[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]


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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.

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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, CTPRegulations@fda.hhs.gov.

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\
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    \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.
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    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\
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    \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.
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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\
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    \4\ For more information, we refer you to the April 2012 notice.
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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\
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    \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).
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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\
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    \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.
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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.
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    \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).
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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
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                                                  Carcinogen (CA), Respiratory Toxicant (RT), Reproductive or
                 Constituent                         Developmental Toxicant (RDT), Poisonous Chemical (PC)
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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
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[[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


