
[Federal Register Volume 77, Number 64 (Tuesday, April 3, 2012)]
[Notices]
[Pages 20034-20037]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-7727]


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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 
and Tobacco Smoke; Established List

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; establishment of a list.

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SUMMARY: The Food and Drug Administration (FDA) is establishing a list 
of harmful and potentially harmful constituents (HPHCs) in tobacco 
products and tobacco smoke (the established HPHC list) as required by 
the Federal Food, Drug, and Cosmetic Act (the FD&C Act).

FOR FURTHER INFORMATION CONTACT: Carol Drew, Center for Tobacco 
Products, Food and Drug Administration, 9200 Corporate Blvd., 
Rockville, MD 20850-3229, 877-287-1373.

SUPPLEMENTARY INFORMATION:

I. Introduction

    On June 22, 2009, the President signed the Family Smoking 
Prevention and Tobacco Control Act (Tobacco Control Act) (Pub. L. 111-
31) into law. The Tobacco Control Act amended the FD&C Act (21 U.S.C. 
301 et seq.) by, among other things, adding a new chapter granting FDA 
important new authority to regulate the manufacture, marketing, and 
distribution of tobacco products to protect the public health. Section 
904(e) of the FD&C Act (21 U.S.C. 387d(e)), as added by the Tobacco 
Control Act, 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.''
    The Agency has considered comments solicited from the public, as 
well as scientific and other information, and has developed a list of 
tobacco product constituents it currently believes are harmful or 
potentially harmful to health. We are establishing this list as table 1 
of this document as required by section 904(e) of the FD&C Act. In this 
document, we are also providing information about related actions, 
including the Agency's guidance discussing the meaning of HPHC, the 
criteria the Agency used to help develop the established HPHC list, the 
reasons the Agency may add or remove constituents from the established 
HPHC list consistent with the directive of section 904(e), and the 
addition of quantities to the list.

II. Background

    On January 31, 2011, FDA announced the availability of a guidance 
entitled `` `Harmful and Potentially Harmful Constituents' in Tobacco 
Products as Used in Section 904(e) of the Federal Food, Drug, and 
Cosmetic Act'' (76 FR 5387) (available at www.fda.gov/TobaccoProducts/GuidanceComplianceRegulatoryInformation) (HPHC final guidance). This 
guidance represents the Agency's current thinking on the meaning of the 
term ``harmful and potentially harmful constituent'' in the context of 
implementing section 904(e) of the FD&C Act. It states: ``FDA believes 
that the phrase `harmful and potentially harmful constituent' includes 
any chemical or chemical compound in a tobacco product or in tobacco 
smoke: (a) That is or potentially is inhaled, ingested, or absorbed 
into the body; and (b) that causes or has the potential to cause direct 
or indirect harm to users or non-users of tobacco products'' (HPHC 
final guidance at page 2). The HPHC final guidance includes examples of 
constituents that have the potential to cause direct harm and examples 
of constituents that have the potential to cause indirect harm: 
``Examples of constituents that have the `potential to cause direct 
harm' to users or non-users of tobacco products include constituents 
that are toxicants, carcinogens, and addictive chemicals and chemical 
compounds. Examples of constituents that have the `potential to cause 
indirect harm' to users or non-users of tobacco products include 
constituents that may increase the exposure to the harmful effects of a 
tobacco product constituent by: (1) Potentially facilitating initiation 
of the use of tobacco products; (2) potentially impeding cessation of 
the use of tobacco products; or (3) potentially increasing the 
intensity of tobacco product use (e.g., frequency of use, amount 
consumed, depth of inhalation). Another example of a constituent that 
has the `potential to cause indirect harm' is a constituent that may 
enhance the harmful effects of a tobacco product constituent'' (HPHC 
final guidance at page 2).
    On May 1, 2010, a subcommittee of the Tobacco Products Scientific 
Advisory Committee (TPSAC),\1\ the Tobacco Product Constituents 
Subcommittee (the subcommittee), was established and charged with 
making preliminary recommendations to TPSAC on the HPHCs in tobacco 
products and tobacco smoke. The subcommittee held public meetings on 
June 8 and 9, 2010, and July 7, 2010. Prior to these meetings, FDA 
solicited data, information, and/or views on HPHCs in tobacco products 
and tobacco smoke from the public.\2\ At these meetings the 
subcommittee:
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    \1\ Information about TPSAC as well as information and 
background materials on TPSAC meetings are available at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/TobaccoProductsScientificAdvisoryCommittee/default.htm.
    \2\ See 75 FR 22147 (April 27, 2010) and 75 FR 33814 (June 15, 
2010). Information submitted to the public docket for each of these 
meetings is available at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/TobaccoProductsScientificAdvisoryCommittee/ucm222977.htm and http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/TobaccoProductsScientificAdvisoryCommittee/ucm222978.htm.
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     Reviewed example lists of HPHCs in tobacco products and 
tobacco smoke developed by other countries and organizations;
     Identified criteria for selecting carcinogens, toxicants, 
and addictive chemicals or chemical compounds in tobacco products and 
tobacco smoke;
     Identified chemicals or chemical compounds that met the 
identified criteria;
     Confirmed the existence of methods for measuring each 
chemical or chemical compound identified; and
     Identified other potentially important information or 
criteria for measuring HPHCs in tobacco products or tobacco smoke, such 
as smoking machine regimens to be used in measuring HPHCs.

[[Page 20035]]

    The subcommittee made preliminary recommendations to TPSAC.
    On August 30, 2010, TPSAC held a public meeting to deliberate on 
the recommendations from the subcommittee. Prior to this meeting, FDA 
published a notice in the Federal Register soliciting data, 
information, and/or views from the public on the issues to be discussed 
at this meeting.\3\ FDA asked what criteria TPSAC recommended the 
Agency use for determining whether a constituent is a carcinogen, 
toxicant, or addictive chemical or chemical compound that should be 
included on the established HPHC list. As a result of its discussions, 
TPSAC recommended to the Agency the following criteria for selecting 
the established HPHC list:
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    \3\ See 75 FR 47308 (August 5, 2010). Information submitted by 
the public to the docket for this meeting is available at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/TobaccoProductsScientificAdvisoryCommittee/ucm232799.htm.

 Constituents identified as known or probable human carcinogens 
by either the International Agency for Research on Cancer (IARC), the 
U.S. Environmental Protection Agency (EPA), or the National Toxicology 
Program;
 Constituents identified as possible human carcinogens by IARC 
or EPA and/or identified by the National Institute for Occupational 
Safety and Health as potential occupational carcinogens;
 Constituents identified by EPA or the Agency for Toxic 
Substances and Disease Registry (ATSDR) as having adverse respiratory 
or cardiac effects;
 Constituents identified by the California Environmental 
Protection Agency as reproductive or developmental toxicants;
 Constituents having, based upon a review of the peer-reviewed 
literature, evidence of at least two of the following measures of abuse 
liability (addiction):
    [cir] Central nervous system activity;
    [cir] Animal drug discrimination;
    [cir] Conditioned place preference;
    [cir] Animal self-administration;
    [cir] Human self-administration;
    [cir] Drug liking;
    [cir] Signs of withdrawal; and
 Constituents banned in food (for smokeless tobacco products).

    On August 12, 2011, FDA published a notice in the Federal Register 
(76 FR 50226) (the August 12 notice \4\) stating that the Agency had 
tentatively concluded that it should consider a constituent meeting the 
criteria listed in that document to be harmful or potentially harmful, 
such that the constituent should be included on the HPHC 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 August 12 notice also included a list of constituents that 
was developed by applying this approach to available information and 
requested that interested persons submit scientific and other 
information concerning the harmful and potentially harmful constituents 
in tobacco products and tobacco smoke. The August 12 notice stated that 
the Agency was particularly interested in comments on the following 
issues: (1) The criteria FDA should use in determining whether a 
constituent is harmful or potentially harmful such that it should be 
included on the established HPHC list; (2) whether any chemicals or 
chemical compounds not listed should be added because they are harmful 
or potentially harmful, including supporting scientific or other 
information; and/or (3) whether any chemicals or chemical compounds 
should be removed because they are not harmful or potentially harmful, 
including supporting scientific or other information.
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    \4\ ``Harmful and Potentially Harmful Constituents in Tobacco 
Products and Tobacco Smoke; Request for Comments,'' 76 FR 50226 
(August 12, 2011).
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    The Agency has considered all of the comments submitted to the 
docket for the August 12 notice and has reviewed scientific and other 
information submitted to support these comments. Based on the 
information before it and its own knowledge and expertise, FDA 
concludes that it should consider a constituent meeting the criteria 
proposed in the August 12 notice to be harmful or potentially harmful, 
such that it should be included on the HPHC list, unless other 
scientific information obtained by or submitted to the Agency shows 
that the constituent is not, in fact, harmful or potentially harmful. 
Applying these criteria, and after consideration of comments and 
supporting information submitted to the docket for the August 12 
notice, FDA has developed the established list of harmful and 
potentially harmful constituents in tobacco products and tobacco smoke 
as table 1 of this document.
    Three constituents included on the list we published for comment in 
the August 12 notice are not included in table 1. Based on information 
submitted to the docket and our review of the scientific literature, we 
have determined not to include dibenz[a,h]acridine, dibenz[a,j]acridine 
and 7H-dibenz[c,g]carbazole on the established HPHC list at this time 
because there is not sufficient evidence that they are found in tobacco 
products or tobacco smoke. This decision is based on information 
presently before us, and may be revised, consistent with the directive 
in section 904(e) of the FD&C Act that FDA periodically revise the 
established list as appropriate.
    We note that certain metals on the established HPHC list 
(beryllium, cadmium, chromium, cobalt, lead, mercury, nickel, and 
selenium) may exist in tobacco products and tobacco smoke in the 
elemental form and/or in compounds. Both the elemental and compound 
forms are harmful and/or potentially harmful under our criteria. 
Identification of a metal on the established HPHC list therefore refers 
to the metal regardless of whether it is found in its elemental form or 
as a metal-bound compound. For example, beryllium includes both 
elemental beryllium and beryllium found in beryllium compounds.
    FDA recognizes that the established HPHC list may not include all 
constituents that are ``harmful or potentially harmful.'' For example, 
several of the criteria described in this document depend on a chemical 
or chemical compound being both studied and listed by another entity, 
such as constituents identified by EPA or ATSDR as having adverse 
respiratory or cardiac effects. The fact that a constituent has not 
been so identified by EPA or ATSDR could be because it has not been 
adequately studied or has not yet been systematically reviewed by 
relevant Agencies, rather than because the constituent does not have 
adverse respiratory or cardiac effects. Moreover, FDA has only focused 
on the five disease outcomes of cancer, cardiovascular disease, 
respiratory effects, developmental or reproductive effects, and 
addiction. FDA intends to review other disease outcomes to assess 
whether additional chemicals or chemical compounds in tobacco products 
or tobacco smoke are harmful or potentially harmful constituents that 
contribute to the risk of other diseases.
    In addition, the criteria FDA has selected are limited to those 
that relate to carcinogens, toxicants, and addictive chemicals or 
chemical compounds in tobacco products and tobacco smoke. We intend to 
consider whether additional criteria should be selected to help 
identify other classes of harmful or potentially harmful chemicals and 
chemical compounds for inclusion on the established HPHC list, and 
whether individual constituents should be added. Just as these types of 
new information may lead to additions to the established HPHC list, FDA 
recognizes

[[Page 20036]]

that it may become aware of new scientific information about 
constituents of tobacco products that make it appropriate to remove one 
or more of the constituents that appear on the list. Thus, FDA will 
continue to review scientific information about tobacco product 
constituents. For these reasons and consistent with the directive of 
section 904(e) of the FD&C Act, FDA intends to periodically revise as 
appropriate the established HPHC list.
    Currently, the established HPHC list in table 1 does not contain 
quantities of the HPHCs by brand and subbrand. Beginning June 22, 2012, 
sections 904(a)(3) and 904(c)(1) of the FD&C Act require tobacco 
product manufacturers and importers or their agents to submit a list of 
constituents, including smoke constituents as applicable, identified by 
FDA as harmful or potentially harmful to health in each of their 
tobacco products, by brand and by quantity in each brand and subbrand. 
Elsewhere in this issue of the Federal Register, FDA is publishing a 
notice announcing the availability of a draft guidance for industry to 
assist persons reporting to FDA the quantities of harmful and 
potentially harmful constituents in tobacco products and tobacco smoke. 
FDA intends to use the data and information submitted under sections 
904(a)(3) and 904(c)(1) to, as directed by section 904(d)(1) of the 
FD&C Act, place on public display the list of HPHCs established under 
section 904(e), by brand and by quantity in each brand and subbrand, in 
a format ``that is understandable and not misleading to a lay person.''

    Table 1--Established List of the 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),  cardiovascular
           Constituent                 toxicant (CT), reproductive or
                                       developmental toxicant (RDT),
                                               addictive (AD)
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Acetaldehyde.....................  CA, RT, AD
Acetamide........................  CA
Acetone..........................  RT
Acrolein.........................  RT, CT
Acrylamide.......................  CA
Acrylonitrile....................  CA, RT
Aflatoxin B1.....................  CA
4-Aminobiphenyl..................  CA
1-Aminonaphthalene...............  CA
2-Aminonaphthalene...............  CA
Ammonia..........................  RT
Anabasine........................  AD
o-Anisidine......................  CA
Arsenic..........................  CA, CT, RDT
A-[alpha]-C (2-Amino-9H-           CA
 pyrido[2,3-b]indole).
Benz[a]anthracene................  CA, CT
Benz[j]aceanthrylene.............  CA
Benzene..........................  CA, CT, RDT
Benzo[b]fluoranthene.............  CA, CT
Benzo[k]fluoranthene.............  CA, CT
Benzo[b]furan....................  CA
Benzo[a]pyrene...................  CA
Benzo[c]phenanthrene.............  CA
Beryllium........................  CA
1,3-Butadiene....................  CA, RT, RDT
Cadmium..........................  CA, RT, RDT
Caffeic acid.....................  CA
Carbon monoxide..................  RDT
Catechol.........................  CA
Chlorinated dioxins/furans.......  CA, RDT
Chromium.........................  CA, RT, RDT
Chrysene.........................  CA, CT
Cobalt...........................  CA, CT
Coumarin.........................  Banned in food
Cresols (o-, m-, and p-cresol)...  CA, RT
Crotonaldehyde...................  CA
Cyclopenta[c,d]pyrene............  CA
Dibenz[a,h]anthracene............  CA
Dibenzo[a,e]pyrene...............  CA
Dibenzo[a,h]pyrene...............  CA
Dibenzo[a,i]pyrene...............  CA
Dibenzo[a,l]pyrene...............  CA
2,6-Dimethylaniline..............  CA
Ethyl carbamate (urethane).......  CA, RDT
Ethylbenzene.....................  CA
Ethylene oxide...................  CA, RT, RDT
Formaldehyde.....................  CA, RT
Furan............................  CA
Glu-P-1 (2-Amino-6-                CA
 methyldipyrido[1,2-a:3',2'-
 d]imidazole).

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Glu-P-2 (2-Aminodipyrido[1,2-      CA
 a:3',2'-d]imidazole).
Hydrazine........................  CA, RT
Hydrogen cyanide.................  RT, CT
Indeno[1,2,3-cd]pyrene...........  CA
IQ (2-Amino-3-methylimidazo[4,5-   CA
 f]quinoline).
Isoprene.........................  CA
Lead.............................  CA, CT, RDT
MeA-[alpha]-C (2-Amino-3-methyl)-  CA
 9H-pyrido[2,3-b]indole).
Mercury..........................  CA, RDT
Methyl ethyl ketone..............  RT
5-Methylchrysene.................  CA
4-(Methylnitrosamino)-1-(3-        CA
 pyridyl)-1-butanone (NNK).
Naphthalene......................  CA, RT
Nickel...........................  CA, RT
Nicotine.........................  RDT, AD
Nitrobenzene.....................  CA, RT, RDT
Nitromethane.....................  CA
2-Nitropropane...................  CA
N-Nitrosodiethanolamine (NDELA)..  CA
N-Nitrosodiethylamine............  CA
N-Nitrosodimethylamine (NDMA)....  CA
N-Nitrosomethylethylamine........  CA
N-Nitrosomorpholine (NMOR).......  CA
N-Nitrosonornicotine (NNN).......  CA
N-Nitrosopiperidine (NPIP).......  CA
N-Nitrosopyrrolidine (NPYR)......  CA
N-Nitrososarcosine (NSAR)........  CA
Nornicotine......................  AD
Phenol...........................  RT, CT
PhIP (2-Amino-1-methyl-6-          CA
 phenylimidazo[4,5-b]pyridine).
Polonium-210.....................  CA
Propionaldehyde..................  RT, CT
Propylene oxide..................  CA, RT
Quinoline........................  CA
Selenium.........................  RT
Styrene..........................  CA
o-Toluidine......................  CA
Toluene..........................  RT, RDT
Trp-P-1 (3-Amino-1,4-dimethyl-5H-  CA
 pyrido[4,3-b]indole).
Trp-P-2 (1-Methyl-3-amino-5H-      CA
 pyrido[4,3-b]indole ).
Uranium-235......................  CA, RT
Uranium-238......................  CA, RT
Vinyl acetate....................  CA, RT
Vinyl chloride...................  CA
------------------------------------------------------------------------


    Dated: March 23, 2012.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2012-7727 Filed 3-30-12; 11:15 am]
BILLING CODE 4160-01-P


