[carbonato(2-)]tetrahydroxytrinickel

Endpoint summary

Additional information

Only limited information characterizing the genetic toxicity of nickel hydroxycarbonate was identified. The data on in vitro genotoxicity of nickel hydroxycarbonate is limited but sufficient. In the study by Montaldi et al. (1985) nickel hydroxycarbonate is reported to increase the frequency of sister chromatid exchanges (SCE) in cultured hamster ovary cells. In the Montaldi et al. (1987) study, chromosome aberrations and micronucleus induction were also studied, with a positive result. In the Fletcher et al. (1994) study, some exposure levels of nickel hydroxycarbonate are reported to increase the frequency of thio-guanine resistant mutants in mammalian CHO cells containing the bacterial gpt gene. These effects could be due to methylation of the gpt transgene rather than true mutations. Another study characterizing the genetic toxicity of nickel hydroxycarbonate is an OECD guideline in vitro study. Bioservice Scientific Laboratories (BSL, 2008) conducted a thymidine kinase locus mutation study using mouse lymphoma L5178Y cells with and without metabolic activation over short (4 hour) and long (24 hour) exposure durations. There was no biologically significant increase in mutation frequencies under any of the experimental conditions; thus nickel hydroxycarbonate was non-mutagenic in this study.

The data on in vivo genotoxicity of nickel hydroxycarbonate is limited to studies conducted by Ciccarelli et al. (1981, 1982). Ciccarelli et al. (1982) examined lesions in nuclei from the kidney, liver, lung, and thymus gland cells in male rats following intraperitoneal (i. p.) administration. In kidney nuclei, dose-dependent DNA-protein cross-links, interstrand crosslinks, and single-strand breaks were observed. Lung nuclei showed low levels of single-strand breaks that were repaired by the end of the study period. The authors concluded that the potential for nickel hydroxycarbonate exposures to induce kidney and lung DNA damage may correlate with nuclear nickel (II) concentrations.

The available in vitro and in vivo data regarding the potential mutagenicity of Ni hydroxycarbonate are inconclusive. Collectively, the available data are conflicting given that in vitro data from a standard OECD guideline compliant assay using mouse lymphoma L5178Y cells indicated that nickel hydroxycarbonate was not genotoxic. However, exposures in rats indicated that nickel hydroxycarbonate induced DNA damage in renal and pulmonary cells using non physisological routes of exposure. Therefore, in vivo data from an oral guideline compliant study with Ni sulphate is also considered here in an overall weight-of-evidence approach. A study conducted by Oller and Erexson (2007) aimed to evaluate the ability of nickel sulphate hexahydrate to induce micronuclei in polychromatic erythrocytes (PCEs) in rat bone marrow. The results of this study demonstrated that repeated exposures to nickel sulphate hexahydrate did not induce statistically significant increases in micronucleated PCEs at any dose examined, even though nickel levels in plasma and bone marrow were increased >30 times and 4 times, respectively, over controls. Regarding inhalation effects, read across from a study conducted with nickel subsulphide is possible (Benson et al., 2002).This study found that inhalation exposures to nickel sulphate and nickel subsulphide at toxic levels can cause genotoxicity in the respiratory tract in vivo. However, only Ni₃S₂ exposure (0.6 mg/m³, 0.44 mg Ni/m³) significantly increased epithelial and nonepithelial cell proliferation after 3 and 13 weeks.

During the preparation of the 2008/2009 European Union Risk Assessment for Nickel Carbonate (applicable for nickel hydroxycarbonate), the Specialised Experts (April 2004) considered the classification for mutagenicity of nickel sulphate, nickel chloride, nickel nitrate and nickel hydroxycarbonate. They concluded that nickel sulphate, nickel chloride and nickel nitrate should be classified as Muta. Cat. 3; R68 (European Commission, 2004). This conclusion was based on evidence of in vivo genotoxicity in somatic cells, after systemic exposure and a consideration that the possibility that the germ cells are affected could not be excluded.

The Specialised Experts concluded that there was insufficient evidence for classification of nickel hydroxycarbonate and they did not consider that further testing of effects on germ cells was practicable (European Commission, 2004). Nevertheless, the Technical Classification and labeling Committee later agreed to classify nickel hydroxycarbonate as Muta. Cat. 3; R68 (now Muta. 2; H341 according to the CLP). Despite conflicting data regarding the genetic toxicity of Ni hydroxycarbonate, this compound is currently classified as a mutagen Muta. 2; H341 (1st ATP to the CLP).Recently, there has been some recognition that nickel compounds may be genotoxic carcinogens with a practical threshold (see SCOEL 2009 report inAppendix C2).

 

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

The available in vitro and in vivo data regarding the potential mutagenicity of Ni hydroxycarbonate are inconclusive.Despite conflicting data regarding the genetic toxicity of Ni hydroxycarbonate, this compound is currently classified as Muta. 2; H341 (1st ATP to the CLP). Recently, nickel compounds have been recognized as genotoxic carcinogens with threshold mode of action in ECHA RAC opinion on nickel and nickel compounds OELs (see ECHA 2018 report discussion inAppendix C2).

Value used for CSA:Genetic toxicity: positive

Justification for classification or non-classification

Ni hydroxycarbonate is classified as Muta. 2; H341 according to the 1st ATP to the CLP Regulation. Background information can be found in the discussion section.