council recommend octob test relat place market proprietari medicin product eec council european commun regard treati establish european econom commun articl thereof regard propos commiss regard opinion european parliament regard opinion econom social committe council direct eec januari led approxim provis laid law regul administr action relat proprietari medicin product member state direct eec eec continu approxim develop principl set direct eec council direct eec lai gener framework test proprietari medicin product list type test conduct defin principl examin applic author place proprietari medicin product market experi shown conduct content test defin precis make ident implement commun direct test carri applic examin nation author note guidanc order prevent differ interpret implement standard protocol refer direct eec promot free movement proprietari medicin product test design evalu qualiti safeti efficaci proprietari medicin product constantli adapt account latest scientif technic knowledg give rise wast resourc laboratori anim highli desir note guidanc period revis account state art note guidanc drawn requir agreement nation author progress harmon essenti commun level promot intern recognit test medicin product conduct accord note tend render unnecessari repetit test product intend export countri pharmaceut committe committe proprietari medicin product consult measur contain recommend recommend member state ensur conduct test present result applic author place proprietari medicin product market compli principl adher methodolog set note guidanc annex hereto examin evalu accord note guidanc applic market author luxembourg octob council presid moraiti oj oj oj oj oj annex repeat dose toxic note guidanc applic chapter part annex direct eec view grant market author drug introduct purpos studi obtain inform toxic product repeat exposur medicin product anticip order assess made risk result therapeut administr product take account product biotransform durat studi determin propos man intend durat human exposur period administr suggest guidanc correl durat repeat dose toxic studi propos durat human exposur drug gt pic file quot quot gt human exposur longer term frequent discontinu administr result total period exposur month period year retent bodi singl dose drug prolong durat repeat dose toxic studi month conduct toxic studi month durat subacut toxic studi week durat design carri manner act rang find studi longer term investig reason administr high dose leav anim aliv end studi last month administr low dose prevent develop toxic gener specif regard repeat dose toxic studi annex direct eec part toxicolog pharmacolog test state test show inter alia toxic threshold quot repeat dose toxic test intend reveal physiolog patholog induc repeat administr activ substanc combin activ substanc examin determin relat dosag gener desir test perform short term last week long term durat depend condit clinic purpos determin experi toxic dose rang product quot threshold determin cross repeat dose toxic studi conceiv demonstr sign toxic impli select speci long term studi prior market desir regard metabol pharmacokinet drug speci close similar man usual spectrum laboratori anim repeat dose studi signific differ metabol account evalu result desir pharmacolog target organ pharmacolog effect product speci involv therapeut effect envisag man practic dosag rout frequenc administr plan promot load anim organ product metabolit suffici demonstr target organ term harm secondari effect design protocol account pharmacokinet drug continu administr drug suffici high dose princip stage reach load drug organ build steadi state reach adapt organ load regard pharmacolog target organ biotransform enzym excretori mechan case metabol pathwai activ due overload primari detox pathwai result toxic metabolit form phase manifest target organ toxic manifest failur physiolog function ultim patholog administr product repeat dose toxic studi suffici regard dosag durat reach final stage type toxic produc excess dose multipl therapeut dose produc toxic assess drug practic administ dosag produc target organ toxic circumst evid produc highest dose drug system absorb specif regard drug administr drug qualiti activ substanc present pattern impur product market drug substanc final dosag form shown impur significantli quantiti qualiti test batch step ascertain toxic drug oral physic characterist particl size import physic characterist stabil materi repeat dose toxic studi state case batch activ substanc repeat dose toxic studi state batch identifi batch batch repeat dose toxic studi higher degre puriti intend final product drug diet drink water establish stabl medium excipi time test accord criteria activ substanc durat administr durat studi relat durat propos therapeut man rout administr technic feasibl product administ rout intend man desir pharmacolog effect demonstr rout shown rout consid administr inhal discuss appendix quantiti drug absorb propos site administr pharmacokinet studi product administ food drink water applic give assur reason amount drug ingest absorb dose incorpor test substanc diet drink water requir regular adjust amount drug diet drink water compens growth chang consumpt addit system toxic possibl local toxic site applic due attent case applic skin intravagin applic intraven intramuscular rectal subcutan intra articular intrathec conjunctiv intranas aural applic drug inhal frequenc administr steadi state load organ product reach administ dai week administr drug anim conduct basi reason rate elimin slow frequent administr accept rapid rite elimin gastric intoler make administ product dai dose level treatment includ high dose select purpos caus target organ toxic fail specif toxic limit volum dose toxic studi month durat dose deriv subacut toxic test week durat design carri dose rang find studi low dose suffici produc pharmacodynam effect desir therapeut effect produc blood level compar expect produc effect man intermedi dose geometr high dose low studi includ control group special case posit control group consider appli pharmacodynam effect toxic hypoglycaemia antidiabet agent serv investig rational dose level select pro drug product administ pro drug convers activ drug demonstr speci studi specif pertain experiment anim anim speci choic character speci chosen basi similar man regard pharmacokinet includ biotransform product pharmacodynam effect drug demonstr speci provid inform margin therapeut toxic effect investig justifi choic speci strain spf anim increas studi sex equal number male femal anim size treatment group size treatment group consid attent size treatment group toxicolog import effect due treatment reveal size treatment group larg permit sacrific anim interv end studi interf final statist analysi size treatment group larg anim retain complet period dose revers toxic end treatment evalu background knowledg rang variabl studi speci strain relev consider group size size control treatment group limit practic financi reason human consider number speci purpos repeat dose toxic studi provid anim model repeat administr product man model extrapol man depend larg extent qualit similar anim model man unknown reduc risk error extrapol due effect lack effect peculiar speci speci rodent choic speci justifi anim husbandri high level anim husbandri requir environment condit control diet constant composit measur obtain condit record report observ pre treatment control valu control data coloni small mammal morpholog biochem physiolog variabl case larger anim pre treatment valu obtain anim studi monitor studi gener monitor gener monitor carri studi includ food intak bodi weight haematolog clinic chemistri urinanalysi ophthalmolog ecg gener behaviour select techniqu choic test current state knowledg anim speci rodent ecg ophthalmolog special examin requir accept conduct limit number anim dose level frequenc monitor frequenc monitor addit pre treatment studi final monitor adapt manifest toxic pharmacokinet drug test perform includ collect blood sampl monitor perform control affect experiment anim influenc final interpret toxic test result food intak product administ food attent effect product food consumpt allow made consequ effect drug intak termin monitor termin observ complet autopsi conduct anim histopatholog perform organ tissu high dose control group list tabl rodent examin lower dose group restrict organ tissu show patholog autopsi speci small number anim histopatholog tissu list conduct anim dose organ examin microscop wax block slide prepar conserv year date market examin requir peculiar distribut drug necessit histopatholog studi immuno interfer expans growth immunolog recognit import made pai attent interfer immunolog system drug belong intend activ interfer undesir side effect interfer infect carcinoma import examin spleen thymu lymph node macroscop microscop termin toxic studi effect immun system test present knowledg field rapidli increas test investig immunolog effect drug reli state scientif knowledg moment conclus conclus drawn studi investig appendix list tissu studi histolog repeat dose toxic studi gross lesion tissu mass tumor includ region lymph node blood smear case anaemia enlarg thymu lymphadenopathi lymph node mammari gland salivari gland sternebra femur vertebra includ bone marrow pituitari thymu trachea lung heart thyroid oesophagu stomach small intestin swiss roll method colon liver gall bladder pancrea spleen kidnei adren bladder prostat test ovari uteru brain coron section level ey spinal cord appendix conduct toxic studi inhal introduct medicin product intend administr human inhal aerosol pharmacolog activ substanc solid liquid state vapor gase mention product inhal anaesthet aerosol gener drug materi form particl deliv propel principl biolog inact toxicolog studi conduct inhal pharmacokinet administr inhal differ qualit quantit pattern rout administr drug propel interact bodi inhal product local effect airwai short term effect effect ciliari function sign local irrit long term effect emphysema bronchiti malign aerosol administr drug obtain local effect respiratori system ii purpos obtain system effect line airwai absorpt activ compound iii circumv alter drug gastro intestin tract circumst toxicolog studi drug perform rout administr extens toxicolog investig rout administr perform inhal studi plan case local act compound mucolyt agent toxicolog investig rout administr exist relev plan toxicolog studi inhal consider exist toxicolog pharmacolog knowledg substanc physico chemic properti inform activ substanc physico chemic properti provid toxicolog studi addit inform provid characterist aerosol includ distribut particl droplet size activ substanc physico chemic specif substanc substanc propel propel system studi propos final product propel system investig standard activ substanc dose schedul administr method administr depend natur substanc intend man acut studi reason administ substanc directli airwai nasotrach tube tracheotomi quantiti administ determin directli case long term exposur studi quot head quot quot nose quot exposur chamber mask inhal bodi exposur deposit drug skin pelt upper airwai amount swallow account determin dose substanc administ demonstr method administr ensur substanc reach desir site dose level studi dose level control group singl dose repeat dose studi level drug exposur achiev alter concentr substanc inhal alter durat exposur select dose level principl appli toxic studi rout reason select dose level durat studi durat studi relat extent propos human exposur pharmacokinet metabol metabol pattern drug administ inhal differ pattern observ rout administr investig determin pharmacokinet metabol differ relev interpret toxicolog studi conduct inhal rout biotransform occur lung possibl enzym induct process consider anim experiment anim studi free pulmonari infect low incid pulmonari patholog number experiment anim group adequ statist analysi determin durat experi number observ measur interim sacrific made exposur period rodent rodent speci repeat exposur studi observ interim monitor termin studi conduct toxic studi attent paid local effect drug administ repeatedli special studi ciliari function microflora blood level monitor drug propel method assess absorpt drug propel perform interv repeat dose studi termin examin conclus studi anim subject autopsi examin tissu conduct toxicolog studi studi conduct inhal rout lung weigh anim histopatholog examin conduct tissu expos level respiratori tract lymphoid tissu present result conclus drawn manner toxic studi investig draw conclus studi annex ii reproduct studi note guidanc applic chapter part annex direct eec view grant market author drug gener statement studi drug effect reproduct conduct drug manner reveal presenc effect mate behaviour effect result fetal loss fetal abnorm damag offspr life fertil product abnorm young due damag male femal gamet ii interfer preimplant implant stage develop conceptu iii toxic effect embryo iv toxic effect fetu matern physiolog produc secondari effect embryo fetu vi effect uterin placent growth develop vii interfer parturit viii effect postnat develop suckl progeni matern lactat ix late effect progeni specif guidelin interpret note guidanc appreci rigid requir univers applic interpret flexibl relat propos drug justif choic studi select speci embryotox studi conduct mammalian speci rodent fertil perinat studi conduct speci metabol drug speci similar man desir includ speci desir speci long term toxic studi studi speci help conflict result obtain initit speci speci strain studi dosag dose conduct dose level high dose evid matern toxic produc decreas bodi weight gain low dose suffici produc pharmacodynam effect similar desir therapeut effect produc blood level compar requir produc effect appli pharmacodynam effect toxic intermedi dose geometr high low dose dose conduct propos rout rout clinic administr dose schedul investig drug effect reproduct includ embryotox studi dose period embryogenesi organogenesi speci rodent fertil studi conduct speci dose commenc male femal anim suffici time propos mate effect drug gametogenesi reveal dose anim mate dose partner event posit find reproduct defect studi repeat dose anim mate undos partner mate dose femal continu dose pregnanc half femal kill gestat prefer dai expect date parturit fetus remov caesarean section examin remaind femal allow litter rear progeni perinat studi conduct speci dose cover period gestat end organogenesi parturit extend period lactat wean number anim adequ number anim dose level enabl valid assess made except primat minimum number dose level suggest embryotox studi pregnant femal rodent pregnant femal rodent fertil studi femal male perinat studi pregnant femal speci suggest adequ number dose anim control clear conclus drawn studi hous diet full detail hous cage condit anim full specif diet includ addit provid pharmacokinet conduct reproduct studi account pharmacokinet drug pregnant anim level exposur fetu drug determin technic evalu examin made fetus anim dose period embryogenesi anim kill fetus remov caesarean section anim number corpora lutea implant site visibl determin special techniqu salewski method resorpt weight sex individu fetus record individu fetus examin extern abnorm adequ examin skeleton viscera made fetus obviou abnorm found examin conduct special attent paid abnorm high number resorpt studi teratogen effect earli stage pregnanc fertil studi femal kill period gestat fetus deliv caesarean section inform record number corpora lutea implant site resorpt weight sex individu fetus individu fetus examin skelet viscer abnorm anim dose fertil studi allow litter rear progeni stage wean larg number progeni subsequ investig allow live reach matur late effect drug progeni term auditori visual behaviour impair assess reproduct function determin progeni allow male femal litter dose anim breed produc litter brother sister mate envisag femal dose pre post natal period allow litter spontan progeni examin wean anim kill end lactat subject autopsi examin circumst progeni allow live reach matur reproduct capac assess late effect drug progeni term behaviour visual auditori impair determin conclus investig requir draw conclus result studi indic evid advers effect drug reproduct function evid advers effect reproduct function data inadequ draw conclus studi omit investig justifi omiss appendix durat gametogenesi rodent studi dose male minimum dai femal minimum dai prior mate anim dai ag commenc dose present stage knowledg time regard accept annex iii carcinogen potenti note guidanc applic chapter part annex direct eec view grant market author drug strongest evid compound carcinogen hazard man epidemiolog human carcinogen found carcinogen experiment anim evid substanc carcinogen anim carcinogen man difficult declar compound carcinogen man shown carcinogen anim studi extrapol man difficult arbitrari procedur ideal analyz mechan involv increas incid experiment tumour determin mechan involv specif biochem pathwai format proxim carcinogen applic man criteria extrapol base vari agent consider project dosag mode administr hand speci site incid tumour requir test dosag likelihood carcinogen risk man increas high yield malign tumour involv specif tissu test anim test substanc rout man dosag equal lower induc minim toxic good evid threshold level increas yield benign tumour malign tumour higher dosag reduct latenc interpret constitut risk man circumst agent gener regard potent risk easili reconcil benefit therapeut compound requir carcinogen studi carcinogen studi requir circumst medicin administ regularli substanti period life continu minimum period month frequent intermitt manner total exposur similar substanc chemic structur suggest carcinogen potenti substanc concern due specif aspect biolog action therapeut class member produc posit carcinogen result ii pattern toxic long term retent drug metabolit detect previou studi iii find mutagen test short term carcinogen test carcinogen test regard substanc question patient life expect shorter chemic reveal carcinogen hazard man circumst alter drug varieti condit carcinogen test insolubl substanc absorb requir formal carcinogen studi speci strain select carcinogen studi requir conduct speci metabol handl drug speci prefer show similar metabol man cogniz speci strain respons similar chemic speci strain high incid spontan tumour format avoid undertak studi select speci strain sensit carcinogen posit control requir routin spontan tumour incid strain record dosag rout frequenc dose dose conduct propos clinic rout administr relev evid absorpt provid frequenc dose daili dose level carcinogen test conduct dose level top dose produc minimum toxic effect weight loss failur growth minim target organ toxic target organ toxic demonstr failur physiolog function ultim patholog lowest dose order time maximum human therapeut dose dose produc pharmacolog effect anim middl dose geometr high low dose except principl occur toxic dose drug high multipl therapeut dose circumst accept top dose set approxim time human therapeut dose technic feasibl practic featur anim good gener health initi maintain studi high standard anim husbandri essenti special precaut inhal volatil carcinogen test pharmaceut qualiti batch es character ag anim commenc studi carcinogen studi commenc wean anim accustom diet surround durat studi recommend practic conduct studi month rat month mous hamster surviv rate high advantag extend studi month rat month mous lifespan anim surviv control number anim group routin test mice rat hamster suggest sex anim treat group control group sex dose vehicl rout case drug administ diet composit diet commerci diet variabl step provid uniform diet durat carcinogen studi full specif diet addit monitor carcinogen studi design obtain maximum amount inform anim investig undertaken elicit addit toxicolog data prejudic prime purpos evalu drug carcinogen potenti inform absorpt distribut metabol drug drug accumul enzym induc determin toxic studi statist design studi experiment design select cage anim treatment control group distribut anim hous elimin bia due effect local environment factor ii anim alloc random experiment unit cage method achiev random state iii practic reason handl larg number anim decid stagger start studi desir group repres start equal number studi conduct stagger start time batch anim enter studi state termin investig autopsi full autopsi made anim dy studi kill poor condit conclus studi surviv anim sacrif full autopsi conduct anim previous demonstr toxic effect topic investig haematolog biochem investig help interpret lesion found histopatholog carcinogen screen microscop examin carri list tissu organ high dose anim control ii tissu anim group macroscop lesion kind found autopsi result tumour occur organ tissu iii tissu organ examin mid low dose group macroscop normal list tissu microscop examin anim dy kill studi toxic screen previous demonstr toxic effect aspect investig haematolog biochem investig help interpret lesion found attent paid site applic drug administ oral rout principl report carcinogen studi definit neoplasm tumour regard popul abnorm cell uncontrol increas prolif activ defin morpholog function featur malign neoplasm invad surround tissu metastasis gener term tumour consid benign malign basi histopatholog appear correl pathologist charg biolog behaviour previou experi occur tumour displai compar characterist tumour convent histopatholog term welldefin classif present data instanc find summar treatment group control group separ keep sex separ term number anim examin individu gross microscop examin number percentag anim tumour identifi type tissu distinguish malign benign tumour frequenc distribut total number tumour found anim tumour type total number malign tumour found anim tumour enumer grade multipl tumour time interim death time appear mass start clinic palpat progress eventu histopatholog analysi data form analysi test statist signific type data basic experiment design statist procedur state respons assess wai total incid tumour bear anim ii total incid tumour iii incid tumour involv specif tissu iv incid tumour judg malign latent period tumour appear actuari approach analysi direct assess presenc effect substanc studi shown contrast respons treatment group set respons control group set assess effect dose relat shown trend respons low mid high dose group assess statist independ profession statist advic order assess influenc factor death test anim diseas prematur kill anim clinic detect tumour test statist signific assess presenc effect dose relationship intention data experi requir approach data test substanc regard potenti increas risk neoplast chang respons materi increas latent period materi decreas compound regard possess power activ anim respons affect evid dose respons presenc effect rais incid tumour treat compar control anim signific mechan postul defin develop tumour circumst identifi remark exampl includ pathwai peculiar speci griseofulvin porphyrin metabol mous sever stimul endocrin gland dog develop physic featur peculiar test speci vesic calculi rat circumst result increas incid reduc latenc malign tumour ii increas incid benign tumour iii local induct tumour site inject short term carcinogen studi evalu compound mutagen screen desir techniqu involv short term test chemic mutagen carcinogen capabl replac formal carcinogen test anim mean evalu drug carcinogen potenti short term studi give posit result formal carcinogen studi drug develop give neg result preclud formal studi advis reason paragraph conclus conclus studi drawn investig appendix list tissu studi histolog carcinogen studi gross lesion tissu mass tumor includ region lymph node blood smear case anaemia enlarg thymu lymphadenopathi lymph node mammari gland salivari gland sternebra femur vertebra includ bone marrow pituitari thymu trachea lung heart thyroid oesophagu stomach small intestin swiss roll method colon liver gall bladder pancrea spleen kidnei adren bladder prostat test ovari uteru brain coron section level ey spinal cord annex iv pharmacokinet metabol studi safeti evalu drug anim note guidanc applic chapter part annex direct eec view grant market author drug introduct note concern time absorpt distribut excret drug metabol relat safeti step evalu drug data essenti assess level drug metabolit kinet blood bodi fluid organ obtain inform relationship target organ toxic blood bodi fluid organ concentr drug assess possibl enzym induct cumul drug repeat administr choos anim speci toxicolog studi basi similar man handl drug determin relev toxic studi man drug specif specif physic chemic properti drug substanc stabil prepar provid label drug posit label molecul specif activ materi state consider select posit label metabol fate method data level drug metabolit blood bodi fluid organ excreta obtain physic chemic biolog method investig justifi detail method valid reproduc includ specif precis accuraci studi time pharmacodynam effect provid addit inform label drug attent fact measur label bodi fluid correspond unmodifi drug includ label metabolit conjug attent possibl isotop exchang endogen compound speci anim speci studi laboratori pharmacolog toxicolog investig reason select speci preliminari studi kinet metabol drug human subject provid inform choos anim speci repeat dose toxic studi drug administr dose rout drug administr relat propos clinic drug rout select ensur absorpt drug relev human usag present result inform present item absorpt fraction absorpt kinet ii distribut princip organ tissu time bodi fluid iii blood plasma serum half life iv plasma protein bind character pattern metabolit excreta practic identif major metabolit vi rout time excret drug metabolit vii biliari excret major rout elimin possibl enterohepat recycl investig viii quantit account fate administ dose attempt ix possibl enzym induct investig enzym induct found relev context propos drug examin conclus conclus drawn studi context object paragraph annex fix combin product note guidanc applic chapter ii part annex direct eec view grant market author drug justif applic requir justifi combin activ ingredi propos fix combin product consid accept propos combin base valid therapeut principl individu fix combin assess potenti advantag clinic situat disadvantag order determin product meet requir standard protocol respect efficaci safeti potenti advantag fix combin includ improv therapeut toxic ratio result potenti therapeut effect simplif therapi result improv patient complianc disadvantag fix combin includ fact combin meet averag patient ideal formul individu accumul advers reaction combin principl consid ration half life durat action compon differ significantli necessarili appli shown combin clinic valid differ respect compon intend enhanc absorpt compon intend exert effect success inclus ingredi counteract advers effect compon consid justifi advers reaction commonli occur inclus compon intend produc unpleas side effect mean prevent abus undesir substanc critic dosag rang narrow therapeut index suitabl inclus fix combin indic indic claim fix combin product presenc compon justifi indic product formul dose proport compon present recommend quot indic quot recogn diseas state dysfunct state syndrom patholog entiti individu compon fix combin intend reliev simultan symptom diseas state proper regard individu symptom indic fix combin occur diseas treat symptom constitu irrelev safeti efficaci permiss distinguish extent studi requir case fix combin correspond close combin widespread provid reliabl document studi requir case combin essenti drug involv combin quantit composit unusu compon safeti studi anim fix combin gener rule perform activ ingredi proport present product studi requir compon extens safe human ident similar combin long period safeti combin document efficaci safeti fix combin product investig man recogn combin found bibliograph data accept case test combin clinic compon order defin role plai total interact possibl interact compon consid pharmaceut pharmacokinet pharmacodynam interact appear applic submit data establish interact occur recogn defin advers effect ground expect fix combin product substanti harm give rise frequent advers effect individu compon applic provid evid occur therapeut advantag combin increas efficaci outweigh disadvantag dosag combin product safe effect recommend dosag rang combin pack principl applic fix combin product appli assess prepar consist medicin product combin pack product intend simultan sequenti administr chemic combin complex substanc type dissoci prior absorpt activ compon regard applic provis fix combin substanc chemic entiti