1 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 Supp ort 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(Bromomet hyl)

- 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 7 5

- 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

summ ary 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, NTP2 RoC backgrou nd documents were not available so the summary profile, primary NTP studies and IARC monographs were reviewed. For purposes of clarity, t he specific references reviewed for each chemical are listed (chemical

- by

- chemical) at the end of this

memo.
Through out 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 Guidelin es for Carcinogen Risk Assessment, the NTP RoC evaluates the scientific literature and publicly available , p eer

- reviewed technical reports of human and laboratory studies to evaluate whether substances are possible human carcinogens. Neither the NTP RoC n or 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 condit ions 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 “C riteria for the technical adequacy of animal carcinogenicit y studies have been published and should be used as guidance to judge the accep tability 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 assessme nts 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 spe cific assessment of whether the modes

- of

action 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 carcino gen” 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 anticipa ted 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 eviden ce 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 anti cipated 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 how3 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. Nationa l 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 27 709.

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 F 344/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(bromometh yl)

- 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 Corpora tion, 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.4 IARC. 2000. Some Industrial Chemicals. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 77. Lyon, France: Internationa l 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 Toxicol ogy 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. Pre pared 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 Hum an 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 A gency 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 Human5 Services, Public Health Service, National Toxi cology 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 Counsel ors. 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. Depa rtment 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, Tec hnology 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 Ja nuary 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.6 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 277 09.

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. Pr epared 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 Huma ns, 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 Nit roarenes. 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

– Nitroar enes (Selected) Substance Profile. Released January 31, 2005. U.S. Department of Health and7 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 Contrac t 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 - Nitroa nisole

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 Pa rk, 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, Inte grated 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 R isk 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. Dep artment 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 He alth and Human Services, Public Health Service, National Toxicology Program, Research Triangle Park, NC 27709.8 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 Chemic als. 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

– Phenolphth alein 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 Phenolphtha lein. 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.

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 Pr ogram. 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 p p.
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 Progr am, 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 Co unselors. Prepared by, Integrated Laboratory Systems, Research Triangle Park, NC 27709. NIEHS Contract No. N01

- ES

- 25346.9 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 Evaluati on 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. Relea sed 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 R ats 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 Som e 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 b y, 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 Eva luation of Carcinogenic Risk of Chemicals to Humans, vol. 63. Lyon, France: International Agency for Research on Cancer. 558 pp.