PHARMACOLOGY

 SINGLE-DOSE TOXICITY STUDIES ::

As per Schedule Y single dose toxicity studies are to be carried out in 2 rodent species (mice and rats ) using the same route as intended for humans In addition unless the intended route of administration in humans is only intravenous at least one more route is used in one of the species to ensure systemic absorption of the drug This route should depend on the nature of the drug A limit of 2g/kg (or 10 times the normal dose that is intended in humans whichever is higher ) is recommended for oral dosing Animals are observed for 14 days after the drug administration and minimum lethal dose (MLD) and maximum tolerated dose (MTD) are established if possible the target organ of toxicity should also be determined Mortality is observed for up to 7 days after parenteral administration and up to 14 days after oral administration Symptoms signs and mode of death are reported with appropriate macroscopic and microscopic findings where necessary LD 10 and LD50 are reported preferably with 95 per cent confidence limits if LD50 cannot be determined reasons for the same are stated 

        In single Dose Toxicity Study each group should contain at least 5 animale 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 14 days Signs of intoxication effect on body weight gross pathological chantains should be reported it is desirable to include histo-pathology of grossly affected organs if any 

    The dose causing severe toxic manifestations or death has to be defined in the case of cytotoxic anticancer agents and the post-dosing observation period should be 14 days Mice should first be used for determination of MTD Findings should then be confirmed in rat for establishing linear relationship between toxicity and body surface area in case of nonlinearity data of the more sensitive species should be used to determine the Phase 1 starting dose Where rodents are known to be poor predictors of human toxicity (e.g.antifolates ) or where the cytotoxic drug acts by a novel mechanism of action MTD is established in non rodent species