Document 2JpvD33K90bogvNX7DE30KpVr

special Le7n-s2O9r99aCloCTeriantoRlaotsgy Study of Experiment You: conducted At: Dosing Period: Study Director: 066070020 SRiakfeertyLaEbvoarlautaotriioens,LabIoncr.atory St. Paul, Minnesota MFeabzrcuhar2y6, 9,19811981 through E.G. Gortner EZG. Gortaer LaaTaste ASneinmiaolr RReesperaordcuhctTieocnh-nToelroagtiosltogy Study pirector Sin BI BG. Lamprecht, DW, Fb ak Date esearch Veterinary Pathologist Pps i 1Y 25% RH,7. Case; DW,BD bate MFaantaegleyr,EvPaaltuhaotlioogny=LTaobxoirsaotloorgyy 004260 1 Summary TlheinssesspeexcpioalsedrattotTe-r2a9t9ol9oCgoyC dsutruidnygwatshe cpoenrdiuocdteodf sopregcainfoigceanlelsyist.o evaluate rat The objectives roefpotrhteedstiundya wperreevitoousdetteerramtionleogay nsot-uedfyfecatnd dotosedelsecvreilbeof thteheaplpenesraanbcneoromfaltihtey olreansllyabdnoosremdalwiittyh iTn-w2e9a9n9CloiCngatrat0s,. 25,Gro2u.p5sorof 0.ti2m5emam/aktae/ddafyemoanledaryasts 6 wetrherough 15 of of gestation. gestation while tAhpeprroexsitmaotfeltyheonfee-mhaallefs owfertehe alfleomwaeldes twoerleittkeirllaenddonraidsaey 20 their pups to weaning. Since this abnormal. Tshteudylewnsasficnodnidnugcstedo,bsetrhveedlenasrefiinndtienrgpsretheadveasbeaenffroeuenhdandnotsectotiboening artifact observed of in faetnuosmeasl ofaraelal odfosleengsrofuipbse,r diengcelnuedriantgiotnh.e cTohnetrollensgroaurpt.ifaTchtewa2s5 tmhge/kgc/odntaryoldogsreougproiunpciidnecnicdee.nceThoef the artifact histological was significantly appearance of the higher than lens findings waemroeng thtehe sdaomsee ingroaulpl dionsceidegnrcoeuspsweirneclduudeintgoththee cmoanntrnoelr group. The differences and frequency in which the artifact T-2999CoC in uwtaserocreexaptoesdedandratthefetluismeistatdiiodnsnotinhhaevreenctomipnouintsd-vriesluaatleidzalteinosn. changes. Wleeansnlinnucgleruast paubpnsormwahliicthiehsa.d beTheen feixnpdoisnegd oifn nuotelreonstonuTc-l2e9u9s9CoaCbnodrimdalniottiehsavein wweeraenlianngsartsiufpapcotrtasndthneotcoanctleusriaotnogetnhiact the lens change. findings in the rat fetuses TTh-e299f9eCtoaCl ilnenustefriondienxgpsoseodbsefrevtuesdesunadnedr wtehaenldiinsgssecdtiidngnomtichraovsecocpoempwoeurned-arretliafatcetd. lens changes. 004261 2. 7-2999CoC2 was labeled a teratogen of the lens because malities were observed at the 75, 37.5 and 25 mg/kg/day dose -atology study (Riker Experiment Number 0680TROG10). The iTy-2a9n9d9CtcoCdesstcurdiybewetrhee atoppedaertearnmcieneofatnhoe-elfefnesctabndoorsmeallielvietlyof The study was sponsored by the 3 Commercial Chemical Minnesota and was conducted by the Safety Evaluation aboratories, Inc., St. Paul, Minnesota. Six sets of ition and groups were List of the pdroisnecdipbaeltwpeaerntiFceibpraunatrsy a9ndandsupMaerrcvhiso26r,y sund in Appendices I and IT respectively. s study were conducted according to the Good Laboratory lations and the Safety Evaluation Laboratory Standard 5n f(osreesAppepciemnednisx,IIrIawfdoartaQuaalnditya cAospsyuraofncetheUniftinsatlatreempeonrtt).is afety Evaluation Laboratory's record archives. Dawley derived CD rats were obtained from Charles River 4, Wrialnmdionmgtnounm,beMrassstaacbhlues.ettTsh,e arnatds,assriagnngeidngcaignesweaigchctordfirnogm to ere then divided into four groups of 72 animals each. The {in six sets and the body weight data were interpreted in h rfaltosorwseraendhofursoendtsinindivaidtueamlpleyratinurehanagnidnghusmtiadiintlyescsonsttreoellled ter were available ad libitum. The lights were on a 12 hour 'asyerwveeidghdtasilvyerferormecdoaryde3d tohnroduagyhs203,of6, ge9,sta1t2,ion15faonrdab20noromfal x groups were dosed with T-2999CoC suspended daily in corn nsde v0.o2l5ummeg/okfg/5damyg./kgThbey suspensions were administered daily oral intubation with a syringe 1-tipped intubation needle to the rats on days 6 through 15 indicated by sperm-positive vaginal smear). 7-2999CC ed by 3 Commercial Chemical Division, St. Paul, Minnesota alf of the females were killed on gestational day 20. ALL ire fixed in Bouin's fixative and the heads were freehand 1sdoinssteeccthininqguem.icroTshceopper.esenFceetalofspleecnsimefnisndwiintghs wviesrieble lens idea in paraffin, sectioned at 5-6 microns, stained with An and examined histologically. The remaining females were 1a1r g06r8a0dTeR0P0M2-03)422) 7 Chow, Ralston Purina Co., St. Louis, 0 (04262 3 allowed to litter in plastic shoe box cages bedded with ground corn cobs. On dbaiyomi21croofscolpayctaotrioinndtihreecetyeosphotfhatlhmeoscwoepayn.lingTshewewreeanleixnagminreadtsbywerselitthelnampkilled asnedctitohneeidr eaytes5-w6ermeicrfoinxse,d isntai1n0e%dbwuiftfherehdemaftoromxaylliinn, anidmbeeoddseidn ianndpaervaaflfuiant,ed histologically. Results and Discussion The first objective of this special lens teratology study was to determine a no-effect dose level of the lens abnormality reported in a previous teratology study. Since this study was conducted, the lens findings have been found not tiontbeerparbentoerdmaals. a Tfhreeelheannsd fsiencdtiinognsinogbasretrivfeadcutndoefrathneormdailsseacrteaingofmilcernosscfoipbeerare degeneration. The fetal rat lens finding was incorrectly interpreted as a teratogenic change in Riker Experiment Number 0680TRO010 and, therefore, the first objective of this study was not valid. The fetal lens findings were observed to occur in individual fetuses of all dtohseeargeraouposf ithnecleumdbirnygontahle cnounctlreuosl,graolutph.ougThhea lveanrsietfyindoifngmsorwpehroeloglioccaallized to appearances were present within that location. The range of morphological daipspceoalroarnacteisonasofobtsheervleednsunndeerar tthhee dainstseercitoicnegntmriaclrosrceogipoen ienxctleudneddi:ng a from beneath the lens epithelium to half-way through the lens posteriorly, a cleft at the anteriocentral lens region or a combination of lens discoloration and the presence of a cleft. Hveissitcolleogirceamlnlayn,t atnhde ccolnesfitstveads oafsapacseepaorpaetnieodnuopfaptritmhaeryvelsetnasgefiobfertsheofletnhse embryonal nucleus from the lens epithelial cells. The dark streak dfirseceohlaonrdatsieocntioofnedtheacreomsbsryotnhaelanruecaleoufsnroersmualltepdrimfarroym eleintsh.erfitbheer ldeengsenbereaitnigon or an artifact being created in the lens during freehand sectioning accentuating the area of normal primary lens fiber degeneration. The aifferences in the appearance of the lens artifact in individual fetuses aanndd dfriefqfueernecnycesinamwhoincghtthheedaorsteifgarcotupvaisnccirdeeantceeds waenrdethleargleilmyitadtueiontso itnhehermeanntnerin its visualization. Statistically significant differences occurred among the incidences of fetuses observed to have the lens artifact. The 25 mg/kg/day ose group incidence was significantly higher than the 0 mg/kg/day dose group incidence (Table 1). of the morphological The artifact was the same appearance described under tinhealdlissdoescetignrgoumpiscrorsecgoapredleasnsd regardless of the statistical comparisons among the group incidences of the artifact. T-2999CoC in utero exposed fetuses did not have compound-related changes in their lenses. 004263 a Tahpepeasreacnocned oofbjetchetivleensofsbtnhoisrmasipietcyialinlweenasnltienrgatorlatoagywhsitcuhlyhavdasbeteondeesxcproisbeed tinhe OWbtjeercotitvoe1-a2l9s9o5CwoaCs.notAgavianl,id.sincAeLLtheyeesfeotfalthleensveafnilnidnigngrvaatss waenreartoibfsaecrtv,edthbiys CClietfhternosr1iat fleatmaplblieonmsicnruocslceoapry oopraciintdyirweecrteopchhtahearlvmeodscionpya.ny oNfeitthheerleansleesnsof "donsyeowfeatnhleinwgeandlidinghsavein&thleenscoonptarcoiltyo,x bcuotmptohuendo-ptarceiattyeddiodffneoptrinign.volvOenethheigh NZeeatnallinnugclleeunsses(Tianblaell2).doseThegrocurpysstmaaldleinheisatpopleoagriacnacellyofsethcetiocneendterasndofsttahiened E76pecliennesnsnuculnesuusitasbbnloermfaolriteiveasluaintivoenanolfinignsdisvuipdupaolrtsletnhsefciobenrcsl.usioTnhethfaitnditnhge of Tens finding in the rat fetuses were an artifact and not a teratogenic change. 7T-o2v8e95cienCbvoatsh msattuedrynarlelpylictaotxeisc.toThtehecpormepgonuanndtcdaaumssedofthethetox25icmigt/ykgo/fdaryedudcoseed eBeatnweebondydaywseig5htandsai1n2 doufrignegsttahteiodnosfionrgthiente2r5vmalg./kg/TdheaymedaonseveSirsohutp gvaasined ethiagtnifsiacnaentilnytelrvoavler (tThaabnleth3e).weight gained by the 0 ag/ko/day dose group during NLoeacvoenspogurnodu-prse.lateSdixcliinntiucbaaltiosnigdnesatwhesreoccchusrerrevdedduirninagnythoef sthteudtyhr(eAeppceonmdpixouVn)d. One 25 mg/kg/day dose group dam died during parturition. 004264 5. Table 1 SpecRieaslultLsensofOrDailssTeecrtaitnoglMoigcyroSstcuodpyicofObTs-e2r99v9aCtoiConsinofRats Gestational Day 20 Fetal Lens . cDroosuep 0 mg/5/day 25 mg/g/day 2.5 mg/g/day 0.25 mg/q/day Dams. 28 22 27 26 FEextaunsiensed 202 225 an 279 DFeatmusseHsavWiintgh LNens Findin.gs 3 ra 1. 82? . 67 1" 54 FLeentsuses with FNindings + a a ss 282 59 22 a 16 2sicgonrirfeicctainotnlyp <h0i.g0h5e)r than the control (Chi-square with Yates 004265 6. Table 2 ResultsSpofecOicaullaLrensExaOmrailnatTieornatoFliongdyingSstudoyf PofupsT-2at995DCaoyC21inofRatLgactation DGorsoeup 0 mg/kg/day Noof. TNoutmabler Dems of vups 2 201 25 mg/ke/day 30 263 2.5 ng/ks/aay 28 266 0.25 mo/kg/day 26 211 Abnorm. Found AFbonuonrdm. Findings 208 3 Corneal Opacity wBiitlhatoepraalcitcoyrneal ulcer Leentltaregyeed g=r2osXslnyormal size, lens may be absent 262 1 Otopag3ueo'calreoackof lens = 1 263 3 oQfuesctoirnoenaable cloudy area 209 2 Corneal opacity 004266 E> Table 3 SpeciaMleaLennsBoOdryalWeTiegrhattoGlaoigny (Sg)tudoyf oPfregTn-a2n9t99CRoaCtsin Rats Between Weighings with Standard Deviations mg/kg/day 25 mg/kg/day 2.5 mg/ke/day 0.5 mg/ks/day 0 mg/kg/any 25 mg/kg/day 2.5 mg/kg/day 0.25 ng/ke/aay First Replicate Av 6 9 12 15 20 STANMEDAENV 102.99 72.49 62.18 452.65 29.710 STANC.imeDaENV 163.19 11.251 43.e9f16.217 24.760 STAN.MEDAENV 10.303 42.35 131.34 133.07 30.625 STAN. MDEEANV 93.14 72.42 12.435 47.351 29.649 second Replicate DAY 6 5 12 15 20 STAN.(MDEEAVN 53.e1 62.16 6338 62.59522748 STAN.imDeEaVN 11.289 61.93 62.72% 72.3115731 STANMEDAENV 5.298 52.17 7.286% 72.8112746 STAN. MDEEAVN 7.362 62.08 6.278 72.3126698 2 significantly lower than the control (Dunnett's t test p < 0.05) 004267 8. Appendix 1 TITLE: Protocol for a Special Lens Oral Teratology Study of T-2999Coc in Rats OBJECTIVE: cAaupsuerdifideevdelgorpamdeentoafl Tl-e2n9s95aCbonCorwmaaslitteireastoagteni75c, to37t.h5eanedye 25and mg/kg/day in a rat teratology study (Riker Experiment Number n0o6-8e0TfRf0e0c1t0)d.oseThleeveolbjeofctitvheesloefnsthaebnostrumdayliatryeatnod tdoetedremsicnreibea the appearance of the lens abnormality in the weanling rats. The PsrtaucdtyicweillRebgeulactoinodnusctaendd atchceordSaifnegtytoBvtahelua1t9i78onGLoaobdorLaatboorrya'tsory Standard Operating Procedures. SPONSOR: 3 Commercial Chemical Division, St. Paul, Minnesota. TESTING FACILITY: Safety Evaluation Laboratory, Riker Laboratories, Inc., st. Paul, Minnesota. STUDY DIRECTOR: E. G. Gortner START OF DOSING: February, 1981. TEST SYSTEM: One hundred and ninety-two sexually mature, time mated Sprague-Dawley derived female rats from Charles River Breeding Lwaibtohrawtiorreiemseswhilflloboershoaundsedfroinntshanigninagtesmtpaeirnlaetsusrestaenedlhucmagiedsity controlled room. This strain of rat will be used because it was ruesaeddiliyn tahveailparbelvei.ousPutreirnaatoLlaobgoyrasttourdyy aCnhdowtainmde wmaatteerd wfielmlalebse are available ad libitum, The lights will be on a 12 hour light/dark cycle. TEST SYSTEM IDENTIFICATION: Each animal will be ear tagged and will be indicated on the outside of the cage. that number RANDOMIZATION: The animals will generated random nbuembaesrssigtnaebdlec.ages according to a computer- CONTROL ARTICLE: Corn oil. TEST ARTICLE: T-2999Coct. ANALYTICAL SPECIaFcItCeArTnIiOnNeSd:byThteheteSsptonsaorrtic(l3eM CcoommmpeorsciitailonChaenmdicpaulritgryouwpi)llprbieor to the start of the study and at the end of dosing. 2 Pu-3924 (technical grade FM-3422) 004268 5. DOSAGE LEVELS ANcoDrnEXoPiElRIMdEaiNlTy.DESITGhNe: tesTthearttesitcleartsiucslpeenswiiolnl be suspended in and the control aarytsicl6esthrwoiullghbe15adofmingiessttearteidonbyaccoorarldinignttuobatthieonfotlolotwhiengr:ats on Dose Group Dose Level Group size High Mia LCoonwtrol 225.5mmoo//kkog//adaayy wIgR 00.m2o5/mkog//kdga/yaay a wg The oral route teratogenicity orfesuadlmtiendisbytratthiiosnrwoiultle be in used because the previous teratology study. No dietary contaminants are known to interfere with the test article. Tgheestaatniiomnalsforwialblnobremaolbsecrlviendicadlaisliygnfsr.om Bdaoydy3wetihgrhotusghwi2l0lobfe rraetcsordwieldl obne ddayossed3, a6c,cor9,din1g2,ly 1u5sianngd a20coofnsptraengtndaonscey and the volume of 5 ml/kg of body weight. Approximately of gestation. oAnlel-hoaflfthoefirthpeupfsemwaillels will be killed on day be fixed in Bouin's 20 : steoclhuntiiqoune.andThteheprheesaednscewilofl beeyefraebeno-rhmaanlditsieecstiownieldl by be the Wilson determined usesnitngtothehisdtiospsaetchtifnogrmimcircorsocsocpoep.id eSxealmeicntateiyoen.sectTiheonsremcaaninbieng efyeemsaleosf nweiolnlatbeesawlillolwebdeteoxalmiitnteerd.toOndetdeayrmi21neofthelapcrteasteinocnetohfe lens abnormalities. DATA ANALYSIS AfNoDrFIaNnAaLlysRiEsPORoTf: theThdeatparopiossethdesCthait-issqtuiacrael method to be used for percent of maobnntohrsmalaifttieers.dayTh2e1 opfroploascetdatidoanteanfdorthtehe pufpinaelye reepxoamrthaiss 2-3 been completed (approximately second quarter, 1981). Amendment to the oral Teratology PSrtoutdyocoolf fTo-r29a99CSopCeciianlRLaetnss wAnilladdbietidoinvaildendumabmeorngofthreatdsosewilglroubepsadadsedfotlolowtsh:is study. The 96 new animals Dose Group Dose Level No. of Animals nHiagh Low Control 225.5mmgg//kkgg//aaaayy 224 0.25 ma/kg/day mg/kg/day, 24 20 The reason for this amendment is a reduced number of pregnant animals in the first two groups of animals. 004269 10. Appendix II List of Principal Participating Personnel Nang Edwin G. Gortner Elden G. Lamprecht Gary C. Pecore Vinkateswa Pothapragoda Loren O. Wiseth FuncTION study Director Veterinary Pathologist Supervisor - Animal Care Commercial Chemical - Analytical Technician 004270 APPENDIX 111 un. STATEMENT OF QUALITY ASSURANCE STUDY NUMBER: __0680TRO020 TITLE: SPECIAL LENS ORAL TERATOLOGY STUDY OF T 2999C0C in Rats ACuodmiptlsianacned/oArudiitnsupneicttiofnosr wtehree apbeovrefortmietdledby sttuhdey,Rikaenrd reported to the study director and to management as follows: Date Performed Date Reported 12 February 1981 23 February 1981 12 February 1981 24 February 1981 18 March 1981 18 March 1981 31 March 1981 25 & 27 April 1981 23 March 1981 24 March 1981 6 April 1981 29 April 1981 21 December 1981 21 December 1981 004271 ap Riker Laboratories, Inc. 12/23/58) BE -- -- - - 12. APPENDIX TV ~ Test and/or Control Article Characterization or. -2999C0C = 1. Tthienenitdecnhtairtayctsetrrienzgatthi,onsunoiffortmhietyt,estcomanpdo/soiftiocno,ntrpoulritsyubosrtanoctehserhpaever- been determined and documented as of oe 2. Tihneclmuedtihnogdtohfeirsyanmtohuenstisaonrd othreigmientohofdthOef btieosatsasnady c(oLnftarpoplliscuabbsltea)nceiss, documented. vor 4 no 3. The stability of the test and/or control substances have bepn deter- mined or will be determined as of Conpletioe of theSued), Tchoerdsa.bove information and documentation are located in the sponsor's re- SpBonseorle Tre teD, a1te981 or pon: 4CCD Analytical Req. No. 16474 October 28, 1980 -- som 19793 0 004272 Appendix V Special Lens Oral Teratology Study of T-2999CeC in Rats IndainvdiduSatlanBdoadryd WDeeivgihattsion(sg) fwoirthPrMeegananntBoAdnyimWaelisghts Replicate 1 . AY 3 6 9 12 15 20 MG/KG/DAY NNRR 11113302 128052 222216 224578 227757 239088 334613 NNIRR 11113334 219340 225010 226446 229712 331074 337672 MMIRR 11115501 119750 221152 223402 226227 223920 233357 NNIiRR 11115532 220086 223216 224482 226628 227935 230726 NNIARR 11115749 118972 221178 224404 225649 230630 237866 NNIRR 11118810 212814 224151 220667 229437 322073 431465 NNIARR 11116928 222046 224266 226469 228596 236214 420771 NNIRR 11129090 220060 222298 225555 228746 331187 339925 NNIIRR 11220012 210973 221215 226256 225834 321884 430579 NNiRR 11421148 117357 222166 224532 226842 330092 430973 NNiRR 11441165 210813 224165 223734 225966 232368 343292 MNIARR 11441373 117724 220254 222455 225512 320672 438331 NNIIRR 11443345 117547 210640 220255 224292 227632 334557 NNIRR 11443563 119726 223223 226488 228785 331061 431937 NR 1454 173 211 208 235 266 345 STAMNEANDEV 1179.34 1262.17 1254.59 1296.66 2279.25 473.692 NON PREGNANT ANIMALS NNARR 11117301 119841 222038 224207 224545 224603 227438 MIR 1171 195 208 230 245, 249 27 NNIIRR 11127189 129019 223159 224428 250eX 252 266@ NNIRR 11441337 118844 222159 223435 223228 224511 227598 2 animal aie 004273 a - 2. appendixVv (Continued) Special Lens Oral Teratology Study of T-2999CiC in Rats Ind`iavnidduSatlanBdoedcys DWeeivgihattsion(s3)fwoirthPreegannantBodAynimHaelisghts . Replicat2e oR 3 6 5 12 15 20 & HoKaroRY NWiiRk Nik 11446e12 1463 126165 175 221319 205 223509 232 227583 267 2e7z4 285 337400 +354 NNiikk Nik 11446645 14e1 116973 235 221250 260 224410 296 227648 320 229985 345 33853 437 NNiikk 11445032 211836 223151 223675 226923 320168 336998 NNiRr Nik 11440054 ise1 121907537 222341 203 225405 229 228787 253 i29r8 278 431780 396 NNiikk 1230724 110969 222347 226429 229754 233953 431580 NiR 2375 163 206 235 266 296 370 : NNNiiIkkR 22337768 2394 219190 214 223401 244 22e9s: 253 220947 267 33o317 32 43724 345 NNiikk 22330965 120945 222312 224508 229605 329165 342616 NNiRk Nik 22339967 2414 221170 167 224453 213 222673833 33u053 275 3333:02 298 431827 377 NNNAiRRR NiR 222444212053 2425 112880655 20> 222225069 252 222348054 267 322218964491 323804571 325 343934819 406 NNiikk Nik 22442465 2443 211722 208 220370 246 225261 265 223655 298 234313 327 233180 416 NNNiIiRRR NR 222244446446s625 212190540 174 222333188 205 2224543101 215 222877617 236 32319818 251 333878320 298 STANw.emnDEV 151.979 1262.94 1275.07 1298.09 2340.54 4307.43 004274 NON PREGNANT ANIMALS NR 244 197 223 207 238 248 262 NAR 2377 184 208 231 236 248 256 NiR 2424 196 236 253 283 315 394 Appendix V (Continued) 1s. Special Lens Oral Teratology Study of T-2999CoC in Rats IndainvidduSatlanBdoadryd WDeeviigahttison(sg) fwoirthPrMeegananntBodAnyimWaelisghts Replicate 1 AY 2 6 9 12 15 28 `25 MG/KG/DAY - __OO0IiRR 11113365 221124 224218 226358 227354 321437 325528 -- {|0OI1RR 11113378 213680 226013 221768 228114 320272 324818 01R 1156 192 223 238 251 264 305 jootikr 11117528 126327 216653 229000 321174. 325438 432391 O0i1Rk 11117834 220141 223478 225611 225772 226858 236717 OO011RR 11118867 119998 222256 223496 225648 237061 336669 OOi1RR 11220046 127152 129461 220673 222 246 368@ OR OR 1221 1418 213855 225471 226670 228719 239144 347050 01k 01k 1415 1420. 160 195 201 248 213 278 216 297 236211 333819 O0I1RR 11442221 116647 2210@9 223236 223535 226765 334522 01k 0iR 1438 1435 1179@2 220382 222469 226613 226738 335575 0O011kR 11444401 119901 212666 225341 22656@ 229509 337627 OO011RR 11444525 118911 221289 225482 222238 229866 338724 STANM.EANDEV 231.934 262.214 222.495 227.545 282.061 453.582 | NON PREGNANT ANIMALS 0011RR 11113555 222244 223570 224668 225427 225760 227720 OiR 01k 1157 1159 118972 129283 223260 222200 221340 223373 0011RR 11118835 221155 223386 225335 225440 227425 228675 . OO011RR 11220035 124126 220256 221390 223385 225436 225651 O1R 1207 219 233 240 240, 249 265 |0011RR 11242506 210568 212825 213965 200_% 206 233 Antual died 004275 16. Appendix V (Continued) Special Lens Oral Teratology Study of T-2999CoC in Rats IndainvidduSatlanBdoadryd WDeeivgihattsion(sg) fwoirthPreMgeannantBodAynimWaelisghts : Replicat2e DAY 3 6 5 12 15 20 25 MG/KG/DAY 01k O1R 1466 1468 181 242 203 280 229 308 258 326 275 356 343 442 01k 1465 205 236 255 281 299 38L O1R 1470 186 205 230 248 266 323 __O1R 1486 158 208 222 247 270 362 O1R 1487 200 225 244 275 288 366 O1R 1488 199 225 246 279 363 381 01k 1489 203 239 256 278 303 405 01R OiR 1450 1563 207 204 234 234 256 253 227738 229754 335681 OO0011RR 21530749 118592 222234 223577 229610 321786 414 338 O1R 2380 214 247 272 296 328 390 O1R O1R 2381 2382 262 195 228 219 251 234 225738 229627 239443 O1R 2383 195 229 249 271 295 352 O1R O1R 2395 2400 183 195 174 230 217 250 226349 229636 336320 OiR 2461 194 217 233 257 281 343 O1R 2462 188 239 269 250 3ii 385 O1R O1R 2403 2416 199 233 220 260 234 279 326550 237396 431554 01R O01R 2417 2428 222 215 258 250 275 256 361 275 330 291 412 334 0O1iRR 22443310 220083 224416 226633 225839 332105 363 399 O011RR 22444487 211931 214995 222559 226471 266 288 348 342 O1R 2449 206 247 249 252 281 349 O1R O1R 2450 2464 189 193 2144 225 224 237 225447 227794 334533 O1R 2465 196 228 243 266 253 371 MEAN 200 230 249 274 294 365 STAN. DEV 15.6 20.9 18.5 20.8 23.8 31.5 004276 NON PREGNANT ANIMALS O1R 1467 184 215 234 251 263 287 O1R 2427 196 226 228 229 240 255 01R 2429 195 230 241 239 250 268 O1R 2451 152 228 234 225 237 255 wm. Appendix V (Continued) Special Lens Oral Teratology Study of T-2999CeC in Rate IndainvdiduSatlanBdoadryd WDeeviigahttison(s5)fwoirthPreMgenaanntBodAynimWaelieshts Replicate 1 . oAv : 6 5 12 15 20 25 Me/Ka/DA - PiR 1140 150 215 234 232 243 254 PPPiiIRRR 111111446420 222020479 222334286 222756057 232066051 322727681 224767751 PIR 1161 154 224 252 266 292 327 PPPiiiRRR 111111666429 112562625 222025738 222742295 222519783 223831804 233238053 Pik 1169 i77 156 217 238 271 347 PPPiIiRRR 111111959102 212015548 222334003 222655113 222876142 33312152 443169115 PPiiRR 11226089 126215 220500 222618 229435 237370 344112 . PPiIRR 11221110 220455 222667 234174 323634 328718 342770 PPAIRR 11422233 126065 221450 226413 227785 235147 34090 PPAiRk 11442245 1iv7e7 222233 224522 223763 229925 337954 PPiikR 11442463 113557 119556 221187 221280 226416 333359 PPIiRR 11444445 117507 220358 223704 224532 2lo8v4 336692 PIR 1446 153 195 221 244 238 325 PPPiIiRRR 111444554787 441658212 212191505 222313616 222333050 222876754 333327777 MEAN 191 224 246 260 298 355 STAN. DEV 26.@ 22.1 23.0 28.6 31.7 53.2 NON PREGNANT ANIMALS PPiIRR 11114431 116777 220067 221399 222436 224556 227532 PPIIRR 11117643 119540 224075 223155 224217 223572 226406 PPPIiIRkR 111212172252 111974197 211851477 212292766 21166,2 2130@ 223 PIR 1427 183 214 232 234 239 258 2 anima) ates 004277 18. Appendix V (Continued) Special Lens Oral Teratology Study of T-2999CcC in Rats IndainvdiduSatlanBdoadryd WDeeviigahttison(sg)fwoirthPreMgenaanntBoAdnyimWaelisghts Replicat2e AY. 2 6 9 12 15 20 2.5 MG/KG/DA PPIIRR 11447712 213944 226283 226437 324145 233978 433898 PAR 1473 185 210 237 267 296 359 PPIIRR 11447745 119769 222039 223436 227518 320803 335856 PIR 1491 209 248 262 296 317 398 PIR 1492 195 212 243 259 285 348 PIR 1493 205 235 261 283 315 400 PIR 1494 218 251 269 35 335 410 PPIIRR 11459055 210953 222253 224435 226790 229980 336810 PIR 1506 191 214 240 269 286 369 PIR 2384 189 2143 243 268 302 361 PPIIRR 22338856 220393 224556 226822 239153 332485 440344 PIR 2387 192 226 243 272 296 358 PIR 2388 151 220 247 268 297 356 PIR 2484 226 257 281 316 350 432 PIR 2406 200 223 248 274 305 373 PPIIRR 22440078 220025 223314 225533 228852 331156 339982 PAR 2418 196 223 241 265 292 356 PIR 2419 225 249 278 384 333 412 PIR 2433 196 239 249 274 302 390 PIR 2434 222 264 277 303 330 406 PIR 2453 154 225 246 272 299 373 PIR 2454 203 232 248 267 284 335 PPiARR 22445565 221117 224443 225665 228863 329155 344183 PIR 2466 199 229 239 263 292 374 PIR 2467 197 225 245 278 300 384 MERN 204 233 254 279 307 384 STAN. DEV 13.9 16.1 14.5 18.4 18.9 27.2 004278 NON PREGNANT ANIMALS PIR PIR 2405 2432 192 199 220 233 223482 224475 225576 227702 PiR 2435 202 240 262 277 304 336 PAR 2436 224 259 273 271 281 289 PIR 2452 198 228 240 242 249 261 Appendix V (Continued) 1. Special Lens Oral Teratology Study of T-299%CcC in Rats IndainvdiduSatlanBdoadryd WDeeivgihattison(s3) fwoirthPrMeegannantBoAdnyimWaelisghts Replicate 1 : AY 3 6 9 12 15 20 . 25 MG/KG/D GGIIRR 11114486 129175 221465 227364 320661 323993 339557 GGIRR 11116668 211909 223256 224672 224888 234184 236629 `QIR {01R 1177 1193 222 213 243 236 251 259 266 286 322605 329866 GGIIRR 11119954 126155 220329 226133 228174 322350 424142 QQIIRR 11115976 221058 224275 224714 229653 329046 435632 GQIiRR 11221143 125078 222247 224426 225676 225999 237658 QIR GIR 1215 1216 212 207 223338 225416 227679 331017 338941 QQIRR 11222147 210855 223172 222589 227447 321724 338352 QQIIRR 11422285 127185 221581 224647 225906 330215 337379 QQIRR 11443205 210766 214929 226332 226550 227842 236699 GQIRR 11443312 127068 220513 223822 221763 238344 346299 QGIIRR 11444498 219161 224346 228519 229846 332008 432661 QQIRR 11445510 210847 225377 228669 229846 333198 443187 GIR 1452 186 228 253 252 312 409 MEAN STAN. DEV 201 14.1 232 15.5 254 18.0 269 23.0 300 27.9 523.674 NON PREGNANT ANIMALS QQIRR 11114475 118736 220073 223324 225413 224650 225616 QQIIRR 11114655 119752 212887 215944 221776 228238 227492 004279 QIR GGIIRR 1167 i11i6r9c 196 119522 222224011 222445547 222665347 227525ob 225788 {G1R 1459 182 213 242 246 255 277 l01R 1468 177 225 251 237 256 269 2animal died Appendix V (Concluded) Spectal Lens Oral Teratology Study of T-2999CoC in Fats IndainvdiduSatlanBdoadryd DWeeviigahttison(s5)fwoirthPraMgenanantBoAdnyimWaelisshts Replicate 2 . oR x 6 9 12 15 20 .25 MG/KG/D @iR 1476 246 248 283 324 345 454 GGQiiiRRf 111444777987 212106427 222412377 222536278 232870368 323930631 343086896 GGiiRR 11445660 222028 224255 227433 229793 331088 338837 GGiiRR GiR 111544059078 223084 i6z 223635 212 224695 233 325154 261 236332 294 328738 357 GiikR 215368s5 2260s0 223412 226573 229793 333024 437188 Giiff QiR 22339910 2332 210884 167 224061 218 226067 237 321280 265 323542 290 421613 362 iGikr GiR 223430: 2410 125030 208 222364 225 225374 252 226819 281 331138 387 339843 376 GGiiRR 22441121 221132 224400 225670 226972 239281 432591 GGiiRk GiR 22442103 2421 125005 163 224259 215 227524 244 236066 269 331332 282 432557 316 GG@iiiRRR 22443367 2439 210683 1952 224151 238 222625155 225800 267 226710 313 330202 398 GQiiRR GiR 22444410 2457 220086 196 224414 224 223565 239 227799 272 333060210 336531 382 QGiikR 22445596 211523 224265 227462 320624 322940 339653 GGiiRR 22448601 117637 222234 224367 226757 320804 327835 GGiiRR 2244668s 123560 222706 223963 235196 238480 346589 STANv. enDEV 1240.26 452.344 1275.46 2208.26 2326.50 4357.38 NON PREGNANT ANIMALS Gir 1499 151 215 226 238 234 243 Q1R 1567 186 201 212 215 223 234 004280 =. -