[carbonato(2-)]tetrahydroxytrinickel

Endpoint summary

Description of key information

Value used for CSA (read-across from Nickel sulphate or Nickel subsulphide):

NOAEL (oral, systemic, animal, read-across from Ni sulphate): 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

There was a relative lack of data characterizing the toxicity following repeated exposures to nickel (hydroxy)carbonate. The two studies available were non-traditional assays aimed at evaluating the effects of exposures to nickel hydroxycarbonate via feed on growth, feed utilization, and tissue aberrations in male bovine, as well as milk production, milk composition, animal health or feed consumption in lactating cows. Male cows exposed to 250 ppm (and higher) nickel hydroxycarbonate in feed for eight weeks had reduced growth rates and feed intake (O’Dell et al. 1970a). The same group of investigators (O’Dell et al., 1970b) fed lactating cows nickel hydroxycarbonate via the diet over a six week period. Very little of the dietary nickel was detected in the milk samples, and there was no observable effect on milk production, milk composition, animal health, or feed consumption.

No data were available characterizing endpoints other than the limited data in bovine by O’Dell et al. (1970a, b). As no traditional data were available evaluating repeated toxicity following oral or inhalation routes of exposure, data from other nickel compounds are used to read-across toxicity information to Ni hydroxycarbonate.  

Data for repeated-dose toxicity of Ni hydroxycarbonate via oral exposure are read-across from Ni sulphate. 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 exposure by gavage of 2.2 to 11 mg Ni/kg bw/day (as Ni sulphate hexahydrate). 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 characterization for oral repeated dose toxicity. This read-across is considered to be a very conservative estimate for the potential toxicity of Ni hydroxycarbonate as the oral absorption of Ni ion from Ni hydroxycarbonate is likely to be lower than from Ni sulphate. This is supported by findings from acute oral toxicity studies where the NOAEL of Ni hydroxycarbonate was found to be significantly higher than that of Ni sulphate (383 mg Ni/kg/day vs. 22 mg Ni/kg/day) (EPSL, 2009a, b). 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).

Data on repeated-dose toxicity via inhalation for Ni hydroxycarbonate are read-across from Ni subsulphide. While substance-specific data have recently been generated on the acute inhalation toxicity of Ni hydroxycarbonate, conclusions regarding chronic toxicity are mainly based on relative bioaccessibility in synthetic lung fluids and are complemented by the recent acute inhalation data. A comprehensive read-across assessment of various nickel compounds was recently completed based on the bioaccessibility of nickel in synthetic lung fluids combined with in vivo verification data for three source nickel substances, Ni sulphate, Ni oxide, and Ni subsulphide. To estimate bioavailability via the inhalation route of exposure various nickel substances were subjected to bioaccessibility testing (KMHC, 2010). The bioaccessibility-based read-across paradigm incorporating these data is presented in a summary document that is included as Appendix B2 to the CSR.  Bioaccessibility data for the inhalation route of exposure can provide important information regarding the potential bioavailability and subsequent toxicity for inhalation endpoints such as acute and chronic inhalation toxicity. In this assessment, relative bioaccessibility from different nickel substances in extracellular (interstitial and alveolar) and intracellular (lysosomal) synthetic lung fluids were compared to that of the source substances. An evaluation of the lysosomal data demonstrated that the bioaccessibility of Ni hydroxycarbonate in lysosomal fluid is closest to that of Ni sulphate and Ni subsulphide. Further to this, however, the comprehensive read-across paradigm concluded that relative bioaccessibility in extracelluar fluids is a more robust indicator of respiratory toxicity than lysosomal fluid. Therefore, considering the results for the interstitial and alveolar fluids, the relative release data provide more definitive support for read-across from Ni subsuphide than for Ni sulphate for this endpoint. Release of Ni (II) ion from the Ni hydroxycarbonate sample was 1.65% (expressed as % Ni/gram sample) in interstitial fluid compared to the release of Ni (II) ion from Ni subsulphide (3.60%) and Ni sulphate (12.80%) (see KMHC, 2010 and Appendix B2). Taking into account all of the available information, evaluation of the data suggests that the bioaccessibility of Ni hydroxycarbonate in lung fluids is most similar to that of Ni subsulphide and hence repeated dose toxicity via inhalation should be read-across from Ni subsulphide. The read across from Ni subsulphide for repeated dose respiratory toxicity is consistent with the recent results from acute inhalation toxicity studies. The LC₅₀ for hydroxycarbonate for the most sensitive sex (males) was 0.24 g/m³ in rats (MMAD=1.9 µm); the LC₅₀ for nickel subsulphide in male rats was 1.35 g/m³ (MMAD=3.0 µm). [Note: if the same particle size would have been used in both studies, the differences in LC₅₀s are expected to have been smaller.] For comparison, the LC₅₀ for nickel sulphate was even higher at 2.48 g/m³.

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. 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/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 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 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 (A/B) hyperplasia, inflammation, fibrosis, and lymphoid hyperplasia of the lung-associated lymph nodes. 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 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 following information is taken into account for any hazard / risk assessment:

ORAL: Data for repeated-dose toxicity of Ni hydroxycarbonate via oral exposure are read-across from Ni sulphate. 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 exposure by gavage of 2.2 to 11 mg Ni/kg bw/day (as Ni sulphate hexahydrate). 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 characterization for oral repeated dose toxicity.

INHALATION: Data on repeated-dose toxicity via inhalation for Ni hydroxycarbonate 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; 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 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 hydroxycarbonate 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.