20034 Federal Register / Vol. 77, No. 64 / Tuesday, April 3, 2012 / Notices 

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. 

2See 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/TobaccoProducts

ScientificAdvisoryCommittee/ucm222977.htm and 

http://www.fda.gov/AdvisoryCommittees/

CommitteesMeetingMaterials/TobaccoProducts

ScientificAdvisoryCommittee/ucm222978.htm. 

IV. 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. Identify comments with the 

docket number found in brackets in the 

heading of this document. Received 

documents may be seen in the Division 

of Dockets Management between 9 a.m. 

and 4 p.m., Monday through Friday. 

V. Electronic Access 

Persons with access to the Internet 

may obtain an electronic version of this 

guidance document at http://www.

regulations.gov and http://www.fda.gov/ 

TobaccoProducts/GuidanceC

omplianceRegulatoryInformation/

default.htm. 

Dated: March 23, 2012. 

Leslie Kux, 

Assistant Commissioner for Policy. 

[FR Doc. 2012–7766 Filed 3–30–12; 11:15 am] 

BILLING CODE 4160–01–P 

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. 

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/GuidanceCompliance

RegulatoryInformation) (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 nonusers 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. 

mstockstill on DSK4VPTVN1PROD with NOTICES

Federal Register / Vol. 77, No. 64 / Tuesday, April 3, 2012 / Notices 20035 

3See 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. 

4 ‘‘Harmful and Potentially Harmful Constituents 

in Tobacco Products and Tobacco Smoke; Request 

for Comments,’’ 76 FR 50226 (August 12, 2011). 

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): 

Æ Central nervous system activity; 

Æ Animal drug discrimination; 

Æ Conditioned place preference; 

Æ Animal self-administration; 

Æ Human self-administration; 

Æ Drug liking; 

Æ 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 7Hdibenz[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 

mstockstill on DSK4VPTVN1PROD with NOTICES

20036 Federal Register / Vol. 77, No. 64 / Tuesday, April 3, 2012 / Notices 

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, 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-a-C (2-Amino-9H-pyrido[2,3-b]indole) ......................................................................................................................... CA 

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-methyldipyrido[1,2-a:3’,2’-d]imidazole) ........................................................................................... CA 

mstockstill on DSK4VPTVN1PROD with NOTICES

Federal Register / Vol. 77, No. 64 / Tuesday, April 3, 2012 / Notices 20037 

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—Continued 

Constituent 

Carcinogen (CA), 

respiratory toxicant (RT), 

cardiovascular toxicant 

(CT), reproductive or 

developmental toxicant 

(RDT), 

addictive (AD) 

Glu-P-2 (2-Aminodipyrido[1,2-a:3’,2’-d]imidazole) .......................................................................................................... CA 

Hydrazine ........................................................................................................................................................................ CA, RT 

Hydrogen cyanide ........................................................................................................................................................... RT, CT 

Indeno[1,2,3-cd]pyrene ................................................................................................................................................... CA 

IQ (2-Amino-3-methylimidazo[4,5-f]quinoline) ................................................................................................................ CA 

Isoprene .......................................................................................................................................................................... CA 

Lead ................................................................................................................................................................................ CA, CT, RDT 

MeA-a-C (2-Amino-3-methyl)-9H-pyrido[2,3-b]indole) .................................................................................................... CA 

Mercury ........................................................................................................................................................................... CA, RDT 

Methyl ethyl ketone ......................................................................................................................................................... RT 

5-Methylchrysene ............................................................................................................................................................ CA 

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) .................................................................................................. CA 

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-phenylimidazo[4,5-b]pyridine) .............................................................................................. CA 

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-pyrido[4,3-b]indole) ................................................................................................. CA 

Trp-P-2 (1-Methyl-3-amino-5H-pyrido[4,3-b]indole ) ...................................................................................................... CA 

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 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2012–N–0001] 

Peripheral and Central Nervous 

System Drugs Advisory Committee; 

Notice of Meeting 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice. 

This notice announces a forthcoming 

meeting of a public advisory committee 

of the Food and Drug Administration 

(FDA). The meeting will be open to the 

public. 

Name of Committee: Peripheral and 

Central Nervous System Drugs Advisory 

Committee. 

General Function of the Committee: 

To provide advice and 

recommendations to the Agency on 

FDA’s regulatory issues. 

Date and Time: The meeting will be 

held on May 24, 2012, from 8:30 a.m. to 

5 p.m. 

Location: FDA White Oak Campus, 

Building 31, the Great Room, White Oak 

Conference Center (Rm. 1503), 10903 

New Hampshire Ave., Silver Spring, MD 

20993–0002. Information regarding 

mstockstill on DSK4VPTVN1PROD with NOTICES