Harmful and Potentially Harmful Constituents in Tobacco Products; Established List; Proposed Additions; Request for Comments
| Citation | 84 FR 38032 |
| Record Number | 2019-16658 |
| Published date | 05 August 2019 |
| Section | Notices |
| Court | Food And Drug Administration |
Federal Register, Volume 84 Issue 150 (Monday, August 5, 2019)
[Federal Register Volume 84, Number 150 (Monday, August 5, 2019)]
[Notices]
[Pages 38032-38035]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-16658]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2012-N-0143]
Harmful and Potentially Harmful Constituents in Tobacco Products;
Established List; Proposed Additions; Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; request for comments.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA or the Agency) is
requesting comments, including scientific and other information,
concerning whether additional harmful and potentially harmful
constituents (HPHCs) in tobacco products and tobacco smoke should be
added to the Agency's list of HPHCs (the HPHC established list). This
information will assist the Agency in determining whether any or all of
the 19 constituents listed in this document should be added to the HPHC
established list.
DATES: Submit either electronic or written comments by October 4, 2019.
ADDRESSES: You may submit comments as follows:
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2012-N-0143 for ``Harmful and Potentially Harmful Constituents in
Tobacco Products; Established List; Proposed Additions; Request for
Comments.'' Received comments will be placed in the docket and, except
for those submitted as ``Confidential Submissions,'' publicly viewable
at https://www.regulations.gov or at the Dockets Management Staff
Office between 9 a.m. and 4 p.m., Monday through Friday.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to Dockets Management Staff. If you do not wish your
name and contact information to be made publicly available, you can
provide this information on the cover sheet and not in the body of your
comments and you must identify this information as ``confidential.''
Any information marked as ``confidential'' will not be disclosed except
in accordance with 21 CFR 10.20 and other applicable disclosure law.
For more information about FDA's posting of comments to public dockets,
see 80 FR 56469, September 18, 2015, or access the information at:
https://www.fda.gov/regulatoryinformation/dockets/default.htm.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Eric Mandle or Nathan Mease, Center
for Tobacco Products, Food and Drug Administration, Document Control
Center, Bldg. 71, Rm. G335, 10903 New Hampshire Ave., Silver Spring, MD
20993-0002; 1-877-287-1373, [email protected].
SUPPLEMENTARY INFORMATION:
[[Page 38033]]
I. Background
The Family Smoking Prevention and Tobacco Control Act (Tobacco
Control Act), enacted on June 22, 2009, amends the Federal Food, Drug,
and Cosmetic Act (FD&C Act) by, among other things, adding a new
chapter (chapter IX) granting FDA the authority to regulate the
manufacture, marketing, and distribution of tobacco products to protect
the public health generally and to reduce tobacco use by minors (Pub.
L. 111-31). Cigarettes, cigarette tobacco, roll-your-own (RYO) tobacco,
and smokeless tobacco were immediately subject to chapter IX.
For other kinds of tobacco products, the statute authorizes FDA to
issue regulations ``deeming'' them to be subject to chapter IX. FDA
published a final rule on May 10, 2016 (81 FR 28974) (the Deeming
Rule), deeming all products that meet the statutory definition of
``tobacco product'' set forth in section 201(rr) of the FD&C Act (21
U.S.C. 321(rr)), including components and parts, but excluding
accessories of deemed products, to be subject to chapter IX of the FD&C
Act.\1\
---------------------------------------------------------------------------
\1\ This final rule, ``Deeming Tobacco Products To Be Subject to
the Federal Food, Drug, and Cosmetic Act, as Amended by the Family
Smoking Prevention and Tobacco Control Act,'' 21 CFR part 1100, is
available at https://www.gpo.gov/fdysys/pkg/FR-2016-05-10/pdf/2016-10685.pdf.
---------------------------------------------------------------------------
Section 904(e) of the FD&C Act (21 U.S.C. 387d(e)) requires FDA to
establish, and periodically revise as appropriate, ``a list of harmful
and potentially harmful constituents, including smoke constituents, to
health in each tobacco product by brand and by quantity in each brand
and subbrand.'' FDA first established the list on April 3, 2012 (77 FR
20034) (the April 2012 notice).\2\ The list currently contains 93 HPHCs
(the HPHC established list). The April 2012 notice describes the
history of the HPHC established list, and for additional background, we
refer readers to that notice and the notice FDA published in the
Federal Register on August 12, 2011 (76 FR 50226) (the August 2011
notice), in which we solicited public comment, including scientific and
other information, concerning the HPHCs in tobacco products and tobacco
smoke, including which constituents should be included on the HPHC
established list, and the criteria used in determining whether a
constituent is harmful or potentially harmful such that it should be
included on the HPHC list.\3\
---------------------------------------------------------------------------
\2\ ``Harmful and Potentially Harmful Constituents in Tobacco
Products and Tobacco Smoke; Established List,'' 77 FR 20034 (April
3, 2012).
\3\ ``Harmful and Potentially Harmful Constituents in Tobacco
Products and Tobacco Smoke; Request for Comments,'' 76 FR 50226
(August 12, 2011). The August 2011 notice and the April 2012 notice
are collectively referred to as the Federal Register notices.
---------------------------------------------------------------------------
II. Proposed Changes to the HPHC List
A. Application of Existing Criteria to Deemed Products; Proposed
Addition of Glycidol and Ethylene Glycol to the HPHC List
As discussed previously, when the Agency established the HPHC
established list, the tobacco products that were subject to its
authorities under chapter IX of the FD&C Act were limited to
cigarettes, cigarette tobacco, RYO tobacco, and smokeless tobacco
products. Since then, however, the FDA's tobacco product authorities
were extended under the Deeming Rule to all products, including
components and parts (but excluding accessories of deemed products)
that meet the statutory definition of tobacco product, including
electronic nicotine delivery systems (ENDS). Therefore, consistent with
section 904(e) of the FD&C Act, the Agency is considering revising the
HPHC established list to reflect the current range of tobacco products
now subject to the Agency's tobacco product authorities as well as the
Agency's growing scientific expertise with respect to all tobacco
products.
1. Glycidol
FDA has tentatively concluded that in revising the HPHC established
list, the Agency should continue to apply the criteria that were
originally applied when determining whether a constituent should be put
on the list. Glycidol is a thermal byproduct of glycerol, a common
component in e-liquids. In other words, glycidol can form and appear in
the aerosol when a glycerol-containing solvent such as an e-liquid is
heated and aerosol is produced (Refs. 1-2). Following a review of the
data concerning degradation of glycerol, FDA has applied the original
criteria and tentatively concluded that glycidol should be included on
the HPHC established list, unless other scientific information obtained
by or submitted to the Agency shows that the constituent is not, in
fact, harmful or potentially harmful. The International Agency for
Research on Cancer (IARC) has identified glycidol as a probable
carcinogen (Ref. 3). As discussed in the April 2012 notice, FDA has
concluded that it should consider a constituent meeting this criterion
to be harmful or potentially harmful, such that it should be included
on the HPHC established list, unless other scientific information
obtained by or submitted to the Agency shows that the constituent is
not, in fact, harmful or potentially harmful.\4\
---------------------------------------------------------------------------
\4\ For more information, we refer you to the April 2012 notice.
---------------------------------------------------------------------------
2. Ethylene Glycol
In accordance with the original criteria, FDA has tentatively
concluded that ethylene glycol should also be included on the HPHC
established list, unless other scientific information obtained by or
submitted to the Agency shows that the constituent is not, in fact,
harmful or potentially harmful. In 2015, the California Environmental
Protection Agency identified ethylene glycol (ingested) as a
reproductive toxicant based on its developmental toxicity (Ref. 4).\5\
As discussed in the April 2012 notice, FDA has concluded that it should
consider a constituent meeting this criterion to be harmful or
potentially harmful, such that it should be included on the HPHC
established list, unless other scientific information obtained by or
submitted to the Agency shows that the constituent is not, in fact,
harmful or potentially harmful. Ethylene glycol has been identified in
e-liquids, indicating that this compound may be used to replace
glycerol and propylene glycol (Refs. 5 and 6).\6\
---------------------------------------------------------------------------
\5\ Users of tobacco products can be exposed to ethylene glycol
through ingestion as well as other routes of administration. For
example, during use of inhaled products, a fraction of the aerosol
is deposited in the mouth-throat area and is swallowed, resulting in
subsequent systemic exposures to aerosol constituents via the oral
route.
In June 2015, ethylene glycol was added to the list of chemicals
known to the State of California to cause reproductive toxicity
under Proposition 65, or the Safe Drinking Water and Toxic
Enforcement Act of 1986, Health and Safety Code section 25249.5 et
seq. See https://oehha.ca.gov/proposition-65/crnr/ethylene-glycol-ingested-listed-reproductive-toxicant (accessed October 2018).
\6\ The Agency has expressed concern about ethylene glycol in e-
liquid tobacco products before. See the Deeming Rule (81 FR 28974 at
29029).
---------------------------------------------------------------------------
B. Addition of a Criterion for Identifying Constituents That Cause or
Have the Potential To Cause Harm
Furthermore, at this time, FDA has tentatively concluded that the
Agency should apply one additional criterion when determining whether a
constituent should be included on the HPHC established list.
Specifically, FDA tentatively concludes that in addition to the
previously described criteria, the following criterion also should be
applied for determining whether a constituent should be included on the
HPHC established list, unless other scientific information obtained by
or submitted to the Agency shows that the constituent is not, in fact,
harmful or potentially harmful:
Constituents identified by the National Institute for
Occupational
[[Page 38034]]
Safety and Health (NIOSH) as having adverse respiratory effects.
FDA believes that having the additional criterion described in this
document for use in determining whether a constituent is harmful or
potentially harmful will be beneficial. We have tentatively identified
17 constituents that meet this criterion. They are: Acetic acid,
acetoin, acetyl propionyl, benzyl acetate, butyraldehyde, diacetyl,
ethyl acetate, ethyl acetoacetate, ethylene glycol (as discussed in
section II.A., this compound also meets one of the criteria that were
originally applied), furfural, glycerol, isoamyl acetate, isobutyl
acetate, methyl acetate, n-butanol, propionic acid, and propylene
glycol. As part of the Centers for Disease Control and Prevention
(CDC), NIOSH is the Federal agency responsible for conducting research
and making science-based recommendations to prevent work-related
illness and injuries, including those related to human health hazards
and respiratory disease from inhalation exposures to toxicants. In
reaching the tentative conclusion described above, the Agency notes
that FDA already considers whether NIOSH has identified a constituent
as a potential occupational carcinogen in determining whether that
constituent should be included on the HPHC list.\7\
---------------------------------------------------------------------------
\7\ See the April 2012 notice (77 FR 20034 at 20035). In this
notice, FDA concluded that it should adopt the criteria proposed in
the August 2011 notice.
---------------------------------------------------------------------------
C. Proposed Addition of Diethylene Glycol to the HPHC List
FDA has proposed diethylene glycol (DEG) as an HPHC because we are
concerned that a product that contains either glycerol or propylene
glycol also could be contaminated, perhaps inadvertently, by DEG. The
acute health consequences from exposure to DEG-contaminated products
may be serious and irreversible (Ref. 7). Poisoning because of DEG is
not a common occurrence. Most of the documented cases of illness and
death from DEG poisoning have been outbreaks where DEG was substituted
in pharmaceutical preparations for the glycols or glycerine
constituents customarily used (Ref. 8). Toxicity can result from
ingestion \8\ or dermal exposure to DEG-contaminated products (Refs. 9-
10). Inhalation exposure to DEG-contaminated products also can have
serious health consequences (Refs. 11 and 12). Suppliers of glycerol
and propylene glycol can dilute them with DEG (Refs. 13 and 14) and
manufacturers, unaware of the added DEG, can use the contaminated
glycerol or propylene glycol in tobacco products. Although FDA has no
reason to believe that U.S. suppliers of glycerol and propylene glycol
currently use DEG, FDA has detected DEG in e-liquids and ENDs aerosol
(Refs. 15 and 16).\9\ Therefore, the Agency has tentatively concluded
that DEG should be included on the HPHC established list.
---------------------------------------------------------------------------
\8\ For more information on DEG, including a discussion of
ingestion toxicity, we refer you to FDA's guidance for industry
Testing of Glycerin for Diethylene Glycol (available at https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm070347.pdf.
\9\ The Agency has expressed concern about DEG in tobacco
products before. See the Deeming Rule (81 FR 28974 at 29031) and the
proposed deeming rule (79 FR 23141 at 23157).
---------------------------------------------------------------------------
D. Proposed Addition of 19 Toxicants to the HPHC List
Applying all the criteria discussed earlier in this document and
using available information, FDA tentatively concludes that the 19
toxicants in table 1 should be added to the HPHC established list. This
tentative conclusion is consistent with our definition of ``harmful and
potentially harmful constituent'' as set forth in the Agency guidance
entitled ``Harmful and Potentially Harmful Constituents' in Tobacco
Products as Used in Section 904(e) of the Federal Food, Drug, and
Cosmetic Act'' (Revised) dated August 2016 (the HPHC Guidance) in that
the Agency has reviewed data regarding constituents identified in
tobacco products and their smoke, including in e-liquids and in
aerosols of ENDS products that are, or potentially are, inhaled,
ingested, or absorbed into the body, including as an aerosol (vapor) or
any other emission.
Table 1--List of the Additional Chemicals and Chemical Compounds Identified by FDA as Harmful and Potentially
Harmful Constituents in Tobacco Products and Tobacco Smoke
----------------------------------------------------------------------------------------------------------------
Carcinogen (CA), Respiratory Toxicant (RT), Reproductive or
Constituent Developmental Toxicant (RDT), Poisonous Chemical (PC)
----------------------------------------------------------------------------------------------------------------
Acetic Acid................................. RT
Acetoin (also known as 3-hydroxy-2-butanon3. RT
Acetyl propionyl (also known as 2,3- RT
pentanedione).
Benzyl acetate.............................. RT
Butyraldehyde............................... RT
Diacetyl.................................... RT
Diethylene glycol........................... PC
Ethyl Acetate............................... RT
Ethyl Acetoacetate.......................... RT
Ethylene Glycol............................. RT, RDT
Furfural.................................... RT
Glycerol.................................... RT
Glycidol.................................... CA
Isoamyl Acetate............................. RT
Isobutyl Acetate............................ RT
Methyl Acetate.............................. RT
n-Butanol................................... RT
Propionic Acid.............................. RT
Propylene Glycol............................ RT
----------------------------------------------------------------------------------------------------------------
[[Page 38035]]
III. Identification of HPHCs Is an Ongoing Effort
FDA recognizes that there may be constituents that are ``harmful or
potentially harmful'' that FDA neither included on the established HPHC
list nor proposed to be added to that list per table 1. The criteria
described previously in the April 2012 notice and the additional
criterion described in this document generally depend on a chemical or
chemical compound being studied and identified by FDA or another
regulatory entity as having adverse effects that are relevant to
cancer, cardiovascular, respiratory, developmental, or reproductive
effects. That a constituent has not been so identified by FDA or other
entities could be because it has not been adequately studied or has not
yet been systematically reviewed. Consistent with our obligations under
section 904(e) of the FD&C Act, FDA intends to continue:
Our efforts to review other disease outcomes to assess
whether additional chemicals or chemical compounds in tobacco products
or tobacco smoke, including chemicals or chemical compounds in the
emissions from the range of tobacco products now deemed to be subject
to chapter IX of the FD&C Act, are harmful or potentially harmful
constituents that contribute to the risk of other diseases;
Our consideration of whether additional or different
criteria should be selected to help identify other classes of harmful
or potentially harmful chemicals and chemical compounds for inclusion
on the HPHC established list and whether individual constituents should
be added; and
Our efforts to review new information to determine if it
would be appropriate to remove one or more of the constituents that
appear on the HPHC established list, or to add additional constituents
to the list.
IV. Request for Comments and Information
FDA is soliciting public comment on this notice, including
scientific and other information on the following topics:
The additional criterion FDA is proposing to use when
determining whether a constituent should be added to the HPHC
established list;
Whether any chemicals or chemical compounds not listed in
table 1 should be included because they are harmful or potentially
harmful, including supporting scientific or other information; and
Whether any of the chemicals or chemical compounds listed
in table 1, including as a result of the proposed criterion, should not
be included because they are not harmful or potentially harmful,
including supporting scientific or other information.
Interested persons may submit to the Dockets Management Staff (see
ADDRESSES) either electronic or written comments regarding this
document.
V. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses, as of
the date this document publishes in the Federal Register, but websites
are subject to change over time.
1. Laino, T., C. Tuma, A. Curioni, et al., ``A Revisited Picture
of the Mechanism of Glycerol Dehydration,'' Journal of Physical
Chemistry A, 115(15):3592-3595, 2011. https://doi.org/10.1021/jp201078e.
2. Sleiman, M., J. Logue, V. Montesinos, et al., ``Emissions
from Electronic Cigarettes: Key Parameters Affecting the Release of
Harmful Chemicals,'' Environmental Science & Technology, (50)9644-
9651, 2016. https://doi.org/10.1021/acs.est.6b01741.
3. IARC Monographs on the Evaluation of Carcinogenic Risks to
Humans, Vol. 77, at 482 (2000). https://monographs.iarc.fr/wp-content/uploads/2018/06/mono77.pdf.
*4. Borghardt, J.M., C. Kloft, and A. Sharma, ``Inhaled Therapy
in Respiratory Disease: The Complex Interplay of Pulmonary Kinetic
Processes,'' Canadian Respiratory Journal, 2018, doi:10.1155/2018/
2732017. http://downloads.hindawi.com/journals/crj/2018/2732017.pdf.
5. Dionex Corporation, ``Determination of Ethylene Glycol and
Diethylene Glycol in a Sorbitol Solution,'' Application Note 246,
LPN 2505, Sunnyvale, CA, 2016. https://assets.thermofisher.com/TFS-Assets/CMD/Application-Notes/AN-246-IC-Ethylene-Diethylene-Glycol-Sorbitol-LPN2505-EN.pdf.
6. Hutzler, C., M. Paschke, S. Kruschinski, et al., ``Chemical
Hazards Present in Liquids and Vapors of Electronic Cigarettes,''
Archives of Toxicology, 88(7): 1295-1308, 2014. https://doi.org/10.1007/s00204-014-1294-7.
7. Diethylene Glycol Poisoning (Cal. Poison Control System) Dec.
21, 2012, available at https://calpoison.org/news/diethylene-glycol-poisoning (last accessed on October 10, 2018).
8. Schep, L.J., R.J. Slaughter, W.A. Temple, and D. M. Beasley,
``Diethylene Glycol Poisoning'' Clinical Toxicology, 47(6):525-535
at 526, 2009. https://doi.org/10.1080/15563650903086444.
9. Devoti, E., E. Marta E. Belotti, et al., ``Diethylene Glycol
Poisoning from Transcutaneous Absorption,'' American Journal of
Kidney Diseases, 65(4):603-606, 2015. https://doi.org/10.1053/j.ajkd.2014.07.032.
*10. National Industrial Chemicals Notification and Assessment
Scheme, Existing Hazard Assessment Report, Diethylene Glycol (DEG),
Australian Government Department of Health and Ageing (June 2009).
https://www.nicnas.gov.au/__data/assets/word_doc/0018/37323/Diethylene-glycol-DEG-hazard-assessment.docx.
*11. Health Council of the Netherlands. ``Diethylene glycol;
Health-based recommended occupational exposure limit.'' https://www.healthcouncil.nl/documents/advisory-reports/2007/10/17/diethylene-glycol.
12. Sanina Y., ``Remote Consequences of Chronic Inhalation of
Diethylene Glycol,'' Gigiena I Sanitariia (1968).
*13. FDA Guidance for Industry, ``Testing of Glycerin for
Diethylene Glycol,'' May 2007, available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/testing-glycerin-diethylene-glycol.
*14. August 2, 1996, CDC Morbidity and Mortality Weekly Report.
https://www.cdc.gov/mmwr/PDF/wk/mm4530.pdf.
*15. Varlet, V. et al., ``Toxicity Assessment of Refill Liquids
for Electronic Cigarettes,'' International Journal of Environmental
Research and Public Health 2015, 12, 4796-4815. https://www.mdpi.com/1660-4601/12/5/4796.
*16. FDA Memorandum, ``Evaluation of E-Cigarettes,'' from B.
Westenberger, CDER/OPS/OTR, to M. Levy, Center for Drug Evaluation
and Research, Office of Compliance, May 4, 2009.
Dated: July 30, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-16658 Filed 8-2-19; 8:45 am]
BILLING CODE 4164-01-P
