Single dose and repeat dose toxicity studies of phytopharmaceutical leads

Single dose and repeat dose toxicity studies of phytopharmaceutical leads

Single dose and repeat dose toxicity studies of phytopharmaceutical leads (as per new CT rules of CDSCO, 2019) as detailed below. (a) Single dose acute oral toxicity in two species (rats and mice) – GLP study • Each group should contain at least five animals of either sex. At least four graded doses should be given. Animals should be exposed to the test substance in a single bolus or by continuous infusion or several doses within 24 hours. • Animals should be observed for 14 days. Signs of intoxication, effect on body weight, gross pathological changes should be reported. It is desirable to include histopathology of grossly affected organs, if any. • Animals should be observed for 14 days after the drug administration, and Minimum Lethal Dose (MLD) and Maximum Tolerated Dose (MTD) should be established. • Mortality should be observed for up to 14 days after oral administration. • Symptoms, signs and mode of death should be reported, with appropriate macroscopic and microscopic findings where necessary. LD10 and LD50 should be reported preferably with 95 percent confidence limits. If LD50 cannot be determined, reasons for the same should be stated. (b) 10-days dose range finding study (non-GLP) in rats by oral route. • At least four graded doses including control should be given, and each dose group as well as the vehicle control should consist of a minimum of five animals of each sex. Animals should be exposed to the test substance daily for 10 consecutive days. • Highest dose should be the maximum tolerated dose of single-dose study. Animals should be observed daily for signs of intoxication (general appearance, activity and behavior etc), and periodically for the body weight and laboratory parameters. Gross examination of viscera and microscopic examination of affected organs should be done. (c). 28-days repeat dose toxicity study in rats (GLP): • Four groups – control, low dose, intermediate dose, high dose. • 6-10 rats/sex/group Daily dosing by proposed clinical route at three dose levels should be done with highest dose having observable toxicity, mid dose between high and low dose, and low dose. The doses should preferably be multiples of the effective dose and free from toxicity. Observation parameters should include cage side observations, body weight changes, food or water intake, blood biochemistry, haematology and gross and microscopic studies of all viscera and tissues.

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