Nickel sulphide

Endpoint summary

Description of key information

Value used for CSA:

• NOAEL (oral, systemic, animal, read-across from Ni sulphate hexahydrate): 2.2 mg Ni/kg bw/day (Heim et al., 2007)
• LOAEC (inhalation, local, animal, read-across from Ni subsulphide): 0.11 mg Ni/m³ =  0.15 mg Ni₃S₂/m³ (Dunnick et al., 1995)

Additional information

No robust studies characterizing repeated dose toxicity following oral exposures or dermal contact with Ni sulphide were identified. Data for repeated-dose toxicity via oral exposure are read-across from Ni sulphateIn 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 with Ni sulphate, 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 (Heimet 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 Heimet 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 Ni subsulphide. A comprehensive read-across assessment was recently completed based on bioaccessibility data in synthetic lung fluids of various nickel compounds combined within vivoverification data for three source nickel substances. The read-across paradigm presented in a summary document in Section 7.2.2 and inAppendix B2to the CSR enables grouping of target Ni substances according to bioaccessibility in interstitial and/or lysosomal fluid as demonstrated.  The outcome of this assessment indicates that the inhalation toxicity of Ni sulphide should be read-across from Ni subsulphide.  Toxicity associated with repeated inhalation exposures to Ni₃S₂were well characterized by a series of studies in rats and mice. These studies were generally conducted by the same group of researchers, and were part of, or associated with, a comprehensive bioassay conducted by the National Toxicology Program (NTP, 1996). Durations of exposure ranged from 12 exposure days up to 2 years. Though general signs of toxicity were evaluated, much of the focus was on toxicity associated with pulmonary endpoints. One additional study evaluating toxicity following repeated exposures to Ni₃S₂was also evaluated.

Following 12 days of exposure to Ni₃S₂at doses ranging from 0.6-10 mg/m³, rats and mice experienced significant toxicity at exposure levels of 5 mg/m³and higher (Bensonet al. 1987). Toxicities included labored respiration, emaciation, dehydration, decreased weight gain, altered organ weights, and mortality in some cases. Histopathological analyses revealed that the respiratory tract was the major target for Ni₃S₂toxicity based on observations of necrotizing pneumonia, emphysema, or fibrosis in exposed rats, and lesions in the nasal epithelium and lung. However, other toxicities, including atrophy of the thymus, spleen, and liver, as well as testicular degeneration were observed in both rats and mice. A more in-depth, time course evaluation of exposure to lower doses (0.6 or 2.5 mg Ni₃S₂/m³for up to 22 days resulted in dose- and time-dependent effects (Bensonet al. 1995). Exposure-related toxicities included decreases in body weight, increased lung weight, morphological changes (e. g., nasal lesions, degeneration of olfactory epithelium), and a number of biochemical effects associated primarily with inflammation (e. g., increased alveolar macrophages, hyperplasia of bronchiolar epithelial cells, presence of inflammatory cells in bronchial lumen, LDH activity). Similar findings were noted following 13 weeks of exposure to Ni₃S₂(0.15 to 2.5 mg/m³; Dunnicket 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. In a complimentary study, Bensonet al. (1989) reported on additional endpoints in rats and mice exposed to Ni₃S₂for 13 weeks. Biochemical and cytological changes in bronchiolar lavage fluid (BALF) were analyzed in addition to histopathological changes. Significant and dose-dependent effects in a number of biochemical and cytological parameters (e. g., levels of lactate dehydrogenase, β-glucuronidase, percentage of neutrophils and macrophages in lavage fluid) as well as tissue damage (e. g chronic inflammation, macrophage proliferation) were observed. A separate study reported labored breathing, lung foci, enlarged lymph nodes, and nasal and lung lesions (e. g., chronic inflammation associated with this exposure scenario in rodents).

Repeated dose toxicities associated with 2 years of exposure to Ni₃S₂included a variety of clinical observations, body and organ weight changes, and altered tissue histopathology (Dunnicket al. 1995). Chronic exposure to concentrations up to 1 mg Ni₃S₂/m³were 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 (A/B) 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.

Only one repeated dose toxicity study was located for Ni sulphide. Though it did not meet all criteria (i.e., multiple doses), it did directly evaluate nickel sulphide and utilize a route of exposure relevant to human health. In this study, male Wistar rats were exposed via inhalation to 8.8 mg/m³aerosols for 7 hours/day, 5 days/week up to 1 month (Tanakaet al. 1988). At the end of the exposure period, the only noted lesions in treated rats were minimal focal pneumonia in 2 of the 5 treated rats). For the treated rats examined 6 months after the termination of exposure, dacryoadenitis was observed in 3 of 5 animals, and suppurative rhinitis occurred in all 5 animals.

 

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) (Heimet 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 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 inAppendix B1of the CSR.

INHALATION: Data are read-across from Ni subsulphide. Exposure related toxicities were noted following 13 weeks of exposure to Ni₃S₂(0.15 to 2.5 mg/m³; Dunnicket 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. The LOAEC from this study is 0.15 mg Ni₃S₂/m³. Similar effects were onbserved in a two-year study, with a LOAEC 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.

Value used for CSA:

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

LOAEC (inhalation, local, animal, read-across from Ni subsulphide): 0.11 mg Ni/m³= 0.15 mg Ni₃S₂/m³(Dunnick et al., 1995)

Justification for classification or non-classification

Ni sulphide is classified as STOT RE 1; H372 according to the 1st ATP to the CLP. Background information on this topic can be found in the discussion section.