Registration Dossier

Administrative data

Description of key information

Value used for CSA: sensitising (skin)

Value used for CSA: not sensitising (respiratory)

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Data characterizing sensitization were limited to two skin sensitization studies conducted according to OECD Guideline Test #406 – Skin Sensitization indicated that green nickel oxide was not a contact sensitizer in guinea pigs, assuming that both studies were conducted using green nickel oxide. Both studies relied on an initial sensitization phase followed by a challenge phase, and collectively evaluated skin sensitization following dermal (both studies) and intradermal exposures (only one study).

The most recently conducted study (EPSL, 2009d) used the Buehler Methods to evaluate the sensitization potential of repeated topical applications of a nickel oxide sinter (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 (FDRL, 1986). 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 sulphate 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 sulphate (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 (assumed to be green nickel oxide) 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 sulphate or vehicle controls. The authors concluded that under the conditions of this study, NiO (assumed to be green nickel oxide) failed to cause sensitization in female albino guinea pigs while nickel sulphate did cause dermal contact sensitization. 

Collectively, these two studies provide sufficient data to characterize skin sensitization potential following dermal or intradermal exposure to green nickel oxide, assuming that the FDRL study tested green nickel oxide. The available data indicate that green nickel oxide does not present a skin sensitization health hazard in guinea pigs under the conditions evaluated. 

The results of a comprehensive bioaccessibility testing program evaluating release of Ni ion in synthetic sweat from various Ni compounds indicate that green nickel oxide releases significantly less nickel (II) ion compared to nickel substances known to be skin sensitizers, including nickel sulphate and nickel metal, suggesting very low or no sensitization potency. In this same testing black nickel oxide released significantly more than both green nickel oxide and nickel oxide, with black nickel oxide releasing similar amounts to nickel metal. A comprehensive summary on this topic is provided in Section 7.4.1 of IUCLID and as Appendix B3. The bioaccessibility data for black nickel oxide suggest that it may be a skin sensitizer and therefore the current classification of nickel oxide as a skin sensitizer in the CLP is supported. The bioaccessibility data for green nickel oxide suggest that it may not be a skin sensitizer. This is supported by earlier results in a Guinea pig GMPT test that were positive for nickel sulphate and negative for green nickel oxide. Since the bioaccessibility method has not yet been validated in vivo for skin sensitization no change to the existing classification for green nickel oxide is proposed within this registration file.

Because the Ni2+ ion is considered exclusively responsible for the immunological effects of nickel (Menné 1994), the data is read across from nickel sulphate for DNEL derivation for risk characterization. Additional information on nickel sulphate is summarized in the Nickel Sulphate IUCLID dossier Section 7.10.4. One of these studies, a meta-analysis of published patch test studies by Fischer et al. (2005) has been used as the basis for the derivation of a DNEL for dermal elicitation/sensitization with nickel sulphate as described in Section 5.11. The aim of the study by Fischer et al. (2005) was to assess thresholds of response by making a statistical analysis of available dose-response studies with a single occluded exposure and comparing the results to thresholds from other modes of exposure. Eight occluded Ni dose-response studies were selected based on statistical considerations. The statistical analysis showed that 5% of a sensitized population reacts to 0.44 µg Ni/cm2 and 10% react to 1.04 µg Ni/cm2. In another study with a single open application, 7.8% of sensitized persons responded to a dose 6x higher than the dose to which 10% reacted in occluded exposure. The NOAEL of 0.00044 mg Ni/cm2 from the Fischer et al. (2005) study is carried forward as the basis for the derivation of DNEL for dermal elicitation/sensitization. The Ni ion release in synthetic sweat from Ni oxide relative to that released from Ni sulphate were used to derive a DNEL for Ni oxide that takes into account its lower Ni ion release in sweat. See Appendix B3.

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

Ni oxide is currently classified as a dermal sensitizer (Skin Sens. 1;H317) according to the 1st ATP to the CLP Regulation. A recent study evaluating the bioaccessibility of a series of Ni compounds in synthetic sweat indicated very low nickel ion release from green Ni oxide suggesting very low or no sensitization potency, and moderate nickel ion release from black Ni oxide. The low nickel ion release for green nickel oxide as an indication of low potential for being a skin sensitizer is supported by earlier results in a Guinea pig GPMT test that were positive for nickel sulphate and negative for nickel oxide (assumed to be green NiO). The bioaccessibility data for black nickel oxide suggest that it may be a skin sensitizer and therefore the current classification of nickel oxide as a skin sensitizer in the CLP is supported. The bioaccessibility data for green nickel oxide suggest that it may not be a skin sensitizer. Since the bioaccessibility method has not yet been validated in vivo for skin sensitization 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.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

No animal or human studies were identified characterizing respiratory sensitization following exposure to nickel oxide. While there is some evidence from exposure to indicate that some more water-soluble nickel compounds may be considered as a respiratory sensitiser in humans, the available data is not considered sufficient for classification of Ni oxidebut the possibility cannot be ruled out due to association of soluble nickel compounds with type I allergic reactivity and respiratory reactions.

 

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

The available data are not considered sufficient for classification as a respiratory sensitizer.

Value used for CSA:not sensitising

Justification for classification or non-classification

Ni oxide is currently classified as Skin Sens. 1;H317 in the 1st ATP to the CLP Regulation. .Background information can be found in the discussion section.

Ni oxide is not classified as a respiratory sensitizer according to the 1st ATP to the CLP Regulation. Background information can be found in the discussion section.