[Animal toxicity studies of probucol (author's transl)]

The oral LD50 of probucol in rats and mice was found to be higher than 5 000 mg/kg. Subacute toxicity studies failed to show any toxic effect in rats and monkeys which received 3 000 and 200 mg/kg/24 h respectively for 90 days. Chronic toxicity studies were carried out in rats during 2 years and in monkeys during 8 years. Daily oral doses of up to 800 mg/kg in rats and 500 mg/kg in monkeys had no demonstrable toxic effects; in particular, there were no differences on electron microscopy between liver sections of monkeys treated for 8 years and those of untreated monkeys. In dogs, probucol proved non toxic when given for 14 days. However, during more prolonged administration (90 days) sudden death occurred in some animals, which was unrelated to dosage or to duration of treatment. Additional studies showed that probucol sensitizes dog myocardium to epinephrine, thereby inducing ventricular fibrillation. This effect was not observed in other animal species and is considered as specific to dogs. A special study was performed in monkeys, which received high doses of probucol (equivalent to 4-15 times the human dose) associated with an atherogenic diet containing 100 times more cholesterol than their normal diet and large quantities of fats. Some monkeys fainted and died; ECG tracings revealed no other abnormality than an increase in the length of QTc. Cardiac toxicity cannot be extrapolated from animal to man, since heart monitoring failed to show any abnormality in patients treated with probucol. No mutagenic or carcinogenic effects were observed in rats, and teratological and reproduction studies carried out in rats and rabbits gave negative results.