Document 3QNR3nD0ErnmjNOB3m2Q0j5a0
ATtotxaiccohlmoegnytsSttuodLieetstearntdoOCt.heArueIrnfdoartmeadtiMoanyon25P,F2O00A0 A
Teratology
1) Teratology Studyof T-2998CoC in Rats
2)
Oral Rangefinder Studyof T-2998CoC in Pregnant Rats, Riker Laboratories, Inc, Study No. 0680RR0018, February 25, 1981
b) IFnicn.alSRteupdoyrtN,oO.r0a6l8T1eTrRatOoLl1o0g,yDSetucdeymobfeTr-1259,91898C1o,CwiitnhRAatmse,nRdimkeerntLatboorFaitnoarlies,
Report, December 22, 1981 and Protocol
2) Teratology Studyof T-3141CoC in Rabbits 2) OIrnacl, RSatnugdeyfNion.de0r6S8t1uRdBy0o3f31T-,3N1o4v1eCmobCerin18P,re1g9n8a1nt Rabbits, Riker Laboratories,
b)
Final Report, Laboratories,
Oral Inc.,
TSetruadtyoNloog.y0S6t8u1dTyBo0f3T98-,31F4e1bCruoaCryin2R3a,bb1i9t8s2,
Riker
) 3WiMntIenrtetomaDlRCoRrircekserp,onddaetnecdeFreebraunaalryyti5c,al19a8n2alyses of T-3141CoC, from LD
3)
Letter re `Franklin
fDu.rtGhreifrftietsht,idnagtferdoNmoEv. eMmabresrha1l9l,
Johnson, 1982
Jefferson
Medical
College
to
Dr.
4) M3aMyM2e6,mo199re8,FeCn9c5laonsdian1n4g3aTnearlaytsoisloofgty,hefreoymeMlaenrsvdCeafescetto Georjean Adams, dated
.
7
02025
oral rangefinder Study of T-2996CoC in Pregnant Rats
Experiment No.: Conducted at:
Dosing Period: Study Director:
ossorso018 RSitk.ePrauLla,borMaitnonreiseost,a Inc. January 20, 1980 to January 29, 1960 E.G. Gortner
ESBeBend aTyateer SReinziaolr RTeesreaatroclhosyTecRhenporloodguicsttion Stusy Director
E3G0.0mTamAprefcnaem, pBsWd,dFD2/247B8ate Research Veterinary Pathologist
Psp 7
2
ANanrager, Pathooelogy-Toxicolosy Tw
Satets Evaloacion Laboratory
C3026
1
.
Introsuction
ihT"iieuystiyovrEwaEaatlsa1rsapainno0dgn0es0vfocairosnecgdecrofbonyrdsutMcuatdseyCudobmsbvmeayesqructeihcnaeotlndSuoCacrhfeteeletmdyictateSlorvaatDdloiuelvstoitessiryioionnns,ecLuadbStyoth.reaitunPoparpuryela,r,te.RdoiskeeTthe
ieSemoetroaafttdonnrrceieseswf,iotrhIsntuchc,eh SSstatefuedtiFyeass.lD,vaWlmiuemsnteissotonotrsaL.gaeboTrlhaoetcoartsyit'ousndySfwotarasndtachreodndsuOacvpteerddaattaiinngand
TLaoboonrsatootry'tshereficnoarld raerpcohritvesi.s maintained in the Safety Evaluation
Nethots
RIFihtviierrrtcyr-fisenieixdniatntiegmleyL-aabrtoeermdavteoSdrpyrfawrgeourmee-tauhvseleedsyhiidnpepritihnevgedsbtouxfdeeysm.albeyThArenaitmsaanlifmraColmasreCwhearreles
SSSeoefnraeoirgnmreearspasatndbtyhePlvaetcrotepiscaanildn vtrhooewrsk.iTancgkThdeoofwnf.caatgseTsavteefrreromhtohuetsheeSdtuldeifyntdiDtvioirdeucratilosrlhytasisnigned
TCSeeamntpseeirrnagvteursreee.aianavdnaedislsahbulmseitdeiealtdyclcaiogbeinstturmov.iltlhedThueirroeolmi.mgehsthsPurfwilenroaeorsoLnabanoadra1tf2orrohnyotusrChoinw &nd
Lioht/aack cycle.
hToer 577
1aa2bn,n7no9ar5lmsaalndvecrl2e0inioocfbaslesrevssetidgantsid.oanilByaonddfyrotvmheeidgarnyattss3
twdehorrseoedugrheaccodcraoydreddi20nognolfydaugyesssitnag3.tio6,n
ii1nn0s0c.uo7ir7nn5t.%od5to0seoarndvo25laudmmaeian/oikfstae5aryBadLt/odkagirolfoyupbbsoydyoorfwale6igcihanttt.suboanTt-io2dn9ay9s8aCtcCdotvshaerssougosfhusp11e55n0,doefd
SJKeristiiuiametasitoibnoy.ncoenArvitcchoaenltsoadlmieslgocracovauatp.ioonfOn6anrddaaytesac2h0reoucfteeirvgueesds,taotniilnoycnlcuodtrhinengroaiitltssbvyceoronertaelnts,
lTGae6sc5a0ueTsxReaOm0i0tSnueodanpdriemve0i6do5iu0asTtRaItlOeyIr0s)ttoowlidotgahytecsrhtieunmdeiiceasilfl(ytRhierkeealrnaitBmeradplercvioazmsepnotupnrdeNgsonsa:rnets.ulted in
fJeetrueseaslseittnakecnerAattogdaeynic20cohfanggeesstaitniotnheanldensexaofmintehde efoyre,ey&efev fetuses
Sonormaiities.
EBfilroooeontdtShseaomepslaemasendfaartcosmdoatnyhre2dea0yorfa20tsgeofsitnacteeisaoscnah.tidoonsL.eivegrTroeusppepwcleiarnsemeanstasvkaeemrpnelebsaelfsaoornedtatlknieevner
hectnns vere frozen and submitted to the sponsor.
Romsies ans piscussion
TeGTohei"esgtahaotttreiaolgnad)aiundrmiaionincgdicsunttrhorertaetpdrieeorbsnieuoltdtwofeoeifTnn-2doa9rang9yya8snCdooe6gCaetanhnaestd.si91s50Ao,f(dtago1ye0xs0si,ct6at7s5itt,ofhner5co0tuignhoofrth12e5r5eod1mfu3gc0/ekdg/bdoadyy 23/ks/any done group (Table 1). he tuo nonpregnant 150 ma/kg/day Tate had a more severe effect on body
2B riekteirnExperiment No. 0630RAO018 .
03027
2.
wESaeyvieghthureioynnadrlayoysti9nacoofcnotnitsnhieednecsretaubdolynedtaahmyasnount1th1,eofp1r2weegainngadhntt13.ahingdhThoendeospervaesgdnaamosnbtse(rdAvapempdsendotfiox
TChleini1c0a0,l s75i,ons50aannddga25inemdg/kwge/idgahyt daotsecogmrpoaurpasbledidlevmoetlshatvoethaebno0rmmagl/kg/day
group.
mFao/ukrg/faentyusedsosewergerouepxsamifonredeyferomchaenagcehs.of Soctioned had eye changes consisting of
AfLoLurofdamtsheinreatdheabl1e50featnudse25s one or more of the following:
AJaueyvoeremthalrreoinutsgihecsltehfeotcscl,aerndrsaerdokrisndtirsteohaerkgasrnauinnezneidlnoglceanotsnieo-nfhiaablsefrstthoo(sTetahbroleebes-e2qr).uvaerdtTehirens ltohefenstthueo
pBort5eu0vdTiyRo0ua0sp1p0et)aerroeandtoclmhooegrmyeicspatrluoldnyioeusnrcele(adRtiektdehrancoEmxippnoeurtnihdmese.nptrTehNveoiso:uasbno0srt6mu8ad0liTieRts0.i0e0s8 Ianinndtthehis
pPeronemevoiromfuaislbiertssytudwfihoeirscm,hingtahpeptehetaerreeadmtbortgyoeonnbiaecl aenlfefnasercrtensuwtcalseiunas;dedvefevolelollpoompwemenedtntbayolf seetyhceeondparriymary
aGebneerrcaaltimoonrsphooflotghiecasleccohnadnagreysloecnscurfribeedrinofthtihse rfeatnaglefinuncdleeruss.tudTyhweitshame
7-2998C0C.
conclusion Ttthenereato1ob5lj0oegncygti/vkseat/uddoyafywdaedstoesmeremtilneivinengl thawniosuulpsdtpuebdrey.daonseTahpeplervaoebplorvieafotreresahnuilgtohsradlsousegrgaetisnt athraatt EGSaeeirrnaa.ttoolgoeIgnnyicadstdeaifdftyeicotbnecotfaoustleehnesoftoaxbtihnceortemofaxflieiccttyefovfafsecrteodbosufecrevrdeeddbuocdayenddwebiiosgdyhltiwkeegilagiynh,ttotbhee reproduced in a teratology study.
003028
BESTCOPYAvAUABLE
Tabie 1 oral RaingnefinBoddeyr WSteubdgyhtofGaiTn-s29o9f8CporCeginnanPtreaRmaatnst Rats
With Standard Deviations (3)
ee ge Bay ese = ax an ze
control 150 mg/kg/day 100 b/kg/any 75 ma/xs/tay
Swe oaae
Sahau re 1dneadn Claeasl
fwem dzee anve gseuaa naerizwaa wa0eazams ane dorw an1npaze
50 mg/kg/day
SauOEin TE T2rv anvei
25 mg/kg/day
24 16 aa an s2
2 gignificantly higher than the control (Dumett's test p <0.05)
03029"
a
Table 2 ROartailosRaonfgeFfeitnudseersSwtiutdhy BoyfeT-Ch2a9n9g8eCsoCtionFePtruesgensantExRaamtisned
High Dose Grow (150 ma/ke/ay)
16/16
Low Dose Group (25 mg/kg/day)
150152
2 Fonoeurfefteutsusneosteexxaamniinneeddfbreocmauesaecheyoef afrocuhritdeacmsture destroyed in sectioning
02020
a satin surs , etnn pBarEneSmTiaCoOtnPssYAVAMABLE .. it robis 9 nm or
a J ro m DBSe eo em.
03031
BESTCOPY AVAILABLE on miaststoyLriSsTsm vemr smoy woneins a ---- EY-- eeees-- cam-- [ -- A --
. 03032
appendix 3 (oncinded) BESTCOPY AVAILABLE . ocat Rangefinder Seudy of T-2998Coc in Pregnant Fats IndividuSahlanBdoedryaWeDiegkhatsro(n5) foarndPHreeamnanBsodyTatWseishs
JR TEs nn sa srs fmRaiebe iRGmzOAaoRme eGsnNas mEsPse mOseZrEozoseiia modaeer HMMEROEED ODaSEE EoDEODOEIRDZ E I O a oa E oal Stelveriev aabmd 1s5e6 4s0e0 cseed sseede heee
TT. ts mer wn w= ct some-- 25 nares sHSiEpIEsOeIzE aOaeEe aEfmesDIz2Ee zBRnEIaMEed mEmE SEe EIR oallED EJOE EDS stenvt enev 2a5a a5zor6 4z8e3n a5zee om8oT AEzor NEN PREGHFNT ANIHALS sik ne as aes ms zee wes am
.
}
03033