Nickel di(acetate)

Carcinogenicity

Description of key information

ORAL: Data are read-across from a negative oral carcinogenicity in rats with Ni sulphate. A well-conducted OECD 451 study in rats (Heim et al 2007) 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).

INHALATION: Data for nickel acetate are read-across from Ni sulphate. 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).

DERMAL: As oral exposure to nickel sulphate does not show any carcinogenic potential, and systemic dermal absorption of nickel is lower than oral absorption, cancer via dermal exposure is not a concern for Ni sulphate or any other nickel compound including nickel acetate.

Justification for classification or non-classification

Nickel acetate is classified as Carc. 1A; H350i in the 1st ATP to the CLP Regulation. Background information regarding this classification and its application only to the respiratory tract after inhalation, is provided in the 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

No robust studies that characterized the carcinogenicity of nickel acetate were identified. A few animal studies examining the carcinogenicity of nickel acetate by oral and other routes of exposure (intramuscular implants and intraperitoneal) were identified and included in IUCLID section 7.7. The results from studies using non physiological routes of exposure have either been negative (e.g., Payne, 1964) or have shown low incidence of injection site tumors at very high exposure levels (e.g., Pott et al., 1989). Drinking water studies of nickel acetate in rats and mice showed no exposure-related neoplasms (Schroeder et al., 1974; Schroeder and Mitchener, 1975). Data on the oral and inhalation carcinogenicity of Ni acetate are read-across from Ni sulphate. A comprehensive read-across assessment was recently completed based on bioaccessibility data in synthetic lung fluids of various nickel compounds combined with in vivo verification data for three source nickel substances. The read-across paradigm for inhalation presented in a summary document in Section 7.2.2 and in Appendix B2 of this CSR enables grouping of target Ni substances for classification of inhalation toxicity according to bioaccessibility in interstitial and/or lysosomal fluid. Although this paradigm was designed to assess potential for toxicity, the bioaccessibility data provide information that can be combined with knowledge of mode of action of different nickel compounds. The outcome of this assessment indicates that Ni acetate would behave most similarly to Ni sulphate in terms of potential for inhalation carcinogenicity (KMHC, 2010 and Appendix B2). Similarly, the oral carcinogenicity of nickel acetate can be read across from Ni sulphate (Appendix B1).

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 the most toxic compounds for the respiratory tract but by themselves did not induce tumors even at exposure levels corresponding to the maximum tolerated dose. A possible model based on the Ni bioavailability at critical intracellular sites has been described to help reconcile all these possibilities (Goodman et al., 2009, 2011). 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 (a water soluble nickel compound) following oral administration has been studied in several studies with rats and dogs and no neoplasms were observed. The most recent 2-year carcinogenicity study in rats by oral gavage was performed according to OECD 451 guidance and did not show a carcinogenic potential for exposure to nickel sulphate following oral administration (Heim et al., 2007). 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 (as a surrogate for water soluble nickel compounds) 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. These results can be read across to nickel acetate.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 acetate or nickel sulphate in experimental animals have been located. However, toxicokinetic data indicates that systemic absorption of nickel from water soluble nickel compounds through the skin is very low (≤ 2%). As oral exposure does not show systemic carcinogenicity, it seems reasonable to assume that cancer is not a relevant endpoint for dermal exposure.

Epidemiology Data

As discussed in the European Union Risk Assessment for Nickel Sulphate report (2008/2009), epidemiological studies from three nickel refineries processing sulphidic nickel ores have demonstrated elevated risk of lung and nasal cancer in workers exposed to dust containing nickel sulphate and/or nickel chloride 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 and/or nickel chloride 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 water soluble nickel 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 epidemiological evidence (without the animal data) was reviewed by the Specialised Experts 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. Likewise, 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 exposureto soluble nickel compounds (e.g., nickel sulphate and nickel chloride) and increased respiratory cancer risk in at least three separate cohorts.”

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 also applied to the epidemiological, animal and mode of action data. Based on their evaluation, the authors considered that certain epidemiological data, but not all, suggest that soluble nickel exposure leads to increased cancer risk in the presence of certain insoluble nickel compounds. In the authors’ opinion, there was only limited evidence for its carcinogenicity in humans. They noted 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 effectsin vivobecause 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 effectsin vivoor 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.”

However, as discussed above, the Specialized Experts had concluded in 2004 that the epidemiological evidence (from workers with mixed exposures) alone was sufficient to classify nickel sulphate and nickel acetate in Category 1, known to be carcinogenic to man.Hence, Ni acetate carries the carcinogenicity classification of Carc. 1A; H350i via inhalation.