Naphthenic acids, nickel salts

Carcinogenicity

Description of key information

The carcinogenicity potential for naphthenic acids, nickel salts will be derived based on the toxicological information for the assessment entity nickel:

The US National Toxicology Program (NTP, 1996a) study of the carcinogenicity potential of nickel sulphate after inhalation exposure is considered to be a guideline compliant, robust study demonstrating a lack of carcinogenicity in the experimental animals after inhalation.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Naphthenic acids, nickel salts is expected to be an inhalation carcinogen, since epidemiological evidence for carcinogenesis via inhalation for the moiety nickel is available. The source substance nickel sulfate is legally classified as inhalation carcinogen category 1A (H350i) on the basis of human epidemiological data.

Thus, naphthenic acids, nickel salts is classified according to regulation (EC) 1272/2008 as inhalation carcinogen Carc Cat. 1A (H350i).

Additional information

Nickel

 

INHALATION: The US National Toxicology Program (NTP, 1996a) study of the carcinogenicity potential of nickel sulphate after inhalation exposure is considered to be a guideline compliant, robust study demonstrating a lack of carcinogenicity in the experimental animals after inhalation.

ORAL: 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 the CSR.

DERMAL: The available data concerning dermal exposure are too limited for an evaluation of the carcinogenic potential in experimental animals following dermal contact to nickel sulphate. However, 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. Studies via other routes of exposure and promoter studies provide at most limited evidence of carcinogenicity of nickel sulphate in animals.

 

Epidemiology Data

As discussed in the 2008/2009 European Union Risk Assessment for Nickel Sulphate, epidemiological studies from at least three nickel refineries processing sulphidic nickel ores have demonstrated elevated risk of lung and nasal cancer in workers exposed to dust containing nickel sulphate in the presence of variable amounts of water insoluble nickel compounds. These refineries were: the Clydach refinery in,; therefinery in; and the Harjavalta refinery in. Among electrolysis workers at therefinery inthe association between respiratory cancer and exposure to nickel sulphate was not observed.

In Clydach (Doll et al., 1990; Easton et al., 1992; Sorahan and Williams, 2005; Grimsrud and Peto, 2006), elevated risk for death from lung or nasal cancer was found in workers employed in the hydrometallurgy department. Exposure to nickel sulphate also took place in other departments and there was evidence of a dose-response between soluble nickel exposure and increased cancer risk in workers with high oxidic and/or sulfidic exposure but not when oxidic and sulfidic exposures were low. At therefinery, both lung and nasal cancer mortality risks were elevated (Doll et al., 1990; Andersen et al., 1996; Grimsrud et al., 2002; 2003). A dose-response was demonstrated for lung cancer according to duration of work in the electrolysis departments. In a regression analysis, a dose-response for lung cancer and cumulative exposure to water-soluble nickel (nickel sulphate and nickel chloride) was observed after adjustment for age, smoking (ever smoker versus never smokers), and cumulative exposure to oxidic nickel. The effect from sulphidic nickel was not addressed but for oxidic nickel a modest increase in risk was also observed. The study suggested a multiplicative effect of smoking and nickel exposure. A 2002 case-control study within the same cohort, also demonstrated a dose-response between lung cancer and water-soluble nickel after adjustment for smoking (life-time habits). An increase in risk from exposures to other forms of nickel irrespective of dose could not be excluded.

The refinery in Harjavalta also treated a sulphidic nickel concentrate, as did the two refineries in Clydach and. Elevated risk for lung and nasal cancers was demonstrated in the group of workers with nickel sulphate exposures (Doll et al., 1990; Anttila et al., 1998). No adjustment for smoking could be performed in the analyses of lung cancer risk. No dose-response was found, but the number of cancer cases was low. The electrolysis workers at therefinery were exposed mainly to nickel sulphate until 1942 and from that year exposures contained a mixture of sulphate and chloride. In contrast to the three cohorts described above, lung cancer mortality risks were not elevated among the electrolysis workers with no exposure in leaching, calcining or sintering plant (Roberts et al., 1989; Doll et al., 1990). In addition, there were no nasal cancer cases among these workers.

The 2008/2009 European Union Risk Assessment for Nickel Sulphate concluded that the epidemiological data demonstrated “a positive association in a dose-dependent manner between exposure to soluble nickel compounds (e.g., nickel sulphate) and increased respiratory cancer risk in at least three separate cohorts.”

The epidemiological evidence (without the animal data) was reviewed by the Specialised Experts at their in April, 2004. The Specialised Experts concluded that the epidemiological evidence was sufficient to classify nickel sulphate in Category 1, known to be carcinogenic to man. The Specialised Experts considered the data to be sufficient to establish a causal association between the human exposure to the substances and the development of lung cancer and they considered that there was supporting evidence for this conclusion from more limited data on nasal cancer (2008/2009 European Union Risk Assessment for Nickel Sulphate).

A recent review of the carcinogenicity data for soluble nickel compounds applied the Bradford Hill criteria of causality to the epidemiological evidence in support of the carcinogenicity of soluble nickel compounds (Goodman et al., 2009). A weight of evidence analysis was later applied to the epidemiological, animal and mode of action data. Based on their evaluation, the authors considered that some epidemiological data, but not all, suggest that soluble nickel exposure leads to increased cancer risk in the presence of certain insoluble nickel compounds. In their opinion, there was only limited evidence for its carcinogenicity in humans. They note that although there is no evidence that soluble nickel acts as a complete carcinogen in animals, there is some evidence from the animal data that soluble nickel may act as a tumor promoter. Goodman et al.(2009) go on to state: “Finally, the mode-of-action data suggest that soluble nickel compounds are not able to cause genotoxic effects in vivo because they cannot deliver sufficient nickel ion to nuclear sites of target cells. Although the data do suggest several possible non-genotoxic effects of the nickel ion, it is unclear whether soluble nickel compounds can elicit these effects in vivo or whether these effects, if elicited, would result in tumor promotion. Overall, the mode-of-action data equally support soluble nickel as a promoter or as not being a causal factor in carcinogenesis at all.” Goodman and coworkers concluded: “The weight of evidence does not clearly support a role for soluble nickel alone in carcinogenesis.”

As discussed above, the Specialized Experts had concluded in 2004 that the epidemiological evidence was sufficient to classify nickel sulphate in Category 1, known to be carcinogenic to man.

 

Naphthenic acid

No data available

 

Naphthenic acids, nickel salts

The carcinogenicity potential for naphthenic acids, nickel salts will be derived based on the toxicological information for the assessment entity nickel:

The US National Toxicology Program (NTP, 1996a) study of the carcinogenicity potential of nickel sulphate after inhalation exposure is considered to be a guideline compliant, robust study demonstrating a lack of carcinogenicity in the experimental animals after inhalation.