Document YawMg7Nk5zZor09wv6K0L0r0

2 70% PREPCTEIVC3E: WIECT29 Mili: 01 AR226-1542 STATUS REPORT COMBINED REPEATED DOSE TOXICITY STUDYWITH REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENINGTEST WITH T-7601 ADMINISTERED BY ORAL GAVAGE IN WISTAR RATS November 4,2003 8:25AM NOTNOOXTOSXubPsrtoajneccte31815377167818 Page 1017 . T7601 NOTOX Project 385717 `SUMMARY OF RESULTS SSttaurdtymasttianrg: 2014.4Auluygu2s0t023003 NDeelcirvoeprysyofoftemrises 21871A0u3g1usAtu2g0u0s3t 2003 Necropsy of females and pups 01 to 05 September 2003 location: Group. moDkogsbewliedvealy| | FomNaulmebser|ofaFnoifmeamlesl_es_|| Animalsnumbers males | femaies | | F 2T Ts 0T 10 t"0 to | orto rao | ats | | sie0 | Fs4 Tso 1000T10 0 [Ho 0 T3 3 1| |4 0 7s1t8r0 0o || MORTALITY GGriooupp21: NNoommrotraalltityy.. GGrroowupp34:: 7MFaeolmfeatlr3ee3at6wm5aenswta.fsoMukanildleedd3ei8andweaxotsnredKmioliylsed1d2iuneoeftxroreeparmtomilesanptos.nedMoaafylteh2e434uotfwerracusastfumoseutnntad.fdtFereadmdealoilnveerd7ya7.y a29sofktirleeadtminenetx,tremis on day 14 of treatment. Female 78 was found doad on day CLINICALSIGNS 11, Tgrreoautpm(e1n0t0r0eolaktoed).clinical signs were noted in the mid dose group (150 mg/kg)7and the high dose Al 1000 mg/kg, these consisted of lethargy, hunched posture, uncoordinated`movements, |\ 7 dssweaelcilrvieatnaigsoneo,dfctlhhorecoogmmeoondtiaoacrlrayrcoetigrvitiothnyo,aeqanudiocfakbthdbeoremeaeytneh,iangnp,dlolseanrboeoucuttr,eoldne,raenrsepadiprdpaietsiacoronal,onrucarelaetasi,nodnswopaftlouslriosi.wner,esdpairramtoieons,, | Nl At 150 mig, these consisted of saivation and diarhosa. AhRilasoltpooersicciaaanldwcoasnastlrovoabltsdieaortnvaeowdefrraeattaasiolsfoowotbiinssceisrtdvreeanidcneiananttdh1ea5og0tehaetnhrdagt1ra0oru0ep0sh,moguhisokewgde,vTaehnridsartiesaawtmietuhdcinhuntlhdoeweemrhiteisncoifdence conditions of this study. FUNCTIONAL OBSERVATIONS Nstorecnhgtahngnesthweetrreeaotbesdearnviemdalisn,hewahreinngcaobmiplay,repdap(iollcaornytrroeflleaxn,imsatlasti.c righting reflex and grip The variation in motor activity id not indicate &relation with eaiment, Page20f7 . T7601 NOTOX Project 385717 BODYWEIGHTS wsBieogidngyfhitwceoaisngst.hytdseacnrdeabsoeddydwueriignhgttgraeiantmoefntm.alSeevseorfalthmea1l0e0s0imgth/iksg0rdoouspe ag1rso6uSphwoewreedstsaetvisetriecablloydy hbFioesdmyaplewreeisoidg.ohftBtghoaediyhniwdguehreiisgnthgdstooshfefpgerrmeoa-ulmpeasisnhofgowtpheeerdihosdit.gahtTeisshttricedaeollsfyeesmi0agrnloieufsipcaawlnestrloyesdh8eo1cw5reedadesacerdbeabosoyeddywedwiuegrihigtnhgt1s55asnd opfrefgemnaalnecsy ianntdhilsacgtraotuipon.. Ths decrease was not statistically significant due to he Imited number mNoatgreabtomdeyntwerieglahtteddaye.ffects on body weights and body weight gain were observed a 50 and 150 QOD CONSUMPTION dpFueorroiidondgc.opSrntesa-tuimmsapttiticianolgns(iamgnanldiefrieaclanandtcievfeewma1a0sl0ed)r,ecaoacnnhsdeudfmprfoirfiofooondowdceocrnoesnusdmuepmctpriteoianosnedduarndiudnrgpirenolgsatttihmveeatc1io0nm6gpdlce(otmneasleuemasp)ttmaineodnnt lactation (females). mNiodraenadtlmoewndroasetegdrouepffse.ct on food consumplion and relative food consumption were observed at HAEMATOLOGY hTihgehefsotlldoowsineggsrtoatuipstaictatllhyeseignndifoifcatnrteaditfmfeenrtences of haematology parameters were recorded in the + increased eryiocytes count (males and females) ++ + iinnccrreeaasseedd increased mhhaaeeeammnoagtclooocrbrpuilsn(cmcuoalnlacreesvnotarlnaudtmifeoen(mma(almleaesls)e)s and females) +inicnrceraeasseedd mmeeaann ccoorrppuussccuullaarr hhaaeemmoogglloobbiinn c(omnacleenst)ration (males) increased ed cel distribution widh (males), These findings were considered to be treatment relate crIenhcatonhrecdee5d0. mAgsikngoddoossee grreloautpioansshtiatpiswtaicsalolbysseirgnviefdi,cahntilsyfiinncdriengasweafos cpoantseildeetrsecdo(u0ntbeinCfaeumsaeldesbywas No other statistically significant efects upon haematlogy parameters were noted. Page 307 . T7501 NOTOX Project 385717 CLINICAL BIOCHEMISTRY. iTnhtehefohlilgohweinsgt sdtoatsiestgicraolulypsaitgntihfeiceanntddoiffrfaeirmeennctoe:fs lncal biochemistry parameters were recorded ++ iinnccrreeaasseedd aallkaanliinneeapmhionsopthreatnassfeer(amsael(emsa)les) + + iinnccrreeaasseedd turriegayc(emraildees)(males) ++ iinnccrreeaasseedd cihnloorrgiadneic(mpahloessp)horus. ++ ddeeccrreeaasseedd abislpiarrubtiante(faemmianloeisr)ensferase (females) + increased albumin (females), These findings were considered to be treatment related. crIoenlnoarstgiiadonenirscheidpphtooorsbpceohororfreulnasotiwtvaoexsifcidoneldcoigrniegcsaaslweesdrigeinninfaoillcleatndrc,eea.tthmeeInntorggraonuipcspthootshpehosraumsedeexctreneta,seSiwnacse no dose MACROSCOPIC FINDINGS cAotntnreolc,ro5p0s,y,15re0sapnedci1v0e0y0, mthgrheke,gfdoours,esgervoeunpsanwderfeifaefefnecatneidm.als (out of twenty anima) in the YTFeoitu.srsfhmioanudlilendsgrwienavteshaelnohwtihgeohbteshseetrrdvtoehsdisenfgirntdohiuenptghaipseproefgatrrooexuidpcsot.looHhgiiacsvatelopsyaietglnhliooflwioicgsayhn,cneh.oadtuhlaes(onson)t tbheeeenpipdeirdfyomrimdeesd. acTanhndrneileebfatanimisamenaddliasbnuodlfatsrhheyomw1p0eh0dn0oimsdogel.aktgeMdaddloaesrek34grrewodaufspopcdauirsedtoysnpctoahnnetniatvnhaeylomiususesld,y,.dsaMhakolwreee3dd3dbiewsgacisonlnopiaunrrgtaltayiuotnoayfsilsu.ngs gFreiedamdnaidlsgehrd7oi8wsncsohtlooowgureeatdthiedoranorwkfihrtehtdehedsitksiocdomnlaeoycu.hraatniodn moaf ntyhedmaerskernetderfiocciyomnpbhotnhosdiedeasndof tthhee etfryamdursenal dtTihwsioccokalenoniuemrdaedllismcioatfeinctghuermi,1dg0ae0c0coefmntgthiuekasgttegodrmloaoucbphu,lwaearrnpeartketigelurelndaoirfnsteuhxretfrveaemcires,.ofeMntalhaelrefgo3erd8e wsIvtaeosrmaaecnmhad,cairaretkecdir,sehdshcoonwteedntas corfattheeriufroirnmarryetbrlaacdiidoenrs.. Female 77 was emaciated and showsd a fore stomach wih many pInihet150 mgkg dose group, female 65 was kiled in exremis and showed a prolapseofthe Page dof7 . T7601 NOTOX Project 385717 KdIiindscncieodyel(nostu)ar.latfriieondnddioinfsghsthdteihsatcthoywlmeouurrsea,toidboasnrekorfvrteehddediGinsutcohoedloehunirugahmtei,sotnwadotfoesrieyg-hgctrlmeoaaurnpdciiynbscutllsuadorendltyphemelpvuhitcneroduidsle,a.trioendodfisthhe. tIhncyimduesn,taslefvienrdailngrsedodbissehrfvoecdi ionntthheyomtuhse,rliggrhoturpesdcdoinssciosltoeudraotfioinsoofltatheec/tmhaynmyusd,ardkarrekdrfeodci on the dliivsecr,olpoeulrvaitciodinolaftitonhoefltihveer akniddneryi(ghst),maanldopiebcuilaarinltyhmrpohatnroedgei,ona,cicseonltauteadt/esdevleorbaullagrrapya-ttwehrinteoffotchie.on galdarnednsa.l glands, exophtaimus of right eye, constricted spleen and several tan foci on the ciloral ``ocfTohnnedosiettiofoxininscodoiflnotgghiacrsaelsotsbuidgsyne.irfviAceladntchieen.riantcsiodfentchiesoabgseeravnedd,sttrhaeisnethsaitgnasrewheoruestehderaefnodretrceoantseidduenrdeedr(t0heb.e "grTohuepf.inTdhiings ofifnadninugtiesrrueslcatoendtationainngofelusitdr,owuasscyncolteesdtfaogrefaenmadltehe7r1efaonrde 7a9phoyfstihoelohgiigchefsintdidnogs,e. ORGAN WEIGHTS teInphiytdhmieudshyimwgiehdieegsshttwdseorasfeensgetrcaortiousppts.iyc.amlalRlyeeslsiagtsniihvfoiecwoaenrtdglaysntianwtciesritegiahcsatelsdl.yosfibgrnaiifnic,ahntelayrd,eicvreer,assepdlebeon,dytewsetiegsh,tasnadnd Tabhseolfuetmealaendbordelyatwieviegihvtesrowfetihgihstgsraonudp wreelraetivaeishoeasrtattwisetiigcahltlsy swiegrniefisctaanttilsytidcaelclryesaisgneidf,icaanntdlytheir iTnhcerseaeseadb.errations could be caused by the reduced body weights, however, for a correct innottearvpareitlaatbiloenywete. have to take the histopathologic results into account. Unfortunately, these are gNroousptsa.tistical significant differences in organ weights were observed in 50 and 150 mlkg dose MICROSCOPIC EXAMINATION No results available ye. Page5of7 : T7601 NOTOX Project 385717 REPRODUCTION Table I. Reproduction Data "Naber of females paired Mated Pragnant Liters with ling pups CoGnitrool1 10 10 0 10 SGormogwh?a 10 0 9 9 G1i5o0wmpg3kg 0 10 8 s 100G0iomwgpdkg s 4 3 All females mated within four days of pairing. bRyepfroourdupcrieognnaonfcifeesmaoluetsooffntihnee 1m0a0t0edmfgekmagledso.seOngreooufphweassenpergeatginvaenltyfaeffmeaclteeds.fTehmiaslwea7s6)shcoowdn Ssaploenwtsaknieosutasilnyinogn. dAasya1r2espuolsl-ocnoiytuvme;eallniteecrrsowpistyh tvhiisngfepmuaplse wsehroewerdeciomrpdleadntianttihoinsigreosupa.tTehris ggraovuep.ise toa decreased fertiity index, conception rate and gestation index In the highest dose Reproduction parameters up to 150 mg/kg body weight/day were found to be within normal limits. BREEDING DATA Duration of gestation was not affected by treatment sIntaatllisttriecaatlmseintgngfrcoaunpts,y dpoesctrneaatasledlovsisbwilalsysitnadtiesxtifcoarllayilsrigenaitfimceannttlygrionucprse.aseHdo.weTviesr,retshuelsieed in a f1i0n0d0inmgsg/wkegr.e considered unrelated to eat ment at 50 and 150 mgkg, and are dificult (0 asses at A(cLoSn0siastnidng1o5f01m3 gpu,psiantc5r0eamsge/dkpgosainndata5lpluopsss awfa1s5m0aminalky)d,ueantodtahse tlhoessnoufmobneercofomIvpnlgepluiptser oinnddeaxywe4roefrleagcaatridoendwtoasbecounnsaifdfeecrteeddtboybethneotremsatlf,etmheacthtahnegseesdoinsepolsotvneast.al 1035 and viabiry AHLow1e0v0e0r,gnker,s sitesemdisftcoubte0aatsesnedsesncbryefeodripnogodrabtraeaesditnhgispgerrofuoprmcaonnsciestrsegoafrodnilnyg3potsetrnsa.tal ss between days 010.4 post partum. Page 6 of 7 T7601 NOTOX Project 385717 BUPS dMeecarneabsoeddyowneidgahytss 1ofapnudp4sdpuerringgroluapctaitnitohn.e highest dose group were statistically significantly dInayth1e (5f0emmagllekgpudposs)eagnrdouapy, s4ta(timsatlicealalnydsifgenimfailceanptulypsd)e.crTheiassefdindbiondgywwaesignhottscwoensriedmereeadsutroebed.on otfrehailsmteonrti.carlelcaotnetdr,olsdiantcae. pMuopreboovdeyr,wenioghdtossei-nrtehleatcioonntsrhoilpgwraosupnowteerd.e very close to the upper mit Other effects upon pup body weights during lactation period were not established. iClnicnriecaasleds.ignFsinwdeirngesncootnesdisitneadllogfroauspmsa,llb,utcotlhdeoirncpaildeenacpepienatrhaenc1e0,00anmdg/liktgegorronuop mwiaks. sOlingehtlpyup oMfatchreosccoonptrioclegxraomuipnasthioowneodf panupasbsreenvteatlaeld small appearance, no milk and cannibalism. The oinbcsiedrevnecdedoefcsrmeaallsepdupbsodwyawseiignhctresansetdhisn gtrhoeuhpi.ghest dose group. This corresponded with the Page7of7