would reduce the number of new and fatal cases of esophageal cancer
among continuing smokeless tobacco users and may reduce the risk of
pancreatic cancer as well.

1. Estimated Impact of Proposed NNN Standard on New and Fatal Oral
Cancers
    The analysis in section IV.C suggests that the estimated lifetime
cancer risk (ELCR) would drop by approximately 65 percent under the
scenario where the proposed product standard for smokeless tobacco
products was fully implemented, and while assuming that all other
variables remained constant (e.g., user habits). Thus, over time, FDA
expects implementation of the proposed product standard to reduce the
number of incident cases (i.e., those new cases of oral cancer that
occur over time in the smokeless tobacco user population) and fatal
cases of oral cancer by reducing the concentrations of a potent oral
carcinogen in smokeless tobacco products (Ref. 107). To estimate the
potential impact of the standard on morbidity and mortality, we first
model the annual number of new cases and deaths from oral cancer that
are attributable to smokeless tobacco use in the United States. We then
estimate the number of these cases, both those new cases that occur
(incident cases) and those that are fatal, that would be prevented as a
result of the proposed standard by reducing the population attributable
risk by 65 percent. Relative risk estimates used to model the
population attributable risk come from a published systematic review
and meta-analysis of studies of oral cancer among U.S. smokeless
tobacco users (Ref. 100).
    More specifically, as described in section IV.C of this document,
FDA estimates, by comparing its calculation of the ELCR using the NNN
levels of currently marketed U.S. smokeless tobacco products to its
calculation of the hypothetical ELCR using the proposed standard, that
meeting the standard would result in, on average, a 65 percent
reduction in the excess lifetime cancer risk due to NNN among U.S.
smokeless tobacco users. Given the apparently predominant role of
nitrosamines in smokeless tobacco cancer risk, we assume that the 65
percent reduction can be applied directly to the excess oral cancer
risks attributable to smokeless tobacco in general. Public comment is
sought on the strength of the assumptions underlying this approach to
estimate the anticipated public health effects of the rule, and whether
alternative approaches may exist. Commenters should provide evidence
supporting alternative assumptions or approaches to estimating likely
reduction in incidence of oral cancers associated with an
implementation of the proposed product standard.
    The analysis quantifies the estimated public health impact of the
proposed product standard in terms of new and fatal cases of oral
cancer. Oral cancer is used as the endpoint of interest because of the
established strong relationship between smokeless tobacco use and oral
cancer risk, as well as the identification of NNN as a known, potent
oral carcinogen. There are also a relatively large number of published
estimates of oral cancer risk among U.S. smokeless tobacco users.
    As described in this section, we also expect the standard to reduce
the risk of esophageal cancer and it may reduce the risks of cancer at
additional sites. However, limited data are available to permit direct
quantification of this health benefit (Ref. 100). As such, we focus
here on estimating the potential benefits of the proposed product
standard in reducing the number of new and fatal cases of oral cancer
in the United States.
    We use the population attributable risk formula introduced by Levin
(Ref. 108) and subsequently used extensively by the CDC in its Smoking-
Attributable Mortality, Morbidity, and Economic Costs (SAMMEC)
methodology for modeling smoking-attributable mortality (Ref. 109).
Population attributable risk (PAR) is calculated as the proportion of
cases of disease that are attributable to the risk factor as:
[GRAPHIC] [TIFF OMITTED] TP23JA17.001

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

Table 5--Prevalence of Current Smokeless Tobacco Use and Number of Newly Diagnosed and Fatal Cases of Oral Cancer in the United States, by Age Group and
                                                                     Sex, U.S. 2010
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                             Smokeless         Newly
                                                            tobacco use   diagnosed oral    Oral cancer    Attributable    Attributable    Attributable
                                                          prevalence \1\   cancer cases     deaths \2\      oral cancer     oral cancer    fraction (%)
                                                                (%)             \2\                            cases          deaths
--------------------------------------------------------------------------------------------------------------------------------------------------------
Males:

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

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

    Table 6--Estimated Oral Cancer Cases, Deaths, and Corresponding Life Years Lost Attributable to Smokeless
                                             Tobacco Use, U.S. 2010
----------------------------------------------------------------------------------------------------------------
                                                                                Life years lost due to
              Attributable new oral cancer cases                   Attributable oral        attributable oral
                                                                     cancer deaths            cancer deaths
----------------------------------------------------------------------------------------------------------------
1,300.........................................................                      300                    4,900
----------------------------------------------------------------------------------------------------------------
Note: Smokeless tobacco attributable oral cancer cases and deaths are rounded to the nearest hundred and
  estimated from information presented in table 5 including the U.S. summary relative risk value reported by
  Boffetta et al. (Ref. 100), as revised by FDA.

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

    Table 7--Projected Cumulative Difference in New Oral Cancer Cases and Oral Cancer Deaths Attributable to
   Smokeless Tobacco Use in the U.S. and Corresponding Life Years Gained Due To Implementation of the Proposed
                                                    Standard
----------------------------------------------------------------------------------------------------------------
                                                                              Cumulative
                                                          Cumulative         difference in      Cumulative life
   Years after full implementation of the standard       difference in       attributable        years gained
                                                      attributable cases        deaths
----------------------------------------------------------------------------------------------------------------
10 years............................................               4,500                 500               1,500
20 years............................................              12,700               2,200              15,200
----------------------------------------------------------------------------------------------------------------
Note: Estimates in the table are rounded to the nearest hundred.

2. Additional Public Health Benefits From Reducing Oral Cancer
    As a result of this proposed rule, we estimate considerable public
health benefit to the United States resulting from reduced risk of oral
cancer among smokeless tobacco users due to reductions in NNN (and
concomitant reductions in NNK) levels in smokeless tobacco. The public
health impact of oral cancer is estimated to be considerable in size.
In the United States, about 65 percent of oral cancer patients survive
at least 5 years with disease and those individuals who survive oral
cancer can face profound challenges and reductions in quality of life.
    Oral cancer patients and survivors can face major functional
problems when performing basic tasks of daily living such as eating and
talking. Treatment procedures can result in disfigurement or other
serious cosmetic problems that also adversely impact quality of life
(Ref. 116). Surgical treatments for head and neck cancers have been
found to be associated with subsequent self-image issues and social
isolation that increased with the level of disfigurement (Ref. 117).
Patients with head and neck cancers also report high levels of anxiety
and depressive symptoms (Ref. 116), and even long-term survivors report
high levels of psychological distress (Ref. 118).
    In the United States in 2010, approximately $3.63 billion annually
was spent on medical treatment and followup care for all head and neck
cancers (Ref. 119), which includes cancers of the oral cavity, pharynx,
larynx, nasal cavity, and salivary glands (Ref. 120). The proposed
standard will benefit public health by preventing thousands of new oral
cancer cases and deaths caused by smokeless tobacco use over the next
two decades.
3. Unquantified Potential Reductions in Other Cancers
    In addition to reducing the risk of oral cancer, lower levels of
NNN in smokeless tobacco under the proposed standard are expected to
lower the risk of esophageal cancer. Smokeless tobacco use has been
identified as a cause of esophageal cancer (Refs. 1, 2) and NNN has
been directly linked to esophageal cancer in numerous animal studies
(Ref. 8) and in an epidemiological study of smokers (Ref. 77). However,
limited data are available, so the health benefit cannot be directly
quantified.
    Pancreatic cancer has also been identified as causally related to
smokeless tobacco use (Refs. 1, 2). Lower levels of NNN (and potential
reductions in NNK) in U.S. smokeless tobacco under the proposed
standard have the potential to reduce the incidence of pancreatic
cancer. Boffetta et al. reported the relative risk of pancreatic cancer
from four studies of U.S. smokeless tobacco users to be elevated (i.e.,
a relative risk of 1.4), although not statistically significant. Yet,
estimates of pancreatic cancer relative risks have not consistently
been reported to be higher in U.S. smokeless tobacco studies compared
with Scandinavian snus product studies (Refs. 100, 114).
    Lower levels of NNN in smokeless tobacco may also reduce the
incidence of laryngeal and prostate cancers. Lee and Hamling's (Ref.
114) review found U.S. smokeless tobacco use was significantly
associated with laryngeal cancer in four studies including one study
that adjusted for cigarette smoking. More recently, Zhou et al. (Ref.
122) found that use of smokeless tobacco for 10 or more years was
associated with elevated risk of laryngeal cancer. Lee and Hamling
(Ref. 114) also found a statistically significant association between
U.S. smokeless tobacco use and prostate cancer. Although NNN has not
specifically been linked with an increased risk of these cancers, it is
a potent carcinogen and smokeless tobacco product use can result in
exposure throughout the human body.
    Given that U.S. smokeless products contain high amounts of NNK, and
NNK is a recognized systemic lung carcinogen (Ref. 8) in experimental
animals, potential reductions in NNK levels in smokeless tobacco as a
result of the proposed NNN standard may lead to some reduction in lung
cancer risk. There is some evidence linking smokeless tobacco use to
lung cancer (Ref. 121), although a definitive association has not been
established in authoritative reviews (Refs. 3, 4).

B. The Likelihood That Existing Users of Tobacco Products Will Stop
Using Such Products

    Although data are lacking on perceptions of smokeless tobacco
toxicants, including NNN, and cessation, there is some evidence on
users' motivations for quitting smokeless tobacco. Some studies suggest
that concerns about developing health problems are among the common
motives that smokeless tobacco users provide for quitting (Refs. 123,
124). These studies suggest that if the proposed standard affects
consumer perceptions about the harms of smokeless tobacco use, it may
influence their cessation motivations. Specifically, if current
smokeless tobacco users interpret an NNN product standard to mean the
health risks from smokeless tobacco use will be lower after the
standard is in effect, this might reduce some users' motivations to
quit. It is worth noting, however, that while the magnitude of risk
would be changed by implementation of the proposed standard,
appreciable cancer risk would remain. Accordingly, users would still
have a strong incentive to quit. FDA, therefore, does not expect the
proposed product standard to appreciably discourage cessation of
smokeless tobacco products in such a way as to offset the beneficial
public health impact from reduced cancer risk.
    Although data are lacking on perceptions of smokeless tobacco
product toxicants, including NNN and the effect of awareness on
cessation behaviors, prevalence of smokeless tobacco use would need to
increase substantially in order to offset the reduction in cancer risk
expected as a result of this rule. The magnitude of the change needed
can be estimated using the population attributable risk calculation
presented in section V.A.1 of this document. The calculation

includes the product of the excess relative risk (RR-1) and the
prevalence of smokeless tobacco use. Therefore, smokeless tobacco use
prevalence would need to nearly triple in order to completely offset
the expected reduction in excess lifetime cancer risk to the equivalent
of approximately one-third of the baseline cancer risk.
    While there is evidence that exposure to media can lead to health
behavior changes (Refs. 126, 127), it is unclear whether media coverage
of this proposed product standard would promote sustained behavior
change in the form of increased or decreased likelihood of smokeless
tobacco cessation.
    Methods used to reduce NNN levels as a result of this proposed rule
may or may not produce changes that affect the sensory experiences of
smokeless tobacco use. Consumers' sensory experiences can in turn
influence their perceptions of product harms (Refs. 128, 129, 130),
which can impact product use. However, for moist snuff, which
constitutes the overwhelming majority of the smokeless tobacco market
in the United States (Ref. 131), manufacturers have already identified
ways to reduce nitrosamine content without negatively impacting the
taste or user experience (see sections IV.C and IV.E of this document).
Smokeless tobacco products are heavily flavored and the presence of
flavors is a significant driver of consumer acceptance of these
products (Ref. 70). The proposed standard does not prevent the addition
of flavors to offset any changes in the taste of the product due to the
methods used to reduce NNN to meet the proposed standard.

C. The Likelihood That Non-Users Will Start Using Tobacco Products

    The proposed product standard is not expected to substantially
increase, if at all, the likelihood that those who do not use smokeless
tobacco will take up the product. Public perception is that smokeless
tobacco use has some potential harms (Refs. 76, 133, 134, 135, 136). At
this time we are not aware of direct scientific evidence demonstrating
that the proposed smokeless tobacco product standard would influence
consumers' perceptions of product appeal, relative risk, and absolute
risk, or behaviors. Even if the proposed standard were to result in
some changes to perceptions and behaviors, FDA believes that they would
not offset the beneficial public health impact from reduced cancer
risk. As described in this section, FDA estimates that the prevalence
of smokeless tobacco use would have to nearly triple in order to offset
the expected excess cancer risk reduction due to the proposed rule.
    Data are not available on consumers' awareness and perceptions of
NNN in smokeless products, although a single published study in a U.S.
adult sample of smokers and non-smokers found awareness of and
knowledge about NNN in cigarette smoke was low, particularly in
comparison to other constituents (Ref. 125). Although there is very low
awareness of NNN as a constituent, it is possible that some non-users
of smokeless tobacco will be aware of the proposed standard and
interpret it to mean that smokeless tobacco is less harmful than other
tobacco products and this could, in turn, affect smokeless tobacco
initiation. Research suggests that risk perceptions of tobacco use--
that is, judgments about its harmfulness--can influence tobacco
initiation (Refs. 137, 138). However, if the proposed standard were to
result in additional uptake of smokeless tobacco use in the population,
this could either decrease or increase the expected health benefits of
the proposed standard. If cigarette smokers who would not otherwise
quit smoking completely switched to smokeless tobacco products as a
result of this standard, we would expect additional reduction in risk
to these individual users. If cigarette smokers became dual users of
cigarettes and smokeless tobacco products, this could have varying
impacts depending on the extent to which such dual use led to
substantial reductions in cigarette consumption or led to delayed
cessation of tobacco products altogether. Conversely, the anticipated
net population health benefits of the standard would be reduced if it
led substantial numbers of never or former tobacco users to begin or
resume using smokeless tobacco products.
    In the case that some adolescents and young adults become aware
that FDA is taking steps to reduce the harmfulness of smokeless tobacco
products, FDA expects that any impact on smokeless tobacco initiation
would be limited. First, smokeless tobacco initiation among youth has
been shown to be associated with social influences such as actual or
perceived peer use (Refs. 139, 140) to a greater extent than
perceptions of the long-term health effects. Further, youth curiosity
about smokeless tobacco is lower than curiosity about cigars or
cigarettes (Ref. 141), suggesting that fewer adolescents are at risk
for future use, compared to many other tobacco products. Thus, at the
population level, very few adolescents are likely to be aware that FDA
is taking an action related to NNN in smokeless tobacco products, and,
even if there were some awareness, given that the standard is related
to reducing long-term health effects, it is unlikely to have an impact
on youth initiation.
    It is possible that some former users could potentially relapse
back to smokeless tobacco use due to perceptions of lower risk.
Although specific data on relapse among smokeless users is not
available, there is some data on relapse among smokers. For example,
predictors of relapse for smokers who reported they had quit between
study waves were assessed in one of the few studies assessing relapse
in the general population and not part of a clinical trial. Neither the
perceived costs of smoking (such as thoughts about the harms of
smoking) nor benefits of quitting (including health benefits) were
related to relapse (Ref. 142). However, nicotine dependence is related
to relapse among smokers (Refs. 143, 144); and because smokeless
tobacco products also deliver nicotine, FDA expects that the same
reason for relapse would apply to former smokeless tobacco users and
that changes to perceptions of costs and benefits would have little
effect on relapse rates. Overall, the extent to which the proposed
standard may influence behaviors of non-users and former users is
likely to be minimal since health-related reasons are not among the
main drivers of smokeless tobacco use initiation or relapse. Finally,
HHS plans to continue developing and implementing public education
campaigns to help prevent initiation of all tobacco products, including
smokeless tobacco.

D. Conclusion

    NNN is a potent carcinogenic agent found in smokeless tobacco and,
along with NNK, another TSNA, is a major contributor to the elevated
cancer risks associated with smokeless tobacco use. Oral and esophageal
tissues have been identified as targets for NNN-induced
carcinogenicity, when NNN was administered orally in animal studies,
which indicates some concordance with effects observed at these sites
in epidemiologic studies. NNN levels in most smokeless tobacco
manufactured in the United States are higher than NNN levels in
smokeless tobacco manufactured in Sweden. Oral cancer risks in U.S.
smokeless tobacco users are elevated compared to the oral cancer risks
in Scandinavian users. The proposed product standard is expected to
reduce tobacco-related harms by reducing the levels of NNN in smokeless
tobacco products sold in the United States, thereby reducing the risk
of oral

cancer in smokeless users. By our estimates, in the 20 years following
implementation of the proposed product standard, approximately 12,700
new cases of oral cancer and approximately 2,200 oral cancer deaths
would be prevented in the United States. Moreover, during that 20-year
period, approximately 15,200 life years would be gained as a result of
the proposed standard. This represents a substantial benefit to the
public health. Because oral cancer is associated with significant
impacts on health and quality of life, we expect positive public health
benefits due to prevention of new and fatal cancer cases. We also
expect the proposed product standard to reduce the risk of esophageal
cancer among smokeless tobacco users, and it may reduce the incidence
of other cancer types; however, there is limited data available to
directly quantify this health benefit.
    Based on currently available evidence discussed previously, we do
not anticipate the proposed standard would have behavioral impacts on
smokeless tobacco initiation, cessation, switching to other products,
or dual use in a way that would offset the public health benefits of
the reduced cancer risk that would result from the proposed standard.
Even if the proposed standard were to result in some instances of
decreased smokeless tobacco cessation or increased initiation among
non-users of tobacco, we would not expect the magnitude of these
effects to be comparable to the public health benefits of the proposed
rule. As described in this section, FDA estimates that the prevalence
of smokeless tobacco use would have to nearly triple in order to offset
the excess cancer risk reduction expected due to the proposed rule. In
addition, to the extent that cigarette smokers who cannot or will not
quit smoking are motivated to switch completely to smokeless tobacco
due to perceptions of lower risk, this complete switching could result
in additional benefits to public health through reduced risks to these
individual users.
    Accordingly, for the reasons discussed in this section, we find
that the proposed standard is appropriate for the protection of public
health. It would reduce the cancer risk posed by smokeless tobacco
products and FDA does not expect that the product standard would
increase the likelihood that non-users would initiate tobacco or
decrease the likelihood that users will quit tobacco use. Even if the
proposed standard were to result in some instances of decreased
smokeless tobacco cessation or increased initiation among non-users of
tobacco, we would not expect the magnitude of these effects to offset
the benefits of the reduced cancer risk.

VI. Description of Proposed Regulation

A. General Provisions (Proposed Subpart A)

1. Scope (Proposed Sec.  1132.1)
    Proposed Sec.  1132.1 identifies the scope of products that would
be subject to this NNN product standard. FDA intends for this proposed
standard to cover finished smokeless tobacco products, which are
defined in proposed Sec.  1132.3 (proposed Sec.  1132.1(a)). This
includes moist snuff, snus, dry snuff, chewing tobacco, and some
dissolvables. Some dissolvable tobacco products do not meet the
statutory definition of ``smokeless tobacco product'' because they do
not contain cut, ground, powdered, or leaf tobacco; instead, these
products contain nicotine extracted from tobacco. Dissolvable products
that do not meet the statutory definition of ``smokeless tobacco
product'' are not covered by this proposed rule. As previously noted,
this rule focuses on smokeless tobacco products because different
measures are required to address NNN in other tobacco products.
    Proposed Sec.  1132.1(b) states that no person may manufacture,
distribute, sell, or offer for sale or distribution within the United
States a finished smokeless tobacco product that is not in compliance
with this part. For example, FDA would not consider finished smokeless
tobacco products to be in compliance with this part if they exceed the
NNN level set forth in proposed Sec.  1132.10, the package label does
not have a manufacturing code or expiration date, or the package label
has a manufacturing code or expiration date that has been altered,
mutilated, destroyed, obliterated, obstructed, concealed, or removed in
whole or in part.
    This provision is not intended to restrict the manufacture of
smokeless tobacco products intended for export. Consistent with section
801(e)(1) of the FD&C Act, a tobacco product intended for export shall
not be deemed to be in violation of section 907 or this product
standard, if it meets the criteria enumerated in section 801(e)(1) of
the FD&C Act, including not being sold or offered for sale in domestic
commerce.
    Proposed Sec.  1132.1(c) explains that tobacco retailers and
distributors will not be considered in violation of this part as it
relates to the sale or distribution or offer for sale or distribution
of finished smokeless tobacco products that exceed the NNN level set
forth in Sec.  1132.10 if they: (1) Store and transport the finished
smokeless tobacco products according to the package label, (2) do not
sell or distribute or offer for sale or distribution finished smokeless
tobacco products past their expiration date, except to return expired
products to the manufacturer, (3) do not conceal, alter, or remove the
expiration date or storage conditions on the package label, and (4) do
not sell or distribute or offer for sale or distribution finished
smokeless tobacco products that are open or have broken seals.
    FDA is proposing this exception for tobacco retailers and
distributors because they cannot reasonably know or confirm by testing
whether the smokeless tobacco products they are selling or distributing
or offering for sale or distribution comply with the proposed NNN
level. Provided that the tobacco retailers and distributors meet the
requirements set forth in proposed Sec.  1132.1(c)(1) through (4), FDA
will not consider them to be in violation of part 1132 as it relates to
the sale or distribution or offer for sale or distribution of products
that exceed the NNN level set forth in proposed Sec.  1132.10.
    We note that tobacco retailers and distributors would need to meet
all of the requirements in proposed Sec.  1132.1(c) in order to be
considered in compliance with this part as it relates to the sale or
distribution or offer for sale or distribution of smokeless tobacco
products that exceed the NNN level set forth in proposed Sec.  1132.10.
A retailer or distributor who, for example, covers the expiration date
or storage conditions with a sticker, changes the expiration date, or
scratches off the expiration date or storage conditions on the package
label would not meet the requirements in proposed Sec.  1132.1(c)(3).
Furthermore, a retailer who sells finished smokeless tobacco products
that are open or have broken seals would not meet the requirements in
proposed Sec.  1132.1(c)(4), because doing so could lead to changes in
the NNN level, especially if it is exposed to heat or humidity.
2. Definitions (Proposed Sec.  1132.3)
    Proposed Sec.  1132.3 provides the definitions for the terms used
in the proposed rule. Several of these definitions are included in the
FD&C Act or have been used in other regulatory documents.
     Batch: FDA proposes to define ``batch'' as a specific
identified amount of a finished smokeless tobacco product produced in a
unit of time or quantity and that is intended to have the same
characteristics. As stated in section 910(a)(3)(B) of the FD&C Act,

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

the Virgin Islands, American Samoa, Wake Island, Midway Islands,
Kingman Reef, Johnston Atoll, the Northern Mariana Islands, and any
other trust territory or possession of the United States.
3. Incorporation by Reference (Proposed Sec.  1132.5)
    Proposed Sec.  1132.5 identifies the materials that FDA proposes to
incorporate by reference in this part. Information that is incorporated
by reference would have the same force and effect as language
explicitly stated in the codified. Under the proposed rule, a tobacco
product manufacturer would be required to follow procedures and methods
for testing as described in any standards incorporated by reference,
unless the manufacturer meets the requirements in Sec.  1132.16 for an
alternative test method.
    FDA is proposing to incorporate by reference a validated method
developed by FDA's SRL to be the standard test method for NNN in
smokeless tobacco products (proposed Sec. Sec.  1132.5(a) and 1132.14).
As discussed in section IV.F of this document, the results from the
test method demonstrate a high level of specificity, accuracy, and
precision in measuring a range of NNN levels across a variety of
smokeless tobacco products.
    If the proposed incorporation by reference is approved by the
Office of the Federal Register and incorporated in the final rule,
interested parties would be able to examine the incorporated material
at the National Archives and Records Administration (NARA) and at FDA's
Division of Dockets Management (proposed Sec.  1132.5(b)), and obtain
copies of the standard test method by contacting FDA's Center for
Tobacco Products at the addresses and/or Web sites listed in proposed
Sec.  1132.5(b)(2).
    If FDA subsequently determines that a test method, which has been
incorporated by reference in a final rule, should be replaced with
another method or updated, FDA will update the regulation in accordance
with the Administrative Procedure Act (5 U.S.C. 553) and obtain
approval of the change to the incorporation by reference in accordance
with 1 CFR part 51.
    Proposed Sec.  1132.5(c) explains that if tobacco manufacturers or
testing laboratories using these standards find an inconsistency
between a material incorporated by reference in this part and
definitions or methods described by FDA in proposed part 1132, the
definitions or methods in proposed part 1132 take precedence.

B. Product Requirements (Proposed Subpart B)

1. NNN Level (Proposed Sec.  1132.10)
    For the reasons discussed in section IV of this document, FDA is
proposing that the mean level of NNN in any batch of finished smokeless
tobacco products must not exceed 1.0 [micro]g/g of tobacco (on a dry
weight basis) at any time through the product's labeled expiration date
as determined by testing in compliance with Sec.  1132.12. Under the
proposed rule, manufacturers would be required to test their finished
smokeless tobacco products using the standard test method in Sec.
1132.14 or the alternative test method in Sec.  1132.16.
    In proposing to set the limit in terms of a batch mean, FDA has
tentatively determined that the mean value is more appropriate than a
limit applied to each unit produced from the entire batch of a product,
given that the cancer risk is due to long term and repeated exposure,
and given the variability of NNN in this agricultural product. Although
we expect some degree of variability in NNN to exist in smokeless
tobacco products, we recognize there may be circumstances where there
could be wide ranges in the variability of NNN for some smokeless
tobacco products, resulting in reduced consistency among the units
produced and reduced predictability of compliance with a standard
requiring that each unit meet a specific limit. FDA is requesting
scientific data that could be used to determine the expected
distribution of individual results for samples for a per-batch mean
limit of an NNN level of 1.0 [micro]g/g of tobacco on a dry weight
basis (see proposed Sec.  1132.10). FDA also requests comment on the
compliance implications of the currently proposed approach.
    NNN-related cancer risk is due to long term and repeated exposure
to NNN. Under the currently proposed approach, as long as the mean of
each batch consistently conforms to the NNN level of 1.0 [micro]g/g of
tobacco (on a dry weight basis) in accordance with Sec.  1132.10, FDA
expects that the long term impact from an occasional exposure to a
product with slightly higher NNN level will be offset by the exposure
to slightly lower levels. Therefore, any random variation that may
exist is not expected to negatively impact the public health benefit of
the proposed standard, which is based on reduction of excess lifetime
cancer risk.
    FDA also is considering an alternative approach that includes
setting a standard where the specified NNN level of 1.0 [micro]g/g of
tobacco (on a dry weight basis) would apply to all units produced from
the entire batch, rather than to a per-batch mean. This alternative
approach would thereby require the manufacturer to ensure compliance of
each unit made from a batch despite some expected random variation of
the NNN level between units. This could further increase the public
health benefits of this product standard. However, in instances where
manufacturers determined that some units within a batch had levels of
NNN above the limit and others had levels below the limit, this
alternative approach could add costs for manufacturers (e.g., costs of
rejecting or reworking the batch) or require them to manufacture
product with NNN levels lower than the NNN level of 1.0 [micro]g/g of
tobacco (on a dry weight basis) in order to minimize the risk of having
to reject a batch based on random variation. FDA currently believes
that this is not necessary to achieve the public health goals of the
proposed standard, but invites input on this point.
    We invite comments on FDA's proposed approach and on the
alternative approach and their implications for compliance with the
limit, and public health impact. We also invite comments or information
on batch sampling methods or other approaches manufacturers might use
to determine compliance with an absolute limit on all units produced
from a batch given the expected variability of NNN in relevant
products.
2. Product Testing (Proposed Sec.  1132.12)
    Proposed Sec.  1132.12 contains provisions for the testing of
smokeless tobacco products. FDA is proposing to require two types of
testing--stability testing and batch testing.
    a. Stability testing. Proposed Sec.  1132.12(a) would require each
tobacco product manufacturer to conduct testing to assess the stability
of the NNN level in its finished smokeless tobacco products. Given the
variability of NNN levels in current smokeless tobacco products (see
section IV.B.1 of this document), stability testing would help ensure
that the NNN level in finished smokeless tobacco products is being
properly monitored and controlled and that it remains in conformance
with the proposed limit through the product's labeled expiration date.
The initial stability testing would establish the rate of change of the
NNN level for a product and the annual stability testing would identify
any changes to the rate of change of the NNN level in that product.
    Manufacturers would be required to use the results of stability
testing to establish and verify the product's expiration date and
storage conditions

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

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

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

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

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

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

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

proposed NNN limit.\4\ We welcome information and comments on this
provision.
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    \4\ Based on comments provided by the Alcohol and Tobacco Tax
and Trade Bureau (TTB), we understand that this process would likely
constitute the manufacture of tobacco products for purposes of the
Internal Revenue Code. Under the Internal Revenue Code, the
manufacture of tobacco products requires a permit as a manufacturer
of tobacco products from TTB. As we understand TTB's permitting
requirements, entities lacking a manufacturing permit, including
importers, may not engage in manufacturing activities. We also
understand that certain provisions of the Internal Revenue Code
prohibit importers of tobacco products from repackaging tobacco
products after such products are released from customs custody.
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C. Labeling and Recordkeeping Requirements (Proposed Subpart C)

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

    In addition, proposed Sec.  1132.32(c) would require that the
records kept under this part be retained for at least 4 years from the
date of commercial

distribution of the finished smokeless tobacco product that is the
subject of the record. However, for records relating to alternative
test methods under Sec.  1132.16, the required 4-year retention period
would be for a period not less than 4 years after the last date the
method that is the subject of the record is used (e.g., 4 years from
the last date the manufacturer used an alternative test method). FDA
has selected 4 years as a means to help ensure that the records would
be available for at least one biennial FDA inspection under sections
704 and 905(g) of the FD&C Act.
    FDA considered not requiring specific recordkeeping requirements
and, instead, allowing the manufacturer to determine recordkeeping
needs but, FDA believes that detailed recordkeeping requirements are
necessary to confirm that the finished smokeless tobacco products are
in compliance with the proposed standard. For example, requiring
manufacturers to fully document their stability testing protocols and
test results will enable FDA to confirm that the manufacturer's test
method and protocols are adequate to meet the requirements of part
1132. In addition, requiring nonconforming product records will help
the manufacturer and FDA determine the extent of the nonconformity and,
as applicable, the locations where the nonconforming products have been
distributed, in the event of a recall or enforcement action (e.g.,
seizure).

VII. Proposed Effective Date

    FDA proposes that any final rule on the tobacco product standard
for NNN that may issue based on this proposal become effective 3 years
after the date of publication of the final rule. FDA believes this
approach would allow adequate time for developing any necessary changes
in technology to achieve the NNN level, for any changes made to
manufacturers' tobacco purchasing choices and curing methods, and for
any preparation or changes needed in facilities. In addition, FDA
believes that it will provide adequate time for manufacturers to seek
and obtain marketing authorization from FDA for their new tobacco
products. New tobacco products are subject to enforcement if they are
on the market without FDA authorization.
    Therefore, after the effective date of a final rule for this
proposed tobacco product standard, no person would be allowed to
manufacture, distribute, sell, or offer for sale or distribution within
the United States any finished smokeless tobacco product that does not
comply with the rule. After the effective date of the final rule,
manufacturers would not be allowed to introduce into domestic commerce
any finished smokeless tobacco product that does not comply with the
requirements of the final rule, irrespective of the date of
manufacture. However, retailers would be permitted to sell-off existing
inventory of noncompliant finished smokeless tobacco products
manufactured before the effective date for 60 days after the effective
date of the final rule. FDA notes that keeping products with higher NNN
levels on the market for an extended period of time after the effective
date of the rule is not in the interest of public health.

VIII. Incorporation by Reference

    FDA is proposing to incorporate by reference the test method
entitled, ``Determination of N-nitrosonornicotine (NNN) in Smokeless
Tobacco and Tobacco Filler by HPLC-MS/MS,'' LIB No. 4620, January 2017
(Ref. 79). You may obtain a free copy of the material proposed to be
incorporated from the Docket at www.regulations.gov or from the Food
and Drug Administration, Center for Tobacco Products, 10903 New
Hampshire Ave., Silver Spring, MD 20993, 1-888-463-6332.
    This is a technical document developed by FDA specifically for use
in tobacco testing facilities. FDA developed this test method for NNN
in order to streamline the testing process and reduce testing costs.
Other available methods test for all TSNAs while this test method is
limited to NNN. As such it is a highly specific method that reduces
testing costs while ensuring that the results from the test method
demonstrate a high level of specificity, accuracy, and precision in
measuring a range of NNN levels across a variety of smokeless tobacco
products.
    This test method relies on several ISO standards for determining
moisture content in tobacco and tobacco products--ISO 6488:2004, ISO
6488:2004/Cor 1:2008, and ISO 16632:2013. FDA is not proposing to
incorporate these standards by reference. You may purchase a copy of
the ISO standards from the International Organization for
Standardization, 1, ch. de la Voie-Creuse, Case Postale 56, CH-1211,
Geneva 20, Switzerland, or from the American National Standards
Institute, 1899 L Street NW., 11th Floor, Washington, DC 20036, or on
the Internet at http://www.iso.org or www.ansi.org. We note that these
ISO standards are relatively inexpensive (about $50 each) and may
already be used by tobacco testing facilities.
    For the reasons set forth in this section, FDA considers the test
method proposed to be incorporated by reference to be reasonably
available and usable by testing facilities (see 1 CFR 51.5(a) and
51.7).

IX. Economic Analysis of Impacts

    We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct us to assess all costs
and benefits of available regulatory alternatives and, when regulation
is necessary, to select regulatory approaches that maximize net
benefits (including potential economic, environmental, public health
and safety, and other advantages; distributive impacts; and equity). We
have developed a comprehensive Economic Analysis of Impacts that
assesses the impacts of the proposed rule. We believe that this
proposed rule is an economically significant regulatory action as
defined by Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because many smokeless tobacco products may need to be
reformulated, and reformulation represents the main driver of the costs
of the rule, we tentatively find that the proposed rule would have a
significant economic impact on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $146 million, using the most current (2015) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
result in an expenditure in any year that meets or exceeds this amount.
    The proposed rule would establish a product standard for all
finished smokeless tobacco products. Specifically, the proposed rule
would require that all finished smokeless tobacco products comply with
a limit for NNN in such products in order to be marketed and
distributed for sale in the United States. This proposed product
standard would require that the mean level of NNN in any batch of
finished

smokeless tobacco products not exceed 1.0 [micro]g/g of tobacco (on a
dry weight basis) at any time through the product's labeled expiration
date as determined by product testing. The proposed standard also