Nickel bis(dihydrogen phosphate)

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

No studies were identified characterizing the genotoxicity of nickel bis(dihydrogen phosphate). Data regarding genotoxicity of nickel bis(dihydrogen phosphate) are read-across from Ni sulphate.

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 seenin 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 bis(dihydrogen phosphate). Whilst some effects are seen in males (e.g. sperm abnormalities) there is little evidence for heritable effects on the germ cells.

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).Since nickel bis(dihydrogen phosphate) is read across from Ni sulphate it carries a classification as Muta. 2;H341.

 

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

Data regarding genotoxicity are read-across from Ni sulphate. For water soluble nickel compounds, 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 heritable 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 ECHA 2018 report discussion in Appendix C2).

Genetic toxicity in vivo

Description of key information

No studies were identified characterizing the genotoxicity of nickel bis(dihydrogen phosphate). Data regarding genotoxicity of nickel bis(dihydrogen phosphate) are read-across from Ni sulphate.

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 seenin 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 bis(dihydrogen phosphate). Whilst some effects are seen in males (e.g. sperm abnormalities) there is little evidence for heritable effects on the germ cells.

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).Since nickel bis(dihydrogen phosphate) is read across from Ni sulphate it carries a classification as Muta. 2;H341.

 

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

Data regarding genotoxicity are read-across from Ni sulphate.For water soluble nickel compounds, 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 heritable 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 ECHA 2018 report discussion in Appendix C2).

Justification for classification or non-classification

Nickel bis(dihydrogen phosphate) is classified as Muta. 2: H341 based on the read-across from and harmonized classification of nickel sulphate in the CLP Regulation.