HCO-60, a polyoxyethylene castor oil derivative, is used as a solubilizer in the injectable formulations of lipophilic agents. This study was performed to examine the toxicity of HCO-60 in various experimental animals including dogs, monkeys, rabbits, guinea pigs and rats. With 1.25 or 2.5 mg/kg of HCO-60 injected i.v. to dogs, blood pressure decreased, flush, swelling and itching appeared after injection, and with 10 mg/kg of HCO-60 there was additionally a decrease of spontaneous motility. In the two higher dose groups, these symptoms paralleled an increase of histamine levels. Since degranulation was observed after injection in the mast cells of the skin, but not in the liver of dogs, the histamine in the plasma was considered to be released from the mast cells of the skin. Pretreatment with diphenhydramine, a H1-receptor antagonist, suppressed the decrease of blood pressure induced by HCO-60. These findings show that the toxicity of HCO-60 is associated with histamine release from the mast cells. No symptoms occurred in monkeys, rabbits, guinea pigs or rats with 50 or 100 mg/kg of i.v. of HCO-60, and there was no change in plasma histamine levels. This study demonstrated that the toxicity of HCO-60 is species specific to dogs among the animals tested.