Chromium trichloride

Carcinogenicity

Description of key information

chromium(III) compounds are considered non-carcinogenic by oral exposure

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Species:

rat

Quality of whole database:

In total 4 chronic studies by oral route for chromium(III) compounds are available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Chromium(III) compounds were investigated for chronic toxicity in three studies with dosing to rats and in one study with application to mice.

MacKenzie (1958) reported about a chronic study with rats exposed to Cr(III)Cl3 in drinking water at a concentration of 3.6 mg chromium(III)/kg bw/day for a period of 1 year. Chronic oral exposure to chromium(III) compounds did not result in any target organ toxicity in rats. No change in body weight, macroscopic or microscopic pathology, or clinical chemistry variables were noted in this study. The results suggested a no-observed-effect level (NOEL) of 3.6 mg trivalent chromium/kg bw/day (equivalent to 11 mg CrCl3/kg bw/d or 18.5 mg CrCl3.6H2O/kg bw/d). However, it is unclear whether a detailed investigation for carcinomas was performed and thus this study is of limited relevance for carcinogenicity assessment.

Ivankovic (1975) assessed carcinogenicity of chromium(III) by dosing concentrations of 1, 2 and 5% Cr2O3 in the feed over a period of 2 yr (600 treatment days) with a total consumption between 360 and 1800 g Cr2O3/kg body weight. All doses were tolerated by rats without signs of chronic toxicity. The dose received can be recalculated to 600, 1200 and 3000 mg Cr2O3/kg bw/d accordingly based on 600 days feeding period. The body-weight curves of the treated animals showed no differences from those of the untreated controls and the median survival times in all three dosage groups were comparable with that of the controls. No macroscopic or histological post-mortem findings could be causally related to the Cr2O3 treatment. The lack of any carcinogenic action of Cr2O3 is of particular importance. The type and frequency of the tumours appearing in the experimental and control animals were comparable; mammary fibro-adenomas and the hypophyseal adenomas are ‘spontaneous’ tumours characteristic of strains of BD rats. No increase in tumour incidence was seen at any dose and as a result orally administered Cr2O3 has no carcinogenic action in rats even when excessive doses are given. Although water solubility of Cr2O3 is very low compared to chromium trichloride hexahydrate, the doses applied in this study were extraordinary high (up to 3 g/kg bw/d).

The U.S. National Institutes of Health Public Health Service (2010) assessed carcinogenicity of chromium picolinate monohydrate (CPM, CAS No. 27882-76-4), a chromium(III) dietary supplement for human consumption, in rats and mice.

In male rats in the 2-year study, there was a significant exposure-related increase in the incidence of preputial gland adenoma at 10,000 ppm; the incidence exceeded the historical control ranges for feed studies and for all routes of exposure. Proliferative lesions of the preputial and clitoral glands (the clitoral gland is the corresponding accessory sex gland in females) constitute a morphological continuum, and separation of these into categories of hyperplasia, adenoma, and carcinoma is based largely on cytological features and degree of altered growth pattern (Copeland-Haines and Eustis, 1990). Lesions classified as hyperplasia are considered preneoplastic. Although the increase in the incidence of preputial gland adenoma at 10,000 ppm appeared to be treatment-related, this increase was considered to be equivocal evidence of carcinogenic activity because of the lack of an exposure concentration-response (1/50, 1/50, 7/50 and 4/50 in 0, 2000, 10000 and 50000 ppm dose groups respectively), absence of increased incidences in neoplasms in the corresponding tissue in females, lack of progression to carcinoma, and lack of preneoplastic lesions. There were no biologically significant increases in the incidences of neoplasms in any other tissue in male rats, or in any tissue in female rats or male or female mice. Therefore, this finding was considered equivocal in male rats. In female rats no indication for carcinogenicity was seen.

In male and female mice in this 2-year study, there were no significant exposure-related increases in the incidence of neoplasms. There were no biologically significant increases in the incidences of neoplasms in any other tissue in male or female mice, when dosed up to 50,000 ppm in diet, equivalent to average daily doses of approximately 250, 1,200, or 6,565 mg/kg to males and 240, 1,200, or 6,100 mg/kg to females) for 105 weeks.

In conclusion, considering the weight of evidence of the findings by MacKenzie, Ivankovic and the US National Institutes of Health Public Health Service, chromium(III) compounds are considered non-carcinogenic by oral exposure, although equivocal results were seen in male rats, which were lacking a dose-response relationship and a corresponding finding in female rats.

Justification for selection of carcinogenicity via oral route endpoint:
weight of evidence approach