Document D4oy4GqwodVeny0n5X6EZrDB

ARRIE-0193 April 27,2000 2 i " _ Sone Seneration aReproductionSNtuOlEsoLf EOSInvestication inR 7$2 Draft Study Outline Study Objectives: This study will serve as a follow-up study to CombOri al(ngae vagde) Rats (Argus Protocol are as follows: 418-008, 3M study number T-6295.9). The objectives of the study 1). ptoredveetnetromrinaentwahgeotnhiezreotrhenoatdvceor-saedmmiantiesrtnraatliaonndoffemtealvaelffoencitcs (arceidduocredchmoalteesrtenraollbcoadny swuerivgihvtalg)aionb,seirnvcreedasinedthpeerpcreenvtiosutsilslbtourdny,;daencdreased birth weight and decreased pup 2) 10 refinetheno observed effect level (NOEL). GLP Status: A GLP study included in the final report. with appropriate QA audits; a signed QUA statement to be Animals: Female Harlan CD rats. 0D.o4semgG/rkogupPsF:OST;hi0r.te8enm:g/VkeghiPcFlOeSC;on1trmogl/;kMgevPaFlOoSn;ic1.A2cimdg/CkogntProOl;S;Cho1l.e6smtger/oklgCPonFtOrSo;l; `1m.g6/mkgg/PkFgOPSF+OSMe+vamleovnailconAiccida;ci2d;mg1./6kmggP/FkgOSP+FcOhSol+esctheolreoslterol; 2 mg/kg PFOS; 2 Number Per Group: 312 22-28 in groups 1-3 & 8-13;16-20 in groups 4-7. TOTAL: 246- Test Article: Compound will `compound identity and purity. be furnishedbythe Reserve sample to Sponsor who be retained. is responsible for TChoempveohuicnlde (A0d.m5i%nisTtwreaetino8n0: iFnedmeailoensizoenldyw,adtaeirl)ywoirlallbientpurbeaptaiorne,ddwoeseeklvyo.luPmFeOSSmlw/iklgl.be. wpirlelpbaerepdrdeapialryeadsfaressuhstpweincseiodnaiinlyideniodneiizoenidzweadtweartewri.thCh0o.l5e%steTrwoleewinll80b.e pMreevpaalroendicfraecsihd daily in olive oil. continue through Compound administration will day 4 postnatal. (see table 1). tart 6 weekspriorto mating and 04594 DJP.agLeueltoktesr nom [a TEer [L_]VehicleConwol T3040| DeionizedFO | 0.5% Tween80_|Deionized10| e id ela = Te a [[oampgpJrieos| -- No |Camgi|grmroAs] [[6ZiJ2immggkgePprrOoSs--TTi1662200INNAA [8 |16mpkePFOS 12228 NA | imaiePFOS| NA | |l2mgigPFos | NA | |i6mghgPFOS | NA | [ l [RLL =CEEr ERE L THSoR)a ) T m==nhteeE d r[RERE |aeaR meTe0)) [I[2mghgPros [mm| -- Na | sugigeros| WA] Samplesofdosing preparations willbecollected once during the six weeks prior to `mating, once during gestation and once during the postnatal period. Aportion of each of these samples will be frozen and shipped to the Sponsor for possible analysis. A backup sample of each will be retained by the `how dosing preparations were made. testing facility. Records will be maintained on Clinical Observations: Twice daily - approximately one hour after dosing and again 4-6 `hours later. Body Weights: Weekly except when females are cohabiting with males during mating. Food Consumption: Weekly except when females are cohabiting with males during mating. Mating: After 6 weeksofcompound administration, one male (Argusbreeder colony) p`wriellsbeencceoo-ifnshpaebritmedpowsiittihveeavcahgifneamlalsem.earA.feTmhaeledawyiollfbmeatdientegrsmhianleldbeascmoanstiedderuepdodn ath0ye ofgestation. mees Pre-Birth Sacrifice and Examination: Just prtoi delo iverry (morningofday 21 of g`aesspthaytxiioant)i6o-n8apnrdecgensaanrteafne-msaelcetsioinn groups will be p1e-r3faonrdme8d-.13AwtielrlmbienaslacbroifdiycewdebigyhCtOf,or each Adnaimmaalnsdwailploboelendectreorpmsiniaeld baonddyanwyeiggrhotsfsolreseiaocnhslwiittlelrbweildlesbceroibbteadianneddarencdorredceodr.ded. 04595 Apr, 200 Serum/plasma and liver samples will be taken from cach dam and her pups (pup samples apnoaollyezdebdyfloirttLerD)La,ndHDmLil,ktwoitlallbcehocloelslteecrotle,dafnrdomtreigalcyhcedraimd.es.LiPvlearsamnadmesvearluomniwcilalcbide sleervealssawmiplllebsewmiellasbuerefdro.zMenil(k-2w0ilCl)beanadnaslhyizpepdedfoorntdortayliccheolteostKerriosl.J. Additional liver Hansen, Ph.D., and 3M Environmental Technoloagndy Safety Services, 935 Bush Avenue, Building 2-3E-09, St. fPraoulz,enMiNn l5iq5u1i3d3n-i3t3r3o1gefnoarnPdFsOhSipapneadlyosnis.drAy ipcoerttiootnohefeSpaocnhsolrivfeorrspaomspslieblweilflutbuereflash electron microscopy. analysis (i.e., liver adenine nucleotides & HMG-CoA reductase inhibition). Additional liver tissue willbe collected and fixed in gluteraldehyde for possible future analysis by Female Parturition: Remaining rats will be allowed to deliver their litters. Pup Examinations: Pups will be counted, sexed, weighed and observed for moribundity/mortality on postnatal days 0, 1,2, 3 and 4. Rats Found Dead or Moribund: Rats that die oraresacrificed because of moribund condition or abortion will be examined for cause of death or moribund condition on the edxatyentthepoosbssiebrlvea.tWiohneins mpaosdsei.blAeb,otrhteefdolfeltouwsiensgasnpde/coirmienn-sutweirlolbpuepcsowlillelctbeedeaxnadmiannaeldystios the performed: Rats will be necropsied Serumvplasma and liver and any samples gwriolslsbleestiaoknesnw(iilnldbiveiddeuaslclryibfeodr acancdhrdecaomrdaend.dher pups c`phuoplessatmeprollesanpdootlreigdlybcyerliidteesr.).PLliavsemraanmdevsaelrounimcwialclidbeleavenlaslywzielld bfeormLeDasLu,reHdD.LM,iltoktawlill bseamcpollelsecwtieldl fbreomfreoazcehn d(-a2m0aCn)daanndaslhyizpepdefdorontdotrayl cihcoeletsoteKrroils.J.AHdadintsieonn,alPhli.vDe.r a3nMd sera Environmental Technology and Safety Services, 935 Bush Avenue, Building 2-3E-09, St. Pfaruolz,enMiNn l5i5qu1i3dn3i-t3r3o3g1enfoarnPdFsOhSipapneadlyosins.drAy ipocrtteoiotnhoefSepaocnhsolirvefrorspaomspslieblweilflutbuereflash analysis (i.e., liver adenine nucleotides & HMG-CoA reductase inhibition). Additional elliveecrtrtoinssmuiecwriolslcobpeyc.olMlyeoctceadrdainadlftiixsesdueinwiglllutbeercaolldleehcytdeed ffoorrppoossssiibblleehfiusttuoreloagnyalaynsdis by electron microscopy. Dalal yof4thPeoisrtpnuaptsalwiSlalcrbiefiscaecraifnidceEdxbaymiCnOa;tiaosnp:hySxiixatteieonn toon2d0adyafmosurinpoesatncahtadlo.sAetgerromuipnaanld body weight for cach dam aanpood led terminal body weight for cach litter will bo obtained and recorded. Animals will be necropsied and any gross lesions will be described and recorded. SerunVplaasnmda liver samples will be taken from each dam and her pups (pup samples pooled by sex for each litter) and milk samples will be collected from each dam. Liver and serum willbe analyzed for LDL, HDL, total cholesterol and triglycerides. Plasma mevalonic acid levels will be measured. Milk will becollected from each dam and analyzed for total cholesterol. Additional liver and serum " samples will be frozen (-20C) aaondd shifshippeod onn dry ice to Kris J. Hansen, Ph.D., 04596 oe Page3 of 5 sr 3M Environmental Technology and Safety Services, 935 Bush Avenue, Building 2-3E- 09, St. Paul, MN 55133-3331 for PFOS analysis. Aportionofeach liver sample will be flash frozen in liquid nitrogen and shipped on dry ice to the Sponsor for possible future lainvaelrystiisss(uie.ew.,illlivbeer acodlelneicnteednuacnldeoftiixdeedsi&n gHluMtGer-aCldoeAhydreedfuocrtapsoessiinbhliebiftuitoun)r.e Additional analysis by ePluepcstr(o2nmmailcersosacnodpy2.fMeymaolceasr)difaolr ptoissssuieblweilhlibsetocloolglyeactneddfelreocmtreoancmhicdraosmcaopnyd.four of her Table 2 - Scheduled Sacrifices (N`dams/group/Sacrifice) IREll cll llid [] =]CAa EE NGarmouep 2ECo1l|i33=n% EE a|e 0Sl|eeIE|53E|2E (|E E8 [(S7kEel |sT E(A2|.SE94 q9E.E4QEE 2 (HHE4IEEEH2] EE TTTT FT] BEo (RCdyEi-1)e l rt l rl e l 04597 --_ Study Director: Deanna J. Lucbker, M.S. 3M Corporate Toxicology 3M Medical Department 3SaMintCePnatuel,r BMlNdg.55212404--21E0-0002 Telephone 651/737.1374 FAX 651/733.1773 Alternative Study Director: J3oMhnCoBruptoernkaotfefT,oPxhi.cDo.l,oDgyABT, CIH 3M Medical Department 3M Center Bidg. 220-2E-02 Saint Paul, MN 55144-1000 Telephone 651/733.1962 FAX 651/733.1773 In-Life Phase Investigator: Argus Analytical Phase Investigator: 1) Argus 2) Kris J. Hansen, Ph.D., 3M Environmental Technology and Safety Services, Bldg. 02-3E-09 935 Bush Avenue, Building 2-3E-09, St. Paul, MN 55133-3331 TFeAlXe6pShUoTnIeB665117/6778.6018 April 27, 2000 -- 04598 DJP.agLeueSbokefr