commiss direct ec decemb amend council direct eec place plant protect product market commiss european commun regard treati establish european commun regard council direct eec juli place plant protect product market amend direct ec articl thereof annex ii iii direct eec set requir dossier submit applic inclus activ substanc annex author plant protect product annex ii iii applic precis detail requir inform circumst condit technic protocol data gener provis introduc order permit applic prepar file introduc precis regard data requir toxicolog metabol studi activ substanc provid section part annex ii introduc precis regard data requir toxicolog studi plant protect product provid section part annex ii measur provid direct accord opinion stand committe plant health adopt direct articl direct eec amend part annex ii section head toxicolog metabol studi activ substanc replac annex hereto part annex iii section head toxicolog studi replac annex ii hereto point introduct annex ii iii replac relev gener test guidelin latest adopt version refer annex case studi initi entri forc modif annex inform gener suitabl internation nation valid test guidelin absenc thereof test guidelin accept compet author point introduct annex ii iii word ad end refer made annex eec method consist transpos method develop intern organ oecd member state accept requir inform gener latest version method initi studi eec method updat articl member state bring forc law regul administr provis compli direct januari immedi inform commiss thereof member state adopt provis refer direct accompani refer time offici public procedur refer adopt member state articl direct enter forc februari articl direct address member state brussel decemb commiss rené steichen member commiss oj oj annex toxicolog metabol studi introduct inform provid provid prepar activ substanc suffici permit evalu made risk man handl plant protect product activ substanc risk man aris residu trace remain food water addit inform provid suffici permit decis made activ substanc includ annex condit restrict inclus annex classifi activ substanc hazard establish relev accept daili intak adi level man establish accept oper exposur level aoel hazard symbol indic danger risk safeti phrase protect man anim environ includ packag contain identifi relev aid measur diagnost therapeut measur event poison man permit evalu made natur extent risk man anim speci fed consum man risk target vertebr speci ii investig report potenti advers effect found routin toxicolog investig includ effect organ special system immunotox neurotox undertak report addit studi investig probabl mechan involv establish noael observ advers effect level assess signific effect biolog data inform relev assess toxicolog profil substanc test report iii context influenc impur toxicolog behaviour essenti studi submit detail descript specif materi mention section point provid test conduct activ substanc specif manufactur prepar author radiolabel materi requir permit iv studi conduct activ substanc produc laboratori pilot plant product system studi repeat activ substanc manufactur justifi test materi essenti purpos toxicolog test assess case uncertainti bridg studi submit serv basi decis repetit studi case studi dose extend period dose prefer singl batch activ substanc stabil permit vi studi actual achiev dose mg kg bodi weight conveni unit report dose diet util test compound distribut uniformli diet vii result metabol process treat plant result process treat product termin residu consum worker defin annex iii point expos substanc activ substanc identifi metabolit mammal carri toxic studi compon termin residu demonstr consum worker exposur substanc constitut relev risk health toxicokinet metabol studi relat metabolit degrad product conduct toxic find metabolit evalu result relat activ substanc viii administr test substanc depend main exposur rout case exposur ga phase perform inhal studi oral studi studi absorpt distribut excret metabol mammal limit data restrict test speci rat requir area data provid inform design interpret subsequ toxic test rememb inform interspeci differ crucial extrapol anim data man inform percutan penetr absorpt distribut excret metabol oper risk assess detail data requir area exact requir depend result obtain test substanc aim test test provid suffici data permit evalu rate extent absorpt tissu distribut rate extent excret test substanc relev metabolit identif metabolit metabol pathwai effect dose level paramet result singl versu repeat dose investig circumst requir singl dose toxicokinet studi rat oral rout administr dose level repeat dose toxicokinet studi rat oral rout administr singl dose level conduct report case perform addit studi speci goat chicken test guidelin commiss direct eec novemb adapt technic progress ninth time council direct eec approxim law regul administr provis relat classif packag label danger substanc part toxicokinet acut toxic studi data inform provid evalu suffici permit identif effect singl exposur activ substanc establish toxic activ substanc time characterist effect full detail behaviour gross patholog find post mortem mode toxic action rel hazard rout exposur emphasi estim toxic rang involv inform gener permit activ substanc classifi accord council direct eec inform gener acut toxic test assess hazard aris accid situat oral circumt requir acut oral toxic activ substanc report test guidelin test carri accord annex commiss direct eec juli adapt technic progress seventeenth time council direct eec approxim law regul administr provis relat classif packag label danger substanc method bi percutan circumst requir acut percutan toxic activ substanc report test guidelin local system effect investig test carri accord direct eec method inhal circumst requir inhal toxic activ substanc report activ substanc ga liquifi ga fumig includ smoke gener aerosol vapour releas prepar fog equip vapour pressur gt pa includ prepar enclos space warehous glasshous includ prepar powder signific proport particl diamet gt µm gt weight basi includ prepar appli manner gener signific proport particl droplet diamet lt µm gt weight basi test guidelin test carri accord direct eec method skin irrit aim test test provid potenti skin irrit activ substanc includ potenti revers effect observ circumst requir skin irrit activ substanc determin test guidelin sever skin effect produc effect exclud test guidelin acut skin irrit carri accord direct eec method ey irrit aim test test provid potenti ey irrit activ substanc includ potenti revers effect observ circumst requir ey irrit test conduct test guidelin sever effect ey produc test guidelin acut ey irrit determin accord direct eec method skin sensit aim test test provid suffici inform assess potenti activ substanc provok skin sensit reaction circumst requir test carri substanc sensit test guidelin test carri accord direct eec method short term toxic short term toxic studi design provid inform amount activ substanc toler toxic effect condit studi studi provid data risk handl prepar activ substanc short term studi provid essenti insight cumul action activ substanc risk worker intens expos addit short term studi provid inform design chronic toxic studi studi data inform provid evalu suffici permit identif effect repeat exposur activ substanc establish relationship dose advers effect toxic activ substanc includ noael target organ relev time characterist poison full detail behaviour patholog find post mortem specif toxic effect patholog produc relev persist revers toxic effect observ discontinu dose mode toxic action rel hazard rout exposur oral dai studi circumst requir mandatori perform dai short term studi rang find test conduct report result identif adapt respons mask chronic toxic studi test guidelin test carri accord direct eec method oral dai studi circumst requir short term oral toxic dai activ substanc rat dog report evid dog significantli sensit data extrapol result obtain man month toxic studi dog conduct report test guidelin direct eec part chronic oral toxic test rout circumst requir assess oper exposur addit percutan studi volatil substanc vapour pressur gt pascal expert judgment requir decid short term studi perform oral inhal exposur test guidelin dai dermal direct eec method dai dermal direct eec part chronic dermal toxic studi dai inhal direct eec method dai inhal direct eec part chronic inhal toxic studi genotox test aim test studi predict genotox potenti earli identif genotox carcinogen elucid mechan action carcinogen avoid respons artifact test system excess toxic dose vitro vivo assai mutagen approach regard gener guidanc import flexibl approach adopt select test depend interpret result stage vitro studi circumst requir vitro mutagen test bacteri assai gene mutat test clastogen mammalian cell test gene mutat mammalian cell perform test guidelin accept test guidelin direct eec method salmonella typhimurium revers mutat assai direct eec method vitro mammalian cytogenet test direct eec part vitro mammalian cell gene mutat test vivo studi somat cell circumst requir result vitro studi neg rest consider relev inform includ toxicokinet toxicodynam physico chemic data data analog substanc test vivo studi vitro studi metabol system previous vitro cytogenet test posit vivo test somat cell metaphas analysi rodent bone marrow micronucleu test rodent conduct vitro gene mutat test posit vivo test investig unschedul dna synthesi mous spot test conduct test guidelin accept test guidelin direct eec method micronucleu test direct eec part mous spot test direct eec method vivo mammalian bone marrow cytogenet test chromosom analysi vivo studi germ cell circumst requir result vivo studi somat cell posit vivo test germ cell effect justifi necess conduct test consid case case basi take account inform toxicokinet anticip exposur suitabl test examin interact dna domin lethal assai potenti inherit effect possibl make quantit assess herit effect recogn view complex quantit studi requir strong justif long term toxic carcinogen aim test long term studi conduct report relev data inform activ substanc suffici permit identif effect repeat exposur activ substanc suffici identifi advers effect result exposur activ substanc identifi target organ relev establish dose respons relationship identifi toxic sign manifest observ establish noael similarli carcinogen studi relev data inform activ substanc suffici permit hazard human repeat exposur activ substanc assess suffici identifi carcinogen effect result exposur activ substanc establish speci organ specif tumour induc establish dose respons relationship genotox carcinogen identifi maximum dose elicit advers effect threshold dose circumst requir long term toxic carcinogen activ substanc determin except circumst claim test unnecessari claim fulli justifi toxicokinet data demonstr absorpt activ substanc occur gut skin pulmonari system test condit long term oral toxic carcinogen studi year activ substanc conduct rat test speci studi combin carcinogen studi activ substanc conduct mous test speci genotox mechan carcinogen suggest argu case support relev experiment data includ elucid mechan involv provid standard refer point treatment respons concurr control data histor control data help interpret carcinogen studi submit histor control data speci strain maintain similar condit contemporan studi inform histor control data provid includ identif speci strain supplier specif coloni identif supplier geograph locat laboratori date studi perform descript gener condit anim maintain includ type brand diet amount consum approxim ag dai control anim begin studi time kill death descript control group mortal pattern observ end studi pertin observ diseas infect laboratori examin scientist respons gather interpret patholog data studi statement natur tumour combin produc incid data dose test includ highest dose test select basi result short term test time plan studi concern basi metabol toxicokinet data highest dose level carcinogen studi elicit sign minim toxic slight depress bodi weight gain caus tissu necrosi metabol satur substanti alter normal lifespan due effect tumour long term toxic studi carri separ highest dose level elicit definit sign toxic caus excess lethal higher dose caus excess toxic consid relev evalu made collect data compil report incid benign malign tumour combin clear evid benign tumour malign time similarli dissimilar tumour benign malign occur organ combin report purpos interest avoid confus terminolog develop american societi toxicolog pathologist hannov tumour registri reni nomenclatur report tumour system identifi essenti biolog materi select histopatholog examin includ materi select provid inform lesion identifi gross patholog examin relev elucid mechan action special histolog stain techniqu histochem techniqu electron microscop examin conduct report test guidelin studi carri accord direct eec part chronic toxic test carcinogen test combin chronic toxic carcinogen test reproduct toxic advers reproduct effect main type impair male femal fertil impact normal develop progeni development toxic effect aspect reproduct physiolog male femal effect pre natal post natal develop investig report except circumst claim test unnecessari claim fulli justifi standard refer point treatment respons concurr control data histor control data help interpret reproduct studi submit histor control data speci strain maintain similar condit contemporan studi inform histor control data provid includ identif speci strain supplier specif coloni identif supplier geograph locat laboratori date studi perform descript gener condit anim maintain includ type brand diet amount consum approxim ag dai control anim begin studi time kill death descript control group mortal pattern observ end studi pertin observ diseas infect laboratori examin scientist respons gather interpret toxicolog data studi multi gener studi aim test studi report relev data inform activ substanc suffici permit identif effect reproduct repeat exposur activ substanc suffici identifi direct indirect effect reproduct result exposur activ substanc identifi enhanc gener toxic effect note short term chronic toxic test establish dose respons relationship identifi toxic sign manifest observ establish noael circumst requir reproduct toxic studi rat gener report test guidelin test carri accord direct eec part gener reproduct toxic test addit organ weight reproduct organ report supplementari studi interpret effect reproduct inform perform supplementari studi order provid inform separ male femal studi segment design domin lethal assai male fertil cross mate treat male untreat femal vice versa effect spermatogenesi effect oogenesi sperm motil mobil morpholog investig hormon activ development toxic studi aim test studi report relev data inform activ substanc suffici permit effect embryon foetal develop repeat exposur activ substanc assess suffici identifi direct indirect effect embryon foetal develop result exposur activ substanc identifi matern toxic establish relationship observ respons dose dam offspr identifi toxic sign manifest observ establish noael test give addit inform enhanc gener toxic effect pregnant anim circumst requir test carri test condit development toxic determin rat rabbit oral rout malform variat report separ glossari terminolog diagnost principl malform variat report test guidelin test carri accord direct eec part teratogen test rodent rodent delai neurotox studi aim test test provid suffici data evalu activ substanc provok delai neurotox acut exposur circumst requir studi perform substanc similar relat structur capabl induc delai neurotox organophosph test guidelin test carri accord oecd guidelin toxicolog studi toxic studi metabolit refer introduct point vii supplementari studi relat substanc activ substanc routin requir decis supplementari studi made case case basi supplementari studi activ substanc case carri supplementari studi clarifi observ effect studi includ studi absorpt distribut excret metabol studi neurotox potenti studi immunotoxicolog potenti studi rout administr decis supplementari studi made case case basi take account result toxicolog metabol studi import exposur rout studi requir design individu basi light paramet investig object achiev medic data prejudic provis articl council direct eec novemb protect worker risk relat chemic physic biolog agent work practic data inform relev recognit symptom poison effect aid therapeut measur submit specif refer investig antidot pharmacolog safeti pharmacolog anim provid relev effect potenti antagonist poison investig report data inform relev effect human exposur qualiti confirm valid extrapol made conclus reach respect target organ dose respons relationship revers toxic effect data gener accident occup exposur medicin surveil manufactur plant personnel report occup health surveil programm support detail inform design programm exposur activ substanc exposur chemic submit report feasibl includ data relev mechan action activ substanc report includ data person expos manufactur plant applic activ substanc efficaci trial inform sensit includ allergen respons worker expos activ substanc provid includ relev detail incid hypersensit inform provid includ detail frequenc level durat exposur symptom observ relev clinic inform direct observ clinic case poison incid report open literatur relat clinic case poison incid refere journal offici report submit report follow studi undertaken report complet descript natur level durat exposur clinic symptom observ aid therapeut measur appli measur observ made summari abstract inform support level detail document confirm valid extrapol anim data man identifi unexpect advers effect specif human observ exposur gener popul epidemiolog studi support data level durat exposur conduct accord recogn standard epidemiolog studi submit diagnosi poison determin activ substanc metabolit specif sign poison clinic test detail descript clinic sign symptom poison includ earli sign symptom full detail clinic test diagnost purpos provid includ full detail time cours involv relev ingest dermal exposur inhal vari amount activ substanc propos treatment aid measur antidot medic treatment aid measur event poison actual suspect event contamin ey provid therapeut regim event poison contamin ey includ antidot full inform base practic experi exist case theoret ground effect altern treatment regim relev provid contraind regim relat gener medic problem condit expect effect poison expect effect durat effect poison includ impact type level durat exposur ingest vari time period exposur ingest commenc treatment summari mammalian toxic evalu summari data inform provid paragraph submit includ detail critic assess data context relev evalu decis make criteria guidelin refer risk man anim aris extent qualiti reliabl data base relev light find respect analyt profil batch activ substanc paragraph bridg studi conduct paragraph iv relev data submit assess toxicolog profil activ substanc manufactur argu basi assess data base relev decis make criteria guidelin justif submit noael propos relev studi basi data scientif reason propos establish adi aoel activ substanc submit oj oj standard system nomenclatur diagnost criteria guid toxicolog patholog oj guidelin good epidemiolog practic occup environment research develop chemic manufactur associ epidemiolog task group part epidemiolog resourc inform centr eric pilot project annex ii toxicolog studi proper evalu toxic prepar suffici inform acut toxic irrit sensit activ substanc addit inform mode toxic action toxicolog profil toxicolog aspect activ substanc submit context influenc impur compon toxicolog behaviour essenti studi submit detail descript specif materi provid test conduct plant protect product author acut toxic studi data inform provid evalu suffici permit identif effect singl exposur plant protect product assess establish toxic plant protect product toxic plant protect product rel activ substanc time characterist effect full detail behaviour gross patholog find post mortem mode toxic action rel hazard rout exposur emphasi estim toxic rang involv inform gener permit plant protect product classifi accord council direct eec inform gener acut toxic test assess hazard aris accid situat oral circumst requir acut oral test carri applic justifi satisfact compet author articl council direct eec invok test guidelin test carri accord direct eec method bi percutan circumst requir acut percutan test carri applic justifi satisfact compet author articl council direct eec invok test guidelin test carri accord direct eec method inhal aim test test provid inhal toxic rat plant protect product smoke gener circumst requir test carri plant protect product ga liquifi ga smoke gener formul fumig fog equip vapour releas prepar aerosol powder signific proport particl diamet lt µm gt weight basi appli aircraft case inhal exposur relev activ substanc vapour pressur gt pa enclos space warehous glasshous appli manner gener signific proport particl droplet diamet lt µm gt weight basi test guidelin test carri accord direct eec method skin irrit aim test test provid potenti skin irrit plant protect product includ potenti revers effect observ circumst requir skin irrit plant protect product determin test guidelin sever skin effect produc effect exclud test guidelin test carri accord direct eec method ey irrit aim test test provid protenti ey irrit plant protect product includ potenti revers effect observ circumst requir ey irrit test conduct test guidelin sever effect ey produc test guidelin ey irrit determin accord direct eec method skin sensit aim test test provid suffici inform assess potenti plant protect product provok skin sensit reaction circumst requir test carri activ substanc formul sensit properti test guidelin test carri accord direct eec method supplementari studi combin plant protect product aim test case carri studi refer point combin plant protect product product label includ requir plant protect product plant protect product adjuv tank mix decis supplementari studi made case case basi take account result acut toxic studi individu plant protect product possibl exposur combin product concern inform practic experi product concern similar product data exposur oper exposur risk plant protect product depend physic chemic toxicolog properti plant protect product type product undilut dilut rout degre durat exposur suffici inform data gener report permit assess extent exposur activ substanc toxicolog relev compound plant protect product occur propos condit provid basi select protect measur includ person protect equip oper label estim oper exposur aim estim estim made suitabl calcul model order permit evalu oper exposur aris propos condit circumst requir estim oper exposur complet estim condit estim made type applic method applic equip propos plant protect product take account requir result implement classif label provis direct eec handl undilut dilut product type size contain mix load oper applic plant protect product climat condit clean routin mainten applic equip estim made assumpt oper person protect equip estim made assumpt oper effect readili obtain protect equip feasibl oper protect measur label estim account measur oper exposur aim test test provid suffici data permit evalu oper exposur aris propos condit circumst requir actual exposur data relev exposur rout report risk assess health base limit exceed case result estim oper exposur provid point accept oper exposur level aoel establish context inclus activ substanc annex limit valu establish activ substanc toxicolog relev compound plant protect product accord council direct eec council direct eec june protect worker risk relat exposur carcinogen work exceed actual exposur data report calcul model data estim provid point case dermal exposur import exposur rout dermal absorpt test result acut dermal studi altern test provid data order refin estim provid point test condit test realist exposur condit take account propos condit bystand exposur bystand expos applic plant protect product suffici inform data report provid basi select condit includ exclus bystand treatment area separ distanc aim estim estim made suitabl calcul model order permit evalu bystand exposur aris propos condit circumst requir estim bystand exposur complet estim condit estim bystand exposur made type applic method estim made assumpt bystand person protect equip measur bystand exposur requir estim concern worker exposur worker expos applic plant protect product enter treat field premis handl treat plant plant product residu remain suffici inform data report provid basi select protect measur includ wait entri period estim worker exposur aim estim estim made suitabl calcul model order permit evalu worker exposur aris propos condit circumst requir estim worker exposur complet estim condit estim worker exposur made crop task carri estim made data exposur expect assumpt worker person protect equip estim made assumpt worker effect readili obtain protect equip feasibl estim made data gener amount dislodg residu propos condit measur worker exposur aim test test provid suffici data permit evalu worker exposur aris propos condit circumst requir actual exposur data relev exposur rout report risk assess health base limit exceed case result estim worker exposur provid point aoel establish context inclus activ substanc annex limit valu establish activ substanc toxicolog relev compound plant protect product accord council direct eec eec exceed actual exposur data report calcul model data estim provid point dermal exposur import exposur rout dermal absorpt test altern test provid data order refin estim provid point test condit test realist exposur condit take account propos condit dermal absorpt aim test test provid measur absorpt activ substanc toxicolog relev compound skin circumst requir studi conduct dermal exposur signific exposur rout risk assess health base limit exceed case result estim measur oper exposur provid point aoel establish context inclus activ substanc annex limit valu establish activ substanc toxicolog relev compound plant protect product accord council direct eec eec exceed test condit principl data vivo rat skin absorpt studi report result estim vivo skin absorpt data incorpor risk assess remain indic excess exposur perform vivo compar absorpt studi rat human skin test guidelin element oecd guidelin design studi account result skin absorpt studi activ substanc toxicolog data relat activ substanc copi notif safeti data sheet submit context direct eec commiss direct eec march defin lai detail arrang system specif inform relat danger prepar implement articl council direct eec submit formul inform submit oj oj