COMPARISON OF THE TOXICITY OF CITRAL IN F344 RATS AND B6C3F(1) MICE WHEN ADMINISTERED BY MICROENCAPSULATION IN FEED OR BY CORN-OIL GAVAGE

A study of the potential effects of microencapsulation on the toxicity of citral was conducted in 14-day continuous feeding studies with bot h sexes of F344 rats and B6C3F1 mice. Toxicity by the feeding route wa s compared with that from bolus doses of the neat chemical in com oil administered by gavage. Both sexes of rats and mice were given diet co ntaining 0, 0.63, 1.25, 2.5, 5 and 10% citral microcapsules. These fee d formulations were equivalent to daily doses of 0, 142, 285, 570, 114 0 and 2280 mg citral/kg body weight for rats and 0, 534, 1068, 2137, 4 275 and 8550 mg citral/kg body weight for mice. The daily gavage doses were 0, 570, 1140 and 2280 mg citral/kg body weight for both sexes of rats, and 0, 534, 1068 and 2137 mg citral/kg body weight for both sex es of mice. Citral microcapsules administered in the diet did not caus e mortality in mice or rats. Toxicity was confined to decreases in bod y weight at the 10% concentration in mice, at the 5 and 10% concentrat ions in rats, and decreases in absolute weights of the liver, kidney a nd spleen at the 10% concentration in rats. The only histopathological change observed was minimal to mild hyperplasia and/or squamous metap lasia of the respiratory epithelium in the anterior portion of the nas al passages of rats fed 5 or 10% citral microcapsules. By contrast, ci tral gavage caused mortality in five out of five male and female mice at 2137 mg/kg body weight, and in two out of five male mice at 1068 mg /kg body weight. There were dose-related increases in absolute liver w eights of male and female mice. Cytoplasmic vacuolization of hepatocyt es occurred in all female mice gavaged with 1068 and 2137 mg citral/kg body weight, and in male mice from the 2137 mg/kg dose group. Necrosi s, ulceration and/or acute inflammation of the forestomach occurred in the high-dose mice of both sexes. Inflammation and/or hyperplasia of the forestomach occurred in about half of the male and female mice dos ed with 1068 mg citral/kg. Citral gavage at doses that were equivalent to up to 10% in the diet (2280 mg/kg body weight) did not cause toxic ity in rats, except for minimal hyperplasia of the squamous epithelium of the forestomach in high-dose males. Microencapsulated citral given in the diet has distinct advantages as an alternative route of admini stration for long-term studies: the microencapsulation process prevent s the normally rapid degradation of the chemical; continual ingestion from the diet mimics the human route of exposure; and higher doses of the chemical can be attained in the animal model to maximize the detec tion of potential toxic or carcinogenic responses.