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Reference Dose for Chronic Oral Exposure (RfD) 

0273

Nickel subsulfide; CASRN 12035-72-2

Human health assessment information on a chemical substance is included in the IRIS database 

only after a comprehensive review of toxicity data, as outlined in the IRIS assessment 

development process. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II 

(Carcinogenicity Assessment for Lifetime Exposure) present the conclusions that were reached 

during the assessment development process. Supporting information and explanations of the 

methods used to derive the values given in IRIS are provided in the guidance documents located 

on the IRIS website. 

STATUS OF DATA FOR Nickel subsulfide

File First On-Line 09/30/1987

Oral RfD Assessment (I.A.) no data

Inhalation RfC Assessment (I.B.) no data

Carcinogenicity Assessment (II.) on-line 01/01/1991 

_I. Chronic Health Hazard Assessments for Noncarcinogenic Effects

_I.A. Reference Dose for Chronic Oral Exposure (RfD)

Substance Name — Nickel subsulfide

CASRN — 12035-72-2

Not available at this time.

Integrated Risk Information System

http://www.epa.gov/iris/subst/0273.htm

Last updated on Thursday, August 09, 2012

http://www.epa.gov/iris/subst/0273.htm
_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)

Substance Name — Nickel subsulfide

CASRN — 12035-72-2

Not available at this time.

_II. Carcinogenicity Assessment for Lifetime Exposure

Substance Name — Nickel subsulfide

CASRN — 12035-72-2

Last Revised — 01/01/1991

Section II provides information on three aspects of the carcinogenic assessment for the substance 

in question; the weight-of-evidence judgment of the likelihood that the substance is a human 

carcinogen, and quantitative estimates of risk from oral exposure and from inhalation exposure. 

The quantitative risk estimates are presented in three ways. The slope factor is the result of 

application of a low-dose extrapolation procedure and is presented as the risk per (mg/kg)/day. 

The unit risk is the quantitative estimate in terms of either risk per ug/L drinking water or risk per 

ug/cu.m air breathed. The third form in which risk is presented is a drinking water or air 

concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. The rationale 

and methods used to develop the carcinogenicity information in IRIS are described in The Risk 

Assessment Guidelines of 1986 (EPA/600/8-87/045) and in the IRIS Background Document. IRIS 

summaries developed since the publication of EPA's more recent Proposed Guidelines for 

Carcinogen Risk Assessment also utilize those Guidelines where indicated (Federal Register 61

(79):17960-18011, April 23, 1996). Users are referred to Section I of this IRIS file for 

information on long-term toxic effects other than carcinogenicity. 

_II.A. Evidence for Human Carcinogenicity

__II.A.1. Weight-of-Evidence Characterization

Classification — A; human carcinogen 

Basis — Increased risks of lung and nasal cancer in humans exposed to nickel refinery dust, most 

of which was believed to have been nickel subsulfide; increased tumor incidences in animals by 

several routes of administration in several animal species and strains; and positive results in 

genotoxicity assays form the basis for this classification. 

__II.A.2. Human Carcinogenicity Data

Sufficient. The lung and nasal cancer risk seen for nickel subsulfide, a major constituent of nickel 

refinery dust, is attributable to the formerly high dust and nickel subsulfide levels at sulfide nickel 

matte refineries. At Copper Cliff and Port Colborne, Ontario, populations showing elevated lung 

and nasal cancer worked in what were considered the dustier areas of the refineries. Greatest 

exposures were to nickel subsulfide, nickel sulfide, nickel oxide, coke particles, and polycyclic 

aromatic hydrocarbons at Copper Cliff (INCO, Ltd., 1976) and nickel subsulfide, nickel sulfate, 

and nickel oxide at Port Colborne (Roberts et al., 1982). 

Roberts et al. (1982) reported that the calcining/sintering process at Port Colborne was dusty 

(SMR for lung cancer = 298 and for nasal cancer = 9412) and caused similar exposures to those 

http://www.epa.gov/iris/subst/0273.htm
at the Clydach, Wales calcining sheds (SMR for lung cancer = 510 and for nasal cancer = 26,667) 

(Peto et al., 1984). Roasting/smelting workers at Kristiansand, Norway were exposed to "dry 

dust" containing nickel subsulfide and nickel oxide and had the highest risk of nasal cancer (SMR 

= 4000) and an elevated risk of lung cancer (SMR = 360) (Magnus et al., 1982). The high cancer 

response in the electrolytic tankhouse workers of this plant (SMR for lung and nasal cancer are 

550 and 2600, respectively) is the one apparent contradiction to the hypothesis that the 

pyrometallurgical process and nickel subsulfide exposures are responsible for the observed cancer 

increases. In the electrolytic tankhouse, workers are exposed primarily to nickel sulfate, nickel 

metal, copper and nickel oxides, and nickel chloride. These increases were not observed in the 

electrolysis operations at Port Colborne (Roberts et al., 1984). In the study of refinery and 

nonrefinery workers at a nickel refinery in West Virginia, nasal cancer was exclusive to the 

refinery workers, with an SMR of 2443 (Enterline and Marsh, 1982). No large excess of lung 

cancer was observed in either refinery (SMR = 118) or nonrefinery (SMR = 107.6) employees. 

The data do show a dose- response relationship between cumulative nickel exposure and lung 

cancer response (allowing for a 20-year latent period). 

__II.A.3. Animal Carcinogenicity Data

Although nickel subsulfide is the most studied nickel compound, only one study has used 

inhalation as the route of exposure. Ottolenghi et al. (1974) exposed Fischer 344 rats to an 

airborne nickel subsulfide concentration. The design of the experiment included two 

subtreatments in a 2**4 factorial arrangement: a total of 467 rats of both sexes (factor 1) were 

preexposed to nickel subsulfide, 0.97 mg Ni/cu.m, 6 hours/day, 5 days/week, for 1 month (factor 

2), and then followed by a second treatment of an intraveous injection with 

hexachlorotetrafluorobutane (HTFB), an agent used to induce pulmonary infarction (factor 3). The 

fourth factor was the actual treatment (after the injection factor) with nickel subsulfide for 78 to 

80 weeks, followed by 30 weeks of observation before terminal sacrifice. Fewer than 5% of the 

nickel subsulfide group were alive at the end of 108 weeks, as compared with 31% of the 

controls. The lungs were the major organ affected by the nickel subsulfide treatment. No 

differences in response were attributed to sex differences or the injections of HTFB. The lung 

effects included hyperplasia, metaplasia, adenomas, and adenocarcinomas equally in both males 

and females. These changes and tumors occurred in both the bronchiolar and alveolar regions of 

the lung. 

Studies comparing species and strain, route of administration, organ sensitivity, and doseresponse characteristics of nickel subsulfide carcinogenesis have been performed and reviewed by 

Sunderman (1984) and Gilman and Yamashiro (1985). While there are definite differences in 

tumor response between species/strain and route of administration, different experimental 

conditions among laboratories make cross-comparison difficult. Sunderman (1984) reported a 

dose-response relationship for tumor induction by nickel subsulfide following intrarenal and 

intramuscular injections. Numerous studies have shown nickel subsulfide to be a potent 

carcinogen by injection. All routes of administration have led to positive tumor induction except 

three: buccal brushing of Syrian golden hamsters, submaxillary implantation into Fischer 344 rats 

(Sunderman et al., 1978), and intrahepatic injection of Sprague-Dawley rats (Jasmin and 

Solymoss, 1978) and Fischer 344 rats (Sunderman et al., 1978). Although Kasprzak et al. (1973) 

reported no pulmonary tumors in Wistar rats given 5 mg nickel subsulfide intratracheally, 

bronchial metaplasia was increased from 31% to 62% when 5 mg nickel subsulfide was 

administered with benzpyrene (2 mg). Nickel subsulfide pellets implanted into heterotopic 

tracheas which were grafted in Fischer 344 rats produced mainly sarcomas with a low yield of 

carcinomas (Yarita and Nettesheim, 1978). 

http://www.epa.gov/iris/subst/0273.htm
Huntington, WV (Enterline and Marsh, 1982) (maximum 

likelihood estimates only)

Copper Cliff, Ontario (Chovil et al., 1981)

Clydach, Wales (Peto et al., 1984)

Kristiansand, Norway (Magnus et al., 1982) 

Midpoint of range for refinery workers 

__II.A.4. Supporting Data for Carcinogenicity 

Nickel subsulfide induces morphologic transformation in Syrian hamster embryo (Casto et al., 

1979) and baby hamster kidney (BHK-21) cell cultures (Hansen and Stern, 1983), sister 

chromatid exchange in human lymphocytes (Saxholm et al., 1981), and DNA strand breaks 

(Robison and Costa, 1982). Nickel as nickel subsulfide has been observed to concentrate in the 

cell nucleus in in vitro assays (Sunderman, 1984). 

_II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure

Not available.

_II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure

__II.C.1. Summary of Risk Estimates

Inhalation Unit Risk — 4.8E-4 per (ug/cu.m) 

Extrapolation Method — Additive and multiplicative 

Air Concentrations at Specified Risk Levels: 

Risk Level Concentration

E-4 (1 in 10,000) 2E-1 ug/cu.m

E-5 (1 in 100,000) 2E-2 ug/cu.m

E-6 (1 in 1,000,000) 2E-3 ug/cu.m

__II.C.2. Dose-Response Data for Carcinogenicity, Inhalation Exposure

Estimates of Incremental Unit Risks for Lung Cancer due to Exposure to 1 ug Ni/cu.m for a 

Lifetime Based on Extrapolations from Epidemiologic Data Sets

Study Relative Risk 

Mode

Refinery workers 1.5E-5 - 3.1E-5

Nonrefinery workers 9.5E-6 - 2.1E-5

1.1E-5 - 8.9E-5

8.1E-5 - 4.6E-4

1.9E-5 - 1.9E-4

2.4E-4

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__II.C.3. Additional Comments (Carcinogenicity, Inhalation Exposure)

Since nickel subsulfide is a major component of nickel refinery dust and has been shown to 

produce the highest incidence of tumors for nickel compounds in animals (supported by in vitro 

studies), the incremental unit risk estimate of nickel refinery dust [2.4E-4 per (ug/cu.m)] may be 

used with a multiplication factor of 2 to account for the roughly 50% nickel subsulfide 

composition. If the two observed nasal cancer deaths and expected nasal cancer deaths are 

included for refinery workers in Huntington, WV, the incremental unit risk increases to 1.3E-4. 

The average relative risk model was applied to the Huntington, WV and Copper Cliff, Ontario data 

sets. Data sets from nickel refineries in Huntington, WV (Enterline and Marsh, 1982); Copper 

Cliff, Ontario (Chovil et al., 1981); Clydach, Wales (Peto et al., 1984); and Kristiansand, Norway 

(Magnus et al., 1982) provide information available either for choice of model or for separation of 

risk by the type of nickel exposure. The dose-response data for nasal cancer were not used for 

risk estimation since nasal cancer risk from nickel is thought to be an occupational hazard 

associated only with the pyrometallurgical process and is not found in the general public to the 

same extent as lung tumors. 

For the four data sets analyzed, both the additive and multiplicative excess risk models were 

fitted whenever possible. The relative risk or multiplicative model follows the assumption that the 

background cause-age- specific rate at any time is increased by an amount proportional to the 

cumulative dose up to that time. The model assumes the SMR is linearly related to dose and is 

constant for a set cumulative exposure. Excess mortality for a set cumulative exposure is 

constant over time, and excess risk remains constant once exposure ceases. The relative risk 

model differs from the additive risk model in that the latter model assumes that the excess 

cause-age-specific rate is increased by an amount proportional to the cumulative exposure up to 

that time. 

The unit risk estimates ranged from 2.2E-5 to 9.2E-4 per (ug/cu.m). This is 2 times the 

incremental unit risk for nickel refinery dust: 1.1E-5 to 4.6E-4 per (ug/cu.m). The midpoint of the 

range, 4.8E-4 per (ug/cu.m), is taken as the incremental unit risk due to a lifetime exposure to 

nickel subsulfide. 

The unit risk should not be used if the air concentration exceeds 20 ug/cu.m, since above this 

concentration the unit risk may not be appropriate. 

__II.C.4. Discussion of Confidence (Carcinogenicity, Inhalation Exposure)

Four data sets, all from human exposure, offer a range of incremental unit risk estimates that are 

consistent with each other. Upper-limit incremental unit risks for nickel subsulfide exposure have 

been estimated from a rat inhalation study (Ottolenghi et al., 1974). They range from 2.7E-3 to 

6.1E-3 per (ug/cu.m), with the maximum likelihood estimates ranging from 1.8E-3 to 4.1E-3 per 

(ug/cu.m). This range is the consequence of a variety of assumptions for species differences 

using pooled treated animals vs. pooled controls. These estimates are approximately one order of 

magnitude greater than those obtained from the human studies. 

_II.D. EPA Documentation, Review, and Contacts (Carcinogenicity Assessment)

__II.D.1. EPA Documentation

Source Document — U.S. EPA, 1986 

http://www.epa.gov/iris/subst/0273.htm
The 1986 Health Assessment Document has received both Agency and external review. 

__II.D.2. EPA Review (Carcinogenicity Assessment)

Agency Work Group Review — 04/01/1987 

Verification Date — 04/01/1987 

Screening-Level Literature Review Findings — A screening-level review conducted by an EPA 

contractor of the more recent toxicology literature pertinent to the cancer assessment for Nickel 

subsulfide conducted in November 2001 identified one or more significant new studies. IRIS users 

may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 

(202)566-1676.

__II.D.3. EPA Contacts (Carcinogenicity Assessment)

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, 

at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address). 

_III. [reserved]

_IV. [reserved] 

_V. [reserved]

_VI. Bibliography 

Substance Name — Nickel subsulfide

CASRN — 12035-72-2

Last Revised — 07/01/1993

_VI.A. Oral RfD References

None

_VI.B. Inhalation RfC References

None

_VI.C. Carcinogenicity Assessment References

Casto, B.S., J. Meyers and J.A. DiPalo. 1979. Enhancement of viral transformation for evaluation 

of the carcinogenic or mutagenic potential of inorganic metal salts. Cancer Res. 39: 193-198. 

Chovil, A., R.B. Sutherland and M. Halliday. 1981. Respiratory cancer in a cohort of sinter plant 

workers. Br. J. Ind. Med. 38: 327-333. 

Enterline, P.E. and G.M. Marsh. 1982. Mortality among workers in a nickel refinery and alloy 

manufacturing plant in West Virginia. J. Natl. Cancer Inst. 68: 925-933. 

http://www.epa.gov/iris/subst/0273.htm
Gilman, J.P.W. and S. Yamashiro. 1985. Muscle Tumorigenesis by Nickel Compounds. In: 

Progress in Nickel Toxicology: Proceedings of the Third International Conference on Nickel 

Metabolism and Toxicology, September 1984, Paris, France. S.S. Brown and F.W. Sunderman, Jr. 

Ed., Blackwell Scientific Publication, Oxford, United Kingdom. p. 9-22. 

Hansen, K. and R.M. Stern. 1983. In vitro toxicity and transformation potency of nickel 

compounds. Environ. Health Perspect. 51: 223-226. 

INCO (International Nickel Company). 1976. Nickel and its inorganic compounds (including nickel 

carbonyl compounds). A supplementary submission to the National Institute for Occupational 

Safety and Health by International Nickel Inc. 

Jasmin, G. and B. Solymoss. 1978. The topical effects of nickel subsulfide on renal parenchyma. 

Adv. Exp. Med. Biol. 91: 69-83. 

Kasprzak, K.S., L. Marchow and J. Breborowicz. 1973. Pathological reactions in rat lungs following 

intratracheal injection of nickel subsulfide and 3,4- benzpyrene. Res. Commun. Chem. Pathol. 

Pharmacol. 6: 237-245. 

Magnus, K. A. Andersen and A. Hogetveit. 1984. Cancer of respiratory organs among workers at 

a nickel refinery in Norway. Int. J. Cancer. 30: 681-685. 

Ottolenghi, A.D., J.K. Haseman, W.W. Payne, H.L. Falk and H.N. MacFarland. 1974. Inhalation 

studies of nickel sulfide in pulmonary carcinogenesis of rats. J. Natl. Cancer Inst. 54: 1165-1172. 

Peto, J. H. Cuckle, R. Doll, C. Hermon and L.G. Morgan. 1984. Respiratory cancer mortality of 

Welsh nickel refinery workers. In: Nickel in the Human Environment: Proceedings of a Joint 

Symposium, March, 1983. IARC Scientific Publ. No. 53. International Agency for Research on 

Cancer, Lyon, France, p. 36-46. 

Roberts, R.S., J.A. Julian and D.C.F. Muir. 1982. A study of cancer mortality in workers engaged 

in mining, smelting and refining of nickel. Programme in Occupational Health Faculty of Health 

Sciences, McMaster University Hamilton, Ontario. 

Roberts, R.S., J.A. Julian, D.C.F. Muir and H. Shannon. 1984. Cancer mortality associated with 

the high-temperature oxidation of nickel subsulfide. In: Nickel in the Human Environment: 

Proceedings of a Joint Symposium: March 1983. International Agency for Research on Cancer, 

Lyon, France. p. 23-39. 

Robison, S.H. and M. Costa. 1982. Induction of DNA strand breakage by nickel compounds in 

cultured Chinese hamster ovary cells. Cancer Lett. 15: 35-40. 

Saxholm, H.J.K., A. Reith and A. Brogger. 1981. Oncogenic transformation and cell lysis in 

C3H/10T1/2 cells and increased sister chromatid exchange in human lymphoctytes by nickel 

sulfide. Cancer Res. 41: 4136-4139. 

Sunderman, F.W. Jr. 1984. Recent advances in metal carcinogenesis. Ann. Clin. Lab. Sci. 14(2): 

93-122. 

Sunderman, F.W. Jr., S.K. Shen, J.M. Mitchell, P.R. Allpass and I. Damjnov. 1978. Embryotoxicity 

and fetal toxicity of nickel in rats. Toxicol. Appl. Pharmacol. 43: 381-390. 

http://www.epa.gov/iris/subst/0273.htm
Date Section Description

U.S. EPA. 1986. Health Assessment Document for Nickel and Nickel Compounds. Prepared by the 

Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, 

Research Triangle Park, NC. EPA/600/8- 83/012FF. 

Yarita, T. and P. Nettesheim. 1978. Carcinogenicity of nickel subsulfide for respiratory tract 

mucosa. Cancer Res. 38: 3140-3145. 

_VII. Revision History

Substance Name — Nickel subsulfide

CASRN — 12035-72-2

03/01/1988 II.C.3. Text clarified

03/01/1990 VI. Bibliography on-line

06/01/1990 IV.A.1. Area code for EPA contact corrected

09/01/1990 II.A.3. Sunderman citation year corrected

09/01/1990 II.A.4. Sunderman citation year corrected

09/01/1990 VI.C. Sunderman 1983 citation year corrected to 1984

01/01/1991 II. Text edited

01/01/1991 II.C.1. Inhalation slope factor removed (global change)

01/01/1992 IV. Regulatory actions updated

04/01/1992 IV.A.1. CAA regulatory action withdrawn

07/01/1993 VI.C. References alphabetized correctly

04/01/1997 III., IV., 

V.

Drinking Water Health Advisories, EPA Regulatory Actions, and 

Supplementary Data were removed from IRIS on or before April 1997. 

IRIS users were directed to the appropriate EPA Program Offices for this 

information.

12/03/2002 II.D.2. Screening-Level Literature Review Findings message has been added.

_VIII. Synonyms

Substance Name — Nickel subsulfide

CASRN — 12035-72-2

Last Revised — 09/30/1987

• 12035-72-2

• HEAZLEWOODITE

• Nickel Subsulfide

• NICKEL SUBSULPHIDE

• NICKEL SULFIDE

• alpha-NICKEL SULFIDE (3:2) CRYSTALLINE

• NICKEL SULPHIDE

• NICKEL TRITADISULPHIDE

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