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Administrative data

Description of key information

Value used for CSA:

NOAEL (oral, systemic, animal data): 2.2 mg Ni/kg bw/day read-across from nickel sulphate hexahydrate (Heim et al., 2007)

LOAEC (inhalation, local, animal data): 0.11 mg Ni/m3 read-across from nickel subsulphide (based on 0.15 mg Ni subsulphide/m3; Dunnick et al., 1995)

Key value for chemical safety assessment

Additional information

No information characterizing toxicity following repeated doses to nickel (di)hydroxide was identified.

Data for repeated-dose toxicity via oral exposure are read-across from Ni sulphate. In addition, a summary document on the read-across assessment and systemic oral toxicity of nickel compounds can be found as a background document in Appendix B1 of the CSR (and Section 7.5.1 of IUCLID).  

In a 2-year OECD 451 carcinogenicity study, decreased body weight gain ranging from 4% to 12% was recorded (males and females combined) following oral gavage of 2.2 to 11 mg Ni/kg bw/day. A dose-related reduced survival achieving statistical significance at the two highest dose levels was seen in females (Heim et al.,2007). The LOAEL of 6.7 mg Ni/kg bw/day based on reduced body weight and increased mortality together with a NOAEL of 2.2 mg Ni/kg bw/day from the Heim et al.(2007) study is taken forward to the risk characterisation for oral repeated dose toxicity.

Data for repeated-dose toxicity via inhalation exposure are read-across from nickel subsulphide. A comprehensive read-across assessment was recently completed based on bioaccessibility data in synthetic lung fluids of various nickel compounds combined in vivo verification data for three source nickel substances. The read-across paradigm presented in a summary document in Section 7.2.2 and in Appendix B2 of this CSR enables grouping of target Ni substances for classification purposes according to bioaccessibility in interstitial and/or lysosomal fluid. The outcome of this assessment indicates that Ni dihydroxide should be read-across from Ni oxide for acute inhalation toxicity. For repeated dose toxicity, read-across from Ni subsulphide is the more conservative approach based on bioaccessibility data in lysosomal fluid. The most relevant repeated-dose studies from Ni subsulphide extend from 13 weeks to 2 years of exposure. Several studies evaluated toxicity at the end of exposure, and some also included evaluation of toxicity one to three months following the cessation of exposure. Toxicity was evaluated in rats and mice. Endpoints generally included evaluation of body and organ weight changes, assessment of tissue damage (primarily in lung), mortality and gross toxicity, and alterations in serum or bronchoalveolar lavage fluid (BALF) chemistry.

The most robust data characterizing toxicity following repeated doses of nickel subsulphide was reported in a series of publications by Dunnick and colleagues (1989, 1995; Benson et al.1990). These studies were associated with a comprehensive bioassay conducted by the National Toxicology Program (NTP) that compared the toxicity of nickel sulphate, Ni3S2 and NiO (NTP, 1996).

After 13 weeks of exposure to Ni3S2 (0.15 to 2.5 mg/m3; Dunnick et al.1989) in both rats and mice, no exposure-related mortality was observed, though changes in bodyweight and lung weights were significantly impacted. Additional toxicities included inflammation in the nasal cavity, bronchial lymph nodes and the lung, alveolar macrophage hyperplasia, chronic active inflammation, and olfactory epithelial atrophy. Of interest, rats were more sensitive than mice to the effects of inhaled nickel in this study. Repeated dose toxicities associated with 2 years of exposure to Ni3S2 included a variety of clinical observations, body and organ weight changes, and altered tissue histopathology (Dunnick et al.1995). Chronic exposure to concentrations up to 1 mg Ni3S2/m3 were not associated with increased mortality or adverse changes in body weight. However, time- and dose-dependent increases in lung weights were observed, which was thought to be due to inflammation. This conclusion was based on histopathological analyses which revealed alveolar/bronchiolar hyperplasia, inflammation, fibrosis, and lymphoid hyperplasia of the lung-associated lymph nodes. The most critical effects were pulmonary fibrosis, chronic inflammation, and proteinosis. For these effects, a LOAEC of 0.11 mg Ni/m3 (MMAD = 2.17 µm) was identified in rats and a LOAEC = 0.44 mg Ni/m3 (MMAD=2.24 µm) was identified in mice.

Given the robust nature of the available studies with nickel subsulphide and based on read across, the data appear sufficient to characterize the toxicity of nickel dihydroxide following repeated inhalation exposure.

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

ORAL: Data are read-across from Ni sulphate. A 2-year oral carcinogenicity study reported a NOAEL of 10 mg/kg body weight/day (2.2 mg Ni/kg b. w. /day) and a LOAEL of 30 mg/kg body weight/day (6.7 mg Ni/kg b. w. /day). The LOAEL of 6.7 mg Ni/kg bw/day based on reduced body weight and increased mortality together with a NOAEL of 2.2 mg Ni/kg bw/day is taken forward to the risk characterisation. A summary document on this topic is provided as a background document in section 7.5.1 of IUCLID and in Appendix B1of this CSR.

INHALATION: Exposure related toxicities were noted following 13 weeks of exposure to Ni3S2 (0.15 to 2.5 mg/m3) in both rats and mice. No exposure-related mortality was observed, though changes in bodyweight and lung weights were significantly impacted. Additional toxicities included inflammation in the nasal cavity, bronchial lymph nodes and the lung, alveolar macrophage hyperplasia, chronic active inflammation, and olfactory epithelial atrophy. Similarly a chronic two year inhalation study with 0.15 and 1 mg/m3 demonstrated a LOAEC for respiratory effects of 0.11 mg Ni/m3 (MMAD = 2.17 µm) in rats and a LOAEC = 0.44 mg Ni/m3 (MMAD=2.24 µm) in mice.

DERMAL: Testing by the dermal route has been waived as described in Section 7.5.3 of IUCLID.

Justification for classification or non-classification

Ni dihydroxide is classified for repeated dose toxicity as STOT RE 1; H372, according to the 1st ATP to the CLP Regulation. Supporting information can be found in the discussion section for this endpoint.