Nickel(III) oxy hydroxide

Carcinogenicity

Description of key information

ORAL: Data are read-across from Ni sulfate.  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 B6 of the CSR.
INHALATION: Data are read-across from Ni oxide. The most robust and environmentally relevant carcinogenicity study for NiO was conducted as part of a National Toxicology Program study on the toxicity and carcinogenicity of NiSO4, Ni3S2 and NiO (Dunnick et al. 1995). Following inhalation of NiO for up to two years (6 hr/d, 5 d/wk, two exposure levels), the authors characterized the evidence for lung tumor formation in rats as “some” as opposed to “no” or “clear. ” In mice, the authors characterized the evidence for NiO carcinogenicity in the lung as “equivocal.” Taken together the epidemiological (see IUCLID section 7.10.2) and animal data suggest that at least some forms of nickel oxide can be carcinogenic to the respiratory tract of humans after inhalation. The same would apply to nickel oxyhydroxide.
DERMAL: Read-across from Ni sulfate.  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.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

11 mg/kg bw/day

Carcinogenicity: via inhalation route

Endpoint conclusion

Dose descriptor:

NOAEC

0.5 mg/m³

Justification for classification or non-classification

Ni monoxide and Ni dihydroxide are classifed for carcinogenicity via the inhalation route of exposure (Carc. 1A; H350i) according to the 1st ATP to the CLP regulation. As the data characterising the carcinogenicity of Ni monoxide and Ni dihydroxide are read-across to Ni oxyhydroxide and there are no data to disprove the carcinogenic potential of Ni oxyhydroxide the same is applied for classification. Therefore Ni oxyhydroxide is classified for carcinogenicity via the inhalation route (Carc. 1A; 350i) of exposure.

Additional information

There are no data on the carcinogenic potential of Ni oxyhydroxide available. Data on the oral carcinogenicity of Ni oxyhydroxide are read-across from Ni sulphate which represents the worst case scenario for oral absorption of Ni. 

ENDPOINT SUMMARY INFORMATION FROM THE 2008/2009 EU NI SULPHATE RISK ASSESSMENT: 

The carcinogenicity of Ni sulphate following oral administration has been studied in two old non-guideline studies with rats and dogs; no neoplasms were revealed in either rats or dogs in these studies. A 2-year carcinogenicity study with rats performed according to OECD 451 did not show any carcinogenic potential of exposure to Ni sulphate following oral (gavage) administration. Data on other Ni compounds are limited to a drinking water study of Ni acetate in rats and mice in which no exposure-related neoplasms was observed. In conclusion, there is sufficient oral carcinogenicity data to show that Ni sulphate does not show any carcinogenic potential in experimental animals following oral administration.

In addition, a background document summarizing the potential of Ni compounds to cause cancer via the oral route of exposure can be found in theattached document entitled, "Background-Oral Carcinogenicity for all Ni Compounds" (Section 7.7) and in Appendix B6 of this CSR.

For risk characterization purposes, data to assess the inhalation toxicity and carcinogenicity of Ni oxyhydroxide are read-across from Ni oxide. A comprehensive read-across assessment was recently completed based on bioaccessibility data in synthetic lung fluids of various Ni compounds combined in vivo verification data for three source Ni 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 of inhalation toxicity according to bioaccessibility in interstitial and/or lysosomal fluid.  Although this paradigm was designed to assess potential for toxicity, the bioaccessibility data provide information that can be combined with knowledge of mode of action of different Ni compounds. The outcome of this assessment indicates that Ni oxyhydroxide would behave most similarly to Ni oxide in terms of potential for inhalation carcinogenicity. The route of exposure of most relevance to humans is inhalation, and thus the most robust and applicable study for characterizing carcinogenicity associated with chronic exposure 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. These authors reported that inhalation of 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/m³NiO. In B6C3F1 mice, adenomas and carcinomas were observed only in females at 2.5 mg/m³but not 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. Based on these collective findings, the authors characterized the evidence for lung tumor formation and adrenal medullary tumors in rats as “some” as opposed to “no” or “clear”. In mice, the authors characterized the evidence for NiO carcinogenicity in the lung as “equivocal.” In contrast to these findings, Haratake et al. (1992) did not find any tumorous lesions in rats exposed to 1 mg NiO/m³(black or green) for six months. Following an additional 12-month observation period in which no additional treatment-related tumors were found, the authors concluded that neither green nor black NiO showed any apparent promoting effects on tumorigenesis.

Kasprzak and coworkers conducted the most comprehensively-reported intramuscular study; interim findings were presented by Kasprzaket al., (1980) and complete study findings by Kasprzaket al., (1983). In this study, the carcinogenic potency of three Ni(II) hydroxide preparations were evaluated:, colloidal Ni(II) hydroxide, DRY, air-dried Ni(II) hydroxide; and CRST, crystalline industrial Ni(II) hydroxide. The carcinogenic activity of the investigated Ni(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 Ni(II) hydroxide 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 Ni compounds, including Ni dihydroxide. The author concluded that based on comparison to tumor incidence associated with exposure to other Ni compounds tested, findings support the generality that the more soluble the Ni compound the greater its toxicity and the less its carcinogenicity. In a similar assessment, the RTECS file for Ni 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 Ni 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 Ni compounds.

The epidemiological evaluation of the carcinogenic risk for different Ni species has some limitations. There are no available cohorts exclusively exposed to a single Ni species. Several epidemiological studies evaluating exposure to Ni dihydroxide in workers were identified. Specifically, four studies were associated witha battery factory in Sewden (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 Ni-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 Ni dihydroxide, 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 Ni. None of the studies specifically characterized the concentrations of Ni dihydroxide at the factory. Sivulka (2005) indicated that these activities can result in varied exposure measurements, some with relatively high concentrations. 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 Ni and the risk of lung cancer. Because relative risks were highest in workers with the lowest cumulative exposures to cadmium and Ni (< 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 Ni-using industry workers who were not concomitantly exposed to sulfidic Ni. 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 Ni. Ni dihydroxide and Ni oxyhydroxide are water insoluble compounds that, when present, can be considered as part of the oxidic Ni exposure. The epidemiological studies that looked at workers exposed to oxidic Ni are described in detail in the Ni 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 Ni workers and found an association between increased respiratory cancer risks and exposure to oxidic Ni compounds present during the processing and refining of sulfidic Ni ores. These exposures included Ni-Cu oxides, complex Ni oxides and in some cases Ni hydroxide. By contrast workers exposed to oxidic Ni in the refining of lateritic ores or in Ni alloy manufacturing did not demonstrate elevated cancer risks. These exposures were mainly to complex Ni oxides devoid of copper.

One high risk cohort is that of workers employed at aNi refinery in Norway (Andersen et al., 1996).It is difficult however to interpret the findings reported by Andersen et al., (1996), given that neither Ni hydroxide nor Ni oxyhydroxide were specifically evaluated. Rather, exposures to Ni substances were evaluated based on four categories, and Ni hydroxide was grouped in with all water soluble Ni compounds. Note: other studies cited here (Doll et al., 1990) and in the general Ni literature do not group Ni hydroxide with soluble forms for Ni; rather Ni hydroxide is grouped with the oxidic forms. Ni oxyhydroxide is also grouped with the oxidic Ni compounds. In addition to soluble Ni, this study showed some evidence that long term exposure to oxidic Ni was related to an excess lung cancer risk. Importantly this study showed that cigarette smoking in combination with exposure to oxidic and soluble Ni 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 Ni 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 Ni 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 discussed in IUCLID section 7.10.2 and the animal data on Ni dihydroxide as well as the studies with Ni oxide suggest that even though some forms of oxidic Ni appear to be carcinogenic to the respiratory tract of humans after inhalation, the role of Ni dihydroxide in human inhalation carcinogenicity is not clear. 

As there are neither studies nor epidemiological data available that characterize the carcinogenic potential of Ni oxyhydroxide the data characterizing the carcinogenic potenitial of Ni dihydroxide are read-across to Ni oxyhydroxide. The results of the bioaccessibility studies in different simulated body fluids showed that the data on carcinogenicity of the oxidic Ni compounds, like Ni oxide and Ni dihydroxide can be read-across to Ni oxyhydroxide.

Data on the dermal carcinogenicity of Ni oxyhydroxide is read-across from Ni sulfate. As oral exposure to Ni 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.