Trinickel disulphide

Endpoint summary

Description of key information

Value used for CSA:

NOAEL (oral, systemic, animal): >11,000 mg Ni₃S₂/kg bw/day (or >8,000 mg Ni/kg bw/day) (EPSL, 2008)

NOAEC (inhalation, systemic, animal): 0.206 mg Ni₃S₂/L air (or ~126 mg Ni/m³ air) (EPSL, 2010)

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Dose descriptor:

LD50

Acute toxicity: via inhalation route

Endpoint conclusion

Dose descriptor:

LC50

Value:

1 140 mg/m³ air

Additional information

Two background documents describing the use of Ni subsulphide as a source substance for read-across of oral and inhalation toxicity to other nickel compounds has been attached to Sections 7.2.1 and 7.2.2 of IUCLID and included in the CSR as Appendices B1and B2. 

 

Many studies were identified characterizing the acute toxicity of Ni₃S₂ in rodents following oral or intratracheal instillation. In addition, one acute inhalation toxicity study was recently completed, and no studies characterizing acute toxicity following dermal contact were identified. The most well-characterized endpoint associated with rodent exposures to Ni₃S₂ was mortality; GLP guideline-based studies were available for both oral and inhalation exposures.

 

A robust GLP, guideline-based study was conducted by Eurofins Product Safety Laboratory (EPSL, 2008) and reported the findings of the acute oral toxicity of Ni₃S₂ as determined by the acute toxicity up and down procedure in female rats. Following a single oral exposure to 11,000 mg/kg Ni₃S₂, all animals survived, gained body weight, and appeared healthy and active during the study. No signs of gross toxicity, adverse pharmacologic effects, abnormal behavior, or gross abnormalities were observed. Based on these findings, the acute oral LD₅₀ of Ni₃S₂ was estimated to be greater than 11,000 mg/kg b. w. in female rats.

 

Eurofins Product Safety Lab (EPSL, 2010) characterized lethality associated with acute inhalation. This GLP, guideline-based study exposed rats (nose-only) for four hours to nickel subsulphide (3 dose groups) and monitored survivial, body weight, and a number of clinical endpoints. Under the conditions of this study, the acute inhalation defined LC₅₀ of nickel subsulphide was 1.352 mg/L (95% CI of 0.3371 to 5.422 mg/L) in male rats and 0.9237 mg/L (95% CI of 0.5215 to 1.6359 mg/L) in female rats. The average inhalation LC₅₀ is calculated to be 1.14 mg/L (MMAD =3 µm).

 

Lower LD₅₀ estimates were reported in an intratracheal instillation study conducted by Fisher et al. (1984).The findings demonstrated the importance of physical form in the evaluation of pulmonary toxicity and lethality ofNi₃S₂ particles of different size. Fine particles (1.8 μm) were clearly more toxic and lethal than the coarse particles (13.3 μm), with reported LD₅₀ values of 4 and 50 mg/kg, respectively; lethality was associated with pulmonary hemorrhage and possible congestion and edema.

 

Several studies also evaluated cellular, biochemical, and histological endpoints following intratracheal exposures. Benson et al. (1984) exposed F344 rats to 0.01 to 1.0 μmol Ni₃S₂ and reported moderate multifocal alveolotis and dose-dependent increases in a number of biochemical parameters. In a 1986 study, this group of authors evaluated similar endpoints and correlated findings with the concentration of nickel in lung tissues following a similar exposure paradigm (0.01 to 1.0 μmol). Levels of Ni in the lung were virtually identical after 1 and 7 days of exposure to Ni₃S₂ (1 μmol Ni), but elevated relative to untreated animals. No significant biochemical, cytological, or histopathological changes were detected in nickel-exposed animals 1 day following administration. However, dose-related responses were observed following 7 days of exposure, indicating acute toxicity associated with exposure to Ni₃S₂. Acute toxicity following intratracheal exposure in mice (0.5 mg/kg Ni₃S₂ in 20 μL PBS) was also reported by Finch et al. (1987). Observations of lethargy, pulmonary hemmorraging, increased bodyweights and lung weight, and increased cell yields and polymorphonuclear (PMN) cells in lung lavage fluid led the authors to conclude that Ni₃S₂ was acutely toxic in mice. Collectively, these data are indicative of acute toxicity following intratracheal exposure to Ni₃S₂ in rodents.

 

Though not studied using a relevant route of exposure, strain susceptibilities associated with Ni₃S₂ were also reported by Rodriguez et al. (1996). Male mice injected with single doses (0.5 to 10 mg/site) resulted in strain-dependent susceptibility in mortality, necrotic/inflammatory kidney damage, and changes in bodyweight, indicating Ni₃S₂ induced both local and distal tissue pathologies.

 

Taken together, the available data indicate that Ni₃S₂ can be acutely toxic in rodents following inhalation and intratracheal instillation under laboratory conditions (inhalation LC₅₀= 0.9237mg/L for most sensitive gender). However, following oral exposure, Ni₃S₂ was not acutely toxic at doses up to 11,000 mg/kg in rats (8,000 mg Ni/kg). Thus, the data clearly indicate the importance of accounting for strain susceptibilities, exposure route, dose, and particle size when evaluating acute toxicity.

 

As oral and inhalation routes of exposure are more relevant and data for these have been provided, testing for acute dermal toxicity is therefore waived based on this information.

 

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

ORAL: Ni subsulphide was not acutely toxic at doses up to 11,000 mg Ni₃S₂/kg in rats (8,000 mg Ni/kg/day).

INHALATION: Ni₃S₂ can be acutely toxic in rodents following inhalation and intratracheal instillation under laboratory conditions (inhalation LC₅₀= 0.9237 mg Ni₃S₂/L for most sensitive gender; NOAEC=126 mg Ni/m³, MMAD=3.0 µm).

DERMAL: No risk characterisation will be conducted for acute dermal toxicity. Acute systemic effects are not relevant due to the very low dermal absorption of nickel. Acute local effects are covered by the long term DNEL based on prevention of dermal sensitization.

Justification for classification or non-classification

Ni subsulphide does not have a harmonized classification for oral or dermal acute toxicity, according to the CLP regulation. However in 2021, a new harmonized inhalation classification of Acute Tox. 3: H331 was published in the 17th ATP to the CLP Regulation. Therefore, this REACH submission reflects a harmonized classification for acute toxicity via inhalation as Acute Tox. 3: H331. Acute toxicity via the oral and dermal routes of exposure will remain unclassified. Supporting information can be found in the discussion section for this endpoint.