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EC number: 215-572-9
CAS number: 1332-65-6
Although the available animal and human data on the carcinogenicity of copper and its compounds are deficient in several respects, the findings do not raise concerns with respect to carcinogenic activity. Consequently, further tests investigating this end-point are not recommended. The studies on carcinogenicity also give information on the chronic effects of copper on rats and mice. The studies, although limited, indicate that at the doses tested, the pivotal endpoint was a reduction in weight gain at the highest dose rates tested. These results indicate that the NOAEL values derived from the sub-chronic effects observed in the NTP study, 1993 could be regarded as worst case for the risk assessment of. copper and copper compounds.
All available studies on the carcinogenicity of copper are public
domain studies and therefore, taken in isolation are of limited value
to ascertain the carcinogenic potential copper compounds. This
is due to the fact that these studies are limited due to shorter
exposure periods (<2 years) and group sizes being small. However, when
the 3 studies summarised below are assessed on an overall balanced
approach, the information from these studies does give useful
information as to the carcinogenic potential of copper compounds.
dose levelsfrequency of application
Oral, diet 9 months
Rat, Sprague-Dawley, male 50 or 58 animals/group
1 ppm, 800 ppm (0.05, 40 mgCu/kg/bw/day)
Liver necrosis and transitional nodules in the liver (3/32) and transitional nodules in the liver (1/32) was observed at 40 mgCu/kg/bw/day whereas one kidney tumour (1/42) was observed in the low copper group (not thought significant). Decreased body weight gain and increased mortality were found in the high copper group. Exposure to known carcinogens increased the incidence of liver necrosis and transitional nodules and each induced a similar incidence of liver tumours in rats fed excess copper or copper-deficient diets.
In the DMN group, 17/30 rats on the copper-deficient diet and kidney tumours compared to 0/29 given excess copper. The incidence of AAF-induced extrahepatic neoplasms was apparently reduced by the excess copper diet. (5/30 vs 11/27).
Carlton et al, 1973. Dietary copper and the induction of neoplasms in he rat by acetylaminofluorene and dimethylnitrosamine. Fd. Cosmet. Toxicol. Vol 11, 827-840.
Oral drinking water 46 weeks
Mouse C57BL/6J, female 10-12 animals/group
(app. 10 mgCu/kg/bw/day)
The incidences of ovarian tumours after 46 weeks were 0/10, 0/12, 11/11 and 6/11 in the untreated controls, copper treated mice, DMBA-treated mice and DMBA-copper-treated mice respectively. This suggests that copper sulphate may possibly inhibit DMBA-induced tumour development. CuSO4 had no effect on the incidence of DMBA-induced adenomas of the lung, lymphomas and breast tumours.
Burki & Okita, 1969. Effects of oral copper sulfate on 7, 12 dimethyl
benz(a)anthracene carcinogenesis in mice. Br. J. Cancer Sep. 23(3): 591-596
Oral diet, 30-44 weeks
Rat, Sprague-Dawley, male and female, 23-26 animals/ group
0, 530 or 1600 ppm Cu (approx. 0, 27 or 80 mg Cu/kg b.w./day in males and 0, 40 or 120 mg Cu/kg b.w./day in females).
The growth of rats receiving 1600 ppm Cu as CuSO4 was adversely affected, although organ weights were apparently unaffected (other than increased stomach weight in females). Well-defined abnormalities evident in the 1600 ppm treatment group included ‘bronzed’ kidneys, ‘bronzed’ or yellowish livers, hypertrophied ridges between cardiac and peptic portions of the stomach and blood in the intestinal tract. Histological examination revealed varying degrees of testicular degeneration in rats from both the 530 ppm and the 1600 ppm groups and effects on the liver were seen in both males and females. There were no reports of evidence of neoplasms in any treatment group.
Harrison et al, 1954. The safety and fate of potassium sodium copper chlorophyllin and other copper compounds. Journal of the American Pharmaceutical Association, 43(12): 722-737.
All available studies on the carcinogenicity of copper are public
domain studies and therefore, taken in isolation are of limited value to
ascertain the carcinogenic potential copper compounds and are given a
Quality Criteria of 3 individually. This is due to the fact that these
studies are limited due to shorter exposure periods (<2 years) and group
sizes being small. However, when the 3 available studies are assessed on
an overall balanced approach, they give useful information as to the
carcinogenic potential of copper compounds.
These results indicate that copper sulphate and other copper salts
do not appear to have carcinogenic potential even at very high dose
levels of up to 120 mg Cu/kg/bw/day (Harrison et al., 1954). The data in
Carlton et al, 1973 are especially useful since positive control groups
were added in this study and showed an induction of neoplasms in the
rat, indicating that the exposure period (although not two years) was
long enough for neoplasms to appear if you have a positive carcinogen.
In addition, this study indicates that excess copper may have a
protective effect on known carcinogens.
These animal carcinogenicity studies have been conducted with
copper compounds. Short duration, small sample sizes and limited
histopathologic examination limit the findings of the studies.
Nevertheless, the findings of these studies do not raise concerns with
respect to carcinogenic activity.
Chronic toxicity investigations in these studies, and in
particular, in Harrison et al., 1954, indicate that, as in the pivotal
90-day rat study of Hebert, 1993, the target organs for copper are the
liver and kidney. In addition, the longer duration studies indicate that
the adverse effects do not appear to become more severe over longer
exposure periods (up to one year). This is probably due to the
homeostatic control mechanisms present in animals which would regulate
the uptake and excretion of copper on a daily basis. As adverse effects
are only observed at relatively high levels of copper outside the normal
daily intake of copper for humans (up to 10 mg/day), new chronic studies
extending over a 2 year time period are not expected to add further
insight into the mechanisms of chronic toxicity and carcinogenicity of
copper in humans.
In addition, the available genotoxicity studies support the
indication that copper compounds have no carcinogenic potential. The
studies include Ames assays in Salmonella typhimurium on copper II
sulphate pentahydrate; a micronucleus study on copper II sulphate
pentahydrate and an unscheduled DNA synthesis ex vivo study in rat liver
on copper II sulphate.
The Ames tests indicated that copper sulphate had no mutagenic
activity (Ward, 1994). No evidence of an increase in the incidence of
micronuclei was detected in the mouse micronucleus study when mice were
orally administered two doses of 447 mg/kg copper sulphate, 24 h apart
(Riley, 1994). There was also no evidence of unscheduled DNA synthesis
in the rat liver (Ballantyre, 1994).
These studies are consistent and show a lack of in vitro mutagenic
activity or in vivo clastogenic potential associated with soluble copper
compounds. The results of these studies do not highlight a concern
regarding the genotoxic potential of copper compounds.
Available data on the genotoxicity and carcinogenicity of copper
and its compounds have been considered against EU classification
criteria. The available data for copper compounds do not meet the
criteria requiring classification for carcinogenicity.
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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