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OECD guidelines for toxicity studies:

OECD guidelines for toxicity studies Prepared by : Rucha Trivedi Department : M.Pharm. - 1 st sem. Q.A.(first shift) Guided by : Mrs.Nikita patel Parul institute of Pharmacy 1

INTRODUCTION:

INTRODUCTION OECD= Organization for the economic co-operation and development. Established in 1961 . This test guide line encompasses different area of development like education, health, finance, market, industry and chemicals etc. Headquarter is in Paris (France) . Membership- 34 countries. 2

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The OECD provides a forum in which governments can work together to share experiences and seek solutions to common problems. The mission of the Organisation for Economic Co-operation and Development (OECD) is to promote policies that will improve the economic and social well-being of people around the world .   3

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The OECD   Guidelines for the Testing of Chemicals   is a collection of about 100 of the most relevant internationally agreed testing methods used by government, industry and independent laboratories to identify and characterise potential hazards of new and existing chemical substances , chemical preparations and chemical mixtures. They can also be used for the selection and ranking of candidate chemicals during the development of new chemicals and products and in toxicology research . This group of tests covers health effects. 5

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Eye Irritation Toxicity Guidelines 7

OECD 405 - ACUTE EYE IRRITATION/CORROSION :

OECD 405 - ACUTE EYE IRRITATION/CORROSION Following pre-treatment with a systemic analgesic and induction of appropriate topical anesthesia, the substance to be tested is applied in a single dose to one of the eyes of the experimental animal; the untreated eye serves as the control . The degree of eye irritation/corrosion is evaluated by scoring lesions of conjunctiva, cornea, and iris, at specific intervals. Other effects in the eye and adverse systemic effects are also described to provide a complete evaluation of the effects. The duration of the study should be sufficient to evaluate the reversibility or irreversibility of the effects. 8

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Animals showing signs of severe distress and/or pain at any stage of the test or lesions consistent with the humane endpoints described in this Test Guideline should be humanely killed , and the substance assessed accordingly. Criteria for making the decision to humanely kill moribund and severely suffering animals are the subject of a separate Guidance Document (8). 9

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Oral Toxicity Guidelines 10

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OECD 401 - ACUTE ORAL TOXICITY:

OECD 401 - ACUTE ORAL TOXICITY Information : Following the OECD Council decision, the test 401 ‘Acute Oral Toxicity’ was deleted on 17th December 2002.   12

Acute Oral Toxicity Guidelines:

Acute Oral Toxicity Guidelines TG – 420 (FIXED DOSE PROCEDURE) TG – 423 (ACUTE TOXIC CLASS METHOD) TG – 425 {UP-AND-DOWN-PROCEDURE (UDP)} AIM Identify lowest fix dose causing evident toxicity. Identify lowest fix dose causing mortality. Estimate LD50 Value. DOSE LEVELS fixed doses of 5, 50,300 and 2000(5000) mg/kg & 5 rats per dose levels fixed doses of 5, 50,300 and 2000(5000) mg/kg & 3 rats per dose levels The first animal receives a dose a step below the level of the best estimate of the LD50. If the animal survives , the dose for the next animal is increased by [a factor of] 3.2 times the original dose; if it dies , the dose for the next animal is decreased by a similar dose progression & 5 rats per dose levels METHOD Single dose administered to young adult rats of either sex by oral route and their body weight , toxicity and mortality is observed over 14 days and necropsy at termination is carried out. 13

Subchronic & Chronic Oral Toxicity Guidelines :

Subchronic & Chronic Oral Toxicity Guidelines 14

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Dermal Toxicity Guidelines 15

Dermal Toxicity :

Dermal Toxicity ACUTE : a) ACUTE DERMAL TOXICITY b) ACUTE DERMAL IRRITATION /CORROSION SUBCHRONIC : a) SUBCHRONIC DERMAL TOXICITY: 90-DAY STUDY SUBACUTE : a) REPEATED DOSE DERMAL TOXICITY:21/28-DAY STUDY OTHER : a)SKIN SENSITISATION b) SKIN ABSORPTION : (i) in vivo (ii)in vitro c)SKIN SENSITISATION: LOCAL LYMPH NODE ASSAY d) IN VITRO SKIN CORROSION: TRANSCUTANEOUS ELECTRICAL RESISTANCE TEST METHOD (TER) 16

Dermal Toxicity Guidelines:

Dermal Toxicity Guidelines 17

Skin Absorption : In Vivo Method TG-427:

Skin Absorption : In Vivo Method TG-427 18

Skin Absorption : In Vitro Method TG-428:

Skin Absorption : In Vitro Method TG-428 19

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SKIN SENSITISATION TG -406 SKIN SENSITISATION: LOCAL LYMPH NODE ASSAY TG -429 The test animals are initially exposed to the test substance by intradermal injection. Following a rest period of 10 to 14 days (induction period) , during which an immune response may develop, the animals are exposed to a challenge dose. The extent and degree of skin reaction to the challenge exposure in the test animals is compared with that demonstrated by control animals which undergo sham - treatment during induction and receive the challenge exposure. The basic principle underlying the LLNA is that sensitizers induce proliferation of lymphocytes in the lymph nodes draining the site of test substance application. This proliferation is proportional to the dose and to the potency of the applied allergen and provides a simple means of obtaining a quantitative measurement of sensitization. Proliferation is measured by comparing the mean proliferation in each test group to the mean proliferation in the vehicle treated control group. 21

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SKIN SENSITISATION TG -406 SKIN SENSITISATION: LOCAL LYMPH NODE ASSAY TG -429 _ The ratio of the mean proliferation in each treated group to that in the concurrent VC group, termed the Stimulation Index (SI), is determined, and should be ≥3 before classification of the test substance as a potential skin sensitizer is warranted. 22

OECD 430 - IN VITRO SKIN CORROSION: TRANSCUTANEOUS ELECTRICAL RESISTANCE TEST METHOD (TER) :

OECD 430 - IN VITRO SKIN CORROSION: TRANSCUTANEOUS ELECTRICAL RESISTANCE TEST METHOD (TER)   The test chemical is applied for up to 24 hours to the epidermal surfaces of skin discs in a two-compartment test system in which the skin discs function as the separation between the compartments. The skin discs are taken from humanely killed rats aged 28-30 days. Corrosive chemicals are identified by their ability to produce a loss of normal stratum corneum integrity and barrier function, which is measured as reduction in the TER below threshold level (18). 23

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For rat skin TER , a cut-off value of 5kW has been selected. Generally, chemicals that are non-corrosive in animals but are irritant or non-irritant do not reduce the TER below this cut-off value. Furthermore, use of other skin preparations or other equipment may alter the cut-off value, necessitating further validation. A dye-binding step is incorporated into the test procedure for confirmation testing of positive results in the TER including values around 5 kW. The dye-binding step determines if the increase in ionic permeability is due to physical destruction of the stratum corneum. 24

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Inhalation Toxicity Guidelines 25

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OECD 403 -ACUTE INHALATION TOXICITY :

OECD 403 - ACUTE INHALATION TOXICITY This revised TG 403 has been designed to obtain sufficient information on the acute toxicity of a test article to enable its classification and to provide lethality data (e.g. LD50) for one or both sexes as needed for quantitative risk assessments. This Guideline offers two test methods. 27

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Two test methods Traditional protocol (c x t) protocol groups of animals are exposed to groups of animals are exposed to or a series of concentrations in a a series of multiple concentrations stepwise procedure for a over multiple durations. predetermined duration of usually 4 hours . 28

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Moribund animals or animals obviously in pain or showing signs of severe and enduring distress should be humanely killed and are considered in the interpretation of the test result in the same way as animals that died on test . Criteria for making the decision to kill moribund or severely suffering animals, and guidance on the recognition of predictable or impending death, are the subject of an OECD Guidance Document No. 19 on Humane Endpoints (8). 29

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SUBACUTE INHALATION TOXICITY: 28-DAY STUDY SUBCHRONIC INHALATION TOXICITY: 90-DAY STUDY TG - 412 TG - 413 This revised Test Guideline 412 (TG 412) has been designed to fully characterize test article toxicity by the inhalation route following repeated exposure for a limited period of time (28 days), and to provide data for quantitative inhalation risk assessments. This revised Test Guideline 413 (TG 413) has been designed to fully characterize test article toxicity by the inhalation route for a subchronic duration (90 days ), and to provide robust data for quantitative inhalation risk assessments. Groups of at least 5 male and 5 female rodents are used. Groups of 10 male and 10 female rodents are used. Exposed 6 hours per day for 28 days to.. a ) the test article at three or more concentration levels, b) filtered air (negative control), and/or c) the vehicle (vehicle control). Animals are generally exposed 5 days per week but exposure for 7 days per week is also allowed. Males and females are always tested, but they may be exposed at different concentration levels if it is known that one sex is more susceptible to a given test article. This guideline allows the study director the flexibility to include additional clinical pathology and histopathological evaluations in order to better characterize the toxicity of a test article. 30

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Neurotoxicity Guidelines 31

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DELAYED NEUROTOXICITY OF ORGANOPHOSPHORUS SUBSTANCES FOLLOWING ACUTE EXPOSURE The test substance is administered orally in a single dose to domestic hens. The animals are observed for 21 days for behavioral abnormalities, ataxia, and paralysis . Biochemical measurements are undertaken on hens randomly selected from each group (normally 24 and 48 hours after dosing). Twenty-one days after exposure , the remainder of the hens are killed and histopathological examination of selected neural tissues is undertaken. TG-418 DELAYED NEUROTOXICITY OF ORGANOPHOSPHORUS SUBSTANCES:28-DAY REPEATED DOSE STUDY Daily doses of the test substance are administered orally to domestic hens for 28 days . The animals are observed at least daily for behavioral abnormalities, ataxia, and paralysis , until 14 days after the last dose. Biochemical measurements are undertaken on hens randomly selected from each group (normally 24 and 48 hours after the last dosing). Two weeks after the last dose , the remainder of the hens are killed and histopathological examination of selected neural tissues is undertaken. TG-419 33

OECD 424 - NEUROTOXICITY STUDY IN RODENTS:

OECD 424 - NEUROTOXICITY STUDY IN RODENTS The test chemical is administered by the oral route across a range of doses to several groups of laboratory rodents. Repeated doses are normally required, and the dosing regimen may be 28 days, subchronic (90 days) or chronic (1 year or longer). The procedures set out in this Guideline may also be used for an acute neurotoxicity study. 34

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The animals are tested to allow the detection or the characterization of behavioural and/or neurological abnormalities . A range of behaviours that could be affected by neurotoxicants is assessed during each observation period. At the end of the test, a subset of animals of each sex from each group are Perfused and sections of the brain,spinal cord, and peripheral nerves are prepared and examined. 35

OECD 426 - DEVELOPMENTAL NEUROTOXICITY STUDY :

OECD 426 - DEVELOPMENTAL NEUROTOXICITY STUDY The test substance is administered to animals during gestation and lactation . Dams are tested to assess effects in pregnant and lactating females and may also provide comparative information ( dams versus offspring ). Offspring are randomly selected from within litters for neurotoxicity evaluation . 36

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The evaluation consists of observations to detect gross neurologic and behavioural abnormalities , including the assessment of physical development, behavioural ontogeny, motor activity, motor and sensory function, and learning and memory ; and the evaluation of brain weights and neuropathology during postnatal development and adulthood. 37

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Reproduction toxicity Guidelines 38

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PRENATAL DEVELOPMENTAL TOXICITY STUDY ONE-GENERATION REPRODUCTION TOXICITY STUDY TWO-GENERATION REPRODUCTION TOXICITY STUDY REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST COMBINED REPEATED DOSE TOXICITY STUDY WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST 39

TG – 414 PRENATAL DEVELOPMENTAL TOXICITY STUDY:

TG – 414 PRENATAL DEVELOPMENTAL TOXICITY STUDY 44 40

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The test substance is administered in graduated doses to several groups of males and females. Males should be dosed during growth and for at least one complete spermatogenic cycle (approximately 56 days in the mouse and 70 days in the rat) in order to elicit any adverse effects on spermatogenesis. Females should be dosed for at least two complete oestrous cycles in order to elicit any adverse effects on oestrus by the test substance. The test substance is administered in graduated doses to several groups of males and females. Males should be dosed during growth and for at least one complete spermatogenic cycle (approximately 56 days in the mouse and 70 days in the rat) in order to elicit any adverse effects on spermatogenesis. Females should be dosed during growth and for several complete oestrus cycles in order to detect any adverse effects on oestrus cycle. ONE-GENERATION REPRODUCTION TOXICITY STUDY TG - 415 TWO-GENERATION REPRODUCTION TOXICITY STUDY TG - 416 41

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ONE-GENERATION REPRODUCTION TOXICITY STUDY TG - 415 TWO-GENERATION REPRODUCTION TOXICITY STUDY TG - 416 The animals are then mated . The test substance is administered to both sexes during the mating period and thereafter only to females during pregnancy and for the duration of the nursing period . The test substance is administered to parental (P) animals during their mating , during the resulting pregnancies , and through the weaning of their Fl offspring. At weaning the administration of the substance is continued to Fl offspring during their growth into adulthood, mating and production of an F2 generation , until the F2 generation is weaned. Clinical observations and pathological examinations are performed on all animals for signs of toxicity. 42

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REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST TG – 421 COMBINED REPEATED DOSE TOXICITY STUDY WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST TG - 422 The test substance is administered in graduated doses to several groups of males and females. The test substance is administered in graduated doses to several groups of males and females. Males should be dosed for a minimum of four weeks and up to and including the day before scheduled kill (this includes a minimum of two weeks prior to mating, during the mating period and approximately, two weeks post-mating). Males should be dosed for a minimum of four weeks and up to and including the day before scheduled kill (this includes a minimum of two weeks prior to mating, during the mating period and approximately, two weeks post-mating). The combination of a pre-mating dosing period of two weeks and subsequent mating/fertility observations with an overall dosing period of at least four weeks, followed by detailed histopathology of the male gonads , is considered sufficient to enable detection of the majority of effects on male fertility. The combination of a pre-mating dosing period of two weeks and subsequent mating/fertility observations with an overall dosing period of at least four weeks, followed by detailed histopathology of the male gonads , is considered sufficient to enable detection of the effects on male fertility 43

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REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST TG – 421 COMBINED REPEATED DOSE TOXICITY STUDY WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST TG - 422 Females should be dosed throughout the study. Females should be dosed throughout the study This includes two weeks prior to mating, the duration of pregnancy and at least four days after delivery, up to and including the day before scheduled kill. This includes two weeks prior to mating, the duration of pregnancy and at least four days after delivery , up to and including the day before scheduled kill. Duration of study is dependent on the female performance and is approximately 54 days , [at least 14 days pre-mating, (up to) 14 days mating, 22 days gestation, 4 days lactation]. Duration of study is dependent on the female performance and is approximately 54 days , [at least 14 days pre-mating, (up to) 14 days mating, 22 days gestation, 4 days lactation]. 44

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REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST TG – 421 COMBINED REPEATED DOSE TOXICITY STUDY WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST TG - 422 During the period of administration, the animals are observed closely each day for signs of toxicity . During the period of administration, the animals are observed closely each day for signs of toxicity . Animals which die or are killed during the test period are necropsied and , at the conclusion of the test, surviving animals are killed and necropsied. Animals which die or are killed during the test period are necropsied and , at the conclusion of the test, surviving animals are killed and necropsied. This Screening Test Guideline can be used to provide initial information on possible effects on reproduction and/or development, either at an early stage of assessing the toxicological properties of chemicals In the assessment and evaluation of the toxic characteristics of a chemical the determination of oral toxicity using repeated doses may be carried out after the initial information on toxicity has been obtained by acute testing. 45

OECD 417 - TOXICOKINETICS :

OECD 417 - TOXICOKINETICS Studies examining the toxicokinetics (TK) of a chemical substance are conducted to obtain adequate information on its absorption, distribution, metabolism and excretion , to aid in relating concentration or dose to the observed toxicity, and to aid in understanding its mechanism of toxicity. 46

REFERANCES:

REFERANCES http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788 47

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