Nickel sulphate

Endpoint summary

Description of key information

Value used for CSA:

NOAEL (oral, systemic, animal): 10 mg Ni sulphate hexahydrate /kg bw/day (or 2.2 mg Ni/kg bw/day) (Heim et al. 2007)

NOAEC (inhalation, local, animal): 0.12 mg Ni sulphate hexahydrate /m³ air ( or 0.027 mg Ni/m³air) (Dunnick et al., 1995)

LOAEC(inhalation, local, animal): 0.25 mg nickel sulphate hexahydrate/m³(or 0.056 mg Ni/m³)(Dunnick et al., 1995)

Target organs: respiratory: lung

Additional information

There are several studies that have investigated the repeated toxicity of nickel sulphate via oral and inhalation routes of exposure. Only one set of studies investigating the effects of repeated exposure via the dermal route was identified. The target organ for toxicity caused by repeated exposure to nickel sulphate depends on the route of exposure.

Oral Exposure

In a 3-6-month drinking water study by Vyskocil et al. (1994a), increased urinary albumin was detected in female rats exposed to 6.8 mg Ni/kg bw/day. In a 13-week study conducted by Obone et al. (1999), a LOAEL of 11 mg Ni/kg bw/day was identified for nickel sulphate hexahydrate given in drinking water. At this exposure level, a 4% reduction in body weight and increases in relative organ weights were observed. The NOAEL for these effects was 4.5 mg Ni/kg bw/day. A more recent 90-day study, by gavage, showed 8% body weight reduction at 7-11 mg Ni/kg bw/day (Benson et al., 2002). A 2-year chronic rat study conducted by Ambrose et al. (1976) examined the effects of nickel sulphate hexahydrate administered to rats in the diet. Effects on body weights were also observed in this study, with a NOAEL of 10 mg Ni/kg bw/day and a LOAEL of 100 mg Ni/kg bw/day identified for these effects. The same researchers conducted a 2-year study in dogs (Ambrose et al., 1976), and identified a NOAEL of 75 mg Ni/kg bw/day and a LOAEL of 188 mg Ni/kg bw/day for decreased body weight, lung granulomas, and bone marrow hyperplasia. However, because of the small group size (3 dogs/sex) it is possible that this study missed effects at the lower dose exposure levels. 

 

A more recent 2-year OECD 451 carcinogenicity study found decreased body weight gains ranging from 4% to 12% in rats (males and females combined) following oral gavage administration of 2.2 to 11 mg Ni/kg bw/day. Survival was reduced in a dose-related manner, achieving statistical significance at the two highest dose levels in females (Heim et al., 2007).

 

The kidney has been identified as a target organ for oral toxicity of nickel (e.g., albuminuria) although marked histopathological kidney damage after oral exposure has not been observed (TERA, 1999). A mouse study showed mild tubular nephropathy but at higher dose levels. The increases in urinary albumin were observed at approximately the same dose level as the reduction in body weight. Various effects on the immune system have also been reported after oral exposure to nickel sulphate. The immune effects have been observed at dose levels above those causing body weight loss. Therefore, 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 chronic Heim et al. (2007) study is taken forward to the risk characterisation for oral repeated dose toxicity.

 

A summary of the chronic oral toxicity of Ni compounds can be found in Appendix B1 of the CSR (Section 7.5.1 of IUCLID).

 

Dermal exposure

One set of studies describing toxicity effects after repeated exposure through the skin has been identified (Mathur et al. 1977; 1991; 1992; 1993; 1994) A NOAEL of 40 mg Ni/kg was identified in the Mathur et al. (1977) study for local effects on skin and systemic effects in testis and liver. However, due to the methodological limitations of this study, a NOAEL for toxicity effects via the dermal route is not carried forward to the risk characterisation.  

 

Inhalation exposure

There are several inhalation studies ranging from 12 days to 24 months of exposure that have examined the effects of repeated exposure to nickel sulphate in rats and mice. These studies identified the target organ for toxicity effects of inhalation exposure to nickel sulphate as the respiratory tract, with effects seen in the nose and the lungs.

Following inhalation of nickel sulphate the most serious toxicity effects observed in the respiratory tract are chronic inflammation and fibrosis. The most relevant and sensitive studies to assess chronic effects are the 2-year rat inhalation studies with nickel sulphate hexahydrate (NTP, 1996a; Dunnick et al., 1995). Rats appeared to be more sensitive to the toxicity effects of nickel sulphate by inhalation than mice. Chronic lung inflammation in rats including lung fibrosis was observed at a concentration of 0.056 mg Ni/m³or 0.25 mg nickel sulphate hexahydrate/m³, with a NOAEC of 0.027 mg Ni/m³identified for these effects. Although macrophage hyperplasia was detected at the exposure level of 0.027 mg Ni/m³, this effect was considered an adaptive effect and not an adverse toxicity effect. The LOAEC for repeated dose toxicity via inhalation of 0.056 mg Ni/m³and the NOAEC of 0.027 mg Ni/m³are used in the risk characterization of nickel sulphate.

 

Nickel sulphate fulfils the criteria for classification for repeated dose toxicity via inhalation since chronic lung inflammation including lung fibrosis results from long-term exposure via inhalation to a concentration of 0.056 mg Ni/m³or 0.25 mg nickel sulphate hexahydrate/m³. Ni sulfate was classified as STOT RE 1;H372 in the 1st ATP to the CLP.

 

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

ORAL: 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 on this topic is included in a background document in section 7.5.1 and in Appendix B1 of the CSR.

INHALATION: Chronic lung inflammation including lung fibrosis results from long-term exposure via inhalation to a concentration of 0.056 mg Ni/m³or 0.25 mg nickel sulphate hexahydrate/m³. A NOAEC of 0.12 mg/m³ (0.027 mg Ni/m³, MMAD = 2.5 µm) was identified for these effects (Dunnick et al., 1995).

DERMAL: It was not possible to determine a NOAEL/LOAEL for the dermal route based on the available information.

 

Justification for classification or non-classification

Ni sulphate is classified as STOT RE 1; H372 in the 1st ATP to the CLP Regulation. Background information regarding this classification is provided in the discussion section above.