Document 9J53gwbvbR0bdyOKx521ZjVO5

! . AR126-02% TREC Oral Teratology Srudy of 7-299%0oC in Rabbits | ii; Experiment No. aenductod ats Dosing Period: . : seady Directors ToX20L 0681780212 SRiaktearrtyeLaPtreoaritaumtanatarisiooanrs.sLaboonreatory rez, May 10, 19"8o1nthrough 5. G. cortmer SB Sore /l-52 Ee tn Ze Senior Research Technologist uBnla dTampreibceoi,mpuBo, dFdD1/1/77/v/ae8t2e Research Veterinary Pathologist C Satety MaT lvation LAaboratory BEST COPY AVAILABLE 004192 2 Summary oTNfheeworoZgreaaalnloagnaeddnmeWishniiists)et/rwMaaitsniioknniontoftraeTbr-ba2it9to9sg9eCnodiuCcr.iantgC0o,gmeps1ot5ua,ntid5o-nraaenlldatd1ea.dy5smt6ge/rtkahgtr/oodguaegynhicto18efpfr(eepcgetnrsainotd were not seen on gross, internal or skeletal examinations of rabbit fetuses. os1f-e2nr9e9as9soCroapCthiwioagnshseiimtnbecrsiydoeatnnocdxeilcoofwatnaubtmohbreetri1so5nsomfgo/vrkigat/obdtlaaeyl flreeetvsueoslre.sp.tiTohnTishs,e ei1m5nbcrmryoeo/atKsogexd/idcamiyutmybevrass nfaeneodtnuas1te.as5lmesgxu/prkevgri/ivdeaanlycesddeoepsnoeoirlnenveteholensathwaeilrgehesrufrrdevoeisveaflrloemdvuertlhi.engeambr2y4ohtoouxirciitnycubaantdiopno.or The 5 2b1e-5t2mw9ge9/e9nkCg0/tCdhaecyaiunsleievtdeilam.taitoeNnronaolfcotdmoopsxoiiuncngdi-tarynedolfatthefedaitclleuirrnmeiicntaaoltigosaniignonfsnewttehremeesatnuundbiyqoudoeynltwyoeiignhtthe T-2999CoC treatment of pregnant rabbits. 7Fe-t2a9l99CroaCbb4i1td lneontsecsaufsreomleanlsl compound in utero. daobsneormgarloiutpiseswerien feevtaalluartaebdbihtissteoxlpoogsiecdalltyo. the 004193 2 Introuction This teratolosy studyl in rabbits vas conducted to evaluate the embryotoxic and btthyeera1t`SoagCfeoennriymcerEeevifasfl]eucsttCsiheoomnficLaaolbroarlDalityvoirsayid,omni,nRiikSstet.rerPeLaadubloT,r-a2t9Mo9ir9aiCneoesCs,Ro.tdIncaTehn,ed wsSatt.sudyPcaouwnlad,sucNtsiepndoenebssoytrae:d P2Te6o,rsos1ne5n8te1s.l ocfaTnhceobmpeproofutonoudcnodaldmianinnAdipspt1er1nasdttiioconefstghIreoaunppdrsinwIcFeirpreaelsdpoepsceatdritvibecelitypw:aenetnsaaynd1s0upaenrdviJusnoery PGALrpLaecrptaoitrcitenigo(nbGsrLEo)coferdestgtheuislsats(itsouendssyApvapenredendtihcxeon1dS1ua1cfteeftdoyrBagcvucaaollruidatitynigonAstLosaubtroharenacteGeoUronyditLSatsbatonardtaaetrmodernyt): RTahientsationreadgeinlotchaetioSnafeftoyr Esvpaelciunaetniso,n TLAaDwordaattearya'nsd r4eccoorpdy oarfchsihveesf:inal report is nethots DSCuoetmxcpuhusltlaelnryd-mgaLetanubeorzreaattNeoedrwiTeaZsen,adloanInncdm.i,WshbieDtreensv/eMfria,bnliekP.hi,n fanedaaalessriambebditcsasweesreacocbotradiinnegd tforoma The rabbits; ranging in weidht from r7a60b1bitSso 2ve9r1e7 hgroaumsse,d humdaity controlled wienrdeivtihdaunaldliyviidnedstianitnolesfsoustegerloupcsageosf room. Foods and water were availble i1n8 ad aaniSmeamlpsersetacehr.e libitum The anhde vTLhiietghhdtos3ssnvegwreoefreopnitth8uein1t2aarrhytoiufLriuctlieiaiglnhlityz/idnaigrnksheomcfiyacnolanets.edviSwaaictthhhef0.e5emaamrlleveorifanbpbboieotfloveradesdbiirnlejueeedcditnegd: semen. The day of insemination vas designated day of pregancy- a5Tbh,ne1o2ra,snailm1a5,lcsli1wn0iecraaenldcsh2i5a.genrsv,TehdeBdoafdoiyulrywefgirrgoohumtpssdawyveserree3 rtdohesrceoodurgdhewdit2h9onTo-fg2e9sg9te9astCti0aoCtniaoslnusdpfaeovrneded3, 6, w2aid5ta1hiynaiainstyerrcieondmgedaoiailnldyartuusbi0bn,egr1a5c,acto3hneastntegarnt1o-n5dogmseee/sktvaao/tldiuamoren.alofdTah1yesmLs6/uskptgehnbrsyoiuoegnrhse.l16e.irnecuFb-a2t3i9o5nCoC MLcaihbnaonrreaasctototerariieazsna,dtiocInnocr.nv,aosiSlpt.rcolPvaeiusdlre,adncbMeyimv3eaMssoCtpoarmomve(irAdcpeipdaelnbdyCihxemmmTiVac)l:aylticDailviCsihoenm,istSrty., PaRuilk,er AuFLtoLelrluosswu,irnvgii:vnicnlgumduaimnnbigemraioltfss vcceoornrtepeonretaust,huatnveaestr,sizmeedxatboaenirnegodefstivamitmdiebodlnieaaltefledyrauysteo2s%,.demteTmhrmemeironveoafrtihees and prZeeertsiuoonrdep.stiovenFroelslitothewsai,nngpfltaahtceaeldivnceinuibhaatntsioinnncdpuebrasiteoxod,r, aatnaldl37g0freoCtssusfeofsretaavler2e4a-bKhnioolwrismeadilnicatnuidbeasteixoanmTihened aFCbolnreoarrimniatnlegirtnaianelds.asbtnaAoirnmtiaonltgailtoifeosft.h4e55sThkeefeltefavelotnusreavsbibtihvteraselvietsshaernwienrperreedfsiexrtevodeddeinitnec1at0l8esobkhueoftlfeetraferodr hfeomrsmtaolxiyn,iinembanedddeeodsiinn aPnAdRALeEvianl.uatseedcthiiosnteodlosgtic5a-l6lym.icroTnhsi,s vsetsaindoendeNibetchause a 25 R3ik9e2r 4Exp(etreicmhennitcaNlumgrbaedre 0T6u8-1374R2022)12 Purina Rabbit Grow, Ralston Purina Co., St. Louis, 004194 3. twlahesinssa satrturtduiyef.aacbtnThoiernmraralabitbtiytteriwnaatstohlueosgeyrdats.atsudaiessecwoansd bsepiencgieesvalinuactaesde ctohneculrernesntlfyindwiitnhg Results and Discussion oT(rh15geamnogor/gakelgn/eadsdaimysi)ncidasoutssreeadtdimooaentseorflnoasTlt-2s9toi9xg9inCcioifCtiyctaoonftplryelgomwnoarmneetawnreabibogbhditytswtehdiausnrhittnhgegatihcnoe.ntpreoTrlhiseodh(i0ogfh tfmh5ae/iklgse/tddudatyyo.) gbaTiehntewnemeeitndbdao(y5dsymgw6/ekiaggn/hddta9yb)eoftawnetdehneltsohtweud(fy1i.5r(sTmtagb/dlkeagy/1d,oafyA)pdpodesoinsndegixgarnVod).upthmeTehaeenyndalofso mtTha-et2e9rc9no9anCltorCobltosrdeygarwtoemuiepgn.httoNfgoariancbsobmipatonsud.ndl-orsesleastewdereclinneivcearlssiiggnnisfiwcearnetluynidqiufefetroent from Maternal directly toxicity tdoeacthosmpooucncdu-rrreeldatdeudritnogxitchietys,tuedyv.en of low body weight gain. tNhooudgehatthhse ccooumlpdoubned actatursiebdutmeadternal Airensccororempaptsoieuodnndsi-nrocecilcdauetrnercdeedhwiagosnhlynionticnisdtethnaecteihsitaginhdcapdloelsryecesnigtrgaonguiepficroaafnbtbaibto(srT;taiblohenoswe2v)o.err,tTohttehaelincidence waenrdepenortcendtiafgfeeroefntabforrotmiotnhse ocronttorotlalgrreouspo.rptions of the mid and low dose groups 7-2999CcC dose does hwaadsaemsbirgynoitfoixciacntaltythleovheirghnudmobseer higher number of resorption sites than the olfevevli.ableThefetTu-s2e9s95aCnodC treated high significantly control group (Table 3, Appendix dVLoIis)te.tergrTohdueaptsanumwmeebraeesrusrneoomtfensvtiisganbiwlfeeriecfaennttoultsyesadfifafenfdcetreredenstboyrfprctooimmopnotuhsneidtceoasndtmorifonlitssh.teramtiThdieonafntodolllotohwweing does: lutea annudmbmeeranoffedteuasdwefiegthuts.es, number of implantation sites, number of corpora sTuhrevifveatlu.sesThoef 7-2999CoC high dose treated fetuses control fetuses (Table 2) during hhaidgha dsoisgenidfoiecsanetxlpyerhiiegnhceerd poor neonatal mortality rate than a 24 hour incubation. Survival of nid and low dose fetuses was comparable to controls. VNfIroIo)mm.asjeopsramragalrltoesasncdomnatrlrufonoltremdadtosifeoentsugsreowsueprweedrooeebsseshereavndedcilntuobtbhbeeed ccofonomtrpreoopulan,wds-mrie(dlTaatabenldde. l4,owTAwGpopeefenedtiuxses 90UPS, But not in the high dose group. No internal abnormalities were found. f7Te-ht2eu9s9ie9nsCc.oiCdewTnhecereesonoglfeynesrekaxelclleeypttalinoontfidwnaidsfifngeasresniatgmnoifnfrgoimcfaetnthtuelsyesfihniodfgihnergrasbbiinftocrsidertnhececeeciovofnitnrgfoeltuses 004195 a. nwAoipttphetned1ri3axtrVoiIgbIesIn)is.cpuartTrheedtheoirnadlotsheaedmllieonvwielsdstorstaeetsigtorenodu.opftTh-a2n99i9nCctChetocopnrtergonlangtroruapbb(iTtasblweas5, cMeioonnsetirnoalbsntodaroimenaelNd1Blf1ee1tn9as6le.s rwaeTbhrbeeitrfeoemyuaensid.ndoenrAhloilfstnotilhneoegiafcebatnalolrmealxleanmsilenesantseieiostnhweoerfrehhafedrmaomtmooxfyeltiunsesandof csaiugsneifliecnasntabcnhoarnmgeasl,itiweesreinnoftetraeladraablbeb,itsorexhpaodseaduttoolystihes.comTp-o2u9n9d9CionC autiedrom.ot 004196 5. Table 1 Oral Teratology Study of 7-2999CoC in Rabbits RabbMietasn BBeotdyweWeeniWgehitghGianignsowritlhossSta(ng)darodf PDerveigantainotns Ay 6 5 12 15 18 25 0mg/kgS/TdAaNy. MDEEAVN 47.883 6-0.346 75-.90 66.48 923301102.364 15mg/kg/dayMEAN _ S6 -12 -50 1 10 159 STAN. DEV 31.5 67.7 63.4 73.5 72.4137. 8 5 mg/kSgT/AdNa.y MDEEAVN 45.437 48-.428 7-52.44 6-82.32 66.05S1132.434 1.5 ma/kSgT/AdNa.y MEDAEVN 256.35 77-.20& 55.71 60.241 62.s48 551.718 2 Significantly lower than the control (Dunnett's t test p < 0.05) 004197 Damon mWambesr of omnzar 1s Swng 1 swarm Lsmnoey g$e 8& oie 2 OraBlepresctautcotliovneyBsotrutodrymaonfenT-aasnvdscTnoctalinSRuraviivtaal cronyception matv e Incm Siodnepnicheonotf Tonota1 5 ow ns ow ne ow 16 wom 24 . Pr20 toour nmateion 2 wm 2 " wt ow . wm M wa ue 2 sionteicancly higher than the control (Chi-square with Yates correctionp < 0.05) ork est sge2 s In te a ta ts rt i oie rt omnrRiosli V43E27rTe8E7 nRoseso sCseEnErrion ss neyUsmOaion 11 CcoEon ze em me s smn 15makg/ay 8 208015 38 332% 36 ea ss 3c158 F5 reeman peor 88 se 6s 4.8 s1 es ee a ow * Significantly different than the control (Dumnett's t test p <0.05) a abe Ora Teratology Study of 1-2995CoC in Rabbits Mumber of Fetuses with Gross Findinge Findings Total Fetuses examined smal Runtea Clusbed right forspaw Total normal fetuses Total abnormal fetuses a0nymg/kg/ a1n5ymg/kg/ a5nymg/kg/ a1a.y5 ng/kg/ 81 " 1m 2 (3) % oon Te 2 2 00) 0m 2 2m 2m 7s 55) cm 58 ae zw 53 (on) sm * T(rCehait-mseqnuatregrvoiutphs ) = percent of tYvoaettraesls nceoxotarmrsieincgetndiiofnicpan<tl0y05d)ifferent from the control group 004209 es 9. Table 5 Oral Teratology Study of T-2999CoC in Rabbits Petal Skeletal Findings Findings 0 ma/ks/ day 15 mg/ks/ day Smg/ke/ day . 1.5 mg/kg day Fontanel not closed Frontal not ossified Parietal not ossified Interparietal Holes in both not ossified parietals Holes in one parietal Sternebrae Sternebrae not ossified asymmetrical Sternebrae Sternebrae bipartite fused Sternebrae scrambled Sternebrae misshapen EOxnetrastesrtneerbnreaberameissing Extra sternebrae not ossified 13 ribs 13 ribs spurred 13 ribs floating Ribs forked R1i0bsribfsused ERixbtsramirsisbhsapen Vertebrae scrambled Vertebrae fused Vertebrae misshapen Caudal vertebrae scrambled Total Normal Fetuses Total Abnormal Fetuses Total Number Fetuses 1 (17) 10 (12) 10 (12) 2 3) 3 (4 3@ 23 (28) 709) 3 (@) 4 (5) 2 (3) 4 (5) 1m 2 3) 4 (a) 7 (25) 7 (25) 2m 2m 6 (21) 2m 1) 1a 9 (11) 6 (n 4 (10) 5 (18) 1@ 5 (6) 1 1) 1 1 1 11) 1 25 (31) 8 (29) 56 (69) 20 (71) 81 ET 16 (20) 5 (6) 5 (8) 1 4 (5) 15 (19) 5 (6) 4 (5) 2 (3) 1 1 5 (6) 3 (@ 8 (23) 7 (9) 1 1 7 (12) 8 (14) 8 (14) 2@ 16 (28) 1 1@ 4am 7, (12) 13% (22) 29 (37) 50 (63) 7 20 (an) 34 (59) s8 # csoirgrneicftiicoanntply<0h.i0g5h)er than the control (Chi-square with Yates (1) = percent of total examined 004201 10. Appendix I TITLE: P(rRoitkoecrolExpfeorrimOernatl NTuemrbaetrolo0g6y817S5t0u2d1y2)o.f T-2999octin Rabbits OBJECTIVE: 2eAdznbtirenyrioastttooexlrioecgdya-nsdt2u9dt9ye9rawCitClolgteobneipcrueesgfenfdaenctttosreavotfasluodarutarelilntyghe Ogefneorraglanorgeecnoemseinsd.atioTnhse pofroctheeduFrDeAciosmspuleidesiwnitJahnuttahhreey,per1i9o66d Eg(ov"naGdluuuicadtteeildoinneascofcofrDodrruignRsgeprftooodruthcHetuimoa1nn978SUstGeu"od)oi.desLaTfbhooerrasSttauofdreyytywill be ORpeegrualtaitniognsProacnedduSraefse.ty Evaluation Laboratory's Practice Standard SPONSOR: 34 Commercial Chemical Division, St. Paul, Minnesota. TESTING FACILITY: SInacf.e,tyStE.vaPlauualt,ioMninLnaebsoortaat.ory, Riker Laboratories, STUDY DIRECTOR: E. G. Gortner START OF DOSING: May, 1981. TEST SYSTEM: FiSnaebvbesinttatsiyn-ltfewrsoosmsseDtxueuteacllhllcyaangmdeasLtaubrwoiertahNteowwriirZeeesa,lanIdnc.W,hiwtiel/lMibneikhionused temperature arvaabibliatblwei.ll baendusheudmidbietcyausceonhtirsotlolreidcmaerlosohmc.ofnltorToohrliss diasnttaraaiins of lgivgahitl/adbalrekacdyPcullrieib.nitaunR.abbTihteChloiwghtasndwiwlaltebrewionllabe12 hour TEST SYSTEM IDENTIFICATION: number will be Each animal indicated on twhielloubtesiedaer tagged of the and that cage. FANDOMIZATION:compTuhetera-ngiemnaelreatweidllrabnedoamssniugmnbeedrscatgaebslea.ccording to a CONTROL ARTICLE: Corn oil. TEST ARTICLE: 7-2999CoC. ANALYTICAL SPEE4Cu1Ip1FI)CbAepTrIdOieNotSre:rmtionTtehhdeebtysetsttahretartSipconlseorcom(pIosCiotmimoenrcainadlpuCrhietmiycal dtoessitnga.rticTlhee sspaomnpsloeraswilrlequboeifrertdehespinosntsGuiLdbPyleraengfduorlaattrietothneesn,teinonooff # FM-3924 (technical grade F-3422) 004202 , ---- 1. DOSAGE LEVELSasnuAdsNpDecnoEdnXetPdrEoRliInMaErcNotTrincDlEoeSiIlGwNi:ldlailbTyeh.eadtmTehisentistateresttriecdlaertbyiwciollrelalsbuespension giensttuabtaitoinonactocorthdeinrgabtboittsheonfoldlaoywsin6g:through 18 of D1o5smeg/Lkegv/edlay S mg/ke/aay, 1.m5g/mkgg//kdga/yday Group 7S6ize 1188 18 tTohxeicoirtayl hraosutbeeeonf daedfmiinneidstbryattihoinswriolultebeinusaedrabnegceafuisneder wsittuhdy.theNotesdtieatratriyclceo.ntaminants are known to interfere iOnntrtahveendoauys ofinjberceteidoinng,Of ea1 cmhgfoefmaplietuwiitlalrybelugtieviennizainng haseromtmeionfnieccioaltlloleycitneiddnusceefmrioonmvautNleeadtwiowZnie.tahlanT0dh.e5Whmdlioteoesf/Mwpiinoliolklietndhemndailbleeuted rabbits. OAlfevbeglleo.sotdatTsihaoemnpslafemropwmlieltslhwebielslatmaebkeesnilpxarbeerl-aedbdob,siet,sfraodtzaeynea1ca8hndadnodseday 29 transferred sTahmeplsepso.nsor twoillthebesproensspoonrsifbolreblfooordthleevealnsalyansaelsysoefs.the T29heofangiemsatlastiwoinllfobre observed abnormal cdlaiinliycaflrosmigdnasy. 3 weights will be recorded on days 3, 6, 9, 12, tBohdryough day 15, 18 and c2o9nsotfapnrtegdnoasnecyvoalnudmethoef rabbits 1 ml/kg dosed accordingly of body weight. using a uTtheerufsemaalneds iwtisllcobnetenktisllewdillon bedaeyxa2m9inaendd the ovaries, to determine: number dead), noufmbceorrpoorfarelsuoterap,tinounmbseirteso,f nfuemtbuesresof(1iivmeplaanntaation sbsueirtevpsil,vaaclpeducphienwcekia.gnhtiTnhcaenudbaftogorlrolsosawtinagb3n7doarymaCltihfteoirepsua.ps24wTihhloeluprbupes will atbenromrimnaaltietdieasn.d tThheeireyveisscweirlalebxeamrienmeodvefdo,r buffered formalin for possible processing afinxyedintinernal and histologic cealxleacamoihrnoialntgifoaonnr.d ssutbTahsieenqipunuegpnstwiwstikhlellaelttiahzleanreixbneamrifenidax.teidoninafettehryl -------------------------------- 004203 - 12. DATA ANALYSISbfeoArNDusdeaFdmINfaAonLrdRpaEunPpaOlRTyw:seiisghTtohsfe,tphnreuompbodesatreadoafsrtefa:ettiusstDeiuscn,naeltntum'mesbtehrodstofestto Orfesocroprtpioorna lsuitteeas;, The proposed date Cnhuiabesrquaofreimfporlapnetracteinotn saibtneosrmaanlidtineusm.ber for the final report is 2-3 months a(fatpeprroxdientaatielleyd pfouuprtehxaqmuianratteiro,ns 1h9a8v1)e. been completed ------------------ 004204 13. Appendix 11 List of Principal Participating Personnel nave Eduin G. Gortner Elden G. Lamprecht Gary C. Pecore Bud G. schmidt Loren O. Wiseth FuncTIoN Study Director Veterinary Pathologist Supervisor - Animal Care Riker - Analytical Technician EE ------ 004205 APPENDIX III 2. STATEMENT OF QUALITY ASSURANCE STUDY NUMBER: 0681TB0212 TITLE: Oral Teratology Study of T 2999CoC inRabbits Audits and/or inspections were performed by the Riker CTeopmoprltieadncetoAutdhiet sutnuidty dfiorrectthoer aabnodvetotimtalneadgesmteundty, asand follows: DatePerformed 14 and 19 May 1981 2 June 1981 12 June 1981 18 June 1981 7 July 1981 7-8 July 1981 28 December 1981 30 December 1981 Date Reported 21 May 1981 3 June 1981 12 June 1981 25 June 1981 9 July 1981 16 July 1981 4 January 1982 4 January 1982 004206 ey efEgi Riker Laboratories, Inc. w 1/32l AnminoTx 1v 15. ext and/or Control Article Characterization for -2sacoc 1. TFihoneoenritddeeccnhotairtraysicnteseatrreiansngsdtthid,ooncsuumneoinfftoertmdniataybL,eosftcomapnods/iotrionc,ontpruorlitsyubosrtanoctehserhapveeri-. 2. dTToheceuimmoeeantithneogdd.thofeirsyanmtohuonstisanodr otrheigimnuthoofdthoef btieosatssaanyd c(oLnftraoplpliscuabbsltea)nceiss, veo X 2ne 3. mTieneastoacbiiiiie)y bofe dtehteercmositneadnda/orofcontrolComsplpclarotrsaoncfys Hep.ave penSoduka.ter- hreieabove information and documentation are located in the sponsor's ze- I A Hols TasilleT(at8e . + CoD Analytical Reg. No. 16474 October 26, 1980 rom rss ee 004207 " 16. Appendix IV (Continued) Prestudy aOnrdalPToesrtasttouldoygAynaSltyusdiysofofTt-h2e99C9oCronC in Rabbits Oil Control Article Analyses Peroxide Value Refractive Index Prestusy 1.2 meg/kilo 1.4730 Poststuay 1.8 meg/kilo 1.4700 a---------- 004208 I Oral Teratology Appendix V Study of 1-29996oC in Rabbits IndainvidduBatlandBaorddy Deeivgihattsion(s5)fovritPhreMgenaanntBoAdyniWmeimgihsts bv 3 6 9 a2 15 18 29 MasKarDAY NB 1178 2237 2367 2313 2369 2450 2399 2661 NNNiBBB NAB 111111807109 1154 222042167539 1761 222414044407 1620 222403325155 1613 222403135492 1842 222302019662 1922 222404377485 1976 222637795458 214% NNAIDE NIB 11115965 1157 11674120 2917 11766569 3033 11552786 2973 211755316176 11954232 2705 11952403 2560 2A2971309588 NE 1374 2246 2334 2316 2272 2338 2467, 2674 : NNAIBE 11339765 22436614 22640473 22642150 52549141 22635445 2689e2t6o8 NNNIABBB NB 111333959321 1406 112961303506 2086 212051175176 2130 2212109114752555 2212409220931643 2222010360241057 2222006267907129 s222e204i506s80 STANM.EADNEVI2201.56833272.41534222.04834241.96330242.01130212.21332545558 NON PREGNANT ANIMALS NNABB NB 11327160 1377 i2706330 2028 12500185 2116 11856711 2165 12701874 2196 12710427 2174 42713389 2501 12729717 2401 2antaal ated - intubation error 004209 ee : 18. Appendix V (Continued) Oral Teratology Study of T-2999CoC in Rabbits IndainvidduSatlandBaorddy DWeeviigahttison(sg)fowrithPreMgenaanntBodAyniWmeeisghts DAY 32 6 9 12 15 18 29 15 MG/KG/DAY . 01B O1B 1183 1184 1765 2209 1834 2282 1769 2048 1763 2131 1716 2219 1827 2212 2636 2419 018 O1B 1485 1158 2127 1890 2177 1995 1951 1899 1884 1501 1650 1825 11779889 11559144 01B 018 1195 1200 1826 2055 1690 2102 1737 1967 1686 2008 1762 2064 1823 2152 2002 2152 01B O1E 1261 1211 1896 1963 1926 2018 1671 1943 1561 1948 1613 1988 1560 1992 1753 2205 O1B O01B 1378 1375 2316 1931 2338 2006 2158 1864 2030 1824 1953 1811 1851 1863 2175 1570 01B 01B 1380 1361 1805 1958 1898 2001 1757 1945 1686 1670 1712 1706 18406,% 2087 01B 018 1394 1395 2008 2001 2028 2005 1521 1926 1789 1835 1796 1947 1676 1949 1995 2216 01B O1B 1396 1407 1953 1724 1993 1770 1935 1758 1868 1745 1826 1732 1896 1742 2109 1754 STANM.EADNEV1S1E9.60815200.16712158. 96314138.45515178.47216138.66321210.215 NON PREGNANT ANIMALS 018 018 1182 1397 1987 1690 2105 1788 1845 1638 1928 1559 1932 1515 1508 1531 2106 1752 2 Animal ated ----,,--=e 004210 B 2. Aopentix v (Continued) Grad Teratology Stuey of 298560 tn Rabbits Ind4iv5iduSatlandBaorddy Deeivgihattsion(s3)fovricPheMeapuenrsBoadhyinWeesisghts bv 3 6 9 12 as 18 20 s MarkaoRY PPPiiisSE 1i111l58o76 222361604777 23262076s36 22c25o12e66r 252530548647 2523415527s2 S2214764637 s2s4ee9es4s PPiIsB ii210035 12365739 21390540 i2635745 Z1o964e5 21295404 21539965 Sseueesd PiB 1205 1783 1824 1795 1795 18685 1881 2056 PPPPiIi16SSB i111333206614322 22Z204i15a4107s9 2222204260605056 02s21o100n8s6i3 2ss20oo26i121si3 1Zd26oo2o7e7s3s3 is127e393s075s1 Ssi265aio2sse8 PrP1ii8eE 1ii3339e85s5 2aZri1e6as67 322n11e076s3 24211755s75 I2si63ss0 S1l1e70e26s A12911S356 RsuResL PPiiSE 1id4e0s0 21565335 21595113 21530055 21366648 21s7096 3i502403 o2b1e5n7 P1B 1408 1868 1763 1808 1965 1985 2000 2107 STANM.EADNEV202.112327201.59724201.10S20270.8582125061624270.66S30213.20 NON PREGNANT ANIWALS PiB 1202 2073 2147 P1B 1204 2252 2287 et eo et eo e [3 ee B himtamnd tateesd - intubation error 004211 20. Appendix V (Concluded) Oral Teratology Study of T-2999CoC in Rabbits IndainvdiduSatlandBaorddy DWeeviigahttison(s5)fowirtPhreMgenaanntBoAdnyimWaelisghts DRY 3 6 5 12 15 18 29 1.5 MG/KGDR Q1BB 11115510 12802514 12813250 12805982 12802656 12809455 12911346 22135372 GiB 1152 1653 1706 1744 1769 1806 1793 2014 Q1E8 11220076 11573876 12178968 12170762 12719862 12282663 22502501 001186 11220183 12181710 21196120 o15e1s7 1290178s 11395631, 22003228 22120435 GGiiBB 11336857 21160751 21291463 21271406 21168153 2132 2080 2153eo GQiEB 11338885 22142786 22520110 22313531 22413541 22511856 22253428 22472422 GiB 14062 1822 1897 1963 1967, 2066 2088 2273 QGBE 11440053 22167735 22273342 22269915 2295&2332 25190 26150 STANM.EADNEV27260.35728200.98526260.69323230.22621200.77023201.47722243.246 NON PREGNANT ANIMALS QGiEB 11210939 21394621 21493970 21491302 21939741 21299858 21252750 22509667 GQ118B 11440094 11680517 11786922 11780563 11780703 11685873 11696152 12706583 Animal ated - tneubation error 2 Anizal died 004212 --- 21. AppendixVI Oral Teratology Study of 7-2999CoC in Rabbits Individual Litter Data with Mean Fetus Weights mg/kg/day `ANIMAL NiB 4478 NIE 1175 NIE 1188 NiB 1181 NiE 1154 NiE 1195 NNIiEB 1156 1157 NNIiEB 1210 1374 NiB 1375 NNIiEB 1376 1377 NIB 1396 NiB 1391 NiB 1392 NiE 1353 NIE 1406 VIABLE FETUSES MF TOTAL DEAD FETUSES RESOR PTION IMPLAN TATION CORPRA LUTEA MEAN AVG SITES SITES LITTER TOTALLY 41 5 RERBSORBED 5 42 6 71 8 1 6 9 32 5 38 3 e 5 36 2 4 4 5 6 5 e 6 9 NOT PREGNANT 6 4 18 DEAD e ie NOT PREGNANT NOT PREGNANT 52 7 6 4 1e e e7 10 ABORTED 103 4 35 8 4 e 5 44.1 11 7? doe 2sa s 38 e 6 368 389 8 349 6 353 7 423 6 286 9 424 7 461 ee Pee cc 004213 22. Appendix VI (Continued) Oral Teratology Study of T-2999CoC in Rabbits Individual Litter Data with Mean Fetus Weights 15 mg/kg/aay ANIMAL VIABLE FETUSES MF TOTAL DEAD FETUSES RESOR PTION IMPLAN TATION CORPRA LUTER MEAN AVG SITES SITES 01B 1182 NOT PREGNANT 001186 1163 1184 2 2 2 4 4 6 e . 1 3 s s 6 42.4 6 32.4 01B 1185 ABORTED 018 1198 ABORTED O01 1159 01B 1266 ABO2RTED0 2 24 6 424 001188 1261 1211 LIToeTER2 TOTA2LLY REABSORBED 2 4 7 391 O18 1376 018 1373 LITTER LITTER TOTALLY TOTALLY REABSORBED REABSORBED 018 1386 018 4381 LITTER TOTALLY REABSORBED DEAD' 018 1394 01B 1355 2e 2 42 6 2 4 6 5 7 401 28s O1B 1356 018 1357 3 NOT 14 PREGNANT 4 8 we 288 018 1407 11 2 1 e3 5 242 . 004214 ---------------- 2. Appendix VI (Continued) Oral Teratology Seudy of 7-29990oc in Rabbits Individual Litter Data with Mean Fetus Weights 5mg/kg/day ANIMAL VIMABLFE FETTOUTSAELS FEDTEUASDES TRIEOSONR TIANTFILOANN LCUOTRePRRA tMoEeAN siTes sites PPiBs 11116676 PB 1188 54 43 88 34 7 0 2e 18 8s8 ie 6 z2ena7 ei PPFi1isBB 111221008329 P18 1204 DE1A1D 32 1 DEAD a oz e a e 4 62 6 38.7 & a2 PPiBs 11221025 PB 1382 33 33 67 53 7 oogoo i2s7 e7 PLB 1383 LITTER TOTALLY REABSORBED 6 333ss 8 22 PP1B8 1133885s PB 13% 13 >3 63: 41 5 oog a PiE 1335. DERD ee 6: e5 5o4s i33ms3a45 PE 1400 3 2 5 a 16s 343 P1B 1401 1 Ss 6 a P1B 1408 41 5 a eo 6 1 6 8 40.3 5 34.4 } . 004215 : 24. Appendix VI (Concluded) Oral Teratology Study of T-2999CoC in Rabbits Individual Litter Data with Mean Fetus Weights 1.5 mg/kg/aay ANIMAL Qe 18 11119910 QB GiB 11115532 QB Qs 11220676 Qi QiB 11220085 0Q11B8 11328163 @18 @18 i13e6s7 Qe @18 11436e29 Qi GiB 11446643 018 @1B 11448055 VIAMBLFE FETTUOSTEASL FEDTEUASDES PRTEISOONR TIAMTPILOANN LCUOTREPRRA AMvEeAN SITES SITES 2 2 1 1 3 3 32 5 3 3 6 5 NDOETRDPREGNANT 3 4 5s 4 8 1 8 s DNEOAT4DPR2EGNAN6T 6 LITTER3TOTA5LLY REABSORBED 9 1 4 24 8 3 DEAD 1 8 4 NOT 3 PR2EGNANT0s s NOT PREGNANT S & 4a0o5e 7? 3sa 8 s 3345.01 7 354 7 7 4208.92 5s 47.2 6 326 004216 ---- -------- ---- -- ee-------------- Oms/iy bemde. Findings TRSimnar tlala ane Clube rightforeper Tota normal fetuses Tlemomlltwe a3 88 Nu Appendixviz Oxal Teratology Study of Number of Patuses by Dun T-2999coc vith Gross in Rabbits Findings WM Le) Mew 94 195 Ms 197 17 190 191 193 140s 56 56s 6 a 5s oa, 1 1x ` 2% 8 42 ow6 35s , 010 11 0 0 0 0 4 , Appendix VII (continued) Oral Texatology Study of T-299cac in Rasbits Humber of Fetuses by Dun vith Gross Findings 18 ma/xa/ey dmde. Findings 163 Les 199 11 1% 195 136 1007 Total fetusesexamined 46 2 2 2 6 4 > Totalnormal fatuses Total abnormal fatuses oe 22 26 4 0000ooo 8y&S Appendix VIZ (continued) Oral Teratology Study of Number of Patuses by Dan T-299%cac with Gross in Rabbits Findings Smofa/iay Findings DamNo. 66 1ST M8 169 1203 1205 1m2 12 1396 15 198 1400 Mol 1400 T=emeemi 887 Rented 1 42 6 71a1 3 6 3 5 5 oo TeLmmlfewe 877 Tulgmomlfewses 010 4 0 2 0 6s 02 6 1 6 0 35 oo 5 o 4 o 4 , 2S9s 88 pena VII (concluded) Oxal Teratology Study of 7-2999Coc in Rabbits Wuzbar of Fetuses by Dun with Gross Pindings LS mg/day bamNo. Pinatnge TotSaal Flotusesexamined Raneed Totalnormal fetuses Totalaboormal fatuses 150 191 152 107 1208 1213 160 19 M02 1405 3 1 s2 s1 6FE ss s3s1 303 4 a as a a3 0101 110o 32) 83 r---- HuOmrbalerTOefraFtaotluosgeysSbtyudyDamofwi1t-h29S9k9ecleectailn Rabbits Findings masany Pato. FTroonnttaanlelnontotoscsliofsieedd I M0 Mel 1% 195 11% 197 13 19% 191 193 106 2 . ` 3 SIPtnaetrreinreeptbaaerlatsnatonatoltonsaosstisfioifselsdeidtied F2E a 1a 22 22 53 SStteemmeebbrraass Starmabran bsiypmamreetirtiecal fused 1 H3 2 1 L2 E i oSSnttaeerrsneetbbarrmaaesnbrsaaoiersasmshibaslpseeidnng 11 : aa1 oa a 1E3xtcriadestormabron R1i3bsribfausesdpucrea 1 1soa a1 11 1 1 1122 S$S5 xitbreeammicsisnheapen 11 13 1 K8H Vveerrstaebberaaoe sfucsreaasbiea Vortebrao misshapen 11 1 CHaouldeaslinvebrottehbrpaeaisactraatmsbled 1 1 Holes in one parietal 33 Total normal fetuses Ts 0 3 0 0 3 a a a2 5 Totalabnormal fetuses Total number fatuses 2 0 8 2 3 6 s&s 6 8 2 4 56 8 5 3 6 9 ow 7 ow 4 Aopenaix VEX (Conti) Oral Musbes Tecatolony of Patuses bsytudDyumovfit2h9S9ke6lestalinFimnadsibnigcss IS es/o/tay Dade. Mes us 199 1m 13a 195 196 1407 PFFaroronintetatanalellnnnotoottocscsolionsfieiidsedd 1 Starnibeas not oasifisd 2 11 3 +i2z . oSSntteearrnnSeetbbarrceamesabrsbaiosprammrmittsirrtiieonngl 33'eibe 1 : 2 i3 i g 1o33l3anir"isvaeinslbpoountcthrienpgarietas i13 8 Holes in one paristal i1 a 1 2 i 88 Total normal fatuses 1a 30 2 2 0 a 0 oo Total abnormal fetuses Te 0 0 2s 4 Tol meber fetes 4 6 2 2 2g 4 Appendix VIII (continued) Oral Number Tezatolosy of Fetuses Study of 1-2999cec in Rasbits by Dan with Skeletal Findings Saar Demo. FTornotnatnaellnnototocslsoifsiesdd 1166 1187 1S WE 13 105 122 12 164 165 1398 100 1000 108 2a 52 a ios a SSPtatererimmoeetbdarrlaassnosntostoysmosesitstriiifecidaeld 2 11 Stommabras biparsite To 11 32211aa 11 af, 1 SSttaermneebbriaass sfcorsaemsbled 1Loaai 1 1 S ESxtterrramiedsebtreasrnimbirsasshapen B13 ribs spurred 4a a 2 2 1211 :1 a CRR13neribfaoeFlsoating 1 2 1a Toa HHoolleess Extra siinnteobmnoeetbhrpapasarrineitoeattlaolsssitied2 1 1 1 1 Total normal fatuses ES a Tul mmm fwes Total number fatuses 65120 ss 4 4 5 53 4 5 Se 7 42 6 7 9 6 3 5 5 4 ee Nopendt viz (metas Toccoa sey of 2-5991 bien mbar of Tetunes by ou vith neta ndings EE fFTroeentyealnesgodmiclnoeneedla + NN oa}FENN $ HShNaamommmemmittbeoirriee 1 FI Pro :: sas Y 8gOm 5R5Iwreed \ Csoo}odsdFdI d ` Pelemitwe Temes 13 10 4s 4a 4 4 2 a 4, 4, oat mb ats Sas ew ws a ss RECEIVED cet EMGm..KetGtcoearrstener (original +1) 6. Lampreche WRie hC.. bMeooChoernmick Toxi2Co3Loay V. Pothapragada/L. winter 10 0. Wiseth #ITLE: P(RriokteorcolExpfeorrimOernatl NTeurbaetrolo06g8y 1S2t8u0d3y52o)f T-2999Cockin Rabbits OBJECTIVE: O2AefdmnbtoirernyrgioaasttntoooexlgrioeecgndyeasTnsi-dts2u.9td9ey9rCaTwhotieColgletnobiecpruoesgfenfdaenctttosreaovtfasleueadstuierliyytghethe period Eg(ve"anGleuuriaadtleiloirnneecsoofmoeDnrrduagtRsieopnrfsoordupoclrftuoimctoaehnndeurUSFsetOeuN"ds)ici:easspsluTfiehoodersissnitaeSsheaarr'mscewosieyl,l cond 1966 be ORpeegruaulatctitineogdnsParcocaconedrdduiSrnaegfse.ttyo tEvhaelu1a9t7i8onGooLdabLoarbaotroartyo:rySpeermmrtoicme SEONSOR: 3 Commercial Chemical Division, St. Paul, Minnesota. TESTING FACILITY: ISnacf.e,tyStE.valPauualt,ionMinLnaebsoortaat.ory, Riker Laboratories, STUDY DIRECTOR: E. G. Gortner START OF DOSING: May, 1981. TEST SISTEM: SiSenaembvpbeseitnrtatasiytn-ultfrewresoosnasnDsedtuxetuhecaulhlnlliacydangdmeasLtaubrwoiertahNteowwriirZeeesa,mleasnIhdncWFehoimntiess/tMinnaxCsitnoased aarvvaaabiiblliaatbbllweei.laldPbueLriibuinscaeudnR.abbiebtcTiyahtuesceCohlniohtgwirhsotatlsnoldrewidwicalartlloeerbsc:eewneitntrm)eiassbedizsetreasi.n of hour/aark cycle. TEST SYSTEN InDuEsNbTeIsFICwAiTllIONb:e inSdaicchataendinaonl twhiellcubseeiedaer otfagtgheed eaanvde.that RAMDOUIZATION:compTuhteera-ngiennselrsatweidllrabnedeamssinugmnmeedrs.cacgoenstaa:ccording to a CONTROL ARTICLE: Corn oil. TEST ARTICLE: 7-2999c0c. FANLITIGNL SPd"Eo4ECs1OIi1UPnPIg)Cb.AeTpIrdOiTeNoteSre:rmstpoionTnehtsdehoerbtysewtsattrhtearotSfipcolntesh,oercsto(um3dp4yoCsoianmtdmieornaciascntrdeDpenurerayiittoyanl test article sample asilrlequbiererdespinonGsLibEleeqfuoirarrietceenntion ie 004225 -- DOSAGE LEVELSsanuAdsNpDecnoEdnXetPdrEoRlIiMnEarNctoTrincDlEeoSiIlwGiN:ldlailbTyeh.eadtTmehisentistaterestrtiecadlretbiywciollrelalsbuespension giensttuabtaitoinonactocortdheingrabtobittsheonfoldlaoywsin6g:through 16 of D1o5smeg/Lkeave/lday Group iSsize 51.5mgm/gk/gk/gd/adyay 1188 0 my/kg/day 18 Tstthouexdiyco.irtaylNohraosudtieebteaeonrfydaecdfominintneaidmsitbnryaanttitshoinsarweirloulktneobweninutsaoediranbnetgceearfufisenerder with the test article. Oihnnotmrmtaohvneeendoatuyos oifnidnujbcereceteidooivnnugl,aotfieoa1nc.mhg foTefhmeaplidetouewsiitlawlirlyble ltughtieevniennbiezainng asermteinficcioalllleycteidnsefmroimnaNteewd rabbits. Zweiatlhan0d.5Whmlitoef/Mpionoilkeidn dmailleuted O2lfevPeglleo.sotdatTsihaeomnplsaefmropwmlielslthewbielslatmaebkeesnilxapbreerl-aedbdob,siet,sfrodaztaeyena1ca8hnaddnodseday 29 TLhreanssfpeornrseodr samples. twoillthebesproensspoornsifbolreblfooordthleevealnsalyasneaslysoefs.the eT29oiegohfatnsgiemwsaitllsaltiwobinellrfeobrceoraodbbensdoerrmovanelddacdylasiinli3y,cafl6r,osmi9,gdnasy1.2,3 tBohdryough day 15, 18 ana 2c9onosftanptregdnosaencyvolaunmdetohfe r1amblb/itksg doofsebdodyaccweoirgdhitn.gly using a UnTuthmeebreufrsemoaaflnedscoirtwpsiolrlcaonbetleutnketiasl,lewidnlulmobnebredaoyefxa2fm9eitnauensddesttohe(dlieovtveearrimaeinsna,e: bdgeietaedps)l,,acpenudupmbiweneriagnohftinrcaeunsdboartgportroisosantasb3in7toers,mCalfnioutrmibeaesr.24ofhTohieumrpplusapunsetvaiwtsiialolln Tcthhheeeciker.yevsisThcweielrlafobleelxaormweiimnnoegvdeddaf,yorftihaxeneydpuipinnstebrwunifalfllerabebednotrfemorarmlmiiantlaiitenesd.foarnd piskolesllseitbtalhleenpebxreaomciefnsiasxteiidnogninanafdettehhryilsctalolelcaoogrhiiocnlgexafoanrmdinssatutabiisoneniq.nugenwtTihtehpups alizarin rea. ` 004226 } NALYSISbSfeeoM%xDotrsdpeaPLdnIiNoafAnnoLdcsRiapStunPepaOslR,Tyw:esiigshTthosfe, tpnhreuompbdoeasrteadofasrteaf:teitsutibsuc,mamlsetmarertetehrocdosLaott)o oT{hifetoSrPorrodppeootrsaaeidlleuddtaeptaeuspfnCeohuxriammtsbihqenuaaotFrfiienoianmflsoprlrhaaenpvpteeoarstcebieeonanttno sspsibrtoymessommaeinaiseresSeetber (approximately fourch quarters 199. pronn QD S {"5aolrGTRoeerr2 staentaeorrlcoh7 gyT-enchanporloob agsiesDteai.toa en Director li`+goorC,waseB,7atohGwonl,ogyP--hYToooxipco,loagnyts ty Gvaluation Lavatatory ERVe.sGeW.arcL]ahmpVreJotceohrti,nnarnDyWi,FaPt$hh-o4lo-ggps!aote WTooxCiR.IcolHaegGioartm.ick, He Sponsor Representative Date0/91 004227 ----------_--__Tee ANSIAMFAETLYTOBXVIACLIUTNYTIOSNTUDLYABPORROAPTOOSRNYL !{ ! 4 Terre of aay study 1s to Be co=nducted `on 7Co-o2n99a7n Coor CEerTaTy - The attached protocol details the various aspects of the study and the study will be conducted according to Good Laboratory Practice regulations. The estimated total cost of the study is _s Zseo and it dosing starts fray [2954 + the estimated cost by calendar year is z ZLto wi (P8y + However, it is understood that the sponsoring division will be charged actual tine and materials via the recharge system on project mumber #1003104 + The estinated time from the initiation to completion and xeporting of the study is 7-7 months (NOTE: time estimate includes, as applicable period betueen ordering and receipt of animals, prostudy conditioning and examinations of animals, compound dosing interval, preparation of tissue slides, microscopic examina tion of tissues, preparation of fetuses, detailed examination of fetuses, compilation 21d analyses of data, drafting a report, review and final typing of report). Once the study is approved and the compound, with appropiate analytical data, has been received, the anisals will be ordered. After this point, cancellation of the study will pose multigle problems because tine, space and people have been committed to complete the study. Written confirmation will be necessary for any cancellation and a charge of U to 25% of the remaining estimated cost could be assessed to compensate the testing laboratory. Testing Laboratory Signatures os birectorZr SpyT,ete SiDfertyoPrsaTGurutinon TaboTREaTy Yore,Sw Approval signatures SponsWor irng e(an oie 004228 oaoff! eh =