Nickel(III) oxy hydroxide

Endpoint summary

Description of key information

ORAL: Data are read-across from Ni sulfate. 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 comprehensive summary document on this topic is provided as a backgound document in section 7.5.1 of IUCLID and in Appendix B4 of this CSR.
INHALATION: Data are read-across from Ni oxide. Exposure related toxicities were noted following 13 weeks as well of 2-years of exposure to NiO (Dunnick et al. 1989) in both rats and mice. Adverse effects in rodents were primarily limited to the lung (e. g., increased tissue weight, inflammation, macrophage hyperplasia). The LOAEC from a 13-week study was 2 mg Ni/m3.  And the LOAEC from the chronic study (see IUCLID section 7.7 Carcinogenicity) was 0.5 mg Ni/m3.  

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

2.2 mg/kg bw/day

Study duration:

chronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

LOAEC

0.5 mg/m³

Study duration:

subchronic

Species:

rat

Additional information

No information characterizing toxicity following exposure to repeated doses of nickel oxyhydroxide was identified.

Data for repeated-dose toxicity via oral exposure are read-across from Ni sulfate which was chosen based on the bioaccessibility assessment as worst case scenario. The summary document on oral bioaccessibility and chronic oral toxicity of Ni compounds can be found in the attached background documents entitled "Background-Oral Bioaccessibility Read-Across Paradigm and Results" and "Background-Oral Chronic Exposure Effects" (Section 7.5.1 of IUCLID) and in Appendix B1 and B4 of this CSR. 

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 characterization for oral repeated dose toxicity.

Data for repeated-dose toxicity via inhalation exposure are read-across from Ni Oxide. A comprehensive read-across assessment was recently completed based on bioaccessibility data in synthetic lung fluids of various nickel compounds combined in vivo verification data for three source nickel substances. The bioaccessibility-based paradigm presented in a summary document in Section 7.2.2 and in Appendix B2 of this CSR enables grouping of target Ni substances for classification purposes according to bioaccessibility in interstitial and/or lysosomal fluid. The outcome of this assessment indicates that Ni oxyhydroxide should be read-across from Ni oxide and Ni dihydroxide for inhalation toxicity. Available inhalation studies of NiO ranged in exposure duration from 12 days to lifetime exposures, including 1, 3, 4, 6, 12, 13, 24, and 24+ month durations of nickel oxide inhalation. Several studies evaluated toxicity at the end of exposure, and some also included evaluation of toxicity one to three months following the cessation of exposure. Both green and black nickel oxides were evaluated, though most studies focused on a single dose of green nickel oxide. Toxicity was evaluated in rats, mice and hamsters. Endpoints generally included evaluation of body and organ weight changes, assessment of tissue damage (primarily in lung), mortality and gross toxicity, and alterations in serum or bronchoalveolar lavage fluid (BALF) chemistry.

The most robust data characterizing toxicity following repeated doses of nickel oxide was reported in a series of publications by Dunnick and colleagues (1988, 1989, 1995; Benson et al. 1989). These studies were associated with a comprehensive bioassay conducted by the National Toxicology Program (NTP) that compared the toxicity of nickel sulfate, Ni₃S₂and NiO (NTP, 1996). Toxicity evaluations were conducted following 16 days, 3 months, and two years (exposure on weekdays only) of exposure to green NiO (0, 1.2, 2.5, 5.0, 10, or 30 mg NiO/m³) in F344/N rats and B6C3F1 mice. Endpoints examined included clinical signs of toxicity, body and organ weights, histopathology, and measurement of the concentration of nickel in lung tissue. Following 12-day and 3-month exposures, adverse effects in rodents were primarily limited to the lung (e.g., increased tissue weight, inflammation, macrophage hyperplasia); effects were noted to occur in a dose dependent fashion, and were generally more severe in rats than mice. Following two years of exposure, effects included dose-dependent occurrence of alveolar and bronchiolar hyperplasia, inflammation, fibrosis, lymphoid hyperplasia of the lung-associated lymph nodes, and increases in lung weight. No increased mortality was observed due to NiO exposure of any duration. Relative to the other nickel compounds evaluated, NiO was the least toxic, though it resulted in the highest lung burden of nickel. As such, the authors generally concluded that toxicity to the lung correlated with solubility of the nickel compound rather than the amount of nickel in the lung.

In a series of studies associated with, but not specifically included in the comprehensive NTP bioassay, Benson et al (1989) evaluated biochemical and cytological changes in BALF in rats and mice following 13 weeks or 6 months of exposure to green NiO (0, 0.6, 2.5 or 10 mg/m³). Generally, dose-dependent changes were observed for the majority of endpoints evaluated, including changes in total protein, lactate dehydrogenase, total nucleated cells, the percent of neutrophils and macrophages, macrophage proliferation, interstitial pneumonia and chronic inflammation. The severity and incidence of histopathological findings were evaluated over time in the 6-month exposure study (Benson et al., 1995); effects were generally most severe two months following the initiation of exposure, remained steady until the cessation of exposure. However, the incidence of lesions continued to increase in mice for two months after the termination of exposure, whereas the incidence (but not severity) decreased during the 4-month recovery phase. Based on the findings that changes in biochemical indicators of lung lesions measured in BALF paralleled the nature and incidence of morphological changes (as reported by Dunnick and colleagues), the authors concluded that inhalation of occupationally relevant aerosol concentrations of green NiO can produce toxic effects in the lungs of rodents. The LOAEC from the six month study is 2.5 mg NiO/m³or 2 mg Ni/m³. And the LOAEC from the corresponding chronic study (discussed under the Carcinogenicity section) was 0.5 mg Ni/m³. 

 

Chronic exposure to multiple doses of nickel oxide was also investigated by a number of other groups. Weischer and colleagues (1980a, 1980b) evaluated clinical and clinico-chemical parameters in blood, serum and urine, along with body and organ weight changes and tissue damage associated with exposure to NiO aerosols (three doses) for 21-, 28-, or 120-days in female and male rats. Gender differences were observed in the severity of changes for a number of clinical chemistry endpoints, though data generally suggested that toxicities occurred in a dose-dependent fashion with some exceptions (e.g., organ weight changes). The authors concluded that subchronic NiO inhalation induced lesions in lungs, liver and kidneys in rats.

Though most studies characterizing repeated inhalation toxicity associated with nickel oxide did not report increased mortality, Takenaka et al (1985) observed dose-dependent, significant decreases in mean survival times following exposure to 60 μg/m³or 200 μg/m³in rats. Exposure-dependent decreases in body weight, increased lung weight, and histopathological signs of toxicity were also reported. Following a similar duration of exposure, Tanaka et al (1988) did not see an exposure related effect on body weight gain or mortality following inhalation of NiO (200 μg/m³or 1200 μg/m³) in rats, though significant increases in lung weight and pulmonary lesions were clearly associated with exposure. These authors also evaluated animals 8 months following the cessation of a 12-month exposure and did not note any significant toxicities following long-term exposure. Cho et al (1992) also evaluated toxicity in rats immediately following a 12-month inhalation exposure, and 8 months following cessation of the exposure. Similarly, the authors reported increased lung tissue weight; these authors also reported that NiO exposure resulted in a significant increase in lung lipid concentration following chronic exposure.

Several studies also evaluated the toxicity of repeated inhalation exposure to a single concentration of nickel oxide. Murthy et al (1983) exposed rats to NiO (120 μg/m³) for 12 days, collected BALF, and documented a number of cellular toxicities in macrophages using transmission electron microscopy. Fujita et al (2009) also evaluated toxicity, as well and changes in gene expression, following repeated exposure to a single dose of ultrafine NiO (200 μg/m³) for one month in rats. The authors did not report a significant change in lung weight; however, changes in gene expression in lung tissue were evaluated 3 and 33 days post exposure that were collectively suggestive of acute inflammation and also suggested that damaged tissues undergo repair in the post-exposure period. In a study evaluating the potential co-carcinogenicity of inhaled NiO and cigarette smoke, Wehner et al (1975) exposed hamsters over a lifetime (53.2 μg NiO/L) and reported that NiO exposure did not appear to effect survival. The authors concluded that while the hamsters eventually developed increasingly severe pneumocomiosis in response to the chronic NiO exposures (53.2 μg/L), they did not find a significant carcinogenic effect of the inhaled NiO or a co-carcinogenic effect if cigarette smoke.

Collectively, the available studies demonstrate that repeated inhalation of nickel oxide in laboratory species results in dose-dependent, adverse toxicological responses, primarily in the lung. These responses include, but are not limited to, increased tissue weight and a variety of cellular lesions associated with inflammation and hyperplasia (typically observed in macrophages). Repeated inhalation exposure to nickel oxide typically did not significantly influence mortality rates, body weight changes, nor was it associated with significant adverse effects in tissues other than the lung. Given the robust nature of the available studies with nickel oxide and based on read across, the data appear sufficient to characterize the toxicity of nickel oxyhydroxide following repeated inhalation exposure.

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

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

The rules for adaptation in Column 2 of the 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 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, or in vitro tests indicate significant dermal absorption, or significant dermal toxicity or dermal penetration is recognized 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 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

As the data established to determine the repeated dose toxicity of Ni oxide and Ni dihydroxide are representing the boundaries of the read-across approach to Ni oxyhydroxide the classification for repeated dose toxicity via the inhalation route as T:R48/23 and STOT RE 1; H372, according to the 1st ATP to the CLP Regulation taken over for Ni oxyhydroxide. Supporting information can be found in the discussion section for this endpoint.