exclusion, if applicable. Pursuant to Sec.  25.15(a), all submissions
requesting FDA action require the submission of either a claim of
categorical exclusion or an EA. In accordance with Sec.  25.40(a), an
environmental assessment must include, at a minimum, brief discussions
of: The need for the proposed action; alternatives to the proposed
action as required by section 102(2)(E) of the National Environmental
Policy Act of 1969 (NEPA); the environmental impacts of the proposed
action and alternatives; the agencies and persons consulted during the
preparation of the EA, and the relevant environmental issues relating
to the use and disposal of the tobacco product. Although applicants may
wish to review the categorical exclusions specific to tobacco product
applications at Sec.  25.35, the only categorical exclusion currently
available for a marketing order is for the substantial equivalence
premarket pathway, not for PMTAs. If the applicant believes the action
would qualify for an available categorical exclusion, the applicant
would be required to state under Sec.  25.15(a) and (d) that the action
qualifies for a categorical exclusion, cite to the claimed exclusion,
and state that to the applicant's

knowledge no extraordinary circumstances exist under Sec.  25.21.
    If the new tobacco product resulted from modification(s) to a
legally marketed predecessor product (i.e., a grandfathered tobacco
product or a product that has received marketing authorization from
FDA), the environmental assessment also would be required to include a
statement indicating whether the new tobacco product is intended to:
(1) Replace the predecessor tobacco product once the new tobacco
product receives market authorization and is commercially marketed; (2)
be a line extension of the predecessor tobacco product; (3) be marketed
along with the predecessor product by the same manufacturer; and/or (4)
be marketed along with the predecessor tobacco product by a different
manufacturer (e.g., by a manufacturer other than the manufacturer of
the predecessor tobacco product). The change in what is available in
the marketplace is a factor FDA considers in determining whether the
issuance of a marketing order may significantly affect the quality of
the human environment as part of its NEPA review, e.g., the new product
may present different disposal issues if more product remains after
consumer use or if the materials that the new product is composed of
degrade differently.
    Failure to include an EA in a PMTA is grounds for FDA to refuse to
accept an application and failure to include an adequate EA is
sufficient grounds under Sec.  25.15 for FDA to refuse to file the PMTA
or refuse to issue a marketing order. (See the discussion of proposed
Sec. Sec.  1114.27 and 1114.29 in section VIII.)
8. Summary
    Proposed Sec.  1114.7(h) would require the application to contain a
summary of the application contents in sufficient detail to provide FDA
with an adequate understanding of the data and information in the
application. FDA is proposing to require the summary under authority of
sections 701(a) and 910(b)(1)(G) of the FD&C Act because it will
provide FDA with an understanding of the information contained in the
PMTA and allow FDA to plan and conduct a more efficient review of the
detailed technical information the summary describes. The summary would
also help reviewers understand the product and the accompanying
scientific data more quickly and would allow applicants to highlight
information they believe demonstrates their product should receive a
marketing order. The summary should discuss all aspects of the PMTA and
synthesize the application into a well-structured, unified document.
The summary should serve as a briefing document that highlights the
most important aspects of the application, with each section consisting
of a page or two focused on information that the applicant believes
contributes to a finding that permitting the marketing of the product
would be APPH. The applicant would be required to summarize the content
included in the PMTA in a manner that describes the operation of the
product, the health risks of the new tobacco product, the product's
effect on tobacco use behavior of current users, the product's effect
on tobacco use initiation by nonusers, and the product's effect on the
population as a whole. The summary section would be required to contain
a discussion of the following items, where applicable, and explicitly
identify areas in which there is a lack of information, if any:
     A summary of the product formulation section of the
application. This section should provide a high-level description of
the product formulation section of the application, highlighting
information such as key ingredients, constituent levels, and design
aspects of the product. See the discussion of proposed Sec.  1114.7(i)
in section VII.B.9;
     A summary of the manufacturing section of the application.
This section should provide an overview of the manufacturing section of
the application, including activities at each facility, and
highlighting information such as major aspects of the manufacturing and
controls, especially those that the applicant believes contribute to a
finding that permitting the marketing of the product would be APPH
(e.g., an aspect of the manufacturing process that results in lower
levels of HPHCs than other tobacco products in the same category). See
the discussion of proposed Sec.  1114.7(j) in section VII.B.12.;
     A summary of the health risk investigations section of the
application. This section should briefly describe and synthesize the
findings of each investigation describing:
    [cir] The health risks of the tobacco product to both users and
nonusers of the product and whether the tobacco product presents less
health risk than other tobacco products, such as the risk of cancers
(e.g., lung, mouth, pancreatic), heart disease, stroke, or lung
disease, compared to other categories of tobacco products and other
tobacco products within the category, if known. See the discussion of
proposed Sec.  1114.7(k)(1)(i) in section VII.B.13.a.i.;
    [cir] The impact the product and its marketing will have on the
likelihood of changes in tobacco use behavior of tobacco product users,
including cessation, switching (i.e., to a different tobacco product),
and poly use (i.e., using the new tobacco product in conjunction with
one or more other tobacco products). See the discussion of proposed
Sec.  1114.7(k)(1)(ii) in section VII.B.13.a.ii.;
    [cir] The impact the product and its marketing will have on the
likelihood of tobacco use initiation by tobacco products nonusers,
especially youth and young adults, including among never users and
former users, and the likelihood of poly use and switching behaviors.
See the discussion of proposed Sec.  1114.7(k)(1)(iii) in section
VII.B.13.a.iii.;
    [cir] How users and nonusers perceive the tobacco product and its
label, labeling, and advertising, how the label, labeling, and
advertising affect use intentions, and whether users are able to
understand the labeling and instructions for use and use the product in
accordance with those instructions. See the discussion of proposed
Sec.  1114.7(k)(1)(iv) in section VII.B.13.a.iv.; and
    [cir] The impact of human factors on the health risks to product
users and nonusers including, for example, how various use and misuse
scenarios may impact the health risks posed by the product. See the
discussion of proposed Sec.  1114.7(k)(1)(v)) in section VII.B.13.a.v.
    The proposed rule also would require the summary to contain a
concluding discussion demonstrating how the data and information
contained in the PMTA both constitute valid scientific evidence and
establish that permitting the marketing of the new tobacco product
would be APPH, as determined with respect to the risks and benefits to
the population as a whole, including users and nonusers of the tobacco
product. FDA recommends that this discussion include estimates of the
effect that the new tobacco product may have on the health of the
population as a whole, such as effects on tobacco use initiation
switching and cessation, and reductions in premature mortality, or
increases in life-years lived. The estimates should integrate all of
the information in the PMTA regarding the product and its potential
effects on health, including, but not limited to adverse experiences,
tobacco use behavior, and tobacco use initiation to provide an overall
assessment of the potential effect that the product's marketing has or
may have on overall tobacco-related morbidity and mortality. It is
important to also include information regarding adverse experiences
associated with use of or exposure to a product where the individual
suffering the adverse

experience did not use the product because it can help FDA determine
health risks for nonusers such as the effects of second-hand exposure
or accidental exposure (e.g., skin burns from accidental exposure to
liquid nicotine, harmful effects resulting from a child drinking an e-
liquid, respiratory difficulties from second-hand exposure to an e-
cigarette).
    Additionally, reporting information regarding all adverse
experiences that are temporally associated with the use of or exposure
to the product will help the applicant avoid self-selection bias of
what is reported to FDA and help identify harmful effects that are not
obviously attributable to the product. As an illustration, an applicant
may make an overall assessment of whether the product will have a net
benefit on population health by accounting for potential reductions in
disease risk (compared to other tobacco products) and the potential for
current tobacco users to switch to the new tobacco product, and
weighing that against the potential for nontobacco users to use the
tobacco product and the accompanying potential increases in disease
risks among those new tobacco product users. An applicant should
provide quantitative assessments in the concluding discussion wherever
possible; however, an applicant may provide qualitative assessments
where appropriate for the type of investigation(s) on which the
assessment is based (e.g., focus group or interview-type studies).
    The summary's concluding discussion must also briefly describe why
the data and scientific information on which the applicant relies in
concluding that permitting the marketing of the product would be APPH
constitute valid scientific evidence. Section 910(c)(5)(A) of the FD&C
Act requires FDA to make its determination of whether the marketing of
a new tobacco product is APPH, where appropriate, on the basis of well-
controlled investigations; however, under section 910(c)(5)(B) of the
FD&C Act, where FDA determines that there exists valid scientific
evidence other than well-controlled investigations that is sufficient
to evaluate the product, FDA may use such evidence. As discussed in
more detail in section VIII.D. regarding proposed Sec.  1114.31, FDA
considers valid scientific evidence to be evidence gathered using well-
established or standardized methodologies from which it can be
concluded by qualified experts that there is reasonable assurance of
the reliability of its findings. Thus, if an application contains
information regarding another tobacco product (e.g., published
literature, marketing information) with appropriate bridging studies
and describes the relationship to the product that is the subject of
the application, FDA will review that information to determine whether
it is valid scientific evidence sufficient to demonstrate that
permitting the marketing of a product would be APPH.
9. Product Formulation
    Section 910(b)(1)(B) of the FD&C Act requires that a PMTA contain a
full statement of the components, ingredients, additives, and
properties, and of the principle or principles of operation, of such
tobacco product. Proposed Sec.  1114.7(i) would implement FDA's
interpretation of this statutory requirement, together with its
authority under section 910(b)(1)(G) of the FD&C Act, by requiring a
PMTA to contain the following information:
    a. Components or parts, materials, ingredients, constituents, and
additives. Under the proposed rule, the application would be required
to contain a full statement (i.e., a listing) of the product components
or parts, materials, ingredients other than tobacco, tobacco
ingredients, HPHCs, and the container closure system.
    i. Components or parts. Proposed Sec.  1114.7(i)(1)(i) would
require the application to state the quantity, function, and purpose
of, and where applicable, target specifications of each component or
part in the product. This information should also include an
explanation of how each component or part is, or can be, integrated
into the product design, and the purpose and function of each component
or part. Where the tobacco product contains software components, the
rule would require:
     A description of the software or technology (e.g.,
Bluetooth);
     A description of the purpose of the software or
technology, such as monitoring where the tobacco product is located,
activated, or used;
     A description of the data collected by the software and
how this information will be used by the applicant.
    This information is especially important as it may not be readily
apparent from the component or part's identity what function and
purpose it may serve. For example, software used in or with a product
may have functions and purposed that are not immediately clear, such as
use monitoring and location tracking functions, and may be able to
function in conjunction with other electronic devices, such as a smart
phone.
    ii. Materials. Proposed Sec.  1114.7(i)(1)(ii) would require that
the application include the following information for each material in
the product because materials can affect the performance of the
product. For example, in portioned smokeless tobacco products, the
materials used in the pouch can affect the rate at which nicotine is
released and specifications such as pouch fabric air permeability can
provide information about how quickly nicotine can be delivered to the
consumer. For ENDS, the material used in the construction of an
electrical heater coil influences its resistance and the temperature
reached by the coil, which in turn may affect the type and amount of
HPHCs produced in aerosol. The rule would require:
     The material name and common name (if applicable);
     The component or part where it is located;
     The subcomponent or subpart where it is located (if
applicable);
     The function of the material;
     Quantities (including ranges or means and acceptance
limits);
     Specifications (including quality, grades, and suppliers)
used for the new tobacco product (including any specification
variations, if applicable); and
     Any other material properties that fully characterize the
new tobacco product, such as pouch material porosity or air
permeability for portioned smokeless products. While failure to include
additional material properties to fully characterize the tobacco
product would not serve as the basis for FDA refusing to accept or file
an application under proposed Sec.  1114.27(a)(1), it may slow down the
substantive review process.
    iii. Ingredients other than tobacco. Proposed Sec.
1114.7(i)(1)(iii) would require that the application contain
information on ingredients other than tobacco (information on tobacco
ingredients is addressed in proposed Sec.  1114.7 (i)(1)(iv)). The
required information would include:
     International Union of Pure and Applied Chemistry (IUPAC)
chemical name and common name (if applicable);
     Chemical Abstracts Service (CAS) number or FDA Unique
Ingredients Identifier (UNII). Both the IUPAC and CAS or UNII would be
required to ensure FDA has the relevant information associated with
each identifier and to allow FDA to efficiently differentiate between
similar ingredients;
     The function of the ingredient;

     The quantity of the ingredient, with the unit of measure
(including ranges or means, and acceptance limits);
     The specifications (including purity or grade and
supplier); and
     For complex purchased ingredients, each single chemical
substance would be required to be reported separately.
    Additionally, FDA recommends that an application contain any other
ingredient information to fully characterize the new tobacco product,
as applicable. While failure to include other ingredient information to
fully characterize the tobacco product would not serve as the basis for
FDA refusing to accept or file an application under proposed Sec.
1114.27(a)(1), it may slow down the substantive review process.
    iv. Tobacco ingredients. Proposed Sec.  1114.7(i)(1)(iv) would
require information regarding tobacco ingredients, including:
     The type(s) of tobacco, including grade(s) and variety or
varieties. This information is important to determining the public
health impact of the products because different grades and varieties
have different constituent profiles. The application would also need to
contain information on the applicant's grading system so that FDA
understands the meaning of the grade;
     The quantity, with the unit of measure (including ranges
or means, and acceptance limits), of each tobacco ingredient in the new
tobacco product;
     The specification(s) of tobacco used for the new tobacco
product (with any specification variation, if applicable); and
     A description of any genetic engineering that impacts
characteristics, such as the constituent profile.
    Additionally, FDA recommends a PMTA also contain any other
information about tobacco ingredients to fully characterize the new
tobacco product, as applicable, such as country of origin, which can
affect constituent levels (Ref. 28). While failure to include other
information about tobacco ingredients to fully characterize the tobacco
product would not serve as the basis for FDA refusing to accept or file
an application under proposed Sec.  1114.27(a)(1), it may slow down the
substantive review process.
    If the new tobacco product does not contain tobacco (e.g., rolling
paper or tipping paper), this section of the application would be
required to specifically state that the product does not contain
tobacco.
    FDA is proposing in Sec.  1114.7(i)(1) that ingredient quantities
be reported as mass per gram of tobacco for nonportioned tobacco
products and as mass per portion for portioned tobacco products. These
specific measurements provide consistent, complete information that
would allow FDA to understand the ingredient quantities. In contrast,
if ingredient quantities were reported as percentages, FDA would have
to make assumptions about the denominator used to calculate the
percentage. For example, if xylitol were reported as 10 percent of a
portioned moist snuff, FDA would not able to determine if xylitol was
10 percent of the mass of the tobacco filler or of the entire product
(containing filler, paper, etc.). For more information on uniquely
identifying components, ingredients, and additives and reporting their
quantities, please refer to FDA's guidance for industry ``Listing of
Ingredients in Tobacco Products.''
    v. Constituents. Proposed Sec.  1114.7(i)(1)(v) would require a
full statement of the constituents, including HPHCs and other
constituents, contained within, or emitted from (including its smoke or
aerosol), the product, including any reaction products from leaching or
aging. FDA considers constituents to be properties of the new tobacco
product, a full statement of which is required to be in a PMTA by
section 910(b)(1)(B) of the FD&C Act. The constituents contained
within, and delivered from, the product can be detected through
constituent testing on the product. The constituent testing should
reflect the various conditions under which consumers may use the
product (e.g., light use, typical use, and heavy use) and the types of
products that consumers are likely to use in conjunction with the
product. For example, an open (refillable) e-cigarette should be tested
with a variety of e-liquids that consumers are likely to consume using
the e-cigarette. The reports of constituent testing must be conducted
in the manner required by, and include all information that is
specified in, proposed Sec.  1114.7(i)(1)(v), including the full test
data.
    FDA published an initial list of the constituents that it has
identified as HPHCs in the Federal Register of April 3, 2012, which it
intends to update periodically by providing the public with notice and
the opportunity to submit comments. FDA is currently seeking public
comment on its proposal to add 19 constituents to the established list
of HPHCs.\10\ An application would not be required to contain testing
for all HPHCs on the initial list; rather, it would be required to
contain testing for HPHCs that are contained within and can be
delivered by the type of product and contain a description of why the
HPHCs that were tested are appropriate for the type of product. The
HPHC list can be helpful to applicants in preparing a description of
why the HPHCs for which it tested are appropriate for the product type,
including, where appropriate, why an applicant did not test for certain
HPHCs. For example, a PMTA for a smokeless tobacco product would not be
required to contain testing results for HPHCs that are a byproduct of
combustion (e.g., carbon monoxide) where the product does not contain
or deliver such constituents. However, a PMTA for a tobacco product
that an applicant claims aerosolizes a substance but does not combust
it, such as an e-cigarette or heated tobacco product, should provide
evidence, such as testing for HPHCs that result from complete or
incomplete combustion, to demonstrate that the product is not
combusted. For recommendations on constituent testing for ENDS
products, please see the ``Guidance for Industry, Premarket Tobacco
Product Applications for Electronic Nicotine Delivery Systems.''
Constituent testing data FDA is proposing that a PMTA contain for all
products includes:
---------------------------------------------------------------------------

    \10\ 84 FR 38032 (August 5, 2019).
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     The constituent names in alphabetical order;
     The common name(s);
     The CAS number;
     The mean quantity and variance with unit of measure;
     The number of samples and measurement replicates for each
sample. As stated in proposed Sec.  1114.7(i)(4)(iv), the testing would
be required to be conducted using a sufficient sample size and number
of replicates to substantiate the results of the type of testing
conducted;
     A description of method procedure, method validation
information and rationale for selecting each test method (as would be
required by Sec.  1114.7(i)(4)(v));
     The name and location of the testing laboratory or
laboratories and documentation showing that the laboratory or
laboratories is (or are) accredited by a nationally or internationally
recognized external accreditation organization (as would be required by
Sec.  1114.7(i)(4)(i));
     The length of time between dates of manufacture and
date(s) of testing (as would be required by Sec.  1114.7(i)(4)(ii));
     Storage conditions of the tobacco product before it was
tested. It is important for FDA to understand the storage conditions
before testing because they could affect the quantity of volatile
organic compounds or promote microbial growth in the tobacco product

(as would be required by Sec.  1114.7(i)(4)(iii));
     Reports of constituent testing that include test
protocols, any deviation(s) from the test protocols, quantitative
acceptance criteria, line data, and a summary of the results, for each
applicable parameter (as would be required by Sec.  1114.7(i)(4)(vi);
and
     Complete descriptions of any smoking or aerosol-generating
regimens used for analytical testing that are not standardized or
widely accepted by the scientific community, if applicable (as would be
required by Sec.  1114.7(i)(4)(vii).
    For combusted or inhaled tobacco products, constituent smoke or
aerosol yields from the new product would be required to be determined
using intense and nonintense smoking or aerosol-generating regimens,
where established. Two smoking or aerosol-generating regimens are
required, where established, in order to understand the way that
constituent yields delivered by a tobacco product can change over a
range of different smoking conditions. If constituent yields were only
reported from a single smoking or aerosol-generating regimen, FDA would
have limited and potentially misleading information about constituent
yields produced by a given tobacco product. Many studies demonstrate
that different smoking regimens result in different constituent yields
from the same product (Ref. 29-30). By requiring both an intense and a
nonintense smoking or aerosol generating regimen, where established,
FDA would have a better understanding of quantities of each constituent
that may be produced by the tobacco product when used under different
conditions. If an alternative to the established smoking regimens
(e.g., International Organization for Standardization (ISO) and Health
Canada Intense (HCI) regimens for cigarettes) is used, such as where
intense and nonintense smoking or aerosol generating regimens have not
been established, the applicant would be required to provide an
explanation of why the alternative provides comparable results to the
intense and nonintense smoking regimens.
    vi. Container closure system. Proposed Sec.  1114.7(i)(1)(vi) would
require that the application contain a description of the container
closure system for the new tobacco product, if applicable, including
information describing how the container closure system protects and
preserves the product from damage during transport, environmental
contaminants, and leaching and migration of constituents into the new
tobacco product. The description would also need to describe design
features developed to prevent the risk of accidental exposure, if any
(e.g., child resistant packaging for e-liquids). These descriptions are
important to FDA's review of the product because they will help
demonstrate that the product used by consumers is in the same condition
as that described in the application and manufactured by the applicant,
and also provide information regarding whether the container closure
system has any features that could prevent accidental exposure (e.g., a
feature that prevents e-liquid from being accidentally ingested by
children). Additionally, evidence demonstrates that the container
closure system used can change the characteristics of the product.
Packaging materials constitute the container closure system if
substances within that packaging are intended or reasonably expected to
affect product moisture, e.g., when the manufacturer changes the
container closure system of a moist snuff from plastic to fiberboard,
which can affect microbial stability and TSNA formation during storage.
Another example of this is when menthol or other ingredients are
applied to the inner foil to become incorporated into the consumed
product (Ref. 2). The container closure system may also be intended or
reasonably expected to affect the characteristics of a tobacco product
by impacting the rate of leaching into, and ultimately, the amount of
substances found in, the consumable tobacco product. In fact, it has
been demonstrated that compounds in the container closure system may
also diffuse into snuff and affect its characteristics (Ref. 3). Thus,
for example, packaging material that affects the characteristics of a
tobacco product by impacting the moisture level or shelf life of a
tobacco product is a container closure system (e.g., a plastic versus a
metal container of smokeless tobacco) because a difference in tobacco
moisture is reasonably expected to affect microbial growth in the
product, extraction efficiency, and total exposure to nicotine or the
carcinogens NNN or NNK. For additional examples of container closure
systems that may support a finding that permitting an ENDS to be
marketed would be APPH, see the ``Guidance for Industry, Premarket
Tobacco Product Applications for Electronic Nicotine Delivery
Systems.''
    vii. Statement of tobacco blending, reconstitution, manipulation.
Finally, the proposed rule would require a full statement of the
tobacco blending, reconstitution, or manipulation, where applicable.
This may include manufacturer specifications, and tobacco types,
quantities, and tobacco grading systems. This information is important
because it helps FDA understand the characteristics of the tobacco
product. Information on tobacco grades and grading systems used by an
applicant (where applicable) will help FDA understand the quality of
tobacco used, which can provide important information since the
specified tobacco grades may impact the tobacco chemistry (e.g., the
nicotine content) and, thereby, the chemical composition of the tobacco
product (Ref. 31).
    b. Other properties. Proposed section Sec.  1114.7(i)(2) describes
additional parts of FDA's interpretation of the requirement in section
910(b)(1)(B) of the FD&C Act to provide a full statement of the product
properties and, together with FDA's authority under section
910(b)(1)(G), would require the applicant to provide a full description
of the properties of the tobacco product that includes:
    i. Product dimensions and construction. The product dimensions and
the overall construction of the product using a diagram or schematic
drawing that clearly depicts the finished product and its components
with dimensions, operating parameters, and materials. Under the
proposed definition for finished tobacco product (which includes all
components and parts, sealed in final packaging), the dimensions and
schematic drawings would be required to include the final packaging.
The diagram or schematic is an annotated graphical representation that
will help FDA understand the applicant's nomenclature, how the
components and parts function together, and the overall principles of
operation of the finished tobacco product.
    ii. Design parameters and test data. All design parameters of the
product and test data, specifying nominal values or the explicit range
of values as well as the design tolerance (i.e., upper and lower range
limits), where appropriate. Design parameters can change the health
impact of the tobacco product by affecting the level of constituents
that reach the user or nonuser and are also necessary to fully
characterize a tobacco product. Tables 1 through 20 in proposed Sec.
1114.7(i)(2)(ii)(B) provide the parameters that would be required for
different categories of tobacco products. As part of the full
description of the properties of the tobacco product, the proposed rule
would also require, as included in the tables, a quantitative
description of the performance criteria, including test protocols, line
data, and a summary of the results, for each applicable design
parameter and manufacturing step. The test data is a

required part of the PMTA to demonstrate the product consistently meets
the nominal values or range of values as well as the design tolerance.
The proposed parameters and their importance to understanding their
impact on public health are described below.
    Note that in addition to the parameters listed in tables 8 to 20 of
the draft codified, FDA is also providing additional design parameters
that it recommends including in a PMTA for certain types of deemed
tobacco products in just the preamble. FDA is considering whether it
should require the submission of these additional design parameters as
part of the final rule and is requesting public comment regarding
whether FDA should include these parameters as requirements in the
final rule, whether FDA should recommend or require additional design
parameters, and, if so, the basis for including additional design
parameters.
    Table 1 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
cigarettes. These parameters are a necessary part of the application
because they are needed to fully characterize the product and changes
in these parameters may affect the cigarette's impact on the public
health, as described below:
     Cigarette mass may affect smoke constituent yields (Ref.
32).
     Cigarette length may alter tobacco biomarker levels (Ref.
33).
     Cigarette diameter may affect filter efficiency and, in
turn, smoke constituent yields (Ref. 34).
     Puff count can directly affect smoke constituent yields
(Ref. 35).
     Cigarette draw resistance may result in differences in the
difficulty of pulling air through the tobacco rod and, in turn, affect
smoke constituent yields (Ref. 36).
     Tobacco rod length may alter tobacco biomarker levels
(Ref. 33).
     Tobacco filler mass may affect smoke constituent yields
(Ref. 32).
     Tobacco rod density may modify burn properties and smoke
constituent yields (Refs. 37 and 38).
     Tobacco cut size alters the size of the tobacco pieces,
which may result in more particulate matter (Ref. 39).
     Tobacco moisture may affect puff count (Ref. 40).
     Cigarette paper length and cigarette paper width may
affect smoke constituent yields (Ref. 32).
     Cigarette paper base paper basis weight may affect puff
count and smoke constituent yields (Ref. 41).
     Cigarette paper base paper porosity may affect smoke
constituent yields (Ref. 41).
     Cigarette paper band porosity may affect smoke constituent
yields because band porosity allows for the overall assessment of the
weighted change in air flow through the cigarette paper during active
puffing (Ref. 42).
     Cigarette paper band diffusivity may affect smoke
constituent yields because it mimics air flow during smoldering (Ref.
43).
     Cigarette paper band width may affect ventilation and, in
turn, smoke constituent yields (Ref. 44).
     Cigarette paper band space may affect ignition propensity
and, in turn, puff count (Ref. 45).
     Filter efficiency may affect smoke constituent yields
(Ref. 44).
     Filter diameter, filter mass, filter tow crimping index,
denier per filament, total denier, filter density, and filter length
may affect filter efficiency and, in turn, smoke constituent yields
(Ref. 46).
     Filter pressure drop may affect smoke constituent yields
(Ref. 47).
     Plug wrap, including length, width, basis weight,
porosity, and caliper, contributes to the overall ventilation (Ref.
44).
     Tipping paper, including length, width, and basis weight,
may affect smoke constituent yields (Ref. 48).
     Filter ventilation, including location and number of holes
and rows, may affect smoke constituent yields (Ref. 34).
    Table 2 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
new portioned and non-portioned smokeless tobacco products. These
parameters are a necessary part of the applications because they are
needed to fully characterize the product and changes in these
parameters may affect the smokeless tobacco product's impact on public
health, as described below:
     Tobacco cut size may alter the particle surface area and
accessibility of saliva to get to the surfaces of the tobacco, thereby
affecting the amount and rate of constituents released from the product
(Ref. 49).
     Tobacco moisture may affect microbial growth in the
product, extraction efficiency, and total exposure to nicotine, NNN,
and NNK (Refs. 4 and 5).
     Portion mass may affect user exposure to a tobacco product
and, in turn, HPHCs contained in each portion (Ref. 50).
     Portion length may affect the constituents in each portion
(Ref. 50).
     Portion width may result in a surface area difference,
which is proportional to the amount and rate of constituents released
from the product (Ref. 51).
     Portion thickness may result in a surface area difference,
which is directly proportional to the amount and rate of constituents
released from the product (Ref. 51).
     Pouch material basis weight, pouch material air
permeability, and pouch material caliper influences the interactions
between the tobacco and oral cavity, thereby potentially affecting the
amount and rate of constituents released from the product (Ref. 52).
     Pouch material nicotine dissolution rate is a function of
tobacco cut size and pouch materials, thereby potentially affecting the
amount and rate of constituents released from the product (Ref. 53).
     Pouch material nicotine dissolution extent is a function
of the initial release and duration of the ongoing release, thereby
potentially affecting the amount and rate of constituents released from
the product (Refs. 52 and 54).
    Table 3 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
new roll-your-own (RYO) tobacco rolling paper products. These
parameters are a necessary part of the application because they are
needed to fully characterize the product and changes in these
parameters may affect the rolling paper's impact on public health, as
described below:
     RYO paper length and RYO paper width may alter the surface
area that is available for tobacco packing, thereby affecting the smoke
constituent yields (Ref. 47).
     RYO paper mass may be a result of a surface area or basis
weight difference and, in turn, may affect puff count and smoke
constituent yields (Refs. 41 and 47).
     RYO paper base paper basis weight may affect puff count
and smoke constituent yields (Ref. 41).
     RYO paper base paper porosity may affect smoke constituent
yields (Ref. 41).
     RYO paper band porosity may affect smoke constituent
yields because band porosity allows for the overall assessment of the
weighted change in air flow through the cigarette paper during active
puffing (Ref. 42).
     RYO paper band diffusivity may affect smoke constituent
yields because it mimics air flow during smoldering (Ref. 43).
     RYO paper band width may affect ventilation and, in turn,
smoke constituent yields (Ref. 44).

     RYO paper band space may affect ignition propensity and,
in turn, puff count (Ref. 45).
    Table 4 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
new RYO tobacco tubes. These parameters are a necessary part of the
application because they are needed to fully characterize the product
and changes in these parameters may affect the RYO tube's impact on
public health, as described below:
     Tube mass may affect smoke constituent yields (Ref. 32).
     Tube length may alter tobacco biomarker levels (Ref. 33).
     Tube diameter may affect filter efficiency and, in turn,
smoke constituent yields (Ref. 34).
     Tube paper length and tube paper width may affect smoke
constituent yields (Ref. 32).
     Tube paper base paper basis weight may affect puff count
and smoke constituent yields (Ref. 41).
     Tube paper base paper porosity may affect smoke
constituent yields (Ref. 41).
     Tube paper band porosity may affect smoke constituent
yields since band porosity allows for the overall assessment of the
weighted change in air flow through the cigarette paper during active
puffing (Ref. 42).
     Tube paper band diffusivity may affect smoke constituent
yields because it mimics air flow during smoldering (Ref. 43).
     Tube paper band width may affect ventilation and, in turn,
smoke constituent yields (Ref. 44).
     Tube paper band space may affect ignition propensity and,
in turn, puff count (Ref. 45).
    Table 5 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
new RYO tobacco filtered tubes. These parameters are a necessary part
of the application because they are needed to fully characterize the
product and changes in these parameters may affect the filtered tube's
impact on public health, as described below:
     Tube mass may affect smoke constituent yields (Ref. 32).
     Tube length may alter tobacco biomarker levels (Ref. 33).
     Tube diameter may affect filter efficiency and, in turn,
smoke constituent yields (Ref. 34).
     Tube paper length directly correlates to non-filter tube
length, which may affect smoke constituent yields (Ref. 32).
     Tube paper width may affect smoke constituent yields (Ref.
32).
     Tube paper base paper basis weight may affect puff count
and smoke constituent yields (Ref. 41).
     Tube paper base paper porosity may affect smoke
constituent yields (Ref. 41).
     Tube paper band porosity may affect smoke constituent
yields since band porosity allows for the overall assessment of the
weighted change in air flow through the cigarette paper during active
puffing (Ref. 42).
     Tube paper band diffusivity may affect smoke constituent
yields because it mimics air flow during smoldering (Ref. 43).
     Tube paper band width may affect ventilation and, in turn,
smoke constituent yields (Ref. 44).
     Tube paper band space may affect ignition propensity and,
in turn, puff count (Ref. 45).
     Filter efficiency may affect smoke constituent yields
(Ref. 44).
     Filter diameter, filter mass, filter tow crimping index,
and denier per filament may affect filter efficiency and, in turn,
smoke constituent yields (Ref. 46).
     Total denier, filter density, and filter length may affect
filter efficiency and, in turn, smoke constituent yields (Ref. 30).
     Filter pressure drop may affect smoke constituent yields
(Ref. 47).
     Plug wrap, including length, width, basis weight,
porosity, and caliper, contributes to the overall ventilation (Ref.
44).
     Tipping paper, including length, width, and basis weight,
may affect smoke constituent yields (Ref. 48).
     Filter ventilation, including location and number of holes
and rows, may affect smoke constituent yields (Ref. 34).
    Table 6 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
RYO tobacco. These RYO tobacco parameters are a necessary part of the
application because they are needed to fully characterize the product
and changes in these parameters may affect the RYO tobacco's impact on
public health, as described below:
     Tobacco filler mass may affect smoke constituent yields
when used with rolling paper (Ref. 32).
     Tobacco cut size alters the size of the tobacco pieces,
which may result in more particulate matter (Ref. 39).
     Tobacco moisture may affect puff count when used with
rolling paper (Ref. 40).
    Table 7 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
new RYO tobacco paper tips. These parameters are a necessary part of
the application because they are needed to fully characterize the
product and changes may affect the paper tip's impact on public health,
as described below:
     RYO paper tip length and RYO paper tip width may alter the
surface area that is available for tobacco packing, thereby affecting
the smoke constituent yields (Ref. 47).
     RYO paper tip mass may be a result of a surface area or
basis weight difference and, in turn, may affect puff count and smoke
constituent yields (Refs. 41 and 47).
     RYO paper base paper basis weight may affect puff count
and smoke constituent yields (Ref. 41).
     RYO paper base paper perforation may affect smoke
constituent yields (Ref. 41).
     RYO paper tip ventilation may affect smoke constituent
yields (Ref. 34).
    Table 8 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
filtered, sheet-wrapped cigars. These parameters are a necessary part
of the application because they are needed to fully characterize the
product and changes may affect the cigar's impact on public health, as
described below:
     Cigar length and diameter can directly affect the amount
of tobacco that is burned and, in turn, affect smoke constituent yields
(Ref. 55).
     Tobacco filler mass may affect smoke constituent yields
(Ref. 56).
     Tobacco rod density may modify burn properties and smoke
constituent yields (Refs. 37 and 38).
     Tobacco cut size alters the size of the tobacco pieces,
which may result in more particulate matter (Ref. 39).
     Tobacco moisture may affect puff count (Ref. 40).
     Cigar wrapper and binder porosity may affect smoke
constituent yields (Refs. 58 and 59).
     Filter efficiency may affect smoke constituent yields
(Ref. 44).
     Filter diameter and filter length may affect filter
efficiency and, in turn, smoke constituent yields (Ref. 46).
     Filter pressure drop may affect smoke constituent yields
(Ref. 47).
     Tipping paper length may affect smoke constituent yields
(Ref. 48).
     Ventilation may affect smoke constituent yields (Ref. 56).
    In addition to the parameters that would be required by the
proposed rule, FDA recommends a PMTA for a filtered, sheet-wrapped
cigar also contain the following additional design parameters in table
8a and is specifically requesting

public comments on whether these parameters should be required in the
final rule.

  Table 8a--Additional Design Parameters Recommended To Be Provided for
                      Filtered Sheet-Wrapped Cigars
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Cigar mass (mg).                    Cigar mass (mg).
 Cigar draw resistance (mm H2O).     Cigar draw
                                             resistance (mm H2O).
 Cigar burn rate (mm/s).             Cigar burn rate (mm/
                                             s).
 Cigar wrapper length (mm).          Puff count.
 Cigar wrapper width (mm).           Cigar wrapper
                                             length (mm).
 Cigar wrapper basis weight (g/      Cigar wrapper width
 m\2\).                                      (mm).
 Cigar binder length (mm).           Cigar wrapper basis
                                             weight (g/m\2\).
 Cigar binder width (mm).            Cigar binder length
                                             (mm).
 Cigar binder basis weight (g/       Cigar binder width
 m\2\).                                      (mm).
 Filter mass (mg).                   Cigar binder basis
                                             weight (g/m\2\).
 Filter density (g/cm\3\).           Filter mass (mg).
 Filter tow crimping index.          Filter density (g/
                                             cm\3\).
 Filter total denier (g/9000m).      Filter tow crimping
                                             index.
 Filter denier per filament (dpf).   Filter total denier
                                             (g/9000m).
 Plug wrap length (mm).              Filter denier per
                                             filament (dpf).
 Plug wrap width (mm).               Plug wrap length
                                             (mm).
 Plug wrap basis weight (g/m\2\).    Plug wrap width
                                             (mm).
 Plug wrap porosity (CU).            Plug wrap basis
                                             weight (g/m\2\).
 Tipping paper width (mm).           Plug wrap porosity
                                             (CU).
 Tipping paper basis weight (g/      Tipping paper width
 m\2\).                                      (mm).
 Tipping paper perforation (CU).     Tipping paper basis
                                             weight (g/m\2\).
 Filter ventilation position of      Tipping paper
 holes.                                      perforation (CU).
 Filter ventilation number of
 holes.
 Filter ventilation number of
 rows.
------------------------------------------------------------------------

    FDA recommends including these parameters as part of the
application because they may help fully characterize the product and
may affect its impact on public health:
     Cigar mass reflects the amount of tobacco in a cigar,
which may affect smoke constituent yields (Ref. 56).
     Cigar puff count can directly affect smoke constituent
yields (Ref. 56).
     Cigar draw resistance may result in differences in the
difficulty of pulling air through the tobacco rod and, in turn, affect
smoke constituent yields (Ref. 36).
     Burn rate may affect puff count and, in turn, affect smoke
constituent yields (Ref. 57).
     Cigar wrapper and binder basis weight may affect puff
count and smoke constituent yields (Refs. 36 and 58).
     Cigar wrapper and binder length and width may directly
influence the area through which air is permitted to enter the tobacco
column, which, in turn, may affect puff count and smoke constituent
yields (Ref. 36).
     Filter mass, filter tow crimping index, denier per
filament, total denier, and filter density may affect filter efficiency
and, in turn, smoke constituent yields (Ref. 46).
     Plug wrap, including length, width, basis weight,
porosity, and caliper, contributes to the overall ventilation (Ref.
39).
     Tipping paper, including width, and basis weight, may
affect smoke constituent yields (Ref. 48).
     Ventilation, including location and number of holes and
rows, may affect smoke constituent yields (Ref. 56).
    Table 9 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
unfiltered, sheet-wrapped cigars. These parameters are a necessary part
of the application because they are needed to fully characterize the
product and changes may affect the cigar's impact on public health, as
described below:
     Cigar mass reflects the amount of tobacco in a cigar,
which may affect smoke constituent yields (Ref. 56).
     Cigar length and diameter can directly affect the amount
of tobacco that is burned and, in turn, affect smoke constituent yields
(Ref. 55).
     Tobacco filler mass may affect smoke constituent yields
(Ref. 56).
     Cigar wrapper porosity may affect smoke constituent yields
(Refs. 58 and 59).
     Cigar tip dimensions directly influence the overall cigar
draw resistance and in turn, puff count (Ref. 60).
    In addition to the parameters that would be required by the
proposed rule, FDA recommends a PMTA for an unfiltered, sheet-wrapped
cigar also contain the following additional design parameters as
described in Table 9a and is specifically requesting public comments on
whether these parameters should be required under the final rule.

  Table 9a--Additional Design Parameters Recommended To Be Provided for
                     Unfiltered Sheet-Wrapped Cigars
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Cigar draw resistance (mm H2O).     Cigar draw
                                             resistance (mm H2O).
 Cigar burn rate (mm/s).             Cigar burn rate (mm/
                                             s).
 Tobacco rod density (g/cm\3\).      Puff count.
 Tobacco cut size (mm).              Tobacco rod density
                                             (g/cm\3\).
 Tobacco moisture (%).               Tobacco cut size
                                             (mm).

 Cigar wrapper length (mm).          Tobacco moisture
                                             (%).
 Cigar wrapper width (mm).           Cigar wrapper
                                             length (mm).
 Cigar wrapper basis weight (g/      Cigar wrapper width
 m\2\).                                      (mm).
 Cigar binder length (mm).           Cigar wrapper basis
                                             weight (g/m\2\).
 Cigar binder width (mm).            Cigar binder length
                                             (mm).
 Cigar binder basis weight (g/       Cigar binder width
 m\2\).                                      (mm).
 Cigar binder porosity (CU).         Cigar binder basis
                                             weight (g/m\2\).
 Cigar tip mass (mg) (if             Cigar binder
 applicable).                                porosity (CU).
                                             Cigar tip mass (mg)
                                             (if applicable).
------------------------------------------------------------------------

    FDA recommends including these parameters as part of the
application because they may help fully characterize the product and
changes may affect its impact on public health:
     Cigar puff count can directly affect smoke constituent
yields (Ref. 56).
     Cigar draw resistance may result in differences in the
difficulty of pulling air through the tobacco rod and, in turn, affect
smoke constituent yields (Ref. 36).
     Burn rate may affect puff count and, in turn, affect smoke
constituent yields (Ref. 57).
     Tobacco rod density may modify burn properties and smoke
constituent yields (Refs. 37 and 38).
     Tobacco cut size alters the size of the tobacco pieces,
which may result in more particulate matter (Ref. 39).
     Tobacco moisture may affect puff count (Ref. 40).
     Cigar wrapper and binder basis weight may affect puff
count and smoke constituent yields (Refs. 36 and 58).
     Cigar wrapper and binder length and width may directly
influence the area through which air is permitted to enter the tobacco
column, which, in turn, may affect puff count and smoke constituent
yields (Ref. 36).
     Cigar binder porosity may affect smoke constituent yields
(Refs. 58 and 59).
    Table 10 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
leaf-wrapped cigars. These parameters are a necessary part of the
application because they are needed to fully characterize the product
and changes may affect the cigar's impact on public health, as
described below:
     Cigar mass reflects the amount of tobacco in a cigar,
which may affect smoke constituent yields (Ref. 56).
     Cigar length and diameter can directly affect the amount
of tobacco that is burned and, in turn, affect smoke constituent yields
(Ref. 55).
     Tobacco moisture may affect puff count (Ref. 40).
    In addition to the parameters that would be required by the
proposed rule, FDA recommends a PMTA for a leaf-wrapped cigar also
contain the following additional design parameters as described in
Table 10a. FDA is gaining experience reviewing the design parameters of
deemed tobacco products and is specifically requesting public comments
on whether these parameters should be required under the final rule.

 Table 10a--Additional Design Parameters Recommended To Be Provided for
                           Leaf-Wrapped Cigars
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Cigar draw resistance (mm H2O).     Cigar draw
                                             resistance (mm H2O).
 Cigar burn rate (mm/s).             Cigar burn rate (mm/
                                             s).
 Tobacco filler mass (mg).           Puff count.
 Tobacco rod density (g/cm\3\).      Tobacco filler mass
                                             (mg).
 Tobacco cut size (mm).              Tobacco rod density
                                             (g/cm\3\).
 Cigar wrapper length (mm).          Tobacco cut size
                                             (mm).
 Cigar wrapper minimum width (mm).   Cigar wrapper
                                             length (mm).
 Cigar wrapper maximum width (mm).   Cigar wrapper
                                             minimum width (mm).
 Cigar wrapper basis weight (g/      Cigar wrapper
 m\2\).                                      maximum width (mm).
 Cigar wrapper porosity (CU).        Cigar wrapper basis
                                             weight (g/m\2\).
 Cigar binder length (mm).           Cigar wrapper
                                             porosity (CU).
 Cigar binder minimum width (mm).    Cigar binder length
                                             (mm).
 Cigar binder maximum width (mm).    Cigar binder
                                             minimum width (mm).
 Cigar binder basis weight (g/       Cigar binder
 m\2\).                                      maximum width (mm).
 Cigar binder porosity (CU).         Cigar binder basis
                                             weight (g/m\2\).
                                             Cigar binder
                                             porosity (CU).
------------------------------------------------------------------------

    FDA recommends including these parameters as part of the
application because changes they may help fully characterize the
product and may affect its impact on public health as follows:
     Cigar draw resistance may result in differences in the
difficulty of pulling air through the tobacco rod and, in turn, affect
smoke constituent yields (Ref. 36).
     Burn rate may affect puff count and, in turn, affect smoke
constituent yields (Ref. 57).
     Filler mass (mg) may affect smoke constituent yields (Ref.
56).
     Tobacco rod density may modify burn properties and smoke
constituent yields (Refs. 37 and 38).
     Tobacco cut size alters the size of the tobacco pieces,
which may result in more particulate matter (Ref. 39).

     Cigar wrapper and binder basis weight may affect puff
count and smoke constituent yields (Refs. 36 and 58).
     Cigar wrapper and binder porosity may affect smoke
constituent yields (Refs. 58 and 59).
     Cigar wrapper and binder length, minimum width, and
maximum width may directly influence the area through which air is
permitted to enter the tobacco column, which, in turn, may affect puff
count and smoke constituent yields (Ref. 36).
    Table 11 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
cigar tobacco. These parameters are a necessary part of the application
because they are needed to fully characterize the product and changes
may affect its impact on public health, as described below:
     Tobacco cut size alters the size of the tobacco pieces,
which may result in more particulate matter (Ref. 39).
     Tobacco moisture may affect puff count (Ref. 40).
    In addition to the parameters that would be required by the
proposed rule, FDA would recommend applicants include filler mass (mg)
as additional design parameter in a PMTA for cigar tobacco because it
may affect smoke constituent yields (Ref. 56). FDA is gaining
experience reviewing the design parameters of cigar tobacco and other
deemed tobacco products and is specifically requesting public comments
on whether this parameter should be required in the final rule.
    Table 12 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for a
cigar wrapper. These parameters are a necessary part of the application
because they are needed to fully characterize the product and changes
may affect its impact on public health, as described below:
     Cigar wrapper length, and its minimum width and maximum
width may directly influence the area through which air is permitted to
enter the tobacco column, which, in turn, may affect puff count and
smoke constituent yields (Ref. 36).
    In addition to the parameters that would be required by the
proposed rule, FDA also recommends a PMTA for a cigar wrapper also
contain the following additional design parameters as described in
Table 12a and is specifically requesting public comments on whether
these parameters should be required under the final rule.

 Table 12a--Additional Design Parameters Recommended To Be Provided for
                             Cigar Wrappers
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Cigar wrapper basis weight (g/      Cigar wrapper basis
 m\2\).                                      weight (g/m\2\).
 Cigar wrapper porosity (CU).        Cigar wrapper
                                             porosity (CU).
------------------------------------------------------------------------

    FDA recommends including these parameters as part of the
application because changes they may help fully characterize the
product and may affect its impact on public health as follows:
     Cigar wrapper basis weight may affect puff count and smoke
constituent yields (Refs. 36 and 58).
     Cigar wrapper porosity may affect smoke constituent yields
(Refs. 58 and 59).
    Table 13 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for a
waterpipe. The number of hoses and the waterpipe bowl volume are a
necessary part of the application because they are needed to fully
characterize the product.
    In addition to the parameters that would be required by the
proposed rule, FDA recommends a PMTA for a waterpipe also contain the
following additional design parameters as described in Table 13a and is
specifically requesting public comments on whether these parameters
should be required under the final rule.

 Table 13a--Additional Design Parameters Recommended To Be Provided for
                               Waterpipes
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Hose length (mm).                   Hose length (mm).
 Hose material (mm).                 Hose internal
                                             diameter (mm).
 Hose internal diameter (mm).        Stem length (mm).
 Stem length (mm).                   Stem internal
                                             diameter (mm).
 Stem internal diameter (mm).        Hose Permeability
                                             (CU).
 Hose Permeability (CU).             Bowl diameter (mm).
 Bowl diameter (mm).                 Pressure drop (mm
                                             H2O).
 Bowl shape.                         Water filter
                                             efficiency (%).
 Pressure drop (mm H2O).             Foil length (mm).
 Water filter efficiency (%).        Foil width (mm).
 Foil length (mm).                   Ventilation (%).
 Foil width (mm).
 Ventilation hole distribution.
 Number of ventilation holes.
 Ventilation (%).
 Heating source type.
------------------------------------------------------------------------

    The parameters included in table 13 apply to waterpipes generally.
For products that contain a heating source or waterpipe tobacco,
applications should specify information regarding the heating source
and waterpipe tobacco as described in tables 14 and 15. FDA recommends
including these parameters as part of the application

because they can help fully characterize the product and changes may
affect its impact on public health:
     Hose dimensions (length and diameter) are directly
proportional to air infiltration and affects toxicant yields (Ref. 61).
     Hose material may affect hose permeability, which may
affect smoke constituent yields (Ref. 61).
     Water filtering efficiency is directly proportional to
mainstream smoke and can increase exposure to HPHCs (Ref. 62).
     Pressure drop may result in differences in the difficulty
of pulling air through the waterpipe and, in turn, affect smoke
constituent yields (Ref. 36).
     Waterpipe components or parts, including stem, bowl,
windscreen (foil), and purge valve, impact puffing behavior and
toxicant exposure; therefore, the foil dimensions and ventilation may
affect smoke constituent yields (Ref. 63).
     The diameter of the flow path is directly related to the
resistance to draw, which may affect smoke constituent yields (Ref.
63).
     The aluminum foil perforation pattern (size, number and
distribution of holes) impacts the path of hot gases through the
tobacco mixture, which may affect smoke constituent yields (Ref. 63).
    Table 14 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
waterpipe tobacco. These parameters are necessary to fully characterize
the product and changes may affect its impact on public health as
follows:
     Tobacco cut size alters the size of the tobacco pieces,
which may result in more particulate matter. Finer tobacco cut size may
result in a decrease in filling power and in turn, a larger amount of
tobacco in the bowl (Refs. 39 and 40).
     Tobacco moisture may affect puff count. Moisture
contributes to packing density, thus decreasing void volume (Ref. 40).
    In addition to the parameters that would be required by the
proposed rule, FDA is recommending PMTAs for a waterpipe tobacco also
include the filler mass (mg) because it may affect smoke constituent
yields (Ref. 56) and is specifically requesting public comments on
whether this parameter should be required in the final rule.
    Table 15 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for a
waterpipe heating source. These parameters are necessary to fully
characterize the product and changes may affect its impact on public
health because when combusted, heating sources such as charcoal or wood
cinders expose the user to high yields of toxicants such as carbon
monoxide and polycyclic aromatic hydrocarbons. Therefore, the heating
source temperature may affect smoke constituent yields (Ref. 64).
    In addition to the parameters that would be required by the
proposed rule, FDA recommends a PMTA for a waterpipe heating source
also include the additional design parameters as described in Table 15a
and is specifically requesting public comments on whether these
parameters should be required under the final rule.

 Table 15a--Additional Design Parameters Recommended To Be Provided for
                        Waterpipe Heating Sources
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Charcoal burn rate (mm/s) (if       Charcoal
 applicable).                                temperature ([deg]C) (if
                                             applicable).
 Charcoal mass (mg) (if              Charcoal burn rate
 applicable).                                (mm/s) (if applicable).
 Charcoal density (g/cm\3\) (if      Charcoal mass (mg)
 applicable).                                (if applicable).
 Electrical heater coil resistance   Charcoal density (g/
 (ohms) (if applicable).                     cm\3\) (if applicable).
 Number of coils (if applicable).    Electrical heater
                                             coil resistance (ohms) (if
                                             applicable).
 Coil configuration (if              Coil diameter
 applicable).                                (gauge) (if applicable).
 Coil diameter (gauge) (if           Coil failure
 applicable).                                testing (if applicable).
 Coil failure testing (if            Battery mAh rating
 applicable).                                (mAh) (if applicable).
 Battery mAh rating (mAh) (if        Battery voltage
 applicable).                                operating range (volts) (if
                                             applicable).
 Battery voltage operating range     Battery current
 (volts) (if applicable).                    operating range (amps) (if
                                             applicable).
 Battery current operating range     Power delivery unit
 (amps) (if applicable).                     (PDU) voltage operating
                                             range (volts) (if
                                             applicable).
 Power delivery unit (PDU) voltage   PDU current
 operating range (volts) (if applicable).    operating range (amps) (if
                                             applicable).
 PDU current operating range         PDU wattage
 (amps) (if applicable).                     operating range (watts) (if
                                             applicable).
 PDU wattage operating range         PDU temperature cut-
 (watts) (if applicable).                    off ([deg]C) (if
                                             applicable).
                                             PDU wattage
                                             deviation (watts).
                                             PDU temperature
                                             control deviation ([deg]C).
------------------------------------------------------------------------

    FDA recommends including these parameters (as applicable to the
heating source) as part of the application because they may help fully
characterize the product and changes may affect its impact on public
health:
     When combusted, heating sources such as charcoal or wood
cinders expose the user to high yields of toxicants such as carbon
monoxide and polycyclic aromatic hydrocarbons. Therefore, the heating
source mass, density, temperature, and burn rate may affect smoke
constituent yields (Ref. 64).
    Table 16 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
waterpipe foil. The waterpipe foil length and width are necessary to
fully characterize the product and changes may affect its impact on
public health because waterpipe components or parts windscreen (foil)
impact smoke's puffing behavior and toxicant exposure. Therefore, the
foil dimensions may affect smoke constituent yields. (Ref. 63).
    In addition to the parameters that would be required by the
proposed rule, FDA recommends a PMTA for waterpipe foil also include
the following additional design parameters as described in Table 16a
and is specifically requesting public comments on whether these
parameters should be required under the final rule.

 Table 16a--Additional Design Parameters Recommended To Be Provided for
                             Waterpipe Foil
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Foil length (mm).                   Foil length (mm).
 Foil width (mm).                    Foil width (mm).
 Ventilation hole distribution.      Ventilation (%).
 Number of ventilation holes.
 Ventilation (%).
------------------------------------------------------------------------

    FDA recommends including these parameters as part of the
application because they may help fully characterize the product and
changes may affect its impact on public health:
     Waterpipe components or parts, including the windscreen
(foil) impact smoke's puffing behavior and toxicant exposure.
Therefore, the foil dimensions and ventilation may affect smoke
constituent yields (Ref. 63).
     The aluminum foil perforation pattern (size, number and
distribution of holes) impacts the path of hot gases through the
tobacco mixture, which may affect smoke constituent yields (Ref. 63).
    Table 17 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for a
pipe. The bore diameter, bit length and diameter, and stem length and
diameter are design parameters are necessary to fully characterize the
product.
    In addition to the parameters that would be required by the
proposed rule, FDA recommends a PMTA for a pipe also include the
following additional design parameters as described in Table 17a. FDA
is issuing this list of pipe parameters, which are based upon similar
parameters in other categories of tobacco products, for consideration
and public comment. We are particularly interested in scientific
investigations that support keeping or removing these parameters, or
adding different parameters to the table.

 Table 17a--Additional Design Parameters Recommended To Be Provided for
                                  Pipes
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Moisture drain volume (ml).         Moisture drain
                                             volume (ml).
 Moisture drain location.            Bowl chamber cover
                                             outer diameter (mm).
 Bowl chamber cover outer diameter   Bowl chamber cover
 (mm).                                       inner diameter (mm).
 Bowl chamber cover inner diameter   Draught hole
 (mm).                                       diameter (mm).
 Draught hole diameter (mm).         Bowl chamber
                                             diameter (mm).
 Bottom screen.                      Bow chamber volume
                                             (cm\3\).
 Draught hole shape.                 Pipe pressure drop
                                             (mm H2O).
 Draught hole location.              Two-phase smoke
                                             flow (cc/min).
 Bowl chamber diameter (mm).         Airway volume
                                             (cm\3\).
 Bowl chamber hole shape.            Filter length (mm).
 Bow chamber volume (cm\3\).         Filter pressure
                                             drop (mm H2O).
 Pipe pressure drop (mm H2O).        Filter efficiency
                                             (%).
 Two-phase smoke flow (cc/min).      Pipe ventilation
                                             (%).
 Airway volume (cm\3\).
 Filter length (mm).
 Filter pressure drop (mm H2O).
 Filter efficiency (%).
 Pipe ventilation (%).
------------------------------------------------------------------------

    Table 18 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
pipe tobacco. Tobacco cut size and moisture are design parameters that
are necessary to fully characterize the product.
    In addition to the parameters that would be required by the
proposed rule, FDA recommends a PMTA for pipe tobacco also include
filler mass (mg). FDA recommends the inclusion of this pipe tobacco
parameter based upon similar parameters in other categories of tobacco
products for consideration and public comment. We are particularly
interested in scientific investigations that support keeping or
removing this parameter, or adding different parameters.
    Table 19 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
an ENDS. These parameters are a necessary part of the application
because they are needed to fully characterize the product and changes
may affect its impact on public health, as described below.
     The air flow rate of the ENDS can affect the coil
temperature, e-liquid consumption, and aerosol characteristics such as
particle number concentration, count median diameter, and
PM2.5, which impact aerosol exposure (Ref. 65).
     Coil resistance may affect overall heating element
resistance, thereby influencing heating element temperature. The
heating element temperature may affect toxicant emissions and nicotine
delivery (Refs. 66-70).
     Coil resistance and battery output voltage determine PDU
wattage. PDU wattage determines the amount of heat produced by the
atomizer. PDU wattage or wattage operating range may affect the heating
element temperature, thereby affecting toxicant emissions (Refs. 68 and
70).
     An increase in battery capacity (mAh rating) can increase
the number of puffs the e-cigarette can deliver per vaping session.
Longer vaping sessions

may lead to greater exposure to toxicant emissions (Ref. 69).
     The temperature of the coil can affect the chemical and
physical characteristics of the aerosol delivered to the user. An
increase in coil temperature can increase HPHC levels in the aerosol,
therefore, maximum coil temperature and temperature control deviation
from this maximum coil temperature can affect toxicant emissions and
nicotine delivery (Refs. 67-70).
    In addition to the parameters that would be required by the
proposed rule, FDA recommends a PMTA for an ENDS also include the
following additional design parameters as described in Table 19a and is
specifically requesting public comments on whether these parameters
should be required under the final rule.

 Table 19a--Additional Design Parameters Recommended To Be Provided for
                                  ENDS
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper     acceptance criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 Draw resistance (mm H2O).           Draw resistance (mm
                                             H2O).
 Puff count (for full tank/          Puff count (for
 cartridge) (dimensionless).                 full tank/cartridge)
                                             (dimensionless).
 Atomizer tank/cartridge volume      Atomizer tank/
 (mL).                                       cartridge volume (mL).
 Number of coils (dimensionless).    Coil diameter
                                             (gauge).
 Coil diameter (gauge).              Coil failure
                                             testing (cycles to
                                             failure).
 Coil failure testing (cycles to     Mass of wicking
 failure).                                   material (mg).
 Mass of wicking material (mg).      Wicking rate (mm/
                                             min).
 Wicking rate (mm/min).              Battery voltage
                                             operating range (V).
 Battery voltage operating range     Battery current
 (V).                                        operating range (mA).
 Battery current operating range     PDU voltage
 (mA).                                       operating range (V).
 Power Delivery Unit (PDU) voltage   PDU current
 operating range (V).                        operating range (mA).
 PDU current operating range (mA).   PDU wattage
                                             deviation (W).
------------------------------------------------------------------------

    FDA recommends including these parameters (as applicable to the
ENDS product) as part of the application because they may help fully
characterize the product and changes may affect its impact on public
health:
     Coil and solder, as well as coil coatings, can transfer to
the e-liquid and lead to increased toxicant emissions (Refs. 71 and
72).
     Number of coils present can affect overall atomizer
resistance and distribution of heat dissipation (Ref. 73).
     The position of the coil can increase the possibility of
dry puff conditions and subsequent increased toxicant emissions (Ref.
68).
     E-liquid absorbency of the wick and wicking rate can lead
to dry puff conditions and increased toxicant emissions (Ref. 73 and
74).
     Wicking materials can transfer to the e-liquid and lead to
increased toxicant emissions (Ref. 72).
     Atomizer and cartridge components of e-cigarettes may be
heated repeatedly and aerosolized and can contribute to increased
toxicant emissions (Ref. 66).
     Puff count can differ depending on other puff topography
(e.g., puff duration and puff flow rate), e-cigarette and atomizer
design, and e-liquid parameters. Puff count can also affect total puff
volume, which in turn can affect total toxicant emissions (Ref. 74).
     E-liquid capacity of the atomizer tank/cartridge can
affect total puff volume, which in turn can affect total toxicant
emissions (Refs. 74 and 75).
     Battery/PDU voltage or voltage operating range may affect
the heating element temperature, thereby affecting toxicant emissions
and nicotine delivery (Refs. 67-70).
     Battery wattage or wattage operating range may affect the
heating element temperature, thereby affecting toxicant emissions
(Refs. 68 and 70).
     Coil resistance and battery output voltage determine PDU
wattage. PDU wattage determines the amount of heat produced by the
atomizer. PDU wattage or wattage operating range may affect the heating
element temperature, thereby affecting toxicant emissions (Refs. 68 and
70).
     Atomizer coil temperature (heating element temperature)
may affect toxicant emissions and nicotine delivery (Refs. 67-70).
     PDU wattage deviation may influence heating element
temperature, thereby affecting toxicant emissions (Refs. 68 and 70).
     The temperature of the coil can affect the chemical and
physical characteristics of the aerosol delivered to the user. An
increase in coil temperature can increase HPHC levels in the aerosol,
therefore, maximum coil temperature and temperature control deviation
from this maximum coil temperature can affect toxicant emissions and
nicotine delivery (Refs. 67-70).
     Coil resistance, number of coils, coil gauge, and coil
configuration may affect overall heating element resistance, thereby
influencing heating element temperature. The heating element
temperature may affect toxicant emissions and nicotine delivery (Refs.
66-70).
     Battery type, battery current operating range, battery
failure safety features, battery conformance to standards, and PDU
current operating range are necessary for evaluating battery and PDU
safety. Risks of e-cigarette battery explosion, leakage, fire, or
overheating are a safety concern (Refs. 66 and 76).
     Battery power impacts the delivery of nicotine and the
total emissions of volatile aldehydes (Refs. 77 and 78).
     Battery and PDU voltage impacts the amount of e-liquid
consumed, the vapor temperature, and the total emissions of volatile
aldehydes (Ref. 78).
     The type and amount of wicking material can affect the e-
liquid absorbency of the wick and wicking rate, possibly leading to dry
puff conditions and increased toxicant emissions (Refs. 73 and 74).
     The draw resistance of the ENDS impacts the ease of
drawing air into the ENDS to produce aerosol, which can affect nicotine
and other toxicant delivery to the user (Ref. 79).
    Table 20 in proposed Sec.  1114.7(i)(2)(ii)(B) describes the design
parameters and information on performance criteria to be provided for
an e-liquid. These parameters are a necessary part of the application
because they are needed to fully characterize the product and changes
may affect its impact on public health, as described below:
     The e-liquid volume can affect the delivery of nicotine
and other toxicants to the user (Ref. 74 and 75).

    In addition to the parameters that would be required by the
proposed rule, FDA recommends a PMTA for an e-liquid also contain the
following additional design parameters as described in Table 20a and is
specifically requesting public comments on whether these parameters
should be required under the final rule.

Table 20a--Additional Design Parameters Recommended To Be Provided for E-
                                 liquids
------------------------------------------------------------------------
                                             Provide test data (include
                                            test protocols, quantitative
  Provide target specification with upper    acceptance  criteria, data
        and lower range limits for:          sets, and a summary of the
                                                    results) for:
------------------------------------------------------------------------
 E-liquid boiling point ([deg]C).    E-liquid boiling
                                             point ([deg]C).
 E-liquid viscosity (at 20 [deg]C)   E-liquid viscosity
                                             (at 20 [deg]C).
 E-liquid volume (ml).               E-liquid volume
                                             (ml).
 Particle number concentration (#/   Particle number
 cm\3\).                                     concentration (#/cm\3\).
 Count median diameter (nm).         Count median
                                             diameter (nm).
 PM2.5 ([mu]g/m\3\).                 PM2.5 ([mu]g/m\3\).
------------------------------------------------------------------------

    These parameters are a necessary part of the application because
they may help fully characterize the product and changes may affect the
its impact on public health:
     E-liquid solvent composition can cause variations in e-
liquid boiling point. E-liquid composition, and subsequently e-liquid
boiling point, can affect aerosol particle size distribution and amount
of aerosol produced (Ref. 80).
     Aerosol parameters such as particle number concentration,
count median diameter, and PM2.5 are used to characterize
the amount and size of particles to which the user is exposed.
Epidemiological and clinical studies have shown that exposure to large
amounts of small particles can impair lung function and is correlated
with cardiovascular disease (Refs. 81 and 82).
     E-liquid viscosity and boiling point impact the proportion
of nicotine that is aerosolized (Ref. 83). E-liquid viscosity can also
affect the e-liquid absorbency through the wick and wicking rate,
possibly leading to dry puff conditions and increased toxicant
emissions. Also, the e-liquid viscosity can affect the electronic
cigarette nicotine and other toxicant delivery to the user (Refs. 73
and 74).
     The e-liquid volume can affect the delivery of nicotine
and other toxicants to the user (Refs. 74 and 75).
    iv. Function. The proposed rule would require the application to
contain a description of how the product is intended to function. For
example, this could include a description of how the energy or heating
source is used in or with the product, and how the delivery of the
product's output (e.g., smoke, aerosol, nicotine) is controlled. This
information can be critical to FDA's review of a tobacco product,
including whether the product functions as intended and whether the
application contains data and information that is relevant to the way
in which it is intended to function. For example, if an applicant
states that a product heats or aerosolizes, but does not combust
tobacco or an e-liquid, it would assist FDA in determining whether the
information in the PMTA shows the product functions as intended and
whether the application contains appropriate information regarding this
function (e.g., data regarding relevant HPHCs).
    v. pH of product and nicotine formulation. The proposed rule would
require the PMTA to specify the pH of the product. The pH of the
product is important for FDA to review as part of a PMTA because it can
affect the amount of unprotonated nicotine delivered to the user (Refs.
84 and 85).
    The proposed rule would also require the PMTA to specify the
formulation of the nicotine in the product. The nicotine formulation
would be required to state the type(s) and quantity of nicotine in the
product. Type(s) of nicotine include, but are not limited to,
unprotonated nicotine and nicotine salts (e.g., nicotine lactate,
nicotine benzoate, nicotine pyruvate). The quantity of unprotonated
nicotine is important for FDA to review because the amount and speed of
nicotine delivered by a tobacco product is related to the proportion of
nicotine in a tobacco product that is unprotonated (Refs. 86 and 87).
The types and quantities of nicotine salts in the product are important
for FDA to review because nicotine salt complexes can substantially
increase nicotine delivery relative to free-base nicotine in ENDS
products (Refs. 88-90).
    vi. Fermentation process. For those products that contain fermented
tobacco, the proposed rule would require an application to contain
information on the fermentation process. The proposed rule would
require this information because the fermentation process can result in
different degrees of change in the chemical constituents of the tobacco
(Ref. 91 and 92) and also affect the type and number of microorganisms
in the final product, (Ref. 93) which could potentially affect the
levels of TSNAs and stability of the products during storage. In
addition, the type and amount of the fermentation inoculum can change
the product as a result of directed fermentation (Ref. 94). Therefore,
the application must contain the following information regarding the
fermentation process:
     Composition of the inoculum (starter culture) with genus
and species name(s) and concentration(s) (if applicable).
     Any step(s) taken to reduce microbes present during
product processing (e.g., cleaning of product contact surfaces);
     Specifications and test data for pH, temperature, moisture
content, and water activity;
     Frequency of aeration or turning (if applicable);
     Duration of fermentation;
     Added ingredients; and
     Method used to stabilize or stop fermentation (if
applicable), including parameters of the method (e.g., length of
treatment, temperature) and method validation data to demonstrate that
fermentation is adequately suppressed to preclude further in-package
fermentation that could lead to increases in TSNAs and microbial
content in the final product. Having a process in place to suppress
microbial activity to preclude further in-package fermentation is
important because failing to do so could result in a product that may
have different constituent levels than are specified in the
application; and
     Storage conditions of the fermented tobacco prior to
packaging and duration of storage (if applicable).
    vii. Storage and stability information. The proposed rule would
also require a PMTA to contain product storage and stability
information that establishes the microbial and chemical stability of
the product throughout the stated shelf life. Product storage and
stability information is important for FDA's review of a tobacco
product because

bacterial communities and constituents in tobacco products can change
over time. Information obtained through stability testing could be used
to ensure that the tobacco product is chemically and microbiologically
stable during the expected product storage period and does not result
in changes that could affect the product's potential health risks. If
no shelf life is indicated, an applicant should provide details of
stability over a specified amount of time and justify why that time
period is appropriate. For example, if an applicant believes that 2
years after the date of manufacture is an appropriate time because that
is the typical period of time in which their product is sold to
consumers, an applicant should describe such.
    The proposed rule would require this stability testing information
because product stability is affected by factors such as the
fermentation and stabilization processes (if applicable), addition of
chemical additives to control microbial activity (e.g., preservatives,
metabolic inhibitors, humectants), and water activity (aw)
of the product (Refs. 91 and 95-98). Additionally, factors such as
nitrate/nitrite concentrations, moisture content, microbial content,
storage temperature, and pH are reported to influence the microbial
stability and TSNA formation during storage of tobacco products (Refs.
99-104).
    An application would be required to contain the following storage
and stability information:
     A description of how the shelf life is indicated on the
tobacco product, if applicable. The proposed rule would not require a
tobacco product to indicate the product's shelf life; however, if it is
indicated on the product, the PMTA must describe how it is indicated.
For example, if the tobacco product labeling has a `use by,' `best by,'
or expiration date, a PMTA would have to describe how the date is
determined (e.g., a certain number of days after packaging).
     Testing on the tobacco product in the same container
closure system that will be used if granted a marketing order performed
at the beginning (zero time), middle, and end of the expected storage
time for the chemical and microbial endpoints for the following items:
    [cir] Microbial content data, including total aerobic microbial
count and total yeast and mold count, along with identification of
detected microbiological organisms by genus and species names (if
applicable);
    [cir] pH;
    [cir] moisture content;
    [cir] water activity;
    [cir] TSNAs. The data specifying TSNAs would be required to be
reported as separate amounts for a total TSNAs, NNN, and NNK.
    [cir] nitrate and nitrite levels;
    [cir] preservatives and microbial metabolic inhibitors (if any);
and
    [cir] method of heat treatment or pasteurization used to reduce
microbial loads.
    Accelerated studies, combined with basic stability information on
the components or parts and container closure system (separately), or
the tobacco product (as a whole) may be used to support tentative
expiration dates provided full shelf life studies are not available and
are being conducted. Where data from accelerated studies are used to
project a tentative expiration date that is beyond a date supported by
actual shelf life studies, stability studies must be conducted,
including tobacco product testing at appropriate intervals, until the
tentative expiration date is verified or the appropriate expiration
date is determined.
    As would be required by proposed Sec.  1114.7(i)(4), the reported
stability testing would need to be performed on test samples that
reflect the final tobacco product composition and design (including the
container closure system), and be conducted using a sufficient sample
size and number of replicates to substantiate the results of the type
of testing conducted. Proposed Sec.  1114.7(i)(4) would also require
the test data to contain:
     The name and location of the testing laboratory or
laboratories and documentation showing that the laboratory or
laboratories is (or are) accredited by a nationally or internationally
recognized external accreditation organization;
     The length of time between dates of manufacture and
date(s) of testing;
     The storage conditions of the tobacco product before it
was tested;
     The number of samples and measurement replicates for each
sample; and
     A description of method procedure, method validation
information and rationale for selecting each test method, including
relevant voluntary testing standard; and
     Reports of product formulation testing that include test
protocols, quantitative acceptance criteria, line data, and a summary
of the results, for each applicable parameter.
    viii. Product and packaging design risks and misuse hazards. This
section of an applicant's PMTA is required to contain a review and
assessment of reasonably foreseeable risks associated with the design
of the tobacco product and its packaging that may occur during normal
use of the tobacco product or during any foreseeable misuse of the
product, including user error, which may cause illness, injury, or
death not normally associated with the use of the tobacco product. The
review and assessment would be required to identify the measures taken
to reduce or eliminate each risk associated with the design of the
tobacco product and packaging. Examples of these design risks include,
but are not limited to: Defects in the air permeability of fire
standards compliant banding on cigarette paper that is intended to
allow cigarettes to self-extinguish when left unattended, software
errors or flaws (i.e., bugs) that occasionally result in the product
performing differently than designed; failure of a safety switch to
shutoff a product if it exceeds a certain temperature; and the failure
of a battery design feature to prevent battery from overcharging. The
PMTA would have to contain a review and assessment of each defect,
describing the potential to cause illness, injury, or death and the
measures taken to reduce or eliminate the defects and their potential
impact. FDA is requiring this information under section 910(b)(1)(G) of
the FD&C Act because the potential for the product design or
foreseeable misuse to cause illness, injury, or death provides
information that informs FDA's determination of whether permitting the
marketing of the product would be APPH.
    FDA is requesting public comment regarding the scope of design
risks and misuse hazards that would be required to be included in this
section. Specifically, FDA is requesting input regarding whether the
design risks or misuse hazards for which an application would be
required to contain a review and assessment should be (1) those not
normally associated with the tobacco product, (2) those not normally
associated with the category of tobacco products; or (3) those not
normally associated with all tobacco products generally.
10. Principles of Operation
    Proposed Sec.  1114.7(i)(3) describes FDA's interpretation of the
full statement of the principle or principles of operation required by
section 910(b)(1)(B) of the FD&C Act and would require the PMTA to
contain full narrative descriptions of:
     The way in which a typical consumer will use the new
tobacco product. This includes, for example:
     A description of how a consumer operates the product;

     Where applicable, whether and how a consumer can change
the product design and add or subtract ingredients, such as:
    [cir] E-cigarettes that allow users to change performance features,
such as the temperature, voltage, or wattage;
    [cir] E-cigarettes that allow users to add or subtract e-liquid
ingredients, such as liquid nicotine and flavoring, including instances
where such manipulation is not intended by the manufacturer (e.g., ways
to misuse the product);
    [cir] E-cigarettes that allow users to add, subtract, or substitute
components or parts other than identical replacement parts; and
    [cir] Waterpipes that allow users to add, subtract, or substitute
components or parts other than identical replacement parts, such as
stems and hoses;
     The length of time it takes for a user to consume a single
unit of the product. This may be characterized in multiple ways
depending on the product type, for example, a single unit may include,
but not be limited to one cigarette, one tobacco pouch, or a specified
volume of e-liquid used. FDA requests public comment on appropriate
metrics for determining what should constitute a single unit for
various product types and also whether FDA should require the average
time for all users to consume a single unit, the median time to consume
a single until, or the range of time it takes users to consume a single
unit of the product; and
     Whether the product incorporates a heating source and, if
it does, a description of the heating source.
11. Product Testing and Analysis Information
    Proposed Sec.  1114.7(i)(4) requires that all testing and analyses
of the tobacco product required in Sec.  1114.7(i) be performed on test
samples that reflect the final tobacco product composition and design,
and that they be conducted using a sufficient sample size and number of
replicates to substantiate the results of the type of testing
conducted. FDA is proposing this requirement under its authority in
910(b)(1)(G) because the testing requirements described in this section
are relevant to the subject matter of the application in that it helps
FDA determine whether the product testing and analyses are accurate and
reliable. If the product that is the subject of the PMTA is a component
or part, testing and analyses of the product should be performed with a
range of other components or parts with which a consumer is expected to
use the product (e.g., an e-liquid should be tested in a representative
sample of e-cigarettes in which it is may be used). FDA notes that the
sample size and number of replicates necessary to substantiate the type
of testing may vary according to the type of testing. FDA recommends
that a PMTA contain an explanation of why the applicant believes the
sample size and number of replicates used is sufficient to support the
reliability of the results. Additionally, the applicant would be
required to provide the following information about the testing and
analysis:
     The name and location of the testing laboratory or
laboratories and documentation showing that the laboratory is (or
laboratories are) accredited by a nationally or internationally
recognized external accreditation organization;
     The length of time between dates of manufacture and
date(s) of testing;
     The storage conditions of the tobacco product before it
was tested;
     The number of samples and measurement replicates for each
sample;
     Description of method procedure, method validation
information and rationale for selecting each test method, including
relevant voluntary testing standards;
     Reports of all product formulation testing, including line
data, test protocols, quantitative acceptance criteria, and a summary
of the results, for each applicable parameter. Please note that an
applicant would be required to retain source data under proposed Sec.
1114.45; and
     Complete descriptions of any smoking or aerosol-generating
regimens used for analytical testing that are not standardized or
widely accepted by the scientific community, if applicable. Where the
applicant is not using a widely recognized and standardized regimen,
such as the ISO or HCI regimens, the PMTA would need to contain
complete description of the regimen.
12. Manufacturing
    Section 910(b)(1)(C) of the FD&C Act requires a PMTA to contain
full descriptions of the methods used in, and the facilities and
controls used for, the manufacture, processing, and, when relevant,
packing and installation of, the tobacco product. Proposed Sec.
1114.7(j) provides FDA's interpretation of this requirement, together
with its authority under section 910(b)(1)(G) of the FD&C Act, stating
that these descriptions must include information regarding all
manufacturing facilities, include descriptions of design controls, and
be sufficiently detailed to demonstrate that the product meets
manufacturing specifications and can be manufactured in a manner
consistent with the information submitted in the PMTA.
    Additionally, because FDA must, under section 910(c)(2)(B) of the
FD&C Act, deny a PMTA that does not demonstrate compliance with
regulations issued under section 906(e) of the FD&C Act, the
descriptions contained in the manufacturing section must demonstrate
the means by which the processes comply with any applicable tobacco
product manufacturing practices regulation issued under section 906(e).
FDA has not yet issued a regulation under section 906(e) of the FD&C
Act, so demonstrating compliance with such regulations is not currently
required; however, FDA intends to issue regulations under section
906(e), and once such regulations are effective, applicants must
demonstrate that their methods, facilities, and controls comply with
that rule to receive a marketing order under section 910(c)(1)(i)(A) of
the FD&C Act.\11\ Until a final rule issued under section 906(e) of the
FD&C Act is effective, FDA will evaluate the manufacturing process
information and consider whether the product can be manufactured in a
manner consistent with the information submitted within the application
as part of its determination of whether the marketing of the new
tobacco product would be APPH. As part of this evaluation, FDA may
conduct inspections as described in proposed Sec.  1114.27 to verify
the information and data submitted in the application.
---------------------------------------------------------------------------

    \11\ In establishing the effective date of a regulation under
section 906 of the FD&C Act, FDA must provide for a ``reasonable
period of time for . . . manufacturers to conform to good
manufacturing practices,'' and small tobacco product manufacturers
will have at least 4 additional years to comply. See section
906(e)(1)(B) of the FD&C Act. FDA anticipates that manufacturers
preparing PMTA applications before any regulation under 906(e) is
finalized will have sufficient time to prepare applications that
demonstrate that their methods, facilities, and controls comply with
such a rule before the applicable effective date. For PMTA
applications submitted before any regulation under 906(e) is
finalized, FDA generally expects the review of such applications
will be concluded prior to the effective date.
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    The process by which a tobacco product is manufactured is important
to FDA's determination of whether a new tobacco product is APPH because
it demonstrates the likelihood that a tobacco product will be
manufactured in accordance with the specifications set forth in the
PMTA. A tobacco product that fails to conform to the PMTA's
specifications, referred to as a ``nonconforming tobacco product,''
could result in a defective product and increase the product's risk
compared to what would normally be expected from

use of the product as characterized in the PMTA. Additionally, a
nonconforming tobacco product constitutes a different tobacco product
than the one authorized in the marketing order, which would render a
nonconforming tobacco product adulterated under section 902(6)(B) of
the FD&C Act. A nonconforming tobacco product can be the result of a
number of issues, including design defects, failures of or problems
with purchasing controls, inadequate process controls, improper
facilities or equipment, inadequate training, inadequate manufacturing
methods and procedures, or improper handling of the tobacco product.
    Nonconforming tobacco products have been highlighted in the news.
For example, in 2017, a manufacturer of smokeless tobacco products
issued a voluntary recall of certain products after receiving
complaints of foreign metal material, including sharp metal objects, in
its smokeless tobacco products. After the recall, the manufacturer
investigated whether the contamination was a result of the
manufacturing practice or a deliberate act by an individual to
contaminate the product. FDA is also aware of other instances where
smokeless tobacco products contained rocks or metal shavings as well as
other nontobacco related materials (NTRMs) (e.g., glass, nails, pins,
wood, dirt, sand, fabric, cloth, and plastics) in finished tobacco
products. These NTRMs can cause cuts or lacerations to the lips and
gums or result in broken teeth. This proposed regulation provides
requirements for how manufacturers would be required to handle
complaints in similar situations, as well as the subsequent
investigation, evaluation, and corrective and preventive actions they
would need to take to address such issues.
    FDA also has observed during inspections that tobacco product
manufacturers have received complaints regarding nonconforming tobacco
products that contain contaminants and hazards such as biological
materials (e.g., mold, mildew, hair, fingernails) and chemical hazards
(e.g., ammonia, cleaning agents, and kerosene). Caustic cleaning
chemicals may cause the consumer to experience adverse health effects
not normally associated with tobacco use, such as vomiting, nausea,
allergic reactions, dizziness, numbness, or headaches.
    Nonconforming tobacco products may also contain higher levels of a
constituent than the consumer is expecting and that the product is
supposed to have as characterized by the PMTA. For example, FDA is
aware of the variability of nicotine among certain ENDS products and
that the labeling may not accurately reflect the actual levels of
nicotine in those products. In one study, researchers found that actual
nicotine amounts differed from labeled amounts by more than 20 percent
in 9 out of 20 original e-cigarette cartridges tested, and in 3 out of
15 refill cartridges tested (Ref. 105). FDA has observed on inspections
that some e-liquid manufacturers do not have established procedures to
conduct activities or maintain records of their manufacturing
processes, including but not limited to calibration of equipment,
documenting the identity or purity of their ingredients, and testing
final product to confirm that it meets established specifications such
as the concentration of nicotine. A finished ENDS that contains a
nicotine concentration higher than the established specification can be
more addictive (Refs. 106 and 107). Similarly, a cigarette that does
not conform to its pH specification can deliver nicotine in a different
speed and amount to the user which can impact the tobacco product's
toxicity and addictiveness (Ref. 45). Exposure to nonconforming
products in this circumstance can result in user exposure to increased
levels of nicotine, which can lead to increased addictiveness.
    Nonconforming products may also contain defects that can cause the
tobacco product to be more harmful. For example, an ENDS product may
have a defect that contributes to an increased risk of fire and/or
explosion. The ENDS product, during use or foreseeable misuse, can
expose consumers to increased harm if the device catches fire or
explodes resulting in serious burns that would not be expected from use
of the product (e.g., Ref. 108).
    Given the dangers associated with nonconforming (including
contaminated) tobacco products, FDA is proposing to evaluate an
applicant's manufacturing process information to help determine whether
the marketing of a new tobacco product would be APPH, specifically
considering whether the manufacturer explains controls it would
establish and maintain to prevent the manufacture and distribution of
nonconforming products that may have an adverse effect on public
health.
    The manufacturing section of a PMTA must contain the following
information in the manufacturing section to meet the requirements of
proposed Sec.  1114.7(j) and to help FDA determine if it conforms to
the requirements of section 906(e) of the FD&C Act:
     A listing of all manufacturing, packaging, storage, and
control facilities for the product, including the name, address, and
FEI number for each facility, if applicable, and a contact name and
telephone number for a representative from each facility;
     A narrative description, accompanied by a list and summary
of all standard operating procedures (SOPs) and examples of relevant
forms and records for the following categories of information for all
manufacturing, design controls, packing, and storage for the tobacco
product:
    [cir] Manufacturing and production process activities at each
establishment, including a description of each establishment, all
production steps, process controls, process specifications with
relevant acceptance criteria, and monitoring and acceptance activities;
    [cir] Managerial oversight and employee training related to the
manufacture, processing, packing, and installation of the tobacco
product, as applicable;
    [cir] Monitoring procedures and manufacturing controls for product
design, product characteristics, and changes in products,
specifications, methods, processes, or procedures, including a hazard
analysis that details the correlation of the product design attributes
with public health risk, as well as any mitigation strategies
implemented;
    [cir] Activities related to identifying and monitoring suppliers
and the products supplied (including, for example, purchase controls
and product acceptance activities);
    [cir] Handling of complaints, nonconforming products and processes,
and corrective and preventative actions;
    [cir] Testing procedures carried out before the product is released
to market, including:
    [ssquf] A list and summary of any standards used for all testing
methods;
    [ssquf] Validation or verification activities for all test methods
used to ensure that the tobacco product meets specifications;
    [ssquf] Documentation of accreditation information for all testing
laboratories;
    [ssquf] Complete description of smoking or aerosol-generating
regimes used for analytical testing, if any;
    [ssquf] Tobacco product specifications (including any physical,
chemical, and biological specifications) and acceptance criteria for
those specifications; and
    [ssquf] Reports of release testing performed on finished products
to demonstrate conformity with established specifications, including
test protocols, line data, and a summary of the results for each
applicable testing.

13. Health Risk Investigations
    Under section 910(b)(1)(A) of the FD&C Act, a PMTA must contain
full reports of all information, published or known to, or which should
be reasonably known to, the applicant concerning investigations which
have been made to show the health risks of the tobacco product and
whether the tobacco products present less risk than other tobacco
products. Proposed Sec.  1114.7(k) sets forth FDA's proposed
interpretation of this requirement, together with its authority in
section 910(b)(1)(G), in three parts: (1) The types of investigations
that would be considered investigations into the health risks of the
product and whether the tobacco product presents less risk than other
products; (2) the documentation an application would be required to
contain to demonstrate that the application contains all published
investigations; and (3) the information that would constitute a full
report of an investigation.
    a. Types of investigations and analyses. FDA interprets the
information required under section 910(b)(1)(A) of the FD&C Act,
together with its authority under section 910(b)(1)(G) of the FD&C Act,
to include the health risk investigations specified in proposed Sec.
1114.7(k)(1). Under the proposed rule, applicants would be required to
submit full reports (as described in proposed Sec.  1114.7(k)(3)) of
all information published or known to, or which should reasonably be
known to, the applicant regarding the types of investigations described
in proposed Sec.  1114.7(k)(1). Applicants would be required to submit
full reports of these investigations, regardless of whether they
support or are adverse to the application, or are conducted within or
outside the United States.
    Proposed Sec.  1114.7(k)(1) requires an application to contain
health risk investigations that are published, known to, or should
reasonably be known to an applicant. This proposed requirement would
ensure that FDA understands the full scope of the health risk
investigations for a new tobacco product. It does not require a PMTA to
contain each type of health risk investigation described in this
section beyond what is published, known to, or should reasonably be
known to, an applicant and, applicants should not interpret this
proposed section to be a list of investigations that it must conduct to
receive a marketing order. While a PMTA must contain substantive
information regarding certain categories of information set forth in
Sec.  1114.27(b)(i)(ii) to be filed by FDA as described in section
VIII.B., an applicant has some flexibility in determining how to use
existing information to support a PMTA for their product and what types
of additional investigations it may need to conduct to provide FDA with
information that demonstrates that permitting the marketing of its new
tobacco product would be APPH. Applicants may want to review the areas
of scientific investigation listed in this proposed section in an
effort to determine whether there are gaps in the existing scientific
information regarding its product that it may need to fill by
conducting a new study regarding its tobacco product. As discussed in
the description of Sec.  1114.31 in section VIII.D., acceptance and
filing of a PMTA does not mean that it has sufficient scientific
information necessary to obtain a marketing order.
    An applicant may choose to conduct one of the health risk
investigations described in Sec.  1114.7(k)(1) to help demonstrate the
health risks of a new tobacco product; however, it should be clear that
the proposed rule is not requiring applicants to conduct these studies
beyond what may be necessary to generate substantive information to
meet the filing requirements set forth in proposed Sec.
1114.27(b)(1)(ii). While the proposed rule is not requiring applicants
to conduct studies beyond what may be necessary to generate substantive
information to meet the filing requirements set forth in Sec.
1114.27(b)(1)(ii), if such studies, together with other information in
the PMTA, do not show that permitting the marketing of the new tobacco
product would be APPH, FDA would issue an no marketing order.
Applicants have some flexibility in the particular studies that they
may conduct; an application would not necessarily need to contain each
type of study described in Sec.  1114.7(k) for filing or to receive an
order.
    Proposed Sec.  1114.7(k) would interpret section 910(b)(1)(A)
broadly to ensure FDA has a complete understanding of the existing
information about a new tobacco product; it does not set requirements
for specific studies that must be contained in every single PMTA. The
description of the issuance of no marketing orders (proposed Sec.
1114.33) in section VIII.E. describes circumstances where FDA intends
to issue a no marketing order. The description of the issuance of
marketing order (proposed Sec.  1114.31) in section VIII.D. contains
information regarding FDA's determination of whether there is a showing
that the marketing of a new tobacco product would be APPH.
    The proposed rule would not require an applicant to conduct any of
its own studies for the purposes of the proposed application acceptance
and filing requirements in Sec.  1114.27, except as would be necessary
to meet the filing requirements of proposed Sec.  1114.27(b)(2)(ii).
Should an applicant choose to do so, FDA is providing proposed,
recommendations for consideration throughout this section of the
preamble. In addition to proposed recommendations for specific types of
studies that follow, FDA is making proposed recommendations for three
general topics related to health risk investigations that may help an
applicant prepare a PMTA in some instances: Bridging data from an
investigation conducted using a different product to the product that
is the subject of the application, choosing appropriate comparison
products, and using foreign data.
     Bridging. FDA recognizes that in preparing the health risk
investigations section of a PMTA, an applicant may choose to use data
from a study conducted using a different tobacco product in an attempt
to demonstrate the health risks of the product that is the subject of
the application. The submission of studies using different products is
optional and is not required under the proposed rule. Ideally, a PMTA
will contain studies conducted with respect to the new tobacco product
itself, but the bridging of data from a different product to the new
tobacco product that is the subject of the application may be feasible
for a subset of products or for certain types of studies. If an
applicant lacks data on the product from one or more of the types of
studies listed in this section, the applicant could bridge data
regarding another product, or an earlier version of the product where
appropriate. For example, ``X-flavor'' e-liquids with nicotine
concentrations ranging from 1 milligram per milliliter (mg/mL) to 24
mg/mL may be able to show the health risks of each of the e-liquids
without having to conduct a unique study for each nicotine
concentration of the ``X-flavor'' product if data from a subset of
nicotine concentrations (e.g., low, middle, high) of ``X-flavor''
products may be bridged to other nicotine concentrations of ``X-
flavor'' products. Other examples where data from studies on a smaller
number of products could potentially be bridged to a larger number of
products include smokeless tobacco products available in various pouch
sizes or e-liquids available in various container volumes. If an
applicant chooses to bridge data from a

studied tobacco product to the subject new tobacco product, FDA
recommends that the application contain the rationale and justification
to support the use of bridging studies.
    Where an applicant chooses to bridge to data from a general study
or a study conducted using a different tobacco product, it should
provide a scientific rationale to justify why the study findings apply
to its new tobacco product and any study limitations that may be
relevant. Failure to provide a sufficient justification that such data
can be used to evaluate the new tobacco product would result in FDA
being unable to rely upon it in evaluating the PMTA. There may be
circumstances when an applicant would need to submit additional
substantive information, including bridging studies, as appropriate, to
justify that the results of a general study or a study using a
different tobacco product is relevant to evaluation of its new tobacco
product. Where an applicant seeks to use information from a study
conducted using a different tobacco product in the same product
category, it may need to provide comparative product information or
potentially a bridging study to show the results apply to its specific
new tobacco product. For instance, if an applicant wants to use the
results of an abuse liability study that was conducted on a different
product, an applicant should justify how key similarities between the
products (e.g., product design, nicotine formulation and content)
demonstrate the results of the study apply to its tobacco product. As
another example, national surveys, such as the NYTS, provide
information about trends in tobacco product use by youth and typically
do so for product categories as a whole, rather than specific products.
If an applicant intends to use such survey data to help show the
likelihood of youth initiation with its product, it would need to
explain why results about a product category in general would apply to
its specific product.
    Another example of when a justification or a bridging study may be
needed is when the location or region of a study differs from the
intended locations or regions where the product will be used, which is
further described in the foreign data section below.
     Comparison Products. As part of FDA's consideration under
910(c)(4) of the FD&C Act of the risks and benefits of the marketing of
the new tobacco product to the population as a whole, including users
and nonusers of tobacco products, FDA reviews the health risks
associated with changes in tobacco product use behavior (e.g.,