Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

INHALATION: Nickel metal has been consistently negative for respiratory carcinogenicity in human studies and was also negative in a recent animal inhalation study (Oller et al., 2008).

ORAL: Oral carcinogenicity data for nickel metal are read-across from Ni sulphate. A two-year gavage carcinogenicity study in Fischer 344 rats with nickel sulphate hexahydrate (NiSO4•6H2O) was negative for carcinogenicity (Heim et al., 2007). A summary document on this topic is attached in Appendix B4 of the CSR.

Key value for chemical safety assessment

Additional information

INHALATION CARCINOGENICITY

Epidemiological studies of workers refining and processing sulfidic nickel ores have shown an association between inhalation of mixed exposures containing water soluble nickel compounds (e. g., nickel sulphate and chloride) and water insoluble nickel compounds (e. g., nickel subsulphide, nickel oxides and mixed nickel-copper oxides) and increased respiratory cancer risks. No association was found between exposure to nickel metal dust and increased respiratory cancer risks in a study of 10 cohorts (including sulphidic ore refinery workers), comprising > 100,000 workers (Doll et al., 1990). Post-1990 analyses of the data from the Clydach and Kristiansand refineries show hints of possible correlations between excess cancer risk and nickel metal exposure (Easton et al., 1992; Grimsrud et al., 2002). However, these associations were either not reproduced or lost statistical significance after accounting for confounding exposures. Other post-1990 refinery studies confirmed the negative findings for metallic nickel (Egedahl et al., 2001; Egedahl and Collins, 2009).

While the number of workers involved in these epidemiological studies was relatively modest (ranging from around 700 to several thousand workers, depending on the cohort), these workers had some of the highest estimated exposures to nickel metal (Sivulka, 2005). No association of increased respiratory cancer risk was found with inhalation exposure to metallic nickel (nickel metal and nickel alloys) outside of the nickel refineries (Arena et al., 1998; Sorahan, 2004; and other studies reviewed in Sivulka et al., 2005).Although exposures to metallic nickel were generally low (compared to the producing industry), studies in the nickel using industries did not show statistically increased risks of lung and nasal cancer that were associated with nickel exposure. Furthermore, no dose response with total nickel exposure was observed. While some of the targeted studies were relatively small, others comprised large cohorts of up to 31,000 workers.

Historical injection studies in rats and mice with nickel metal powder resulted in induction of tumors at the site of injection. These studies are difficult to interpret since injection is not an appropriate route of exposure to nickel metal powder. Two intratracheal instillation studies with nickel metal powder gave opposite results; positive in rats (Pott et al., 1987) and negative in hamsters (Muhle et al., 1992). Again this route of administration is less reliable since bolus doses are delivered to the lung, by-passing normal physiological responses.The doses in the intratracheal instillation studies are much higher than the levels that can be achieved in the lungs of animals exposed to nickel powder by inhalation (Oller et al., 2008).

A recent inhalation study with nickel metal powder in rats using OECD recommended protocols showed no induction of respiratory tumors after inhalation of nickel metal powder even at exposure levels showing significant toxicity (Oller et al., 2008). Increased incidence of adrenal gland tumors were observed in this study that were secondary to the respiratory toxicity caused by the exposure to particulates, but were not considered to be nickel ion-related (these tumors were not observed in an oral carcinogenicity study with Ni sulphate that resulted in much higher blood nickel levels).

In conclusion, nickel metal has been consistently negative for respiratory carcinogenicity in human studies and was also negative in a recent animal inhalation study. These carcinogenicity results are consistent with the Nickel ion bioavailability model for respiratory carcinogenicity of nickel substances (Oller et al., 2008). This model indicates that it is the bioavailability of nickel ion at nuclear sites of target respiratory cells that will be associated with tumor induction. There are many factors that can affect the bioavailability of Ni ion from nickel metal (e. g., toxicity, deposition, clearance, cellular uptake and dissolution). The interplay of these factors can explain the lack of carcinogenicity of inhaled respirable size nickel metal powders in animals.

Nickel metal carries a classification as a suspect carcinogen. It is classified as Category 2; H351 carcinogen under GHS and CLP; and Group 2B carcinogen (possible human carcinogen) by IARC (1990). These classifications were based on the lack of human evidence of carcinogenicity, but the presence of positive results for tumor induction in animals after injection or intratracheal instillation. In the late 1990s, the lack of a robust inhalation study lead the EU to mandate the conduct of such a study (conclusion (i), European Union Risk Assessment, 2008). An inhalation study was conducted and it showed no increased respiratory cancer incidence in animals exposed to nickel metal powder. In a weight of evidence approach, this study (Oller et al., 2008) would be given more weight than the results from injection/instillation studies and, together with the epidemiological data, strongly suggests that no carcinogen hazard is apparent for nickel metal.

 

ORAL CARCINOGENICITY (Additional background document provided in Appendix B4 of the CSR)

The lack of oral carcinogenic potential for nickel sulphate hexahydrate can be extrapolated to other soluble and insoluble nickel compounds and to nickel metal. Oral carcinogenicity, if present, will be associated with systemic exposure to Ni(II) ion. Nickel sulphate hexahydrate represents a worst-case scenario for systemic absorption of nickel since nickel sulphate hexahydrate is readily solubilized in gastrointestinal fluid and results in the highest systemic absorption of Ni (II) ions compared to less soluble nickel-containing substances (Ishimatsu et al., 1995). Rats are the best rodent model for studying the oral carcinogenicity of nickel since they have been demonstrated to be sensitive to the carcinogenic effects of nickel by other routes of exposure (e. g., inhalation). The blood Ni levels achieved in rats after oral exposure to nickel sulphate in the carcinogenicity study in rats are higher than the blood levels that can be achieved after inhalation of nickel metal at the Maximum Tolerated Dose (Heim et al., 2007; Oller et al., 2008).

Justification for classification or non-classification

INHALATION: Nickel metal carries a classification as a suspect carcinogen. It is classified as Category 2; H351 carcinogen under the EU CLP; and Group 2B carcinogen (possible human carcinogen) by IARC (1990). These classifications were based on the lack of human evidence of carcinogenicity, but the presence of positive results for tumor induction in animals after injection or intratracheal instillation. The recent animal study by the relevant route of exposure (inhalation) showed no increased respiratory cancer incidence in animals exposed to nickel metal powder, indicating that no carcinogen classification is warranted for nickel metal.

ORAL: The lack of oral carcinogenic potential for nickel sulphate hexahydrate can be extrapolated to other soluble and insoluble nickel substances, including metallic nickel.