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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. Supp orting information and explanations of the methods used to derive the values given in IRISare 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 Assessmen t (II.) on-line 01/01/1991 

### _I. Chronic Health Hazard Assess ments 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 Asse ssment 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 extrap olation procedure and is presente d as the risk per (mg/kg)/day. The unit risk is the quantitative estimate in terms of either risk per ug/L dr inking water or risk per ug/cu.m air breathed. The third form in which ri sk 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 (E PA/600/8-87/045) and in the IRIS Background Document. IRIS summaries developed since the pu blication 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-Evid ence Characterization Classification — A; human carcinogen
Basis — Increased risks of lung and nasal cancer in humans expo sed to nickel refi nery dust, most of which was believed to have been nickel subs ulfide; 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, po pulations 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 subsul fide, nickel sulfate, and nickel oxide at Port Co lborne (Roberts et al., 1982). Roberts et al. (1982) reported that the calcinin g/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.htmat 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 oxid e and had the highest risk of nasal cancer (SMR = 4000) and an elevated risk of lung cancer (SMR = 360) (Magnu s 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 apparentcontradiction to the hypothesis that the pyrometallurgical process and nick el subsulfide exposures are resp onsible for the observed cancer increases. In the electrolytic ta nkhouse, workers are exposed primar ily to nickel su lfate, nickel metal, copper and nickel oxides, and nickel chlo ride. These increases were not observed in the electrolysis op erations at Port Colborne (Roberts et al., 1984). In the study of refinery and nonrefinery workers at a nickel refinery in We st Virginia, nasal cancer was exclusive to the refinery workers, with an SMR of 2443 (Enter line and Marsh, 1982). No large excess of lung cancer was observed in either refinery (SMR = 118) or nonrefinery (S MR = 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 isthe most studied nickel comp ound, only one study has used inhalation as the route of expo sure. 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 to tal of 467 rats of both sexes (factor 1) were preexposed to nickel subsulfide , 0.97 mg Ni/cu.m, 6 ho urs/day, 5 days/week, for 1 month (factor 2), and then followed by a second treatm ent 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 sa crifice. Fewer than 5% of the nickel subsulfide group were alive at the en d of 108 weeks, as compared with 31% of the controls. The lungs were the major organ affect ed by the nickel subsulfide treatment. No differences in response were attr ibuted to sex differences or th e injections of HTFB. The lung effects included hyperplasia, me taplasia, adenomas, and adenocarcinomas equally in both males and females. These changes and tu mors occurred in both the bron chiolar and alveolar regions of the lung. Studies comparing species and st rain, 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 administra tion, different experimental conditions among laboratories make cross-comp arison difficult. Sund erman (1984) reported a dose-response relationship for tu mor induction by nickel subsul fide following intrarenal and intramuscular injections. Numerous studies haveshown nickel subsulfide to be a potent carcinogen by injection. All routesof administration have led to positive tumor induction except three: buccal brushing of Syrian golden hamsters, submaxillary im plantation into Fischer 344 rats (Sunderman et al., 1978), and in trahepatic injection of Spra gue-Dawley rats (Jasmin and Solymoss, 1978) and Fischer 344 rats (Sunderman et al., 1978). Although Ka sprzak 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.htmHuntington, WV (Enterline an d 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 morpho logic transformation in Syrian hamster embryo (Casto et al., 1979) and baby hamster kidney (BHK-21) cell cultures (Han sen 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 Carcin ogenic Risk from Oral Exposure Not available.

_II.C. Quantitative Estimate of Carcinog enic 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 Ca ncer 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 

### http://www.epa.gov/iris/subst/0273.htm_ _II.C.3. Additional Co mments (Carcinogenici ty, 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 un it risk estimate of nick el 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 expe cted 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 Hunt ington, WV and Copper Cliff, Ontario data sets. Data sets from nickel refineries in Hunt ington, 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 info rmation available either for choiceof model or for separation of risk by the type of ni ckel exposure. The dose-response data for nasal cancer were not used for risk estimation since nasal cancer risk from ni ckel is thought to be an occupational hazard associated only with the pyrometa llurgical process and isnot found in the general public to the same extent as lung tumors. For the four data sets analyzed, both the additi ve and multiplicative ex cess risk models were fitted whenever possible. The relative risk or multiplicative model follows the assumption that the background cause-age- specific ra te at any time is increased by an amount proportional to the cumulative dose up to that time. The model assu mes the SMR is linearly related to dose and is constant for a set cumu lative exposure. Excess mortality for a set cumulative exposure is constant over time, and excess ri sk remains constant once exposu re 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 amountproportional 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 re finery dust: 1.1E-5 to 4.6E-4 pe r (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 co ncentration exceeds 20 ug/c u.m, since above this concentration the unit risk may not be appropriate. __II.C.4. Discussion of Confidence (Carcinogenicity, In halation Exposure) Four data sets, all from human exposure, offer a ra nge of incremental unit risk estimates that are consistent with each other. Upper-limit incrementa l unit risks for nickel subsulfide exposure have been estimated from a rat inhalation study (Ott olenghi 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 (C arcinogenicity Assessment) __II.D.1. EPA Documentation Source Document — U.S. EPA, 1986 

### http://www.epa.gov/iris/subst/0273.htmThe 1986 Health Assessment Document has rece ived both Agency and external review. __II.D.2. EPA Review (Car cinogenicity 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 to xicology literature pertinent to th e cancer assessment for Nickel subsulfide conducted in November 2001 identified on e or more significant new studies. IRIS users may request the referencesfor 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 co ncerning 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. CarcinogenicityAssessment References Casto, B.S., J. Meyers and J.A. DiPalo. 1979. Enha ncement of viral transfor mation for evaluation of the carcinogenic or mutageni c potential of inorganic metal sa lts. 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. In d. 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.htmGilman, J.P.W. and S. Yamash iro. 1985. Muscle Tumorigenesi s by Nickel Compounds. In: Progress in Nickel Toxicology: Proceedings of th e Third International Co nference on Nickel Metabolism and Toxicology, Septem ber 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. Heal th Perspect. 51: 223-226. INCO (International Nickel Comp any). 1976. Nickel and its inorgani c 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 effe cts of nickel subsulfideon 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 an d 3,4- benzpyrene. Res. Commun. Chem. Pathol. Pharmacol. 6: 237-245. Magnus, K. A. Andersen and A. Hogetveit. 1984. Cancer of resp iratory 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 pulm onary 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 Sc ientific Publ. No. 53. Internat ional 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. Ca ncer mortality associated with the high-temperature oxidation of nickel subs ulfide. In: Nickel in the Human Environment: Proceedings of a Joint Symposium: March 1983. In ternational Agency for Research on Cancer, Lyon, France. p. 23-39. Robison, S.H. and M. Costa. 1982. Induction of DNA strand brea kage by nickel compounds in cultured Chinese hamster ovary cells. Cancer Le tt. 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 chromati d exchange in human ly mphoctytes by nickel sulfide. Cancer Res. 41: 4136-4139. Sunderman, F.W. Jr. 1984. Recent advances in me tal carcinogenesis. Ann. Clin. Lab. Sci. 14(2): 93-122. Sunderman, F.W. Jr., S.K. Shen, J.M. Mitchell, P. R. Allpass and I. Damjno v. 1978. Embryotoxicity and fetal toxicity of nick el in rats. Toxicol. Appl . Pharmacol. 43: 381-390. 

### http://www.epa.gov/iris/subst/0273.htmDate Section Description U.S. EPA. 1986. Health As sessment Document for Nickel and Ni ckel 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. Carcinogenicit y of nickel subsulfidefor 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-Leve l Literature Review Findin gs 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 

### http://www.epa.gov/iris/subst/0273.htmIRIS Home Chronic HealthHazards for NonCarcinogenic Effects Reference Dose for Chronic Oral Exposure (RfD) • Oral RfD Summary • Principal and Supporting Studies • Uncertainty and Modifying Factors • Additional Studies/Comments • Confidence in the Oral RfD • EPA Documentation and Review

Reference Concentration for Chronic Inhalation

Exposure (RfC) • Inhalation RfC Summary • Principal and Supporting Studies • Uncertainty and Modifying Factors • Additional Studies/Comments • Confidence in the Inhalation RfC • EPA Documentation and Review Carcinogenicity Assessment for Lifetime Exposure Evidence for Human Carcinogenicity• Weight-ofEvidence Characterization • Human Carcinogenicity Data • Animal Carcinogenicity Data • Supporting Data for Carcinogenicity Quantitative Estimate of 

### http://www.epa.gov/iris/subst/0273.htmCarcinogenic Risk from Oral Exposure

• Summary of Risk Estimates • Dose-Response Data • Additional Comments • Discussion of Confidence Quantitative Estimate of Carcinogenic Risk

from Inhalation Exposure • Summary of Risk Estimates • Dose-Response Data • Additional Comments • Discussion of Confidence • EPA Documentation, Review and, Contacts Bibliography Revision History Synonyms 

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