Nickel bis(2-ethylhexanoate)

Endpoint summary

Additional information

Read-across approach

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to dissociate to the organic anion and the metal cation upon dissolution in aqueous media. No indications of complexation or masking of the metal ion through the organic acid were apparent during the water solubility and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products of the metal carboxylate become bioavailable (i.e., in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated metal carboxylate can be described by a combination of the toxicity of these transformation products, i.e., the metal cation and carboxylate anion according to an additivity approach.

 

Nickel bis(2-ethylhexanoate) is the nickel salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding divalent nickel cation and monovalent 2-ethylhexanoate anions. The nickel cation and the 2-ethylhexanoate anion are considered to represent the overall toxicity of nickel bis(2-ethylhexanoate) in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). 

 

A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.

 

Genetic toxicity

No genetic toxicity study with nickel bis(2-ethylhexanoate) is available, thus the genetic toxicity will be addressed with existing data on the dissociation products as detailed in the table below. 

 

Table: Summary of genetic toxicity data of nickel bis(2 -ethylhexanoate) and the individual constituents.

	nickel ion	2-ethylhexanoic acid (CAS# 149-57-5)	nickel bis(2 -ethylhexanoate) (CAS# 4454-16-4)
In vitro gene mutation in bacteria	Negative	Negative	No data
In vitro cytogenicity in mammalian cells or in vitro micronucleus test	Positive	Negative	No data
In vitro gene mutation study in mammalian cells	Positive	Negative	No data
In vivo	Conflicting results	Negative	No data

 

There is clear evidence indicating that Nickel compounds like the chloride and sulphate salts, are genotoxic for mammalian cells in vitro, although this is less clear based on the standard bacterial tests. These compounds are in particular considered as clastogenic. There are a number of in vivo studies in both animals and man. The study by Benson (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. Two recent micronucleus studies were negative: one study was a 2007 guidance compliant repeated dose oral study and the other study was via intraperitoneal administration. 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.

Regarding Nickel sulphate (and other Nickel salts) used here for read-across purposes, 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  (now Muta. 2: H341 under CLP classification). 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).

 

2-ethylhexanoic acid has not shown gene mutation potential in bacteria and mammalian cells as well as in vitro clastogenicity.

There is evidence indicating that Nickel compounds like the chloride and sulphate salts, are genotoxic for mammalian cells in vitro and in vivo. The vitro studies include mainly reliable studies in mammalian cells (Klimisch code 2), which support this conclusion, although this is less clear based on the standard bacterial tests, also included in this file.

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

Nickel 2 -ethylhexanoate is classified as Muta. Cat. 2; H341 in the 1st ATP to the CLP Regulation. Background information regarding this classification is provided in the discussion section above.