Document V5Xqq48x8n1xkmm59D9zyBZK
rSRiPsTaT6295, T-6889.1, T6316.4
AR226- 190
3M MEDICAL DEPARTMENT, CORPORATE TOXICOLOGY
Title: Inter-Species ComparisonofMechanisms Fluorochemical Toxicity following
Intraperitoneal dosing of perfluorooctanesulfonate (PFOS, T-6295) or ammonium perfluorooctanoate (APFO, T-6889) in Rats and Guinea Pigs and oral dosing of N-ethyl
perfluorooctanesulfonamido ethanol (N-EtFOSE, T-6316) in Rats.
Final Report
Date: May 25, 2004
Study Numbers. T-6295.8, T-6889.1, 6316.4
`Strategic Toxicology Study Number: DT15-A
Sponsor: Study Location:
3M Specialty Chemicals Division
3M Center, Building 236 Saint Paul MN 55133-3220
3M Strategic Alternative Toxicology Laboratory
3M Center, Building 270-SB-181 Saint Paul, MN 55133-3220
Study Director:
Andrew M. Seacat Ph.D., DABT Toxicology Specialist
3M Medical Dept. Corporate Toxicology and Regulatory Services
3M Center Building 220-2E-02
Study Toxicologist: Deanna Luebker M.S Senior Toxicologist
3M Medical Dept. Corporate Toxicology and Regulatory Services
In-Life Start Dates In-Life End Dates In-Life Start Dates In-Life End Dates
In-Life Start Date In-Life End Date
Part A: Part A:
Part B: Part B: Part C: Part C:
10/23/1997 and 11/17/1997 11/04/1997 and 12/1/1997
02/10/1998 and 03/11/1998 03/10/1998 and 03/13/1997 09/16/1998 09/18/1998
CONTAIN NO CBI
1
S
DSRTPITTS-A6295.8, T6889.1, T6316.4 `ToafCbontlenets
Part A: Procefdoruarsienglse intraperitonealdosingof PFOS(1.6295)and APFO(T-6389)inmaeratsand.
Fn: rons or
olloawiniglneig.
3 Tonos ofEOS
JECtION OFPFOS A 140
1639
4056.
ry
i
ed
ol id
sos
ssc
is
REPa3rS0Ct0DPIrUSoCcUeHSdSuIrOeSNsvfo1rhepaticperoxisomalgene inductionfollowingoral dosiengofsN-EWs FOSEein rs ts. 6 ]
PaRretsuAltRess:RulatssoPnarttheA.Toxicityofs PFOSam nd APm FOin ae 1 and-- Guinea-- pgs ----o --elr] ?
Liversamplessubmittedfor L-F ABPanalysis fromratsand guineapigs estedinPatA.
J
ParRtEBS:RUeSsuRlAtIsSoPfTAiBme-Coc urseofPFOn Stoxicityatn twodosesin maleand femaleratsan incapigs. -...
PResulaCt:s:RreGsutltus pOiirgasldnPosaitenBgoaf ratsWith20T/KE N-EIFOSE rrr
10
PtA. HStOPBOIORYREPOTL........ someones 12
T"aTbalblee21. PPaarrttAA.. SSumumamrymooffaTTooxrxiicciyittyyooffPPFFOOSS aannddAAPPFFOOiinnmmaallee guinearat. pigs......................1143
``TTaTabablbellS34ee.. PPPaaarrrtttBBBL..iSSvuuemmr1mm0aaBrroyydooyffBBWooeiddgyyhWWtTeei2igg1hh0tt8ss1i0nn RGautisn,eaMFPeaiatgnsss.,a.M.ne.d.a.nS.ts.dvaDrneovdsiSsatetdeirDonenevsnisaeteieonnes........--..................111765
FiFgiugruer2e:1:PPaartt BB::FMeamlaelReaRtaBtoBdoydWyeWiegihgtVhtsVTSiTmei.e........_.__.__._.__.__.__." .ooooorT mroerreg re 13
FFiigguurr34ee::PPaarttBB::FMeamlaelGeuGiuninaePaiPgiBgoBdoydWyeiWgehigthVtSV3 Fig4:uParteB:MaleGuineaPigBodyWeight VsTime.
THTiIme.e..........c.erereroes 2200 __._.........oooeermroerrorrnn 2]
AADpPpEeDnGdEiI1Xxl.PD artAE : TV 1o0thxO OPIfiOPIN FOcORSOLainr dtAPFyeO dsis vnidSdUmuMyal Daher
2223
ApPpPAaerTntEdBiA.x:IGIn.ivUiPdaIuarPlBtNI:RaETEtimoRteacTGBR.oHNuWGirOtUhTPsFOWeiSt.hPIRnOGSI.VA.cU.esleDatao ..ovson vecere ee272257
PaPsrttBB..LMiavleerrWteLWi/goBWBhodty0WeSigUhtIatoRinImalYeacndf.emarleorasrcoembienedodstea SeASnanaelysnis
PartB.FemalraetLiverweight summary...
TT
3208
PaPrartBt..KFiedmnaelyerWateLWiBtgoWBhroadttyioWeSiugmmhatrrya.t.io.in male and female ats combineddata,SAS analyst. PorBt. GUAPIE: INGVGUA DBAs omnes
3368
PPartaBB..KGriudinnteeayPWiegigLihvterto B0oBdoydyWWeiegihgthrttRiaotiinomSaulienaanrdyfemaleguineaSiUgts.siSeAsSat.n.a.l.y.s.iorsr.r.. Appendix IV.Part COraldosiwnitgh N-iE nrtsF .IndVO iduslSstE . ers
4319 3
2
DSRTPITSTA-62958, 6889.1, T6316.4
Introduction
pTehreoxriesseoamraclhpprroelsiefnertaetdioinn tinhirsatrse,pobrutt wnaotsndeecsesisganreiltyoienlguuciidnaetaeptihgesmoercphrainmiastems(,s)bythsaotmineit3iaMte
ffluunocrtoicohnoemfilciavlesr.fTahttey raecsiedabricnhdoibnjgecptriovteesinwse(rLe-toFAdeBtPe)rmiinnbeoitfthhraetsflaunodrogcuhienmeiacaplisgsdaisnrduipftsoth,eto
a`lwtheartLex-tFenAt.BPThleeveilnstearnmde/doiratfeunocbtjieocntaliivteys awnedrethtaotiintviesstthiegadtiesrtuhpethiyopnootfhfeastitsytahcaitdFpCroccoemsspionugnds
gleuaidnienagptiogshiwgihlelrrleesvpeolnsodfdiufnfaesresnotcliya.teFdulrotnhgercohbajienctfaitvteysawceirdes tino tihnevecsyttiogpalteasamn,dacnodmtphaarterathseand
mflouloercouclhaermimceaclhsa;npiesrmfslouofrpoeocrtoaxniessoumlefopnraotleif(ePraFtOiSo,n
in rats and guinea T-6295), N-cthyl
pigs.
Three
6pe8r8f9l)uworeoroectteasnteesdulinfotnhiasmisdtoudeythtahnatolwe(rNe-EeXiFthOeSrEp,reTv-i6o3u1s6l)y aknndowpenr(fSlouohrloeoncituasneofatale.(1A9P9F4;O, T-
Steoshtleednwiuassetthaalt.th1e9s9e3)flourosruoscpheecmtiecdaltsowcoauulsedpienrdouxciespoemreoxpriosloimfeerpartoiloinfienratthieonraitn. Tthheerhay,pboutthensoits
tpheerogxuiisneoamepipgr,olainfdertahteiodnati a tshuepproar,tbeudttnhoatt thyhpeogtuheisniesa.piTghweeerfefepcrteosfenttheedseincoanmpaobsutnrdacstoannd
pionsvtesetripgrateosresntuesdinagt tthheesSeocfileutoyroocfhTeomxiiccaloslohgayvemaelestoinsgubisne2q0ue0n1tl(yWaslhloawceneptear.ox2i0s0o1)m.e Other
p1r9o9l9i;feYraatnigonetwailt.h2s0o02m;eoBfetrhtehisaeucmoemapnodunWdalsliancvei2v0o0i2n).ratsoror in-vitro (Maloney and Waxman
Lin-vFesAtBiPgasteistohleaetfefdefctroofmtcheorsteainfrlautosraonchdemgiucianlesaopnigtshedobsienddiinngthoecfaurfrleuonrtesscteundtylywelrabeeulesdedprtoobe to Lpu-bLlFiAshBePd.elTsheewhdeerteei(lNeadbmbeetfheoldds,19r9e8s;ulLtsucabnkdecroenfcallu.si2o0n0s2o)f,tahned aLr-eFoAnBlyPbarniaelfylysemsewnetrieoned in the results and discussion sectionofthis report.
rGoudiennetas bpiegcsaumsae,ylsiekrevheuamsanbest,ttehseuyrarroegarteesimsotadnetltsofpoerrhouxmisaonmeripsrkoalisfseersastmioenn.t Hthoawnedvoero,thtehre pmeorloecxuilsaormeanpdrobliiofcrhaetmoirscailn mgeencehraanliasnmdsftohratthdeifpfeerrfelnutioartoestuhleforneasmpiodnesseoifn ptahretsiecuslpaerciisesuntcolear. Therefore, the specific aimsofthis study were to:
1. Cthheasreacctoemripzoeutnhdesperoxisomal enzyme and fatty acid binding proteins response in the liver to 2. iPnedrifcoartematnoxeixciptlyantaetstisonsufcohr aasnysethreumspcelciineiscadlicfhfeemreinsctersyiannrdetospolnivseerhtiostthoelsoegcytohmaptoumnadys. 3. Cpoerrrfelluaotreosaunlyfoonbasmeirdveesdaanldtetrhaetiironmseotfatbohleitaebso.ve functions to iver and serum levels of
Methods
w"Trhiistesntudpyr,ot(oDcTo-l1d5aAte)dw9a/s18c/o1n9d9u7cttehdatinhatdhrbeeeesnegampepnrtosv,epdarbtystAh,eB3ManidnsCtiutuntdieonraal abnriomaadllyuse
3
DSRrPITSTA-62958, T-6889., T63164 `ccoommmpiatrteeteh(e 3toMxiIciAtCy UanCd Apneiromxailsoumsealappprloilicfaetriaotnio#n2i0n88m)a.leParrattsAacnodnsmiaslteedguoinafeastpuidgys ddeossiegdnevdiato uinntdrearpeprairttonBe,alwh(iipc.h) cionnjseictsitoendwoitfahdPoFseO-SreosrpAonPsFeOa.ndTthiemer-escuolutrssoeffPoarrtthAe olbesdetrovefduretfhfeercetsstoifng PreFsuOlStsoinfbpoatrhtsmAalaenadndB fleemdatloetrhaetscoanncdlugsuiionneathpaitgLsp.dodsoesdinvgiawianstrnaoptertihteonbeeaslt(rioput.eionjfection. The aEdtmFinOiSsEtraintiPoanr,ttCherefore an exploratory oral dosing procedure in rats was performed with N-
Test Materials structur`eTsohefTe-ancuhmobfertsh,ecchoemmpiocaulndnsamtehsat,waebbrreetveisatteidonisn tuhsiesdsftourdythaerseegsiavmepnlebse,loawn.dTthheecchuermreinctally accepted abbreviations and the ones generally used in thi report for each compound are in bold:
1. Vehicle control (2% Tween 80). 2. T-6295: Perfluorooctane sulfonic acid, potassium salt (perfluorooctanesulfonate),
PFOS, FC-95, Formula: Cf ,$0,- K', MW = 538.1 g/mole).
3. TC-i6F8i8S9C:OONH,'A,mMmoWni=u4m31p.e1rfgl/umoorloeo)c.tanoate (PFOA, APFO, FC-143, Formula: 4. PTe6r3fl1u6o:rooctanNeeseutlhfyolnpaemrifdlouoetrhoyolctaalnceohsoul)l,foNn-aEmiXdFoOeStEh,anEolFO(SarEr,oFwoRrmaunlgae:N-Ethyl
CIFRSONCIHICH,CH:OH, MW = 571.06). 5. LWaybeotrhat-o1r4i6e4s,3L(eWxYen,aM, WKS.=W3y2e3t.h7-91g4/6m4o3l)(wWaYs)o,bwtaaisnaedddefdrotmoCDhTeImSsAynasScpioesnicteive control
dose group for hepatic peroxisome proliferation. `FTohrempurloatoCcfo,l SstOaNteHdCt;h#at;T)-w6o8u68l3d, Nb-ecttehsytledp,ehrofwlueovreoro,ctTa-n6e8s6u8lwfaosnanmoitdete(sFtXe-d1i2n,DSTu1l5f-uAr.amide TM),
Procedures Part A: Proceduresfora single intraperitoneal dosing of PFOS (T-6295) and APFO (T-6889) in
Fboertwpeaertn A1,50a atontdal2o5f01grammalsewreartes apnurdc1h3asmeadlefrgouminCehaarpliegss,R6i-ve8rw.eTehkrseeitnoagfeouarnmdawleeriagthsiongr w`geueinkeaafptiegrsarpreirvatlreaatt3mMen,tagnriomuaplswweerereusaeddm.inFiosltleorweidntgraenatamdeanpttsabtiyoninpterrapieordiotfonneoatl (leisps,thinajnecotnieon,
4
SDRIPTSTA-62958, T-6889.1, T-6316.4
ahtouerquLiDmo5l0arfdorosAePsFtOha.t were less than 40%ofthe rat oral LD 50 for PFOS or the rat ip. 24-
``wmTeahrteeerreicaawllecarutel3as2toelmdubtMiolibiteny 2tpor%tohbTelwehemiegsnh-iens8t0codaronnsdeoiutlshifanotrgctoahuedlodcsobemevpdooelulunimdveser.oedTf5hatemrleLefs/osKrtegh,awndeo4rse0es%ouosfefde.tahcTehhLeteDsdto5s0es Ffroresehacsholtuetsitomnasteofreiaslt. sTuhbsetsaenlceecstwioenroeftphreespeardeodsfeorleevaeclhs idsodsiisngc.ussTehdefdurotsheergrinoutphse aprnodtofcionlal. numberofanimals in each dose group were as follows:
1. g2Cuo%inntTrewoaelepigngr-so8.u0pE.sa.cITnhhaaedndivimteiahoilnc,ilnaetcnhoeontvtreroheliacgtlrmeeoncutopnctcoronontlsriogslrtogeudrpoourpf2eccemoinavsleiedsrtaaetdssoinfagnltdewtoihp.rmeaeilnmejaelrcaett.ison
etfhfaetcrtescoefitvhede nveohtircelaetcmoennttrowleroen ithneclsuudbetdleinentdhpeositnutdsoyftogechneeckinfdourcatinoynpprloannonuendcfeodr
tahnids stthuednyo. Ttrheeatbmieonltocgoincatlroalnrdatcsliwneircaelccohmebmiinsetdr.y data from the vehicle control group
2. cPoFnOcSen.tratioAn =s1in7g.l4emipg.PinFjOeSct/imonLo)fw3a2smgiMvePnFatOaSvionl2u%meTowefeSnm-L8/0K(gfi(nfailnal dose ~
3. A87P.F1O5.mg/KAg)stinog:letoitpa.l itnhjreecetmioanloefra3t2smanMd fAoPurFmOaline2gu%inTewaepeing-s.80 (final
concentration 70 mg/Kg) 10
=13.8 a total
mfogurAmPaFlOe/rmatLs)awndasthgrieveemnaaltea
gvuoilneuamepiogsf5.
mL/Kg
(final
dose
~
4. 5tWo2yt.ae4lt5hfom-u1gr4/m6ma4Ll3eW(raYtWs)awAYnadss)tihgnrige.vleeenmiaatl.eaignvujoielncuteimaoenpioogsff|.WmYL/inKgco(rfninoaill d(foinsa~lec5o2n.c3enmtgra/tKigo)n =to a
0Efxa3m5p0lgefdoorstehecagluciunleataipoingotrhis3c2ammeM10P:F(O0S.3i5p.kga)t(S0.m0U0/5KLgi,kga)s(s5u3m8i.n1gga/nmoalv)e(r0a.g0e32weight mol/L) = 30.1 mg/guinea pig,or approximately 86 mg/Kg PFOS. drAoelsclioanrngdi,emdaatil2ms4mweehdroiueartoseblasynepdrrivdoeardiltfyoortdhmeoorsreitanafglt,ietrdyafiaolrnydtthhseeirdgeunarsfoatfteitr,oonxaoinfcdittahtyendseutcruridonyp.gsytBh.eodFforysltwleofiwogiuhnrtghsotwuherersfeiarfstter seianxcdprioivsfiuidcrueeadlbalnyydiCnuOpmt,etoaanbfdooulgrirctoiscmsaegnseestchrorvooepursgnyihgpohuettr,ftoahrnemdienud-rlioifnneeepaihntahdserefoedcfaetyshwe1e2srtoeurdcdyoa,lyltehc1et4eadpn.oismtAa-ndliosmswae.elrsOewrhegorauensed bftiiosorscmuhaeelsmd(ielcihavyeldr,eankaainlddynseisysu,.bmtSieesttctetesidoanfnsodor fphailsnitcvoreleroagksii)cdaanlneaydn,uatrleiysnsteeessaanbdnyfdelcipgaehnstcwmreiecrarseoswscetoropreye.dplfaSrcooemzdeeninlait1v0e-r98s%0wbeuCrfeff.ourred `pBmelerotfoaubdsoelsdiatmwepifltoehrsmgwaltueitroeenracalondlledehtcyotdeemdoaanntidtnoesrcurbfomopristcyehdbaynfgoheresahriitsnptubolnloocgotiducracelhteaomniasaltynrsayil.syzbeyoerlteectsrtoncommipcoruosncdo,py.
5
9
SDRITSTA-629538, T-6889.1, T:6316.4
Part B: uinea
pPigrsocfeodlulreoswifnoargasiTnigmlee-iCpo.uirnsjeeoctfioPnoFfOSPF(OTS62a9t5t)wotodxoisceist.y
in
male
and
female
rats
and
cBhaosseednofnorthseamrepslueltasnoaflPyaserstwAe(rdeismcoudsisfieeddb.eAlotwi)mtehceoduorssees,ofd3o,se6vo1l2uamneds,2a8nddaythsewtaismecopnoidnutcsted tpoigmsetarseuarteedpweirtohxeiistohmeer p1r6olmigf/erKagtioorn i1n0d0ucmtgi/onKginPtFhOeSl.iver of male and female rats and guinea
A`gutionteaalopfigs2,26r-a8swaenedks20inguaigneeaanpdigwse,ig12himnaglebeatnwdee1n0f1e5m0aalnedr2at5s,0agnrdam1s0 wmearleepaunrdch1a0sfeedmfarleom C`ahnairmlaelsswReirveera.dmFionlilsotweirnegdatnreaadtampetnattsiobnypienrtiroadpoefrintoontealles(sitph)aninojneectiwoene.k afte arrival at 3M,
dEoisghetgrraotuspasnwdeeriegh1t6gmuign/cKagpiPgFsO(S4/saenxd) w10e0remtgr/eKatgedPFinOeSa.chTfoluloimriotcthheemivcoalludmoeseoftgrhoeupL.p.The
osiinnjmgeclteoiioilnpt,.haeinn1j0aec0dtdmiiognnog/fm1t.L5hsemuis1p02e0%nmsTigow/nemoeLfnPP8FF0OOaSSndwsuacsrspeaemtnaisdnigeobnaynwdeaimssuslgosilivvoeinnngaitn2aa00gvolmlagusmtPeiFsosOfuSe1 gimrniL0n/.d5eKrgm.Lt,Ao
the 100 mg/Kg
dmogs/eKggrdouops.eOgnreouapniamnailmaplesr,
andat sexper
aspveocliuesmepoefr 0f.l1uo6rmocLh/eKmigctaol
the animals dose group
in the were
16
sacrifoincdaeyds 3, 6, 12 and 28 post-dose.
Tomngwe/oKvaeghnidicomlaselescgoprneotrruopsleaxannipimemaralsslp,eeaacnicedhsaartte&0c.ev1io6vlemudLmt/ehoKegfv,vehociolcrulremeescoponotnf1rdoilmnLg(/2tK5og%t,hcecoo1r6rnrmoefgsl/pioKnngd2i%dnogTstewoegtrehoneup81.00)0.,One animal per sex per species per dose group were sacrificed on days 3, 6, 12 and 28 post-dose. Ta wsiongmlaeliep.raitnsjreectcieoinveodfaWY100asmagp/osmiLtivseuscpoenntsrioolngorfouWp.YOanteaofvtohleumpeosoitfIivemLco/nKtrgoltoraftosr raectoetiavled mdogs/emoLr 1s0u0spmegns/iKognoWfYW.YThaetaotvhoelrumpoeosifti0v.e1c6onmtLr/olKgrafrecaoetiovtreadladionsgeloefi1p6. mingj/eKctgiodnoosefagr1o0u0p WY. The positive control group rats were sacrificed on day 3 post-dose.
ParCt inrats.
Procedures
for
hepatic
peroxisomal
gene
induction
following
oral
dosing
of
N-EtFOSE
oEftaFdOmSin"EiTshitnerrPaeatsriutolnCt,.sotThfhepreeafptousrrepAaonsaeenwxdapBslorltaeodtgoteronyetorhraeatlceodsnoacsmliupnslgieopsnrfotochreaptdeuirrpoe.xdiionssroiamntasglwwgaaessnnepeoirnfdtouhrcemteibodenswtaisrtsohauNytse-
sEitnWulFdiyOveSwr,Eitafhnodr30tf0owropNd p-mEtNawF-aOEsStycEFhOmoSesstEeabnthoaalstiatcenauasnineaildtyisalliissvecirrneelefifnveiecnrtgasdnaodnseds.eirnTudhmiu.scedAdospdeaolswmeaiotsfoyb2la0sCemodgoA/nKogax/idddiaaeytsaeNryo
(adRcietefitv.air3tyyMsitnMudleiydviwecraaoslvceDarelpactu4.l-aTwt-ee6d3e1tk6o.pb1e)er.iaopdTphrinroxewiehmimacathleeltyhrea2t3asvmweegrra/geKegd/Nods-aeEydtfFwoiOrtShtEh2ec0soemncgso/unmKdpgt/wideoaenykoiNnf-ttEhhteeFOstSuEdy
for two days. A 4 mg/mL. suspensionofN-ECFOSE in 2% Tween 80 was prepared ina glass
6
10
DSRITSAT-6295.8, T-6889.1, T-6316.4
tciosnssueecgurtiinvdeedraayns.d dTewlioverraetds wtoertheedroastesdbywiotrhalthgeavvaehgieclate acodnotrsoel,vo2l%umTewoee5fnm80La/tKagdfoosretvwoolume
poosftS-mdoLs/e.KgLifvoerrtswwoecroenwseeciugthievdeadnadysc.huTnhkesoanfilmiavlesr wweerreeefurtohzaenniiznedliaqnuiddnneictrroopgseinetdhoennpduatyi3n
pceonltyrpirfoupgyatlieonnefvriaolms,bplloaocdedcoollnedctreydibcye ahneadrttphuenncsttuorreeadtatn-e8c0.r.opSseyraunmdwstaosreodbiaati-n8e0d bTyhe ~2g
liver samples induction to:
that
were
flash
frozen
in
liquid
nitrogen
were
sent
on
dry
ice
for
analysisof
gene.
PKreonfdeaslslorB,.DWeapltloafceB,iPohc.hDe.miDs.tAryBaTn.d Molecular Biology Schoolof Medicine 10 University Drive Duluth, MN 55812-2496
Results and Discussion
PartA_Resultsonthe Toxicity ofPEOS andAPFOinrats and guinea pigs.
RIn eatss, tuRhaelrtestPwaesrret:Ano statistically significant body weight ratios were increased following
tcrheaantgmeesntinwibtohdyallwetihgehet.coLmipvoeurnwdesi,g
ht and liverparticularly
to-
APFO; however, these changes were not statistically significant (Table 1; Append 1).
`dTehteecsteironuomfc4li5nimcagl/cdhLemiinsrtartys atrneaaltyesdiswirtehvePaFleOdS.thaGtlcuhcoolessetweraosl swiagsnifliocwaenrtleyd tloowbeerleodwitnhreatlsimit of tcrheeamtiesdtwriytphaPraFmOeStearsndofWrYat.s NtoreasttaetdiswtiitchallAyPsFiOgn.ificant changes occurred in the clinical
TTRh4e8h4is5to7lRo4gi8c4al7 raensdulTtsRf4o3r37)ousthoofwfeodurmaractrsotsrceoaptiedc im.pa.swsietsoh f5w2hmigt/eKsgpotWsYon(tAhneilmiavlernsuumrbfeacres
covered in subchronic
tghriansncualromtiasssuweeraendnoetveidd.ence
of
mononuclear
infiltration.
Multifocal
microscopic
eTnhlearhgiesdtolliovgeircsalarnedsuklitdsnfeoyrs.ratMsatcrreoatsecdopi.ipc. wlietshioAnsPoFfOmo(tatnliemdalblnaucmkbseprosts7oRn04o8n5e1-li5v3e)r wsehroewed ngortaendul(o7mRaO4o8n51t)h.e lMiivcerrossucrofpaiccea.lly, this animal had 2 padofscar tissue with an imbedded.
kTriehpdeanierhy.i,stAoolrllopgoaintccharelerarrsea.tssu,lisnfcolrudoinnegrathetcroenatterdolwigtrhouPpFrOatSs,(h7aRd0n4o83si8g)nisfhiocwaentdcshiagnnsgoefprlievseerntdainmaligveer,
7 I
SRDPITTS-A62953, T-6889.,T:6316.4
Results: GuineapigsPartA Oovneerngiugihntefaoplilgow(iAnngitmraelatnmuemntb.erNo7Gt0i2s5su3e)stwheartewcaosllterceatteeddfwriotmht1ha0t0amngi/maKlgaAnPdFthOe diinietdial body dweeaitghhtis(u3n5k8nog)wonf,thbauttmanaiymahlavies nboeteninccolmudpeoduinndtrheeltaatebdl.esTohresagtuiistniecaalpiagnsaltyrseeast.edTwhiethcPauFsOeS.of hhaadd ssiiggnniiffiiccaannttllyy glroewaetrerwleiivgehrttogabiondsycowmeipgahrtedrattoiocsocntormopl.arTehdetogucionnteraopl.igs treated with APFO Odanmeaogfeforuepraigru.inNeoa psiiggnsitfriecaatnetdcwhiatnhge1s7.w4emreg/pKregseipn.t iPnFtOheSl(iv7eGr,02k2i5dn4e)y,shtoeswteed, soirgpnasoncfrleiavserof wanoyoofutthoeftohtrheeer gcuonitnreoalpgiugisneeaxapmiignse(d7mGi2c2r5o5sc&opi7cGa2l2l5y6()7wGe2r0e04netvherrouagnhal7yGz2e0d13a)n.d wTeirsesues from disposed of.
Liver samples submittedfor L-FABP analysisfrom rats and guinea pigs treated in Part A.
iCseorltaatiinolniovfelrisvaemrpflaetstyfarcoidm bcionntdrionlgapnrodtPeiFnOaSt tthreeaUtneidrvaertssiatnyodfgSuainneaFrpaingcsiwsceore(Aunsiemdfaolsrthe
P7GF0O2S00r4a-t)c.onTtrhoelggouailnoefatphieg,L7FGA0B2P00s5tu-dPyFwOaSsgtuoinaesasepsisg,th7eRe0f4f8e4c4to-cfoFntCrsoolnraLt-aFnAdB7PR0f4u8nc4t8i-on as
edviamleutahtyeldambiyntohneaapbtihlaitlyeonfetshulepfhlounoyr)es-ceunntdefactatnyoaiccidacainda(loDgAuUeD1A1 )- (t5o-bind to L-FABP isolated
`fmraomxirmatusmabnidndgiunignecaappaicgisttyroefatLed-aFnAdBPnotfrtormeaPteFdOwSitthrePaFteOdSraitns vwiivtoh.ouRtesaunltisncsrheoawseedinaKdde.crTehaseed
`complete methods `Nabbefeld 1998).
and
the
results
ofthose
analyses
are
reported
elsewhere
(Lucbker
ef
al.
2002;
o`fTsheohmiesatonliomgiaclasl r1e2suolrtso14fdlaiyvesradftaemratgreeawtimtenhtewviitdhenWcYeo,fsAcPaFrOt,isasnude/oonr PthFeOsSurlfeadceuosfttohceonlsiivedresr nthoattntehceesdsoasreisl,ydtohseebveostlummoedse,lroourtetohfe aodbmjiencitisvtersaotfiotnhaensdtutdhye. tiFumretphoeirnatnsaclhyosseeson fftorispsauretsAfowrere: taobtoarltoerdgaanndicPfaluroBtrinwea,selpelcatnrnoend.microscopy, or peroxisome proliferation from part A were: Part B: Results of Time-Course ofPFOS toxicity a two doses in male and female rats and
guinea pigs,
Results: Rats Part B mAlalinrtaatisnterdeabteoddywiwtehiegihtthserth1a6t wmegr/eKgsiiogrht1l0y0lemsgs/tKhganPcFonOtSroglavianleudeswe(iTgahbtlefo3l,lFoiwgiunrgesdo1sianngda2n).d tSrteataitsetdicaanldancoanltyrsoels,obfubtohdayd wveeriyghltitstluegpgoewsteerdbtehcaatutsheeroeftwheere[noow Nsig(nsitfaiticsatnitcsdinfoftersehnocwens)b.etLwieveern (wAeipgphetnsdiwxer3e).iTnhcreealisveedritnobbootdhymwaeliegahtndrafteiomsalien rraattss wtreeraetesdigwniitfhic1a0nt0lymgi/ncKrgeadsoesdeignrcooumpbsined
5
2
DSRTPITSTA-6295., T-6889.1, T3164
mvaallueesan(dTafbelmea5l,eAlpivpeerntdoibxo3d).y Twehieghftemraalteioravtasluheasdfmroormetohfea1n00inmcgre/aKsge dinoslievgerrotoupbovderysuwseicgohnttrol roabtsieorsvtahtainondiatd ntehecrmoaplseyriantss.oHmyepeorftthroephhiygahnddowsheigtreopuipgrmaetnst(aAtpiponenwdeirxe3n)o.tKeiddbnyeygrwoesisghts and kidney to BW ratios were not significantly affected in ras (Appendix 3).
Results: Guinea pigs Part B
tPhFaOnSmawlaesgmuoinreeatpoixgisc.toThgrueineoefatpihgestfhoaurnfreamtsa,laengduianpepaarpeingtsl,yamnodroenteomxiacletogfueimnaelaepigguitnreeaatpeidgs w1i2t%hof10i0tsmgin/itKigalPbFodOySwie.pi.gdhitebdoyndady 62aaondfytwhaesshtuumdya.neTlhyecruetmhaaniinziendgofnemdaalye6g.uiAlnleaotphiegrlgosutinea ptihgrsouggahionuetdtwheeifgihmteacnodurmsaein(tTaaibnleed4b,oFdiyguwreei4g)hTtshtehagtuwienreea spliigghktildyrleoywteorbtohdayn cwoenitgrhotlrvaatliuoessfrom amlgl /anKigmaPlFs,OSmail.ep.s(aAnpdpefnedmialxeIsIIc)o.mbined, were significantly increased by treatment with 100
Ftheemafalcet tghuaitnteharpeiegosutinofpfarotuircuflaermawleeregufionuenadptiogsbediveedrywistehnisnittihveeftiorsPt F24OShotuorxsicaitfye,redvoisdienngcewditbhya p1i0g0lmosgt/wKegigdhotseuopftoPdFaOyS 6ipno2st5-%docseo.mIonilcoanntdra7st5,%onTeweouetno8ff0oaunrdmtahleeregmuainienainpgigfedmiaeldeagftueirnaea ri.epm.adionsiengof31m0a0lemgg/uKingedaopsiegsofsuPrFvOivSedinan2d5g%aicnoemd woieligahntd f7o5l%loTwiwnegetnre8a0tmaetntt.hat dose, and the
`tTohteheadombisneisrtvreadtitoonxoicfittyhoef1P0F0OmSg/tKogguPiFnOeaSpdiogssedmoisxededinwipatrht2B5.%Noconrenofoitlhmeamyalheavgeuiconnetarpiibgusted
dmiLe/dKfgo,llwohweirnegaispo.naedmmianliestarnadtitohnreoef faem1a0l0emggu/inKega PpiFgOsSdideodswehien n2%theTwseaemen d8o0saetwaavsodleulmieveorefd
biny2or5a%l gcaovmagoeiltoatbaevmoolruemetooxifcItmhLa/n Kwgh.eTnhdeerleiviseraepdrienceadneanqtufeoorusdesloilvuetriyono.fTPhFeOuSseionfccoommoiolil
"iTnhtehreatdo2s4ehporuerpaorraatliLonD-h5as0pfroervPioFuOslSyilnead 2to0:a8c0laecaertdoinfef:erceoncme oiinltshuesopreanlsiLoDn w50aosfdePtFeOrmSiniendrattos.
bsues2p5e1nsmigon/wkags(Ddeeatneremfianl.ed1t9o78b)e. 1I.n2c5on-t2r.a5stg,/tkgh(rGaatborriaellL1D9-765)0. foNroPdFeOatShsionragnraoqsuseloeussions were
aobqsueerovuesds4us8pheonusrisonasfotefrPdFosOiSng(mGaolldeeantnhdafleemfaalle,
rats with a single 1979). Thus, the
oral use
ogafavamgiextduorseeooff2255%0
mg/kg com
ociolntirniabnutaeqduteootuhsesoubsspeernvseidoninocfre2a%sedTtwoexeicnit8y0oafsPtFhOeSvehtoicglueitnoeadepliigvserwhPeFnOScommapyarheadveto an 2%
`Tween 80 vehicle alone.
Conclusions for Part B
Ifnitnrdaipnegrsitionntehails asdtmuidnyislterdattoiotnheofdePcFisOiSonltehdattoitp.hedfoosrimnagtiwoansonfostcathretaipspsruoeporniattheerloiuvtere.oTfhe tadhmeisneicsotrmaptoiuonn,dsa.nd that subsequent studies should be conducted following oral administration of
5
13
SBRrPanT2958, Tas, Tastes
PartC:Results Oraldosingof ratswith 20mg/KgN-EWFOSE.
`There was no apparent effectoftreatment on body weight or liver weight (Appendix IV). No
signs oftoxicity or liver effects were apparent by gross observations at necropsy. The rats used
`dawtear.eoTfhdeiflfievrerenstpeagceismeannsdwienirteialanbaoldyyzewdeifgohrtisn,dtuhcetrieofnoroef,mstRatNisAticfsorwepreeronxoitspoemrefoprromleidfeorantitohnese specific genes. There was no apparent indicationofgene induction by N-EtFOSE by Northern Blot analysis, however the total mRNA was partially degraded in all samples, therefore, a
quantitative analysisofthe results was not performed. Further analysisofthese samples was aborted, and the tissues were disposed of.
Conclusions
`Standard toxicity testsofserum clinical chemistry and microscopic examinationofthe liver
oefbfteacitnseodfiPn FPaOrStsaAnodfAtPhiFsOstthuadny
indicated that male gui
were male rats. In Part
nea
B,
pigs
three
were more
out of four
sensitive to the
female guinea
toxic:
pigs
`and one out of four male guinea pigs died overnight, and the remaining female guinea pig was
sacrificed on day 6 due to excessive weight loss, following i.p treatment with 100 mg/Kg PFOS.
In contrast, noneofthe male or female rats died following 2100 mg/Kg i.p. dose of PFOS.
`These data showed that
toxicityrelative to rats.
the guinea pigs,
The findings in
females in
ths study
lpeadrttoicutlhaer,cownecrleusvieornytsheantsiinttirvaepteoriPtFonOeSa.l
dosing was not the appropriate
conducted following oral admin
routeofadministration, and that
istrationofthese compounds to
subsequent st
test the stated
udies should
hypotheses.
be
An
initial oral dose study with 20 mg/Kg N-EtFOSE in malerats showednoapparent effectsby
gross observations therefore the doses were considered to be low as there were no apparent liver
effects, and the gene induction studies were aborted. Therefore, Oral dosing and higher doses of
N-EtFOSE were deemed necessary for future experiments.
0
1"
DSRTPITSTA62958, T6889.1, T6316. Signatures Prepared by:
Conds JY). Seat Andrew M. Scacat, Ph.D., DABT. `Toxicology Speciali&st Study Director
5/25/2004 Due
i" 1s
SDRTITSTA6295, T-6889., T-6316.4
Part A. Histopathology Report.
Elden Rats
Lamprecht
3M
Lab
Animal
Research
Services:
sRu4bs8ta4nce has bMeaecnrdoisscsooplivcedmlaesasviinmgbaedfdoeadmyinmlaitvreirxsoufrpfraocteceoivnearnedd mionntohinnucslcaerarticseslules..
Its The
interfaceofthe mass and liver consistsoffoamy mononuclear cells.
t7iRss4u8e.47Its substaMnaccerohsapsobpeiecnmdaissssoplrvoetdruldeianvginfgraomfoliavmeyr smuartfraicxeofcporveorteedinbyantdhimnolnaoyneurcolfesacrarcells. "The interfaceof the mass and liver consistof foamy mononuclear cells,
R485] A padofscar tissue with an imbedded granuloma on the liver surface. 7R4837 Multifocal microscopic subehronic granulomas are present in liver. `7mRil4d8p3e8riportalPvaarciueotallatpiloenuroafhoefpaitveorcyitsemsariskerdesleyntth.icSkeonmeed dweigtrherdeaptaiiornotifsshuee.patAocgyetneersamliazyedbe present. All other rats had no significant change present in liver, kidney or pancreas.
Guinea pigs
f7oGa0m2y25a4pp-eAarmaanccreoswciotphicp.orpeacdoonftegnrtsanbuelionmgadtiosussolivnefdlalmemavaitnigo.npTrheesemnattroinx wthheicsuhrrfaecmea.inIsthisasa b`cyoamnpoisnecdroeafsimnognloyntuhcilckealrayceerlolfs,scsaomretiosfsuweh.icShcaarrteiessnugeoringteedrfoarcevsacwuiotlhattehde.liTvehreppaardenicshcyomvae.red No change in liver parenchyma. A second smaller pad is present on another locationof the liver.
7G2255 & 7G2256 - never analyzed and disposed of. 7G2004 - 7G2013 - No significant changes were present in the liver, kidney, testes or pancreas.
2
16
ee
DSRTPITSTA-6295., T-6880.1, T-6316.4
Tables:
Table 1. Part A. Summary ofToxicity of PFOS and APFO in male rats
one Tres
ee
ow]
| TTT 1T 1TT TTT
proightgain lverwt@
--
Tvl al al ws wed velwr ved ed ms wd rrr rr
Tlsal esol val sna] sss]sal vssel soso] sa rau]
1 I~
1T--711
| zo ood wel ool evelvs velsoof vive]oss ed
bmg
1 asol ozo aad oolelsnlowl tose suloro] er
|ex orlew oa ooloa owl toad] sau]oz 1007]
|ewoe wo a eof asdwo oer] slsose]sd
stun
| sol ord worl orl ood]or ees diolselel eu Tel ad el sa sed wl oo sao wel uml eed
run
Teil od el sof ood wlssl soo ef 12s eed)
oT no oolval Natmmol Taalviel
so seaelsd seal ail word
aaa veel
sor 2a
ssa 7] ooo] ead] vl isi ose] von)
feemmonTtos ond es] 17 rnd ssltooolod vialoe ead
feemmo
1 ol sod wl sol ord wo os] oor] ses]se or]
21.. TNhAelNiomtitaopfplDiectabelcetionfor Cholesterol (CHOL)was 45mg/L. * Significantly different from control values by Students T-est
1
17
Co
SDRTPITsTA.2958, T6599, T3164 [ezpaoraumenteTsrablieo2. sPa|rtvAcg. oSum1nm5ad0ry|ofavTgoxi[ci5Ttw0yeroeosfo| PFmOsSfaongd AaP[5Fr0O oibnic1 maleJguuignea pwi[g5e0eTmiomoJ|
EE SD --------
l[ over 1 ooowwal vel mdr sl i] r eed wlr nlm LI rrr
fJoeroasmmparaa 1|11ve0ro o22sd_swesllovoll snadd ssrro oosu]] ssaesild sereoloouss] ssmer]d
fompe I soo oe er onl sud eelox]
foALuuemugta 1|ssieoenr orrara]lssnmaa]lssoorsa]] soorrd] smoesr]ssassss]] JsT atroonn i 1 esln soeifdssrello ssreol] sooodd essreo zsooon]] [JhLeotmrumnol T1ooomlosmanifl sanoeaolssoaso]] sovned]szssuoodls2m0es]] JJkeerm-mmomiotit-- ToT se o oseed sss oxn]svaeeo ll ssodd a7m7on0]ooomo]] lestur Toulwel es sal ved eel sos
2T NaTNort sofpDeateccion oCho(ClODe)wats5rmpll + Sinan dfffomcconnrol vablyeudeens' st
eed coloul md esosod]soredr] raomes]] saeedd saodd wmellswoeull usdod 0s0oe]]sooeon{]rsoawsesl sourro|r sraa.lssoowmn TJseoowwool"ssopwer|] ond oloul urd
w
13
DSRTPITSTA-6295., T-6889.1, T-6316.4
`Table 3. Part B. SummaryofBody Weights in Rats, Means and Std Deviations. [Do(vmegP/kFg)O.S|[PosBta-Dyose[lWieanBodyWeighSia Dv]
[L Feo T7ET35AC 1 Two 03] [ [ emTE e12 2C |w7a[I1z]] [ LE CT OF E J wsm [60[4|] CE 0
[FI TeTv 773] [ LS ET TF e J 2%m 7012)
[Fo15 7] ws Harri] Fetath Ewze r 2 [ [ C F 2s |o 22%mo n [w9a[[27]]
[Cont 5][m0Fore]
[ [C c 1722s To o -- 3as% n m |Rwaa[[7i]]
we
2a
fa)
rd
[[ 5]mz 17]
[ TW w srw |i[2
[vw
[es]Fora]
aLL
we 7 [we|
F [ r Tm e ee 35o |e zi [2]
[ CmC T 7e 5[o W2Ra n | 1s W|[0]
[Cont 72
Ft]
Ov 7 |e a5 w n i]
15 19
SDRTPITSTA-62958, T-6889.1, T-6316.4
``GTeanbdleerDd.osPeaPrFtOSBD.aSyuPmomstaorsyeoMfeaBnoBdWy W(e9)iSgihdDtesvi.n NGuinea Pigs, Means and Std Deviations.
(me)
FFoo CCoonntt 31
w NR wNAO2
FFEo Ccoonntt 26
s 0 wNa 21
FFE osCont 21
BBNa 4
FFo os
63
wuws nA 31
FFo oo.
22
wwa Mx 12
FE o w
13
sNRs N8A 04
Foo Foo
6 12
wm M1 MoM 0
MFo ocoont 21
Mmw om7 o2
MMoo CCoonntt 53
2RNA0 20
Mo Cont Mo cont
s2m mM11
M[o--e
31
mwoNa
MMooes
5
aaiss 2ou5 23
M Mo0 s
1
0 21 ww 7 a
MM11000
53
m 3 mNa
1 2
MM1100 2 "NNM a 0
16
SDRTPisTA6205, T-6889., 63164
Table 5. Part B Liver to Body Weight ratios in rats
EfeT n -- Tma Taa r T+. o--ofo-- or--]
[f[1HB e ooesommosKaePFpOroSs--Tr RRatew[eMarro E T[--s8 TTooonsr--] --TTaSno o-- o r--r|]
[iI Sian=iit--ca --die--fnt feoA m c---- onto--l val--Iu-- e--y--Dfun--ae i--sf t-- 1 o f---- o--ms -- |
v
SRDTEITSTA6205,T-6889., 63164
Figures
Figure1:PartB: FemRaatl Boe dy Weight VsTime. `Time-Course of PFOStoxicity at two doses, 16 mg/Kg and 100mg/Kg.
Female Rat BW Vs Time
m30l0 po Ee
wie et
o ERS
ts
es
RE
ou oa
DaysPostaose
1 22
SRBPrTisTa2958, T6855. T3164
Figure 2: Part B: Male Rat Body Weight Vs Time.
`Time-CoofuPrFsOSe toxicityattwodoses, 16mg/Kgand 100 mg/Kg.
Male Rat BWVs Time
wE E beliE E raE n E m E e
Ei dad =eo l s. ] IRC
wee wm)
ER ahR ha Ss]
Ta su Daya posdoso
om
w
SDRrTieT6295, T6091, T3164.
Figure 3: Part B: Female Guinea Pig Body Weight Vs Time.
`Time-Courseof PFOS toxicityattwo doses, 16 mg/Kgand 100 mg/Kg.
Female Guinea Pig BW Vs Time
w70o0
EERE
smi Er RS eay en
"E E Sr Ta mg ee r
Ts
6 Days Postdon
rom
24
oo
SBRrTisTa2958, Tato,T64
Figure 4:Part B: Male GuiPingBeoday Weight Vs Time.
Time-Courseof PFOS toxaittcwoidotsey s, 16mg/Kgand 100 mg/Kg.
Male Guinea Pig BW Vs Time
7h0o0fr TCae
Ts 5 ou om Oayspostaose
n
B
25
SDRrPITsT-A6295.8, T-6889.1, T6316
Appendix 1. Deviations to the Protocol:
p1.igs perTthreeaptrmoetnotcoglrosutapt,eswitthhat5thterreeatwmoeunltdgrboeuFpisvfoermaatloetaanlodf5fi0ve rfaetmsaalnedra5t0s gaunidngeuainea pigs.
IunsePdaratnAd,aotnoltyalmoafle15anmiamlaelrsawtseraendus1e3d.maTlhergeueinteoafpoiurgsawniemraelsuspeedr tirnPeaatrmteAnt.group were
In Part used.
B,atotalof
20 ratsand
20
guinea
pigs,
10
males
and
10
females
per
species
were
`Thos, in both partAs and B, atotal of 35 rats and 33 guinea pigs were used.
2. The protocol stated that N-ethyl perfluorooctane sulfonamide (FX-12) and NeTthheyslepetrwfoludoorsoeocgtraonuepssuwlefronearmeimdooveetdhafnorlom(FthCe-1p0r,otNo-coElt,FaOnSdE,a pTo-s6i3t1i6ve)cwoonutrlodl,bWeydeotshed-. 14643 (WY), a model persoxisome proliferators, was added as a dose group.
3. The protocol stated that all treatments would be administered in corn oil.
PFOS (T-6295) and Wyeth-14643 (WY)
AwPasFOadm(iTn-i6s8t8e9r)edweirne2a5d%micnoirsnteorile.d
in
2%
Tween
80.
4. The protocol stated that Dunnett's t-test would be performed on all data.
Students ttest were performed instead where noted.
5.
The Dosing
protocolstated by oral gavage
that was
all treatments would performed inPartC.
be
given
by
ip.
dosing.
2
I so
Appendix IL_Part A: Toxicity of PFOS and APFO Individual and Summary Data
-- Nh JWh vn
rr pr ee fe e 3
v |--T--][T--7--CT--1
R
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2
fa pf T =oreo re|d s ci e e a e Fe se se beet
|over@ | 125]159/232] 77]
TT17 53 | Tire]des tes] 14)
[Testis@) |[ 3.3] 3I 4] 20p 35 34] 04| ] 535 o 3 ail32 of
rare Chemisty | Choimg/dl | 52] 63] a7[=7 540 52 45
Tas
--------| Jas | NA | wa|
[Camgidl 1115717] Tiel" 116] 01| ] os ia i tio og
JAlbmg/dL. |INET LCT TM
7 EX SE 5
NX
NY
[BUNmo/dL| Rie
1315]
13]20 153 33]| tal
i 7 1s] 153 14
tee ee ree ees
JALKPUL 271326] STOL 1oo sol
451]250] 334] 80.9] |276] tral719]25] 300] aa
436] 200]337.0] se. too so]sro 53]
[LOHUL
1 "335 7886] 556/301] 14d|] 277 367]
1 340] 334]
55)
[Na+moll | aT 1a3l [emma toa Bel
148]Taz 12 roll aslol
tan 53
aol teal vals] ss so ser
[CREAmgl I" 080s [GSTULTsos
Tos ofl oa oa os 04 | soloof|88 8 so
oq oq
[RIGmg/L| 70731120]361] 70]129]| 57 i758]773] 344]
.
SRDTPITSTA6205,T6889.1, 6316.4
RaFtadhata
I (cont ROma?
E 0 E 70 |EE NEE ] I 7[3|
CTR
le |]
1ol alcala] a] [Peroatm"etsr| an T 2s cT us] T a ovT ]vs ana]a-- sa|2-- sT s0] T ns ] rer
Fo La] Le] 572%
lutgan
|sounss00|] ss |sa oo] sol sro!
seo13a|]"=os5
sersu]s| sr0| ate soa]sto 11s]so
5005s] snoavs]
[[vFtegarino3{|7206%0|] 51o0%6|( G2r5o6|] 3T4r4o|]2306%61|6042]|13906%]|1a8s6c|]a1o8e5]|2Tr5o6e| 2S0o5w|]3041]]
Le |
[ioney@|
00
ao
a3o5s1o3or4|1o4a8s]|0a0o8lo0e0]|a5o7s]]o5ss2][3os4e]| aao3s]] a5o7s]]o0os]]
[F Tests C | a6]30]r 54736( aa 0r s]a1]34] 35r 2]a7] 34]03]
[[CCihmoalmrgGahle|mis5t3y0-- 7860 51 201761 0 805 72|]650 630|]6| 60] 530| G03]53]
[[PCTraoomLspmmoagreall||| i0711152][] 1012110411]10121.141]]11042293[]]110211.671]001464]]]1o226r.1]]]1of12.i01]]]1o111i25]l]Tjoi0rs5]]T1u1i.ia4]]]o00o3s]]]
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|ClinicalChemisty
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3
Le8y Dosepros Part B. Liver Weight to Body Weight ratio in male and female rats combined
data. SAS analysis
mm EN
OO)
| ous
~
PEN
=aA
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S24
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oe
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B03oS5o0o7e7sd7
Observations (orSumWeis)
Ed
ESondueers
DF2 AnaSulmofooyVlasSroaiiaunwoscees |Mem0SOa0u0a%r0e FRaerattoy 7" 0000S 0000089 Prooer
Crow ocomiem Oooo oon
LhoowrelMefoNruaOmnbeevrrayArsooorsMaresa)n Su00E0raTotr
Coient
84 oQooso oQooourms
Low S14NEMurmbrauersaensdaaSpeolMn Deeevdaienass ttiiomnastSe4oDfeevrovaSriuanEceresn
iiea Cont
4B8
0oos0en0so ooo
oooodomisoez
oc0oao0sooersss
OiictoMean(pesnMie)ansCompa0r0i0s0o0nT0si0o 0012280 012c2o8n0
Cioent
000011222285 000000000000 DDooovooerso
Apts`Comfopreaach!prariusi0sn0gsSotdnentss
AssDiHLSD 2106800 cont
DITIS 1116/98 study
11600 Cont
0000D046t0E8S 0038
0000004810685 0008
000002039488 001143
(CoPmospiatriivsevoanlsuweisshhaocowntproiolclsusoifnmgeDaunnsnethat Mareetsihgonidficantly diferent.
A1b0s0(2O4L2S25D5 000812080
C1o6nt
00.000020088617
dPiofseirteinvte.valuesshow paisofmeansthatare signfcanty
2
ois 16st ty
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fon]
=Part B. Male or oe rat LW/BW ratio summary
ZEN
APE Ny
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DTIS 11/16/98 study
C1o6nt
00000080896 00001280681 0O0o1t8e8a1t
P(CoomspaireisvoanlsuweisshhaocwopnatriorlsousfimnegaDnusnntehtattsarMeesitghndificant diferent.
AbS(D2I7-0IL6)S0D2
Cont
C1o0n0t is
00021612743 "00tads
aPiofseirteinvte.values shaw paofmieasns that are significantly
31
DIIS 111698 study
Part B. Female rat Liver weight summary
a
WG)ByDosePFOS= ImGKG)
|
SAA z3 wl = 7
A
LNA]1
T -- NI
NE 4MAh
v\
Tw
wohm,A n e
[--
00s
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|
RRFSosqoulMreeaAngSquare Eror Mean ofResponse
Baoaiat0dse0z2ae1st ar
haanatons or SumWets)
"
prSoours
OF2 AnaSulomfyoVlarsrSiomiaanrscmses MeaanSamare rFoRaniso 7 dss joes paw
Cow : 2300 eer ager
Liovedaan foNruOmnboevTra AerorMawean SiCEormomr
oint
P 4 jR oss i or
Liow
S14NEoorrabrreusrsanecs SpsoDMloeevadanetosntsSeGoDfeeyrovaSridancEeraan Toukm ems Gas
Cbyont
>i Torses crussr oomsenes
OttsoMeantp eanM)eans Compar0i0so0nTos0o
i
E90
oteoi6
o1r7i4ca0os0nn0
Som
G00 oto doses
Aptas"Comfopreaach|prairiusi0sn0gsSotudnentss
Ae0s(0iL5D 2302464a100 ome6 27o%o
2
36
DITIS 111698 study
Co1nt
oA2r7s2 224818445782 S2845w47702
`PoCsieovalwmuietshpsahcoowanptariiodrlrluosifinmg eDsuannnteohtsattnrMeetsshiogndificant diferent.
As10(0D2L70S5D02 1644o1n5t.
C1o8nt
2a5s01766s8
dPiofseirteinvte.valuesshow pairofmeansthatare significantly
3
an Part B. Female
Ta
rat LW/BW ratio Summary I~
[--
S go NLL A a oO) _
.
os
<> M \IY
Ne
TM
|
= stingTs T=A N w D Ss
UareeFreevdosorors RENE etre
i5 oisnu
Semienn Suan oe on%
S= f soarsw)or sgEIrmTSyNumemEumm,ty rsTmeoiesmaseems orwrarwem
EIaI uyo[ T{rEomya smTumig
b5Loo Sor rt1Tesoppodmts atoso(oAstmlorvresroSauesni
& Poon ame DonreesPT owT e oe omlt
oem oiom
&.
hwla soomme aomoehs
Aonp%oComnptors rJco!"pow lsosstw osol omom
"
DTIS 11/16/98 smdy
C1ont
0000001023717 0000180022 00.00m081072
`CoPmopsairtivseovnaslwuietshsahocwonptraoilsousfimngeaDnusntnheattsaMreetshiogdicanty diferent.
270)802
A1b0s0(OLSD 0.00C0o5n4t
C1osnt
2"o0o0t0e7291
dPiofseirtehnte.values show pairsofmeans tht are signifcanty
35
oss -- Part B. Kidney Weight to Body Weight ratio in male and female rats combined
data. SAS analysis.
lmEL
.
o
s
DTIS 111696 study
OSnuemwmaayryAonfovFta. RsRSqquuiarree Ad RoMooatnoefaRneSsqpuoanrseeEror `Observations (or Sum Wets)
[01e09e12 0000000463158
2
NSooduerc!e
OF Ana'SloufmyvoalsrSiqiaunascees 2 000000005
MeanS2qu5a%r8e
0F0Ra6t5o
EnCmoowrl 17 00000000000605655 33u872e77 P0r93o6b0
LevelMeansfoNruOmnbeevrayAnovMaean Suro
10180
88 o0o0o0ss oooomz
Cont
4 000250 000031
Std EMreraornussaensdapSodolDeedvieasttiiomnasteofrorvariance
1L1e0v0el
Numbe5r onMesan 000S0usDteEv 8 000s 0000744
SWE0m0M00e1a8n. 000026
Cont
4 0004250 0000500 000025
D1i0M0eanfMeanMt]eans Compa0r0i0so0n00s0.00 000000108 0.00o01n2t5
C1o6nt
0000000001030 000.0000000103 00..000000010250
Alphas`Comparisons for eachpir us0in0gsStudent
AbsOLSD 2.10t980100
18 Cont
11080
000000008855 000000008855 000000006677
cont
00067 000057 000052
CoPmospiatriivseovnaslwueisshhaocwonpolaousfiimngeaDsnusmnheattsarMeetsihgoidfcantydiferent.
237d1l72
As10(0OILSD 1s
000C0o7n8t "000078
cont
"000104
aPioesrieinvte.valuesshow paisofmeans that are sigifcanty
37
1 e|saR m||a|n] C aTE[g11a1]
pet| ||[inhode pot||[RH
fLootdof[ [ |||pe a ersd T isessse.d fmeodf[LiHLIg nTA1)L1E enEE dd ld Agu inhwl(hsW Ln O 5 L0H
" -- Pa B.Gr uint ea Pig Liver to Body Weight Ratio Summary Statistics:
| INT<TETON TT
*- CY | ao -
>
om | ERTPA
mE OosrOSIgD
0s
WnContal
oon
"3
DTIS 11/16/98 study
OSunmemvaaryyAnofovFiet RReSqauuiarreeAd] RNoaotnoefaRnesSpqounasree Error Observations(orSum Wets)
0"008098255448 00000421468877
18
SMooudrecle Er3 or
OF Analys'iSsoimfoVlaSrqiaunacrees MeanSqure FRaio 32 000000000080053088 00000000000053 P0r4o0b8o4F 1s 000008544 0000005 06723
LevelMeansfoNruOmnbeewray AnavaMean Si Emor
110s0
45 oooosmearsso ooooosoe
Cont
4 oowrso ooor2e
StdMEenaornusseansd pSoIolDeevdieasttiiomnasteofervariance
L1e0v0el Number"coMezan oSouoDr2osve SidEm0M00e0a8n3
co1nt
34 o00oiu0E7r5s0 00000023437054 0o0g0o0t8e8s.
DMeanii MeanMte]ans Comparison1s00
110
0000000003080
Cont
200015
00001S6 0000000101020
0001c5o0n0t 00000010102050
Aphaz`Comparisons fr eachparusi0n0gsStudents
216!087
Ab1s0(0DifHLSD 0010080 0001981 0.0o0n2t3
C1o8nt
0000000213 000000226196 000.00201368
CaPomspitaitveovnasluweisnshaocwpoacisoufnmseaBnns tehatt aHreersnoidficanty diferent.
2463|58
As10(0O-LSD 0.00413030
C1o6nt
""000000323883
dPiofseitrievnetvalues show pairsofmeathnatasre significant
DTIS 11/16/98 study
Part B. Kidney Weightto Body Weight ratio in male and female guinea pigs. SAS
analysis
cen8;Dosepros
00s. AAA N joo NL
= =VO O ome
-- A NN
10
"
soars
| Seooweest aergan
ao 95
DITIS 111698 study
O`nSeuwmmaayrAynoofvFat RRRsoqaoutrrMeeeaAnGSquare Error M`OebasenrvoaftRieonsspo(onrsSeum Wats)
05o2s0e0s4e87 00000004444837
15
NSooduels
oF Analys'iSsuofmVoafrSiqaunwcees 2 000000338
MeaTnoSoabuoanrze
FR8a5t6i3
CEmoorl 21 000000000000253763 4109985t0e77 0P0ro0b4>8F
LevelMeansfoNruOmnbeevray AnovMaean
100
" ooss0
Somooo
Co16nt
47 oooooioas o0oo0ootT
51d EMreoarnsusaensdaSptodoDleevdieatsitoinmsateof orvariance
10Le0vel 16
Number4 osMesan 0SouoD0esv0 SwEm00M0e0a2n5 7 0004s 000038 000014
Cont
4 0004250 000000 000025
DifMeariiHMeanMt]eans Comparison0s0
100
0000000
000C1o0n00t
0.00110176
CEoSnt
00"1001011 0000000001010 00..000000100070
Apha=`Comparisonsforeachpairusi0n0g sStudents
Abs(DifLSD 217!882100 Cont
1
C1o0n0t ES
0000000038187 0000s2
0000000038187 00005
000000050025 000052
`CoPmopsiatriivseovnaslwuieshshaocwopntariolsuosfinmgeaDunnsntehtattsarMeestiogdifcantydiferent.
245dl055 Abs(DILSD
100
C1o0n0t
0000000027189
1s
0.000415
rPoseitnivtevasesshow paisofmeathnatasre signifcanty
2
DIS 11/1698sudy
Appendix IV. Part C Oral dosing with N-E(FOSE in rats. Individual data.
Animai#
Gende 0
DoseN-EFOSE (damygs.Kgidafortwo
Specie 5
BW a@
BW @(@
LW(LWB 9W
Sadcaryipfoiscte dose
[Necropsy [Date
89RO217 M Control R6 246 M Control R7 26 M Conrol
Rat 3846388717.3 0.045 Rat 41634204201 0.048 Rat 45374612219 0.047
3 snes 3 ness 3 onese
R027 M
20Rat 5237 539302 0056 3 oness
6R027 M
20Rat 48564884238 0049 3 ness
7BRo217 M
20Rst 4673 503238 0.047 3 ones
8
RNaottse,we20rmegd/oKsgeidsonawpopcroonsxecium3iv0ae0tdpapeymsl,iynSt1h1e6/d1i8e9t8,and 9/17/1998with20mg/kg/dayN-
EIFOSE, then sacrificed on 9/13/1998.
"
DIS 111698 study
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BSeulrftohniaatuem,ea,nJd,Na-nedthWya-lplaecref,luKo.roBo.c(t2a0n0e2s)u.lfPoenrfalmuiodrooeotchtaannoola;te,PePreorxfilusoormoeocPtroalnieferation
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(S1o9h9l4e)n.iuEsf,feAc.tsKo.,fpAenrdfelrusosroono,ctKa.,noBieergasctiradned,poAt.e,nStppyedreovxoilsdo,m0e. paronldifDeeratPoirerirner,aJt.--Wo.n
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WPlieavrleflr.laucPoehr,aorKo.mctaBacn.oelLsuuTclobfxkoiencrao,tleD1a2.,n1d9,02-B-3u(.tNe-nehtohfyfl,peJr.fLl.u,oarnodocSteaanceastu,lfAo.naMm.id(o2)0-0e1t)h.yl alcohol are:
peroxisome proliferators in rats, but not guinea pigs. Toxicologist 60, 348 Abstract ID:
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Q.
Xie,
Y.,
Alexson,
S.
E.,
Nelson,
B.
D.,
and
DePierre,
J.
W.
(2002).
Iinmvmoulnvoemmoednutloafttihoenpcearuosxeidsboymepperroolxifiesroamteorp-raocltiifveartaetdorrsecienpmtiocre.alBphiaocinhethmePharmacol 63,
1893-900.
"
48