Abstract

The acute oral LD₅₀ of coumarin in propylene glycol for male albino rats was calcualted at 0.29 gm./kgm ± 0.03 mgm./kgnm.; the acute oral LD50 of coumarin in corn oil for male albino rats was calculated at 0.52 gm./kgm. ± 0.03 gm./kgm.

Ad libitum feeding of coumarin to male albino rats at levels of 200 parts per million and 1000 parts parts per million (ppm), for 90 days, reduced growth but produced no deaths, and no histopathological liver or kidney changs. Organ weights of the livers, kidneys, spleens, and testes obtained at autopsy from the test animals were comparable to those of the controls.

Coumarin incorporated in the diet of male and femal albino rats for a 90-day period at levels of 50 ppm, 250 ppm, and 2500 ppm, and fed in mutually pair-fed diets, elicited no significant untoward nutritional effects at the two lower levels, as measured by weight gains or food efficiency; significant supression in food efficiency was produced by the 2500 ppm level. Gross and microscopic liver pathology and increased liver weights were produced at the 2500 ppm dietary level but not at the lower levels.

Coumarin, administered to dogs for time intervals ranging from eight to nineteen days in oral doses of 100 mgm./kgm./day in powdered form or dissolved as a 4.0 per cent solutin in propylene glycol, produed deficinite liver damage as evidence by the clinical observations, biochemical studies, and gross amid microscopic pathology. Two dogs followed for a period of 40 to 61 days after receiving the last oral dose of coumarimi at 100 mgm./kgm/day were found to have recovered from the toxic manifestations of eoumarin as evidenced by gross signs and laboratory studies. Autopsy findings were without evident gross pathology, and histological examination revealed the initially damaged liver tissue to be under going the processes of healimg and repair.

The suitability of coumarin for sustained use as a flavor additive for foods and pharmaceuticals cannot be defined properly, soley on the basis of the acute and subacute toxicity studies herein reported. These studies of a short-term nature make apparent, however, the need for long-term feeding studies to determine a safe upper limit of use, if any, for the compound.