Nickel bis(2-ethylhexanoate)

Endpoint summary

Description of key information

The key value is exclusively based on the presence of nickel in the substance. Main studies selected were conducted according to or were similar to OECD guidelines no 406. Other studies concerned open epicutaneous application tests or modified Draize. Nickel and nickel containing substances are considered to cause dermal sensitization in humans. Exposure to the nickel salts of sulphate and chloride caused significant sensitization in treated patients with a NOEL of 45 mg Ni/L. Permeation rate of the nickel ion depends on the solubility of the salt. Although the water solubility of nickel bis(2-ethylhexanoate) is relatively low , the fact that 2-ethylhexanoic acid is readily absorbed by the skin may facilitate the absorbtion of nickel. Hence, the key value based on the study data of other nickel salts than nickel bis(2-ethylhexanoate) is probably also valid for this substance.

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

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.

 

Sensitisation

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

 

Table: Summary of skin sensitisation 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)
Skin sensitisation	sensitising	not sensitising	sensitising (read-across)

 

 

In five well-performed maximalization tests the results showed a potential skin sensitisation of Ni applied as NiSO₄ (FDRL et al., 1986, Goodwin et al., 1981, Lamminausta et al., 1985, Maurer et al., 1979 and Rohold et al., 1991). In addition, in three well documented open or occlusive epicutaneous tests (Lammintausta et al., 1985, Maurer et al., 1979 and Nielsen et al., 1992), authors showed that application of NiSO₄ did cause dermal contact sensitization in female albino guinea pigs. Furthermore, two studies were included, which exhibited no skin sensitization. Although performed in compliance with OECD guideline 406, results from these animal studies should be interpreted with caution when extrapolating to humans.

A patch test on 430 patients showed that exposure to NiCl₂ concentrations of 0.1 to 2.0% resulted in an average response of 9% of the patients exposed with a min. of 6% and a maximum of 12%. Exposure of 430 patients to 5% NiSO₄ resulted in 11% response. Exposure to 2% NiCl₂induced irritation in 6% of the patients, whereas this was 2% for NiSO₄. A higher permeation rate for Ni in NiCl₂exposed skins appeared to be related with a higher risk of irritation. NOEL for sensitization corresponds with 0.01% NiCl₂.

For 2-ethylhexanoic acid, in a guinea pig maximization assay (Berol Kemi AB, 1979), 0/10 female Dunkin-Hartley guinea pigs exhibited a response 48 h after induction and challenge with 5 % (w/w) and 2 % (w/w) aqueous 2-ethylhexanoic acid solution, respectively. The intracutaneous injections were performed with 1 % (w/w) aqueous 2-ethylhexanoic acid solution. In summary, there is no evidence of a notable sensitization potential of 2-ethylhexanoic acid.

Since nickel bis(2-ethylhexanoate) is already classified as sensitizing based on the presence of nickel, there is no need for further testing.

 

Justification for classification or non-classification

Skin sensitisation:

Concerning 2-ethylhexanoic acid, no data is available. But Nickel compounds and Nickel bis(2-ethylhexanoate) are legally classified as dermal sensitizers. So Nickel bis(2-ethylhexanoate) was classified as a dermal sensitizer.

 

Respiratory sensitisation:

Nickel bis(2-ethylhexanoate) is legally classified as Respiratory Sensitisation 1.