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EC number: 227-873-2
CAS number: 6018-92-4
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.
Based on the available epidemiological data
on nickel sulphate, Trinickel dicitrate needs to be classified:
EU: Carcinogen Category 1: R49
CLP: Category 1A Carcinogenicity
There are no carcinogenicity studies for Trinickel
dicitrate. However, extensive data exist for the read-across substance
The data are taken from the EU-RAR for
nickel sulphate, dated 2008.
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).
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
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.
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:
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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