OECD 407

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OECD Guidelines For The Testing of Chemicals:

OECD Guidelines For The Testing of Chemicals Prepared By: Tirath Mehta M.Pharm . Sem III Pharmacology Roll No.: 26

INTRODUCTION :

INTRODUCTION Test Guideline 407 is for Repeated dose 28-days oral toxicity study in rodents. Adopted in 1981 & revised in 1995.

PRINCIPLE OF THE TEST :

PRINCIPLE OF THE TEST Test substance is orally administered daily in graduated doses to experimental animals for a period of 28 days. During the period of administration animals are observed closely, each day for signs of toxicity. Animals which die during the test are necropsied & at conclusion of the test surviving animals are euthanised and necropsied .

PRINCIPLE OF THE TEST (cont..):

PRINCIPLE OF THE TEST (cont..) A 28 day study provides information on effects of repeated oral exposure. It can also provide information on the selection of concentrations for longer term studies. The data derived from using the TG should allow for characterization of test substance toxicity, for an indication of the dose response relationship & determination of the No-Observed Adverse Effect Level (NOAEL).

DESCRIPTION OF THE METHOD :

DESCRIPTION OF THE METHOD Selection of animal species Housing and feeding Preparation of animals Preparation of doses

Selection of animal species :

Selection of animal species Preferred rodent species is the rat. Other rodent species may be used but a detailed justification should be given. Weight variation of animals used should not exceed ± 20% of the mean weight of each sex.

Housing and feeding :

Housing and feeding Temperature : 22°C (± 3°C). Relative humidity : 30% - 70%. Lighting should be artificial, the photoperiod being 12 hours light, 12 hours dark. For feeding, conventional laboratory diets are used with an unlimited supply of drinking water. No more than five animals should be housed per cage.

Preparation of animals :

Preparation of animals Healthy young adult animals are randomly assigned to control and treatment groups. Animals are kept in their cages for at least five days prior to start of study to allow for acclimatisation to laboratory conditions.

Preparation of doses :

Preparation of doses Test compound is administered by gavage or via the diet or drinking water. Method of oral administration is dependent on the purpose of study, & physical/chemical/ toxico -kinetic properties of the test material.

PROCEDURE :

PROCEDURE

Number and sex of animals :

Number and sex of animals At least 10 animals (five female & five male) should be used at each dose level. If interim euthanasia are planned, the number should be increased by the number of animals scheduled to be euthanised before the completion of study.

Dosage :

Dosage At least three test groups and a control group should be used. If there are no suitable data available, a range finding study may be performed to aid the determination of the doses to be used. If a vehicle is used in administering test substance, control group should receive vehicle in the highest volume used.

Dosage (cont..):

Dosage (cont..) The highest dose level should be chosen to induce toxic effects but not death. Thereafter, a descending sequence of dose levels should be selected with a view to demonstrate any dosage related response and no-observed-adverse effects at the lowest dose level (NOAEL).

Administration of doses :

Administration of doses The animals are dosed with test substance daily 7 days each week for a period of 28 days. The volume should not exceed 1 ml/100g body weight except in the case of aqueous solutions where 2 ml/100 g body weight may be used.

Observations :

Observations General clinical observations should be made at least once a day. At least twice daily, all animals are observed for morbidity and mortality. In the fourth exposure week sensory reactivity to stimuli of different types (e.g. auditory, visual and proprioceptive stimuli), assessment of grip strength and motor activity should be conducted.

Observations (cont..):

Observations (cont..) Functional observations conducted in fourth exposure week may be omitted when the study is conducted as a preliminary study to a subsequent subchronic (90-day) study. At necropsy, the oestrus cycle of all females could be determined (optional) by taking vaginal smears which can assist in histological evaluation of estrogen sensitive tissues.

Body weight and food/water consumption :

Body weight and food/water consumption All animals should be weighed at least once a week. Measurements of food consumption should be made weekly. If the test substance is administered via the drinking water, water consumption should also be measured weekly.

Haematology :

Haematology Haematocrit Haemoglobin concentrations Erythrocyte count Reticulocytes Total and differential leucocyte count Platelet count Measure of blood clotting time.

Clinical biochemistry :

Clinical biochemistry To investigate major toxic effects in tissues such as kidney and liver. Investigations of plasma or serum include Na, K, glucose, total cholesterol, urea, creatinine , total protein and albumin, at least two enzymes indicative of hepatocellular effects (such as alanin aminotransferase , aspartate aminotransferase , alkaline phosphatase , γ- glutamyl trans-peptidase and glutamate dehydrogenase ), and bile acids.

PATHOLOGY:

PATHOLOGY Gross necropsy The liver, kidneys, adrenals, testes, prostate + seminal vesicles, thymus, spleen, brain and heart of all animals should be trimmed of any adherent tissue & their wet weight taken as soon as possible after dissection to avoid drying. Histopathology Full histopathology should be carried out on the preserved organs & tissues of all animals in the control and high dose groups.

Data :

Data All data should be in tabular form showing for each test group : the no. of animals at the start of the test, the no. of animals found dead during the test or euthanised for humane reasons and the time of any death or euthanasia, the no. showing signs of toxicity, a description of the signs of toxicity observed, including time of onset, duration, and severity of any toxic effects.

Data (cont..):

Data (cont..) When possible, numerical results should be evaluated by generally acceptable statistical method. Comparisons of the effect along a dose range should avoid the use of multiple t-tests.

Test report :

Test report Test substance: - physical nature, purity and physicochemical properties; - identification data. Vehicle : justification for choice of vehicle, if other than water. Test animals : species/strain used; No., age and sex of animals; source, housing conditions, diet, etc.; individual weights of animals at the start of the test. justification for species if not rat

Test report (cont..):

Test report (cont..) Test conditions : rationale for dose level selection; details of test substance formulation/diet preparation, achieved concentration, stability and homogeneity of the preparation; details of administration of test substance; details of food and water quality. Optional endpoints investigated : list of optional endpoints investigated.

Test report (cont..):

Test report (cont..) Results: body weight/body weight changes; food & water consumption; toxic response data by sex and dose level, including signs of toxicity; nature, severity & duration of clinical observations; sensory activity, grip strength and motor activity assessments; haematological tests with relevant base-line values; clinical biochemistry tests with relevant base-line values; body weight at euthanasia and organ weight data; necropsy findings; a detailed description of all histopathological findings; statistical treatment of results, where appropriate.

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Discussion of results. Conclusions.

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