Document YG7yoKV20JjMD2Lwq31x3pBVD

418-011:PAGE F-1 FINAL PILOT REPORT StudyTitle Oral (Gavage) Dosage-Range Developmental Toxicity Study of N-EtFOSE in Rats Sponsor's Study Number: T-6316.7 Author Raymond G. York, Ph.D., DABT (Study Director) Study Completed On 10 December 1998 (Final Pilot Report) PerformingLaboratory Argus Research Laboratories, Inc. 905 Sheehy Drive, Building A Horsham, Pennsylvania 19044-1207 LaboratoryProjectID Argus Research Laboratories, Inc., Protocol Number: 418-011P 003750 418-011:PAGE F-2 : 418-011P:PAGE 2 PROTOCOL 418-011P: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS SUBJECT ABSTRACT I. Purpose ABLE OF CONTENTS n Methods mn. Results IV. Conclusion Figure 1. Maternal Body Weights. Table 1. Clinical and Necropsy Observations - Summary Table 2. Maternal Body Weights - Summary Table 3. Maternal Body Weight Changes - Summary Table 4. Maternal Absolute Feed Consumption Values (g/day) - Summary Table 5. Table 6. Maternal Relative Feed Consumption Values (g/kg/day) - Summary (Caesarean-Sectioning Observations - Summary PAGE 4 6 6 7 9 10 1 13 15 17 19 21 1003751 418-011:PAGE F-3 : 418011P.PAGE 3 SUBJECT PAGE Table 7. Litter Observations (Caesarean-Delivered Fetuses-) Summary 23 Table 8 Fetal Gross External Alterations -- Summary 25 Table 9. Clinical Observations - Individual Data 27 Table 10. Necropsy Observations - Individual Data 31 Table 11. Maternal Body Weights - Individual Data 35 Table 12. Maternal Feed Consumption Values - Individual Data 42 Table 13. Caesarean-Sectioning Observations - Individual Data 46 Table 14. Litter Observations (Caesarean-Delivered Fetuses) - Individual Data 50 Table 15. Fetal Sex, Vital Status and Body Weight - Individual Data 54 ATTACHMENT 1 - PROTOCOL AND AMENDMENT 58 003752 418-011:PAGE F-4 - 418.011PPAGE 4 TITLE: ORAL (GAVAGE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-EFOSE IN RATS ARGUS RESEARCH LABORATORIES, INC. PROTOCOL NUMBER: 418-011P SPONSOR'S STUDY NUMBER: T-6316.7 ABSTRACT Fifty-six presumed pregnant Cr:CDGBR VAF/Plus (Sprague-Dawley) rats were randomly assigned to seven dosage groups [eight per group (Groups| through VdIaIi)l.y toSutshpeesnesniaotnusroalflyt-hbereNd-fEetmFaOlSeErawtesroenaddamyisni6sttehrreodugohral1l7y ovfiapgraevsaugmeedonce gestation (DGs6 to 35 mg/kg/day. The 17) at dosages dosage volume of 0 was (Vehicle), 5 mLikg, 1, 5, 10, adjusted 20, 25 and daily on the basis of the individual body weights recorded immediately before administrationof the testarticle. dCahielyckbseffoorrevidaobsilaigtye,wearpeprmoaxidmeattewliyceondaeilyh.ourClaifntiecralaodmbisneirsvtartaitoinosn waenrdetrheecnofroduerdto psioxsthoduorssagleatepre.riTohd.esBeoodbysewreviagthitosnwsewreerereaclosroderdecdoaridleydduornicneg dtahielydodusraigneg athned postdosage periods 8,10, 12, 14, 16, 18 and and feed 20. consumption values were recorded on DGs 0, 4, 6, Aolflcroartpsowrearleutseaac,riifmipcleadntoantiDonGs2i0tesanadndexuatemriinneedcofnotretnhtse.nuAmbgerorsasnndecdirsotprsibyutoifon the thoracic, abdominal and pelvic viscera was performed. Fetuses were weighed and examined for gross external alterations and sex. All rats survived until scheduled sacrifice. Clinical observations during gestation ccohnrsoimdoedraecdrytorrearthmeeanto-rreelmaatceidatwieornealtitmihteed20toasnidng3l5e rmagt/skwgi/tdhacyhdroomsoargheisn.orCrlhienai,cal observations No additional of localized alopecia and emaciation necropsy observations occurred. were confirmed at necropsy. 003753 418-011:PAGE F-5 . 418.011PPAGE S Body weight gains and absolute and relative feed consumption values for the entire dosage period (calculated as DGs 6 to 18), the entire interval after initiation of treatment (DGs 6 to 20) and the entire gestation period (DGs 0 to 20) were reduced in the 10 mg/kg/day and higher dosage groups, compared to the control group. Reduced fetal body weights occurred at the 25 and 35 mg/kg/day dosages, relative to the control group (-8.5% and -13.8%, respectively). No other Caesarean-sectioning or litter parameters were affected by dosages of the test article as high as 35 mg/kg/day. One litte in the 35 mg/kg/day dosage group consisted of two early resorptions and 13 fetuses with cleft palate (two also had whole body edema). These fetal findings were considered genetic in origin and not test article-elated. Based on the resultsofthis dosage-range finding study, dosages of 0, 1, 5, 10 and 20 mg/kg/day were recommended for the full developmental toxicity study of N-EtFOSE in rats. 043754 418-011:PAGE F-6 . 418.011PPAGE 6 I. Purpose: `The purposeofthis study was to provide information for the selection of dosages to be used in the developmental toxicity (embryo-fetal toxicity and teratogenic potential) study of N-EtFOSE administered orally via gavage to Cr:CDBR VAF/Plus presumed pregnant female rats. Il. Methods": The test article, N-EtFOSE [lotbatch number FM-3829 (30035, 30037, 30039)], was received on 20 May 1998, and stored at room temperature. The vehicle was 2% Tween 80 in reverse osmosis membrane processed deionized water (R.O. deionized water). The Tween 80 was received from J.T. Baker, Philipsburg, New Jersey, on 22 May 1998, and was stored at room temperature. `The R.0. deionized water is available from a continuous source at the Testing Facility and is maintained at room temperature. The prepared vehicle was stored at room temperature. Test article formulations were prepared daily. Fifty-six presumed pregnant Cr:CDBR VAF/Plus (Sprague-Dawley) rats were randomly assigned to seven dosage groups [eightper group (Groups | through VID]. Suspensions of the test article were administered orally via gavage once daily to these naturally-bred female rats on days 6 through 17 of presumed gestation (DGs 6 to 17) at dosages of 0 (Vehicle), 1, 5, 10, 20, 25 and 35 mg/kg/day. The dosage volume was 5 mL/kg, adjusted daily on the basis of the individual body weights recorded immediately before administration of the test article. Checks for viability were made twice daily. Clinical observations were recorded daily before dosage, approximately one hour after administration and then four to six hours later. These observations were also recorded once daily during the postdosage period. Body weights were recorded daily during the dosage and postdosage periods and feed consumption values were recorded on DG 0, 4, 6, 8,10, 12, 14, 16, 18 and 20. a. Detailed descriptions of all procedures sed in the conductofthis study are provided in the appropriate sectionsofthis report and in the attached protocol and amendments. Deviations from the Protocol and Standard Operating Procedures of the Testing Facility are available in the raw data. 003755 418-011:PAGE F-7 . 418.011PPAG7E All rats were sacrificed on DG 20 and examined for the number and distribution of corpora lutea, implantation sites live and dead fetuses and early and late resorptions. A gross necropsyof the thoracic, abdominal and pelvic viscera was performed. Fetuses were weighed and examined for gross external alterations and sex. Ul. Results: A i ind Necropsy Observation: Individual Data - Tables 9 and 10) -Table 1; AA. Mortality All rats survived until scheduled sacrifice. A2. Clinical Observations Clinical observations during gestation considered treatment-related were limited to single rats with chromorhinorrhea, chromodacryorrhea or emaciation at the 20 and 35 mg/kg/day dosages. All other clinical observations were considered unrelated to the test article because: 1) the incidences were not dosage-dependent; and/or 2) they occurred in only one rat. These observations included localized alopecia on the limbs, underside, back and/or neck. A3. Necropsy Observations Clinical observations of localized alopecia and emaciation were confirmed at necropsy. No additional necropsy observations occurred. B. Maternal Body Weights and Body Weight Changes (Figure 1; Summaries -Tables 2 and 3; Individual Data -Table 11! Maternal body weight gains in the 10 mg/kgiday and higher dosage groups were decreased, compared to the control group on gestation days (DGs) 6 to 8 and 8 to 10. Body weights were decreased for the 25 mg/kg/day and higher dosages on DGs 1010 12, 12 to 14 and 14 to 16. Matemal body weight gains in the 1, 5, 10, 20, 25 and 35 mg/kg/day dosage groups were generally comparable to control values postdosage (DGs 18 to 20) 003756 418-011:PAGE F-8 . 418.011PPAG8E Rpeefrlieocdti(ncgaltchuleasteedefafsecDtsGosf 6thteot1e8s)t,atrthiecleen,twiereigihnttegrvaailnsafftoerrtihnietieanttiiornoefdotrseaagtement (DGs 6 to 20) 10 mg/kg/day and and thhiegheenrtidroesgaegsteagtrioonuppse,ricoodm(paDrGed0ttoot2h0e)cwonetrreolrgerdouucpe.d in the gMratoeurpnsawlebroedygewneeiraglhltys caonmdpabroadbylweetioghctongtarionlsvafolruetsheov1earneda5chmgin/tkegr/vadlatyadbuolsaatgede. C. VMaatleurensa(lSAubmsmoalruitees(-g/Tdaabyl)easn4d aRneldat5;ivIendi(vai/dkuaa/ldayD)atFaee-dTaCbolnes1u2m)ption Absolute and relative feed consumption valuesforthe 10 mg/kg/day and higher dinotsearvgaelsgdruoruipnsg wteheredodescargeeaspeedri,odco(mDpGasre6dt0to8,th8etc0on1t0r,ol10grtoou1p2,at1a2llttoa1b4u,la1t4edto 16 and 16 to 18). Maternal feed consumption valuesforthe 1, 5, 10, 20, 26 and 35 mg/kg/day dosage groups were generally comparable to control values postdosage (DGs 18 to 20). Reflecting these effects of the test article, absolute and relative feed ecnotnisruemipntteirovnalvaafltueersinfiotriatthioeneonftitrreeadtomseangte(pDerGio6d t(oca2l0c)ulaantdedtahse eDnGtisr6e gteost1a8t)i,otnhe period (DGs 0 to 20) were reduced in the 10 mg/kg/day andhigher dosage groups, compared to the control group. Adbossoalguetegraonudpsrewlaetrievegfeeneedraclolnyscuommpptairoanbvlaeltuoescofnotrrtolheva1launesd o5vmerg/ekagc/hdaiynterval tabulated. D. tChareosuagrhea8;n-SIendcitviiodnuialngDaatnad-LiTtatberleOsbs1e3rvtahtriooungsh (Summaries 15) - Tables 6 Caesarean-sectioning 8 (100%), 8 (100%), 8 observations were (100%), 8 (100%) based on 8 (100%),7 (87.5%), and 8 (100%) pregnant rats with live litters in the seven respective dosage groups. Reduced fetal body weights occurred at the 25 and 35 mg/kg/day dosages, relative to the control group (-8.5% and -13.8%, respectively). This observation was considered an effect of the test article because it was dosage-dependent 003757 418-011:PAGE F-9 . 418.011PPAGE 8 and occurred at the dosages in which there was maternal toxicity observed (decreased body weight and feed consumption values). No other Caesarean-sectioning or liter parameters were affected by dosages of tihmpeltaensttatairtoincsl,e laisttehrisgihzea,sl3iv5e fmegt/uksge/sd,arye.soTrhpteiolnitste(reaavrelyraagnedslfaotre)c,odrapomrsawliuttheaa,ny resorptions and percent live male fetuses were comparable among the 0 Vehicle), 1, 5, 10, 20, 25 and 35 mg/kg/day dosage groups. No dams had all rnoersmoarlb.ed conceptuses, there were no dead fetuses and all placentae appeared Totals of 109, 93, 116, 110, 118, 116 and 114 live fetuses were evaluated for external gross alterations in the seven respective dosage groups. No fetal gross external alterations were observed at dosages up to 25 mg/kg/day. One litter (a1n0d65103)fientutshees3w5itmhgc/lkegft/dpaalyadteos(atgwoe aglrsoouphacdonwshioslteedboofdytweodeeamral)y.reTshorepsteiofnestal findings were considered genetic in origin and not test article-related. IV. Conclusion: Based on the resultsofthis study, dosagesof 0 (Vehicle), 1, 5, 10 and 2st0udmyg/ikngr/adtsay(4o1f8N-0-1E1t).FOTShEear1emrg/ekcgolmdmaeynddoesdafgoretihs eexdpeevcetleodpmtoenbteala tnoox-icity tohbsee2rv0abmlge/-kegf/fedcaty-ldeovselag(eNOisEeLx)pfeocrtbeodthtompartoedruncale amnatdeermnbarlytoo-xfiectitayl (tdoxeiccriteya,saendd tmoaxtiecirtnyal(dbeocdryeawseeidghfettaalnbdofdeyedweciognhstusmapntdiopnosvsailbuleys)dealnadyemdinoissmiaflicadteivoen)l.opmental 7 Lull. 00z 9. Fr Alan M. Hoberman, Ph.D., DABT Date Director of Research Aeon L TIC soe Rekhond G.Yorn .DABT Date Associate Director {Research and Study Director 003758 MATERNAL BODY WEIGHTS Figur1e - | |e| g2e== EEi - =| EE Jo I" PC 5&8 gem 77, p A A. 8 SEAT Se Iz -- |en = sons mh Surdor dGtsorbihondow bw a | .i &3 i3 iol  mo Br Lunn a sw LI g5 B- gg i p ii 3 RN wm m--ion mmtm wim wma " mr men wma maaan wane or oso, wens wosme sss as eas .f 3 g33 wos a n. ie3 wonnss 0. ans nas mn men : : ess aes ses va wn wwe -- me an ni - ae cL 2 2Gomi Serres days hreugh 1 of guntation. .8 Pos 3z e oaras a wonnss.0. oe eae weans.. a se mae oe ers sa anes 41 was aa ares as as aa mss ee 8 i3 d Gg we a oars 1a a Cann on wanss.0. mn wn ass ve ----na mm as waza a orsan FLIERcm iain or , 8& iE0d3 Q mun mer wan aia 38 main mm"m W>W i. in a s.on . ve EERE Rn drs i. 28 HI 8I som. Inommu: noom:inoon:n a uresears chun 37 of entation. : iEI & omnnoommoomEn om men ome TIThomnoominoozin nmin CE ,# 3 id EE rw ale wba ata i oa : : : : MPeA reA0 wen -- me ee tane a. Bomage sccurredoadays Chiough 17ofgestatica. g. ;& Ei3 zz PT 3 -_ IomnomEond oie wit In uit TM i2 w=. Tries. er reyboom AOA cssspcesonts TT, re , S-- i: : 3 gmre . " 8J e merma eases 6. was: Peep pprpt a was: ma - sss: me - wre: ma = = SR HPE B [J 8 Hm we men ene mem E LRrr rw mien nl ;f Ha i t Sg33 .i 3 :3g an 8 8 a ,& [I a ui Bim ATES TOMES ccsssssveotoas ersnenas senses. 2 8 Eo: [3I R BR 8 v NJ Eo i:oe Ei Ss2AiohvenmsEenrievminscs SS :f L2 I] EEL mm i Womomen ESEEEE oe ro 3 IR id  FREE, 3 :E ig mm mm gs o " 8 @ EEE EH EH i 2 Ht} ew mw ob i ims mmr i BEES TEEMma ma umn AkTissAras Soma AkTieevesAras Soma , gPE od3 2 gH orEms .BN g8 &g BWOOE}: 11 LLoimEpieeEnEs .; % 8 s 88 8 :& :giE g23 Poo tHE EER or s s8 ELI |3 ii 3 OE e EES E EEBEERBES RR HE ;R LI gg d mE nane a RRR C BEI RR RR LE EE EE ,8 ii3 gE OBOE OBOE BE OEE EB EEE GB .8 LI 8 Tr een2 2 vs _-- ---- ,HI i RT i gS-oma w mowaMOM OM OH ON OH OB OBE DOB CS ommom om mon i. os8 iI orOR EE Tr rrr: Ba i SU . ii ii & mar EET A .E [I ee g 2 [SS fk Ei0d3 Pt  myLE A ---- & miiiiEiiiiiiiiitiEitg - HE fF SJ om Pip rbep bei Edrs 3 3 if 2 ph irm i m TE HEREEEEEEEEERREE E] S I rsrveissesseedesertLesseeiesors Sooesesasss,oseessussss Tasirtmuenss Sootirauasssossormnseeiins soassseiuss Mossssess .E 1  rb oreBehon. & 0B TTT ovowmomom oon ,& ii Pi 8 eo EPG Foo Ei 8g. S ---- j= th 3 So EP rR A 3 rirrintoirmpiosrnasstossassisisss Eesssorinngn JRO, corssssprrassesssseesseoeeesicigs horses corer .; 8f ii LI  igE 83 ios  TG ai 8 Sl id 3 n i8 J g MIERRRREEEE EEL 8 oo a a i A wi pi BBR BBAA ai SAE TT HM unco reniovat ~"Fim.sho Vi Pon peo 1 So ,& 1 8 g 3 gZ gJR EmeUwLM ERm m R R mR A h R ELEh s , gw RR RR Bee AASEARREHEE nanan J sBtE a Re AL ErLt Ts t|ShBOaB b aht hLhE LASo i 8 Sk :. E3k i [HI i FI} o morcmEEL REREAD EERE mo RRERERRIRYEREE. a gs at RI, LL xboa eh eh 5 m mnESEEEERREAERDEREERhTE H.I f Gn un EE Er.och rcsVo och has RAR] g: g =oiRRRentr ith nan BE. 8 LINEmi m Ar RB RL rai L Es mie mfe 1hin .E 418-011:PAGE F-58 . 418-011P:PAGE 58 ATTACHMENT 1 PROTOCOL AND AMENDMENT 003807 418-011:PAGE F-59 . 418-011P:PAGE 50 researc Argus90R5esSehaerechhyLDarbiovrea,tBourileksi,nIgncA. A Asonarontes HorTsRhIaEmU, SPaSnnDayFiva1n8i)a 19a0s4e4? ------ EE ---- err. PROTOCOL 418-011P SPONSOR'S STUDY NUMBER: T-6316.7 STUDYTITLE: PURPOSE: TESTINGFACILITY: STUDY DIRECTOR: SPONSOR: STUDYMONITOR: ALTERNATE STUDYMONITOR: Oral (Gavage) Dosage-Range Developmental Toxicity Study of N-EtFOSE in Rats s`Tehleecptuiornpoosfedoofstahgiesssttuodbyeisustoedprionvtihdeedienvfoerlmoaptmieonntfaolr the otfoxNic-tEyt(FeOmbSrEyoa-dfmeitnailsttoexriceidtyoraanlldy teratogenic via gavage potential) to study C.CDBR VAF/Plus presumed pregnant female rats. 9Ar0g5uSshReeesheyarDrcihveL,abBouriadtionrigeAs, Inc. Horsham, Pennsylvania 18044-1297 Telephone: (215) 443-6710 Telefax: (215) 443-8567 Raymond G. York, Ph.D., DABT Associate Director of Research 33MM TCoexntiecro,loBguyilSdeirnvgi2c2es0-2E-02 St. Paul, Minnesota 55144-1000 TMealrevpihnoTn.e:Case(,612D).V7.3M3.,-5P1h8.0D. Telefax: (612) 733-1773 ATenlderpehwonMe.: Se(a6c1a2t), 6P7h5.-D3.161 Telefax: (612) 733-1773 003808 418-011:PAGE F-60 E 418011P:PAG6E0 Protocol 418.0110 Page 2 REGULATORYCITATIONS: U.S. Food and Drug Administration (1994). International Conference on Harmonisation; Guideline on detectionoftoxicity to reproduction for medicinal products. Federal Register, September 22, 1994, Vol. 59, No. 183. 2U1.SC. FFRooPdanatn5d8.Drug Administration. Good Laboratory Practice Regulations; Final Rule. Japanese MiniosfHtearltyh and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. European Economic Community (1989). Council decision on 28 July 1989 on the acceptance by the European Economic Communityof an OECD decision/recom`mendation on compliance with principles ofgood laboratorypractice. Official Journal of the European Communities: Legislation. 32 (No. L 315; 28 October): 1-17. REGULATORY COMPLIANCE: This study will be conducted in the regulations cited above inthatthe TsesptiinorgftiFahtceilGitoyopderLsaobnonrealtowirlyl Pardahcetriecteo(tGhLeP)Standard Operating Procedures for laboratory operations and data collection. The Testing Facility Quality Assurance Unit (QAU) will not audit the protocol, the raw data, the reports or the critical phases of the study. All changes or revisionsofthis protocol shall be documented, signed by the Study Director and the Sponsor, dated and maintained with the protocol. STUDYSCHEDULE: See ATTACHMENT 1 to the protocol. 003809 418-011:PAGE F-61 . 418011PPAG6E1 Protocol 418.011 Page3 TA ESTRTIANC DVEL HICE LE: Identification: TestArticle: NPhaymsei:cal Description: LSpoetc/iBfaitcchGrNavuimtbye:r: Pury: Expiration Date: WNa-xEyIFsOolSiEd.. "F1M7-.3920 (30035, 30037, 30039). 99.1% May, 2000. IwintfhortmhaetiSopnonosnort.he identity, composition, strength and purtyofthe test article is on file Vehicle: 2De%ioTnwizeeednWat8e0r)i.n RSeuvpeprlsieerOasnmdosloitsidMeentmibfircaatnioenoPfroTcweesseend8De0itoonibzeeddWoactuemren(tRe.Od.in the raw data. tNoeibteheprrethseenStpionntshoervneohirctlheetShattudwyouDlidreicnttoerrfiesraewwairtehotfhearneysupottseonfttiahliscosnttuadym.inTahnetrsefiokerley, no analyses other than those mentioned in this protocol willbe conducted. Safety Precautions: fGolromvuelsa,timoanskpr,eappaprraotpiroinaatnedeyademipnriosttercattiioonn.anTdhae nMiaftoerrmiafliaSbafceotayt DaarteatoShbeeewto(rMnSdDuSri)ngis attached to the protocol (ATTACHMENT 2) Storage: VBeuhlikcTleesCtoAmrtpioclnee:nts: PPrreeppaarreedd VFeohrimcullea:tions: RRoooomm tteemmppeerraattuurree. RFrooozmente(m-p2e0raCt)ure. AJlullitaenstGaurltbiicnlseksih,iMpmeantsntoo ftaFheorTgmeusltaeitnigornFsac,ialtttyhsehopurledviboeusaldydcrietesdseadddtroetshse attention and of telephone number. cSahritpomnesnsthsosuhlodubled lianbcelluedde aipnpfroorpmraitaitoenlyc.onTcehrenirencgipsiteonrtasgheocuolnddibteionnostiafinedd sinhaipdpvianngceof shipment. 003810 418-011:PAGE F-62 5 418.011P-PAGE 62 Protocol 418011P Pages [EQRMULATION: Ereqou fPreepn aractioyn: Formulations (suspensions) will be prepared daly at the Testing Facility. Vehicle wil be prepared weeklyatthe Testing Facilty. Detailed preparation procedures are attachedtothis protocol (ATTACHMENT 3). AdjustfomrPeurnitty: `The test article will be considered 100% pure for the purpose of dosage calculations. TestingFacilityReserveSamples: The Sponsor will reserve a sample (1 g) of eachlotofthe bulk test article sed during tthhee cveohuircsleeocfotmhipsonsetundtys. uTsheed TdeusrtiinnggtFhaeccilotuyrsweiolfrtehsiesrvsetuadys.amSpalmepl(5esmLwi)llobfeeascthorleodt of under the previously cited conditions. ANALYSES: `Samples additional to those described below may be takenif deemed necessary during the course of the study. BulkTestArticleSampling: NInofoarnmaaltyisonesoonftthheesbtuabliklitteysotfatrhtieclbeuwliklltebsetacrotnicdluectisedondufrilienwgitthhethceouSrpsoenosofrt.his study. AnalysesofPreparedFormulations: AcotntdhuecrteeqduedsutrionfgtthheeScpoounrssoero,fntoheansatludyys.esHoofwperveepra,rerdectoersdtsarwtiilcllebefomramiunltaatiinonesdwtioll be document how the test article formulations were prepared. DISPOSITION: Prepared formulations willbediscardedatthe Testing Facilty. All remaining bulk test article will be retumed to the Study Monitor at the previously cited address. 003811 418-011:PAGE F-63 + 418-011PPAGE 63 Protocol 418-011 Pages ESTSYSTEM: SpeciaendsRe/asSont forrSealecitin on: TbehceauCsre::CD1)BBitRisVoAnFe/mPlaumsmal(iSapnrasgpueec-iDeaswlaecyc)erpattewdaasnsdewliedcetleyd uassedthtehrToeusgthSouytstem itonxdiucsittryyltfeorrantoongceiniicniitcya)l s2)tutdhiiessstorfadinevhealsopbmeeenntadlemtooxnisctitryat(eemdbrtyoob-efesteanlsitive to dFeavceilloiptmye;natanld t4o)xtinhse;t3e)sthiasrttoircilecailsdpahtaarmaancdoleoxgpiecrailelnycaecetxiivsetain tthheesTpeesctiiensgand strain. Number: PInoiptiuallaptoipounlasteiloenctaecdclfiomrastteudd:y: 7556 vmiartgiendffeemmaalleerartast.s (8 per dosage group). BW odyeiganh dAgte: wFheimcahletirmaetsthweiyl wbiellobredeerxepdecttoehdatvoebbeodatylweeaisgth6t0sodfay2s0o0fgagteo.22A5ctguaelacbhodatyrweeciegiphtt,sawtill be recorded the day after receipt and will be documented in the raw data. Sex: bFeemuasleedraotnslywialsl bberegeidveernstahnedteasrteanrtoitclce.onsMiadleererdatspofatohfrethtseamTeesstoSuyrscteeamn.d strain will Source: Charles River Laboratories, Inc. The rats will be shipped in fitered cartons by air freight and/or truck from Charles River Laboratories, Inc. to the Testing Facilty. Identification: CRoa.t,sInacr.e,pNeor.maMnSePntTly20i1d0e1n)t.ifieMdaulseinrgatMs oanreelgivseenlfu-npiieqruceinpgeeramrantaegnst(iGdeenytiBfiacnadtioannd Tag FneummableersrautpsoanreasassisgingmneednttteomptohreaTreystniunmgbFearcisliatty'rsebceriepetdaerndmagliveernatunpiopquuleatpieornm.anent identification numbers when assignedtothe study on the basisof day 0of presumed gestation body weights. 003812 418-011:PAGE F-64 . 418.011P.PAGE 64 Protocol 41P8a0g1e1s7 ANIMALHUSBANDRY: `AlalndcaUgseeosfizLeasbaornadthooruysAinnigmcaolndsi.tions are in compliance with the Guideforthe Care Housing: d"Tuhreinrgattshweiclobhaebiitndaitviiodnuaplelryiohdo.usDeudriinngstcaoihnalbeistsatsitoene,l,ewaicrhe-pbaoirttoofmreadtscwailglebseexhcoeupsted in tbheesmaacrliefircaetdsbceafgoer.e pNarotunreisttioinngismeaxtpeercitaelds.will be supplied because the female rats will RTooemAimr, peraatnduHumridiety: fTrheeshaainrimtahlatrohoams biseienndeppaesnsdeednttlhyrosuugphpl9i9ed.9w7it%hHatEPleAasftiteernsc(hAairnogCelsepaenrhroouormo)f. 100% cRoonsotmanttelym.peRraotoumrehwuimllidbietymawiilnltaalisnoedbeatm6on4itFor(e1d8cCo)nsttoan7t3lyFa(n2d6mCa)inatnadinmeodniatto3r0e%d to 70% Light Amaninatuationmeatdi.caElalcyhcodnatrrkolpleerdio1d2-whiolurbleiggihnt:a1t2-1h8o0u0r dhaourrksflEuSoTr.escentlight cycle wil be. Diet: Rats will be given Certified Rodent ad libitum from individual feeders. Diet#5002 (PMI Nutrition Intemational) available Water Water wil be availableadlibitumfrom individual bottles attachedto the cagesorfrom an automatic watering access system. All water will be from a local source and passed througha reverse osmosis membrane before use. Chiorine will be added to the tphraonce1s.s2epdpwmatcehrloarsinae baatcttehreitositmaeto;fpraoncaleysssies.dwWaatteerriisseaxnpaelcytzeeddtmoocnotnhtlayinfonropomsosribele bacterial contamination and twice annually for possible chemical contamination. Contaminants: 1N0eibteheprretsheenStpionntshoercnerotriftiheed dSiteutdoyrDiinretchteodrriisnkaiwnagrweaotferanatylpeovteelnstitahlatcownotualmdininatnetrfserlei:kely pwietrhfotrhmeerdesbuylttsoheftfheiesdsstuupdpyl.ieTrhoerretfhoorsee,mneontainoanleydseisn otthihserprtohtaoncotlhwoislel broeuctionnedluycted. 003813 418-011:PAGE F-65 . 418.011P-PAGE 65 Protocol 418P0a1g1e7?. RANDOMAINDZCOAHAT BITIATOIONN: cUopmopnutaerrri-vgale,nmeraaeteadnrdafnedmoamleurnaittss.wiAlfltebreaacscsliimganteidont,oviinrdgiivnifdueamlahloeruastisngwiollnbtehe basis of wCiolhlacbointseidstwiotafh bmraeexdiemrummaolfefriavtes,daoynse. mFaelmearlaet preartsfweimtahlespreatr.maTthoezocaohoabbisteartvieodn ipneraiod sconmsiedoefartehdretovabgeiantaldcaoynt0eonftspraends/uomread cgoepsutlataitoonryapnldugasosbisgenrevdedtoininsdiitvuidwiulallbheousing. Hgeeanletrhaytemdat(weedigfhetm-aolrederraetds)wirlalnbdeomaiszsaitginoendptroocdeodsuargees.groups based on computer- ADMINISTRATION: RR outee andasfoo rChon ice: Tdiheetaorryalro(ugtae,vatghee)erxoaucttedwoassagseelceacntebdefoarccuusreatbeelcyauasdem:ini1s)teirnedc;omapnadri2)sointiswiotnhethoef the possible routes of human exposure. Meat ndFh reqo uend cy: gFeesmtaatlieonr,attshweilplerbieodgoivfeonrtghaentoegsenteasritisc.le oDnocseagdaeislywiolnl bdeayasdj6usttherdofuogrhth1e7 omfopsrterseucemnetdly recorded body weight and given at approximately the same time each day. Ratfi orDo osan ge Saelel ctie on: Dosages will be selectedbythe Sponsor on the basis of previous studies conducted with the test article 003814 DCosaogenLecveles, ntrataindVoolnumess: 418-011:PAGE F-66 418.01PPAGE 88 Protocol 418P.a0g1e1s0 CrTeTowmen| oT5|eosovvacomene|n CoTe + 1 02 [&|eusoursonmmve|n CwTos[+Ts|eosoneconmmn|n CoTTTT sssonmT onmmen | eT TvTTeuvonveonmem|n CvToIo[o [ susoneT rouomen | La ow ToSe| res TO +TO |T5e|sesoncommm|n TA ESTSN , ALANY DMES ASURE EMENS TS: Viability: All Periods: At least twice daily. COlinibcal servanda iorGteneiralAoppenaransce: Acclimation Period: Weekly. Predosage Period: Dosage Period: Day 0of presumed gestation. Twice dally. Once approximately one hour postdosage and then four to six hours later. Postdosage Period: `Once daily. Clinical observations may be recorded more frequently than cited above,ifdeemed `appropriate by the Study Director and/or Study Monitor. -- Acclimation Period: Predosage Period: Dosage Period: Postdosage Period: Weekly. Days 0 and 4 of presumed gestation. Daily. Daily. 003815 418-011:PAGE F-67 . 418.011PPAGE 67 Protocol 418.011P Pages [EeedConsumptionValues (recorded and tabulated): Predosage Period: Days 0 and 4 of presumed gestation. Dosage Period: Days 6, 8, 10, 12, 14 and 16of presumed gestation. Postdosage Period: Days 18 and 20 of presumed gestation. rFeepeldenciosnhstuhmepfteieodn. vTahleuessemiantyerbvaelsrewiclolrndoetdbmeotraebuflraetqeude.ntly f tis necessary to MatingPerformance: Mating wil be evaluated daily during the cohabitation period and confirmed by oobbsseerrvvaetdioinn osifts.permatozoa in a smear of the vaginal contents and/or a copulatory plug Caesarean-Sectioning Observations: RbaetrsewmilolvbeedCfareosmatrheeanu-tseerucstiaonndedploanceddayin2i0ndoifvipdruealsucomnetdaigneesrtsa.tioTnh.eTrahtes fwieltlubsees wil `examined for number and distribution of: Corpora Lutea. I[mPpllaacnetnattaieonthSaitteasp.pear abnormal (size, color or shape) will be noted in the raw data] (LAilvievaenfdetDuesaids dFeeftiunseeds.as one that respondtos stimuli; a dead fetus is defined as daetaedrmfefteutsuessthdaetmodnosetsrantoitnrgesmpaornkdedtotosteimxutlrieamnedautthoatlyissisnoatremacroknesdildyeraeudtotloyzbeed; late resorptions.) Early and Late Resorption. `(oArcgoannocgeepnteussisishdaesfioncecdurarseda;lfattheirsesiosrnpottitohnefictasise,gtrohsescloyenvciedpetnutsthiastdefined as an early resorption.) 003816 418-011:PAGE F-68 + 418-011PPAGE 68 Protocol 41P8a-g0e11190 EstalObservations: Faentdudseeasdwifletbueseesxawimllinbeedefxoarmsienxeadnfdorfogrrgorsossesxteextmearlnaalltaelrtaetriaotnisotnos.thLeateextreenstorppotsisoinbsle. `bTeheubsoeddytwoediegthetrmoifneeaictherfefteutsalwiblol dbyewreeicgohrtdeadv.eraOgnelsy. boFdeytuwseeisghwtisthofgriovsesfeetxutseemsalwill alterations willbe fixed in Bouin's solution; all other fetuses willbediscarded. Representative photographsoffetal gross extemal alterations wil be taken. MET OF H SACRO IFID CE: Raantisntwrialpebreitsoancerailfiicnejdecbtyiocnaorfbeounthdiaonxaisdieaassoplhuytxiioant(ioBne.utLhiavneafseitaus-eDs Swpielcbiael,sacrificed by manufactured by Schering-Plough Animal Health). NECROPSY: Gevraolsusatlieosnio(nastwaiblleboefrreatanidnoemd uinnintesuwtirlallbbeufufseerdedto1s0e%lefcotromanleincofnotrroplosgsriobluepfruattufrreom wtihsiscuhesalfloirsasnuyespoesxsaibmlienehidstaotpnaethcorloopgsicyawlielvbaleuraettiaoinnsedo,f ignroosrsdelrestioonpsr)o.vidUenlceosnst.rol specifically cited below, all other tissues wil be discarded. ScheduledSacrifice: On day 20of presumed gestation, female rats will be Caesarean-sectioned, and a agprpoasrsenntelcyronposnyprofegtnhaentthorraatcsicwi,llabbdeosmtianianledanwidthpe1lv0i%c vaimscmeornaiwiulml bseufpiedrefotromceodn.firUmtetriheof absence of implantation sites. RatsFoundDeadorMoribund: Ratsthatdie or are sacrificed becauseofmoribund condition, abortion or premature doeblsievrevraytwiiolnl bisemeaxdaem.inTehdeforrattshewilclabueseeoxfamdienaetdh oforrmgorroisbsunledsicoonnsd.itPiornegonnatnhceydsataytutsh.e. and uterine contentsoffemale rats will be recorded. Aborted fetuses andor delivered fpeutpussewsi.ll Ubteereixoafmaipnpeadretnottlhyeneoxntpernetgpnoasnstibrlaet,suwsililngbethsetasianemdewmiethth1o0d%s daemsmcorinbieudmfor sulfide to confirm the absence of implantation sites. 003817 418-011:PAGE F-69 5 418-011PPA6GE9 Protocol 41Pa8g-e01111 STATISTICAL EVALUATION: Aapvperroapgrieastea.ndAdpdeirtcieonnatlagpersocweildlubreescaalncdu/laotreda.nalLyistteesr vmaalyuebsewiplerbfeorumseeddifwhdeereemed `appropriate. DATAACQUISITION,VERIFICATIONANDSTORAGE: Data will be hand- and/or computer-recorded. Records will be reviewed by the Study oDriirgeicntaolrraencdolrodrsawpilplrobperisattoeremdainnatgheemaercnhtivpeesrosfotnnheelTweistthiinng21Facdiaiytys.afAtlelrogreingienraaltidoant.a wAillll be bound and indexed. Acopy of all raw data wil be suppliedtothe Sponsor upon ryeeqaureasftt.erPmraeisleirngvoefdtthiessdureasttwiflilnablersetpoorrte,daatfttehrewhTiecshtitnigmeFatchielSypaotnsnoorcwhialrgbeefcoornotnaec.ted to determinethedisposition of these materials. REC TOO BEMR AIND TAINS ED: PTreosttoAcrotlicalen,dVAehmiecnldemaenndtlso.r Reagent Receipt, Preparation and Use. ARnainmdaolmiAzcaqutiisointiSocnh.edules. TMraetaintgmeHnitst(oirfyp.rescribed by Staff Veterinarian). GCleinneicraallOCbosmermveanttiso.ns and/or General Appearance. FBeoeddy WCeoingshutmsp.tion Values. GCareossasreNaenc-rSoepcstyioOnbisnergvaatnidonFse.tal Observations. OPhrogtaongWreaipghhst(si (rieqrueiqrueidr)e.d). SFteueddyaMnadinWtaetnearnAcnea(lyrsoeosm.and environmental records) Packing and/or Shipment Lists. 003818 418-011:PAGE F-70 : 418.011PPAGE 70 Protocol 41Pa8g0e11192 KPEEYRSONNEL: EDixreeccuttoirvoefDiRreescetaorrcoh:f RAelsaenarMc.h:HoMbielrdmreadn,S.PhCh.rDi.s,tiDaAn,BPTh.D., ATS ADssiociraoteefDLicarbetocrtoaortoorfryROepseeraartciohnasn:dJSothundyF.DiBraemcteotr:, BR.aSy.mond G. York, Ph.D. DABT MMaannaagegreoorffASntiumdaylCoOopredriantaitoinosn:anVdalMeemrbiAee.r,ShIanrstpietru,tiMon.aSl. Animal Care and Use Committee: Dena C. Lebo, V.M.D. MCoannsaugltearnto,f VReetgeurliantaorryyPCaotmhpolliogayn:ce:W.KRatahyleBernowAn.,MDo.rVa.nM,.,M.PSh..D. ACVP REPORT: Ailmemtetdeiratreeployrftoflolrowtihnegpcuormppolseetoifondoofsathgeeisne-ilfeectpihoansfeo.r the full study will be prepared Aressuultmsmaanrdy croenpcolrutswiiolln;bteabplreepoafrceodntiennctlsu;dicngo:pyaobfsttrhacet,prsoutomcmoal;riaemsenofdmtheentmse;thsoudsm,mary ainncdluidnedidvaidsuaalntaabplpeesn;dainxdtortehpoertfuslolfstsuudpyporretpiorntg.daTthae(iSfpaopnprsooprriwaitlel)r.ecTeihvee raenpeorctowpilyl obfe: the draft report andtwocopies of the final report. INSTITUTIONALANIMAL CAREANDUSECOMMITTEESTATEMENT: `InTshteitpurtoiconeadluArneismdaelscCrairbeedanidn tUhsisepCrootmomciotltehea.veAblepernorceevdiuerweesdbdeystchriebeTdesitnitnhgisFapcriolttoyc'osl that involve study animals will be conducted in a manner to avoidorminimize discomfort, distress or pain to the animals. `nTehceesSspiotnysfoorr'scosnidguncattiunrgetbheisloswtuddoycaunmdentthseftahcettfhacatttthhiast iinsfnoortmaatniounnnceocnecsesranriinlgythe duplicative study may be obtained from the Sponsor. No altemnative (in vitro) procedures were available for meeting the stated purposesofthe study. 003819 418011:PAGE F-71 . 418.011P.PAGE 71 Protocal 41P8a-g0e11193 REFERENCES: 1. CThersitsst.ianE,nvMi.rSo.nmaenndtaVloyPtreokt,ecPt.iEo.n(A1g9e82n)c.y,IWnaVsihviongRteopnr,odDu.cCt.ivNeaatinodnaMluTteacghenniiccaitly Information Service, U.S. Departmentof Commerce, Springfield, VA 22161. 2. Cnharlitsrteixaon,neM.(SP.ro(c1e9e8d4i)n.gsReopfrNoadlutcrteixvoenetoSxiycmitpyoasnidumt,erNateowloYgyorekvaAlcuaatdieomnsyooff Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10. 3. LCaonntgr,oPl.DLa.t(a19i8n8t)h.e ECmhabrrlyeosRainvderFeCtratl:DCeDveBlRopRmaetn.taClhaTroxliecsitRyiv(eTerrLaatboolroagtyo)ries, Inc., Wimington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.) 4. LInasbtoirtuatteoorfyLAanbiomraaltso.ryNaAtniiomnaall RAecsaoduermcyesPr(e1s9s96,)W.asGhuiindgetfoonr,thDe.C.Care and Use of 5. ISmaplleawnstkatiioEn.ss(t1e9l6l4e)n. aFmrUbteemreusthdoedreRzatutme.mAarkcrho.skPaotphiols.chEexnp.NaPchhawremaiksovl.on 247:367. 003820 . PROTOCOLAPPROVAL: FOR THE TESTING FACILITY /fon _ nde. rgek. Dearlove, Ph.D., DABT Associate Directorof Research Rayr G. York, Ph Associate Director of `Study Director \ JABT rch [NY MDeeUmnsbaeeCrC.,omLIemnbisott,utteVie.oMn.aDl.Animal Care and FOR THE SPONSOR Denes: [lac SMtaurvdiynMTo.niCtaosre, D.V.M., Ph.D. 418-011:PAGE F-72 aisorippAcE 72 Protocol 41P8a.g0e111P4 10-1vr-9p Date fo-30u=98 Date a Date 1 Bans L195 Date 003821 418-011:PAGE F-73 ` 418-011P.PAGE 73 ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE 003822 + ATTACHMENT 1 418-011:PAGE F-74 418-011P:PAGE 74 ProtocoPla4g1e8-100111P2 STUDYSCHEMATIC DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY* RFaemtasle DoSstaargteof. Cohabitation PrDeasyu6moefd Gestation CSaecetsiaorneinagn'DEonsdaogfe | PDraeys1u7meodf Gestation PDraeys2u0meodf Gestation Dosage Period. a. For additional details see "Tests, Analyses and Measurements" section of the. b. pFreottaolcoelv.aluations (all fet-uexsteernsal examinations). 003823 + ATTACHMENT 1 418-011:PAGE F-75 418011PPAGE 75 ProtocolPa41g8e.20011129 SCHEDULE* 16 JUN 98 22JUN9BPM-27 JUNSBAM 23JUN 98-27 JUN 98 29 JUN 98-14 JUL 98 13JUL 98-17 JUL 98 240UL98 29SEP 98 Arrival Date - Acciimation Begins. Cohabitation Period. Day 0of Presumed Gestation. pDroessaugmeePdergeisotdat(iDoany).s 6 through 17 of pCareessaurmeeadn-gSeesctattiioonni)n.g Period (Day 20 of Letter Report. `Summary Report. a The study initiation dateisthe date the Study Director signs the protocol. 003824 418-011:PAGE F-76 . 418011P-PAGE 78 ATTACHMENT 2 MATERIAL SAFETY DATA SHEET 003825 418-011:PAGE F-77 MDAATTEARISAHLEETSAFETY 3TMM Center N-E4FOSE 418-01P PAGE 77 S5t5.144Pa-u1l0,00Minnesota 1-800-364-3577 or (612) 737-6501 (24 hours) CAUon2ptyorrriiaggshnttti,son1r9fe9os8re,rvtehMdei.nnpeusCropotopasyeiMnigonfiannpgdr/ooparnedrldMyoawnnuultfoiaalcditizunirgnignogfSHCtohpmirpsoadnuyc.ts 35} atprhlieloorwiendafgorrpemreaomtveiinodtnediitsshaoctob:ptiaeidnedinffruomll3Mw,ithandno changes unless 2) Ghiesittrhiebruttehde cwoiptyh tnhore tihnetenotriiogninaolf iesarnriensgolda oprrofoitthertuheirseeon. DTIRVAIDSEIONNA:VE:3H CHEMICALS 1DFNo-O1M0BEFRL/UUO.RPA.DC.Brand Fluorochemical Alconol 9988-.00221111..11151735..77 0000--5511113355-.0092419455..23 9988-.00221111-.16168230.-06 ISSZUFE.Do:00Jza.n0u5a7r2y229, 1c998+ DSOUCPUEMRESNETD:ES:10N-o3v7e7m8b-e7r 05, 1997 0000--5511113355--0180544329--32 1. INGREDIENT CAS. NO. PERCENT PPPEEERRRFFFLLLUUUOOORRROOOHOHECEXTPAATNNAEENSSEUUSLLUFFLOOFNNOAANMMAIIMDDIOODOAALLACCLOOCHHOOOHLLO..L..|........... 341649515-.9093--23 68555.73.7 38.00.0 2.0 +- 79.00.0 - 6.0 P~PEERRFFLLUUOGRROOPBEUNTTAANNEESSUULLFFOONNAAMMIIDDOOALACLOCHOORLO.L. ........ 3648454595.-8792--36 21..00 -- 36..00 2. PHYSICAL DATA BOILING POINT:.........vevens GB1. m118 CHg VAPOR PRESSURE:...........0os0 <Ca1l0emabg20 C VAPOR DENSITY:......vvoneenns >ca1l.0c A@P2E0)C. SEOVLAUPBOIRLAITTIYONINRAWTAET:E.R.:....................... <neg1i.i0g,BUOAGs1 SPECIFIC GRAVITY:.............. ca(.of1m.e7ltW)aters) PPERRC.E.NT.ViOsLeATuIaLnE:i.i.s.i.e..ieeeivsueeennss N0I%A VIMSEGLOTISNTGTYP: LOoIoinNeeTi0n..e.i.s.0e0e.n0ss NNIIDD 003826 anheaviarinme. NID . Not Determined N/A - Not Applicable CA - Approximately 418-011:PAGE F-78 MSDS: FC-10 FLUORAD Brand Fl:uorochesical Alcohol January 29, 1998 418.011P-PAGiHe78 PAGE 2 2. PHYSICAL DATA (continued) APPAEmAbReArNCwEaxAyNDsolODiOdR: 3. FIRE AND EXPLOSION HAZARD DATA FFLLAASMHMPAOBLIENT:LI.M.I.T.S....L.E.L.ic.o.s.e.e.e.e.s. M>/A148 C Setaflash AFLUATMOMIAGBNLIETIOLNIMTITESMP-EUREALT:U..R.E.:.......... NIA N/A EXWTaItNeGrU,ISHCIaNrGboMnEDdIiAo:xide, Dry chemical, Foan SPEWPCeoIasrAiLtfiuvFeIlRlEpprreFosItsGeuHcrTetIiNvGoerPRcpOlrCoeEtsDhsUiuRnrgEe,S:deimnacnldudibnrgeathhelimnegt,appsaerlaft-ucso,ntabiunnekde,r coat Gpnrdotepacnttisv,e cbaonvdesrinagroufnodr earxmpso,sedwaiasrteasandofletghse, hefaadc.e mask, and UNU`SSeUeALHaFzIaRrEdouAsNDDeEcXoPmLpOoSsIiOtNioHnAZAsReDcSt:ion for products of combustion. 4. REACTIVITY DATA STABILITY: Stable INNCoOtMPaApTpIlBiIcLaIbTlYe.- MATERIALS/CONDITIONS TO AVOID: HAZARDOUS POLYMERIZATION: Hazardous polymerization Will not occur. HACSZuaAlrRfbDuoOrnU,SMoDHnyEodCxrOioMdgPeeOnSIaTnFdIlOuNoCraiPrdRbeOo,DnUCDTTioSox:xiicdeV,apoOrxsi,desGasoefsNiotrroPgaernt,icuOlxaitdeess. of 5. ENVIRONMENTAL INFORMATION SPIRLeLferREStPoONoStEh:er sections of this MSDS for physical and health hazards, respiratory iprnoftoercmtaitoino,n vreengtairldaitnigon, and preesrisdounea.l prPoltaceectiivneaeqU.uSi.pmeDnOtT.-appCroolvleedctcosnptialilneedr.material. Clean up 003827 IIILAIULIA Char nerarmined N/A - Not Applicable CA - Approximately 418-011:PAGE F-79 MSDS: FC-10 FLUORAD Brand Fluorochemical Alcohol January 29, 1998 5. ENVIRONMENTAL INFORMATION (continued) 418-011P-PAGE 79 PAGE 3 RECoTOfnMcMiaEnNceDroaEmtbDeusDtIiSniPbOlaSeApLme:artmeirtitaeld. haCzoamrdbouusstiwoanstperodiuncctisnerwaitllorininclutdhee pHFresence Dispose of waste product in a facility permitted To accept chemical waste. . ENVLIaRbOoNrMaEtNoTrAyL tDeAsTtAs: showed (Pinephales promelas) - Nnoo mbioordteaglriatdyataitonw.ate9r6-sHart.uraLtDiSoOn.FathNeoad Minnow sTteantgitshtiicnal3l0ydasyignFiatfhiecaadntMienffneocwt eogng 019 bioconcentration of FC-10 into % hatch, % fry study. suLravbivTaels,tswesihgohwte,d and 200 muscle fillets of channel catfish REGVUoLlAaTtOiRlYe OIrNgFaOnRMiAcTICOoNm:pounds: N/A. VOC Less H20 & Exempt Solvents: N/A. TTShCiAs, prEoIdNuECcSt, cCoOmSpLl,iesAICwSithandtheKorcehae.mical registration requirements of EPFICRREA HHAAZZAARRDD: CLNAoSS:PRESSURE: No REACTIVITY: No AGUTE: Yes CHRONIC: Yes 6. SUGGESTED FIRST AID EYE CONTACT: Inmediately flush eyes with large amounts of water. Get immediate medical attention. SKIcINonnntCeOadNniTiaAntCaeTtl:eydwacslhothsiknign. WiItfhsisgoanps/sayndmptloamrsgeocacmuoru,ntscaolfl water. Remove a physician. Wash contaminated clothing before reuse and dispose of contaminated shoes. INHALATION: It signs/sysptoms occur, remove person to fresh air. If signs/synptons continue, call a physician. IFCIaSmlWmlAeLdLaiOaWtpEehDly:ysicasiandirIeMcMEtDeIdATbEyLYm.ediIcfalswaplelroswoendn,el.indNuecveervogmiivteinagnything by mouth to an unconscious person. 003828 IIIT IR in mavarmined NIA - Not Aoplicable CA - Approximately 418-011:PAGE F-80 MSDS: FC-10 FLUORAD Brand Flyuorocheaical Alcohol January 29, 1998 PaAtGEer4PAAR 7. PRECAUTIONARY INFORMATION EYEvoPiRdOTEeCyTeIOcNo:ntact. Wear safety lasses with side shields. SKIeBNatPnROd"TTeEhCidTnI:OcKNop:natibaruc.tty.lofrWgueblbaoervre.sapmpaUrdsoeeprfioranotemeogTrlhoemvoerfseolWlohofewnitnngehamnfadotlleilrnoigwailnt(ghsi)s are Teroanal protection tems as necessary to prevent skin contact: Coveralls. REeCTeOeMioEEbNnoaDiunEsDotanVpEpvNrevToonIptLrimAilaTaiaItntOetiNao:inlnociaeslminsoetsxihoaanudssetqubavetelen,otilurasetecioosanap.epnrdoePpdrroiavetixedpeosruserusefpfiilrciaimteiotnrsty. protection. RESNSNPvIeIoGRL8AswsTiOabnRprapYernaotPtveRheOidTn.aEgnCdrToeIfsiOpnNia:riaarctbcooorrrsndeanbacmseaetedwriitoanhl.OaiSrHbSAoerlrneeecgtulcaootnniecoenonsft:ratthiehoanflofl-oflsoawsikngdust Setpirator, full-face supplied air respirator. PREBOVeEeNhToItOeNnsaotcO,FouAgaCnrCalInykDEmNioTrtAhLSseoIoaNkpGESWaThnIedOnNw:autseirn.g thHiasshprhoadnudcst.afWtaesrhhaenxdploisnegd and before eating. RECSOeMoMrEeNDuEaDySTfOrRaAsGEh:eat. Kesp container closed nen not in use. FIRNEonfAlNaDsmEaXbPlLeO.SION AVOIDANCE: OTHooNEeenRtt`asPhnmeRioEknCmiaAnasgUzi:TaoInnOdSNomuAoosRkfiYndtgheIecNWFoOhtmRiopMlboAaesTciIctuOoisNoi:nnagndp/TrohoridsucstmposrkoedmuecnattndiocanlneedadreisTnoulsttehcetiniofnorm4atofion This HOS. JMIS HAZARD RATINGS: HPEEARLSTOHN:AL1PROFTLEACMTMIAOBNI:LITXY:(S1ee pRErAeCcTaIuVtIiToYn:s, 0section 7.) EXPOSURE LIMITS 003829 INGREDIENT VALUE UNIT TE AUTH SKIN PPEERRFFLLUUOGRROOHOCETXAANNEESSUULLFFOONNAANMIIOOOO AALLCCOOHHOOLL...... 00..11 MMGG//MM33 TTWWAA 3SMM Y PAERLFCLOURODRLOHEPoTArKEoSULFONAMIDO eeceee 01 MOMS TRA GM Y ire - mer Applicable CA - Approximately 418-011:PAGE F-81 : MSDS: FG-10 FLUORAD Brand Fluorochemical Alcohol Jaruary 29, 1998 EXPOSURE LIMITS (continued) 418.011PPAGE 81 PAGE 5 INGREDIENT VALUE UNIT TYPE AUTH SKIN PERFLUOROBUTANESULFONAMIDO ALCOHOL... 0.1 MG/M3 TWA aM ~PAELRCFOLHUOOLR.OPoEoNTnANeEnSeUrLFnOeNnAMnIeDeOcmneenes 0.1 MOMS TWA SM Y t+heSKIpNoteNOnTtAiTaIlONc:ontrLiisbtuetdionsutbosttanhceesoveirnadlilcateexdpowsiutrhe b'yY' thuendecrutSaKnIeNousrefreoruteto ibyncdliurdeicntg mcuocnotuasctmewmibtrhanteheansdubsetyae,ncee.itheVrehibcyleasirbcoanrnealotre,r msokrien apbasrotripctuiloanr.ly, SZOaUmR:CE OF3MEXPROeScUoRmEmenLdIeMdITExDApToAs:ure Guidelines 8. HEALTH HAZARD DATA EYENoCOaNdTvAeCrTs:e health effects are expected from eye contact. SKIPNrodCuONcTtACiTs: not expected to be irritating to the skin. Meaxytenbededabtsionreb.ed through the skin and persist in the body for an INWHaAyLATbIeONa:bsorbed by inhalation and persist in the body for an extended ime. IFInSgHeALsLtOiWoEnD:is not a likely route of exposure To this product. qIulalnnetsistiemsayofocctuhrisafmtaetreriaals.ingle swallowing of relatively large MUTNAoGtENmIuCtIaTgYe:nic in in-vitro assays. RE`PSRuObDsUtCaTnIcVeE/wDaEsVEnLoOtPHtEeNrTaAtLogTeOnXiIcNSi:n the rat at doses as high as 30 milligrams per kilogram per day via oral route. OTHTEhiRsHEpAroLdTuHctHAZisARDnotINkFOnRoMwAnTItOoN:Contain any substances regulated under California Proposition 65. A Product Toxicity Susmary Sheet is available. 003830 S234setisavasastisterntirisansannneitiandt et rte fh. arreritately 418-011:PAGE F-82 : MSDS: FC-10 FLUORAD Brand Fluorochesical Alcohol January 29, 1998 SECTION CHANGE DATES HEADING SECTION CHANGED SINCE November 05, 1997 ISSUE 418011PPAGE 82 PAGE 6 Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately TbheecionrrfeocrtmataisonofitnhethdisatMeatiesrsiuaedl.SafGeMtyMAKDEaStaNOShWeAeRtRA(NMTSIDESS), isEXbPeRlEiSeSvEeDdORto MIEMRPLCIHEADN,TABIINLCILTUDYINOGR, FIBUTTNESNSOTFOLRIMAITEPDARTTOI,CULAANRY IPUMRPPLOISEED WOARRRCAONURTSYEOFOF nPEeRtFhOeRrMANtChEe OR aM UprSoAdGuEctOFiTsRAfDiEt. forUsearpaisrtirceuslpaonrsipbulreposfoeradndetesrumiitnaibnlge for Ucasner'asffemcetthotdheofuseuseandoraapppplliiccaattiioonn.of aGi3veMnprtohdeucvta,riestoymeofoffawchticohrsatrheat tuhneiquuseelry weviatlhuiantethetheus3eMr'sprokdnuocwtlsdtgoedaentdermcoinnterowlh,ethietrisitesissenftitialforthaat particular purpose and suitable for user's method of use or application. D3iMunepetrroroovritsdh,eesoremiminosftsoeiromnapstoisoosnribiainllitteeylreattchitaortnosnieclinefcottrhraiosniacsintfaorrasmneasrtfvieiorcne,matyo3Mhimatvasekecsursetnsooumletresd. rinefporremsaetnitoantioonbstaiasnetdofritosm caodmaptlaebtaesneesmsayornoatccubreacays.curIrnenatddiatsiotnh,e information in the MSDS available directly from SM. 003831 418-011:PAGE F-83 ` 418-011P:PAGE 83 ATTACHMENT 3 TEST ARTICLE AND CONTROL ARTICLE PREPARATION PROCEDURE 003832 418-011:PAGE F-84 - 418011P-PAG8E4 ATTACHMENT 3 Version: 418Pr-o0to1co0l84J1U8N019189) Page 1 of 3 TEST ARTICLE AND CONTROL ARTICLE PREPARATION PROCEDURE Test Article: N-EtFOSE Vehicle: 2% Tween 80, in R.O. Water A. Purpose: oTfhdeopsuargpeosseuosfptehnissiopnrsocoefdNu-reEtiFs OtoSEpraovniddethaemceontthrooldafrotrictlheefoprreopraarlation `administration to rats on Argus Study 418-011. B. General Information: 1. All suspension containers will be labeled and color coded. Each label will specify the protocol number, test article identification, Argus batch number, concentration, dosage level, preparation date, expiration date and storage conditions. 2a. XSu_spenDsailoyns willbe_pr_epareWde:ekly _ For__daysofuse 2b. _Ve_hicleDawiiyl be prepaXre_d: Weekly _For__daysofuse 3. Suspensions wil be prepared at afinal dosage volume of5 mLkg. 4. XSa_fety:Gloves, lab coat, goggles or safety glasses and faceshield X_C HDuasltf--MFiascte RReessppiirraattoorr -- Ful-Face Respirator/Positive Pressure Hood Tyvek Suit/Apron 5. Dosage solutions adjusted for Free base and % Purity. -- Yes _X_ No (Calculations based on 100%) __ FreeBase __ Pury 6. Sampling requirements: Cited in protocol. 7. Storage: Cited in protocol. 003833 418-011:PAGE F-85 ` 41801PPAGE 85 ATTACHMENT 3 Version: 41P8r-o0t1o1c7o(l0341J8U.N091819) Page2of3 TEST ARTICLE AND CONTROL ARTICLE PREPARATION PROCEDURE NOTE: tTheestloarwtidcolseawgilel.beOnprceepatrheedfianaslavosleruimalesdialruteioanchfireovmedt,hesihrigbhardsosaaregetotobe `addedtothe containers; mixing should occur during sampling andor `administration. C. PreparationofVehicle 1. Add the required amount of R.O. deionizedwaterto an appropriately labeled container. Heat the waterto 50C, 5C, add the required `amount of Tween 80 and mix until uniform (See TEST ARTICLE CALCULATIONS). D. Test Article Suspension Preparation: 1. Toprepare the 7-mg/mL, Group Vil suspension, add the required amount of test article (See TEST ARTICLE CALCULATIONS) into an appropriately sized, labeled container. Add the required amount of vehicle and heat the mixture to 80C, 25C for approximately 30 minutes. 2. Once the test article has dissolved; spin over night while the solution cools. (Be sure there is a visible vortex, this will achieve the desired emulsion.) 3. Toprepare the S.mg/mL, Group VI suspension, remove the required `amount of stock suspension (Group VI) (See TEST ARTICLE CALCULATIONS), add the required amount of vehicle and mix 4. Toprepare the 4-mg/mL, Group V suspension, remove the required `amount of stock suspension (Group VI) (See TEST ARTICLE CALCULATIONS), add the required amountofvehicle and mix. 5. Topreparethe 2-mg/mL, GroupIVsuspension, removethe required amount of stock suspension (Group V) (See TEST ARTICLE CALCULATIONS), add the required amountofvehicle and mix. 003834 418.011:PAGE F-86 . 418011PPAG86E ATTACHMENTS Version: 418.P0ro1t1o7co(l0341J8U.N0911B7) TEST ARTICLE AND CONTROL ARTICLE PREPARATION PROCEDURPaEge dots 6. Taomporuenptaorfsstthoeck1s-umsgpiemnLs,iGonro(uGprolulpsuIsV)pe(nSseieonT,ErSeTmAovReTIthCeLrEequired CALCULATIONS), add the required amount of vehicle and mix. 7. Taomopurnetpaorfestthoeck0.s2u:smpgeinmsLi,onG(rGoruopupll sIusp(eSneseioTnE,SrTeAmoRvTeICtLheErequired CALCULATIONS), add the required amount of vehicle and mix. Witten by: 2 Approved by: 2 enlog, 4Tprtt Clarfication: '"{No "_ Yes (See attached ciarification form.) IntialsiDate: (lout I Epp foofor 003835 418-011:PAGE F-87 : 418.011PPAGE 87 . gu Ecs , ArgusS0R5esSehaaracnhyLDarbvoer,atBourileksi,nngeA. --------------L--ABO--RAT--ORI--ES ------------------Ho--rT sh--am,s--ePr saan--ineey--.na0n--1i9a4--4195--58478 PROTOCOL 418-011P ORAL (GAVAGE) DOSAG`EO-FRNA-NEGIEFODSEEVIENLROAPTMSENTAL TOXICITY STUDY SPONSOR'S STUDY NUMBER: T-6316.7 Amendment1 - June 18, 1998 1. ClO inib cal serv and/a orGt eneri alAo ppen arans ce (page 8 of the protocol): dCionsiacgael oabdsmienrivsattriaotnisonduarnidngotnhceedaopspargoxeipmeartieoldywoinlelbheotuarkpeonsttwdiocseadgaei,l,raptrhieorrtthoan ance approximately one hour postdosage and thenfourto six hours later. ReaforsChoangne: TofhitshechoathnegrerweaprsomduacdteiavetltdheeverleoqpumeesnttaolftthoxeicSitpyostnusdiotersoumsaitncghthtehestaimmee tfersatmes ice peg S foe 1305 04 it `AssociatEe Dirbeeacrtioorveo,fPRhe.sDe.a,rDcAhBT Date ARsasyociate DiYroerctko,r of ResearchST Date `and Study Director LDienea C.nLeCbol, Va.MiD.m spduDnatcey DMaeninsT.iCasT e, DVn M. PhD.MhDate MeUmsbeerC,omInmsititteuteional Animal Care and Study Monitor 003836 APPENDIX G HISTORICAL CONTROL DATA 003837 418-011:PAGE G-1 soos or RaPRGmDaUrCTIVE INDICES parson ows 1995 - uz 1997 suaER or sToDEs 0 [-------- rest 2132 reosmamDEaArD ise3 orArsvoErRTsDD CAESARoErANnaStEsCTFIROENGIRNAGYT AT 1957 JoNCognEcRaporFusRALTSTWTITEH SINGLE RssonraavEe> so Asonres 0 MEAN or v + erzuare 52.8 AVERAGE # CORPORA LUTER 1.3 AVERAGE # THPLANTATIONS 1.6 aveRaGe LITTER s1zE AvERAGE # Live FETUSES 0s AVERAGE # DEAD FETUSES 01 AVERAGE # RESORPTIONS 0s AVERAGE EARLY RBSORPTIONS 0.7 AVERAGE # TATE RESORPTION 0.0 RMAENAGEN/SoTrUDAY (64.0-100) sano 2.5-10.0) isn.) (en) 16 (0-1.6) (0-0.2) 003838 418-011:PAGE G-2 STORY OF REP@RODmUrCTIVE INDICES AVERAGE DANS WITH ANY RESORPTIONS AVECRoANGCEEPT%USDEASNSRWESIOTRHBAEDLL AVEMROARGEEL+IVDEAMFSETWUSIETSH ONE OR AVE(R%ANGAELESSE/XLIRTATTIEOR,) AVERAGE FETAL BODY WEIGHT (0) AVERAGE FOR MALES (G) AVERAGE FOR FEMALES (G) AVE`RcAoGnEca4pTDuEsAEDS/OLRITRTEESRORBED MEAN or % wa 01 99.9 50.2 3.47 3.56 3.37 50 'RMAENAGNE/oSrTU%DY (075.0) (0-45) (95.4-100) (42.1-57.0) (3.10-3.78) (3.17-3.90) (2.98-3.66) (010.9) 003839 418-011:PAGE G-3 SUMMARY OF MATERNAL NECROPSY OBSERVATIONS co Rat P+ERsIuODes JUNE 1995 - JUNE 1997 120 ## RRAATTSS PTREESGTNEADNT 22537897 + RaTs DIED + RATS ABORTED a o # RATS DELIVERED # RATS WITH 100% RESORPTION 439 1 EOXBTSEERRVNAATLIONS Rednosseubasntda/nocre marooutuhnd Inbcrioskoerns mainsda/loirgmniesdsing Chromodacryorrhea AWhliotpeecisaubstance present eiynesanterior chamber of MEAN Nov 1 0.06 2 0.08 2 0.08 3 0.32 RANGE /STUDY ow . 0-1 (0-3.3) 0-2 (0-6.7) 00--32 ((00--61.07.)0) 1 0.04 0-1 (0-4.2) Gross LESIONS SUBMANDIBULADRaLrYkMPrHedNODES JUGULAR VEINDistended with blood cups Subcutaneous fat, dark redon ventral side THORACIC CAVITY Tilled with light red fluid THOUS Discolored areas Large AxIzza Mass present 1 0.04 0-1 (0-3.3) 1 0.08 0-1 (0-3.3) 10.04 0-1 (0-3.3) 1 0.04 0-1 (0-4.0) 21 00..0084 00--21 ((00--64..70)) 10.04 0-1 (0-4.0) 003840 418-011:PAGE G4 SUMMARY OF MATERNAL NECROPSY RAT OBSERVATIONS ross Leszons LIvER Adhesion between left llaatteerraallalbodboemiannadllweafltl `STOMACH INTESSTtoImNaEch, fluid-filled Stomach and intestines distended Intestines, wemiptthygas Cocun contained a black substance BACK Spine, protrusion of bone poonrtdioornsal thoracic xIoNEY(S) Pelvis, slight/moderste wailtlhaotuitonfwliutihd or Paetlvliast,iomnarked/extreme Mottled Large sCmoarltlex pitted Lett; pelvis contained yellow fluid ABDOMINAL CAFViIlTlYed with light red fluid spLEEn Twosewrhoistael asruerafsacoen BLADDER Fluid-illed Wall thick, contained onecalculi NoMvEAN 1 0.04 1 0.06 11 00..0044 10.04 1 0.04 17 0.66 52 00..1098 2 0.08 11 00..0048 1 0.06 1 0.04 1 0.04 1 0.04 1 0.08 RANoowGE /STUDY + 0-1 (0-4.0) 0-1 (0-4.0) 00--11 ((00--44..00)) 0-1 (0-4.0) 0-1 (0-4.0) 0-2 (0-12.5) 00--11 ((00--44..00)) 0-1 (0-4.0) 00--11 ((00--43..04)) 0-1 (0-6.0) 0-1 (0-4.0) 0-1 (0-4.0) 0-1 (0-4.0) 0-1 (0-12.5) 003841 418-011:PAGE G5 SUMMARY OF MATERNAL NECROPSY OBSERVATIONS Rar GROSS LESIONS ReTERS Distended with clear fluid VAGINA/CERVIXCorvix distended with fluid Cervix contained a thick, brown substance Cerrvedi,x cgeolnattaiinnoeudsa dark Cersvuibxstacnocnetained green, Vavgiisncaoucsontfaliuniedd brown, viscous fluid vrERus Contained red-brown fluid and one dead, brown Rigthottushorn, absent Right horn, threadlike Left horn, lumen absent oonvarciearnviceanld, enddi;stended with clear fluid Right hora, clear masses, contained gelatinous substance rorELTINB Lesion present MEAN x ov 1 0.04 1 0.04 1 0.04 1 0.04 1 0.04 1 0.04 12 00..0048 1 0.04 1 0.04 1 0.04 10.04 RANGE /STUDY ow . 0-1 (0-4.0) 0-1 (0-4.0) 0-1 (0-4.0) 0-1 (0-4.0) 0-1 (0-4.0) 0-1 (0-2.1) 00--11 ((00--41.60.)7) 0-1 (0-2.1) 0-1 (0-4.0) 0-1 (0-4.0) 0-1 (0-3.3) 003842 418-011:PAGE G6 SUNORY OF FETAoL> REXATTERNAL ALTERATIONS PERIOD JUNE 1995 - JUNE 1997 + + STUDIES LITTERS INCLUDED EXAMINED 86 1785 # LIVE FETUSES EXAMINED 25613 ALTERATION EAD Exencephaly Hematoma Microcephaly EYES Eye bulges depressed Lids open Microphthalaia avs Lowset. swour short TONGUE Absent: PALATE cere Eos PL 055 00..2092 LF 11 00..0060 LF 11 00..0060 RANoGE /sTUDY + 00--11 (0-4.5) (0-0.4) 00--11 (0-2.2) (0-0.2) 00--11 (0-4.0) (0-0.3) L 14 0.80 0-2 (0-12.5) F L 151 00..0066 00--21 ((00--04.29)) F 1 0.00 0-1 (0-0.3) L 1 0.06 0-1 (0-4.0) ? 1 0.00 0-1 (0-0.3) LF 33 00.2071 00--11 ((00--01.29.)5) I 2 041 0-1 (0-4.2) Fr 2 0.01 0-1 (0-0.3) L 1 0.06 0-1 (0-4.0) 1 0.00 0-1 (0-0.3) L 4 0.23 0-1 (0-45) FP 4 0.02 01 (0-0.4) L: LITTER INCIDENCE Pt PETAL INCIDENCE 003843 418-011:PAGE G-7 SUMMOFAFRETYAL EXTERNAL ALTERATIONS maT ALTERATION EX Micrognathis Agnathia EE L F s5 LF 11 RANGE /ST.UDY 0.29 002 0-1 0-1 (0-4.5) (0-0.3) 00..0006 0-1 (0-12.5) 0-1 (0-0.9) sopY dena. I 2 041 0-1 (0-4.5) 2 0.01 0-1 (0-0.4) Umbilical hernia LFP 77 00..0430 0-1 (0-16.7) 0-1 (0-1.1) Gastroschisis LF 11 00..0060 0-1 (0-4.0) 0-1 (0-0.2) Trunk short L307 0-2 (0-9.1) F 3 0.01 02 (0-0.7) Spina bifida L 1 0.06 0-1 (0-4.0) F 1 0.00 0-1 (0-0.2) Extra limb pro- 1 truding fromback F 1 1 0.06 0.00 0-1 0-1 (0-4.5) (0-0.4) Hematona. L 1 0.06 0-1 (0-2.4) F 1 0.00 0-1 (0-0.2) `PLACENTA Enlarged L 1 0.06 0-1 (0-16.7) F 1 0.00 0-1 (0-1.1) oRzLIMBS Twodigits present L onforepaw F EnLINES Rotated TL aos. No opening present LrT 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) 2 001 0-1 (0-0.4) Ls LITTER INCIDENCE 7: FETAL INCIDENCE 003844 418-011:PAGE G-8 SUMMARY OF FETAL EXTERNAL ALTERATIONS RAT ALTERATION TAIL Threadlike agenesis split short. constricted xs 15 0.29 5 0.02 L 3 0.17 P 3 0.00 L 1 0.06 P 1 0.00 Lo 2 0.1 F 2 0.01 11 0.06 F 1 0.00 RANGE /STUDY . 0-1 (0-5.3) 0-1 (0-0.4) 0-1 (0-4.5) 0-1 (0-0.3) 0-1 (0-4.5) 0-1 (0-0.4) 0-1 (04.3) 0-1 (0-0.3) 0-1 (0-2.4) 0-1 (0-0.2) L: LITTER INCIDENCE P: PETAL INCIDENCE 003845 418-011:PAGE G9 SUMMARY OF FETAL SOFT TISSUE ALTERATIONS maT PERIOD # STUDIES INCLUDEDJUNE 1995 - JUNE 199376 # LITTERS EXAMINED # FETUSES EXAMINED 84s 6091 BRAIN ves PALATE TonGuE aa BEART ALTERATION Lateral ventricles, moderate dilation Lamtaerrkaledvednitlraitciloens, Thimradrkveedntdriilcaltei,on Lateral and third vent- ricles, irregularly shaped Microphthalaia Clare small Absent Micrognathia Septal defect RANGE/STUDY Noyom on L 1 0.2 F 1 0.02 L 1 0.2 FP 1 0.02 LF 11 00.202 0-1 (0-3.4) 0-1 (0-0.6) 0-1 (0-4.2) 0-1 (0-0.6) 00--11 ((00--04..62)) L 1 0.12 0-1 (0-4.2) F 1 0.02 0-1 (0-0.6) L 3 0.35 0-1 (0-4.0) T 3 0.05 0-1 (0-0.6) L 2 0.24 0-1 (0-4.0) F 2 0.03 0-1 (0-0.6) LF 11 00..022 00--11 ((00--40..36)) L 1 0.12 0-1 (0-4.0) F 1 0.02 0-1 (0-0.6) L? 11 00..022 00--11 ((00--40..60)) LF 11 00..022 00--11 ((00--40..06)) L: LITTER INCIDENCE F: FETAL INCIDENCE 003846 418-011:PAGE G-10 SUMMARY OF FETAL SOPT TISSUE @ maT ALTERATIONS ALTERATION vesseLs Innontnate, absent FLP Innminate, arises on 1ezt. L F subclavian artery, absent L F Ductus arteriosus, L absent. F umbilical artery, displaced L r situs inversus 1F Aorta, descends to right 1 F Pulmonary artery, descends to right L behind aorta T Lows Right apical, cardiac and diaphragmatic L lobes appear as one Intermediate lobe, F IL absent F BopY dems L F ABDOMINALSCiAtVuIsTYinversus of liver, intestines, stomach, Kispdlneeeyn,s pancreas and LF xipwEYS Pelvis, slight dilation L F RANGE/STUDY Nova 88 00..9153 1 1 0.12 0.02 1 0.2 1 0.02 1 0.2 1 10 01..0128 11 0.8 1 0.2 10.02 1 0.12 1 0.02 0-2 (0-8.0) 0-2 (0-1.2) 00--11 ((00--40..06)) 0-1 (0-3.4) 0-1 (0-0.6) 0-1 (0-3.4) 00--21 ((00--80..36)) 0-2 (0-1.2) 0-1 (0-4.2) 0-1 (0-0.6) 0-1 (0-4.0) 0-1 (0-0.6) 1 1 0.2 0.02 0-1 0-1 (0-4.0) (0-0.6) 1 0.2 0-1 (0-4.0) 1 1 0.02 0.2 0-1 0-1 (0-0.6) (0-4.0) 1 0.02 0-1 (0-0.6) 1 0.2 0-1 (0-4.0) 1 0.02 0-1 (0-0.6) 1 0.12 0-1 (0-4.0) 1 0.02 0-1 (0-0.6) 1 0.12 0-1 (0-3.7) 1 0.02 0-1 (0-0.6) L: LITTER INCIDENCE Pi FETAL INCIDENCE 003847 418-011:PAGE G-11 SUMMARY OF FETAL SOFT TISSUE ALTERATIONS maT ALTERATION sereEn Absent RETERS Distanded `RANGE/STUDY Eos Nn LFr 11 00..022 00--11((00--04..50)) L 2 0.24 0-2 (0-8.7) F 3 0.05 0-3 (0-1.7) Li LITTER INCIDENCE Fi FETAL INCIDENCE 003848 418-011:PAGE G-12 SCMMARY OF FETAL SKELETAL RAT ALTERATIONS PERIOD # STUDIES INCLUDED JUNE 1995 - JUNE 1997 35 # + LITTERS FETUSES EXAMINED EXAMINED 820 6318 ALTERATION sxuLL Prontal(s): incompletely or Panroitetaols(ssi)f:iednot ossified Nasal(s): short Basisphenoid: incompletely ossified sphenoid: irregularly shaped ~ Orbit amall on Masxhiolrltae and Premaxillae: Skull: incompletely or Skunlolt: ossfiufsieedd VERTEBRAE Cervical: Arch, open Fused Thoracic: Centrum, bifid + Centra, unilateral ossification + Centrum, niontcoomspslieftieeldy or Lt LITTER INCIDENCE FP: FETAL INCIDENCE x ov L 2 0.24 FT 2 0.03 IL 22 00..2043 FL 33 00..0356 FL 11 00..0122 LPF 11 00..1022 LF--32 00..2034 L 3 0.36 FL 32 00..0256 F 3 0.05 L 1 012 ? 1 0.02 I 11 00..022 LF 11 00.022 LF 7717 81.2626 L 8 0.98 r 8 0.13 FL 34 00..3066 `RANGE/STUDY om on 0-1 (0-4.2) 0-1 (0-0.6) 00--11 ((00--60..26)) 00--11 ((00--40..26)) 00--11 ((00--04..05)) 00--11 ((00--40..05)) 00--11 ((00--04.6-)0) 0-1 (0-42) 00--11 ((00--40..26)) 0-2 (0-1.2) 0-1 (0-4.0) 0-1 (0-0.5) 00--11 (0-4.0) (0-0.5) 00--11 (0-4.0) (0-0.5) 00--89 ((00--42.97.)6) 0-2 (0-8.0) 0-2 (0-1.0) 00--23 ((00--81..38)) 003849 418-011:PAGE G-13 SUIORY OF FETAL mSaKrELETAL ALTERATIONS VERTEBRAE (COANLTT).ERATION Thoraci+c c(ocnotnrta.,) fused + Arch, open + Azcn, small Boy FLo1l 00202 LF 11 00202 Lr 11 00202 Lumbar: : + + + Centrum, bifid contra, fused ocerntnrouts,ossiinfcioemdpletely oArrchneost, osisnicfoiuepdletely 1, present Arch, open ocaosnitfriac,atuinoinlateral rL 22 00.2043 FLo1l 00.202 FL 32 00..0254 FL21105 01..3833 rL11 00202 LF110022 Ir 22 00.0234 Sacral: None, present + Arch, open rL11 00202 L 11 00202 caudal: Nome present : 1, present LF 11 00202 Lr 1100022 ranscervical Rib(s) present one or more, wavy oneossoirfmioerde,(hiynpcooplmapslteitce)l,y or not ossified Lro3321 o3.s78 LP7834 51.3366 FLoS333 40..082 LFsi LyIETTTALERINICNICDIEDNECNCEE 003859 'RAoomNGE/STaUDY 00--11 ((00--04..52)) 0011 ((00-04..50)) 00-a1 ((00--30.54)) 00-11 ((00-03..58)) 001 ((00-04..63)) 00-32 ((00--18..38)) 00.43 ((00-21.21.)0) 0011 ((00--04.36) 0011 ((00-04..50 00-11 ((00-04..62)) 0011 ((00-06.36) o0l1 ((00--40..05)) 00-411 ((00--04.36)) 0011 ((00-04..83)) 00-s5 (0-20.0) (02.7) 0-0.175 ((00--381..3)8) 00--59 ((00--52.20.)7) 418-011:PAGE G-14 SRY OF FETAL RSaKrELETAL ALTERATIONS Rams (coNT.)AuTERATION Tused spe vo segoents ov L 33 00..0356 I 22 00..023 Lr 1100022 omRANGE/STUDY 00-11 ((00--08.36)) 0011 ((00:-04..50)) 0011 ((0003..57)) nsUDBuRpIlOiKcated LT1100022 0011 ((00--03..84)) sTaoRnmeERoArZmore incompletely Duopalsiicfaiteedd or mot cesified rused Asymmetric LF113644 21.36.090 0-01-17 ((00--63.32.)3) L 1100.202 00-11 ((00--03084)) 1 11001022 0011 ((0003..57)) FL110020 0011 ((0004.:52)) PenPiusbla(es) and/or Ischium(a): L139 Pubnicso(nepnl)e:taliyncoormpnloetteoluysified LF121244 suobaissi(etsi)e:d not ossified 1885 F8 Iscohriunso(ta)osssifiinscdompletely PL 7500 31.65.495 0-01-69 ((00-33.90.)1) 21.39.350 0-0-196 ((00--83.59.)1) 00.9183 00-33 ((00-.11.36.)8) 61.110 00-94 ((00--1467.)7) sorMseLtIaNcEasrpals: 1, present + 2, present Foredigite: 2, present Forephalanges: 1, present LT1100022 LF110022 LF110022 FL 11 00.212 001 ((00--04.36)) 0011 ((000-.463)) 0011 ((00.04..63)) 00.11 ((00-04..63)) L7s: LrIETTTaELRcIINDCRIDNECNECE 003851 418-011:PAGE G-15 SUMMARY OSFxaFLEETTAALL AOVSESRIAFGIECSATION SITES (CAESAREAN-SECTIO>NErDarDAY 20 GESTATION) en+ oZSarnrurp:Eimzss BmcLvvouDE>g 1995 - JE 199=7 m2 + Forosms Eu ses SKELETAL AVERAGES Vveonmrzaaz TmaoRRvAicoInC: Zsoancaanrn Riscs a(npasirs) Sroawmas Sxrrpsnotao cavrEns FoRzEAWS a(vCearlacguelaptaerd aLsian) scEaTAncnARaPALS bPiaoniiaTnsaEs IDPS a(vCeazlacguelapteerd 1asimb) JaanmanTianesazs bPiacirarnsaEs rros/urrEn MEAN 'RANGE/STUDY 0.80 (0.69035) 173.00008 (2.59_-13.35) SSl0e0 ((2si9e6s-3s.o00)) 1d0e2s ((13s.50s-13s.08) 1S0s0 ((0a.3s8s-1e.s00)) oss (0.54-1.00) 0S.0e0 ai~e SSloos (es=os 0S.l0e0 auss--acon aslo6 (71s) 003852 418-011:PAGE G-16 SUMMARY OF FETAL SKELETAL OSSIFICATION AVERAGES SITES co RAT (CABSAREAN-SECTIONED DAY 21 GESTATION) PERIOD: 4 STUDIES JUNE INCLUDED 1995 - JUNE 1997 2 # LITTERS EXAMINED # FETUSES EXAMINED 48 78 SKELETAL AVERAGES mVyEoRTEBRAE CERVICAL THORACIC LUMBAR sacRAL CAUDAL Riss (pairs) STERNUM MANUBRION STERNAL CENTERS XIPHOID FoREPAWS (Calculated as average per limb) careaLs METACARPALS PDRIAGLIATNSGES HINDPAWS a(vCearlacguelapteerd as limb) TARSALS MpEeTA1TTAsRSALS `PRALANGES FETUS/LITTER MEAN RANGE/STUDY 0.97 (0.96-0.97) 7.00 -- 13.04 (13.02-13.06) 35..0906 (5.94---5.98) 7.46 (7.23-7.67) 13.03 (13.01-13.05) 1.00 -- 3.98 (3.97-3.98) 1.00 - 0.00 -- 3.98 (3.98-3.99) 5.00 -- 7.64 (7.53-7.75) 0.02 -- 4.61 (4.60-4.62) 5.00 -- 5.84 (5.78-5.89) 003853 APPENDIX H STATEMENT OF THE STUDY DIRECTOR 003854 42PRIMED!ICA 418-011:PAGE HA Aris Reseach LaberatrIisc Sine rDe3 Bali `Telephone: (215) 443-8710 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 final report accurately reflects the raw data obtained during the performance of the study. No significant deviations from the U.S. Food and Drug Administration (FDA) Good Laboratory Practice Regulations; Final Rule*, the Japanese Ministry of Health and Welfare (MHW) Good Laboratory Practice StanfdoraSarfetdy Studies on Drugs and the European Economic Community (EEC) Council decision on 28 July 1989 on the acceptance bythe European Economic Community of an OECD decision/recommendation on compliance with principlesofgood laboratorypractice" occurred that affected the quality or integrity of the study. nd G. York, Associate Director of and Study Director WN (2-DR9E , DABT Date Research a. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. b. Japanese Ministry of Health and Welfare (1988). Good Laboratory Practice Stanfd ora Sar fetdy Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. . European Economic Community (1989). Council decision on 28 July 1989 on the acceptance by the European Economic Community of an OECD decision/recommendation on compliance with principles of good laboratory practice. Official Journal of the European Communities: Legislation. 32(No. L 315; 28 October): 1-17. 003855 APPENDIX | QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT 003856 ~PRIMEDICA 418-011:PAGE I-1 ArSoogouShy\oanteerSaitrdsoee, sen QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT `Study Director: Raymond G. York, Ph.D., DABT Executive Director of Research: Mildred S. Christian, Ph.D., Fellow, ATS Protocol 418-011: Oral (Gavage) Developmental Toxicity Study of N-EtFOSE in Rats Sponsor's Study Number: T-6316.7 The draft protocol for this study was audited for adherence to U.S. Food and Drug Administration (FDA) Good Laboratory Practice Regulations, Japanese Ministry of Health and Welfare (MHW); Good Laboratory Practice Standard for Safety Studies on Drugs, and European Economic Community (1989) council decision on 28 July 1989 on the acceptance by the European Economic Community of an OECD decision/recommendation on compliance with principles. of good laboratory practice on 13 JUL 98. Critical phases of this study were inspected five times; study information and raw data were audited twice (see tables 1 and 2 for dates and phases/data). The draft final report and the raw data for this study [except for Appendix F, the Pilot Report, which was conducted in the spirit of Good Laboratory Practice (GLP)] were compared and audited for accuracy, for adherence to protocol requirements, and for adherence to U.S. Food and Drug Administration (FDA) Good Laboratory Practice Regulations, Japanese Ministry of Health and Welfare (MHW); Good Laboratory Practice Standard for Safety Studies on Drugs, and European Economic Community (1989) council decision on 28 July 1989 on the acceptance by the European Economic Communityof an OECD decision/recommendation on compliance with principles of good laboratory practice between 12 NOV 98 and 02 DEC 98, and for revisions requested by the Sponsor on 10 DEC 98 and 17 DEC 98. 003857 418-011:PAGE I-22 This study was conducted according to U.S. Food and Drug Administration (FDA) Good Laboratory Practice Regulations, Japanese Ministry of Health and Welfare (MHW); Good Laboratory Practice Standard for Safety Studies on Drugs, and European Economic Community (1989) council decision on 28 July 1989 on the acceptance by the European Economic Community of an OECD decision/recommendation on compliance with principles of good laboratory practice. Dims Barbara J. Pelefson, BA. DireocftOpoerrations and Compliance eteHusk Rpdtar 1c . Date Heather L. Rabuttino, M.S. Date Quality Assurance Supervisor and Principal Auditor 003858 TABLE 1 CRITICAL PHASES INSPECTED 418-011:PAGE I-3 Cohabitation Date of inspection: 21 AUG 98 Date results reported to the Study Director and Management: 21 AUG 98 Test Article Preparation Date of inspection: 02 SEP 98 Date results reported to the Study Director and Management: 28 SEP 98 Test Article Administration - Gava Date of inspection: 03 SEP 98 Date results reported to the Study Director and Management: 28 SEP 98 Blood Collection Date of inspection: 10 SEP 98 Date results reported to the Study Director and Management: 10 SEP 98 Caesarean-Sectioning Date of inspection: 10 SEP 98 Date results reported to the Study Director and Management: 28 SEP 98 003859 418-011:PAGE 14 . TABLE 2 RAW DATA AUDIT(S) The following study information and raw data were audited on 08 OCT 98, and 15 OCT 98 to 17 OCT 98: Protocol. Protocol amendments. List of personnel and computer operator codes. Error codes and codes for clinical sign observations. Animal receipt, randomization, physical examination and acclimation. In-lfe transaction record. Feed consumption. Cohabitation. Caesarean-sectioning. Maternal gross observations. Fetal gross observations. Fetal fixative assignment Fetal visceral examination. Fetal skeletal examination. Necropsy. Tissue packing lists. Male breeder colony records. General comments. Study maintenance records. Temperature and relative humidity reports. Feed and water analyses. Edit requests. Dosage volumes. Deviations. Data review page. Key for test facility computer back-up record abbreviations. Blood collection data and packing lists. `The resultsofthis audit were reported to the Study Director and Management on 21 OCT 98. 003860 418-011:PAGE I-5 on 0T8hOeCfoTll9o8wiangndst1u0dyOiCnTfo9r8m:ation and raw data were audited Vehicle receipt, preparation and use. Test article receipt, preparation and use. Test article packing lists. `The results of this audit were reported to the Study Director and Management on 21 OCT 98 003861 `Summary N-E(FOSE Rat Teratology StudyNumbers: IM T-6316.7, Argus 418-011 `30C03o7,m3p00o&39u)Lno9t8d:.25N%-pEu(rFeO(SSEMI(DN-AEntahlyylt-iPcearlfRleuqoureosotcy5a2n4e8s9u)lfAonnaalmyitdiocaElthDaoncoulm)en-tLaottioFnM3fi9le2d3al(o3n0g0w3i5t,h inal report. Note - sume lot a use in two-year rat carcinogenicity study (T-6316, Covance 6329-212). `StudyTitle; Oral (Gavage) Developmental Toxicity Study of N-EGFOSE in Rats ReportDate: 17 December 1998 `dSatiuldy MoroanliitnotruSbautmimona)royf:N-(EAwFOrSbEiyattMdatorsveeilnneTv.elCaofse0),Pr1,e5g,na10n,taandf2e0mamlge/sk,g2/5dpaeyrognroduapys,w6etrhergoiuvgehn17 of ggeessttaattiioonn.. TAhpperroaxtifmeattueselsywohniceh-hhadoafbltehefenfeextpuosessedweirneuteexraomdiunreidngfoorrsgaonfogtiesnssuies(vwiescrercalo)llcehcatendgeast daanyd2ot0hoerf hTahlefrweewreereexnaomicnoemdpofournsdkerleeltaatledchcalnigneisc.al signsof ticity in the dosedrat dams. A body weight effect, re"Tdhuiscebodbdyodweyiwgehitgehftfgcatincosr,roeclcautrerdedwiitnhthreedpurceegdnafnotofdecmoanlseusmipntihoinghiensttthwsoadmoesetlweovegrlosu--ps.10T&he20mamtekrn.al ltitotxeirpcairtaatyme1t0e&rs2(0cmogrp/okragwluatsear,efilmepcltaendtaitntiohne,puitpesrassirzee,dnucuedmpuobpfwelevireghfest.usT,hceraewroarsllanytoeerfefseocrtptoinoonts,heprup saenxotrherareatftleaicntyiodono)osf meavetle.mIanctroexiacsietdyadeltahyeesde doosssiefilcevaetliso.n sites were oundi 10 &20 mg/g fetuses N`coomcpomopuonudnwda-srneolattfeodusnodftt toibsseuteeorratsokegleentiaclimnatlhfeorramta. tionswerefoundatanydoselevel.Thus,the ``TThheefemtaatlemtmoaxlictoNxOicENLOwEaLsawlasso 5mmgg/kkgg.. NTeOrTatEo:geDniocsNepOrEepLarianttihoenrsaatwmpalses>w2e0remcgo/lklge.ctedtwice duringthestudyandthesesampleswere sent0 3asMsiEgvnierdoarsmmtoexnitcaolkiAnneatliyctiscaatlellitbeoraantiomraylsin(3B/lgdrgou2.p eLxickeepwtiscoen,trsoalmpalnedshwiegrhedcoosleleSc/tgerdoufpr).omTehxetrsaefaenmiamlaelss `lwievrerekfirloemdporneggneasnttdaatmisd,oanyfet1u8se(sdaaynapelacleansttdaoss(ep)oaonldetbhyefloitltlero)wfirnogmsaumteprluse.swTehreesceolslaemcptleeds:wseerreumfaronzden aannadlysseinst otfot3heMseEvsiarmopmlmeeshnatadl10Asnableyteincadlolnaebotrhaetroerfyorien, Btlhdsge2a.naAltyttiicmaleorefstuhlitsswseurmemanroyt,iJncalnuudaerdy i1n99th9e, final report nor in this summary. 003862