Nickel sulphate

Carcinogenicity

Description of key information

Value used for CSA (route: oral):

NOAEL: 11 mg Ni/kg bw/day (50.0 mg Ni sulphate hexahydrate/kg bw/day)

Value used for CSA (route: inhalation):

NOAEC: 0.11 mg Ni/m³ MMAD = 2.25 uM (0.50 mg Ni sulphate hexahydrate/m³ air)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

50 mg/kg bw/day

Carcinogenicity: via inhalation route

Endpoint conclusion

Dose descriptor:

NOAEC

0.5 mg/m³

Justification for classification or non-classification

Ni sulphate has been classified as Carc. 1A; H350i in the 1st ATP to the CLP Regulation. Background information regarding this classification is provided inthe discussion section above. In addition, a background document that discusses the potential of Ni compounds to cause cancer via the oral route of exposure can be found 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 or dermal exposure.

Additional information

Animal Data

Inhalation studies with nickel sulphate hexahydrate (MMAD = 2.1-2.5 µm; GSD ~ 2) have been performed in rats and mice (NTP 1996a). No exposure related neoplasms were observed in rats (F344/N) or in mice (B6C3F1) after exposure for two years at concentrations up to 0.11 mg Ni/m³ or 0.22 mg Ni/m³, respectively. These results are in contrast to those obtained with crystalline nickel subsulphide and green (high calcining temperature) nickel oxide. Inhalation studies with nickel oxide (NTP, 1996b) and nickel subsulphide (NTP, 1996c) showed some evidence and clear evidence, respectively, for carcinogenic activity following inhalation exposure in rats, and there was equivocal evidence for nickel oxide in female mice.

The different results obtained with nickel sulphate, nickel oxide, and nickel subsulphide raise questions as to whether these compounds differ in their mode of action or carcinogenic potency. The role of respiratory toxicity on carcinogenicity is also an important consideration. Water soluble nickel compounds are some of the most toxic of the nickel compounds for the respiratory tract but induced no tumors even at exposure levels corresponding to the maximum tolerated dose. A possible model for tumor initiation based on the Ni bioavailability at critical intracellular sites has been described to help reconcile all these possibilities (Oller et al., 2008; Goodman et al., 2009). It is postulated that there are many factors that can affect the bioavailability of nickel at key intracellular sites and that if these factors preclude Ni to be available at nuclear sites in sufficient amounts, no tumors will be induced. This could be the case for soluble nickel compounds that are very toxic to the lungs, and this toxicity limits the exposure levels that can be tolerated. In addition, these compounds are cleared from the lungs very quickly, and the Ni ion released extracellularly is very poorly taken up by the cells. The possibility that exposure to soluble nickel compounds may enhance the development of tumors initiated by other carcinogens cannot be excluded based on the data from animals experiments with single exposures.

The carcinogenicity of nickel sulphate following oral administration has been studied in rats and dogs and no neoplasms were observed in either of these two animal species (see Ambrose et al., 1976; IUCLID, section 7.7). However, these studies were old and not guideline compliant; therefore some uncertainties remained. A recent 2-year carcinogenicity study in rats by oral gavage has been completed (Heim et al., 2007). This study was performed according to OECD 451 guidance and it did not show a carcinogenic potential for exposure to nickel sulphate following oral administration. In conclusion, there is sufficient oral carcinogenicity data to show that nickel sulphate does not show a carcinogenic potential in experimental animals following oral administration. The negative results from the oral study are consistent with the negative results from the inhalation study in rats and provide supporting evidence for the low intracellular uptake and rapid excretion of water soluble nickel compound.

In addition,a background document that discusses the potential of Ni compounds to cause cancer via the oral route of exposure can be found in Appendix B1 of the CSR (and IUCLID Section 7.7).

No data regarding carcinogenicity following dermal contact to nickel sulphate in experimental animals have been located. In conclusion, the available data are too limited for an evaluation of the carcinogenic potential in experimental animals following dermal contact to water soluble nickel compounds. As oral exposure does not show carcinogenicity, it seems reasonable to assume that cancer is not a relevant endpoint for dermal exposure.

Studies on the carcinogenicity of nickel sulphate following intramuscular or intraperitoneal injections have been performed in rats. The results have either been negative (e.g., Kasprzak et al., 1983) or have shown low incidence of injection site tumors at very high exposure levels (e.g., Pott et al., 1989). It should be noted that these routes of administration are irrelevant for human beings who will only be exposed via inhalation, oral intake or dermal contact to nickel sulphate.

Three studies with nickel sulphate in experimental animals suggest a promoter effect of nickel sulphate, if applied locally to the nasopharynx or the oral cavity, or by the feed to pups from initiated dams; however, the indications are rather weak. Goodman et al. (2009) considered these data and concluded that although several possible non-genotoxic effects of the nickel ion have been described, it is not clear whether soluble nickel compounds can elicit these effects in vivo or whether these effects, if elicited, would result in tumor promotion.

A background document that discusses the potential of Ni compounds to cause cancer via the oral route of exposure can be found in Appendix B1 of the CSR (and IUCLID Section 7.7).

 

Epidemiology Data

As discussed in the European Union Risk Assessment for Nickel Sulphate (2008-2009), epidemiological studies from at least three nickel refineries processing sulphidic nickel ores have demonstrated elevated risk of lung and nasal cancer in workers exposed to dust containing nickel sulphate in the presence of variable amounts of water insoluble nickel compounds. These refineries were: the Clydach refinery in Wales, UK; the Kristiansand refinery in Norway; and the Harjavalta refinery in Finland. Among electrolysis workers at the Port Colborne refinery in Canada the association between respiratory cancer and exposure to nickel sulphate was not observed.

In Clydach (Doll et al., 1990; Easton et al., 1992; Sorahan and Williams, 2005; Grimsrud and Peto, 2006), elevated risk for death from lung or nasal cancer was found in workers employed in the hydrometallurgy department. Exposure to nickel sulphate also took place in other departments and there was evidence of a dose-response between soluble nickel exposure and increased cancer risk in workers with high oxidic and/or sulfidic exposure but not when oxidic and sulfidic exposures were low. At the Kristiansand refinery, both lung and nasal cancer mortality risks were elevated (Doll et al., 1990; Andersen et al., 1996; Grimsrud et al., 2002; 2003). A dose-response was demonstrated for lung cancer according to duration of work in the electrolysis departments. In a regression analysis, a dose-response for lung cancer and cumulative exposure to water-soluble nickel (nickel sulphate and nickel chloride) was observed after adjustment for age, smoking (ever smoker versus never smokers), and cumulative exposure to oxidic nickel. The effect from sulphidic nickel was not addressed but for oxidic nickel a modest increase in risk was also observed. The study suggested a multiplicative effect of smoking and nickel exposure. A 2002 case-control study within the same cohort, also demonstrated a dose-response between lung cancer and water-soluble nickel after adjustment for smoking (life-time habits). An increase in risk from exposures to other forms of nickel irrespective of dose could not be excluded.

The refinery in Harjavalta also treated a sulphidic nickel concentrate, as did the two refineries in Clydach and Kristiansand. Elevated risk for lung and nasal cancers was demonstrated in the group of workers with nickel sulphate exposures (Doll et al., 1990; Anttila et al., 1998). No adjustment for smoking could be performed in the analyses of lung cancer risk. No dose-response was found, but the number of cancer cases was low. The electrolysis workers at the Port Colborne refinery were exposed mainly to nickel sulphate until 1942 and from that year exposures contained a mixture of sulphate and chloride. In contrast to the three cohorts described above, lung cancer mortality risks were not elevated among the electrolysis workers with no exposure in leaching, calcining or sintering plant (Roberts et al., 1989a,b; Doll et al., 1990). In addition, there were no nasal cancer cases among these workers.

The European Union Risk Assessment for Nickel Sulphate (2008-2009) concluded that the epidemiological data demonstrated “a positive association in a dose-dependent manner between exposure to soluble nickel compounds (e.g., nickel sulphate) and increased respiratory cancer risk in at least three separate cohorts.”

The epidemiological evidence (without the animal data) was reviewed by the Specialised Experts at their in April, 2004. The Specialised Experts concluded that the epidemiological evidence was sufficient to classify nickel sulphate in Category 1, known to be carcinogenic to man. The Specialised Experts considered the data to be sufficient to establish a causal association between the human exposure to the substances and the development of lung cancer and they considered that there was supporting evidence for this conclusion from more limited data on nasal cancer (European Union Risk Assessment for Nickel Sulphate, 2008-2009).

A recent review of the carcinogenicity data for soluble nickel compounds applied the Bradford Hill criteria of causality to the epidemiological evidence in support of the carcinogenicity of soluble nickel compounds (Goodman et al.,2009). A weight of evidence analysis was later applied to the epidemiological, animal and mode of action data. Based on their evaluation, the authors considered that some epidemiological data, but not all, suggest that soluble nickel exposure leads to increased cancer risk in the presence of certain insoluble nickel compounds. In their opinion, there was only limited evidence for its carcinogenicity in humans. They note that although there is no evidence that soluble nickel acts as a complete carcinogen in animals, there is some evidence from the animal data that soluble nickel may act as a tumor promoter. Goodman et al..(2009) go on to state: “Finally, the mode-of-action data suggest that soluble nickel compounds are not able to cause genotoxic effects in vivo because they cannot deliver sufficient nickel ion to nuclear sites of target cells. Although the data do suggest several possible non-genotoxic effects of the nickel ion, it is unclear whether soluble nickel compounds can elicit these effects in vivo or whether these effects, if elicited, would result in tumor promotion. Overall, the mode-of-action data equally support soluble nickel as a promoter or as not being a causal factor in carcinogenesis at all.” Goodman and coworkers concluded: “The weight of evidence does not clearly support a role for soluble nickel alone in carcinogenesis.”

As discussed above, the Specialized Experts had concluded in 2004 that the epidemiological evidence was sufficient to classify nickel sulphate in Category 1, known to be carcinogenic to man.

 

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

 

INHALATION: Data on respiratory carcinogenicity associated with inhalation exposure to nickel chloride and/or Ni sulphate (in mixed nickel exposures) from multiple human studies are considered (e.g., Oller et al., 2014; Grimsrud et al., 2002). Ni sulphate has been classified as Carc. 1A; H350i in the 1st ATP to the CLP Regulation.

ORAL: A well-conducted OECD 451 study in rats did not show any carcinogenic potential of nickel sulphate following oral administration.A summary document that discusses this topic can be found in Appendix B1 of the CSR (and IUCLID Section 7.7).

 

DERMAL: The available data concerning dermal exposure are too limited for an evaluation of the carcinogenic potential in experimental animals following dermal contact to nickel sulphate. However, 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.

Studies via other routes of exposure and promoter studies provide at most limited evidence of carcinogenicity of nickel sulphate in animals.