
[Federal Register Volume 76, Number 156 (Friday, August 12, 2011)]
[Notices]
[Pages 50226-50230]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-20502]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2011-N-0271]


Harmful and Potentially Harmful Constituents in Tobacco Products 
and Tobacco Smoke; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; request for comments.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is requesting comments, 
including scientific and other information, concerning the harmful and 
potentially harmful constituents (HPHCs) in tobacco products and 
tobacco smoke. This information will assist the Agency in establishing 
a list of HPHCs in tobacco products and tobacco smoke (the HPHC list).

DATES: Submit either electronic or written comments by October 11, 
2011.

ADDRESSES: Submit electronic comments to http://www.regulations.gov. 
Submit written comments to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Identify comments with the docket number found in 
brackets in the heading of this document.

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. Background

    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 Federal Food, Drug, 
and Cosmetic Act (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 generally and to reduce tobacco 
use by minors. 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.'' 
Section 904(e) of the FD&C Act also requires that FDA ``publish a 
public notice requesting the submission by interested persons of 
scientific and other information concerning the harmful and potentially 
harmful constituents in tobacco products and tobacco smoke.''
    The Agency has solicited scientific and other information from 
interested persons and has developed a list of tobacco product 
constituents it currently believes are harmful or potentially harmful 
to health. Although the Agency's work to date reflects consideration of 
substantial scientific and other information, we believe that 
additional information from the public may be beneficial to the Agency 
before it establishes the list described in section 904(e) of the FD&C 
Act. We are therefore publishing the Agency's

[[Page 50227]]

current list as table 1 of this document and requesting public comment 
as described in section II of this document. In this section of the 
document, we are also providing information about the Agency's guidance 
on HPHCs, the criteria that the Agency used to help develop the list, 
and reasons the Agency might add or remove constituents.
    On June 10, 2010, FDA announced the availability for public comment 
of a draft guidance for industry and FDA staff entitled ``Harmful and 
Potentially Harmful Constituents' in Tobacco Products as Used in 
Section 904(e) of the Federal Food, Drug, and Cosmetic Act'' (75 FR 
32952). FDA announced the availability of the final guidance on January 
31, 2011 (76 FR 5387) (available at http://www.fda.gov/TobaccoProducts/GuidanceComplianceRegulatoryInformation) (HPHC final guidance). This 
final 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, the Agency established a subcommittee of the 
Tobacco Products Scientific Advisory Committee (TPSAC), \1\ the Tobacco 
Product Constituents Subcommittee (the subcommittee), and charged the 
subcommittee with making preliminary recommendations to TPSAC on 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, and at the June 
meeting, presentations were made by interested persons.\2\ At these 
meetings the subcommittee:
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

     Reviewed example lists of HPHCs 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.
    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 HPHC list. As a result of its discussions, TPSAC 
recommended to the Agency the following criteria for selecting the HPHC 
list:
---------------------------------------------------------------------------

    \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, likely, probably, or 
possible human carcinogens by the U.S. Environmental Protection Agency 
(EPA);
     Constituents identified as known, probable, or possible 
carcinogens by the International Agency for Research on Cancer (IARC) 
including IARC Group 1 (carcinogenic to humans), IARC Group 2 (probably 
carcinogenic to humans), and IARC Group 2B (possibly carcinogenic to 
humans);
     Constituents identified as human carcinogens or reasonably 
anticipated to be human carcinogens by the National Toxicology Program 
(NTP);
     Constituents identified as potential occupational 
carcinogens by the National Institute for Occupational Safety and 
Health (NIOSH):
     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 (CA EPA) 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).
    FDA believes having criteria for use in determining whether a 
constituent is harmful or potentially harmful will be beneficial. FDA 
carefully evaluated the data, information, and views on HPHCs in 
tobacco products provided by TPSAC and the public, in light of the 
Agency's own knowledge and expertise, and taking into consideration its 
HPHC final guidance. Based on this evaluation, FDA tentatively 
concludes that it should use the criteria listed previously in this 
document in determining whether a constituent should be included on the 
HPHC list. Specifically, FDA has tentatively concluded that it should 
consider a constituent meeting these criteria 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

[[Page 50228]]

not, in fact, harmful or potentially harmful. Applying this approach to 
the criteria and the available information, FDA developed table 1 of 
this document.
    FDA recognizes that table 1 of this document may not include all 
constituents that are ``harmful or potentially harmful.'' For example, 
the criteria described previously in this document generally 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. Similarly, the criteria FDA 
has tentatively 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 HPHC list, and whether individual constituents should 
be added. Just as these types of new information may lead to additions 
to the list, FDA recognizes 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. For these reasons, FDA will continue to review scientific 
information about tobacco product constituents. FDA intends to do this 
both before and after it establishes its list of HPHCs for the purpose 
of section 904(e) of the FD&C Act, consistent with the directive in 
section 904(e) that the Agency periodically revise the list as 
appropriate.

II. Request for Comments and Information

    FDA is soliciting public comment, including scientific and other 
information, concerning the HPHCs in tobacco products and tobacco 
smoke. We are particularly interested in comments from the public on 
the following topics:
     The criteria FDA should use in determining whether a 
constituent is harmful or potentially harmful such that it should be 
included on the HPHC list;
     Whether any chemicals or chemical compounds not listed in 
table 1 of this document should be added because they are harmful or 
potentially harmful, including supporting scientific or other 
information; and/or
     Whether any of the chemicals or chemical compounds listed 
in table 1 of this document should be removed because they are not 
harmful or potentially harmful, including supporting scientific or 
other information.

III. Submission of Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either electronic or written comments regarding this 
document. It is only necessary to send one set of comments. It is no 
longer necessary to send two copies of mailed comments. Identify 
comments with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday.

 Table 1--List of the Chemicals and Chemical Compounds Identified by FDA
 as Harmful and Potentially Harmful Constituents in Tobacco Products and
                              Tobacco Smoke
------------------------------------------------------------------------
                                   Carcinogen (CA), respiratory toxicant
                                    (RT), cardiovascular toxicant (CT),
           Constituent                 reproductive or developmental
                                       toxicant (RDT), addictive (AD)
------------------------------------------------------------------------
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

[[Page 50229]]

 
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]acridine..............  CA, CT
Dibenz[a,j]acridine..............  CA
Dibenz[a,h]anthracene............  CA
Dibenzo[c,g]carbazole............  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).
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 ).

[[Page 50230]]

 
Uranium-235......................  CA, RT
Uranium-238......................  CA, RT
Vinyl acetate....................  CA, RT
Vinyl chloride...................  CA
------------------------------------------------------------------------


    Dated: August 9, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-20502 Filed 8-11-11; 8:45 am]
BILLING CODE 4160-01-P


