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Where data are not available for the nickel oxalate, data for other inorganic nickel compounds (i.e. structurally related substances) that are expected to have similar or higher bioavailability can be used for read across.  For human health endpoints, it is the bioavailability of Ni2+at target site(s) that in most cases determines the potential occurrence and severity of the systemic effects to be assessed for the read across of nickel substances. Therefore, similarity of toxicity is estimated by comparing data for solubility in simulated human body fluids (e.g. gastric, lysosomal, and interstitial fluids) as well as in vivo and human data, where available.  For mutagenicity, data for inorganic nickel substances of similar release of the nickel ion for the relevant route of exposure can be used for read across.  For nickel substances, the read-across strategy is predicated on the assumed presence and bioavailability of a common metal anion (e.g., Ni2+) in biological fluids after exposure to nickel compounds. This is a reasonable assumption for the majority of inorganic compounds and some organic compounds (e.g., metal salts of some organic acids) (ICCM, 2007; OECD, 2007; and ECHA, 2008), provided no significant effect of the other constituents is expected. The oxalate ion is not of concern since oxalate (i.e. oxalic acid) has not been demonstrated to be mutagenic (Sayato et al., 1987; Ishidate et al., 1984).

Data for inorganic nickel substances of higher bioavailability (i.e. higher nickel ion release) can be used as a worst-case approach. This approach is not considered to be as representative of the mutagenicity potential for nickel oxalate as read across from an inorganic nickel substance of a similar bioavailability and mode of action, but in the absence of access to data on nickel oxalate the higher nickel ion concentration generated by the higher nickel ion-releasing substance for read across results in higher nickel ion bioavailability and associated mutagenicity potential. The substance used for read across is nickel sulfate hexahydrate. Because of the higher solubility (and bioavailability of nickel ions) of nickel sulfate compared to nickel oxalate, the worst-case approach is used for read across. Since data for nickel sulfate hexahydrate demosntrate that it is mutagenic, nickel oxalate is also considered to be mutagenic using read-across data as the worst-case.




ECHA. 2008. Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.6: QSARs and Grouping of Chemicals (Available from ECHA website:


ICMM [International Council on Mining and Metals]. 2007. Health Risk Assessment Guidance for Metals (HERAG) (available from ICMM website:

Ishidate M Jr, Sofuni T, Yoshikawa K, Hayashi M, Nohmi T, Sawada M, Matsuoka A. 1984. Primary mutagenicity screening of food additives currently used in Japan. Food Chem Toxicol. 22(8):623-36.


Kirby Memorial Health Center. 2010. Bioaccessibility of nickel oxalate (soluble nickel analyses in simulated gastric, interstitial, and lysosomal fluids). Study Sponsor: Metallo-Chimique. Report Date: 2010-06-30.

OECD [Organisation for Economic Co-operation and Development]. 2007. Guidance on Grouping of Chemicals. Series on Testing and Assessment Number 80 (Available from the OECD website:$FILE/JT03232745.PDF).

Sayato, Y., Nakamuro, K., Ueno, H. 1987. Mutagenicity of products formed by ozonation of naphthoresorcinol in aqueous solutions. Mutation Research. Vol. 189, no. 3. p. 217-222.

Endpoint Conclusion:

Justification for classification or non-classification

No data are available for nickel oxalate; therefore, read-across to more soluble nickel species is used. From the data reviewed above there is clear evidence indicating that nickel sulphate is genotoxic in vitro, and in particular, is clastogenic. There are also a number of in vivo studies.

In Vitro

For nickel sulphate hexahydrate, Larramendy et al. (1981) conducted a Sister Chromatid Exchange Assay (SCE) with Syrian Hamster Embryos and a chromosome aberration assay with human lymphocyte cultures. In the SCE assay, treatment increased the frequency of SCEs in hamster embryo cells in a dose dependent manner. Nickel sulphate hexahydrate also increased the number of chromosomal aberrations in human lymphocytes relative to the control. In another SCE assay, Wulf (1980) also found that nickel sulfate produced a significant increase in the number of sister chromatid exchanges. In the only gene mutation information identified for nickel sulphate, treatment with nickel sulfate failed to produce a statistically significant increase in the number of reverse mutations in S. typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 and E.Coli strain (DG1153) in the absence of metabolic activation.

In Vivo

For nickel sulphate hexahydrate, Oller and Erexson (2007) performed an in vivo micronucleus assay according to OECD Test Guideline 474. In this study, male Sprague-Dawley rats received 3 daily gavage doses up to 500 mg/kg day. Treatment failed to induce a significant increase in the percent of micronucleated erythrocytes in either bone marrow or peripheral blood.

The study by Benson et al. (2002) shows that nickel sulphate given by inhalation seems to induce inflammation and genotoxicity in lung cells at approximately the same concentrations. The results from some of the other animal studies are conflicting. Results of two recent micronucleus studies, one after oral and one after intraperitoneal administration are negative. Evidence from human studies is limited.

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

The opinion of the Specialised Experts has been sought with regard to the classification of nickel sulphate as Muta. Cat. 3; R68 at their meeting in April 2004. The Specialised Experts concluded that nickel sulphate, nickel chloride and nickel nitrate should be classified as Muta. Cat. 3; R68. This conclusion is 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).

Further testing in an in vivo comet assay in lung cells after inhalational exposure is also considered to be unnecessary for the purposes of risk characterisation. A positive result would not alter the conclusions for the classification as a mutagen, and a negative result would not be regarded as sufficient evidence to justify the use of a threshold approach in the carcinogenicity risk characterisation. Hence, further testing for this effect would not produce additional information that would significantly change the outcome of this risk assessment.

Using a weight of evidence approach nickel sulphate is classified as Muta. Cat. 3; R68 and Muta. 2:H341 in the 1st ATP to the CLP.