Document npON6Q200yLBmdRNe2meRo3ma

I FINAL REPORT PROTOCOL 418-011 ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS SPONSOR'S STUDY NUMBER: T-6316.7 FINAL REPORT DATE: 17 DECEMBER 1998 PROTOCOL 418-011 ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS SPONSOR'S STUDY NUMBER: T-6316.7 TABLE OF CONTENTS SUB-JECT 1. SUMMARY AND CONCLUSION A. Methods B. Results C. Conclusion ii. DESCRIPTION OF TEST PROCEDURES A. Conduct of Study A.1. Sponsor A.2. TestingFacility A.3. Study Number A.4. Sponsor'sStudy Number A.5. Purpose ofthe Study A.6. Study Design PAGE 1-1 1-1 1-2 1-4 11-1 11-1 11-1 11-1 11-1 11-1 11-1 11-1 SUB-JECT A..7. RegulatorCyompliance A 8. ownershipoftheStudy A.9. StudyMonitor A.10. AlternateStudy Monitor A.1 1- Study Director A. 12. Technical Performance A.13. Report Preparation A. 14. Report Review A. 15. Date Protocol Signed A. 16. Dates of Technical Performance A.17. Records Maintained B. Test ArticleInformation B.1. Description B.2. Lot/Batch Number B.3. Date Received and Storage Conditions B.4. SpecialHandling Instructions B.5. Analysis of Activity C. Vehicle Information C. 1. Description C.2. Lot Number C.3. Date Received and Storage Conditions C.4. Special Handling Instructions PAGE 11-1 11-2 11-2 11-2 11-2 11-2 11-2 11-2 11-2 11-3 11-3 11-3 11-3 11-3 11-3 11-3 11-4 11-4 11-4 11-4 11-4 11-4 SUBJECT C.5. AnalysisofPurity D. Test ArticlePreparation D.l. Sample Information E. Test System E.1. Species E.2. Strain E.3. Supplier(Source) E.4. Sex E.5. RationaleforTest System E.6. Test System Data E.7. Breeder Male Rat Data E.8. Method of Randomization E.9. System of Identification F. Husbandry F.1. Research FacilitRyegistration F.2. Study Room F.3. Housing F.4. Lighfing F.5. Sanitization F.6. Feed F.7. Feed Analysis F.8. Water PAGE 11-4 11-4 11-5 11-5 11-5 11-5 11-5 11-5 11-6 11-6 11-6 11-6 11-6 11-7 11-7 11-7 11-7 11-7 11-7 11-7 11-7 11-8 SUB-JECT F.9. Water Analysis G. Methods G.l. Dosage Administration G.2. RationaleforDosage Selection G.3. Route ofAdministration G.4. RationaleforRoute ofAdministration G.5. Frequency ofAdministration G.6. Length ofStudy G.7. Method of Study Performance G.8. Gross Necropsy G.9 StatisticAanlalyses 111. RESULTS A. MortalityC,linicaalnd Necropsy Observations A. 1. Mortality A.2. ClinicaOlbservations A.3. Necropsy Observations B. MaternalBody Weights and Body Weight Changes C. MaternalAbsolute(g/day)and Relative(g/kg/day) Feed Consumption Values D. Caesarean-Sectioningand LifterObservations E. FetalAlterations E. 1. Summary ofFetalAlterations E.2. FetalGross ExternalAlterations iv PAGE 11-8 11-8 11-8 11-9 11-9 11-9 11-9 11-9 11-9 11-10 11-12 111-1 111-1 111-1 lii-i 111-1 111-1 111-2 111-2 111-3 111-3 111-4 SUB_JECT E.3. FetalSoftTissueAlterations E.4. FetalSkeletaAllterations REFERENCES PAGE 111-4 111-5 111-7 APPENDIX A -REPORT FIGURE Figure1. MaternaBlody Weights A-1 APPENDIX B -REPORT TABLES Table 1. ClinicOablservation-sSummary B-1 Table2. NecropsyObservation-sSummary B-2 Table3. MaternaBlodyWeights- Summary B-3 Table4. MaternaBlody WeightChanges- Summary B-5 Table5. MaternaAlbsoluteFeed ConsumptionValues(g/day-) Summary B-6 Table 6. MaternaRlelativFeeed ConsumptionValues(g/kg/da-y) Summary Table 7. Table 8. Table 9. Caesarean-SectionngiObservation-sSummary LifteOrbservation(sCaesarean-DeliveFreetduses-) Summary FetaAllteratio-nSsummary Table10. FetalGrossExternaAllteratio-nSsummary Table11. FetalSoftTissueAlteratio-nSsummary Table12. Table13. FetalSkeletaAllteratio-nSsummary FetalOssificatiSointes-Caesarean-DeliverLeidve Fetuses(Day20 ofGestation-)Summary Table14. ClinicOablservation-sIndividuDaalta B-7 B-8 B-9 B-10 B-11 B-12 B-13 B-16 B-17 v SUBJECT Table 15. Table 16. Table 17. Table 1B. Necropsy Observations- IndividuaDlata MaternalBody Weights -IndividuaDlata MaternalFeed Consumption Values - IndividuaDlata Caesarean-SectioningObservations- IndividuaDlata PAGE B-23 B-29 B-44 B-50 Table 19. Lift6Orbservations(Caesarean-DeliveredFetuses)- IndividuaDlata B-56 Table 20. FetalSex, VitalStatusand Body Weight - IndividuaDlata B-62 Table 21. FetalAlteration-sIndividuaDlata B-74 APPENDIX C - PROTOCOL AND AMENDMENTS C-1 to C-33 APPENDIX D - DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING D-1 APPENDIX E - TEMPERATURE AND RELATIVE HUMIDITY REPORT E-1 APPENDIX F - PILOT REPORT APPENDIX G - HISTORICAL CONTROL DATA APPENDIX H - STATEMENT OF THE STUDY DIRECTOR F-1 to F-87 G-1 to G-16 H-1 APPENDIX I- QUALITY ASSURANCE STATEMENT UNIT FINAL REPORT 1-1to 1-5 vi 418-01 1:PAGE 1-1 TITLE: ORAL (GAVAGE) DEVELOPMENTAL OF N-ETFOSE IN RATS TOXICITY STUDY ARGUS RESEARCH LABORATORIES, INC. PROTOCOL NUMBER: 418-011 SPONSOR'S STUDY NUMBER: T-6316.7 1. SUMMARY AND CONCLUSION A. Methodsa Twenty-five Crl:CDOBR VAF/Plus@ (Sprague-Dawley) presumed pregnant femaleratswere assignedtoeach offivedosage groups (Groups IthroughV). Nineteenadditionaflemale ratswere assignedto one offivedosage groupsfor thesatellistteudy(threef,ivet,hree,threeand fiveratsassignedtoGroups I throughV, respectively)T.he testarticleN,-ETFOSE, or vehicle2,% TweenoD 80 inReverse Osmosis Membrane Processed DeionizedWater (R.O.Deionized Water),was administeredviagavage once dailytofemaleratson days 6 through 17 ofpresumed gestation(DGs 6 through17).Dosages of0 (Vehicle)1,,5,10 and 20 mg/kg/daywere administeredata dosage volume of5 mukg, adjusted dailyon thebasisof individuablody weights. The female ratswere observed forviabiliattyleasttwiceeach day ofthestudy. The ratswere alsoexamined forclinicaolbservationsofeffectsofthetestarticle, abortionsp,rematuredeliverieasnd deaths beforeand approximatelyone hour afterdosage (DGs 6 through17),and once dailyduringthe postdosageperiod. a. Detailedescriptionosfallproceduresused intheconductofthisstudyare providedintheappropriatesectionsofthisreportand inAPPENDIX C (PROTOCOL AND AMENDMENT). 418-011:PAGE 1-2 Body weightswere'recordedon DGs 0 and 4 and dailyduringthe dosage and postdosage periods.Feed consumption valueswere recordedon DGs 0,4, 6,8, 10, 12, 14, 16, 18 and 20. Allratsinthe main studywere sacrificebdy carbon dioxideasphyxiationon DG 20 and a gross necropsy ofthe thoracic,abdominal and pelvicviscerawas performed. The number ofcorporaluteaineach ovary was recorded.The uterusofeach ratwas examined forpregnancy, number and distributioofn implantationsl,iveand dead fetusesand earlyand lateresorptions.Each fetus was identifiewde,ighed and examined forsex and gross externalalterations. Approximatelyone-halfofthe fetusesineach liftewrere examined forsofttissue alterationasnd the remainingfetusesineach liftewrere examined forskeletal alterations. Rats inthe satellitsetudywere sacrificeodn DG 18. Blood samples were collectedand centdfuged.The liverwas excised,weighed and sectioned. Fetuseswere examined grosslytothe extentpossibleas describedforrats assigned tothe main study. Fetuses and placentaewere pooled per lifterA.fter completionofsample collections,erum, liversection,fetaland placentalsamples were shippedto the Sponsor foranalysis. B. Results No deaths,abortionsor premature deliverieosccurredduringthe study. Allrats surviveduntilscheduled sacrificoen gestationday 20 (DG 20). Allclinicaalnd necropsy observationswere consideredunrelatedtothe test article. Maternalbody weight gainswere significantrleyduced ingroups administered 5 mg/kg/day and higherdosages ofthe testarticleT.he effectwas minimaland transientinthe 5 mg/kg/day dosage group, occurringonlyon DGs 8 to 10. Inthe 10 mg/kg/day dosage group,significanrteductionsinmaternalbody weight gains occurredon DGs 6 to8 and 10 to 12,followedby a significainntcreaseinweight gain on DGs 14 to 16. The 20 mg/kg/day dosage group had significawnetight lossfollowedby significanrteductionsinmaternalbody weight gain on DGs 8 to 14 and 16 to 18. These effectsof the testarticlreesultedina tendency for reduced weight gain inthe 10 mg/kg/day dosage group and significant reductionsinthe 20 mg/kg/day dosage group forthe entiretreatmentperiod (DGs 6 to 10),the entireintervaalfterinitiatioofntreatment (DGs 6 to20) and the entiregestationperiod(DGs 0 to 20). Maternalbody weightswere 418-011P:AGE 1-3 significarnetdluyceirndthe10and20 mg/kg/dadyosagegroupson DGs 11 throug1h3and8 throug2h0,respectively. Bodyweightasndbodyweighgtainwsereunaffectbeydthe1 mg/kg/day dosageofthetesatrticle. The absolutfeedconsumptivoanluewas significarnetdluyceidnthe 10 mg/kg/dadyosagegroupon DGs 6to8 andabsolutaendrelatifveeed consumptiovnaluewseresignificarnetdluycedinthe20 mg/kg/dadyosage groupfortheentirdeosageperioadndatalilntervawlisthitnhipseriodT.he absolutfe edconsumptiovnaluecontinuetdobesignificarnetdluyceadndthe relatifveeedconsumptiovnaluetendetdobereducedinthe20 mg/kg/day dosagegroupdurintghe.postdosiangteervaTlh.eseeffecotfsthe20 mg/kg/day dosageofthetesatrticrleesultiendsignificarnetdluycedabsolutaendrelative feedconsumptivoanlueosn DGs 6 to20andDGs 0 to20. Absolutaend relatifvee dconsumptiovnaluewsereunaffectbeyddosagesof thetesatrticalsehighas5 mg/kg/day. Fetablodyweight(stotamla,leand/ofremalew)eresignificarnetdluycedinthe 10and20 mg/kg/dadyosagegroupsa,scomparedtothecontrgorloupvalues. DosagesofN-ETFOSEashighas20mg/kg/dadyidnotaffecatnyother Caesarean-sectioonrilnigttpearrameterTsh.e liftaevreragefsorcorporlautea, implantatiloinfst,seirzesl,ivfeetuseesa,rlryesorptiopnesr,cenrtesorbed conceptuseasndpercenmtalefetuseass,wellasthenumbersofdamswithany resorptiornwsithviablfeetusewserecomparablienthefivdeosagegroups anddidnotsignificadnitflfyeNro. damshadliftweirtshalclonceptuses resorbeadn,dtherweerenodeadfetuseosrlatreesorptioAnlsl.placentae appearendormalA.llofthesevaluewserewithitnherangesobserved historicaatltlhyeTestinFgacility. Reversibdleelayisnfetaolssificataisosnociatweidththesignificarnetdluyced fetablodyweightisnthe10and20 mg/kg/dadyosagegroupsw,ereevidenats significraendtuctioinntsheliftaevreragefsorossificeadudavlertebrianethe 10and20 mg/kg/dadyosagegroupsanda significiannctreasienthefetal incidenocfewavyribisnthe20 mg/kg/dadyosagegroup. Allothefretaglrossexternaslo,ftissuaendskeletaallterati(omnaslformations andvariatiownesr)econsideruendrelatteodthetesatrticbleecause:1)the incidencweesrenotdosage-dependeanntd;/o2r)theincidencweesrewithin rangesobservehdistoricaatltlhyeTestinFgacility. 418-011:PAGE 1-4 C. Conclusion On thebasisofthesedata,thematernalno-observable-effect(-NlOeEvLe)lof N-ETFOSE is5 mg/kg/day (the10 and 20 mg/kg/day dosages caused biologically importantand statisticaslilgynificanrteductionsinbody weight gains orweight losses,and the 20 mg/kg/day dosage also persistentlryeduced the absoluteand relativfeeed consumption values).The developmental NOEL isalso 5 mg/kg/day (the10 and 20 mg/kg/day dosages significantrleyduced fetalbody weights and caused minimal,but statisticalsliygnificanrteversibldeelays in ossificatioonfthe caudal vertebrae;the 20 mg/kg/day dosage alsosignificantly increasedthe incidenceofwavy ribs,an additionarleversibldeelay inossification associatedwiththe reduced fetalbody weights). MildredS. ChristianP,h.D.,Fellow,ATS Date ExecutiveDirectorof Research Alan M. Hoberman, Ph.D., DABT. Date Directorof Research R@ n_"di@ntnoodrGrk.@l,Y@ro_rkt,nPrhl BT Date Associate Directorof R ar@rcchh and Study Director 418-011:PAGE 11-1 li. DESCRIPTION OF TEST PROCEDURES A. Conduct of Study: A.l. Sponso: 3M CorporateToxicology,3M Center, Building220-2E-02, St. Paul, Minnesota 55144-1000 A.2. Testing Facilily: Argus Research Laboratories,Inc.,905 Sheehy Drive,BuildingA, Horsham, Pennsylvania 19044-1297 A.3. Study Number: 418-011 A.4. Sponsor's Study Number: T-6316.7 A.5. Purpose of the Study: The purpose ofthisstudy was to detectadverse effectsof N-ETFOSE on Crl:CDOBR VAF/Plus@ presumed pregnantfemale ratsand development ofthe embryo and fetusconsequent to exposure ofthe dam from implantatiotno closureofthe hard palate.This study evaluatedICH Harmonised Tripartite Guidelinestages C and D ofthe reproductiveprocess. A.6. Study Design: The requirementsofthe InternationaClonference on Harmonisation(ICH) Harmonised TripartitGeuideline('w)ere used as the basisofstudydesign. A.7. Regulatory Compliance: The studywas conducted incompliancewithGood LaboratoryPractice(GLP) regulationosfthe U.S.Food and Drug Administratio(nFDA)(')t,heJapanese Ministryof Healthand Welfare (MHW)(')and the European Economic Community . (EEC)(4) There were no significandteviationsfrom the GLP regulationtshat affectedthe qualityor integritoyfthe study. QualityAssurance Unitfindings derivedfrom the inspectionsduringthe conduct ofthisstudy are documented 418-01 1:PAGE 11-2 and,have been providedtothe Study Directorand the TestingFacility Management. A.B. Ownership of the Study: The Sponsor owns the study. Allraw data,analyses,reportsand preserved tissuesare the propertyofthe Sponsor. A.9. Study Monitor: Marvin T. Case, D.V.M.,Ph.D. A.10. AlternateStudy Monitor: Andrew M. Seacat, Ph.D. A.11. Study Director: Raymond G. York, Ph.D.,DABT (AssociateDirectorof Research) A.12. Technical Performance: John F. Barnett,B.S. (DirectorofLaboratoryOperations) KristenlandolaSherer,B.S.(Research Associate/FetaElvaluation) Sharon Adamski (LaboratoryTechnician) A.13. Report PMRgration: Raymond G. York,Ph.D.,DABT Jo Ann Frazee,M.S. (StudyCoordinator) Susan K. Bradshaw, B.S. (DataManagement Specialist) Karen G. Parker,A.A. (AdministrativAessistant) A.14. Report Revie : Alan M. Hoberman, Ph.D, DABT (Directoorf Research) MildredS. ChristianP,h.D.,Fellow,ATS (ExecutiveDirectorof Research) A.15. Date Protocol Signed: 29 July 1998 418-01 1:PAGE 11-3 A.16. Date; of TechnicPa-lerformance: Rat ArrivalDate CohabitationPeriod Day 0 of Presumed Gestation(DG 0) Dosage Period(DGs 6 through17) ToxicokinetiScample Collection and Caesarean-SectioningPeriod (DG 18)- SatellitSetudy Caesarea n-SectioningPeriodMain Study(DG 20) 11 AUG 98 18 AUG 98 PM -23 AUG 19 AUG 98 -23 AUG 25 AUG 98 -09 SEP 98 AM 98 98 10 SEP 98 08 SEP 98 - 12 SEP 98 A.17. Records Maintained: The originarleport,raw data and reservesamples ofthe testarticlaend vehicle are retainedinthe archivesofArgus Research LaboratoriesI,nc.Any preserved tissuesare retainedinthe archivesofthe TestingFacilitfyorone year afterthe mailingofthe draftfinalreport,afterwhich time the Sponsor willdecide theirfinal dispositionP.repared formulationswere discardedatthe TestingFacility. Unused bulktestarticlweillremain atthe TestingFacilituyntilitsdispositioins decided by the Sponsor. B. Test ArticleInformation: B.I. Description: N-ETFOSE -a waxy solid B.2. Lot/Batch Number: FM-3929 [30035,30037, 30039 (Expiratiodnate: May 2000)] B.3. Date Received and StoracieConditions: The testarticlweas receivedon 20 May 1998, and storedatroom temperature. Prepared formulationswere storedrefrigerated. B.4. Special Handling Instructions: Standard safetyprecautions(use ofprotectivcelothingg,loves,dust-mist respirators,afetygoggles or safetyglassesand a face-shieldw)ere taken when handlingthe bulktestarticlaend prepared formulations. 418-01 1:PAGE 11-4 B.S. Analysis of PurLty: Informationregardingthe identityc,omposition,strength,and purityofthe test articlieson filewiththe Sponsor. C. VehicleInformation: C.l. Description: 2% Tween@ 80 inReverse Osmosis Membrane Processed DeionizedWater (R.O.DeionizedWater). C.2. LotNumber: M03HO5 C.3. Date Received and Stora e CondiiiMg: The vehiclewas receivedon 8 July1998 from J.T.Baker,Phillipsburg, New Jersey,and storedatroom temperature.R.O. DeionizedWater isavailable from a continuoussource attheTestingFacilitaynd ismaintainedat room temperature. C.4. SpecialHandlingInstructions: Standard safetyprecautions(useof protectivcelothingg,loves,dust-mist respiratosra,fetygogglesorsafetyglassesand a face-shieldw)ere takenwhen handlingthe vehicle. C.5. AnalysisofPurily: Neitherthe Sponsor northe Study Directowras aware ofany potential contaminantslikeltyobe presentinthe vehiclethatwould interferweiththe resultsofthisstudy. D. Test Article Preparation: Suspensions of N-ETFOSE were prepared dailyat concentrationsof 0, 0.2,1, 2 and 4 mg/mL. The testarticlweas considered100% pure forthepurpose of dosage calculations. 418-01 1:PAGE 11-5 D.l. SamRie Information: Sample Type Concentration (allevels) Bulk Test ArticleReserve Vehicle Reserve Components N/A N/A Tween 0 80 R.O. Deionized 1 Water Size 2 mV Ig Date Retained 25 AUG 980 09 SEP 98r 25 AUG 98 5 mL 25 AUG 98 5 mL 25 AUG 98 I Storage Conditions Frozen Room Temperature Room Temperatur Room Temperature Date Shipped To Shipped Sponsor 26 AUG 98 10 SEP 98 TestingFacility 01 OCT 98 Archives TestingFacility 01 OCT 93888] Archives TestingFacility 01 OCT 98 Archives a. Duplicatesamples were taken from the firsatnd lastpreparationon the day prepared. One sample ofeach setwas shipped tothe Sponsor foranalysis.The remainingsamples were retainedatthe TestingFacilitays backup samples. b. Firstday of preparation. C. Last day of preparation. Homogeneity and stabilitoyfprepared formulationsare on filewiththe Sponsor. D.2. AnalyticalResults: Concentrationsamples (2 mL) were taken on the firsatnd lastdays of preparationforanalyses by 3M EnvironmentalTechnology and Safety Services. The resultsofthese analyses were not availableatthe time ofthisreport. E. Test System: E.I. Species: Rat E.2. Strain: Crl:CDOBR VAF/PlusO (Sprague-Dawley) E.3. Supplier(Source): Charles RiverLaboratories,Inc.,Raleigh,NorthCarolina E.4. Sex: Female (Note:Male ratswere used onlyforthe purposes ofbreedingand are not consideredpartofthe Test System.) 41 B-01I:PAGE 11-6 E.S. Rationale for Test System: The Crl:CDOBR VAF/PlusO (Sprague-Dawley) ratwas selected as the Test System because: 1) itisone mammalian speciesaccepted and widelyused throughoutindustryfornonclinicasltudiesofdevelopmentaltoxicit(yembryo-fetal toxicity/teratogenic2i)ttyh)i;sstrainhas been demonstrated to be sensitivteo developmental toxins;3) historicadlata and experienceexistatthe Testing Facility('a-n7d)4;) the testarticliesbiologicalalcytiveinthisspeciesand strain. E.6. Test System Data: Number ofRats Approximate Date of Birth Approximate Age atArrival Weight (g)on the Day afterArrival Weight (g)at Study Assignment E.7. Bree lerMale Rat Data: Number of Rats Approximate Date ofBirth Approximate Age atArrival Weight (g)on the Day afterArrival Weight (g)atStudy Assignment 190 08 AUG 98 64 days 195-234 210-251 Shipment 1 Ship e@nt 2@ 110 120 13 JAN 98 26 JAN- 98 87 days 75 days 300-356 300-356 498-784 E.8. Method of Random Lization: Upon arrivalr,atswere assigned to individuahlousing on the basisof computergenerated random units.Female ratswere assignedto one offivedosage groups (Groups Ithrough V),25 ratsper dosage group,usinga computergenerated (weight-orderedr)andomizationprocedure based on body weights recordedon DG 0. Nineteen additionaflemale ratswere assignedto one of five dosage groups forthe satellitsetudy(threef,ive,three,threeand fiverats assignedto Groups IthroughV, respectivelyu)sing a computer-generated randomizationbased on body weights recordedon DG 0. E.9. System of Identification: Each ratwas individualliydentifiewditha Monel@ self-piercienagr tag (Gey Band and Tag Co.,Inc.,No. MSPT 20101) inscribedwiththe rat'sdesignated unique permanent number. Cage tags were marked withthe study number and permanent ratnumber. 418-01 1:PAGE 11-7 F. Husbandry: F.1 liasit[rAatRiSoLn-: USDA RegistratioNno. 23-R-099 under the Animal WelfareAct,7 U.S.C.2131 etseq. F.2. stud t-Roo-ms: The study rooms were maintainedunder conditionsof positiveairflowrelativteo a hallwayand independentlysuppliedwitha minimum often changes per hour of 100% freshairthathad been passed through99.97% HEPA filter(sAiroCleans room). Room temperatureand humiditywere monitoredconstantlythroughout the study. Room temperaturewas targetedat640F to790F (I8"C to 26"C); relativheumiditywas targetedat30% to70%. See APPENDIX E (TEMPERATURE AND RELATIVE HUMIDITY REPORT). F.3. Hqy-sll-ng: Rats were individuallhyoused except duringthe cohabitatiopneriod.During cohabitatione,ach pairofmale and female ratswas housed inthe male rat's cage. Allcage sizesand housing conditionswere incompliancewiththe Guide forthe Care and Use ofLaboratoryAnimals('). F.4. Ugbting: An automatically-controlflleudorescentlightcyclewas maintainedat12-hours light1:2-hoursdark,witheach dark periodbeginningat 1900 hours EST. F.S. Sanitization: Cage pan linerswere changed approximatelythreetimes each week. Cages were changed approximatelyevery otherweek. F.6. Feed: Ratswere givenad libituamccesstoCertifieRdodent Diets#5002 (PMI NutritioInnternationaSlt,.Louis,Missouri)inindividuafleeders. F.7. Feed Analysis: Analyses were routinelpyerformed by the feed supplier.No contaminantsat levelsexceeding the maximum concentrationforcertifiefdeed or deviationsfrom 418-01 1:PAGE 11-8 expected nutritionraelquirementswere detectedby these analyses. Copies of the resultsofthe feed analysesare availableinthe raw data. Neitherthe Study Directornor the Sponsor was aware ofany agent presentin the feed thatwas known to interferweiththe resultsofthisstudy. F.8. Water: Localwater thathad been processed by passage througha reverseosmosis membrane (R.O.water)was availabletothe ratsad libitumfrom individuawlater bottlesattachedtothe cages and/orfrom an automaticwateringsystem. Chlorinewas added to the processed water as a bacteriostat. F.9. WateLAnAlysis: The processed water isanalyzed twiceannuallyforpossiblechemical contamination(LancasterLaboratoriesL,ancaster,Pennsylvania)and monthly forpossiblebacteriaclontamination(AnalyticaLlaboratoriesI,nc.,Chalfont, Pennsylvania).Copies ofthe resultsofthe water analyses are availableinthe raw data. Neitherthe Study Directornor the Sponsor was aware of any agent presentin the water thatwas known to interferweiththe resultsofthisstudy. G. Meth_ods: G.I. Dosage Administration: Dosage Group 11 Number of Rats 25+31 25+51 Dosage Concentration (mg/kg/day) (mg/mL) 0 (Vehicle) 0 1 0.2 Dosage Volume (mukg) 5 5 Assigned Numbers Main Study 12801 - 12825 SmabterlslitSetu5dyO SatellitSetud l@122557733;1-2125775y5] 12826 - 12850 12576 - 12580 111 25+30 5 1 IV 25+38 10 2 ::@25 + 58 20 4 5 12851 - 12875 12581 - 12583 5 12876 - 12900 12584 - 12586 5 12901 - 19295 12587 - 12591 Fhetestarticlweas considered 100% pureforthe purpose of dosage @iculations. a. Rats assigned to the satellitgeroup forblood collection. The testarticlweas considered100% pure forthe purpose of dosage calculations. 418-01 1:PAGE 11-9 G.2. Rationale for Dosa!ge Selection: Dosages were selected on the basis of a dosage-range study (Argus Research LaboratoriesI,nc.,Protocol418-011 P) thattested0, 1,5, 10, 25 and 35 mg/kg/day. Inthatstudy,body weight gain was decreased at 10 mg/kg/day and higherdosages, and feed consumption values were reduced atalldosages tested. G.3. Rou B of Ldmin:istra_tion: Oral (gavage) G.4. Rati nale for Route of Administration: The oral(gavage) routewas selectedforuse because: 1) incomparison withthe dietaryroute,the exactdosage can be accuratelyadministered;and 2) itisa proposed routeof human exposure. G.5. Freg jenc fof Administration: Appropriatedosages ofthe testarticlweere administeredorally(viagavage) once dailytofemale ratson DGs 6 through 17. Dosages of0 (Vehicle)1,,5, 10 and 20 mg/kg/day ofthe testarticlweere administeredata dosage volume of 5 mukg, adjusteddailyon the basisofthe individuablody weightsrecorded beforedosage. The ratswere dosed at approximatelythe same time each day. G.6. Length of Study: Approximately4 weeks G.7. Method @f Studv Performance: Afteracclimation1,90 healthyvirginfemale ratswere placed intocohabitation with 190 breedermale rats(one male ratper female ratinthe male rat'scage). Female ratswithspermatozoa observed ina smear ofthe vaginalcontents and/ora copulatoryplug insituwere consideredto be at DG 0 and returnedto individuahlousing. The female ratswere observed forviabilitayt leasttwiceeach day ofthe study and forgeneralappearance weekly duringacclimationand on DG 0. The rats were alsoexamined forclinicaolbservationsofeffectsofthe testarticle, 418-011: PAGE 11-10 abortionsp,rematuredeliverieasnd deathsbeforeand approximatelyone hour afterdosage (DGs 6 through171),and once dailyduringthe postdosageperiod. Body weightswere recordedweekly duringacclimationo,n DGs 0 and 4 and dailyduringthedosage and postdosage periods(DGs 6 through20).Feed consumption valueswere recordedon DGs 0,4, 61 8, 10,12,14,16,18 and 20. G.8. Gross NecropSyb: Rats Assigned tothe Main Study: Allratswere sacrificebdy carbon dioxideasphyxiationon DG 20,Caesareansectionedand a gross necropsy ofthethoracica,bdominal and pelvicviscera was performed.Uteriofapparentlynonpregnantratswere stainedwith10% ammonium sulfidteoconfirmtheabsence ofimplantatiosnites(gT)i.ssueswith gross lesionswere preservedinneutralbuffered10% formalinforpossiblefuture evaluationa;llothermaternaltissueswere discarded. The number ofcorporaluteaineach ovarywas recorded.The uterusofeach rat was excisedand examined forpregnancy,number and distributioofn implantationsl,iveand dead fetusesand earlyand lateresorptionsA.n early resorptiownas definedas one inwhich organogenesiswas notgrosslyevident. A lateresorptiownas definedas one inwhich the occurrenceoforganogenesis was grosslyevident.A livefetuswas definedas a term fetusthatresponded to stimuliN.onrespondingterm fetusesare consideredtobe dead (therewere no dead fetuses).Dead fetusesand lateresorptionasredifferentiatbeydthe degree ofautolysipsresent;marked to extreme autolysiisndicatetdhatthefetus was a lateresorption. Each fetuswas removed from the uterus,placedinan individuaclontainerand identifiweidtha tagnotingthestudynumber, littenrumber, uterinedistribution and fixativeE.ach fetuswas subsequentlyweighed and examined forsex and grossexternalalterationsL.ivefetuseswere sacrificebdy an intraperitoneal a. See APPENDIX D (DEVIATIONS FROM THE PROTOCOL AND STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY), item 1. b. A tableof random unitswas used to selectone controlgroup ratfrom which alltissuesexamined at necropsywere retainedi,norderto provide controltissuesforany possiblehistopathologiceavlaluationosfgross lesions. 41 B-01 1:PAGE 11-11 injectionfBeuthanasiag-D Special(Schering-PlougAhnimal Health). Photographs ofgrossexternalfetalalterationasreavailableintheraw data. Approximatelyone-halfofthefetusesineach littweerre examined forsofttissue alterationusingan adaptationofWilson'ssectionintgechnique(loT)h.e fetuses were initialfliyxedinBouin'ssolutions;ectionswere storedinalcohol.The remainingfetusesineach littweerre evisceratedc,leared,stainedwithalizarin redS("),fixedinalcoholand examined forskeletaallterationsS.keletal preparationwsere retainedinglyceriwniththymoladded as a preservative. atelliStteud : On DG 18,ratsassignedto thetoxicokineteivcaluationwere sacrificeadnd the followinsgamples collectedB.lood samples (approximatel4ymL per rat)were collectefdrom the inferiovrena cava intoserum separatortubes and centrifuged. The resultinsgerum (approximatel2y mL) was immediatelyfrozenon dryiceand maintainedfrozen(-700C)untislhipmenttothe Sponsor foranalysis.The liver was excised,weighed,and a sample section(laterallobe)was frozenand retainedat-700C untislhipment tothe Sponsor foranalysis. Ratswere Caesarean-sectionedand fetuseswere examined grosslyto the extentpossibleas describedabove forratsassignedtothe main study.Fetuses and placentaewere pooledper littaenrd retainedfrozen(-700C)untislhipment tothe Sponsor foranalysis.Aftercompletionofsample collectiosne,rum, liver section(laterallobe)f,etaland placentalsamples were shipped(frozenon dry ice)tothe Sponsor foranalysis. 418-011: PAGE 111-2 G.9. StatisticalAnalyses: The followingschematic representsthe statisticalnalyses of data: Tyge ofTest' 1. Parametric 11.NonparametriCb A. Bartieft'TseSf.d A. Kruskal-WalliTsest (:@-75%ties) F Significant at p:!@00.5 Nonparametric Not Significant 1 AnalysisofVariance I Significant atp:50.05 I Dunn's Test Not Significant Significant at p:@0.05 I Dunnett'sTest Not Significant B. Fisher'sExact Test (>75% ties) 111.Test forProportionData Variance Test forHomogeneity ofthe BinomialDistribution -------------- a. Statisticalsliygnificanptrobabilitiaerse reportedas eitherp:50.05or p:50.01. b. Proportiondata are not includedinthiscategory. c. Used onlyto analyzedata withhomogeneity of variance. d. Test forhomogeneity of variance. 418-01 1:PA GE 11-13 Clinicaolbservationand otherproportiondatawere analyzedusingthe Variance (12) Test forHomogeneity oftheBinomialDistribution Continuousdata (e.g.m,aternalbody weights,body weightchanges,feed consumption valuesand littearveragesforpercentmale fetuses,percent resorbedconceptuses,fetalbody weights,fetalanomaly dataand fetal ossificatisointedata)were analyzedusingBartietCTsest of Homogeneity of Variances("a)nd theAnalysisofVariance(14,) when appropriat[ei.e.B,artlett's Testwas notsignifica(npt>0.05)]I.ftheAnalysisofVariancewas significant (p:50.05)D,unnett'sTeSt(I 5) was used to identiftyhestatisticsailgnificancoefthe individuaglroups. IftheAnalysisofVariancewas notappropriatiei.e.B,artlett's Testwas significa(npt:50.05)t]h,eKruskal-WalliTsest(")was used,when less than orequalto75% tieswere present.Incases where theKruskal-WalliTsest was statisticaslilgynifica(npt:@,0.05D)u,nn's Method of MultipleComparisonS(17) was used toidentiftyhestatisticsailgnificancoefthe individuaglroups. Ifthere were greaterthan 75% ties,Fisher'EsxactTest(")was used toanalyzethe data. Count data obtainedatCaesarean-sectioninogfthedams were evaluatedusing the proceduresdescribedabove forthe Kruskal-WalliTsest("). Dam 12868 (5mglkg/day dosage group)had a littecronsistinogffivelivefetuses and two earlyresorptionasnd dam 12889 (10 mglkg/daydosage group)had a liftceornsistinogfthreelivefetuses.Because such occurrencescan abnormally skew thedistributioofndata(")s,tatisticaanlalyseswere made withand without thevaluesfortheseratsand litterMsa.ternalbody weights,feed consumption valuesand Caesarean-sectiondataforthese dams and littewresre excluded from summarizationand statisticaanlalyses;allvaluesare presentedon the individuatlables. 418-011:PAGE 111-1 Ill. RESULTS A. Mortalily,Clinical and Necropsy Observations (Summaries - Tables 1 and 2: Individual Data - Tables 14 and 16) A.I. Mortailly No deaths, abortions or premature deliveriesoccurred during the study. Allrats surviveduntislcheduled sacrificoen gestationday 20 (DG 20). A.2. ClinicalObservations Allclinicaolbservationswere consideredunrelatedtothe testarticlbeecause: 1)the incidenceswere not dosage-dependent; 2)the observationsoccurredin onlyone rat;and/or 3)the observationsare common events inthe laboratory environment. Clinicaolbservationsincludedlocalizedalopeciaon the underside, limbsand/orneck, ungroomed coat,coldtotouch and fused second and third digitson the rightforepaw. A.3. Necropsy Observations The only necropsyfindingwas a tan area (0.6cm x 0.8 cm) on the median lobe ofthe liverinone 20 mg/kg/day dosage group dam (12913).This observation was consideredunrelatedto the testarticlbeecause itoccurredinonlyone rat. B. Maternal Bodv Weights and Bodv WeicihtChanges (FigureI-. Summaries -Tables 3 and 4: IndividualData -Table 16) Maternalbody weight gains were significantrleyduced (p:!@0.0o5rp:50.01)in groups administered5 mg/kg/day and higherdosages ofthe testarticleT.he effectwas minimaland transientinthe 5 mg/kg/day dosage group, occurring onlyon DGs 8 to 10. Inthe 10 mg/kg/day dosage group,significanrteductions (p-<0.05i)nmaternalbody weight gains occurredon DGs 6 to 8 and 10 to 12, followedby a significanitncrease(p-<0.05i)nweightgain on DGs 14 to 16. The 20 mg/kg/day dosage group had significanwteightloss(p:50.01o)n DGs 6 to 8 followedby significanrteductions(p:!@0.0o5r p:!@0.01i)nmaternal body weight gainon DGs 8 to 14 and 16 to 18. These effectsofthe testarticlreesultedina tendency forreduced weight gain inthe 10 mglkg/day dosage group and significanrteductions(p:!@0.0i1n)the 20 mg/kg/day dosage group forthe entire treatmentperiod(calculateads DGs 6 to 18),the entireintervaalfterinitiatioofn treatment(DGs 6 to 20) and the entiregestationperiod(DGs 0 to 20). Maternal 418-011: PAGE 111-2 body weights were significantlryeduced (p:!@0.0o5r p:50.01)inthe 10 and 20 mg/kg/day dosage groups on DGs 11 through14 and 8 through20, respectively. Body weightsand body weight gainswere unaffectedby the 1 mg/kg/day dosage ofthe testarticle. C. Maternal Absolute (g/day)and Relative(9/kg/day)Feed Consumption Values (Summaries -Tables 5 and 6: IndividualData -Table 17J The absolute(g/kg/day)feed consumption valuewas significantrleyduced (p@50.05i)nthe 10 mg/kg/day dosage group on DGs 6 to 8 and absolute(g/day) and relativ(eg/kg/day)feed consumption valueswere significantrleyduced (p:!:,0.i0n1t)he 20 mg/kg/day dosage group forthe entiredosage period (calculateads DGs 6 to 18) and atallintervalwsithinthisperiod.The absolute feed consumption value continuedtobe significantrleyduced (p-.@0.0a1n)d the relativfeeed consumption value tended to be reduced inthe 20 mg/kg/day dosage group duringthe postdosage interva(lDGs 18 to 20). These effectsof the 20 mg/kg/day dosage ofthe testarticlreesultedinsignificantrleyduced (p:!@0.0a1b)soluteand relativfeeed consumption values on DGs 6 to 20 (the entireintervaalfterthe firsdtosage was administered)and DGs 0 to 20 (the entiregestationperiod). Absoluteand relativfeeed consumption valueswere unaffectedby dosages of thetestarticlaes high as 5 mg/kg/day. The significanrteduction(p:!@0.0i5n)the relativfeeed consumption value inthe 1 mg/kg/day dosage group on DGs 6 to 8 was consideredunrelatedtothe testarticlbeecause the value was not dosagedependent. D. Caesarean-Sectioninci and -LitteOrbservations (Summaries -Tables 7 and 8: IndividualData -Tables 18 through 2Q) Pregnancy occurred in24 (96%), 23 (92%), 24 (96%), 25 (100%) and 24 (96%) ofthe ratsinthe 0 (Vehicle)1,,5,10 and 20 mg/kglday dosage groups, respectivelyO.ne 5 mg/kg/day dosage group liftecronsistedoffivelivefetuses and two earlyresorptionsa,nd one 10 mg/kg/day dosage group liftecronsistedof three livefetuses.Because such occurrencescan abnormallyskew the distributioofnthe data(19)v,aluesforthese dams and litterwsere excludedfrom data summarization and statisticaanlalyses. As a resultC,aesarea n-sectioning observationswere based on 24, 23, 23, 24 and 24 pregnantdams. 418-011: PAGE 111-3 Fetalbody weights (totalm,ale and/orfemale)were significantrleyduced (p.0-.@05 orp:@,0.01i)nthe 10 and 20 mg/kg/day dosage groups,as compared tothe controlgroup values. The reduced fetalbody weightsinthe 10 and 20mg/kg/day dosage groups were a reflectioonf body weight reductionofthe dams atthese higherdosage levels.Dosages ofN-ETFOSE as high as 20 mg/kg/day did not affectany otherCaesarea n-sectioninogrlifteprarameters. The liftearverages forcorpora lutea,implantationsl,iftesrizes,livefetuses,earlyresorptions, percentresorbedconceptuses and percentmale fetuses,as wellas the numbers ofdams with any resorptionsor withviablefetuseswere comparable inthe five dosage groups and did not significantdliyffer.No dams had lifterwsithall conceptuses resorbed,and therewere no dead fetusesor lateresorptions.All placentaeappeared normal. Allofthese valueswere withinthe ranges observed historicalaltythe TestingFacility. E. FetalAlterations(Summaries -Tables 9 through 13: IndividualData Table Zlj Fetalalterationwsere definedas: 1)malformations(irreversibclheanges that occur at low incidencesinthisspeciesand strain)a;nd 2)variation(scommon findingsinthisspecies/straina,nd reversibldeelays or accelerationisn development). Liftearverages were calculatedforspecififcetalossificatiosnites as partofthe evaluationofthe degree offetalossification. Fetalevaluationswere based on 342, 349, 347, 354 and 326 DG 20 Caesareandeliveredlivefetusesin24, 23, 24,25 and 24 lifterisnthe 0 (Vehicle)1,,5, 10 and 20 mg/kg/day dosage groups,respectivelyE.ach fetuswas examined for gross externalalterationsO.f these respectivefetuses166, 167, 169, 170 and 158 were examined forsofttissuealterationasnd 176, 182, 178, 184 and 168 were examined forskeletalalterationasnd fetalossificatiosniteaverages. E.I. Summary of FetalAlterations(Summa!y -Table 9; IndividualData Table 211 Inthe fiverespectivedosage groups,litterwsithfetuseswithalterationpsresent numbered6 (25.0%)8,(34.8%)4,(16.7%)7,(28.0%)and8 (33.3%).The numbers offetuseswithany alteratioonbservedwere 15 (4.4%),10 (2.9%), 6 (1.7%),8 (2.2%)and 12 (3.7%),and thepercentagesoffetuseswithany alteratiownere 4.4%, 2.8%, 1.6%, 2.1% and 4.0%, inthese same respective dosage groups. a. See APPENDIX G (HISTORICAL CONTROL DATA). 418-011: PAG E 111-4 Reversibledelays infetalossification@"a,s"s)ociatedwiththe significantly reduced (p@@0.05orp:50.01)fetalbody weights inthe 10 and 20 mg/kg/day dosage groups,were evidentas significanrteductions(p:!@0.05i)nthe lifter averages forossifiedcaudal vertebraeinthe 10 and 20 mg/kg/day dosage groups and a significanitncrease(p:!@0.0i5n)the fetalincidenceofwavy ribsin the 20 mg/kg/day dosage group. Allotherfetalgross external,softtissueand skeletalalteration(smalformations and variationsw)ere consideredunrelatedtothe testarticlbeecause: 1)the incidenceswere notdosage-dependent; and/or 2) the incidenceswere within ranges observed historicalaltythe TestingFacility. E.2. FetalGross ExternalAlterations(Summary -Table 10: Individual Data - Table 21) E.2.a. Malformations One 10 mg/kg/day dosage group fetus(12885-15)had a shorttrunkand absent tail.Subsequent skeletalexaminationofthisfetusrevealedthatonlyfour cervicalvertebraewere presentand thattherewere no thoracic,lumbar,sacral or caudal vertebrae,or ribs.This fetusalso had a variationinpelvicossification (thepubes were notossified). E.2.b.Variations No gross externalvariationosccurredinthe fetusesinthisstudy. E.3. FetalSoftTissue Alterations(Summarv -Table li: IndividualData Table 21) E.3.a.Malformations No fetalmalformationswere identifieadt visceraelxamination. E.3.b.Variations E.3.b.i.Vessels Three controlgroup fetuses(12801-10;12810-10;12821-6),one 1 mg/kg/day dosage group fetus(12834-14)and two 5 mg/kg/day dosage group liftermates 418-011:PAGE 111-5 (12860-5,-9)had th6 umbilicaalrterydescendingtothe lefotfthe bladder. These fetuseshad no externalfindingsand no othersofttissuealterations. Two 1 mg/kg/daydosage group fetuses(12826-12;12837-9)had an absent innominateartery.No additionaallterationosccur-reidnthese fetuses. E.3.b.2.Lungs One controlgroup fetus(12822-4)had an absentapicallunglobe,and one 1 mg/kg/daydosage groupfetus(12850-16)had an absent diaphragmaticlung lobe.No additionaallterationosccurredinthesefetuses. E.3.b.3.Kidneys Two controlgroup fetuses(12802-11;12803-2)and one 10 mg/kg/daydosage group fetus(12877-14)had slightormoderate dilatioonfthepelvisofone or both kidneys,a reversibldeevelopmentaldelay(22) . No additionaallterations occurredinthesefetuses. E.4. FetalSkeletalAlteration(sSummaries -Tables 12 and 13,Individual Data -Table 21) E.4.a.Malformations Externallmyalformed 10 mg/kgldaydosage group fetus12885-15 had onlyfour cervicavlertebraeand no thoracicl,umbar,sacralor caudalvertebraeor ribsa,s wellas a variatioinnpelvicossificati(onnotossifiepdubes),as previously described. E.4.b.Variations E.4.b.l.Skull A largenasal-frontsaultureoccurredinone 10 mg/kg/daydosage group fetus (12893-13).No additionaallterationosccurredinthisfetus. E.4.b.2.Ribs A cervicarlibatthe7thcervicavlertebraa, common variatioinnthisstraionf rat(23,) occurredin0, 3, 1,3 and 4 fetusesfrom 0,2, 1,3 and 4 lifterisnthe ,0(Vehicle)1,,5,10 and 20 mg/kg/daydosage groups,respectivelyT.hese fetuseshad no otherexternalor skeletaallterations. 418-01 1:PAGE 111-6 Wavy ribs,a reversibldeelayinossificati(o2n1,)occurred inone 1 mg/kg/day dosage group fetus(12848-1)and seven (p:!@0.0250) mg/kg/day group fetuses (12904-1;12909-5,-7,-10,-12;12919-3,-9).One 20 mg/kg/day dosage group fetus(12909-7)alsohad incompletelyossifiedribs.The significanitncreasein the fetalincidenceofwavy ribsinthe 20 mg/kg/day dosage group was considereda treatment-relateddevelopmental delay,associatedwiththe significantrleyduced (p:!@0.0o5r p<0.01) fetalbody weights inthisdosage group. E.4.b.3.Sternum Delayed sternalossificatio(nincompletelyossifiedor not ossifiedlststernebra) occurredin7,2**,1**,1**and 1**fetusesfrom 3,2, 1,1 and 1 lifterisnthe 0 (Vehicle)1,,5, 10 and 20 mg/kg/day dosage groups,respectivelyO.f these fetuses,one controlgroup fetus(12802-1)had incompletelyossifiedpubes in additionto an unossifiedlststernalcentrum. E.4.b.4.Pelvis The ischiaand/orpubes were incompletelyor not ossifiedin3,0,2,2 and 0 fetusesfrom 1,0, 1,2 and 0 lifterisnthe 0 (Vehicle)1,,5, 10 and 20 mg/kg/day dosage groups,respectivelyO.ne fetusinthe controlgroup (12802-1)and one 10 mg/kg/day dosage group fetus(12885-15)had additional skeletalalterationass, previouslydescribed. E.4.b.5.FetalOssificationSiteAverages The liftearverages forossifiedcaudal vertebraeper fetuswere significantly reduced (p!@0.05i)nthe 10 and 20 mg/kg/day dosage groups. These delays in caudal vertebralossificatiownere consideredeffectsofthetestarticlaessociated withthe significantrleyduced (p:!@0.0o5rp:!@0.01f)etalbody weights inthese dosage groups. Analyses ofthe average numbers offetalossificatiosnitesper fetusdidnot revealany otherstatisticaslilgynificandtifferencesamong the fivedosage groups. Ossificatioonf the hyoid,vertebrae(cervicalt,horacic,lumbar and sacral)r,ibs,sternum (manubrium, sternalcentersand xiphoid)f,orelimbs (carpalsm,etacarpalsand phalanges)and hindlimbs(tarsalsm,etatarsalsand phalanges)occurredatsimilarincidencesinlifterisnalldosage groups. All values were withinthe ranges observed historicalaltythe TestingFacility. Significantldyifferenftrom the vehiclecontrolgroup (p@50.01). 418-011:PAGE 111-7 REFERENCES 1 U.S.Food and Drug Administratio(n1994).InternationCaolnferenceon Harmonisation;Guidelineon detectionoftoxicittyo reproductiofnor medicinalproducts.FederalRegister,September 22, 1994,Vol.59, No. 183. 2. U.S.Food and Drug AdministrationG.ood LaboratoryPractice RegulationsF;inalRule. 21 CFR Part58. 3. Japanese Ministryof Health and Welfare (1988). Good Laboratoiy Practice Standard forSafety Studies on Drugs, Pharmaceutical Affairs Bureau,April1,1983, amended October 5, 1988. 4. European Economic Community (1989). Councildecisionon 28 July 1989 on the acceptance by the European Economic Community ofan OECD decisionlrecommendation on compliance withprinciplesofgood laboratorypractice.OfficiaJlournal ofthe European Communities: Legislation3.2(No.L 315;28 October):1-17. 5. Christian,M.S. and Voytek, P.E. (1982). In Vivo Reproductive and Mutagenicity Tests. Environmental Protection Agency, Washington, D.C. NationalTechnicalInformatioSnervice,U.S.Department ofCommerce, SpringfielVdA, 22161. 6. ChristianM,.S.(1984).Reproductivetoxicitaynd teratologeyvaluationosf naltrexone(ProceedingsofNaltrexoneSymposium, New York Academy ofSciences,November 7,1983),J.Clin.Psychiat4.5(9):7-10. 7. Lang, P.L.(1988). Embryo and FetalDevelopmental Toxicity(Teratology) ControlData in the Charles River Crl.CD7BR Rat. Charles River LaboratoriesI,nc.W,ilmington,MA 01887-0630. (Database providedby Argus Research LaboratoriesI,nc.) 8. Institutoef Laboratory Animal Resources(1996).GuidefortheCare and Use of Laboratory Animals. NationalAcademy Press, Washington, D.C. 9. Salewski,E. (1964).FArbemethode zum makroskopischenNachweis von ImplantationsstelalmenUterusder Rafte.Arch.Pathol.Exp.Pharmakol. 247:367. 418-011:PAGE 111-8 10. WilsonJ,.G.(1965).Methodsforadministerianggentsand detecting malformatioinnsexperimentalnimals.TeratologyP.r,inciplaensd TechniquesW,ilsonJ,.G.and Warkany,J.(eds.U)n,iversiotfyChicago Press,pp.262-277. 11. StaplesR,.E.and SchnellV,.L.(1964).Refinemenitnrapidclearing techniquientheKOH-alizarriendS methodforfetablone.StainTechnol. 39:61-63. 12. SnedecorG,.W. and Cochran,W.G. (1967)V.ariancteestfor homogeneitoyfthebinomiadlistributiSotna.tistiMceatlhods,6thEdition, IowaStateUniversiPtryess,Ames, pp.240-241. 13. Sokal,R.R.and RohlfF,.J.(1969).Bartlettte'sstofhomogeneityof variancesB.iometryW,.H. Freemanand Co.,San Francisco, pp.370-371. 14. Snedecor,G.W. and Cochran,W.G. (1967)A.nalysiosfVariance. StatistiMceatlhods,6thEditionI,owaStateUniversiPtryess,Ames, pp.258-275. 15. DunneftC,.W.(1955).A multiplceomparisonprocedurfeorcomparing severatlreatmentwsitha controlJ..Amer.StatA.ssoc.50:1096-1129. 16. Sokal,R.R.and RohlfF,.J.(1969).Kruskal-WalTleisst.Biometry, W.H. Freemanand Co.,San Franciscop,p.388-389. 17. Dunn,O.J.(1964).Multiplceomparisonussingranksums. Technometric6s(3):241-252. 18. SiegelS,.(1956).NonparametriSctatistfiocrstheBehavioraSlciences, McGraw-HilNle,w York,pp.96-104. 19. Zambrama,M.A.and Greenwald,G.S.(1971).Effectosffetaolvarian and placentwaelightofvariounsumberoffetuseisntherat.Biolo.f Reprod.4:216-223. 20. CollinTs.,F.X.W,elsh,J.J.B,lack,T.N.,WhitbyK,.E.and O'Donnell, M.W.,Jr.(1987).Potentiraelversibiolfistkyeleteaflfectisnratsexposed inuterotocaffeineF.d.Chem. Toxic2.5(g):647-662. 21. NishimuraM,.,lizukaM,.,lwakiS,.and Kast,A.(1982).Repairabiloifty Drug-induce"dWavy Ribs"inRatOffsprinAgr.znemi.-Forsc/hD.rugRes. 32(ilN)r,.12.,pp.1518-1522. 418-01 1:PAGE 111-9 22. Woo, D. and Hoar, R. (1972)."ApparentHydronephrosis"as a Normal Aspect of Renal Development inLate Gestationof Rats: The Effectof Methyl SalicylateT.eratology6:191-196. 23. Khera, K.S.(1981).Common fetalaberrationsand theirteratologic significancea: review. Fund. and Appl.Toxicol.1:13-18. I APPENDIX A REPORT FIGURE 400 380 360 340 &320 300 280 -260 240 220 ---- ---- -- MATERNAL BODY WEIGHTS Figure 1 1 IT - 10 11 12 13 4 15 16 17 8 19 20 DAY OF GESTATION I APPENDIX B REPORT TABLES PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY TABLE I (PAGE 1): CLINICAL OBSERVATIONS - SUMMARY STUDY OF N-ETPOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP I ii III IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 1 5 10 ----------------------------------------------------------------------------------------------------------------- MAXIMUM POSSIBLE INCIDENCE 375/ 25 375/ 25 375/ 25 375/ 25 MORTALITY 0 0 0 LOCALIZED ALOPECIA: TOTAL UNDERSIDE LIMBS NECK 12/ 1 0/ 0 12/ 1 0/ 0 29/ 3 28/ 3 2/ 1 0/ 0 9/ 3 7/ 2 0/ 0 2/ 1 15/ 2 11/ 1 7/ 2 0/ 0 UNGROOMED COAT 0/ 0 0/ 0 0/ 0 0/ 0 COLD TO TOUCH 0/ 0 0/ 0 0/ 0 0/ 0 RIGHT FOREPAW: SECOND AND THIRD DIGITS FUSED 0/ 0 0/ 0 4/ 1 0/ 0 ----------------------------------------------------------------------------------------------------------------- STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS. MAXIMUM POSSIBLE INCIDENCE = (DAYS X RATS)/NUMBER OF PATS EXAMINED PER GROUP ON DAYS 6 THROUGH 20 OF PRESUMED GE NIN = TOTAL NUMBER OF OBSERVATIONS/MMBER OF RATS WITH OBSERVATION, a. Dosage occurred on days 6 through 17 of presumed gestation. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY TABLE 2 (PAGE 1): NECROPSY OBSERVATIONS - SUMMARY STUDY OF N-ETPOSE IN PATS (SPONSOR@S STUDY NUMBER: T-63 ---------------------------------------------------------------------------------------------------------------- DOSAGE GROUP I DOSAGE (MG/KG/DAY)a III IV 0 (VEHICLE) 5 10 ----------------------------------------------------------------------------------------------------------------- RATS EXAMINED N 25 25 25 25 MORTALITY N 0 0 0 0 APPEARED NORMAL N 25 25 25 25 LIVER: MEDIAN LOBE, TAN AREA N 0 0 0 ----------------------------------------------------------------------------------------------------------0------ a. Dosage occurred on days 6 through 17 of presumed gestation. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY TABLE 3 (PACE 1): MATERNAL BODY WEIGHTS - SUMMARY STUDY OF N-ETPOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 ------------------------------------------------------------------------------------------------------------------ DOSAGE GROUP I ii III IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 1 5 10 ----------------------------------------------------------------------------------------------------------------- RATS TESTED N 25 25 2S 25 PREGNANT N 24 23 24 25 INCLUDED IN ANALYSES N 24 23 23b 24c MATERNAL BODY WEIGHT (G) DAY 0 MEAN+S.D. 230.8 + 9.9 231.0 + 9.6 230.1 + 10.5 230.5 + 10.0 DAY 6 M M +S.D. 267.1 + 12.1 265.4 + 14.0 265.4 + 15.4 263.2 + 12.5 DAY 7 MEAN+S.D. 271.3 + 12.7 269.0 + 14.2 271.5 + 15.0 267.3 + 12.2 DAY 8 DAY 9 MEAN+S.D. MEAN+S.D. 276.1 + 12.6 200.8 + 13.1 273.8 + 14.4 277.5 + 13.8 274.6 + 16.1 [ 22]d 277.6 + 17.0 268.1 + 14.7 272.2 + 14.1 DAY 10 MEAN+S.D. 285.2 + 13.6 283.2 + 15.4 281.6 + 18.2 277.1 + 13.6 DAY 11 MEAN+S.D. 290.6 + 14.8 287.8 + 15.8 287.9 + 17.3 279.6 + 13.4* DAY 12 MEAN+S.D. 295.1 + 15.3 291.6 + 16.0 291.9 + 17.7 283.5 + 14.4* DAY 13 MEAN+S.D. 300.7 + 16.2 297.8 + 17.1 296.5 + 20.2 289.2 + 17.1* DAY 14 MEAN+S.D. 305.4 + 17.1 304.0 + 17.7 301.8 + 21.0 293.3 + 18.0* DAY fI a. b. c. d. DAY 15 = DAY OF GESTATION MFAN+S.D. 7 313.0 + 17.6 311.4 + 17.8 309.5 ------------------------------------- = NUM13ER OF VALUES AVERAGED Dosage occurred on days 6 through 17 of gestation. Excludes values for dam 12868, which had a litter consisting of 7 conceptuses. Excludes Excludes values for dam 12889, which had a litter a value that was not recorded, consisting of 3 conceptuses. Significantly different from the vehicle control group value (P<0.05). Significantly different from the vehicle control group value (p<0.01). + 22.1 302.9 16.5 ---------------------------- PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN PATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 3 (PAGE 2): MATERNAL BODY WEIGHTS - SUMMARY ------------------------------------------------------------------------------------------------------------------ DOSAGE GROUP I ii III IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 1 5 10 ----------------------------------------------------------------------------------------------------------------- PATS TESTED N 25 25 25 25 PREGNANT N 24 23 24 25 INCLUDED IN ANALYSES N 24 23 23b 24c MATERNAL BODY WEIGHT (G) DAY 16 MEAN+S.D. 323.5 + 19.3 321.3 + 18.5 321.3 + 22.7 314.4 + 18.4 DAY 17 MEAN+S.D. 336.5 + 19.6 333.3 + 17.8 333.6 + 23.4 325.2 + 19.1 DAY 18 MEAN+S.D. 350.3 + 19.9 348.6 + 19.3 348.5 + 24.7 338.4 + 20.9 DAY 19 MEAN+S.D. 364.8 + 19.5 363.3 + 20.6 363.9 + 27.5 352.8 + 20.3 DAY 20 MEAN+S.D. 388.7 + 21.6 386.7 + 23.2 386.6 + 29.4 375.7 + 23.0 ----------------------------------------------------------------------------------------------------------------- DAY = DAY OF GESTATION a. Dosage occurred on days 6 through 17 of gestation. b. Excludes values for dam 12868, which had a litter consisting of 7 conceptuses. C. Excludes values for dam 12889, which had a litter consisting of 3 conceptuses. significantly different from the vehicle control group value (p<o. 01) . PROTOCOL 418-011- ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 4 (PAGE 1)@ MATERNAL BODY WEIGHT CHANGES - SUMMARY ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP I III IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 5 10 ----------------------------------------------------------------------------------------------------------------- RATS TESTED N 25 25 25 25 PREGNANT N 24 23 24 25 INCLUDED IN ANALYSES N 24 23 23b 24c MATERNAL BODY WEIGHT CHANGE (G) DAYS 0 - 6 MEAN+S.D. +36.3, + 8.7 +34.4 + 12.0 +35.3 + 10.9 +32.6 + 8.2 DAYS 6 - 8 DAYS 8 - 10 DAYS 10 - 12 MEAN+S.D. MEAN+S.D. MEAN+S.D. +9.0 + 4.3 +9.1 + 4.0 +9.9 + 4.2 +8.4 + 3.0 +9.4 + 3.4 +8.4 + 5.0 +9.9 + 6.8 [ 22]d +6.0 + 4.6* 1 22]d +10.3 + 5.6 +4.9 + 5.4* +9.0 + 5.3 +6.4 + 4.5* DAYS 12 - 14 MEAN+S.D. +10.3 + 4.4 +12.3 + 4.8 +9.9 + 5.3 +9.8 + 5.6 DAYS 14 - 16 MEAN+S.D. +18.1 + 6.6 +17.3 + 4.7 +19.5 + 4.5 +21.1 + 3.9* DAYS 16 - 18 MEAN+S.D. +26.8 + 3.8 +27.3 + 5.7 +27.3 + 5.2 +24.0 + 6.2 DAYS 6 - IS MEAN+S.D. +83.2 + 11.4 +83.3 + 11.2 +83.1 + 11.9 +75.2 + 12.0 DAYS 18 - 20 MEAN+S.D. +38.3 + 6.3 +38.1 + 7.3 +38.0 + 7.9 +37.2 + 6.0 DAYS 6 - 20 MEAN+S.D. +121.5 + 13.2 +121.3 + 15.9 +121.1 + 16.0 +112.5 + 15.1 DAYS 0 - 20 MEAN+S.D. +157.9 + 17.9 +155.7 + 20.3 +156.5 + 24.3 +145.1 + 18.9 ----------------------------------------------------------------------------------------------------------------- DAYS = DAYS OF GESTATION I I = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 6 through 17 of gestation. b. Excludes values for dam 12868, which had a litter consisting c. Excludes values for dam 12889, which had a litter consisting d. Excludes values that were not recorded. Significantly different from the vehicle control group value Significantly different from the vehicle control group value of 7 conceptuses. of 3 conceptuses. (p<0.05). (p@so.01). PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER; T-631 TABLE 5 (PAGE 1) : MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY ----------------------------------------------------------------------------------------------------------------- DOSAGE DOSAGE GROUP (MG/KG/DAY)a I ii III IV 0 (VEHICLE) 1 5 10 ----------------------------------------------------------------------------------------------------------------- RATS TESTED N 25 25 25 25 PREGNANT N 24 23 24 25 INCLUDED IN ANALYSES N 24 23 23b 24c MATERNAL FEED CONSUMPTION (G/DAY) DAYS DAYS 0- 6 6- 8 MEAN+S.D. MEAN+S.D. 21.5 + 3.0 [ 23]d 24.6 + 3.1 21.1 + 3.3 23.0 + 2.0 21.6 + 3.0 24.1 + 3.6 21.1 + 3.3 22.4 + 2.8* DAYS 8 - 10 MEAN+S.D. 23.9 + 2.3 22.9 + 1.9 22.6 + 3.0 22.6 + 2.4 DAYS 10 - 12 DAYS 12 - 14 MEAN+S.D. MEAN+S.D. 24.6 + 3.2 25.7 + 2.8 23.5 + 2.4 24.5 + 2.8 24.0 + 2.5 24.7 + 3.4 23.6 + 2.3 [ 23]d 23.9 + 3.0 DAYS 14 - 16 MEAN+S.D. 26.0 + 3.4 25.2 + 3.0 25.7 + 3.6 26.1 + 2.8 DAYS 16 - 18 MEAN+S.D. 27.6 + 2.3 26.6 + 2.8 27.2 + 3.3 26.2 + 2.7 DAYS 6 - 18 MEAN+S.D. 25.4 + 2.3 24.3 + 1.9 24.7 + 2.7 24.2 + 1.9 DAYS 18 - 20 MEAN+S.D. 26.4 + 2.4 25.2 + 2.8 25.9 + 3.1 24.9 + 2.7 DAYS 6 - 20 MEAN+S.D. 25.5 + 2.2 24.4 + 1.9 24.9 + 2.7 24.2 + 1.9 DAYS 0 - 20 -------------------- MEAN+S.D. 24.6 + 2.4 23.4 + 2.1 23.9 + 2.7 23.3 + 2.1 ------------------------------------------------------------------------------------------- DAYS = DAYS OF GESTATION [ I = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 6 through 17 of gestation. b. Excludes values for dam 12868, which had a litter consisting of 7 conceptuses. c. Excludes values for dam 12889, which had a litter consisting of 3 conceptuses. d. Excludes values that were incorrectly recorded, as well as those associated with Significantly different from the vehicle control group value (p:SO.05). Significantly different from the vehicle control group value (p@0.01) . spillage. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 6 (PAGE 1) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP I ii III IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 1 5 10 ----------------------------------------------------------------------------------------------------------------- RATS TESTED N 25 25 25 25 PREGNANT N 24 23 24 25 INCLUDED IN ANALYSES N 24 23 23b 24c MATERNAL FEED CONSUMPTION (G/KG/DAY) DAYS 0 - 6 DAYS 6 - 8 MEAN+S.D. MEAN+S.D. 85.5 + 10.1 1 23)d 90.3 + 8.4 84.4 + 11.4 85.3 + 5.5* 86.4 + 9.8 89.0 + 10.2 85.1 + 12.1 83.9 + 8.5 DAYS 8 - 10 MEAN+S.D. 85.1 + 6.4 82.3 + 5.0 81.3 + 8.5 82.9 + 7.3 DAYS 10 - 12 DAYS 12 - 14 MEAN+S.D. MEAN+S.D. 84.4 + 8.7 85.4 + 6.3 81.8 + 6.5 82.3 + 6.9 83.5 + 6.9 83.1 + 8.6 84.3 + 6.2 ( 23]d 82.5 + 8.0 DAYS 14 - 16 MEAN+S.D. 82.7 + 8.6 80.6 + 7.2 82.7 + 8.9 86.0 + 8.6 DAYS 16 - 18 MEAN+S.D. 82.0 + 6.0 79.6 + 8.2 81.5 + 8.3 80.5 + 7.7 DAYS 6 - 18 MEAN+S.D. 84.6 + 4.5 81.7 + 4.2 83.0 + 5.8 83.1 + 4.1 DAYS 18 - 20 MEAN+ S. D. 71.6 + 5.6 68.8 + 6.2 70.6 + 6.3 70.0 + 6.1 DAYS 6 - 20 MEAN+S.D. 82.2 + 4.2 79.3 + 4.2 80.8 + 5.6 80.7 + 4.2 DAYS 0 - 20 MEAN+S.D. 80.2 + 4.3 77.8 + 4.4 79.4 + 5.8 79.0 + 4.9 --------------------------------------------------------------------------------------------------------------- DAYS = DAYS OF GESTATION I I = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 6 through 17 of gestation. b. Excludes values for dam 12868, which had a litter consisting of 7 conceptuses. c. Excludes values for dam 12889, which had a litter consisting of 3 conceptuses. d. Excludes values were incorrectly recorded, as well as those associated with spillage. Significantly different from the vehicle control group value (p@iO0.5) . Significantly different from the vehicle control group value (p<O.01) . PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 7 (PAGE 1) : CAESAREAN- SECTIONING OBSERVATIONS - SUMMARY ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP I ii III IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 1 5 10 ----------------------------------------------------------------------------------------------------------------- RATS TESTED N 25 25 25 25 PREGNANT N 24( 96.0) 23( 92.0) 24( 96.0) 25(100.0) RATS PREGNANT AND CAESAREAN-SECTIONED ON DAY 20 OF GESTATION N INCLUDED IN ANALYSES N CORPORA LUTEA MEA.N+S. D. IMPLANTATIONS MEAN+S. D. LITTER SIZES MEAN+S.D. LIVE FETUSES N MEAN+S.D. DEAD FETUSES N RESORPTIONS MEAN+S. D. EARLY RESORPTIONS N MF.AN+S. D. LATE RESORPTIONS N DAMS WITH ANY RESORPTIONS N(%) '24 24 17.1 + 1.8 15.1 + 1.8 14.2 + 1.8 342 14.2 + 1.8 0 0.9 + 1.2 21 0.9 + 1.2 0 12( 50.0) 23 23 17.2 + 1.9 15.6 + 2.0 IS.2 + 2.1 349 15.2 + 2.1 0 0.4 + 0.6 10 0.4 + 0.6 0 9( 39.1) 24 23b 17.2 + 2.1 15.6 + 1.4 14.9 + 1.9 342 14.9 + 1.9 0 0.8 + 1.2 18 0.8 + 1.2 0 ll( 47.8) 25 24c 16.8 + 2.0 IS.1 + 1.3 14.6 + 1.6 351 14.6 + 1.6 0 0.5 + 0.8 12 0.5 + 0.8 0 9( 37.5) DAMS WITH ALL CONCEPTUSES RESORBED N 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) DAMS WITH VIABLE FETUSES N 24(100.0) 23 (100.0) 23(100.0) 24(100.0) PLACENTAE APPEARED NORMAL N 24(100.0) 23(100.0) 23(100.0) 24(100.0) ---------------------------------------------------------------------------------------------------------------- a. Dosage occurred on days 6 through 17 of gestation. b. Excludes values for dam 12868, which had a litter consisting of 7 conceptuses. C. Excludes values for dam 12889, which had a litter consisting of 3 conceptuses. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 8 (PAGE 1) : LITTER OBSERVATIONS (CAESAREAN -DELIVERED FETUSES) - SUMMARY ------------------------------------------------------------------------------------------------------------------ DOSAGE GROUP I ii III IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 1 5 10 ------------------------------------------------------------------------------------------------------------------ LITTERS WITH ONE OR MORE LIVE FETUSES N 24 23 24 25 INCLUDED IN ANALYSES N 24 23 23b 24c IMPLANTATIONS MEAN+S.D. 15.1 + 1.8 15.6 + 2.0 15.6 + 1.4 15.1 + 1.3 LIVE FETUSES N MEAN+S.D. 342 14.2 + 1.8 349 15.2 + 2.1 342 14.9 + 1.9 351 14.6 + 1.6 LIVE MALE FETUSES N 166 171 165 180 t LIVE MALE FETUSES/LITTER MEAN+S.D. 48.8 + 13.1 48.8 + 12.2 48.6 + 11.8 51.7 + 10.6 LIVE FETAL BODY WEIGHTS (GRAMS)/LITTER MALE FETUSES FEMALE FETUSES MEAN+S.D. MEAN+S.D. MEAN+S.D. 3.50 + 0.50 3.61 + 0.50 3.38 + 0.52 3.36 + 0.22 3.48 + 0.23 3.25 + 0.24 3.39 + 0.20 3.50 + 0.22 3.30 + 0.19 3.32 + 0.20* 3.38 + 0.20** 3.25 + 0.23 t RESORBED CONCEPTUSES/LITTER MEAN+S.D. 5.5 + 7.2 2.8 + 5.1 + 7.7 3.4 + 5.0 ----------------------------------------------------------------------------------------------------------------- a. Dosage occurred on days 6 through 17 of gestation. b. Excludes values for dam 12868, which had a litter consisting of 7 conceptuses. C. Excludes values for dam 12889, which had a litter consisting of 3 concpetuses. Significantly different from the vehicle control group value (p<0.05). Significantly different from the vehicle control group value (p@0. 01) . PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 9 (PAGE 1): FETAL ALTERATIONS - SUMMARY ------------------------------------------------------------------------------------------------------------------ III IV DOSAGE GROUP I 5 10 DOSAGE (MG/KG/DAY)a 0 (VEHICLE) --------------- ---------- ------------------------------------------------------------------------------------- LITTERS EVALUATED N 24 23 24 25 354 FETUSES EVALUATED N 342 349 347 354 LIVE N 342 349 347 ------------------------------------------------------------- ------------------------------------------------- LITTERS WITH FETUSES WITH ANY ALTERATION OBSERVED N(%) 6( 25.0) 8( 34.8) 4( 16.7) 7( 28.0) FETUSES WITH ANY ALTERATION OBSERVED N(%) 15( 4.4) io( 2.9) 6( 1.7) 8( 2.2) W FETUSES WITH ANY ALTERATION/LITTER MEAN+S.D. 4.4 + 10.3 2.8 + 4.4 1.6 + 3.9 2.1 + 3.9 -------------------------- --------- ----------------------------------------------------------------------------- a. Dosage occurred on days 6 through 17 of gestation. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 10 (PAGE 1): FETAL GROSS EXTERNAL ALTERATIONS - SUMMARY ------------------------------------------------------------------------------------------------------------------ DOSAGE GROUP I ii III IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 1 5 10 ------------------------------------------------------------------------------------------------------------------ LITTERS EVALUATED N 24 23 24 25 FETUSES EVALUATED N 342 349 347 354 LIVE N 342 349 347 354 ------------------------------------------------------------------------------------------------------------------ BODY: TRUNK SHORT LITTER INCIDENCE FETAL INCIDENCE N(%) N(%-) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 1( 4.0) 1( 0.3) TAIL: ABSENT LITTER INCIDENCE N(%) 0( 0.0) 0( 0.0) 0( 0.0) 1( 4.0) FETAL INCIDENCE N(%) 0( 0.0) 0( 0.0) 0( 0.0) 1( 0.3) ----------------------------------------------------------------------------------------------------------------- a. Dosage occurred on days 6 through 17 of gestation. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 11 (PAGE l)-. FETAL SOFT TISSUE ALTERATIONS - SUMMARY ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP I ii III IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 1 5 10 ----------------------------------------------------------------------------------------------------------------- LITTERS EVALUATED N 24 FETUSES EVALUATED N 166 LIVE N 166 ----------------------------------------------- 23 24 25 167 169 170 167 169 170 ----------------------------------------------------------------- VESSELS: LITTER FETAL UMBILICAL INCIDENCE INCIDENCE ARTERY DESCENDS N(t) N(%) TO THE LEFT OF URINARY 3( 12.5) 3( 1.8) BLADDER 1( 4.3) 1( 0.6) 1( 4.2) 2( 1.2) 0( o.o) 0( 0.0) VESSELS: LITTER FETAL INNOMINATE, INCIDENCE INCIDENCE ABSENT N(%) N(%) 0( 0.0) 0( 0.0) 2( 8.7) 2( 1.2) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) LUNGS: DIAPHRAGMATIC J,ITTER INCIDENCE FETAL INCIDENCE LOBE, ABSENT N (%) N(%) 0( 0.0) 0( 0-0) 1( 4.3) 1( 0.6) o( o.o) 0( 0.0) 0( 0.0) 0( 0.0) LUNGS: APICAL LOBE, LITTER INCIDENCE FETAL INCIDENCE ABSENT N(%) N(%) 1( 4.2) 1( 0.6) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0-0) 0( 0.0) 0( 0.0) KIDNEYS: LITTER FETAL PELVIS, SLIGHT INCIDENCE INCIDENCE DILATION N(t) N(%) 2( 8.3) 2( 1.2) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0-0) 0( 0.0) KIDNEYS: PELVIS, MODERATE DILATION LITTER INCIDENCE N(t) 0( 0.0) 0( 0.0) o( o.o) 1( 4.0) FETAL INCIDENCE N(t) 0( 0-0) o( o.o) 0( 0.0) 1( 0.6) ---------------------------------------------------------------------------------------------------------------- a. Dosage occurred on days 6 through 17 of gestation. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONS.OR'S STUDY NUMBER: T-631 TABLE 12 (PAGE 1): FETAL SKELETAL ALTERATIONS - SUMMARY (See footnotes on the last page of this table.) ----------------------------------------------------------------------------------------------------------------- III IV DOSAGE GROUP I 5 10 DOSAGE (MG/KG/DAY)a 0 (VEHICLE) ----------------- -------- - ---------------------------------------------------------------- LITTERS EVALUATED N 24 18223 17284 18245 176 184 FETUSES EVALUATED LIVE N N 176 182 178 ----------- ------------------------------------------------------------------------------------------------- SKULL: NASAL - FRONTAL, LITTER INCIDENCE FETAL INCIDENCE SUTURE LARGE N(%) N(%) o( 0.0) o( 0-0) 0( 0.0) o( 0.0) 0( 0.0) 0( 0.0) 1( 4.0) 1( 0.5) CERVICAL VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE CERVICAL RIB PRESENT AT 7TH CERVICAL N(%) o( 0.0) N(%) o( 0-0) VERTEBRA 2( 6.7) 3( 1.6) 1( 4.2) 1( 0.6) 3( 12.0) 3( 1.6) CERVICAL VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE 4 PRESENT N(%) N(%) o( 0.0) 0( 0.0) 0( 0.0) 0( o.o) 0( 0.0) o( o.o) 1( 4.0) 1( 0.5)b THORACIC VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE THORACIC VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE THORACIC VERTEBRAE: LITTER INCIDENCE FETAL INCIDENCE 0 PRESENT N(t) N(t) 0( 0-0) 0( 0-0) ARCH, NOT OSSIFIED N(%) N(%) 0( 0.0) 0( 0-0) CENTRUM, NOT OSSIFIED N(%) 0( N(%) 0( 0.0) 0-0) 0( 0.0) o( o.0) 0( 0-0) 0( 0.0) 0( 0.0) o( o.o) 0( 0-0) 0( 0.0) 0( 0.0) 0( 0-0) 0( 0.0) o( 0.0) 1( 4.0) 1( 0.5)b 1( 4.0) 1( o.s)b 1( 4.0) 1( 0.5)b LUMBAR VERTEBRAE: 0 PRESENT LITTER INCIDENCE FETAL INCIDENCE N(t) N (!k) o( o.0) 0( 0-0) 0( 0.0) o( o.0) o( 0.0) 0( 0-0) 1( 4.0) 1( 0.5)b LUMBAR VERTEBRAE: ARCH, LITTER INCIDENCE FETAL INCIDENCE NOT OSSIFIED N(%) N(%) o( 0-0) 0( 0.0) 0( 0.0) o( o.0) 0( 0.0) o( 0.0) 1( 4.0) 1( 0.5)b LUMBAR VERTEBRAE: CENTRUM, NOT OSSIFIED 0( 0-0) 0( 0-0) 0( 0-0) 1( 4.0) LITTER INCIDENCE N(t) N(%) 0( 0.0) 0( 0.0) 0( 0-0) 1( 0.5)b ------F-E-TA-L---I-NC-I-D-EN-C-E-------------------------------------------------------------------------------------------- PROTOCOL 418-011-. ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 12 (PAGE 2) ! FETAL SKELETAL ALTERATIONS - SUMMARY (See footnotes on the last page of this table.) ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP I ii III IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 1 5 10 ----------------------------------------------------------------------------------------------------------------- LITTERS EVALUATED N 24 23 24 25 FETUSES EVALUATED N 176 182 178 184 LIVE N 176 182 178 184 ----------------------------------------------------------------------------------------------------------------- SACRAL VERTEBRAE: 0 PRESENT LITTER INCIDENCE FETAL INCIDENCE N(!k) N(%) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 1( 4.0) 1( 0.5)b SACRAL VERTEBRAE: ARCH, LITTER INCIDENCE FETAL INCIDENCE NOT OSSIFIED N(%) N(%) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) o( o.o) o( o.o) 1( 4.0) 1( 0.5)b SACRAL VERTEBRAE: CENTRUM, LITTER INCIDENCE FETAL INCIDENCE NOT OSSIFIED N(t) N(%) CAUDAL VERTEBRAE: 0 LITTER INCIDENCE FETAL INCIDENCE PRESENT N(%) N(%) 0( 0.0) 0( 0.0) o( o.o) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 1( 4.0) 1( 0.5)b 1( 4.0) 1( 0.5)b RIBS: WAVY LITTER INCIDENCE FETAL INCIDENCE N(%) N(t) 0( 0.0) 0( 0.0) 1( 4.3) 1( 0.5) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) RIBS: 0 PRESENT LITTER INCIDENCE FETAL INCIDENCE N(t) N(!k) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 1( 4.0) 1( 0.5)b RIBS: NOT OSSIFIED LITTER INCIDENCE FETAL INCIDENCE N(%) N(%) 0( 0-0) 0( 0-0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 1( 4.0) 1( 0.5)b RIBS: INCOMPLETELY OSSIFIED (HYPOPLASTIC) LITTER INCIDENCE N(%) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0-0) FETAL INCIDENCE N(!k) 0( 0.0) 0( 0-0) 0( 0.0) 0( 0.0) ------------------------------------------------------------------------------------------------------------- PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 12 (PAGE 3): FETAL SKELETAL ALTERATIONS - SUMMARY - -- - -- - - -- - -- - - -- -- - - -- - - - - - - - ---- -- - -- - -- - -- - -- - -- - -- - - - -- - -- - - -- - -- - - -- - -- - - - -- - - - -- - - -- - -- -- -- -- - -- - - -- - -- - - -- - DOSAGE GROUP I ii III IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 1 5 10 ------------------------------------------------------------------------------------------------------------------ LITTERS EVALUATED N 24 23 24 25 FETUSES EVALUATED N 176 182 178 184 LIVE N 176 182 178 184 ----------------------------------------------------------------------------------------------------------------- STERNAL CENTRA: STTMMARIZATION incompletely ossified and not sternal centra) LITTER INCIDENCE FETAL INCIDENCE (Includes ossified N(%) N(%) 3( 12.5) 7( 4.0) 2( 8.7) 2( 1.1)** 1( 4.2) 1( 0.6)** 1( 4.0) 1( 0.5)** STERNAL CENTPA: IST, LITTER INCIDENCE FETAL INCIDENCE INCOMPLETELY N(%) N(%) OSSIFIED 2( 4( 8.3) 2.3) 1( 4.3) 1( 0.5) 1( 4.2) 1( 0.6) 1( 4.0) 1( 0.5) STERNAL CENTRA: 1ST, NOT LITTER INCIDENCE FETAL INCIDENCE OSSIFIED N(t) N(%) 1( 4.2) 3( 1.7)d 1( 4.3) 1( 0.5) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) PELVIS: SUMMARIZATION (Includes incompletely ossified pubes and ischia, and not ossified pubes) LITTER INCIDENCE N(%) FETAL INCIDENCE N(%) 1( 4.2) 3( 1.7) 0( 0.0) 0( 0.0) 1( 4.2) 2( 1.1) 2( 8.0) 2( 1.1) PELVIS: PUBIS, INCOMPXETELY LITTER INCIDENCE FETAL INCIDENCE OSSIFIED N(%) N(!k) 1( 4.2) 3( 1.7)d 0( 0.0) o( o.o) 0( 0.0) 0( 0.0) 1( 4.0) 1( 0.5) PELVIS: PUBIS, NOT LITTER INCIDENCE FETAL INCIDENCE OSSIFIED N(%) N(!k) 0( 0.0) 0( 0.0) o( o.o) 0( 0.0) 0( 0.0) o( o.o) 1( 4.0) 1( 0.5)b PELVIS: ISCHIUM, INCOMPLETELY OSSIFIED LITTER INCIDENCE N(%) o( 0.0) 0( 0.0) 1( 4.2) 0( 0-0) FETAL INCIDENCE N(t) 0( 0-0) 0( 0.0) 2( 1.1) 0( 0.0) ----------------------------------------------------------------------------------------------------------------- a. Dosage occurred on days 6 through 17 of gestation. b. Fetus 12885-15 had other skeletal alterations. C. Fetus 12909-7 had other skeletal alterations. d. Fetus 12802-1 had other skeletal alterations. ** Significantly different from the control group value (p<O.01) . PROTOCOL 416-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 13 (PAGE 1): FETAL OSSIFICATION SITES - CAESAREAN-DELIVERED LIVE FETUSES (DAY 20 OF GESTATION) - SUMMARY ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP I ii III IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 1 5 10 ----------------------------------------------------------------------------------------------------------------- LITTERS EXAMINED N 24 23 23 24 FETUSES EXAMINED N 176 182 178 184 LIVE N 1'76 182 178 184 ----------------------------------------------------------------------------------------------------------------- OSSIFICATION SITES PER FETUS PER LITTER HYOID MEAN+S.D. 0.97 + 0.08 0.98 + 0.06 0.98 + 0.06 0.97 + 0.06 VERTEBRAE CERVICAL THORACIC LUMBAR SACRAL CAUDAL RIBS (PAIRS) MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. 7.00 + 13.08 + 5.91 + 3.00 + 4.96 + 0.00 0.14 0.14 0.00 1.08 13.06 + 0.10 7.00 + 13.05 + 5.95 + 3.00 + 4.89 + 0.00 0.09 0.09 0.00 0.41 13.03 + 0.06 7.00 + 13.07 + 5.92 + 3.00 + 4.74 + 0.00 0.17 0.17 0.00 0.37 13.04 + 0.10 7.00 + 13.10 + 5.89 + 3.00 + 4.70 + 0.00 0.19 0.20 0.00 0.23* 13.09 + 0.17 STERNUM MANUBRIUt4 STERNAL XIPHOID CENTERS MEAN+S.D. MEAN+S.D. MEAN+S.D. 0.99 + 3.70 + 0.98 + 0.04 0.55 0.08 1.00 + 3.56 + 1.00 + 0.00@ 0.33 0.00 1.00 + 3.80 + 1.00 + 0.00 0.24 0.00 1.00 + 3.68 + 1.00 + 0.02 0.25 0.02 FORELIMB b CARPALS METACARPALS DIGITS PHALANGES MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. 0.00 + 3.72 + 5.00 + 5.20 + 0.00 0.27 0.00 0.73 0.00 + 3.73 + 5.00 + 5.12 + 0.00 0.29 0.00 0.30 0.00 + 3.68 + 5.00 + 5.04 + 0.00 0.31 0.00 0.18 0.00 + 3.72 + 5.00 + 5.09 + 0.00 0.27 0.00 0.28 HINDLIMB b TARSALS MEAN+S.D. 0.00 + 0.00 0.00 + 0.00 0.00 + 0.00 0.00 + 0.00 METATARSALS MEAN+S.D. 3.99 + 0.28 4.00 + 0.00 4.00 + 0.00 4.00 + 0.02 DIGITS MEAN+S.D. 5.00 + 0.00 5.00 + 0.00 5.00 + 0.00 5.00 + 0.00 PHALANGE:S MEAN+S.D. 4.82 + 0.90 5.00 + 0.00 5.00 + 0.00 4.98 + 0.12 ---------------------------------------------------------------------------------------------------------------- a. Dosage occurred on days 6 through 17 of gestation. b. Calculated as average per limb. Significantly different from the vehicle control group value (plO.05). PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOn'S STUDY NUMBER: T-631 TABLE 14 (PAGE 1): CLINICAL OBSERVATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- RAT # DESCRIPTION ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12801 NO ADVERSE FINDINGS 12802 NO ADVERSE FINDINGS 12803 NO ADVERSE FINDINGS 12804 NO ADVERSE FINDINGS 12805 NO ADVERSE FINDINGS 12806 NO ADVERSE FINDINGS 12807 NO ADVERSE FINDINGS 12806 NO ADVERSE FINDINGS 12809 NO ADVERSE FINDINGS 12810 NO ADVERSE FINDINGS 12811 NO ADVERSE FINDINGS 12812 NO ADVERSE FINDINGS 12813 NO ADVERSE FINDINGS 12814 NO ADVERSE FINDINGS 12815 NO ADVERSE FINDINGS 12816 NO ADVERSE FINDINGS 12817 NO ADVERSE FINDINGS 12818 NO ADVERSE FINDINGS 12819 NO ADVERSE FINDINGS 12820 NO ADVERSE FINDINGS 12821 NO ADVERSE FINDINGS 12822 DG( 8- 19) LOCALIZED ALOPECIA: LIMBS DG( 20 ALOPECIA NO LONGER APPARENT 12823 NO ADVERSE FINDINGS 12824 NO ADVERSE FINDINGS 12825 NO ADVERSE FINDINGS ---------------------------------------------------------------------------------------------------------------- DG = DAY OF PRESUMED GESTATION PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 14 (PAGE 2) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- RAT # DESCRIPTION ------------------------------------------------------------------------ DOSAGE GROUP 11 1 MG/KG/DAY --------------------------------------------------------------------------------------------------------------- 12826 NO ADVERSE FINDINGS 12827 NO ADVERSE FINDINGS 12828 NO ADVERSE FINDINGS 12829 NO ADVERSE FINDINGS 12830 12831 DG( 9- 19) DG( 19- 20) NO ADVERSE LOCALIZED LOCALIZED FINDINGS ALOPECIA: ALOPECIA: UNDERSIDE LIMBS a 12832 NO ADVERSE FINDINGS 12833 NO ADVERSE FINDINGS 12834 DG( 14- 19) LOCALIZED ALOPECIA: UNDERSIDE DG( 20 ALOPECIA NO LONGER APPARENT 12035 NO ADVERSE FINDINGS 12836 NO ADVERSE FINDINGS 12837 NO ADVERSE FINDINGS 12838 NO ADVERSE FINDINGS 12839 NO ADVERSE FINDINGS 12840 NO ADVERSE FINDINGS 12841 NO ADVERSE FINDINGS 12842 12843 NO ADVERSE NO ADVERSE FINDINGS FINDINGS 12844 NO ADVERSE FINDINGS 12845 NO ADVERSE FINDINGS 12846 NO ADVERSE FINDINGS 12847 NO ADVERSE FINDINGS 12848 NO ADVERSE FINDINGS 12849 DG( 10- 20) LOCALIZED ALOPECIA: UNDERSIDE a 12850 NO ADVERSE FINDINGS -------------------------------------------------------------------------------------------------------------- DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 14 (PAGE 3): CLINICAL OBSERVATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- RAT # DESCRIPTION ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 111 5 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12851 NO ADVERSE FINDINGS 12852 NO ADVERSE FINDINGS 12853 NO ADVERSE FINDINGS 12854 NO ADVERSE FINDINGS 12855 NO ADVERSE FINDINGS 12856 NO ADVERSE FINDINGS 12857 NO ADVERSE FINDINGS 12858 DG( 18- 20) LOCALIZED ALOPECIA: UNDERSIDE a 12859 NO ADVERSE FINDINGS 12860 NO ADVERSE FINDINGS 12861 NO ADVERSE FINDINGS 12862 NO ADVERSE FINDINGS 12863 DG( 17- 20) LOCALIZED ALOPECIA: UNDERSIDE a 12864 NO ADVERSE FINDINGS 12865 NO ADVERSE FINDINGS 12866 DG( 19- 20) LOCALIZED ALOPECIA: NECK a 12867 NO ADVERSE FINDINGS 12868 DG( 17- 20) RIGHT FOREPAW: SECOND AND THIRD DIGITS FUSED a 12869 NO ADVERSE FINDINGS 12870 NO ADVERSE FINDINGS 12871 NO ADVERSE FINDINGS 12872 NO ADVERSE FINDINGS 12873 NO ADVERSE FINDINGS 12874 NO ADVERSE FINDINGS 12875 NO ADVERSE FINDINGS ---------------------------------------------------------------------------------------------------------------- DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 14 (PAGE 4): CLINICAL OBSERVATIONS - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ PAT # DESCRIPTION ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP IV 10 MG/KG/DAY ------------------------------------------------------------------------------------------------------------------ 12876 NO ADVERSE FINDINGS 12877 NO ADVERSE FINDINGS 12878 NO ADVERSE FINDINGS 12879 NO ADVERSE FINDINGS 12880 NO ADVERSE FINDINGS 12881 NO ADVERSE FINDINGS 12882 NO ADVERSE FINDINGS 12883 12884 12085 12886 12887 12888 12BB9 12890 12891 DG( 10- 20) DG( 18- 20) NO ADVERSE NO ADVERSE NO ADVERSE NO ADVERSE NO ADVERSE NO ADVERSE NO ADVERSE NO ADVERSE LOCALIZED LOCALIZED FINDINGS FINDINGS FINDINGS FINDINGS FINDINGS FINDINGS FINDINGS FINDINGS ALOPECIA: ALOPECIA: UNDERSIDE a LIMBS a 12892 NO ADVERSE FINDINGS 12893 12894 12895 12896 DG( 17- 20) NO ADVERSE LOCALIZED NO ADVERSE NO ADVERSE FINDINGS ALOPECIA: FINDINGS FINDINGS LIMBS a 12897 NO ADVERSE FINDINGS 12898 NO ADVERSE FINDINGS 12899 NO ADVERSE FINDINGS 12900 NO ADVERSE FINDINGS ----------------------------------------------------------------------------------------------------------------- DG = DAY OF PRESUMED GESTATION a. observation confirmed at necropsy. PROTOCOL 418-011: OPAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 14 (PAGE 5): CLINICAL OBSERVATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- RAT # DESCRIPTION ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP V 20 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12901 12902 NO ADVERSE NO ADVERSE FINDINGS FINDINGS 12903 NO ADVERSE FINDINGS 12904 NO ADVERSE FINDINGS 12905 NO ADVERSE FINDINGS 12906 NO ADVERSE FINDINGS 12907 NO ADVERSE FINDINGS 12908 12909 DG( 10- 20) NO ADVERSE FINDINGS LOCALIZED'ALOPECIA: LIMBS a 12910 NO ADVERSE FINDINGS 12911 NO ADVERSE FINDINGS 12912 12913 DG( 13- 20) NO ADVERSE FINDINGS LOCALIZED ALOPECIA: UNDERSIDE a 12914 NO ADVERSE FINDINGS 12915 12916 12917 12918 12919 DG( 16- 20) DG( 16- 20) NO ADVERSE NO ADVERSE NO ADVERSE LOCALIZED LOCALIZED FINDINGS FINDINGS FINDINGS ALOPECIA: ALOPECIA: UNDERSIDE a UNDERSIDE 12920 NO ADVERSE FINDINGS 12921 NO ADVERSE FINDINGS 12922 NO ADVERSE FINDINGS 12923 NO ADVERSE FINDINGS 12924 DG( 17- 20) LOCALIZED ALOPECIA: LIMBS a 12925 DG( 15- 17) COLD TO TOUCH DG( 15- 17) UNGROOMED COAT ---------------------------------------------------------------------------------------------------------------- DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. PROTOCOL 418-011: OPAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 14 (PAGE 6): CLINICAL OBSERVATIONS - INDIVIDUAL DATA ------------------------------------------------------------- ---------------------------------------------------- RAT DESCRIPTION --------------------------------------------------- SATELLITE DOSAGE GROUP I ------------------------------------------------------------- 0 (VEHICLE) MG/KG/DAY ------------- 12573 12574 12575 NO ADVERSE NO ADVERSE NO ADVERSE FINDINGS FINDINGS FINDINGS ----------------------------------------------------------- SATELLITE DOSAGE GROUP Il ----------------------------------------------- 1 MG/KG/DAY -------------------------- 12576 NO ADVERSE FINDINGS 12577 NO ADVERSE FINDINGS 12S78 NO ADVERSE FINDINGS 12579 NO ADVERSE FINDINGS 12580 NO ADVERSE FINDINGS -------- -------------------------------------- ------------------------------------- SATELLITE DOSAGE GROUP 111 5 MG/KG/DAY ----------- ----------------------------------------------- ------------------------ - ----------------------------------------------------- 12581 NO ADVERSE FINDINGS 12582 DG( 17- 18) LOCALIZED ALOPECIA: UNDERSIDE a 12583 NO ADVERSE FINDINGS -------- ---------------------------------------------------------------------------- 10 MG/KG/DAY SATELLITE DOSAGE GROUP IV ------------------------------------------------------------------------------------- --------------------------------------------------- 12584 NO ADVERSE FINDINGS 12585 NO ADVERSE FINDINGS 12586 NO ADVERSE FINDINGS ------------------------------------------------------------------------------------- 20 MG/KG/DAY SATELLITE DOSAGE GROUP V -------------------- ---------------------------------------------------------------- ------------------------ ----------- --------------- 12587 NO ADVERSE 12SB8 NO ADVERSE 12589 NO ADVERSE 12590 NO ADVERSE '12591 NO ADVERSE ---------------------------------------------- FINDINGS FINDINGS FINDINGS FINDINGS FINDINGS ------------------------------------- ---------------------------- DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 15 (PAGE 1) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP RAT DAY OF PREGNANCY DOSAGES DOSAGE (MG/KG/DAY) NUMBER NECROPSY STATUS ADMINISTERED OBSERVATIONS ----------------------------------------------------------------------------------------------------------------- I 0 (VEHICLE) 12801 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12802 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12803 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12804 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12805 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12806 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12807 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12808 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12809 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12810 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12811 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12812 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12813 DG 20 NP 12 ALL TISSUES APPEARED NORMAL. 12814 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12815 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12816 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12817 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12818 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12819 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12820 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12820 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12821 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12822 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12823 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12824 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12825 DG 20 p 12 ALL TISSUES APPEARED NORMAL. ---------------------------------------------------------------------------------------------------------------- P PREGNANT NP = NOT PREGNANT DG DAY OF GESTATION PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 15 (PAGE 2): NECROPSY OBSERVATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP RAT DAY OF PREGNANCY DOSAGES DOSAGE (MG/KG/DAY) NUMBER NECROPSY STATUS ADMINISTERED OBSERVATIONS ----------------------------------------------------------------------------------------------------------------- ii 1 12826 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12827 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12828 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12829 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12830 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12831 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12832 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12833 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12834 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12835 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12836 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12837 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12838 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12839 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12840 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12841 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12842 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12843 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12844 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12845 DG 20 NP 12 ALL TISSUES APPEARED NORMAL. 12846 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12847 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12848 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12849 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12850 DG 20 p 12 ALL TISSUES APPEARED NORMAL. ---------------------------------------------------------------------------------------------------------------- P PREGNANT NP = NOT PREGNANT DG DAY OF GESTATION PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 15 (PAGE 3): NECROPSY OBSERVATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP RAT DAY OF PREGNANCY DOSAGES DOSAGE (MG/KG/DAY) NUMBER NECROPSY STATUS ADMINISTERED OBSERVATIONS ----------------------------------------------------------------------------------------------------------------- III 5 12851 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12852 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12853 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12854 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12855 DG 20 NP 12 ALL TISSUES APPEARED NORMAL. 12856 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12857 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12858 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12859 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12860 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12861 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12862 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12863 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12864 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12865 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12866 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12867 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12868 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12869 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12870 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12871 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12872 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12873 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12874 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12875 DG 20 p 12 ALL TISSUES APPEARED NORMAL. ---------------------------------------------------------------------------------------------------------------- P PREGNANT NP = NOT PREGNANT DG DAY OF GESTATION PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 15 (PAGE 4): NECROPSY OBSERVATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP RAT DAY OF PREGNANCY DOSAGES DOSAGE (MG/KG/DAY) NUMBER NECROPSY STATUS ADMINISTERED OBSERVATIONS ----------------------------------------------------------------------------------------------------------------- IV 10 1287G DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12877 DC 20 p 12 ALL TISSUES APPEARED NORMAL. 12878 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12879 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12880 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12881 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12882 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12883 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12884 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12885 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12886 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12BB7 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12888 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12889 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12890 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12891 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12892 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12893 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12894 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12895 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12896 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12897 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12898 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12899 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12900 DG 20 p 12 ALL TISSUES APPEARED NORMAL. ---------------------------------------------------------------------------------------------------------------- P PREGNANT NP = NOT PREGNANT DG DAY OF GESTATION PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 15 (PAGE 5): NECROPSY OBSERVATIONS - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ DOSAGE GROUP RAT DAY OF PREGNANCY DOSAGES DOSAGE (MG/KG/DAY) NLTMBER NECROPSY STATUS ADMINISTERED OBSERVATIONS -- - - -- - -- - - -- - - - -- - -- - -- - - --- - - - -- -- -- - -- - -- - -- -- - -- - - - -- - -- - - - -- - -- - -- - - -- - - -- - -- - - -- - - - -- - -- - -- - -- - -- - - -- -- - - -- v 20 12901 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12902 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12903 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12904 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 3.2905 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12906 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12907 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 3.2908 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12909 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12910 DG 20 NP 12 ALL TISSUES APPEARED NORMAL. 12911 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12912 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12913 DG 20 p 12 LIVER: MEDIAN LOBE, TAN AREA (0.6 CM ALL OTHER TISSUES APPEARED NORMAL. -------- 12914 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12915 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12916 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12917 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12918 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12919 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 3.2920 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12921 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12922 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12923 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12924 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 12925 DG 20 p 12 ALL TISSUES APPEARED NORMAL. ------------------------------------------------------------------------------------------------------- P PREGNANT NP = NOT PREGNANT DG DAY OF GESTATION PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 15 (PAGE 6): NECROPSY OBSERVATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- SATELLITE DOSAGE GROUP RAT DAY OF PREGNANCY DOSAGES DOSAGE (MG/KG/DAY) NUMBER NECROPSY STATUS ADMINISTERED OBSERVATIONS ----------------------------------------------------------------------------------------------------------------- I 0 (VEHICLE) 12573 DG 18 p 12 ALL TISSUES APPEARED NORMAL. 12574 DG 18 p 12 ALL TISSUES APPEARED NORMAL. 12575 DG 18 p 12 ALL TISSUES APPEARED NORMAL. ii 1 12576 DG 18 p 12 ALL TISSUES APPEARED NORMAL. 12577 DG 18 p 12 ALL TISSUES APPEARED NORMAL. 12578 DG 18 p 12 ALL TISSUES APPEARED NORMAL. 12579 DG 18 p 12 ALL TISSUES APPEARED NORMAL. 12580 DG 18 p 12 ALL TISSUES APPEARED NORMAL. III 5 12581 DG 18 p 12 ALL TISSUES APPEARED NORMAL. 12582 DG 18 p 12 ALL TISSUES APPEARED NORMAL. 12583 DG 18 p 12 ALL TISSUES APPEARED NORMAL. IV 10 12584 DG IS p 12 ALL TISSUES APPEARED NORMAL. 1258S DC 18 p 12 ALL TISSUES APPEARED NORMAL. 12586 DG 18 p 12 ALL TISSUES APPEARED NORMAL. v 20 12587 DG 18 p 12 ALL TISSUES APPEARED NORMAL. 12588 DG 18 p 12 ALL TISSUES APPEARED NORMAL. 12589 DG 18 p 12 ALL TISSUES APPEARED NORMAL. 12590 DG 18 p 12 ALL TISSUES APPEARED NORMAL. 12591 DG 18 p 12 ALL TISSUES APPEARED NORMAL. ---------------------------------------------------------------------------------------------------------------- P PREGNANT NP = NOT PREGNANT DG DAY OF GESTATION PROTOCOL 418-011; ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 16 (PAGE 1): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 --------------------------------------------------------------------------------------------------------------- 0 (VEHICLE) MG/KG/DAY ----R-AT---# - --------D-OS-A-GE---G-R-O-UP---1------------------------------------------------------------------------------------ 12801 P 226. 261. 272. 277. 254. 284. 262. 286. 263. 297. 270. 304. 274. 312. 280. 319. 316. 282. 327. 325. 288. 331. 12802 p 12803 P 212. 236. 242. 267. 250. 285. 292. 292. 301. 310. 269. 317. 273. 269. 279. 281. 12804 P 12805 P 221. 242. 245. 256, 255. 276. 256. 278. 261. 281. 270. 262. 286. 275. 288. 283. 294. 285. 299. 288. 310. 292. 316. 299. 12806 P 12807 P 229. 224. 252. 263. 256. 273. 266. 284. 285. 293. 290. 299. 293. 299. 300. 308. 304. 317. 309. 317. 314. 321, 12808 P 12809 P 244. 228. 267. 262. 277. 276, 290. 280. 287. 291. 288. 295. 297. 292. 301. 290. 308. 307. 308. 316. 295. 318. 320. 303. 12810 P 12811 P 247. 238. 273. 253. 283. 257. 284. 265. 276. 281. 289. 289. 291. 291. 298. 294. 12812 P 232. 254. 257. 266. 267. 270. 27-3. 273. 279. 277. 283. 293. 278. 285. 299. 289. 290. 303. 287. 312. 286. 316. 288. 325. 12813 NP 12814 P 228. 240. 274. 288. 284. 292. 286. 287. 294. 298. 303. 310. 12815 P 12816 P 226. 230. 259. a 271. 275. 274. 277. 256. 279. 279. 259. 205. 262. 292. 266. 297. 272. 301. 281. 307. 288. 304. 289. 12817 p 12818 P 220. 237. a 249. 277. 280. 283. 295. 296. 309. 309. 316. 323. a 268. 268. 273. 279. 283. 287. 266. 299. 12819 P 12820 P 234. 242. aa 2265S6.. 226712.. 274. 276. 281. 287. 22B8B7.. 229995-. 302. 12821 P 222. a 260. 266. 271. 277. 283. 285. 30S. 309. 322. 322. a 280. 283. 291. 298. 258. 299. 259. 266. 268. 270. 276. 12822 P 12823 P 245. 215. a 249. 248. 249. 256. 264. 262. 261. 270. 268. 270. 12824 P 219. a 253. 249. 265. 272. 273. 287. 294. 295. 301. 312. ----1-2-82-5---P -------2-3-0-.------2-46-.------2-6-2-.--------------------------------------------------------------------------- P = PREGNANT NP = NOT PREGNANT (VALUES DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) a. Value was not recorded. EXCLUDED FROM AVERAGES) PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 16 (PAGE 2): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAY 17 18 19 20 ------------------------------------------------------------------------- RAT # DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY --------- ----------------------------------------------------------------------------- 12801 p 354. 367. 379. 400. 12802 P 309. 323. 340. 356. 12803 P 373. 387. 401. 429. 12804 P 312. 323. 337. 367. 12805 P 345. 366. 374. 393. 12806 P 326. 338. 350. 376. 12807 P 333. 353. 365. 385. 12808 P 354. 367. 378. 402. 12809 P 367. 383. 387. 421. 12810 p 342. 350. 366. 391. 12811 P 325. 343, 354. 382. 12812 P 322. 341. 351. 378. 12813 NP 292. 293. 295. 311. 12814 P 360. 366. 387. 420. 12815 P 343. 357. 373. 402. 12816 P 341. 353. 365. 388. 12817 P 323. 336. 350. 375. 12818 P 354. 370. 382. 399. 12819 P 12820 P 12821 P 313. 328. 334. 329. 340. 346. 347. 357. 363. 367. 382. 394. 12822 P 360. 374. 396. 419. 12823 P 308. 323. 334. 355. 12824 P 306. 315. 336. 347. 12825 P 344. 358. 384. 400. -------------------------------------------------------------------------------------- P = PREGNANT NP = NOT PREGNANT (VALUES DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). EXCLUDED FROM AVERAGES) PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 16 (PAGE 3): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAY 0 4 ---------------------------------- 6 7 8 9 10 11 12 13 14 -------------------------------------- --------------------------------------- RAT # DOSAGE GROUP Il I MG/KG/DAY ------------------------------------- - --------------------- --------------------------------------------------- 12826 P 224. 258. 273. 280. 284. 12827 P 236. 248. 261. 264. 264. 12828 P 212. 249. 269. 277. 276. 12829 P 212. 224. 234. 245. 243. 12830 P 228. 256. 260. 264. 275. 12831 P 238. 252. 268. 273. 274. 12832 P 227. 244. 254. 260. 264. 12833 P 239. 261. 274. 275. 281. 12834 P 22S. 236. 249. 252. 253. 12835 P 230. 274. 293. 298. 302. 12836 P 220. 247. 259. 265. 264. 12837 P 240. 248. 2S5. 249. 268. 12838 P 12839 P 228. 243. 239. a 253. 281. 253. 286. 261. 292. 12840 P 230. a 263. 268. 270. 12841 P 222. a 272. 273. 279. 12842 P 234. a 278. 280. 289. 12843 P 222. a 241. 246. 252. 12844 P 12845 NP 242. 217. a 281. 282. 287. a 233. 232. 228. 12846 NP 230. a 257. 258. 263. 12847 P 236. a 263. 261. 270. 12848 P 240. 256. 267. 268. 272. 12849 P 237. 260. 274. 282. 284. 12850 p 248. 272. 202. 287. 293. ----------------------------------------------------------- 288. 272. 286. 241. 275. 284. 293. 274. 284. 244. 277. 286. 295. 279. 293. 248. 280. 296. 309. 286. 302. 257. 287. 292. 268. 277. 279. 284. 284. 292. 290. 289. 257. 265. 267. 274. 291. 273. 310. 275. 311. 281. 316. 282. 269. 266. 275. 267. 282. 270. 282. 274. 292. 300. 308. 315. 278. 283. 288. 292. 285. 292. 295. 303. 293. 302. 304. 303. 256. 262. 266. 264. 290. 294. 304. 303. 227. 232. 234. 234. 266. 269. 268. 269. 275. 277. 284. 285. 274. 284. 288. 288. 290. 298. 301. 303. 296. 302. 310. 317. ------------------------------------- 314. 291. 298. 257. 291. 302. 207. 292. 279. 326. 292. 284. 288. 321. 302. 312. 308. 270. 311. 230. 272. 289. 298. 317. 320. 322. 291. 312. 259. 292. 311. 295. 298. 284. 333. 296, 296. 290. 325. 309. 320. 314. 276. 314. 239. 277. 303. 305. 322. 324. -------------- p= DAY ALL a. PREGNANT NP = NOT PREGNANT (VALUES - DAY OF PRESUMED GESTATION WEIGHTS WERE RECORDED IN GRAMS (G). Value was not recorded. EXCLUDED FROM AVERAGES) PROTOCOL 418-011; ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 16 (PAGE 4): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ PREGNANCY STATUS DAY 17 le 19 20 ---------------------------------------------------------------------------------------------------- RAT # DOSAGE GROUP 11 1 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12826 p 352. 364. 371. 396. 12827 P 317. 323. 340. 362. 12828 P 350. 366. 363. 402. 12829 P 293. 306. 324. 331. 12830 P 323. 346. 360. 378. 12831 P 340. 356. 370. 394. 12832 P 322. 340. 343. 373. 12833 P 310. 335. 340. 357. 12834 P 323. 337. 354. 381. 12835 P 354. 362. 376. 391. 12836 P 313. 327. 342. 359. 12837 P 327. 341. 353. 383. 12838 P 319. 333. 344. 372. 12839 P 357. 377. 396. 418. 12840 P 343. 362. 378. 408. 12841 P 351. 364. 374. 402. 12842 P 346. 368. 382. 414. 12843 P 306. 313. 333. 352. 12844 P 342. 358. 372. 412. 12845 NP 235. 239. 240. 245. 12846 NP 265. 266. 261. 265. 12847 P 326. 346. 359. 387. 12848 P 340. 363. 384. 405. 12849 P 350. 365. 388. 407. 12850 P 354. 367. 391. 411. -------------------------------------------------------------------------------------------------- P = PREGNANT NP = NOT PREGNANT (VALUES DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) EXCLUDED FROM AVERAGES) PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 16 (PAGE 5) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 ----------------------------------------------------------------------------------------------------------------- RAT # DOSAGE GROUP 111 5 MG/KG/DAY ---------------------------------------------------------------------------------------------------- 12851 P 12B52 P 12853 P 225. 223. 222. 268. 253. 259. 278. 265. 274. 288. 267. 273. 292. 276. 278. 295. 281. 2BO. 303. 278. 288. 310. 283. 290. 314. 285. 299. 325. 292, 302. 330. 298. 308. 12854 12855 12856 12857 12858 12859 12860 12861 12862 12863 12864 12865 12866 12867 12868 12869 12870 12871 12872 12873 12874 12875 P NP P P P P P P P P P P P P pb P P P P P P P 232. 244. 228. 246. 219. 233. 230. 227. 210. 221. 228. 220. 247. 214. 240. 236. 238. 230. 252. 233. 242. 236. 267. 259. 249. 264. 236. 254. 262. 238. 238. 247. a a a a a a 264. 249. 271. 2SB. 269. 252. 267. 269. 256. 276. 235. 281. 275. 236. 248. 260. 272. 246. 289. 245. 278. 270. 278. 252. 281. 274. 282. 265. 289. 275. 259. 281. 244. 286. 282. 254. 251. 265. 275. 256. 296. 247. 279. 268. 284. 261. 286. 278. 287. 267. 290. 282. 256. 282. 260. 292. 291. 255. 254. 270. 279. 255. 301. 246. 279. 281. 285. 258. a 284. 293. 263. 294. 283. 266. 287. 260. 297. 281. 260. 258. 273. 264. 246. 301. 246. 281. 281. 284. 261. 302. 286. 297. 265. 302. 285. 271. 291. 263. 296. 296. 267. 258. 275. 283. 250. 307. 249. 287. 283. 290. 261. 304. 290. 305. 266. 300. 285. 279. 300. 273. 303. 300. 268. 265. 283. 297. 251. 311. 256. 291. 292. 298. 272. 310. 294. 304. 282. 299. 286. 2@S. 306. 269, 301. 306. 268. 269. 290. 300. 273. 321. 258. 292. 296. 299. 275. 318. 298. 311. 281. 300. 280. 279. 312. 268. 316. 312. 274. 276. 288. 303. 266. 326. 265. 289. 302. 310. 274. 327. 301. 318. 284. 312. 271. 283. 320. 273. 320. 317. 273. 282. 290. 316. 271. 333. 266. 297. 307. 311. 279. 327. 314. 321. 290. ---------------------------------------------------------------------------------------------------------------- PDAY ALL a. b. PREGNANT NP = NOT PREGNANT (VALUES = DAY OF PRESUMED GESTATION WEIGHTS WERE RECORDED IN GRAMS (G) Value was not recorded. Dam 12868 had a litter consisting of EXCLUDED FROM 7 conceptuses; AVERAGES) values excluded from group averages and statistical ana PROTOCOL 418-011- ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 16 (PAGE 6): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAY 17 18 19 20 ----------------------------------------------------------------------------------------------------------------- RAT # DOSAGE GROUP 111 5 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12851 P 364. 381. 397. 416. 12852 P 333. 353. 367. 393. 12853 P 346. 362. 378. 400. 12854 P 347. 368. 384. 399. 12855 NP 274. 268. 272. 282. 12856 P 320. 333. 348. 376. 12857 P 358. 374. 389. 420. 12858 P 296. 313. 320. 341. 12859 P 361. 374. 388. 421. 12860 P 12861 P 350. 300. 361. 309. 380. 318. 409. 341. 12862 P 315. 330. 338. 363. 12863 P 12864 P 314. 338. 331. 357. 342. 368. 357. 400. 12865 P 310. 324. 338. 358. 12866 P 368. 388. 403. 429. 12867 P 294. 308. 317. 344. 12868 P a 315. 330. 333. 349. 12869 P 337. 352. 368. 394. 12870 P 346. 355. 387. 405. 12871 P 307. 320. 331. 342. 12872 P 355. 372. 372. 400. 12873 P 339. 355. 383. 400. 12874 P 359. 373. 402. 422. 12875 P 315. 323. 352. 361. ---------------------------------------------------------------------------------------------------------------- P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) a. Dam 12868 had a litter consisting of 7 conceptuses; values excluded from group averages and statistical ana PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 16 (PAGE 7): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA ---------------------------------- ------------------------------------------------------------------------------ PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 ------------------------------------------------------------------------------------------------------------------ RAT # DOSAGE GROUP IV 10 MG/KG/DAY ------------------------------------------------------------------------------------------------------------------ 12876 12877 12878 12879 12880 12881 12882 12883 12884 12885 12886 12887 12888 12889 12890 12891 12692 12893 12894 12895 12896 12897 12898 12899 12900 -------- P 219. 266. 278. 286. 290. 229872.. 320809.. 229960.. 320904.. 321928.. 332046.. PP 223102.. 226422.. 227437.. 227543.. 2257B6.. 264. 268. 270. 266. 275. 277. P 228. 244. 254. 258. 260. 262. 268. 270. 275. 274. 276. P 230. 248. 258. 258. 259. 267. 268. 272. 274. 279. 282. p 211. 235. 236. 242. 231. 239. 247. 250. 150. 246. 246. P 244. 254. 274. 277. 282. 288. 229915.. 229946.. 320968.. 331038.. 331181.. PP 224244.. aa 227564.. 228740.. 228662.. 228783.. 282. 280. 283. 298. 292. P 237. a 270. 274. 274. 228747.. 228769.. 229814.. 229806.. 229878.. 320904.. PP 2234S7.. aa 226769.. 227739.. 227839.. 288. 291. 296. 301. 308. 314. P 239. a 270. 272. 273. 227782.. 227813.. 228741.. 227980.. 229871.. 320813.. Pb 228. P 242. aa 226734.. 227721.. 227731.. 280. 282. 281. 293. 297. 297. P 236. a 256. 262. 262. 265. 269. 272. 274. 280. 286. P 226. a 256. 265. 263. 260. 263. 265. 275. 282. 289. P 232. a 278. 276. 278. 286. 229549.. 229657.. 327013., 321733.. 321730.. PP 222211.. aa 225434.- 225512.. 224524.. 225567.. 267. 266. 267. 269. 279. P 236. a 271. 275. 273. 226785.. 227891.. 228842., 228884.. 229971.. 320912.. PP 223430.. 265a. 226796.. 227789.. 228775.. 284. 286. 297. 297. 301. 310. P 220. 244. 256. 261. 260. 266. 262. 270. 274. 277. 285. P 226. 237. 248. 246. 254. 250. 261. 259. 265. 268. 276. -------------------------------------------------------------------------------------------------------- P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) a. Value was not recorded. b. Dam 12889 had a litter consisting of 3 conceptuses; values excluded from group averages and statistical ana PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 16 (PAGE 8) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAY 17 --------------------- 18 19 20 ------------------------------------------------------------------------------------------ RAT # DOSAGE GROUP IV 10 MG/KG/DAY --------------------- ------------------------------------------------------------------------------------------- 12876 p 358. 360. 375. 390. 12877 P 329. 344, 354. 378. 12878 P 313. 329. 346. 374. 12879 P 309. 326. 342. 367. 12880 P 314. 333. 341. 372. 12881 P 280. 282. 298. 310. 12082 P 358. 378. 385. 420. 12883 P 348. 365. 373. 392. 12884 P 320. 334. 344. 371. 12885 P 330. 344. 358. 378. 12886 P 315. 332. 344. 379. 12887 P 349. 360. 373. 396. 12888 P 329. 337. 351. 369. 12889 P a 289. 301. 309. 321. 12890 P 328. 339. 354. 374. 12891 P 306. 318. 331. 349. 12892 P 319. 328. 347. 371. 12093 P 348. 369. 383. 412. 12894 P 309. 321. 341. 364. 12895 P 307. 313. 328. 343. 12096 P 331. 345. 355. 360. 12897 P 326. 335. 344. 374. 12898 P 350. 365. 390. 414. 12899 P 314. 327. 352. 364. 12900 P 314. 338. 359. 375. -------------------- ----------------------------------------------------------------------------- ------------- P= DAY ALL a. PREGNANT NP = NOT PREGNANT (VALUES = DAY OF PRESUMED GESTATION WEIGHTS WERE RECORDED IN GRAMS (G) Dam 12889 had a litter consisting of EXCLUDED FROM 3 conceptuses; AVERAGES) values excluded from group averages and statistical ana PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 16 (PAGE 9): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA --------- -------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 ----------------------------------------------------------------------------------------------------------------- RAT # DOSAGE GROUP V 20 MG/KG/DAY ---------------------------------------------------------------------------------------------------- 12901 12902 12903 12904 12905 12906 12907 12908 12909 12910 12911 12912 12913 12914 12915 12916 12917 12918 12919 12920 12921 12922 12923 12924 12925 -------- P 219. 243. 254. 254. 264. 269. 266. 273. 277. 282. 286. P 229. 244. 251. 252. 259. 256. 258. 264. 265. 271. 274. p 211. 249. 260. 260. 263. 258. 267. 271. 276. 267. 282. P 227. 255. 261. 263. 259. 265. 264. 266. 260. 264. 256. P 222. 242. 259. 258. 261. 261. 269. 272. 269. 277. 279. P 228. 242. 254. 253. 257. 259. 263. 266. 274. 269. 280. P 230. 251. 271. 278. 276. 276. 272. 267. 283. 290. 286. P 238. 254. 268. 268. 276. 275. 272. 283. 285. 284. 285. P 239. 257. 266. 265. 267. 275. 271. 271. 274. 268. 278. NP 212. 243. 253. 254. 259. 251. 256. 260. 247. 243. 246. P 215. 241. 253. 251. 252. 253. 258. 259. 260. 263. 268. P 224. a 256. 258. 262. 259. 264. 266. 274. 287. 287. P 243. a 272. 274. 274. 278. 282. 280. 284. 286. 292. P 225. a 274. 279. 274. 284. 285. 290. 295. 300. 301. p 237. a 267. 279. 275. 278. 282. 289. 292. 287. 290. P 248. a 275. 260. 256. 264. 263. 245. 238. 250. 264. P 236. a 254. 252. 250. 251. 252. 252. 257. 263. 266. P 245. a 265. 266. 245. 248. 258. 263. 264. 266. 264. 271. 279. 277. 272. 268. 276. 276. PP 222282.. aa 226595.. 225570.. 253. 254. 250. 256. 272. 266, 281. P 230. a 268. 271. 273. 273. 277. 280. 278. 278. 281. p 233. a 259. 258. 251. 251. 255. 259. 260. 260. 258. P 240. 268. 278. 279. 269. 271. 277. 276. 281. 280. 292. P 234. 250. 259. 262. 255. 257. 256. 266. 261. 258. 272. P 240. 260. 273. 270. 262. 253. 263. 270. 258. 247. 235. ------------------------------------------------------------------------------------------------------- P = PREGNANT NP = NOT PREGNANT (VALUES DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Value was not recorded. EXCLUDED FROM AVERAGES) PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 16 (PAGE 10): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA ------------ ---------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAY 17 18 19 20 ----------------------------------------------------------------------------------------------------------------- RAT # DOSAGE GROUP V 20 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12901 P 313. 320. 333. 360. 12902 P 295. 310. 320. 337. 12903 P 309. 322. 329. 353. 12904 P 279. 292. 301. 309. 1290S P 294. 310. 323. 350. 12906 P 306. 320. 337. 352. 12907 1) 301. 310, 328. 352. 12906 P 313. 323. 330. 352. 12909 P 303. 315. 323. 343. 12910 NP 239. 240. 245. 252. 12911 P 296. 303. 321@ 345. 12912 P 309. 322. 338. 364. 12913 P 310. 317. 333. 354. 12914 P 336. 337. 355. 384. 12915 P 325. 338, 350. 379. 12916 P 304. 317. 330. 352. 12917 P 294. 30S. 322. 343. 12918 P 294. 302. 325. 335. 12919 P 311@ 322. 335. 347. 12920 P 298. 313. 322. 347. 12921 P 313. 325. 339. 358. 12922 P 283. 292. 298. 323. 12923 P 328. 346. 366. 385. 12924 P 303. 307. 325. 341. 12925 P 247. 272. 284. 303. ---------------------------------------------------------------------------------------------------------------- P = PREGNANT NP - NOT PREGNANT (VALUES DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). EXCLUDED FROM AVERAGES) PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 16 (PAGE 11): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA .................................................... ------------------------------------------------------------- PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 ---------------------------------------------------------------------------------------------------------------- ----R-A-T---# ----------S-AT-E-L-LI-T-E----D-O-SA-G-E---G-R-OU-P---1------------------ 12573 p 236. 12574 P 233. 12575 P 24B. --------------------- 254. 266. 271. 271. 259. 273. 2BO. 280. 269. 283. 288. 293. -------------------------------------- 0 (VEHICLE) MG/KG/DAY ---------------------------------------------------- 279. 283. 293. 296. 301. 305. 290. 295. 299. 304. 309. 318. 296. 299. 305. 309. 314. 320. ------------------------------------- ------------- DAY 17 18 --------------------------------------------------------------------------------- 12573 p 332. 347. 12574 P 34B. 367. 12575 P 350. 366. ------------------------------------------------------------ P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (C) PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 16 (PAGE 12): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 ----------------------------------------------------------------------------------------------------------------- RAT # SATELLITE DOSAGE GROUP 11 1 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12576 P 227. 244. 253. 259. 260. 260. 267. 272. 280. 285. 290. 1257? P 12578 P 12579 P 12580 P 245. 221. 232. 248. 259. 232. 253. 261. 280. 258. 269. 273. 282. 257. 271. 272. 284. 260. 282. 277. 290. 265. 282. 280. 296. 271. 288. 291. 301. 271. 292. 296. 306. 278. 294. 302. 308. 278. 302. 305. 318. 286. 309. 312. ------------------------------------------------------------------------------------------------------------------ DAY 17 18 ----------------------------------------------------------------------------------------------------------------- 12576 P 312. 339. 12577 P 358. 382. 12578 P 314. 343. 12579 P 343. 367. 12580 P 353. 370. ----------------------------------------------------------------------------------------------------------------- P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 16 (PAGE 13) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA ------------------------------------------------------------- ------------------------------------------------- PREGNANCY 4 6 7 8 9 10 11 12 13 14 ------S-TA-T-US-----D-A-Y---0----------------------------------------------------------------------------------------- RAT # SATELLITE DOSAGE GROUP 111 5 MG/KG/DAY -------------- ---------------------------------------------------------------------------------------------------- 12581 P 228. 244. 257. 250. 274@ 258. 279. 256. 283. 258. 290. 267. 291. 272. 295. 282. 306. 338. 287. 305. 344. 12582 P 12583 P 243. 251. 260. 275. 271. 296. 306. 309. 313. 319. 322. 328. ------------------------------------------------------------------------------------------------------------------ DAY 17 18 -------------------------------------------------------------------------------------------------- 12581 p 316. 334. 12582 P 338. 360. 12583 P 389. 412. ------------------------------------------------ P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). AVERAGES) ------------- PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 16 (PAGE 14): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA ------------------------------------------------ ----------------------------------------------------------------- PREGNANCY STATUS DAY 0 4 6 7 B 9 10 11 12 13 14 --- --------------------------------------------------------------------------------------------------------------- RAT # SATELLITE DOSAGE GROUP IV 10 MG/KG/DAY ------------------------------------------------------------------------------------------------------------------ 12564 P 228. 252. 265. 269. 272. 270. 274. 287. 275. 290. 281. 296. 290. 303. 290. 308. 12585 p 242. 26S. 276. 273. 273. 275. 277. 277. 283. 282. 283. 290. 289. 294. 296. 12586 P 250. 262. ----------------------------------------------------------------------------------------------------------------- DAY 17 18 ----------------------------------- 12584 P 318. 340. 12585 P 334. 351. 12586 P 323. 339. ----------------------------------------------- P = PREGNANT DAY = DAY OF NP = NOT PREGNANT PRESUMED GESTATION (VALUES EXCLUDED ALL WEIGHTS WERE RECORDED IN GRAMS (G) FROM AVERAGES) PROTOCOL 418-011-. ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN PATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 16 (PAGE 15): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 --------------------------------------------------------------------------------------------------------------- RAT # SATELLITE DOSAGE GROUP V 20 MG/KG/DAY -------------------------------------------------------------------------------------------------- 12587 P 228. 232. 249. 232. 243. 241. 243. 258. 260. 249. 255. 12588 P 243. 262. 282. 286.. 289. 288. 287. 291. 289. 294. 305. 12589 P 221. 240. 256. 252. 270. 2SB 266. 262. 268. 267. 268. 256. 268. 246. 274. 254. 279. 267. 280. 268. 284. 12590 P 12591 p 236. 249. 267. 288. 292. 293. 295. 300. 306. 302. 297. 295. ----------------------------------------------------------------------------------------------------------------- DAY 17 18 -------------------------------- 12587 p 294. 319. 12588 P 346. 360. 12589 P 299. 321. 12590 P 314. 336. 12591 P 345. 362. ------------------------------------------------------------------------- P = PREGNANT NP = NOT PREGNANT DAY = DAY OF PRESUMED GESTATION (VALUES EXCLUDED FROM AVERAGES) ALL WEIGHTS WERE RECORDED IN GRAMS (G). PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 17 (PAGE 1): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA --------- -------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAYS 0 - 4 4- 6 6- 8 8 - io lo - 12 12 - 14 14 - 16 16 - 18 18 - 20 ---------------------------------------------------------------------------------------------------- 0 (VEHICLE) MG/KG/DAY RAT # DOSAGE GROUP 1 --------- -------------------------------------------------------------------------------------------------------- 12801 12802 12803 12804 12805 12806 12807 12808 12809 12810 12811 12812 12013 12814 12815 12816 12817 12818 12819 12820 12821 12822 12823 12824 12825 -------- P 56. 48. 52. 50. 50. 60. 50. 60. 59. P 54. 40. 43. 44. 47. 49. 50. 49. 52. P 82. 51. 55. 53. 57. 59. 62. 63. 60. P 86. 44. 42. 41. 32. 44. 50. SO. 52. P 79. 47. 51. 49. 55. 52. 46. 55. 54. P S3. 41. 49. 48. 47. 51. 45. 54. 53. P 71. 51. 52. 50. 49. 51. 45. 50. 53. P 96. 45. 61. 49. 51. 47. 52. 63. 56, P 91. 47. 57. 49. 53, 61. 64. 50. 51. P 103. 45. 53. 47. 50. 56. 46. Se. 58. P 88. 35. 51. 44. 40. 44. 40. 52. 48. P 190.a a 48. 48. 49. 47. 46. 48. 48. NP 89. 45. 49. 53. 41. 44. 51. 54. 43. P 102. 54. 48. 50. 50. 54. 58. 61. 59. P 94. 49. 50. 47. 49. 49. 53. 60. 56. P 97. 56. 56. 53. 57. 53. 58. 59. 53. P 74. 43. 45. 45. 46. 48. 53. 52. 45. P 104. 61. 58. 62. 62. 63. 65. 61. 60. P 85. 39. 43. 41. 44. 47. 46. 49. 45. P 81. 42. 44. 42. 48. 50. 54. 55. 57. P 84. 44. 49. 51. 48. 52. 54. 51. 53. P as. 47. 53. 52. 54. 55. 62. 55. 51. P 71. 45. 41. 44. 42. 43. 47. 54. 48. P 81. 46. 3S. 45. 47. 45. 48. 54. 50. P 80. 44. 44. 44. 44. 54. 53. 53. 44. ------------------------------------------------------------------------------------------------------- P= DAYS ALL a. PREGNANT NP = NOT PREGNANT (VALUES = DAYS OF PRESUMED GESTATION WEIGHTS WERE RECORDED IN GR-AMS (G). Value appeared incorrectly recorded EXCLUDED FROM AVERAGES) and was excluded from group averages and statistical analyses. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 17 (PAGE 2): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAYS 0 - 4 4 - 6 6 - 8 8 - 10 10 - 12 12 - 14 14 - 16 16 - 18 18 - 20 ----------------------------------------------------------------------------------------------------------------- RAT # DOSAGE GROUP Il I MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12826 P 82. 49. 49. 47, 4B. 56. 55. 57. 55. 12827 P 71. 41. 42. 43. 45. 47. 41. so. 45. 12828 P 91. 47. 49. 45. 50. 47. 45. 58. 57. 12829 P 14. 41. 44. 33. 40. 43. 47. 51. 44. 12830 P 90. 38. 48. 45. 43. 45. 46. 55. 52. 12831 P 89. 48. 49. 50. 50. 54. 52. 60. 57. 12832 P 87. 43. 48. 46. 44. 40. 46. 46. 46. 12833 P 90. 45. 45. 47. 36. 43. 40. so. 40. 12034 P 73. 44. 40. 43. 44. 45. 47. 60. 55. 12835 P 101. 57. 55. 47. 52. 62. 64. 60. 55. 12836 P 91. 47. 46. so. 49. 52. 49. 50. 40. 12837 P 87. 30. 39. 47. 46. 40. 49. 58. 55. 12838 P 70. 40. 43. 43. 41. 50. 44. 50. 48. 12839 P 95. 47. 50. 48. 50. 51. 54. 55. S2. 12840 P 80. 49. 49. so. 55. 56. 62. 62. 60. 12841 P 86. 47. 45. 48. 50. 55. 56. 42. 47. 12842 P 93. 50. 51. 51. 47. S2. 54. 58. 54. 12843 P 76. 36. 41. 43. 45. 42. 47. 48. 46. 12844 P 94. 52. 48. 47. 56. 49. 57. 54. 57. 12845 NP 69, 35. 77. 47. 42. 66. a 40. 43. 12846 NP 64. 40. 45. 46. 45. 45. 32. 33. 30. 12847 P 77. 39. 40. 44. 45. 43. 51. 52. 49. 12848 P 82. 43. 44. 42. 44. 45. 50. 49. 44. 12849 P 82. 45. 49. 47. 51. 56. 52. 54. S2. 12850 P 86. 46. 44. 48. 52. 48. 52. 43. 51. ---------------------------------------------------------------------------------------------------------------- P= DAYS ALL a. PREGNANT = DAYS WEIGHTS Spilled NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) OF PRESUMED GESTATION WERE RECORDED IN GRAMS (G) feed precluded the calculation of this value. PROTOCOL 418-011: ORAL, (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 17 (PAGE 3): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA ------------------------- ---------------------------------------------------------------------------------------- PREGNANCY STATUS DAYS 0 - 4 4 - 6 6 - 8 8 - 10 10 - 12 12 - 14 14 - 16 16 - 18 18 - 20 -- - -- - -- - - -- - - - - -- - -- - - - - - --- --- - -- - - -- - - -- - -- - - -- - -- -- - -- - - -- - -- - - - -- - -- - - - -- - -- - - - -- -- - - -- - - -- - - - -- - -- - -- - -- - - RAT # DOSAGE GROUP 111 5 MG/KG/DAY ---------------------------------------------------------------------------------------------------------------- 12851 P 12852 P 97. 48. S3. 52. 55. 55. 59. 61. 54. 48. 45. 47. 44. 43. 49. 48. 53. 51. 12853 P 12854 P 12055 NP 69. 49. 49. 48. 50. 54. 46. 57. 59. 103. 39. 60. 51. 41. 48. 48. 69. 57. 81. 40. 47. 41. 38. 32. 37. 31. 34. 12856 P 12857 P 88. 38. 39. 47. 41. 47. 50. 58. 52. 103. 49. 50. 49. 50. 55. 56. S2. 57. 12858 P 78. 32. 42. 41. 43. 39. 40. 45. 45. 12859 P 101. 57. 63. 55. 52. 58. 58. 65. 61. 12860 P 103. 57. 58. 49. 56. 63. 67. 62. 59. 12861 P 12862 P 12863 P 78. 33. 47. 47. 45. 47. 43. 52. 53. 82. 44. 47. 47. 47. 48. 46. 59. 51. 80. 42. 46. 45. 48. 42. 40. 46. 44. 12864 12865 12866 12867 12868 12869 12870 P P P P Pa P P 96. 54. 53. 46. 58. 58. 61. 63. 60. 56. 54. 41. 29. 39. 37. 53. 51. 46. 95. 52. 57. 51. 52. 53. 60. 57. 52. 76. 43. 36. 38. 45. 45. 49. 48. 44. 87. so. 48. 48. 49. 46. 58. 54. 52. 76 . 43. 48. 46. 53. 46. 51, 50. 49. 87. 44. 45. 42. 44. 52. 54. 53. 54. 12871 P 71 35. 40. 37. 46. 38. 45. 43. 35. 12872 P 90 44. 46. 45. 49. 50. 43. 48. 52. 12873 P 83. 52. 52. 42. 50. 59, 55. 56. 53. 12874 P 12875 P 96. 46. 51. 52. 50. 50. 59. 54. 54. 81. 46. 37. 36. 46. 44. 53. 51. 48. ---------------------------------------------------------------------------------------------------------------- P= DAYS ALL a. PREGNANT NP = NOT PREGNANT (VALUES = DAYS OF PRESUMED GESTATION WEIGHTS WERE RECORDED IN GRAMS (G). Dam 12868 had a litter consisting of EXCLUDED FROM 7 conceptuses; AVERAGES) values excluded from group averages and statistical ana PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 17 (PAGE 4): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAYS 0 - 4 4 - 6 6 - 8 8 - 10 10 - 12 12 - 14 14 - 16 16 - 18 18 - 20 ----------------------------------------------------------------------------------------------------------------- RAT # DOSAGE GROUP IV 10 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12876 P 101. 56. 54. 52. 50. 54. 56. 46. 50. 12877 12878 12879 12880 12881 12882 12883 12884 12885 12886 12887 12888 12889 12890 12891 12892 12893 12894 12895 12896 12897 12898 12899 P P P P P P P P P P P P Pa P P P P P P P P P P 88. 20. 94. 90. 77. 86. 88. 84. 70. 100. 86. 85. 74. 84. 94. 91. 87. 74. 67. 77. 78. 92. 77. 47. 36. 45. 43. 26. 48. 52. 43. 43. 50. 47. 51. 48. 48. 44. 40. 51. 47. 35. 46. 43. 51. 47. 49. 42. 49. 43. 35. 51. 47. 49. 45. 50. 53. 46. 45. 40. 46. 42. 45. 32. 37. 37. 46. 48. 47. 50. 46. 43. 45. 38. 49. 47. 52. 47. 54. SO. 46. 42. 45. 46. 39. 49. 43. 45. 37. 44. 39. 43. 50. 41. 53@ 44. 37. 54. 48. 46. 47. 53. 53. 50. 41. 51. 48. 47. b 44. 39. 49. 45. 46. 48. 50. 40, 41. 47. 31. 53. 50. 48. 47. 50. 54. 54. 46. 49. 50. 55. 54. 35. 44. 47. 44. 52. 47. 50. 48. 46. 48. 43. 45. 56. 53. 52. 55. 59. 56. 43. 53. 48. 49. 59. 55. 45. 50. 47. 60. 54. 47. 56. 56. 54. 43. 57. 52. 55. 50. 55. 56. 57. 50. 55. 52. 56. 62. 53. 43. 52. 40, 60. 49. 48. 54. 55. 48. 38. 54. 49. 54. 44. 59. 52. 49. 48. 48. 45. 55. 56. 51. 39. 48. 45. 57. 46. 12900 P 77. 38. 41. 36. 41. 50. 66. 53. 51. ---------------------------------------------------------------------------------------------------------------- P= DAYS ALL a. PREGNANT NP = NOT PREGNANT (VALUES = DAYS OF PRESUMED GESTATION WEIGHTS WERE RECORDED IN GRAMS (G) Dam 12889 had a litter consisting of EXCLUDED FROM 3 conceptuses; AVERAGES) values excluded from group averages and statistical ana b. Spilled feed precluded the calculation of this value. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 17 (PAGE 5) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ PREGNANCY STATUS DAYS 0 - 4 4 - 6 6 - 8 8 - 10 10 - 12 12 - 14 14 - 16 16 - 18 18 - 20 ------------------------------------------------------------------------------------------------------------------ RAT # DOSAGE GROUP V 20 MG/KG/DAY ------------------------------------------------------------------------------------------------------------------ 12901 P 49. 45. 46. 42. 44. 50. 49. 45. 46. 12902 P 83. 43. 41. 37, 41. 44. 40. 50. 40. 12903 P 71 . 48. 45. 43. 46. 42. 35. 46. 52. 12904 P 68. 44. 38. 41. 34. 31. 35. 37. 39. 12905 P 83. 45. 39. 43. 40. 46. 45. 48. 49. 12906 P 83.. 42. 38. 37. 45. 47. 40. 48. 46. 12907 P 12900 P 9-7. 52. 49. 40. 39. 49. 43. 40. 49. 98. 49. 50. 47. 47. 49. 45. 41. 42. 12909 P 12910 NP 92. 46. 38. 47. 40. 33. 33. 47. 48. 84. 44. 38. 37. 36. 31. 32. 31. 41. 12911 P 12912 P 12913 P 12914 P 12915 P 12916 P 12917 P 84. 46. 39. 39. 39. 43. 48. 46. 40. a 3.. 43. 41. 41. 47. 50. 49. 51. 51. B7. 45. 39. 47. 40. 46., 49. 40. 46. 90. 51. 42. 45. 55. 50. 53. 45. 49. 101. 44. 45. 44 . 51. 46. 53. 56. 54. 80. 44. 29. 31. 9. 42. 53. 52. 47. 76. 40. 37. 30. 33. 39. 39. 44. 45. 12918 P 68. 52. 26. 30. 39. 37. 34. 40. 46. 12919 P 79. 44. 39. 45. 31. 41. 52. 48. 43. 12920 P 74. 43. 34. 29. 45. 42. 38. 41. 40. 12921 P B5. 46. 43. 39. 39. 35. 48. 48. 44, 12922 P 76. 42. 33. 33. 37. 35. 37. 42. 41. 12923 P 89. 49. 35. 34. 39. 41. 48. 49. 50. 12924 P '75. 42. 34. 30. 37. 33. 41. 42. 37. 12925 P 90. 48. 31. 28. 32. 12. 16. 36. 38. ----------------------------------------------------------------------------------------------------------------- P = PREGNANT DAYS = DAYS ALL WEIGHTS NP = WOT PREGNANT (VALUES OF PRESLTMED GESTATION WERE REC:ORDED IN GRAMS (G) EXCLUDED FROM AVERAGES) PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 17 (PAGE 6) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAYS 0 - 4 4 - 6 6 - 8 8 - 10 10 - 12 12 - 14 14 - 16 16 - 18 ----------------------------------------------------------------------------------------------------------------- RAT # SATELLITE DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12573 P 12574 P 87. 48. 44. 48. 50. 48. 42. 45. B9. 48. 49. 50. 52. 52. 44. 45. 12575 P 97. 53. 56. 50. 57. 59. 64. 62. ---------------------------------------------------------------------------------------------------------------- RAT # SATELLITE DOSAGE GROUP Il I MG/KG/DAY -------------------------------------------------------------------------------------- 12576 P 85. 42. 47. 43. 48. 46. 53. 43. 12577 P 92. 56. 53. 52. 52. 50. 55. 54. 12578 P 71. 40. 42. 43. 44. 42. 50. 48. 12579 P 86. 47. 53 . 48. 46. 49. 53. 51. 12580 P 78. 41. 39. 45. 48. 49. 57. 52. ---------------------------------------------------------------------------------------------------------------- RAT # SATELLITE DOSAGE GROUP 111 5 MG/KG/DAY ---------------------------------------------------------------------------------------------------------------- 12581 P 82. 52. 42. 40. 53. 57. 52. 55. 12582 P 85. 43. 41. 46. 45. 47. 51. 48. 12583 P 92. 49. 54. 50. 49. 56. 60. 55. -------------------------------------------------------------------------------------------------- RAT # SATELLITE DOSAGE GROUP IV 10 MG/KG/DAY --------------------------------------------------------------------------------------------------------------- 12584 P 83. 48. 46. 45. 46. 48. 54. 46. 12585 P 90. 42. 40. 49. 53. S5. 53. 48. 12586 P 85. 43. 42. 43. 40. 41. 51. 32. ---------------------------------------------------------------------------------------------------------------- RAT SATELLITE DOSAGE GROUP V 20 MG/KG/DAY --------------------------------------------------------------------------------------------------------------- 12587 P 74. 37. 23. 34. 42. 32. 53. 46. 12588 P 85. so. 48. 41. 42. 50. 51. 44. 12589 P 76. 42. 44. 33. 24. 44. 40. 39. 12590 P 90. 46. 43. 40. 42. 44. 55. 47. 12591 P 100. 57. 54. 44. 43. 32. 61. 52. ------- -------------------------------------------------------------------------------------------------------- P = PREGNANT DAYS = DAYS ALL WEIGHTS NP - NOT PREGNANT (VALUES OF PRESUMED GESTATION WERE RECORDED IN GRAMS (G) EXCLUDED FROM AVERAGES) PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 18 (PAGE 1) : CAESAREAN- SECTIONING OBSERVATIONS - INDIVIDUAL DATA --------- ------------------------------------------------------------------------------------------------------- --------VI-A-B-L-E --F-E-T-US-E-S----- --D-E-AD---FE-T-U-SE-S-----EA-R-LY---R-E-SO-R-P-T-IO-N-S---LA-T-E--R-E-SO-R-P-T-IO-N-S----IM-P-L-AN-T-A-T-IO-N----S-IT-E-S- --c-o- SEX RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGH RAT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL 0 ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12801 9 4 8 5 13 0 0 0 0 1 1 0 0 0 8 6 14 8 12802 9 5 9 5 14 0 0 0 1 0 1 0 0 0 10 5 is 10 12803 9 7 8 8 16 0 0 0 0 0 0 0 0 0 8 8 16 9 12804 5 8 5 8 13 0 0 0 0 0 0 0 0 0 5 8 13 6 12805 7 8 8 7 15 0 0 0 0 0 0 0 0 0 8 7 15 10 12806 9 6 9 6 15 0 0 0 0 0 0 0 0 0 9 6 15 9 12807 6 8 4 10 14 0 0 0 1 1 2 0 0 0 5 11 16 5 12808 7 5 6 6 12 0 0 0 2 3 5 0 0 0 8 9 17 9 12809 8 10 10 8 18 0 0 0 0 0 0 0 0 0 10 8 18 10 12810 6 4 0 10 10 0 0 0 0 00 00 00 00 00 05 109 1140 57 1122881121 47 107 5a 96 1144 00 00 00 01 0 1 0 0 0 9 6 15 10 12813 NOT PREGNANT 12814 7 9 7 9 16 0 0 0 2 1 3 0 0 0 8 10 18 9 12815 6 9 8 7 15 0 0 0 2 0 2 0 0 0 10 7 17 10 12816 7 5 5 7 12 0 0 0 2 0 2 0 0 0 7 7 14 7 12817 8 7 6 9 15 0 0 0 0 0 0 0 0 0 6 9 15 6 12818 3 10 9 4 13 0 0 0 1 1 2 0 0 0 10 5 15 12 12819 5 10 10 5 15 0 0 a 0 1 1 0 0 0 10 6 16 11 12820 6 8 a 6 14 0 0 0 0 1 1 0 0 0 a 7 15 12821 10 5 7 a 15 0 0 0 0 0 0 0 0 0 7 8 is 12822 10 5 7 8 15 0 0 a 0 0 0 0 0 0 7 8 is 7 12823 8 6 11 3 14 0 0 0 0 1 1 0 0 0 11 4 is 12 12824 4 8 6 6 12 0 0 0 0 0 0 0 0 0 6 6 12 7 12825 7 11 a 10 18 0 0 0 0 0 0 0 0 0 8 10 18 8 ---------------------------------------------------------------------------------------------------------------- M = MALE PLACENTAE F = FEMALE APPEARED NORMAL UNLESS NOTED OTHERWISE. I PROTOCO L 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 18 (PAGE 2): CAESAREAN -SECTIONING OBSERVATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION SITES co ---------------- ---------------- -- - ------------------------ ---------------- ---------------- SEX RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGH RAT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL 0 ---------------------------------------------------------------------------------------------------------------- DOSAGE GROUP II I MG/KG/DAY 12826 8 6 9 5 14 0 0 0 0 0 0 0 0 0 9 5 14 12 12827 5 8 7 6 1138 00 00 00 00 10 10 00 00 00 117 77 1148 118 0 0 8 7 15 8 12828 10 8 11 7 12829 8 6 7 7 14 0 0 0 1 0 0 1 0 0 0 0 0 8 7 15 9 12830 7 8 8 7 15 0 0 0 0 0 1 0 1 0 0 0 12 5 17 12 12831 6 10 11 5 16 0 0 0 1 0 1 0 0 0 7 8 15 10 12832 7 7 6 86 1143 00 00 0 1 0 1 0 0 0 8 6 14 8 12833 10 3 12834 9 6 7 5 10 is 0 0 0 0 0 0 0 0 .0 5 10 15 5 12835 3 6 2 7 9 0 0 0 0 0 0 1 0 0 0 0 0 8 8 16 8 12836 6 9 7 8 15 0 0 0 1 0 1 0 1 0 0 0 8 7 12837 4 10 7 7 14 0 0 0 0 0 0 0 0 0 0 0 9 6 15 9 12838 8 7 9 6 15 0 0 0 0 0 0 0 7 10 17 7 12839 6 11 7 10 17 0 0 0 0 0 0 0 0 0 0 0 9 8 17 9 12840 11 6 9 8 17 0 0 0 0 0 0 0 9 a 17 9 1122684412 99 87 109 86 1176 00 00 00 0 0 0 0 0 0 10 67 1146 107 12843 5 8 7 6 13 0 0 0 0 1 1 0 0 0 7 12844 6 11 11 6 17 0 0 0 0 0 0 0 0 0 11 6 12845 NOT PREGNANT 12846 NOT PREGNANT 12847 11 7 14 4 IB 0 0 0 0 0 0 0 0 0 14 4 18 15 12848 7 11 13 s 18 0 0 0 0 0 0 0 0 0 13 5 18 13 12849 9 6 9 6 15 0 0 0 0 0 0 0 0 0 9 6 is 11 18 7 12850 7 9 7 9 16 0 0 0 0 2 2 0 0 0 7 -------------------------------------------------------------------------------------------------------------- M = MALE PLACENTAE F = FEMALE APPEARED NORMAL UNLESS NOTED OTHERWISE. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER; T-6316 TABLE 18 (PAGE 3): CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION SITES COR ------------------------ ---------------- ---------------- ---------------- ---------------- ----- SEX RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT RAT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL ov ------------------------------------------------------------------------------------------------------------------ DOSAGE GROUP 111 5 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12851 7 8 4 11 is 0 0 0 1 0 1 0 0 0 5 11 16 6 12852 8 8 6 10 16 0 0 0 0 0 0 0 0 0 6 10 16 6 12853 5 9 10 4 14 0 0 0 0 1 1 0 0 0 10 5 15 10 12854 6 10 7 9 16 0 0 0 0 0 0 0 0 0 7 9 16 8 12855 NOT PREGNANT 5 9 14 0 0 0 0 0 0 0 0 0 5 9 14 5 12856 5 9 12857 11 8 9 10 19 0 0 0 0 0 0 0 0 0 9 10 19 12 12858 7 7 5 9 14 0 0 0 1 0 1 0 0 0 6 9 15 6 12859 10 7 10 7 17 0 0 0 0 0 0 0 0 0 10 7 17 10 12860 7 8 6 9 15 0 0 0 1 01 12 00 00 00 79 95 1146 109 1122886612 67 68 88 47 1125 00 00 00 10 0 0 0 0 0 a 7 15 8 12863 5 9 4 10 14 0 0 0 1 0 1 0 0 0 5 10 15 5 12864 6 8 10 4 14 0 0 0 0 0 0 0 0 0 10 4 14 12 12865 5 10 7 a 15 0 0 0 1 1 2 0 0 0 8 9 17 8 12866 9 10 11 8 19 0 0 0 0 0 0 0 0 0 11 8 19 11 12867 9 5 4 10 14 0 0 0 0 0 0 0 0 0 4 10 14 5 12868 1 4 2 3 5 0 0 0 0 2 2 0 0 0 2 5 7 7 12869 9 6 7 8 15 0 0 0 0 0 0 0 0 0 7 8 is 7 12870 6 10 6 10 16 0 0 0 0 0 0 0 0 0 6 10 16 6 12871 8 6 6 8 14 0 0 0 0 2 2 0 0 0 6 10 16 6 12872 9 5 9 5 14 0 0 0 0 0 0 0 0 0 9 5 14 10 12873 5 9 4 10 14 0 0 0 1 0 1 0 0 0 5 10 is 5 12874 7 9 7 9 16 0 0 0 0 1 1 0 0 0 7 10 17 7 12875 8 2 2 8 10 0 0 0 4 1 5 0 0 0 6 9 15 7 ---------------------------------------------------------------------------------------------------------------- M = MALE PLACENTAE P = FEMALE APPEARED NORMAL UNLESS NOTED OTHERWISE. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 18 (PAGE 4): CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION SITES COR ---------------- ----- ----------- ------------ ---------------- ---------------- - -------------- SEX RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT RAT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL 0 ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP IV 10 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12876 9 6 8 7 1154 00 00 00 00 00 00 00 00 00 89 75 1145 119 0 3 12 15 4 12877 6 8 9 5 12878 7 8 3 12 15 0 0 0 0 0 0 0 0 0 0 0 8 7 15 10 12879 9 6 a .7 15 0 0 0 0 0 0 0 0 0 0 0 0 9 6 is 11 128BO 8 7 9 6 15 0 0 0 1 1 2 0 0 0 9 5 14 10 12881 6 6 a 4 12 0 0 0 0 0 0 0 0 0 0 7 10 17 8 12882 6 11 7 10 17 0 0 o-, 1 2 3 0 0 0 6 17 6 12083 8 6 5 9 14 0 0 0 0 0 1 1 0 0 0 9 13 9 12884 6 6 9 3 12 0 0 0 0 0 0 0 0 9 8 17 10 14 10 1122880856 99 84 98 85 1137 00 00 0 1 0 1 0 0 0 96 105 16 6 12887 8 8 6 10 16 0 0 0 0 0 0 0 0 0 0 0 0 7 7 14 8 12888 6 7 7 6 13 0 0 0 0 1 0 1 0 0 0 0 2 1 3 11 12889 1 2 2 1 3 0 0 0 0 0 1 0 1 0 0 0 5 11 16 5 12890 7 8 4 11 15 0 0 0 0 0 0 0 0 6 7 13 6 12891 8 5 6 7 13 0 0 0 0 0 0 0 0 0 0 0 8 7 15 8 12892 5 10 8 7 15 0 0 0 0 0 0 0 11 5 16 14 8 1122889934 107 67 118 56 1164 00 00 00 0 1 1 0 0 0 8 7 1155 7 12895 8 6 6 8 14 0 0 0 1 0 1 0 0 0 7 5 8 9 14 5 14 0 0 0 0 0 0 0 0 0 0 0 0 6 9 is 9 12896 6 8 5 9 12897 7 8 6 9 is 0 0 0 0 0 0 0 0 0 0 0 11 7 18 11 12898 6 12 11 7 18 0 0 0 0 0 1 0 1 0 0 0 8 6 14 8 12899 10 3 7 6 13 0 0 0 0 0 0 0 0 10 6 16 11 12900 9 7 10 6 16 0 0 0 ---------------------------------------------------------------------------------------------------------------- M = MALE PLACENTAE F = FEMALE APPEARED NORMAL UNLESS NOTED OTHERWISE. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 18 (PAGE 5): CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- --------V-IA-B-L-E---FE-T-U-S-ES----- --D-E-A-D --F-ET-U-S-ES----- EA-R-L-Y--R-E-SO-R-P-T-IO-N-S--- LA-T-E--R-E-SO-R-P-T-IO-N-S---- IM-P-L-AN-T-A-T-IO-N----S-IT-E-S- --c-o- SEX RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGH RAT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL 0 ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP V 20 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12901 11 6 9 a 17 0 0 0 0 0 0 0 0 0 9 8 17 9 12902 4 8 7 5 12 0 0 0 1 0 1 0 0 0 9 5 14 11 12903 8 6 a 6 14 0 0 0 1 0 1 0 0 0 9 6 15 10 12904 2 8 6 4 10 0 0 0 1 2 3 0 0 0 7 6 13 8 12905 5 7 6 6 12 0 0 0 0 0 0 0 0 0 6 6 12 7 12906 6 7 7 6 13 0 0 0 1 0 1 0 0 0 8 6 14 8 12907 6 3 0 9 9 0 0 0 0 1 12 00 00 00 03 1130 1106 84 1122990089 68 84 37 115 1142 00 00 00 00 21 1 0 0 0 7 6 13 9 12910 NOT PREGNANT 4 5 a 13 0 0 0 1 0 1 0 0 0 6 8 14 6 12911 9 12912 7 6 9 4 13 0 0 0 0 0 0 0 0 0 9 4 13 11 12913 7 5 5 7 12 0 0 0 1 0 1 0 0 0 6 7 13 9 12914 8 7 12 3 15 0 0 0 0 0 0 0 0 0 12 3 15 12 12915 8 6 8 6 14 0 0 0 1 2 3 0 0 0 9 8 17 9 12916 8 8 8 a 16 0 0 0 0 1 1 0 0 0 6 9 17 8 12917 10 4 9 5 14 0 0 0 1 01 11 00 00 00 1102 54 1156 1112 1122991189 58 106 126 3a 1145 00 00 00 00 0 0 0 0 0 6 8 14 6 12920 8 8 9 7 16 0 0 0 0 0 00 00 00 00 97 77 1146 107 1122992212 67 85 77 75 1142 00 00 00 01 02 3 0 0 0 8 7 15 8 12923 7 7 8 6 14 0 0 0 0 0 0 0 0 0 a 6 14 8 12924 7 8 8 7 is 0 0 a 0 0 0 0 0 0 8 7 15 8 12925 11 5 9 7 16 0 0 0 0 0 0 0 0 0 9 7 16 9 --------------------------------------------------------------------------------------------------------------- M = 14ALE P = FEMALE PLACENTAE APPEARED NOR14AL UNLESS NOTED OTHERWISE. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR-S STUDY NUMBER: T-6316 TABLE 18 (PAGE 6): CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA --------- ------------------------------------------------------------------------------------------------------- --------V-IA-B-L-E---FE-T-U-SE-S----- --D-E-AD---F-ET-U-S-ES-----EA-R-L-Y--R-E-SO-R-P-T-IO-N-S--- LA-T-E--R-E-SO-R-P-T-IO-N-S----IM-P-L-AN-T-A-T-IO-N----S-IT-E-S- --c-o- RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGH RAT HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL 0 ----------------------------------------------------------------------------------------------------------------- SATELLITE DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12573 12 3 15 0 0 0 1 0 1 0 0 0 13 3 16 13 12574 9 9 18 0 0 0 0 0 0 0 0 0 9 9 is 12 12575 6 1 7 0 0 0 0 0 0 0 0 0 6 1 7 6 ---------------------------------------------------------------------------------------------------------------- SATELLITE DOSAGE GROUP 11 1 MG/KG/DAY ---------------------------------------------------------------------------------------------------------------- 12576 11 3 14 0 0 0 1 0 1 0 0 0 12 3 is 15 12577 7 11 18 0 0 0 0 0 0 0 0 0 7 11 18 8 12578 6 10 16 0 0 0 0 1 1 0 0 0 6 11 17 8 12579 10 5 15 0 0 0 0 0 0 0 0 0 10 5 is 10 12580 10 4 14 0 0 0 0 1 1 0 0 0 10 5 15 11 ----------------------------------------------------------------------------------------------------------------- SATELLITE DOSAGE GROUP 111 5 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12581 6 7 13 0 0 0 0 2 2 0 0 0 6 9 15 6 12582 13 5 18 0 0 0 0 0 0 0 0 0 13 5 le 14 12583 13 7 20 0 0 0 0 0 0 0 0 0 13 7 20 13 ---------------------------------------------------------------------------------------------------------------- SATELLITE DOSAGE GROUP IV 10 MG/KG/DAY ---------------------------------------------------------------------------------------------------------------- 12584 9 6 15 0 0 0 2 0 2 0 0 0 11 6 17 14 12585 6 10 16 0 0 0 0 0 0 0 0 0 6 10 16 6 12506 8 5 13 0 0 0 0 1 1 0 0 0 8 6 14 9 --------------------------------------------------------------------------------------------------------------- SATELLITE DOSAGE GROUP V 20 MG/KG/DAY ----------------------------------------------------------------------------------------------------------- 12587 9 5 14 0 0 0 0 0 0 0 0 0 9 5 14 9 12588 9 6 15 0 0 0 0 0 0 0 0 0 9 6 15 9 12589 7 7 14 0 0 0 0 0 0 0 0 0 7 7 14 7 12590 11 3 14 0 0 0 1 1 2 0 0 0 12 4 16 12 12591 9 7 16 0 0 0 1 0 1 0 0 0 10 7 17 10 -------------------------------------------------------------------------------------------------------------- PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. PROTOCOL 418-011: OPAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 19 (PAGE 1): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ NUMBER OF LIVE AVERAGE FETAL ---- CONCEPTUSES ------ FETUSES BODY WEIGHT (G) RESORBED ------------------------------------------------------------------------------------------------------------------ PAT # MALE FEMALE TOTAL MALE FEMALE TOTAL a N N t ------------------------------------------------------------------------------------------------------------------ DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12801 12802 12803 12804 12005 12806 12807 12808 12809 12810 12811 12012 9 4 13 3.62 3.37 3.54 14 9 5 14 2.03 1.69 1.98 is 9 7 16 3.49 3.46 3.48 16 5 8 13 3.63 3.44 3.51 13 7 8 15 3.64 3.55 3.59 15 9 6 15 3.64 3.36 3.53 is 6 a 14 3.39 3.51 3.46 16 7 5 12 3.70 3.42 3.58 17 8 10 18 5.25 S.11 5.17 18 6 4 10 3.58 3.14 3.40 10 4 10 14 3.78 3.51 3.59 14 7 7 14 3.54 3.24 3.39 15 1 7.1 1 6.7 0 0.0 0 0.0 0 0.0 0 0.0 2 12.5 5 29.4 0 0.0 0 0.0 0 0.0 1 6.7 12813 NOT PREGNANT 12814 7 9 16 3.77 3.45 3.59 18 2 11.1 12815 6 9 15 3.56 3.43 3.48 17 2 11.8 12816 7 5 12 3.62 3.35 3.51 14 2 14.3 12817 8 7 15 3.44 2.85 3.17 is 0 0.0 12818 3 10 13 3.76 3.49 3.55 is 2 13.3 12819 5 10 15 3.27 3.01 3.10 16 1 6.2 12820 6 8 14 3.52 3.38 3.44 15 1 6.7 3.2821 10 5 15 3.31 3.14 3.25 15 0 0.0 12822 10 5 15 3.54 3.16 3.41 15 0 0.0 12823 8 6 14 3.84 3.87 3.85 15 1 6.7 12824 4 8 12 3.87 3.42 3.57 12 0 0.0 12825 7 11 18 3.96 3.66 3.78 18 0 0.0 ----------------------------------------------------------------------------------------------------------------- a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 19 (PAGE 2): LITTER OBSERVATIONS (CAESAREAN -DELIVERED FETUSES) - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- NUMBER OF LIVE AVERAGE FETAL ---- CONCEPTUSES ------ FETUSES BODY WEIGHT (G) RESORBED ----------------------------------------------------------------------------------------------------------------- RAT # MALE FEMALE TOTAL MALE FEMALE TOTAL a N N !k ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP II I MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12826 8 6 14 3.33 2.94 3.16 14 0 0.0 12827 5 8 13 3.39 3.21 3.28 14 1 7.1 12828 12829 12830 12831 12832 12833 12834 12835 10 8 18 3.53 3.27 3.41 18 a 6 14 3.00 3.03 3.01 is 7 8 15 3.77 3.60 3.68 15 6 10 16 3.48 3.18 3.30 17 7 7 14 3.12 2.98 3.05 15 10 3 13 3.30 3.27 3.30 14 9 6 15 3.48 3.35 3.43 15 3 6 9 3.68 3.49 3.55 9 0 0.0 1 6.7 0 0.0 1 5.9 1 6.7 1 7.1 0 0.0 0 0.0 12836 6 9 15 3.48 3.20 3.32 16 1 6.2 12837 4 10 14 3.85 3.67 3.72 is 1 6.7 12838 a 7 is 3.48 3.21 3.35 15 0 0.0 12839 12840 6 11 17 3.42 3.22 3.29 17 11 6 17 3.23 2.85 3.10 17 0 0.0 0 0.0 12841 12842 12843 12844 9 8 17 3.46 3.18 3.33 17 9 7 16 3.78 3.56 3.68 16 5 8 13 3.74 3.58 3.64 14 6 11 17 3.90 3.63 3.72 17 0 0.0 0 0.0 1 7.1 0 0.0 12845 NOT PREGNANT 12846 NOT PREGNANT 12847 11 7 18 3.29 2.96 3.16 18 0 0.0 12848 "7 11 18 3.36 3.08 3.19 18 0 0.0 12849 9 6 is 3.52 3.24 3.41 15 0 0.0 12850 '7 9 16 3.34 3.05 3.18 18 2 11.1 ---------------------------------------------------------------------------------------------------------------- a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NMBER: T-631 TABLE 19 (PAGE 3): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) ---- CONCEPTUSES ------ RESORBED ------------------------------------------------------------ -------------------------------------- ------------- RAT # MALE FEMALE TOTAL MALE --------------------- -------------------------------------- FEMALE TOTAL a N N t -------------------------------------- ------------- DOSAGE GROUP 111 ------------------------------------------------------------ 12851 12852 12853 12854 7 8 15 3.69 8 8 16 3.34 5 9 14 3.78 6 10 16 3.52 5 MG/KG/DAY ---------------------------------------------------- 3.36 3.51 16 1 6.2 3.20 3.27 16 0 0.0 3.65 3.70 15 1 6.7 3.07 3.24 16 0 0.0 12855 12856 NOT PREGNANT 5 9 14 3.55 3.24 3.35 14 3.34 3.16 3.26 19 0 0.0 0 0.0 12857 11 8 19 3.43 3.49 15 1 6.7 12858 7 7 14 3.55 17 0 0.0 12859 10 7 1175 33..2802 33..52S0 33..2607 16 1 6.2 2 14.3 12860 7 86 12 3.12 2.98 3.04 14 12861 6 15 2.95 2.91 2.93 15 0 0.0 12862 12863 7 8 14 3.67 3.37 3.48 15 1 6.7 5 9 3.52 3.62 14 0 0.0 12864 6 8 14 3.76 3.44 3.52 17 2 11.8 12865 5 10 15 3.67 3.21 3.31 19 0 o.0 12866 9 .10 19 3.42 3.34 14 0 0.0 12867 9 5 14 3.44 3.15 3.35 3.16 3.19 7 2 28.6 0.0 12868 1 46 155 3.35 3.20 3.29 15 0 12869 9 16 3.69 3.40 3.51 16 0 0.0 12870 12871 68 106 14 3.46 3.26 3.37 16 3.32 3.19 3.27 14 2 12.5 0 0.0 12872 9 5 14 3.41 3.45 15 1 6.7 5 9 14 3.54 3.59 17 1 5.9 12873 12874 7 9 16 3.66 3.54 15 5 33.3 12875 8 2 10 3.68 3.38 3.62 --------------------------------------------------------------------------------------------------------------- a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. PROTOCOL 418-011: OPAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 19 (PAGE 4): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- NUMBER OF LIVE AVERAGE FETAL ---- CONCEPTUSES ------ FETUSES BODY WEIGHT (G) RESORBED ----------------------------------------------------------------------------------------------------------------- RAT # MALE FEMALE TOTAL MALE FEMALE TOTAL a N N t ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP IV 10 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12876 9 6 15 3.67 3.59 3.64 is 0 0.0 12877 6 8 14 3.27 3.08 3.16 14 0 0.0 12878 7 8 15 3.53 3.34 3.43 15 0 0.0 12879 9 6 is 3.39 3.46 3.42 is 0 0.0 12880 8 7 15 3.32 3.08 3.21 15 0 0.0 12881 6 6 12 3.12 2.82 2.97 14 2 14.3 12882 6 11 17 3.69 3.43 3.52 17 0 0.0 12883 8 6 14 3.40 3.30 3.36 17 3 17.6 12804 12885 6 6 12 3.18 3.14 3.16 13 1 7.7 9 a 17 3.26 2.86 3.07 17 0 0.0 12886 12887 12888 12889 12890 12891 12892 9 4 13 3.60 3.45 3.55 14 8 8 16 3.21 2.95 3.08 16 6 7 13 3.01 2.98 3.00 14 1 2 3 3.47 3.66 3.60 3 7 a 15 3.24 3.04 3.14 16 8 5 13 3.82 3.52 3.70 13 5 10 15 3.60 3.43 3.49 15 1 7.1 0 0.0 1 7.1 0 0.0 1 6.2 0 0.0 0 0.0 12893 10 6 16 3.39 3.26 3.34 16 0 0.0 12894 12895 12896 12897 7 7 14 3.55 3.69 3.62 is 1 6.7 a 6 14 3.25 3.18 3.22 is 1 6.7 6 8 14 3.48 3.34 3.40 14 0 0.0 7 8 15 3.38 3.41 3.40 is 0 0.0 12898 12899 12900 6 12 18 3.22 3.23 3.22 is 10 3 13. 3.31 3.24 3.29 14 9 7 16 3.22 3.25 3.24 16 0 0.0 1 7.1 0 0.0 ---------------------------------------------------------------------------------------------------------------- a. TOTAL = SUM OF FETAL WEIGHTS/NMBER OF LIVE'FETUSES. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NLTMBER: T-6316 TABLE 19 (PAGE 5): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA ---------------------------------------------------------------------------------------------------------------- NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) ---- CONCEPTUSES ------ RESORBED ---------------------------------------------------------------------------------------------------------------- RAT # MALE FEMALE TOTAL MALE FEMALE TOTAL a N N Ik ------------------------------------------------------------------------------------------------------------------ DOSAGE GROUP V 20 MG/KG/DAY --------------------------------------------------------------------------------------------------------------- 12901 12902 12903 12904 12905 12906 12907 12900 12909 11 6 17 3.28 3.07 3.21 17 0 0.0 4 8 12 3.23 3.05 3.11 14 2 14.3 8 6 14 3.21 3.00 3.12 15 1 6.7 2 8 10 3.20 3.01 3.04 13 3 23.1 5 7 12 3.34 3.28 3.31 12 0 0.0 6 7 13 3.41 3.24 3.32 14 1 7.1 6 3 9 2.96 2.86 23..9035 1106 12 1120..S0 68 84 1142 33..1152 22..9688 2.97 13 1 7.7 12910 NOT PREGNANT 4 13 3.27 2.95 3.17 14 1 7.1 12911 12912 9 7 6 13 3.74 3.34 3.55 13 0 0.0 12913 7 5 12 2.97 23..9290 23..9382 1135 10 70..70 12914 12915 8a 76 1154 33..4539 3.20 3.42 17 3 17.6 12916 8 8 16 3.05 2.85 2.95 17 1 5.9 2.82 3.07 15 1 6.7 12917 12918 10 4 14 3.18 5 10 15 3.27 3.05 3.12 16 1 6.2 12919 8 6 14 3.24 2.99 3.13 14 0 0.0 3.35 3.09 3.22 16 0 0.0 12920 12921 06 88 1164 3.36 3.27 3.31 14 0 0.0 12922 7 5 12 3.18 33..0275 33..1345 i14s 30 200..00 12923 12924 77 78 1145 33..4349 3.13 3.25 is 0 0.0 12925 11 5 16 2.91 2.91 2.91 16 0 0.0 ---------------------------------------------------------------------------------------------------------------- a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NTJMBER: T-6316 TABLE 19 (PAGE 6): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) ---- CONCEPTUSES ------ RESOREED ------------------------------------------------------------------------------------------------------------------ RAT # TOTAL TOTAL a N N t ------------------------------------------------------------------------------------------------------------------ SATELLITE DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12573 15 1.15 16 1 6.2 12574 18 1.19 18 0 0.0 12575 7 1.43 7 0 0.0 --------------------------------------------------------------------------------------L------------------------ SATELLITE DOSAGE GROUP 11 1 MG/KG/DAY ------------------------------------------------------------------------------------------------------------------ 12576 14 1.31 is 1 6.7 12577 18 1.38 18 0 0.0 12578 16 1.28 17 1 5.9 12579 15 1.37 15 0 0.0 12580 14 1.46 15 1 6.7 --------- ------------------------------------------------------------------------------------------------------- SATELLITE DOSAGE GROUP 111 5 MG/KG/DAY --------- ------------------------------------------------------------------------------------------------------- 12581 13 1.43 15 2 13.3 12582 18 1.30 18 0 0.0 12583 20 1.34 20 0 0.0 ----------------------------------------------------------------------------------------------------------------- SATELLITE DOSAGE GROUP IV 10 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- 12584 15 1.22 17 2 11.8 12505 16 1.17 16 0 0.0 12586 13 1.26 14 1 7.1 ---------------------------------------------------------------------------------------------------------------- SATELLITE DOSAGE GROUP V 20 MG/KG/DAY ---------------------------------- ----------------------------------------------------------------------------- 12587 14 1.16 14 0 0.0 12588 15 1.35 15 0 0.0 12589 14 1.32 14 0 0.0 12590 14 1.41 16 2 12.5 12591 16 1.32 17 1 5.9 ---------------------------------------------------------------------------------------------------------------- a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316. TABLE 20 (PAGE 1): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------- 4 5 6 7 8 9 10 11 12 13 14 is 16 17 is 19 2 ------------ --------F-ET-U-S -------1-----2----3-------------------------------------------------------------------------------------- 0 (VEHICLE) MG/KG/DAY --------D-OS-A-GE---G-R-O-UP---1----------------------------------------------------------------------------------------- RAT # 12801 12802 12803 12604 12805 12806 12807 12808 12809 12810 12811 12812 CLa B/ 9 10/ 9 9/ 8 6/11 10/ 7 9/ 7 5/12 9/11 10/ 9 5/10 7/ 9 10/ 6 MA 3.54 MA 2.01 MA 3.28 MA 3.44 FA 3.47 MA 3.65 MA 3.41 FA 3.43 FA 5.33 FA 2.95 FA 3.46 FA 3.61 MA 3.90 FA 1.70 MA 3.60 FA 3.50 MA 3.84 FA 3.36 PA 3.64 E FA 5.24 FA 3.21 FA 3.38 MA 3.40 FA 3.31 FA 1.94 MA 3.72 MA 3.72 FA 3.62 MA 3.67 FA 3.62 E FA 4.95 FA 2.96 FA 3.72 MA 3.33 FA 3.15 FA 1.83 FA 3.44 FA 3.43 FA 3.48 MA 3.62 E FA 3.75 FA 5.36 MA 3.84 FA 3.30 MA 3.47 MA MA 3.41 3.SB MA MA 1.89 2.01 FA MA 3.66 3.82 FA / FA 3.18 3.53 FA FA 3.30 3.49 MA MA 3.81 3.31 MA MA 3.02 3.63 MA FA 3.91 3.35 FA MA 5.03 5.52 MA MA 3.81 3.34 MA FA 3.81 3.61 FA E 3.41 MA 3.64 E FA 3.24 FA 3.46 FA 3,59 FA 3.18 FA 3.81 MA 3.58 FA 4.86 M.A 3 55 FA 3.75 MA 3.40 MA / MA 3.84 3.48 FA MA 1.82 2.06 MA / MA 3.40 3.26 FA MA 3.51 3.36 MA / MA 2.14 1.95 FA FA 3.88 3.51 E MA 2.12 FA 3.08 FA 3.51 MA 2.05 MA 3.39 MA 3.80 FA 2.15 MA 3.30 MA 2.08 MA 3.65 ' FA FA MA MA 3.41 3.53,3.59 3.51 FA / MA MA MA 3.91 3.42 3.99 3.41 FA FA MA FA 3.27 3.49 3.62 3.50 FA FA MA MA 3.30 3.09 3.60 3.27 MA / FA FA E 3.82 3.18 3.38 FA MA MA / FA 5.06 5.08 5.47 4.83 FA 3.45 MA 3.51 MA 3.46 FA 3.60 MA 3.57 FA 5.05 MA 3.88 FA 3.52 MA 3.76 MA 3.41 MA 3.80 FA 5.41 MA 3.63 MA 3.85 E MA 3.65 MA 4.91 MA 3.72 FA 3.34 FA 3.50 E 14A 5.32 MA MA FA 3.54 3.39 3.46 FA FA FA MA FA MA t4A 3.56 3.45 3.46 3.86 3.43 3.77 3.68 MA FA / FA MA FA FA FA t4A 3.56 3.23 3.32 3.66 2.68 3.19 3.26 4.00 FA 3.43 FA 3.47 E MA 4.84 MA 3.57 MA 5.43 MA 5.43 ----1-2-81-3- ---------N-OT---P-RE-G-NA-N-T---------------------------------------------------------------------------------- M = MALE F CLS = CORPORA = FEMALE A = ALIVE LUTEA/OVARY FETAL E = EARLY RESORPTION "/' DENOTES BODY WEIGHTS WERE RECORDED IN GRAMS POSITION (G). OF CERVIX PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 20 (PAGE 2): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- FETUS # 1 2 3 4 5 6 7 a 9 10 11 12 13 14 is 16 17 18 19 ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY ---------------------------------------------------------------------------------------------------------------- RAT # CLs 12814 9/10 1281S 10/ 9 FA 3.37 E E MA FA MA FA FA MA MA FA FA FA 3.77 3.65 3.80 3.55 3.44 4.03 3.61 3.22 3.36 3.46 E FA MA MA FA MA 3.62 3.76 3.78 3.39 3.65 E FA FA MA MA FA MA FA FA FA FA FA MA MA MA FA 3.32 3.70 3.52 3.35 3.36 3.45 3.57 3.43 3.57 3.04 3.41 3.80 3.62 3.65 3.36 12816 7/ 7 E MA FA MA FA MA 3.85 3.53 3.40 3.45 3.36 E FA FA FA MA MA MA MA 3.09 3.28 3.38 3.81 3.76 3.64 3.54 12817 12818 12819 12820 12821 12822 12823 6/ 9 12/ 6 ll/ 6 8/ 7 11/10 7/10 12/ 5 MA 3.67 FA 3.14 FA 2.91 FA 3.36 MA 3.13 MA 3.46 MA 3.68 MA 3.78 FA 3.29 FA 3.30 MA 3.46 MA 3.15 FA 3.17 MA 3.45 MA 3.25 FA 3.80 FA 2.77 FA 3.80 MA 3.43 FA 2.71 FA 3.60 FA 2.99 MA 3.60 MA 3.13 MA 3.27 FA 3.22 MA 3.78 MA 3.56 FA 1.82 FA 3.43 FA 3.37 FA 3.55 MA 3.80 MA 3.89 MA 4.20 FA 3.25 E FA 2.90 MA 3.63 MA 3.08 MA 3.58 MA 3.86 FA 3.13 FA 3.30 MA 3.01 FA 3.30 MA 3.27 FA 3.34 FA 4.40 FA 2.93 MA 3.90 FA 2.70 FA 3.27 MA 3.19 MA 3.45 FA 3.97 FA 3.22 MA 3.77 FA 2.85 MA 3.42 MA 3.32 MA 3.19 FA 3.52 MA 3.35 FA 3.71 MA 3.29 FA 3.22 MA 3.40 MA 3.38 MA 4.28 MA 3.29 E FA 3.07 FA 3.22 FA 3.06 MA 3.34 MA 3.97 MA 3.73 FA 3.54 MA 3.53 E FA 3.18 FA 3.31 MA 3.68 FA 2.63 FA 3.35 FA 3.02 MA 3.72 FA 3.09 FA 3.27 FA 3.65 MA 3.16 FA 3.56 FA 3.21 FA 3.31 MA 3.32 MA 3.48 E MA 3.31 FA 3.77 E MA 3.60 FA 3.13 MA 3.80 FA 4.09 MA 3.41 12824 7/ 7 FA MA MA FA MA MA / FA FA FA FA FA FA 3.59 4.00 3.86 3.91 4.00 3.63 2.99 3.20 3.38 3.40 3.52 3.37 12825 8/10 FA FA MA FA FA MA MA FA / FA MA MA FA FA FA MA FA MA FA 3.67 3.59 3.97 3.74 3.54 4.08 4.05 3.59 3.61 3.98 3.75 3.69 3.58 3.69 3.80 3.78 4.12 3.75 ---------------------------------------------------------------------------------------------------------------- M = MALE F = FE14ALE A = ALIVE CLs = CORPORA LUTEA/OVARY FETAL E = EARLY RESORPTION "/" DENOTES BODY WEIGHTS WERE RECORDED IN GRAMS POSITION (G). OF CERVIX PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 20 (PAGE 3): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 2 ------------------------------------------------------------------------------------------------------------------ DOSAGE GROUP II I MG/KG/DAY ------------------------------------------------------------------------------------ RAT # CLs 12826 12/ 5 FA MA FA MA MA MA MA MA FA / FA MA MA FA FA 2.26 3.30 3.22 3.42 3.14 3.31 3.46 3.56 3.16 2.89 3.33 3.12 2.95 3.19 12827 B/ 9 12828 Il/ 8 FA 2.95 FA 3.29 MA 3.39 MA 3.57 FA 3.12 MA 3.53 FA 3.55 MA 3.26 FA 3.21 MA 3.59 FA 3.16 MA 3.50 MA / MA 3.30 3.60 FA MA 3.47 3.65 MA 3.40 MA 3.35 FA 3.09 MA 3.23 MA 3.24 FA 3.23 FA 3.30 FA 3.08 E FA 3.05 FA 3.32 MA 3.63 FA FA 3.49-3.12 MA FA 3.98 3.44 12829 12830 12831 12832 12833 12834 8/ 8 9/ 7 12/ 5 10/10 S/ 6 5/10 MA 2.88 MA 3.85 FA 3.32 MA 3.24 FA 3.46 FA 3.49 E FA 3.60 MA 3.22 FA 3.00 MA 3.40 FA 3.41 FA 3.13 FA 3.58 FA 3.25 E MA 3.42 FA 3.14 MA 3.05 FA 3.76 FA 2.89 FA 2.79 E MA 3.41 FA MA 3.16 3.45 FA FA 3.63 3.77 FA MA 3.26 3.22 MA FA 3.13 3.20 MA MA 3.07 3.20 PA / FA 3.40 3.42 MA 3.03 FA 3.59 E MA 3.16 MA 3.45 MA 3.38 FA 3.14 MA 3.80 FA 3.29 FA 3.03 MA 3.09 MA 3.34 MA 2.79 PA 3.19 FA 3.23 MA 3.36 MA 3.56 MA 3.70 MA 2.72 PA 3.65 FA 2.95 MA 2.93 MA 2.95 MA 3.72 FA 2.99 MA 3.33 FA 3.07 FA 2.91 MA 3.33 MA 3.57 FA 2.86 MA 3.48 FA 3.41 FA 2.98 FA 3.08 MA 3.52 FA 2.89 MA 4.14 MA 3.34 MA 3.04 MA 3.56 FA 3.25 MA 3.07 MA 3.88 MA 3.49 MA 3.02 FA 3.27 MA 3.18 MA 3.01 MA 3.92 FA 3.18 FA 2.93 MA 3.49 MA 3.76 MA 3.85 12835 9/ 8 MA FA / FA FA FA MA FA MA FA 3.52 3.60 3.73 3.80 2.36 3.77 3.92 3.76 3.52 12836 8/10 FA B FA FA FA KA FA FA MA MA MA FA MA FA 14A FA 2.84 3.06 3.19 3.18 3.47 3.63 3.30 3.39 3.20 3.91 3.36 3.64 3.06 3.29 3.23 12837 8/ 8 FA FA MA E FA FA FA FA FA FA MA MA FA FA MA 3.54 3.49 3.74 3.80 3.69 3.78 3.64 3.58 3.74 3.84 3.91 4.26 3.14 3.92 12838 9/ 6 MA FA FA MA MA FA MA MA FA / FA MA MA FA FA MA 3.12 3.2S 3.43 3.60 3.46 3.51 3.67 3.23 2.40 3.26 3.84 3.51 3.17 3.46 3.39 ----------------------------------------------------------------------------------------------------------------- M = MALE F = FEMALE A = ALIVE CLs = CORPORA LUTEA/OVARY FETAL E = EARLY RESORPTION "/" DENOTES BODY WEIGHTS WERE RECORDED IN GRAMS POSITION (G). OF CERVIX PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 20 (PAGE 4): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 ---------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 11 1 MG/KG/DAY ------------------------------------------------------------------------ RAT # CLs 12839 7/11 12840 9/10 12841 9/ 8 12842 10/ 6 12843 7/ 8 12844 ll/ 8 12845 FA 2.69 FA 2.90 FA 3.39 FA 3.18 FA 3.66 MA 3.70 NOT FA MA 3.32 3.40 MA MA 3.19 3.33 MA FA 3.69 3.14 MA MA 3.54 3.81 MA FA 3.34 3.57 FA FA 3.94 3.49 PREGNANT FA 2.91 MA 3.11 MA 3.56 MA 4.17 FA 3.51 FA 3.75 FA 3.16 t4A 3.68 MA 3.25 MA 3.97 14A 3.99 FA 3.65 MA 3.37 FA 2.96 FA 3.13 FA 3.60 FA 3.40 FA 3.74 F.A / MA 3 23 3.49 MA MA 3.19 3.13 MA FA 3.31 2.62 MA MA 3.84 3.70 MA FA 3.39 3.58 MA MA 3.73 3.93 FA 3.27 FA 3.03 MA 3.53 FA 3.82 FA 3.41 MA 3.88 MA 3.09 MA 3.31 MA 3.60 FA 3.66 FA 3.62 FA 3.5S FA 3.11 MA 3.07 MA 3.13 MA 3.51 FA 3.91 MA 4.22 FA 3.33 FA 2.56 F.A 3 29 MA 3.81 MA 3.98 FA 3.36 FA 3.23 FA 2.86 FA 3.32 FA 3.52 E FA 3.58 MA 3.63 FA 2.79 MA 3.43 MA 3.65 MA 4.02 FA 3.43 FA FA 3.36 3.87 MA t4A 3.24 3.17 FA FA 3.11*3.44 FA FA 3.77 3.39 MA FA 3.93 3.92 MA 3.51 MA 3.12 MA 3.68 FA 3.51 12846 NOT PREGNANT 12847 15/ 6 MA MA MA MA MA MA MA FA MA FA FA FA FA FA MA MA MA FA 2.80 3.07 2.97 3.28 3.62 2.80 3.03 3.28 3.24 2.74 2.92 2.92 2.65 3.78 3.45 3.52 3.21 3.63 12848 13/ 7 MA MA FA MA FA MA FA MA FA FA FA FA FA MA FA MA FA FA 3.31 2.99 3.78 3.08 3.40 3.18 3.27 3.26 2.86 3.09 3.15 3.06 3.16 3.01 3.43 3.04 3.12 3.19 12649 9/ 6 MA FA MA MA FA FA FA MA MA MA FA FA MA MA MA 3.72 3.31 3.45 3.60 3.40 3.07 3.36 3.58 3.49 3.35 3.30 3.03 3.65 3.46 3.39 12850 7/12 FA MA KA FA MA FA MA MA FA FA E E FA FA FA MA FA MA 3.39 3.66 3.32 3.45 3.14 3.14 3.37 3.25 2.95 2.91 3.23 3.00 3.07 3.46 2.33 3.18 ----------------------------------------------------------------------------------------------------------- M - MALE F = FEMALE A = ALIVE CLS = CORPORA LUTEA/OVARY FETAL E = EARLY RESORPTION "/" DENOTES BODY WEIGHTS WERE RECORDED IN GRAMS POSITION (G). OF CERVIX PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NLTMBER: T-6316 TABLE 20 (PAGE 5): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 2 ------------------------------------------------------------------------------------------------------------------ DOSAGE GROUP 111 5 MG/KG/DAY ------------------------------------------------------------------------------------------------------------------ RAT # 12851 CLs 6/12 12852 6/11 12853 10/ 7 12854 8/10 12855 FA 3.42 FA 3.09 MA 3.26 MA 3.57 NOT MA E 3.57 FA MA 3.31 3.29 FA MA 3.52 3.87 FA FA 2.90 3.21 PREGNANT MA 3.55 FA 3.22 FA 3.65 MA 3.44 MA / PA 3.80 3.25 MA MA 3.23 3.58 FA PA 3.48 3.76 FA MA 2.98 3.43 FA 3.13 MA 3.12 FA 3.82 MA 3.50 MA 3.77 MA 3.44 FA 3.50 FA 2.96 FA 3.34 FA 3.10 MA 3.66 FA 2.29 FA 3.20 FA 2.98 FA 3.35 FA 3.24 FA 3.54 MA 3.36 MA 4.00 FA 3.24 MA 3.84 FA 3.21 MA 4.09 MA 3.59 MA 3.48 MA 3.30 E FA 3.50 FA 3.52 MA 3.39 FA 4.03 MA 3.56 PA 3.48 FA 3.29 FA 3.75 FA 3.18 MA 3.82 FA 3.38 FA 3.24 12856 S/ 9 FA MA FA FA MA FA MA FA FA FA FA MA FA MA 3.35 3.57 3.10 3.56 3.61 3.16 3.47 3.47 2.68 3.43 3.16 3.61 3.21 3.49 12857 12/11 ?4A MA FA MA MA MA MA MA FA MA FA MA MA MA FA FA FA FA FA 3.31 3.30 3.34 3.50 3.28 3.49 3.40 3.31 3.45 3.18 3.13 3.19 3.21 3.56 3.14 2.61 3.24 2.93 3.44 12858 6/11 MA FA MA E FA FA / MA MA FA FA MA PA MA FA MA 3.59 3.83 3.88 3.50 3.73 3.25 3.73 3.13 3.34 3.38 3.47 3.32 2.99 3.70 12859 10/ 7 MA MA FA FA FA MA MA MA MA FA MA MA FA FA MA MA FA 3.21 3.19 3.15 3.26 3.24 3.31 3.29 3.21 3.22 3.28 2.97 3.22 3.21 3.12 3.26 3.15 3.17 12860 9/11 MA E MA MA FA MA MA FA MA FA FA MA FA FA FA FA 3.54 3.43 3.64 3.70 4.31 4.00 3.50 3.85 3.47 3.55 3.95 3.51 3.53 3.36 3.76 12861 10/ 8 MA MA E FA FA MA FA MA MA / MA PA E FA FA 2.84 3.13 2.91 2.92 3.26 2.89 3.07 3.40 2.99 2.87 3.06 3.20 12862 8/ 7 MA FA FA FA MA MA FA MA / FA MA MA FA FA MA FA 2.93 2.77 3.02 3.13 2-96 3.13 2.81 2.70 2.77 3.04 2.89 2.99 3.00 3.02 2.76 12863 5/10 MA MA FA FA E / FA MA MA FA FA FA FA PA FA MA 3.65 3.48 3.40 3.37 3.64 3.78 3.75 3.19 3.24 3.47 3.56 3.14 3.29 3.69 ----------------------------------------------------------------------------------------------------------------- M = MALE F - FEMALE A = ALIVE CLs = CORPORA LUTEA/OVARY FETAL E = EARLY RESORPTION /" DENOTES BODY WEIGHTS WERE RECORD;D IN GRAMS POSITION (G). OF CERVIX PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NMBER: T-6316 TABLE 20 (PAGE 6): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA ---------------------------------------------------------------------------------------------------------------- FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 111 5 MG/KG/DAY --------------------------------------------------------------------------------------- RAT # CLs 12864 12/ 5 FA FA MA MA FA FA FA FA MA MA / FA MA MA FA 3.51 3.46 3.54 3.77 3.60 3.49 3.67 3.73 3.97 3.91 3.36 3.48 3.90 3.37 12865 12866 12867 B/ 9 11/11 5/10 FA 3.32 FA 2.70 MA 4.00 FA 3.22 FA 3.08 MA 3.53 FA 3.86 FA 3.15 FA 3.25 E FA 2.84 MA 3.46 MA 3.87 FA 3.18 MA 3.21 FA 3.42 FA 3.38 KA 3.10 FA 3.30 MA 3.30 MA 3.53 MA 3.28 MA 3.41 MA 3.16 FA 3.49 FA 3.46 FA 3.03 FA 3.50 FA 3.35 MA 3.53 MA 3.65 FA 3.43 FA 3.00 FA 3.77 MA 3.39 FA 3.38 FA 3.38 FA 3.57 MA 3.44 MA 3.84 MA 3.34 FA 3.08 FA 3.18 MA 3.51 E MA 3.44 MA 3.72 MA 3.30 MA 3.44 MA 3.68 12868 7/ 6 PA FA / FA FA MA E E 12869 12870 12871 12872 12873 12874 12875 7/ 8 6/11 6/11 10/ 6 5/13 7/10 7/ 9 3.22 MA 3.50 PA 3.48 14A 3.26 FA 3.21 FA 3.55 MA 3.67 E 3.46 FA 3.38 MA 3.92 FA 3.46 MA 3.36 E MA 3.53 E 3.13 MA 3.30 MA 3.91 FA 3.33 MA 3.34 FA 3.78 MA 3.75 E 2.81 FA 3.30 FA 3.28 MA 3.62 MA 3.45 MA 3.71 MA 3.67 MA 4.04 3.35 MA FA 3.22 3.20 FA FA 3.32 3.09 MA FA 3.72 3.55 FA MA 3.15 3.25 PA / FA 3.26 3.34 MA FA 3.79 3.62 FA E 3.51 MA FA MA 3.35 3.01 3.19 MA 3.64 FA MA 3.61 FA MA 3.37 E 2.66 3.34 FA MA 3.29 3.50 FA FA 3.02 2.90 MA / FA FA 3.16 FA 3.59 E 3.66 3.43 MA FA MA 3.73 3.25 3.76 FA 3.21 FA 3.63 MA 3.29 MA 3.11 FA 3.57 FA 3.36 E MA 3.44 FA 3.22 FA 3.21 FA 3.12 MA 3.56 FA 3.53 MA 3.56 MA 3.41 MA 3.68 MA 3.58 MA 3.37 MA 3.57 FA 3.39 MA 3.71 MA 3.55 FA 3.49 MA 3.19 MA 3.44 MA 3.18 FA 3.77 MA 3.43 MA 3.20 FA 3.75 E MA 3.07 MA 3.68 MA 3.58 MA 3.62 FA 3.07 FA 3.33 MA 3.54 FA 3.65 FA 3.28 MA 3.57 FA 3.45 MA 3.46 FA 3.54 FA 3.92 ---------------------------------------------------------------------------------------------------------------- M = 14ALE F = FEMALE A = ALIVE CLS = CORPORA LUTEA/OVARY FETAL E = EARLY RESORPTION "/" DENOTES BODY WEIGHTS WERE RECORDED IN GRAMS POSITION (G). OF CERVIX I PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 20 (PAGE 7)-. FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP IV 10 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- PAT # CLa 12876 9/ 8 MA FA FA MA FA MA MA MA FA MA MA MA FA MA FA 3.48 3.62 3.64 3.79 3.21 3.55 3.49 3.91 3.63 3.46 3.62 3.84 3.62 3.89 3.81 12877 11/ 6 FA MA FA MA MA FA FA FA FA / MA MA MA FA FA 2.93 3.13 3.07 3.28 3.23 2.88 3.28 2.95 3.27 3.40 3.44 3.14 3.08 3.16 12878 4/12 MA FA MA / MA MA FA FA FA MA MA MA FA FA FA FA 3.80 3.88 3.82 3.36 3.44 3.20 3.30 3.63 3.31 3.40 3.60 3.34 3.15 3.00 3.18 12879 10/ 9 FA FA MA FA FA FA MA MA MA MA MA MA MA MA FA 3.21 3.83 3.61 3.34 3.49 3.44 3.08 3.60 3.41 3.20 3.55 3.10 3.62 3.31 3.45 12880 ll/ 9 FA MA MA FA FA MA FA FA MA FA MA MA MA FA MA 3.01 3.40 3.65 3.01 3.19 3.30 3.16 3.25 3.21 2.83 3.17 3.35 3.23 3.11 3.28 12681 10/ 5 FA E MA FA MA MA MA FA FA MA FA FA E MA 2.31 3.03 2.91 3.03 3.07 3.27 2.88 2.93 2.95 2.89 3.00 3.39 12882 8/11 MA FA FA FA MA FA FA MA MA FA MA FA FA FA FA FA MA 3.39 3.64 3.86 3.57 3.60 3.61 3.15 3.85 3.56 3.23 3.79 3.19 3.06 3.66 3.44 3.28 3.93 12883 6/11 FA FA MA MA MA E MA FA MA FA MA MA FA E FA E MA 3.38 3.23 3.89 3.20 3.28 3.46 3.42 3.69 3.34 3.31 3.19 3.12 3.29 3.18 12884 9/ 6 FA MA FA MA FA MA MA FA MA MA FA E FA 3.02 3.41 3.23 2.97 3.02 3.24 3.09 3.00 3.52 2.84 3.19 3.40 12885 10/ 9 FA FA MA MA MA MA FA MA FA FA MA MA MA MA FA FA FA 3.02 3.15 3.52 3.38 3.22 3.24 3.17 3.44 3.01 2.87 3.36 2.10 3.76 3.32 1.67 3.00 3.03 12886 10/ 7 MA FA FA MA MA MA E MA PA MA FA MA MA MA 3.61 3.21 3.61 3.71 3.53 3.47 3.80 3.82 3.16 3.15 3.41 4.00 3.72 12887 6/10 FA FA MA MA MA MA / MA FA FA MA PA FA MA FA FA MA 3.08 2.88 3.28 2.95 3.26 3.16 3.38 3.04 3.19 3.17 2.71 2.91 3.27 2.90 2.90 3.23 12888 8/10 MA FA FA FA MA MA MA FA FA E FA FA MA MA 3.03 3.01 3.16 2.88 3.05 2.90 2.8S 2.83 3.07 2.99 2.95 2.96 3.27 ---------------------------------------------------------------------------------------------------------------- M = MALE F = FEMALE A = ALIVE CLs = CORPORA LUTEA/OVARY FETAL E = EARLY RESORPTION "/" DENOTES BODY WEIGHTS WERE RECORDED IN GRAMS POSITION (G). OF CERVIX PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 20 (PAGE 8): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 is 16 17 18 19 2 ------------------------------------------------------------------------------------------------------------------ DOSAGE GROUP IV 10 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- RAT # CLs 12889 Il/ 4 FA MA / FA 3.54 3.47 3.79 12890 5/11 MA MA FA FA E / MA MA FA MA FA FA PA FA MA MA FA 3.25 3.55 3.44 2.99 3.04 3.18 3.20 3.34 2.15 3.39 3.09 3.26 3.20 3.16 2.84 12891 6/ 7 MA FA MA MA FA FA MA MA MA MA MA FA FA 3.46 3.49 3.88 3.87 3.82 3.39 3.74 3.9B 4.06 3.93 3.63 3.29 3.59 12892 B/ 7 FA FA FA FA FA FA FA MA FA MA FA MA MA MA FA 12893 12894 14/ 7 8/ 7 3.31 FA 3.24 FA 3.41 MA 3.27 FA 3.56 FA 3.30 FA 3.43 FA 3.42 MA 3.38 MA 3.48 MA 3.41 FA 3.34 FA 3.21 FA 3.16 FA 3.75 MA 3.48 MA 3.71 FA 3.08 MA 3.52 MA 3.51 MA 3.50 KA 3.37 FA 3.63 MA 3.31 E 3.58 MA 3.02 MA 3.52 MA 3.52 FA 3.42 MA 3.45 MA MA 3.49 12895 7/ 8 3.24 MA 3.00 3.74 MA 3.17 3.72 KA 3.43 3.55 14A 3.16 3.58 MA 3.27 3.72 MA 3.35 3.60 3.66 3.32 E MA MA 3.35 3.26 3.52 FA 3.04 4.16 FA 3.2S FA 3.20 3.50 FA 2.92 3.68 FA 3.11 3.73 FA 3.55 12896 5/10 12897 9/ 9 12898 11/ 8 FA 3.07 MA 3.19 FA 3.00 MA 3.65 FA 3.53 MA 3.18 FA 3.41 FA 3.51 MA 2.77 KA 3.53 FA 3.63 FA 3.15 MA 3.12 MA 3.59 FA 3.03 FA 3.39 FA 3.54 FA 3.19 FA 3.19 FA 3.53 FA 3.24 MA 3.56 MA 3.29 FA 3.14 FA 3.40 FA 3.08 MA 3.46 FA 3.44 FA 3.30 MA 3.26 14A MA 3.36 3.69 FA MA 3.18 3.65 FA / MA 3.25 3.16 FA 3.54 MA 3.18 FA 3.19 FA 3.29 MA 3.41 FA 3.44 MA 3.33 FA 3.38 FA 3.36 MA FA 3.47 3.36 12899 S/ 7 MA FA FA MA FA MA MA E / MA MA MA MA MA MA 3.34 3.12 3.23 3.47 3.36 3.44 3.18 3.20 3.03 3.37 3.68 3.11 3.29 12900 Il/ 6 MA MA MA FA MA FA FA FA FA MA MA MA MA FA FA MA 2.96 2.95 3.47 3.39 3.00 3.05 3.35 3.59 3.37 3.31 3.56 3.12 3.22 2.66 3.33 3.43 ----------------------------------------------------------------------------------------------------------------- M = MALE F = FEMALE A = ALIVE CLS = CORPORA LUTEA/OVARY FETAL E = EARLY RESORPTION 11/1'DENOTES BODY WEIGHTS WERE RECORDED IN GRAMS POSITION (G). OF CERVIX PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 20 (PAGE 9): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP V 20 MG/KG/DAY ---------------------------------------------------------------------------------------------------------------- RAT # CLB 12901 9/ 8 12902 ll/ 6 12903 10/ 7 12904 B/ 7 12905 7/ 6 12906 8/ 6 12907 8/10 12908 4/14 12909 9/ 8 12910 MA 3.17 FA 2.93 FA 3.08 FA 3.01 MA 3.37 FA 3.10 MA 2.50 FA 3.09 PA 2.47 NOT MA MA MA MA 3.37 3.23 3.11 3.06 E MA 3.48 FA 3.01 MA 3.37 FA 3.00 E MA 3.31 MA 3.27 FA MA FA E 3.16 3.10 2.99 FA FA MA FA 3.10 3.37 3.76 3.37 MA MA FA MA 3.44 3.48 3.11 3.49 FA 2.43 MA 3.49 FA 3.13 MA MA 2.85 3.20 FA / MA 3.01 3.02 MA MA 3.31 3.10 FA 2.90 FA 3.05 MA 3.01 PREGNANT FA 2.94 MA 3.07 MA 3.32 FA 2.92 MA 3.24 FA 3.37 MA 3.17 MA 3.08 FA 2.38 FA 3.03 FA 2.70 FA 2.85 FA 2.86 FA 3.04 E E FA 2.80 MA 2.88 FA 2.82 E MA 2.80 FA 3.09 FA 3.44 MA 3.38 MA 3.11 FA 2.61 MA 3.32 MA 3.16 FA 3.07 FA 3.12 E FA 3.22 MA 2.96 MA 2.94 MA 3.16 E FA 3.25 MA 3.16 FA 3.04 E FA 3.46 FA 3.17 FA 3.25 FA 3.22 MA 3.23 FA 3.12 MA 3.37 MA 3.16 MA 3.30 MA 3.12 FA 3.34 FA 3.12 MA 2.97 FA 3.27 FA 3.18 MA 3.09 FA 3.13 MA 3.19 FA 3.24 MA 3.17 FA 2.76 MA 3.40 FA 3.41 FA 2.84 FA 2.89 MA 3.59 FA 3.09 FA 3.07 MA 3.40 MA. 3.18 MA FA 3.71 3.37 E MA 3.03 MA 2.99 FA 2.92 MA 3.26 E MA 3.38 12911 6/ 8 E FA MA MA MA FA MA MA FA MA FA MA MA MA 3.15 3.12 3.29 2.97 3.07 3.37 3.40 2.54 3.22 3.05 3.25 3.47 3.32 12912 Il/ 4 FA FA FA MA FA FA MA MA MA / MA MA FA MA 3.06 3.34 3.15 3.82 3.98 3.49 3.62 3.57 4.10 3.52 3.64 2.99 3.89 12913 9/ 8 MA 14A E 14A FA FA MA MA FA MA MA FA FA 2.94 3.26 3.39 3.08 3.06 2.41 2.98 3.11 2.93 2.91 2.72 2.98 ---------------------------------------------------------------------------------------------------------------- M = MALE F = FEMALE A = ALIVE CLS = CORPORA LUTEA/OVARY FETAL E = EARLY RESORPTION "/" DENOTES BODY WEIGHTS WERE RECORDED IN GRAMS POSITION (G). OF CERVIX PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 20 (PAGE 10): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 2 ------------------------------------------------------------------------------------------------------------------ DOSAGE GROUP V 20 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- RAT # CLS 12914 12/ 4 FA MA MA FA FA FA MA PA MA MA MA FA / FA MA MA 3.06 3.16 3.59 3.37 2.79 3.27 3.40 3.35 3.32 3.35 3.71 3.32 3.24 3.37 3.53 12915 9/13 FA MA FA E MA MA FA FA MA / MA FA E E MA MA MA FA 2.94 3.58 3.41 3.43 3.65 2.98 2.99 3.72 3.27 3.21 3.87 3.38 3.81 3.66 12916 B/ 9 FA MA MA FA MA MA MA MA FA E FA MA FA FA FA FA MA 2.58 3.03 3.11 2.94 3.33 3.16 2.76 3.02 2.64 2.90 3.15 3.34 3.05 2.61 2.75 2.86 12917 ll/ 6 MA MA MA E MA MA MA FA FA MA FA FA MA KA MA 3.13 3.07 3.07 3.39 3.22 3.24 2.79 2.77 3.12 2.76 2.94 3.14 3.37 3.02 12918 12/ 5 FA FA FA FA MA FA MA FA FA MA FA MA E FA MA FA 2.57 3.22 2.89 3.08 3.10 2.87 3.34 3.25 3.26 3.30 3.02 3.11 2.99 3.50 3.35 12919 6/ 8 MA FA MA MA 14A MA MA FA MA FA MA FA FA FA 3.05 2.87 3.15 3.61 3.26 3.17 3.22 3.07 3.28 2.97 3.14 3.00 3.05 2.97 12920 10/ 9 FA MA MA MA MA MA FA FA MA FA MA F.A MA FA FA FA 3.25 3.52 3.31 3.32 3.43 3.23 2.91 3.17 3.43 3.03 3.28 3 16 3.26 2.93 3.15 3.14 12921 7/10 t4A FA FA FA MA MA MA FA MA FA FA MA FA FA 3.66 3.26 3.14 3.28 3.39 2.71 3.44 3.20 3.23 3.31 3.34 3.73 3.34 3.27 12922 B/ 8 MA FA MA E MA FA FA MA E E MA 14A FA MA FA 2.80 2.95 3.36 3.58 3.35 2.96 2.96 3.16 3.06 3.07 3.38 3.01 12923 B/ 6 MA MA MA FA FA FA FA FA FA MA MA MA MA FA 3.54 3.39 3.16 3.08 3.58 3.24 3.38 2.94 3.12 3.55 3.55 3.31 3.58 3.44 12924 B/ 8 MA MA FA MA MA FA PA MA FA FA FA MA MA FA PA 3.27 2.92 3.45 3.68 3.61 2.98 2.93 3.59 3.10 3.03 3.26 3.04 3.63 3.47 2.85 12925 9/ 9 MA FA FA FA MA MA MA MA FA / MA MA FA KA MA MA MA 2.45 2.65 3.04 3.17 3.17 2.79 2.74 2.93 2.93 2.86 3.06 2.76 2.82 3.08 3.06 3.06 ---------------------------------------------------------------------------------------------------------------- M - MALE F = FEMALE A = ALIVE CLs = CORPORA LUTF-A/OVARY FETAL E = EARLY RESORPTION "/" DENOTES BODY WEIGHTS WERE RECORDED IN GRAMS POSITION (G). OF CERVIX PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631 TABLE 20 (PAGE 11): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------- FETUS # 1 2 3 4 s 6 7 8 9 10 11 12 13 14 15 16 17 18 19 ---------------------------------------------------------------------------------------------------------------- SATELLITE DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY ------------------------------------------------------------------------------------- RAT # CLs 12573 13/ 3 12574 12/12 E A 1.12 A 0.80 A 1.21 A 1.08 A 1.27 A 1.15 A 1.17 A 1.07 A 1.29 A 1.16 A 1.20 A 1.34 A 1.12 A 1.23 A 1.20 A A 1.28 1.11 A/ A 1.19 1.09 A 1.32 A 1.24 A 1.26 A 1.31 A/ A A 1.09 0.06al.22 A A A 1.32 1.10 1.18 A 1.05 A 1.19 A 1.12 1.18 12575 6/ 6 A A A A A A/ A 1.36 1.49 1.43 1.27 1.45 1.44 1.57 -------- ------------------------------------------------------------------------------------------ SATELLITE DOSAGE GROUP II I MG/KG/DAY --------------------------------------------------------------------------------------------------------------- 12576 15/ 5 12577 8/12 12S78 8/11 A 1.17 A 1.08 A 1.17 A A 1.05 1.17 A A 1.38 1.51 A A 1.35 1.28 A 1.21 A 1.40 A 1.27 A 1.30 A 1.45 A 1.28 A A A 1.29 1.36 1.36 A A/ A 1.39 1.47 1.36 A/ A A 1.29 1.23 1.24 A 1.38 A 1.45 A 1.28 A 1.32 A 1.39 A 1.30 A 1.42 A 1.42 A 1.36 E/ A 1.46 A A 1.49 1.31 E A 1.23 A 1.42 A 1.44 A 1,30 A 1.46 A 1.45 A 1.30 A 1.30 A 1.18 A 1.29 A 1.38 A 1.29 12579 10/ 5 A A A A A A A A A A A A A A A 1.32 1.32 1.23 1.39 1.34 1.46 1.50 1.36 1.26 1.26 1.52 1.51 1.34 1.28 1.50 12580 ll/ S A A A A A A A A A A A A 1.23 1.39 1.49 1.50 1.51 1.46 1.52 1.49 1.39 1.54 1.48 1.36 E A A 1.55 1.54 ------------------------------------------------------------------------------------------------- SATELLITE DOSAGE GROUP 111 5 MG/KG/DAY ------------------------------------------------------------------------------------- 12581 6/ 9 12582 14/ 7 12583 13/11 A 1.24 A 1.10 A 1.49 A 1.42 A 1.12 A 1.26 A 1.55 A 1.34 A 1.27 A 1.54 A 1.21 A 1.48 A 1.37 A 1.37 A 1.26 A/ A 1.47 1.32 A A 1.23 1.40 A A 1.45 1.30 A A 1.31 1.47 A A 1.43 1.50 A A 1.35 1.19 A 1.51 A 1.29 A 1.30 A 1.45 A 1.26 A 1.52 E A 1.22 A 1.29 E A 1.32 A 1.05 A 1.44 A 1.29 A 1.30 A 1.52 A 1.43 A 1.43 A 1.32 A 1.44 A 1.02 A 1.38 A 1.49 A 1.45 1.34 ---------------------------------------------------------------------------------------------------------------- A = ALIVE E = EARLY RESORPTION -/- DENOTES POSITION OF CERVIX CLS = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G). a. Value presumed incorrectly recorded; value excluded from group averages. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NLTMBER: T-6316 TABLE 20 (PAGE 12): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 is 16 17 18 19 2 ----------------------------------------------------------------------------------------------------------------- SATELLITE DOSAGE GROUP IV 10 MG/KG/DAY ----------------------------------------------------------------------------------------------------------------- PAT # CLs 12584 14/ 8 E A A E A A A A A A A/ A A A A A A 1.28 1.18 1.29 1.17 1.39 1.30 1.26 1.17 1.24 1.04 1.12 1.26 1.18 1.15 1.21 12585 6/10 A A A A A A/ A A A A A A A A A A 1.18 1.32 1.25 1.30 1.19 1.07 1.17 1.10 0.71 1.21 1.17 1.30 1.20 1.13 1.24 1.17 12586 9/ 7 A A A A A A A A/ A E A A A A 1.25 1.25 1.35 0.99 1.44 1.30 1.26 1.13 1.27 1.27 1.23 1.35 1.35 ----------------------------------------------------------------------------------------------------------------- SATELLITE DOSAGE GROUP V 20 MG/KG/DAY ---------------------------------------------------------------------------------------------------------------- 12587 9/ 5 A A A A A A A A A A A A A A 1.03 1.15 1.16 1.25 1.17 1.07 1.13 1.12 1.19 1.05 1.23 1.32 1.17 1.26 12588 9/ 6 A A A A A A A A A A A A A A A 1.25 1.27 1.32 1.28 1.47 1.11 1.42 1.35 1.28 1.40 1.36 1.37 1.47 1.47 1.38 12589 7/ 7 A A A A A A A/ A A A A A A A 1.25 1.26 1.30 1.31 1.34 1.30 1.32 1.11 1.35 1.29 1.40 1.32 1.49 1.38 12590 12591 12/ 4 10/ 9 A 1.25 A 1.20 A 1.37 A 1.28 A 1.56 A 1.36 A 1.38 A 1.36 A 1.38 A 1.37 A 1.43 A 1.17 A 1.31 A 1.22 E A 1.35 A 1.25 A 1.36 A A 1.41 1.32 E/ A 1.31 A/ E 1.52 A 1.41 A 1.30 A 1.65 A 1.40 A 1.50 A 1.34 A 1.46 A 1.29 A 1.32 ----------------------------------------------------------------------------------------------------------------- A = ALIVE E = EARLY RESORPTION CLa = CORPORA LUTEA/OVARY FETAL "/" DENOTES BODY WEIGHTS POSITION OF CERVIX WERE RECORDED IN GRAMS (G). PROTOCOL 418-011: OPAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 21 (PAGE 1) : FETAL ALTERATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY ---------------------------------------------------------------------------------------------------------------- SPECIMENS GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION SKELETAL WITH ANY RAT NUMBER ALTERATIONS N(t) NIN DESCRIPTION NIN DESCRIPTION NIN DESCRIP ----------------------------------------------------------------------------------------------------------------- 12801 1( 7.7) 0/13 1/ 6 FETUS 10 VESSELS: UMBILICAL 0/ 7 ARTERY DESCENDS LEFT OF URINARY TO THE BLADDER 12802 6( 42.8) 0/14 1/ 7 FETUS 11 KIDNEYS: DILATION, PELVIS, right SLIGHT S/ 7 FETUS 1 STERNAI NOT OSS PELVIS INCOMP bilate FETUS PELVIS INCOMP left FETUS STERNA NOT OS FETUS PELVIS INCOMP bilate FETUS STERNA NOT OS 12803 1( 6.2) 0/16 1/ 8 FETUS 2 KIDNEYS: PELVIS, SLIGHT 0/ 8 DILATION, bilateral ---------------------------------------------------------------------------------------------------------------- NIN - NUMBER OF SPECIMENS WITH ALTERATIONS /NUMBER OF SPECIMENS EXAMINED PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316. TABLE 21 (PAGE 2): FETAL ALTERATIONS - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ 0 (VEHICLE) MG/KG/DAY DOSAGE GROUP 1 --------------------------------------------------------------------------------------------------- SPECIMENS GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION -------------SKELETAL WITH ANY RAT ALTERATIONS NUMBER N(t) NIN DESCRIPTION NIN DESCRIPTION ---------------------------------- --------------------------------------------------- 12804 0( 0.0) 0/13 0/ 6 NIN DESCRIP -------------------------0/ 7 12805 o( o.o) 0/15 0/ 7 0/ 8 12806 0( 0.0) 0/15 0/ 7 0/ 8 12807 0( 0.0) 0/14 0/ 7 0/ 7 12808 0( 0.0) 0/12 0/ 6 0/ 6 12809 0( 0.0) 0/18 0/ 9 0/ 9 12810 1( 10.0) 0/10 1/ 5 FETUS 10 VESSELS: UMBILICAL ARTERY DESCENDS TO THE 0/ 5 LEFT OF URINARY BLADDER 12811 12812 0( 0.0) 0( 0.0) 0/14 0/14 0/ '7 0/ 7 0/ 7 0/ 7 12813 NOT PREGNANT 12814 0( 0.0) 0/16 0/ 8 0/ 8 12815 0( o.o) 0/15 0/ 7 0/ 8 12816 0( 0.0) 0/12 0/ 6 0/ 6 12817 0( 0.0) 0/15 0/ 7 0/ 8 12818 0( 0.0) 0/13 0/ 6 0/ 7 0/ 7 0/ 8 12819 0( o.o) 0/15 ------- -------------------------------------------------------------------------------------------------------- NIN . NUMBER OF SPECIMENS WITH ALTERATIONS /NUMBER OF SPECIMENS EXAMINED PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316. TABLE 21 (PAGE 3): FETAL ALTERATIONS - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------- 0 (VEHICLE) MG/KG/DAY D-O-SA-G-E---G-RO-U-P---1 ---------------------------------------------------------------------------------------------------- SPECIMENS GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION SKELETAL I WITH ANY RAT ALTERATIONS DESCRIPTION NIN DESCRIPTION NIN DESCRIP N-U-MB-E-R --------N-(-t)---------NI-N---------------------------------------------------------------------------------------- 12820 0( 0.0) 0/14 0/ 7 0/ 7 12821 4( 26.7) 0/15 '1/ 7 FETUS 6 VESSELS: UMBILICAL ARTERY DESCENDS TO THE 3/ 8 FETUS 7 STERNAL INCOMPL LEFT OF URINARY BLADDER FETUS I STERNAL INCOMPL FETUS 1 STERNAL INCOMPL 12822 2( 13.3) 0/15 1/ 7 FETUS 4 LUNGS: APICAL ABSENT LOBE, 1/ 8 FETUS 9 STERNA INCOMP 12023 0( 0.0) 0/14 0/ 7 0/ 7 12824 o( o.0) 0/12 0/ 6 0/ 6 0/ 9 0/ 9 1-2-8-25--------o-(---o-.-o-)-----0-/-18------------------------------------------------------------------------------------- NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED PROTOCOL 418-011: ORAL (GAVAGF-) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316. TABLE 21 (PAGE 4): FETAL ALTERATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 11 1 MG/KG/DAY --------------------------------------------------------------------------------------- SPECIMENS GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION SKELETAL WITH ANY RAT ALTERATIONS NUMBER N(t) NIN DESCRIPTION NIN DESCRIPTION NIN DESCRIP ---------------------------------------------------------------------------------------------------------------- 12826 1( 7.1) 0/14 1/ 7 FETUS 12 VESSELS: INNOMINATE, 0/ 7 ABSENT 12827 12628 12829 12830 12831 12832 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 2( 14.3) 0/13 0/16 0/14 0/is 0/16 0/14 0/ 6 0/ 8 0/ 7 0/ 7 0/ 8 0/ 7 0/ 7 0/10 0/ 7 0/ 8 0/ a 2/ 7 FETUS 4 CERVICI CERVIC) 7TH CE right FETUS CERVIC CERVIC 7TH CE right 12833 0( 0.0) 0/13 0/ 6 0/ 7 12834 1( 6.7) 0/is 1/ 7 FETUS 14 VESSELS: UMBILICAL 0/ 8 ARTERY DESCENDS TO THE LEFT OF URINARY BLADDER ---------------------------------------------------------------------------------------------------------------- NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED PROTOCOL 418-011; ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 21 (PAGE 5): FETAL ALTERATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 11 1 MG/KG/DAY ---------------------------------------------------------------------------------------------------------------- SPECIMENS GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION SKELETAL WITH ANY RAT ALTERATIONS NUMBER N(%) NIN DESCRIPTION NIN DESCRIPTION NIN DESCRIP ----------------------------------------------------------------------------------------------------------------- 12835 0( 0.0) 0/ 9 0/ 4 0/ 5 12836 0( 0.0) 0/15 0/ 7 0/ 8 12837 1( 7.1) 0/14 1/ 7 FETUS 9 VESSELS: ABSENT INNOMINATE, 0/ 7 12838 12839 12840 0( 0.0) 0( 0.0) 1( 5.9) 0/15 0/17 0/17 0/ 7 0/ 8 0/ 8 0/ a 0/ 9 1/ 9 FETUS STERNA INCOMP 12841 12842 0( 0.0) 1( 6.2) 0/17 0/16 0/ a 0/ 8 0/ 9 1/ a FETUS CERVIC CERVIC 7TH CE right 12843 12844 0( 0.0) 0( 0.0) 0/13 0/17 0/ 6 0/ 8 0/ 7 0/ 9 12845 NOT PREGNANT ---------------------------------------------------------------------------------------------------------------- NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316. TABLE 21 (PAGE 6): FETAL ALTERATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 11 1 MG/KG/DAY --------------------------------------------------------------------------------------- SPECIMENS GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION SKELETAL I WITH ANY RAT NUMBER ALTERATIONS N(t) NIN DESCRIPTION NIN DESCRIPTION NIN DESCRIP ----------------------------------------------------------------------------------------------------------------- 12846 12847 12848 NOT PREGNANT o( o.o) 1( 5.6) 0/18 0/18 0/ 9 0/ 9 0/ 9 1/ 9 FETUS 1 RIBS: W 10th 12849 0( 0.0) 0/15 0/ 7 0/ 8 12850 2( 12.5) 0/16 1/ 8 FETUS 16 LUNGS: DIAPHRAGMATIC 1/ 8 FETUS 1 STERNAL LOBE, ABSENT NOT OSS --------------------------------------------------------------------------------------------------------------- NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316. TABLE 21 (PAGE 7) : FETAL ALTERATIONS - INDIVIDUAL DATA ------------------------------------------------------------------------------------------------------------------ 5 MG/KG/DAY D-O-SA-G-E---G-RO-U-P--1-1-1----------------------------------------------- ------------------------------------------------ SPECIMENS GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION SKELETAL E WITH ANY RAT NUMBER ALTERATIONS N (!k) MIN DESCRIPTION NIN DESCRIPTION NIN DESCRIPT -------------------------------------------------------------------------------------- ----------------------- 12851 o( o.o) 0/15 0/ 7 0/ 8 12852 0( 0.0) 0/16 0/ 8 0/ 8 12853 0( 0.0) 0/14 0/ 7 0/ 7 12854 0( 0.0) 0/16 0/ a 0/ 8 12855 12856 12857 12858 12859 NOT PREGNANT 0( 0.0) 0( 0.0) 0( o.o) 2( 11.8) 0/14 0/19 0/14 0/17 0/ 6 0/ 9 0/ 7 0/ 8 0/ 8 0/10 0/ 7 2/ 9 FETUS 1 PELVIS: INCOMPL right FETUS 1 PELVIS: INCOMPI right 12860 2( 13.3) 0/15 2/ 7 FETUS 5 VESSELS: UMBILICAL ARTERY DESCENDS TO THE LEFT OF URINARY BLADDER 0/ 8 FETUS 9 VESSELS: UMBILICAL ARTERY DESCENDS TO THE LEFT OF URINARY BLADDER --------------------------------------------- ---------------------------------------------------------------- NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED PROTOCOL 418-011-. ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NLTMBER: T-6316. TABLE 21 (PAGE 8) : FETAL ALTERATIONS - INDIVIDUAL DATA ---------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 111 5 MG/KG/DAY -------------------------------------------------------------------------- SPECIMENS GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION SKELETAL E WITH ANY RAT ALTERATIONS NIN DESCRIPTION NIN DESCRIPT N-U-MB-E-R---------N -(-1;-)-------N-IN------D-E-SC-R-IP-T-IO-N----------------------------------------------------------------------------- 12861 o( o.o) 0/12 0/ 6 0/ 6 12862 0( 0-0) 0/15 0/ 7 0/ 8 12863 1( 7.1) 0/14 0/ a 1/ 6 FETUS 1 STERNAL INCOMPL 12864 12865 0( 0.0) 1( 6.7) 0/14 0/15 0/ 7 0/ 7 0/ 7 1/ 8 FETUS 6 CERVICA CERVICA 7TH CER left 12866 o( o.o) 0/19 0/ 9 0/10 12867 o( o.o) 0/14 0/ 7 0/ 7 12868 o( o.o) 0/ 5 0/ 2 0/ 3 12869 o( o.o) 0/15 0/ 7 0/ 8 12870 0( 0.0) 0/16 G/ 8 0/ 8 12871 12872 0( 0.0) 0( 0.0) 0/14 0/14 0/ 7 0/ 7 0/ 7 0/ 7 12873 0( o.o) 0/14 0/ 7 0/ 7 12874 0( 0.0) 0/16 0/ 8 0/ a 12875 0( 0.0) 0/10 0/ 5 0/ 5 -------------------------------------------------------------------------------------------------------------- MIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316. TABLE 21 (PAGE 9) : FETAL ALTERATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- 10 MG/KG/DAY D-O-SA-G-E---G-RO-U-P---TV--------------------- ------------------------------------- ------------------------------------- SOFT TISSUE EXAMINATION SKELETAL SPECIMENS GROSS EXTERNAL EXAMINATION WITH ANY RAT ALTERATIONS NIN DESCRIPTION NIN DESCRIP N-U-MB-E-R --------N--(%-)--------N-IN-------D-ES-C-RI-P-TI-O-N------------------------------------------------------------------------- 12876 0( 0.0) 0/15 0/ 7 0/ 8 12877 1( 7.1) 0/14 1/ 7 FETUS 14 KIDNEYS: PELVIS, 0/ 7 MODERATE DILATION, right 12878 12879 12880 12881 12882 o( o.o) 0( 0.0) 0( 0.0) o( 0.0) 1( 5.9) 0/15 0/15 0/15 0/12 0/17 0/ 7 0/ 7 0/ 7 C/ 6 0/ 8 0/ 8 0/ 8 0/ 8 0/ 6 1/ 9 FETUS CERVIC CERVIC 7TH CE left 12883 0( 0.0) 0/14 0/ 7 0/ 7 0/ 6 0/ 6 1-2-8-8-4 --- ---0-(---0-.-0-)------0/-1-2------------------------------------------------------------------------------------- NIN = NUMBER OF SPECIMENS WITH ALTEPATIONS/NUMBEROF SPECIMENS EXAMINED PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 21 (PAGE 10) FETAL ALTERATIONS - INDIVIDUAL DATA ---------------------------------- ----------------------------------------------------------------------------- DOSAGE GROUP IV 10 MG/KG/DAY ------------------------------------------------------------------------- SPECIMENS GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION SKELETAL WITH ANY RAT ALTERATIONS N(%) NIN DESCRIPTION NIN DESCRIPTION NIN DESCRIP N-U-MB-E-R ---- ------------------------------------------------------------------------------------------------------- 12885 1( 5.9) 1/17 FETUS BODY: TAIL: 15 TRUNK SHORT ABSENT 0/ 8 1/ 9 FETUS I CERVICA PRESENT THORACI PRESENT ARCH, N bilate CENTRLD Ist - LUMBAR PRESEN ARCH, bilate CENTRU lot - SACRAL PRESEN ARCH, bilate CENTR lot - CAUDAL PRESEN PELVIS OSSIFI RIBS: NOT OS bilate ---------------------------------------------------------------------------------------------------------------- NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a. Excluded from ossification site group averages and statistical analyses. PROTOCOL 418-011: ORAI. (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316 TABLE 21 (PAGE 11) FETAL ALTERATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- DOSAGE GROUP IV 10 MG/KG/DAY -- - -- - -- - - -- - - -- - - - --- - - - - ---- -- - -- - - -- - - -- - - -- - -- - - -- - -- - -- - - -- - -- - - - -- - - -- - -- - - -- - - -- - -- - -- - - -- - - -- - - -- -- - - -- - - SPECIMENS GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION SKELETAL WITH ANY RAT NUMBER ALTERATIONS N(%) NIN DESCRIPTION NIN DESCRIPTION NIN DESCRIP ---------------------------------------------------------------------------------------------------------------- 12886 12887 12888 0( 0.0) o( o.o) 2( 15.4) 0/13 0/16 0/13 0/ 6 0/ 8 0/ 6 0/ 7 0/ 8 2/ 7 FETUS 1 PELVIS INCOMP left FETUS STERNA INCOMP 12889 12890 0( 0.0) 1( 6.7) 0/ 3 0/15 0/ 1 0/ 7 0/ 2 1/ 8 FETUS CERVIC CERVIC 7TH CE left 12891 0( 0.0) 0/13 0/ 6 0/ 7 12892 0( 0.0) 0/15 0/ 7 0/ 8 ---------------------------------------------------------------------------------------------------------------- NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316. TABLE 21 (PAGE 12): FETAL ALTERATIONS - INDIVIDUAL DATA -------------------------- -------------------------------------------------------------------------------------- DOSAGE GROUP IV 10 MG/KG/DAY -------------------------------------------------------------------------- SPECIMENS GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION SKELETAL WITH ANY RAT NUMBER ALTERATIONS N(%) NIN DESCRIPTION NIN DESCRIPTION NIN DESCRIP ---------------------------------------------------------------------------------------------------------------- 12893 1( 6.2) 0/16 0/ 8 1/ 8 FETUS 1 SKULL: SUTURE 12894 12895 12896 12897 12898 0( 0.0) o( o.o) 0( 0.0) o( o.o) 1( 5-6) 0/14 0/14 0/14 0/15 0/18 0/ 7 0/ 7 0/ 7 0/ 7 0/ 9 0/ 7 0/ 7 0/ 7 0/ a 1/ 9 FETUS I CERVICY CERVIC 7TH CE right 12899 0( 0-0) 0/13 0/ 6 0/ 7 12900 0( 0.0) 0/16 0/ 8 0/ 8 --------------------------------------------------------------------------------------------------------------- NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S T-6316. STUDY NUMBER-. TABLE 21 (PAGE 13) : FETAL ALTERATIONS - INDIVIDUAL DATA ----------------------------------- ------------------------------------------------------------------------------ DOSAGE GROUP V 20 MG/KG/DAY -------------------------------------------------------------------------- --------------------------------------- SPECIMENS GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION SKELETAL E WITH ANY PAT ALTERATIONS NIN DESCRIPT NUMBER N(%) NIN DESCRIPTION NIN DESCRIPTION ------------------------------------------------------------------------------------------------------------------ 12901 0( 0.0) 0/17 0/ 7 0/10 12902 0( 0.0) 0/12 0/ 6 0/ 6 12903 0( 0.0) 0/14 0/ 7 0/ 7 12904 1( 10.0) 0/10 0/ 5 1/ 5 FETUS 1 RIBS: W 7th and 12905 12906 12907 0( 0.0) 0( 0.0) 1( 11.1) 0/12 0/13 0/ 9 0/ 6 0/ 6 0/ 4 0/ 6 0/ 7 1/ 5 FETUS I STERNAL NOT OSS 12908 1( 7.1) 0/14 0/ 7 1/ 7 FETUS 5 CERVICA CERVICA 7TH CER left 12909 4( 33.3) 0/12 0/ 6 4/ 6 FETUS 5 RIBS: 4th - I ------------------------------------------------------------ ---------------------------------------------------- NIN = NUMBER OF SPECIMENS WITH ALTEP-ATIONS/NUMBER OF SPECIMENS EXAMINED PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPOSSOR'S STUDY NUMBER: T-6316. TABLE 21 (PAGE 14): FETAL ALTERATIONS - INDIVIDUAL DATA --------- -------------------------------------------------------------------------------------------------------- DOSAGE GROUP V 20 MG/KG/DAY --------- -------------------------------------------------------------------------------------------------------- SPECIMENS GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION SKELETAL WITH ANY RAT NUMBER ALTERATIONS N (t) NIN DESCRIPTION NIN DESCRIPTION NIN DESCRIP ----------------------------------------------------------------------------------------------------------------- 12909 (CONT) FETUS 7 RIBS: W 12th, 1 INCOMPL (HYPOPL 9th - I 12th FETUS I RIBS: W Ilth, 1 ioth FETUS I RIBS: W ilth, I 12910 12911 12912 NOT PREGNANT 0( 0.0) 1( 7.7) 0/13 0/13 0/ 6 0/ 6 0/ 7 1/ 7 FETUS CERVIC CERVIC 7TH CE left 12913 o( o.o) 0/12 0/ 6 0/ 6 12914 0( 0.0) 0/15 0/ 7 0/ 8 12915 0( o.o) 0/14 0/ 7 0/ 7 12916 0( 0.0) 0/16 0/ 8 0/ a --------------------------------------------------------------------------------------------------------------- NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN PATS (SPONSOR'S STUDY NUMBER: T-6316. TABLE @l (PAGE 15): FETAL ALTERATIONS - INDIVIDUAL DATA ----------------------------------------------------------------------------------------------------------------- 20 MG/KG/DAY D-O-SA-G-E---G-RO-U-P--V----------------------------------------------------------------------------------------------------- SPECIMENS GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION SKELETAL E WITH ANY RAT NUMBER ALTERATIONS N(%) NIN DESCRIPTION NIN DESCRIPTION NIN DESCRIP ----------------------------------------------------------------------------------------------------------------- 12917 0( 0.0) 0/14 0/ 7 0/ 7 12918 12919 o( o.o) 2( 14.3) 0/15 0/14 0/ 7 0/ 7 0/ 8 2/ 7 FETUS 3 RIBS: W 4th - 1 12920 1( 6.2) 0/16 0/ 8 FETUS 9 RIBS: W 4th - 1 FETUS 1 CERVICA CERVICP 7TH CE left 12921 12922 12923 0( 0.0) o( o.o) 1( 7.1) 0/14 0/12 0/14 0/ 7 0/ 6 0/ 7 0/ 7 0/ 6 1/ 7 FETUS CERVIC CERVIC 7TH CE bilate 12924 0( 0.0) 0/15 0/ 7 0/ 8 0/ 8 0/ 8 1-2-9-25--------0-(---0-.0-)------0-/-1-6------ -------------------------------------------------------------------------- NIN = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBEROF SPECIMENS EXAMINED I APPENDIX C PROTOCOL AND AMENDMENTS 418-011:PAGE C-1 lie...-*14ZL14EDICA Argus Research Laboratories. Inc. 905 Sheehy Drive, Building A Homham, PA 190" Telephone: (216) 443-8710 Tolefax* (215) 443-8587 PROTOCOL 418-011 SP6NSORIS STUDY NUMBER: T-6316.7 STUDY TITLE: PURPOSE: TESTING FACILITY: STUDY DIRECTOR: SPONSOR: STUDY MONITOR: ALTERNATE STUDY MONITOR: Oral(Gavage)DevelopmentalToxicitSytudyof N-ETFOSE inRats The purpose ofthisstudyistodetectadverseeffectsof N-ETFOSE on Crl:CDOBR VAF/PlusO presumed pregnant femaleratsand developmentoftheembryo and fetus consequent toexposure ofthedam from implantatiotno closureofthe hard palate.ThisstudyevaluatesICH Harmonised TripartiGtueidelinestagesC and D ofthe reproductivperocess. Argus Research LaboratoriesI,nc. 905 Sheehy Drive,BuildinAg Horsham, Pennsylvania19044-1297 Telephone: (215)443-8710 Telefax: (215)443-8587 Raymond G. York,Ph.D.,DABT AssociateDirectoorfResearch 3M ToxicologyServices 3M CenterB,uildin2g20-2E-02 St.Paul,Minnesota 55144-1000 MarvinT. Case, D.V.M.,Ph.D. Telephone: (651)733-5180 Telefax: (651)733-1773 Andrew M. Seacat,Ph.D. Telephone: (651)575-3161 Telefax: (651)733-1773 418-011:PAGE C-2 Protocol418-011 Page 2 REGULATORY CITATIONS. U.S.Food and Drug Administratio(n1994).internationCaolnferenceon HarmonisationG;uidelineon detectionoftoxicityoreproductiofnormedicinalproducts. FederalRegisterS,eptember 22, 1994,Vol.59,No. 183. U.S.Food and Drug AdministrationG.ood LaboratoryPracticeRegulabons;FinalRule. 21 CFR Part58. Japanese MinistroyfHealthand Welfare(1997).Good LaboratoryPracticeStandard forSafetystudieson Drugs, MHW OrdinanceNumber 21, March 26,1997. European Economic Community (1989).Councildecisionon 28 July1989 on the acceptanceby theEuropean Economic Community ofan OECD docisiorvrecommendationon compliancewithprincipleosfgood laboratorpyractice.OfficiaJlournalof theEuropean Communities:Legislation3.2(No.L 315;28 October):1-17. REGULAT IRY COMPLIANC : Thisstudywillbe conductedincompliancewiththeGood LaboratoryPractice(GLP) regulationscitedabove. Allchanges or revisionsof thisprotocolshallbe documented, signed by the Study Directorand the Sponsor, dated and maintained withthe protocol. The QualityAssurance Unit (QAU) willauditthe protocol,the raw data and the report, and willinspect criticaplhases of the study inaccordance withthe Standard Operating Procedures ofArgus Research Laboratories,Inc. The finalreportwillinclude a statement signed by the Study Directorthatthe report accuratelyreflectsthe raw data obtained duringthe performance ofthe study and that allapplicableGLP regulationswere followed inthe conduct of the study. Should significandteviationsfrom GLP regulationsoccur,each willbe described indetail, togetherwith how the deviation might affectthe qualityor integritoyf the study. SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDU See ATTACHMENT 1 tothe protocol. 418-011:PAGE C-3 Protocol418-011 Page 3 TEST ARTICLE AND VEHICLE: ldenfification TestArticle: Name: PhysicalDescription: Lot/BatchNumber SpecificGravity: Purity: ExpirationDate: N-ETFOSE. Waxy solid. FM-3929 (30035,30037, 30039). -1.7. 99.1%. May,2000. Informatioonn theidentityc,omposition,strengthand purityofthetestarticlieson file withthe Sponsor. Vehicle: 2% TweenOD 80 inReverse Osmosis Membrane Processed DeionizedWater (R.O. DeionizedWater).Supplierand lotidentificatioofnTweendD 80 willbe documented in the raw data. NeithertheSponsor nor the Study Directorisaware ofany potentiaclontaminantslikely to be presentinthe vehiclethatwould interferweiththe resultsofthisstudy.Therefore, no analysesotherthan those mentioned inthisprotocolwillbe conducted. SafqW Precautions: Gloves,mask, appropriateeye protectionand a uniformaabcoatareto be worn during formulatiopnreparationand administrationT.he MaterialSafetyData Sheet (MSDS) is attachedtotheprotocol(seeATTACHMENT 2). Stomge: Bulk Test Article: VehicleComponents: Prepared Vehicle: Prepared Formulations: Room Temperature. Room Temperature. Room Temperature. Refrigerate(dsamplesto be frozen). Alltestarticlsehipments totheTestingFacilitsyhouldbe addressed totheattentioonf JulianGulbinskiM,anager ofFormulations,atthe previouslycitedaddress and telephone number. Shipments shouldincludeinformationconcerningstorageconditionsand shipping cartonsshouldbe labeledappropriatelyT.he recipiensthouldbe notifieidnadvance of shipment. 418-011:PAGE C-4 Protocol418-011 Page 4 FORMULATIO-N: Froguengy of PrepArat-lQ-n-: Formulations suspensions willbe prepared weekly at the Testing Facility. Detailedpreparation procedures are attached to thisprotocol(ATTACHMENT 3). AdoustmenLtor PuriW: The testarticlewillbe considered 100% pure forthe purpose of dosage calculations. Testing F iciii Reserve Samples: The Testing Facilitwyillreservea sample (I g) of each lotof bulktestarficluesed during the course ofthisstudy. The Testing Facilitwyillreservea sample (5 ml) of each lotofvehicle components used during the course ofthe study. Samples willbe stored under the previouslycitedconditions. ANALYSE : Samples additionalto those described below may be taken ifdeemed necessary during the course of the study. Bulk Test ArticleggnWliLnA: No analyses of the bulk testarticlweillbe conducted duringthe course of thisstudy. Informationon the stabilitoyfthe bulk testarticleison filewith the Sponsor. Anal ises :)fP 'Rared Formulation At the request ofthe Sponsor, no analyses of prepared testarticlfeormulationswillbe conducted during the course ofthe study. Homogeneity and stabilitiynformationison filewiththe Sponsor. However, records willbe maintained to document how the test articlfeormulationswere prepared. Concentration ofTest ArticleFormulations: Concentratioofnthepreparefdormulatiownislbleve6fieddurintghecourseofthis study. Duplicatesamples (2 mL each) willbe taken from the firsatnd lastpreparation on the day prepared. One sample of each set willbe shipped foranalysis;the remaining samples willbe retainedat the Testing Facilitays backup samples. Backup samples willbe stored under the previouslycitedconditionsand discarded atthe Testing Facilityupon request ofthe Sponsor. 41 B-01 1:PAGE C-5 protocol418-011 Page 5 S h iP Rin-q-Ln-s-t-crtg'-Ons: Samples to be analyzed willbe shipped (frozenon dry ice)to: KiisJ. Hansen, Ph.D. 3M Environmental Technology and Safety Services 935 Bush Avenue Building2-3E-09 St.Paul, Minnesota 55133-3331 Telephone: (612)778-6018 Telefax: (612)778-6176 The recipientwillbe notifiedin advance of sample shipment. DISPO ITI-ON: Prepared formulationswillbe discarded at the Testing FacilityA.llremaining bulktest articlweillbe returnedto the Study Monitor atthe previouslycitedaddress. TEST SYSTEM: Species/Strain and Reason for Selection: The Crl:CDOBR VAF/Plusg (Sprague-Dawley) ratwas selected as the Test System because: 1) itisone mammalian species accepted and widely used throughout industryfornonclinicalstudiesof developmental toxicit(yembryo-fetal toxicity/teratogenici2t)y)t;hisstrainhas been demonstrated to be sensitiveto developmental toxins;3) historicadlata and experience existatthe Testing Facility('-a3n)d;4) the testarticleispharmacologicallyactiveinthisspecies and strain. Numbe Initiaplopulation acclimated: Population selected forstudy: Population assigned to satellitsetudy: Body Weightgnd Age: 190 virginfemale rats. 125 mated female rats(25 per dosage group). 19 mated female rats(fiveper GroupsIIandV and three per Groups 1,111and IV) assigned to toxicokinetiecvaluation. Female rats willbe ordered to have body weights of 200 g to 225 g each at receipt,at which time they willbe expected to be at least60 days of age. Actual body weights will be recorded the day afterreceiptand willbe documented inthe raw data. The weight range willbe includedinthe finalreport. 418-011:PAGE C-6 Protocol418-011 Page 6 S_ex: Female mts willbe giventhetestarticleM.ale mts ofthesame sourceand straiwnill be used onlyas breedersand are notconsideredpartoftheTestSystem. soume: CharlesRiverLaboratoriesI,nc. The ratswillbe shipped infilterecdartonsby airfreighatnd/ortruckfrom CharlesRiver LaboratoriesI,nc.t,othe TestingFacility. Id o nt1f-ci-a-it-0a-: Ratsare permanentlyidentifieudsingMoneW self-piercienagrtags(Gey Band and Tag Co.,Inc.,No. MSPT 20101). Male ratsaregivenuniquepermanentidentification numbers upon assignmenttotheTestingFac7i]itbyrseedermale ratpopulation. Female ratsare assignedtemporary numbers atreceiptand givenuniquepermanent identificatniuomnbers when assignedtothestudyon thebasisofday 0 ofpresumed gestatiobnody weights. A NI-MA L HU-S B-DA_NRY: All cage sizes and housing conditions are in compliance with the Guide forthe Care and Use of Laboratory Animals(41 Hg si"n : The ratswillbe individualhloyused instainlessteelw,ire-bottomedcages except duringthecohabitatiopneriod.Duringcohabitatione,ach pairofratswillbe housed in themale ratscage. No nestingmaterialwsillbe suppliedbecause thefemaleratswill be sacrificebdeforeparturitiiosnexpected. Room A7ir,_Te@em@tu ra@n dH@urWic@r:l The animalroom isindependentlysuppliedwithatleasttenchanges per hour of100% freshairthathas been passed through99.97% HEPA filte(rAsiroCleanO room). Room temperaturewillbe maintainedat64OF (180C)to79-F (26-C)and monitored constantlyR.oom humiditywillalsobe monitoredconstantlaynd maintainedat30% to 70%. Light An automaticallcyontrolle1d2-hour light1:2-hourdarkfluorescenltighctyclewillbe maintained.Each darkperiodwillbeginat1900 hoursEST. 418-011:PAGE C-7 Protocol418-011 Page 7 9:1 Ratswillbe givenCertifieRdodent DietO#5002 (PMI Nutdbon intemationala)vailable ad libitufmrom individuafleeders. Water Waterwillbe availablead libitufmrom individuablottleasttachedtothecages orfrom an automaticwateringaccess system. AJIwater willbe from a localsource and passed througha reverseosmosis membrane beforeuse. Chlorinewillbe added tothe processedwateras a bacteriostaptr;ocessed water isexpectedtocontainno more than1.2ppm chlorineatthetimeofanalysis.Water isanalyzedmonthlyforpossible bacteriaclontaminationand twiceannuallyforpossiblechemicalcontamination. Contaminants: Neither the Sponsor nor the Study Director is aware of any potentialcontaminants likely to be presentinthe certifieddietorinthe drinkingwateratlevelsthatwould interfere withthe resultsofthisstudy. Therefore,no analyses otherthan those routinely performed by the feed supplieror those mentioned inthisprotocolwillbe conducted. RANDOMIZATION AND COHABITATIO : Upon ardval,male and female ratswillbe assigned to individuahlousing on the basis of computefgenerated random units.Afteracclimation,virginfemale ratswillbe cohabited with breeder male rats,one male ratper female rat.The cohabitationperiod willconsistof a maximum of fivedays. Female ratswith spermatozoa observed ina smear ofthe vaginal contents and/or a copulatoryplug observed in situwillbe considered to be at day 0 of presumed gestationand assigned to individualhousing. Heafthy mated female ratswillbe assigned to dosage groups based on computergenerated (weight-ordered)randomization procedures. ADMINISTRATIO . Route and Reason forChoice: The oral(gavage) route was selectedforuse because: 1)incomparison with the dietaryroute,the exact dosage can be accuratelyadministered;and 2) itisone of the proposed routesfor clinicaulse. Method and -Froguenc : Female ratswillbe given the testarticloence dailyon days 6 through 17 of presumed gestation,the period oforganogenesis. Dosages willbe adjustedforthe most recently recorded body weight and given atapproximately the same time each day. 418-011:PAGE C-8 Protocol 418@-011 Page 8 Rat! nale fforDosacle Selection: Dosages were selectedon the basis of a dosage-range study (Argus Research Laboratories,Inc.,Protocol418-011 P) thattested 0. 1,5, 10,25 and 35 mg/kg/day. In thatstudy,body weight gain was decreased at 10 mg/kg/day and higher dosages, and feed consumption values were reduced at alldosages tested. Dosag- ns a n d V o 1-u-m-9-8: Dmne Group V Nuff"r Dma" ofRaft I imeXda,V, 25+r __IyAhicis 25+5' 1 2+5@30 25+30 25 + 5* ConcentmLWbnan 0 0.-2 1 120 4 Dmge Volum =U.*A. 5 5 5 5 ArousBatch Nuffow - B-41"I I-A(Day.month.Ye B-418.01I-WDav.Morith.YeaO 8418-01 I-B(Day.Month.Tew B-41841 I-C(Pay.Month.Year) D Do Month.Year) The testarticlwelibe considered100% pureforthe purposeofdosagecalculations. 8, Rat& assignedtothe solonitegroup forblood colkmuon. TESTS. A IALY SAND MEASUREMENTS: MliabiriW: AllPeriods: Clin Acclimation Period: Predosage Period: Dosage Period: At leasttwice daily. r General eamnce: Weekly. Day 0 of presumed gestation. Twice daily.Priorto dosage administrationand once approximately one hour postdosage. Postdosage Period: Once daily. Clinicalobservations may be recorded more frequentlythan citedabove, ifdeemed appropriate by the Study Directorand/or Study Monitor. Body3yqigLhts: Acclimation Period: Predosage Period: Weekly. Day 0 and 4 of presumed gestation. 418-011:PAGE C-9 Protowl 418-011 Page 9 Dosage Period: Daily. Postdosage Period: Daily. Food Consumption Valu0s (recordedand tabulated): Predosage Period: Day 0 and 4 ofpresumed gestation. Dosage Period: Days 6,8, 10,12,14 and 16 ofpresumed gestation. Postdosage Period: Days 18 and 20 ofpresumed gestation. Feed consumptionvaluesmay be recordedmore frequentliyfitisnecessaryto replenishthefeed.These intervalwsillnotbe tabulated. Mating Pe formance: Matingwillbe evaluateddailyduringthecohabitatiopneriodand confirmedby observationofspermatozoaina smear ofthevaginalcontentsand/ora copulatorpylug observed insitu. Caesarean-SectioningObservations: Rats willbe Caesarean-sectionedon day 20 ofpresumed gestation.The fetuseswill be removed fromthe uterusand placedinindividuaclontainersT.he ratsmfilble examined fornumber and distributioofn.- Corpora Lutea. ImplantatioSnites. [Placentaeappearance(sizec,olororshape ifabnormal)willbe notedintheraw data]. Liveand Dead Fetuses. (A livefetusisdefinedas one thatrespondstostimulia;dead fetusisdefinedas a term fetusthatdoes not respond tostimulaind thatisnotmarkedlyautolyzed; dead fetusesdemonstratingmarked toextremeautolysiasreconsideredto be late resorptions.) Earlyand LateResorptions. (A conceptusisdefinedas a lateresorptioinfitisgrosslyevidentthat organogenesishas occurred;ifthisisnotthecase,the conceptusisdefinedas an earlyresorptipn.) 418-011:PAGE C-10 Pmtocol 418-011 Page 10 Fetal Observations: Gross Eggmal Alterationsand Sex: Fetuses willbe examined forsex and forgross externalalterations.Late resorptions and dead fetuses also willbe examined forsex and forgross externalalterationtsothe extentpossiblebut such observationswillnot be included ineitherdata summarization or statisticanlalyses. Body Weights and Identification The body weight ofeach fetus willbe recorded. Only body weights of livefetuseswill be used to determine liftefretalbody weight averages. Fetuses willbe tagged with identificatinoontingstudy number, littenrumber, uterinedistributioannd fixative. SoftTissue Examination Approximately one-halfof the fetusesineach littewrillbe examined forsofttissue alterationsby using an adaptation ofWilson's sectioningtechnique(r".The fetuseswill be initialfliyxedinBouin's solution;sections willbe retainedinalcohol. SkeletalExamination: The remaining fetuses (approximatelyone-half ofthe fetusesineach lifterw)illbe examined forskeletalalterationsafterstainingwith alizarinred S(G).The fetuseswillbe initialfliyxedinalcohol;skeletalpreparationswillbe retainedinglycerinwiththymol added as a preservative. Representative photographs offetalgross, softtissueand skeletalalterationswillbe taken. METHOD OF SACRIFICE: Rats willbe sacrificedby carbon dioxideasphyxiation. Livefetuses willbe sacrificedby an intraperitoneailnjectionof euthanasia solution(Beuthanasiao-D Special, manufactured by Schering-Plough Animal Health). NECROPSY: Gross lesionswillbe retainedin neutralbuffered 10% formalinforpossiblefuture evaluation(a tableof random unitswillbe used to selectone controlgroup ratfrom which alltissuesexamined at necropsy willbe retained,inorder to provide control tissuesforany possiblehistopathologicaelvaluationsof gross lesions).Unless specificallcyitedbelow, allother tissueswillbe discarded. 418-011:PAGE C-1 1 ProtDcol41 B-01 1 Page II SatellifRats Assigned toToxicokinetiScample Col-le-c-t-i-on: On day 18 ofpresumed gestatio(ntheday followintghelastdosage),ratsassignedto thetoxicokineteivcaluationwillbe sacrificeadnd thefollowinsgamples collected. Bloodsamples (approximatel4y mL perrat)willbe collectefdromtheinferiovrena cava intoserum separatortubesand centrifugedT.he resultinsgerum (approximatel2ymL) willbe immediatelyfrozenon dryiceand maintainedfrozen(-700C)untislhipmentto theSponsor foranalysis.The livewrillbe excised,weighed,and a sample section (laterallobe)willbe frozenand retainedat-700C untislhipmenttotheSponsor for analysis. Rats willbe Caesarean-sectionedand fetuseswillbe examined grosslytothe extent possibleas describedabove forratsassignedtothe main study.Fetusesand placentaewillbe pooledperlittearnd retainedfrozen(-70*C)untislhipmenttothe Sponsor foranalysis Aftercompletionofsample collectiosne,rum,livesrection(laterallobe)f,etaland placentaslamples willbe shipped(frozenon dryice)toKrisJ.Hansen, Ph.D.,atthe previouslcyitedaddressforanalysis.Both therecipienatnd the StudyMonitorwillbe notifieidnadvance ofsample shipment. Scheduled Sacrifice: On day 20 ofpresumed gestationf,emaleratswillbe Caesarean-secfioneda,nd a grossnecropsyofthethoracica,bdominaland pelvicviscerawillbe performed.Uteriof apparentlynonpregnantratswillbe stainedwith10% ammonium sulfidteoconfirmthe absence ofimplantatiosnitesm. Rats Found Dead-or Moribund: Rats that die or are sacrificed because of moribund condition, abortion or premature deliverwyillbe examined forthecause ofdeathormoribund conditioonn theday the observabon ismade. The ratswillbe examined forgrosslesions.Pregnancystatus and uterinecontentsoffemaleratswillbe recorded.Abortedfetusesand/ordelivered pups willbe examined tothe extentpossibleu,singthe same methods describedfor fetuses.Uteriofapparentlynonpregnantratswillbe stainedwith10% ammonium sulfidteoconfirmthe absence ofimplantatiosnitesm. 418-011:PAGE C-1 2 Protocol418-011 Page 12 PROPOSED STATISTIC kL METHODS(8-14): Averages and percentages willbe calculated.Uittevralueswillbe used where appropriate.Additionalproceduresand/oranalysesmay be performed,ifappropriate. jype ofTe 1. Parametric TeStl-d A. Bartietts li.Nonparamet A. Kruskal-WallisTest (-e.75%ties) Significantat p:50.05 Not Significant F- Significanattp:r.0.05 Not Significant Nonparametric Analysis of Variance I Dunn's Test Significantat p:!@0.05 1 Dur tt'sTest Not Significant B. Fisher'sExact Test (>75% ties) 111.Test for Progortion Data Variance Test forHomogeneity of the Binomial Distribution a. Statisticalsliygnificantprobabilitieasre reported as eitherp.-@0.05or p:!;0.01. b. Proportiondata are not includedinthiscategory. c. Used only to analyze data with homogeneity ofvariance. d. Test forhomogeneity of variance. 418-011:PAGE C-13 Protocol418-011 Page 13 DATA ACQUISITION, VERIFICATION AN STORAGE: Datawillbe hand- and/orcomputer-recorded.Recordswillbe reviewedby theStudy Directoarnd/orappropriatemanagement personnelwithin21 days aftergeneration.All originarlecordswillbe storedinthearchivesofthe TestingFacilityA.lloriginadlatawill be bound and indexed.A copy ofallraw datawillbe suppliedtotheSponsor upon request.Preservedtissueswillbe storedattheTestingFacilitaytno chargeforone yearaftermailingofthe draftfinalreporta,fterwhichtimetheSponsor willbe contacted to determinethe dispositioonfthesematerials. RECORDS TO BE MAINTAINED Protocoalnd Amendments. TestArticleV,ehicleand/orReagent Receipt,Preparatioannd Use. AnimalAcquisition. RandomizationSchedules. Mabng History. Treatment(ipfrescribedby StaffVeterinarian). GeneralComments. ClinicaOlbservationsand/orGeneralAppearance. Bloodand TissueSample CollectionP,rocessingand Shipment. Body Weights. Feed Consumption Values. Caesarean-Sectioninagnd FetalObservations. Gross NecropsyObservations. Organ Weights. Photographs(ifrequired). Study Maintenance(room and environmentalrecords). Feed and Water Analyses. Packingand/orShipment Lists. KEY PERS @NNEL: F-xecutivDeirectoorfResearch: MildredS. Chdstian,Ph.D.,Fellow,ATS DirectoorfResearch: Alan M. Hoberman, Ph.D.,DABT AssociateDirectoorf Research and Study DirectorRaymond G. York,Ph.D.,DABT DirectoorfLaboratoryOperations:John F.BarnettB,.S. Manager ofStudyCoordination:ValerieA. Sharper,M.S. Manager ofAnimal Operationsand Member, InstitutioAnnailmal Care and Use Committee: Dena C. Lebo,V.M.D. Manager ofRegulatoryCompliance: KathleenA. Moran,M.S. ConsultantV,eterinaryPathology:W. Ray Brown, D.V.M.,Ph.D.,ACVP 418-011:PAGE C-14 Protocol418-011 Page 14 FINAL REPORT: A comprehensivedrafftinarleportwillbe preparedon completionofthestudyand will be finalizefdollowincgonsultatiowniththe Sponsor.The reportwillincludethe Wlowing: Summary and Conclusion. ExperimentalDesign and Method. EvaluationofTest Results. Appendices: Figures,Summary and IndividuaTlablesSummarizingtheAbove Data,Protocoland AssociatedAmendments and DeviationsS,tudyDirectoes GLP ComplianceStatement,ReportsofSupportingData (iafppropriatea)nd QAU Statement. INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMEN The proceduresdescribedinthisprotocolhave been reviewedby theTestingFacility's InstitutioAnnailmalCare and Use Committee. Allproceduresdescribedinthisprotocol thatinvolvestudyanimalswillbe conductedina manner toavoidorminimize discomfortd,istresosrpaintothe animals. The Sponsoes signaturebelow documents thefactthatinformatiocnoncerningthe necessityforconductingthisstudyand thefactthatthisisnotan unnecessarily duplicativsetudymay be obtainedfrom the Sponsor. No alternati(vienvitro) procedureswere availablfeormeetingthe statedpurposesofthestudy. REFERENCES: 1 . Christian, M.S. and Voytek, P.E. (1982). In Vivo Reproductive and Mutagenicity Tests. Environmental Protection Agency, Washington, D.C. National Technical InformationService,U.S. Department ofCommerce, SpringfieldV,A 22161. 2. ChristianM,.S.(1984).Reproductivetoxicitaynd teratologeyvaluationosf naltrexone(Proceedingsof NaftrexoneSymposium, New York Academy of Sciences, November 7, 1983). J.Clin.Psychiat.45(9):7-10. Lang, P.L. (1988). Embryo and Fetal Developmental Toxicity(Teratology) 3. Control Data in the Charles River Cri.CDOBR Rat Charles River Laboratories, Inc.,Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories,Inc.) 4. Institutoef Laboratory Animal Resources (1996). Guide forthe Care and Use of Labor-atoryAnimals. National Academy Press, Washington, D.C. 418-011:PAGE C-1 5 Protocol418-011 Page 15 5. Wilson, J.G. (1965). Methods foradministeringagents and detecting malformations inexperimental animals. Terstology.'Principlesand Techniques (VvllsonJ,.G. and Warkany, J.,eds.),Universityof Chicago Press, pp. 262-277. Staples,R.E. and Schnell,V.L. (1964). Refinement inrapid clearingtechnique in 6. the KOH-alizarin red S method forfetalbone. Stain Technol. 39:61-63. 7. Salewski,E. (1964). Fgrbemethode zum makroskopischen Nachweis von Implantationsstelleanm Uterus der Rafte. Arch. Pathol.Exp. Pharmakol. 247:367. Snedecor, G.W. and Cochran, W.G. (1967). Variance testforhomogeneity of B. the binomial distributionS.tatisticaMlethods, 6th Edition,Iowa State University Press, Ames, pp. 240-241. 9. Sokal, R.R. and Rohif,F.J.(1969). BarUett'stestof homogeneity of variances. Biometry,W.H. Freeman and Co., San Francisco,pp. 370-371. 10. Snedecor, G.W. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition,Iowa State University Press, Ames, pp. 258-275. Dunneft, C.W. (1955). A multiplecomparison procedure forcomparing several 11. treatments with a control.J.Amer. Stat.Assoc. 50:1096-1129. 12. Sokal, R.R. and Rohif, F.J.(1969). Kruskal-WallisTest. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389. 13. Dunn, O.J. (1964). Multiplecomparisons using rank sums. Technometdcs 6(3):241-252. 14. Siegel, S. (1956). Nonparametric Statisticsfor the Behavioral Sciences, McGraw-Hill, New York, pp. 96-104. PROTOCOL OKPPROVAL: FOR THE TESTING FACILITY Alan M. Hoberman, Ph.D.,DABT Directorof Research nndda@GG. York, h.D, DDAABBTT AAssssoc4ioacaiDDai--iryreocettoco;@r0 s@eeaarrcchh Study Director Dena C. Lebo, V.M.D. Member, InstitutionaAlnimal Care and Use Committee FORTHESPONSOR 1 -1 @. -- if Marvin T. Case, D.V.M., Ph.D. Study Monitor 418-011:PAGE C-16 Protocol418-011 Page 16 Date Date Date Date 418-011:PAGE C-17 I ATTACHMENTI SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE ATTACHMENT I 418-011:PAGE C-1 8 Pmtocol 41 B-011 Page 1 of2 STUDY SCHEMATIC DEVELOPMENTAL TO)GCITY STUDY Cohabitation StartOf Dosage Female Rats Day 7 of Presumed Gestation End of Dosage Caesarean-- Sectioningb Day 17 of Presumed Gestation Day 20 of Presumed Gestation Dosage Period a = For additionaldetailssee "Tests,Analyses and Measurements" section ofthe protocol b = Fetal evaluations (all- external,112 per litte-r softtissueor skeletaq A-rrACHMENT 1 41 B-01 1:PAGE C-1 9 ProtDcol418-011 Page 2 of2 SCHEDULEO 11 AUG 98 18 AUG 98 PM -23 AUG 98 AM 19 AUG 98 23 AUG 98 25 AUG 98 -09 SEP 98 08 SEP 98 - 12 SEP 98 02 DEC 98 ArrivaDlate -AcclimationBegins. CohabitafionPeriod. FirstPossibleDay 0 ofPresumed Gestation. LastPossibleDay 0 ofPresumed Gestabon Dosage Period(Days 6 through17 ofpresumed gestation). Caesarean-SectioningPeriod (Day 20 of presumed gestation). DraftFinalReport. a. The studyinitiatidoante isthe datetheStudy Directosrignsthe protocol. 418-011:PAGE C-20 I ATTACHMENT 2 MATERIAL SAFETY DATA SHEET 418-011:PAGE C-21 MA7ERIAL SAFETY DA:-,ASHEET 3M N - E4 P05E- 3M Center St. Paul, Minnesota 55144-1000 1-800-364-3577or (612)737-6501(24 hours) Copyright,igge, MinnesotaMining and ManufacturingCompany. All rightsreserved. Copying and/ordownloadingof this informationfor the purposeof properlyutilizing3M products is allowedprovidedthat: 1) the informationis copied in full with no changesunless prior agreementis obtainedfrom 3M, and 2) neitherthe copy nor the originalis resoldor otherwise distributedwith the intentionof earninga profitthereon. DIVISION: 3M CHEMICALS TRADE NAME: FC-10 FLUORAD Brand Fluorochomical Alcohol ID NUMBER/U.P.C.: 96-0211-1113-7 00-51135-09495-2 98-0211-1183-0 98-0211-1575-7 00-51135-02145-3 98-0211-6620-6 ZF-0002-0572-2 ISSUED: January 29, 1998 SUPERSEDES: November 05, 1997 DOCUMENT: 10-3778-7 00-51135-09542-3 00-51135-10439-2 -- ----- - -------- ------ ----------- --- ---- ----- ------------------- -- ------ ----- 1. INGREDIENT C.A.S. NO. PERCENT ----------------------------------------------------------------------- PERFLUOROOCTANESULFONAMIDO ALCOHOL ...... 1691-99-2 80.0 - 90.0 PERFLUDROHEXANESULFONAMIDO ALCOHOL ...... 34455-03-3 3.0 - 7.0 PERFLUOROHEPTANESULFONAMIDO ALCOHOL..... 68555-73-7 2.0 - 6.0 PERFLUOROBUTANESULFONAMIDO ALCOHOL ...... 34449-89-3 2.0 . 6.0 PERFLUOROPENTANESULFONAMIDO ALCOHOL ..... 68555-72-6 1.0 - 3.0 -----------------------------------------------------------------------2. PHYSICAL DATA ----------------------------------------------------------------------- BOILING POINT:.............c.a...1.18 C 0 1 mm Hg VAPOR PRESSURE: .............c .1.0.mmHg Calc @ 20 C VAPOR DENSITY: .............>..1..0.Air=l Calc @ 20 C. EVAPORATION RATE: .............1..0 BuOAc=l SOLUBILITY IN WATER: .........<n.e.glig. SPECIFIC GRAVITY: ...........c.a...1.7 Water=l (ofmelt) PERCENT VOLATILE: ...........0..96. pH: .....................N./A VISCOSITY: ...........*.*.****N/D MELTING POINT: ..............N/.D... ------------------------------------------------------------------- 418-01 1:PAGE C-22 MSDS: Fr.-icFLWRAD Brand F]LjjorochosicalAlcohol January 29, 1998 PAGE 2 ------------------------------------------------------------------------- 2. PHYSICAL DATA (continued) ------------------------------------------------------------------------- APPEARANCE AND ODOR: Amber waxy solid ------------------------------------------------------------------------3. FIRE AND EXPLOSION HAZARD DATA ------------------------------------------------------------------------- FLASH POINT: ...............>..1.48. C Setaflash FLAMMABLE LIMITS - LEL: .......N./A FLAMMABLE LIMITS - UEL: .......N.IA AUTOIGNITION TEMPERATURE: ......NIA EXTINGUISHINMGEDIA: Water, Carbon dioxide, Dry chemical, Foam SPECIAL FIRE FIGHTING PROCEDURES: Wear full protectiveclothing,includinghelmet, self-contained, positive pressure or pressure demand breathing apparatus, bunker coat and pants, bands around arms waist and legs, face mask, and protective covering for expo;ed areas of the head. UNUSUAL FIRE AND EXPLOSION HAZARDS: See Hazardous Decomposition section for products of combustion. ---------------------------------------------------------------------------4. REACTIVITY DATA ------------------------------------------------------------------------- STABILITY: Stable INCOMPATIBILITY - MATERIALS/CONDITIONS TO AVOID: Not applicable. HAZARDOUS POLYMERIZATION: Hazardous polymerization will not occur. HAZARDOUS DECOMPOSITION PRODUCTS: Carbon Monoxide and Carbon Dioxide, Oxides of Nitrogen, Oxides of Sulfur, Hydrogen Fluoride,Toxic Vapors, Gases or Particulates. -------------------------------------------------------------------------5. ENVIRONMENTAL INFORMATION -------------------------------------------------------------------------- SPILL RESPONSE: Refer to other sectionsof this MSDS for informationregarding physical and health hazards,respiratoryprotection,ventilation,and personal protectiveequipment. Collect spilledmaterial. Clean up residue. Place in a U.S. DOT-approved container. --------------------------------------------------- 418-011:PAGE C-23 MSDS: FC-lo FLUORAD Brand Flu1 orochomical Alcohol ,january29, 1998 PAGE 3 ------------------------------------------------------------------------- 5. EWIROWENTAL INFORMATION (continued) ---------------------------------------------------------------- REC"ENDED DISPOSAL: Incineratein a permitted hazardous waste incineratorin the presence of a combustiblematerial. Combustion productswill include HF. Disposeof waste product in a facility permittedto accept chemical waste. ENVIRONMENTAL DATA: Laboratorytests showed no biodegradation. 96-Hr. LD50 Fathead Minnow (Pimephalespromelas) - No mortality at water saturation. No statisticallysignificanteffect on % hatch,% survival,weight, and length in 30 day Fathead Minnow egg fry study. Lab tests showed 200 fold bicconcentrationof FC-10 into muscle filletsof channel catfish. REWLATORY INFORMATION: Volatile organic Compounds: N/A. VOC Less M20 & Exempt Solvents: N/A. This product complies with the chemical registrationrequirementsof TSCA, EINECS, CDSL, AICS and Korea. EPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: Yes ---------------------------------------------------------------------------6. SUGGESTED FIRST AID - ----- ---------- -- --- ------ ---- ------ -------------------- -- --------- --------- EYE CONTACT: Immediatelyflush eyes with large amounts of water. Get immediate medical attention. SKIN CONTACT: Immediatelywash skin with soap and large amounts of water. Remove contaminatedclothing. If signs/symptomsoccur, call a physician. Wash contaminatedclothing before reuse and dispose of contaminated shoes. INHALATION: If signslsymptomsoccur, remove person to fresh air. If signs/symptomscontinue, call a physician. I F SWALLOWED: Call a physician IMMEDIATELY. If swallowed, induce vomiting immediatelyas directed by medical personnel.Never give anything by mouth to an unconscious person. - ----- - ---- ---- ------- -- ---- --- ---- --- -------------------- ------ ------- ------ 418-011:PAGE C-24 MSOS: FC-10 FLUORAD Brand Fl1uorochanical Alcohol january 29, 1998 PAGE 4 ------------------------------------------------------------------------7. PRECAUTIO W Y INFORMATION -------------------------------------------I---------------------------------- EYE PROTECTION: Avoid eye contact. Wear safety glasseswith side shields. SKIN PROTECTION: Avoid skin contact. Wear appropriategloves when handling this material. A pair of gloves made from the followingmaterial(s)are recommended: butyl rubber. Use one or more of the following personal protectionitems as necessaryto prevent skin contact: coveralls. REC"ENDED VENTILATION: Use with appropriatelocal exhaust ventilation. Providesufficient ventilation to maintain emissions below recommendedexposure limits. If exhaust ventilationis not adequate,use appropriaterespiratory protection. RESPIRATORY PROTECTION: Avoid breathingof airborne material. Select one of the following NIOSH approved respirators based on airborne concentrationof contaminants and in accordance with OSHA regulations: half-mask dust respirator,full-facesuppliedair respirator. PREVENTION OF ACCIDENTAL INGESTION: Do not eat, drink or smoke when using this product. Wash exposed areas thoroughly with soap and water. Wash hands after handling and before eating. RECOMMENDED STORAGE: Store away from heat. Keep container closed when not in use. FIRE AND EXPLOSION AVOIDANCE: Nonflammable. OTHER PRECAUTIONARY INFORMATION: No smoking: Smoking while using this product can result in contaminationof the tobacco and/or smoke and lead to the formation of the hazardousdecomposition products mentionedin section 4 of this MSDS. HMIS HAZARD RATINGS: HEALTH: I FLAMMABILITY: 1 REACTIVITY: 0 PERSONAL PROTECTION: X (See precautions, section 7.) EXPOSURE LIMITS INGREDIENT VALUE UNIT TYPE AUTH SKIN* -------------------------------------------------------------------------- PERFLUOROOCTANESULFONAMIDO ALCOHOL ... o.1 MG/M3. TWA 3M y PERFLUOROHEXANESULFONAMIDO ALCOHOL ... 0.1 MGIM3 TWA 3M y PERFLUOROHEPTANESULFONAMIDO ALCOHOL ........................0...1.. MG/M3 TWA 3M y --------------------------------------------------------- 418-011:PAGE C-25 MSOS: FC-10 FLUORAD Brand Flu1orachemical Alcohol jor.uary 29, 1998 PAGE 5 EXPOSURE LIMITS (continued) VALUE UNIT . TYPE AUTH SKIN* I-N-G-RE-D-IE-N-T------------------------------------------------------------------- PERFLUOROBUTANESULFONAMIDO ALCOHOL ... 0.1 MG/m3 TWA 3m y PR=ARLFCLOUHOORLOPE.NT.A.NE.SU.L.FO.N.AM.ID.O..............0..1... MG/M3 TWA 3m y SKIN NOTATION: Listed substances indicated with 'Y' under SKIN referto the potentialcontributionto the overallexposure by the cutaneousroute including mucous membrane and eye, either by airborne or, more particularly, by direct contactwith the Substance. Vehicles can alter skin absorption. SOURCE OF EXPOSURE LIMIT DATA: ---3-M-:----3M--R-e-co-m-m-e-nd-e-d--Ex-p-o-s-ur-e--G-ui-d-e-l-in-e-s---------------------------------------- --S-.--HE-A-LT-H--H-A-ZA-R-D--DA-T-A-------------------------------------------------------- EYE CONTACT: No adverse health effects are expected from eye contact. SKIN CONTACT: Productis not expectedto be irritatingto the skin. May be absorbedthrough the skin and persist in the body for an extended time. INHALATION: May be absorbed by inhalation and persist in the body for an extended time. IF SWALLOWED: Ingestionis not a likely route of exposureto this product. Illnessmay occur after a single swallowingof relativelylarge quantitiesof this material. MUTAGENICITY: Not mutagenic in in-vitro assays. REPRODUCTIVEIDEVELOPMENTAL TOXINS: Substance was not teratogenic in the rat at doses as high as 30 milligramsper kilogram per day via oral route. OTHER HEALTH HAZARD INFORMATION: This product is not known to contain any substances regulated under California Proposition65. A Product Toxicity Summary Sheet is available. ------------------------------------------------------------------------- 418-011:PAGE C-26 MSDS: FC-10 FLUORAD Brand Flu1orochosical Alcohol january 29, 1998 PAGE 6 -------------------------------------------------------------------------- sr=CTION CHAN-G-E --DA-T-ES----------------------------------------------------------........a.. HEADING SECTION CHANGED SINCE November 0.15,1997 ISSUE -------------------------------------------------------------------------Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately --------------------------------------------------------------------------- The informationin this Material Safety Data Sheet (MSDS)is believed to be correct as of the date issued. 3M MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR COURSE OF PERFORMANCE OR USAGE OF TRADE. User is responsible for determining whether the 3M product is fit for a particularpurposeand suitablefor user's method of use or application. Given the varietyof factorsthat can affect the use and application of a 3M product, some of which are uniquely within the user's knowledgeand control,it is essentialthat the user evaluatethe 3M product to determinewhetherit is fit for a particular purpose and suitable for user's method of use or application. 3M provides information in electronicform as a serviceto its customers. Due to the remote possibility that electronictransfer.may have resulted in errors, omissionsor alterationsin this information,3M makes no representationsas to its completenessor accuracy. In addition, information obtained from a database may not be as current as the irg+nv-mmi-inn in tho mqnr available directlv from 3M. 418-011:PAGE C-27 I ATTACHMENT 3 TEST ARTICLE PREPARATION PROCEDURE 418-011:PAGE C-28 ATTACHMENT 3 TEST ARTICLE AND CONTROL Protocol418-011 Vemion: 418-011 (28JUL 98) Page 1 of 3 ARTICLE PREPARATION PROCEDURE TestArticle: N-ETFOSE Vehicle: 2% Tween(D 80,inR.O.Water A. Purpose:The purpose ofthisprocedureistoprovidea method fbrthepreparation ofdosage suspensions of N-ETFOSE and the controlarticlfeororal administratiotnoratson Argus Study418-011. B. GeneralInformation: I Allsuspensioncontainerswillbe labeledand colorcoded. Each labelWill specifythe protocolnumber, testarticliedentificaboAnr,gus batch number, concentrationd,osage levelp,reparatiodnate,expiratiodnate and storageconditions. 2a. Suspensionswillbe prepared: Daily X Weekly - For__ daysofuse 2b. Vehiclewillbe prepared: Daily X Weekly - For_ daysofuse 3. Suspensionswillbe prepared ata finadlosage volume of 5 mL/kg. 4. Safety: X Gloves,labcoat,goggles orsafetyglassesand faceshield X Dust-MistRespirator Half-FaceRespirator Full-FaceRespirator/PositiPvreessureHood Tyvek Suit/Apron 5. Dosage suspensionsadjustedforFree base and % Purity. Yes X No (Calculatiobnassed on 100%) Free Base Purfty 6. Samplingrequirements:Citedinprotocol. 7. Storage:Citedinprotocol. 418-011:PAGE C-29 ATTACHMENT 3 TEST ARTICLE AND CONTROL ARTICLE Protocol418-011 Version:418-011 (28 JUL 98) Page 2 of3 PREPARATION PROCEDURE NOTE: Test articlweillbe preparedas a seriadlilutiofnromthehighdosage to thelowdosage. Once thefinalvolumes areachieved,stirbarsaretobe added tothe containersm;ixingshouldoccurduringsamplingand/or administration. C. PreparationofVehicle 1 . Add the requiredamount ofR.O. deionu:edwatertoan appropriately labeledcontainer.Heatthewaterto 50 5"C,add therequiredamount of TweenO 80 and mix untiulniform(See TEST ARTICLE CALCULATIONS). D. TestArticlSeuspension Preparation: I. To preparethe4.0-mg/mL, Group V suspension,add the requiredamount oftestarticl(eSee TEST ARTICLE CALCULATIONS) intoan appropdatelysized,labeledcontainerA.dd therequiredamount of vehicleand heat the mixtureto80 5"C forapproximatel3y0 minutes. 2. Once the testarticlheas dissolveds;pinovernightwhilethe solution cools.(Besurethereisa visiblveortext,hiswillachievethedesired emulsion.) 3. To preparethe 2.0-mg/mL,Group IVsuspension,remove the required amount ofstocksuspension(GroupV) (See TEST ARTICLE CALCULATIONS), add the requiredamount ofvehicleand mix. 4. To preparethe 1.0-mg/mL,Group IIIsuspension,remove the required amount ofstocksuspension(GroupIV)(SeeTEST ARTICLE CALCULATIONS), add the requiredamount ofvehicleand mix. 418-011:PAGE C-30 ATTACHMENT 3 TEST ARTICLE AND CONTROL ARTICLE ProtDcol418-011 Version:418-011 (28JUL 98) Page 3 of 3 PREPARATION PROCEDURE 5. To preparethe0.2-mg/mL,Group 11suspension,remove the required amount ofstocksuspension(Group 111()See TEST ARTICLE CALCULATIONS), add therequiredamount ofvehicleand mix. Writtenby: Approved by- Date: Tf-ita-9jr Clafificationx: Nmno*s s ((sSeeeattachedclarificatfioornm.) Initials/DatLUe(: q-,2( O@riPRIMMICA 418-01 1:PAGE C-31 905 Argus Research Laboratories. Inc. Sheehy Drive, Building A Horsham, PA 19044 Telephone: (215) 443-8710 Tolefax: (215) 443-8587 PROTOCOL 41 B-011 ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS SPONSOR'S STUDY NUMBER: T-6316.7 Amendment 1 - 12 August 1998 1 . Frequencyof Prei2arati(opnage4 and page I ofAttachment3 totheprotocol): Formulations(suspensionsw)illbe prepareddailyattheTestingFacilitrya,ther than weekly. Reason forChang Thischa correctstheprotocol. cna is Iiaancnto.Hr0obermnaanrn,cPohr.rD5.;,D5A) BT D ate =nd"( 3 Yo PUh- DABT Date @D rDeir@efctoorf Reeseeaarc@hh Associ e nirecto search Study Director Dena C. Lebo,V.M.D. DCt; MarvinT.Case,D.V.M.,Ph.D. Date Member, InstitutioAnnailmalCare and Study Monitor Use Commfttee -P@RMEDICA 41Ml 1:PAGE C-32 Argus Research Laboratories,Inc. 905 Sheehy Drive,BuildingA Homham, PA 19044 Telephone: (215)443-8710 Telefax:(215)443-8587 PROTOCOL 418-011 ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS SPONSOR'S STUDY NUMBER: T-6316.7 Amendment 2 - 11 December 1998 1 S12onso (page 1 ofthe protocol): The Sponsor is3M CorporateToxicology,ratherthan 3M ToxicologyServices. ,Reason forChange: This change was made atthe requestof the Sponsor. 2. Soecies/Straiannd Reason forSelection(page 5 ofthe protocol): The testarticliesbiologicallayctive,ratherthan pharmacologicallyactiveinthis strain. Reason forChange: This change was made atthe requestofthe Sponsor to correctthe protocol. 3. Route and Reason forChoice (page 7 ofthe protocol): The oral(gavage)routeisa possiblerouteof human exposure,ratherthan the one proposed forclinicaulse. 418-01 1:PAGE C-33 Amendment 2 Protocol418-011 Page 2 Reason foLgha-n-qe-: Thischange was made attherequestoftheSponsor to correcthe protocol. 0 h. .,DABT Date AAU@n n .Hoberman@,Ph.D.,DABT ma DiirreectorRroPfeRresseeaarrchp Date R mond Associ t ir 0 search Study Dire r Ll -Der..9 Date MarvinT. Case, D.V.M.,Ph.D. Date Dena C. Lebo, V.M.D. Member, InstitutioAnnailmal Care and Study Monitor Use Committee I APPENDIX D DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 418-011:PAGE D-1 DEVIATIONS FROM THE PROTOCOL AND STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 1. 26 AUG 98 (Day4 ofpresumedg,estationC)l:inicoablservatioannsd body weightswere notrecordefdorthefollowirnagts: Dosage Group 1 11 111 IV v Dosage (mg/ka/day) -0(Vehicle) 1 5 10 20 Assigned Numbers 12814-12816 12839- 12847 12864- 12872 12883-12897 12912-12922 Thisdeviatiodnidnotadverselayffecttheoutcomeofthestudybecauseit occurrebdeforeinitiatoifotnhedosageperiodand representassmalllossof dataacrossalldosagegroups. Alldeviationasredocumentedintherawdata. RhX2#d G. York,Phg.,QABT AssoomteDirectorf@!sejrch and StudyDirector Date I TEMPERATURE APPENDIX E AND RELATIVE HUMIDITY REPORTS ARGUS 418-011:PAGE E-1 Temperature and RelativeHumidity Report Location:Room 04 Protocol Number: 418-011 Range of Dates: 11 -Aug-I998 13:45 to 12-Sep-1998 10:26 Target Range: Species: Rat Total Number of Days: Total Number of Hours: TotalNumber of Data Points: Temperature 64OF to 79*F 33 764.49 766 RelativeHumidity 30% to 70% 33 764.49 766 Mean (SD): Maximum: Median: Minimum: Number of Points inRange (%): Number of PointsHigh (%): Number of PointsLow (%): 69.3 70.2 69.3 67.7 766 0 0 Report Generated: 23-Oct-1998 at09:15 0.4) (100.0) (0-0) (0-0) 47.7 54.1 47.7 41.3 766 0 0 2.4) (100.0) (0.0) (0-0) COMMENTS: REVIEWED BY: DATE: Cumulativeby Location(v04.01.97) I APPENDIX F PILOT REPORT 418-011:PAGE F-1 FINAL PILOT REPORT Study Title Oral(Gavage) Dosage-Range DevelopmentalToxicityStudyofN-ETFOSE inRats Sponsors StudyNumber: T-6316.7 Aut_hor Raymond G. York,Ph.D.,DABT (StudyDirector) Study Comi)letedOn 10 December 1998 (FinalPilotReport) PerformingLaboralM Argus Research LaboratoriesI,nc. 905 Sheehy Drive,BuildingA Horsham, Pennsylvania19044-1297 Laborato!jyr@ Argus Research LaboratoriesI,nc.P,rotocolNumber: 418-011P 418-011:PAGE F-2 418-011 P:PAGE 2 PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS TABLE OF CONTENTS SUB_JECT ABSTRACT 1. Purpose li. Methods 111. Results IV. Conclusion Figure1. MaternalBody Weights Table 1. Clinicaalnd Necropsy Observations- Summary Table 2. MaternalBody Weights - Summary Table 3. Maternal Body Weight Changes - Summary Table4. MaternaAlbsolutFeeedConsumptioVnalues(g/day-) Summary Table 5. MaternalRelativeFeed Consumption Values (g/kg/day-)Summary Table 6. Caesarean-SectioningObservations- Summary PAGE 4 6 6 7 9 10 11 13 15 17 19 21 41B-01:PAGE F-3 41B-01P:PAGE 3 SUB.JECT Table 7. LifteOrbservations(Caesarean-DelivereFdetuses)Summary Table 8 FetalGross ExternalAlteration-sSummary Table 9. Table 10. ClinicaOlbservations- IndividuaDlata Necropsy Observations-IndividuaDlata Table 11. Table 12. Table 13. Table 14. MaternalBody Weights- IndividuaDlata MaternalFeed Consumption Values- IndividuaDlata Caesarean-SectioninOgbservations- IndividuaDlata LifteOrbservations(Caesarean-DelivereFdetuses)IndividuaDlata Table 15. FetalSex,VitalStatusand Body Weight IndividuaDlata ATTACHMENT 1 - PROTOCOL AND AMENDMENT PAGE 23 25 27 31 35 42 46 50 54 58 418-011:PAGE F-4 41 B-01 1P:PAGE 4 TITLE: ORAL (GAVAGE) DOSAGE-RANGE STUDY OF N-ETFOSE IN RATS DEVELOPMENTAL ARGUS RESEARCH LABORATORIES, INC. PROTOCOL NUMBER: 418-011P SPONSOR'S STUDY NUMBER: T-6316.7 TOXICITY ABSTRACT Fifty-spirxesumed pregnantCrl:CDOBR VAF/Plus@ (Sprague-Dawley)ratswere randomlyassignedtoseven dosage groups [eightper group (Groups Ithrough Vll)].Suspensionsofthe N-ETFOSE were administeredorallyviagavage once dailytothese naturally-brefdemale ratson days 6 through17 ofpresumed gestation(DGs 6 to 17)atdosages of0 (Vehicle)1,,5,10,20,25 and 35 mg/kg/day.The dosage volume was 5 mukg, adjusteddailyon thebasisof the individuablody weightsrecordedimmediatelybeforeadministratioonfthe testarticle. Checks forviabiliwteyre made twicedaily.Clinicaolbservationswere recorded dailybeforedosage, approximatelyone hour afteradministratioannd thenfourto sixhourslater.These observationswere alsorecordedonce dailyduringthe postdosageperiod.Body weightswere recordeddailyduringthedosage and postdosage periodsand feed consumption valueswere recordedon DGs 0,4, 6, 8, 10,12,14,16,18 and 20. Allratswere sacrificeodn DG 20 and examined forthenumber and distribution ofcorporalutea,implantatiosnitesand uterinecontents.A gross necropsyof thethoracica,bdominal and pelvicviscerawas performed.Fetuseswere weighed and examined for gross externalalterationsand sex. AllratssurviveduntislcheduledsacrificeC.linicaolbservationsduringgestation consideredtreatment-relatweedre limitetdo singleratswithchromorhinorrhea, chromodacryorrheaoremaciationatthe20 and 35 mg/kg/daydosages. Clinical observationsoflocalizeadlopeciaand emaciationwere confirmedat necropsy. No additionanlecropsy observationsoccurred. 418-01 1:PAGE F-5 418-011 P:PAGE 5 Body weight gains and absoluteand relativfeeed consumption valuesforthe entiredosage period(calculateads DGs 6 to 18),the entireintervaalfter initiatioofntreatment(DGs 6 to 20) and the entiregestationperiod(DGs 0 to 20) were reduced inthe 10 mg/kg/day and higherdosage groups,compared tothe controlgroup. Reduced fetalbody weightsoccurredatthe 25 and 35 mg/kg/day dosages, relativteothe controlgroup (-8.5% and -13.8%, respectively)N.o other Caesarean-sectioningor litteprarameters were affectedby dosages ofthe test articlaes highas 35 mg/kg/day. One litteirnthe 35 mg/kg/day dosage group consistedoftwo earlyresorptionsand 13 fetuseswithcleftpalate(two alsohad whole body edema). These fetalfindingswere consideredgeneticinoriginand not testarticle-related. Based on the resultsofthisdosage-range findingstudy,dosages of 0, 1,5, 10 and 20 mg/kg/day were recommended forthe fulldevelopmental toxicitsytudy of N-ETFOSE inrats. 41 B-011:PAGE F-6 41 B-01 I P:PAGE 6 EgMose: The purpose ofthisstudywas to provideinformationforthe selectionof dosages tobe used inthe developmentaltoxicit(yembryo-fetatloxicitaynd teratogenic potentials)tudyofN-ETFOSE administeredorallyviagavage to Crl:CDOBR VAF/PlusS presumed pregnantfemale rats. ii. Meth_odsi: The testarticleN,-ETFOSE [lot/batcnhumber FM-3929 (30035,30037, 30039)], was receivedon 20 May 1998,and storedatroom temperature.The vehicle was 2% TweenO 80 inreverseosmosis membrane processeddeionizedwater (R.O.deionizedwater).The Tween@ 80 was receivedfrom J.T.Baker, PhilipsburgN,ew Jersey,on 22 May 1998, and was storedatroom temperature. The R.O. deionizedwater isavailablferom a continuoussourceattheTesting Facilitaynd ismaintainedatroom temperature.The preparedvehiclewas storedat room temperature.Test articlfeormulationwsere prepareddaily. Fifty-spirxesumed pregnantCrl:CDOBR VAF/PlusID(Sprague-Dawley)ratswere randomlyassignedtoseven dosage groups [eightpergroup (GroupsIthrough Vll)].Suspensionsofthe testarticlweere administeredorallvyiagavage once dailytothese naturally-brfeedmale ratson days 6 through17 ofpresumed gestatio(nDGs 6 to 17)atdosages of0 (Vehicle)1,,5,10,20,25 and 35 mg/kg/day.The dosage volume was 5 mukg, adjusteddailyon thebasisof theindividuablody weightsrecordedimmediatelybeforeadministratioonfthe testarticle. Checks forviabiliwteyre made twicedaily.Clinicaolbservationswere recorded dailybeforedosage,approximatelyone hour afteradministratioand thenfourto six hours later.These observations were also recorded once dailyduring the postdosageperiod.Body weightswere recordeddailyduringthedosage and postdosage periodsand feed consumption valueswere recordedon DGs 0,4, 6. 8, 10,12,14,16,18 and 20. a. Detaileddescriptionosf allproceduresused intheconductofthisstudy areprovidedinthe appropriatesectionsofthisreportand intheattached protocoland amendments. Deviationsfrom the Protocoland Standard OperatingProceduresoftheTestingFacilitayreavailableintheraw data. 418-011:PAGE F-7 418-011 P:PAGE 7 Allratswere sacrificeodn DG 20 and examined forthe number and distribution ofcorporalutea,implantatiosnitesliveand dead fetusesand earlyand late resorptionsA. grossnecropsyofthe thoracica,bdominal and pelvicviscerawas performed.Fetuseswere weighed and examined forgrossexternalalterations and sex. 111. Results: A. MortalilyC,linicaland Necropsy Observations(Summarv - Table 1: IndividualData -Tables 9 and-"O A.I. Mortarity Allratssurviveduntislcheduled sacrifice. A.2. ClinicaOlbservations Clinicaolbservationsduringgestationconsideredtreatment-relatweedre limited to singleratswithchromorhinorrheac,hromodacryorrheaor emaciationatthe 20 and 35 mg/kg/daydosages. Allotherclinicaolbservationswere consideredunrelatedtothetestarticle because: 1)the incidenceswere notdosage-dependent;and/or2)theyoccurred inonlyone rat.These observationsincludedlocalizeadlopeciaon the limbs, underside,back and/orneck. A.3. Necrot)svObservations Clinicaolbservationsof localizeadlopeciaand emaciationwere confirmedat necropsy. No additionanlecropsy observationsoccurred. B. Maternal Body Weights and Elod Weiaht Chancies (Figure I.; Summaries -Tables 2 and 3: IndividualData -Table 11) Maternalbody weightgainsinthe 10 mg/kg/dayand higherdosage groups were decreased,compared tothe controlgroup on gestatiodnays (DGs) 6 to8 and 8 to 10. Body weightswere decreased forthe25 mg/kg/dayand higherdosages on DGs 10 to 12,12 to14 and 14 to 16. Matemal body weightgainsinthe 1,5, 10,20,25 and 35 mg/kg/daydosage groups were generallycomparable to controlvaluespostdosage(DGs 18 to20). 418-011:PAGE F-8 41 B-01IP:PAGE 8 Reflectintghese effectsofthetestarticlwee,ight gainsforthe entiredosage period(calculateads DGs 6 to18),theentireintervaalfterinitiatioofntreatment (DGs 6 to20) and theentiregestationperiod(DGs 0 to20)were reduced inthe 10 mg/kg/dayand higherdosage groups,compared tothe controlgroup. Maternalbody weightsand body weightgainsforthe 1 and 5 mg/kg/day dosage groups were generallycomparable to controlvaluesovereach intervatlabulated. C. Matemal Ielafive (glkglday)-Feed ConayMpti_on Values (Sum nari s - Tables 4 and 5: lntiividual Data - Table 12) Absolute and relative feed consumption values for the 10 mg/kg/day and higher dosage groupswere decreased,compared to thecontrolgroup atalltabulated intervaldsuringthe dosage period(DGs 6 to 8,8 to 10,10 to12,12 to 14,14 to 16 and 16 to 18).Maternalfeedconsumptionvaluesforthe 1,5,10,20, 25 and 35 mg/kg/day dosage groups were generallycomparable tocontrolvalues postdosage(DGs 18 to20). Reflectintgheseeffectsofthetestarticlea,bsoluteand relativfeeed consumptionvaluesforthe entiredosage period(calculateads DGs 6 to 18),the entireintervaalfterinitiatioofntreatment(DGs 6 to20)and theentiregestation period(DGs 0 to20)were reducedinthe 10 mg/kg/dayand higherdosage groups,compared to thecontrolgroup. Absoluteand relativfeeed consumption valuesforthe 1 and 5 mg/kg/day dosage groupswere generallycomparable tocontrolvaluesover each interval tabulated. D. Caesarea i-Sectioniigand Li er 0 )servation(sSummaries - Lable_6s throug 18,. 1idivi lual Data - Ta )Ies 13 throu-qb 151 Caesarean-sectioninogbservationwsere based on 8 (100%),7 (87.5%), 8 (100%),8 (100%),8 (100%),8 (100%) and 8 (100%) pregnantratswithlive lifterisntheseven respectivedosage groups. Reduced fetalbody weightsoccurredatthe25 and 35 mg/kg/day dosages, relativteothecontrolgroup (-8.5%and -13.8%,respectivelyT)h.is observation was consideredan effectofthetestarticlbeecause itwas dosage-dependent 418-011:PAGE F-9 41 B-01 1 P:PAGE 9 and occurredatthedosages inwhich therewas maternaltoxicitoybserved (decreasedbody weightand feed consumptionvalues). No otherCaesarean-sectioing or litteprarameterswere affectedby dosages of thetestarticlaes highas 35 mg/kg/day.The liftearveragesforcorporalutea, implantationsl,iftseirze,livefetuses,resorption(searlyand late)d,ams withany resorptionasnd percentlivemale fetuseswere comparable among the 0 Vehicle)1,,5,10,20,25 and 35 mg/kg/daydosage groups. No dams had all resorbedconceptuses,therewere no dead fetusesand allplacentaeappeared normal. Totalsof 109,93,116, 110,118, 116 and 114 livefetuseswere evaluatedfor externalgrossalterationisnthe seven respectivdeosage groups. No fetalgross externalalterationwsere observed atdosages up to25 mg/kg/day.One lifter (10650)inthe35 mg/kg/daydosage group consistedoftwo earlyresorptions and 13 fetuseswithclefptalate(twoalsohad whole body edema). These fetal findingswere consideredgeneticinoriginand nottestarticle-related. IV. Conclusion: Based on the resultsofthisstudy,dosages of0 (Vehicle),1,5, 10 and 20 mglkg/dayofN-ETFOSE are recommended forthedevelopmentaltoxicity studyinrats(418-011).The 1 mg/kg/daydosage isexpectedtobe a noobservable-effect-le(vNeOlEL) forboth maternaland embryo-fetatloxicitayn,d the20 mg/kg/daydosage isexpectedtoproduce maternaltoxicit(ydecreased maternalbody weightand feed consumptionvalues)and minimaldevelopmental toxicit(ydecreasedfetalbody weightsand possiblydelayedossification). c Alan M. Hoberman, Ph.D.,DABT Date Directorof Research 0r34ele ond G. York,W, AssociateDirector Study Director to -Dg.-99 DABT Date earch and 400 380 360 340 320 3t)t) 280 260 240 220 MATERNAL BODY WEIGHTS Figure 1 0 (VEHICLE)MGA(G m I MGMWDAY 5 MGA(G/DAY 10 MGIKGIDAY -ez 20 MGIKGID" 25 MGIKGIDAY 17 lO I'l 1'2 1'3 1'4 1'5 1'6 DAYS OF GESTATION ! - 8 1 9 20 35 MGIKGIDAY PROTOCOL 418-OIIP: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T TABLE I (PAGE 1) : CLINICAL AND NECROPSY OBSERVATIONS - SUMMARY ---------------------------------------------------------- --------------------------------------------------------------- I ii III IV DOSAGE GROUP 0 (VEHICLE) 1 5 10 DOSAGE (MG/KG/DAY)a -------- --------------- ----- ---------------------------------------------------------------------------------------------- MAXIMUM POSSIBLE INCIDENCE 120/ 8 120/ 8 120/ 8 120/ 8 MORTALITY 0 0 0 0 LOCALIZED ALOPECIA: TOTAL LIMBS UNDERSIDE BACK NECK 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 15/ 2 B/ I 7/ 1 0/ 0 1/ 1 0/ 0 a/ 0 0/ 0 0/ 0 0/ 0 EMACIATION 0/ 0 0/ 0 0/ 0 0/ 0 CHROMORHINORRHEA 0/ 0 0/ 0 o/ 0 0/ 0 CHROMODACRYORRHEA 0/ 0 0/ 0 0/ 0 0/ 0 PERSISTENT ADVERSE CLINICAL OBSERVATIONS WERE CONFIRMED AT NECROPSY, NO ADDITIONAL GROSS LESIONS WERE IDENTIFIED ----------- ---------------------------------------- ---------------------------------------------------------------------- MAXIMUM POSSIBLE INCIDENCE - (DAYS x RATS)/NUMBER OF RATS EXAMINED PER GROUP ON DAYS 6 THROUGH 20 OP PRESUMED GESTATION. NIN = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION. a. Dosage occurred on days 6 through 17 of presumed gestation. PROTOCOL 418-011P- ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR-S STUDY NUMBER: T TABLE 1 (PAGE 2): CLINICAL AND NECROPSY OBSERVATIONS - SUMMARY ---------------------------------------------------------------------------------------------------------------------------- v vi Vil DOSAGE GROUP 20 25 35 -D-O-S-A-GE---(-M-G-/-KG-/-D-A-Y)-a---------------------------------------------------------------------------------------------------------- MAXIMUM POSSIBLE INCIDENCE 120/ 8 120/ 8 120/ 8 MORTALITY LOCALIZED ALOPECIA: TOTAL LIMBS UNDERSIDE BACK NECK 0 0/ 0 0/ 0 0/ 0 ol 0 0/ 0 0 7/ 1 0/ 0 7/ 1 6/ 1 0/ 0 0 20/ 2 12/ 1 B/ I a/ I 0/ 0 EMACIATION 0/ 0 0/ 0 4/ 1 CHRO140RHINORRHEA 0/ 0 0/ 0 1/ 1 CHROMODACRYORRHEA 3/ 1 0/ 0 0/ 0 PERSISTENT ADVERSE CLINICAL OBSERVATIONS WERE CONFIRMED AT NECROPSY, NO ADDITIONAL GROSS LESIONS WERE IDENTIFIED ------------------------------------------------------------------ ------------------------------------------------------- KAXIMUM POSSIBLE INCIDENCE - (DAYS x RATS)/NUMBER OF RATS EXAMINED PER GROUP ON DAYS 6 THROUGH 20 OF PRESUMED GESTATION. NIN - TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION. a. Dosage occurred on days 6 through 17 of presumed gestation. PROTOCOL 418-OlIP: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: I TABLE 2 (PAGE 1) ; MATERNAL BODY WEIGHTS - SUMMARY --------------------------------------- ----------------------------------------------------------------------------------- DOSAGE GROUP 11 111 IV 1 5 20 DOSAGE (NO/KG/DAY)a 0 (VEHICLE) 1 ------------------------- ------------------------------------------------------------------------------------------------ RATS TESTED N a 8 PREGNANT N 7 8 BODY WEIGHT IG) DAY 0 HEAN+S.D. 235.9 + 10.3 236.4 + 12.6 236.4 + *8.4 236.0 + 8 DAY 4 MEAN+S. D. 262.4 + 15.2 254.7 + 10.3 258.0 + 9.0 255.0 + 11 DAY 6 MEAN+S. D. 266.4 + 13.9 264.4 + 16.3 263.9 + 10.2 257.8 + 12 DAY 7 HEAN+S. D. 269.4 + 16.6 266.3 + 14.9 266.5 + 9.4 259.0 + 14 DAY 0 HEAN+S.D. 274.6 + 17.0 270.4 + 16.6 271.8 + 8.7 260.9 + I DAY 9 HEAN+S.D. 278.9 + 17.2 276.6 + 16.2 276.1 + 9.8 264.4 + 1 DAY 10 MEAN+S. D. 285.6 + 19.0 282.7 + 15.5 281.4 + 9.8 268.9 + I DAY 11 HEAN+S. D. 290.4 + 19.4 284.4 + 17.9 286.9 + 11.0 274.8 + I DAY 12 MEAN+S.D. 295.4 + 18.2 291.7 + 18.6 288.4 + 8.5 280.4 + I DAY 13 MEAN+S.D. 302.6 + 20.5 296.6 + 16.5 293.4 + 9.9 283.4 + 2 DAY 14 MEAN+S.D. 306.8 + 21.9 302.4 + 16.5 297.5 + 6.9 288.2 + I DAY 15 MEAN+S.D. 313.1 + 21.9 307.8 + 17.a 304.4 + 9.6 296.1 + 2 DAY 16 MEAN+S.D. 323.0 + 24.0 320.0 + 21.6 314.5 + 9.5 303.8 + 2 DAY 17 MEAN+S.D. 334.4 + 24.0 330.1 + 22.6 326.1 + 10.0 313.4 + DAY 18 MF.AN+S. D. 350.1 + 29.0 348.0 + 23.6 342.5 + 8.5 326.2 + DAY 19 MEAN+S.D. 367.2 + 29.0 360.6 + 26.6 3S7.8 + 11.2 341.2 + DAY 20 MF.AN+S. D. 385.6 + 31.8 378.7 + 32.3 375.0 + 9.9 3S9.1 4 ------------------------- ---------------------------------------------------------------------------------------------- DAY . DAY OF GF.STATION a. Dosage occurred on days 6 through 17 of gestation. PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T TABLE 2 (PAGE 2): MATERNAL BODY WEIGNTS - SUMMARY ----------------------------------------------------- ---------------------------------------------------------------------- DOSAGE DOSAGE GROUP (MG/KG/DAY)a v vi Vil 20 25 35 -------------------------- ------------------------------------------------------------------------------------------------- PATS TESTED N a 8 PREGNANT N 8 8 BODY WEIGNT (G) DAY 0 MEAN+S.D. 236.2 + 8.0 236.0 + 6.5 236.5 + 0.2 DAY 4 MEAN+S.D. 258.5 + 8.2 257.9 + 12.6 255.2 + 11.3 DAY 6 DAY 7 MEAN+S.D. HEA.N+S.D. 262.1 + 8.2 260.6 + 8.1 264.0 + 14.2 262.0 + 15.8 261.1 + 10.5 261.9 + 9.4 DAY 8 HEAN+S.D. 263.1 + 9.0 264.4 + 16.5 262.6 + 7.2 DAY 9 14EAN+S.D. 268.5 + 12.5 269.2 + 16.3 265.0 + 9.3 DAY 10 P4EAN+S.D. 270.1 + 12.6 272.1 + 15.2 265.6 + 11.4 DAY 11 14EAN+S.D. 276.5 + 13.7 274.1 + 15.0 266.9 + 10.9 DAY 12 MEAN+S.D. 200.9 + 12.5 276.0 + 17.8 267.2 + 12.2 DAY 13 DAY 14 MEAN+S.D. MEAN+S.D. 285.6 + 15.3 288.1 + 12.9 277.0 + 16.7 276.8 + 18.7 267.8 + 16.9 269.4 + 20.7 DAY 15 HEAN+S.D. 295.1 + 17.1 281.0 + 19.2 274.0 + 25.8 DAY 16 MEAN+S.D. 305.6 + 18.2 289.9 + 21.6 283.8 + 30.1 DAY 17 MEAN +S. D. 318.2 + 18.6 301.6 + 23.5 289.0 + 34.6 DAY 18 mEAN+S.D. 330.9 + 21.3 318.0 + 22.3 302.0 + 39.7 DAY 19 14EAN+S.D. 344.2 + 22.5 332.0 + 22.4 318.1 + 41.8 DAY 20 MEAN+S.D. 363.5 + 22.1 345.8 + 20.4 336.1 + 41.6 -- - --- -- --- - --- - - --- -- --- - - - ------- --- -- --- --- -- -- --- -- -- -- -- --- -- --- - --- --- - --- -- --- --- -- -- --- -- ---- -- --- -- -- -- -- -- --- -- DAY . DAY OF GESTATION a. Dosage occurred on days 6 through 17 of gestation. PROTOCOL 418-OIIP: ORAL (GAVAGE) DOSAGE-PANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T TABLE 3 (PAGE 1); MATERNAL BODY WEIGHT CHANGES - SUMMARY ---------------------------------------------------------------------------------------------------------------------------- I IT III IV DOSAGE DOSAGE GROUP (MG/KG/DAY)a 0 (VEHICLE) 1 5 10 ---------------------------------------------------------------------------------------------------------------------------- RATS TESTED N a a 8 PREGNANT N 8 7 6 BODY WEIGHT CHANGE (G) DAYS 0- 6 HEAN+S.D. +30.5 + 10.3 +28.0 + 7.2 +27.5 + 5.6 +21.8 + 6 DAYS DAYS 6- a 8 - 10 MEAN+S.D. HEAN+S.D. +8.2 + 4.3 +11.1 + 2.9 +6.0 + 3.4 +12.3 + 1.5 +7.9 + 2.3 +9.6 + 3.1 +3.1 + 11 +8.0 + 5 DAYS 10 - 12 HEAN+S.D. +9.6 * 4.0 +9.0 + 5.4 +7.0 + 2.9 +11.5 + 6 DAYS 12 - 14 HEAN+S.D. 411.4 + S.0 +10.7 + S.8 +9.1 + 3.1 +7.9 + 3 DAYS 14 - 16 DAYS 16 - 18 MEAN+S.D. HEAN+S.D. +16.2 + 6.7 +27.1 + 7.4 +17.6 + 8.0 +28.0 + 4.7 +17.0 + 2.2 +28.0 + 4.5 +15.5 + 3 +22.5 + 4 DAYS 6 - 18 DAYS 18 - 20 MEAN+S.D. HEAN+S.D. +83.8 + 20.5 +35.S + 7.0 +83.6 + 10.4 +30.7 + 11.4 +78.6 + 8.8 +32.5 + 5.1 +68.5 + 13 +32.9 + 6 DAYS 6 - 20 HEAN+S.D. +119.2 + 24.4 +114.3 + 21.2 +111.1 + 11.1 +101.4 + I DAYS 0 - 20 MEAN+S.D. +149.8 + 33.1 +142.3 + 26.4 +138.6 + 12.2 *123.1 + 2 ------------------------------------------------------------------------------------------------------------------------- DAYS - DAYS OF GESTATION a. Dosage occurred on days 6 through 17 of gestation. PROTOCOL 418-011P; ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T TABLE 3 (PAGE 2): MATERNAL BODY WEIGHT CHANGES - SUMMARY ---------------------------------------------------------------------------------------------------------------------------- DOSAGE DOSAGE GROUP (MG/KG/DAY)a v vi Vil 20 25 --------------3-5--------------------------- ----------------------------------------------------- --------------------------- RATS TESTED N a a PREGNANT N 8 8 BODY WEIGHT CHANGE (G) DAYS 0 6 HEAN+S.D. +25.9 + 7.6 +28.0 + 9.4 +24.6 + 6.6 DAYS 6 8 MF.AN+S.D. +1.0 + 4.8 +0.4 + 4.5 +1.5 + 6.7 DAYS 8 10 MP-AN+S.D. +7.0 + 5.6 +7.8 + 4.5 +3.0 + 7.2 DAYS 10 12 MEAJN+S.D. +lo.8 + 3.6 +3.9 + 7.6 +1.6 + 10.5 DAYS 12 14 MF.AN+S.D. +7.2 + 2.4 +0.8 + 6.2 +2.1 + 13.4 DAYS 14 16 MF-AJR+S.D. +17.5 + 7.9 .13.1 + 11.3 +14.4 + 11.1 DAYS 16 18 Mr%M+S.D. +25.2 + 4.8 +28.1 + 9.3 +16.2 + 11.7 DAYS 6 18 MEAN+S.D. +68.8 + 15.4 +54.0 + 13.9 +40.9 + 42.3 DAYS 18 20 MF,"+S.D. +32.6 + 3.4 +27.8 + 7.6 +34.1 + 4.5 DAYS 6 20 HEAN+S.D. +101.4 + 16.1 +si.B + 11.9 +75.0 + 44.6 DAYS 0 20 N PAN +S. D. +127.2 + 21.0 +109.8 + 14.0 +99.6 + 44.4 -------- ------ ------------------------ ------------------------------------------------------------------------------------------ DAYS - DAYS OF GESTATION a. Dosage occurred on dayi3 6 through 17 of gestation. PROTOCOL 418-OlIP: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T TABLE 4 (PAGE 1) : MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY -------------------------- -------------------------------------------------------------------------------------------------- DOSAGE DOSAGE GROUP (MG/KG/DAY)a I 0 (VEHICLE) III IV 5 10 -- --- -- -- -- -- --- -- -- -- --- - - ----- -- --- -- -- --- -- --- -- --- -- -- --- -- -- -- --- -- -- --- -- --- --- --- -- -- -- -- --- - ---- -- --- -- --- -- --- -- -- - RATS TESTED N 8 8 PREGNANT N 7 FEED CONSUMPTION (G/DAY) DAYS 0 - 6 MEAN+S.D. 23.6 + 3.6 21.9 + 2.9 23.5 + 1.0 21.3 + 2. DAYS 6 - 8 MEAN+S.D. 25.9 + 5.4 23.5 + 2.4 22.0 + 4.6 19.1 + S. DAYS 0 - 10 HEAN+S.D. 25.4 + 3.2 24.1 + 2.5 24.2 + 1.1 20.8 + 2. DAYS 10 - 12 DAYS 12 - 14 DAYS 14 - 16 MEAN+S.D. HEAN+S.D. MEAN+S.D. 26.2 ( 28.1 1 24.2 + 3.7 7]b + 8.2 7]b + 2.3 23.1 + 2.0 27.9 + 5.2 25.1 + 3.0 24.4 + 2.2 23.5 + 2.5 23.4 + 2.5 22.6 + 2. 22.7 + 3 21.1 + 2 DAYS 16 - 18 HEAN+S.D. 25.9 + 2.6 25.5 + 4.4 25.4 + 1.7 22.2 + 2 DAYS 6 - 18 HEAN+S.D. 25.9 + 3.4 24.8 + 1.6 23.8 + 1.4 21.4 + 2 DAYS 18 - 20 MEAN+S.D. 26.2 + 3.0 26.2 + 2.0 24.8 + 2.2 24.0 + 3 DAYS 6 - 20 HEAN+S.D. 25.9 + 3.2 25.0 + 1.6 24.0 + 1.3 21.8 + 2 DAYS 0 - 20 MEAN+S.D. 25.2 + 3.1 24.1 + 1.8 23.8 + 0.9 21.7 + 2 ------------------------- -------------------------------------------------------------------------------------------------- DAYS - DAYS OF GESTATION I I . NUMBER OF VALUES AVERAGED a. Dosage occurred on days 6 through 17 b. Excludes values that were associated of gestation. with spillage. PROTOCOL 418-OlIP- ORAL (GAVAGEI DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER! T TABLE 4 (PAGE 2): MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY ---------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP v vi Vil DOSAGE (KG/KG/DAY)a 20 25 35 ---------------------------------------------------------------------------------------------------------------------------- RATS TESTED N a 8 8 PREGNANT N 8 a FEED CONSUMPTION (G/DAY) DAYS 0 6 MEAN*S.D. 24.6 + 3.3 22.0 + 2.7 22.6 + i.5 DAYS 6 8 MEAN*S. D. 21.2 + 3.3 19.8 + 3.7 21.1 + 2.7 DAYS 8 10 MEAN+S. D. 22.2 + 4.4 20.9 + 2.4 20.1 + 3.5 DAYS 10 12 MEAN+S. D. 23.1 + 3.0 20.1 + 2.4 18.9 + 5.3 DAYS 12 14 DAYS 14 16 HEAN+S. t). NEM+S. 1:). 23.1 + 3.4 22.6 + 5.4 16.6 + 3.3 17.8 + 5.8 20.1 + 8.7 18.1 + 7.2 DAYS 16 - 18 MEAN+S. D. 23.4 + 3.7 21.0 + 3.3 18.6 + 5.6 DAYS 6 - 18 MEAN+S. D. 22.6 + 3.3 19.4 + 2.6 19.5 + 4.2 DAYS 18 - 20 MEAN+S. D. 23.8 + 2.1 21.5 + 1.6 24.2 + 4.3 DAYS 6 - 20 MEAN+S. D. 22.8 + 3.1 19.7 + 2.3 20.2 + 4.1 DAYS 0 - 20 MEAN+S. D. 23.4 + 2.8 20.4 + 2.1 20.9 + 3.0 --------------------------------------------------------------------------------------------------------------------------- DAYS - DAYS OF GESTATION a. Dosage occurred on days 6 through 17 of gestation. PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE-PJKNGE DEVELOPMENTAL TOXICITY STUDY OF N ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 5 (PAGE 1) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY -- --- -- -- -- --- - --- - ---- --- - - ------- --- -- -- --- -- --- -- -- --- -- -- -- -- -- -- --- -- --- --- - -- -- --- -- -- --- -- --- --- -- -- --- --- -- --- --- -- DOSAGE GROUP 1 11 111 IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 1 s 10 - --- --- - --- -- -- -- -- -- -- --- - - ---- ---- --- --- -- -- --- -- --- -- -- -- -- -- -- --- -- -- --- --- -- --- -- --- --- -- -- --- -- --- --- -- -- --- ---- -- -- - RATS TESTED N 8 8 PREGNANT N 7 8 FRED CONSUMPTION (G/KG/DAY) DAYS 0 6 MEAN+S.D. 92.2 + 11.2 86.7 + 9.8 93.1 + @.7 85.1 + 7 DAYS 6 8 MEAN+S.D. 95.5 + 16.5 88.1 + 8.3 82.5 + 17.8 72.9 + 19 DAYS 8 10 MEAN+S.D. 90.7 + 7.5 87.2 + 7.6 87.6 + 4.5 78.4 + 6 DAYS 10 22 DAYS 12 14 DAYS 14 16 HEAN+S.D. MEAN+S.D. HEAN+S.D. 90.0 ( 93.4 I 77.1 + 8.8 7)b + 26.7 7)b + 7.2 80.5 + 4.2 95.1 + 23.5 80.8 * 7.6 85.6 + 7.8 80.3 + 9.2 76.5 + 8.1 e2.8 + 3 79.7 + 6 71.3 + 7 DAYS 16 18 MEAN+S.D. 77.3 + 5.8 76.3 + 9.6 77.7 + 5.6 70.4 + 4 DAYS 6 18 MEAN+S.D. 86.4 + 9.6 84.2 + 5.0 81.4 + 5.7 75.5 + 5 DAYS 18 20 MEAN+S.D. 71.4 + 7.8 72.4 + 3.3 69.2 + 5.5 69.9 + DAYS 6 20 HEAN+S.D. 83.8 + 8.9 82.1 + 4.5 79.1 + 5.1 74.5 + DAYS 0 20 MEAN+S.D. 83.2 + 7.6 80.8 + 4.5 00.4 + 3.6 75.5 + -------------------------------------------------------------------------------------------------------------------------- DAYS - DAYS OF GESTATION ( I - NUMBER OP VALUES JKVEPAGED a. Dosage occurred on days 6 through 17 of gestation. b. Excludes values that were associated with spillage. PROTOCOL 416-OlIP: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAI, TOXICITY STUDY OF N-ETFOSS IN RATS (SPONSOR'S STUDY NUMBER: T TABLE 5 (PAGE 2) ! MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY ---------------------------------------------------------------------------------------------------------------------------- v vi Vil DOSAGE GROUP 20 25 35 -D-O-S-A-GE---(-M-G-/-KG-/-D-A-Y)-a-------------------------------------------------- ------------------------------------------------------- RATS TESTED N a 8 8 PREGNANT N 8 8 FEED CONSUMPTION (G/KG/DAY) DAYS 0 6 HEAN+S.D. 98.1 + 13.5 86.8 + 8.0 90.2 + 4.1 DAYS 6 8 N EA.N + S. D. 80.8 + 10.5 74.5 + 10.1 80.5 + 10.4 DAYS 0 10 MF-AN+S.D. 62.6 + 13.8 77.7 + 5.4 75.9 + 11.8 DAYS 10 12 HEMN+S.D. 83.7 + 9.1 73.1 + 7.3 70.8 + 19.3 DAYS 12 14 HEAN+S.D. 80.7 + 9.8 59.8 + 9.4 74.2 + 32.8 DAYS 14 16 HEM+S.D. 75.8 + 16.0 62.3 + 19.0 63.9 + 25.3 DAYS 16 - 18 14EAN+S.D. 73.2 + 9.1 69.2 + 8.8 62.6 + 15.4 DAYS 6 - 18 14 EAN + S. D. 79.0 + 8.9 69.2 + 5.9 71.2 + 13.4 DAYS 18 - 20 N F.AN +S. D. 68.8 + 4.1 64.9 + 4.6 76.1 + 9.3 DAYS 6 - 20 14EAN+S.D. 77.1 + 7.6 68.4 + 4.6 71.6 + 11.9 DAYS 0 - 20 MEAN+S.D. 80.8 + 7.1 72.0 + 3.6 75.7 + 7.9 7 ------------------------- ------------------------------------------------------------------------------------------------ DAYS - DAYS OF GESTATION a. Dosage occurred on days 6 through 17 of gestation. PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T TABLE 6 (PAGE 1) : CAESAREAN- SECTIONING OBSERVATIONS - SUMMARY ---------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 1 11 iri IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 1 5 10 ---------------------------------------------------------------------------------------------------------------------------- RATS TESTED N 8 8 8 8 PREGNANT N it) S(IOO.O) 7( 87.5) S(IOO.G) B(IOO.O) RATS PREGNANT AND CAESAREAN-SECTIONED ON DAY 20 OF GESTATION N CORPORA LUTEA N PAN + S. D. IMPLANTATIONS MEAN+S.D. LITTER SIZES MFJW+S.D. LIVE FETUSES N t4EAN+S.D. DEAD FETUSES N RESORPTIONS HEAN+S.D. EARLY RESORPTIONS N MEAN+S.D. LATE RESORPTIONS N MEAN+S.D. DAMS WITH ANY RESORPTIONS N (t) 8 16.0 + 2.6 14.0 + 4.5 13.6 + 4.6 109 13.6 + 4.6 0 0.4 + 0.7 3 0.4 + 0.7 0 0.0 + 0.0 2( 25.0) 7 15.7 + 2.6 13.6 + 3.2 13.3 + 3.0 93 13.3 + 3.0 0 0.3 + 0.5 2 0.3 + 0.5 0 0.0 + 0.0 2( 28.6) 8 16.0 + 1.8 15.2 + 1.8 14.5 + 1.7 116 14.5 + 1.7 0 0.8 + 1.2 6 0.8 + 1.2 0 0.0 + 0.0 3( 37.5) 16.0 * 2 14.4 + I 13.8 + I 110 13.8 + 0 0.6 + 4 0.5 + 1 0.1 + 4( SO.0) DAMS WITH ALL CONCEPTUSES RESORBED N 0 0 0 0 DAMS WITH VIABLE FETUSES N (t) 8(100.0) 7(100.0) 8(100.0) 8(100.0) PLACENTAE APPEARED NORMAL N (%) B(IOO.01 7(100.0) 8(100.0) 8(100.0) --------------------------------------------------------------------------------------------------------------------------- a. Dosage occurred on days 6 through 17 of gestation. PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE- RANGE, DEVELOPMENTAL TOXICITY STUDY OF H-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T TABLE 6 (PAGE 2): CAESAREAN -SECTIONING OBSERVATIONS - SUMMARY ---------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP v vi vit DOSAGE (MG/KG/DAY)a 20 25 35 ---------------------------------------------------------------------------------------------------------------------------- RATS TESTED N a a a PREGNANT N(t) 0(100.0) e(loo-0) 8(100.0) RATS PREGNANT AND CAESAREAN-SECTIONED ON DAY 20 OF GESTATION N CORPORA LUTRA 14EAN+S.D. IMPLANTATIONS MEAN+S.D. LITTER SIZES HEAN+S.D. LIVE FETUSES N 14EAN+S.D. DEAD FETUSES N RESORPTIONS MEAN+S.D. EARLY RESORPTIONS N MEAN+S.D. LATE RESORPTIONS N MEAN+S.D. DAMS WITH ANY RESORPTIONS N(t) 8 15.5 + 2.1 15.1 + 1.7 14.8 + 1.8 lie 14.9 + 1.8 0 0.4 + 0.5 3 0.4 + 0.5 0 0.0 + 0.0 3( 37.5) 8 15.9 + 2.8 14.9 + 2.8 14.5 + 2.6 116 14.5 + 2.6 0 0.4 + 0.7 3 0.4 + 0.7 a 0.0 + 0.0 2( 25.0) 16.2 + 3.4 15.1 + 2.2 14.2 + 2.4 114+ 14.2 2.4 0 0.9 + 1.1 7 0.9 + 1.1 0+ 0.0 0.0 4( 50.0) DAMS WITH ALL CONCEPTUSES RESORBED N 0 0 DAMS WITH VIABLE FETUSES N (ti) a(loo.0) 8(100.0) 8(100.0) PLACENTAE APPEARED NORMAL N(%) e(IOO.O) 8(100.0) B(IOO.O) ----------------------------------------------------------------------------------------------------------- a. Dosage occurred on days 6 through 17 of gestation. PROTOCOL 418-OlIP: ORAL (GAVAGE) DOSAGE-P.ANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 7 (PAGE 1) : LITTER OBSERVATIONS (CAESAREAN -DELIVERED FETUSES) - SUMMARY --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP I III IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 5 10 --------------------------------------------------------------------------------------------------------------------------- LITTERS WITH ONE OR MORE LIVE FETUSES N 8 IMPLANTATIONS MEAN+S.D. 14.0 + 4.5 13.6 + 3.2 15.2 + 1.8 14.4 + LIVE FETUSES N MEAN+S.D. 109 13.6 + 4.6 93 13.3 + 3.0 116 14.5 + '1.7 110 13.6 + LIVE KALE FETUSES N 49 42 59 50 t LIVE KALE FETUSES/LITTER MEAN+S.D. 43.1 + 14.3 42.8 + 22.2 50.5 + 13.0 46.7 + I LIVE FETAL BODY WEIGHTS (GRAMS)/LITTER MALE FETUSES FEMALE FETUSES HEAN+S.D. MEAN+S.D. MEAN+S.D. 3.40 + 0.47 3.53 + 0.47 3.30 + 0.44 3.43 + 0.22 3.56 + 0.23 3.36 + 0.21 3.28 + 0.17 3.37 + 3.ie + 0.21 o.is 3.34 + 0 3.42 + 0 3.25 + 0 1 RESORBED CONCEPTUSES/LITTER HEAN+S.D. 2.7 + 5.6 1.8 + 3.0 4.6 + 6.9 4.4 + --------------------------------------------------7 ----------------------------------------------------------------------- a. Dosage occurred on days 6 through 17 of gestation. PROTOCOL 418-011p: OPAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T TABLE 7 4PAGE 2): LITIRER OBSERVATIONS (CAESAREAN- DELIVERED FETUSES) - SUMMARY ------------------------- DOSAGE GROUP DOSAGE (MG/KG/DAY)a ------------------------- LITTERS WITH ONE OR MORE LIVE FETUSES -------------------------------------------------------------------------------------------------- v vi Vil 20 25 35 -------------------------------------------------------------------7----------------------------- N IMPLANTATIONS MEAN+S.D. 15.1 + 1.7 14.9 + 2.8 15.1 + 2.2 LIVE FETUSES N HEAN+S.D. lis 14.6 + 1.8 116 14.5 + 2.6 114 14.2 + '2.4 LIVE MALE FETUSES N 66 59 58 t LIVE MALE FETUSES/LITTER 14EAN+S.D. 55.3 + 9.1 49.2 + 13.8 50.4 + 15.3 LIVE FETAL BODY WEIGHTS (GRA14S)/LITTER KALE FETUSES FEMALE FETUSES HEAN+S.D. HEAN+S.D. MEAN+S.D. 3.24 + 0.15 3.34 + 0.17 3.13 + 0.14 3.11 + 0.18 3.21 + 0.21 3.03 + 0.20 2.93 + 0.46 3.03 + 0.45 2.83 + 0.44 t RESORBED CONCEPTUSES/LITTER ------------------------ HEAN+S.D. 2.6 + 3.6 2.4 + 4.4 5.9 + 7.5 ------------------------------------------------------------------------------------------------- a. Dosage occurred on days 6 through 17 of gestation. PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF H-ETPOSE IN RATS (SPONSOR'S STUDY NUMBER: T TABLE 6 (PAGE 1): PETAL GROSS EXTERNAL ALTERATIONS - SUMMARY - ---- -- -- --- - --- -- - -- -- - -- -- --- -- -- --- -- -- --- -- -- --- -- --- -- --- -- - -- --- -- -- --- ---- -- -- --- --- - --- -- --- -- -- - -- -- --- --- --- -- ---- DOSAGE GROUP I III IV DOSAGE (MG/KG/DAY)a 0 (VEHICLE) 5 10 ---------------------------------------------------------------------------------------------------------------------------- LITTERS EVALUATED N 8 7 8 8 FETUSES EVALUATED N 109 93 116 110 LIVE N 109 93 116 110 ---------------------------------------------------------------------------------------------------------------------------- BODYs EDEMA LITTER INCIDENCE FETAL INCIDENCE N (1) N(t) 0( 0.0) 0( 0.0) 0( 0.0) o( o-C) o( o.ol 0( 0.0) o( o.o) 0( 0.0) PALHTE: CLEFT LITTER INCIDENCE N 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) PETAL INCIDENCE N(t) 0( 0.0) 0( 0.0) 0( 0-0) 0( 0-0) ---------------------------------------------------------------------------------------------------------------------------- a. Dosage occurred on days 6 through 17 of gestation. PROTOCOL 418-OlIP-. ORAL IGAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T- TABLE 6 (PAGE 2): FETAL GROSS EXTERNAL ALTERATIONS - SUMMARY ---------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP v vi Vil DOSAGE (MG/KG/DAY)a 20 25 35 ---------------------------------------------------------------------------------------------------------------------------- LITTERS EVALUATED N 8 a 8 FETUSES EVALUATED N lie 116 114 LIVE N 118 116 214 -------------------------- ------------------------------------------------------------------------------------------------- BODY: EDEMA LITTER INCIDENCE FETAL INCIDENCE N(t) N(t) 0( 0.0) 0( 0..0) 0( 0-0) 0( 0.0) 1( 12.S) 2( l.Sib,c PALATE: CLEFT LITTER INCIDENCE FETAL INCIDENCE N(t) N(l) 0( 0-0) 0( 0.0) 0( 0-0) o( o.0) 1( 12.5) 13( 11.4)b,c ---------------------------------------------------------------------------------------------------------------------------- a. Dosage occurred on days 6 through 17 of gestation. b. Fetus 10650-1 had other gross external alterations. c. Fetus 10650-10 had other gross external alterations. PROTOCOL 418-OlIP! ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS ISPONSOR'S STUDY NUMBER: T TABLE 9 (PAGE 1) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA -- -- -- --- -- --- -- -- -- -- -- --- - - -- ------ -- -- -- --- -- -- -- --- -- --- -- -- --- -- -- --- - --- --- -- -- --- -- ---- -- -- -- -- --- --- -- --- --- -- --- --- RAT # DESCRIPTION ---------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY ---------------------------------------------------------------------------------------------------------------------------- 10601 NO ADVERSE FINDINGS 10602 NO ADVERSE FINDINGS 20603 NO ADVERSE FINDINGS 10604 NO ADVERSE FINDINGS 10605 NO ADVERSE FINDINGS 10606 NO ADVERSE FINDINGS 10607 NO ADVERSE FINDINGS 10608 NO ADVERSE FINDINGS --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP Il 1 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10609 NO ADVERSE FINDINGS 10610 NO ADVERSE FINDINGS 10611 NO ADVERSE FINDINGS 10612 NO ADVERSE FINDINGS 10613 NO ADVERSE FINDINGS 10614 NO ADVERSE FINDINGS 10625 NO ADVERSE FINDINGS 10616 NO ADVERSE FINDINGS --------------------------------------------------------------------------------------------------------------------------- DG - DAY OF PRESUMED GESTATION PROTOCOL 418-OlIP: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETPOSE IN RATS (SPONSOR'S STUDY NMBER: T TABLE 9 (PAGE 2) - CLINICAL OBSERVATIONS - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------------- RRT 0 DESCRIPTION --------------------------------------------------------------------------------- DOSAGE GROUP 111 5 NG/KG/DAY --------------------------------------------------------------------------------- 10617 DG( 23- 20) LOCALIZED ALOPECIAs LIMBS a 10610 NO ADVERSE FINDINGS 10619 NO ADVERSE FINDINGS 10620 No ADVERSE FINDINGS 10621 NO ADVERSE FINDINGS 10622 NO ADVERSE FINDINGS 10623 NO ADVERSS FINDINGS 10624 DG( 14- 20) LOCALIZED ALOPECIA: UNDERSIDE a DG( 20 ) LOCALIZED ALOPECIA: NECK a --------------------------------------------------------------------------------------------- DOSAGE GROUP IV 10 NO/KG/DAY ------------------------------------------------------------------- 1062S 20626 10627 10629 NO ADVERBS NO ADVERSE NO ADVERSE NO ADVERSE FINDINGS FINDINGS FINDINGS FINDINGS 10629 10630 10631 NO ADVERSE NO ADVERSE NO ADVERSE FINDINGS FINDINGS FINDINGS 10632 NO ADVERSE FINDINGS --------------------------------------------------------------------------------------------- DO . DAY OF PRESUMED GESTATION a. observation confirmed at necropsy. PROTOCOL 418-OlIP: OPAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETPOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 9 (PAGE 3): CLINICAL OBSERVATIONS -,INDIVIDUAL DATA --------------------------- ---------------------------------------------------------------------------------------------- RAT # DESCRIPTION -------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP V 20 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10633 NO ADVERSE FINDINGS 10634 NO ADVERSE FINDINGS 10635 10636 NO ADVERSE NO ADVERSE FINDINGS FINDINGS 10637 DG( 15- 17) CHROMODACRYORRHEA 10638 NO ADVERSE FINDINGS 10639 NO ADVERSE FINDINGS 10640 NO ADVERSE FINDINGS --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP VI 25 MG/KG/DAY -------------------------------------------------------------------------------------------------------------------------- 10641 NO ADVERSE FINDINGS 10642 NO ADVERSE FINDINGS 10643 DG( 14- 20) LOCALIZED ALOPECIA: UNDERSIDE a DG( IS- 20) LOCALIZED AEOPECIA: BACK a 10644 NO ADVERSE FINDINGS 10645 NO ADVERSE FINDINGS 10646 NO ADVERSE FINDINGS 10641 NO ADVERSE FINDINGS 10648 NO ADVERSE FINDINGS -------------------------------------------------------------------------------------------------------------------------- DG @ DAY OF PRESUMED GESTATION a. Obaervation confirmed at necropsy. PROTOCOL 416-OIIP: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NU14BER: T TABLE 9 (PAGE 4): CLINICAL OBSERVATIONS - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------------- RAT # DESCRIPTION ---------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP VIT 35 MG/KG/DAY ---------------------------------------------------------------------------------------------------------------------------- 10649 NO ADVERSE FINDINGS 10650 DG( 13- 20) LOCALIZED ALOPECIA: UNDERSIDE a DG( 13- 20) LOCALIZED ALA3PECIA: BACK a DG( 17- 20) EMACIATION a 106si NO ADVERSE FINDINGS 10652 NO ADVERSE FINDINGS 10653 DG ( 8- 19) LOCALIZED ALOPECIA: LIMBS DG( 20 ALOPECIA NO LONGER APPARENT 10654 NO ADVERSE FINDINGS 10655 NO ADVERSE FINDINGS 10656 DGI 12 CHROMORHINORRHEA ---------------------------------------------------------------------------------------------------------------------------- DG - DAY OF PRESUMED GESTATION a. observation confirmed at necropsy. PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T TABLE 10 (PAGE 1) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA ---------------------------- ------------------------------------------------------------------------------------------------ DOSAGE GROUP RAT DAY OF PREGNANCY DOSAGES (MG/KG/DAY) NUMBER NECROPSY STATUS ADMINISTERED OBSERVATIONS a --------------------------0- - ------------------------------------------------------------------------------------------------ I 0 (VEHICLE) 10601 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10602 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10603 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10604 DO 20 p 12 ALL TISSUES APPEARED NORMAL. 10605 DO 20 p 12 ALL TISSUES APPEARED NORMAL. 10606 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10607 Dr. 20 p 12 ALL TISSUES APPEARED NORMAL. 10608 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 1 10609 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10610 DG 20 NP 12 ALL TISSUES APPEARED NORMAL. 10611 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10612 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10613 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10614 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10615 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10616 DG 20 p 12 ALL TISSUES APPEARED NORMAL. --------------------------------------------------------------------------------------------------------------------------- P - PREGNANT NP . NOT PREGNANT DG - DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 9) for external observations confirmed at necropsy. PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-63 TABLE 10 (PAGE 2): NECROPSY OBSERVATIONS - INDIVIDUAL DATA -------------------------------------------------------- --------------------------------------------------------------------- DOSAGE GROUP PAT DAY OF PREGNANCY DOSAGES STATUS ADMINISTERED OBSERVATIONS a ---------------------------- (MG/KG/DAY) NUMBER NECROPSY -------------------------------------------------------------------------------------------------- III 5 10617 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10610 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10619 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10620 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10621 DG 20 p 12 ALL TISSUES ALL TISSUES APPEARED APPEARED NORMAL. NORMAL. 1100662223 DDGG 2200 pp 1122 ALL TISSUES APPEARED NORMAL. 10624 DG 20 p 12 ALL TISSUES APPEARED NORMAL. IV 10625 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10 10626 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10627 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10628 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10629 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10630 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10631 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10632 DG 20 p 12 ALL TISSUES APPEARED NORMAL. ----------------------------------------------------------------------------------------------------------------------------- P . PREGNANT NP - NOT PREGNANT DG - DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations for external observations table (Table 9) confirmed at necropsy. PROTOCOL 418-011P: OPAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 10 (PAGE 3): RECROPSY OBSERVATIONS - INDIVIDUAL DATA - --- -- -- -- -- --- -- --- -- -- --- - ------- -- -- --- --- -- -- -- -- -- --- -- -- --- -- --- -- --- -- --- -- -- -- --- - ---- -- --- --- -- -- -- -- --- --- -- --- -- DOSAGE GROUP PAT DAY OF PREGNANCY DOSAGES (KG/KG/DAY) NUMBER NECROPSY STATUS ADMINISTERED OBSERVATIONS a --------------------------------------------------------------------------------------------------------------------------- v 20 10633 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10634 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10635 Dri 20 p 12 ALL TISSUES APPEARED NORMAL. 10636 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10637 D(I 20 p 12 ALL TISSUES APPEARED NORMAL. 10638 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10639 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10640 DG 20 p 12 ALL TISSUES APPEARED NORMAL. vi 2S 10641 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10642 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10643 DO 20 p 12 ALL TISSUES APPEARED NORMAL. 10644 DO 20 p 12 ALL TISSUES APPEARED NORMAL. 10645 D(I 20 p 12 ALL TISSUES APPEARED NORMAL. 10646 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10647 D(; 20 p 12 ALL TISSUES APPEARED NORMAL. 1064e DG 20 p 12 ALL TISSUES APPEARED NORMAL. -------------------------------------------------------------------------------------------------------------------------- P - PREGNANT UP . NOT PREGNANT DG - DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 9) for external observations confirmed at necropsy. PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 10 (PAGE 4); NECROPSY OBSERVATIONS - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP RAT DAY OF PREGNANCY DOSAGES (MG/KG/DAY) NUMBER NECROPSY STATUS ADMINISTERED OBSERVATIONS a --------------------------------------------------------------------------------------------------------------------------- vii 35 10649 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10650 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10651 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10652 DC 20 p 12 ALL TISSUES APPEARED NORMAL. 10653 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10654 DG 20 p 12 ALL TISSUES APPEARED NORMAL. 106SS DG 20 p 12 ALL TISSUES APPEARED NORMAL. 10656 DG 20 p 12 ALL TISSUES APPEARED NORMAL. --------------------------------------------------------------------------------------------------------------------------- P . PREGNANT NP - NOT PREGNANT DG - DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 9) for external observations confirmed at necropsy. PROTOCOL 418-OlIP: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 11 (PACE 1) : MATEFTJNAL BODY WEIGHTS - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------------- RAT # DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 15 --------------------------------------------------------------------------------------------------------------------------- 10601 p 10602 P 10603 P 10604 P 10605 p 10606 p 10607 P 10608 p 218. 227. 242. 245. 238. 232. 250. 235. 236. 253. 276. 278. 261. 273. 273. 249. 244. 263. 286. 280. 260. 275. 269. 254. 242. 270. 292. 290. 261. 271. 272. 257. 247. 273. 300. 293. 263. 280. 277. 264. 252. 281. 303. 299. 267. 284. 280. 265. 257. 287. 314. 306. 270. 294. 285. 273. 265. 291. 318. 312. 274. 301. 291. 271. 270. 295. 321. 315. 282. 310. 288. 282. 274. 308, 335. 322. @85. 313. 295. 209. 274. 311. 341. 325. 289. 321. 301. 292. 282. 318. 348. 334. 297. 325. 301. 300. --------------------------------------------------------------------------------------------------------------------------- DAY 17 is 19 20 --------------------------------------------------------------------------------------------------------------------------- 10601 p 310. 319. 335. 361. 10602 P 330. 361. 371. 399. 10603 P 377. 400. 412. 432. 10604 P 353. 371. 390. 414. 10605 p 315. 329. 347. 362. 10606 P 348. 363. 392. 405. 20607 P 310. 315. 332. 338. 10608 p 324. 343. 359. 374. -------------------------------------------------------------------------------------------------------------------------- PDAY ALL PREGNANT, UP . NOT PREGNANT (VALUES - DAY OF PRESUMED GESTATION WEIGHTS WERE RECORDED IN GRAMS (G) EXCLUDED FROM AVERAGES) PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T TABLE 11 (PAGE 2): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA ---------------------------------------------------------------------------------------------------------------------------- RAT # DOSAGE GROUP Il I MG/KG/DAY ---------------------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 15 --------------------------------------------------------------------------------------------------------------------------- 10609 p 10610 NP 241. 235. 267. 247. 276. 250. 278. 251. 286. 255. 289. 240. 296. 256. 302, 260. 309. 261. 313. 268. 321. 259. 330. 263. 10612 p 256. 250. 285. 282. 289. 295. 301. 306. 307. 313. 314. 321. 10612 P 10613 P 219. 24S. 246. 270. 251. 280. 255. 282. 260. 265. 265. 291. 272. 296. 276. 297. 283. 309. 290. 310. 292. 321. 298. 324. 10614 P 10615 P 10616 p 230. 225. 239. 256. 243. 251. 258. 241. 260. 262. 243. 262. 267. 245. 261. 274. 250. 272. 261. 259, 274. 276. 256. 278. 288. 258. 288. 291. 268. 291. 290. 279. 300. 300. 280. 302. --------------------------------------------------------------------------------------------------------------------------- DAY 17 is 19 20 --------------------------------------------------------------------------------------------------------------------------- 10609 p 351. 373. 386. 412. 10610 NO 266. 270. 265. 265. 10611 p 10612 P 353. 325. 374. 342. 389. 357. 409. 383. 10613 P 354. 369. 384. 408. 10614 P 311. 328. 331. 337. 10615 P 297. 318. 325. 344. 10616 p 320. 332. 352. 358. --------------------------------------------------------------------------------------------------------------------------- PDAY ALL PREGNANT NP - NOT PREGNANT (VALUES - DAY OF PRESUMED GESTATION WEIGHTS WERR RECORDED 3:N GRAMS (G) EXCLUDED FROM AVERAGES) PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 11 (PAGE 3): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA -- -- --- -- -- -- -- --- - --- --- - - - ------- --- --- - --- --- -- --- -- -- --- -- -- -- -- --- -- --- --- - -- -- --- --- -- -- -- -- ---- -- --- -- --- --- -- -- -- -- RAT # DOSAGE GROUP 111 5 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 15 --------------------------------------------------------------------------------------------------------------------------- 10617 P 242. 265. 270. 272. 277. 281. 286. 287. 291. 292. 295. 302. 10618 P 244. 264. 273. 276. 280. 285. 291. 299. 300. 306. 310. 316. 10619 P 223. 243. 249. 253. 260. 264. 274. 278. 283. 293. 294. 304. 10620 p 229. 258. 265. 266. 272. 277. 280. 286. 290. 302. 300. 307. 10621 P 230. 256. 251. 256. 263. 267. 270. 279. 276. 260. 289. 293. 10622 P 236. 260. 268. 270. 274. 276. 280. 287. 268. 288. 294. 297. 10623 P 240. 248. 250. 260. 264. 267. 272. 273. 280. 2e2. 287. 296. 10624 P 247. 270. 277. 279. 284. 292. 298. 306. 299. 304 311. 320. --------------------------------------------------------------------------------------------------------------------------- D" 17 is 19 20 --------------------------------------------------------------------------------------------------------------------------- 10617 P 316. 334. 344. 371. 10619 P 339. 351. 366. 384. 10619 P 327. 341. 355. 380. 10620 P 324. 342. 352. 377. 10621 P 321. 339. 358. 373. 10622 P 326. 340. 365. 369. 10623 P 313. 334. 345. 3S7. 10624 P 341. 359. 377. 389. --------------------------------------------------------------------------------------------------------------------------- PDAY ALL PREGNANT NP - NOT PREGNANT (VALUES - DAY OF PRESUMED GESTATION WEIGHTS WERE RECORDED IN GRAMS (G) . EXCLUDED FROM AVERAGES) PROTOCOL 418-OlIP: ORAL (GAVAGE) DOSAGE-R.ANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETPOSE IN RATS (SPONSOR'S STUDY NTIMBER: T TABLE 11 (PAGE 4): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA ----------------------- --------------------------- --------------------------- -------------------------- -------------------- RAT # DOSAGE GROUP IV 10 MG/KG/DAY ---------------------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 is ---------------------------------------------------------------------------------------------------------------------------- 10625 P 242. 268. 275. 275. 281. 285. 295. 298. 301. 309. 311. 317. 10626 P 223. 234. 237. 239. 240. 243. 250. 252. 256. 259. 262. 264. 10627 P 237. 258. 264. 266. 270. 273. 276. 279. 278. 285. 287. 292. 10626 P 10629 P 10630 P 235. 244. 234. 254. 270. 254. 2S3. 269. 257. 256. 276. 244. 262. 282. 233. 265. 286. 246. 270. 286. 249. 278. 299. 256. 20S. 307. 268. ;89. 308. 260. 292. 316. 269. 302. 322. 276. 20631 P 227. 244. 243. 248. 248. 252. 252. 255. 262. 264. 272. 279. 20632 P 246. 258. 264. 268. 271. 265. 273. 281. 286. 293. 297. 317. --------------------------------------------------------------------------------------------------------------------------- DAY 17 is 19 20 --------------------------------------------------------------------------------------------------------------------------- 20625 P 341. 345. 365. 364. 10626 P 276. 269. 299. 312. 10627 P 311. 327. 332. 353. 2062B P 319. 330. 349. 364. 10629 P 340. 356. 377. 39e. 10630 P 297. 306. 321. 342. 10631 P 294. 315. 330. 342. 10632 P 327. 342. 357. 378. --------------------------------------------------------------------------------------------------------------------------- P @ PREGNANT NP . NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY - DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-011P: ORAL. (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 11 (PAGE 5) : 14ATERNAL BODY WEIGHTS - INDIVIDUAL DATA ---------------------------------------------------------------------------------------------------------------- --------- RAT I DOSAGE GROUP V 20 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 is --------------------------------------------------------------------------------------------------------------------------- 10633 P 239. 259. 267. 268. 273. 277. 278. 282. 289. 295. 296. 304. 10634 P 232. 260. 260. 256. 264. 269. 272. 280. 282. 290. 290. 303. 10635 P 224. 244. 247. 24e. 251. 251. 246. 249. 255. 255. 261. 257. 10636 P 228. 260. 269. 268. 273. 283. 284. 290. 288. 299. 292. 308, 10637 P 244. 259. 262. 260. 260. 266. 266. 275. 278. 281. 290. 294. 10636 P 237. 250. 254. 254. 251. 255. 262. 270. 278. 281. 2e3. 29S. 10639 P 240. 266. 268. 272. 271. 2es. 284. 293. 298. 304. 306. 311. 10640 P 247. 270. 270. 260. 262. 262. 269. 273. 279. 280. 267. 289. --------------------------------------------------------------------------------------------------------------------------- DAY 17 is 19 20 --------------------------------------------------------------------------------------------------------------------------- 10633 P 326. 334. 351. 372. 10634 P 327. 342. 352. 376. 10635 P 277, 2eS. 293. 314. 10636 P 10637 P 338. 31e. 356. 326. 366. 340. 367. 363. 10636 P 316. 326. 342. 358. 10639 P 331. 347. 362. 376. 10640 P 313. 331. 348. 362. --------------------------------------------------------------------------------------------------------------------------- P - PREGNANT NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY - DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL. 418-OlIP: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBERT TABLE 11 (PAGE 6) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------------- PAT I DOSAGE GROUP VI 25 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- PRSETGANTAUNSCY DAY 0 4 6 7 a 9 10 11 12 13 14 is ----------- --------------------------------------------------------------------------------------------------------------- 10641 P 240. 256. 264. 256. 262. 269. 265. 274. 273. 275. 274. 286. 10642 P 221. 237. 240. 236. 239. 242. 247. 247. 244. 245. 248. 261. 10643 P 247. 265. 270. 268. 269. 276. 281. 288. 288. 292. 291. 298. 10644 P 236. 262. 270. 267. 264. 270. 278. 277. 281. 282. 270. 263. 10645 P 244. 270. 275. 275. 270. 282. 283. 285. 301. @94. 301. 303. 10646 P 233. 249. 249. 247. 246. 250. 255. 258. 261. 262. 256. 254. 10647 P 22B. 249. 260. 261. 266. 273, 276. 274. 272. 276. 279. 264. 10648 P 239. 275. 284. 266. 291. 292. 292. 290. 288. 290. 295. 299. -------------------------------------------------------------------------------------------------------------------------- DAY 17 18 19 20 -------------------------------------------------------------------------------------------------------------------------- 10641 p 304. 314. 329. 349. 10642 P 291. 297. 304. 323. 10643 P 333. 345. 360. 377. 10644 P 273. 303. 324. 340. 10645 P 325. 337. 356. 359. 10646 P 276. 265. 302. 316. 10647 P 299. 320. 329. 336. 10648 P 322. 343. 352. 364. ------------------------------------------------------------------------------------------------------------------------- P . PREGNANT NP - NOT PREGNANT (VALUES DAY - DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDEL) IN GRAMS (G) EXCLUDED FROM AVERAGES) PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 11 (PAGE 7): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------- RAT I DOSAGE GROUP VII 35 MG/KG/DAY ------------------------------------------------------------------------------------------------------------------- ------- PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 is --------------------------------------------------------------------------------------------------------------------------- 10649 P 244. 252. 258. 260. 264. 264. 267. 268. 274. 276. 281. 286. 10650 P 237. 2S3. 266. 264. 269. 261. 268. 260. 252. 235. 223. 216. 10651 P 222. 245. 251. 254. 262. 267. 268. 275. 278. 279. 285. 292. 10652 P 227. 243. 248. 250. 249. 251. 256. 258. 260. 266. 269. 27S. 10653 P 246. 269. 276. 275. 269. 276. 274. 281. 279, 280. 277. 289. 10654 P 231. 256. 261. 268. 267. 273. 274. 276. 281. 259. 289. 297. 10655 P 238. 249. 2S4. 252. 255. 254. 242. 248. 252. 258. 266. 271. 10656 P 247. 275. 275. 272. 266. 274. 276. 269. 262. 287. 26S. 266. --------------------------------------------------------------------------------------------------------------------------- DAY 17 le 19 20 --------------------------------------------------------------------------------------------------------------------------- 10649 P 291. 305. 316. 332. 10650 P 207. 200. 220. 239. 10651 P 316. 334. 350. 374. 10652 P 293. 304. 316. 343. 20653 P 300. 326. 331. 350. 10654 P 313. 327. 347. 364. 1065S P 269. 302. 324. 337. 10656 P 303. 320. 341. 350. -------------------------------------------------------------------------------------------------------------------------- P - PREGNANT NP - NOT IPREGNANT (VALUES DAY - DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) EXCLUDED FROM AVERAGES) PROTOCOL 418-OIIP: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBERI T TABLE 12 IPAGE 1) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA ---------------------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAYS 0 - 4 4 - 6 6 - 8 8 - 10 10 - 12 12 - 14 14 - 16 16 - 18 18 - 20 --------------------------------------------------------------------------------------------------------------------------- PAT # DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10601 p 76. 45. 40. 44. 45. 44. 47. 54. 49. 10602 P 93. S6. 49. 49. a a 48. 53. 54. 10603 P 97. 56. 56. 54. S6. 61. 54. 61. 54. 10604 P 115. 62. 64. 61. 60. 55. 45. 53. 61. 10605 P 87. 44. 40. 43. 44. 46. 44. 50. 52. 10606 p 103. 51. 56. 53. 57. 55. 51. 54. 56. 10607 P 89. 47, 68. 57. 60. 90. 55. 46. 53. 10608 p 72. 37. 42. 46, 45. 43. 43. 44. 40. --------------------------------------------------------------------------------------------------------------------------- RAT I DOSAGE GROUP II I MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10609 p 97. 50. 49. 50. 50. 51. 50. 53. 53. 10610 NP so. 44. 44. 39. 43. 42. 37. 49. 36. 10611 p 77. 55. 51. 52. 49. 47. 50. 59. 57. 10612 P 94. 46. 51. S4. 47. 52. 52. 57. 54. 10613 P 93. 53. 46. 49. 46. 54. 60. 62. 57. 10614 P 94. 43. 51. 50. 48. 58. 53. 44. 47. 10615 p 61. 38. 41. 40. 38. 78. 41. 42. 51. 10616 P 76. 42. 40. 43. 45. 51. 4S. 40. 48. --------------------------------------------------------------------------------------------------------------------------- P - PREGNANT DAYS - DAYS ALL WEIGHTS a. Spilled NP . NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) OF GESTATION WERE RECORDED IN GRAMS (G) feed precluded the calculation of this value. PROTOCOL 418-OlIP: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: T TABLE 12 (PAGE 2): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA ------------------------------------------------------------------ --------------------------------------------------------- PREGNANCY STATUS DAYS 0 - 4 4 - 6 6 - 8 8 - 10 10 - 12 12 - 14 14 - 16 16 - 18 18 - 20 ---------------------------------------------------------------------------------------------------------------------------- RAT I DOSAGE GROUP 111 5 MG/KG/DAY ---------------------------------------------------------------------------------------------------------------------------- 10617 P 90. 48. 45. 45. 45. 40. 45. 49. 49. 10618 p 94. 56. 22. 48. 50. 52. 51. 55. 53. 10619 p 86. 49. 49. 51. 56. 54. 53. 56. 56. 10620 P 95. 50. 50. 49. 54. 48. 46. 48. 44. 10621 P 90. 46. 44. 47. 46. 51. 48. 51. 52. 10622 P 95. 47. 47. 48. 46. 42. 36. 47. 50. 10623 P 90. 44. 45. 47. 44. 46. 48. 53. 43. 10624 P 103. 46. 50. 52. 50. 43. 47. 48. 50. ---------------------------------------------------------------------------------------------------------------------------- RAT # DOSAGE GROUP IV 10 MG/KG/DAY ---------------------------------------------------------------------------------------------------------------------------- 1062S P 91. 50. 45. 48. 48. 46. 44. 48. 50. 10626 P 66. 33. 31. 38. 40. 35. 35. 37. 36. 10627 P 90. 56. 47. 43. 45. 40. 34. 46. 50. 10620 P 05. 42. 44. 45. 48. 50. 47. 46. 52. 10629 P as. 45. 47. 49. 50. 55. 46. 51. 55. 10630 P 65. 46. 14. 35. 44. 40. 38. 39. 49. 10631 P 77. 40. 36. 38. 40. 47. 45. 39. 41. 10632 P 88. 43. 41. 37. 49. 50. 49. 49. 51. --------------------------------------------------------------------------------------------------------------------------- P - PREGNANT DAYS - DAYS ALL WEIGHTS NP - NOT PREGNANT (VALUES OF GESTATION WERE RECORDED IN GRAMS IG). EXCLUDED FROM AVERAGES) PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN PATS (SPONSOR'S STUDY NUMBER: TABLE 12 (PAGE 3): MATERNAL FEED CONSLYMPTION VALUES - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAYS 0- 4 4- 6 6- 8 8 - 10 10 - 12 12 - 14 14 - 16 16 - 10 18 - 20 --- -- --- -- -- -- -- - --- --- -- -- --- --- - ----- ---- --- -- -- --- --- -- -- --- -- -- -- --- -- --- --- -- ---- -- -- -- -- -- -- --- -- ---- -- --- -- --- --- --- RAT I DOSAGE GROUP V 20 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10633 P so. 50. 47. 46. 47. 48. 46. 51. 48. 10634 P 89. 47. 41. 44. 46. 43. 47. 49. 44. 10635 P 78. 48. 31. 28. 33. 31. 21. 35. 41. 10636 P 105. 62. 45. 57. 44. 48. 59. 59. 53. 10637 P 87. 48. 41. 42. SO. 48. 48. 52. 51. 10638 P 140. 47. 40. 44. 51. 48. 46. 43. 44. 10639 P 95. 54. 54. 54. 52. 50. 46. 41. 51. 10640 P 103. 47, 41. 40. 47. 53. 49. 44. 49. --------------------------------- ------------------------------------------------------------------------------------------ RAT I DOSAGE GROUP VI 25 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 20641 P 86. 48. 36. 40. 41. 33. 38. 37. 40. 10642 P 79. 42. 32. 34. 35. 25. 41. 41. 38. 20643 P 83. 47. 40. 4S. 46. 38. 44. 53. 48. 10644 P 94. sil 38. 45. 43. 25. 11. 40. 46. 10645 P 91. S4. Si. 45. 47. 40. 46. 39. 45. 20646 P 73. 38. 31. 35. 37. 27. 26. 32. 43. 10647 P 75. 38. 38. 45. 38. 39. 40. 48. 42. 10648 P 102. 54. 50. 46. 34. 39. 38. 46. 42. --------------------------------------------------------------------------------------------------------------------------- P - PREGNANT DAYS = DAYS ALL WEIGHTS NP - NOT PREGNANT (VALUES OF PRESUMED GESTATION WERE RECORDED IN GRA14S iG). EXCLUDED FROM AVERAGES) PROTOCOL 418-011P: OPAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETPOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 12 IPAGE 4) : MATERNAL PEED CONSUMPTION VALUES - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------------- PREGNANCY STATUS DAYS 0 - 4 4 - 6 6 - 8 8 - 10 10 - 12 12 - 14 14 - 16 16 - 18 18 - 20 --------------------------------------------------------------------------------------------------------------------------- RAT I DOSAGE GROUP VII 35 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10649 P 86. 46. 41. 41. 43. 41. 39. 38. 43. 10650 p 87. 49. 45. 39. 17. 2. 1. 13. 34. 10651 p 94. 53. 49. 46. 45. 42. 45. 51. 52. 10652 P 60. 43. 40. 38. 41. 39. 42. 44. 46. 10653 P 95. 55. 48. 43. 47. 46. 41. 35. 62. 10654 P 89. 46. 44. 46. 45. 46. 40. 36. 52. 10655 P 82. 47. 37. 25. 39, 64. 43. 43. 55. 10656 P 90. 42. 33. 42. 26. 42. 39. 38. 44. --------------------------------------------------------------------------------------------------------------------------- P - PREGNANT DAYS - DAYS ALL WEIGHTS UP - NOT PREGNANT (VALUES OF PRESUMED GESTATION WERE RECORDED IN GRAMS (C). EXCLUDED FROM AVERAGES) PROTOCOL 418-OlIP: ORAL IGAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN PATS (SPONSOR'S STUDY NUMBER: TABLE 13 (PAGE 1) : CAESAREAN -SECTIONING OBSERVATIONS - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------------- VIABLE FETUSES ------------------------ DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION SITES ---------------- ---------------- ---------------- ---------------- CORPORA LUTE -------------- SEX RAT # M F RIGHT LEFT HORN TOTAL RIGHT LEFT HORN TOTAL RIGHT LEFT HORN TOTAL RIGHT LEFT HORN TOTAL RIGHT LEFT HORN TOTAL RIGHT LEFT OVARY TOT --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10601 6 7 6 7 13 0 0 0 0 0 0 0 0 0 6 7 13 6 7 1 10602 5 10 11 4 is 0 0 0 1 0 1 0 0 0 12 4 16 12 5 1 10603 12 5 9 a 17 0 0 0 0 0 0 0 0 0 9 a 17 11 6 1 10604 5 10 3 12 15 0 0 0 0 0 0 0 0 0 3 12 is 4 12 1 10605 6 5 8 3 11 0 0 0 0 2 2 0 0 0 a 5 13 a 6 1 10606 6 9 5 20 is 0 0 0 0 0 0 0 0 0 5 10 15 5 11 1 10607 1 3 1 3 4 0 0 0 0 0 0 0 0 0 1 3 4 5 8 1 10606 8 11 10 9 19 0 0 0 0 0 0 0 0 0 10 9 19 10 10 2 --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 11 1 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10609 11 s 7 9 16 0 0 0 0 0 0 0 0 0 7 9 16 7 11 1 10610 NOT PREGNANT 10611 2 13 8 7 15 0 0 0 0 1 1 0 a 0 a a 16 9 9 10612 5 9 7 7 14 0 0 0 0 0 0 0 0 0 7 7 14 9 9 10613 9 6 9 6 15 0 0 0 0 1 1 0 0 0 9 7 16 10 7 10614 1 6 1 6 7 0 0 0 0 0 0 0 0 0 1 6 7 5 7 1061S 7 6 4 9 13 0 0 0 0 0 0 0 0 0 4 9 13 5 9 ----1-0-6-16----7----6------6------7-----1-3------0------0------0------0-----0------0------0------0------0------6------7-----13-------6 -----7------- N - KALE PLACENTAE F - FEMALE APPEARED NORMAL UNLESS NOTED OTHERWISE. PROTOCOL 418-OlIP: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 13 (PAGE 2): CAESAREAN -SECTIONING OBSERVATIONS - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------------- VIABLE FETUSES ------------------------ DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION SITES ---------------- ---------------- ---------------- ---------------- CORPORA LUTE -------------- SEX RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RAT I N p HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TOT --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 111 5 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10617 7 6 7 6 13 0 0 0 0 1 1 0 0 0 7 7 14 7 7 1 10618 3 10 4 9 13 0 0 0 1 1 2 0 0 0 5 10 15 7 10 2 10619 7 9 10 6 16 0 a 0 0 0 0 0 0 0 10 6 16 10 7 1 10620 8 7 6 9 is 0 0 0 3 0 3 0 0 0 9 9 18 9 9 1 10621 9 6 9 6 is 0 0 0 0 0 0 0 0 0 9 6 is 10 6 1 10622 7 8 7 8 15 0 0 0 0 0 0 0 0 0 7 a is 7 6 1 10623 7 5 4 8 12 0 0 0 0 0 0 0 0 0 4 8 12 4 9 1 10624 11 6 6 21 17 0 0 0 0 a 0 0 0 0 6 11 17 6 12 1 --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP IV 20 MG/KG/DAY -------------------------------------------------------------------------------------------------------------------------- 10625 S 10 11 4 15 0 0 0 1 0 1 0 0 0 12 4 16 13 8 10626 7 3 3 7 10 0 0 0 0 0 0 0 1 1 3 a 11 3 9 10627 6 7 9 4 13 0 0 0 0 1 1 0 0 0 9 5 14 9 5 10628 8 7 5 10 is 0 0 0 0 0 0 0 0 0 5 10 15 6 10 10629 6 9 8 7 15 0 0 0 0 0 0 0 0 0 a 7 is 6 7 10630 8 5 10 3 13 0 0 0 0 0 0 0 0 0 10 3 13 10 5 10631 S 10 11 4 15 0 0 0 0 0 0 0 0 0 11 4 15 12 6 10632 5 9 6 8 14 0 0 0 2 0 2 0 0 0 8 8 16 8 9 -------------------------------------------------------------------------------------------------------------------------- N - MALE PLACENTAE F - FEMALE APPEARED NORMAL UNLESS NOTED OTHERWISE. PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 13 (PAGE 3): CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA --------------------------------------------------------------------------------------------- ---------------------------- VIABLE FETUSES ------------------------ DEAD FETUSES EARLY RESORPTIONS LATE RESORPTLONS IMPLANTATION SITES ---------------- ---------------- ---------------- ---------------- CORPORA LUT ------------- SEX RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RAT 4 N F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TO -------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP V 20 MG/KG/DAY -------------------------------------------------------------------------------------------------------------------------- 10633 9 5 4 10 14 0 0 0 0 0 0 0 0 0 4 10 14 4 11 20634 9 7 a a 16 0 0 0 0 0 0 0 0 0 a a 16 8 8 10635 5 6 7 4 11 0 0 0 0 1 1 0 0 0 7 t 22 7 5 10636 8 7 7 a is 0 0 0 1 0 1 0 0 0 a a 16 a a 10637 8 7 9 6 15 0 0 0 0 0 0 0 0 0 9 6 is 9 6 10638 6 a 6 a 14 0 0 0 0 0 0 0 0 0 6 6 14 6 a 10639 9 7 8 a 16 0 0 0 0 1 1 0 0 0 a 9 17 8 9 10640 12 5 7 10 17 0 0 0 0 0 0 0 0 0 7 10 17 a 11 -------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP VI 25 MG/KG/DAY -------------------------------------------------------------------------------------------------------------------------- 10641 4 9 7 6 13 0 0 0 0 0 0 0 0 0 7 6 13 7 6 10642 9 7 7 9 16 0 0 0 0 0 0 0 0 0 7 9 16 7 10 10643 8 7 9 6 is 0 0 0 0 0 0 0 0 0 9 6 15 9 a 10644 13 s a 10 is 0 0 0 1 1 2 0 0 0 9 11 20 9 11 10645 7 7 6 a 14 0 0 0 0 0 0 0 0 0 6 a 14 a a 10646 7 6 5 a 13 0 0 0 0 0 0 0 0 0 5 a 13 7 a 10647 3 7 2 8 10 0 0 0 1 0 1 0 0 0 3 8 11 3 a 10648 8 9 10 7 17 0 0 0 0 0 0 0 0 0 10 7 17 11 7 -------------------------------------------------------------------------------------------------------------------------- N - MALE PLACENTAE F - FEMALE APPEARED NORMAL UNLESS NOTED OTHERWISE. PROTOCOL 418-OlIP; ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETPOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 13 (PAGE 4)-. CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------------- VIABLE FETUSES ------------------------ DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION SITES ---------------- ---------------- ---------------- ---------------- CORPORA LUTI -------------- SEX RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RAT # N p HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TO -------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP VII 35 MG/KG/DAY -------------------------------------------------------------------------------------------------------------------------- 10649 3 a 6 5 21 0 0 0 1 1 2 0 0 0 7 6 13 7 6 10650 5 8 5 8 13 0 0 0 2 1 3 0 0 0 7 9 16 8 9 10651 9 8 10 7 17 0 0 0 0 0 0 0 0 0 10 7 17 10 a 10652 8 6 7 7 14 0 0 0 0 0 0 0 0 0 7 7 14 7 a 10653 6 7 a 5 13 0 0 0 1 0 1 0 0 0 9 5 14 9 5 10654 7 10 9 a 17 0 0 0 0 1 1 0 0 0 9 9 is 9 13 10655 9 3 5 7 12 0 0 0 0 0 0 0 0 0 5 7 12 5 7 10656 11 6 9 8 17 0 0 0 0 0 0 0 0 0 9 a 17 9 10 -------------------------------------------------------------------------------------------------------------------------- N - MALE PLACENTAS F - PEKALS APPEARED NORMAL UNLESS NOTED OTHERWISE. PROTOCOL 418-OllPi ORAL (GAVJKGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETPOSE IN RATS (SPONSOR'S STUDY NUMBER: T TABLE 14 (PAGE 1): LITTER OBSERVATIONS ICAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA ---------------------------------------------------------------------------------------------------------------------------- NUMBER OF LIVE AVERAGE FETAL ---- CONCEPTUSES ------ FETUSES BODY WEIGHT (G) RESORBED ---------------------------------------------------------------------------------------------------------------------------- RAT 0 MALE FEMALE TOTAL MALE FEMALE TOTAL a N N t ---------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10601 6 7 13 3.54 3.43 3.48 13 0 0.0 10602 s 10 is 3.71 3.SO 3.57 16 1 6.2 10603 12 5 17 3.91 3.71 3.BS 17 0 0.0 10604 5 10 15 3.68 3.44 3.52 is 0 0.0 10605 6 5 11 3.94 3.57 3.78 13 2 IS.4 10606 6 9 15 3.62 3.42 3.50 is 0 0.0 10607 1 3 4 2.45 2.30 2.34 4 0 0.0 10608 8 11 19 3.38 3.06 3.20 19 0 0.0 --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 11 1 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10609 11 s 16 3.37 3.29 3.35 16 0 0.0 10610 NOT PREGNANT 10611 2 13 is 4.01 3.64 3.69 16 1 6.2 10612 s 9 14 3.53 3.48 3.50 14 0 0.0 10613 9 6 15 3.50 3.39 3.46 16 1 6.2 10614 1 6 7 3.31 2.96 3.01 7 0 0.0 1061S 7 6 13 3.69 3.44 3.58 13 0 0.0 10616 7 6 13 3.50 3.33 3.42 23 0 0.0 --------------------------------------------------------------------------------------------------------------------------- a . TOTAL - SLTM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. PROTOCOL 418-OllPt OPAL IGAVAGE) DOSAGE-PANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETPOSE IN RATS ISPONSOR'S STUDY NUMBER: T TABLE 14 (PAGE 2): LITTER OBSERVATIONS ICAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------------- NUMBER OF LIVE AVERAGE PETAL ---- CONCEPTUSES ------ FETUSES BODY WEIGHT (C) RESORBED --------------------------------------------------------------------------------------------------------------------------- PAT # MALE FEMALE TOTAL MALE FEMALE TOTAL a N N t --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 111 5 MG/KGIDAY --------------------------------------------------------------------------------------------------------------------------- 10617 10618 10619 10620 10621 7 6 13 3.63 3.32 3.49 14 3 10 13 3.40 3.19 3.24 is 7 9 16 3.16 2.91 3.03 16 6 7 25 3.36 3.36 3.37 is 9 6 is 3.62 3.29 3.48 15 1 7.1 2 13.3 0 0.0 3 16.7 0 0.0 10622 7 a 15 3.02 3.07 3.05 is 0 0.0 10623 10624 7 5 12 3.44 3.08 3.29 12 0 0.0 11 6 17 3.31 3.22 3.28 17 0 0.0 --------------------------------------------------------------------------------------------------------------------------- DOSAGN GROUP IV 10 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10625 10626 10627 5 10 15 3.08 3.30 3.22 16 7 3 10 3.73 3.19 3.57 11 6 7 13 3.42 3.33 3.37 14 1 6.2 1 9.1 1 7.1 10628 10629 10630 10631 8 7 is 3.47 3.38 3.43 15 6 9 15 3.51 3.26 3.36 is a 5 13 3.42 3.14 3.32 13 5 10 15 3.43 3.45 3.44 15 0 0.0 0 0.0 0 0.0 0 0.0 10632 5 9 14 3.27 2.92 3.05 16 2 12.5 -------------------------------------------------------------------------------------------------------------------------- a. TOTAL - SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. PROTOCOI, 416-OlIP: OPAI, (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 14 (PAGE 3); LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------------- NU14BER OF LIVE AVERAGE FETAL ---- CONCEPTUSES ------ FETUSES BODY WEIGHT (G) RESORSED --------------------------------------------------------------------------------------------------------------------------- RAT 0 14ALE FE14ALE TOTAL MALE FEMALE TOTAL a N N t --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP V 20 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10633 9 5 14 3.54 3.24 3.43 14 0 0.0 10634 9 7 16 3.26 3.04 3.16 16 0 0.0 10635 5 6 11 3.25 3.11 3.18 12 i 6.3 10636 a 7 15 3.54 3.37 3.46 16 1 6.2 10637 a 7 15 3.17 2.92 3.05 15 0 0.0 10630 6 a 14 3.50 3.19 3.32 14 0 0.0 10639 9 7 16 3.33 3.16 3.25 17 1 5.9 20640 12 5 17 3.12 3.01 3.09 17 0 0.0 -------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP VI 2S MG/KG/DAY -------------------------------------------------------------------------------------------------------------------------- 10641 4 9 13 3.46 3.31 3.35 13 0 0.0 10642 9 7 16 3.12 2.89 3.02 16 0 0.0 10643 10644 1064S a 7 is 3.45 3.35 3.40 15 0 0.0 13 5 is 2.90 2.80 2.87 20 2 10.0 7 7 14 3.16 3.02 3.09 14 0 0.0 10646 7 6 13 3.05 3.02 3.03 13 0 0.0 10647 3 7 10 3.43 3.02 3.14 11 1 9.1 10648 8 9 17 3.10 2.05 2.96 17 0 0.0 -------------------------------------------------------------------------------------------------------------------------- a. TOTAL - SUM OF FETAL WEIGHTS/NtIMBER OF LIVE FETUSES. PROTOCOL 418-OlIP: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 14 (PAGE 4): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA --------------------------------------------------------- ----------------------------------------------------------------- NUMBER OF LIVE AVERAGE PETAL --- CONCEPTUSES ------ FETUSES BODY WEIGHT (G) RESORBED -------------------------------------------------------------------------------------------------------------------------- RAT I MALE FEMALE TOTAL MALE FEMALE TOTAL a N N t --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP VII 35 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10649 3 a 11 2.80 2.54 2.61 13 2 15.4 10650 5 a 13 1.98 1.85 1.90 16 3 18.8 10651 9 8 17 3.24 3.16 3.20 17 0 0.0 106S2 8 6 24 3.23 2.94 3.11 14 0 0.0 10653 6 7 13 3.25 3.04 3.14 14 1 7.1 10654 7 10 17 3.21 2.9S 3.06 is 1 5.6 106S5 9 3 12 3.30 3.07 3.24 12 0 0.0 10656 11 6 17 3.25 3.07 3.19 17 0 0.0 --------------------------------------------------------------------------------------------------------------------------- a. TOTAL - SUN OF PETAL WEIGHTS/NUMBER OF LIVE FETUSES. PROTOCOL 418-OIIP: ORAL (GAVAGE@ DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 15 (PAGE 1) ; FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA -- -- -- --- - --- -- --- --- -- -- --- -- --- - - - ------ --- --- --- -- -- --- -- -- -- --- -- --- --- -- --- -- --- -- -- -- --- -- -- --- --- -- --- - ---- -- -- -- -- FETUS N 1 2 3 4 5 6 7 a 9 10 11 12 13 14 15 16 17 le 19 20 21 -------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 1 0 (VEHICLE) MG/KG/DAY -------------------------------------------------------------------------------------------------------------------------- RAT I CLa 10602 6/ 7 FA MA PA KA FA FA / FA MA FA FA MA MA MA 3.34 3.64 3 .28 3 . 6 1 3 .4 0 3 .6 8 3 .3 4 3.24 3.65 3.30 3.49 3.64 3.65 10602 12/ 5 14A PA FA MA 14A FA E FA FA FA FA FA / PA FA MA MA 3.37 3.38 3.55 3.31 3.69 3.19 3.57 3.58 3.29 3.59 3.71 3.52 3.63 4.00 4.18 10603 11/ 8 FA PA MA FA 14A MA MA MA MA / MA FA MA MA MA MA FA MA 3.59 3.84 4.14 3.79 3.70 3.92 4.03 3.93 3.69 3.82 3.74 3.80 3.85 3.90 3.90 3.58 4.26 10604 4/12 t4A PA PA FA KA FA FA MA PA FA MA MA FA FA FA 3.81 3.54 3.86 2.62 3.74 3.35 3.38 3.73 3.39 3.13 3.53 3.60 3.72 3.58 3.81 10605 S/ 6 FA PA PA KA KA FA FA MA MA E E MA MA 3.41 3.67 3.69 4.08 3.82 3.69 3.41 3.90 3.95 3.85 4.06 10606 5/11 FA PA FA PA KA / MA 14A PA MA FA FA FA FA MA MA 3.80 3.56 3.48 3.61 3.68 3.71 3.68 3.47 3.57 3.07 3.40 3.07 3.31 3.42 3.64 10607 5/ 8 14A / FA FA FA 2.45 2.35 2.41 2.14 10608 20/10 MA FA FA MA PA FA FA FA PA MA / MA PA MA MA MA FA MA FA PA 3.13 3.19 3.22 3.22 2.76 3.29 3.29 2.93 2.95 3.66 3.20 3.12 3.45 3.34 3.44 2.97 3.59 2.86 3.11 -------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 11 1 MG/KG/D" -------------------------------------------------------------------------------------------------------------------------- 10609 7/11 MA FA MA IFA KA MA MA MA FA MA MA MA FA MA PA MA 3.39 3.15 3.29 3.64 3.45 3.73 3.07 3.27 3.17 3.28 3.43 3.29 3.29 3.23 3.18 3.60 10610 NOT PREGNANT 10611 9/ 9 FA FA FA FA FA MA FA FA FA PA FA E FA FA FA MA 3. 84 3.60 3 .39 3 . 82 3. 56 4. 06 3 .59 3. 93 3. 47 3 .50 3 .46 3.82 3.68 3.70 3.96 10612 9/ 9 KA FA PA KA MA FA FA MA FA FA PA FA MA PA 3.23 3.50 3.44 3.55 3.86 3.72 3.23 3.27 3.45 3.48 3.45 3.43 3.74 3.62 10613 10/ 7 FA 14A FA IFA KA FA MA FA MA / MA MA MA MA MA FA E 3.18 3.44 3.62 3 .36 3.52 3.31 3.44 3.41 3.52 3.39 3.35 3.38 3.59 3.87 3.47 10614 S/ 7 FA / FA PA FA FA MA FA 2.95 2.94 2.77 3 .06 3.22 3.31 2.84 10615 5/ 9 MA PA FA FA / MA MA FA MA MA FA FA MA MA 3.59 3.21 3.61 3 .50 3.50 3.64 3.57 3.96 3.80 3.31 3.45 3.63 3.71 10616 6/ 7 FA MA KA IFA FA MA / PA MA MA MA FA MA FA 3.33 3.56 3.66 3 .41 3.06 3.39 3.39 3.70 3.36 3.33 3.49 3.54 3.30 -------------------------------------------------------------------------------------------------------------------------- N - MALE F - PEKALE A - ALIVE CLa - CORPORA LUTEA/OVARY FETAL E - EARLY RESORPTION L = LATE RESORPTION BODY WEIGHTS WERE RECORDED IN GRAMS (G) . "/" DENOTES POSITION OF CERVIX PROTOCOL 418-OlIP; ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF H-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 15 (PAGE 2); FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------------- FETUS N 1 2 3 4 5 6 7 8 9 10 11 12 13 14 is 16 17 is 19 20 21 --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP 111 5 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- RAT # CLe 10617 7/ 7 MA MA MA FA PA MA MA / PA MA MA FA PA E PA 3.39 3.35 3.99 3.36 3.39 3.87 3.74 3.01 3.40 3.69 3.07 3.54 3.56 10618 7/10 KA 8 PA PA PA / FA FA FA FA MA MA FA E PA FA 3.67 3.29 3.14 3.54 2.97 3.07 3.11 3.20 3.26 3.26 3.14 3.22 3.26 10619 10/ 7 KA FA KA PA MA MA FA FA MA FA / PA MA FA MA FA FA 3.36 3.36 3.25 2.96 3.12 3.17 3.11 2.63 2.89 2.60 2.99 3.29 2.56 3.15 2.80 3.20 10620 9/ 9 PA MA E E MA FA MA E FA FA MA FA MA FA MA MA MA FA 3.20 4.00 3.52 3.51 3.28 3.40 3.38 3.26 3.43 3.31 3.07 2.72 3.49 3.43 3.46 10622 10/ 6 FA KA 14A MA MA MA PA MA FA FA FA 14A MA FA MA 2.91 3.55 3.57 3.56 3.59 3.72 3.32 3.55 3.56 3.08 3.47 3.67 3.50 3.40 3.83 10622 7/ 8 KA FA KA 14A FA FA MA / FA FA MA t4A KA FA FA FA 3.25 3.20 3.10 3.18 3.07 2.85 2.54 2.95 3.10 3.04 3.32 2.72 3.38 3.16 2.86 10623 4/ 9 PA MA KA MA / PA KA MA FA FA FA KA MA 2.96 3.28 3.40 3.34 3.24 3.81 3.41 3.02 3.13 3.04 3.40 3.46 10624 6/12 FA FA MA MA PA MA / MA MA FA MA MA MA PA MA MA MA PA 3.20 3.11 3.23 3.44 3.40 3.32 3.17 3.27 3.20 3.36 3.40 3.35 3.06 3.10 3.59 3.22 3.28 --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP IV 10 MG/KGIDAY --------------------------------------------------------------------------------------------------------------------------- 10625 13/ 8 14A 14A FA FA 14A 2.64 3.09 2.76 3.49 3.34 E FA FA FA FA FA MA / PA FA MA FA 3.33 3.52 3.44 3.16 3.45 3.13 3.26 3.59 3.20 2.96 10626 3/ 9 PA 14A MA / FL MA FA MA MA MA FA MA 3.71 4.02 3.74 1.68 3.78 3.42 3.57 3.76 3.51 2.44 3.72 10627 9/ 5 PA PA PA MA MA MA FA FA FA PA MA 9 MA MA 3.25 3.30 3.17 3.77 3.49 3.50 3.56 3.40 3.17 3.47 3.74 3.40 2.64 10626 6/10 FA FA MA MA FA FA MA PA MA PA FA MA KA MA MA 3.24 3.66 3.59 3.63 3.30 3.05 3.41 3.48 3.28 3.43 3.50 3.52 3.44 3.24 3.65 10629 S/ 7 FA 14A FA FA FA FA FA FA MA MA FA MA PA MA MA 3.13 3.60 3.39 3.65 3.31 2.94 3.50 2.85 3.51 3.22 3.34 3.50 3.22 3.46 3.7S 10630 10/ 5 MA PA PA MA MA 14A MA FA FA FA MA MA MA 3.08 3.10 3.26 3.52 3.33 3.40 3.33 3.08 3.26 3.00 3.51 3.62 3.61 10631 12/ 6 14A FA MA PA FA FA FA FA MA MA FA FA FA MA FA 3.32 3.61 3.30 3.52 3.23 3.20 3.39 3.30 3.44 3.63 3.52 3.54 3.48 3.47 3.71 10632 S/ 9 FA FA MA E MA FA FA E FA FA FA MA MA FA FA MA 3.08 3.02 3.47 3.30 3.15 1.49 3.01 3.12 3.10 2.63 3.40 3.26 3.07 3.48 --------------------------------------------------------------------------------------------------------------------------- M - MALE F - FEMALE A - ALIVE CLO - CORPORA LUTEA/OVARY PETAL E - EARLY RESORPTION L = LATE RESORPTION BODY WEIGHTS WERE RECORDED IN GRAMS (G). "/" DENOTES POSITION OF CERVIX PROTOCOL 418-OlIP! ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF H-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER; TABLE 15 (PAGE 3): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA ------------------------------------ --------------------------------------------------------------------------------------- FETUS # 1 2 3 4 s 6 7 a 9 10 11 12 13 14 is 16 17 is 19 20 21 ----------------------------------- ---------------------------------------------------------------------------------------- DOSAGE GROUP V 20 MG/KG/DAY ------------------------------------ --------------------------------------------------------------------------------------- RAT # CLe 10633 4/11 MA PA MA MA / FA MA FA PA MA MA FA MA MA MA 3.79 3.65 3.70 3. 65 2.BB 3.58 3.03 3.34 3.56 3.34 3.29 3.53 3.42 3.25 10634 S/ 8 FA MA FA MA MA MA 14A MA PA PA FA FA MA MA MA FA 2.80 3.11 3.18 3.43 3.07 3.22 3.43 3.16 2.63 3.26 3.24 3.24 3.43 3.32 3.18 2.95 10635 7/ 5 PA KA FA FA FA MA PA FA MA MA MA E 3.29 3.48 3.19 3.31 3.14 3.15 2.81 2.93 3.19 3.15 3.29 10636 S/ 0 MA PA MA E FA PA FA FA FA FA MA MA MA MA MA MA 3.35 3.26 3.64 3.50 3.45 3.35 3.57 3.00 3.46 3.53 3.59 3.61 3.71 3.48 3.44 10637 9/ 6 FA FA 14A MA MA MA FA FA FA FA MA PA MA MA MA 2.50 2.89 3.02 3.12 3.15 3.12 2.94 3.21 2.87 2.94 3.19 2.99 3.36 3.14 3.23 10638 G/ 8 KA PA FA MA PA PA FA MA FA MA PA MA PA MA 3.50 3.09 3.53 3.49 3.06 3.31 3.09 3.16 3.22 3.33 2.84 3.69 3.41 3.82 10639 S/ 9 MA MA MA PA FA MA FA MA / KA E MA PA FA PA MA FA MA 10640 8/11 3.34 3.52 3.75 3.34 3.40 3.24 2.71 3.58 3.09 MA MA KA KA PA MA MA MA FA MA 3.25 3.19 3.37 3.25 3.34 2.83 2.83 FA PA MA MA FA MA MA 3.21 3.21 3.43 3. 19 3.05 3.04 2.99 3.16 3.00 3.28 2.99 3.14 3.13 3.06 2.87 2.77 3.04 --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP VI 25 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- 10641 7/ 6 FA FA MA FA FA FA MA MA FA PA FA FA MA 3.49 3.42 3. 69 3 .4 7 3.14 3.22 3.21 3.53 3.11 3.30 3.24 3.38 3.40 10642 10643 10644 10645 7/10 9/ 8 9/11 S/ 8 PA 3.05 KA 3.44 MA 2.92 PA 3.05 FA 2.68 FA 3.33 MA 2.64 PA 3.16 MA 3.17 FA 3.41 FA 2.79 MA 3.26 MA 3.07 PA 3.44 PA 2.81 f4A 3.26 MA 3.07 MA 3.68 PA 2.83 MA 3.05 FA 3.02 MA 3.52 E FA 3.06 MA 3.26 MA 3.47 MA 3.10 MA 3.02 FA 2.90 FA 3.33 MA 2.97 FA 3.01 MA 3.15 FA 3.25 MA 3.00 FA 3.16 FA 2.88 MA 3.51 MA 3.01 MA 3.34 MA 3.06 FA 3.17 MA 2.74 FA 2.97 t4A 3.24 PA 3.51 B MA 3.13 FA 2.92 MA 3.22 PA 2.66 MA 3.09 MA 3.20 MA 3.25 MA 2.89 FA 2.76 FA 2.76 MA 3.51 MA 3.02 MA 2.89 MA 2.81 MA 2.95 FA 2.90 MA 2.89 MA 2.73 10646 10647 7/ 8 3/ 8 KA3.07 FA FA 3.04 E FA 3.16 FA t4A 3 .02 t4A MA / MA 2.97 2.95 FA FA FA 3.02 MA MA 3.13 FA FA 2.77 FA FA 3.15 FA MA 3.12 MA MA 3.07 FA 2.98 3.25 3.18 3 .37 3.18 2.66 3.61 2.84 2.92 3.12 3.32 10648 ll/ 7 KA FA MA MA FA FA MA FA PA MA / MA MA MA FA FA FA FA 2.99 2.90 3.12 2.77 3.12 2.73 3.15 2.95 2.75 3.26 3.12 3.19 3.17 3.03 2.76 2.81 2.59 ----------------- ----------------- ---------------------------------------------------------------------------------------- M - MALE F - FEMALE A = ALIVE E - EARLY RESORPTION L . LATE RESORPTION "/" DENOTES POSITION OF CERVIX CLa - CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 4le-011P: ORAL (GAVAGE) DOSAGE-PANGE DEVELOPMENTAL TOXICITY STUDY OF H-ETFOSE IN RATS (SPONSOR'S STUDY NUMBER: TABLE 15 (PAGE 4): PETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA --------------------------------------------------------------------------------------------------------------------------- FETUS N 1 2 3 4 5 6 7 a 9 10 11 12 13 14 is 16 17 18 19 20 21 --------------------------------------------------------------------------------------------------------------------------- DOSAGE GROUP VII 35 MG/KG/DAY --------------------------------------------------------------------------------------------------------------------------- RAT # CLe 10649 7/ 6 PA E PA KA FA t4A KA PA E PA PA PA FA 2.36 2.61 2.85 2.44 2.80 2.75 2.35 2.61 2.30 2.57 3.08 10650a S/ 9 PA PA PA E E PA MA E MA MA FA FA MA FA PA KA 2.01 1.75 2.08 2.20 2.15 2.04 2.12 1.66 1.14 1.64 2.02 1.95 1.95 10651 10/ 0 PA MA PA FA FA PA t4A KA MA FA / MA MA MA MA FA 14A Pik 3.04 3.34 3.03 3.13 2.96 3.35 3.25 3.03 3.14 3.22 2.98 3.19 3.35 3.20 3.10 3.66 3.46 10652 7/ 8 MA 14A KA FA MA MA FA PA MA FA MA FA MA FA 3.07 3.29 3.51 3.07 3.27 3.00 2.88 3.19 3.21 3.20 3.45 2.72 3.04 2.59 10653 9/ 5 FA KA KA FA FA MA 14A FA E FA FA MA MA FA 3.04 3.20 3.09 2.71 2.90 3.46 2.93 3.22 3.27 2.94 3.29 3.55 3.17 10654 9/13 FA KA PA FA MA MA FA FA FA MA FA E FA MA MA MA FA FA 2.76 3.03 3.06 3.20 2.97 3.22 2.86 2.80 3.12 3.21 2.98 2.81 3.46 3.37 3.24 3.01 2.87 10655 S/ 7 KA 14A 14A FA FA PA MA MA MA MA MA MA 3.23 3.36 3.40 3.17 3.23 2.82 3.53 3.32 3.03 3.21 3.10 3.52 10656 9/10 kh FA 14A PA FA MA 14A MA MA MA PA FA MA FA KA MA MA 3.37 3.30 3.12 2.SS 3.22 3.35 3.33 3.S2 3.13 3.22 3.11 3.36 3.45 2.56 3.21 2.64 3.25 --------------------------------------------------------------------------------------------------------------------------- N - MALE F - FEMLE A . ALIVE 8 @ EARLY RESORPTION L - LATE RESORPTION "/* DENOTES POSITION OF CERVIX CLa = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G). a. Fetuses 106SO-1 and 10650-10 had cleft palate and an edematous body, and fetuses 10650-2, 10650-3. 10650-6, 10650-7, 10650-11, 10650-12, 10650-13, 10650-14, 10650-15 and 10650-16 had cleft palate. 418-011:PAGE F-58 1 418-011 P:PAGE 58 AT7ACHMENT 1 PROTOCOL AND AMENDMENT RESFARM 418-011:PAGE F-59 418-011 P:PAGE 59 Argus Research Laboratories,Inc. 905 Sheehy Drive, Building A Homham, Pennsylvania 19044 T: (215)443-8710 F: (215)"34587 PROTOCOL 41 B-011 P SPONSOR'S STUDY NUMBER: T-6316.7 STUDY TITLE: PURPOSE: TESTING FACILITY: STUDY DIRECTOR: SPONSOR: STUDY MONITO ALTERNATE STUDY MONITOR: Oral.(Gavage) Dosage-Range Developmental ToxicityStudy of N-ETFOSE in Rats The purpose of thisstudy isto provide informationforthe selectionof dosages to be used inthe developmental toxicit(yembryo-fetaltoxicitaynd teratogenicpotentials)tudy of N-ETFOSE administeredorallyviagavage to Crl:CDOBR VAF/Pius4D presumed pregnant female rats. Argus Research Laboratories,Inc. 905 Sheehy Drive,BuildingA Horsham, Pennsylvania 19044-1297 Telephone: (215)443-8710 Telefax: (215)443-8587 Raymond G. York, Ph.D.,DABT Associate Directorof Research 3M Toxicology Services 3M Center, Building220-2E-02 St.Paul, Minnesota 55144-1000 Marvin T. Case, D.V.M., Ph.D. Telephone: (612)733-5180 Telefax: (612)733-1773 Andrew M. Seacat, Ph.D. Telephone: (612)575-3161 Telefax: (612)733-1773 418-011:PAGE F-60 41 B-011P:PAGE 60 Protocol41 B-01 IP Page 2 REGULATORY CITATION U.S. Food and Drug Administration (1994). International Conference on Harmonisation;Guidelineon detectionof toxicittyo reproductionformedicinalproducts. Federal Register,September 22, 1994, Vol.59, No. 183. U.S. Food and Drug Administration.Good Laboratory PracticeRegulations;FinalRule. 21 CFR Part 58. Japanese Ministryof Health and Welfare (1997). Good Laboratory PracticeStandard forSafety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997, European Economic Community (1989). Council decisionon 28 July 1989 on the acceptance by the European Economic Community of an OECD decisionlrecommendation on compliance withprinciplesof good laboratorypractice.OfficiaJlournal of the European Communities: Legislation.32 (No. L 315; 28 October): 1-17. REGULATORY COMPLIANCE: This studywillbe conducted inthe spiriotf the Good LaboratoryPractice(GLP) regulationscitedabove inthatthe Testing Facilitpyersonnelwilladhere to the Standard Operating Procedures forlaboratoryoperationsand data collectionT.he Testing FacilitQyualityAssurance Unit(OAU) willnot auditthe protocol,the raw data,the reportsor the criticaplhases ofthe study. Allchanges or revisionsof thisprotocolshallbe documented, signed by the Study Directorand the Sponsor, dated and maintained with the protocol. STUDY SCHEDULE: See ATTACHMENT 1 to the protocol. 418-011:PAGE F-61 418-011 P:PAGE 61 Pmtocol4l8-OllP Page 3 TEST ARTICLE AND VEHICL identification: Test_Article: Name: Physical Description: Lot/BatchNumber: SpecificGravity: Purity: ExpirationDate: N-ETFOSE. Waxy solid. FM-3 929(30035,30037,30039). -1.7.' 99.1%. May, 2000. Informationon the identityc,omposition,strengthand purftyof the testarticlieson file withthe Sponsor. Vehicle: 2% TweenOD 80 in Reverse Osmosis Membrane Processed Deionized Water (R.O. Deionized Water). Supplierand lotidentificatioofnTweenO 80 to be documented in the raw data. Neitherthe Sponsor nor the Study Directorisaware of any potentialcontaminants likely to be present inthe vehiclethatwould interferweiththe resultsof thisstudy. Therefore, no analyses other than those mentioned inthisprotocolwillbe conducted. Safety Precautions: Gloves, mask, appropriateeye protectionand a uniform/labcoat are to be wom during formulationpreparationand administration.The MaterialSafety Data Sheet (MSDS) is attachedto the protocol(ATTACHMENT 2). Storage: Bulk Test Article: Vehicle Components: Prepared Vehicle: Prepared Formulations: Room temperature. Room temperature. Room temperature. Frozen (-200C). Alltestarticlsehipments to the Testing Facilitsyhould be addressed to the attentionof JulianGuibinski,Manager of Formulations,atthe previouslycitedaddress and telephone number. Shipments should includeinformationconcerning storage conditionsand shipping cartonsshould be labeledappropriately.The recipientshould be notifiedinadvance of shipment. 418-011:PAGE F-62 418-011 P:PAGE 62 Pmtocol 41 B-01IP Page 4 FORMULATION: Freauency of Preparation: Formulations(suspensions)willbe prepared dailyat the Testing FacilityV.ehiclewillbe prepared weekly atthe Testing Facility. Detailedpreparationprocedures are attachedto thisprotocol(ATTACHMENT 3). Adjustment forPuri : The testarticlweillbe considered 100% pure forthe purpose of dosage calculations. Testing FacilityReserve SamRis : The Sponsor willreserve a sample (1 g) of each lotofthe bulktestarticluesed during the course ofthisstudy. The Testing Facilitwyillreserve a sample (5 mL) of each lotof the vehiclecomponents used duringthe course of thisstudy. Samples willbe stored under the previouslycitedconditions. ANALYSE : Samples additionalto those described below may be taken ifdeemed necessary during the course ofthe study. Bulk Test ArticleSamong: No analyses of the bulktestarticlweillbe conducted duringthe course of thisstudy. Informationon the stabilitoyf the bulk testarticlieson filewiththe Sponsor. Analyses of Preg)amd Formulations: At the request ofthe Sponsor, no analyses of prepared testarticlfeormulationswillbe conducted duringthe course ofthe study. However, recordswillbe maintained to document how the testarticlfeormulationswere prepared. DISPOS_ITION: Prepared formulations willbe discarded atthe Testing Facility.Allremaining bulk test articlweillbe returnedto the Study Monitor atthe previouslycitedaddress. I- 418-011:PAGE F-63 418-011 P:PAGE 63 Pmtoeol 41 B-011P Page 5 TES SYSTEM: SROciss/St rainand Reason for Selection: The Crt:CDIDBR VAF/PlusO (Sprague-Dawley)ratwas selectedas the Test System because: 1) itisone mammalian species accepted and widelyused throughout industryfornonclinicasltudiesof developmental toxicit(yembryo-fetal toxicitytteratogenici2t)yt)h;isstrainhas been demonstrated to be sensitiveto developmental toxins;3) historicadlata and experience existatthe Testing Facility('a-n3d);4) the testarticliespharmacologicallyactiveinthe species and strain. Numbs : Initiaplopulationacclimated: 75 virginfemale rats. Populationselectedforstudy: 56 mated female rats(8 per dosage group). Body leicihatnd Aci : Female ratswillbe ordered to have body weights of 200 g to 225 g each at receipt,at which time they willbe expected to be at least60 days of age. Actual body weights will be recorded the day afterreceiptand willbe documented inthe raw data. Aex: Female ratswillbe given the testarticle.Male ratsof the same source and strainwill be used onlyas breeders and are not considered partof the Test System. Source: Charles River Laboratories,Inc. The ratswillbe shipped infilterecdartons by airfreightand/ortruckfrom Charles River Laboratories,Inc.,to the Testing Facility. ldenfif_ication: Rats are permanently identifieudsing Mone[ID seff-piercinegar tags (Gey Band and Tag Co., Inc.,No. MSPT 20101). Male ratsare given unique permanent identification numbers upon assignment to the Testing Facility'bsreeder male ratpopulation. Female ratsare assigned temporary numbers at receiptand given unique permanent identificatinounmbers when assigned to the study on the basis of day 0 of presumed gestationbody weights. 418-011:PAGE F-ro4 41 B-01IP:PAGE 64 Pmtocol 418411 P Page 6 ANIMAL HUSBANDRY: All cage sizes and housing conditions are in compliance with the Guide for the Care and Use of Laboratory AnimaIJ4). Housing: The rats willbe individuallyhoused in stainless steel,wire-bottomed cages except during the cohabitationperiod. During cohabitation,each pairof ratswillbe housed in the male rat'scage. No nestingmaterialswillbe suppliedbecause the female ratswill be sacrificedbefore parturitioinsexpected. Room Air.Temperature and Humidi : The animal room isindependentlysuppliedwith at leastten changes per hour of 100% freshairthathas been passed through 99.97% HEPA filter(sAiroClearvO room). Room temperaturewillbe maintained at 64*F (18*C) to 79*F (260C) and monitored constantly.Room humiditywillalso be monitored constantlyand maintained at 30% to 70%. idgm: An automaticallycontrolled12-hour lightI:2-hour dark fluorescentlightcyclewillbe maintained. Each dark periodwillbegin at 1900 hours EST. Diet: Rats willbe givenCertifiedRodent DietO #5002 (PMI NutritioInnternationala)vailable ad libitumfrom individuafleeders. Water: Water willbe availablead libitumfrom individuablottlesattachedto the cages or from an automaticwatering access system. Allwater willbe from a localsource and passed through a reverse osmosis membrane before use. Chlorinewillbe added to the processed water as a bacteriostatp;rocessed water isexpected to containno more than 1.2 ppm chlorineat the time of analysis.Water isanalyzed monthly forpossible bacterialcontamination and twice annuallyforpossiblechemical contamination. Contaminants: Neitherthe Sponsor nor the Study Directorisaware of any potentialcontaminants likely to be present inthe certifieddietor inthe drinkingwater at levelsthatwould interfere withthe resultsof thisstudy. Therefore,no analyses otherthan those routinely performed by the feed supplieror those mentioned inthisprotocolwillbe conducted. 41MI 1:PAGE F-65 418-011P:PAGE65 Pmtocol 418-011P Page 7 RAN )OM[ZATION AND COHABITATIO Upon arrival,male and female rats willbe assigned to individual housing on the basis of computer-generated random units.Afteracclimation,virginfemale ratswillbe cohabitedwith breeder male rats,one male ratper female rat.The cohabitationperiod willconsistof a maximum offivedays. Female ratswith spermatozoa observed ina smear of the vaginalcontents and/or a copulatoryplug observed insituwillbe considered to be at day 0 of presumed gestationand assigned to individualhousing. Heafthy mated female ratswillbe assigned to dosage groups based on computergenerated (weight-ordered)randomizationprocedures. ADMINI @TRATION: Route a idReason for Choice: The oral(gavage) routewas selectedforuse because: 1) in comparison withthe dietaryroute,the exact dosage can be accuratelyadministered;and 2) itisone ofthe possibleroutesof human exposure. Method and Frenuency: Female ratswillbe given the testarticloence dailyon days 6 through 17 of presumed gestation,the periodof organogenesis. Dosages willbe adjusted forthe most recently recorded body weight and given at approximatelythe same time each day. Rationale forDosaae Selection: Dosages willbe selectedby the Sponsor on the basis of previous studiesconducted with the testarticle. 418-011:PAGE F-66 41 B-01 IP:PAGE 66 Pmtocol41"l 1P Page 8 Dosage Levels.Concentmtions and Volumes: Dosage Grouc Number ofRats Dosage Concentration Dmgo Volume (MLkgiday).=LML Amus BatchNumber I a 0 (Veh 0 5 9418411 P-A(Day.Month.Year) 0.2 5 B-418-011P-B(Day.Month.Year) 1 5 B-418411P-C(Day.Month.Year) IV 10 2 5 B-418-011P-D(Day.Month.Year) v a vi 8 20- _4 25 5 5 E"18-01IP-E(Day.Month.Year) 5 B-418-0I1-P-F(Day.Month.Year) Vil 35 7 5 B-416-011-P ThetestsnidevAUbeconsiftre1d00% pureforthepwpose ofdosagecalculabons. onth.Year) TESTS, ANALYSES AND MEASUREMEN Viabirity: All Periods: At leasttwice daily. ClinicalObservations and/or General AS)R6arance: AcclimationPeriod: Weekly. Predosage Period: Dosage Period: Day 0 of presumed gestation. Twice daily.Once approximatelyone hour postdosage and then fourto sixhours later. Postdosage Period: Once daily. Clinicaolbservationsmay be recorded more frequentlythan citedabove, ffdeemed appropriateby the Study Directorand/or Study Monitor. Body Weights: AcclimationPeriod: Weekly. Predosage Period: Dosage Period: Postdosage Period: Days 0 and 4 of presumed gestation. Daily. Daily. 418-011:PAGE F-67 418-011P:PAGE 67 Protocol41 B-011P Page 9 Feed Consumption Values (recorded and tabulated): Predosage Period: Dosage Period: Days 0 and 4 ofpresumed gestation. Days 6,8, 10,12,14 and 16 ofpresumed gestation. Postdosage Period: Days 18 and 20 of presumed gestation. Feed consumptionvaluesmay be recordedmore frequentlfyfitisnecessaryto replenisthhe feed.These intervalwsillnotbe tabulated. Mating Performance: Matingwillbe evaluateddailyduringthecohabitatiopneriodand confirmedby observationofspermatozoa ina smear ofthevaginalcontentsand/ora copulatoryplug observed in situ. Caesarean-SectioningObservations: Rats willbe Caesarean-sectionedon day 20 ofpresumed gestation.The fetuseswill be removed fromthe uterusand placedinindividuaclontainers.The ratswillbe examined fornumber and distributioofn: Corpora Lutea. ImplantatioSnites. [Placentaethatappear abnormal (sizec,olororshape)willbe notedintheraw data.] Liveand Dead Fetuses. (A livefetusisdefinedas one thatrespondstostimulia;dead fetusisdefinedas a termfetusthatdoes notrespond tostimulaind thatisnotmarkedlyautolyzed-, dead fetusesdemonstratingmarked toextreme autolysiasre consideredto be lateresorptions.) Earlyand LateResorptions. (A conceptusisdefinedas a lateresorptioinfitisgrosslyevidentthat organogenesishas occurred;ifthisisnotthe case,theconceptusisdefinedas an earlyresorption.) 418-011:PAGE F-68 418-OlIP:PAGE68 Pmtocol41 Ml 1P Page 10 FetalObservations: Fetuses willbe examined forsex and forgross externalalterationsL.ate resorptions and dead fetuseswillbe examined forgross externalalterationtso the extentpossible. The body weight of each fetuswillbe recorded. Only body weights of livefetuseswill be used to determine littefretalbody weight averages. Fetuses withgross extemai alterationwsillbe fixedinBouin'ssolution;allotherfetuseswillbe discarded. Representativephotographs of fetalgross externalalterationwsillbe taken. METHOD OF SACRIFIC : Rats willbe sacrificedby carbon dioxideasphyxiation.Livefetuseswillbe sacrificedby an intraperitoneailnjectioonfeuthanasia solution(Beuthanasiao-D Special, manufactured by Schering-PloughAnimal Health). NECRO.PSY: Gross lesionswillbe retainedinneutralbuffered10% formalinforpossiblefuture evaluation(a tableof random unitswillbe used to selectone controlgroup ratfrom which alltissuesexamined at necropsy willbe retained,inorder to provide control tissuesforany possiblehistapathologicaelvaluationsof gross lesions).Unless specificallcyitedbelow, allother tissueswillbe discarded. Scheduled Sacrifice: On day 20 of presumed gestation,female ratswillbe Caesarean-sectioned, and a gross necropsy of the thoracic,abdominal and pelvicviscerawillbe performed. Uteriof apparentlynonpregnant ratswillbe stainedwith 10% ammonium sulfideto confirmthe absence of implantationsites(S). Rats Found Dead or Moribund: Rats thatdieor are sacrificedbecause of moribund condition,abortionor premature deliverywillbe examined forthe cause of death or moribund conditionon the day the observationismade. The ratswillbe examined forgross lesions.Pregnancy status and uterinecontentsof female ratswillbe recorded. Aborted fetusesand/or delivered pups willbe examined to the extentpossible,using the same methods described for fetuses. Uteriof apparentlynonpregnant ratswillbe stainedwith 10% ammonium sulfideto confirmthe absence of implantationsdes(s). 41 Ml 1:PAGE F-69 418-011P:PAGE 69 Pmtocol 41 B-01 1P Page 11 STATISTICAL EVALUATION: Averages and percentageswillbe calculatedL.ittevralueswillbe used where appropriateA.dditionaplroceduresand/oranalysesmay be performedifdeemed appropriate. DATA ACQUISITION, VERIFICATION AND STORAGE: Data willbe hand- and/orcomputer-recorded.Records willbe reviewedby the Study Directoarnd/orappropriatemanagement personnelwithin21 days aftergeneration.All originarlecordswillbe storedinthe archivesoftheTestingFacilityA.lloriginadlatawill be bound and indexed.A copy ofallraw datawillbe suppliedtotheSponsor upon request.Preservedtissueswillbe storedattheTestingFacilitayt no chargeforone yearaftermailingofthe draftfinalreporta,fterwhich timethe Sponsor willbe contacted todeterminethedispositioonfthese materials. RECORDS TO BE MAINTAINE Protocoland Amendments. TestArticleV,ehicleand/orReagent Receipt,Preparationand Use. Animal Acquisition. RandomizationSchedules. Mating History. Treatment(ifprescribedby StaffVeterinarian). General Comments. ClinicaOlbservationsand/orGeneralAppearance. Body Weights. Feed Consumption Values. Caesarean-Sectioningand FetalObservations. Gross Necropsy Observations. Organ Weights(ifrequired). Photographs(ifrequired). StudyMaintenance(room and environmentalrecords). Feed and Water Analyses. Packingand/orShipment Lists. 418-01 1:PAGE F-70 418-011 P:PAGE 70 Pmtowl 41B-011P Page 12 KEY PERSONNEL: Executive Director of Research: Mildred S. Christian, Ph.D., ATS Directorof Research: Alan M. Hoberman, Ph.D.,DABT Associate Directorof Research and Study Director Raymond G. York, Ph.D.,DABT Directorof LaboratoryOperations: John F. Barnett,B.S. Manager of Study Coordination:ValerieA. Sharper, M.S. Manager ofAnimal Operations and Member, InstitutionAanlimal Care and Use Committee: Dena C. Lebo, V.M.D. Manager of Regulatory Compliance: Kathleen A. Moran, M.S. Consultant,VeterinaryPathology: W. Ray Brown, D.V.M., Ph.D.,ACVP REPORT: A lettereportforthe purpose of dosage selectionforthe fullstudy willbe prepared immediately followingcompletion of the in-lifpehase. A summary reportwillbe prepared includinga:bstract,summaries of the methods, resultsand conclusion;tableof contents;copy of the protocol;amendments; summary and individuatlables;and reportsof supportingdata (ifappropriate).The reportwillbe includedas an appendix to the fullstudy report.The Sponsor willreceiveone copy of the draftreportand two copies of the finalreport. INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMEN The procedures described inthisprotocolhave been reviewed by the Testing Facility's InstitutionAanlimal Care and Use Committee. Allprocedures described inthisprotocol thatinvolvestudy animals willbe conducted ina manner to avoid or minimize discomfort,distressor pain to the animals. The Sponsoes signaturebelow documents the factthatinformationconcerning the necessityforconductingthisstudy and the factthatthisisnot an unnecessarily duplicativestudy may be obtained from the Sponsor. No alternativ(einvitro) procedures were availableformeeting the statedpurposes of the study. 418-011:PAGE F-71 418-011 P:PAGE 71 Pmtocol41Ml 1P Page 13 REFERENCES: I ChristianM,.S. and Voytek, P.E. (1982). In Vivo Reproductiveand Mutagenicity Tests. Environmental ProtectionAgency, Washington, D.C. NationalTechnical InformationService,U.S. Department of Commerce, SpringfieldV,A 22161. 2. ChristianM,.S. (1984). Reproductivetoxicitaynd teratologyevaluationsof naltrexone(Proceedings of Naftrexone Symposium, New York Academy of Sciences,November 7, 1983),J. Clin.Psychiat.45(9):7-10. 3. Lang, P.L. (1988). Embryo and Fetal Developmental Toxicity (Terstology) Control Data in the Cha)les River CH.-CDWR Rat. Charles River Laboratories, Inc.,Wilmington,MA 01887-0630. (Data base providedby Argus Research Laboratories,Inc.) 4. Instituteof Laboratory Animal Resources (1996). Guide forthe Care and Use of Laboratory Animals. National Academy Press, Washington, D.C. 5. Salewski,E. (1964). Filrbemethode zum makroskopischen Nachweis von lmplantationsstelleanm Uterus der Rafte. Arch. Pathol.Exp. Pharmakol. 247:367. PROTOCOL APPROVAL: FOR THE TESTING FACILITY UOMA .Dearlove,Ph.D., DABT Associate Directorof Research 'j-'@ @@ Itii \. R ay@C, G. York,oP fle(4A rcIhBT Associate Director Study Director Dena C. Lebo, V.M.D. Member, InstitutionAanlimal Care and Use Committee FOR THE SPONSOR Marvin T. Case, D.V.M., Ph.D. Study Monitor 418-011:PAGE F-72 418-011 P:PAGE 72 Protocol418-011 P Page 14 Date /0-4&-1V-9 Date Date Date 41 B-01 1:PAGE F-73 I 418-011P:PAGE 73 ATTACHMENT i SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE ATTACHMENT 1 418-01 1:PAGE F-74 418-011 P:PAGE 74 PmtoCol 418-011P Page 1 of2 DOSAGE-RANGE STUDY SCHEMATIC DEVELOPMENTAL TOXICITY STUDY@ Startof Dosage Cohabitation Female Rats Day 6 of Presumed Gestation CaesareanSectionin!gP End of Dosage Day 17 of Presumed Gestation Day 20 of Presumed Gestation Dosage Period. a. For additionaldetailssee "Tests,Analyses and Measurements" sectionof the protocol. b. Fetalevaluation(salfletuses-extemalexaminations). ATTACHMENT 1 418-011:PAGE F-75 418-011 P:PAGE 75 PMtocol 418-011 P Page 2 of 2 SCHEDULEO 16 JUN 98 22 JUN 98 PM - 27 JUN 98 AM 23 JUN 98 - 27 JUN 98 29 JUN 98 - 14 JUL 98 13 JUL 98 - 17 JUL 98 24 JUL 98 29 SEP 98 ArrivalDate - Acclimation Begins. Cohabitation Period. Day 0 of Presumed Gestation. Dosage Period (Days 6 through 17 of presumed gestation). Caesarean-Sectioning Period (Day 20 of presumed gestation). Letter Report. Summary Report. a. The study initiatiodnate isthe date the Study Directorsigns the protocol. 418-011:PAGE F-76 1 418-011 P:PAGE 76 ATTACHMENT 2 MATERIAL SAFETY DATA SHEET 418-01 I:PAGE F-77 MATERIAL SAFETY DA'.RA SHEET 3M N - E+ POSE' 418-011 P*PAG E 77 3M Center St. Paul, Minnesota 55144-1000 1.800-364-3577 or (612) 737-6501 (24 hours) Copyright, 1998, Minnesota Mining and Manufacturing Company. All rights reserved. Copying and)or downloading of this information for the purpose of properly utilizing 3M products is allowed provided that: 1) the information is copied in full with no changes unless prior agreement is obtained from 3M, and 2) neither the copy nor the original is resold or otherwise distributed with the intention of earning a profit thereon. DIVISION: 3M CHEMICALS TRADE NAME: FC-10 FLUORAD Brand Fluorochomical Alcohol ID NUMBER/U.P.C.: 98-0211-1113-7 00-51135-09495-2 98-0211-1183-0 98-0211-1575-7 00-51135-02145-3 98-0211-6620-6 ZF-0002-0572-2 ISSUED: January 29, 1998 SUPERSEDES: November 05, 1997 DOCUMENT: 10-3778-7 00-51135-09542-3 00-51135-10439-2 -------------------------------------------------------.-.-.-.-.-.-.-....... 1. INGREDIENT C.A.S. NO. PERCENT ----------------------------------------------------------------------------- PERFLUOROOCTANESULFONAMIDO PERFLUOROHEXANESULFONAMIDO PERFLUDROKEPTANESULFONAMIDO PERFLUOROB(JTANESULFONAMIDO PERFLUOROPENTANESULFONAMIDO ALCOHOL ...... ALCOHOL ...... ALCOHOL ..... ALCOHOL ...... ALCOHOL ..... 1691-99-2 34455-03-3 68555-73-7 34449-89-3 68555-72-6 80.0 3.0 2.0 2.0 1.0 - 90.0 . 7.0 - 6.0 . 6.0 . 3.0 ----------------------------------------------------------------------------2. PHYSICAL DATA ----------------------------------------------------------------------------- BOILING POINT: ...............c.a.. lie C @ 1 mm Hg VAPOR PRESSURE: ..............<..10 mmHg Calc @ 20 C VAPOR DENSITY: ...............>..1.0 Air=l Calc @ 20 C. EVAPORATION RATE: ............<..1.0 BuOAcal SOLUBILITY IN WATER: ..........n.eglig. SPECIFIC GRAVITY: .............ca.. 1.7 Water=l (of melt) PERCENT VOLATILE: .............0.% pH: ........................N/.A... VISCOSITY: ..................N./D.. MELTING POINT: ...............N./D. ............................................................................ Ahhr-tivintinntN-in . Not Determined N/A - Not Applicable CA - Approximately 418-011:PAGE F-78 MSDS: FC-10 FLUORAD Brand Fluorachomical isnuary 29, 1998 Alcohol 418-011 P:PAGE 78 PAGE 2 ........................................................................... 2. PHYSICAL DATA (continued) ........................................................................... APPEARANCE AND ODOR: Amber waxy solid ----------------------------------------------------------------------------3. FIRE AND EXPLOSION HAZARD DATA ----------------------------------------------------------------------------- FLASH POINT: ................>..1.48 C Setaflash FLAMMABLE LIMITS - LEL: ........t4/A FLAMMABLE LIMITS - UEL: ........N/A AUTOIGNITION TEMPERATURE: ......N/A EXTINGUISHING MEDIA: Water, Carbon dioxide, Dry chemical, Foam SPECIAL FIRE FIGHTING PROCEDURES: wear full protective clothing, including helmet, self-contained, positive pressure or pressure demand breathing apparatus, bunker coat and pants, bands around arms, waist and legs, face mask, and protective covering for exposed areas of the head. UNUSUAL FIRE AND EXPLOSION HAZARDS: See Hazardous Decomposition section for products of combustion. ----------------------------------------------------------------------------- 4. REACTIVITY DATA ---------------------------------------------------------------------------- STABILITY: Stable INCOMPATIBILITY - MATERIALSICONDITIONS Not applicable. TO AVOID: HAZARDOUS POLYMERIZATION: Hazardous polymerization will not occur. HAZARDOUS DECOMPOSITIONPRODUCTS: Carbon Monoxide and Carbon Dioxide, Oxides of Nitrogen, Oxidesof Sulfur, Hydrogen Fluoride, Toxic Vapors, Gases or Particulates. ........................................................................... S. ENVIRONMENTAL INFORMATION ........................................................................... SPILL RESPONSE: Refer to other sections of this MSOS for information regarding physical and health hazards, respiratory protection, ventilation, and personal protective equipment. Collect spilled material. Clean up residue. Place in a U.S. DOT-approved container. ........................................................................... kiln- lintnotarminedN/A - Not ApplicableCA - Approximately 418-011P:AGE F-79 MSDS: FO-10 FLUORAD srand Fluarochomical Alcohol january 29, 1998 418-011P:PAGE 79 PAGE 3 .................................................................... 5. ENVIRONMENTAL INFORMATION (continued) .............f.t-.-.-.-.------------------------------------------------------ RECOMMENDED DISPOSAL: Incineratein a permittedhazardouswaste incineratorin the presence of a combustiblematerial. Combustionproductswill includeHF. Disposeof waste product in a facilitypermittedto acceptchemical waste. ENVIRONMENTAL DATA: Laboratorytests showed no biodegradation. 96-Mr. LD50 Fathead Minnow (Pimephalespromelas)- No mortalityat water saturation. No statisticallysignificanteffecton % hatch,% survival,weight,and length in 30 day Fathead Minnow egg try study. Lab tests showed200 fold bioconcentratioonf FC-10 into muscle filletsof channelcatfish. REGULATORY INFORMATION: volatile Organic Compounds: NIA. VOC Less H20 & Exempt Solvents: N/A. This productcomplieswith the chemicalregistrationrequirementsof TSCA, EINECS, COSL, AICS and Korea. EPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: Yes -------------------------------------------------------------------------6. SUGGESTED FIRST AID -------------------------------------------------------------------------- EYE CONTACT: Immediatelyflush eyes with large amounts of water. Get immediate medical attention. SKIN CONTACT: Immediatelywash skin with soap and large amounts of water. Remove contaminatedclothing.If signs/symptomsoccur, call a physician. Wash contaminatedclothing before reuse and dispose of contaminated shoes. INHALATION: If signs/symptomsoccur, removepersonto fresh air. If signs/symptomscontinue,call a physician. IF SWALLOWED: Call a physician IMMEDIATELY.If swallowed, induce vomiting immediatelyas directed by medical personnel.Never give anythingby mouth to an unconscious person. -------------------------------------------------------------------------- &off% &I-* MIA - Not ADolicable CA - Approximately 41B-011:PAGE F-80 MSOS: FC-10 FLUORAD Brand FlucrochosicalAlcohol January 29, 1998 418-011P:PAGE 80 PAGE 4 ............................................................................. 7. PRECAUTIONARY INFORMATION ........................................................................... EYE PROTECTION: Avoid eye contact. Wear safety glasses with side shields. SKIN PROTECTION: Avoid skin contact. Wear appropriate gloves when handling this material. A pair of gloves made from the following material(s) are recommended: butyl rubber. Use one or more of the following personal protection items as necessary to prevent skin contact: coveralls. RECOMMENDED VENTILATION: Use with appropriate local exhaust ventilation. Provide sufficient ventilation to maintain emissions below recommended exposure limits. If exhaust ventilation is not adequate, use appropriate respiratory protection. RESPIRATORY PROTECTION: Avoid breathing of airborne material. Select one of the following NIOSH approved respirators based on airborne concentration of contaminants and in accordance with OSHA regulations: half-mask dust respirator, full-face supplied air respirator. PREVENTION OF ACCIDENTAL INGESTION: Do not eat, drink or smoke when using this product. Wash exposed areas thoroughly with soap and water. Wash hands after handling and before eating. RECOMMENDED STORAGE: Store away from heat. Keep container closed when not in use. FIRE AND EXPLOSION Nonflammable. AVOIDANCE: OTHER PRECAUTIONARY INFORMATION: No smoking: Smoking while using this product can result in contamination of the tobacco and/or smoke and lead to the formation of the hazardousdecompositionproductsmentionedin section4 of this MSDS. HMIS HAZARD RATINGS: HEALTH: 1 FLAMMABILITY: I REACTIVITY: 0 PERSONAL PROTECTION: X (See precautions, section 7.) EXPOSURE LIMITS INGREDIENT VALUE UNIT TYPE AUTH SKIN* ............................................................................. PERFLUOROOCTANESULFONAMIDO ALCOHOL ... 0.1 MG/M3@ TWA 3m y PERFLUOROHEXANESULFONAMIDO ALCOHOL ... 0.1 MG/M3 TWA 3M y PERFLUOROHEPTANESULFONAMIDO ALCOHOL ............................ 0.1 MG/M3 TWA 3m y ............................................................................. ..,P% Li-@ Id/A - fynt Acalicable CA - Approximately 418-011:PAGE F-81 MSOS: FC-10 FLUORAD Brand Fluorachanical Alcohol January 29, 1998 41&011P-PAGE 81 PAGE 5 EXPOSURE LIMITS (continued) INGREDIENT VALUE UNIT TYPE AUTH SKIN* ----------------------------------------------------------------------------- PERFLUOROBUTANESULFONAMIDD ALCOHOL... 0.1 me/m3 TWA 3m y PERFLUOROPENTANESULFONAMIDO ALCOHOL ..........................0..1. MG/M3 TWA 3m y SKIN NOTATION: Listed substances indicated with 'Y' under SKIN refer to the potential contribution to the overall exposure by the cutaneous route including mucous membrane and eye, either by airborne or, more particularly, by direct contact with the substance. Vehicles can alter skin absorption. SOURCE OF EXPOSURE LIMIT DATA: - 3M: 3M Recommended Exposure Guidelines ----------------------------------------------------------------------------S. HEALTH HAZARD DATA ........................................................................... EYE CONTACT: No adverse health effects are expected from eye contact. SKIN CONTACT: Product is not expected to be irritating to the skin. May be absorbed through the skin and persist in the body for an extended time. INHALATION: May be absorbed by inhalation and persist in the body for an extended time. IF SWALLOWED: Ingestion is not a likely route of exposure to this product. Illness may occur after a single swallowing of relatively large quantities of this material. MUTAGENICITY: Not mutagenic in in-vitro assays. REPRODUCTIVE/DEVELOPMENTAL TOXINS: Substance was not teratogenic in the rat at doses as high as 30 milligrams per kilogram per day via oral route. OTHER HEALTH HAZARD INFORMATION: This product is not known to contain any substances regulated under California Proposition 65. A Product Toxicity Summary Sheet is available. ............................................................................ kila kl^* A"mlir-okla IA - Annroyimatalv 41B-011:PAGE F-82 MSDS: FO-10 FLUORAD Brand Fluorachosical Alcohol January 29, 1998 41 B-01IP:PAGE 82 PAGE 6 ............................................................................ SECTION CHANGE DATES ----------------------------------------------------------------------------- HEADING SECTION CHANGED SINCE November 05, 1997 ISSUE ----------------------------------------------------------------------------Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately ----------------------------------------------------------------------------- The information in this Material Safety Data Sheet (MSDS) is believed to be correct as of the date issued. 3M MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR COURSE OF PERFORMANCE OR USAGE OF TRADE. User is responsible for determining whether the 3M product is fit for a particular purpose and suitable for user's method of use or application. Given the variety of factors that can affect the use and application of a 3M product, some of which are uniquely within the user's knowledge and control, it is essential that the user evaluate the 3M product to determine whether it is fit for a particular purpose and suitable for user's method of use or application. 3M provides information in electronic form as a service to its customers. Due to the remote possibility that electronic transfer.may have resulted in errors, omissions or alterations in this information, 3M makes no representations as to its completeness or accuracy. In addition, information obtained from a database may not be as current as the information in the MSDS available directly from 3M. 418-011:PAGE F-83 1 418-011 P:PAGE 83 ATTACHMENT 3 TEST ARTICLE AND CONTROL ARTICLE PREPARATION PROCEDURE 418-011:PAGE F-84 418-011 P:PAGE 84 ATTACHMENT 3 TEST ARTICLE AND CONTROL ARTICLE Pmtocol 41 B-011P Vemion:418-011P (09 JUN 98) Page 1 of3 PREPARATION PROCEDURE Test Article: N-ETFOSE Vehicle: 2% Tween4D 80, in R.O. Water A. Purpose: The purpose of this procedure isto provide a method forthe preparation of dosage suspensions of N-ETFOSE and the control articlefor oral administration to rats on Argus Study 418-011 P. B. General Information: 1 . All suspension containers willbe labeled and color coded. Each label will specify the protocol number, test articleidentificationA,rgus batch number, concentration, dosage level,preparation date, expiration date and storage conditions. 2a. Suspensions willbe prepared: X_ Daily - Weekly - For@__ days of usei 2b. Vehicle willbe prepared: - Daily X Weekly - For@__ days of use 3. Suspensions willbe prepared at a finaldosage volume of 5 mukg. 4. Safety: X - Gloves, lab coat, goggles or safety glasses and faceshield X - Dust-Mist Respirator - Hatf-Face Respirator - Full-Face Respirator/Positive Pressure Hood - Tyvek Suit/Apron 5. Dosage solutions adjusted for Free base and % Purity. Yes X No (Calculations based on 100%) Free Base _ Purity 6. Sampling requirements: Cited in protocol. 7. Storage: Cited in protocol. 41 B-01 1:PAGE F-85 418-011P:PAGE 85 ATRACHMENT 3 TEST ARTICLE AND CONTROL Pmtocol418-011P Version4:18-011P (09JUN 9 Page 2 of3 ARTICLE PREPARATION PROCEDURE NOTE: Testarticlweillbe preparedas a serialdilutiofnrom thehighdosage to the lowdosage. Once thefinalvolumes are achieved,stibrarsareto be added tothe containersm;ixingshouldoccurduringsamplingand/or administration. C. PreparationofVehicle 1 . Add the requiredamount of R.O. deionizedwaterto an appropriately labeledcontainer.Heat the waterto 500C, d-5*C,add the required amount ofTweenOD 80 and mix untiluniform(See TEST ARTICLE CALCULATIONS). D. TestArticlSeuspension Preparation: 1 . To preparethe7-mg/mL, Group Vilsuspension,add the requiredamount oftestarticl(eSee TEST ARTICLE CALCULATIONS) intoan appropriatelsyized,labeledcontainer.Add therequiredamount of vehicleand heatthe mixtureto 800C, :t5"Cforapproximately30 minutes. 2. Once thetestarticlheas dissolveds;pinovernightwhilethe solution cools.(Be surethereisa visiblveortex,thiswillachievethedesired emulsion.) 3. To preparethe5-mg/mL, Group Vi suspension,remove the required amount ofstocksuspension(GroupVil)(See TEST ARTICLE CALCULATIONS), add therequiredamount ofvehicleand mix. 4. To preparethe4-mg/mL, Group V suspension,remove the required amount ofstocksuspension(Group VI)(See TEST ARTICLE CALCULATIONS), add the requiredamount ofvehiclaendmix. 5. To preparethe2-mg/mL, Group IV suspension,remove therequired amount ofstocksuspension(GroupV) (See TEST ARTICLE CALCULATIONS), add therequiredamount ofvehicleand mix. 41 B-011:PAGE F-86 418-011 P:PAGE 86 ATRACHMENT 3 TEST ARTICLE AND CONTROL ARTICLE Pmtocol 418-011 P Vemion:418411 P (09 JUN 98) Page 3 of3 PREPARATION PROCEDURE 6. To prepare the 1-mg/mL, Group IIIsuspension, remove the required amount of stock suspension (Group IV)(See TEST ARTICLE CALCULATIONS), add the requiredamount of vehicleand mix. 7. To prepare the 0.2@-mg/mL,Group 11suspension, remove the required amount of stock suspension (Group 111()See TEST ARTICLE CALCULATIONS), add the requiredamount of vehicleand mix. Written by: r, Apprnvtpordhiv- Clarification: No Yes (See attached clarificatifoonrm.) Initials/Date a@1404, RESEA)WH -4 rggp LADMATORM 41 B-01 1:PAGE F-87 418-011P:PAG E 87 Argus Ressamh LaboratoriesI,nc. 905 Sheehy Drive,BuildingA Horsham, Pennsylvania 190" T: (215)"3-6710 F: (215) 4434587 PROTOCOL 418-011P ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL OF N-ETFOSE IN RATS TOXICITY STUDY SPONSOR'S STUDY NUMBER: T-6316.7 Amendment 1 -June 18,1998 1. clinical.Observatiaonnds/orGeneralAr)pearance(page 8 oftheprotocol): Clinicaolbservationsduringthedosage periodwillbe takentwicedaily,priorto dosage administratioand once approximatelyone hourpostdosage,ratherthan once approximatelyone hour postdosage and thenfourtosixhours later. Reason forChange: Thischange was made atthe requestofthe Sponsor tomatch thetimeframes oftheotherreproductive/developmenttaolxicitsytudiesusingthesame test 4-ticle. t7 e"o e EAearlove, Ph.D.,DABT Date Raym%@. York@P-h. Date AssociateDirectorofResearch AssociateDirectorof'R@e.@archT and Study Director Dena C. Lebo,V.M.D. Date MarvinT.Case, D.V.M.,Ph.D. Date Member, InstitutioAnnailmal Care and Study Monitor Use Committee I APPENDIX G HISTORICAL CONTROL DATA 418-011:PAGE G-1 summmy or REPRODUCTIVE CD RAT INDICZS pimod NUMBER NUMBER OF STUDIES OF RATS i juNZ 199S --JMM TESTED PREGNANT FOUND DEAD ABORTED DELIVERED 1997 97 2132 1967 3 0 0 NUMBER OF PATS PREGNANT AT CAESAREAN-SECTIONING 19S7 NUMBER OF RATS WITH SINGLE CONCEPTUS LITTER: LIVE 5 RZSORBED 0 ABORTED 0 MEAN or PREGNANT AVERAGE CORPORA LUTEA AVERAGE IMPLANTATIONS AVERAGE LITTER SIZE AVERAGE LIVE PETUSICS AVERAGE DYAD FZTUSES AVERAGE # RESMTPTIONS AVERAGE # EARLY R39SORPTIONS AVERAGE # LATE RESORPTIONS 92.8 17.3 15.6 14.8 0.1 0.8 0.7 0.0 PANGE/STUDY MEAN or % (64.0-100) (15.2-21.0) (12.9-18.0) (11.8-17.0) (0-1.1) (0-1.6) (0-1.6) (0-0.2) 418-011:PAGE G-2 SUMMARY Op REPRODUCTIVE CD RAT INDICMS MEAN or AVERAGE % DAMS WITH ANY RESORPTIONS AVERAGE % DA14S WITH ALL CONCZPTUSES RZSORBZD AVERAGE % DAMS WITH ONZ OR MORE LIVE FETUSES AVERAGE sZX PJLTIO, (% MALES/LITTZR) AVERAGE PETAL BODY WEIGHT (G) AVERAGE FOR MALES (G) AVERAGE FOR FEMALES (G) AVERAGE % DEAD OR RESORBED CONCEPTUSES/LITTER 48.4 0.1 99.9 50.2 3.47 3.56 3.37 5.0 PANGS/STUDY MEAN or (0-75.0) (0-4.5) (95.4-100) (42.1-57.0) (3.10-3.78) (3.17-3.90) (2.98-3.66) (0-10.9) 41"l 1:PAGE G-3 summm or MATERNAL NECROPSY CD RAT OBSERVATIONS PERIOD STUDIZS RATS TESTED RATS PREGNANT RATS DIED RATS RATS RATS ABORTED DELIVERED WITH 100% JUNE 1995 RESORPTION - JUN 1997 120 2579 2387 4 0 439 1 EXTERNAL OBSERVATIONS Red substance around nose and/or mouth Incisors misaligned broken and/or missing Chromodacryorrhea Alopecia White substance present in anterior chamber of eyes MEAN N t RANGE N /STUDY % 1 0.04 0-1 (0-3.3) 2 0.08 0-2 (0-6.7) 2 0.08 0.-2 (0-6.7) 3 0.12 0-3 (0-10.0) 1 0.04 0-1 (0-4.2) GROSS LESIONS SUBMANDIBULAR LYMPH NODES Dark red JUGULAR VEIN Distended with blood CHEST Subcutaneous fat, dark red on ventral side THORACIC CAVITY Filled with light red fluid THYMUS Discolored areas Large AXILLA Mass present 1 0.04 0-1 (0-3.3) 1 0.04 0-1 (0-3.3) 1 0.04 0-1 (0-3.3) 1 0.04 0-1 (0-4.0) 2 0.08 0-2 (0-6.7) 1 0.04 0-1 (0-4.0) 1 0.04 0-1 (0-4.0) 418-011:PAGE G-4 SUMMARY or MATEPML NECROPSY CD RAT OBSERVATIONS LIVER GROSS LESIONS Adhesion between left lateral lobe and left lateral abdominal wall MM N RANGE /STUDY N 1 0.04 0-1 (0-4.0) STOmAM/iNTZSTINZ stomach, fluid-filled stomach and intestines distended with gas intestines, empty Cecm contained a black substance 1 0.04 0-1 (0-4.0) 1 0.04 0-1 (0-4.0) 1 0.04 0-1 (0-4-0) 1 0.04 0-1 (0-4.0) BACK spine, protrusion of bone on dorsal thoracic portion 1 0.04 0-1 (0-4.0) KIDNEY(S) pelvis, slight/moderatO dilation with or without fluid pelvis, marked/ext dilation Mottled Large small cortex pitted Left; pelvis contained yellow fluid 17 0.66 0-2 (0-12-5) s 0.19 0-1 (0-4-0) 2 0.08 0-1 (0-4.0) 2 0.08 0-1 (0-4.0) 1 0.04 0-1 (0-4.0.) 1 0.04 0-1 (0-3-4) 1 0.04 0-1 (0-4-0) ABDOMINAL CAVITY yllled with light red fluid 1 0.04 0-1 (0-4.0) SPLMIN Two white areas on serosal surface 1 0.04 0-1 (0-4.0) BLADDER Pluid-filled Wall thick, contained one calculi 1 0.04 0-1 (0-4.0) 1 0.04 0-1 (0-12.5) 41 B-01 1:PAGE G-5 SUMMARY OIF X&TERMLL NECROPSY CD RAT OBSZMMTIONS URETERS GROSS LESIONS Distended with clear fluid MM N RANGE N /STUDY 1 0.04 0-1 (0-4.0) VAG:ENA/CZRVIX Cervix distended with fluid cervix contained a thickr brown substance Cervix contained a dark red, gelatinous substance cervix contained greens, viscous fluid Vagina contained brown, viscous fluid 1 0.04 0-1 1 0..04 0-1 1 0.04 0-1 1 0.04 0-1 1 0.04 0-1 (0-4.0) (0-4.0) (0-4.0) (0-4.0) (0-2.1) UTERUS contained red-brown fluid and one dead, brown fetus Right horn, absent Right horn, threadlike Left horn, lumen absent on cervical end; ovarian end, distended with clear fluid Right horn, clear masses, contained gelatinous substance 1 0.04 0-1 (0-4.0) 2 0.08 0-1 (0-16.7) 1 0.04 0-1 (0-2.1) 1 0.04 0-1 (0-4.0) 1 0.04 0-1 (0-4.0) FORELIMB Lesion present 1 0.04 0-1 (0-3.3) 418-011:PAGE G-6 SUW.MY OF FETAL ig=RNAL CD RAT ALTERATIONS PERIOD junz STUDIES INCLUDED LITTERS ZXMINZD LIVE FETUSES EXMINED lggs - juNE 1997 86 1745 25613 ALTERATION HEAD Exancephaly Hamtnma Nicrocaphaly RANGE /STUDY N N t L S 0.29 0-1 (0-4.5) F 5 0.02 0-1 (0-0.4) L 1 ().06 0-1 (0-2-2) F 1 0.00 0-1 (0-0.2) L 1 0.06 0-1 (0-4.0) F 1 o.00 0-1 (0-0-3) EYES F.ARS SNOUT Eye bulges depressed Lids open Kicrophthalmia Low set Short L 14 0.80 0-2 (0-12.5) F 15 0.06 0-2 (0-0.9) L 1 0.06 0-1 (0-4.2) p 1 0.00 0-1 (0-0.3) L 1 0.06 0-1 (0-4.0) p 1 0.00 0-1 (0-0.3) L 3 0.17 0-1 (0-12.5) p 3 0.01 0-1 (0-0.9) L 2 0.11 0-1 (0-4.2) F 2 0.01 0-1 (0-0.3) TONGUE PALATE Absent Cleft L 1 0.06 0-1 (0-4.0) p 1 0.00 0-1 (0-0.3) L 4 0.23 0-1 (0-4.5) p 4 0.02 0-1 (0-0.4) L.: LITTER INCIDENCE F: FETAL INCIDENCE 41 B-011:PAGE G-7 summma or PZTAL zxTERNAL CD RAT ALTZRATIONS ALTZRATION JAWS micrognathia L p Agnathia L p BODY Edema L p Umbilical hernia L p Gastroschisis L p Trunk short L p Spina bifida L F Extra limb pro- L truding from back P Hematoma L p PLACENTA Enlarged L FORELIMBS Two digits present L on forepaw p HINDLIMBS Rotated L ANUS No opening present L F MNGE /STUDY N N 5 0.29 S 0.02 1 0.06 1 0.00 0-1 (0-4.5) 0-1 (0-0.3) 0-1 (0-12.5) 0-1 (0-0.9) 2 0.11 0-1 (0-4.5) 2 0.01 0-1 (0-0.4) 7 0.40 0-1 (0-16.7) 7 0.03 0-1 (0-1.1) 1 0.06 0-1 (0-4.0) 1 0.00 0-1 (0-0.2) 3 0.17 0-2 (0-9.1) 3 0.01 0-2 (0-0.7) 1 0.06 0-1 (0-4.0) 1 0.00 0-1 (0-0.2) 1 0.06 0-1 (0-4.5) 1 0.00 0-1 (0-0.4) 1 0.06 0-1 (0-2.4) 1 0.00 0-1 (0-0.2) 1 0.06 0-1 (0-16.7) 1 0.00 0-1 (0-1.1) 1 0.06 0-1 (0-4.3) 1 0.00 0-1 (0-0.3) 1 0.06 0-1 (0-4.0) 1 0.00 0-1 (0-0.2) 2 0.11 0-1 (0-4.5) 2 0.01 0-1 (0-0.4) L: LITTER INCIDENCE F: PETAL INCIDENCE 418-011:PAGE G-8 SUWARY OF NTAL EXTERNAL CD RAT ALTERATIONS ALTERATION TAIL Threadlike Agensain split Short constricted RANGE /STUDY N % N % L 5 0.29 0-1 (0-5.3) p 5 0.02 0-1 (0-0.4) L 3 0.17 0-1 (0-4.5) F 3 0.01 0-1 (0-0.3) L 1 0.06 0-1 (0-4.5) p 1 0.00 0-1 (0-0.4) L 2 0.11 0-1 (0-4.3) F 2 0.01 0-1 (0-0.3) L 1 0.06 0-1 (0-2.4) F 1 0.00 0-1 (0-0.2) L: LITTER INCIDENCE F: FETAL INCIDENCE 41 B-011:PAGE G-9 smoom OF PETAL SOFT TISSUE ALTZMTIONS CD RAT PERIOD STUDIES LITTERS FETUSES INCLUDED ZXAMINED EXAKINED JUNE 1995 - JUNE 1997 36 845 6091 BRAIN EYES PALATE TONGUE JAW HEART ALTERATION Lateral ventricles, L moderate dilation p Lateral ventricles, L marked dilation F Third ventricle, L marked dilation F Lateral and third vent- ricles, Irregularly L shaped F RANGE/STUDY N N 1 0.12 0-1 (0-3.4) 1 0.02 0-1 (0-0.6) 1 0 12 0-1 (0-4.2) 1 0:02 0-1 (0-0.6) 1 0.12 0-1 (0-4.2) 1 0.02 0-1 (0-0-6) 1 0.12 1 0.02 0-1 (0-4.2) 0-1 (0-0.6) xlcrophthalmia L 3 0.36 0-1 (0-4.0) r 3 0.05 0-1 (0-0.6) cleft L 2 0.24 0-1 (0-4.0) p 2 0.03 0-1 (0-0.6) small Absent L 1 0.12 0-1 (0-4.3) p 1 0.02 0-1 (0-0.6) L 1 0.12 0-1 (0-4.0) F 1 0.02 0-1 (0-0.6) Kicrognathia L 1 0.12 0-1 (0-4.0) P 1 0.02 0-1 (0-0.6) septal defect L 1 0.12 0-1 (0-4.0) P 1 0.02 0-1 (0-0.6) L: LITTER INCIDENCE F: PETAL INCIDENCE 418-011:PAGE G-1 0 SUMVARY OF FETAL SOFT TISSUE CD RAT ALTERATIONS VESSLPLS ALTERATION RRNGE/STUDY Nt N % Innom:Lnate, absent L p innominate, arises on L left p Subclavian artery, L absent p Ductus arterlosus, L absent . 7 umbilical artery, L displaced p situs invermus L p Aorta, descends to right L F 8 0.95 a 0.13 1 0.12 1 0.02 1 0.12 1 0.02 1 0.12 1 0.02 10 1.18 11 0.18 1 0.12 1 0.02 1 0.12 1 0.02 0-2 0-2 0-1 0-1 0-1 0-1 0-1 0-1 0-2 0-2 0-1 0-1 0-1 0-1 (0-8-0) (0-1-2) (0-4.0) (0-0-6) (0-3-4) (0-0-6) (0-3.4) (0-0.6) (0-8.3) (0-1.2) (0-4.2) (0-0.6) (0-4.0) (0-0.6) Pulmonary arterys, descends to right behind aorta L 1 0.12 0-1 (0-4.0) p 1 0.02 0-1 (0-0.6) LUNGS BODY Right apical, cardiac and diaphragmatic lobes appear as one intermediate lobe, absent Ed a L 1 0.12 0-1 (0-4.0) F 1 0.02 0-1 (0-0.6) L 1 0.12 0-1 (0-4-0) F 1 0.02 0-1 (0-0.6) L 1 0.12 0-1 (0-4.0) F 1 0.02 0-1 (0-0.6) ABDomiNAL cAvITY sltus Lnverous of liver, intestines, stomach, spleen, pancreas and L kj.dneys p 1 0 12 0-1 (0-4.0) 1 0:02 0-1 (0-0.6) KIDNEYS Pelvis, slight dilation L F 1 0.12 0-1 (0-3.7) 1 0.02 0-1 (0-0.6) L: LITTER INCIDENCE F: FETAL INCIDENCE 41 B-011:PAGE G-1 1 SUMMMM olp PETAL SoIrT TISSUE CD RAT ALTERATIONS SPLEEN ALTERATION Absent URETERS Distended P.ANGE/STUDY N N % L 1 0 12 0-1 (0-4.0) p 1 0:02 0-1 (0-0.5) L 2 0.24 0-2 (0-8.7) p 3 0.05 0-3 (0-1.7) L: LITTER INCIDENCE ir: PZTAL INCIDENCE 418-011:PAGE G-12 SUMMARY OF FETAL SKMZTAL CD RAT ALTERATIONS PERIOD STUDIES LITTERS FETUSES INCLUDED EXAMINED EXAMINED junz 1995 - JUNE 1997 35 820 6318 ALTERATION SRI= Frontal( )s incompletely or L not oo:ified F Parietal(a): not ossified L F Nasal(s): Short L p Basisphenoid: incompletely L ossified F Sphenoid: irregularly shaped L F small F Maxillao and Premaxillao: L short F skull: incompletely or L not ossified F skull: fused L F RANGE/STUDY N N 2 0.24 2 0.03 0-1 (0-4-2) 0-1 (0-0.6) 2 0.24 2 0.03 3 0.36 3 0.05 0-1 (0-4-2) 0-1 (0-0-6) 0-1 (0-4.2) 0-1 (0-0.6) 1 0.12 0-1 (0-4-0) 1 0.02 1 o.ii 0-1 (0-0-5) 0-1 (0-4.0) 1 0.02 0-1 (0-0-5) " n '34 - n-I -(0-4,-04.2 0.03 0-1 (0-0-6) 3 0.36 0-1 (0-4.2) 3 0.05 0-1 (0-0.6) 2 0.24 3 0.05 1 0.12 0-1 (0-4.2) 0-2 (0-1.2) 0-1 (0-4.0) 1 0.02 0-1 (0-0.5) VERTEBRAE Cervical: Arch, open Fused L 1 0.12 F 1 0.02 L 1 0.12 F 1 0.02 Thoracic: Contrum, bifid L 71 8.66 F 77 1.22 : Centra, unilateral L a 0.98 ossification p 8 0.13 : contrum, incompletely or not ossified L 3 0.36 7 4 0.06 0-1 (0-4.0) 0-1 (0-0.5) 0-1 (0-4.0) 0-1 (0-0.5) 0-8 (0-29-6) 0-9 (0-4.7) 0-2 (0-8.0) 0-2 (0-1.0) 0-2 (0-8.3) 0-3 (0-1-8) L: LITTER INCIDENCE F: FETAL INCIDENCE 418-011:PAGE G-1 3 SUMmMa OF "TAL SKMMAL CD RILT ALTERATION VERTEBRRZ (CONT-) Thoracic (COnt-) : contra, fused L p : Arch, open L F : Arch, small L p ALTZRATIONS RRNGE/STUI)Y N N 1 0.12 1 0.02 1 0.12 1 0.02 1 0.12 1 0.02 0-1 (0-4.2) 0-1 (0-0-5) 0-1 (0-4-0) 0-1 (0-0-5) 0-1 (0-3.4) 0-1 (0-0.5) Lumbar: contrum, bifid L 2 0.24 r 2 0.03 : contra, fused L 1 0.12 F 1 0.02 : centnim, incompletely L 2 0.24 or not ossified P 3 0.05 : Arches, incompletely L 15 1.83 or not ossified F 21 0.33 1, present L 1 0.12 p 1 0.02 : Arch, open L 1 0.12 r 1 0.02 : Centra, unilateral ossification L 2 0.24 r 2 0.03 Sacral: None, present Arch, open L 1 0.12 F 1 0.02 L 1 0.12 F 1 0.02 0-1 0-1 0-1 0-1 0-2 0-3 0-3 0-4 0-1 0-1 0-1 0-1 0-1 0-1 (0-3-8) (0-0-5) (0-4.3) (0-0-6) (0-8.3) (0-1-8) (0-12.0) (0-2.1) (0-4.3) (0-0.6) (0-4.0) (0-0.5) (0-4.2) (0-0-6) 0-1 (0-4.3) 0-1 (0-0.6) 0-1 (0-4.0) 0-1 (0-0.5) Caudal: None present 1, present L 1 0.12 F 1 0.02 L 1 0.12 F 1 0.02 0-1 (0-4.3) 0-1 (0-0-6) 0-1 (0-4.3) 0-1 (0-0-6) RIBS Cervical Rib(s) present one or more, wavy one or more, incompletely ossified (hypoplastic), or not ossified L: LITTER INCIDENCE F: FETAL INCIDENCE L 31 3.78 0-5 (0-20.0) F 32 0.51 0-5 (0-2-7) L 44 5.36 0-7 (0-31.8) P 73 1.16 O-lS (0-8.3) L 33 4.02 P 53 0.84 0-5 (0-22.7) 0-9 (0-5.0) 418-011:PAGE G-1 4 SUMMRY Olp MTAL SXELETAL CD RAT ALTERAT:EON RIBS (CONT.) ?used L F split L F Two segments L p ALTL?ATIONS RMGIC/STMY N N 3 0.36 3 0.05 2 0.24 2 0.03 1 0.12 1 0.02 0-1 (0-4-3) 0-1 (0-0.6) 0-1 (0-4.0) 0-1 (0-0.5) 0-1 (0-3.7) 0-1 (0-0-5) MANUBRIUM Duplicated L 1 0.12 0-1 (0-3.8) p 1 0.02 0-1 (0-0.4) STERNEBRAE one or more incompletely ossified or not ossified Duplicated Fused AsymmOtric L 114 P 164 L1 F1 L1 ip 1 L1 p1 13.90 2.60 0.12 0.02 0.12 0.02 0.12 0.02 0-7 0-11 0-1 0-1 0-1 0-1 0-1 0-1 (0-33.3) (0-6-2) (0-3.8) (0-0.4) (0-3.7) (0-0.5) (0-4.2) (0-0.5) PELVIS Pubin(es) and/or Ischium(a): incompletely or not ossified Pubia(es): incompletely ossified Pubia(es): not ossified Ischium(a): incompletely or not oselfled L 139 P 224 L 114 P 185 L8 F8 L 50 r 70 16.95 3.54 13.90 2.93 0.98 0.13 6.10 1.11 0-9 0-16 0-9 0-16 0-3 0-3 0-4 0-9 (0-39.1) (0-9.0) (0-39.1) (0-8.9) (0-13.6) (0-1.6) (0-16-7) (0-4.7) FORELIMBS metacarpals: 1, present 2, present Foredigits: 2, present Forephalanges: 1, present L 1 0.12 0-1 (0-4.3) P 1 0.02 0-1 (0-0.6) L 1 0.12 0-1 (0-4.3) F 1 0.02 0-1 (0-0.6) L 1 0.12 0-1 (0-4.3) F 1 0.02 0-1 (0-0.6). L 1 0.12 0-1 (0-4.3) P 1 0.02 0-1 (0-0.6) L: LITTER INCIDENCE F: PETAL INCIDENCE 418-011:PAGE G-1 5 SUMMM olr prZTAL OSSIFICATION SITES S' TAL AVERAGES CD RAT (CAZSApj=-SZCTIONED DAY 20 GESTATION) PZRIOD: STUDIES LITTERS FETUSES juNS INCLUDED ZXANINZD ZXAKINED 1995 JUNE 1997 33 772 5944 SIMLETAL AVERAGES HYOID VERTEBRAE CERVICAL THORACIC LUMBAR SACRAL CAUDAL RIBS (pairs) STERNUM MANUBRIUM STERNAL CENT M XIPHOID FoRzpAWS (Calculated average per CARPALS METACHRPALS DIGITS PHALANGES HINDPAWS (Calculated average per TARSALS METATARSALS DIGITS PHALANGES as limb) as limb) FZTUS/tITTER MEAN RRNGZ/STUDY 0.84 (0.69-0.95) 7.00 13.03 5.97 3.00 4.83 13.02 1.00 3.57 0.99 (12.99-13.15) (5.85-6.00) (2.96-3.00) (4.35-5.21) (12.99-13.08) (0.98-1.00) (3.26-3.85) (0.94-1.00) 0.00 3.49 5.00 5.05 (3.33-3.62) (4.90-5.27) 0.00 3.99 5.00 4.96 (3.93-4.04) (4.77-5.13) 418-011:PAGE G-16 SUMMARY OF FZTAL OSSZFZR-ATZON SXZLZTAL AVERAGES SITES CD RAT (C,AZSAPJL%N-SZCTIONZD DAY 21 GZSTATION) PZRIOD: STUDIES LITTERS FZTUSZS JUNE INCLUDED EXAMINED EXAMINED 1995 juNE 1997 2 48 374 SKZLETAL AVERAGES ERYOID VERTEBRAE CERVICAL THOR&CIC LUMEHR SACRAL CAUDAL RIBS (Pairs) STERNUM MANUBRIUM STERNAL CENTERS XIPHOID pop.zpaws (calculated as average per limb) CASTPALS METACARPALS DIGITS PHALANGES HINDPAWS (Calculated average per as limb) TARSALS METATARSALS DIGITS PHALANGES T=S/Ll ME" RRNGZ/STUDY 0.97 (0.96-0.97) 7.00 13.04 5.96 3.00 7.46 13.03 (13.02-13-06) (5.94-5.98) (7.23-7.67) (13.01-13.05) 1.00 3.98 1.00 (3.97-3-98) 0.00 3.98 5.00 7.64 (3.98-3.99) (7.53-7.75) 0.02 4.61 5.00 5.84 (4.60-4.62) (5.78-5-89) I STATEMENT APPENDIX H OF THE STUDY DIRECTOR riPMiWDICA 418-01 1:PAGE H-1 Argus Research LaboratoriesI,nc. 905 Sheehy Drive,BuildingA Horsham, PA 19044 Telephone:(215)443-8710 Telefax:(215)443-8587 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS SPONSOR'S STUDY NUMBER: T-6316.7 STATEMENT OF THE STUDY DIRECTOR This finalreportaccuratelyreflecttshe raw data obtainedduringthe performance ofthe study. No significandteviationsfrom the U.S. Food and Drug Administratio(nFDA) Good LaboratoryPracticeRegulations;FinalRule',the Japanese Ministryof Healthand Welfare (MHW) Good LaboratoryPractice Standard forSafetyStudieson Dnigsband the European Economic Community (EEC) Councildecisionon 28 July 1989 on the acceptance by the European Economic Community ofan OECD decisionlrecommendationon compliancewith principleosf good laboratorpyractic6occcurredthataffectedthe qualityor integritoyf the study. 1'6n( nd G York, P DABT AssociateD rectorof esearch and Study Director Date a. U.S. Food and Drug AdministrationG.ood LaboratoryPractice Regulations;FinalRule. 21 CFR Part58. b. Japanese Ministryof Health and Welfare (1988). Good Laboratory Practice Standard forSafety Studies on Drugs, MHW Ordinance Number 2 1,March 26, 1997. C. European Economic Community (1989). Councildecisionon 28 July 1989 on the acceptance by the European Economic Community ofan OECD decisionlrecommendationon compliance withprinciplesofgood laboratorypractice.OfficiaJlournalofthe European Communities: Legislation3.2(No. L 315;28 October):1-17. I QUALITY ASSURANCE APPENDIX I UNIT FINAL REPORT STATEMENT ijPRMEDICA 418-01 I:PAGE 1-1 Argus Research Laboratories,Inc. 905 Sheehy Drive,BuildingA Horsham, PA 19044 Telephone: (215) 443-8710 Telefax:(215) 443-8587 QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT Study DirectorR:aymond G. York, Ph.D.,DABT ExecutiveDirectorof Research: MildredS. ChristianP,h.D.,Fellow,ATS Protocol418-011: Oral(Gavage) DevelopmentalToxicityStudy of N-ETFOSE in Rats Sponsor's Study Number: T-6316.7 The draftprotocolforthisstudywas auditedforadherence to U.S. Food and Drug Administratio(nFDA) Good LaboratoryPracticeRegulations,Japanese MinistryofHealthand Welfare (MHW); Good LaboratoryPracticeStandard for SafetyStudieson Drugs,and European Economic Community (1989)council decisionon 28 July1989 on the acceptance by the European Economic Community ofan OECD decision/recommendationon compliance withprinciples ofgood laboratorypracticeon 13 JUL 98. Criticaplhases ofthisstudywere inspectedfivetimes;study information and raw data were auditedtwice(see tables1 and 2 fordatesand phases/data). The draftfinalreportand the raw data forthisstudy[exceptfor Appendix F,the PilotReport,which was conducted inthe spiriotf Good LaboratoryPractice(GLP)]were compared and auditedforaccuracy,for adherence to protocolrequirements,and foradherence to U.S. Food and Drug Administratio(nFDA) Good LaboratoryPracticeRegulationsJ,apanese Ministry of Healthand Welfare (MHW); Good LaboratoryPracticeStandard forSafety Studieson Drugs,and European Economic Community (1989)councildecision on 28 July1989 on the acceptance by the European Economic Community of an OECD decision/recommend ationon compliance withprincipleosf good laboratorypracticebetween 12 NOV 98 and 02 DEC 98,and forrevisions requested by the Sponsor on 10 DEC 98 and 17 DEC 98. 418-011: PAGE 1-2 This studywas conducted accordingto U.S. Food and Drug Administratio(nFDA) Good LaboratoryPracticeRegulations,Japanese Ministry of Healthand Welfare (MHW); Good LaboratoryPracticeStandard forSafety Studieson Drugs,and European Economic Community (1989)councildecision on 28 July 1989 on the acceptance by the European Economic Community of an OECD decision/recommendationon compliance withprincipleosfgood laboratorypractice. /BBarrbba,arorIaraJ;o.iP 'oon,:sBB..AAA.. DirectoorfP..pIeerrtfinons and Compliance Date Heather L.Rlaa'uufitninoMI,.S. Date QualityAssurance Supervisor and PrincipaAluditor TABLE 1 CRITICAL PHASES INSPECTED 418-01 1:PAGE 1-3 Cohabitation Date ofinspection:21 AUG 98 Date resultsreportedtotheStudy Directorand Management: 21 AUG 98 TestArticlePregaration Date ofinspection:02 SEP 98 Date resultrseportedtothe Study Directorand Management: 28 SEP 98 TestArticlAedministratio-nGavacie Date ofinspection:03 SEP 98 Date resultsreportedtothe Study Directorand Management: 28 SEP 98 Blood Collection Date ofinspection:10 SEP 98 Date resultsreportedtothe Study Directoarnd Management: 10 SEP 98 Caesarea n-Sectionnig Date ofinspection:10 SEP 98 Date resultrseportedtothe Study Directorand Management: 28 SEP 98 418-011: PAGE 1-4 TABLE 2 RAW DATA AUDIT(S) The followinsgtudyinformatioannd raw datawere audited on 08 OCT 98, and 15 OCT 98 to 17 OCT 98: Protocol. Protocolamendments. Listofpersonneland computer operatorcodes. Errorcodes and codes forclinicaslign observations. Animal receipt,randomization,physicalexaminationand acclimation. In-lifteransactionrecord. Feed consumption. Cohabitation. Caesarean-sectioning. Maternalgross observations. Fetalgross observations. Fetalfixativaessignment. Fetalvisceralexamination. Fetalskeletalexamination. Necropsy. Tissue packing lists. Male breeder colony records. General comments. Study maintenance records. Temperature and relativheumidityreports. Feed and water analyses. Editrequests. Dosage volumes. Deviations. Data review page. Key fortestfacilitcyomputer back-up recordabbreviations. Bloodcollectidoantaand packinglists. The resultsofthisauditwere reportedtothe Study Directorand Management on 21 OCT 98. 418-011: PAGE 1-5 The followingstudy informationand raw data were audited on 08 OCT 98 and 10 OCT 98: Vehiclereceiptp,reparationand use. Test articlreeceiptp,reparationand use. Test articlpeacking lists. The resultsofthisauditwere reportedtothe Study Directorand Management on 21 OCT 98.