420-Acute Oral Toxicity – Fixed Dose Procedure

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1、OECD/OCDE420Adopted:th17December2001OECDGUIDELINEFORTESTINGOFCHEMICALSAcuteOralToxicity–FixedDoseProcedureINTRODUCTION1.OECDGuidelinesfortheTestingofChemicalsareperiodicallyreviewedinthelightofscientificprogressorchangingassessmentpractices.TheoriginalGuideline420wasadoptedinJu

2、ly1992asthefirstalternativetotheconventionalacutetoxicitytest,describedinTestGuideline401.Basedontherecommendationsofseveralexpertmeetings,revisionwasconsideredtimelybecause:i)internationalagreementhadbeenreachedonharmonisedLD50cut-offvaluesfortheclassificationofchemicalsubstan

3、ces,whichdifferfromthecut-offsrecommendedinthe1992versionoftheGuideline,andii)testinginonesex(usuallyfemales)isnowconsideredsufficient.2.Traditionalmethodsforassessingacutetoxicityusedeathofanimalsasanendpoint.In1984,anewapproachtoacutetoxicitytestingwassuggestedbytheBritishTox

4、icologySocietybasedontheadministrationataseriesoffixeddoselevels(1).Theapproachavoidedusingdeathofanimalsasanendpoint,andreliedinsteadontheobservationofclearsignsoftoxicityatoneofaseriesoffixeddoselevels.FollowingUK(2)andinternational(3)invivovalidationstudiestheprocedurewasado

5、ptedbytheCouncilasaTestGuidelinein1992.Subsequently,thestatisticalpropertiesoftheFixedDoseProcedurehavebeenevaluatedusingmathematicalmodelsinaseriesofstudies(4)(5)(6).Together,theinvivoandmodellingstudieshavedemonstratedthattheprocedureisreproducible,usesfeweranimalsandcausesle

6、sssufferingthanthetraditionalmethodsandisabletoranksubstancesinasimilarmannertotheotheracutetoxicitytestingmethods(TestGuidelines423and425).3.GuidanceontheselectionofthemostappropriatetestmethodforagivenpurposecanbefoundintheGuidanceDocumentonAcuteOralToxicityTesting(7).ThisGui

7、danceDocumentalsocontainsadditionalinformationontheconductandinterpretationofGuideline420.4.DefinitionsusedinthecontextofthisGuidelinearesetoutinAnnex1.INITIALCONSIDERATIONS5.Itisaprincipleofthemethodthatinthemainstudyonlymoderatelytoxicdosesareused,andthatadministrationofdoses

8、thatareexpectedtobelethalshouldbeavoided.Also,dosestha