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Toxicological information

Carcinogenicity

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Description of key information

ORAL: Data are read-across from Ni sulfate.  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 can be found in the attached document entitled, "Background-Oral Carcinogenicity for all Nickel Compounds" (Section 7.7 of IUCLID) and in Appendix B6 of the CSR.
INHALATION: Data are read-across from Ni subsulfide. 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 (NTP 1996, Dunnick et al. 1995). 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. Epidemiological studies addressing the carcinogenicity of nickel subsulphide, some of which included specific exposures to Ni hydroxycarbonate, are also considered.
DERMAL: Read-across from Ni sulfate. 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.

Key value for chemical safety assessment

Justification for classification or non-classification

Ni hydroxycarbonate is classified as Cat.1:R49 and 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.

 

In addition, a background document summarizing the potential of Ni compounds to cause cancer via the oral route of exposure can be found in the attached document entitled, "Background-Oral Carcinogenicity for all Nickel Compounds" (Appendix B6 to 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

Due to the structural similarities of Pentanickel Octahydroxide Carbonate and Nickel Hydroxycarbonate, all information in this section is relevant for Pentanickel Octahydroxide Carbonate (see section 13 for full discussion of read-across strategy).

Summary from the 2008/2009 European Union Risk Assessment for Nickel Carbonate (applicable to nickel hydroxycarbonate):

Studies on the carcinogenicity of nickel carbonate following intramuscular implants or intraperitoneal injections have been performed in rats; tumours were observed following both administration routes [Payne, 1964 and Pott et al. 1990].

The Pott et al. (1992) study reported that i.p. administration of 1 mg nickel hydroxycarbonate once a week for 25 weeks resulted in a tumor incidence that was not statistically difference from the concurrent controls but was statistically elevated compared to the historical controls. It should be noted that these routes of administration are irrelevant for humans who will only be exposed via inhalation, oral intake or dermal contact to nickel hydroxycarbonate. Animal data regarding the potential carcinogenicity of Ni hydroxycarbonate are limited to these aforementioned studies. As no information regarding carcinogenicity of nickel hydroxycarbonate following inhalation, oral, or dermal exposure in experimental animals have been located, data from other nickel compounds are used to read-across carcinogenicity information to Ni hydroxycarbonate.  

Data on the oral carcinogenicity of Ni hydroxycarbonate are read-across from Ni sulfate. The 2008/2009 European Union Risk Assessment for Nickel Sulfate states:

The carcinogenicity of nickel sulphate following oral administration has been studied in two old non-guideline studies with rats and dogs; no neoplasms were revealed in either rats or dogs in these studies. 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. Data on other nickel compounds are limited to a drinking water study of nickel acetate in rats and mice in which no exposure-related neoplasms was observed. In conclusion, there is sufficient oral carcinogenicity data to show that nickel sulphate does not show any carcinogenic potential in experimental animals following oral administration.

The lack of oral carcinogenic potential for nickel sulfate hexahydrate can be extrapolated to other soluble and insoluble nickel compounds. Nickel sulfate hexahydrate represents a worst-case scenario for systemic absorption of nickel since nickel sulfate hexahydrate is readily solubilized in gastrointestinal fluid and results in the highest systemic absorption of Ni (II) ions compared to less soluble nickel-containing substances (Ishimatsu et al.,1995). A background document summarizing the potential of Ni compounds to cause cancer via the oral route of exposure can be found in the attached document entitled, "Background-Oral Carcinogenicity for all Nickel Compounds" (Section 7.7) and in Appendix B6 of this CSR.

Data for carcinogenicity of Ni hydroxycarbonate via inhalation exposure are read-across from Ni subsulfide. A comprehensive read-across assessment of various nickel compounds was recently completed based on the bioaccessibility of nickel in synthetic lung fluids combined within vivoverification data for three source nickel substances, Ni sulfate, Ni oxide, and Ni subsulfide. To estimate bioavailability via the inhalation route of exposure various nickel substances were subjected to bioaccessibility testing (KMHC, 2010). The bioaccessibility-based read-across paradigm incorporating these data is presented in a summary document that is included as Appendix B2 to the CSR.  Bioaccessibility data for the inhalation route of exposure can provide important information regarding the potential bioavailability and subsequent toxicity for inhalation endpoints such as acute and chronic inhalation toxicity. Although this paradigm was designed to assess the potential for toxicity, the bioaccessibility data provide information that can be combined with knowledge of mode of action of different nickel compounds to assess potential for inhalation carcinogenicity. In this assessment, relative bioaccessibility from different nickel substances in extracellular (interstitial and alveolar) and intracellular (lysosomal) synthetic lung fluids were compared to that of the source substances. Taking into account all of the available information, the bioaccessibility of Ni hydroxycarbonate in lung fluids appears most similar to that of Ni subsulfide and hence repeated carcinogenicity via inhalation is read-across from Ni subsulfide.

The most robust and relevant carcinogenicity study for Ni3S2was conducted as part of a National Toxicology Program (1996) studies on the toxicity and carcinogenicity of NiSO4, Ni3S2and NiO (Dunnicket al.1995). Following inhalation of Ni3S2for 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.

Several epidemiological studies investigated the association between occupational exposure to a variety of nickel substances and respiratory cancer. In one of these cohorts, the nickel refinery at Kristiansand (Norway), nickel hydroxycarbonate was reported to be present (Doll et al., 1990; Andersen et al., 1996; Grimsrud et al., 2002). These studies looked at the associations between increased cancer risks and exposures to the main forms of nickel (soluble, metallic, sulphidic, oxidic), but a separate analysis for nickel hydroxycarbonate was not carried out. For this reason we relied on the more robust analyses performed for Ni subsulphide. Several studies evaluating the association between occupational exposure to nickel and disease (primarily cancer) were identified for Ni3S2. 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), andprovide information pertaining to exposures to sulfidic nickel and associated cancer risks, mainly those pertaining to lung and nasal cancers. As might be expected, 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, Wales 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., 1989; 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 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.   

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 Huntington. It is also possible that the exposures to sulfidic nickel estimated based on a leaching method (Zatka et al, 1992) may have been miss assigned 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. As mentioned above, the nickel exposures in the Norwegian cohort included nickel hydroxycarbonate (Doll et al., 1990; Andersen et al., 1996; Grimsrud et al., 2002). Although nickel hydroxycarbonate if often considered as part of the “oxidic” fraction of the nickel exposure, in some of the analyses of this cohort, the nickel hydroxycarbonate exposure was considered to be part of the “water soluble nickel fraction.” However, for the purpose of classification for carcinogenicity, reading across from nickel subsulphide to nickel hydroxycarbonate is justified by the read across approach. Therefore, based on nickel subsulphide, the evidence indicates that nickel hydroxycarbonate should be considered carcinogenic to the respiratory tract of humans after inhalation.