herbal smokeless as ``safer than cigarettes,'' but rated cigars and
kreteks as more harmful.
    (Response) Many consumers believe that noncigarette tobacco
products, including cigars, are less harmful than cigarettes. Although
the overall study population did rate cigars as more harmful, there
were subgroups (such as African Americans and non-Hispanic whites) that
rated cigars from ``a little safer'' to ``much safer.'' Deeming all
tobacco products, including premium cigars, to be subject to chapter IX
of the FD&C Act will help to alleviate mistaken beliefs that certain
tobacco products are safe alternatives to cigarettes by virtue of the
fact that they are not subject to FDA regulation.
    (Comment 94) A few comments also stated that premium cigar use
among young adults is irrelevant because Congress did not task FDA with
protecting young adults who are lawfully permitted to purchase tobacco
products.
    (Response) FDA is concerned with tobacco use by all age groups,
including young adults and adults who may lawfully purchase these
products. The Tobacco Control Act charges FDA with protecting the
public health generally, not only the health of minors (section 3 of
the Tobacco Control Act). Nevertheless, FDA is particularly concerned
with tobacco use by youth and young adults, as they are uniquely more
susceptible to becoming addicted to nicotine than adults or older
smokers. As discussed in the NPRM, most tobacco users begin using prior
to the age of 18 and believing they will be able to quit. However, most
youth are unable to stop tobacco use once they become addicted.
Accordingly, FDA is taking steps to reduce the potential harm to youth
and young adults from tobacco products.
    (Comment 95) Many comments expressed concerns regarding flavored
cigars, including flavored premium cigars, and their effect on youth
initiation. Some comments concluded there is no evidence that minors
consume flavored premium cigars, relying on one study in which the
flavored premium cigar brands of youth use accounted for only a
fraction (0.1 percent) of the less than 4 percent reported use of
premium cigar brands (Ref. 59).
    (Response) FDA is announcing that it intends in the future to issue
a proposed product standard that, if finalized, would eliminate
characterizing flavors in all cigars including cigarillos and little
cigars.
    (Comment 96) Some comments argued that premium cigars do not pose
youth access issues because manufacturers and retailers do not market
them to youth (i.e., they are not cheap, candy- and fruit-flavored, or
easy to access) and age verification is already required at the point
of sale limiting access to adults only. They relied, in part, on FDA's
statements in the 1996 tobacco youth access rule in which FDA stated
there was insufficient evidence of youth cigar use to warrant cigar
regulation (61 FR 44396). The comments stated there is no evidence that
the situation has changed since then and that exempting premium cigars
from tobacco product regulation is also warranted because youth do not
use premium cigars to any significant degree.
    (Response) FDA disagrees. The Agency's statement regarding the
availability of evidence to support cigar regulation was made 18 years
ago and based on the evidence available at that time. In fact, FDA
explicitly stated that there was insufficient evidence to regulate
cigars ``at this time'' (i.e., 1996) (61 FR 44396 at 44422). Moreover,
the 1996 rule was issued under the authority of the FD&C Act prior to
the passage of the Tobacco Control Act. Consequently, one of the
reasons FDA did not assert jurisdiction over cigars in the 1996 rule
was because it did not have sufficient evidence ``that these products
satisfy the definitions of drug and device in the act'' (61 FR 44396 at
44423). Cigars, including premium cigars, clearly do satisfy the
definition of a ``tobacco product'' and evidence has become available
since 1996 indicating that youth and young adults use cigars, including
premium cigars (Refs. 59, 68, 90).

C. Patterns of Use Do Not Preclude Users From Experiencing Negative
Health Effects

    Proponents of Option 2 claimed that patterns of use preclude
premium cigar smokers from experiencing the negative health effects of
tobacco smoke because they smoke infrequently and do not inhale.
However, despite our explicit requests in the NPRM, the comments did
not include data indicating that premium cigar smokers are not subject
to disease risk and addiction. FDA's responses to comments regarding
these issues are included as follows.
    (Comment 97) Many comments stated that a majority of cigar users
are occasional smokers (two to six cigars per week) and do not inhale
(citing Refs. 69, 75). They also indicated that premium cigar use does
not lead to addiction. Finally, some comments noted that occasional
cigar users have not been studied in epidemiological research, and data
for the lowest level of cigar users (one to two cigars per day) do not
reveal mortality rates that are significantly different from nonsmokers
(Refs. 69, 79). However, other comments included evidence suggesting
increased disease risk and nicotine dependence among infrequent cigar
users and those reporting they do not inhale.
    (Response) FDA disagrees that patterns of use preclude premium
cigar users from experiencing the negative health effects of these
products. All cigars produce toxic cigar smoke (Refs. 35, 69). In
addition, studies have shown that cigar smoking can cause several
different types of cancer even without inhalation (Refs. 69, 104). For
example, one study found an increased risk in head and neck cancers in
people who were not cigarette smokers but had previously smoked only
cigars (Ref. 104).
    While inhaling cigar smoke poses much higher morbidity and
mortality rates than not inhaling, significant risk still exists for
those who do not inhale. Researchers found that the risk of stomach
cancer mortality was significantly higher among cigar users who
reported they did not inhale when compared to those who did not use
tobacco products (Ref. 105). Additionally, among primary cigar smokers
reporting that they do not inhale, relative mortality risk was still
highly elevated for oral, esophageal, and laryngeal cancers (Ref. 83).
A recent systematic review of cigar smoking and mortality summarized
the results of 22 published studies from 16 different prospective
cohorts and found that primary cigar smoking was associated with
increased risk of mortality from all causes, several types of cancers,
coronary heart disease, and aortic aneurysm compared to nonsmokers
(Ref. 82). Mortality risks were greater with increasing number of
cigars smoked per day and self-reported level of inhalation; however,
primary cigar smokers reporting no inhalation still had highly elevated
mortality risks for oral, esophageal, and laryngeal cancers compared to
nonsmokers (id.). In addition, even if they do not intend to inhale and
are not aware that they are doing so, most cigar smokers do inhale some
amount of smoke (Refs. 32, 34).
    Although studies indicate that some cigar smokers may absorb less
tobacco smoke, they also show that all cigar smoking is harmful.
Regardless of whether cigar smokers inhale, they are

still subject to the addictive and other adverse health effects of the
product through absorption of nicotine and harmful constituents (Refs.
32, 81).
    (Comment 98) Supporters of Option 2 claimed that premium cigar
smokers use cigars less frequently than cigarette and smokeless tobacco
users and, therefore, premium cigars should either not be regulated or
should be subject to less regulation. They relied upon a study showing
that the adult prevalence of everyday or occasional use of cigarettes
was 18 percent and 2.6 percent for smokeless tobacco products, compared
to 2 percent for cigars, cigarillos, and little filtered cigars (Ref.
106).
    (Response) Although the prevalence of cigar smoking in the U.S.
population is lower than cigarette smoking, use of cigars still
presents health risks. Researchers estimate that regular cigar smoking
was responsible for approximately 9,000 premature deaths or almost
140,000 years of potential life lost among adults 35 years or older in
2010 (Ref. 68). As stated in the previous response, all cigars produce
toxic cigar smoke (Refs. 35, 69). Any cigar use exposes the mouth and
throat to tobacco smoke and studies have shown that cigar smoking can
cause several different types of cancer even without inhalation (Refs.
69, 104). Health risks still exists for those who do not inhale. For
example, researchers found that the risk of stomach cancer mortality
was significantly higher among cigar users who reported they did not
inhale when compared to those who did not use tobacco products (Ref.
107). Additionally, among primary cigar smokers reporting that they do
not inhale, relative mortality risk was still highly elevated for oral,
esophageal, and laryngeal cancers (Ref. 83). Therefore, all cigars
expose users to toxic and cancer-causing substances and increase the
risk of harm. Basing an exemption for premium cigars on current use
patterns would be inappropriate given that patterns may change over
time and in response to regulation. Consequently, FDA has concluded
that deeming all cigars, including premium cigars, is appropriate for
the protection of the public health.

D. Responses to Other Cigar Comments

    (Comment 99) Some comments expressed concern that if FDA did not
deem all tobacco products subject to regulation, the tobacco industry
would adjust its products to fit the exemption for premium cigars in
Option 2 and preferential economic treatment of certain manufacturers
would result. These comments argued that just as manufacturers of roll-
your-own tobacco changed their roll-your-own product to classify it as
pipe tobacco to take advantage of positive tax treatment, manufacturers
would seek similar ways to circumvent regulations and continue
marketing products that are detrimental to public health.
    (Response) Because FDA has selected Option 1 deeming all cigars,
rather than a subset, for this final rule, these comments are moot.
    (Comment 100) Many comments stated that it is important for FDA to
regulate all tobacco products, including cigars, pipe tobacco, and e-
cigarettes in the same way, and that the Agency should ensure that a
consistent set of regulatory criteria is applied to all tobacco
products and nicotine delivery systems. According to the comments,
failure to regulate all tobacco products would provide incentives for
manufacturers to market new tobacco-based or tobacco-derived products
that are unregulated and may induce people to switch to the unregulated
products.
    (Response) FDA agrees that it is appropriate for the protection of
the public health to regulate all tobacco-derived products meeting the
definition of ``tobacco product.'' There is inherent risk in all
tobacco-derived products. Further, the Agency agrees that use patterns
may change (and have changed) over time and in response to regulation.
    (Comment 101) At least one comment expressed concern that FDA
relied upon an abstract presented at the Conference for the Society for
Research on Nicotine and Tobacco (SRNT) as a basis for proposing Option
1. The comment stated that because the abstract was not a full peer-
reviewed research article, stakeholders were unable to adequately
respond to the claims made.
    (Response) FDA disagrees. Additional analysis of the data that was
the subject of this SRNT abstract was conducted and a paper was
published and submitted to the docket, allowing for stakeholders to
comment on it (Ref. 90). The abstract presented at SRNT also was not
the sole basis for proposing Option 1. FDA appropriately characterized
this as preliminary data and included additional data and information
to support this proposed option. In addition, FDA has supplemented the
information and data supporting Option 1, as discussed in section VII,
to provide additional evidence of premium cigar use by youth and young
adults and to illustrate that the patterns of use for premium cigars do
not preclude users from negative health effects.
    (Comment 102) Comments urged FDA to adopt a category-specific
approach to regulation of cigars in order to more effectively address
the variations in use patterns, manufacturing, and ingredients across
the product category. Other comments, however, urged FDA to broadly
regulate all cigars in the same way to reduce initiation and current
use among youth. More specifically, comments advocated prohibiting
flavors, including menthol, in all cigars, prohibiting self-service
displays, and establishing minimum pack size requirements for all
cigars.
    (Response) Although the statute does not require FDA to make any
public health finding in order to deem tobacco products, the Agency has
determined that cigar use presents health risks and that all cigars
should be brought under its regulatory authority. However, FDA is
providing a compliance policy that will provide additional time for
manufacturers of newly deemed products to comply with certain
requirements, and which will reduce the burdens on manufacturers as
they become regulated by FDA for the first time. As explained elsewhere
in this document, FDA is announcing that it intends in the future to
issue a proposed product standard that would eliminate characterizing
flavors in all cigars including cigarillos and little cigars.
    (Comment 103) Some comments supporting Option 2 argued that FDA is
not obligated to deem all tobacco products that meet the statutory
definition of ``tobacco product.'' They also stated that the intent of
the Tobacco Control Act was to target tobacco products marketed to
children and products that cause addiction, which is why ``cigarette''
and ``little cigar'' were specifically defined in the Tobacco Control
Act and large and premium cigars were not similarly defined. Thus, they
claim exempting premium cigars is consistent with Congress' intent that
premium cigars not be regulated, which they state is further evidenced
by introduction of such legislation in Congress.
    (Response) FDA agrees that the Agency is not obligated to deem all
tobacco products but disagrees with comments purporting to explain
Congress' intent to only regulate products marketed to children. The
purpose of the Tobacco Control Act was to provide authority to FDA to
regulate tobacco products and protect not only the health of minors,
but also the health of the public overall (section 3 of the Tobacco
Control Act). While use of tobacco products by youth was and continues
to be a significant focus of the law, it is clear that Congress did not
intend that the Tobacco Control Act reach only products marketed to
children, as they included many

provisions applicable to tobacco products marketed to adults.
    (Comment 104) Many comments expressed concern that premium cigar
regulation would impose considerable costs and place excessive burdens
on small businesses without quantifiable benefits. In particular, many
comments stated that premarket review would be cost-prohibitive for
premium cigar manufacturers, effectively eliminating their ability to
release special editions and seasonal blends. They also claimed that
HPHC testing and reporting and other regulatory requirements like the
prohibition on free samples would be equivalent to a de facto ban on
premium cigars. They also expressed concern about the political and
economic impact of premium cigar regulation on two foreign nations
given the potential impact on production and exports of their premium
cigars to the United States.
    Some comments also argued that an exemption for premium cigars is
appropriate, because premium cigars are unique in the way that they are
made, marketed, sold, purchased, and used. They stated that regulation
would stifle innovation in the premium cigar market, devastate a long-
time social and cultural phenomenon, and limit the freedoms of
businesses and consenting adults to sell and purchase a legal product.
    (Response) FDA understands these concerns. The Agency has
determined that cigar use presents health risks and that all cigars
should be brought under its regulatory authority.
    To assist newly regulated firms, FDA is announcing in this final
rule a compliance policy to address some of the possible burdens
suggested by comments (section IV.D). For example, FDA does not intend
to enforce the premarket review requirements against cigar
manufacturers that make tobacco blending changes to address the natural
variation of tobacco (e.g., tobacco blending changes due to variation
in growing conditions) in order to maintain a consistent product.
However, FDA intends to enforce the premarket requirements for products
that have tobacco blending changes (including those involved in
seasonal and boutique blends) that are intended to alter chemical or
perception properties of the new tobacco product (e.g., nicotine level,
pH, smoothness, harshness). FDA also is working to determine an
appropriate compliance policy to deal with HPHCs for newly deemed
products and is intending to issue guidance regarding HPHC reporting,
and later a testing and reporting regulation as required by section
915, with enough time for manufacturers to report given the 3-year HPHC
reporting compliance period. As noted elsewhere in this document, FDA
does not intend to enforce the reporting requirements for newly deemed
products before the close of the 3-year compliance period, even if the
guidance is issued well in advance of that time. In addition, as
discussed in section IV.D, FDA is announcing a compliance policy for
small-scale tobacco product manufacturers (which likely would include
premium cigar manufacturers), which states that FDA generally intends
to grant small-scale tobacco manufacturers additional time to respond
to SE deficiency letters and to not bring enforcement action against
those small-scale tobacco product manufacturers who submit ingredient
lists within 12 months of the effective date of the rule, and is
granting these manufacturers an additional six-month compliance period
for the requirements to submit tobacco health documents. FDA believes
that this compliance policy will help to assist these manufacturers
with regulatory compliance.
    FDA also understands concerns from cigar retailers about the effect
that a ban on free samples could have on their ability to promote new
products. FDA wishes to clarify that allowing prospective adult buyers
to smell or handle a cigar is not considered the distribution of a
``free sample'' for the purpose of 21 CFR 1140.16 as long as the
product is not actually consumed in the retail facility and the
prospective buyer does not leave the facility with a free tobacco
product (whole or part). Affording adult consumers the opportunity to
handle the product will give them the ability to feel the resistance of
the cigar's structure, and allow them to clearly see the color of the
product, which is an indication of the fermentation period for the
tobacco. It also will allow users to capture the aroma of the cigar and
the box (if the cigar is sold in a package). Therefore, it would not be
considered a free sample if a prospective buyer smells the cigar while
handling it. We believe that in most circumstances, other retail
facilities, including ENDS retail establishments, can similarly allow
customers to touch, hold, and smell their products without violating
the free sample ban. However, if the prospective buyer lights and draws
or puffs on the cigar to keep the cigar lit, or otherwise uses the free
cigar or leaves the retail establishment with a free cigar, this would
constitute a ``free sample'' in violation of Sec.  1140.16.
    (Comment 105) Many comments requested that the exemption for
premium cigars be extended to hand-operated, vintage machine-made
cigars. Comments stated such cigars are indistinguishable from handmade
premium cigars, are sold on the same shelves as premium cigars, and do
not resemble mass-market cigars. The comments further argued that
consumers perceive them to be just like value-priced handmade cigars
and treating them differently would create significant enforcement
issues for FDA. They stated that, without an exemption, manufacturers
of these products would be forced to close and eliminate jobs,
negatively impacting the regional economy where such cigars are
produced.
    (Response) As already stated, FDA has selected Option 1 deeming all
cigars, rather than a subset, for this final deeming rule. Therefore,
all cigars, including hand-operated, vintage machine-made cigars, are
deemed and subject to the requirements of chapter IX of the FD&C Act
and implementing regulations. Concerns noted by some comments about the
burdens of regulation are addressed in sections IV.C and IV.D.
    (Comment 106) At least one comment expressed concern that retailers
may not be able to determine whether a cigar meets all of the elements
of the final definition of a ``covered cigar.'' Therefore, the comment
stated that retailers should not be liable for a manufacturer's
improperly labeled premium cigars (similar to the retailer ``safe
harbor'' for required warning labels and advertising in the proposed
cigarette graphic warning rule (75 FR 69524 at 69535, November 12,
2010)).
    (Response) FDA has selected Option 1, which requires all cigars
(rather than a subset) to include the textual health warnings. FDA also
notes, however, that Sec.  1143.5(a)(4) does provide a retailer ``safe
harbor'' for required warning labels for packaging that contains a
health warning; is supplied to the retailer by a manufacturer,
importer, or distributor who has the required state, local, or Alcohol
and Tobacco Tax and Trade Bureau (TTB)-issued license or permit, if
applicable; and is not altered by the retailer in a way that is
material to the requirements of Sec.  1143.5. Retailers must have the
required warnings on advertisements as stated in Sec.  1143.5(b)(1).
    (Comment 107) Some comments stated that FDA has the authority to
assert jurisdiction over all cigars and differentially apply
regulations to certain cigars if shown to be appropriate based on
scientific evidence. Thus, according to the comments, if it were
established that premium cigar risk is of a different nature and degree
than the

risks of other types of cigars based on who uses them and how they are
used, the Agency could apply its authority in a way that fits the risks
posed by the product. These comments concluded that because of this, it
is unnecessary and would be inappropriate to completely exempt premium
cigars.
    Similarly, some comments applied the notion of a ``continuum of
risk'' to cigars. They stated that premium cigars are at the lower end
of the spectrum (Ref. 76) due to the common usage patterns (i.e.,
described as most frequently used by adults, on special occasions, and
users do not inhale). Therefore, they urged that FDA regulate premium
cigars in line with the notion of a continuum of risk.
    (Response) FDA agrees that a continuum of nicotine-delivering
products does exist as demonstrated by the lower levels of toxicants in
ENDS in comparison to cigarettes, and may warrant different
requirements for products at different ends of this continuum. However,
commenters have not substantiated their claims that the patterns of use
for premium cigars preclude users from negative health effects.
Instead, as discussed throughout this section, cigar use poses a
greater risk than not smoking, and lack of inhalation do not prevent
the onset of cigar-related morbidity and mortality. Therefore, FDA has
concluded that it is appropriate for all cigars to be brought under its
regulatory authority.
    (Comment 108) Several comments stated that it would be
inappropriate and inaccurate for FDA to treat ``cigars'' as a single
homogenous category or to simply overlay the existing regulatory
framework for cigarettes onto the diverse suite of deemed products.
They further stated that because of the significant differences among
cigar products, it is critical that FDA distinguish between the
specific cigar subtypes in determining whether any, some, or all cigars
should be subject to regulation. If FDA were to do otherwise, they
believe the Agency would risk establishing an arbitrary and capricious,
overly broad regulatory scheme that fails to meet its burden to protect
the public health without imposing undue burden on the industry.
    (Response) FDA disagrees. Upon review of comments and scientific
evidence, FDA has determined that all cigars present a risk to public
health and, consequently, should be deemed.
    (Comment 109) A few comments discussed different regulatory
approaches for make-your-own cigar products (e.g., cigar wrappers and
cigar tobacco). At least one comment suggested treating these products
as cigars while others urged regulation of them in a manner similar to
cigarette papers and roll-your-own tobacco.
    (Response) With this final rule, make-your-own cigar products,
including cigar wrappers and cigar tobacco, are tobacco products and
subject to FDA's tobacco control authorities under chapter IX of the
FD&C Act. Cigar wrappers containing tobacco or tobacco-derived nicotine
and cigar tobacco packaged and sold individually are also subject to
the warning requirement for ``covered tobacco products'' found in Sec.
1143.3.
    (Comment 110) At least one comment stated that FDA should not
permit manufacturers to self-classify their products as cigarettes or
cigars, and if premium cigars are exempted, should not permit self-
classification of cigars as premium or nonpremium.
    (Response) Regardless of how they may be classified by their
manufacturers, cigars and cigarettes will be classified based on the
definitions included in this final rule.
    (Comment 111) A few comments argued that bias existed for any study
or analysis cited in the NPRM that was written or contributed to by FDA
employees. These comments were concerned that FDA employees generating
and analyzing data did so to support the proposed regulation of cigars.
    (Response) FDA disagrees. FDA notes that most of the studies cited
in the NPRM that were authored by FDA employees have been published in
peer-reviewed journals. Where the NPRM discussed research results
presented at a professional conference, SRNT, but not yet included in a
peer-reviewed journal, FDA clearly stated so and specifically requested
comment (79 FR at 23151). That research has since been published (Ref.
90).
    (Comment 112) Some comments criticized the methodologies used by
researchers in studies FDA cited in the NPRM (e.g., Ref. 59). For
example, they claimed that the Delnevo, et al. study regarding youth
use of flavored cigars (id.) was flawed, because the study cites any
use of the brand by youth as use of the flavored variety of that cigar
brand (even though the respondent might use an unflavored variety of
that cigar). The comments had additional concerns regarding the study,
such as missing data on cigar brand from 13 percent of cigar smokers,
as well as concerns about whether study participants provided accurate
information regarding cigar brand used, and whether the study
population was representative of the U.S. population. Other comments
stated that studies in peer-review journals are politically biased and
that studies that oppose tobacco product regulation are often
prohibited from publication.
    (Response) The Delnevo, et al. publication found that youth and
young adults are significantly more likely than older adults to prefer
cigar brands that are more likely to be flavored (Ref. 59). Because no
national data directly compared youth and adult flavored cigar use
within the same study, Delnevo and colleagues conducted an ecological
analysis combining data from the 2010-2011 NSDUH on cigar brand smoked
most often, with Nielsen data indicating the percent of the cigar
brands' market share that are labeled as flavored cigar products. These
results, coupled with information on the prevalence of flavored cigar
use from studies restricted to youth or to young adults, provide
additional indirect evidence of the popularity of flavored cigars among
younger cigar smokers as compared to older adult cigar smokers.
Especially when coupled with research results on the prevalence of
flavored cigar use in studies restricted to youth or young adults, this
study provides additional supporting evidence of the widespread appeal
of flavored varieties of these products among young Americans. The
comments noted that, in the 2010-11 NSDUH, 13 percent of cigar smokers
did not report a usual cigar brand and expressed concern about the
ability of those who reported their usual cigar brands to do so
accurately. Some cigar smokers may in fact not actually have a cigar
brand they smoke most often and consequently did not provide a brand
response, while other respondents may have chosen not to provide their
usual brand information. Among the latter group, missing data is always
a concern, although there is no evidence from the study to suggest that
those who provided brand information were systematically different than
those who did not. Additionally, the comments did not provide evidence
to substantiate the concern that respondents were not reporting the
brand names they actually used. Lastly, FDA does not agree with
concerns about representativeness of the survey. The NSDUH is designed
to be representative of the U.S. civilian, non-institutionalized
population, ages 12 and older (http://www.samhsa.gov/data/population-data-nsduh). FDA does not rely on any single study to support decisions
included in this final rule. FDA cited many peer reviewed studies in
the NPRM and relies upon many peer-reviewed studies to support the
decisions included in this final rule, including the Delnevo
publication.

VIII. Regulation of Electronic Nicotine Delivery Systems (Including E-
Cigarettes) and the Continuum of Nicotine-Delivering Products

    In the preamble to the NPRM, FDA noted that there are distinctions
in the health risks presented by various nicotine-delivering products.
FDA requested comment as to how e-cigarettes should be regulated based
on this continuum of risk. We explained that some studies have revealed
the existence of toxicants in both the e-cigarette liquid and the
exhaled aerosol of some e-cigarettes but that we do not have sufficient
data to determine what effects e-cigarettes have on public health at
the population level. We also noted that some individuals report using
e-cigarettes to successfully quit smoking, but we expressed concerns
about dual use of e-cigarettes and combusted tobacco products and the
possibility that flavored e-liquids are leading children to initiate
tobacco use with e-cigarettes.
    In this final rule, FDA clarifies that although there are many
types of ENDS (including e-cigarettes, e-cigars, e-hookah, vape pens,
personal vaporizers, and electronic pipes), all are subject to FDA's
chapter IX authorities with this final deeming rule. Comments regarding
e-cigarettes, including comments on how the products should be
regulated in light of this continuum, and FDA's responses are discussed
in the following sections.

A. Terminology

    (Comment 113) Some comments expressed confusion as to what is
encompassed by the term ``e-cigarette.'' Other comments stated that the
``electronic smoking devices'' covered under this deeming rule should
include e-cigarettes, e-cigars, e-hookah, and vape pens.
    (Response) FDA agrees that electronic nicotine delivery systems or
ENDS are sold under several different names including e-cigarettes, e-
cigars, e-hookah, vape pens, personal vaporizers, and electronic pipes.
These products all meet the definition of ``tobacco product'' and,
therefore, under this rule, all are subject to FDA's tobacco control
authorities, regardless of a novel name or heating source. In addition,
the definition of tobacco product includes components and parts (the
objects intended or reasonably expected to be used with or for the
human consumption of a tobacco product that are not accessories) (e.g.,
e-liquids, tanks, cartridges, pods, wicks, atomizers), which, under
this rule, have also been deemed to be subject to FDA's authority under
chapter IX of the FD&C Act.

B. Prevalence

    In the NPRM, FDA expressed concern about the increase in prevalence
of the newly deemed products, particularly the alarming rise in e-
cigarette use by middle school and high school students. The comments
included peer-review studies, focus group results, and data regarding
the prevalence of ENDS use.
    (Comment 114) Some comments noted that it was difficult to fully
ascertain prevalence of use of these products because they are sold
under many different names. However, they generally agreed that the
prevalence of e-cigarette use has increased in recent years, citing
peer-reviewed studies and data from state or regional surveys (e.g.,
Ref. 108). For example, comments cited the 2013 North Carolina Youth
Tobacco Survey (NCYTS) and expressed concern that, while the current
cigarette smoking rates among North Carolina high school students
decreased in recent years, the overall current use of tobacco products
increased from 22.5 percent in 2011 to 24.5 percent in 2013. In
particular, the rate of e-cigarette use increased from 1.7 percent in
2011 to 7.7 percent in 2013, and 2.7 percent of high school students
who had never tried a cigarette indicated that they were considering
using e-cigarettes in the next year.
    However, some of these comments believed that the data showing an
increase in e-cigarette use among youth and young adults only reflects
their experimentation (and not long-term use) and that there are no
data showing that this experimentation leads to long-term use or dual
use with combusted tobacco products. Others stated that although e-
cigarette use may be increasing among youth and young adults, this
increase is due to the fact that young adult smokers are switching to
e-cigarettes, as are adult smokers.
    (Response) FDA agrees with comments stating that the prevalence of
use of the newly deemed tobacco products has been increasing, which
further substantiates the need for this final rule. FDA remains
concerned about the rise in use of newly deemed products by youth and
young adults, particularly the increase in use of ENDS. As we stated in
the NPRM and throughout this document, long-term studies are not yet
available to determine whether these youth and young adults are only
experimenting with tobacco use, becoming established ENDS users or dual
users, or transitioning to combusted products. In addition, there is
not sufficient evidence to conclude that youth and young adults are
using ENDS as a means to quit smoking.
    (Comment 115) Many comments contended that the great majority of e-
cigarette users consist of former smokers and those trying to quit
smoking, rather than those who are initiating tobacco use with e-
cigarettes (e.g., Ref. 109). The comments included data from regional
surveys indicating that even where there has been a significant
increase in youth and young adult e-cigarette use, the increase is seen
in experimenters and not daily users. For example, a few comments
referred to a report commissioned by Public Health England which
referred to a study that found that only 1 percent of 16 to 18-year-old
never smokers have experimented with e-cigarettes and few, if any,
progress to sustained use (Ref. 110).
    (Response) Data reported by the CDC's National Center for Health
Statistics (NCHS), which provides the first estimates of e-cigarette
use among U.S. adults from a nationally representative household
interview study, indicate that current cigarette smokers and recent
former smokers (i.e., those individuals who quit smoking within the
past year) were more likely to use e-cigarettes than long-term former
smokers (i.e., those individuals who quit smoking more than one year
ago) and adults who had never smoked (Ref. 24). In addition, the CDC
states that current cigarette smokers who had tried to quit smoking in
the past year were more likely to use e-cigarettes than those who had
not tried to quit (id.). It is noted that it cannot be determined by
the research findings: (1) Whether former cigarette smokers who now
exclusively use e-cigarettes would have ceased smoking cigarettes
regardless of e-cigarette use; and (2) whether the e-cigarette use
preceded or followed smoking cessation. Similar patterns have been
observed in Europe, where researchers found that ``e-cigarette use was
more likely among smokers who had made a past year quit attempt'' when
compared to smokers who had not (Ref. 111). As discussed in further
detail in response to Comment 144, a meta-analysis of 15 cohort
studies, 3 cross-sectional studies, and two clinical trials (one RCT,
one non-RCT) found that cigarette smokers who also used e-cigarettes
had statistically significantly worse quit rates than those cigarette
smokers who did not use e-cigarettes (Ref. 112).
    However, FDA also remains concerned about the dramatic rise in ENDS
use among youth; between 2011 and 2014, past 30 day e-cigarette use
among high school students increased nearly 800 percent from 1.5
percent in 2011 to 13.4 percent in 2014 (Ref. 22),

and between 2011 and 2013, the number of never-smoking youth who had
reported ever using an e-cigarette increased 3-fold, from 79,000 to
more than 263,000 youth (Ref. 113). The Surgeon General has stated that
adolescents appear to be particularly vulnerable to the adverse effects
of nicotine on the central nervous system (Ref. 9), and ENDS may
deliver as much nicotine as other tobacco products (Ref. 114).
    FDA is investing in long-term, population-level research, such as
the PATH Study, to help assess the likelihood that previous nonusers of
tobacco who experiment with ENDS will initiate regular tobacco use over
time. Such longitudinal studies can further assess the factors
associated with potential smoking cessation among e-cigarette users.
    (Comment 116) The comments generally agreed that youth are
increasingly using e-cigarettes, but disagreed as to the product's
impact on nicotine addiction. As FDA noted in the proposal and as
discussed by many comments, the CDC found that ever use of e-cigarettes
by middle and high school students in the United States increased from
3.3 percent in 2011 to 6.8 percent in 2012 (Ref. 108). While the
majority of comments recognized an increase in dual use, some suggested
that this was not an issue because youth are using e-cigarettes to quit
smoking, resulting in some dual use until they can completely abstain
from conventional cigarettes (Ref. 115).
    (Response) FDA remains concerned about the rise in ENDS use among
youth and young adults as well as the trends in dual use of ENDS and
combusted products in both youth and adults (Ref. 116). In addition, as
stated in the NPRM and throughout this final rule, all tobacco products
are potentially addictive and some ENDS may deliver as much nicotine as
other tobacco products (Ref. 20). The Surgeon General has stated that
adolescents appear to be particularly vulnerable to the adverse effects
of nicotine on the central nervous system (Ref. 9). FDA believes that
this final deeming rule, along with the minimum age restrictions and
health warning requirements, is an important step toward combatting
this rise in tobacco product use among youth and young adults.
    A recently published paper by Friedman (Ref. 42) looked at youth
smoking rates in states that enacted early bans on sales of e-
cigarettes to minors and concluded, based on state-level data available
through 2013, that the decline in adolescent smoking rates slowed in
states that enacted restrictions on access to ENDS by minors before
January 2013, relative to states that did not. Given the various issues
with this study (see previous discussion regarding this publication in
response to comment 33), FDA acknowledges this paper as a first attempt
to study potential impacts of youth ENDS access restrictions, but
emphasizes that further research will be needed to explore the effects
of this rule on product switching and dual usage.

C. Toxicity and Nicotine in E-Liquid and Aerosol

    Although FDA noted in the NPRM that we do not currently have
sufficient data about e-cigarettes and similar products to fully
determine what effects they have on the public health, we identified
concerns regarding the toxicants in e-liquid and the exhaled aerosol
and the nicotine delivery from e-cigarettes. Comments were divided on
the safety and toxicity of e-liquids, e-cigarettes, and the exhaled
aerosol.
    (Comment 117) The comments expressed concerns that e-cigarette
users subject themselves to dangerous constituents, including
formaldehyde and other toxicants. One comment stated that the release
of formaldehyde occurs only when the voltage on e-cigarettes is set to
4.8 volts or higher (Ref. 67). Some comments also submitted studies
showing the existence of other e-liquid constituents, including
prescription weight loss and erectile dysfunction drugs (Ref. 117).
    (Response) Studies show that e-liquid tobacco products contain
nicotine, propylene glycol, glycerin, tobacco specific nitrosamines,
tobacco alkaloids, carbonyls, ethylene glycol, diacetyl, and acetyl
propionyl (Refs. 19, 118, 119). Chemicals such as nicotine, carbonyls,
tobacco specific nitrosamines, heavy metals, and volatile organic
compounds have been identified in e-cigarette aerosols (Refs. 19, 118,
119, 120, 121, 122).
    In addition, several studies substantiated the data included with
comments, finding that flavored e-liquids contain chemicals that could
be dangerous to consumers when inhaled. For example, researchers in one
study tested 159 e-liquids with sweet flavors, such as toffee,
chocolate, and caramel, and found that almost three quarters of the
samples (74 percent) contained diacetyl or acetyl propionyl (Ref. 123),
both of which pose known inhalation risks (e.g., Ref. 124). Among those
that tested positive, nearly half of the e-liquids in the study could
expose users to levels that exceed recommended workplace limits for
breathing these chemicals (Ref. 123). An additional recent study
analyzed 51 types of flavored e-cigarettes for total mass of diacetyl,
2,3-pentanedione, and acetoin (Ref. 125). Researchers detected diacetyl
above the laboratory limit of detection 39 of the 51 flavors tested,
ranging from limit of qualification (LOQ) to 239 [mu]g/e-cigarette.
2,3-pentanedione and acetoin were also detected in 23 and 46 of the 51
flavors tested at concentrations up to 64 and 529 [mu]g/e-cigarette
(id.). It is noted that the study involved a convenience sample of 51
types of flavored e-cigarettes and may not be representative of the
types of e-liquids currently available to users. Absent a regulatory
standard, FDA acknowledges that it may not be possible to account for
the wide variability of concentrations of constituents in the flavors
of current ENDS products. Another study analyzed 30 e-cigarette liquids
and found that many flavors, including cotton candy and bubble gum,
contained aldehydes, a class of chemicals that can cause respiratory
irritation, airway constriction, and other effects (Ref. 126).
Specifically, researchers noted that two flavors, a dark chocolate and
a wild cherry, would expose e-cigarette users to more than twice the
recommended workplace safety limit for the aldehydes vanillin and
benzaldehyde (id.). Similarly, researchers found that several cinnamon-
flavored e-liquids contained a chemical, cinnamaldehyde, which
researchers stated was highly toxic to human cells in laboratory tests
(Ref. 127).
    Some studies have found that lower levels of toxicants are observed
in e-cigarette aerosols than in combusted tobacco smoke (Ref. 122). FDA
recognizes that specific product design parameters, such as voltage,
can affect toxicant deliveries (Ref. 67). For example, some ENDS
devices and some power levels of operating ENDS devices have been
reported to deliver more formaldehyde than other ENDS products and
conventional cigarettes (Refs. 67, 128, 129) and can affect the public
health. In addition, a 2010 study conducted by the Virginia
Commonwealth University determined that in a controlled evaluation of
smokers na[iuml]ve to the use of e-cigarettes and using a particular
model of e-cigarette, acute effects of using the product did not result
in measurable levels of nicotine or carbon monoxide, although e-
cigarettes did suppress nicotine/tobacco abstinence symptom ratings
(Ref. 130). Moreover, a recent evaluation of the relative health risks
of ENDS products conducted by Public Health England has drawn attention
to scientific reviews concluding that ENDS

are ``likely to be much less, if at all, harmful to users or
bystanders'' and a prior paper that reported the findings from an
international expert panel of academics. Employing an analysis model
that quantifies the relative health harms of 12 tobacco products using
a series of 14 harm criteria, the expert panel determined that while
cigarettes scored 100 percent in their assessment of maximum relative
harm, ENDS products were rated to have only 4 percent maximum relative
harm, which contributed to Public Health England's assessment that ENDS
are around 95 percent safer than smoking combusted cigarettes (Ref.
131; see Refs. 76, 132).
    The recent evaluation's use of the prior paper has several
limitations, and the prior paper itself observed that it was reporting
outcomes based on the decision-conferencing process from a group of
experts who were selected without any ``formal criterion,'' though
``care was taken to have raters from many different disciplines'' and
primarily based on geographic location ``to ensure a diversity of
expertise and perspective'' (Ref. 76). In addition, the authors
acknowledge that there is a ``lack of hard evidence for the harms of
most products on most of the criteria'' (Refs. 76, 133, 134). The
authors did not explain what scientific information was available to
the experts upon which they should base their ratings. The authors did
not explain the derivation of the quantitative assessment of each harm
criterion. It is unclear if the authors carried out or referenced a
quantitative risk analysis, a standard practice when assessing relative
risk, nor did the authors indicate that they used mean levels of
exposure to HPHCs in users or other quantitative evidence as an
approximation of risk. In addition, population effects appear to be
largely outside the scope of this analysis since the manuscript did not
address the likelihood that the characteristics of the products would
make them more or less likely to appeal to new users, be used in
conjunction with other tobacco products or discourage quitting. They
did not describe an assessment of population effects such as a
quantitative assessment of youth use prevalence. FDA does not find the
beliefs reported in the prior paper (Ref. 76) to be sufficiently
conclusive on the relative risks of using different tobacco
products.\14\ However, previous studies detected the presence of
aldehydes, especially formaldehyde, in the vapor from some ENDS to
exist at levels much lower than in cigarette smoke (Ref. 132).
Moreover, across several Japanese brands evaluated by another
researcher in a self-published Web site, under some use conditions,
ENDS released 1/50th of the level of formaldehyde released by
cigarettes (Ref. 135). The highest level detected was six times lower
than the level in cigarette smoke (id.). A clinical investigation
comparing the levels of toxicants and carcinogen metabolites in the
urine of e-cigarette users and combusted cigarette users found that e-
cigarette users had significantly lower levels of all evaluated
toxicants, which included acrolein and crotonaldehyde (Ref. 136). But
other research, published as a letter to the editor of the New England
Journal of Medicine, reported that ENDS devices operated at 5 volts
delivered a mean of 390+/-90 [mu]g per 10 puff sample which is greater
than 150 [mu]g, the estimated average delivery of formaldehyde than
conventional cigarettes. No formaldehyde-releasing agents were detected
when ENDS were operated at 3.3 volts (Ref. 128). A subsequent peer-
reviewed article on 5 variable-power ENDS devices found large
variations in formaldehyde delivery across devices (Ref. 129). The
first device yielded more formaldehyde than combustible cigarettes at
every power level tested, and the second device delivered more
formaldehyde at the highest power level tested; the remaining three
devices delivered less formaldehyde than combustible cigarettes at all
power levels tested (id.) The same research found that aldehyde
delivery varied by 750-fold from one ENDS device to another (id.). The
article referenced in one comment (Ref. 67) reported that increasing
the voltage from 3.2 to 4.8 volts increased formaldehyde, acetaldehyde,
and acetone levels from 4-fold to over 200-fold.
---------------------------------------------------------------------------

    \14\ In addition, at least one source has identified other flaws
with the expert panel employed in the Nutt et al. report, including
potential conflicts of interest and no prespecified expertise on
tobacco control among the panel members (Ref. 133).
---------------------------------------------------------------------------

    (Comment 118) The comments in support of limited or no regulation
for e-cigarettes cited studies showing that e-cigarette use resulted in
improvements in many health indicators of former cigarette smokers.
Most of these comments relied upon published literature concluding
that, despite the lack of long-term health data, e-cigarettes are
``likely to be much less, if at all, harmful to users and bystanders''
(Ref. 132). They also noted that clinical studies to date indicate that
e-cigarettes generally are well-tolerated and do not produce serious
adverse events following use for up to 24 months (Refs. 107, 137). Many
relied upon an analysis of the 47 e-cigarette adverse event reports FDA
received from 2007 to 2012, which found that only 8 of them were
considered serious (e.g., pneumonia, congestive heart failure,
disorientation, seizure, hypotension, facial burns, chest pain and
rapid heartbeat, infant choking on an e-cigarette cartridge, loss of
vision) (Ref. 138).
    Some comments also stated that e-cigarettes provide subjective
health benefits to current smokers. For example, in one Internet survey
of 1,347 current e-cigarette users, among those who were former
smokers, 75 percent reported improved breathing, less coughing, and
feeling healthier overall after switching to e-cigarettes (Ref. 139).
They also claimed that e-cigarette use leads to improved sense of smell
and taste and general physical status (Ref. 109). In addition, they
stated that some of the harms caused by smoking can be reversed by
switching to e-cigarettes (Ref. 140).
    (Response) FDA agrees that the majority of reported adverse events
appear to have been not serious. The FDA adverse event reporting system
has inherent limitations as a measure of the impact of e-cigarettes
since ENDS are a newly deemed product and reporting adverse events
associated with tobacco products (including e-cigarettes and other
ENDS) is voluntary; therefore, the reports received may have
underrepresented the true number and types of adverse events associated
with ENDS. The data cannot be used to calculate incidence (occurrence)
rates or to estimate risk. Moreover, FDA has concerns with relying upon
the types of short-term studies provided in the comments. Short-term
studies fail to analyze the exposure risk of tobacco use and inhalation
that damage health over a lifetime of repeated, extended exposure.
Given the relatively new entrance of ENDS on the market, consumers have
not had the duration of use for researchers to fully assess the
morbidity and mortality effects for ENDS on either the individual or
the population.
    FDA recognizes that completely switching from combusted cigarettes
to ENDS may reduce the risk of tobacco-related disease for individuals
currently using combusted tobacco products, given the products'
comparative placements on the continuum of nicotine-delivering
products. A recent review from Public Health England (discussed in
greater detail in response to Comment 117) suggests substantial
reductions in the exposure to harmful constituents typically associated
with smoking in ENDS products compared to cigarettes, and that most of
the chemicals causing smoking-related

disease from combusted tobacco use are absent and the chemicals that
are present pose limited danger (Ref. 131). A scientific review of
published studies of the toxicity of certain e-liquids found that ``[e-
cigarette] aerosol can contain some of the toxicants present in tobacco
smoke, but at levels which are much lower. Long-term health effects of
[e-cigarette] use are unknown but compared with cigarettes, [e-
cigarettes] are likely to be much less, if at all, harmful to users or
bystanders'' (Ref. 132). ENDS products have been found in some studies
to release aldehydes at much lower levels than that in cigarette smoke,
with one Web site posting stating that, across several Japanese brands,
under some use conditions, that ENDS products release 1/50th the level
of formaldehyde released in cigarettes (Ref. 133).
    However, study results have been inconsistent about the effects of
these products. Some short-term studies suggest that ENDs may not
affect heart rate, cardiac function, lung function, or complete blood
count indices to the extent of conventional cigarettes (Refs. 130, 141,
142). A literature search, however, concluded that the current
scientific evidence on short-term effects are limited and there are no
adequate data on long-term health effects (Ref. 143). Other studies
have demonstrated increase in mean heart rate and inflammatory measures
(such as white blood cells) and changes in lung function after use
(Refs. 141, 142, 144, 145). Some research has found that there are some
ENDS devices and some power levels of operating ENDS devices that
deliver more formaldehyde than other ENDS products and conventional
cigarettes (Refs. 67, 128, 129). Further, the review by Hajek et al.
(Ref. 132) referred to in this comment as showing health benefits and
finding a lack of negative health effects of e-cigarettes, may have
limited generalizability due to the variability of e-cigarette
products. The authors expressly recognized that there are many
deficiencies in the available data.
    (Comment 119) Some comments believed that FDA should not be
concerned about e-liquids because they are restricted to the same
nicotine levels as other products (e.g., cigarettes, hookah, smokeless
tobacco, NRTs).
    (Response) FDA disagrees with comments stating that the Agency
should not be concerned with ENDS use. First, a direct comparison of
the nicotine level in cigarettes (and other currently regulated tobacco
products) with the nicotine level in e-liquids is not a particularly
helpful or relevant comparison. More helpful and clinically meaningful
is the comparison between the amount of nicotine delivered to the user
after using a cigarette (or other conventional tobacco product) versus
the amount of nicotine delivered after using an ENDS (Ref. 146).
Therefore, even if an e-liquid has the same nicotine level, it may
deliver a different level of nicotine than the comparator product. It
is also possible that comparable nicotine delivery consistently
produced by ENDS that meet the requirements of the Tobacco Control Act
may increase the facilitation of product switching from cigarettes to
ENDS--which could (with appropriate regulatory oversight) potentially
reduce the overall health harm caused by combusted tobacco. Further
research is necessary to determine the causal factors that influence
product switching from cigarettes to ENDS (or vice versa) and the
subsequent health impacts.
    Second, FDA disagrees with the notion that e-liquids are restricted
to the same level of nicotine as other tobacco products. E-liquids are
available in a wide range of nicotine concentrations, but delivery to
the user is based on multiple factors, including the humectant in the
e-liquid, the temperature to which the e-liquid is heated, the user
experience, device designs, and design modifications (Ref. 147). Data
suggest that experienced ENDS users are able to achieve clinically
significant nicotine levels and levels similar to those generated by
traditional cigarettes (Refs. 114, 148, 149, 150). Moreover, heating
the e-liquids to higher temperatures and using the ENDS in ways other
than intended (e.g., dripping the e-liquid directly onto the atomizer)
may result in nicotine delivery that is actually higher than that of a
conventional cigarette (Ref. 16).
    Third, FDA disagrees with the premise that the Agency should not be
concerned with tobacco products that may have lower nicotine levels
than cigarettes or other tobacco products, as may be the case with some
ENDS. Even if ENDS products have lower levels of nicotine, they still
have the potential to addict users, particularly youth and young
adults, as discussed in section VIII.C. As the Surgeon General has
stated, nicotine is the primary addictive substance in tobacco products
(Ref. 9). Regardless of the nicotine content of the tobacco products,
FDA believes that deeming tobacco products will result in significant
public health benefits and that the additional restrictions imposed by
this rule are appropriate for the protection of the public health.
    (Comment 120) One comment expressed concern about the lack of
research regarding the environmental impacts of e-cigarette use and
storage.
    (Response) FDA is funding studies regarding environmental impacts
due to ENDS manufacturing, use, and disposal following use. In
addition, FDA has been conducting a series of public workshops to
obtain information on e-cigarettes and their impact on public health.
Potential environmental impacts were discussed during the first
workshop (79 FR 55815, September 17, 2014).
    (Comment 121) Some comments expressed concern about the health
effects of propylene glycol exposure from e-cigarette use. They also
stated that the use of glycerol and propylene glycol, both of which are
humectants, may cause uninformed users to become inadvertently
dehydrated.
    (Response) FDA recognizes that information about the health effects
of the constituents in e-liquids and ENDS aerosols in both users and
nonusers is limited and that this issue should be explored to better
understand the impacts of these products on the population health.
    (Comment 122) As FDA noted in the NPRM, one study detected
diethylene glycol in one e-cigarette cartridge (79 FR 23142 at 23157).
A few comments took issue with FDA's reliance on the study, because the
amount of diethylene glycol reported was so low that it was unlikely to
cause harm to consumers and had not been replicated in other scientific
studies to date.
    (Response) FDA appropriately characterized this study in the NPRM,
stating that diethylene glycol ``was found in only 1 of 18 cartridges
studied and it was not found at all in another 16 studies'' (79 FR
23142 at 23157). FDA agrees that the amount found was low, but
reiterates that diethylene glycol is a toxicant and, therefore, is a
cause for concern.
    (Comment 123) We received many comments regarding the safety of the
aerosol that is emitted from e-cigarettes. These comments expressed
concern that individuals incorrectly believe that the aerosol emitted
from e-cigarettes is harmless and stated that e-cigarette aerosol is
not simply water ``vapor,'' as is sometimes advertised (Ref. 151). They
provided studies indicating that the primary or mainstream and exhaled
or secondhand e-cigarette aerosols have been found to contain at least
10 chemicals known to cause cancer, birth defects, or other
reproductive harm (Ref. 65). They also noted that potentially harmful
constituents have been identified in some e-liquids and their aerosol,
including tobacco-specific nitrosamines, heavy metals, and

carbonyls, albeit at significantly lower levels than in cigarette smoke
(Refs. 65, 118, 152, 153, 154, 155, 156). Studies have shown that the
primary aerosol contains measurable amounts of nicotine, which can have
an impact on both users and nonusers (Ref. 144, 147).
    We also received comments stating that the aerosol is completely
harmless or significantly less harmful than tobacco smoke from
combusted tobacco products; the comments included data from peer-
reviewed publications (Refs. 144, 156, 157, 158), a presentation at a
professional conference (Ref. 159), and individual company testing.
These comments also submitted research that was not peer-reviewed,
which stated that there were no key tobacco smoke toxicants in e-
cigarettes (Ref. 160).
    (Response) FDA recognizes that the aerosol that is exhaled by users
of some e-cigarettes and similar electronic apparatus may not pose as
much harm as smoke emitted from combusted tobacco products. However,
given that studies do indicate that both nicotine and other toxicants
are found in the exhaled aerosol, limiting exposures must be
considered. (See section XII regarding the potential for product
standards and tobacco product manufacturing practices on manufacturers
of newly deemed products.) In the absence of short- and long-term
studies on the potential impact of secondary exposure to aerosol, FDA
cannot conclude that the aerosol is harmless. Moreover, as stated
throughout this document, the Tobacco Control Act does not require that
FDA make a finding that a product is harmful in order to deem it to be
subject to chapter IX of the FD&C Act; FDA is authorized to deem any
product that meets the definition of a ``tobacco product'' pursuant to
section 901 of the FD&C Act.
    (Comment 124) A few comments stated that the aerosol must be safe
because the primary constituents of the liquid that generate the e-
cigarette aerosol are propylene glycol and glycerin. They stated that
inhalation of such constituents is harmless because they are designated
as ``generally recognized as safe'' (GRAS) by FDA. They cited animal
inhalation studies showing limited toxicological effects from either
propylene glycol or glycerin (e.g., Ref. 161).
    (Response) FDA disagrees with comments claiming that the aerosol is
safe due to certain components being recognized as GRAS. It is
important to note that the definition of food additive in section
201(s), and its exclusion of GRAS substances, relates to intended uses
that may reasonably be expected to result, directly or indirectly, in
its becoming a component or otherwise affecting the characteristics of
any food (section 201(s) of the FD&C Act). E-liquid is not food or
intended for ingestion; therefore, the fact that propylene glycol and
glycerin have been designated GRAS for food does not necessarily mean
that these components are safe for inhalation. (See additional
responses in this section of the document regarding FDA's concerns with
ENDS aerosol.)
    (Comment 125) Several comments that stated that e-cigarettes are
harmless cited one study in which the author concluded that there ``is
no serious concern about the contaminants such as volatile organic
compounds'' in the e-cigarette ``vapor'' and that tobacco-specific
nitrosamine (TSNA) levels in the ``vapor'' are just as hazardous as
those TSNAs in NRT products (Ref. 162). Some of these comments
specifically asked why FDA did not include this study in the proposed
deeming rule.
    (Response) FDA has considered these findings and agrees that the
exhaled aerosol from ENDS users is potentially less hazardous than
secondhand smoke from combusted cigarettes. However, FDA disagrees with
the author's conclusion that exposure to aerosol (``vapor'') ``pose[s]
no apparent concern'' (Ref. 162). FDA recognizes that the aerosol that
is exhaled by users of some e-cigarettes and similar electronic
apparatus may not pose as much harm as smoke emitted from combusted
tobacco products. However, given that studies do indicate that both
nicotine and other toxicants are found in the exhaled aerosol, limiting
exposures must be considered. FDA has repeatedly noted the potential
benefits and need for additional information regarding ENDS and,
therefore, the research included in the NPRM accurately summarized the
state of the research on e-cigarettes (and the other newly deemed
products) at the time it was drafted.
    (Comment 126) A few comments claimed that there are many e-liquids
on the market that do not contain nicotine and, therefore, e-liquids
should not be regulated. Other comments provided studies that showed
that e-cigarettes deliver nicotine but noted that delivery is dependent
on the e-cigarette apparatus and liquid type, the rate at which the
nicotine is delivered, and the user's experience with e-cigarette use
(Ref. 130).
    (Response) FDA is aware that, although some ENDS and e-liquids are
marketed as nicotine free, as stated in section VIII.D, studies have
found that certain types of ENDS do not have consistent quality and the
labels may not accurately reflect the amount of nicotine in the e-
liquid. The World Health Organization (WHO) also has noted that the
level of nicotine delivered in currently marketed ENDS varies widely
depending on product characteristics, user puffing behavior and
nicotine solution concentration, leaving smokers unaware of the
nicotine levels they are receiving (Ref. 163). In addition, FDA agrees
that many factors influence the delivery of nicotine. For example, an
experienced ENDS user may be exposed to amounts of nicotine similar to
those delivered by cigarette smoking (Ref. 114). Also, as stated
earlier, nicotine-free e-liquid that is intended or reasonably expected
to be used with or for the human consumption of tobacco products in
most cases would be a component or part of a tobacco product and,
therefore, within the scope of this rule. These products will be
evaluated on a case-by-case basis.
    (Comment 127) Many comments discussed the possibility of nicotine
poisoning due to improper access to, or use of, e-liquids. Most of
these comments expressed concerns about the growing number of calls to
poison control centers due to accidental nicotine poisoning. Others
believed this concern was overstated and noted that many drugs can
cause poisoning if stored improperly. They stated that the addition of
child-resistant containers would alleviate this concern. Some also
noted that e-cigarette users self-titrate the nicotine dosage, so
concerns about overdosing should be minimal (Ref. 84).
    (Response) FDA is concerned about the risk of nicotine poisoning in
both users and nonusers. The CDC has reported more than 2,400 calls to
U.S. poison control centers for e-liquid exposure between September
2010 and February 2014 (Ref. 164). In another study of 1,700 e-liquid
exposures reported to U.S. poison control centers from June 2010
through September 2013, children 5 years of age or younger represented
the largest proportion of e-liquid exposures and the group with the
greatest increase in exposures per month in the first three quarters of
2013 (Ref. 165). Studies show that nicotine in sufficient
concentrations, either when ingested or in contact with the skin, can
result in serious or fatal poisoning and is concerning (Refs. 166,
167). Symptoms of toxicity include nausea, vomiting, seizures, coma,
cardiovascular instability, respiratory arrest, and sometimes death.
Although there was disagreement among the comments as to the level of
nicotine that causes

poisoning, the nicotine content of many refillable vials could be toxic
to adults and children regardless of the measurement used. Accordingly,
elsewhere in this issue of the Federal Register, FDA has made available
draft guidance, which when final will describe FDA's current thinking
regarding some appropriate means of addressing the premarket
authorization requirements for newly deemed ENDS products, including
recommendations for exposure warnings and child-resistant packaging
that would help support a showing that the marketing of a product is
appropriate for the protection of the public health. In addition, FDA
issued an ANPRM prior to this deeming rule, seeking comments, data,
research, or other information that may inform regulatory actions FDA
might take with respect to nicotine exposure warnings and child-
resistant packaging.
    (Comment 128) Some comments compared the poison risks of nicotine
against other household products, noting that the incidence of nicotine
poisoning is significantly lower than for other household products
(Ref. 168).
    (Response) Regardless of the incidence of nicotine poisoning in
comparison to poisonings attributed to other household products, the
dramatic rise in nicotine poisoning from e-liquid exposures is very
concerning. FDA is taking under advisement the submitted data regarding
nicotine poisoning and suggestions for measures that FDA can take in a
separate rulemaking to address the issue, including establishment of
tobacco product manufacturing practice regulations under section 906(e)
and tobacco product standards under section 907 of the FD&C Act. In
addition, as stated previously, FDA issued an ANPRM prior to this
deeming rule seeking comments, data, research, or other information
that may inform regulatory actions FDA might take with respect to
nicotine exposure warnings and child-resistant packaging. Moreover,
elsewhere in this issue of the Federal Register, FDA has made available
draft guidance, which when final will describe FDA's current thinking
regarding some appropriate means of addressing the premarket
authorization requirements for newly deemed ENDS products, including
recommendations for exposure warnings and child-resistant packaging
that would help support a showing that the marketing of a product is
appropriate for the protection of public health.
    (Comment 129) Comments were divided as to whether nicotine is
dangerous to humans. Some comments stated that liquid nicotine is
completely benign (and that FDA should not regulate e-cigarettes given
the lack of harms). They claimed that FDA's findings regarding NRTs
illustrate that nicotine is not carcinogenic to humans. (See
``Modifications To Labeling of Nicotine Replacement Therapy Products
for Over-the-Counter Human Use,'' 78 FR 19718, April 2, 2013.) Other
comments stated that although nicotine has some side effects, it is
significantly less hazardous than the toxicants ingested with combusted
products. Still others claimed that nicotine is very dangerous.
    Comments that claimed that nicotine is dangerous cited studies
showing that although nicotine may not be a primary carcinogen, it
likely promotes cancers established through angiogenic (promoting of
blood vessels in tumors) effects (e.g., Ref. 169). The comments also
noted that the 2014 Surgeon General's Report stated that the health
risks of nicotine are more serious than previously thought and that FDA
should consider this when evaluating the impacts of the newly deemed
products on vulnerable populations. Others believed that nicotine is so
dangerous that individuals should be required to obtain a certification
before being permitted to acquire and handle it.
    (Response) In the proposed deeming rule, FDA recognized the impact
of nicotine on a youth's brain (see 79 FR 23142 at 23153 and 23154) and
also noted poisoning concerns. The inhalation of nicotine (i.e.,
nicotine without the production of combustion) is of less risk to a
user than the inhalation of nicotine delivered by smoke from combusted
tobacco products. However, limited data suggests that the
pharmacokinetic properties of inhaled nicotine can be similar to
nicotine delivered by combusted tobacco products. Thus, inhaled
nicotine from a non-combustible product may be as addictive as inhaled
nicotine delivered by combusted tobacco products. Researchers recognize
that the effects from nicotine exposure by inhalation are likely not
responsible for the high prevalence of tobacco-related death and
disease in this country (Refs. 10, 11). Although nicotine has not been
shown to cause the chronic disease associated with tobacco use, the
2014 Surgeon General's Report noted that there are risks associated
with nicotine (Ref. 9 at 111). For example, nicotine at high enough
doses has acute toxicity (id.). Nicotine exposure during fetal
development has lasting adverse consequences for brain development
(id.). Nicotine also adversely affects maternal and fetal health during
pregnancy, contributing to multiple adverse outcomes such as preterm
delivery and stillbirth (id.). Further, data suggest that nicotine
exposure during adolescence may have lasting adverse consequences for
brain development (id.). Some studies also have found that nicotine can
have detrimental effects on the cardiovascular system and potentially
disrupt the central nervous system (Refs. 14, 15). See also section
VIII.C discussing the increase in poisoning due to accidental nicotine
ingestion.
    FDA is not stating that nicotine is harmless. Unlike ENDS, which
have not been reviewed by FDA, the NRT products mentioned in the
comments are regulated and have undergone premarket review by FDA's
Center for Drug Evaluation and Research (CDER) and been found to be
safe and effective before obtaining authorization to enter the market
(sections 505 and 506 of the FD&C Act). The Agency does not have
sufficient data to be able to conclude that consumers are inhaling only
nicotine, and no other chemicals or toxicants, when using ENDS.
Although ENDS likely do not deliver the same level of toxicants as
cigarettes, studies show that there are dangers associated with ENDS
use and that exhaled aerosol is not simply ``water vapor,'' as some
believe. (See section VIII.C for additional discussion about the
toxicants in ENDS vapor.)
    (Comment 130) At least one comment suggested that to help address
the dangers of nicotine and its use in future tobacco products,
manufacturers registering future products with FDA should provide
documents demonstrating the accuracy of stated nicotine levels and that
the products are diacetyl and acetyl propionyl free.
    (Response) FDA agrees with the need to carefully monitor future
tobacco products and to evaluate the toxicological concern of chemical
ingredients, such as diacetyl and acetyl propionyl, in e-liquids and
that statements about the nicotine concentration in the e-liquid as
well as the amount of nicotine that will be delivered to the user are
accurate. FDA's review of SE reports and PMTAs under sections 905 and
910 of the FD&C Act will often include analysis of the chemicals
included in the products. In addition, the requirements to submit
ingredient listings under section 904 and HPHC testing data under
sections 904 and 915 are expected to alert FDA to the existence of
these HPHCs in e-liquids.
    (Comment 131) Many comments expressed concerns regarding the high

cost associated with testing for HPHCs in each individual e-liquid and
e-cigarette product. They suggested that FDA use enforcement
discretion, as the Agency has done previously, to reduce the regulatory
burden for e-cigarette manufacturers. For example, they noted that FDA
has compliance policies for the submission of SE reports for certain
product modifications and HPHC reporting. To reduce the regulatory
burden, they suggested that FDA not require ingredient disclosure of
all unique e-liquid products under section 904(a)(1) of the FD&C Act
because such a requirement is unreasonable given the many different e-
liquid formulations in these retail establishments. They stated that in
lieu of ingredient listings, FDA should accept a table of all
ingredients used in e-liquids along with use-level (concentration)
ranges (i.e., minimum and maximum percentages) of those ingredients in
their products. These comments further suggested that FDA allow
companies to simply amend their ingredients lists when altering
products rather than requiring them to submit PMTAs.
    (Response) Once this rule becomes effective, newly deemed products
automatically become subject to chapter IX and all of its provisions
applicable to tobacco products, without exception. Therefore, all
manufacturers and importers of the newly deemed products will be
subject to the requirements under sections 910, 905, and 904 of the
FD&C Act upon the effective date of this final rule.
    However, FDA has established a compliance policy for certain
circumstances. See section IV.D describing the compliance policy
regarding certain provisions and small-scale tobacco product
manufacturers.

D. Quality Control

    In the NPRM, FDA recognized previous instances of lack of quality
control for certain e-cigarette products (79 FR 23142 at 23149). FDA
indicated that the premarket review requirements that will
automatically apply to the newly deemed products can help to address
quality control concerns.
    (Comment 132) Many comments expressed concern regarding the lack of
controls in place for the mixing of e-liquids. They stated that these
liquids are often mixed by individual consumers or employees of e-
cigarette retail establishments who may lack training or knowledge of
guidelines for handling such products. Several retailers of e-liquids
submitted comments stating that they have controls in place to ensure
the safety of their e-liquids.
    (Response) FDA understands the comments' concerns about the safety
of e-liquids. As stated previously, FDA issued an ANPRM prior to this
deeming rule seeking comments, data, research, or other information
that may inform regulatory actions FDA might take with respect to
nicotine exposure warnings and child-resistant packaging. Also,
elsewhere in this issue of the Federal Register, FDA is announcing the
availability of a draft guidance, which when finalized will provide
FDA's current thinking regarding some appropriate means of addressing
the premarket authorization requirements for newly deemed ENDS
products, including recommendations for exposure warnings and child-
resistant packaging that would help support a showing that the
marketing of a product is appropriate for the protection of public
health. FDA also intends to consider these and other issues during its
premarket review of these products. Further, after the effective date
of this rule, FDA can exercise its authorities under the Tobacco
Control Act to take additional steps to address the safety of e-
liquids.
    (Comment 133) Some comments included data regarding the variations
among the nicotine levels in e-liquids, including data showing that the
nicotine levels of the products are not accurately reflected in the
nicotine concentration stated on the labels. For example, one study
found nicotine content labels to be highly inaccurate and determined
that products claiming to be nicotine-free actually contained high
levels of nicotine (Ref. 170). Other comments stated that the
variations are no longer as significant among the newer e-cigarette
products, and that newer studies reported more consistent nicotine
levels (Ref. 171).
    Many comments cited several studies of newer e-cigarettes which
continued to find wide variability in e-cigarette engineering,
including nicotine concentrations in e-liquid, that were inconsistent
with the information contained on the product label (Ref. 16). For
example, one 2014 study of e-liquid refills found that the actual
nicotine level of 65 percent of the e-liquids deviated by more than 10
percent from the nicotine concentrations printed on the labels (Ref.
17). Other studies found variability among nicotine concentrations, but
the nicotine levels were equivalent to or lower than advertised (Refs.
18, 19). In one study, researchers stated that the total amount of
nicotine in the e-liquid studied was potentially lethal if an
individual were to drink it or absorb it through the skin (Ref. 18).
They based this finding on the lethal level of nicotine being in the 10
to 60 milligram (mg) range; however, other comments claimed the lethal
dose of nicotine is actually much greater (Ref. 172).
    Some comments expressed concern that this rule does not address the
possibility of a dangerous contamination of a batch of e-liquid because
it does not include quality control measures or product standards that
could prevent such contamination. They believed that FDA's authority to
establish tobacco product manufacturing requirements or product
standards in the future was insufficient to address this concern.
    (Response) FDA is aware of the variability of nicotine among
certain ENDS and that the labeling may not accurately reflect the
nicotine levels. After this rule becomes effective, FDA has the
authority to issue tobacco product manufacturing practice regulations
under section 906(e) of the FD&C Act to address this issue. The PMTA
process (particularly, the requirement to submit information on
manufacturing methods) also provides a mechanism through which products
that are more harmful or addictive than products on the market at the
time of submission would be denied entrance to the market. Moreover,
immediately upon the effective date of this rule, if FDA determines
that an e-liquid has been contaminated and is therefore adulterated
under section 902 or that it is misbranded under section 903 of the
FD&C Act because its labeling is false or misleading, it can initiate
enforcement action such as a seizure, injunction, or criminal
prosecution.
    (Comment 134) A few comments expressed concern that FDA may limit
the availability of e-liquids to established manufacturers only and
prohibit individuals from mixing their own e-liquids. These comments
stated that they need access to products of reasonable potency, high
purity, and high quality.
    (Response) This final deeming rule places some restrictions on the
sale and distribution of tobacco products, such as minimum age
restrictions, but it does not bar sales to individuals generally.
    (Comment 135) At least one comment noted that, although there have
been fires due to mishandling of e-cigarette batteries, cases of
accidental poisoning, and concerns about functionality, the ``de facto
regulations'' that are in place, ``namely brand equity, potential civil
liability, and word-of-mouth'' have been effective in helping the
market evolve and controlling behavior.
    (Response) FDA disagrees. FDA's adverse event reporting system has

inherent limitations as a measure of the impact of e-cigarettes since
ENDS are a newly deemed product and reporting adverse events associated
with tobacco products (including e-cigarettes and other ENDS) is
voluntary. FDA remains concerned about adverse events associated with
ENDS use, including overheating and exploding batteries as reported in
the news, and the vast evidence that accidental nicotine poisoning is
increasing in the wake of growing e-cigarette use. Toward that end,
elsewhere in this issue of the Federal Register, FDA has made available
draft guidance, which when final will describe FDA's current thinking
regarding some appropriate means of addressing the premarket
authorization requirements for newly deemed ENDS products, including
compliance with existing voluntary standards for ENDS batteries. In
addition, concerns remain regarding quality control, which could impact
the functionality of these products. FDA believes that the automatic
statutory provisions that will apply to these products as a result of
this deeming rule, in conjunction with additional authorities under the
law that FDA can exercise after the effective date, will help address
these concerns.
    (Comment 136) At least one comment sought clarification as to why
FDA expressed concern about quality control issues for e-cigarette
products but not for combusted products that contain thousands of toxic
constituents.
    (Response) FDA is concerned about quality control for all tobacco
products and will continue to monitor these products to determine if
there are quality control issues. FDA's premarket review of the newly
deemed products will increase product consistency. For example, FDA's
oversight of the constituents of e-cigarette cartridges would help to
ensure quality control related to the chemicals and their quantities
being aerosolized and inhaled. Quality control issues will also be
addressed in a tobacco product manufacturing practices regulation that
FDA intends to issue at a later date. Also, FDA may take enforcement
action if an ENDS or any other tobacco product is adulterated or
misbranded within the meaning of the FD&C Act.
    (Comment 137) A few comments expressed concerns regarding the
quality of e-cigarettes manufactured overseas. They stressed the
importance of issuing regulations to require the registration of
foreign establishments so that FDA knows the identity of foreign
manufacturers and the products they import into the United States.
    (Response) FDA agrees with comments' concerns regarding quality
control and the safety of ENDS manufactured both domestically and in
other countries. One of the immediate benefits of deeming ENDS is that
all newly deemed products, including ENDS, that meet the definition of
``new tobacco product'' will be subject to the premarket authorization
requirements in sections 905 and 910 of the FD&C Act. In addition, FDA
has announced its intention in the Unified Agenda to issue a NPRM that
would apply the registration and listing requirements of section 905 to
foreign establishments.
    (Comment 138) Some comments suggested that to properly regulate e-
cigarettes, given their position on the continuum of nicotine-
delivering products, FDA should regulate these products based on the
size of the manufacturer--which is generally smaller than the size of
companies that manufacture cigarettes and smokeless tobacco products.
They also suggested that FDA stagger the compliance periods for
submission of PMTAs so that smaller companies have additional time to
prepare their submissions.
    (Response) Section IV.D has additional information about compliance
periods for small-scale tobacco product manufacturers. FDA's compliance
policy for the submission of SE reports, SE exemption requests, and
PMTAs for all manufacturers of deemed products is included in section
IV.C.
    (Comment 139) One comment recommended that FDA collaborate with
other Federal Agencies, including the National Institutes of Health
(NIH), CDC, and the Substance Abuse and Mental Health Services
Administration (SAMHSA), as well as international agencies including
the EU, to continue research on tobacco products and increase
surveillance and other enforcement of quality control and other issues.
    (Response) FDA agrees. FDA intends to continue to review available
studies and fund studies on tobacco products, including studies on ENDS
initiation, use (including transitions to other tobacco products and
multiple use), perceptions, dependence, and toxicity (Ref. 173). FDA
also has been conducting a series of public workshops to obtain
additional information on e-cigarettes and their impact on public
health (79 FR 55815). These workshops will help to inform FDA's
development of future rules and policies that have an impact on ENDS.
Additional regulations regarding ENDS will be subject to the
requirements of the APA.
    (Comment 140) Some comments stated that FDA should regulate
materials used in the manufacture of e-cigarette components and
packaging that come into direct contact with e-liquids. They noted that
improper e-cigarette construction and e-liquid packaging materials
could also result in hazardous leachates or degradation of products in
the e-liquid that may become aerosolized and inhaled upon use.
    (Response) With this final rule, FDA is deeming all products,
except for accessories of newly deemed products, that meet the
definition of ``tobacco products'' under section 201(rr) of the FD&C
Act, which includes the components and parts (including packaging of
such products). FDA will consider the issues raised by the comments
when it develops a NPRM on tobacco product manufacturing practices.

E. Misperceptions

    In the NPRM, FDA noted its concerns regarding consumer
misperceptions of currently unregulated products, particularly e-
cigarettes. Many comments provided data to substantiate those concerns
and others provided data and personal stories regarding the potential
benefits of e-cigarettes. Other comments indicated that, based on these
potential benefits, they believed e-cigarettes to be safe tobacco
products.
    (Comment 141) Many comments stated, but did not provide supporting
data, that e-cigarettes: (1) Are approximately 99 percent less
hazardous than cigarettes; (2) are only consumed by smokers and former
smokers who quit by switching to e-cigarettes; and (3) have not been
found to create nicotine dependence in any nonsmoker. They also stated
that there is no evidence that ingesting e-liquid leads to fatalities.
    (Response) As discussed throughout this document, FDA agrees that
use of ENDS is likely less hazardous for an individual user than
continued smoking of traditional cigarettes. One self-selected
comparison reported that across several Japanese brands, under some use
conditions, ENDS released 1/50th of the level of formaldehyde released
by cigarettes (Ref. 135). The highest level detected was six times
lower than the level in cigarette smoke (id.). But other research,
published as a letter to the editor of the New England Journal of
Medicine, reported that ENDS operated at 5 volts delivered a mean of
390+/-90 [mu]g per 10 puff sample which is greater than 150 [mu]g, the
estimated average delivery of formaldehyde than conventional cigarettes
(Ref. 128). No formaldehyde-releasing agents were detected when ENDS
were operated at

3.3 volts (Ref. 128). A subsequent peer-reviewed article on 5 variable-
power ENDS devices found large variations in formaldehyde delivery
across devices (Ref. 129). The first device yielded more formaldehyde
than combustible cigarettes at every power level tested, and the second
device delivered more formaldehyde at the highest power level tested;
the remaining three devices delivered less formaldehyde than
combustible cigarettes at all power levels tested (id.) The same
research found that aldehyde delivery varied by 750-fold from one ENDS
device to another (id.). The article referenced in one comment (Ref.
67) reported that increasing the voltage from 3.2 to 4.8 volts
increased formaldehyde, acetaldehyde, and acetone levels from 4 to over
200-fold.
    Nevertheless, as discussed in section VIII.F, evidence shows that
while most ENDS are consumed by smokers and former smokers (e.g., Refs.
109, 110), some consumers (including youth and young adults) are
initiating tobacco use with ENDS. Several studies have found that ENDS
users, particularly experienced ENDS users, are able to achieve
nicotine exposures similar to cigarette smokers (Refs. 114, 148, 149,
150). Although no studies have been done to-date assessing the
development of dependence among non-smokers, several studies have found
that ENDS users, particularly experienced ENDS users, are able to
achieve nicotine exposures similar to cigarette smokers and that
nicotine is a known addictive substance. Fourth, as discussed in
section VIII.D, the incidence of nicotine poisoning has been on the
rise and has resulted in severe poisonings and hospitalization (Ref.
174). In December 2014, after the close of the comment period for the
NPRM, media reported the first death of a toddler from accidental
poisoning from e-liquid (Ref. 175). Regulation of ENDS will help to
alleviate consumer misperceptions such as those expressed in the
comments.
    (Comment 142) Many comments stated that e-cigarettes should be
regulated given their appeal to youth and young adults and the belief
that e-cigarettes are less harmful than conventional cigarettes. They
agreed with FDA's concern that a failure to regulate the newly deemed
products could reinforce consumers' existing confusion and
misinformation about these products. However, other comments stated
that FDA's concerns about youth's misperception of the safety of e-
cigarettes should not be a factor in FDA's decision to regulate them.
They stated that regulation cannot remedy the fact that many youth
affirmatively disregard available safety information.
    (Response) As FDA stated in its proposal, many people may believe
that certain tobacco products covered by this rule present fewer health
risks when compared to that of cigarettes (79 FR 23142 at 23158 and
23159), which is supported by some of the emerging scientific
literature demonstrating that some ENDS products, operated at some
power levels, may have lower delivery of harmful constituents and
toxicants than that of combusted cigarettes (see discussion on the
health harms of ENDS in response to Comment 117). In fact, a recent
telephone survey of 1,014 adults indicates that a majority of American
adults surveyed (nearly two-thirds, 65 percent) believe e-cigarettes
are harmful to the health of the people who use them and 23 percent
believe that they are not harmful (Ref. 176). In addition, 44 percent
believe that electronic cigarettes are less harmful than combusted
cigarettes while 32 percent thought they were equally harmful (id.). Of
particular note, the survey found that ``[t]hose who have ever used e-
cigarettes are significantly less likely than never-users to believe
that e-cigarettes and marijuana are harmful to the health of people who
use them, and more likely to believe in the benefits of e-cigarettes
when it comes to smoking cessation'' (id.).
    Although FDA expects that youth understanding and appreciation of
the health effects and risks of certain newly deemed tobacco products
will be improved if they are also FDA-regulated, that is only one of
the many public health benefits that will accrue from deeming them
subject to the FD&C Act, as discussed in the NPRM (79 FR 23142 at 23148
and 23149).
    (Comment 143) Some comments expressed concern that the increase in
e-cigarette use in places where cigarette smoking is not currently
allowed creates confusion, particularly among children, who often
cannot tell the difference between smoking and e-cigarette use. They
referred to unpublished research and anecdotal evidence indicating that
when children see pictures of people using e-cigarettes they report
that someone is smoking.
    Other comments disagreed, stating that e-cigarette use will more
likely lead to normalization of e-cigarettes rather than cigarettes
(Ref. 110). They stated that one study found that daily smokers (aged
18 to 35 years) who observed individuals using e-cigarettes only
increased the smoker's desire for an e-cigarette, and not for a
conventional cigarette (Ref. 177).
    (Response) FDA is concerned that the growth in ENDS use,
particularly among youth and young adults, could lead to the re-
normalization of cigarette smoking. The Surgeon General recognized that
adolescents are particularly vulnerable to visual cues to smoke and to
social norms, making this an even greater concern (Ref. 49). FDA
believes that subjecting ENDS to its tobacco control authorities, and
requiring compliance with the various statutory and regulatory
requirements (e.g., ingredient listing and others), will help to
address the common misunderstanding that these products are safe to
use.

F. Use as a Cessation Product

    In the preamble to the NPRM, FDA recognized that some consumers may
use ENDS in tobacco cessation attempts. We note that if an ENDS product
seeks to be marketed as a cessation product, the manufacturer must file
an application with FDA's Center for Drug Evaluation and Research
(CDER) and no ENDS have been approved by FDA as effective cessation
aids.
    Recently published population-wide data from the CDC's NCHS, which
provides the first estimates of e-cigarette use among U.S. adults from
a nationally representative household interview study, indicates that
current cigarette smokers and recent former smokers (i.e., those
individuals who quit smoking within the past year) were more likely to
use e-cigarettes than long-term former smokers (i.e., those individuals
who quit smoking more than one year ago) and adults who had never
smoked (Ref. 24). Among current cigarette smokers who had tried to quit
smoking in the past year, more than one-half had ever tried an e-
cigarette and 20.3 percent were current e-cigarette users (id.).
    (Comment 144) Comments were divided regarding the viability of e-
cigarettes as a smoking cessation product. Some comments contended that
the actual patterns of e-cigarette use, citing a meta-analysis showing
the rapid penetration of the youth market and high levels of dual use
among both adults and adolescents, will lead to a lower probability
that smokers using e-cigarettes will quit smoking cigarettes (Ref. 16).
They also cited another study in which, although 85 percent of e-
cigarette users reported that they were using e-cigarettes to quit
smoking, they were no more likely to have quit smoking than nonusers of
e-cigarette (Ref. 178).
    However, consumers and manufacturers of e-cigarettes provided
information showing positive impacts of e-cigarettes on cessation,
including

personal anecdotes from former smokers (Ref. 132). For example, they
cited a 1-year multinational study where researchers found that among
smokers who were using e-cigarettes at the baseline, 22 percent had
quit smoking after 1 month and 46 percent had quit smoking after 1 year
(Ref. 179). In a survey of adults in the United Kingdom who tried to
quit smoking at least once in the past year, respondents who used e-
cigarettes had a higher quit rate (20 percent) than those who used NRTs
like patches or gum (10 percent) or those that did not use a cessation
aid (15 percent) (Ref. 180). These comments also asserted evidence that
e-cigarette use, at a minimum, leads to decreased cigarette use (e.g.,
Refs. 107, 181). One comment also noted that tribes use e-cigarettes as
an alternative to smoking and to promote cessation.
    (Response) As we have stated throughout this document, we recognize
that there is emerging data that some individual smokers may
potentially use ENDS to transition away from combustible tobacco
products. For instance, prospective studies of varying duration
examining the efficacy of e-cigarettes as cessation devices suggest
their potential to decrease combustible cigarette use as well as
promote abstinence from combustible cigarettes (Refs. 107, 149, 182,
183, 184). Three randomized controlled clinical trials (Ref. 107, 149,
184) report that e-cigarettes may help some smokers to stop smoking.
The trial that compared e-cigarettes to nicotine replacement therapy
found verified abstinence in all experimental groups, but no
significant difference among e-cigarettes, placebo e-cigarettes (i.e.,
e-cigarettes with no nicotine), and nicotine patches in six-month
abstinence rates (Ref. 184). Achievement of abstinence was
substantially lower than the optimistic estimates on which the power
calculation and study sample size were based, and thus, the researchers
could conclude no more than that ``among smokers wanting to quit,
nicotine e-cigarettes might be as effective as patches for achieving
cessation at 6 months'' (id.). It is possible that longer term
prospective studies may--or may not--demonstrate statistically
significant cessation outcomes for e-cigarettes in relation to
conventional nicotine replacement therapies (id). It is noteworthy that
a third of the participants allocated to the e-cigarettes groups in
this study reported continued product use at 6 months, suggesting that
they might have become long-term e-cigarette users (id.). However, some
systematic reviews of available evidence indicate that there is
currently insufficient data to draw a conclusion about the efficacy of
e-cigarettes as a cessation device (Refs. 185, 186). The Cochrane
Collaboration's systematic review and meta-analysis assessed
approximately 600 scientific records to include two randomized
controlled trials and 11 cohort studies on e-cigarettes and smoking
cessation in their review (Ref. 186). As the Cochrane review judged
RCTs to be at low risk of bias, the investigators combined results from
two randomized controlled trials, totaling over 600 people, and
conducted a quantitative meta-analysis. Results indicated that using e-
cigarettes with nicotine was associated with increased smoking
cessation as compared with e-cigarettes without nicotine. Investigators
also found evidence that using e-cigarettes with nicotine also helped
more smokers reduce the amount they smoked by at least half compared to
e-cigarettes without nicotine. However, the authors cautioned that
``the small number of trials, low event rates and wide confidence
intervals around the estimates mean that our confidence in the result
is rated `low'.'' (Ref. 186) In addition, the authors observed that
``the overall quality of the evidence for our outcomes was rated `low'
or `very low' because of imprecision due to the small number of
trials'' (id.). Another meta-analysis of the same two trials of e-
cigarettes with and without nicotine found comparable results (Ref.
187). The authors also reported a pooled estimate of cessation among
nicotine e-cigarette users, but the lack of non-e-cigarette control
groups in the studies prevented them from comparing the efficacy of e-
cigarettes against no e-cigarette use and against standard
interventions for cessation, such as nicotine patches (id.).
    An alternate systematic review and meta-analysis of approximately
600 scientific records to include 15 cohort studies, 3 cross-sectional
studies, and two clinical trials (one RCT, one non-RCT) examined the
association between e-cigarette use and cessation in observational
epidemiological studies and clinical trials; all 20 studies compared
smoking cessation rates for e-cigarette users against control groups of
smokers who did not use e-cigarettes (Ref. 112). This meta-analysis
found overall that odds of quitting cigarettes were on average 28
percent lower for smokers who used e-cigarettes than those who did not
(odds ratio = 0.72, with 95 percent confidence interval 0.57 to 0.91)
(Ref. 112). Of note, this meta-analysis included chiefly observational
studies whose control groups were not randomized, and included a wide
range of designs as well as variable exposures and outcome definitions
(id.). While some potential confounders were controlled for in most of
the studies, the investigators acknowledged that there may be other
unidentified confounders that could be a source of bias. This potential
bias as well as other limitations described may impact interpretability
of the overall findings (id.).
    We also note that ENDS have not been approved as effective
cessation aids. FDA remains committed to supporting long-term
population-level research that will help fill in current data gaps.
    (Comment 145) At least one comment suggested that FDA provide
physicians with guidelines about e-cigarette use, including its health
impact and efficacy as a cessation tool.
    (Response) To the extent the comment is about ENDS products that
are drugs because they are marketed for cessation, an ENDS product
marketed for therapeutic purposes is a drug or device subject to FDA's
regulations and laws for those products.
    (Comment 146) A few comments expressed concern that FDA
misrepresented certain studies in the NPRM and would not consider
research released since the issuance of the NPRM, particularly
regarding the effectiveness of e-cigarettes as a cessation tool.
    (Response) FDA has considered the preliminary evidence regarding
the effectiveness of ENDS to help smokers quit or to reduce their
consumption of combusted tobacco products. There is some indication
that such products may have the potential to help some individual users
to quit using combusted tobacco products or to reduce their use of such
products, as reported by scientific literature describing a small
number of randomized controlled trials evaluating the impact of ENDS
use on smoking outcomes (Refs. 137, 148, 184) and pilot studies
evaluating ENDS use on smoking reduction and cessation (Refs. 182,
183). But other evidence is to the contrary. Beyond the meta-analysis
discussed in section V(B)(3), a year-long study of over 5,000 20-year-
old Swiss men found that, even after adjusting for nicotine dependence,
individuals who were smokers at the start of the study and who reported
e-cigarette use at the end of the study were more likely to still be
smoking and more likely to have made one or more unsuccessful quit
attempts at the end of the year than individuals who were smokers at
the start and who reported no e-cigarette use (Ref. 188). The most
important consideration is that ENDS are not an

FDA-approved cessation product. If an ENDS manufacturer wishes to make
a cessation claim or otherwise market its product for therapeutic
purposes, the company must submit an application for their ENDS to be
marketed as a medical product.
    (Comment 147) Some comments expressed concern that e-cigarette
users are developing an addiction to nicotine while seeking to overcome
their smoking addiction and that the lack of regulation makes it
difficult for users to know the nicotine level that they need in their
e-cigarettes to overcome their addiction. They stated that for
cigarette smokers who are trying to replace their cigarette-derived
nicotine with e-cigarettes, ingredient listing and other requirements
are vital to ensure that users know how much nicotine they are
ingesting.
    (Response) By deeming ENDS, FDA has ensured that these products are
now subject to requirements related to ingredient and HPHC reporting,
among other requirements. In addition, the registration and listing
requirements and premarket applications will provide FDA with vital
information as to the extent of ENDS use and how many ENDS products
consumers are using on a daily basis.
    (Comment 148) Some comments perceived the newer generation of e-
cigarettes to be less addictive than combusted cigarettes and closer in
profile (including risk profile) to NRTs (Ref. 76). They noted the
limited number of significant adverse events resulting from e-cigarette
use and claimed that such adverse events are not distinguishable from
NRTs (Ref. 184). Some comments also believed that FDA should consider
the advantages that e-cigarettes have (as compared to NRTs) when
establishing the regulatory approach for these products, including the
fact that they offer appealing visual, tactile, and gestural
similarities to cigarettes, and that e-cigarettes provide quicker
nicotine delivery than NRTs (Ref. 189).
    (Response) As we have stated throughout this document, we recognize
that individual smokers may report cessation benefits from ENDS and
that preliminary research outcomes from randomized controlled trials
indicate that ENDS may decrease some individuals' cigarette consumption
and promote cessation. However, the risk profile is likely to be
different as compared to NRTs, and the long-term risks associated with
chronic use of ENDS are unknown. Finally, contrary to ENDS, the
nicotine patch and other NRTs were found to be safe and effective by
FDA's CDER after reviewing premarket applications containing data and
information establishing safety and effectiveness. No ENDS has yet been
approved by CDER.
    (Comment 149) Comments in support of limited or no regulation of e-
cigarettes stated that these products have a positive impact on the
public health at the population level. They cited online surveys and
convenience store data showing that most e-cigarette users do not use
additional tobacco products (see section VIII.H) and claimed that FDA
cherry-picked the evidence regarding dual use in the NPRM. They also
claimed FDA did not adequately assess the reduction in smoking that
would result from increased e-cigarette use and, as a result, the
Agency underestimated the potential positive impacts of e-cigarettes on
the public health at the population level.
    (Response) Many provisions of the FD&C Act call for a population-
level public health analysis that takes into account the population as
a whole, including users and nonusers of tobacco products (e.g.,
section 906(d) of the FD&C Act). Even products that are less toxic than
combusted tobacco products on an individual user basis may increase
public health harms if, for example, they encourage nonusers to start
using tobacco products that can lead to lifelong nicotine addiction.
    As we have stated throughout the document, FDA has examined data
regarding health harms generally associated with all of the categories
of tobacco products regulated under this rule (including ENDS, which
FDA recognizes may potentially provide cessation benefits to some
individual smokers). FDA is regulating these products in accordance
with this knowledge and will continue to regulate as we learn more
about the potential for product-specific health harms. FDA recognizes
that some ENDS users report that the products have the potential to
help individual users to quit smoking. However, FDA's responsibility is
to assess the population health impact of ENDS, including increasing
youth use, as well as the frequency of dual use of ENDS and combusted
tobacco products. FDA believes that data from long-term population
level studies, such as the PATH Study, will help to provide information
about the overall population health impacts of ENDS.
    (Comment 150) Many comments provided personal stories and peer-
reviewed studies to illustrate the benefits of e-cigarettes as a
cessation product and to request that FDA treat this product category
differently based on where the product falls within the continuum of
nicotine delivering products. For example, they suggested that FDA
differentiate between substances that contain tobacco and those that
are derived from tobacco and provide a separate regulatory approach for
each product category.
    Some comments also suggested that FDA tailor its regulatory
approach based on the type of electronic apparatus--e.g., advanced
refillable personal vaporizers (ARPVs) or open-system vapor products
versus ``cigalike'' products (ready for use products that look like
cigarettes and are sold in convenience stores). These comments believed
FDA should only deem ``cigalike'' products that are ready for
consumption, because they are easily accessible to youth and have been
associated with quality control issues (see section VIII.D). They noted
that ARPVs and other open systems are significantly more expensive than
``cigalike'' products and are only offered in vape or specialty shops.
They compared this to Option 1 (to deem all cigars) and Option 2 (to
deem all cigars except premium cigars) and suggested that FDA should
have provided similar options for regulating different e-cigarettes.
They also expressed the need for a different regulatory approach for
ARPVs because they provide users with the best opportunity to cease
using combusted tobacco products (Ref. 190). However, other comments
provided focus group research in which smokers rated cigalikes to be
significantly more satisfying than ARPVs and asked for a minimal
regulatory approach for cigalikes.
    Further, some comments stated that it was not feasible to regulate
ARPVs. They stated that the wide varieties of e-liquids available at e-
cigarette retail establishments and the ability of users to customize
their experience, including by altering the product's voltage/wattage,
puff duration, coil resistance, cartridge/battery duration, and design
aesthetics, make oversight, application review, and other regulation
untenable.
    Other comments stated that, instead of establishing a different
regulatory approach, FDA should ban ARPVs because there is greater risk
associated with their use and children may tamper with them. They
suggested that if FDA does not ban these products, FDA should require
the disclosure of all ingredients in e-liquids and other vaporized
nicotine products in both their pre-use and vapor states.
    (Response) To the extent that comments are asserting that FDA
should not regulate ENDS or subject them to certain provisions, FDA
disagrees with these comments, especially given that

ENDS use among youth and young adults is increasing. Although recent
data on young adults and adults indicate that ENDS users are more
likely to be former cigarette smokers and current cigarette smokers who
have tried to quit (e.g., Ref. 24), there is still some use among adult
non-tobacco users, particularly among young adults. In addition, the
rapid increase in use among adolescents is concerning. FDA also remains
concerned that ARPVs present the risk of accidental nicotine poisoning.
In addition, researchers recently reported that the new generation of
high voltage ENDS may put users at increased risk of negative health
effects (Ref. 67) and that ARPVs have the potential for increased abuse
liability (e.g., Refs. 109, 132, 171). FDA will continue to monitor
research regarding the health effects of different types of ENDS and
may tailor the regulatory requirements accordingly.
    (Comment 151) Some comments requested that FDA either exempt e-
cigarette products from the deeming regulation or strike the entire
proposal for e-cigarettes and replace it with what they considered a
more science-based approach or with rules that address good
manufacturing practices and consumer safety, given their potential for
use as cessation products.
    (Response) FDA disagrees. This final deeming rule is a foundational
rule that will provide many public health benefits, as described in the
NPRM (79 FR 23142 at 23148 and 23149), and will provide FDA with
critical information about the health risks of ENDS and other newly
deemed products, including data from ingredient listing submissions and
reporting of HPHCs required under the FD&C Act. Also, once this rule
becomes effective, newly deemed products may be subject to additional
regulations. For example, FDA has the authority under section 906(e) of
the FD&C Act to issue a rule establishing tobacco product manufacturing
practices, and this authority applies to deemed products. FDA also has
the authority under section 907 of the FD&C Act to establish product
standards for deemed products, including requirements with respect to
packaging. The Agency issued an ANPRM prior to this deeming rule,
seeking comments, data, research, or other information that may inform
regulatory actions FDA might take with respect to nicotine exposure
warnings and the use of child-resistant packaging. In addition,
elsewhere in this issue of the Federal Register, FDA has made available
a draft guidance for public comment, which when final will describe
FDA's current thinking regarding some appropriate means of addressing
the premarket authorization requirements for newly deemed ENDS
products, including recommendations for nicotine exposure warnings and
child-resistant packaging that would help to support a showing that the
marketing of a product is appropriate for the protection of the public
health.
    (Comment 152) Some comments stated that e-cigarettes should be
subject to little or no FDA regulation, because e-cigarettes inhibit
withdrawal symptoms in users with a history of relapse (Ref. 191) and
lead to reduction and cessation in asthmatic smokers (Ref. 107).
    (Response) FDA disagrees. Although ENDS may potentially provide
cessation benefits to individual smokers, no ENDS have been approved as
effective cessation aids. If an ENDS manufacturer wishes to make a
cessation claim, the company must submit an application for their ENDS
to be marketed as a medical product.

G. Modified Risk Claims

    In the NPRM, FDA noted that it expects public health benefits
through the application of section 911 of the FD&C Act to the newly
deemed tobacco products. Historically, certain users have initiated and
continued using certain tobacco products based on unauthorized modified
risk claims and consumers' unsubstantiated beliefs. Application of
section 911 will prohibit the introduction into interstate commerce of
MRTPs unless FDA issues an order permitting their marketing.
    (Comment 153) A few comments expressed concern that imposition of
section 911 of the FD&C Act will force e-cigarette manufacturers to
implicitly lie by not permitting them to tell consumers that their
products are safer alternatives to conventional cigarettes, to
advertise that they do not contain tobacco, and to state that they are
``smoke free.'' They added that the public already overwhelmingly
believes that e-cigarettes are reduced risk products and, therefore,
the section 911 requirements are irrelevant (Refs. 178, 192). However,
other comments stated that manufacturers should be prohibited from
making cessation claims without providing scientific evidence to
support their efficacy as a cessation mechanism.
    (Response) FDA disagrees with concerns that ENDS manufacturers will
not be able to make claims that properly represent their products.
Section 911 is one of the provisions of the statute that applies
automatically to deemed products. It was included in the FD&C Act to
protect consumers from manufacturers making invalid or unsubstantiated
claims, as many had done with respect to their designation of
cigarettes as ``light,'' ``low,'' or ``mild.'' The mistaken belief that
``light'' and ``low-tar'' cigarettes were safer than other cigarettes
prompted many smokers to switch to such products instead of quitting
altogether. Section 911 will prevent consumers from being similarly
misled by ensuring a manufacturer may not make unsubstantiated claims.
Manufacturers that have data to substantiate modified risk claims for a
particular product can submit an MRTP application so that FDA can
determine that the product meets the statutory standard and can issue
an order authorizing it to be marketed as an MRTP.
    As Congress recognized,

[u]nless tobacco products that purport to reduce the risks to the
public of tobacco use actually reduce such risks, those products can
cause substantial harm to the public health to the extent that the
individuals, who would otherwise not consume tobacco products or
would consume such products less, use tobacco products purporting to
reduce risk. Those who use products sold or distributed as modified
risk products that do not in fact reduce risk, rather than quitting
or reducing their use of tobacco products, have a substantially
increased likelihood of suffering disability and premature death.
The costs to society of the widespread use of products sold or
distributed as modified risk products that do not in fact reduce
risk or that increase risk include thousands of unnecessary deaths
and injuries and huge costs to our health care system.

(section 2(37) of the Tobacco Control Act).

    (Comment 154) Some comments believed that e-cigarettes should only
be authorized as MRTPs, rather than new tobacco products via the PMTA
or SE pathways, because that would allow them to meet the predominant
expectations of consumers.
    (Response) FDA disagrees. The Tobacco Control Act requires all new
tobacco products, including MRTPs, to go through premarket review and
obtain a marketing authorization order via the PMTA, SE., or SE
exemption pathways. A manufacturer who wants to sell a product for use
to reduce harm or risk of tobacco-related disease can also obtain
authorization to market an MRTP if the manufacturer submits an
application under section 911 of the FD&C Act and FDA issues such an
order.
    (Comment 155) A comment suggested that to address unauthorized
modified risk claims, we add the following language to the final rule:
No vapor product or alternative nicotine product shall be considered to
be ``sold or

distributed for use to reduce harm or the risk of tobacco-related
disease associated with commercially marketed tobacco products'' solely
because its label, labeling, or advertising uses the following phrases
to describe such product and its use: ``not consumed by smoking,''
``does not produce smoke,'' ``smokefree,'' ``without smoke,'' ``no
smoke,'' or ``not smoke.''
    (Response) Section 911 of the FD&C Act requires FDA to assess MRTP
claims for specific products. Therefore, FDA will evaluate products on
a case-by-case basis to determine whether they are ``sold or
distributed for use to reduce harm or the risk of tobacco-related
disease associated with commercially marketed tobacco product'' as
stated in section 911. However, we note that e-cigarettes and similar
ENDS products are not ``smokeless'' products, as the user is inhaling
constituents (which are different from a smokeless tobacco product, as
defined in the Tobacco Control Act). In addition, FDA is aware that
some ENDS might heat their product to a level high enough to cause
combustion.
    (Comment 156) Many comments stated that the NPRM may promote
conventional tobacco use because e-cigarette manufacturers will be
unable to inform smokers that their products are safer alternatives or
that they do not contain tobacco. They believed the NPRM weakens the
impact that the e-cigarette industry might otherwise exert on the
tobacco industry.
    (Response) FDA disagrees. First, this final rule does not prohibit
ENDS manufacturers from making claims that they are safer than
conventional tobacco products if they can provide evidence to satisfy
the requirements and obtain marketing authorization from FDA under
section 911 of the FD&C Act. Second, FDA believes that ENDS could serve
as alternatives to combusted tobacco products.

H. Dual and Polytobacco Use

    In the NPRM, FDA noted its concerns that adult consumers may use
one or more of the proposed deemed products in conjunction with
cigarettes or other tobacco products. FDA also noted that studies
suggest that some noncigarette tobacco users may go on to become
addicted cigarette smokers (79 FR 23142 at 23159).
    It is also recognized that some dual users of ENDS and cigarettes
may be transitioning away from combustible tobacco use and that such
transient periods of dual use may not present greater health risks than
that observed during sole use of combustible tobacco. In a peer-
reviewed study published recently in Cancer Prevention Research,
investigators evaluated users of a single brand of ``cig-a-like'' ENDS
and found that both cigarette smokers who switched to using the
evaluated ENDS products and those who switched to dual use of the
evaluated ENDS and cigarettes all demonstrated significant reductions
in exposure to carbon monoxide and the toxicant acrolein (Ref. 194).
    (Comment 157) Many comments expressed concern that the rate of dual
use of e-cigarettes and combusted tobacco products is high,
particularly among middle and high school students (Ref. 16). They
stated that adolescents do not use e-cigarettes as cessation aids but
rather use them in conjunction with conventional cigarettes (Ref. 193;
see Ref. 194). They also indicated that this dual use and the fact that
youth who experiment with e-cigarettes are 7.7 times more likely to
become established smokers than those who do not experiment (Ref. 116)
suggest that e-cigarette use leads to increased use of combusted
tobacco products. However, they noted that we need long-term studies
like FDA's PATH Study to confirm that assertion. Some comments also
stated that cigarette smokers who use a second tobacco product even
occasionally are at higher risk for continued tobacco use (Ref. 195).
    Other comments believed that dual use should not be a concern,
generally relying upon an Internet study of more than 19,000 e-
cigarette users in which dual users had decreased from 20 to 4
cigarettes per day by the end of the study (Ref. 109). Some comments
also expressed the belief that, because clinical studies show that e-
cigarettes deliver only modest concentrations of nicotine to novice e-
cigarettes users (Ref. 196), this would also be the case for nonsmoking
youth and young adults and, therefore, would make the possibility of
addiction less likely. Others argued that advanced e-cigarette products
deliver nicotine more effectively, making adult consumers less likely
to dual use or revert back to smoking. In addition, they claimed that
if e-cigarettes were acting as a gateway to cigarette use, the current
increase in e-cigarette use would lead to a corresponding increase in
youth cigarette use (which has not occurred). In fact, they said an
overlap of combusted tobacco and e-cigarette use is necessary if a
tobacco user begins e-cigarette use to transition away from combusted
tobacco consumption.
    (Response) FDA is aware of dual use of ENDS and combusted tobacco
products and is concerned about the potential impact of this practice
on nicotine addiction and cessation. FDA also is concerned because this
dual and polytobacco use pattern appears to be common among adolescents
and young adults (Ref. 197). However, recent CDC NCHS data on young
adult and adult use patterns of e-cigarettes indicate that former
smokers and current smokers trying to quit are more likely to use e-
cigarettes than former smokers who quit smoking more than 1 year ago
and those who had never smoked (Ref. 24). These results indicate that
dual use of tobacco may also be present during the transitional phase
when smokers of combusted tobacco products are attempting to quit,
which is also supported by personal stories included in the comments.