Nickel(III) oxy hydroxide

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

Ni monoxide, as well as Ni dihydroxide are currently classified as a dermal sensitizer (R43) according to the 1st ATP to the CLP Regulation. However, a recent study evaluating the bioaccessibility of a series of Ni compounds in synthetic sweat indicated very low nickel ion release from oxidic nickel compounds, including Ni monoxide and Ni dihydroxide, suggesting very low or no sensitization potency. This is supported by earlier results in a GMPT test that were positive for Ni sulfate and negative for Ni oxide. While no change to the existing classification is proposed within this registration file, a complete summary of the testing program including results and discussion are provided in Section 7.4.1 of IUCLID and as Appendix B3 in this CSR. Data from studies on Ni oxide are provided for read-across purposes. Furthermore there are data on the sensitizing effect of Ni in humans provided in IULCID section 7.10.4 showing that Ni acts as skin sensitizer in humans.

Data characterizing sensitization potential of Ni oxide were limited to two skin sensitization studies; no studies evaluating respiratory sensitization were identified. Two skin sensitization studies conducted according to OECD Guideline Test #406 – Skin Sensitization indicated that nickel oxide was not a contact sensitizer in guinea pigs. Both studies relied on an initial sensitization phase followed by a challenge phase, and collectively evaluated skin sensitization following both dermal and intradermal exposures.

The most recently conducted study (EPSL, 2009c) used the Buehler Methods to evaluate the sensitization potential of repeated topical applications of a nickel oxide green (composed of 98% Nickel oxide and 1.5% Cobaltous oxide), also described as dark grey nickel oxide green, in a preliminary test and a main test (induction, challenge and rechallenge). For the preliminary test, the highest non-irritating concentration (HNIC) of 68% w/w was determined following a single 6-hour exposure of 0.4 g of 90%, 68%, 45% or 23% w/w mixture, and thus was used as the challenge dose in the main test. During the induction phase of the main test, a 90% w/w mixture of the test substance in mineral oil (0.4 g) was topically applied to 20 healthy test guinea pigs, once each week for a three-week induction period. Twenty-seven days after the first induction dose, a challenge dose (0.4 ml of 68% w/w mixture in mineral oil) was applied to a naive site on each surviving guinea pig. Approximately 24 and 48 hours after each induction and challenge dose, the animals were scored for erythema. Three and five animals, of twenty, had positive responses (incidence) at 24 and 48 hours, respectively; the severity was 0.53 and 0.50, respectively. However, because of higher than expected irritation scores in the naive control animals after the challenge dose, study authors could not determine if a sensitization response had occurred and thus conducted a rechallenge phase using a lower concentration. Seven days after the primary challenge, 0.4 ml of a 45% w/w mixture of the test substance in mineral oil was applied to a naïve site in the test animals; a new group of naive control animals (n=10) was also exposed. In the rechallenge phase, no test animals had an incidence of positive response at 24 or 48 hours, and severity was 0.15 and 0.10, respectively. Thus, the study report concluded that under the current test conditions, this nickel oxide green was not considered to be a contact sensitizer. It should be noted that the Buehler Method, as with other animal models for evaluating potential dermal sensitizers, may not be sufficient for assessing nickel-containing compounds. Therefore, the results of this study should be interpreted with caution.

Similar findings were also reported by the Food & Drug Research Laboratories (1986) several years prior. In this evaluation using the guinea pig maximization test (GPMT), guinea pigs were sensitized to nickel via intradermal injection with 0.1 mL 1% (w/v) nickel sulfate in distilled water and 0.1 ml Freund’s complete adjuvant. Eight days later, each site was further sensitized by a topical exposure to nickel sulfate (0.3 mL 5% w/v) and occluded for 48 hr. On day 22 after the initial sensitization injections, virgin sites and original injection sites were challenged and occluded for 24 hr with nickel sulphate, 0.2 g NiO moistened with propylene glycol, or propylene glycol. The challenge sites were scored for erythema and edema via the Draize method at 24 and 48 hr after removal. The erythema scores in animals challenged with NiO were 0 at 24 and 48 hr for animals previously sensitized with nickel sulfate or vehicle controls. The authors concluded that under the conditions of this study, NiO failed to cause sensitization in female albino guinea pigs while nickel sulfate did cause dermal contact sensitization.

Collectively, these two studies provide sufficient data to characterize skin sensitization potential following dermal or intradermal exposure to nickel oxide. The available data indicate that nickel oxide does not present a skin sensitization health hazard in guinea pigs under the conditions evaluated. The outcome of bioaccessibility testing (Appendix B3) suggests that a similar conclusion can be drawn for Ni dihydroxide.These data are read-across to Ni oxyhydroxide as Ni monoxide and Ni dihydroxide are representing the boundaries of the read-across approach and Ni oxyhydroxide belongs to the group of oxidic Ni compounds. Additionally the fact that a sensitizing effect of Ni compounds was not provable in the animal model supports that no further animal testing should be conducted. Ni oxyhydroxide is expected to be not sensitizing in the animal model. Nevertheless there are data available showing that Ni compounds have a senstizing effect in humans (see IUCLID section 7.10.4). In conclusion, based on animal and human data and the fact that Ni dihydroxide and Ni oxide are classified as a dermal sensitizer (Skin Sens. 1; H317), as worst case assumption Ni oxyhydroxide is expected to be a skin sensitizer.

Migrated from Short description of key information:
Ni monoxide, as well as Ni dihydroxide is currently classified as a dermal sensitizer (R43) according to the 1st ATP to the CLP Regulation. However, a recent study evaluating the bioaccessibility of a series of Ni compounds in synthetic sweat indicated very low nickel ion release from oxidic nickel compounds, including Ni monoxide and Ni dihydroxide, suggesting very low or no sensitization potency. This is supported by earlier results in a GMPT test that were positive for nickel sulfate and negative for nickel oxide. While no change to the existing classification is proposed within this registration file, a complete summary of the testing program including results and discussion are provided in Section 7.4.1 of IUCLID and as Appendix B3 in the accompanying CSR. These data are read-across to Ni oxyhydroxide as Ni monoxide and Ni dihydroxide are representing the boundaries of the read-across approach. Additionally the fact that a sensitizing effect of Ni compounds was not provable in the animal model supports that no further animal testing should be conducted. Ni oxyhydroxide is expected to be not sensitizing in the animal model. Nevertheless there are data available showing a sensitising effect of Ni in humans (see IUCLID section 7.10.4). Because there are no data to disprove a sensitizing effect of Ni oxyhydroxide, it is expected to be a skin sensitizer.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

No studies were identified characterizing respiratory sensitization following exposure to nickel oxyhydroxide. A few case reports in 1970’s and 1980’s suggest that nickel sulphate may be a respiratory sensitiser in humans. Considering the number of workers that have been exposed to soluble nickel compounds in the refining and metal finishing industry over the years, the number of reported cases is very small. No data regarding respiratory sensitisation in animals have been located. A recent comprehensive review of the available literature regarding the potential of soluble Ni compounds to induce respiratory sensitization is extensively reviewed in the background document attached in Section 7.4.2 and provided as Appendix B7 to the CSR. However, the available bioaccessibility data (summarized in IUCLID Section 7.2.2 and CSR Appendix B2) indicate Ni oxyhydroxide behaves most like Ni oxide, which is not considered to be a respiratory sensitizer.

Migrated from Short description of key information:
No studies were identified characterizing respiratory sensitization following exposure to nickel oxyhydroxide. Based on a recent literature review (Appendix B7), the available data for soluble nickel compounds may not be considered sufficient for classification as a respiratory sensitizer.
In addition, the comparison of bioavailable data for NiOOH and NiO/Ni(OH)2 (summarized in IUCLID Section 7.2.2 and CSR Appendix B2) indicate that values for NiOOH are similar to Ni oxide, which is not considered to be a respiratory sensitizer. Nevertheless, as Ni dihydroxide is currently classified as respiratory sensitizer and there are no data to disprove a respiratory sensitization effect of Ni oxyhydroxide, it is considered to be a respiratory sensitizer.

Justification for classification or non-classification

Ni monoxide, as well as Ni dihydroxide is currently classified as a dermal sensitizer (Skin Sens. 1; H317) according to the 1st ATP to the CLP Regulation. However, a recent study evaluating the bioaccessibility of a series of Ni compounds in synthetic sweat indicated very low nickel ion release from Ni dihydroxide suggesting very low or no sensitization potency. This is supported by earlier results in a Guinea pig GMPT test that were positive for nickel sulfate and negative for oxidic nickel. While no change to the existing classification is proposed within this registration file, a complete summary of the testing program including results and discussion are provided in Section 7.4.1 of IUCLID and as an Appendix B3 in the accompanying CSR.

Ni dihydroxide is classified as Resp. Sens. 1:H334 according to the 1st ATP to the CLP Regulation. However, the available bioaccessibility data in synthetic lung fluids (summarized in IUCLID Section 7.2.2 and CSR Appendix B2) indicate Ni oxyhydroxide behaves most like Ni oxide. As Ni oxide is not considered a respiratory sensitizer.

As Ni monoxide and Ni dihydroxide are representing the boundaries for the read-across approach to Ni oxyhydroxide the data reported are used for read-across. There are no data to disprove the skin and respiratory sensitizing effect of Ni oxyhydroxide. Therefore the classification of Ni dihydroxide is taken over for Ni oxyhydroxide and is considered to be a skin, as well as a respiratory sensitizer as worst case assumption.