A safety assessment of coumarin taking into account species-specificity of toxicokinetics

Coumarin (1,2-benzopyrone) is a naturally occurring fragrant compound found in a variety of plants and spices. Exposure to the general public is through the diet and from its use as a perfume raw material in personal care products. High doses of coumarin by the oral route are known to be associated with liver toxicity in rodents. Chronic oral bioassays conducted in the 1990s reported liver tumors in rats and mice and lung tumors in mice, raising concerns regarding the safety of coumarin. Since then, an extensive body of research has focused on understanding the etiology of these tumors. The data support a conclusion that coumarin is not DNA-reactive and that the induction of tumors at high doses in rodents is attributed to cytotoxicity and regenerative hyperplasia. The species-specific target organ toxicity is shown to be related to the pharmacokinetics of coumarin metabolism, with data showing rats to be particularly susceptible to liver effects and mice to be particularly susceptible to lung effects. A quantitative human health risk assessment that integrates both cancer and non-cancer effects is presented, confirming the safety of coumarin exposure from natural dietary sources as well as from its use as a perfume in personal care products.