Nickel dichloride

Endpoint summary

Additional information

There are two relevant nickel chloride studies on the in vitro gene mutation in bacteria. Both studies are negative, showing that nickel chloride has no gene mutation effects in bacteria. This is consistent for all nickel substances, which have no-to-low gene mutation effects in bacteria. However, bacterial mutation studies for nickel substances are not informative, as noted in ECHA’s 2015 Endpoint Specific Guidance. There are limited studies for nickel chloride gene mutation in mammalian cells. The available studies show some mammalian gene mutation effects of nickel chloride. Some of these studies reported positive mammalian gene mutation effects at cytotoxic concentrations and/or in a dose-dependent manner. The weak in vitro mammalian cell gene mutation effects of nickel chloride is confirmed by several in vivo somatic cell genotoxicity studies with mixed results. Some of the studies are negative, whilst one of the Drosophila studies shows a weak positive gene mutation effect. Some of the positive in vivo somatic cell genotoxicity studies show dose-dependency of the effects. These confirm that there are thresholds for the gene mutation effects of nickel chloride.

There is evidence that the effects seen on DNA damage and repair in vitro are also seen in vivo. In a recent and well performed comet assay on Swiss albino mice there is clear evidence that nickel chloride induces DNA strand breaks in vivo on leukocytes after a single oral dose (Danadevi et al. 2004). There was a statistically significant effect at all dose levels (1.55 – 49.45 mg/kg bw) and treatment times except in the second week post treatment. The maximum effect was seen after 48h in accordance with the slow absorption of nickel chloride and indicating repair at later sampling times. This study confirms that the DNA damaging effect of nickel chloride seen in vitro is also seen in vivo.

The studies of most relevance are those that demonstrate whether or not the clastogenic effects seen in vitro are also seen in vivo. There are seven studies on chromosomal aberrations or bone marrow micronucleus in vivo. In five studies, nickel chloride was given intraperitoneally and in two studies it was given orally. Oller and Erexson (2007) examined the protocols used in these studies compared to current accepted guidelines for this kind of in vivo studies. According to Oller and Erexson (2007), the studies by Deknudt and Leonard (1982), Chorvatovicoca (1983), Sharmaet al(1987), Mohanty (1987), and Sobti and Gill (1989) had design issues that made the results equivocal, even if they were considered to be negative or positive by their authors. The Dhir et al. (1991) intraperitoneal study can be considered as a clear positive study while the Morita et al(1997) intraperitoneal study was clearly negative. All thestudies were carried out in mice, although different strains of mice were used. There is no obvious explanation for the differences in theconclusions of the different studies. The estimated absorbed dose at which the Dhir et al. (1991) study was positive was lower than that estimated to be present in the Morita et al(1997) negative study. A guidance compliant oral study of micronucleus in bone marrow of rats repeatedly exposed to nickel sulphate hexaydrate yielded negative results even though elevated Ni levels were measured in blood and bone marrow of exposed animals (Oller and Erexson, 2007). This guideline compliant study can be read across to nickel chloride and adds to the weight of evidence for in vivo mutagenicity. Similarly a repeated dose inhalation study with nickel sulphate hexahydrate in rats can be read across to nickel chloride (Benson et al., 2002). This study found that inhalation exposures to soluble nickel at toxic levels can cause genotoxicity in the respiratory tract in vivo. However, no read-across is required nor performed for the oral micronucleus study in bone marrow of rats (Oller and Erexson, 2007) and the repeated dose inhalation study (Benson et al., 2002).

Some studies have been carried out to see whether there are effects on germ cells. One of the bone marrow micronucleus tests (Sobti & Gill, 1989) found morphological changes in spermatozoa after oral administration. A dominant lethal test in mice (Deknudt & Léonard, 1982) found that treatment decreased significantly the incidence of pregnant females and the mean number of implanted embryos, but did not increase the post-implantation loss. The authors of the mouse study suggest that this is consistent with the results of Jacquet & Mayence (1982) with nickel nitrate and is seen as evidence for germ cell toxicity. [It should be noted that there is evidence of post implantation losses in 2-generation studies in rats (SLI, 2000a,b.]. Studies in man (Waksvik & Boysen, 1982, Waksvik et al. 1984, Deng et al., 1983, 1988) are very limited and cannot be used as evidence that nickel exposure induces chromosomal aberrations in exposed workers.

The genotoxicity of nickel chloride has been extensively reviewed. There is clear evidence indicating that nickel chloride induces DNA strand breaks and is clastogenic in vitro. Animal studies provided conflicting results regarding whether the nickel ion can induce DNA strand breaks (at non cytotoxic levels) and chromosome aberrations in somatic cells in vivo. Data from in vivo micronucleus studies are conflicting.

There are no definitive studies on germ cells, and little evidence concerning hereditable effects on germ cells. The effects seen in the Sobti & Gill (1989) study as well as the Deknudt & Léonard, (1982) dominant lethal study may reflect toxic effects on germ cells rather than chromosomal damage.

The opinion of the EU Specialised Experts was sought in 2004 with regard to the classification of nickel chloride for mutagenicity. The Specialised Experts 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. Hence the possibility that the germ cells are affected cannot be excluded. The Specialised Experts did not consider that further testing of effects on germ cells was practicable (European Commission, 2004).

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

The genotoxicity of nickel chloride has been extensively reviewed. There is clear evidence indicating that nickel chloride induces DNA strand breaks and is clastogenic in vitro. Animal studies indicate that nickel chloride may induce DNA strand breaks and chromosome aberrations in somatic cells in vivo. Data from in vivo micronucleus studies are conflicting. There are no definitive studies on germ cells, and little evidence concerning hereditable effects on germ cells. Recently, nickel compounds have been recognized as genotoxic carcinogens with threshold mode of action in the ECHA RAC opinion on nickel and nickel compounds OELs (see ECHA 2018 report discussion in Appendix C2).

Value used for CSA:Genetic toxicity: positive

Justification for classification or non-classification

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