Toxicity Evaluation

Toxicity of the test substance is determined by the oral or intraperitoneal route in two or three adult albino mice of either sex and usually 15 to 20 g in weight. The test material is suspended in 0.1% agar or in 10% gum acacia in distilled water. Concentrations are so adjusted that a 20 g mouse receives a volume of 0.2 ml. The initial dose is at a level of 400 or 500 mg/kg going up or down by a factor of 2. Occasionally, an interval of 1.5 is used for closer approximation. Doses higher than 1000 mg/kg are not generally used. Control animals are administered only the vehicle. The animals are observed for 5 to 6 hours after dosage for toxic symptoms. If death occurs during this time, the cause of dealth is recorded. The approximate LD50 is estimated and the maximum tolerated dose is also recorded for use in subsequent investigations.

6.1 Regulatory Toxicity

Regulatory toxicity studies of the test substance are carried out only after the pharmacological activity is confirmed, and baseline data is generated regarding the effective dose, lethal dose and maximum tolerated dose. These studies are carried out with the potential drug before it is passed on to clinicians to Phase I and II clinical trials. The studies needed are : (i) acute toxicity;

(ii) repeated dose study; (iii) subacute toxicity study; (iv) reproductive studies, (v) teratological study; (vi) prenatal and post natal study; (vii) carcinogenic study and (viii) mutagenic study.

6.2 Reproductive Studies

Reproductive studies important for clinical Phase II trials are : (i) study of fertility and general reproductive performance; (ii) teratological study, and

(iii) prenatal and postnatal studies. The study is needed to determine the effect of a given drug on gonadal function, estrus cycles, mating behaviour, conception rates and early stages of gestation. The observations recorded are: number and distribution of embryos in each uterine horn, presence of empty implantation sites, embryo undergoing resorptions, abnormal condition in the uterus, gestation period, litter size, stillborn, litter weight, gross anomalies.

6.3 Teratological Study

Teratological study of test substance is needed to determine the potential of a test substance for embryotoxicity and/or teratogenic effects. The observation recorded are : number of corpora lutea in each ovary, number of implantation in each horn, correlation of the foetal placement in each horn with the number of corpora lutea in each ovary, number of foetuses, number of live foetuses, number of dead foetuses, number of resorptions, early/late, weight of foetus, external anomaly in the foetus, and visceral/skeletal anomaly in the foetus.

6.4 Pre- and Postnatal Study

Pre- and postnatal study is needed to observe the effects of test substance on the newborn when administered to the mother during the last trimester of pregnancy and through the period of lactation. The observation recorded are: duration of gestation, type of labour and delivery, litter size, litter weight at birth day four, day 21 and at weaning, effect on lactation, litter morbidity and mortality.

6.5 Carcinogenic Study

Carcinogenic study is needed to determine the carcinogenicity of the test agent in both sexes of two species and is designed to cover the greater part of the animal's life span.

6.6 Mutagenic Study

A variety of short-term tests are conducted on test substance to predict the mutagenic as well as carcinogenic activity of chemicals. The test carried out are: (i) DNA damage tests in bacteria, (ii) gene mutation tests in bacteria,

(iii) chromosomal aberration tests in vitro, (iv) micronucleus test in mice, and (v) dominant lethal tests in rodents.

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