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OECD 420 / 423 / 425 GUIDELINES

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OECD GUIDELINES:

OECD GUIDELINES Presented by P.Balaji (Research Scholar) Department of Pharmacy Annamalai University

OECD :

OECD ORGANISATION FOR ECONOMIC CO-OPERATION AND DEVELOPMENT Toxicity tests - investigation of a new drug involve Acute, Sub acute and chronic toxicity . Acute toxicity is involved in estimation of LD50 (the dose which has proved to be lethal (causing death) to 50% of the tested group of animals).

OECD 420 , 423 & 425:

OECD 420 , 423 & 425

OECD General Guidelines:

OECD General Guidelines Traditional methods for assessing acute toxicity use death of animals as an endpoint. In 1984, a new approach - acute toxicity testing was suggested by the British Toxicology Society based on the administration at a series of fixed dose levels. Avoid using death of animals & Observation – sign of toxicity

General Guidelines cont…:

General Guidelines cont… INITIAL CONSIDERATIONS: Only moderately toxic doses are used Administration of doses - lethal should be avoided cause marked pain and distress due to corrosive or severely irritant actions showing signs of severe and enduring distress Hazardous - Globally Harmonised System (GHS) for the classification of chemicals which cause acute toxicity

General Guidelines cont…:

General Guidelines cont… Testing laboratory: All available information on the test substance. Identity and chemical structure of the substance Physico-chemical properties The results of any other in vitro or in vivo toxicity tests on the substance Toxicological data on structurally related substances Above information is necessary – human & starting dose

General Guidelines cont…:

General Guidelines cont… Selection of animal species: Rodent species Females are used (More Sensitive) Test is conducted in males, adequate justification should be provided. Nulliparous and non-pregnant 8 and 12 weeks old

General Guidelines cont…:

Housing and feeding conditions: Room Temp: 22ºC (+3ºC) RH is at least 30% and preferably not exceed 70% Lighting should be artificial – 12h (D/L) Feeding – conventional laboratory diets & Water Group-caged by dose, but the number of animals per cage & Clear observations of each animal General Guidelines cont…

General Guidelines cont…:

General Guidelines cont… Preparation of doses: Rodents, the volume should not normally exceed 1mL/100g of body weight Use of an aqueous Solution / suspension / emulsion is recommended For vehicles - toxicological characteristics of the vehicle should be known

General Guidelines cont…:

General Guidelines cont… Administration of doses: Gavage using a stomach tube or a suitable intubation canula Unusual circumstance that a single dose is not possible - dose may be given in smaller fractions over a period not exceeding 24 hours Animals should be fasted prior to dosing After the substance has been administered, food may be withheld

General Guidelines cont…:

General Guidelines cont… OBSERVATIONS: After dosing at least once during the first 30 minutes, Special attention given during the first 4 hours, periodically during the first 24 hours / 14 days Signs of toxicity appear and disappear are important

General Guidelines cont…:

General Guidelines cont… OBSERVATIONS: (Cont…) Skin and fur Eyes and mucous membranes Respiratory & circulatory Autonomic and central nervous systems Somatomotor activity and behaviour pattern Tremors, convulsions, salivation, diarrhoea , lethargy, sleep and coma Urine analysis

General Guidelines cont…:

General Guidelines cont… Pathology: All test animals (survive / death) – gross necroscopy (Microscopical examinations of each organs – evidence of gross pathology) Organs - brain, colon, heart, kidneys, liver, lungs, oesophagus , rectum, sciatic nerve, spleen, sternum with bone marrow, stomach, thyroid / parathyroid, trachea, urinary bladder and uterus. They were subjected to histopathological examination

General Guidelines cont…:

General Guidelines cont… Body weight: Individual weights of animals – before test substance admn , one week after & end of the test – survive animals Wt. of the organs - liver, kidneys, adrenals, epididymis , thymus, spleen, brain, heart, uterus and testes/ovaries

OECD 420:

OECD 420 The original Guideline 420 was adopted in July 1992 Fixed dose method does not require the death of animals as an endpoint Animals used: 5 female rats Dose: 5, 50, 300 & 2000 mg / kg Upper fixed dose level of 5000 mg/kg - reasons of animal welfare concern, testing of animals in GHS Category 5 ranges Sighting study & main study – carried out

OECD 420 cont…:

OECD 420 cont… GHS category 1 5mg/kg 1 animal Animal dies Terminate the study Further confirm Second animal dosed at 5 mg/kg Sighting study

OECD 420 cont…:

OECD 420 cont… Main study 5 animals One animal from the sighting study dosed at the selected dose level together with an additional four animals

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OECD 420 cont…

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OECD 423 (Acute toxic class method):

OECD 423 (Acute toxic class method) Guideline 423 was adopted in March 1996 Second alternative to the conventional acute toxicity test The expected number of deaths is typically not more than 3 Similar to OECD 420 No sighting study Mortality is endpoint

OECD 423 cont…:

OECD 423 cont… Animals Used: 6 Female Animals Dose: 5 , 50 , 300 & 2000 mg / kg (Starting at any dose) PRINCIPLE OF THE TEST: no further testing is needed, dosing of three additional animals, with the same dose dosing of three additional animals at the next higher or the next lower dose level.

OECD 423 cont…:

OECD 423 cont…

OECD 423 cont…:

OECD 423 cont…

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OECD 423 cont…:

OECD 423 cont…

OECD 423 cont…:

OECD 423 cont… TESTING AT DOSES ABOVE 2000 MG/KG: 3 Animals Dosing Dosing LD 50 value 5000 mg / kg I st animal dies 2000 mg / kg I st animal survives 5000 mg / kg Only One of the three animal dies 5000 mg / kg

OECD 425:

OECD 425 1985 – Bruce – Acute toxicity of chemicals Up & down method Minimizing the number of animals Revision of guidelines 420 & 423 Start dose: Believed just below LD50 or 175 mg/kg Increase-decrease usually x 3.2 (dose progression of factor) antilog of 1/(the estimated slope of the dose-response curve), 48 h between animals

OECD 425 cont…:

OECD 425 cont… Find dose level - outcome - death or no death LD50 is calculated 5 Female animals used Test dose of 2000 or exceptionally 5000 mg/kg, may be used Limit test & main test should be performed

OECD 425 cont…:

OECD 425 cont… Limit test at 2000 MG/KG: 1 Animal Conduct Test dose (1 + 4) Animal dies Main test Animal survives LD 50 3 Animal dies 4 Animals Limit test is terminated & main test performed

OECD 425 cont…:

OECD 425 cont… The LD50 is less than the test dose (2000 mg/kg or 5000 mg / kg) when three or more animals die. o xoxx , o xxox , o oxxx Main test The LD50 is greater than the test dose (2000 mg/kg or 5000 mg / kg) when three or more animals survive. o oooo , o oxoo , o oxoo Limit test 5000 mg / kg

OECD 425 cont…:

OECD 425 cont… Test dose Receives Survive Dies Receives The dose progression factor 3.2 and should remain constant throughout testing. First animal Secondanimal Higher dose Secondanimal Lower dose

OECD 425 cont …:

OECD 425 cont … When there is no information on the slope of the substance to be tested, a dose progression factor of 3.2 is used. Using the default progression factor, doses would be selected from the sequence 1.75, 5.5, 17.5, 55, 175, 550, 2000 (or 1.75, 5.5, 17.5, 55, 175, 550, 1750, 5000 for specific regulatory needs). If no estimate of the substance’s lethality is available, dosing should be initiated at 175 mg/kg.

REFERENCES:

REFERENCES www.oecd-ilibrary.org/environment/test-no-420-acute-oral-toxicity-fixed-dose-procedure_9789264070943-en www. oecd .org/data oecd /17/50/1948370. pdf www. oecd .org/data oecd /17/51/1948378.pdf

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