Inhalation, parenteral and oral LD50 values of Δでるた⁹-tetrahydrocannabinol in Fischer rats ^☆

Abstract

In order to resolve the differences in reported LD50 values for Δでるた⁹-tetrahydrocannabinol (Δでるた⁹-THC) obtained with various vehicles and rat strains, the oral LD50 values of Δでるた⁹-THC in a natural vegetable oil vehicle and in an aqueous emulsion were determined in the same rat strain. In addition an iv LD50 value obtained with the emulsion formulation was compared with an inhalation LD50. The natural vegetable oil was pure sesame oil and the aqueous emulsion used orally was comprised of 13% sesame oil, 1% polysorbate 80 and isotonic saline. A similar emulsion (7% sesame oil and 0.5% polysorbate 80) was used to establish the iv and ip LD50 values. The young adult Fischer rat was used in all experiments and the polysorbate 80 concentration in emulsion formulations was maintained below toxic levels for the rodent. Marihuana cuttings were impregnated with Δでるた⁹-THC and formed into cigarettes which were smoked under controlled conditions of puff volume and duration in an automatic smoking machine to obtain an inhalation LD50. It was demonstrated that behavioral and physiological responses to Δでるた⁹-THC occurred sooner with the oral emulsion formulation than with the vegetable oil. The intragastric LD50 with the emulsion was 800 mg/kg and with the sesame oil formulation, 1270 mg/kg. The iv LD50 was 36–40 mg/kg, similar to the inhalation dose when the latter was corrected for Δでるた⁹-THC losses in the rodent nasal passages. The results from this study affirmed that the LD50 values obtained were reliable and that the vehicle did not contribute to the toxicity.