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 ORAL: Data are read-across from Ni sulphate. A well-conducted OECD 451 study in rats did not show any carcinogenic potential of nickel sulphate following oral administration. A summary document on this topic can be found in the attached document entitled, " Background-Oral Carcinogenicity for all Nickel Compounds" (Section 7.7 of IUCLID) and in Appendix B1 of this CSR.
    
    
    

INHALATION: Inhalation carcinogenicity information can be derived from epidemiological data (e.g. ICNCM, 1990) with inhalation exposure to nickel dihydroxide, in mixed exposures. Additionally, inhalation carcinogenicity data are read-across from nickel subsulphide and/or nickel oxide 2-year animal inhalation exposure studies. These studies demonstrated that exposures to oxidic nickel compounds, such as nickel dihydroxide, are associated with carcinogenicity of the respiratory tract.

DERMAL: Read-across from Ni sulphate. As oral exposure to nickel sulphate does not show any carcinogenic potential, there are good reasons to assume that cancer is not a relevant end-point with respect to dermal exposure either.

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Additional information

Several investigators have evaluated the carcinogenic potential of nickel hydroxide in rats following intramuscular exposure; studies evaluating carcinogenicity following oral, inhalation, or dermal exposure, or evaluations in other non-human species, were not identified. Kasprzak and coworkers conducted the most comprehensively-reported intramuscular study; interim findings were presented by Kasprzak et al., (1980) and complete study findings by Kasprzak et al., (1983). In this study, the carcinogenic potency of three nickel(II) hydroxide preparations were evaluated: COL, colloidal nickel(II) hydroxide, DRY, air-dried nickel(II) hydroxide; and CRST, crystalline industrial nickel(II) hydroxide. The carcinogenic activity of the investigated nickel(II) hydroxides indicated that potency was greatest for the CRST followed by the DRY, with negative results for the COL. However, the relatively fastest dissolving nickel(II) hydroxide COL preparation was the most toxic one based on its injurious effects on the kidneys.

As part of an effort to evaluate rhabdomyosarcomas, Gilman (1966) evaluated the tumorigenic activity of multiple nickel compounds, including nickel hydroxide. The author concluded that based on comparison to tumor incidence associated with exposure to other nickel compounds tested, findings support the generality that the more soluble the nickel compound the greater its toxicity and the less its carcinogenicity. In a similar assessment, the RTECS file for nickel hydroxide (RTECS, 2008) also noted that a dose of 60 mg/kg administered intramuscularly in rats was associated with musculoskeletal tumors at the site of application. The available data indicate that intramuscular exposure to at least some forms of nickel dihydroxide can result in carcinogenic activity, primarily rhabdomyosarcomas, in rats under laboratory conditions. However, when interpreting these findings it is important to note that intramuscular exposure is not a relevant route of human exposure for nickel compounds.

Data on the oral carcinogenicity of nickel dihydroxide are read-across from Ni sulphate as Ni sulphate represents a worst-case scenario for systemic absorption of nickel since nickel sulphate hexahydrate is significantly more readily solubilized in gastrointestinal fluid than Ni dihydroxide and results in the highest systemic absorption of Ni (II) ions (Ishimatsu et al., 1995). A 2-year carcinogenicity study with rats performed according to OECD 451 did not show any carcinogenic potential of exposure to nickel sulphate following oral (gavage) administration.The carcinogenicity of nickel sulphate following oral administration has been studied in several studies with rats and dogs and no neoplasms were observed.There is sufficient oral carcinogenicity data to show that nickel sulphate does not show any carcinogenic potential in experimental animals following oral administration. Likewise, less bioavailable Ni compounds (like Ni dihydroxide) are also not expected to have any oral carcinogenic potential. In addition, a background document summarizing the potential of Ni compounds to cause cancer via the oral route of exposure can be found in the attached document entitled, " Background-Oral Carcinogenicity for all Nickel Compounds" (Section 7.7) and in Appendix B1of this CSR.No data regarding carcinogenicity following dermal contact to nickel dihydroxide or nickel sulphate in experimental animals have been located. However, toxicokinetic data indicates that systemic absorption of nickel from water soluble nickel compounds through the skin is very low (≤ 2%). As oral exposure does not show systemic carcinogenicity, it seems reasonable to assume that cancer is not a relevant endpoint for dermal exposure to nickel sulphate nor nickel dihydroxide.

For risk characterization purposes, data on the inhalation carcinogenicity of nickel dihydroxide are read-across from nickel subsulphide and nickel oxide. A comprehensive read-across assessment was recently completed based on bioaccessibility data in synthetic lung fluids of various nickel compounds, combined with in vivo verification data for three source nickel substances. The read-across 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 of inhalation toxicity according to bioaccessibility in interstitial and/or lysosomal fluid. Although this paradigm was designed to assess potential of toxicity, the bioaccessibility data provide information that can be combined with knowledge of mode of action of different nickel compounds. The outcome of this assessment indicates that although Ni dihydroxide behaves most similarly to Ni oxide in terms of bioaccessibility in interstitial fluid, it behaves similarly to Ni subsulphide regarding bioaccessibility in lysosomal fluid. Therefore, animal carcinogenicity studies for Ni oxide and Ni subsulphide are considered. The most robust and environmentally relevant carcinogenicity study for Ni3S2 was conducted as part of a National Toxicology Program study on the toxicity and carcinogenicity of NiSO4, Ni3S2, and NiO (Dunnick et al.1995; NTP, 1996). Following inhalation of Ni3S2 for up to two years (6 hr/d, 5 d/wk, two exposure levels), a dose-dependent incidence of lung tumors (combined adenomas and carcinomas) was observed in F344/N rats. Benign and malignant pheochromocytomas of the adrenal medulla were also observed in male rats. In contrast, no exposure-related neoplasms were found in any B6C3F1 male and female mice. For both species, survival was generally similar between exposed and control animals, though bodyweight was lower in exposed animals.

The most robust and applicable study for characterizing carcinogencity associated with chronic exposure to NiO was that reported by Dunnick and colleagues (1995), in which the findings of a 2-year bioassay conducted by the National Toxicology Program were reported (NTP, 1996a). These authors reported that inhalation of a high-calcining temperature (green) NiO caused lung neoplasms in F344 rats and B6C3F1 mice exposed chronically (two years) for 6 hr/day (3 dose groups tested in both species). In rats, adenomas and carcinomas were observed in the lungs of both male and female rats at concentrations ≥ 1.25 mg/m3 (a statistically significant increase in tumors was not observed at 0.62 mg/m3), and pheochromocytomas at the highest dose of 2.5 mg/m3 NiO. In B6C3F1 mice, adenomas and carcinomas were observed only in females at 2.5 mg/m3 but not at 5.0 mg/m3 (a statistically significant increase in tumors was not observed at 1.25 mg/m3), thus demonstrating a lack of dose-response relationship in mice. No other exposure-related neoplasms were found in rats or mice.

The epidemiological evaluation of the carcinogenic risk for different nickel species has some limitations. There are no available cohorts exclusively exposed to a single nickel species.Several epidemiological studies evaluating exposure to nickel hydroxide in workers were identified. Specifically, four studies were associated with a battery factory in Sweden (Kjellstrom et al., 1979, Andersson et al., 1983, Elinder et al., 1985, Jarup et al., 1998) and one study with a battery factory in the UK (Sorahan and Esmen, 2004). The Swedish studies were prompted by an initial, yet comprehensive, report published by Friberg (1950) detailing the findings of clinical and laboratory assessments of nickel-containing, alkaline manufacturing facility dust. Several epidemiological evaluations of this cohort followed, though many of them were focused on health effects associated with cadmium exposure (note: cadmium-specific studies were not reviewed for this report). Fewer studies evaluated nickel hydroxide, either alone or as a confounder with cadmium exposure. The four studies reporting on epidemiological evaluations of Swedish battery workers were primarily focused on evaluating mortality associated with exposure to cadmium and nickel. None of the studies specifically characterized the concentrations of nickel hydroxide at the factory. Sivulka (2005) indicated that these activities can result in varied exposure measurements, some with relatively high concentrations ( ≈ 2-4 mg Ni/m3, inhalable nickel).In the UK study, the relative risk for lung cancer for the overall cohort (926 workers) was not statistically elevated. Moreover, there was no significant trend of relative risks increasing either with year of hire or with period since first employed (Sorahan and Esmen, 2004).

In the latest of the Swedish battery workers studies (Jarup et al., 1998), there was an increased overall risk of lung cancer mortality, but no exposure response relationship between cumulative exposure to cadmium or nickel and the risk of lung cancer. Because relative risks were highest in workers with the lowest cumulative exposures to cadmium and nickel (< 0.25 mg Ni/m3x year) and the shortest durations of exposure (< 20 years latency), the authors concluded that the excess risks seen were "most likely explained by exposures to carcinogens in other industries." Two nasal cancer cases were seen in these battery workers. This is the only instance in which statistically significant nasal cancers have been seen in nickel-using industry workers who were not concomitantly exposed to sulfidic nickel. As was believed to be the case for the lung cancers seen in these battery workers, it may be that these nasal cancers were due to previous employment in other workplaces. 

There are several epidemiological studies that have looked at the associations between respiratory cancer risks and exposures to oxidic nickel. Nickel hydroxide is a water insoluble compound that, when present, can be considered as part of the oxidic nickel exposure. The epidemiological studies that looked at workers exposed to oxidic nickel are described in detail in the Nickel Oxide CSR. One example of such study (Doll et al., 1990) will be briefly described here. The Doll study looked at 10 different cohorts of nickel workers and found an association between increased respiratory cancer risks and exposure to oxidic nickel compounds present during the processing and refining of sulfidic nickel ores. These exposures included Ni-Cu oxides, complex nickel oxides and in some cases nickel hydroxide. By contrast workers exposed to oxidic nickel in the refining of lateritic ores or in nickel alloy manufacturing did not demonstrate elevated cancer risks. These exposures were mainly to complex nickel oxides devoid of copper.

One high risk cohort is that of workers employed at a nickel refinery in Norway (Andersen et al., 1996). It is difficult however to interpret the findings reported by Andersen et al., (1996) for nickel hydroxide given that nickel hydroxide was not specifically evaluated. Rather, exposures to nickel substances were evaluated based on four categories, and nickel hydroxide was grouped in with all water soluble nickel compounds. Note: other studies cited here (Doll et al., 1990) and in the general nickel literature do not group nickel hydroxide with soluble forms for nickel; rather nickel hydroxide is grouped with the oxidic forms. In addition to soluble nickel, this study showed some evidence that long term exposure to oxidic nickel was related to an excess lung cancer risk. Importantly this study showed that cigarette smoking in combination with exposure to oxidic and soluble nickel appears to produce synergistic effects (Andersen et al.,1996). The author’s conclusion was that it was not possible to state with certainty which specific nickel compounds were carcinogenic.

Despite a range of exposure metrics (from years of employment to a more sophisticated job exposure matrix) and an equally diverse range in analyses (i. e., simplistic to sophisticated analyses accounting for confounding variables, etc.), results were relatively consistent in that significantly increased risks of mortality from a wide variety of cancers were generally not observed among nickel hydroxide-exposed workers. Increased risks of lung and/or nose and nasal cancer were noted, but they were not consistently significant, nor were consistent dose-response relationships observed.

Taken together the epidemiological and animal data on nickel hydroxide as well as the studies with nickel oxide and nickel subsulphide suggest that even though some forms of oxidic nickel appear to be carcinogenic to the respiratory tract of humans after inhalation, the role of nickel dihydroxide in human inhalation carcinogenicity is not clear. 

Justification for classification or non-classification

Ni dihydroxide is classified for carcinogenicity via inhalation as Carc. 1A: H350i according to the 1st ATP to the CLP Regulation. Supporting information can be found in the discussion section for this endpoint.