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 Department of Health and Human Services Food and Drug Administration [Docket No. FDA-2011-N-0271]
 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 
                    ( print 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: 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: 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): ○ Central nervous system activity; ○ Animal drug discrimination; ○ Conditioned place preference; ○ Animal self-administration; ○ Human self-administration; ○ Drug liking; ○ 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 
                    ( print 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
Constituent
Carcinogen (CA), respiratory toxicant (RT), cardiovascular toxicant (CT), reproductive or developmental toxicant (RDT), addictive (AD)Acetaldehyde
CA, RT, ADAcetamide
CAAcetone
RTAcrolein
RT, CTAcrylamide
CAAcrylonitrile
CA, RTAflatoxin B1
CA4-Aminobiphenyl
CA1-Aminonaphthalene
CA2-Aminonaphthalene
CAAmmonia
RTAnabasine
ADo-Anisidine
CAArsenic
CA, CT, RDTA-α-C (2-Amino-9
                            *H*
                            -pyrido[2,3-
                            *b*]indole)
CABenz[
                            *a*]anthracene
CA, CTBenz[
                            *j*]aceanthrylene
CABenzene
CA, CT, RDTBenzo[
                            *b*]fluoranthene
CA, CTBenzo[
                            *k*]fluoranthene
CA, CTBenzo[
                            *b*]furan
CABenzo[
                            *a*]pyrene
CABenzo[
                            *c*]phenanthrene
CABeryllium
CA1,3-Butadiene
CA, RT, RDTCadmium
CA, RT, RDT( print page 50229)Caffeic acid
CACarbon monoxide
RDTCatechol
CAChlorinated dioxins/furans
CA, RDTChromium
CA, RT, RDTChrysene
CA, CTCobalt
CA, CTCoumarin
Banned in foodCresols (o-, m-, and p-cresol)
CA, RTCrotonaldehyde
CACyclopenta[
                            *c,d*]pyrene
CADibenz[
                            *a,h*]acridine
CA, CTDibenz[
                            *a,j*]acridine
CADibenz[
                            *a,h*]anthracene
CADibenzo[
                            *c,g*]carbazole
CADibenzo[
                            *a,e*]pyrene
CADibenzo[
                            *a,h*]pyrene
CADibenzo[
                            *a,i*]pyrene
CADibenzo[
                            *a,l*]pyrene
CA2,6-Dimethylaniline
CAEthyl carbamate (urethane)
CA, RDTEthylbenzene
CAEthylene oxide
CA, RT, RDTFormaldehyde
CA, RTFuran
CAGlu-P-1 (2-Amino-6-methyldipyrido[1,2-
                            *a:*
                            3',2'-
                            *d*]imidazole)
CAGlu-P-2 (2-Aminodipyrido[1,2-
                            *a:*
                            3',2'-
                            *d*]imidazole)
CAHydrazine
CA, RTHydrogen cyanide
RT, CTIndeno[
                            *1,2,3-cd*]pyrene
CAIQ (2-Amino-3-methylimidazo[4,5-
                            *f*]quinoline)
CAIsoprene
CALead
CA, CT, RDTMeA-α-C (2-Amino-3-methyl)-9
                            *H*
                            -pyrido[2,3-
                            *b*]indole)
CAMercury
CA, RDTMethyl ethyl ketone
RT5-Methylchrysene
CA4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)
CANaphthalene
CA, RTNickel
CA, RTNicotine
RDT, ADNitrobenzene
CA, RT, RDTNitromethane
CA2-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)
CANornicotine
ADPhenol
RT, CTPhIP (2-Amino-1-methyl-6-phenylimidazo[4,5-
                            *b*]pyridine)
CAPolonium-210
CAPropionaldehyde
RT, CTPropylene oxide
CA, RTQuinoline
CASelenium
RTStyrene
CAo-Toluidine
CAToluene
RT, RDTTrp-P-1 (3-Amino-1,4-dimethyl-5
                            *H*
                            -pyrido[4,3-
                            *b*]indole)
CATrp-P-2 (1-Methyl-3-amino-5
                            *H*
                            -pyrido[4,3-
                            *b*]indole )
CA( print page 50230)Uranium-235
CA, RTUranium-238
CA, RTVinyl acetate
CA, RTVinyl chloride
CA
 Dated: August 9, 2011. Leslie Kux, Acting Assistant Commissioner for Policy.


# Footnotes

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.* Back to Citation
 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.* Back to Citation
 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.* Back to Citation


[FR Doc. 2011-20502 Filed 8-11-11; 8:45 am] BILLING CODE 4160-01-P