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Carcinogenicity

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INHALATION: Contrary to the views expressed by the authors of the 2008/2009 EU NICKEL SULPHATE RISK ASSESSMENT, the US National Toxicology Program study of the carcinogenicity potential of nickel sulfate 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), where it is explained why data on nickel sulfate can be extrapolated to all soluble nickel compounds, including nickel fluoride.
DERMAL: The available data concerning dermal exposure are too limited for an evaluation of the carcinogenic potential in experimental animals. However, as oral exposure to nickel soluble compounds do 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.
As described in the attached document entitled, " Background-Oral Carcinogenicity for all Nickel Compounds" (Section 7.7 of IUCLID) Nickel sulfate hexahydrate represents a worst-case scenario for systemic absorption of nickel since nickel sulfate 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; Hayman et al., 1984), such as Nickel fluoride.

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Additional information

Animal Data

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

Inhalation studies of nickel sulphate hexahydrate (mass median aerodynamic diameter of 1.8-3.1 + 1.6-2.9 μm) have been performed in rats and mice (NTP 1996a); no exposure related neoplasms were observed in neither rats (F344/N) nor mice (B6C3F1) after exposure to nickel sulphate hexahydrate by inhalation in concentrations up to 0.11 mg Ni/m3 or 0.22 mg Ni/m3, respectively for 2 years. It should be noted, as discussed in the Background document in support of the individual Risk Assessment Reports, that some arguments have been raised that the negative evidence from the NTP studies on nickel sulphate cannot be considered definitive. Inhalation studies on nickel oxide (NTP, 1996b reference not reported here]) and nickel subsulphide (NTP, 1996c [reference not reported here]) showed some evidence and clear evidence, respectively, for carcinogenic activity following inhalation in rats, and there was equivocal evidence for nickel oxide in female mice. The results of the NTP studies on nickel sulphate, nickel oxide, and nickel subsulphide raise the question of whether soluble forms of nickel differ from insoluble forms of nickel in carcinogenic potential or in potency in experimental animals following exposure by inhalation; however, the available data are not sufficient for an evaluation of this question. For further details, the reader is referred to the Background document in support of the individual Risk Assessment Reports. No other data considered as being relevant for the conclusion on the carcinogenicity of nickel sulphate in experimental animals following inhalation have been located. In conclusion, the available data on carcinogenicity of various nickel compounds, is considered as being insufficient for a conclusion on the carcinogenic potential of nickel fluoride in experimental animals following inhalation.

The carcinogenicity of nickel 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 nickel sulphate following oral (gavage) administration. Data on other nickel compounds are limited to a drinking water study of nickel acetate in rats and mice in which no exposure-related neoplasms was observed. In conclusion, there is sufficient oral carcinogenicity data to show that nickel soluble compounds do not show any carcinogenic potential in experimental animals following oral administration.

No data regarding carcinogenicity following dermal contact to nickel soluble compounds in experimental animals have been located. Data on other nickel compounds are limited to a study in male hamsters in which no tumours developed in the buccal pouch, oral cavity, or intestinal tract following painting on the mucosa of the buccal pouches with α-nickel subsulphide. In conclusion, the available data are too limited for an evaluation of the carcinogenic potential in experimental animals following dermal contact to nickel compounds.

Studies on the carcinogenicity of nickel sulphate following intramuscular injections or implants, or intraperitoneal injections have been performed in rats; tumours were observed following administration by intraperitoneal injections and by intramuscular implants but not by intramuscular injections. Data on other nickel compounds show that these compounds, with a few exceptions, produce local tumours following injection at various sites to experimental animals. In conclusion, the available data show that nickel compounds, with a few exceptions, produce local tumours following injection at various sites to experimental animals. It should be noted that these routes of administration are irrelevant for human beings who will only be exposed via inhalation, oral intake or dermal contact to nickel fluoride. However, the positive findings in these studies might be considered as part of the weight of the evidence when evaluating the carcinogenic potential of nickel fluoride to human beings.

Three studies evaluating the promoting effect of nickel sulphate in experimental animals have been located, which may indicate a promoter effect of nickel sulphate, if applied locally to the nasopharynx or the oral cavity, or by the feed to pups from initiated dams; however, the indications are rather weak. Data on nickel chloride and nickel metal indicate that these compounds also might have a promoting effect. In conclusion, the available data indicate that nickel sulphate, nickel chloride, and nickel metal might have a promoting effect in combination with selected initiators. However, based on the available studies, it is not possible to draw any conclusion regarding a promoting potential of nickel sulfate as well as of other nickel compounds. Furthermore, such information is difficult to use with respect to evaluating the carcinogenic potential of nickel sulphate.

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).

 

Epidemiology

As discussed in the 2008/2009 EU NICKEL SULPHATE RISK ASSESSMENT report, epidemiological studies from 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, 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. 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. 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. In addition, there were no nasal cancer cases among these workers.

The 2008/2009 EU NICKEL SULPHATE RISK ASSESSMENT concluded that the epidemiological data demonstrated “a positive association in a dose-dependent manner between exposure to soluble nickel compounds (e.g., nickel fluoride) 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 fluoride 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 EU NICKEL SULPHATE RISK ASSESSMENT).

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 certain 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 limited evidence of carcinogenicity from the animal data. 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.”

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

FOR AN EXTENSIVE DISCUSSION, REFER TO THE NICKEL SULFATE DOSSIER WHICH IS BASED ON THE CONCLUSIONS EXPLAINED IN THE 2008/2009 EUROPEAN UNION EXISITING SUBSTANCE RISK ASSESSMENT OF NICKEL (EU RAR) (EEC 793/93)

Justification for classification or non-classification

Ni fluoride belongs to the group 028 -029 -00 -4 in the 1st ATP to the CLP Regulationategory and it has been classified as Carc. Cat. 1: R49 and Carc. 1A; H350i . The same classification, with the same specific concentration limits is maintained also for the hydrated form.

Background information regarding this classification is provided in the discussion section above.

Regarding route of exposure, the 2008/2009 EU NICKEL SULPHATE RISK ASSESSMENT report indicates “Whilst there is clear evidence for the carcinogenicity of nickel compounds in humans following inhalation, evidence for lack of a carcinogenic potential has been found in an OECD 451 study with oral administration of nickel sulphate to rats (CRL, 2005) [ also referred to as Heim et al. 2007]. The available data concerning dermal exposure are too limited for an evaluation of the carcinogenic potential in experimental animals. 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. “

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" (Appendix B5). In summary, absence of oral carcinogenicity of the nickel (II) ion demonstrates that the possible carcinogenic effects of nickel-containing substances in humans are limited to the inhalation route of exposure and the associated organ of entry (i. e., the respiratory tract). After inhalation, respiratory toxicity limits the systemic absorption of Ni (II) ion to levels below those that can be achieved via oral exposure.

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