Pharmacologic and toxicologic studies on N,N-diethyltoluamide : I. N,N-diethyl- m-toluamide

Abstract

Data are presented on the physiologic effects of N,N-diethyl- m-toluamide ( m-DET, diethyltoluamide) on experimental animals by various routes of administration. 1. 1. The acute oral LD 50 for male and female rats was found to be 2.0 ml/kg (2 gm/kg), with 19 20 confidence limits of 1.83 to 2.19. 2. 2. Intravenously in rabbits, doses of 50 mg/kg were not fatal. Doses of 75 mg/kg and larger were rapidly fatal. Five daily injections of 25 mg/kg produced no cumulative toxic effects. 3. 3. Single dermal applications of 2 or 4 ml/kg, approximately equivalent to 6–16 ml per rabbit, held in contact with the depilated intact or abraded trunk of rabbits for 24 hours produced mild to moderate erythema (irritation), without evidence of systemic toxicity. No evidence of erythema was present on the fifth day following application. 4. 4. Repeated dermal application to the depilated trunk of rabbits for 13 weeks produced no evidence of systemic toxicity. However, mild to moderate dermal irritation, desquamation, coriaceousness, dryness of the skin, and fissures developed following repeated applications and prolonged contact with the skin, which persisted throughout the experiments. All skin lesions, with the exception of some scarring, cleared after about 3 weeks following last application of m-DET. 5. 5. On five human volunteer subjects, repeated daily applications of m-DET to the face and arms for 5 consecutive days produced only slight irritation of the face and nose, with some desquamation about the nose. On one human subject, repeated daily applications to the face on 3 consecutive days for 6 weeks produced desquamation around the nose, slight tingling sensation, and dryness of the face. During the 4-day rest period between applications all the symptoms disappeared. 6. 6. No cutaneous reactions interpreted as sensitization were observed in guinea pigs following dermal application of m-DET. 7. 7. Instillation of m-DET into the eyes of rabbits produced moderate to marked edema of the nictitating membrane, lacrimation, conjunctivitis and pus with varying degrees of corneal injury as revealed by fluorescein staining. After 5 days all eyes appeared normal. 8. 8. By inhalation no systemic toxic reactions were observed in rats exposed 8 hours a day, 5 days a week for 7 weeks to air saturated with m-DET. No toxic effects were observed in rats exposed for 6 hours to an aerosol of m-DET. No gross or significant microscopic changes were found. 9. 9. Male and female rats maintained on diets containing 0.01, 0.05, 0.1, 0.5, and 1% m-DET, respectively, for approximately 200 days showed no signs of toxicity. Rats on 1% m-DET showed a slight decrease in growth which was not associated with food consumption. Significant increases in organ-to-body-weight ratios were observed in the testes of rats on 0.1, to 0.5, and 1% diets, in the liver of male rats on 0.5 and 1% diets, in the liver and spleen of female rats on the 1% diet, and in the kidneys of both male and female rats on the 1% diet. No gross or significant histopathologic changes were observed. 10. 10. The in vitro effects of m-DET in concentrations of 1: 5000 on the rat uterus and 1: 10000 on the rabbit ileum caused depression in amplitude of rhythmic contraction. The effect on both the uterus and ileum was not permanent since contractions were restored after washing, and the response to acetylcholine or barium chloride was unaltered. 11. 11. In rabbits, m-DET in doses of 5 mg/kg produced a slight but evanescent fall in blood pressure, with only mild respiratory stimulation.