Trinickel disulphide

Endpoint summary

Description of key information

Value used for CSA:

NOAEL (oral, systemic, rat): 2.2 mg Ni/kg bw/dayas nickel sulphate hexahydrate (read-across: Heim et al 2007)

LOAEC (inhalation, local, rat): 0.11 mg Ni/m³ = 0.15 mg Ni₃S₂/m³ (Dunnick et al, 1995)

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

LOAEC

0.15 mg/m³

Study duration:

subchronic

Species:

rat

Additional information

Data for repeated-dose toxicity of Ni subsulphide 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.

Toxicity associated with repeated inhalation exposures to Ni₃S₂ was 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. 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 Ni₃S₂ was also evaluated. No robust studies characterizing repeated dose toxicity following oral exposures or dermal contact were identified. Following 12 days of exposure to Ni₃S₂ at doses ranging from 0.6-10 mg/m³, rats and mice experienced significant toxicity at exposure levels of 5 mg Ni₃S₂/m³ and higher (Benson et 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 Ni₃S₂ toxicity 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/m³ for up to 22 days resulted in dose- and time-dependent effects (Benson et 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; 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. In a complimentary study, Benson et al.(1989) reported on additional endpoints in rats and mice exposed to Ni₃S₂ for 13 weeks. Biochemical and cytological changes in bronchiolar lavage fluid (BALF) were analyzed in addition to histopathologicalchanges. 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 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.

A single study evaluating toxicity following repeated exposures via intratracheal instillation demonstrated the importance of physical form in the evaluation of pulmonary toxicity (Fisher et al., 1984). Two different sized particles were instilled into the lungs of mice for up to 4 weeks (one exposure per week), resulting in a greater mortality from fine particles than course particles following a single exposure, though similar lethality rates were observed following four exposures. Toxicity was first clinically manifested as rough hair coats, weight loss, and anorexia. Mortality as a result of exposure occurred from one to four days following exposure; animals that survived this period generally recovered. Collectively, these data indicate that Ni₃S₂ is associated with a variety of toxicological endpoints (primarily adverse effects to the respiratory system) following repeated inhalation exposures in rodents; however, adverse effects are clearly time- and dose- dependent.

The evidence from human studies of an association between irregular opacities detected in chest X-rays and exposures to nickel subsulphide are suggestive of a possible association but effects were mild (Berge and Skyberg, 2003; Muir et al., 1993).

 

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) (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 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 B1 of the CSR.

INHALATION: Exposure related toxicities were noted following 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. Similarly a chronic two year inhalation study (Dunnick et al, 1995) 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 subsulphide 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.