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Carcinogenicity

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Description of key information

No tumours observed in animal studies on relevant exposure routes (oral or inhalation).
In humans, inhalation exposure to nickel compounds increases the incidence of neoplasms.

Key value for chemical safety assessment

Justification for classification or non-classification

Based on the available epidemiological data on nickel sulphate, Trinickel dicitrate needs to be classified:

EU: Carcinogen Category 1: R49

CLP: Category 1A Carcinogenicity

Additional information

There are no carcinogenicity studies for Trinickel dicitrate. However, extensive data exist for the read-across substance nickel sulphate.

The data are taken from the EU-RAR for nickel sulphate, dated 2008.

 

Animal data

Long-term inhalation experiments with nickel sulphate hexahydrate have been performed in male and female rats (F344/N) and mice (B6C3F1) (NTP 1996a). No carcinogenic activity was found from inhalation of nickel sulphate when the tumour yield was compared between exposed animals and controls. Due to high acute toxicity, the maximum nickel dose obtained with nickel sulphate was not as high, in general, as that obtained with less soluble nickel compounds: Nickel subsulphide tested at 0.11 mg Ni/m3 for two years was positive in rats (NTP 1996b) while nickel sulphate hexahydrate tested at the same concentration of 0.11 mg Ni/m3 was negative. However, it has to be stressed that the NTP inhalation studies of rats and mice clearly indicate that exposure to nickel sulphate hexahydrate can induce respiratory toxicity manifested by inflammation and fibrosis in rats and mice and that chronic inhalation of nickel sulphate hexahydrate at concentrations above those that cause chronic inflammation may enhance the carcinogenicity of concomitant exposures to respiratory carcinogens such as nickel subsulphide, certain nickel oxides and/or cigarette smoke (non genotoxic mechanism). Furthermore, there may be specific effects from water-soluble nickel, other than that of inflammation, which can induce and promote the development of cancer.

Two old studies of limited reliability in rats and dogs (Ambrose et al. 1976) and one well-conducted OECD 451 study in rats(Heim et al. 2007) on orally administered nickel sulphate were negative. Three oral promoter studies had deficiencies in the documentation but suggested a promoter effect, confirming results seen for other water-soluble nickel compounds (Ou et al. 1980, Liu et al. 1983, Ou et al. 1983).

With respect to other routes of administration, intraperitoneal injections led to carcinogenic activity in rats (Pott et al. 1989 and 1992), and some activity was reported (in an abstract only) after implantation of pellets intramuscularly in rats (Payne 1964). By contrast, intramuscular injection studies in rats with the hydrated and anhydrous forms of nickel sulphate were negative (Gilman 1962, Kasprzak et al. 1983).

 

Human data

Epidemiological studies from three nickel refineries processing sulphidic nickel ores have demonstrated elevated risk of lung and nasal cancer in workers exposed mainly to nickel sulphate in the presence of variable amounts of water insoluble nickel compounds: the Clydach refinery in Wales, UK (Doll et al. 1990); the Kristiansand refinery in Norway (Doll et al. 1990, Andersen et al. 1996, Grimsrud et al. 2000, Grimsrud et al. 2002, Grimsrud et al. 2003) and the refinery in Harjavalta, Finland (Anttila et al. 1998). Among electrolysis workers at the Port Colborne refinery in Canada the association between respiratory cancer and exposure to nickel sulphate was not clear (Doll et al. 1990).

In Clydach, elevated risk for death from lung or nasal cancer was found in workers employed in the hydrometallurgy department where nickel sulphate was the dominating form of nickel in the exposures. Exposure to nickel sulphate also took place in other departments, and there was evidence of a dose-response relationship with cancer risk, in workers with high oxidic and/or sulfidic exposure when the data were cross-tabulated. Regression analyses offering adjustment for exposure to other types of nickel or adjustment for work in other high-risk departments also showed a dose-response. No exposure measurements existed, but the high risks left no doubt as to their occupational origin. In the nickel refinery groups exposed mainly to nickel sulphate for more than 5 years, the lung cancer risk was 3 times higher than expected from national data. Nickel chloride was not used in the production. It was not possible to adjust for tobacco smoking, but the increase in lung cancer risk was far too high to be explained by confounding from smoking. The risk of nasal cancer in the same group was reported to be more than 100 times the expected rates in the general population. The nasal cancer risk is only slightly affected by smoking habits.

At the Kristiansand refinery, nickel sulphate was the dominating exposure in the electrolysis departments between 1910 and 1952. The overall lung cancer risk in the Norwegian refinery workers has been elevated with a factor of 3 compared to the national rates. For the cohort as a whole, the risk for nasal cancer has been 18 times the expected rates in the general population, mainly affecting workers employed before 1952. A dose-response has been demonstrated for lung cancer according to duration of work in the electrolysis departments. The lung cancer rates suggested a higher risk among electrolysis workers compared to other high-risk groups (as roaster and smelter workers). Those employed for the first time before 1945 seem to have a higher risk than those employed in later years. These results concerning the period before 1952 give strong evidence of an association between cancer risk and exposure to nickel sulphate. Additional data from later years, although not restricted to nickel sulphate, support these findings. In 1952, the process was changed in some of the electrolysis departments, leading to a replacement of 80% of the nickel sulphate by nickel chloride. Still, the same elevated lung cancer risk has been found among workers employed between 1952 and the 1970s as in those employed before 1952. In a regression analysis, a dose-response was demonstrated for lung cancer according to cumulative exposure to water-soluble nickel (nickel sulphate and nickel chloride) with adjustment for age, smoking (ever smoker versus never smokers), and cumulative exposure to oxidic nickel. A recent case-control study performed within the same cohort (Grimsrud et al. 2003), used cumulative exposures to four forms of nickel computed from a new exposure matrix, which was based largely on personal full-shift measurements and speciation analyses in dusts and aerosols. The earlier finding of a dose-response between lung cancer and water-soluble nickel was confirmed in the analyses, which offered an optimal adjustment for smoking (life-time habits), and adjustment for exposure to less soluble forms of nickel.

The refinery in Harjavalta also treated a sulphidic nickel concentrate, as did the two refineries in Clydach and Kristiansand. Elevated risk for lung and nasal cancers was demonstrated in the group of workers where nickel sulphate was the dominating form of nickel in the working atmosphere. The historical nickel exposures were well documented. 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 the Port Colborne refinery were exposed mainly to nickel sulphate until 1942 and from that year subjected to a mixed sulphate and chloride exposure. It was not possible to ascribe the mortality from respiratory cancer in this group to the exposure to nickel sulphate only.

The epidemiological data summarised above demonstrates 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.

 

References:

Andersen A, Engeland A, Berge SR, Norseth T. (1996): Exposure to nickel compounds and smoking in relation to incidence of lung and nasal cancer among nickel refinery workers. Occup Environ Med 53: 708-13.

Anttila A, Pukkala E, Aitio A, Rantanen T, Karjalainen S (1998): Update of cancer incidence among workers at a copper/nickel smelter and nickel. Int Arch Occup Environ Health 71: 245-50.

Doll R, Andersen A, Cooper WC, Cosmatos I, Cragle DL, Easton D et al. (1990): Report of the International Committee on Nickel Carcinogenesis in Man. Scand J Work Environ Health 16: 1-82.

Gilman, I. P. W. (1962): Metal carcinogenesis. II. A study of the carcinogenic activity of cobalt, copper, iron and nickel compounds. Cancer Res 22: 158-162.

Grimsrud TK, Berge SR, Norseth T, Andersen Aa. (2000): Assessment of historical exposures in a nickel refinery in Norway. Scand J Work Environ Health 26: 338-345.

Grimsrud TK, Berge SR, Haldorsen T, Andersen A (2002): Exposure to different forms of nickel and risk of lung cancer. Am. J. Epidemiol156: 1123-1132.

Grimsrud TK, Berge SR, Martinsen JI, Andersen A (2003): Lung cancer incidence among Norwegian nickelrefinery workers 1953-2000. J. Environ. Monit 5: 190-197.

Kasprzak, KS, Gabryel P, Jarczewska K (1983): Carcinogenicity of nickel II hydroxide and nickel II sulphate in Wistar rats and its relation to the in vitro dissolution rates. Carcinogenesis 4: 275-280.

Liu T et al. (1983): The role of nickel sulphate in inducing nasopharyngeal carcinoma (NPC) in rats (Abstract). In: Cancer Research Reports – WHO Collaborating Centre for Research on Cancer, Vol. 4, Guangzhou, China. Cancer Institute of Zhongshan Medical College, p. 48-49.

NTP [National Toxicology Program] (1996a): Technical Report on the toxicology and carcinogenesis studies of nickel sulfate hexahydrate (CAS NO. 10101-97-0) in F344/N rats and B6C3F1 mice. (Inhalation studies). NTP Technical Report No. 454. NIH Publication No. 96-3370. National Institutes of Health, Springfield (VA). Washington DC. pp. 376. Cited in the EU-RAR for nickel sulphate, 2008.

NTP [National Toxicology Program] (1996b): Technical Report on the Toxicology and carcinogenesis studies of nickel subsulfide (CAS no 12035-72-2) in F344/N rats and B6C3F1 mice (inhalation studies). NTP Technical Report No 453. NIH Publication No 96-3369. National Institutes of Health, Springfield (VA). Washington DC. Cited in the EU-RAR for nickel sulphate, 2008.

Ou B, Liu Y, Huang X, Feng G (1980): The promoting action of nickel in the induction of nasopharyngeal carcinoma in rats (in Chinese). In: Cancer Research Reports – WHO Collaborating Centre for Research on Cancer, Vol. 2, Guangzhou, Cancer Institute of Zhongshan Medical College, p. 3-8.

Ou B, Liu Y, Zheng G (1983): Tumour induction in next generation of dinitropiperazine-treated pregnant rats (Abstract). In: Cancer Research Reports – WHO Collaborating Centre for Research on Cancer, Vol. 4, Guangzhou, China, Cancer Institute of Zhongshan Medical College, p. 44-45.

Payne WW (1964): Carcinogenicity of nickel compounds in experimental animals (Abstract No. 197). Proc. Am. Assoc. Cancer Res. 5: 50.

Pott, F., Rippe, R. M., Roller, M., Csicsaky, M., Rosenbruch, M. Huth F. (1989): Tumours in the abdominal cavity of rats after intraperitoneal injection of nickel compounds. In: Proceedings of the International Conference on heavy Metals in the Environment. Geneva, 12-15 September 1989. Vol. 2. Ed.: Vernet JP. World Health Organisation, Geneva. p. 127-129.

Pott, F., Rippe, R. M., Roller, M., Csicsaky, M., Rosenbruch, M. Huth F. (1992): Carcinogenicity of nickel compounds and nickel alloys in rats by intraperitoneal injection. In Nickel in Human Health: Current Perspectives. Advances in Environmental Sciences and Technology. Nieboer E, Nriagu JO (Eds.). John Wiley & Sons, New York. 1992. pp. 491-502.

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