COUMARIN
(Group 3)
VOL.: 77 (2000) (p. 193)
CAS No.:
5. Summary of Data Reported and Evaluation
5.1 Exposure data
Coumarin is a natural product occurring in the essential oils of a large number of plants, such as cinnamon, cassia, lavender and woodruff. It is used for its fragrance in many personal care products (perfumes, deodorants, soaps) and in tobacco, in household and industrial products to mask unpleasant odours and, in some countries, as a flavouring agent in food and beverages. It has also been used to treat several medical conditions. Exposure to coumarin may occur from its production, its natural presence in many plants and essential oils, and its several industrial, medical and consumer uses.
5.2 Human carcinogenicity data
No data were available to the Working Group.
5.3 Animal carcinogenicity data
Coumarin has been adequately tested by oral administration in two experiments in mice and in one experiment in rats. In mice of one strain, it produced increases in lung tumours (adenomas and carcinomas) in both males and females and in hepatocellular adenomas in females. There was no increase in tumour incidences in another strain of mouse. In one study in rats, coumarin produced a low incidence of renal tubule adenomas in males, seen only after step-sectioning of the kidney. Three other studies in rats could not be evaluated.
5.4 Other relevant data
Coumarin is rapidly and extensively absorbed after topical or oral administration to human subjects. It undergoes very extensive metabolism along two major pathways,7-hydroxylation and ring-opening to ortho-hydroxyphenylacetaldehyde. There are numerous minor metabolites, many of which are secondary products from the primary metabolites. The relative extent of these two major pathways is highly variable between species. Ring-opening predominates in rodents, while 7-hydroxylation is particularly evident in humans.
In humans exposed to coumarin for treatment of various clinical conditions, a few cases of hepatotoxicity have been reported. However, a clear relationship between the dose of coumarin and the hepatotoxic responses observed has not been established. The target organs for coumarin toxicity are primarily the liver in rats and the liver and lung in mice. There are marked species differences in these responses, with the mouse being particularly susceptible to coumarin-induced Clara cell injury. Coumarin is hepatotoxic in rats and mice. Hamsters and gerbils are resistant to acute coumarin-induced hepatotoxicity. In vitro, coumarin is toxic in either hepatocytes or liver slices from rats, mice, rabbits and guinea-pigs, whereas monkey and human cells and/or slices appear to be resistant.
No data on reproductive and developmental effects in humans were available. No signs of teratogenicity were observed in mice, rats, rabbits or miniature pigs.
No data were available on the genetic and related effects of coumarin in humans.
Coumarin did not induce micronuclei in mice in vivo and was not mutagenic in Drosophila melanogaster. It was weakly positive in induction of micronuclei in human cells in vitro, but failed to induce unscheduled DNA synthesis in human liver cells in vitro. Coumarin induced sister chromatid exchanges without metabolic activation and chromosomal aberrations with metabolic activation, but not micronuclei or gene mutations in mammalian cells in vitro. It was mutagenic in only two out of 11 Salmonella typhimurium strains tested, with metabolic activation.
Coumarin was antimutagenic in various assays, but also had co-mutagenic properties.
5.5 Evaluation
No epidemiological data relevant to the carcinogenicity of coumarin were available.
There is limited evidence in experimental animals for the carcinogenicity of coumarin.
Overall evaluation
Coumarin is not classifiable as to its carcinogenicity to humans (Group 3).
For definition of the italicized terms, see Preamble Evaluation.
Previous evaluations: Vol. 10 (1976); Suppl. 7 (1987) (p. 61)
Synonyms
See Also:
Toxicological Abbreviations
Coumarin (ICSC)
Coumarin (WHO Food Additives Series 16)
Coumarin (IARC Summary & Evaluation, Volume 10, 1976)