using the alternative test standard test method and a complete the notification and only with respect to method 60 calendar days after FDA explanation, with scientific rationale the subcategories of finished smokeless receives the notification as set forth in and supported by appropriate data, tobacco products that were the subject paragraph (f) of this section unless FDA including a complete copy of the testing of the notification. Other manufacturers notifies the manufacturer that the protocol, to demonstrate that the interested in similar or identical alternative test method has not been alternative test method meets or exceeds alternative test methods must submit demonstrated to meet or exceed the the performance criteria of the standard their own notifications following the performance criteria of the standard test test method set forth in § 1132.14; and procedures of this section. method set forth in § 1132.14. (ii) Any data and information from (f) Action on notifications. FDA will (b) Contents of notification of an other studies comparing the alternative acknowledge the receipt of a alternative test method. The test method to the standard test method. notification of an alternative test

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method. Manufacturers may implement plan or plans for all batch testing products in the population to be an alternative test method beginning 60 required in § 1132.12(b) based on a valid sampled. calendar days after FDA receives the statistical rationale to ensure that the (4) Test samples for stability testing notification of alternative test method finished smokeless tobacco product must be taken within 7 days of the unless FDA notifies them otherwise. consistently conforms to the NNN level manufacturing date and tested in (1) If a notification is complete when set forth in § 1132.10. The sampling accordance with § 1132.12(a). Test received, the 60 calendar day period plan must ensure that samples taken are samples for batch testing must be taken begins on the date FDA receives the representative of an entire batch and are from each batch and tested within 30 notification. randomly selected and collected from calendar days of the manufacturing (2) If any element required under each batch for testing. To account for date. The amount of material acquired paragraph (b) of this section is missing the variability of NNN in the finished during sampling must be sufficient for from a notification, FDA will not accept smokeless tobacco products, the the test methods in §§ 1132.14 or the notification submission and will following factors must be based on 1132.16, including any repeats that may inform the manufacturer. adequate statistical criteria: The be necessary (e.g., because test material (3) If FDA determines that an confidence intervals, the level of was damaged prior to or during alternative test method has not been necessary precision, and the number of analysis). Samples must be randomly demonstrated to meet or exceed the finished products sampled. The selected in accordance with the performance criteria of the standard test sampling plan must take into account applicable sampling plan and the method set forth in § 1132.14, FDA will the manufacturing quality history of the samples must be taken within the same inform the submitter. If FDA informs the manufacturer. Each sampling plan must day. submitter during the 60 calendar day fully describe the sampling (5) Sampling must be performed by period, the submitter must not methodology, with scientific rationale, persons who have sufficient education, implement the alternative test method. incorporate all sources of variability training, and experience to accomplish If FDA determines that an alternative (including variability of the analytic the assigned functions. test method does not comply with this method and the NNN levels), and (6) Each test sample must be section after the 60 calendar day period, describe the sample size needed identified so that the following FDA will provide a written (including a full description of how the information can be determined: determination to the submitter and the sample size is calculated) consistent (i) Full identification of the smokeless submitter must immediately cease using with the sampling design to achieve the tobacco product sampled, including the alternative test method. sampling objective. The sampling plan product subcategory, brand, subbrand, (4) Acceptance of a notification must also fully describe the criteria the package size and quantity of product submission does not constitute a finding manufacturer will use to make a (mass and, if portioned, count) and, for by the Agency that the alternative test decision to accept or reject each batch. portioned tobacco products, the size method meets or exceeds the (c) Sampling procedures. Test (mass) of each portion; performance criteria of the standard test samples must be collected and (ii) The manufacturing code or, for method set forth in § 1132.14. examined in accordance with the samples for initial stability testing with no manufacturing code, an identifying § 1132.18 Sampling plans and procedures. following procedures: (1) Test samples for initial real-time code created by the manufacturer; (a) Sampling plan for stability testing. (iii) The date on which the sample and accelerated stability testing are to Each tobacco product manufacturer was taken; must design and implement a sampling consist of: (iv) The sampling location (including plan or plans for all stability testing (i) Smokeless tobacco product that has the address of the facility and specific required in § 1132.12(a) based on a valid been manufactured using the same location within the facility where the statistical rationale to demonstrate that production processes as products sample was taken); the finished smokeless tobacco manufactured for consumer use and (v) The name of the person(s) who product’s expiration date is appropriate packaged in the identical package that collected the sample; and under the intended storage conditions. will be used for the finished smokeless (vi) The location where the sample The sampling plan must ensure that tobacco product, but it need not have will be stored and tested (including the samples taken are representative and the product package label; or facility name and address). randomly selected. To account for the (ii) Finished smokeless tobacco (7) Samples sent for testing must be variability of the NNN in smokeless product as it is intended to be sold or packed securely with adequate tobacco products, the following factors distributed to consumers. protection against damage (e.g., must be based on adequate statistical (2) Test samples for annual real-time mechanical damage, severe changes in criteria: The confidence intervals, the stability testing and batch testing are to humidity or temperature) and sent to level of necessary precision, and the consist of the finished smokeless the testing facility by the most number of finished products sampled. tobacco product as it is intended to be expeditious means, arriving no later Each sampling plan must fully describe sold or distributed to consumers and not than 3 calendar days after shipment. A the sampling methodology, with of a separate production sample. list of the samples in each shipment scientific rationale, incorporate all (3) All test samples must be stored must be sent to the testing facility under sources of variability (including according to the intended storage separate cover. variability of the analytic method and conditions for the finished smokeless (8) All samples for a specific stability NNN levels), and describe the sample tobacco product, except that test or batch test must be tested at the same size needed (including a full description samples for initial accelerated stability facility. of how the sample size is calculated) testing must be stored in accordance (9) Once test samples arrive at the consistent with the sampling design to with § 1132.12(a)(3)(iii). A tobacco testing facility they must be inspected, achieve the sampling objective. product manufacturer must include all accounted for, and stored under the (b) Sampling plan for batch testing. of its factories, stock rooms, finished smokeless tobacco product’s Each tobacco product manufacturer warehouses, and other locations intended storage conditions (e.g., room must design and implement a sampling containing finished smokeless tobacco temperature or refrigeration) except that

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test samples for initial accelerated product is determined to be out of values in the following format: ‘‘Expires stability testing must be stored in conformance with the requirements of on month/day/year.’’ accordance with § 1132.12(a)(3)(iii), and § 1132.10, or a finished smokeless (c) If the manufacturer determines by a report that includes the following tobacco product’s expiration date must stability testing that meets the information must be generated for the be shortened due to the results of requirements in § 1132.12 that the stability or batch test and be maintained annual real-time stability testing, or if finished smokeless tobacco product by the tobacco product manufacturer in FDA notifies a tobacco product must be stored in a refrigerator, the accordance with § 1132.32: manufacturer that a distributed finished package label must state ‘‘Keep (i) Full identification of the smokeless smokeless tobacco product does not Refrigerated.’’ tobacco product, including product conform to the requirements of this part. (d) It must be possible to determine subcategory, brand, subbrand, package The investigation must include, but is from the manufacturing code the history size and quantity of product (mass and, not limited to, examination of all of the manufacturing, processing, if portioned, count) and, for portioned relevant processes, operations, records, packaging, labeling, holding, and initial tobacco products, the size (mass) of each complaints, any corrective actions distribution of the product from records portion; taken, and any other relevant sources of maintained by the tobacco product (ii) The manufacturing code or, for information concerning the manufacturer. samples for initial stability testing with nonconforming product. The § 1132.32 Recordkeeping requirements. no manufacturing code, an identifying investigation must be fully documented, code created by the manufacturer; including any materials reviewed, name (a) Each facility that manufactures (iii) The date on which samples were of the person(s) making the disposition tobacco products subject to this part taken, if available; decisions, justification for the must establish and maintain records of (iv) The locations where samples were disposition decisions, results of the following information: drawn (including the address and retesting, decisions with respect to (1) Full documentation of stability specific locations within any facilities reworking, and followup resulting from testing protocols and the results of where samples were taken), if available; the investigation. initial and annual stability testing under § 1132.12(a), including all information (v) The number of test samples drawn; (c) Rejection of nonconforming (vi) Complete records of the samples specified in § 1132.12(c); product. Tobacco product (2) All investigations under received and tested, including the date manufacturers must reject a batch of a of receipt, the identifier of all persons § 1132.12(a)(4)(v); finished smokeless tobacco product if (3) The source data and results of who tested the samples, and the test the mean of the representative samples results. batch testing conducted to determine from the batch does not conform to the conformance with § 1132.10, including (10) For batch testing only, each batch requirements of this part unless a must be withheld from commercial all information specified in § 1132.12(c); disposition decision and justification to (4) All notifications of an alternative distribution until it has been sampled release the batch is made after an and tested, and a decision has been test method and all related investigation shows that the batch meets correspondence under § 1132.16; made by the tobacco product the requirements of this part. manufacturer that it may be released for (5) All source data for alternative test (d) Rework of nonconforming product. commercial distribution. method validation; If appropriate, a manufacturer may (6) All sampling plans and reports § 1132.20 Expiration date. rework a batch of a finished smokeless under § 1132.18; All finished smokeless tobacco tobacco product that does not conform (7) Documentation that the persons products must have an expiration date to the requirements of this part. The performing sampling under § 1132.18 established by stability testing. The reworked batch of finished smokeless have sufficient education, training, and expiration date must be set no later than tobacco product must be determined to experience to accomplish the assigned the final date the manufacturer can conform to all the requirements of this functions; demonstrate the finished smokeless part with a disposition decision and (8) All identification, investigation, tobacco product conforms to § 1132.10 justification before it may be released segregation, and disposition decision when stored under its intended for commercial distribution. procedures under § 1132.22(a); and conditions (e.g., room temperature or (9) All nonconforming product Subpart C—Labeling and refrigeration). investigations and rework under Recordkeeping Requirements § 1132.22(b) and (d). § 1132.22 Nonconforming product. § 1132.30 Package label requirements. (b) The records must be legible and (a) General requirements. Tobacco written in English. Documents that have product manufacturers must establish The package of a finished smokeless been translated from a foreign language and maintain procedures to identify, tobacco product must have a label that into English must be accompanied by investigate, segregate, and make includes the manufacturing code, the foreign language version of the disposition decisions about expiration date, and, if applicable, document and a certification by the nonconforming finished smokeless storage conditions for the smokeless manufacturer’s authorized tobacco products in order to prevent tobacco product as follows: representative (which could be a U.S. their release for commercial (a) The information must be printed agent for the manufacturer) that the distribution. on or permanently affixed to the English language translation is complete (b) Investigation. The tobacco product package in a manner that assures it will and accurate. All records must be manufacturer must conduct an remain on the packaging or label readily available for inspection and investigation to determine the extent of through the expected duration of use of copying or other means of reproduction the nonconformity and, as applicable, the product by the consumer. It must by FDA upon request during an the locations where the nonconforming appear clearly, legibly, and indelibly in inspection. Requested records that are products have been distributed if the the English language. maintained offsite must be made mean of the representative samples from (b) The expiration date must appear available within 24 hours or, if that is any batch of finished smokeless tobacco on the packaging in two-digit numerical not feasible, as soon as possible before

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the close of the inspection. Records that period of not less than 4 years from the the method that is the subject of the can be immediately retrieved from date of commercial distribution of the record is used. another location, including by computer finished smokeless tobacco product that Dated: January 12, 2017. or other electronic means, meet the is the subject of the record, or, for Leslie Kux, requirements of this paragraph. records relating to alternative test Associate Commissioner for Policy. (c) Copies of all records required methods under § 1132.16, for a period of [FR Doc. 2017–01030 Filed 1–19–17; 8:45 am] not less than 4 years after the last date under this part must be retained for a BILLING CODE 4164–01–P

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