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Additional information

The in vitro gene mutation study in bacteria with nickel sulphate is negative. Bacterial reverse mutation study with S. typhimurium was negative for all the strains tested at all doses of nickel sulphate using a modified media that prevented precipitation of the nickel ions. However, an in vitro gene mutation study in L5178Y mouse lymphoma mammalian cells was positive with a LOED of 500 µg/ml. In vitro cytogenicity study (chromosomal aberrations) in mammalian cells or in vitro micronucleus study with nickel sulphate have been positive. A study reporting positive in vitro chromosomal aberrations in rat lung epithelial cells, which would have been appropriate, was not considered relevant and scored K4 because the nickel sulphate doses were not reported.

The in vivo studies with nickel sulphate have produced mixed results. Two studies (a K1 and a K2) looking at micronucleus in bone marrow of rats (oral) and mice (intraperitoneal) exposed repeatedly to nickel sulphate were negative (Oller and Erexson, 2007; Morita et al., 1997); two K3 studies looking at the oral induction of micronucleus in mice indicated positive results (Sharma et al., 1987; Sobti and Gill, 1989). A study by Benson et al. (2002) showed that nickel sulphate given by inhalation seemed to induce genotoxicity (DNA damage) in lung cells at the same or higher concentrations at which it induces inflammation after repeated exposures. Evidence from human studies is limited. There are no definitive tests of nickel compounds on the germ cells but evidence for a possible effect is limited. Whilst there is evidence that the nickel ion reaches the testes, no effect on spermatogonial cells was seen in the Mathur et al. (1978) study with nickel sulphate. The effects seen in spermatozoa in the Sobti & Gill (1989) study with several water soluble Ni compounds may reflect toxic effects on germ cells rather than chromosomal damage. In addition, a dominant lethal test (Deknudt & Léonard, 1982) with water soluble Ni compounds, was negative and these results are relevant for nickel sulphate. Whilst some effects are seen in males (e.g. sperm abnormalities) there is little evidence for inheritable effects on the germ cells. Taken together, the in vitro and in vivo studies indicate that nickel sulphate is a weak genotoxicants with thresholds.

In April 2004, the Specialised Experts concluded that nickel sulphate, nickel chloride and nickel nitrate should be classified as Muta. Cat. 3; R68 (now Muta. 2: H341 under CLP classification). This conclusion was based on evidence of in vivo genotoxicity in somatic cells, after systemic exposure (the 2007 negative oral MN study was not available at that time). Hence the possibility that the germ cells are affected could not be excluded (European Commission, 2004).

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

For water soluble nickel compounds like nickel sulphate, there is evidence indicating that they are weak genotoxicants in vitro, and may exhibit clastogenic activity. Some in vivo studies with nickel sulphate have been positive while two recent micronucleus studies via oral and intraperitoneal injection were negative. Evidence from human studies is limited. There are no definitive studies on germ cells, and little evidence concerning hereditable effects. Nickel sulphate and other water soluble nickel compounds carry a harmonized Muta. 2: H341 CLP classification. 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 discussion of ECHA 2018 report in Appendix C2).

Justification for classification or non-classification

Nickel sulphate is classified as Muta. 2:H341 in the 1st ATP to the CLP Regulation.