Document JZyLBj994dnYE5K4qNOeyzNe

! . prsTeOn NAMBLE AFR--e2=2e--6--s---=0o5s4!63 TonITLITY Oral Teratology Study of T-2998CoC in RAYE cms 5 I S Tn t SLBeEnnde spores Eun homed aiust Sri ener semmeioger p Moe, t REo iEorerss wh 03034 1. Sumsary OtroalpreagdnmainntistSrpartaigoune-Doafwl7e-y29r9a8tCsoCduartindgosdesaysof60,thr1o50u,gh501,5 o1f.5gaensdtat0i.o0n5 m(gp/ekrgi/oddaoyf orregparnoodguecnteisvies)trvaacst cnoontteenmtbsryooftoxthiec daanmds.didThneotcoamfpfoeucntdtdheidonvoatriecsausoer abnormal tGerroasst,ogeinnitcernianl,theorrastk.eletal malformations of the fetuses. T-2998CoC was not 7an-i2m9a9l8sC.oC aIdtmicnaiussterdatsiiognnifwiascanmtaltyernlaolwlmyeatnoxibcodytowetihgeht1s50dumrgi/nkgg/dtahey ddoossienggroup dionsteervgarlo.up. Toxic clinical signs and deaths occurred in only the 150 mg/kg/day 003035 2. Introduction TTbyehrias3tHotgCeeornmaimtceorlecofisfayelcstCtshuedmoyfi?caoilnralrDlaiytvsissiavoamnsi,nicsSottn.edruecFdtaeldT,-2t9Mo9i0neCnvoeacslhoj.taateaTnhtdehevsatesubdrycyoowntedosuxcitscepdonabsnydoretdhe vSTouortets1ye9teP5ra1olf.usc"toimpoprnooutnLadacbeoalrdamtaionnrdiys,1t4rsaRttiikoeofnr LGthraeobuopprerationvrceiirepesa,ldopnIaendcr.t,ibceitSptwa.enetnFsauAlpa,rndilMisnu6npeeasrnovdtiasA:oprriyl personel can be found in Appendices I and 11 respectively. KFGrp1aecrkpaiotcrietn.igo(npGsrLoP)cofedruetrgheiusslats(itsouendesyApvaepnredendtichxoendSTuaIcfXteetfdyoraIcvgcauolarluidacitynigonAstosLuatrbahonercaetGooroUydnitLSatsbatonardtaaetrmodernyt). nThien.tsationreedstinlotchaetiSoanfefroyr ESvpaelcuianetniso,n LFaabvordaattoarya'nsd r4eccoorpdy aofrchtihveesf.inal report is netboss TBirneeadimnagteLdabSoprraatgourey,DaWviileryindgetroinv,edMaCsOsarcahtussewtetrse,obantdainaesdsigfnreodm CcahgaersleasccRoirvdeirng to v0e7rC2eo0a8phuostueesaerrs-sg,uinnwederiravetieddutahelfnlaynddioinvmiehneaudnmgbieinrngsto tsatfbaoluiern.legsrsTouhpessteTeoalfts,3c2agseaasnnigmviainltgsh inevaicrwhee.'igmhetsThhefrfTolamotosr1s67 iSneailtirbolnetsadinlaibitveurnp.eratTuhreelaingdhtshumwiedrietyonco&nt1r2ohloluerd Floiognh.t/daTrokodctycalnedswater vere t5Thh0eo0rFamnaiglsessltcsaltiinvoienrcealancdbssiegtrnheev.edratdBsaoidldyyosweefdirognhatcscdoarwyedri3engtlhryreocsuoegrhidnegddaaaync2o0dnasyotsfang3t,esdt6,aotsie9,onvo1l2fu,omre15ofand5 G2l1e/ckigtiSefdboadtyerveidsahitl.y atThe0, fi1v5e0,g5r,oup1s.5weorre0d.o0s5emdg/vkigt/hda1y-.299T8-C2o9C98aCioaCsolvavsed in Swnicmuibnaitsiroanredneeddalie.lytobythoeralfatientounbadtaiyoen vitthhroaugehyci1n5geofeqguesitpapteidonvit(hdaya 0bailnld-itciaptpeedd bCyomseprecriaaclposCihveimviecalvagbiinviaaliomne,stS)t.. FIa-l2,396MCioncnesaontaalys(iAsppveensdipxroTvV)i.ded by vX1a2riseusrvainvdinwgtearnuiea,alencvieerdeinsgacritisficceodnteonntsd,ayve2r0ebyexecmeirnveicdalimmdeidsilaotcealtyionfoand the iAGbamtnbaoerrrnmianoifetiFteehsse,orfpotAliploponvrionxsgii:tmeast,emlupysubpetrwvoe-oitfghhiciroadrspaonrodaf tslehuxet,eaf,AentdunsueamsnbyevreGrroeofsspvriesfsbeetlarelvefdetuinses, SSlkceolneatlalfonrorcmlaelairitnigesa.na Astpapirnoixnigastofelytheonsek-etlheitrodnofvitthhealfioscaursiens vreedrsfofidxeedtecitn SdBhoeeutienar'misisnmeescotvliiunstgicoenrmailcfroorasbcnSoouprbems,aeldiuatelilnetse.yferesIeenhcatonifdodnesrsewctiottihoenvifainlngudaitbnyegstl,heensplWuifslisnodsneilnegscsetchsmeeiyeqenueundteor SSiaccrtoinosn,s swtiatihnoeudt wlietnha hfeimnadtionxgyslivnereandineboesdidnedanidn epxearmeifnteidn,hissetcotlioogniecdalalty.5-6 B2Rriekeirlxperizent No. 0691TROLI0 Purina Laboratory Chow, Ralston Purina Co., St. Louis, MO 03036 3. Results and Discussion 7-2998C0C administered during the period of organogenesis was toxic to the high dose group (150 mg/kg/day) Tats in causing low mean body weights during the ddoosseinggropuepriorda.ts wAteiggheesdtastiiognnailficdaanystly9, le1s2satnhdan15co(nTtarbolles1,(0Ampgp/ekngd/idxayV))., tThheehigh Bmge/akng/mdaatye)r,nalandboldyowwe(i0g.h0t5smgo/fkgt/hdeayi)ntdeorsmeedgiraotueps(5wmegr/ekgn/odteyd)i,ffemriednt(1f.5rom the controls throughout the study. gArbonuopr.malThcrleienicraaltssiingntshewehrieghobsdoesrevegdroaunpd ddieeadt.hs AoLcLcutrhrreedeonoflythien rtahteshithgahtddoiseed Twheeresuartvaxiivcinganhdigthwodoosfetrhaetsratdsidwneorte hpaavlee afobrnoromnael tcolitnwiocadlayssigbnesforaneddseiatghn.s of toxicity did not occur in lover dose animals. 7-2998C0C was not tract contents of ethmebrydoamtso.xicThaendmdeiadn nnoutmbearffeocftmatlhee, ovfaermailees, ortotraelpraondducdteiavde fetuses, and mean tfheetumseawneignhutmsberof oftheresfooruprtiTo-n299s8iCteosC, doismeplagnrtouaptsionwerseitenso,t csoirgpnoirfaicalnuttleya aifferent from the control (Table 2, Appendix VI). 73)-,299no8rC04C1ddiTd-2n9o9t8CccaCusetrecaotmmpeonutndp-rroedluacteedfeatbanlorsmkaellegtraolssmafleftoarlmaftiinodnisngs(Ta(bTlaeble4, Appendix VII). A significant higher incidence of the skeletal finding of one msitneorrnebsrkaeeletmailssianbgerroactcuirornedandinwatshenhoitghcodnossiedergreodupa.malOfneormsatteironnebrianctmhiisssisntgudyi.s a dFiufrtfheerre,ntthaemonigncitdheencceonotfrolthegrofuipndianngd otfheonleowesrtertnherbereaetrmeiastsmienngt wgarsoupnso.t The ianbceirdreantcieosnsofversekelneottaldifffiendrienngtsamaosnsgocitahteedfiwviethtrdeealtamyeendt ogrsosuipfsi.cation and rib Agrofueptaslinlecnlsudifnignditnhge wcaosntoroblsergvroeudp.to oThcecurlenisn ifinnddiivnigdsualwerfeetulsoecsaloifzedalltodotshee awreerae opfrestehnetewmibtrhyoinnalthnautclleoucsa,tioanl.thouTghhe aravnagerieotfymoofrpmhoorlpohgoilcoaglicaaplpeaaprpaenacresancases onbesaerrvtehde uanndteerriotcheentdriaslsecrteigniognmiecxrtoesncdoipneg ifrnocmludbeedn:eaathditshceolloernastieopnitohfelithuem lens to hoarlfa-wcaoymbitnharotuigohn tofhelelnesnsdpiossctoelroiroartliyo,n aandcletfhte aptrestehenceantoferiaoccelenfttr.al lens region Thhiestolpenasthofliongdiincgasllyobsaserveeidtheurndear ftrheeehdanidssescetcitnigonimnigcroasrctoipfeactweroef interpreted a normal area of porfimtahreylelnesnsvefsiibecrledergeemnnearnattiaonnd. conThseistceledftofwaas saepsapraacteionopeofnepdriupmaraty the vestage lens fibers of the embryonal discoloration of tnhuecleeumsbryfornoaml thneuclleenuss erpeistuhletleidalfrcoemllesi.theTrhethedarlkensstbreeaikng afnreeahratinfdacstectbieoinngedcraecraotsesd the area of in the lens normal during primary lens freehand and fiber degeneration sectioning or | accentuating the area of normal primary lens fiber degeneration. The 603037 a deviefnfearmeonncgesdoisnetgherouappspewaerraencelarogfeltyheduleenstoatrhteifmaacntneirn ainnddivfirdeuqaulencfyetuisnewshiacnhd the uanrdteirfactthevdasisscercetaitnegd maincdrotshceoplei.mitaHtiisotnoslogiinchaelrleyn,t tihnevliesnusalairztiinfgactthewaasrttihfeacstame tihne adllissdeocsetinggromuipcsrorsecgoapred.lessT-2o9f98tChceC moinrpuhtoelroogicexaplosaepdpefaertaunscees ddeisdcrinobtedhauvneder compound-related changes in their lenses. 03038 5. able 1 Mean MoartaleriTaelratBoodlyogWyeiSgthutdsy woifthT-2S3t9a8nCdoaCrdiDnevRiaattsions Dose Groups 0 mg/kg/day 150 mo/kg/day $ mg/kg/day 1.5 mg/kg/day 0.05 mg/kg/day mrovyee3er6pr8 12 r as s20mse STAN. MEDAENV 1518.61 252.243 212.514 220.76 22I.A3G 273.860 STAN vEDFENV 142.002 152.218 225.2568202.96322Z5.e5alZe8 y MERN 261 zon Sz EE 3a IE STAN. DEV 12.1 13.9 14.6 17.1 26.@ 30 @ MERN 155 218 245 263 301 363 STAN. DEV 15. 3 14.6 15.9 15.5 17.8 26.7 MEAN 19% 22S 24m 273 306 380 STAN. DEY 13 8 16.2 18 2 21.8 23.2 32 4 2Significantly lover than the control group (Dunnett's t test p < 0.05) 603039 te 2 Mean LitOtreralDTuetsaat4ondloFgaytuSstuWdeyigohftsT-w2i9t9h00S0tcanidnarRdatebeviations? cesvpe o mAY/MY WmAYSY SmaI LSmAY O05mA GPRE UNIGNSOF VHIFNE FETuUSiES eTom vBev421s 4Lse s2e% stewWieas21 52:110303 sumi2es 5Ziizsiz a`aLs ciw1i2e 1387 2aSs zese sr f2ev 5Le1423: ms0e RELTEEWEOS no we weeo waee meea 0aa: SWHEiSGRePTION es og eLso oass a4as oGdf INESLAUNETSATION 03 25 0EH niev FsHe 120:s CWOiRePnORA wa 16 wuLe wiuez 1E0H1 uieE ePEmRN sWT aa oa a0z3 aa33 8aa3 oasz mn sgn iis ten om cet om reso <0 8 == E 8823 7. Ending Fing e Total Fetuses Examined Runted Small Umbilical hernia Total Normal Fetuses Total Abnormal Fetuses Table 3 OrNaulrbTeerraotfolPoegtyusSetsudwyitohf GTr-o2s9s98FCionCdiinngRsadts 0 m/kg/day 156 1 --- 195 1 To mg/kg/day 240 --- --- -- 140 o sp ma/ks/day me/kg/day ms/kggasy 29 162 m --- --- -- - 2 --- --- --- 1 29 160 210 o 2 1 # T(rCehait-mseqnutaregrpoup<s0.w0e5r)e not significantly different from the control group 03041 --------EE ---------------------- 6. Table 4 NumbeOrraalndTPeerracteonltogoyfSFteutduyseosf w7i-t2h998SCkoeCletionnRFaitsndings p Skeelemton Findings Po/kg/day ma/IkmT /day me/kg/day ma/1kos/day me/kesday HFoolnetanienllferonntoatl closed PFarroinettaallss nnototososssiiffiieedd 24 (18) 17 (13) 18 as) 14 as) 17 an so 151aas s 0 aa s Ionstseirfpiaerdietals not 17 (a13n) 113 aaas 253a 6s ( 3 @ StSteemmeebbrraaebinpotarotsistiefied OSnteemnsetberraeebraaseymmeitsrsiicnagl 40 (67) 14 (10) 641 60 10 ao 101 (67) 12 @ no (en 13 azn 95so (66) 18 az TFoourstsetmeernberbareaemimsissisnigng 290 (1(57)) 27mGn 26 a(g5) 12 a@n 23 a@s 1133 rriibbss spurred Wavy ribs a 2 3ow 7G 102 ao) 7 5ao3 3 1ow s6 (5) 66 @ OPnreotbroudsyionverotnebrriabes bipartite 355 (@26 157ame) 0s(o20) v+ as@ 33 @@ 3 an Tobipbaodriteiste vertebrae &@ 2@ u 2@ 6 Thbrieepabrotidtiees vertebrae 1 3@ 2 ow onmeisbsoidyngof vertebrae 1 Total Number of Fetuses Total Abnormal Fetuses Total Normal Fetuses 136 126 (83) 0m 97 82 s 1502 16 (on) Wo n2 9 63) 1 an us 127 (6) 2a aa 2ReSisgunlittsicafnrtolmyonheishfeetrust'haanrethmeisscionntgrol grow (Chi-square p < 0.05) () = percent of total examined 03042 5. Table 5 NunberOraalndTePrearcteonltogyofSFteutduyseosf wTi-t2h998ICnctCernianlRFaitnsdings T8 reatroams % 5 is os B intemae l Fine dingse mg/kgI /day mg/kg/day mg/kg/edO ayy||mmge/lkvgg/idaayy |mSgs/skgo/fdiayn Feftiunsdeisngwsith lens 5 (8) A dlaernks osftroenaek eivnethe A dtahreklesntsreaokf o&necleevfet in A ocnleefteyein the lens of 5 (@) A bcoltehfeeyiensthe lens of Hydronephrosis Enlarged renal pelvis 17 (29) Abdoofmibnlaolodcavity full [ae un ee? 2 sm s az 1@ 1@ 3m 2 (3 ow TToww 1m, ae) 3@ 6 (2) 6 a2 s as) 1@ 5 (8 zo 2 oo 1@ 10 (16) 3 Total Normal Fetuses Total Abnormal Fetuses Total Fetuses Examined 3 (63 22 (37) 60 0 00 13 0) a se en 9s an & 3 08 12 eo a 4 on 1 en 6 2()sig=npiefricceannttlyofditfoftearlenetxamfirnomedthe control group (Chi-square p < 0.05) 03043 10. Appendix 1 TITLE: EPrxopteorcionlentforNumObrearl T06e8r1aTtRoOlTo1g0y).Study of T-2098Coc in Rats (Riker OBJECTIVE: AtertaetroagteonliocgyefsfteudcytswiolflorbealluysedadtmoineivsatleuraetdeT-t2he998eCmobCryottooxpircegnaanndt rwaittsh dtuhreinggenetrhaelperreicoodmmoefndaotrigaonnosgeonfestihse. POATheispsruoecdediunreJancuoamrpyl,ies Ot1of966Dtrhue(g"sG1u97if8odrelGioHnoudemsanLafbUorosreaR)te.oprryodTuhPcertaicsottniucdeyStuwRdieilgeluslabtefioorcnosnSdauafcnedttyedSEavafeactlcyuoartdiionng Evaluation Laboratory's Standard Operating Procedures. `SPONSOR: 4 commercial Chemical Division, St. Paul, Minnesota. TESTING FACILITY: sSta.fetPayulE,vaMliunanteisoontaL.aboratory, Riker Laboratories, Inc., STUDY DIRECTOR: E. G. Gortner START OF DOSING: April, 1981. TEST SYSTEM: dOenreivheudndrfeemdalaendrattesn fsreoxmuaClhlayrlmeasturRei,vertimBeremeadtiendg SLapbroargauteo-rDyawlweilyl bsaentdrahiofnruosnoetfds rianitn ahwainltgleimnpgbeersauttsaueirdnelebaesncsdausshteuemeilodficthayigsestcoornwiticrtaohlllweicdroentrromooemls.hdaftTlahoiosrasnd tainmdevmaatteerdwiflelmalbeesavaareilarbelaedilayd 12 hour light/dark cycle. alviabiiltuamb.le. ThePurliingahtsLawbiolrlatobrey oCnhoaw TEST SYSTEM IDENTIFICATION: be indicated onEatchhe aonuitmaslidewilolf tbhee ecaarget.agged and that number will RANDOWIZATION: geTnheeraatneidmalrsandwoimllnubmebearsssigtnabelde.cages according to a computer- CONTROL ARTICLE: Corn oil. TEST ARTICLE: T-2998C0C. ANALYTICAL SPECdIeFtIeCrATmIiOnNeSd:byTthheetSepsotnsaorrtic(l3e,CocmommeprocsiiatlioCnheamnidcaplurigrtoyupw)illpriboer to the start of the study and at the end of dosing. DOSAGE LEVELS ANcoDrnEXPoiElRIMdEaNilTy.DESITGhNe: teTshteatretsitcleartsiucslpeenswiiolnl baendsucsonpternodledaritnicle wtihlrlougbhe a1d5moifnisgteesrteadtiobny aorcaclordiinntgubattoiotnhetofotlhleowirnagt:s on days 6 2 rc-143 03044 u. Dose Level Group size S15m0g/mk9g//kdga/yday 1.5 mg/kg/day 2222 00.m0g5/kmgg//dkagy/day 222222 ZTSitheuetdjiaoerrsyelschoTonowtueatdneinorafandtiasodlmaairbneeilsektdnroawt1ni-o2n9to98wCiionlctlerwbafeseruewseelwdlitbhaencstaeunrsmeecnomtsettabooolisa article. ISgoeecsaotrradtieimdoanlosnfordvaiaylsblno3b,rema6o,lbs9ce,lrivne1i2d,cadla15islaiyngndfsr.2o0m Bdoadyy 3wethirgonueshwidlayy of pregnancy L2o0 of Sweoifgaht.ceoresnsiy using a constant dose volume of 5 mlsa/dgtahfe sraatgs SseTaiorctgeeecrdf.:oetmneaulnmetbsserwwiiolflll bfbeeetukseiexlsalmeid(nleiodvne tdaoanydde2dt0eearadmn)id,net:mhuemnboeuvrmabreoirfes,osfesusetveeerrrupisrienana Giiinaroisroomunaiilmoniuctsahibneseisorq,luuoetfiAopinpnrpfoloxarinmtsaauttbiesolenyqusoeinntete-st,fhrierpedu-phoafvnedtihgsehecptuaipnosgniwpniugtosebeybeCrfyixed mjSoibnoeessyoePcuatxsihnegcftmooirrc.rmoisccrtooopsecd.oeptiecrSmeleiexncaetmiaennyayetivosinescctaesiroandlsesamcbeandnorbnmeeaclesistesiaeersytosbeyinthea DexuapmeinwaitlilonbeafftiexredTchleienarreeitmnhaygilnainnadglcsoathpaopilrnoixfnoigrmawtsiuetblhsyesqtiuwieoen-attrhiissrrdessseeroncti ine PATA NALYSIS MnCDeeinFgInaNaAslLytlRiuEamRbOeNoIrf:otfheTfhedetautpsareospa,roes:meudmbDseturamteoitfstt'irsceaslorptmteeistothnodfsortgoembeanussetdop Dfpimoppoploanonenttahatebinoaonfrtmseairltietdsieetasan.idlendTuhmpebueprpreooxpfaomscieondraptodiraoatneslfuotreatheChsifiitens.eqiumereneapneeerriss C1ts (approximately third quarter, 1981). have been esmsien Amendment. to Protocol VSVoiillul}cyooBbpooeonnettaCrbdoeliensaurTsatptieec)nldeewdiflolirnbEcexoprcenhraionmige)endtdaNfirulomymbeasrso0rm6o8ro1aiTs)ROiTsIs0wc(orracl tTehreattoelsotgyarsttiucdlyeof ffoorritciloentrafnocretbhbyeetdwoirhseosloetlhvesitnsugtday1r-tw2i9lo9lf6Cbtoehces1suntbewmdaiytteeardmdmtyoceinm, reCootemmPnPerorotcthioaacplorla,Cghaedbmauitcaanslaolgturhtoeiuopns of dosing. 03045 22. Appendix II List of Principal Participating personnel we savin G. Gortner Elden G. Lamprecht Gary c. Pecore . Vinkateswa Pothapragoda Loren 0. Wiseth Fmerson Stugy Director Veterinary Pathologist Supervisor = Animal Care Commercial Chemical - Analytical Technician 03046 ` Appendix IIT 13. STATEMENT OF QUALITY ASSURANCE STUDY NUMBER: e0681m TRO110 ote TITLE: rOraall TeTreraattoollooggyySSttuuddyyooffTT22999988CCooCCiinnRRaattss ACuodmiptlsianacned/Aourdiitnsupneicttiofnosr wtheereapboevrefortmietdledbysttuhdey,Rikanedr reported follows: to the study director and to management as Date Performed Date Reported 9,14,16 April 1981 20 April 1981 20 August 1981 7 December 1381 14 December 1981 21 April 1981 21 April 1981 28 August 1981 14 Decenber 1981 14 December 1981 Dsah nceoAun dit Riker Laboratories, Inc. 1S leon bey ate /7Y) -- 03047 1. Appendix Iv Prestudy and PoststuWdayterAnaSloylsuitsionofsT-2998CeC Distilled Dose Level Expected Prestua Analysis Fostetudy mg/kg 150 mg/kg 5 mg/kg 1.5 ng/kg 0.05 mg/kg 0.0 mg/ml 30.0 mo/ml 1.0 mg/ml 0.3 mg/ml 0.01 mg/ml 0.0 ppm. 30.328 mg/m 0.983 mg/ml 0.268 ma/ml 0.0087 mg/ml 0.00 ppn 31.0 ng/ml 0.92 mg/m) 0.33 mg/m) 0.0092 mg/ml 2 Pregnant rats were dosed at 5 ml/kg T-2998CoC 03048 BESTCOPYAvaABLE ** mrr- siteaseabsloetoSoesAeipspnveened(oi6oVf)xf nn2-da2e9e9w00nsoi2 euacdes 03049 . BEST COPY AVAIlABLE ** Appendix v (Continued) IndWiOivrtiahdlusSTltearnoadtdaoyrldoWgeDyiegvShittaustdiyo(n5os)f FaTon-rd2HP9re9eaCgnnCaBnoitdnymRaWacetsisghts EEE 150 Mao cGiiff GIR lese:n Sei: i2e1s4 130 szien cto iarsee zes canbi 28 2se3e shi wiozr so OOFF OIF o30i0:5 deii 2131:5 isd a23:5 zea ozeie oie zseeir ze: sseerb 2h 1saa So GO0I1FFF iF 33G60e61a:7E oss 21i15i47 oi 2ai243:a16 21c%8o:1s sie e2sre6d zornea cr: ses 3a366@ ioe . GiiFk GIF 3308658% ois 122m cme 1G5i4a cio s2si5oi5i noes zed 2s6eis ee s1o4s6 she GGF1 GZaorria lZiio eissn zireen 2241,1 G25a4r idaets Cif 30TI 137 218 185 ed a STANweDnEV13c.o0z15cas4 25z.ac5 26ss 252.852 2636d HOM PREGNANT ANNALS OiIfF Oif 3e6o1s0 ois 11834s 1c: gzeeae er 1a7rs3 os saezsz cer 225a:z si szee:s sa iiOfFR ae38rs6r:5 111958527 22Z40a51x s4ze5ir3e 222e4sel s23e6ea zsmossa 2 nial ated 03050 BESTCOPY AVAILABLE IntiovriaclunedzaDtoooAtrpopnweynadisistxatcy((3oC)fonu2tni9to9nma5ede)0n0oisn apcessahte ion Stanaara eations Pos peemmand pe ov 3 6s a as 5 mookeoy PFPiiirr Fi Geseotsns Se iziooo::n i: ezssee i 9s2aa sa sszeeess sn nGannr Gar oiiemd il FFPiien Pi dSleoexsm Go oi1sc i: iiHORsGoTer Li Im esIne om LiuEir oa aoonex es FPRiioe dGdeeenm rn fos fimoifoe fa BY sb SEEoppr ERD skaefE IE hEaleEo ome ome oien PPRPiiioee dGGGoooorsose iOEmn BnSnn Ha oti ofZ oswom oZsaenEEaoaEsene kieE OLE RPriiie me SGleoelrwse den niZoi oih IF OD s3En23s22eH IE O23 lINhfE ain 34S Fin lot me oh IN MEE stannentev 12co 4z3s5 23a7s: W5zTrT 3a0z LaEsSe Non PRESENT AIHA PIR sesz os zie se zes ass re 03051 18. Appendix V (Continued) Oral Teratology Study of T-2998CoC in Rats IndWiivtidhuaSltaBnoddayrdWeDiegvhitastio(ng)s Faonrd MPeraengnaBnodtyRaWtesights RY =e os 12 1s zo 1.5 MGAKGIDR GIF GIF 3030 3031 178 183 221002 222346 225661 22343 235678 GCI1RF 33063223 214825 222171 22451% 226712 235215 MS 360 GIF G1F 3034 3035 136 175 213 265 242 234 271 252 les me 390 28 GR GIR 3037 3038 158 20% 223135 22461e 223813 z29r: d5i2z CCFF 03043D3 211333 236 222 ec 2% 233 Ze: ze 23% eon 340 GGIRR 3388885 11834% 2Z0e0 224335 227611 0282a 3d7i3n CGIRF 33808553 113355 222414 224315 226614 239 278 378 31 G01Rk 33602521 41783% 210544 2221%5 224514 227815 33548% GORR 33008S4T 2222%1 225414 2277s: 2298%9 23261 33920 GIR 3035 203 222 243 zra ia dan STANM.EANDEV 1515.63 142.168 152.455152.85% zed 47. 368 25. 7 NON PREGNANT ANIMALS Gif GIR 3035 3087 166 18 212 203 237 230 sz 235 271 243 268 261 GIR 3090 151 212 225 244 242 255 03052 ESTLOPY AVAILABLE Grad TeracAoplpoesnydisxewVdy(Coofncl7u.d2ed0)980 in Tata InWdiitvhiduSatlanBdoadrdy WDeeivgihattsion(s3)foarndpMreeapmnenBtodtyarWseights vw zs soa as mw 6s Hoe RRRiiRk Rik GGdaooissss dass c1ma%z Gor 2zi2a sir sasymn ser s2Germre Gee emdesns Gn a1e4a ae RRRiiIffE Rif loZaiodiis dois l1io5ocn7 in hcS1ia4 ch 2iS5is ser Gfsieaoa She Ssloeeer ae im s3e%r FRRiiitef JGGoooi:a tsdoehs esteiesr ssSenon 2sGeien 2Giham aalnna RRRIiiEk GGdenoeams ciifeosss iair ssSeon scSepei eGamsh eionlhe RRRiiiFfE Rie ii31eo0s2 Gis Zi1oo6r:5 aio s0ei4ts ca SLse3ae0 ch b6Gees se ooerbr osoree ie RRRiIIkEE i3311n00s83 Za7oi%r 2o44r Gsseeoee bbSieeerv a2o3e sameeasre Stennenbes 131s 45e2s 4z5e0n 2276s osgme aoaso NON FREGHANT AHL RIE Sess sez ase au 222 2m ze 03053 20. Appendix v InOdriavliduTaelraLtiotleoegry DSatcuadywiotfh7M-e2a9n%6FCe0tCusinWeRiagthsts ANIMAL " VIWRBLFE FETTUOSTAELS FEDTEUASDES 0 mg/kg/day NwEe NR z2233s5%5 NOT46 PRE&3GNANaT8se NWEE SSeeme NE Jeez 45656 11188: oo @ WNiEp GJeemsss me sess & 45 1418 a 5 4 sa WHEE GGeess NE Jesz os& z4 s12 e511 a NMWEER SZZeeessssss 415 175 aa1:zeo6b MNEE ZJeesses NE Zese 4oe zro o:o11 zo: a@ oo NNNEEE JJJeoesdrso NOT4 PRE5GNANT 75 az a MR Geiz 2 8 18 6 STMEAN N14..85D14E63V2S.5E eeee RFETSIOORN TIRSMiTFrILeOAsNN LCOURTFERRA sires e 1a s 1ar8 6e 1iz6 1131 5 ee 1111 1125 as z 6 a13 i ae aaa1z3 i6FO oa1s1 a1 a3 i6 1221 es aa1318 eee= a83 66 1162 1aaz aa85 12033 114 AMvEeAN mF FETUS WT(G) Zase 4is3 zaes a4z5 44:s a314 sacz se 4473 46 4a%1 se s3zs 4as: a4%s 5PaE35E 4a35 44% zdsa 45 s4o6 4 3aza6e a53z554a474s zsusss as4a 4az5 4zs2 4644 03054 2. Appendix VI (Continued) InOdriavliduTaelratLoiltotgeyr SDattuadywiotfh7M-e2a9n96CFoetCusinWeRiagthsts ANIMAL VIMABLFE FETTOUTSAELS DEAL FETUSES 150 mg/xg/day OO11FR 33680685 NOTa PRE7GNANaT1 e O011FF 3016 3011 NOT PREGNANT 5s ze e 0O11FR 33001132 s7 z 5 s18 0O11fF 3014 3015 NOT PREGNANT 4 7 a1 @ OO11FR 33601175 DEAL os @ OF 3eim O1f 3eex 47 8 14 @ 0O1IkF 3300635 18 5& 1a5z e@o OIR 3066 O1F 3857 DEAD NOT PREGNANT OF less O1f 3ecs s 7 a2 4 5 az O01Fk 3670 3o71 1 1zs2 OO11RR 3872 3673 NOT PREGNANT DEAD STANM.EDAENV. 4.5 21 S100 22 23 a0 ee RESOR FTION IMFLAN TATION CORFRA LUTER SITES SITES 2 a3 1z e1 asa s 16 @ 5 10 z1 1az 11a2 3 eo ae 14 s 14 @@ 1a2s 1144 ez e 12 1z 11 @ a s z 16 o 5 1e 10.6 31 111 13 MEAN Ave FETUS hm WT(G) fF 3s 40 338 4.4 44 45 42 43 a1 42 43 33 44.54 4457 4435 E 47248% 4s zs 3iE% 430& z3ss 46 48 38 41 3430 3% 35 37 43 4a as aa3z 03055 Appendix VI (Continued) , InOdriavliduTaelratLiotltoegry DSattuadywiotfhTM-e2a9n98CPeotCusinWeRiagthsts 5AmNaI/MkAgL/dsy VIRMELFE FETTUOSTEASL FDEETAUDSES FFiibF Z30a1o% aEsE]3 FlR FiF 3o21 Zoo: z 5 7 7 ae 13 FR Pik ez: 3023 szs5 112a FFIFR Z3ooi2d5 z5 e5 14= @e FFIiFFE ZZeazre 8 2ER]10 FFFF ZZeeae 44 5& 18se FIFE Fik Zar Ze7s 78 sa a1z2 FFiiF kZeosr 111 sz 12 13 FPiikF ZZoo7g3o sez3 0=s @ FPiER 338e3E21 NOTsPzREGNANoaTz @ FIR Fi 30s: 3034 & 4 &1 107 e STANMEDRENV. 25..22 S2..42101.54 e@.e@ FRTEISOONR TIAMTFILOANN CLUOTREFRRA SITES SITES e1 ae5 1106 o 2 iaz 14 1z e1o a13a 1141 aeo 1a 145 2e a110 1111 10= 116a ee 1122 1132 1e 1313 11 12 2o ao 11a1 e. iz 1z 2 10= 1 eeeS 11170 111&3 MAEYAGN FETMUSFWT(G) 3384 333s 3Z4e 41 Se a4 sz aa 4s a4.24 4a.z4 aaz5 4435 4438 4426 4455 4456 aa14 4a5z 447z a41s 44.65 4487 aa10 sz 43 45 a4 az az 45 43 48 43 a3 az 45 48 43 44.33 4453 aa33 4a3z 03056 BESTCOPY AVAIl ABLE" mrait eeraAnppnendissxoenVoIsr(tConrtio nueed) i0t7s 1.5 mg/kg/day C03057 BESTCOPY AVAILABLE __ rcrseenAnppnendispx VoIt(S concmludeed)ee tes 0.05 mg/kg/day SITES SITES G03058 Smt orm omnamnveswet ors wn oe es me mn sss ws 34 3m ie mr sm mt ms merit a tid Poor rn : = rte tn aa co ta ste een te : TLR rr ee -a32 sa8 % un sume mt LT2 mt 7me rm . Totalmbar retusen vee Tom T Toome, . Sa t| ld . TLL, 23 S2 ; WE RN LR Ore TeratolosyStety ofT-29CinRats - SAVY GamMmber WIS 00 WH NI NI Ni 25 MI OT NI Wm WN 0% 0% wm 0m 0m . Totalmbar Fatumes. "oo : seni 0 atacnabrne missing Fe 3a aL, rasa 2 Ltr te oe ` sa Qt ms omet nm 8g R 2 ; SAAT mma wm wn wn wk 5m on en ee onok emom sm sm ne - rrr Ac a a. ratesite Fourstarmabcas mising Pea : tl ne ' t .28 eis tmce rs my 22 . 3 wR TR mar ee 0020 ss 0 20 wm wn kesn omen ror ite Cr ee, Cosa bbb, Tt 2 &g - 8 n a WI rR LT ; ees 2 Ca + saa Total Weber of Fatuses. EEEEEEEE EE EE EE mn I 82Ho 2 . er 2 Fetus oyoa wi seria indo HO mer buwater oe 01 i300) Wis 6 ois 00s me es so 3 0 en Bard rs ein . 88 8S8 & [spr Ahnemttoin - rm TTT TT TT a a rretbtrsetass nts '' Vs a 3 88 2- 3 EL RE Te . Lswavs cnn 0 wn 6m wn nw on won om ee Total Weber Tetuses. Tr 4 Ta a a 3 3 1 ae 3 aa [ sat Enlarged ost renal poivia + Toa + 2 \ va : 88g8g .:: nn 3 Fea oy el Tearin Bb F 0mA unmber 20 06 300 2008 0T 00 ou 0T 0T ws r we ww) me 0 nnee r es ' 88 g8 > ) 4To an i nb . semuasist Pr 2. 6. Gortner (origina +) Peller on eaten) 2 6. damprecne 2. 5. Jutochs 4. salenn. 2. ober . Neoummic7k. 0. Geiteieh @ 5. sensiscn GB. Steffen3s. 5. Hender+soXn. 1. Tabane 03069 FEoLzGK..ellcGeoarrsten(e0xA(Poirliegsi)nal + 1) WWE.eiGL... MPNeeuaGtrosircsmhoinc+kR.=FA.. bNeelesvoinzr+iRn.n Eo.h) ober EG. Lamprecht GR! Steffen + J. Db. Henderson x. L. Ebbens Amendaent"to StthueayFionfalTR-e3p5o9r9t8Coefc itnheRaOtrsal Teratology ". "01 ExprimTeenstuedN6!1{3/1056/8811TROTIO : Please insert the anended page 3 to the above reprt. Five word changes vers made in the last gnendment to the rtweosulptasragarnadphdsi.scusTshieonstusdeycticsohReofl: utshei'ornaesrp*oertn.ot changed by this SenlorrReeserarch Technolog1i2st/03D/a5te) Animal Teratology Reprosustion ERa.seG2arcLha4mVpremetcehrti,nazByW,PatFhIoDlogi1st/Baavevy re wi ET HFaDTn.aegeCe;asneP.at7ho(owl,Aogy20T5oxicologyeo- ES gafety Evaluanion Lantcors 03070 Of TA-m2e9n9d8eCdoCpaigne R3attso -thEexpOerrailmeTnetraNtoo.lo0g6y81STtRuOd1y10 Results and Discussion ddd3ooo5szs2eei3n9gg9rcop0eucrpiaod(dn1.i50nimAstgt/ekgrgee/sddtaadytu)iroinrnaagltstdhaeiynspcea9r,uisoid1n2goafnldoowrg1m5aenao(nTgaebbnloeedsyis1,wewAiapgsphtetsnodxidixcurVityno:gtthtehhee hhiigghh nm9e/a%ns/mgdaratoyeu)rp,narlaantdsbodlwyoewigwhe(ei0dg.h0t5ssimggno/ifkfsit/chdeaanyti)lnytdeorlsemesesdigratohtuaepns(c5woemnraterKogmlsosdta(y40)i,fmfoeasrikesan/t(aiyfl)re.om controls throu ne the ghout the study. wgAbernrooeurpm.aatla,xTihccrleieannidcraatltswosiinogfnsthtehweehriergahtosbdsowesererveegdpraoalunepd ddieeadt.hs for one AocLcurthrreedeoonflythien rtahvee hciigsht to two days betore serra: daorseea thoexicSiutryvivdiidngnohtighoccduosre inratlsowedriddonsoet ahnaivmealasb.normal clinical signs and sisns of f7r-a2c9t96Cc0oCntewnatssnootf 3fe7tduses, the mean nteuahmbebreydroatmosof.xirceTshaoenrdpmtdeiiaodnnnnsouitmtbeeasrf,feofcitmmpaltlahene,taotvfiaeormnaileess,itoertso,traelcporrowpdneuarcstgiulvyuetea diffemreeannt ffertoums twheeighcotnstroofl th(eTabfloeur2,T-2A9pp9e6nCdoiCxdvois)e. groups were not sisniicansiy SA7iip;ep2re9nn9ledo8birCrx0aCViIddIi)Td.-2n9oA9t8sCci0agCunsietfrieccaoatmnmpteonuthnidpg-rhroeedrluactieendcifedatebannlcoersmokafelletgthreaolsssmkaefllefetotalarlmaftfiiinondndisinnggs(Toa(fnTiaeebnlee4, FfuirntohrerS,kaeetlheetmailisnsciainbdgeernorccaectiuoorfnredathnedinvfaitsnhdeinnohgtisohcfodnoosnisedeergSertdoeurpn&.ebmraalOcfneomrimssatsteiirnongnebvrieansstnmhoiivsssisnegadiys a aiabnfecfrierdraeetnnictoenssaomfwoenrsgeketlnheoettacldoinfftfirenordleinnStgrsoaumaposnsagoncditahtteheedfilvwoeiwtehrtrdeteahltrameyeeendttrgoersaostuimpfesin.ctatgiroonupea:nd The rin GgFrreeotaaulposfleitnnshcelufediminbndrigynogtsnhaelwecrnoeunctlroeobulsse,rgvraeoldutp.htoougTohhcecaurlveanirsniefitinynddioivfnigdsmuaolrwpehrfoeeltoulgsoieccsaalliofsaepadplletaordaocnhsceees SpguaehelasrfreeTruvtpaehrydeesauennndtteerrwiiottchheeinntdritashlsaetcrteligonicgoantmiioecnx.rtoesncdToihpneeg rifarnnocgnleudboeefdn:emaotarhpdhiotslhceooglilocernasaltisaoppniptehoaefrlaintnhceeessloecsos F a combitnhartoiuognh otfhelelnesnsdipossctoelroiroartliyo,n aandcltehfet patrestehenceantoferiaocceinatter.al lens region phTrieismtaosrepynastlheofnlisondgfiinicgbaselrlyodbesagseernvacerdfarteuienohdnae.rndtThsheeectdciilosensfietncgtviaansrgtaimfiasccpratocseocfopoepaenmweeodrmemaulpinastteeertnphreoebtveedstage gSOfifscttohhleeorolametbnirsoynovneaoslficnltueheclreeeummsbnraynfotrnoamalntdhneuccolnleesunissstreepedistuohlfetleaidaslferpcoaemrlaletsii.tohnerTohfethperdairmlkaenrsystbrleeeisnsnsg finery aOfcFrceeaennhtaunaadrttiisnfegacctttihoenbeeadirnegaacrcoorfsesatneotdrhmeailanrpetrahiemoaflreynnsolremdnauslrinpfgirbiemfrarredyeehgalenendnesrsaefsicibtoeinro.nidnetggheeneration 03071 ot :: - co BMeGKwellGceaorsreeme (ortgioat + WRe AC. mNeotCnoernmtok [RECEIVED] || ! RA Prokop 5G. Lanpreche Lol wiseen | | ES, FILE: EpxrpoetroicmoelntfoNrumObrearl0T0e8raetnool,og1ay) Study of T2990coct in Rate (ixer OBJECTIVE: OaeAFdaebtoirernycgioaasttntoooexlgrioeecsndysaanTsid2ta9u.9tt0yeCrToawhCitelolgtpeornboipeccreeudgesnfeafdnetcttosraevovefalueumaeetisesihsthtehe period CEg(ovo"nanGdleuuucicaadtteleildoirnneecsoofmetDonrrduagRtsieopnrfsoodruCcHfutnitaohnnaurSFUeeosuneic)eot:sme.psuifeisosucgreimsnwoairssceohosnnsmuneiyl,t 1966 be OKpeegraaltatilnognsaPrcocaconedrdduiSrnaegfse:ttyo Etvhaelu1a9t7i8onGotodabIoarpeerreenvsescysrEringrisi TSEPSOTNISNORG: FACILI3TY:CoSImamnfeeer.tcyisatBl.iaClPhaueuamlti,icoaMnliLnDainbveoisrsoaittoenc,y,StR.ikPearul,LabMoirmanteosroireas., STUDY DIKECTOR: E.G. Gortner a START OF DOSING: april, 1981. TEST SYSTEM: 3BOStrnoeeersealdhuiuencn-agdDgraeLeusadlbewoaiyrntadhtdoetvrreiyincveewsdiemlxelfuseahbmleallyehomuarstateusrde,ifnretmniamsecmhoimorasnteesodthRiivsetres LtFtaieEbmmoeprVeamritaalottreuydrbeefeuamsneaddlehsbuencaiardeuisteyreoacfdoifnlhltyiorseostslvoearidairncagsanoieeemsm..einntpie'ooesstdesesrtsraiinnyof The Lights wCihlolw baendonwataer12wihlolurbeioanveasialearbslecenscibtibitum. TEST SYSTEM InOuRmVbIeIrFsICwAiTlIlONb:e fnEadcihcataentdaaoln wtihleloubsesiedaes otfagstnegd carnede'that RMDOUIZIATION:GompThuetera-ngieanalcerawtieldlrbaendoamssmiegmnbeedrsc.agceasnlaeccording to a CONZHOL ARTICLE: corn oii. TEST ARTICLE: T2998coc. RALITICAL SPdE"So1CsU1Li1Pn)IgCa.ATpIrdOieNotSre:rmtionTehtdhoebtysetsattrhteacoStfpioclntosh,oerscto(u3md%pyoCsaointmdieorancianncshdeBpuerrniicttytea DOSAGE LEVELSia2nnuAdtsNupDbecanoEtdXniePtodEonRlIintNoaErcNtotThriencDlEeroSaiItlGwsNi:ldlailbTeyh..eadtTaehtsentistateresttriecssleetnyiweillmsleasbbeespension 2 reas according to the followionng:days 6 thresh 1S of sestation 03072 q ri, si J rer BpoOsenaetvaerany 00S1$..n05m5ogn//nrkaoeg)s/vradanagyayiyny . Group22stze z222 = bamTbeettooarboboretlad.il"stmrollsuottueiddiioeefnstasgrdsyhaoicvneoidnsttaremaaidtniiaoontntasbweilmrleaedb1seoeounmsesecdorrsbeectoaenusteeenlsl Sw2TFe0hl.eDs0xfhsetndeSinanisawntilclasyltiunobinea)rfeSobhcreeoraostbhaenssaosercmovsaneoldrdeueddphaeiianlctbyceeontrs6r,toimmn5igde7ian1yy.5i3 eS=cIrhErh2oouash20day Conmtant dose volume of 5 sag ee pease dai s3nUni0utet0mee0brs)euf].rsenonaafulnmedbcseo1rrv5psioolfrlcaonrbteLeuestnoKertispsl,tliewomdinulaobnseibrtedeasosy,fxe2mfn0eetrmeaemnncegdeer"otothte(aLeooeivresaalrriRieLesal,tsion Eonoe CshuibrspeuquoefvnattihofehrpeuaepnhaeangSdIrLsoecbesa.ibamFneeireaitgatibbeyrieLeso.nmmtainetTiiPeonsicmaatSieen SanEdtEpeoiehocscrreshhLoneinxscaiiattqcmiouyapnetagetbtlhymoyictodrhfteeoatsomecs-irotsimphriteieny.sseecsaoarpnStoiyuefelcevtcetimthrseecaneempyrmeauemlmaasmnaaeeebrrnroniormonearslbieRtienirsee?sa,d ui4sn4i0n9g a ' ClearinaglcoahnoalsftoarinisnugbswegiunontSlissheerbiernatLenstion a ais OHA MALYSISFboeEAr0Du0dsraeFDmdILNoaAfnnLodrsRipEatuPnepOasRl,Tvv:aaltnosunmTebhoseef,rpnomrefeonpstsoeaesspceladeofnsstntaeFasctaiitasuntmriiecsenaailieernnomnteototn,hstoold5st2ovo aT(ofhfatepepcrroporrxdpoiaopntroaaastiealdlleuyatdeaapht;ueipcfCeshoixrsaemstaiqhsneuoaantsEsiei.onneFsstoormhrmeopyrme:eerscseaeccstse m"oroaoopnArLonLnEsa1YCa,per ESp eniBor e RDesenarcth TechnoloE gio5n T SArnoiaoyn]DiDreercattoorrosy-memaenson SHAauneRasgser,SvaPtaatahA soitoonsyrpmosxteEceolnlcln?esr RE1 aGse.acetnampVreascahrti,nars FoeaTnciao4ss-sre2 Te oxicon l0.ogia s T il 63infay Speman: Representative 03073 ee