Pentanickel octahydroxide carbonate

Endpoint summary

Description of key information

Oral: Data for repeated-dose toxicity of Ni hydroxycarbonate via oral exposure are read-across from Ni sulfate. 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 sulfate 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 subsulfide.  Exposure related toxicities were noted following 13 weeks of exposure to Ni3S2 ( 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. The LOAEC from this study is 0.11 mg Ni/m3.

Additional information

Due to the structural similarities of Pentanickel Octahydroxide Carbonate and Nickel Hydroxycarbonate, all information in this section is relevant for Pentanickel Octahydroxide Carbonate (see section 13 for full discussion of read-across strategy).

There was a relative lack of data characterizing the toxicity following repeated exposures to nickel hydroxycarbonate. 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 carbonate 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 sulfate. 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 sulfate 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 hydroxycarbonateas theoral 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 sulfate (383 mg Ni/kg/day vs. 22 mg Ni/kg/day) (EPSL, 2009). In addition, a summary document on the chronic oral toxicity of Ni compounds can be found in the attached background document entitled, "Background-Oral Chronic Exposure Effects" (Section 7.5.1 of IUCLID) and in Appendix B4 of the CSR. 

Data on repeated-dose toxicity via inhalation for Ni hydroxycarbonate are read-across from Ni subsulfide. 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 sulfate, Ni oxide, and Ni subsulfide. 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 sulfate and Ni subsulfide. 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 provides more definitive support for read-across from Ni subsufide 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 subsulfide (3.60%) and Ni sulfate (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 subsulfide and hence repeated dose toxicity via inhalation should be read-across from Ni subsulfide. The read across from Ni subsulfide 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 subsulfide 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 sulfate was even higher at 2.48 g/m³.

Toxicity associated with repeated inhalation exposures to Ni3S2 were 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/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. Available data were considered sufficient for characterizing repeated dose toxicity following inhalation exposures, but insufficient for all other routes.

Please note the following in regards to REACH endpoint requirements identified in Column 2 of the REACH Annexes VIII and IX:

Repeated dose toxicity: oral (Chronic Toxicity/STOT-RE:oral)-

The rules for adaptation in Column 2 of the REACH Annex VIII state that,“the short-term toxicity study (28 days) does not need to be conducted if:a reliable sub-chronic (90 days) or chronic toxicity study is available, provided that an appropriate species, dosage, solvent and route of administration were used”. Therefore, the requirement for a short-term study has been waived based on the availability of a 90-day.

 

Repeated dose toxicity: dermal (Chronic Toxicity/STOT-RE:dermal)-

The rules for adaptation in Column 2 of the REACH Annexes VIII and IX state that,“Testing by the dermal route is appropriate if…(1) inhalation of the substance is unlikely…”.  It also states that, “Testing by the dermal route is appropriate if: (1) skin contact in production and/or use is likely; and (2) the physicochemical properties suggest a significant rate of absorption through the skin; and (3) one of the following conditions is met:  toxicity is observed in the acute dermal toxicity test at lower doses than in the oral toxicity test, or  systemic effects or other evidence of absorption is observed in skin and/or eye irritation studies, orin vitro tests indicate significant dermal absorption, or significant dermal toxicity or dermal penetration is recognised for structurally-related substances”. As these conditions are not met and the inhalation route of exposure is considered most likely, testing for chronic dermal toxicity has been waived.

                                                                                            

Repeated dose toxicity: inhalation (Chronic Toxicity/STOT-RE:inhalation)-

The rules for adaptation in Column 2 of the REACH Annex VIII state that,“the short-term toxicity study (28 days) does not need to be conducted if:a reliable sub-chronic (90 days) or chronic toxicity study is available, provided that an appropriate species, dosage, solvent and route of administration were used”. Therefore, the requirement for a short-term study has been waived based on the availability of a 90-day.

 

Justification for classification or non-classification

Ni hydroxycarbonate is classified as T:R48/23 and STOT RE 1;H372 according to the 1st ATP to the CLP. Ni hydroxycarbonate is not classified for repeated dose toxicity via oral or dermal routes of exposure according to the 1st ATP to the CLP Regulation. Background information on this topic can be found in the discussion section.