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 Department of Health and Human Services Food and Drug Administration [Docket No. FDA-2012-N-0143]
 AGENCY: Food and Drug Administration, HHS.
 ACTION: Notice; establishment of a list.
 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: 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.( print 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: 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): ○ 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). 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. 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 
                    ( print 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
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, RDTCaffeic 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*]anthracene
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)
CA( print page 20037)Glu-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 )
CAUranium-235
CA, RTUranium-238
CA, RTVinyl acetate
CA, RTVinyl chloride
CA
 Dated: March 23, 2012. Leslie Kux, 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
 4.
    
                         “Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke; Request for Comments,” 76 FR 50226 (August 12, 2011). Back to Citation


[FR Doc. 2012-7727 Filed 3-30-12; 11:15 am] BILLING CODE 4160-01-P