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Oral Rassintipnrdeegsnansttamtsatoefr29990 i ---- Conducted at: -- E Study Director: cssonscors : SRSiaNefsep,tyaSaEyvesahmluueaartsiiioenonnLaaboorratory Febeuary 1, 1581 co mare 13, 4 E. G. Gortner .; $ MS[ SuEsSpyTEmeTeer?A reesI eeoloCsoipsnatsgr RE[escrIr ee ]Sa eema 6-2 nn i NSMaeneraeeiiaamlr+eB lalo,an Tvn Soovciioeens sityoonny a 004182 Introduction 1 SUaTenhoeisspcoehoonrngaaeulcccrhoresacddpgbpfeyyofritMnhandeersCuobmssmteeuqrducyei'natlvaoCsrhaec)moinctdaeulrcattDeiodvliotsgoiyodnse,eteedSrytm.ininePaustlah,ebiMuiiprnp:neersptdeooyrsesctoluedvyel mrBevooarrlaaaduetlo:lnocMaiLtnainboeonsroattfoaor.ryitSaTahfeSettyasntduBadvryadluwOaapsteiorcnaotnidLnuagcbtoePrdratoocirenyd,uarcecMsoirkfdeoarrncLseaubeewhrieemnsetrerimorseses,ratfInenctT.yh,e maintained in the Safethye ErvaawludaattisonanLdabaorcaotpoyryo'fstrheecofridnalarevmeppemrrrs. se Methods SenTjndeaengytaeondadxweiLatalhbloyr1ammtaogtruiorefes,pNietwIunicZ.te,aarlywaenrldeutWeunisinetidez/iMinnigntihhkoeirnmsotdnueedryi.vvieadEafcehmalfeemirmasbboitrs from diielcuitnedg.semeTnh.e doTehse dwaayreoftheinnsaermtiinfaitciioanllwaysindseesmiignnaatteedd vitthhe ocres say 0 of miresorbpeofoolreed pregnancy. ToopoinaaTr0ouaapaeinoifst2r0a,atnii2om5nalsg1r5o,wuepr1se2.,d9oCmoeondrcu6wrirtmehgn/tkTg-c/2do9an9yt5.rCoelcTahsneuirsmepaelwnedreed tdaasilyterftn com Co itr3ib/n4gi9(as3aareand,7u2F9ri9ib5nbCgeorcdaciyansthceotretnrhrouoilsuignhwger1ae8 opfresgeesnttatwiiotnh bbyothoraslouipnest.udboastmeiisolneiewnteimrat.e constant dose volume Shoioowwn esenadaoovwzeaertseirnhovuaesretedempaivenardiailtvauibrdleueaalanlddy hinumihdaintgyincgonsttarionllleesds rosotme:eosf libitum. The lights c1agmeiskeS.ithoheire patina mpprs A coSnaodfhraty/iedyanrrktiyncSaytci2loe,n.13f1oNrL1a5,bannoi1rm8maaallnsdcw2le9irneiocfoablssuessritvgaentdsi.odnaiaBlnoyddyftrwhoeewmiegreheytson3weasroengyesseotrao>triaocnh i mSit2e0od5ri,aatSneezlosyartitoonMd1eatnedsrumeriavnciehviuinftgetrahunesi,maanliisnmcalwleurdweienseguptirhtesagnnacatonnittz:eendtao,nsveaaibstbhieevsreanswtaeinrseed sooroeeed Results and Discussion Tirst Group of Animals Seo3T0eue0au.tr0althenfsd" faegiCmnoaimlspetosruantddiieoAdnndaotdfostTeh-e29r9tew9loCaotCehdigahdteeradtohdssoesseanodflesv1ie0gr0n,ss s7e5o,fy a5b0oroerin2n5.Ba/okrgl/day com aCroitmtaphcoetu(ndlraedmooatsopooliuerverled2)a:abtorMttehedeootarwlolwelTro-ew2e9ri9n5dCotoshCee ST plervoecless.s ALL dam npeoumnederrelated of resorning their groups had a negat GeSorrraeIealSptiooritgo{iTmoadnblotefhe1t)h.aenimdBaoelscseaulsveeervseolfstetwrhemerienhaitgtoehoddhaetiagthhgetsrotaattbeieoantnoddleacryoamt5m3eednodmeiuvmeLsioenorBpoeadcsiadywesiigghnts dose leveyls.study. Therefore, a second growp of animals were sessgsto Lfaiblbtit 2 B Riker Experiment rn-3024 wo. 0680KBOOIS 004183 HE i | || i | Second Group of Animals 2 DIdIis/ax3no/ordtaalyreasdGurmloitunpiisnwterracetoimopdnuoeunodtfor1en-lo2an9t9e5dCdoeCatahts.dosessmeofthr1e5e, d1e2,ath9s oirn6thmeg/k9g/day FbOorpoonskgee/nxAsb/bodaractykiooGnrrsouppnaesnudmaorbneoisraot.ed oOrnewascsuormvpuionvudienrndggorifenalgsastireeedsooerrepetemiaeocsnh oof(fTaibtnlhteeub2a1)5t.,ion1H2o,ewr9rora,ng TeJbihonree2t"i-o3ng9usnocnoslr,uderiEnegsLpothrepticoonntsrrpotdliiodngsrnooutwperohecacdunrorteidncuocvteehdiessbeocdry9l/wktegoi/gdbhaety cgogarmiopnuopu.antd relateevde.r, sAll dose the T-2999CoC aniamtailso.n (Table 1), but generally it was core Pronounceodmein Conclusion DTsarnre3aa2tc3obtljoegchytaitvsetutdhoyef wd1a5estmegmr/emktign/iwdniatgh adntohseueppseelcervonddoswgeroluepvelaf faonrimaanlso.ralThreabrbeistults Yionig8h,tTAPgbaLitn every uses Matenerdreatamobalsioengntycaestofudyctyohmaspoutnhdererelewalatsedtohueldedsttobnmesi.nanef|apfpmepacrjtooprorfiitaytreedofuhciegtdhhe bdoodsye level. ined roughout pregnancy at the a mg/kg/day dose | ii i 2 | | 004184 I Table 1 i Oral Rangefinder Study of T-2995coc sn 3c in sPreeignneanctaiRnabxbitssons cc BEST COPY AVAILABL Pregnant Rabbits With Standard Deviations (g) || crow 1 | --_--Ry Ss 12 as gs ra/xg/any 100 mg/kg/day 75 ma/xg/asy 50 mg/xg/any 25 mg/kg/day, CXS a an 7 624 ve $422-1T8L7E 2148.56-41323Toe1a4nss W072-i18E5 -xe122zz1z9sv--e14nc 27A1 a45p2 6-7s1e 2zxs2 2--hgos6 "42.25-615834 55554 20-.s24 337. c5 --_--Grow 11 fy aa me/xg/aay VEAL EoRsLe bwndmy dbas10doggo 18 ma/ko/tay S1S2E 2i5i3: 9u8i8 2 a1vad0 ewvet 12 mo/ko/day 20G0E IiEii mwEu 3a-u11 dwaBi dug6 9ma/kg/day SlHbE ~E1A4D3 Blaoid 7H-77Slaaan' e1en4 . 6 mg/kg/day IE E MEI 4B L vue 2 ET111bs 004185 wv 4 Oral Rangefinder Study Table 2 of T-2999coC in Pregnant Rabbits Death and Reproduction Results GDorsoew 0 m3/xg/aay 100 mg/kg/day 75 ma/kg/day 50 mg/kg/day 25 mg/kg/day 0 ma/xa/aay 15 mg/kg/day. 12 mg/kg/day 9 ma/xg/aay ma/kg/day PNruemgbnearnt. 6 6 6 6 6 . 6 5 6 s DiNuerdber 3 6 ` 2 1 1 - 3 0 To of the three dans died before the end of the study. NoFunwbietxhofTotDaamls ReAsboorrbteedd Conceptuses 6 6 6 . 1 1 1 ' 5 004186 . - Aependix 1 Oral RanginefPirnedgenranSttuRdaybboifts1-2995coc HpIoenvadiniavtiBidooudnaylWfoBeriogdphytrsweemWiasenhtcessna(ogv)nicaasnra s BEST COPY AVAILABL Ess az ag ge Uhm WMraEeb MMEE iAdbuede 1G0a7h Dlsuioseok:s ZsuNe lBlioIarEle 2S2U5E5S bl1ie6tt1yh8 ZLaEvDe ZS1a6on4wyMsE.ceneto6oataaateettEgy BIE 37s 23 kaha Sian asvaessh sseasnht Ssaonit SIANHenLEVEZRien13122155baazdi.ss220zsa.raS1281741eazTies Es 12 15 ge 1006 HoheoR GWiEb 118212 sluuess 1s2e5s.s 1d7s4e4e 1do5e0ss a4re0Bgael DuIlEe l1e6d5 ZLuoausl z2e4a7l7 d2s3cxre 2s1e5re9 OLE 17% 303 3252 baaf ogOy . OLE ash 206% Zole 2o22 1e5 zeny 175; 2634 1976 or EE STANVERNDEVAeSEwe751232.u6640ed.ssrad1e926setasssgei4s3sus - s F 004187 Oral Appendix Rangefinder I (Continued) Study of 1-2099cac . in Pregnant Rabbits MDIeenavdniiavtBiiododunyalfWoeBriogdhPytrseWgenWiaignththtsRSat(ngam)nigeaesnrd -- Dy PEs az au og FS Hb my PEIlE FPlEeE G2mms er Scotuem save 1pi5aise hae 1z4i3w1a 157s 1s2m0ad deie 1a1r4r0 teas Ggaa ge PPIALE iIsms tse daeueesd wZaitne Ted g sZuisne Tg 1ohearg TUT anugataes AML Len STHFEWVEvesChUSE027d1ur)3201586%Sas1h7,52cos1e540ws1a4tmty . ------Dy If 3 12 gn gg SB MaKG DRY MCAEE THE 117559 171 6197221 2734 21193133 2723 11371251 2512 g1s360p8 1798wdg670go CLAAEE GLE 14B7:2 184 22105570 2007 22025052 2526 11599557 Zand 1253524g 212o5s4y 117851g8uAs4e7e1s0a 2199 segs . STRNERDEVI2L243536242.60330270.83126153,86Sz01s677som1h7ess 2 Died 004188 & ------ oo x Oral RangAepfpiennddeirx SItu(dCyonotfinTu-ed2)999coc ' in Pregnant Rabbits HDIeenvadiniavtiBidooudnaylfWoeBriogdPhyrtesWgeniWasinhttehsRSat(bagb)nidsaaenrdd --DPy I es az as as 2 Karn RRAAEE KFLAEB 1de0o Lr 1Z7i3a5d come 1sa5s2s 223 1u5s6ens 2092 11s62242 1543 1a5r5i5n 1544 a1uissy 174s 176 Lozz 204% Lubd 185c 1ro4 FBIAEE 1L8s6 227ui1h3 2c7i6s2e z1a5v0s5 21524s5 1758 J1paisd GA 6 STANV.ERNCEVIZ1S6S833210.57Ss2e002423129.044115734114166us3 --_--Py SE aur a as panty MMIEE MMEE SS1I5 SS1173 22175613 41E5P0E% 21133040 11374673 211592%6 1178003% E16S32 1197136% 21180401 Alreasn 2d0s5s 1422 S2i1r21s sein MMIEE SSIPEU 1Z5i3a3w 1 Lice DdEbOuL 1Zrsby 1c8o0u6r D13o0d4a ass Bdeoeetn sore ANFERNDEVAZJZ.ilabo2.0s623s.ensS28s5u.seSckzr.es:220z0e.usPAuatux6 b. ea 004189 Oral Appendix Rangefinder I (Continued) Study of 1-2995c0c : in Pregnant Rabbits DMIeenavdniiavtBiiododunyalfWoeBriogdPhyrtesWgenWiaignththtsRSat(bagb)nidtaasrnda S08 F az oay gp oo. To HL ey GGilf Dip DDAeD CEE lAeEr 1790 Zdiesssu ass causlats 1839 11375500 271s 1s5e6zs dweeiens Ssoelgls DOilbe UAE SDESLS SIS dB7SC 4843 2it5e0s2 1965 e5n07s 15u7 d274e5qs 1904 d2i0a0n% tars sdieeens ong Sseoirde Sos 1565 Saar = ETHPELLRVIgSLSG181E806ae1s607vl178s0 aseensabseenpanpsez5 TTT -- E58 az oan geo 12 WSK DHY TFiibe FiE SEi2e5 BED 710199 1755 2t2e2m2 1867 ivostta 1721 1a5s6i1r 1ota d1o7g6g4 ssaowes 22103251 FTIiE FIE 5523S 40 11%5e52 160% 21b7i6v5 1549 acgnenn 1789 11o5c6ts 1650 1dgeoess ypac pgoooon 1187a251 dois 21a5 , SRN.egDEVATSZ576716169.93141281011417543 1695 1234 sone 1772 13: 200s 2129 e110 S261. 5 004190 - Oral RangAepfpiennddeirx SIeu(aCyonocflupd-esd9ascoc s } KDIeenvadiniavtBiiodiodunnyalPMfreosesrgoonyhPaernseWtgenwiRaiganehbsntbsists(hg)atan?a poanel TTT 6s 5 Mar az iw ao Gde ESeT BoIkE DDEES RdeEn t17e8n5 L2UsMn pUio EzaEg a1gessd IAN 10m A038 E22m47 A13R6T3 130) od e am w 1300 wd Ca CE GGL Seednds GZita 2290096% 2s2o0i0 SieELvein2s175ea2n 5dal2e14S6 T2E05% edLnEnYd 19601518 Loot@ sus RATE 2a 2 ---- Ho Ry 3 s 1z 1% 1s 23 - HFRiIEeE RFiRf E5E5E82 2s12r62e3 5 23 caaasssaee seer ki1n7ed9se2 iss 111507534720 13H 4410T0755F2 ds1e7rvoeene iasssstene Se zane ETEFieeAeEE Lol 200 B50 1522 SNE 1888 2G5S5M8 101 aavseer 194 faeutc gaen AEA de er fone 00.4191