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1-28-2010

MEMORANDUM

SUBJECT: Review of National Toxicology Program (NTP) Cancer Classification 

Data for Sixteen Chemicals 

FROM: Mark Miller, Ph.D.

Toxicologist 

Analytical Support Branch 

TO: Nicole Paquette, Ph.D.

Chief 

Analytical Support Branch 

I have reviewed the supporting data for the NTP Report on Carcinogens (RoC) 

cancer classifications for the following chemicals:

Chemical Abstracts # Chemical Name

81-49-2 1-Amino-2,4-dibromoanthraquinone

3296-90-0 2,2-bis(Bromomethyl)-1,3-propanediol

42397-64-8 1,6-Dinitropyrene

42397-65-9 1,8-Dinitropyrene 

110-00-9 Furan

556-52-5 Glycidol

78-79-5 Isoprene 

93-15-2 Methyleugenol

91-23-6 o-Nitroanisole

7496-02-8 6-Nitrochrysene 

75-52-5 Nitromethane

57835-92-4 4-Nitropyrene

77-09-8 Phenolphthalein

116-14-3 Tetrafluoroethylene

509-14-8 Tetranitromethane

75-02-5 Vinyl Fluoride

Specifically, and where available for each chemical, I reviewed the NTP RoC 

summary profile, the NTP RoC background document, any primary NTP studies, and the 

International Agency for Research on Cancer Research (IARC) monographs cited in the 

NTP RoC summary profile. For two chemicals, glycidol and tetranitromethane, NTP 
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RoC background documents were not available so the summary profile, primary NTP 

studies and IARC monographs were reviewed. For purposes of clarity, the specific 

references reviewed for each chemical are listed (chemical-by-chemical) at the end of this 

memo.

Throughout my review of the NTP documents I found no inconsistencies between 

how the data were interpreted by the NTP and how that same data would be interpreted 

under EPA’s Guidelines for Carcinogen Risk Assessment (March 2005).

Consistent with the EPA Guidelines for Carcinogen Risk Assessment, the NTP 

RoC evaluates the scientific literature and publicly available, peer-reviewed technical 

reports of human and laboratory studies to evaluate whether substances are possible 

human carcinogens. Neither the NTP RoC nor the EPA’s Guidelines for Carcinogen 

Risk Assessment present a quantitative assessment of the risks of cancer associated with 

a given chemical. Rather, they indicate the potential hazard associated with chemicals 

but do not establish the exposure conditions that would pose cancer risks to individuals. 

The EPA guidelines specifically use the NTP criteria for assessing individual 

study inclusion in the assessment of carcinogenicity, stating “Criteria for the technical 

adequacy of animal carcinogenicity studies have been published and should be used as 

guidance to judge the acceptability of individual studies, e.g., NTP, 1984...” (pg. 2-16). 

When reliable studies are available, both the EPA cancer risk assessments and the 

NTP RoC include hazard assessments of human and animal data, human exposure 

assessments, and dose-response assessments in their respective weight of evidence 

determinations for carcinogenicity. Further, they both incorporate physical/chemical 

properties of the chemical as well as a specific assessment of whether the modes-ofaction for adverse effects seen in animal studies would be expected to operate in humans.

In addition, the NTP and the EPA use similar criteria for listing chemicals as 

“reasonably anticipated to be a human carcinogen” or “likely to be carcinogenic to 

humans”, respectively. The EPA Guidelines for Carcinogen Risk Assessment 

specifically detail “likely to be carcinogenic to humans” as a comparable weight of 

evidence term to the NTP classification “reasonably anticipated to be a human 

carcinogen” (pg. 2-53). Supporting data for an agent listed with this EPA descriptor 

includes “an agent that has tested positive in animal experiments in more than one species, 

sex, strain, site, or exposure route, with or without evidence of carcinogenicity in humans”. 

Based on the weight of evidence, the NTP reports have identified each of these chemicals 

as reasonably anticipated to be a human carcinogen. For all but one chemical increased 

tumorigenesis has been observed at multiple sites, in multiple species. The only chemical 

that varied was nitromethane, which was shown to increase the incidence of tumors at 

multiple sites in mice, but only a single site in rats. In all cases the RoC-listed chemicals 

reviewed were reasonably anticipated to be human carcinogens based on sufficient 

evidence of carcinogenicity in experimental animals. 

Given the extensive scientific reviews conducted by the NTP for their RoC 

documents, my review focused on ensuring that there were no inconsistencies with how 
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the Agency would consider the available data. I found no inconsistencies and agree with 

the hazard conclusions of the NTP RoC for each of the chemicals included in the 

proposed rule. Therefore, I believe it would be appropriate for the Agency, for the 

purposes of listing these chemicals on the Toxics Release Inventory, to conclude that 

these chemicals are likely to be carcinogenic to humans, consistent with the NTP 

conclusions. 

References

1-Amino-2,4-dibromoanthraquinone

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens - 1-Amino-2,4-

dibromoanthraquinone Substance Profile. Released January 31, 2005. U.S. Department 

of Health and Human Services, Public Health Service, National Toxicology Program, 

Research Triangle Park, NC 27709.

NTP, 2002. Report on Carcinogens Background Document for 1-Amino-2,4-

Dibromoanthraquinone. September 19, 2002. Prepared for, U.S. Department of Health 

and Human Services, Public Health Service, National Toxicology Program, Research 

Triangle Park, NC 27709. Prepared by, Technology Planning and Management 

Corporation Canterbury Hall, Suite 310, 4815 Emperor Blvd, Durham, NC 27703 

Contract Number N01-ES-85421.

NTP. 1996. Toxicology and Carcinogenesis Studies of 1-Amino-2,4-

Dibromoanthraquinone in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical 

Report Series No 383. Research Triangle Park, NC: National Toxicology Program.

2,2-bis(bromomethyl)-1,3-propanediol

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens - 2,2-

bis(bromomethyl)-1,3-propanediol Substance Profile. Released January 31, 2005. U.S. 

Department of Health and Human Services, Public Health Service, National Toxicology 

Program, Research Triangle Park, NC 27709.

NTP. Report on Carcinogens Background Document for 2,2-bis(Bromomethyl)-1,3-

propanediol (Technical Grade). Prepared for, U.S. Department of Health and Human 

Services, Public Health Service, National Toxicology Program, Research Triangle Park, 

NC 27709. Prepared by, Technology Planning and Management Corporation, 

Canterbury Hall, Suite 310, 4815 Emperor Blvd, Durham, NC 27703 Contract Number 

N01-ES-85421.

NTP. 1996. Toxicology and Carcinogenesis Studies of 2,2-Bis(Bromomethyl)-1,3-

Propanediol (FR-1138) (CAS no. 3296-90-0) in F344/N Rats and B6C31F Mice (Feed

Studies). Technical Report Series No 452. Research Triangle Park, NC: National 

Toxicology Program. 
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IARC. 2000. Some Industrial Chemicals. IARC Monographs on the Evaluation of 

Carcinogenic Risk of Chemicals to Humans, vol. 77. Lyon, France: International Agency 

for Research on Cancer. 529 pp.

Furan

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens - Furan Substance 

Profile. Released January 31, 2005. U.S. Department of Health and Human Services, 

Public Health Service, National Toxicology Program, Research Triangle Park, NC 27709.

NTP, 1999. Report on Carcinogens Background Document for Furan. March 1999. 

Prepared for, November 18-19, 1996, Meeting of the Report on Carcinogens 

Subcommittee of the Board of Scientific Counselors. Prepared by, Integrated Laboratory 

Systems, Research Triangle Park, NC 27709. NIEHS Contract No. N01-ES-25346.

NTP. 1993. Toxicology and Carcinogenesis Studies of Furan (CAS No. 110-00-9) in 

F344 Rats and B6C3F1 Mice(Gavage Studies). Technical Report Series No 402. NIH 

Publication No. 93-2857. Research Triangle Park, NC: National toxicology Program. 286 

pp 

IARC. 1995. Dry Cleaning, Some Chlorinated Solvents and Other Industrial Chemicals. 

IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 

63. Lyon, France: International Agency for Research on Cancer. 558 pp.

Glycidol

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens - Glycidol 

Substance Profile. Released January 31, 2005. U.S. Department of Health and Human 

Services, Public Health Service, National Toxicology Program, Research Triangle Park, 

NC 27709.

NTP, 1990. Toxicology and Carcinogenesis Studies of Glycidol (CAS No. 556-52-5) In 

F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No 374. NIH 

Publication No. 90-2829. Research Triangle Park, NC: National Toxicology Program. 

229 pp.

IARC. 2000. Some Industrial Chemicals. IARC Monographs on the Evaluation of 

Carcinogenic Risk of Chemicals to Humans, vol. 77. Lyon, France: International Agency 

for Research on Cancer. 529 pp.

Isoprene

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens – Isoprene 

Substance Profile. Released January 31, 2005. U.S. Department of Health and Human 
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Services, Public Health Service, National Toxicology Program, Research Triangle Park, 

NC 27709.

NTP, 1999. Report on Carcinogens Background Document for Isoprene. March 1999. 

Prepared for, December 2- 3, 1998, Meeting of the Report on Carcinogens Subcommittee 

of the NTP Board of Scientific Counselors. Prepared by, Integrated Laboratory Systems, 

Research Triangle Park, NC 27709. NIEHS Contract No. N01-ES-25346.

NTP. 1995. Toxicity Studies of Isoprene (CAS No. 78-79-5) Administered by Inhalation 

to in F344/N Rats and B6C3F1 Mice. Technical Report Series No 31, 31. NIH 

Publication No. 95-3354. Research Triangle Park, NC: National Toxicology Program. 

210 pp. 

IARC. 1999. Re-evaluation of Some Organic Chemicals, Hydrazine, and Hydrogen 

Peroxide. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to 

Humans, vol. 71. Lyon, France: International Agency for Research on Cancer. 1589 pp.

Methyleugenol

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens – Methyleugenol 

Substance Profile. Released January 31, 2005. U.S. Department of Health and Human 

Services, Public Health Service, National Toxicology Program, Research Triangle Park, 

NC 27709.

NTP, 2000. Report on Carcinogens Background Document for 2,2-bis(Bromomethyl)-

1,3-propanediol (Technical Grade). December 13 - 14, 2000 Meeting of the NTP Board 

of Scientific Counselors Report on Carcinogens Subcommittee. Prepared for, U.S. 

Department of Health and Human Services, Public Health Service, National Toxicology 

Program, Research Triangle Park, NC 27709. Prepared by, Technology Planning and 

Management Corporation, Canterbury Hall, Suite 310, 4815 Emperor Blvd, Durham, NC 

27703 Contract Number N01-ES-85421.

NTP. 2000. Toxicology and Carcinogenesis Studies of Methyleugenol (CAS NO. 93-15-

2) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No 491. 

Research Triangle Park, NC: National Toxicology Program. 412 pp.

1,6-Dinitropyrene

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens – Nitroarenes 

(Selected) Substance Profile. Released January 31, 2005. U.S. Department of Health and 

Human Services, Public Health Service, National Toxicology Program, Research 

Triangle Park, NC 27709.

NTP, 1999. Report on Carcinogens Background Document for 1,6-Dinitropyrene and 

1,8-Dinitropyrene. Final March 1999. Prepared for, November 18-19, 1996, Meeting of 

the Report on Carcinogens Subcommittee of the NTP Board of Scientific Counselors. 
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Prepared by, Integrated Laboratory Systems, Research Triangle Park, NC 27709. NIEHS 

Contract No. N01-ES-25346.

IARC. 1989. Diesel and Gasoline Engine Exhausts and Some Nitroarenes. IARC 

Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 46. 

Lyon, France: International Agency for Research on Cancer. 458 pp.

1,8-Dinitropyrene

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens – Nitroarenes 

(Selected) Substance Profile. Released January 31, 2005. U.S. Department of Health and 

Human Services, Public Health Service, National Toxicology Program, Research 

Triangle Park, NC 27709.

NTP, 1999. Report on Carcinogens Background Document for 1,6-Dinitropyrene and 

1,8-Dinitropyrene. Final March 1999. Prepared for, November 18-19, 1996, Meeting of 

the Report on Carcinogens Subcommittee of the NTP Board of Scientific Counselors. 

Prepared by, Integrated Laboratory Systems, Research Triangle Park, NC 27709. NIEHS 

Contract No. N01-ES-25346.

IARC. 1989. Diesel and Gasoline Engine Exhausts and Some Nitroarenes. IARC 

Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 46. 

Lyon, France: International Agency for Research on Cancer. 458 pp.

6-Nitrochrysene

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens – Nitroarenes 

(Selected) Substance Profile. Released January 31, 2005. U.S. Department of Health and 

Human Services, Public Health Service, National Toxicology Program, Research 

Triangle Park, NC 27709.

NTP, 1999. Report on Carcinogens Background Document for 6-Nitrochrysene. Final 

March 1999. Prepared for, November 18-19, 1996, Meeting of the Report on 

Carcinogens Subcommittee of the NTP Board of Scientific Counselors. Prepared by, 

Integrated Laboratory Systems, Research Triangle Park, NC 27709. NIEHS Contract No. 

N01-ES-25346.

IARC. 1989. Diesel and Gasoline Engine Exhausts and Some Nitroarenes. IARC 

Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 46. 

Lyon, France: International Agency for Research on Cancer. 458 pp.

4-Nitropyrene

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens – Nitroarenes 

(Selected) Substance Profile. Released January 31, 2005. U.S. Department of Health and 
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Human Services, Public Health Service, National Toxicology Program, Research 

Triangle Park, NC 27709.

NTP, 1999. Report on Carcinogens Background Document for 4-Nitropyrene. Final 

March 1999. Prepared for, November 18-19, 1996, Meeting of the Report on 

Carcinogens Subcommittee of the NTP Board of Scientific Counselors. Prepared by, 

Integrated Laboratory Systems, Research Triangle Park, NC 27709. NIEHS Contract No. 

N01-ES-25346.

IARC. 1989. Diesel and Gasoline Engine Exhausts and Some Nitroarenes. IARC 

Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 46. 

Lyon, France: International Agency for Research on Cancer. 458 pp.

o-Nitroanisole

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens – o-Nitroanisole 

Substance Profile. Released January 31, 2005. U.S. Department of Health and Human 

Services, Public Health Service, National Toxicology Program, Research Triangle Park, 

NC 27709.

NTP, 1999. Report on Carcinogens Background Document for o-Nitroanisole. Final 

March 1999. Prepared for, November 18-19, 1996, Meeting of the Report on 

Carcinogens Subcommittee of the NTP Board of Scientific Counselors. Prepared by, 

Integrated Laboratory Systems, Research Triangle Park, NC 27709. NIEHS Contract No. 

N01-ES-25346.

NTP. 1993. Toxicology and Carcinogenesis Studies of o-Nitroanisole (CAS No. 91-23-6) 

in F344 Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No 416. NIH 

Publication No. 93-3147. Research Triangle Park, NC and Bethesda, MD: National 

Toxicology Program. 482 pp. 

IARC. 1996. Printing Processes and Printing Inks, Carbon Black and Some Nitro 

Compounds. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to 

Humans, vol. 65. Lyon, France: International Agency for Research on Cancer. 578 pp.

Nitromethane

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens – Nitromethane 

Substance Profile. Released January 31, 2005. U.S. Department of Health and Human 

Services, Public Health Service, National Toxicology Program, Research Triangle Park, 

NC 27709.

NTP, 2002. Final Report on Carcinogens Background Document for Nitromethane. 

March 25, 2002. Prepared for, U.S. Department of Health and Human Services, Public 

Health Service, National Toxicology Program, Research Triangle Park, NC 27709. 
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Prepared by, Technology Planning and Management Corporation, Canterbury Hall, Suite 

310, 4815 Emperor Blvd, Durham, NC 27703 Contract Number N01-ES-85421.

NTP. 1997. Toxicology and Carcinogenesis Studies of Nitromethane in F344/N Rats and 

B6C3F1 Mice (Inhalation Studies). Technical Report Series No 461. Research Triangle 

Park, NC: National Toxicology Program. 

IARC. 2000. Some Industrial Chemicals. IARC Monographs on the Evaluation of 

Carcinogenic Risk of Chemicals to Humans, vol. 77. Lyon, France: International Agency 

for Research on Cancer. 529 pp.

Phenolphthalein 

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens – Phenolphthalein 

Substance Profile. Released January 31, 2005. U.S. Department of Health and Human 

Services, Public Health Service, National Toxicology Program, Research Triangle Park, 

NC 27709.

NTP, 1999. Report on Carcinogens Background Document for Phenolphthalein. Final 

March 1999. Prepared for, October 30-31, 1997, Meeting of the Report on Carcinogens 

Subcommittee of the NTP Board of Scientific Counselors. Prepared by, Integrated 

Laboratory Systems, Research Triangle Park, NC 27709. NIEHS Contract No. N01-ES25346.

NTP. 1996. Toxicology and Carcinogenesis Studies of Phenolphthalein (CAS No. 77-09-

8) in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No 465. 

NIH Publication No. 97-3390. Research Triangle Park, NC: National Toxicology 

Program. 354 pp. 

IARC. 2000. Some Antiviral and Antineoplastic Drugs, and Other Pharmaceutical 

Agents. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to 

Humans, vol. 76. Lyon, France: International Agency for Research on Cancer. 522 pp.

Tetrafluoroethylene

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens –

Tetrafluoroethylene

 Substance Profile. Released January 31, 2005. U.S. Department of Health and Human 

Services, Public Health Service, National Toxicology Program, Research Triangle Park, 

NC 27709.

NTP, 1999. Report on Carcinogens Background Document for Tetrafluoroethylene. 

Final March 1999. Prepared for, October 30-31, 1997, Meeting of the Report on 

Carcinogens Subcommittee of the NTP Board of Scientific Counselors. Prepared by, 

Integrated Laboratory Systems, Research Triangle Park, NC 27709. NIEHS Contract No. 

N01-ES-25346.
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NTP. 1997. Toxicology and Carcinogenesis Studies of Tetrafluoroethylene (CAS No. 

116-14-3) in F344 Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series 

No 450. NIH Publication No. 97-3366. Research Triangle Park, NC: National Toxicology 

Program. 321 pp. 

IARC. 1999. Re-evaluation of Some Organic Chemicals, Hydrazine, and Hydrogen 

Peroxide. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to 

Humans, vol. 71. Lyon, France: International Agency for Research on Cancer. 1589 pp.

Tetranitromethane

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens – Tetranitromethane 

Substance Profile. Released January 31, 2005. U.S. Department of Health and Human 

Services, Public Health Service, National Toxicology Program, Research Triangle Park, 

NC 27709.

NTP. 1990. Toxicology and Carcinogenesis Studies of Tetranitromethane (CAS No. 509-

14-8) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series No 

386. NIH Publication No. 90-2841. Research Triangle Park, NC and Bethesda, NC: 

National Toxicology Program. 207 pp.

IARC. 1996. Printing Processes and Printing Inks, Carbon Black and Some Nitro 

Compounds. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to 

Humans, vol. 65. Lyon, France: International Agency for Research on Cancer. 578 pp.

Vinyl fluoride

NTP, 2005. National Toxicity Program. 11th Report on Carcinogens – Vinyl Fluoride 

Substance Profile. Released January 31, 2005. U.S. Department of Health and Human 

Services, Public Health Service, National Toxicology Program, Research Triangle Park, 

NC 27709.

NTP. Report on Carcinogens Background Document for Vinyl Fluoride. Meeting of the 

NTP Board of Scientific Counselors Report on Carcinogens Subcommittee. Prepared for, 

U.S. Department of Health and Human Services, Public Health Service, National 

Toxicology Program, Research Triangle Park, NC 27709. Prepared by, Technology 

Planning and Management Corporation, Canterbury Hall, Suite 310, 4815 Emperor Blvd, 

Durham, NC 27703 Contract Number N01-ES-85421.

IARC. 1995. Dry Cleaning, Some Chlorinated Solvents and Other Industrial Chemicals. 

IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 

63. Lyon, France: International Agency for Research on Cancer. 558 pp.