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Description of key information

Value used for CSA (route: oral):

NOAEL: 11 mg Ni/kg bw/day as nickel sulphate hexahydrate

Value used for CSA (route: inhalation):

LOAEC: 0.11 mg Ni/m³

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Endpoint conclusion
Dose descriptor:
0.15 mg/m³

Justification for classification or non-classification

Ni subsulphide is classified as Carc. 1A; H350i via inhalation route of exposure according to the 1st ATP to the CLP Regulation. Background information can be found in the discussion section.

A document that includes a summary on this topic is provided as a background document in section 7.5.1 of IUCLID and in Appendix B1 of the CSR. In summary, absence of oral carcinogenicity of the nickel (II) ion demonstrates that the possible carcinogenic effects of nickel-containing substances in humans are limited to the inhalation route of exposure and the associated organ of entry (i.e., the respiratory tract). After inhalation, respiratory toxicity limits the systemic absorption of Ni (II) ion to levels below those that can be achieved via oral exposure. 

Additional information

Data on the oral carcinogenicity of Ni subsulphide are read-across from Ni sulphate as Ni sulphate represents a worst-case scenario for systemic absorption of nickel since nickel sulphate hexahydrate is significantly more readily solubilized in gastrointestinal fluid than Ni subsulphide and results in the highest systemic absorption of Ni (II) ions (Ishimatsu et al., 1995). A 2-year carcinogenicity study with rats performed according to OECD 451 did not show any carcinogenic potential of exposure to nickel sulphate following oral (gavage) administration. There is sufficient oral carcinogenicity data to show that nickel sulphate does not show any carcinogenic potential in experimental animals following oral administration. Likewise, less bioavailable Ni compounds (like Ni subsulphide) are also not expected to have any oral carcinogenic potential.A summary document on this topic is provided as a background document in section 7.5.1 of IUCLID and in Appendix B1of the CSR.

Inhalation carcinogenicity information can be derived from epidemiological data (e.g. ICNCM, 1990). These studies demonstrated that exposures to for sulphidic nickel compounds, such as nickel subsulphide, are associated with carcinogenicity of the respiratory tract. Available carcinogenicity animal data from Ni sulphate (oral) and human data from epidemiological studies (inhalation) indicate that nickel subsulphide does not cause carcinogenicity afteroral exposure but does have the potential to cause respiratory tract carcinogenicity after inhalation exposure.

Many studies evaluating carcinogenicity in laboratory species following exposures to Ni3S2 were identified in the peer-reviewed literature. Studies were conducted using a wide range of approaches. The majority of studies assessed carcinogenicity associated with inhalation, intratracheal instillation or intramuscular (i.m.) exposures; however, a number of other routes were also examined, including intratesticular (i.t.), intrahepatic (i.h.), intrarenal (i.r.), intraperitoneal (i.p.), subcutaneous (s.c.), and via heterotopic tracheal transplants. No studies evaluating carcinogenicity associated with oral or dermal exposure were identified. Most studies evaluated mice and rats, though some studies in hamsters were also identified. Carcinogenic effects associated with a wide range of exposure durations (from a single exposure up to 2 years of exposure), as well as a wide range of doses (environmentally relevant levels up to maximum tolerated doses and LD50 levels) were evaluated. Collectively, these studies evaluated carcinogenic potential, species differences in response, dose-dependencies, and exposure-route dependencies.

The most robust and environmentally relevant carcinogenicity study for Ni3S2 was conducted as part of a National Toxicology Program study on the toxicity and carcinogenicity of NiSO4, Ni3S2, and NiO (Dunnicket al.1995; NTP, 1996). Following inhalation of Ni3S2 for up to two years (6 hr/d, 5 d/wk, two exposure levels), a dose-dependent incidence of lung tumors (combined adenomas and carcinomas) was observed in F344/N rats. Benign and malignant pheochromocytomas of the adrenal medulla were also observed in male rats. In contrast, no exposure-related neoplasms were found in any B6C3F1 male and female mice. For both species, survival was generally similar between exposed and control animals, though bodyweight was lower in exposed animals.

Two other long-term inhalation studies also reported carcinogenicity in rats. Ottolenghi et al. (1975) exposed F344 rats to a single dose level of Ni3S2 via inhalation for 78 weeks; treated rats had a significant increase in lung tumors relative to control animals. Mortality between control and treated rats did not differ during the first year, but mortality increased significantly for treated animals during the last 26 weeks of exposure. Haratake et al. (1992) evaluated a different strain of rats, reporting that 6 months of Ni3S2 inhalation (single dose level) resulted in sporadic tumors in various organs 12 months following cessation of exposure in Wistar rats (no tumors observed immediately following exposure). However, because there was not a difference in lung tumors or extrapulmonary tumors between treated and control animals, the authors concluded that Ni3S2 showed no apparent promoting effects on tumorigenesis under the conditions present in this study.

The intratracheal study findings have sometimes shown conflicting results. In the Kasprzak et al.(1973) study, Wistar rats exposed to Ni3S2 via intratracheal instillation did not result in excessive carcinogenicity (only one malignant tumor was found 15 months following exposure). Contrasting evidence was reported by Pott et al.(1987). Following intratracheal administration once per week for 15 consecutive weeks (three dose levels), a generally dose-dependent incidence of tumors (characterized as adenomas, adenocarcinomas, squamous cell carcinomas, or mixed) was reported in Wistar rats.

Consistent with the inhalation findings, two intratracheal instillation studies in mice also resulted in a lack of carcinogenic effects based on tumorigenesis. Fisher et al.(1986) administered Ni3S2 once per week for 4 weeks at concentrations as high as the LD50 in B6C3F1 mice and found no malignant or benign tumors, nor other pathological changes in the lungs of mice maintained until 27 months of age. Similar findings were reported in A/J mice administered Ni3S2 via i.p. and intratracheal routes (McNeill et al.1990). Despite evaluation of a number of exposure scenarios (once per 3 wk for 15 wk, once per 2 wk for 15 wk, or once per wk for 15 wk), repeated exposures to 0.053 or 0.160 mg/kg Ni3S2 did not cause tumors in this study. Additionally, intratracheal instillation of Ni3S2 in Syrian golden hamsters did not result in an increase in pulmonary tumors over controls (Muhle et al.1992).

In addition to the studies previously mentioned, the potential carcinogenic effects associated with Ni3S2 exposure were evaluated in a number of studies that employed exposure routes not directly relevant to human exposure scenarios and hence to human risk assessment. Variations in response among strains were evaluated in animals exposed intramuscularly. Rodriguez et al.(1996) reported that i. m. Ni3S2 exposure resulted in a dose dependent increase in sarcoma tumor incidence over time in three strains of mice. However, clear strain-dependent differences in response were noted: there was a reverse order strain difference in susceptibility based on mortality (C57BL > B6C3F1 > C3H) as compared to carcinogenicity (C3H>B6C3F1>C57BL). The latency of the injection site tumors was shorter in the C3H mice than in B6C3FI and C57BL mice. Additionally, lung tumors (predominantly fibrosarcomas) occurred in C3H and B6C3FI mice, but not in C57BL mice (C57BL mice suffered from leukemia and lymphoma more often than the other mice). Strain differences in response were also noted in intramuscular studies in rats. Ohmori et al. (1999) examined the carcinogenesis of Ni3S2 in two different strains of Wistar rats and found that rats from a certain specific inbred colony were less susceptible (based on tumor incidence and latency) to nickel tumorigenesis in soft tissue than rats in a common closed colony. Yamashiro et al. (1980) observed a higher incidence of site-specific tumors in Fischer rats injected i.m. with 10 mg Ni3S2 as compared to Hooded rats. Further, a higher proportion of the tumors observed in Hooded rats metastasized.

In contrast to these findings, several studies reported tumors in rats at the point of injection following i.m. exposure. Locally occurring rhabdomyosarcomas were observed in all treatment groups within ~200 days of exposure to a variety of forms of Ni3S2 in Fisher rats (Gilman and Herchen 1963). Additionally, most of the tumors exhibited a high incidence of metastases (primarily to the lung). Kasprzak (1974) also reported locally occurring rhabdomyosarcomas in Fisher rats. Results of this study also demonstrated a time-dependent increase in the incidence of tumors (as well as metastases to lung or lymph nodes). Similar findings were noted by Ohmori et al. (1994); 15 of 17 rats exposed to a single i.m. injection of Ni3S2 had tumors at the site of injection (several animals also had metastases to the lymph nodes and lungs). By contrast, i.m. administration of Ni3S2 during gestation did not result in transplacental carcinogenicity in progeny (Sunderman et al. 1981).

Comparisons of carcinogenic responses associated with differential routes of exposure were evaluated in several studies and species. Oskarsson (1979) exposed mice to Ni3S2 i.m., s.c., or to simultaneous i.m and s.c. exposure. Despite exposure route, mice from each group began exhibiting tumors (fibrosarcomas or poorly differentiated mesenchymal tumors) at the injection sites 6 months following injection. Roughly half of all tumor-bearing mice had metastases to the lung, liver, or regional lymph nodes. In hamsters, Sunderman et al. (1977) demonstrated that carcinogenicity was route-dependent based on a comparison of carcinogenic responses following i.m. or topically swabbed (onto the inner buccal pouch) exposure to Ni3S2. Ni3S2 induced multiple sarcomas at the sites of single i.m. injections; however, Ni3S2 did not induce any malignant tumors of the cheek pouches, oral cavity or gastrointestinal tract, despite multiple local applications to the cheek pouches of several groups of hamsters. This group of authors also evaluated route-dependent carcinogenicity in rats. Animals exposed to a single dose of Ni3S2 injected i.m. or i.t. experienced tumors, whereas animals exposed to a single dose i.h., and intraglandularly did not.

Damjanov et al. (1978) reported that a single i.t. injection of Ni3S2 in F344 rats resulted in significant tissue damage as well as a high incidence of sarcomas, which were further classified as fibrosarcomas, malignant fibrous histiocytomas, and rhabdomyosarcomas. No primary tumors were found anywhere other than the testis. Yarita and Nettesheim (1978) examined the carcinogenic potential of 1.0 and 3.0 mg Ni3S2 pellets inserted into heterotopic tracheal transplants, grafted under the dorsal skin of female F344 rats. The system was chosen because it allowed for Ni3S2 to stay in contact with the respiratory mucosa for extended periods of time (i.e., exposure continues as long as the Ni3S2 remains in the lumen). In addition to a number of adverse changes noted in the surrounding tissues, Ni3S2 induced carcinomas in tracheal epithelium. A breakdown of the tumor types indicated a dose-response relationship for sarcoma induction, but not for the induction of carcinomas.

As part of a larger study designed to examine the carcinogenicity of specific fibers, metal compounds and dust, Pott et al. (1987) examined the carcinogenicity of Ni3S2 administered by i.p. injection at the maximum tolerable dose in rats. Sixty-four percent of the animals developed tumors in the abdominal cavity with an average time to tumor formation of 33 weeks. The tumors scored were characterized as sarcomas, mesotheliomas, and carcinomas. Pott et al. (1992) also evaluated the carcinogenicity of Ni3S2 administered by i.p. injection under three exposure regimens in rats: a single 6 mg injection, two consecutive weeks of a single 6 mg injection, and 25 weekly injections of 1 mg. Results indicated a dose (or frequency) -dependent increase in the percentage of animals with tumors (mesotheliomas and sarcomas).

Taken together, data indicate that under laboratory conditions, Ni3S2 has demonstrated carcinogenic potential. However, results are clearly dose-, time-, route-, species- and to some extent strain-dependent. Findings were difficult to compare across studies given the diverse study designs employed. Data were sufficient to characterize carcinogenicity associated with inhalation and i.m. exposure using a weight of the evidence approach.


Several epidemiological studies evaluating the association between occupational exposure to nickel and disease (primarily cancer) were identified. Co-exposures to other nickel compounds as well as other metals was a factor acknowledged by the study authors in each study; however, each of these studies specifically identified nickel subsulphide (or sulfidic nickel) as a primary compound to which some workers were exposed. As is the case in all human studies, “sulfidic” nickel was determined to be present based either upon metallurgical knowledge of the processes to which workers were exposed or some type of analytical technique (e.g. sequential leaching) applied to samples of total nickel.


A series of studies on workplaces in Norway, Wales, Canada (Ontario), and Finland provide information pertaining to exposures to sulfidic nickel and associated cancer risks, mainly those pertaining to lung and nasal cancers. As might be expected, processing and refining of sulphide-containing nickel ores, constituted one of the, if not the sole, primary activities in which workers were engaged. Of these, the studies on Welsh and Ontario workers are the most important in providing insight with respect to the possible role that nickel subsulphide (and other sulfidic forms of nickel) played in inducing these cancers.


In Clydach, very high excess lung and nasal cancer risks were seen in workers hired prior to 1930. Little evidence exists for excess respiratory cancer risks in workers employed at Clydach post-1930 (Peto et al., 1984; Doll et al., 1990; Sorahan and Williams, 2005) although in Grimsrud and Peto (2006) analyses of the Clydach data, increased nasal and lung cancer risk (30%) for workers hired after 1930 are reported.  Where modest risks have been observed, cigarette smoking as a possible etiological factor in causing these risks is highly plausible. Workers hired prior to 1930 were believed to have been exposed to combinations of nickel-copper oxides, sulfidic nickel (including both nickel sulphide and nickel subsulphide), and/or soluble nickel compounds. While other confounding agents were also present (e.g., arsenic), the very high levels of excess nasal cancer deaths present in these workers (Obs., 74; SMR, 21119; CI, 16583-26514; Doll et al., 1990), strongly implicated some form of nickel as contributing to these risks, as workers in other industry sectors where arsenic is also known to be present (e.g., copper smelter workers) have not shown high risks of nasal cancers (Doll, 1984). Moreover, the very high risks of lung cancer (SMR, 393; CI 336-456; Doll et al., 1990) in these workers further suggested a carcinogenic role for some form of nickel, although other confounders such as cigarette smoking and/or arsenic may have contributed to these risks. Post 1990 analyses of the data from the Clydach refinery show hints of possible correlations between excess cancer risk and nickel metal and soluble nickel exposure (Easton et al., 1992). However, these associations were either not reproduced or lost statistical significance after accounting for confounding exposures. The authors indicated that they may have overestimated the risks for metallic (and possibly soluble) nickel and underestimated those for sulfides and/or oxides.


In an international study of ten different nickel cohorts (Doll et al., 1990), workers at Clydach were specifically evaluated for excess respiratory cancer risks associated with exposures to various forms of nickel. Cross classification and workplace analyses of estimated cumulative nickel species were conducted. Excess risks of lung and nasal cancers in linear calcining workers, where nickel subsulphide most certainly would have been present, far exceeded those in copper plant workers, even though exposures to oxidic and soluble nickel compounds were similar for the two groups. Cross-classification analyses of the entire cohort by cumulative nickel also showed the strongest associations of lung and nasal cancer risks in workers with sulfidic nickel exposures; weaker associations with oxidic nickel exposures; and little evidence of an association with soluble nickel in the absence of significant insoluble nickel. 


Excess nasal and lung cancer risks have also been observed in Canadian workers engaged in sintering activities in Ontario (Roberts et al., 1984; Roberts et al., 1989a,b; Doll et al., 1990). In the case of these workers, however, oxidic nickel exposures completely confounded sulfidic nickel exposures. Oxidic nickel exposures in this cohort were mostly to high temperature (green) nickel oxide. This compound demonstrated some evidence of carcinogenicity in inhalation animal studies but is not considered to be the most potent of the oxide compounds based on animal and epidemiological studies. This suggests that the excess respiratory cancers risks seen in the Ontario sinter workers were more likely associated with nickel subsulphide. So, while the oxidic nickel found at Ontario, as well as other confounding agents, including arsenic and cigarette smoking, may have contributed to the excess respiratory cancer risks observed, it is not unreasonable to assume that they would not have been the primary etiological cause of these cancers.   


Additional evidence for a possible association of exposure to sulfidic nickel and respiratory cancer risks can also be found in an analysis of nickel workers employed at Huntington, West Virginia prior to 1947, or in or after 1947. In an update of a study originally conducted by Enterline and Marsh (1982) five additional years of follow-up were added to the cohort (Doll et al., 1990). While no excess risks of lung cancer were observed in the overall cohort hired prior to 1947, a modest dose-response to cumulative sulfidic nickel was seen in workers with fifteen or more years since first employment. A similar dose-response was not seen for other nickel species. Moreover, in workers hired in or after 1947, there was likewise no evidence of increased lung cancer risks. Of the three men thought to have died of nasal cancer in both cohorts, all had either worked in the calcining department (where exposures to sulfidic nickel were relatively high) or in the acid reclaim area (where nickel-copper oxides and sulfuric acid mists would have been present). Both these departments were unique to this facility and would not be representative of the nickel alloying industry as a whole. Thus, the most compelling evidence (albeit if modest) for respiratory cancer risks in this alloy company were for exposures to sulfidic nickel and, possibly, nickel-copper oxides.


With respect to Norway, in its cross-classification analysis of Norwegian workers, Doll et al. (1990) did not find sulfidic nickel exposures to be a significant risk factor at the Kristiansand refinery. This was confirmed in the later analyses of these workers by Andersen et al. (1996) and Grimsrud et al. (2002, 2003) where, after adjusting for smoking and age, no dose-response risk with cumulative exposures to nickel subsulphide was observed. This might be expected as the amount of sulfidic nickel believed to be present at Kristiansand was far less than that at Clydach, Ontario, and even, at Huntington. It is also possible that the exposures to sulfidic nickel estimated based on a leaching method (Zatka et al, 1992) may have been missassigned to the “soluble fraction” (Oller et al., 2009).


With respect to Finland, while most of the onus for any excess respiratory cancer risks in refinery workers has been placed on soluble nickel (Anttila et al., 1998), it should be noted that no dose-response was seen for lung cancers. With respect to the three nasal cancer cases observed in refinery workers, all were seen in workers who stopped working in the facility at or prior to the point in which leaching, solution purification, and precipitate removal were still performed in the tank house (e.g., until 1982) (Kiilunen et al., 1997). While there is some discrepancy between the description by Kiilunen et al. (1997) and that of Anttila et al. (1998) as to the exact time when grinding and leaching were separated from the tank house, because of the long latencies of nasal cancer and the dates of first employment of these three workers (1950s/early-1960s), it is likely that these workers would have been exposed to nickel sulphide and subsulphide in grinding and leaching, thus, raising a possible role of sulfidic nickel in the induction of these nasal cancers. Other confounding factors (i.e., exposures to wood dust or acid mists) may also have played a role in these nasal cancers.                        

Taken together, the epidemiological and animal data provide strong evidence that nickel subsulphide should be considered as carcinogenic to the respiratory tract of humans after inhalation.

Data on the dermal carcinogenicity of Ni subsulphide are read-across from Ni sulphate. As oral exposure to nickel sulphate does not show any carcinogenic potential, there are good reasons to assume that cancer is not a relevant end-point with respect to dermal exposure either.


The following information is taken into account for any hazard / risk assessment:

ORAL: Data are read-across from Ni sulphate. A well-conducted OECD 451 study in rats did not show any carcinogenic potential of nickel sulphate following oral administration.A summary document on this topic is provided as a background document in section 7.5.1 of IUCLID and in Appendix B1of the CSR.

INHALATION: Inhalation carcinogenicity information can be derived from epidemiological data (e.g. ICNCM, 1990). These studies demonstrated that exposures to for sulphidic nickel compounds, such as nickel subsulphide, are associated with carcinogenicity of the respiratory tract. Available carcinogenicity animal data from Ni sulphate (oral) and human data from epidemiological studies (inhalation) indicate that nickel subsulphide does not cause carcinogenicity after oral exposure but does have the potential to cause respiratory tract carcinogenicity after inhalation exposure.

DERMAL: Read-across from Ni sulphate. As oral exposure to nickel sulphate does not show any carcinogenic potential, there are good reasons to assume that cancer is not a relevant end-point with respect to dermal exposure either.