Document GKbvoVvyRrgbvwJk00V6E9p5V

ok PP AR226_ 113] REVISED DRAFT HAZARD ASSESSMENT OF PERFLUOROOCTANOIC ACID AND ITS SALTS U.S. Environmental Protection Agency Office of Pollution Prevention and Toxics Risk Assessment Division September 30, 2002 50 000001 PREFACE aTshsiosciisataepdrweiltihmienxaproysausrseetsosmpeenrtfolfutohreopooctetnatinaaoclihcdaz(aPrFdOsAt)o haundmaints sheaatlst.hTahned tmhaejoernivtiyroofnmtheent tinocxliucdoelsogayrienvfioerwmoaftitohneisstfuodrieasmtmhoatnwieurmepaevrafilluabolreooacstaonfoSicepatceimdb(eAr,PF2O0)0.2.This assessment 000072 -- TaofbColntenets E1x0cauivCehSemuimcmalareyntity 2110 PPhyrsiocodshueomicfcPatFlOiPAroaopnenrdtieiss Sats 2212 UEnvsiroofemPeFnsOtaAlanFadtefs Salts 221 Phowlysis 223232342 BVHoiylodadrteiogllriytasydsation 225 Bioaccumulation 22.6 Soil Adsorption 23 Environmental Exposure 23.1 Dischatro Agier 232 DischtaorWagteer 222433"34 EHnDuvimirasonncmSheotnamtoaraLnlagtnMoeodrnimtgoring 30 Human Heath Hazards 3.1. Metaanb dPo harl maci okis netm ics 333...111.123 DAiHsatlbifb-usltiiifooennSSHtruuuddmpiiaeensstsininiAAnnioimmanallss 33.11.45 MEelaimbionlaitisomn SStutdiousidinnAAinniiemmaasllss 3.2 EpidemiologyStudies 3.2.1 Cross-sectional and Longitudinal Studies 333.222.342 MCoHhrootlmaelosintteeyrSoSlttuSudtdyaydy 33325 SAtcuudtyeoTnanEicitpy SiotfsCuariodneAi(ndMiomerabelissdisty) 333312 OtroahlaSlttuidoinesSuds 333334 EDyeermlamliaStuidoinesSuds 3333"5 MSuktiangeinatiitoynSStuuddiieess 33.65 SDuebvcehlroopnmiecntTaolxiTcoitwyiSityudSiteusdiiensAinnimAanlismals 3.7 Reproductive Toxicity Studies 7| 57 1i2 2 11143 14 15 16 16 16 11i7s6 2 24 22%4 33 33 3n394 @0 52a a5 w @44 64 000003 3.8 Carcinogenicity Studies in Animals 7 3.8.1 Cancer Bioassays 7 3.82 Mode of Action Studies 75 3.82.1 Liver Tumors 75 3.82.2 Leydig Cell Tumors 76 3.8.2.3 Mammary Gland Tumors 7 3.8.2.4 Pancreatic Tumors 7 40 Hazards to the Environment 7 41 Introduction ud 42 Acute Toxicity to Freshwater Species 7% 50 References 85 ANNEX I - Robust Summaries 102 000004 EXECUTIVE SUMMARY Introduction Perfluorooctanoic acid produced synthetically (PFOA) and its sals are fully or through the degradation or fluorinated organic compounds that metabolismofother fluorochemical can be pprroodcuecstss.ingPaFidOsAinisthperipmraordiulcytiuosnedofasflauroeraocptoilveymienrtseramneddifaltueo,rwoehlaistiotmsesrasltasnadreinusotehdearssurfactant umsaens.ufaIcntruerceedntinyetahres,UnliestsedthSatnat6e0s0ormeitmrpiocrtteodn.s pMeorsyteaorfotfhePtFoOxiAcoalnodgyitsstsuadlitesshhaavveebbeeeenn conducted this report, with the ammonium sal of perfluorooctanoic acid, which i referred to as APFO in Environmental Fate and Effects PFOA is persistent in the environment. environmental conditions. It does not hydrolyze, photolyze or biodegrade under pGerrofulnuodrwiantaeterdssaumrpflaecstatnatskehnadneealrevfaitre-dtrPaiFnOinAg acroenacsentthratatuisoends fmiaren-yfiygehatrinsgafftoearmtshecofnotaaminiusneg. "tThheissudrefmacotnasnttrsa,t(e2s) tPheFOfoAlloorwiintsg:pr(e1c)urPsForOsAmieigtrhaetreetxhirstoeudghint-h-eorsowial,safnodr(m3e)d PvFiaOdAegprearsdiasttisonin of-groundwater. PSeFvOerAalhawsilrdalriefleysbpeeceinesfohuanvde ibnefeinshssaammpplleeddarforuonmdtthheeU.wSo.,rlcderttoadientEeurmrionpeealnevceolusnotrfiPesF,OtAh.e UNSoS.r,thiPnaccliufdiicnOgcMeiadnwaanydaAtnoltla,rcthteicBallotciactiaonnsd,Moerdiintefrirsha-nceaatninSgebaisr,dansadmJpalpeasnceosleleacntdedKforroemanthe cLooausitss.ianPaF,OSAouwtahsCafrooulnidnainaandfeIwllimnoiins.k livers from Massachusetts, but not PFOA concentrations in river otter found livers in mink from from `wWaasshniontgdteotnecatneddOarteqguaonntiSftiaatbelsewceornecelnetsrsattihoannstihne oqyusatnetrisficcoaltlieocntleidmiitnotfhe3C6hnegs/agp,ewaektewBt.ayPaFndOA GuofMlexifco of the U.S. coast. "lTohceatcioonncsenutprsattrieoanmsoafndPdFoOwAnsitnresuarmfoafctehweate3rM, smeadniumfeancttsu,rcilnagmsfa,cialnidtyfaitshDecoclalteucrteAdLfrhoamve been dtheeteframciilnietdy.haOdfPtFheOtAhrseuerfdaocwenwsattreeramcownactenetrraatnidosnsedsiimgenniftiscaanmtpllyignrgealtoecrattihoanns,thtehettwwooupclsotsreesatmto stihteesu;psthteretahrmeesitdeos.wnTshteresammalllocsaatmiponlseasliszoe hpardevseendtiemdednettceornmciennattriaotnoiofnssisginginfiifciacnanctelyfogrrefaistherwthhoalne bdiofdfyerePnFt ObAetcwoenecnentthreatuiposntsr.eaTmheanadvedroawgnestPrFeOaAm concentration locations. in clams was not significantly. | 000015 oBfasfeadthoenadamviainlnaobwles,latbhoeractaolrcyuldaattead, BACPFFOfodroAePsFnOotwaapspea1.r8.to Ibnioaasctcuudmyuloaftcearipn,ftihshe.BICnFa rsatnugdeyd from 3.1 109.1 S`emvienrnaolws(pPeicimeesphwaelrees tpersotmeedltaos)a,ssbelsusegtihlelascuuntfeisthox(iLcietpyoomfisAPmaFcOh;rotchheisreusi)n,clwuadteedrthfleeafa(tDhaepadhnia maraegnpar)o,blaenmdataicgrfeoernseavlegraael(rSeealseonnsa.sirTihmecsatpurdiiceosrwmeutruemc).onCdoucmtpeadriwsiotnhsdoifffetrheendtitfefsetresnutbssttaundcieess. Generally material is the ammonium salt or the a major concern and was tetrabutylammonium salt was not sufficiently characterized tested. in these Purity tests. of In the test some tests it a2p7pteoar8e5d%t)hawtas10u0se%d.tesWtactheerm,iacaslolwvaesntu(siesdo,proorpaontohle)rosraachceommibcianlatoifolnesosfberoptuhriwtyas(aupsperdoxiinmoattheelry treesptosr,tfeodr; ntoheoabcvtiuoaulscsotnacteendtrraeatsioonn.s wFeirnaellnyo,fornelpoyrtneodm.inal test chemical concentrations were. Trawneglevdeftreostms 7w0er1e0 8c4o3ndmugc/tLe.d wIittsh ufnactlheeaard wmihnyntohwiss;ra9n6g-ehiLsCsSo0wivdael.uesAs(sbuamseidngonthmeosretasltiutdyi)es are vwaolida.caunted vdauleuetso tfhore blliumeigtialtliosnusnfdiisshcuaslsseodiandbiocvaet,etlhoewsetotxoixciictiyty(v9a6l-u1eLsCiSnd0i5coatfe>4lo2w0,toaxnicdit5y6.9The mg/L). rNainngeeadcfutreomte3st9s1w0e>r1e0c0o0ndmugc/tL.ed Twihtehldoawpehrnivdasluaensdar4e8-ihndEicCaSt0ivevaolfumeosd(ebraasteed toonxiicmimtyo,bibluitzattheion) wide range makes interpretation difficult Seven tests were conducted density, cell counts, and dry with green algae; weights) ranged 96-h from EC50 values (based on growth rat, cell 1.2 to->666 mg/L (the ECS0 cell density value otofxi1c,i0t0y,0 bmags/eLd iosnexthceluadceudtefcrroitmertihai.sTdhiseculsoswieorn)v.alTuheewolouwledravlasloubeeinidnidciactaetsivheiogfhmtoodmeroadteer:ate mtogx/iLci.tyb,absaesdeodnocneltlhecocuhnrtosn,ifcormogdreeernataelgcraietewraisona(ls0o.c1a1l0cumlga/tLe)d.inAone14s-tdudEyC. 50Thviasluiseionfdi4c3ative othfelmoowscthsreonnsiictitvoexitceistty,spbeacsieeds ionntthhee4c4hr%onAiPc FcrOitteersitonsa(m1p0lemg,/dL)a.phnGirdesewnearlegatcheanpepxetarmeodstto be sensitive, and fathead minnows were the least sensitive. Human Health Effects and Biomonitoring oLintgtoleinignf5o-rymeaatri,ohnalifs-alvifaeilsatbuldeycionn9cerrentiinregdtwhoerpkehrasrhamsascugogkesitneodefatAmiPeFcaOsn sinerhuummaPnFs.OAAhnal life obifoac4.c37uymaualraste(rPanFgOe,A1i.n50h~uma1n3s.4.9 years). These data provide evidence of the potential to Animal and toa studies have lesser extent shown that APFO following dermal is well absorbed exposure. In the fpoasltl,owCihnegmoorlailteanwdoriknhearlsathiaovneexbpeoesnure, 000006 `seixgnpiofsiecdantto olalregeindethremaalbsdoorspetsioonfoPfFPOFAO.AItinaptpheeasreswtohrakterdse.rmaUlpoenxproescuorgeimtiaoynhtahvate PpFlaOyAeacdould breedaubcseodrdbeerdmdaelrmeaxlploys,urweosrk(Giplrlaicltaincde,s w19e9r2)e,changed and engineering controls were adopted that oPfFtOhAe bdoidstyriibnuctleusdpirnigmathreiltyesttoistahendliovvearr,yp.lasItmdao,easndnoktipdanretyi,tiaonndtototahelleispsiedrferxatcetnito,nootrhearditpiossseue.s. atinsdsuet.herPeFiOs eAvibdienndcseotofmeanctreroomhoelpeactuiclecsiricnultahteiotniossfuteshelicstoemdpaobuonvde.. PThFeOAuriinsenoisttmheetmaabojloirzreodute of excretion excretion in of PFOA male ras. in the There female rat, while are majorgender dtihfefuerrienneceasndinfetcheeslairmeibnoatthiomnajoofrPrFoOutAesionfats. In f1e0m5ahleinratths,e tsheerhuamlfa-nlidfe2i1s02h4ihn itnhethleivsere.ruTmhaendrap6i0dhexicnrtehteiolnivoefr;PiFnOmAalbeyraftes,matlhee rhaatlsflisifdeuisto abcetliiveeverdentaol bteubhuolramrosneaclrleyticoonn(troorlglaendi,c saicnicdetcraasntsrpaotretdsmyaslteemr)a;tsthtirsearteendalwittuhbuelsatrrasdeicorlethiaovneis enxoctraeptpioenarattoeschoafnPgeFOthAersaitmeiolafreltiomtihnoasteioofn fienmraalse. raTtsh.isHgoernmdoenradlifcfhearenngceeshdausrinnogt pbereengnancy do abserved in primates and humans. TOchceurpeaatrieonlailmidtaetdadaftraomonplPanFtOsAinstehreuUm.Sl.evaenlsd iBnewlogrikuemrsthaatndmatnhuefgaecnteurrael opropuusleatPioFnO.A indicate that the most reported in a wroecreknetrmiena1n99s7erwuams l8e1v.e3lspipnm.worIknenrosnr-aoncgeeupfartoimon0a.l84po1p0ul6a.t4iopnpsm,. seTrhuemhPigFhOesAt level lseevreulms wPeFrOeAmulcevhellsowrearn.gedInfbrootmh3potool1e7d pbplbo.odTbhaenkhisghaemsptlesseraunmd PinFiOnAdivliedvuelasl wseamrpelreesp,omrteeadnin a sampleof children from different geographic regions in the U.S. (range, 1.9 - 56.1 ppb). TEpwiodemmoirotlaolgiitcyasltusdtiuedsi,esaomnortbhiedeiftfyecsttsuodyf,PaFndOAstuidnihesumeaxanmsihnaivneg befefeenctcsoonndutchteeldivoenr,wpoarnkcerresa.s, esencdtoicornianleassywsetlelm,asanadlolnigpiidtumdeitnaalbosltiusdmyo, fhatvheebweoernkecronsduurcvetieldlatnocdeatdea.taIhnaavdedirteicoenn,talycbroesesn- stuhbomuigthterde.cenHtowPeFvOerA,ltehveelsse alrateesstim2ilsatrudtiooesrfhoicguhseprrtihmaanriPlyFoOnSPlFevOelSsrianthweorrkteharns PatFtOhAe,seepvleanns (It should be noted PFOA levels). that PFOS levels in the sampled general population arc much higher than aAndreptrroosstpaetceticvaencceorh.ortAmsotrattailstiitcyalsltyusdiygndiefmiocannsttraastsoecdiaatwioenakwaasssoobcsieatrivoendwiintphroPsFtaOtAe ceaxnpcoesrure tmhoertsatluidtyy;ahsolweenvgetrho,ftheemrpelsuolytmsecnatnniontcbreeadsierde.ctTlhyicsormepsualrtewdabsencoatusoebstehreveexdpoinsuarreeccaetnteguoprdieaste to wtheerelomnogdesitfideudraitniothnes uspoduagthe.t caIrneammoorrebiodfitteyn sftourdpyr,owstoartkeercasnwcietrhttrheeathmiegnhtestthaPnFwOoArkeexrpsowsiutrhes for Tower exposures. 3 000007 lAenvoetlsh:erhoswteuvdeyrr,epnoornteedofanthiencortehaesrehionremsotnraediloelvellesvealnsalinyzweodrkiendriscawtietdhatnhey haidgvheersstePefFfOecAts.seSruomme ochfotlheecyssatmoekienmipnl(oCyeCeKs)wlhevoelpsarintiecmipplaoteydeeisn.theNohopromsoitnievestaussdoycailastoiownewraesinncoltueddebdeitnwaeesntuCdyCoKf ivnalwuoerskearnsd.PTFhOeAr.e dTihdenootthaeprpaevaariltaobblee astnuydsyigenxiafmiciannetddcihfofleersetnecreoslaamnodnogthweorrkseerrsumofcodimfpfoerneenntts terxapnosfseurraese)l.evelHso,weexvceerp,t aPmFoOnAgwoabsesneotwomrekaesrusr(eadspdairretcattleya,mbiutnointdrianrsefeelryasaes taontdalaslaenriunme aflmuiornione. "PTFheOcAroasnsd-scehcotlieosntaelroalndanldontgriitguldyicnearlidsetuldeiveelss.fouInndadpdoistiitoinv,easipgonsiiftiicvaen,tsaisgsnoicfiiacatnitonasssboectiwaetieonn was rseecptoirotneadlbsettuwdye.enTPheFrOeAaraenmdaTn3yhloirmimtoantieonasndtoatnheesgeatsitvuediaesss,oacinadtitohnerweifotrhe,HaDllLofintthheesecrroessusl-ts must be interpreted carefully aInndac2u5t0e-t5o0x0icmitgy/kstgudfioersfienmaalneism,alasn,dt<he10or0a0l mLgD/Sk0g vfaolrumeaslfeoranCdDfreamtaslweeWriest>a5r00ratms.g/Tkhgerfoerwmaasles no mortality following inhalation exposure of 18.6 mg/L for one hour in ats. The dermal LDS0. rianbrbaitbsb,itwshwiales tdheetedratmainreedgatrodbienggproetaetnetritalhasnki2n00i0rimtga/nkcgy.areAcPoFnfOlicistaingp.rimary ocular irritant in APFO is not mutagenic. APFO did not induce mutation incither S.typhimurium or E. coli when tested either with or without mammalian activation. APFO did not induce gene mutation when itnesctueldtuwrie.th AorPwFiOthdoiudtnmoettaibnodluicceacchtriovamtoisonomianlthaebeKr-r1atliionnesoifnChhuimnaesnelhyammpshtoecrytoevsarwyh(eCnHtOe)stceedlls wfoirthisanadbilwiittyh1o0utinmdeutcaeboclhircoamcotsiovamtailonaubeprrtaotciyotnostoinxiCcHcoOncceenltlrsa.tIinonts.h APFO was tested first assay, APFO twice induced both chromosomal aberrations and activation. In the second assay, no polyploidy significant in both the presence and absenceofmetabolic increases in chromosomal aberrations were observed without activation. However, when tested with metabolic activation, APFO induced sceilglnitfriacnasntfoirnmcarteiaosnesasisnacyhirnoCmsosHom10aTl.;abmeorurasteioenmsbarnydoifnipborloybplalsotisdya.ndAiPn FthOe wmaosusneegmaitcirvoeniunclaeus assay. lSiuvbecrhirsotnhiecpsrtiumdaireys tinarrgaettsoarngdanm.icIen wriatthst2u8diaesn,dm9a0l-edsayasreoffaerxmpoorseurseenhsaivtievdeetmhoannstfermaatleeds.that the hDeipeattaorcyelelxuploasruhryepteortArPoFphOy fionr9fe0mdaaleysrartessautlt1e0d0i0npsipgmni(f7i6c.a5ntmign/ckrge/asdeasy)inalnidveirnwmeailgehtraatnsdat dmoasreksedasgleonwdearsd1i0ff0eprepnmce(5thmatg/akcgc/oduanyt)s.foAr tnheadilffoyefrsseencereusmin saenndsitliivvietry.leChvorofenPiclFdOisAetasryh.owed a `exposureofrats 10 300 ppm APFO (14.2 and 16.1 mg/kg/day for males and females, arnesdpelcitviervelleys)iofnosr 2inymeaalressreasnudltfeedmainleisn.crIenaasdedditliiovne,r atensdtikciuldanreymawsesiegshtwse,rheemoabtsoelrovgeidcailn emfafleecstsat 3mg0/0kgpipdmaya)n,dtohvealroiwaensttudbouslaerthesytpeedr.plasia was observe in females after exposure to 30 ppm (1.6. ` 0ooros Ina 90-day study with thesus monkeys, exposure to doses of 30 mg/kg/day or higher resuled in death, lipid depletion in the adrenals, hypocellularityofthe bone marrow, and moderate atrophy ofthe lymphoid follicles in the spleen and lymph nodes. Unlike rodent studies, analysesofthe serum and liver levels did not reveala gender difference in monkeys, but the sample size was very small (N=2)." In a &-month studyofmale cynomolgus monkeys, dosing ofanimals in the 30 mg/kg/day dose group was stopped from days 11-21 becauseoftoxicity. When dosing was. resumed on day 22, animals received 20 mg/kg/day and this group was designated the 30/20 mg/kg/day group. This treatment was also not tolerated and treatment was stopped for 3/6 monkeys. Mortality was observed in one monkey at 3 mg/kg/day and at 30/20 mg/kg/day. "There were no consistent effects on hormone levels. Increased absolute and relative liver weights were noted at 3, 10 and 30/20 mg/kg/day. While there was no evidenceofperoxisome proliferation, there was evidenceofmitochondrial proliferation suggesting a different mode of action than observed in rats. The serum levels were highly variable and should be treated with caution. On day 9oftreatment, the serum levels were 126 + 36.1 g/mL in the 3 mg/kg/day group and 1597 + 2392 pg/mL in the 30/20 mg/kg/day group, and during weeks 26/27, the serum levels were 52.5 + 9.14 ug/L in the 3 mg/kg/day group and 51.5 + 77.6 pg/mL in the 30220 `mg/kg/day group. The LOAEL for this study was 3 mg/ke/day and a NOAEL was not established. Prenatal developmental toxicity studies in ats resulted in death and reduced body weight in dams exposed to oral doses of 100 mg/kg/day or by inhalation to 25 mg/m' APFO. There was no evidenceofdevelopmental toxicity after oral exposure to doses as high as 150 mg/kg/day, while dinehvaellaotpimoennetxaplostuoxriecittoy2s5tumdgy/tmh'erreewsualstead siingnriefdiuccaentd ifnetcarleabsoediyn wsekieglhettsa.l vIanriaatriaobnbsitaforearlexposure to 50 mg/kg/day APFO. There was no evidenceofmatemal toxicity at 50 mg/kg/day, the highest dose tested. Ina two-generation reproductive oxicity study in rats exposed 10.0, 1, 3, 10, and 30 mg/kg/day APEO, significant increases in absolute and relative liver and kidney weights were observed in FO males at | mg/kg/day, while significant reductions in absolute and relative kidney weights were observed in FO females at 30 mg/kg/day. Reproductive indices were not affected in the FO animals. Serum levels of the10 and 30 mg/kg/day groups were measured for FO males after mating and FO females at weaning of the F1 pups. In FO males, the serum levels were 51.19.30 and 45.3:12.6 ug/l, respectively for the 10 and 30 mg/kg/day groups, and in FO females, the serum levels were 0.37:0.0805 and 1.02:40.425 ug/, respectively for the 10 and 30 mg/kg/day roups. In F1 females, there was a significant increase in post weaning mortality,a significant decrease in mean body weight, and a significant delay in sexual maturation at 30 mg/kg/day. In FI males, significant decreases in body weights and body weight gains, and significant changes in absolute liver and spleen weights and in the ratiosofliver, kidney, and spleen weights-tobrain weights were observed in all treated groups. The increase in post weaning mortality and the delay in sexual maturation was also noted in F1 males at 30 mg/kg/day. Reproductive indices were not affected in the FI animals. The LOAEL for the FI females was 30 mg/kg/day, and the NOAEL was 10 mg/kg/day; the LOAEL for F1 males was | mg/kg/day and a NOAEL was not s 000009 determined. The difference in sensitivity is presumed to be related to the gender difference in eliminationofAPFO. No treatment-elated effects were observe in the F2 generation. However, it should be noted that the F2 pups were sacrificed at weaning, and thus it was not possible o ascertain the potential post-weaning effects that were noted in the F1 generation. Carcinogenicity studies in Sprague-Dawley (CD) rats show that APFO is weakly carcinogenic, inducing Leydig cell adenomas in the male ras and mammary fibroadenomas in the females following dietary exposure to 300 ppm for2 years (equivalent to 14.2 mg/kg/day in males and 16.1 mg/kg/day in females). APFO has also been reported to be carcinogenic toward the liver and pancreas of male CD rats at 300 ppm. "The mechanism(s) ofAPFO tumorigenesis is not clearly understood. Available data appear to indicate that the inductionof tumors by APFO is due to a non-genotoxic mechanism, involving activationofreceptors and perturbationsof the endocrine system. There is sufficient evidence to suggest that APFO is a PPARa-agonist and that the liver carcinogenicity/toxicity of APFO is mediated by binding to the peroxisome proliferation activation receptor a (PPAR) in the liver. Recently. IARC (1995) concluded that the liver tumors induced in rodents by PPAR-alpha agonists are unlikely to be operative in humans based on our current understanding ofthe animal mmoadmemoafrayctgiolna.nd nAveaoipllaabslmesdbaytaAsPugFgOesmtatyhatbethdeuiendtouchtoiromnoonfalLeiymdbiaglcaenlcleturemsourlsti(nLgCfTr)omand activation of the PPAR and inductionofthe cytochrome P450 enzyme, aromatase. Preliminary data suggest that the pancreatic acinar cell tumors are related to an increase in serum levelofthe growth factor, cholecystokinin. At his time, the pancreatic, Leydig cell and mammary tumors should be considered relevant to humans. 6 000010 1.0 Chemical Identity Chemical Name: Perfluorooctanoic Acid Molecular formula: C8 H FI5 02 Structural formula: F-CF2-CF2-CF2-CF2-CF2-CF2-CF2-C(=0)X, "The The free acid and some perfluorooctanoate common derivatives anion does not have have the a specific following CAS CAS number. numbers: Free Acid (X=OM#M =H) [335671] Ammonium Salt Sodium Salt Potassium Salt Silver Salt (X=OM#;M=NHd) (X=OM# M=Na) ((XX==O0MM#+; MM==AKg)) [3825:26-1] [335-95-5] [[233359-59-30-038]] Acid Fluoride x=F) [3566-0] Methyl Ester Ethyl Ester (X=CH3) (X= CH2-CH3) [376-272] [3108-245 Synonyms: 1-Octanoie acid, 2.2.3.3.4.4,5,5,6.6,7,7,8,8.8-pentadecafluoroPFOA 1.1 Physicochemical Properties Ftooxritchoilsorgeyposrttu,dipeesrfhlauvoeroboeeetnancooinedauccitdediswciotnhsitshteenatmlymorenfierurmedsatlotaosfPpFeOrAfl.uoMroooscttoafnotihceacid, w"Thhiecthypwiiclallbsetrruecfteurrreedhatso.aasliAnPeaFrOchianinthoifseriegphortt.caPrFboOnAatisomas.comTphleetpheylsyifclaulorcihneamtiecdaolrpgraonpiecrtaiceisd. npoetnetdadbeecalfolwuoarroeoeftoarntohiecfarceiedac[i3d3,5-u6n7l-e1s)s,oithethrewimsoessttactoemd.pleTthee. dTahtaefroerptohretefdreveaapcoird,pressure of 10 mm Hg appears high fora low melting solid when compared to other low melting solids (NcIhOlSorHo)a,cebtuitc iascicdo:nssiosltide;ntMwPith= o6t1hetro 6pe3rflCu;orBiPna=ted18c9omCp;ouVnPds= w0.i1thksPiami(l0a.r75bomilmingHep)oi@nts20 C; (epxeprlfalnuaotrioobnumtaanyoibceatchiadtBthPe=101m20mCv,apVoPr p1r0esmsumreHwgas@m2ea0suCr;edBeaitlsatneienleIvVat2edp. t8e1m1p).eraAtnuoreth(ebrut the temperature inadvertently omitted), as perfluorooctanoic acid is typically handled as a liquid 2165 C (3M data sheet for FC-26). Twhateerfraenedactihde ipserefxlpueocrtoeadlktyolccohmapilnetoenlythdeissusrofcaicaet.e iInnwaaqtuere,oulseasvoilnugtitohnes,aniinodniivcidcuaarlbmoxoylleactueleisn tohfe PFOA anion loosely associate on the water surfice and partition between the air / water 7 000011 tinhteeyrfdaicse.perSseevearnadlmriecpeolrltessnfootremthaatthPigFhOerAcsonacletntsrelaft-iaosnsso.ci(aStiemiastttehre, s1u9r9f2a;ceC,abluftouwrist,h1a9g8i5t;ation Evadlwuaersdasr,ef1o99r7)a.miWcartodeirsspoelrusbiiolinotyfhmaiscebleleens,rerpatohretredthfaonr PtrFueOAso,lubbuiltitity.is uDnculeeatro wthheestehesramteh.ese sPuFrfOaAce-isacatnitviecippraotpeedrtiocsfoofrmPmFuOlAti,plaendlatyheersteisntopcrtoatnooclo/lwaftoerr,thmeuOcEhClDikeshtahkoseefolbasskermveetdhofdo,r PFOS. Therefore, an n-octanolwater parition coefficient cannot be determined. "The available physicochemical properties for the PFOA free acid are: MMPW:: 44514-- 5(BeCils(tBeeiinl,ste1i9n7,5)1975) BP: 189 192 C 736 mm Hg (Beilstein, 1975) VP: Sol. 10 mm Hg @ 25 C (approx) (Exfluor MSDS) - Water: 3.4 g/L (telomeric [MP = 34 C ref. 0.01 - 0.02 mol/L ~4 - 8 g/L) (MSDS from Merck, Fischer, and Chinameilan Intemet sites) pKa: 2.5 (USEPA AR226- 0473) pH (g/L): 2.6 (MSDS Merck) (TAhPeFPO)F,OA[38d2e5ri-v2a6t-i1v]e).ofTghriesatseusbtsctoanncceerwnaasntdhemotessttiwngi:desusbpsrteaandceusfeoritshtehetoaximcmitoyntieustminsgalt performed and has the P-Chem data provided in the Table below. w"TahteerwastoelrubsiolliutbyioliftAy PofFOAPtFoObeh>as1b0e%e.n Iitnwcoanssinsotteendtliynraenpoeratreldi.er sOtnuedy3tMhatstatudcyonrceepnotrrtaetditohnes of o2f0 gA/pLo.llthoeSscoileunttiiofnic"sgeelllliendg" a(33M1,%19aq7.9)s.olTuhteisoneonfumAbPeFrOs.seOenmesauurtphroisrirnegpolrotwedfotrhae sAaPltF,Oin light "pTahritsitviaolnuceoemfifgihctiennottlboge Pacocwura=te5.duAenotothteher easuttihmoartrieonpomrteetdhoand eussteidma(tHeadnsAcPhEaOndloLgeoPo1w97=9)-.0.. Again, the anticipated interfce would make dfeotremramtiinoantoifonaonfelmouglsKiofiwedimlpaoysesribbleet.ween the octanol and water surface Determinationofthe vapor pressure of 7 x vapor pressureof APFO is complicated. 10-5 mm Hg at 20E C, which seems t00 APFO low for had recently reported a a material that sublimates aSsubtlhiemaatmemaotn1i3u0msCal(t.US(E3PMAEAnRv-i2ro2n6me47n3t)a.lALsabtohreattoermyp,er1a9t93u)r.e inTchreeaasemsmfornoimuwmhseanltAbPegFiOns to dbeognionts dteomsounbsltirmaattee,si2mi0l%arowfetihgehstalmopslseunwteiilg2h3t7isCloostrbhyigh1e6r9.(CL.inOest.he1r98s4a)l.ts (DCesc,omKp,oAsgi,tiPobn, oLfi) da1if3fe2r0entCsaflotrstphreosdoudciesumpesralftluaonrdohatep2t5e0n-e2(9l0ossCoffomretthaelsifllvueorrsiadleta.n(dBecialrsbteoinnd1io9x7i5d)e.). This occurs "The physicochemical properties ofPFOA and its common derivatives are summarized in Table | 8 000012 E 2g TI R LP oes fo Jo |--| [RECCOF [335648|-- Twiec |[7 7] [RECO2H [335-671 |55C [189C [10mmHg[3400 [| C(=0)OMe_| 376-27-2 159C. 2.0 Production of PFOA and its Salts Electro-Chemical Fluorination (ECF) process or 2) the telomerization process. The 3M Company was reported to be largest manufacturer and importer of PFOA and its salts in the `material was about 80% linear. In the ECF process to make PFOA, an electric current is passed through asolutionofanhydrous `hydrogen fluoride and an organic feedstock, typically an octanoic acid derivative. The ECF process replaces the carbon-hydrogen bonds on moleculesofthe organic feedstock with carbon fluorine bonds, in an identical manner used to make PFOS. Perfluorination occurs when all the variable mixtureof byproducts and impurities. The product from the ECF process is not a pure chemical, but instead a mixtureof isomers and homologs including higher and lower straight- chain homologs; branched-chain perfluoroalkyl fluoridesofvarious chain lengths; straight-chain, `branched, and cyclic perfluroalkanes and ethers; and other byproducts (3M Company, 2000a). After separation and recoveryofdesired material from the byproducts and impurities of the 000013 (MEoMreG,pr2e0c0i1s)e. pUroSdEucPtAiohnasvnootlloucoaftmePdeFinOsfAoramantdiotnhetahamtmwoonuiludmcoanntdrasdoicdtiuthmissaclltasihm.ave been rperpeovretnetdintgodiUsScEloPsAurbeyin3Mt,hsbruetpohratv.e Sbienecnec1l9a8i5m,edUSasETPSAChAascornefciedievnetdiaaltbotuaslionfesaspipnrfooxrimmaattieolny, 2in5vennottoirfyi.catMioosnstofofrtPhFesOeA-nroetlifaitceadticohnesmwiecraelsftrhoamt cwoemrpeannoitesproetvhieorustlhyanon3Mt.heITnSmCosAtCchaesemsi,cathle nVootliufimceatlieosnsstqhuaanli1f0iemdefroircthteonLsopwerVyoelaru.me Exemption for new chemicals witha production Cbyurrinednutsiprryo,duncotriiosnitvaovlauimlaeblienfionrmUaStEiPonA'fosrCmhaenmuifaccatlurUeprdsatoethSerysttheamn 3(wMhihcahscnoonttabienesn provided iinnfvoorlmuamtieosnaobnovneon4-,p5o2l5ymkge)r.icFuorrtghaenrimcorceh,emtihcearlesismnaonuifnafcotrumraetdioinn otnhetUhenittoetadlSctuamtuelsaotriivmeported p3rModhuacstinoontvcoolmummietsoefd PpuFblOiAclysitnoace icnoitmipallectoemmpehracsiea-loiuztatoifoPn.FOIAn taenrdmsPoFfOoAn--rgeolaitnegdpcrhodeumcitciaolns, acesrittahinasFfLorUPOFROASDanBdraPnFdOSsp-erceilaaltteydmachteemriicaallst.haHtocwoenvtaeirn, 3M has indicated that tis PFOA and is salts such as phasing out FC-26, FC- 118 and FC-143, FX-1001 Manufacturers Group (3M alanrdgeostthecrusst(o3mMerCofomrpPaFnyO,A 2p0r0o0dcu)c.ts,Insapdedciitfiicoanl,ltyhethFelaumomroopnoiluymmersalt, AdePmFaOn)dhfaosriAnPfForOmetdhatth3e MEPhAsthnaottimtewtil(l FbeMGma2n0uf0a2cAtRu2r2i6n-g1300904,)0.00 kTgh/eyrFtMoGmemeatntuhfeacitnudrusitnrgy process is based on telomerization "(Tshuechtealsompeernitzaafltuioornopertohcyelssi,odaicdceo.r.d.iwnigthtoa3pMo'lsymBeurlitzmabalneaentdhyPlieknei,c*coismtphoeurnedact(isounchoafs telogen treetarcatfelduowriotchtheytlheynlee)net,ovfioarfme`eterlaodmiecrasl'.addIintitohni.s pTrhoicsefsosrtmhse aremsiuxlttaunrtetoefloimoedridieosdtihdaetscaarne tbheen rteealcotmeedriszuabtsieoqnupernotcleysst.o fEoirthmera vparroiceetsysoyfieulsdesfuplremdatoemriinaalsn.t.l.y".puDruepsotnratiguhste-schaaninanaacliodgsowuisth an eprvoecnesnsumabreergoenfecraalrlbyomniaxttoumrse.s Coofmpmeerfrlcuioarlinpatreodduccotmspmoaunnudfsacwtiutrhedratnhgreosugofhetvheenteclaormbeorniznautimobners (Renner, 2001). Distillation can be used to obtain pure components (ECT, 1994). Cbuyrirnednutstprryo,duncotriiosnivaovlauimleablienfionrUmaStEiPonA'fsorCmhaenmuifaccatlurUeprdsatoethSeyrsttheanm 3(wMhihcahscnoonttabienesn provided iinnfvoorlmuamtieosnaobnovneon4-,p52o5lykmg)e.riFourrgtahneircmocrhee,mitchearlesimsannoufiancftourrmaetdioinn tohne tUhneitteotdalStcautmeuslaotriviem.ported production volumes of PFOA since initial commercialization. Schienmcieca19l8s5,thaUtSwEePreAnhoatsprreecveiiovuesdlya otnotatlhoefTaSpCprAoxCihmeamtieclayl25Invneonttiofriyc.atiMonosstforofPtFhOeAs-erelated nthoetiLfiocwatiVoonsluwmereeEfxreommptcioomnpafnoirenseowthcehremtihcaanl3sMw.ithInamporsotduccatsieos,n tvhoelnuomteifliecsastitohnasnqu1a0limfeiterdicfor tons per year. 0 00001.4 In termsof on-going production, 3M has not committed publicly to a complete phase-out of PFOA and PFOA-related chemicals as it has for PFOS and PFOS-related chemicals. However, 3M has indicated that it is phasing out certain FLUORAD Brand specialty materials that contain PFOA and is salts such as FC-26, FC-118 and FC-143, FX-1001 and others (3M Company, 20000) AisncilduedefrFormantchee,UGneirtmeadnSyt,atleas,lyO,EanCdDJaMpeanm.beTrhecrouenmtraiyesalthsaobt erespoormteedplryohdauvcetipornodinucntoionn-cOaEpCacDity countries such as China. Following are companies that may manufacture PFOA and its salts (3M Company, 2000b; Directory ofWorld Chemical Producers, 1998; Dynax, 2000; Renner, 2001; SEMI, 2001): OECD + 3M Company (United States) + DuPont (United States) + Exfluor Research Corporation (United States) PCRInc. (United States) + Ciba Specialty Chemicals (Germany) + Clariant (Germany) + Dyneon (Germany) + + EHoneicChhsetmAkSiyinetnhgeessiesllSspc.hAa.ft(i(tGaelyr)many) Miteni SpA. (aly) + Asahi Glass (Japan) ++ DDaaiikniinpp(oJnap(aJna)pan) + Tohkem Products Corporation (Japan) Non-OECD ++ Chenguang Research Instituteof the Chemical Industry (China) Shanhai 3F New Materials Co. Ltd. (China) n 000015 2.1 Uses of PFOA and its Salts PFOA is used mainly asa chemical intermediate, andit salt are used in emulsifier and surfactant applications According to 3M, the vast majority of PFOA is consumed to make the ammonium or sodium salts. 3M also uses PFOA as a reactive intermediate in the industrial synthesisof a luoroacrylic ester. The fluoroacrylic ester is used in an industrial coating application (3M Company, 2000a). "The saltsof PFOA have additional uses, mostly in surfactant and emulsifier applications. These include the following: Processing aid in the industrial synthesisoffluoropolymers and fluoroelastomers such as polytcirafluoroethylene and polyvinylidene fluoride with a variety of industrial and consumer uses (3M Company, 2000a; DuPont, 2000; Daikin, 2001). Pflousotr-opeollaysmteormiezrastipornioprrtoocefsusrithnegraiinddsusitnritahle psrotceassbinigl(o3ifMszuCsaopmtepniasniooyn,ns20o0f0fal)u.oropolymers and Processing aid for factory-applied fluoropolymer coatings on fabrics, metal surfaces, and fabricated or molded parts (3M Company, 2000s). Extraction agent in ion-pair reversed-phased liquid chromatography (Petritis, 1999). Based on the physicochemical propertiesofthe sals of PFOA, they may also have other related surfactant or emulsifier uses as a photographic chemical or in the manufactureofelectronic: components such as semiconductors. These same properties may lead industry to explore PFOA. asa replacement chemical for PFOS in other applications in which PFOA is not currently used. 22 Environmental Fate 22.1 Photolysis Direct photolysisof APFO was examined in two separate studies (Todd, 1979; Hatfield, 2001) and photodegradation was not observed in either study. In the Todd (1979) study, a solution of 50 m/l APFO in 2.8 liters of distilled water was exposed to simulated sunlight at 22:2 C. Spectral energy was characterized from 290-600 nm with a max output at ~360 nm. Direct photolysis ofthe est substance was not detected. However, the author noted that sample purity was not properly characterized which may have contributed to experimental error. In the Hatfield (2001) study, both direct and indirect photolysis were examined utilizing techniques based on EPA and OECD guidance documents. To determine the potentialfordirect photolysis, APFO was dissolved in pH 7 buffered water and exposed to simulated sunlight (Serano 1999; Nubbe, 1995). For indirect photolysis, APFO was dissolved in 3 separate 2 000016 `matrices and exposed to simulated sunlight for periodsoftime from 69.5 to 164 hours. These exposures tested how each matrix would affect the photodegradation of APFO. One matrix was a pl 7 buffered aqueous solution containing H202as a well-characterized sourceofOH radicals T(Ohgeatsae,co1n9d83m;atLruinxakc,ont19a9i2n)e.d FThei2s03tesitnewdattheerptrhoaptehnsaistbyoeefnAsPhFowOnttoougnedneerrgaoteinhdyidrreocxtyplhortaodliycsailss. via a Fenton-type reaction in the presence of natural and artificial sunlight (Kachanova, 1973; Behar, 1966). The third matrix containead standard solutionofhumic material. Neither direct nor indirect photolysis ofAPFO was observed based on loss of sarting material. Predicted degradation products were not detected above their limitsofquantitation. There was no conclusive evidenceofdirect or indirect photolysis whose ratesof degradation are highly dependent on the experimental conditions. Using the ironoxide (Fe203) photoinitiator matrix model. the APFO half-life was estimated to be greater than 349 days. 222 Volatility Impinger studies were performed to examine the volatilityof APFO and PFOS. Solutions of APFO or PFOS containing ammonium acetate in water/1-propanol (50:50) or phase transfer agents e.g., n-alkyldimethylbenzylammonium chloride (3M Environmental Laboratory, 1993) were blown with 280 liters of air at a flow rate of | Limin. (3M Environmental Laboratory, 1993). The results indicate there is some loss of APFO and PFOS, but most ofthe solutions. retained over 80% or moreof the fluorochemicals. The average retention was 92% for both APFO and PFOS. This indicates that there is loss from the solutions. However, some of the solutions, particularly the n-alkyldimethylbenzylammonium chloride solution, appear to retin all the fluorochemicals. These results were reviewed by Dr. Edwin Tuckerof the Chemistry Dept. at the Universityof Oklahoma (3M Environmental Laboratory, 1993). He concluded that itis very unlikely that these fluorochemicals were removed by bubblingair through water due to their very low vapor pressures. He suggested that a more plausible mechanism for loss from the. Solution phase is concentrationofthe surfactants in foam and loss from the bubbled solutions as foam or micro-droplets. In the second part ofthe experiment, air was passed over the fluorochemicals and bubbled through a trainof impingers containing the ammonium acetate solution. It was expected that if any fluorochemicals were present in the air they would be transferred and retainedby the ammonium acetate solution. However, no fluorochemicals were present in either the first or s1e0cEo-n0d7immpmingHegr.. The report concludes that the vapor pressureofboth compounds is less than According to these experiments, APFO and PFOS (potassium salt) have very low volatility and vapor pressure. Quantitative conclusions regarding ratesofvolatilization from water or Henry's Law constant are not possible. However, APFO and PFOS are capableoftransport outof water. Also, the lossofthe fluorochemicals may have been as the free acids, not the salt forms. APFO svaulbildiimtyesofatth1e30teCst (mseetehPohdysfiorcodcehteemrimcianlinPgrovpoelrattiileistySoefcttihoente1s.1t).subTshtearncee.is nToheinsftourdmyatailosnoolnactkhse characterizationof the purity ofthe test substance. 5 000017 2.2.3 Biodegradation Ushsaiknegcaunltaucrcelismtaudtyedmsolduedlgeedianfotcrultuhme,StohaepbiaonddegDreatdeartgieonntoAfssAoPciFaOtiowna'ss pirnveessutmipgtaitvede utessitnfgoar dpergersaednacteoiofna(nRyeimneert,ab1o9l7i8c).proBdoutchtsthoivne-lratyheer aconudrsliequoidf2ch1/r2ommoantthosgirnadpidchiaytdinngotthdaettePcFt OthAe does dneotgrraedaedidlyinuancdteirvgatoebdisodleugdrgaedaitnioocnu.lumIn(aPaecleatAendalsyttuidcya,l,2.2604015).mg/TeLstAPflFasOkswawesrneotprmeepaasruerdaubsliyng miHnPeLrCa/lMsaSlDts smyesdtiemu.m,Se|vmerLalmeotthhaenroslt,udaineds c5o0ndmuLctseedttlbeedtswleuednge1.97A7n-a1l9y8si7sawlsaosdciodnndoutctoebsdewrivteh mAePtFhOodbsiuodseegdriandatthieosne ustsuidnigeswhwaetrepreoibtahebrlyinwseufrfeicsiteanntdlayrddesCcOriDbeadn(di.eB. OnDo dmeestchroipdtsi,onhoowfever, the. erexspuelrtismweenrtea,ltphreorteofcoorles,)doeretmheedreuwnreerleiaibnldeicbaytitohnessoufbmaihtitgehr d(e3gMreCeoomfpaexnpye,ri1m9e7n7t;al3eMrroCro.mpTahney, 1980; 3M Company, 19850; Pace Analytical, 1997). 2.2.4 Hydrolysis `sTthuedy3pMroEcnevdiurroensmewnetraelbLaasbeodroantoEryPA('2s00O1Pa)PTpSerfGourimdeeldianestDuodcyoufmetnhet h8y3d5r.o2l1y1s0is(oEfPPAFO1A99.8);The aaldtehqouuagthe tfhoer pthreosceedsuturdeisesd.oRneostulftulsfiwlelraellbtahseerdeonquthieroebsmeoerfvntetdhsecognuciednetlrianet,iotnhseoyfwPerFeOAmoirne than bpuefrffeorremdaancqeueloiuqsuisdoclhutrioomnastaosgraafpuhnyctwiiotnhofmaismse.spTechtercomheotsreyndaentaelcyttiiocnal(tHePcLhCni/qMuSe)w.as high During the 11.0 overa study, samples were period of 109 days. prepared and Experiments weexraemipneerdfoartmseidx datif5f0ereCntapndH tlheeverlessuflrtsom 1.5 to extrapolated to 25C. Data objective and were rejected. from twoof the pH levels (3.0 Also rejected were the data and 1) obiained filed for pH to meet the data 1.5 because ion quality pairing pleHd ltoevaenltsif(i5c.i0a,ll7y.0l,oawncdon9c.e0)ntirnadtiicoantsedfonroalclletahredienpceubnadteinocnepoerfitodhse.deTgrhaedartesiuolntsraftoerotfhePrFeOmAainoinng oPHf.PFFrOoAmatthe25daCtaispogorelaetderovtehranth9e2tyheraeresp, Hwiltehvetlhse, mitowsatslieksetliymvaatleudetohfat2t3h5e yheyadrrso.lyFtriocmhatlhfe-life `mean value PFOA to be agnrdeaptreerctihsainon9o7fyPeaFrOs.A concentrations, it was estimated the hydrolytic half-life of 225 Bioaccumulation `HTohweeellsteutdail.es(h1a9v9e5)beeexnpocsoendduFcattehdeatdo mdeitnenromwisnetoth2e5pomtge/nltiAalPFfoOr bfioora1c3cudmauylsa.tiAofntoerf1A3PdFaOy.s edexppuorsautrieo,ntohevefrish15wdearyes.theAnftreerm1o9v2edanfdro3m12AhPoFurOs ceoxnptoasmuirneattoedAwPaFtOercaonndtaamnianlaytzeedd for water, the average concentrationofAPFO in fish issue was 44.7 and 46.7 jig/g wet weight (wiv), " 000018 trersapnescfteirvreeldyt.o Acltetahniswaptoeirn,t,tAhePcFoOnceanptpreaatrieodnotfo rAePacFhOstdeeacdryeasstaetde.toTw1e9.n9tyy-igf/oguwrwhoaunrsd abfytr96being rheoluartsivpeolsycto-enxsptoasnutreu,nitihletecsotncteenrtmriantatiioonnhaatd3d6e0crheoaursse.d tTohaeppcraolcxuilmaatteedlyBC8Fpgf/ogr AwPwFaOndwaresmLaSi.nedIt tsehcohunlidqubees,nohtiegdhttheasttqcuheesmtiicoanls hcoanvceenbtereantiroani,seadndabsohuotrtthtiesstsdtuurdaytiroeng.arding the analytical cionnacebnitoraactciuomnusloaftiPoFnOAs,tudSyaonfdca5r0pg(/CyLprriensupsecctairvpeiloy),fo2r82c8adrapywseirneaelxpoowsetdhrtooutgwhosystem m(KaudreuumpeofLahbyodrraotgoeryn,at2e00d1)c.astTohreoilchaenmdicmailxwedasinpraceeptaorneed. foTrheexppoursiutryeobfyPuFsOinAg waadsis1pe0r0s%a.nt PWaFtOeAr qwuaasliftyouwnadstomobneitloowr.edThdaeilcyartphreoxupgohsoeudttothe5duurga/tLiorne.suTlhteedbiinoaacBcCumFuolfatio3.n1 wphoitleenttihael coafrp exposed 0 50 ug/Lshowed a BCFof <5.1 -0.1. Vraspir from the (1979) conducted a 3M Decatur plant. study Two ltootsdoefte3r0mifniesihfwbelrueeguisleld.suOnfnieshlobtiwoaacsceumxuploasteed fluorochemicals toDecaturplant defefaldu,enats fwoer2l1asdatyhes caonndtrtohlefoitshhewreorerihvoemrowgaetneirzoendlyanfdora2n3aldyazyesd. fEorxpfolsuoerdocfihsehm,ibcoatlhs bliyviGnCg,and eTxLtCra,ctasndofGtCh/eMtSis.suesT.herNeowfelrueornoochdeemtieccatlasblweearmeoudenttescotfedAiPn FthOe irnivtehreweattheyrleaxcpetoasteedofristh,oluene oHfoswuebvjeerct, ilnutoerroprcehteamtiiocnaolfs wtheirsestnuotdychisarparcotbelreimzaetdiacnfdorthseevsepreaclifriecaspornost.ocoElffflorueenxtpcoosnucreenotfratthieons effisfhluweantsunsoetdfionuntdh.e sTthuedyr.e wAaddsitailosnoanlloy,iniftowramastinootn konnoawnnailyfstihsoefrethweasTeannyneosppsoertRuinvietrywfaotretrheor odfeptuhreattiwoenloveftdheeadfifsihshpriinotrhteoesfafclriufeincte-.exNpooseexdplgarnouapt.ionThweasstautdtyeamlpstoeddiadsntootwdhiaftfewreanstitahtee cause. between the bioaccumulationofthe test compound and the sorption onto the surfaceofthe fish. 2.2.6 Soil Adsorption d"Tihseilaldesdorwpattieorn-wdietsho5rpgtiBorniollfsAanPdFyOlowaamsssotiuldfioerd2i4n 2h5oumris astolauttieomnpseroaft1u4rCe-olfab1e6l-e1d9ACP.FOThien ssatunddyyrleopaomrtseodila(KWdeloshf109.271 8a)n.dTahKeoKcoocfv1a4luien,dhicoawteivnegrt,haits PquFeOstAiohnaasblheigdhuemotboiltihetylaicnkBroifll accurate information on the purityof the 14C-abeled test substance (Boyd 1993a,b). 1M0.3oodmeytearnsd bFeilelodw (t1h9e9s9o)ilcosunrdfuiccteedinscalmopsleipnrgoxainmditanyatloystiwsooffisraem-tprlaeisnitngakaerncafsrwoimtghraouhnisdtwoartyeorf | raaqnugeionugsffriolmm f1o1r6m1i0ng67f5o0amugu/seL.atPtehrefltuwoorosoictetsanmoaanteywyaesardseatefcetreidtsatusmeaaxtitmhuosmecsoitnecsenhtardatbieoenns discontinued. to relatively These shallow results suggest that groundwater where APFO may it persists. have the potential to migrate through soils 15 000019 2.3 Environmental Exposure 2.3.1 Discharge to Air For 1997, 3M estimated 1950 Ibs. of PFOA-compound (PFOA and related salts) stack releases at its Cottage Grove, MN location and another 4300 Ibs. from Cottage Grove incinerated offsite (3M, 2000). In 1998, 70% ofthe fluoride-containing wastes at 3M's Decatur location were incinerated off-site; incineration is now the primary disposal method for these materials (3M, 2000). For 1999, DuPont estimated stack releasesof24.000 Ibs. APFO at its Washington Works, WV location, plus another 16,000 Ibs. from Washington Works incinerated offsite (DuPont, 2000) "The above data may not accountforall ofthe sourcesofai releasesof PFOA. Other potential Sources addressed in the literature include thermolysis of fluoropolymers (Elis et al, 2001); the. low temperatureof sublimation (~135C) that would yield PFOA from drying, aka sintering, of fluoropolymer made with PFOA as a processing aid; the thermally refractive character of the C- bond (Napoli, et al, 1984; temperature incineration as aTamyelaonr,soeft dale,st1r9u9c0t;iTosnoanfgt,hiets amlo,le1c9u9l8e). that would require very high 2.3.2 Discharge to Water By analogy to PFOS, PFOA discharged to water may remain there, become adsorbed to particulate matter and sediment, and/or be assimilated by organisms. For 1999, 3M estimated PFOA-compound water releofa<3s0,e00s0 Ibs. at its Decatur AL location, and <15,000 Ibs. at iftoslClootwtianggeAGPrFoOvewMatNer location (3M releasesper Company, 2000a,b). location: Washington For 1999, DuPont estimated the Works WV, 55.000 Ibs; Parlin NJ, 300 Ibs. Spruance VA, 150 Ibs.; Chambers Works NJ, 9500 Ibs. (DuPont, 2000). DuPont measured an APFO concentration at is site Washington Works, WY site of 0.552 ug/l from Ohio a 1999 River. drinking water Modeled 1996 sAaPmFpOl-ecoobmtapionuenddfrroelmeaGsEes Pilnadstiiccasteidmamnedaivaetrealgye daonwnnuasltrPeFamOAon the concentrationof0.423 ug/l, with APFO concentrations likely to exceed 1 ug C-8/ about 50% of the time during the year, and likely 10 exceed 10 ug APFO/L about 2.2%ofthe time during the year. 23.3 Discharge to Land 3M reported that land treatmentofsludge from wastewater treatmenta their Decatur, AL location from the ended in Decatur mid-1998; site is now less than 500 lbs. transported to an were disposed offsite landfill to land sludge at that ste from 3M's in 1997. Cottage Sludge Grove, 3M.N900facIbisl.itoyfisAsPeFntO0shaundgiendluasntdrfiiallleldanodfnilslit(e3iMn C19o9m9paatntyh,ei2r0C00h4a.mbb).ersDuWPoornkts,(2N0J00f)aceilsittiy.mated DuPont estimated 2,600 Ibs. APFO transferred offsite to a hazardous waste landfill from their 1 000020 Washingion Works, WV facility. tPhrrieoer olpanedrfaitlilsonosperresautletdedbyinDgurPoounntd'-saWnadshsuirnfgatcoenwaWtoerrkcsonWceYntfraactiliiotyn.s oAfvAerPaFgOe msournfiatcoerweadtaetr concentrations for two landfills `maximum concentration of 33 were ug/L 1in39t2heupge/rLmiatntded18o.ut5faulgl/.L,Arveesrpeacgteivgerloy.undAwatthierrd landfill had caomncaexnitrmautmiognsrofuonrdtwwaotelrancdofinlclesntwrearteio2n53o7f ug/L and 8.83 ug/L, respectively. 15 ug/L (DuPont, 2000). A third landfill had dDruiPnoknitngawlasoterrepwoerltlesdofthtehfeoLlulobweicnkg PAuPblFiOc SceornvceincterDaitsitornisc,t,mdeoawsnusrterdeJaamnuoafrDyu2P0o0n0t,'sinWtahsrheiengton WLuobrekcskWPuVblsiicte:Se0r.v8icueg/DLi,st0r.i4ct4 (ugL/PLS,Da)nrde0p.or3t1e3duAgP/LFO(DucPonocnetn,tr2a00t0i)o.nsofAsof0.2Apupgbuisntd2r0in0k0i,ntghe water at DuPont's Washington Works facility, and 0.2, 0.5. and 0.1 ppb in the three LPSD wells (LPSD, 2000). 23.4 Environmental Monitoring e3fMf'lusenMtu,latin-dCilatnydfSitlludlyearcehpaotretsedamopnlePsFtOaAkencoinncesnitxrcaittiioenss(3fMr,om20w0a1tae)r., sFloudugre,ofsethdeimceintite,s POTW (Decatur, AL; Mobile, AL; Columbus, GA; Pensacola, FL) were "supply" cities that have mLaucniuef,acFtLu)riwnegreor"cinodnutsrtorli"aclituiseeos fthaftludooroncohtemhiacvaelss;igtniwfiocfantthfelcuiotrioecsh(eCmliecvaellaacntdi,viTtiNe;s. Port St. Across all wcti)tiresa.nPgOeTwWasefnfolnu-ednettceocntcteont2r4a4tipopnbs;rtahnegderdinfkrionmg0w.a0t4e0rtroa2n.g4e2wpapsb.noTn-hdeetPeOctTtWo 0s.l0u2d9gepp(bd;rythe l0a.n0d8f3i:lltlheeascehdatiemernatngreanwgaeswnaosn-ncoent-edeettetcot48t.o11.p7p5bpptbhe(sdurryfwacte);waatnedrtrhaenqgueiewtaswantoenr-dreatnegcetwtaos anbono-vdeetreacntgetso,0e.x0c9e7ptppfbo.r tThheeP"OcTonWtroflf"luceintitesansdamsplluedsgegefnienrdailnlgys ifnohraCblietveedltahned,lowwheirchenwdoerfethe intermediate in their ranges. "2T0h0e sMaumlpil-eCsittyakSetnufdryoamlsgoreiennclbuedaends,aampaprlkees,t pboarskkemtussacmlpel,icnogwofmiPlFk,OcAhircekseindumeuisnclet,otcahliocfkoevner ergagnsg,inbgreuapd,toho2t.3d5ognsg,/gc,atwfeisrhe, afonudngdrionutnwdobegerfou(n3dMb,ee2f00s1a3)m.pleMesa(scuornatrbollecqiutainest)i,titewsoofbrPeFadOA, samples (control and sample (supply city). supply cities), two apple samples (supply cities), and one green bean GsiaemspylerdepforrotmedtthheatU.PS.FOcAertwaaisn rEaurreolpyefaonuncdouinntrfiiessh,atnhde Nfiosrht-hcaPtaicnigfwiactOecrebainr,ds.andFiAsnhtawrecrteic lMoicdatwiaoynsa(toGlile,styh,e2B0a0l1t3i)c. anFdisMhe-dciattienrgrabniredansaSmepasl,esJawpearneesceolalnedctKedorferaonm ctohaesUt.sS(.G,iicnscy,lu2d0in0g16) Giesy reported on PFOA in mink and river otter livers from the U.S. (Giesy, 2001). PFOA was " 000021 wfio,unbdutinnaotffeowumnidnikn mliivnerks ffrroomm LMoausissaicahnuas,eStotustaht CaacroonlciennatarantdioIlninroainsg.e oPfF<O1A8 ctoonc1e0n8tnrga/tgi,ondsry.in fiver oter livers 36 nee, wet wt. from Washington and Oregon States were less than the quantification limit of tGhieisCyherseapporetaekdethBaatyPaFnOdAGuwlafsofnoMtedxeitcecotoefdtahtequUa.nS.tifcioaabslte(cGoinecseyn,tr2a0t0i1o)ns.in oysters collected in cGoilelseyctreedpofrrtoemd looncatthieoncsonucpesnttrreataimoansndofdoPwFnOstArienamsourffatcheew3atMerf,acsielditiymeanttDse,cactluarm,s,AaLnd(Gfiiesshy, 320M01f)a.cilOitfy thhaed tPhFreOeAdoswunrfsatcreewaamtweartceorncaenndtrsaetdiiomnesnstigsnaimfpilcainntglylogcraetaitoenrs,thtahne tthweotcwloosuepststtroetahme lsiotceasti(omnesaanlssoofha1d90s0eudgi/mLenatncdon1c0e2n4truagt/iLo,nsvs.sig0n.i0f0i8ca(netslty)garnedat0e.r0t2h8anuyt/hLe);uptshterteharneesidteosw(nwsettrewai.m bmoedaynsPF18O5A5 cuogngce,nt8r9a2tiuogn/fkgo,t2h3e8upusgtrkeavms.lo0c.a08t(ieosnt.w)asan1d1.07.0u9g(/ekstg)(.wetThwte.)a,vwehrialgee tfhiasth fwohrotlhee sdiogwnnifsitcranecaem. loTchaetiaovnewraagse1P06F.O4Augc/okngc;entthreastmiaolnlisnacmlpalmessaitzethperuepvesnttreedamdeltoecratmiionnatwioansof4.38 uggs that for the downstream location was 8.42 ugk. These differences were not significant. fHraonmsetnhe(2T0e0n2n)esrseepeorRtievdecronucpe-natnradtdioonwsnsotfrPeFamOoAfmtehaesouurtefadllfrformomsutrhfeacfeluwoartoecrhesmaimcpalles taken smaamnpulfianctgusriitnesgafbacoivleityanatd D2e0csaittuers AbeLlo(wthteh3eMoutffaaclilliltoycmateinotni,osnpeadceadboavtea).pprTohxeirmeatweelrye220mile cinotnecrevnaltsr.atiNonsooofnfPtFehOeA.samTphleesdtoawknesntfrreoammucposntcrenetarmatoifotnhsoe ffacPilFitOyAhawdermeeaosbusrearbvleed to increase at paopionitntdoawpnpsrtoxriemaamtewlays s3ix9m+4iles12b8elngo/wL.theTohuetfarlelp;ortthestaavteers atgheatPtFheOcAoncsoinscteenntcryatoifonthferPoFm OthAat ocronacdednittriaotniaolnssowuirtcheisnotfhePsFeOtAwoinretghieoanrsesausgsgaemsptlsetdh.e absenceofcither major environmental sinks uMposotdreyarmeapnordtdedowtnhsetcroenacemnotfraatisopinlslooffPfiFrOe-Afiginhtsiunrgffacoeamwattheatr cfornotmaisnterdeapmerlfolcuaotriionnastesdampled tshuerftahcrteaentws,eeikncpluedriinogd pPoFstO-Asp(ilMohoaddyPeFtOaAl,l2e0v0e2l)s.ofUps0.t0r0e8a.0m.0s3u3rfuagc/eL;wactoerrressapmopnldeisngtaken over dthoewsnesmteraesaumrelmeveenltssr.anged from 0.035-10.6 ug/L. Statistical significance was not evaluated for 2.4 Human Biomonitoring `"TThaeblhei2ghpersotvliedveeslssererpuomrtPeFdOtoAdlaetveelisn itnhebogtehneorcacluppaotpiuolnaatliocnoharoertssimainldarintothseogmeenoefrtalhepolpouwleasttion. dlievseclusssiendwboerlkoewr.s exposed to PFOA occupationally. The data are currently limited to those. is 000022 p3eMrflhuaosribneaetnedofcfoemripnoguvnodlsunstianrcyem1e9d7i6c.alSseurruvmeilPlFanOcAe tloevweolrskhearvseabtepelnanmtesatshuatrepdroadnudcereoprorutseed sbiinocmeon1i9t9o3.rinPgrifoorr tPoFtOhiAs thiamve,e obneleyntroetpalorotregdanfioc3rflpuloarnitnse: wCaosttmaegaesuGrreodv.e,TMhNe;reDseulctastuorf, AL and Aalnltowferthpe,pBlealngtisuomf.ferSeudrvseuirlvleainlcleanyceearins ailnlcolfutdehe1s9e9y3e,ar1s9.95T,h1e99179,9819d9a8t,aarnedpo2r0t0e0d,faorltthhoeuDgehcnaottur plant other csoanmspilstinogfaperriaonddsofmorsaalmlpolfteohfe epmlapnltosy.ees; however, volunteers participated in all of the sMienacen 1s9c9r3.um WPoFrOkeArsleavteltshehaCvoettiangcereGarsoevdeslpilagnhtl,ywahtebroethPtFhOeACoetxtpaogseuGrresovaereahnidghDoescta,thuarvpelatnhtes hsiegrhuemstPPFFOOAAlesveerluwmaslev6e.l4s.ppTmhe(rlaatnegset s=a0m.p1l--e 8w1a.s3 ipnpm1)9.97O(nOllyse7n4, eetmapll,oy1e9e9s8bp)a.rtTichiepamteedanin the 1997 surveillance. The otal numberofemployees working at the plant was not reported. AmtatnhesDeercuamtuPrFpOlaAntl,ev2e6l3owafsS01.078emppplmo.yeIetswpaasrthiicgihpearteidnimna2l0e0s0(n(O=ls2e1n5,)ctthaaln,f2e0m0a1la)e.s (Tnh=e45), s1e.r90umanldev1e.l2s3(2p.p3m4,prpems)p.ectFiivevley.empIlnoaydedeitsiohna,dmsaelreumprloedvuecltsigorneaetmeprlothyaenes5 hpapdm,hitghheeBrimoeloagnical LlairmgietstVianlcureeaessetaibnlsisehreudmbPyFthOeA3bMetEwxepeonsu1r9e98Guainddel2i0n00e.CoTmmhiettheigeh.estCellelveolpewraastoirnsahcahdetmhiecal otpeearmatwoarso5n.t0h6epSpcmot(crhagnagred5te- a9mp(p1m2)..70Optphme)r.joTbhceatmeegaornielsevdeildfnoorttheexhriebsittosfutchheamelamrbgeerisncroefasteh.e 3M reports 1999. that thi is due to increased PFOA production at the Decatur plant beginning in SdeecrruemasPedFOslAighltelvyelssinfcore t1h9e9A5n(tOwlesrenp,peltanalt,,ar2e00l1obw)e.r tPhaarntiactipDaetciaotnuirn omredCioctatlagseurGvreoivlel,anacnedathathvee A"TnhtewmeerapnplsacnrtuwmaPsFtOheAhilgevheelstwaitsha0.d8e4vperpmb,eeanndinth2e00hi0g(h2es5t8 sveorluunmteleervesloruetpoofrt3e4d0wwaosrk7e.r0s4).pp. As in the females (n D=ec4a9t,u0r.p0l7anptp,mm)a.leTsh(rnee=e2m0p9l)oyheaedshhigahderlemveelasngrseeartuerm PFOA than 5 levels ppm. (1.03 ppm) than 3M's Specialty fluorochemical rMeastcearricahls(BMuainludfiancgt2u3r6i)n,gcDoinvdiuscitoendLvaobolruanttoarriyesb,iowmhoenrietoermipnlgooyfe4e5s perform employees in 2p0p0m0) (Olsen, ct al. 2001c). The mean PFOA serum level was 0.106 ppm (range 0.008 ~ 0.668 SocecruupmatPioFnOalAelxepvoeslsurien ctoorPpForOaAtesshtoafufldanndotmahnaavgeeorcscuartraed3,MweprleanrtepinorStte.dPa(u3lM, MReNp,orwt,he1r9e99). Fmoeuarnoffor31theemspeleomypeleosyeheasd wsaesrum12.P5FpOpbA. levels greater than the detection limit of 10 ppb. The 1 000023 Data on PFOA levels in trends over time cannot the general population are be established. The mean very limited. serum PFOA They levels are are very recent lower in the so that general population than in workers exposed to PFOA. PCooomlpeadnybl.ooFedb.sa5m,pl1e9s99f;r3omMUC.oS.mpbalnooyd,bMaankys26i,ndi1c9a9t9)e.meTahnePhiFgOheAstlepvoeollseodf3satmopl1e7 rpeppbor(i3cdMwas 2le2veplpsb.areSagemnpelreaslwizearbelceotloletchteeUd.Si.n p1o9p9u8laatnidon19f9or9.sevHeorwaelvreera,sointsc:an1n)obtlboeodasdsounmoresd atrheatatuhensieq.ue gbraonukps tohraitgidnoaellsyncootnnteaccetsesdarfiolryporesfsliebcltetihnecUl.uSsi.onpoipnulthaetsitoundyas adewchloilnee,d 2t)o mpaarntiyciopfatteh,e3b)loonoldy a small number of samples have age, sex, or other demographic aicntfuoarlmlaytbieoennaraenaalvyaizleadblfeoroPnFtOhAe,doannodrs4.) no other data such as oItnhdeirvifdluualorbolcohoedmiscaamlpsluessinfgrohmig3h-dpirfefsesruenrtealgiequpidopcuhlraotmiaotnosgwraeprheyr/eeclecncttlryosapnraalyyzteadnfdoermPmFaOssA and sinpcelcutdreodmeatdruylt(bHlPoLodC/doEnSoMrsS,MaSn)e(ldOelrsleyn,poeptuall.,ati2o0n02p3a,rt2i0ci0p2abt,in2g0i0n2)a.proTshpeecsttiuvdeiesst'updayrtiinciSepaatnttlse, mWeAa.nsanwdercehislidmrielnarfraocrmo2ss3 asltlat3espoppaurltaictiipoantsin(g4.i6n papcblin4i.c2alpptrbia,l.anOdv4e.r9alplpbt,herePspFecOtAivegleyo)m.etTrhiec gfoeuonmde)traincdmtehaeinrsuappnedr 9b5o%untdoslewraenrcee cloimmiptasr(atbhleeparcorpoosrstiaolnlo3fstthuediepso.pulHaotwieovneerx,ptehceteudppteorbreanges wfohretthheerchtihlidsriesntahendreasduullttosfwgeeroegrmaupchhichdiigfhfeerretnhcaensfionr PthFeOeAldelrelvyelpsooprulsaotimoen.othIterisfnaocttocrl,eaIrt sahnodurld=.b7e5n)oatnedd that that PFOS PFOA and did PFOA were not meet the highly correlated criteria for a log nion ramlalthdriesetrsitbuudtiieosn(bra=se6d3o, nr = 70, the Sprhoappoirrtoi-oWniolfkstuebstjeicntsanwyiotfhtvhaelusetsud<ieLs.LOTQh;e haouwtheovresr,suogngleystgetohamtetitrimcamyebaensduweertoetrheepogrrteeadt.erThe detailsofeach study are provided below oBbltoaoidnesdamfprloemssfixroAmme6r4i5cUa.nS.ReaddulCtrobslsoobdlodoodnobrasnk(s33l2ocmaatleeds,in:313LofsemAanlgeesl)e,sa,gCeAs;20-69, were (MiOnlnseeanpoeltiasl/.S,t2.00P2a0u)l., MENac;hCbhalroloodttbea,nNkCw;asBorsetqoune,stMeAd;toPporrotlvaindde, OR, and Hagerstown, MD approximately 10 samples per c1a0c-hyedaornaogrewienrteeravgales, (g2e0n-d2e9r,,3a0n-d39l,oceattico)nf.or each sex. The only demographic factors known for `(T1he91ge0om5e2t.r3ipcpbm.eaMnalseesruhmadPsFiOgnAifliecvaenltlwyahsi4g.h6erpp(pb.< T.0h5e)rgaenogmeetwraisc <mleoawnerPFliOmiAt olfevqeulasnttihtaantion ffeumoarloecshe(m37i.c8alppcobncvse.nt3r2a.t1iopnpsb.). WAhgeenwstarsatniofitedanbyimgpeoorgtraanpthpircedliocctaotrioonf, atdhuelthisgehersutmgeometric mloewaenstfofrroPmFOPoArtwlaansd i(n3.t6hepspab,mprlaensgef:ro2m.1C~har1l6.o7t)t.e, NC The h(i6.g3hepsptb,inrdainvgied:ual2.v1al2u9e.w0a)s and the reported in Hagerstown (52.3 ppb). 20 200077 SSeearttulme PpaFrOtiAciplaevteilnsg wineraesrteupdoyrdteesdifgonre2d3t8o (e1x1a8mimnaelecsogannidti1v2e0fufnecmtailoens)ineladdeurlltys vaogleudnt6e5e-r9s6.in (Olsen etal., available on th2e00p2arbt)i.cipAagntes,."geMnodsetroafndthne puartmicoibfpayneetasrrwserreesuinddeenrcethien aSgeeaottfle$w5earnedthheadonlliyveddatina the Seattle area for over 50 years. T1h.4e ge1o6m.7etprpibc. mTehaenreofwaPsFOnoAsfiogrniafllicsaanmtp(lpe<s0w5a)s 4d.i2ffpeprebn(ce95in%gCe1o,me3t.9r.i-c4m.e5)a.nsThfeorrmaanlgeeswaansd females. PEOA in In simple lincar elderly men and rweogmreesns.ionInanbaoloytssetsr,apagaenawlayssesn,egtahteivmeelayno(pf<th0e5)95as%sotcoilaetreadncweitlhimit for PFOA highly was 9.7 ppb correlated (r w=it7h5)aninupthpiesrs9tu5dy%. confidence limit of 11.3 ppb. PFOS and PFOA were Ainfseactmipolnes,owfa5s98ancahliylzdreedn,foargseesr2u-m12PyFeOarAsloelvde,lpsa(rOtlisceinp,aettailn.g,i2n0a02sct)u.dy oTfhgersoaumppAlesstwreeprteococcal cdoildlneocttemdeient1t9h9e4c-r1it9e9r5iafforromaclhoigldnroernmraelsiddiisntgriibnut2i3onstbaatseesdaondn tthhee DSihsatpriicrtoo-fWCiollkutmesbti,a.ThePFOA aPuFtOhAo.rs Hsougwgeevsetr,thaotnlitymgaeoymbeetrdiuccmteoatnhsewgereraeterrepporrotpedo.rtiTohnoefgseuobmjeetcrtiscwmietahnvoafluePsF<OALLfoOrQalfoorf the had psairgtniicfiipcaannttslywa(ps<4..091)phpibg(he9r5g%eoCIm,et4r.i7c 5.1). mean sTehreumraPnFgeOAwalsev1e.ls9.t0ha5n6.1femppabl.es:Ma5l.e2 children ppb and 4n.e7gaptpibv,elryesapsescotciivaetleyd. wIinthsiPmFplOeAliinneabrotrhegmraelsessioannadnafleymsaelse,s.ageWhweans ssitgrantiiffiiceadntblyy a(gpe,< t0h5e) gAelotmheoturgihctmheeadnatoafwPeFreOAnotwarsepohritgehde,sat agtraagphei4ca(l5.p7repspebn)taatniodnloofwelsotgaPtFaOgeA 1l2ev(e3l.s5fpoprbe).ach state bthyegdeantdaearnldogoikveednstihmeillairmaictredosssatmhpelestsatiezse; fhoorwceavcehr,geintdserd/ilfofciacutlitontosuinbtgerropurept. thIensbeoodattsatrwaipthout caonanlfyisdeesn,ctehelimmietaonoff the 95% tolerance 11.0 ppb. PFOS and lPiFmiOt Afowr ePrFeOhAigwhlaysco1r0.r1elpaptebd with (r = an upper 95% .70) in this study. PFOA and PFHS (perfluorohexanesulfonate) were also correlated (r = 45). aTdhueltas,bocvhield3resnt,udainesd ianndiecladteerlsyimpiolpaurlagteioomn.etrHiocwmeevaenrs, aanndunraenxgpeesctoefdPfFiOndAinagmwoansgthseamlpevleeldof PweErHeSmauncdhMhi7g0her(Nin-mtehtehsyalmpplerefdlcuhoirlodorcetnantehsanulifnonthaemisdaomapcleetdaatd)ulitnscohirlderlend.erlyT.heIseissneortumclelaervels why this occurred, but it i probably du 0 a different exposure pattem in children. eIntaaln,ot2h0e0r1ds)t.udyT,hitrhteyP-oFnOeAdocnoonrcesnatmrpaltieosnwwearse aobntaaliynzeedd finrohmum1a6nmasleeras aanndd l1i5vefresmaamlpelseosve(rOlasnen a1v8e-rmaognethagpeerofiotdhefrmoamlethdeonInotresmwataison5a0l yIenasrtsitu(tSeDfo1r5.t6h,e rAadnvgaen5c-e6m9e)natndoftMheedaivceirnagee(aIgAeMo)f.thTehe hfeemmaolrerhdaogneor(sn w=as164o5ry5e2a%rs),(SmDot1o8r.5v,ehriacnlgee a1c3c-i7d4e)n.t T(hn e=c7auosre2so3f%)d,ehatehadwetrreauimnatr(ancr=an4iaolr 13%). brain tumor (n = 2 or 6%), drug overdose (n = 1 or 3%) and respiratory arrest (n = | or 2 000025 ol3in%vl)e.yr asBnaodmtphl| edssoenrcouormnscaionsntdterdvieobufrt1et0disgssoeuerfutwimesrsoeunel.yo.bStSaaiemnrpeludemsfsrwaoemmrpel2e3fsdroowzneeornresa;otb7ItadAionMneodrasnfdrcoosmnhti5rpimpbleudtoeffdrbollizoveoenrd;ttois3suMe qfuoarnatniatlaytsiivse.lySaasmspalyeesd wuesirnegeHxtPrLacCte-dEuSsMinSgMaSn ainond-epaviarliunagteedxtvrearcstuisonapnruonceexdturraectaenddcwuerrvee.. eExxttreancstiivoen mpartocreidxursep.ikeSsetruudimesvawleurees pfoerrfPoFrOmeAdrtaonegveadlufartoemt<heLprOeQci(s<io3n.0a)nd7a.c0cunrga/cmylo.fthe sAesrsuummiPnFgOtAhelmeviedlpowianst3v.a1luneg/bemtLwweietnhzaergoeoamnedtrLiOcQmesaenroufm 2v.a5lunegf/omrLs.amNpolelsiv<eLr.tOoQs,etrhuemmreaatinos were provided because more than 90% of the individual liver samples were <LOQ. 2 000026 Occupational Exposures (ppm) 1997 (n =74) 64 2000(n- 268) 128 1995 (n = 90) 146 lo1-813 Joos-n270 | uns notreported | * i . 099-130 | . | 19%Lin =35lots) Blood Banks (n = 18), 1998 3 low a om] . | 1 Te Jo] (n =645) i "Geometric mean and 95% confidence intervals were not included in the report. 000027 3.0 Human Health Hazards 3.1. Metabolism and Pharmacokinetics 3.11 Halfife in Humans wThhiecreh atroetalerorygalniimcitfeldudoraitnaeoinn tbhleoohdalsF-eirfuemowfaPsFOmAe.asuWrietdhinthoeneexcweoprtkieorn, onofaot1h9e8r0dasttaudwyerine aavnadilCaobtlteaugnetiGlrJouvnee32M00p0la(nUtsbewaest auln.,de1r9t8a0k).en,Ainhwalhfi-clihfessetruudmysoanmp2l7ersetwierreeesdfrraowmntehveeDreyc6atur smuobnmtihtsteodve(rBuarrSi-syeetaralp.,er2i0o0d0.;TBwuorrisnteetrailm,r2e0p0o2r)t.s dTehscerfiibrisngintheeriremsurletpsortthussugfagrehsatveedbmeeednian lsieferucmalhcaullfa-tliiofensowfePrFeOfAoor tfhe3424fdeamyasl,erwetiitrheaesrwanhgoe opfar1t0i9citpoat1ed30i8n dtahyiss.stTudhye(t6w5o4haingdhe1st30h8alf. days). t"hTeherraenwgeeorefsseevreuraml PliFmOitAatlieovnseltsomtehaiss ufriresdt;an2a)lsyseirsuminwclausdianng:alyz1)edthaeftleirmietaecdhdcaotlaleacvtaiiolnabpleeraiondd tweicthhnoinqlueyso;naendme3a)stuhreermeefnetrepnecre tmiamteerpiearlipodurotnydwifafserneontt ddeatyesrmuisinnegd snliiglhtalfytdeirftfheerefnitrsatn3alsyatimcpalles had and been analyzed. randomerror in An the effort was analytical made to method, iminnviomlivzien9geoxfpetrhiemeonrtiaglinearlro2r7, including subjects. systematic Serum smaemapsluersedweirnetrciopllliceactteedwiftrhomallcatcihmeofpotihnetssufbrjoemctesaocvhersu4bjteicmteapnearliyozdesdsipnanthneinsgam1e50andaalyyst,ical run. alTlhissyswtoeumaltdicalelrorworfiornhsetraetinsttiicnaltheevaalsusaatyioenqouaflltyheapfrfeecctiesdioenoacfhtshaemmpelaesuusreedmefonrthaalndliafsesure that determination pOlfatnht.e 9Threetaivreeersagienaclguedoedfitnhethriestainreaelsyswias,st6h1eryeewaresr,et7hemmaleeasnannudmb2efremoafleyse,arasllwforrokmedthaetDecatur tDheicsagtruorupwawsa2s72.77.9y.ear"sT,heanmdeathnePavFeOrAagveanluuembatersotufdymoinnitthisatiroentwiraeds0w.a7s21p8.p9.m (Arvaenrgaeg0e.B06M-I 1o.f84 ppm, SD = 0.64). "1Tehempmleoayneesehraudma hhalafl-lliiffeefvoralPuFe OthAatweaxsce4e.d3e7dye4a.r3sye(arrasn.geTh1.e502 --fe1m3a.l4e9syheaards,vaSlDue=so3f.533.)1. Only and p3.r9edyiecatrosr.soAfgsec,rBuMmIh,alnfu-lmibveesrionfymeualtrisvawroirakbleedroergryeesasrisonsianncaelyrseetsi.rement were not significant "PTFhiOsAa.nalHyoswiesvhears,astetveemrpatledistsouersesdhuocueledxbpeerniomteendt.alFierrsrto,rtihnetehfefedcettoefrmcionnattiinounedonfaonh-alf-life for `occocnutpaaitnieodnaclo,ncleonwt-rlaetvieolnsexopfolsuuorreoocnhetmhiehcaallslwihfiecihs uvnarkineodwnb.y afSaecctoonrdo,fb3e0c,autshee sduabtjaecctasn"nobtloboed pooled or averaged unless the serum concentration decay curve shows first-order kinetics u 000028 "Third, body. itis not Fourth, knownif there his estimate is amruecihntheirgachteirotnshabnetthwaeternepPoFrtOeAd iannldabotahneirmafllsu.oroFcifhtehm,iscyasltseminattihce errorofthe criteria analytical method could be as high as +/- 20% and still satisfy the data quality 3.1.2 Absorption Studies in Animals dAePrFmaOl iesxwpeolslurbe.sorIbn efdemfaollelorwatisn,gaonraalvearnadgeinohfal7a4t9ionugexopro3su7r%eo, fatnhdetofaluolreisnseerienxttheentadfmoilnlioswtienrged daoqsueeowuasssroleuctoivoenrecdonitnaitnheinugri2nemgwitPhFiOnA4).5(hOrpahfatuergPaFndOASindgoesre,(1b9y80s)t.omTahceh qiunatnutbiattyioonf2nomniioonfiacn fluorine br. recovered in the urine increased to 61% of the dose at hr, 76% at 24 hr, and 89% at 96 mAfatlearratssi,nagtlleeaosratl9d3o9s%eofotfh'e'Cto-tPalFOcAar(bomne-a1n4dwoases,a1b1s.o0rbmegd/katg)24inhsooulrusti(oGnibtosognraonupdsoJfohtnhsroene, 1979). The half-life for elimination oftotal carbon-14 from plasma was 4.8 days. Fo1l,l8oowri8n4g mAgP/FmO3)hceoandc-eonntlryatiinohnasloaftoiorngaenxopfolsuuorreiidnemianlteherabtlso(o6dhsrihdoawy,ed adadyoss/ewrkelfatoi2ronwshkiptowi0t,h tihnietitaelnltehveexlspoosfur1e08peprpiomd,intrhaetms etarenatoerdgaatno8f4lumogr/idme3 b(lKoeondnleedveylsctwaelr,e 119386)p.pm,Im4m7edpipamt,elayndaft1e0r8 ppm in the 1, 8, and 84 mg/m3 dose groups. dSousbecsh)rowniitch dcietrhmearl0,A2P0F, O20t0r,eoartm2e0n0t0inmrga/tksganrdesrulatbebditinse(1l0eavpaptleidcabtliooonds,or5gdaonsoefsl,uo2rrineetldeavyesl,s 5 which increased in a dose-related manner (Kennedy, 1985). aOb'sMoarlpltieoynaonfdPEFbbOiAnsin(1m9a8l1e)acnodndfuecmtaeldeararbbaintgse. fPinFdOinAg (st1u0d0ymwhgic.h i1n0d0ic0amtegs/ksgi,gnaifnidca2n0t0d0ermal wmhei/ckhs wienrsealtihneenslfuitrtreyd)wwiatsh aapppllaisetdictocoalplaprr,oxainmdattheelytr4u0nk%woafsthwerasphpaevdedwitrtuhnikmopfetrhveioaunsimpallasst,ic sinhetehtein2g0.00Thmeg/ekxgpogsruoruep,pe7r5io%d (w3a4s)2i4n htrh,e1d0a0y0sm/gw/ekekg ogvreorup14andday0s.% (M0o/r4t)aliinttyhewa1s001m0g0/%k(g44) rou. Aliqtu-ibdutfyolramumlmaotinoinuwmassalatpopflipeedrdfelrumoarloolcyttaonoraatbebiitns t(hJeohfnosromn,of19t9r5eba)t.ed fabric Liver and as a samples were athneaslaymzeedaast 2c8ondtraoylsvpaolsutesd.osAellfotrottaoltaolrogragnaincicvaflluueosriwnee.reTbheelorewsutlhtespfrracotmictarleaqtueadntaintiamtailosn wliemriet cSoelrluecmteldevaetlsdawyer1eaanldso2baefleorwadtmheinpirsatcrtaitcialonquoafnttihetamtiixontulriemiotrs tohftehtereaatneadlyfsaibrsicf.or sFarmopmletshe phhaavrembaeceonkidneetteicctesdtuidnyth(iJsohstnusdoyn., 1995a),it would be unlikely that any extentofabsorption could 2 000029 3.13 Distribution Studies in Animals oPfFtOheAbdoidsyt.ribIuttdesoepsrinmoatriplayrttiotitohnetloivtehre,lpilpaisdmfar,acatnidonkoirdnaedyi,poasnedttiossauel,esbsuetrdeoxetesntb,inodthteor tissues macromolecules in the tissues. There is evidenceofenterohepatic circulationof the compound. tSoexricuimtyasntdudliyve(rGrciofnfciethntarnadtiLoonsngo,f1P9F80O).A wIenrmeodnekteeyrsmiantetdhein3 rmhge/sukse/mdoanykdeoysse,inmea9n0 sdearyuomral PFOA was 30 females 7 ppm ppm inmales and in liver samples. 58 At p1p0 mmgi/nkfge/mdaaleysd.osAes,tmhealseammeondkoseey,smhaaldesa had 3 mean ppm and serum PFOA of 58 respectively, pmpeamsaunrdedfeamsaolregsan7i5cpfplmu.oridLei.ver levels were 9 and 10 ppm for males and females, fOoplhlaouwigngantdhSeiandgmeirni(s1t9r8a0ti)onmeoafsPurFeOdAiobnyicstfloumoarcihdeianntudbattotiaolnf(l2uomrlionefiannthaequseeoruusmosfolfuetmioanle rats ncoonntiaoinniicnfgl2uomrignePlFeOveAl).13.S6eprupmmfarnodmvriarttsu4a.ll5yharllaofftehritshewaadsmibnoiusntdrattoiocnoomfpoPnFeOnAtshiandtahe scrum aflnudorniodteulletvrealfirlteemraaiblnee.d Dveesrpyitleowth(e0.l0a3rgpepimn)c.reaPsreioirntnooinnitounbiactifolnuoorfinPeFiOnAt,hethseeriuomn,ictahendjonic lneovneiloninicthfelusoerrinuemldeevcerlesaisnesdetroum11.w2erpep0m.0at32 ahnr,d00..3057ppppmm,atre2s4pehcrt,ivaenlyd.0.T08heppnomniaton9i6c hfrl.uoTrihnee authors cleared conclude from the that PFOA serum. is rapidly absorbed from the gastrointestinal tract and rapidly s`Ttwoemnatcyh-fionutrubhaotuirons),aftfeermoarlaelraadtsmihnaidstaramteioannosfeAruPmFnOon(i2omnigc AflPuForOinien l2evmeiloafqu0e.3o5usppsoml,utwihoinlbey male rats had was bound to a a smiemainlarseerxtuemntnoinnitohneicplfalsumoraoinfemleavleel oafnd44f.e0mpalpemr(atHsan(h9i7j.a5rv%ibeotuanld,)1983), APFO tIhnemcaolneceanntdrafteimoanloefa't*sCa-dPmFiOnAi-sdteerriedve'dCr-adPiFoaOcAtivinitpyrionpytlheenbelogolydcwola/swahtiegrhe(r9.a4nudmeollikmign,atiepd), mmaolree rsaltso,wltyheinlimvearlehsad(tt1h/e2h=i9gdhaeysst,PmFaOleAscvons4cenhrt,rafteimoanle(s2,1V%aonfddeonsHeeautv2elhre,ta2l%,o1f99d1o).se Iant t2h8e days) hear, tfeosltliso,wefda,bayntdhegapsltarsomcaneamniduskimdunsecyl.e. Far In lower PFOA females a2 hcronpcoesnttrdaotsieo,ntshweehrieghfesotund in the. tchoantceonrtderra.tioTnhseofavPerFaOgAe (w1e/2refofreoluinmdininattihoenploafsPmFaOfAollforwoemdtbhye ltihveerkiidnnmeya,lelirvaetrsawnadsov11ardiaeyssin e`lciommipnaarteidon(0waansaavpeprraogxeimoaft9eldyay3shrf.or extrahepatic tissues. In females, the average {12 for tissue AVpapnrdoexnimHaetuevleyl 1et1%alo. f(1t9h9e1)cuimnuvleasttiigvaeteddosteheodfisp"o"sCi-tPiFoOnAoifnPfuFsOedA(i0n.0p8erufmuosle/dmmianlex 4ra8t mliivne,r 3.84 umol total) was extracted by the liver during a first pass. In addition, the cumulative percent of 2 ee 000030 PFOA (19%) extracted indicating by the liver at that first-pass 2hempianti(c3u3p%t)akweaosfsPuFbsOtAantmiaalylbyegrseaattuerrabtlhea.n that seen fier 48 min dYiisntreinbuettioaln. a(n1d99a0c)cusmtuuldaiteidotnhoefdiPffFeOreAncaeftbeertawseiennglmeaalnedasnudbfchermoanliecWaidsmtianrisrtartastiinont.heThe single addomsienoifstPerFeOdAin(t5r0ampge/riktgonineaplrtlo0ypy1l0enweeegklyoclodl-rwaattse(r2m0imxatluere,,201:1f,emvaoll.e).0.2S5ubmclh/r1o0n0igc) was. madIm/i1n0i0sgt)rattoionnewoflyPwFeOaAnecdonrsaitsst(e1do8 fma3l,e,101,8afnedma3l0e)m.g/Akfgi/edratyhebysignaglveagdeos(ei,ns0a.9m%pleNsaCwle,re0.5 acdomlilneicstterdaftoironP,FaOnAd idnettehermsiunbacthiroonni1c2,t2es4t-o1n68th(eat2284thhrdaiyn.terTvhales)s,e2r4u4m wanads3c3ol6lehcotuerdsbayftcearrtdhieac sppulnecetnu,reo;vaarfye,rtdesetciasp,iatnadtiaodnitphoesebrtaiisnsuaenwdeartenceoclrloepcstyedsaanmdplfersozferno.mTthhee lbiivoelro,gkiicadlnehya,lfl-ulnigf,e of PPEFOOAA cinontcheentsreartuimonanindtthiesssueemsiwloagsardietthemrimcinpelodt.frIonmtthheesliinngelaer-rdeolsaetisotnusdhyi,pcboentcewneternattiiomneoafnd hPoFuOrsAafinletrhteheseardumminaisntdrattisisouneosfwaPsFOhiAghaebrouint m1a0le%softhtahnefdeomsaelewsasatfaolluntdimien ptehreiosdes.rumTwoeflve rfeemmaaliense,dwihnetrheeassearbuomu.t 40% was in In females, the scrumofmales. PFOA concentration Afier in the 14 days serum, about 3.5%ofthe dose liver, and kidney occurred ninina dtihsecfoenmtailneusouasndfamsahiloens,, irnedsipceacttiinvgeldyi.stiInnctthpehafseemsa.lesT,haehhaallf--liiffeeoifn 6t0hehsrewrausm ewsatsim2a4teadndin1t0h5e rleivtearindeudribnygtthheelfiivresrt,witeewka.s nIontthfeoumnadleisn,tthheelhiaplifd-lfirfaectiinonl.iveIrnwtahse k2i1d0nehyr., tAhlethhaolufglihfePFwaOsA1w4a5shr ianndfe1m3a0lehsrainndfemmaallse,s raensdpemcatlievse,lyr.esPpeFctOiAvelwya.s aInlstohefosupnidcenin, btrhaeihnatlifs-siuef.e wPaFsO7A3 hwraasnndot170 hr sdiegtneicftiacbalnetliyn haidgihpeorsePFtiOssAue.conIncetnhterastuibocnhsroinnitchestsuedryu,msaamnpdletissstuaekseonfomnalthees2v8etrhsudsayfeimnadliecsatiendall dtihsrtereidbuotseedlienvetlhs.e sAefrtuemrosfubractsh.roHniigahcs,cowneclelnatsrastiinognlseo-fdoPseFOadAmiwniesrteraatlisoon,foPuFndOAinwtaheslmiavin,ly mkiadlneesy,exahnibditled,uorfesnmpaeclgteisvealyn,dsfeermaulmesc.oncAetnttrhaethiiognhs doofs1e3.l9ev2ealn(d30$1m.g6/5kgu/gd/amyl),,lfiveemrales and ccoonncceennttrraattiioonnssooff 61..6549 aanndd 44.91.077ugugg/,g,luknigdnceoyncceonntcreanttiroantsioonsfo0f.751a2.n5d42a3n.d7139u.g8/1g,uagn/gd,bsrpalienen 7co.n2c2eungt/rga.tioAnssoigfn0if.i0c4a4ntapnodsi0t.i7v1e0courgr/eg.latTiohneeoxviasrteydcboenttawieneendth1e.1a6dumgi/ngisatnedretdhedotsesetiasncdontthaeined s`icgonnicfeinctarnatticoonrroeflaPtFioOnAbeinttwheenlitvheer,akdimdinneiys.tesrpeldeedno,saenadnldutnhgeocfofnecmeanltersa.tiOonnotfhPe FcoOnAtrawrays,. no oorbgsaenrsvetdhainn 3th0emmga/lkegs/,daasy.10Hmogw/ekvge/rd,ayinpmraoldeusc,etdhehicgohnecrenPtFraOtAioncoinncetnhtersaptlieoenns,itnestthise,saenrdumbraanind correlated positively with the conceniration in the serum. pVlaansdmea,n aHneduvteelsteest oalf. r(a1ts9.92C)adrebmoon-n1s4t-rlaatbeedltehdatPPFFOOAAwcaosvaaldemnitnliystbeirnedds ttoospirxot-ewieneskionltdhemalliveer, Harlan Sprague-Dawley rats in propylene glycoliwater (1:1, viv; 1 ml/kg) at a dose of 9.4 2 000031 ee cuomvoall/ekngt,lyipb.ouNnod tPiFmOeA--ddeeprenidveendt"cChawnegrees ifnoueintdheatr a2bhsol1utae o4nrdreadlyastivpeoscto-ntcreenattrmaentti.onsCoofvalently bcoonucnedntPraFtOioAnowfascorveaplreenstelnytebdobuyn0d.P1FtO0 A w0.a3%sofstighneifitciasnstuley"hCigchoenrteint.theTphleaasbmsaoltuhtaen in the liver. "bTohuendt.esteIsn htaedstst,hecohviaglheenstt brienladtiinvge ocfon"ce"nCt-rPaFtiOoAn1o0faPcFoOnAs-tdaentricvonecdenrtardiaotaicotniovfityalcbouvamliennt(l8y.uM) PinFcOreAasteod hienmaloignleoabrinfawsahsiodnimwiitnhisihnecdrebaysitnhge PadFdOitAiocnoonfcenctyrsatteiionne. buTthneotcomveatlheinotnibnien,disnugggoefsting that protein sulfiydryl groups may be involved. dHuarnihinjgasruvbicehtraol.ni(c1a9d8m7i)nicsotrmaptaiorne.d tPhFe OdiAspwosaistiaodnmoifniPstFeOreAdbbeytwgeaevnagmeatloe4a8ndnefwelmya-lweeWainsetdar rats wanaismacollsleatct0e.d3o,n10t,hean7dth3a0nmdg2/8ktgh d(ianyo0f.9t%heNasCtlu,dy0.(d5imsic/u1s0s0egd)bfeolrow2)8.coAntsetchueteinvdeodfayts.he sUtruidnye, tbhleoopdlawsamsaocoflltehcetmedalveiaractasrdwiearcepsuingcntiufriec.antAltyehaicghhedrotsheanletvehlo,setohfetmheeanfePmFalOeAatcso.nceTnhteramteioanns in 2p4l.a7smuag/PmFlO(10 Amgc/onkcgen)t,raatniodn5s3f.o4r+-th1e1.m2alueg/rmalts(w3e0rmeg4/8kg.)6.+-2T6h.e5 cuogr/rmelsp(odnodsiendgatfi3gumrge/skfgo)r,f8e3m.al1e4 aPtFsOwAerceon2c.e4n3t+r-a5t.io9n6suign/mtlh,e p1l1.a3s4m-a8.of5t9hueg/mmall,eaanndim9a.l0s6+s-u8g.g8e0sutegd/mtlhaitntthheebsiandmienogrsdietre.s oTfhePFOA mcoanycebntercaotmieonssawtuerraetesdigantiftihceacnhtlryonhiicghdeairliyndtohseemlaelveelroatfs,3n0omgsi/gkngi.ficAalntthhoiusgthoptahtehoplloagiscmaal PFOA differences between the sexes were observed at necropsy. "aTdhmeindiisstproastiitoinonaosfwePlFlOaAs iwnaisntsatcutdmiaedleisn amnadlefeWmiaslteasr(rYatlsinaefnteertcaals,tra1t9i89o)n.anTdheestmraaldieolrats (N=20) `woepreeratceadstarnatded10atitnhteacatgmeaolfe2s8wedraeysadamnidniasftieerre5dweesetrkasdiwoelrvealuesreadteisnutbhceutteasntse.ouHsallyfo50f0thueg/kg epuvnecrtyursee.coAntdtdhaeyednudroifntghe14tdesaty(s9behfro)r,etthheectoenstc.enBtlroaotidosnaomfplPeFsOwAerien ctohlelsecetreudmboyfcianrtdacitacmales wstaastisctoincsalildyesriagbnliyfihciagnhtedri(f1fe7r-e4n0cetiimnest)hethsaenruinmtchoencseenrturmaotifoontshbeertgwreoeunpst.heTohtehreer gwraosupnso.. PFOA was similarly bound to the proteins in the serum of males and females. Jeloihmnisnoantieotnalo.f(A1P9F84O).inSvienscteigAatPeFdOtheexeifsftescatsoafnfaenediionngacthpohlyessitoylroagmiicnpeHt,o irtawtsoounldthbeefeexcpalected to a`cdommipnliesxtewrietdhacmhmoloensityurmam'i"nCe-.perTfelnuomraolocetCahnoaartlees(2R.i1vemrg/CmDl)radtiss(s1ol2vweedeikns0.ol9d%, 3N0a0C-l34as2 ag)siwnegrlee cihnotlraevsetnyoruasmidnoesein(2femedl.ratU,rianveeraangdefAecPeFsOsadmopslees13wemrge/kcgo)l.lecFtievdeartatisntweervraelsgifvoern144 %days, at wthheicmheatnimpeetrhceenatnaigmeaolfs PweFrOeAsadcorsifeiceeldimainndatleidveirnstahmepfleecsesweorfcehcoollelsecttyerda.miAnte t1r4edataeyds rpaotsst(d4o3s.e2,-5E.x5c)rewtaison9.i8n-ufroilndetwheasme4a1n%pfeorrtrceaetendotrfaadtsogsaeende6li7m%inaftoredunitnrfeeacteesd braytsu.ntCraerabteodn-r1at4sp(r4e.s4e+-n1t.i0n),the 2 000032 ee relsivpeercrteipvreelsyen(t4e%d a1n2.d1+8-%2.o1fduogseeq,/greasnpedct2i2v.e3ly+)-.6.2Inugpleaqsfmga,intthreelaetveedlasnwderunetSre.a1t+e-d1.r7atus,g cq/ml awnedre141..78+---60..87 ug ug cq/ml cq/ml ianndtr4e.a2t+e-d2a.n4duugnterqe/amtledinrattrs,atreedspaecntdivuenltyr.eaItnedrerdatb,lroeosdpeccetlilvse,ltyh.e levels The htriegahtcmoenncteennthraatnicoens offec"a"l Ce-liAmPiFnOatiinonloivfercaairb2owne-1e4ksneaafrtlery d1o0s-ifnogldasnudggtehestfsactthatthatthecrheolisestyramine enterohepatic circulation of PFOA. "bTeheendriesppoosritteido(noJofhntshoent,et1r9a9b5u4t)y.! aImndmiovnidiuuaml rsaabltboiftspewrefrleuogriovoecntianntoriacveancoiudsindofseemsalate0r,ab4b,it1s6,haansd 2le4vemlad/ikeed awnitdhaipnp5eamriendutneosmioafdlostihnrgou)g.hoSuetrtuhme sstaumdpyle(sthweearneimaanlaltyrzeeatdefdoartttohteal4o0rgmagn/ikcgflduoosreine 216.,4a.n6d.284,mg1/2,kg24d,oasnedd4r8abhbiotusrsweproset1d.o2s5e.ppAmt,24.h0r9s,pspemr,um14o.r9gpanpimc,falnudor4in1e.0lepvpemls, irnestpheec0t,iv4e,ly. `4T8hehrr.e wTahseabiroalpoigdicdaelcrheaalfs-eliifneswearsumonletvheeloorfdetortaol f4orghaonurisc.flTuhoreinteotwalitohrgtainmiec, nfolnuo-rdienteecitnawbhloelaet liver were a2t04u8gh,r4p3osutg,d6o6seugf,oracnodnt5r4oluga.nimals, 4 mg/kg, 16 mg/kg, and 24 mg/kg intravenous doses 3.1.4 Metabolism Studies in Animals VPaFnOdAen(9H.e4uuvmeoll/ektagl.. i(.p1.)9.91P)oionlveedstdiaglatyedurtihnee msaemtpalbeosli(s0m-o4fdaPyFsOpAostintrreaatstmaednmti)niasntderbeidle"Ce`xctormapcotusnadn.alTyizsesduebsy wHePreLCtackoenntfarinoemdraassitnrgelaeterdad4i,oa1c4t,iavnedpe2a8kdealyustipnrgeviidoeunstilcyalwliythto"tChe-pPaFrOenAt to dpreetseernmtinien rtahteipsrseuseesn;cneoofPFPOFAO-Ac-ocnotnatianiinnignghylbirpiiddcloinpjiudgsawteesr.e dOentelcytetdh.e pFalrueonrtidceomcopnocuenntdrawtaisons dinocpslansomtaunadnedrugroindeefbleufoorrienaatnidonaf.ter PFOA treatment were unchanged, indicating that PFOA OfoplhlaouwignagnodraSliandgmienris(t1r98a0t)ioanlosoffPoFunOdAnotocfheamnagleeirnatf.onilcifnleuonricdteall.ev(e1l98i9n)thfeosunedrunmooerviurdiennece of apnhdasfeemIlamleetraatbs.olism of PFOA following a single intraperitoneal PFOA dose (50 mg/kg) in male: 3.15 Elimination Studies in Animals "bTohtehumraijnoerisrtouhteemsaojfeoxrcrroeutticoonfoefxcPrFetOiAonionfmPaFleOAratisn(tVhaenfdeemnalHeeuravte,lwheitlael,th1e99u1r)i.ne aMnadlefeacneds are aftesmaelleimriatnsatweedrePFaOdAm-indiesrtievreedd "C-PFOA in radioactivity rparpoipdylyleinnegtlheycuorlinweawtietrh (99.41%uomfolthkeg,doispe)b.eiFnegmale eNxecgrleitgeidblienrtahdeiofaicrsttiv2i4tybrw,awshirleecomvaelreedraitnstehxecrfeetceedsoofnlfyem6a%loefratths.e dIonsmeailnetrhaattsidmureinpgertiohde.28-day collection period the cumulative excretion of PFOA-derived '"C in urine and feces was 36.4% 2 000033 ee harn,dw3h5il.e1%t,heremsaplecetirvaeslyr.etaTihneedfe3m0a%leofrtaht ereatadimniendislteessretdhadnos1e0a%ftoeft2h8edaadyms.iniTshteerwehdodloes.ebaofdtyer 24 leilgiamtiendatriaotsn ihnajlef-cltiefde in i.p. fweimtahlc"sCw-aPsFOleAs,s tahpapnroonxeimdaayt,elanyd0.i3n% males ofthe iPtFwOaAs-d1e5rdiavyse.d In renal. radioactivity bwialsiaeryxcerxectreedtiionnothfePbFilOe Aaftweas6 ohbrs(eVravneddewnhHeenuvtheelkeitadln.eys19w91e)r.e lNigoatsede.x-related difference in the cJaorhbnosnon14anbdeGtiwbeseonnm(a1l9e8a0n)dobfseemravledraatseaxftdiefarfesrienngclee iinv edxotseent(amneadnradtoeosef: efxecmraeltei,on1o6f.t7omtga/lkg: Hmoaulres1w3h.i1lmega/tkteh)e osfam"eC-tiPmFeOpAe.riFodemmaallee rraattsseexxccrreetteeddeosnsleynt2ia0lplyeraclelontfotfhethdeodsoesvei;amuarlienerants24 ienxctriestseueds8o3f%fevmiaaluerirantesaantd175.d4a%ysvipaosftecdeosseb;ym3a6ledaryatssphoasdt 2do.s8e.%ofNothreaddioosaectiinviltiyvewraasndde1te.c1t%edin plasma at 36 days post dose with lower levels (= 0.5%of the dose) in other organs, AOnpihmaaulgs awnedigShiinngegrap(1p9r8o0x)imiantveelsyti2g5at0edg twheermeeatdambionliisctfearteedobfyPsFtOoAmacinh fienmtaulbeatHioonlt2zmmlanofraatns aaqnudeporuosvisdoeludtiraotncchonotwaiannidngta2pmwagtePrFfOoAr.4.5T,h8e.a2n4i,moarls52w.e5rher.thIenn apdldaicteidoni,nfmoeutrarbaotsliwsemrecapgleasced hirn. meAttatbhoeliesnmdocfagtehseaenxdpefreidmeanltoalw pfelruiooriddteh(e<u0r.i5nep,pfme)cedsieatnadnsdedriusmtilwleerdewactolelrefcoteda. pWeiritohdinof49.56 rhreacfotveerrePdFiOnAthedousrei,nea.n Tavheeraqugaenotift7y4o9fungonoiro3ni7c%folfuotrhienefrlueocroivneeriendtihnetahdemuirniinseteirnecdredaosseed twoas t6h1e%PoFfOtAheddoosseedaatnimharl,s7w6a%santot24sihgrn,iafincdan8t9ly%diatff9e6rehnrt. thUarnintahartyoeftxchreetcioonntoroflioanniicmafllsu.oriFdeecailn "eTxhcereutriionneoffronomnuinodnoicsefdluaonriimnealwsacso4nt.a5i%noefd ntohedaedtmeicntaibslteerneodnidoonsiecaftl5u2or.i5neh.r and 14.3% a1 9 hr. aTnhdesuirxinfaermyaleexcHroetlitosnmoafnAraPtFsOweirneraadtsmiwnaisstienrveedst2igmagtedAbPyFOHanilni2jamriviaqetuael.ou(s1s98o2l)u.tioFnobuyr male asntiommaalcsh wienrtuebatthieonn.plaSceevdenin fmeemtaalbeorlaitssmwecraegeasdmwiintihsrtaetrcedho2wmalnddisttaipllweadtewra.terUraisnceowntarsolcso.llTehcteed aunnidiltoatnailmualosriwneerecosnatcerinfticoefdsactr2u4nhanbdyucrairndeiawcaspudnectteurrme.ineSde,raunmdwnaosnicoolnliecctfeldu.orilnoeniwcafsluoride acanlecsutlhaetteidzeadswtihtehdiIfnafcetrienn.ce.ThFeofrecmloeraarlanacretesrtyuwdiaess coafnAnuPlFaOtedanfdoricnuolnitni,ntuhoeusratisnfwuesrioen of 5% mannitol in "The urinary isotonic bladder wsaalsinaelsaondcatnhneulfaetmeodrfaorarstereiraylwcaosllceacntinounlsatoefduroirne.draIwnitrnagvbelnoouosd psraimmpilensg. idroisteiasteod finu5l.i2-n5.(6mmegth[o1x-y1-43CH],a5mmaoctni1u14m upCerifllmuo)rowaecrteangoiavteen (tsopcaaccth0.a5niumCail/.mgT)heanrdad8i.o8laubgled aidnduliitnioannald 0A.P42F:O0.6in35m%g/mhann"iCt-olAPinFiOsoatnodni9c.6saulgin/ehrwtarsittiahteend iinnufluisnedwaatsaianftueseodfdu0r.2i1nmgl/tmhein. An pexrpoebreinmeecnitds.waWshaedmnintihsetuerriende (a6n5d-6s8ermugm/kcso,lliepc)tiaonnds afdodritthieocnlaelacrlaenacreanscteudteystwsewreerceomppelrfeotrem,ed. 0 000034 ee 2In0%th)eacnudmuulnaltaibveeleedxcArPetFioOn(s8t0u-d9y0,%r)a.ts FwievreepdeorsceedntivmawnintihtaolmiixntiusroetoonfircadsailoilnaebewlaesdiAnfPuFsOed(a1t0a- prartoebeonfeci0.d081wamsimasisnesasnedd ubryinaedmsipneicsitemreinnsgw6e5r-e68comlgle/cktgedipovaerle3a0s-tm3i0nmiinnterpvrailosr.toThtheeeffect of eadxmcirneitsetdra7t6i+o-n2o.f7%APoFfOt.he Tdwoesentiyn-tfhoeururhionuerasndaftheardoraalmeadamninsiesrturmatinoonnioofniAcPfFlOu,orifneemalleveelraotsfhad n0.o3n5i+o-n0i.c11flupoprmi,newlheivleleomfa4l4e.r0a+t-s1h.a7dpepxmc.retAePdFoOnlywa9s.2b+o-u3n.d5%toofatshiemidloarseexatnednthiandtahempelaansmsaeroufm dmiaflfeeraenndcesfebmeatlweereants t(h9e7s.e5x+e-s0i.n25ra%ts.bouTnhd)e. APTFheOcclleeaarraannccee sitnudfieemsadleemroansstwraastesdevmearjaolrtimes gacrteiavteerstcehraenttihoenoifnuolrignacnliecaraacnicdes., rAeddmuicneidstArPaFtOi/oinonuflpirnobcelneeacriandc,ewrhaiticohisntrfoenmgallyesinfhriboimts1t4.h5e rteonal 0.46. APFO reduced from c4l.e6ar1a0n0c.e1w3ausg/rmeidnu/c1e0d0gf.romIn 5.8 t0 mal 0.11 ras, ml/min/100g. however, the Net APFO excretion was APFO/inulin clearance ratio calnedartahencneetwaesxc0r.e1ti7omnio/fmiAnP/1F0O0gw,eArePFvOi/ritunaullliynuncalfefaercatnecdebryatiporowbaesnc0e.i2d2., aInndthneetmAalPeFs,OAePxcFrOetion wdoasse,0.w1h7ilueg/mmailne/smge.xcrIentetdheoncluymu7l.a8ti%oveftexhceredtoisoenosvteudrieas7,-fhermpaelreiorda.ts Perxocbreetneedci7d6a%domifnitshteraAtPioFnO pmroodbiefnieecditdhemacrukmeudllatyirveedeuxccerdetAiPonFcOurelviemfionratmiaolnestoo1n1ly.8s%l.ighTtlhye. aHutohwoervsecro,nicnlufdeemdaltehsat the bfoedmya.leTrhaitspossescersetsoersyamneacchtaivneissemeriestloarcykimnegcohranisirsemlawthivieclhy rianpaicdtliyveeilnimmianlaetersatAsPaFndOafcrcoomuntthse for the greater toxicityof APEO in male rats. WHainshtiajrarravtisedturali.ng(1s9u8b7c)hrcoonmipcarademdintihsetruartiinoanr.y eAliPmFinOatwiaosn aodfmPinFiOsAterbeedtwbeyengamvaalgee atond48fenmeawlleywUreianneedwaasnicmoalllescatted0,on3,t1h0e,7atnhda3n0d m28gt/hkgda(yino0f.t9he%sNtauCdyl., 0A.t5mtlhe/1e0n0dgo)ffotrhe28stcuodny,sebcluotoidvewadasys. wcoelrleecctoeldlevcitaedcafrdrioamctphuencctounrter.olsAatnndecfrroopmsyt,hetigsrsouuepspreeccciimveinnsg 3fo0rmhgi/stkogp/adtahyolPogFiOcA.exaOminnatthieon ssiegvneinftihcadnatlyyofgrtehaeterstuurdiynapreyriPodF,OtAheefxecmreatlieonrattshainn tthhee mlaowleess!(d3o.s1e2+g-r0o.u3p0 (v3s m1g./5k0g+/-0d.a5y7) exhibited emx2c4rhetre/dkgsi)g.nifUinclanitkleytlheessfPemFaOleArtathsa,notnhetihred7atilhyddaoysoefotfhPe FsOtuAd,y walhlitchhreseuggrgoesutpesodfthmatalteheramtasles hPaFdOnAoteqrueaalchteotdhaeisrtdeaaidlyystdaotsee.by seven days. On the 2th day, the males excreted an amount of Hlaabnohriajtaorrvyiberteald.b(e1a9g8l8e)diongvses(t3igmaatleed,t3hefeemxaclree)tiwoenrkeinaenteisctshoeftiPzeFdOwAitihn mtehethboexaygflleudroagn.e aSnidx acanthientterrasvewneorues pdloasceeodfin30bomtgh/ukrgetoefrsPaFfOerAlfaoplalroowteodtobmyycaonndticnyusotuostoimnfyu.siTohnewiatnhim5a%lsmwaenrneitgoilven ssoalmuptlieonwaats1c.o7lmllec/tmeidn.in Utrhienmeidwdalseocofllceacctheduartin1e0 minute intervals sampling period. for 60 min. Probenicid A5 (30 mi blood mg/kg i.) was then administered, and urine and blood samples were again collected as before. Renal 31 000035 cadldeiatriaonncaelodfoPgsFO(2Amawlae,s 2caflecmuallatee)dfwoerrethgeivbeenfo3r0e magn/dkagfiPerFpOrAobeinntercaivdenionujselcyt.ionThpeersieoddso.gsFowuerre tkheepsteidnomgest,apbloalsimsam PcaFgOesA,haanld ibvleoosdwsearmepldeestewrmeirneedc.ollReectneadl icnlteearrmaitntceentraltyefworas30apdpayrso,ximFartoemly 0an.0a3ctmiiviemsienckrge.tionPrmoebcenheacniidsmsigfnoirfiPcFaOnAt.ly rTehdeucpeldatshmeahPaFlOAivcelseoarfanPcFeOinAbwoetrheselxoensg,erinidnictahteing male dogs (473 hand 541 h) than in the female dogs (202 h and 305 hy. "aTdhmeinuirsitnraartyioenxcarsetwieolnloafs PinFiOnAtacwtamsalsetusdaienddifnemmaalleesW(iYsltianrenraett aaflt,er19c8a9s)t.ratTihoneamnadleesrtartasdi(oNl=20) owpeerreatceadstarnatded10atitnthaecatgmeaolfes28wedraeysadamnidniasfttereer5dweesetrkasdiwoelrvealuesreadteisnutbhceutteastnse.ouHsallyf5o0f0tuheg/kg eduvreirnygs9e6cohnrdadayfadsutirnignrlge14indtaryapserbietfoonreealthPeFtOesAt dUorsien(e5w0amsg/ckogl)l.ectBedloiondmesatmapbloelsiswmecraegceosllected bstyicmaulradtioarcypeufnfcetcutreo.n tChaesturraitniaornyaenxdcraedtmiionniostfrPaFtiOoAn.ofeDsutrriandgiotlheofitrhste 2m4alheourrast,s hfaedmaalesirgantisficant ethxecreestterdad7io2l+t-r5e%atm(eNn=t6,)boofththtehedoisnet,acwthaenrdeacassttrhaetiendtamcatlmeasleexscreextceredtPedFoOnAlyin9a+m4o%un(sN=6s)i.milaArftteor efxecmraelteesd(P6F1O-A19i%n uarnidne6f8a+s-te1r4t%h,anretshpeecitnitvaeclty)m.alTeshe(5c0as+t-r1a3t%ed),mabluteslewsistthhoaunttehsetrfaedimoalletsreaantdmetnhte einsttarcotgemnalterseawteadsmcaolness.ideArtabtlhey ehnidgohferth(1e7-te4s0t t(i9m6eshr)),thtahne icnontcheensterratuimoonofofthPeFrOAgrouipnst.heTshcerruemwoafs nPoFOstAatiwsatiscaslilmyisliagrnliyfibcoauntnddibfyfetrheencperoitneitnhse isnerthuemsceornucemnotrfamtailoenss baentduwfeeemnaltehse.other groups. VmaarnkdeednsHeexu-vdeiflfeetraeln.ce(s19in92t4h)e uinrviensatriygeaxtcedrewthioenthoefrPaFnOdAr.ogeCnasstorrateisotnroogfenmsalaerse girnevaotllvyedinicnretahesed (p>ro1d-ufcoledd)btyhetheelitmeisntastiiosnroefspo"n"sCi-blPeFOfoAr(t9h.e4sulmoowl/eklgi,miinpa.t)ioinn uorfinPeF,OdeAmoinnsmtarlaetirnagt.thaCtaastrfaatcitoorn ptleusstos1t7eBr-ocnsetrraedpiloalcheamednntoatfutrhteheprhyesfifeocltogoincaPlFlOevAelerliemdiuncaetdioPnFwOhAercelaismicnaasttiroatnioton plus the same level eaxscrraettsiwointohfiPntFaOcAt.testiIsn. feTmhaulse,riantsm,anleeitrhaetr,otveasrtioesctetroomnyeneoxrerotvsaarnieicnthoimbiytoprlyuseftfeescttosotnerroenneal aofnfePcFteOdAthreenuarlineaxrcyreetxicornetiisoanmoafleP-FsOpeAc,ifdiecmornessptornastei.ngPtrhoabtetnheeciidn,hiwbhiitocrhy ienfhfiebcittsofthteesrteonsatlerone transport effct on smyaslteemr,atsdewcirtehasinetdactthetehstiigsh rate of PFOA renal excretion in castrated males but had no oHfor"mConaaftlerchoraanlgeadsmdinuirsitnrgatpiroen gonfaansidcnoyglenodtosapeopefaarmtomocanuisuema c"hCa-nPgeFOinAt(heGirbasteoonfaneldiJmoihnnatsioonn, d1o98s3e)d. (mAeUaSnodro9sdea,y1s5 mafgt/ekrgc)onacnedptiinodni,vifdouuarlpurreignenasnatmrpaltessawnder2encoonllpercetgendaantt 1f2e,m2a4l,e3r6a,tsawnedr4e8 hours within post dose 24 hours and for baontahlygzreodupfsoorf 'aCtscontent. Essentially all of the '"C was eliminated via urine 2 000036 (F1e9e8d4i).ngoMaflcehorlatesstwyerraemiandemitnoisrattesreednhAaPncFeOd (t2h.e1 fmegca/lmlel)idmiinsastoilovneodfinA0P.F9O% N(JaoChlnsaosnacstianlg.le pinetrrcaevnetnaoguesodfoAsePF(2Omdlorsate,ealvimeirnaagteedAPinFtOhedofescees1o3fmgch/oklge)s.tyArtam1i4ned-atyrseaptoesdt dose, the mean rats (43.2+-5.5) was 9i.n8u-rfionledwtahesm4e1a9%n fpoerrcterenattaegdeoraftdsoasnde 6el7i%mifnoarteudntirneafteecdesrabtys.untreated rats (4.4+-1.0). Excretion 3.2 Epidemiology Studies 3.2.1 Cross-sectional and Longitudinal Studies aAndcrAonsst-wseecrtpiopnlaalntasnawlayssiusondferttheakdeantatofdreotmetrhmein2e00if0tmheerdeicwaelresuarnveyilalsasnocceiaptrioongsrbaemtawtetehne PDeFcOaAtur eatnadl.h,e2m0a0t1ol)o.gyT,hcelidnaitcaalwcehreemiasntarliyesz,edanfodrhaollrmeomnpalloypeaersamfertoemrsboofthvoplluanntteleorcaetmiopnlso.yeMeesa(nOlPseFnO,A msaelreumemlepvleolyseweesreat 1t.h0e3Depcpamtfuorrplaalnlt.malMeaelmepplrooydeuecstiaotntehempAlnotyweeerspatpltahnetDaencdat1u.r90pplapnmt hfaodr all (si1g.n2i8fipcpamn)t.ly Nhoingh-eprro(dpu<ct0i5o)n emmepalnoyseeersumatlebvoetlhsp(l2a.n3t4sphpamd)methaann ltehvoeslesabtetlhoewAn1 tpwpemr.p PplFanOtA wshereurme sleevreulsm wleevreelshiagrheehrigthhaenr otvheeraPlFl.OSInsaedrduimtivoanl,uveaslautesboftohr ptoltaanltso,regsapneicciafllluyortihnee Dweecraeteuvrepnlant higher than the PFOA levels. aMfufletcitvatrheiarbelseulrtesogfretshseionclainniaclaylsceshewmeirsetrcyontedstusc.teTdhteofaodljlusotwifnogrvpaorsisaibblleescwoenrfeouinndcelrusdetdh:at may yperaordsucwtoironkejdobat(tyhees polrannto.),Aplapnots,itaigvee,sbiogdniyfimcaasntsaisnsdoecxia(tBiMonI)w,ascigraerpeotrtteesd/dbaey,twdereinnkPs/FdOayAaanndd achnoalleyssteesr.olAl(cpo=ho.l05c)oannsdumPeFdOpAeranddaytrwiaglsycseirgindiefsic(apnt=i0n0t2h)e. chAolgeestwearosl amlosdo esli,gnwihfiiclaentBMinIboatnhd icingcalruedtetdesinsmthoekeandalpyesreds,aynewiathsersirgeniafcihceadntstfaotristtriicgallycseirgindiefsi.canWcheeinn tbhoethchPolFeOstAeraolndmoPdFeOl,Swwheirlee wPiFtOhAPFrOemAai(npe=d s.i0g4)niafnicdanrtem(pai=ne0d2s)iginnitfhiecatnrtig(lpy=cer0i4de)swmhoednelb.otHhDPLFOwAasannedgaPtFiOveSlywaesrseociated oibnscleurdveeddianndthreemmoadieln.edAstaptoisstiitciavlelyasssiogcniiafticiaonnt((pp==0.10)5)bwehtewneePnFTO3SawnadsPiFnOclAudweadsinaltsoh.e model, cBhMeIm,isctirgya,retthiyerso/iddayo.rahlecmoahtolo/ldoagyy wmeeraesuarlesos swiegrniefisciagnntifiincatnhtelymoadseslo.ciaNtoednewoifthtPheFoOthAerincltihneical regression model pAerlfoongrimteudditnoaldeatnearlmysiinseowfhethtehearboovcecudpaattaioannadlperxepvoisouursemteodifclaulorsoucrhveemiilclaalnsceovreesrulttismewaiss related to (cOhlasnegne,setinalc.l,in2i0c0a1l1)c.hemTihsetrclyinaincdallciphiedmirsesturlitessiinneclmupdleod:yeecshoolfesttheeroAln,tHwDeLrp, atrnidglDyeccearitduers,facilities 5 000037 aallaknaliinneeapmhionsopthraatnassfee,ragsaem(mAaLTg)l,uttoatmayl!antrdandsifreecrtasbeil(iGruGbTin)., aMsepdaritcaatle saumrivneoitlrlaannscfeedraatsaef(rAoSmT)1,995, s1u9b97c,ohaonrdt2t0h0at0 iwnecrleudaendaltyhzoseed wushiongpamratlitciivpaartieadbilne2reogrremssoiroen.meTdhiceaplleanxtasmwsebreetawneaelnyz1e9d9u5sainngd 3 2e0a0s0t.onAe tootthaelr.ofOn1l75y m4a1leemepmlpolyoeyeeseswevroelupnatratriicliypapnatrstiicnipaallte3dsiunrvtehiel2la0n0c0espuerrvieoidlsl.ance and at eWmhpelnoymeeeasnpasretricuimpaPtiFnOg Ainlmeveedliscawlerseurcvoemilplaarneced abtytsheurAvneitlwlearncpepyleaanrt, iPncFrOeAaseldevbeelstwienetnhe1994/95 asnedrum19l9e7vealnsddethcerneadseecdrebaestewdeeslnig1h9tl9y4/b9e5twaenedn11999977aannddt2h0e0n0.incArteatsheedDbeectawteuernpl1a9n9t7, PanFdO2A000. `DeWchaetnuarneamlpylzoeydeuessi,ngthmeriexewdasmoadsetlatimsutlitcialvlayrisaibglneifriecgarntespsoisointiavnedacssoomcbiiantiionngbAenttwweeernpPaFnOdA and sanedruamlscohoblyesstuebrcoolho(rpt=, t0h0e0s8e)asasnodcitartiigolnyscewreidreesl(ipmi=ted.0t0o02t)heovAenrttwiemer.p eWmhpelonyaeneasl(ypze=d b0y05p)laanntd, iHnowpearvteircu,latrh,etahseso2c1iaAtnitownebreptweemepnloPyFeeOsAwahnod ptarritgilcyicpeartieddesinwaasla3lssoursvteaitilsltainccaellyyesairgsni(fpic=an0t0(1p).= "0T2he)rfeowratshensotubagrsiogunpifiincawnhtiacshsoecmiaptliooynebsetpwaeretinciPpFatOeAd iannbdiotrmiognliytcoerriidnegsianm1o9n9g4/D9e5caatnudr2000. workers. There were alkaline phosphatase, GnoGTsi,gnAiSfiTc,anAtLaTss,octiotaatliobnislibreubtiwne,eanndPdFirOeActanbidlicrhubainn,ges over time in HDL, sTehreruem aPrFe OseAvelreavlellsiwmeirteatsiiogtnnoisfitchaent2l0y0h0igchreosrsa-tsetchteioDneaclataunrdplloanngtittuhdainnaalt sthteudAinestwiencrlpudpilnagn:t, 12)) praollfiplaretsicainpdandtesmwoegrreapvhoilucnstebeertsw,e3e)ntehemrepwleroeysoeefvteerhsael DceocnasitsutrenatnddiAfnfetrweenrcepspilnanctlsin(icAanltcwheermpistry elomwperloByMIesae,swcoormkpeadrefdewteorDyeecaarst,urhaedmphliogyheeersalhcaodhollowceornsPuFmpOtAiosn,erhuimghleervemlse,awnerHeDyLouanngder, had bmielairnubtihnyrvoailduehso,rlmoowneer mvaelaunestrtiegnldyecedritdoeb,ealhkiaglhienre),ph4o)sPphFaOtSasaen,dGoGtTh,erApSerTf,luaonrdinAatLeTd cvhaelmuiesc,alasnd acroemaplasroepdrebseecnatusine tthheesye wpelranetsp,la)ceidn itnhteo cqruoasrst-isleecstbioansaeld sotnudPy,FOplSansteproupmuldaitsitroinbsutciaonnnsootnbley awhciercthaiwnerpoeindtififnerteinmtefowraesaccohllseucbtgerdofuopr aenadchoctlinaipcpalliccahbelmeisttorPyFtOesAt,, a6n)do7n)lyPoFnOeAmesaesruurmelmeevneltsat oovnelryalalshmaalvle nbeeun inmocrfeeabmsipnlegooyvereerstpiamretiicniptahteesde einmpallloy3eessa.mplIinnagdpdietriioond,si(n2t4h%e),lodnigfifteurdeinntallasbtsudy aannadlaynzaeldy'bieccaalutseecohfnitqhueessmfaolrlPnFuOmAbewroerfepaursteidciepaacnhtsyear, and female employees could not be 3.2.2 Mortality Study AplarnettrwohsipcehctpivreodcuocheosrtAmPorFtOal(iGtiylslitluadnyd waansd pMearnfdoerlm,ed19o9n3).empAltotyheiessplaatntt,heACPoFttOagperoGdruocvtei,onMwNas limited to the Chemical Division. The cohort consistedof workers who had been employed at 4 000038 atlhleopftlahnet fwoorrkaterlesaswte6remoobnttahisnebdettowedeenteJramniunaeryca1u9s4eo7fadnedaDtehc.eTmhbeerre w19a8s3.alDmoesatth certificates of w`caosmpclaetteegofroilzleodw-buapse(d9on9t.heo5ifr%ajl)olbohfistthoerisets.udyIftpharetyichipaadntbse.enTheempelxopyoesdurfeorstaattulseaostf t|hmeownotrhkeirns ethxepoCsheedmitcoaPlFDOiAv.isiTohn,e tnhuemybweerreofcmoonnsitdhesreedmpelxpooyseedd.inAtlhle oCthheenriscwaelreDicvoinssiiodneprreodvtiodbeed tnhoet pcaurmtuilcaitpiatveedeixnptohsiusrsetumdeya,s3u9re8m(e3n4t8s.meOnftahned 35503w7o(m2e7n8)8 wmeerneadnedce7a4s9edw.omEleenv)eneomfpltohyee0es wwohmoen and 148 exposed ofthe 348 to PFOA. men worked in the Chemical Division, and therefore, were considered cStoamnpdaarreddizteodUM.oSr.taalnidtyMiRnatnieossot(aSwMhRi)t,e daedajtuhstreadtefsorfoargem,ens.ex,Faonrdwroamceenw,eroenlcyalsctuatleatreadteasnwdere available. periodsof The SMRs durationof efomrpmlaolyemsenwetr(e5,st1r0a,tiafniedd2f0orye3arlsa)t.ency periods (10, 15, and 20 years) and 3 eFloervaaltledfe(maalltehoeumgphlonoyteessi,gntihfeicSanMtR) sSMfoRr awlalscafuosrelsyamnpdhofpooriacltliccancacnecresr,wearnedlweassstbhaasned1. oTnhoeloynl3y wdeeartehs.signWihfiecnantelxypolsouwreerstahtaunsexwpaesctceodn,sibdaesreedd,oSn tMheRUf.oSr.alrlatecsa,usfoersobfotdhetahtehCahnedmifocraalllDicvainscieorns workers and the other employees of the plant. In all male workers a the compared to both the U.S. plant, the SMRs were close to 1 and the Minnesota death rates. for mostofthe causesofdeath When latency and duration of when CehmepmliocyamlenDtivwiesiroencwonesriedecroemdp,atrheedretwoeMriennneoseolteavadteeadthSMraRtses., tWhheeSnMeRmpfloroypreoestdaetaethcsanicnetrhefor (w1o.r9k7eerxspeicnttehde).CheTmhiecraelwaDisvialssiooan wstaasti2st.i0c3al(l9y5s%igCniIfi5ca5nt- a4s.5s9o)c.iatTihoinswwiaths lbeansgetdhoonf4emdpelaothysment hinaztahredCmhoedmeilcsa,ltDhievriesliaotnivaenrdispkrofsotraate1c-ayenacrerinmcorretaaslietyi.n eBmapsleodymoennttheinretshueltCshoefmipcraoplorDtiivoinsailon Cwhaesmi1c.1a3l(D9i5vi%siCo1n1f0o1r 1t0oy1e.a27r)s. whIternosceo1m0pa3.r3ed(9t5o%thCeIot1h.e0r2 e-m10p.l6o)yfeoerswionrtkheerspleanmtp.loTyheedSinMtRhe for workers (58). not employed in the Chemical Division was less than expected for prostate cancer A1n997up(dAalteexoafntdheirs, s2t0u01day).wasThceoncdouhcotretdctoonsiinsctleuddoefth3e99d2eawthorekxepresr.ieTnhceeoefligeimbpilliotyyereesqutihrreomuegnht wwearseicnhcraenagseedd ttoo b1eymeaorroefspeemcipflioc.ymeWnotrkaetrtsheweCortetpalgaecGedroivnteop3laenxt,poasnudrethgereoxuppossbuarseecdaotengjoroibes shhisitpopriynginafnodrmaptaicokna:gidnegofifniPteFPOFAOoAcceuxrproesdurtehr(onug=h4o9u2t,tjhoebhsiswthoerryoefcetlhlegpelnaenrta)t;iopnr,obdarbyliengP,EOA Texopwoesruorret(rnan=sie1n6t85e,xpootshuerresc)h;emaincdalnodtiveixspioonsejdobtsowfhleuroreoecxhpemoiscuarlest(onP=FO13A15w,apsripmoasrsiilbylenobnut- with chemical division jobs). 5s 000059 gInrotuhpi,s n26e7w icnohtohret,pr6o0b7abdleeatehxspowseurreeigdreonutpif,ieadn:d4260o4finthtehseendoena-tchxspwoesreed ignrotuhpe. PFWhOeAnexalplosure ehimgphleoryfeoersalwleorfethceomcpaaurseesdotfodtehaetshtaatneamloyrzteda.lityNoranteeos,fSthMeRSMwRersewleerssetshtaatnis1tiocralolnylsyigsnliifgihctalnyt at P= 05. The highest SMR Five deaths were observed r(3e.p8o3rteexdpewcatsed)f.or bladder cancer (SMR = 1.31, 95% CI - 0.4-2 3.05). cAancfeerwoSfMthRe wlaerrgee einlteevsattiendef(orSMemRp=lo1y.e6e7)s,i1n tfhreomdepfainncitreeaPtiFcOcAanecxepros(uSrVeRgr=oup1.:34)2,daenadth|sffrroomm wpreorseta2t.e5 ctainmceesrm(oSrMeRli=kel1y.3t0o).diIenfardodmitcieonr,ebermopvlaoscyueleasridnistehaesdeef(i5nidteeatPhFs OobAseerxvpeods,ur1e.9g4roup expected; 95% CI = 0.84 - 6.03). gIenntihtealporrogbaanbsle(eSxMpoRsu=r2e.7g5r,ou9p5,%3 CS1M=R0.s0h7oul1d5.b3e);noptaendc:reactainccecranocfetrhe(SteMstRis=an1d.2o4,th9er5%maClle = 06..4a3nd22.7c0a)s;esawnedrmealoibgsenravnetdm,erlesapneoctmiaveolfyt.heThskeinSM(SRMfRor=pr1o.s4t2a,t9e 5c%ancCe1r=in0.th1i7s -gr5o.1u1p)w. asOn0l.y861, 0-5). Tblhaedrdeerwearnednoothneortuarbilneaerxycoersgsaenss.in FSouMrRcasinesthweenroeno-besxeprovseeddagnrdouopn,leyx1c.e8p9twfeorrecaenxcpeercotfedth(e95% CI=0.58 5.40), uHupidsatdieffbiecculatusteo itnhteeerpxrpeotstuhreerceastuelgtsoorifesthweeprreosmtoadtiefciaendceinr dtheeatuhpsdabtee.tweOennlyth1e dfeirastthstwuadsy raenpdorttheed dineatthhesdwefoiunlidteheaxvpeosbuereengprloaucpedanindt5hewcehreemoibcsaelrpvleadntinemthpelopyroebeasbleexpeoxspuorseugrerogurpouipn.thAellfirosft these. sPtFudOy.ATwhaes nnoutmbreeproorfteyde.arTshitshaitstihmepsoeretmanptlobyeeceasusweoervkeend |atprtohsetpaltaenctaanncde/rordewaetrheinextphoesdeedfitnoite PemFpOloAyeeexsp"oseuxrpeosgurroeuspwreesrueltmeidscilnasasnifeileedv,attehd SreMsuRltsfoofrtthheegarnoaulpy.sisThceoruclfdorbee,iaflatenryedof the significantly. Tgrhoeuepxwcaesssfmuorrtthaelriatnyailnyzceedrebbarsoevdasocnulnaurmdbieseraosfeyneoatresdoifneemmppllooyymeeesntinatthtehedepfliannitt.e Texhproeseourfethe 5 dtheaanlSsyoecacrusrrbeudt ilneswsotrhkaenrs10wyheoarwse(reSMeRmp=lo1y5e.d03i,n9j5ob%sCw1it=h d3e.f0i2n-ite43P.9F1)O.A eTxhpeoostuhreerf2orocmcourrered 2in0.e2m4p)lofoyreeemspwliotyheelessswitthhangr|eayteearrotfhadnefinyietaerseoxfpodseufrien.iteThPeFSOAMRexwpoassur6e..9 (I9n5o%rdCelr =to 1co3n9firm trheagtiotnhaelrmeosrulttaslirteygarratdeisngwecrereeubrsoevdafsocrultahre rdiesfeearseencweeproepunloattiaonn.artTifhaectroefsudltesatdhidcenrottifcihcaatnegec.oding, ``eWxhpeonsutrheesceatdeegaotrhys),wweorrekefrursthweirthan2a7lyyzeeadrsboyfceuxmpuolsautrieveinexpproosbuabrlee(tPiFmOe-Aweeixgphotseeddajcocbosrdoirntghtoose 56 000040 wdiisteha9seytehaarnsotfhedgefeinneirtaelPpoFpOulAateixopno.sAuredowseer-ere3s.p3ontsiemerselmaotrioenslhikieplwyatso dnioetoofbcseerrevberdovwaistchulyeaarrs of exposure. "cTahneceslrimghotrteaxlcietsysexinpebrliaedndceer actan3cMe'rsinDetchaetcuorhoprlatnta,s a whole should which produces be noted given mostly PROS. the bladder Bladder cAaLncpelranmtortthaalnittyhwe agsene4ratlimpeospuhliagthieornin(wSoMrRke=rs4.w8i1t,h9h5i%ghCiPF=OS0.e9x9p-os1u4r.e06j)ob(sAlaetx3aMnd'esr,De2c0a0t1u6r),, leTvherleseidnewaothrskewresrearerelpoorwteerd,atatnhdeaDllecoafttuhrepmlaonct,cuwrhreerdeinPtFhOeAhiigshuesxepdoassuraengerloauspt.omSeerriunin PFOA fmlaunourfoapcotluyrmeeorfpProFdOuActiboengaorn iastDpercoadtuucreidnas1a99b9y.-pTrhoedruecfto,ret,haPnFatOCAotetxapgoesuGrreosvewi;llholwiekevleyr, the irnecsrpeoansseibaltetfhiosr ptlhaentb.ladIdtesrncoatnccleerardewahtehtshoebrsePrFvOeAd,atPtFhOesSeoprlasntosm;ehootwheevrecrh,efmoilclaolwmuapyshboeuld continue in an effort to shed some light on this observation. plainstdisfifnicceultthteoecxopmopsaurree ctahteergeosruiletssowfetrheemofidrisftiaendd. sAelctohnodumgohrttahleiatuytshtourdsiecslaaitmthtehaCtotthteagneewGerorve. e`Wxiptohsouurtemceaatseugorreidesexaproesmuorerse(ascceurruamteP,FitOiAs sltielvlellsi)k,elityistdhiatffeixcpuoltsutroejumdisgcelatshseifrielciaatbiiolnitoyoccfurtrheed. esuxbp-odsiuvriedecdatiengtooriPeFsOtAh-atexwpeoreseddefgirnoeudp.s,Inantdhetsheecfoinldm pstluadnyt,etmhpelcohyeemeiscaeslsepnltainatlelymprleomyaeiensedweinrethe "nneown-ceatxepgoosreide"s dgroounpo.t tTahkiesiwnatosaacncoefufnotrtdutroamtoiorneoafcceuxrpaotseulryecloarslseinfygtehxpoofseumrpelso;yhmoewnetv.erA,ntohteshee.r ltihmeirteaftoiroenwteortehinsotstiundcyluisdetdhatin1t7hedesattuhdyc.erTtihfeicaitnecsluwseiroen norotexlcolcuastieodnofofrtdheecseeasdeedatehmspcloouyledes and orfewaolrykecrhamnogretatlhietyanatalCyostetsagfoerGtrhoevceau(saensdofDedceaattuhr)thnaetehdasdtoacsomnatlilnuncu.mbAelrthoofucgahsetsh.ereFowlelroew up mare than 200 still relatively additional deaths young. Given the irnescullutdseodfisntuthdiisesanoalnysfilsu,oritoicsheamsimcaallls number in both and the animals cohort and is humans, further analysis is warranted. 3.2.3 Hormone Study sEencdtoicornailnesteufdfieecstswhearvecboenednucatsesdocoinateemdpwliotyheePsFofOAa epxlpaontsuprreodinucainnigmaPlFs;OtAhe(rOelfsoeren,,2etcarlo.,ss1-9982), wMoerdkiecrasl isnur1v9ei9l3la(nnce=, 1h1o1r)maonnde1t9es9t5in(gna=nd80)P.FOSiAxtsye-riugmhtleevmeplslowyeereesowbetraiencedomfomrovnoltuontbeoetrh dseatmepcltiinong ptehratioydesa.r,I5n01i9t9c3o,ultdhehraavnegebeoefnPhFigOhAer)waasnd0-08-011p5ppmp(malitnho1u9g9h58u0sipnpgmthwearsmotshperlaiymimtaosfs scopretcitsorlo,pdheohtyodmreolcrpyiaasnsdary.ostEelreovneenshuloframteon(eDsHEweArSe),asessatyraeddioflr,oFmStHh,e serum samples. 17 gamma- They were: hstyidmruolxaytpirnoggheosrtemroonnec ((T1S7H-H)Pa)n,dfrseeextheostromsotneero-nbei,ntdoitnalg tgelsotbousltienro(neS,HBLGH),. prEolmapcltiony,etehsyrwoeird-e nn 000041. <ipnl3ca0lcuedpdepdim:n,tmoau4nldteixv>pa3or0isaupbrplieen.craetgSetrgaeotsrisisiteoisncabalansmaeleydtshioosn,dtsAheuNisrOesVdeAtro,ucmaonPmdpFaPOreAearPlseFovneOlscA:orl0re-ev1lealptspioamnn,dco1he-fo<fricm1io0epnntepsm,v,alu1e0s- taPlhFcaonOhAo1l0wcpaopsnm.snuomtIpnhtii1go9hn9l,3y,BcooMnrIlr,eyloa1rt2ecdeigmwapirlettohtyeaesn.eysoMfhoastdhtseoefhrtouhrmemoleenvmeepsllsoor>yew1ei0sthphpatmdh,e PfaFonlOdlAo1w5sienigrn uc1mo9v9al5re,ivaetless:lesasge, eHmopwleovyeere,stihnestehele>v3el0sprpanmgePdFfOrAomgraopupproixnim1a9t9e3layn1d0opnlpym$toinov1e99r5.114Thpeprme.forTeh,eriteswelirkeeloyntlhyat4 atgheereoftwhaseneomtpelnoyoeuegsh pinotwheerhtioghdeesttecetxdpiofsfuerreenccaetseginoriy twahsoftethehrelohwiegshtesint bcoattehgo1ri9e9s3.anTdhe19m9e5an (33.3 years categories, and BMI 38.2 was yselairgsh,tlryeshpiegchteirveilny)t.he AhligthheosutgPh FnoOtAsicgantiefgiocrayn.tly different from the other wE1as9t9sr5)an.doitoIlnobw1sa9e9sr5v,heiadglhliln5y 1ec9mo9rp3r.leolyaEetseetdsrawwdiiitothlh lBPeMvFeIOlsA(rinl=etv4he1el,s>>3p03<.0p0pp0mp1mgirnhoa1ud9p9Bi3Mn,Ibaosntdh>ry2=e8a,3ras0l,wtehpor<uegh1010th%iisnheifgfheecrt atuhtahnotrhsepootshteurlaPteFtOhAatgtrhoeupsst;udhyowmeavyern,otthheavdeifbfeereenncseenwsiatsivneotensotautgihstitcoaldleytescigtnainficaasnsto.ciaTthieon obbestewreveanblPeFeOffAecatnldeveesltsrasduigoglebsetceaduisneamneiamsaursetdudsieesru(m55PpFpOmAPleFvOelAs iwnertheelCikDelyratb).eloOwnltyhe3 ePesmFtprOlaAdoiyoaelneldseevisentlrtsahdiisinostlth.eudhyighhaedstPeFxOpAosusreerucmatleegvoerlys cthoiuslhdigshu.ggeTshteaytharlesoshsoulgdgreesltatthiaotnsthhiephbiegthweeren rFerpeoertteastnoesgtaetriovneeawsassochiiagthiloyn cboertrweeleatnedPFwiOtAh asgeeruimn bloetvhels19a9n3datnedsto1s9t9e5r.oneT.heThaeurtheowresrdeidnonot s1t7a-tiHsPt,icaallpyresciugrnsifoirocafntttesrteonsdtsernoontee,dwfaosr PFOA and highest in cither bound the >30 ppm PorFOfrAeegtreosutopstinerboonte.h However, 1993 and p1o9s9s5.ibleInco1n9f9o5u,nPdeFrOsA. wHaoswesviegnri,fitchaentaluythaosrssocsitaatteedtwhiaththi1s7a-sHsPociinatrieognrewsassionbamsoeddeolnstahdejursetseuldtsfor bofeotnweeenemPpFloOyAeean(ddactoartwiesrole,nDotHEpAroSv,idFeSdHi,n tLhHe,raepnodrtS).HBTGh.ere were no significant associations FTihresr,eaalrtchosuevgehratlhedreeswiegnreis2susetsudtyhaytesahrosu(l1d9b9e3 naontded19w9h5e),ntehveaplouaptuilnagtitohnesrweesrueltnootf hiindsespteunddye.nt. pSairxttiyc-icpiagthetdeimnptlhoeyseteusdypairnti1c9i9p5a,tetdhuins broetdhucyienargs.theSepcoondw,oftethhrree swteurdey.31Thfeerweerweemrpelaolyseoevserwyhofew seemcptlioonyaelesdeisnigeinothfertyheeasrtuwdiythdsoeesrunmotPaFlOloAwlfeovrelasnaglryesaitsoerfthtaenmp1o0raplpimt.yofThainrda,sstohceicartoisosn-, Since sthoemhealbfi-olliofgeiocfalPaFcOcAomimsoadtalteiasotn1tyoetahre, ethefafutoheforcPsFstOuAgsg.estFotuhratth,itoisnlpyososnieblseatmhpaltethwearse mtaakyenbefor oefatchhehohorrmmoonneesf,orpeoaoclheodfbltoheodsttuadkyenyeianrsa. shIonrtortdiemretpoegreitodmsohroeualcdchuaravteebmeeeansuusreedmefnotrscafcohr some 3 eesti 000042 tpahretirceispualntts.ofFainfthc,arsloemrepoafptehretahsasolciinakteidonPsFtOhaAt wwietrheimnecarseuasreeddeisntrtahdiisosltaunddy dweecrreedasoende based on PteFsOtoAs,temraonkeinlegveiltsd.iffHiocwuletvetor,cotmotpaalrseerthuemroesruglatns.ic Ffilnuaolrliyn,etwhaersemmeaaysuhraevdeibnetehnatssotmeu.dy instead of measurement errorof someofthe confounding variables. IInn t1h9i9s7s,avmoplluinntgarpyermieoddi,ccahlolseucryvseitlolkainncienw(aCsCaKg)ailnevoeflfsewreedretoaneamlpylzoeydeeins7(4Olesmepn,loeyteaels, t1o998b). odbestcerrvmeidnebiefctahuesyewreerseeaprocshithiavselsyugagsessotcieadttehdatwiptahncsreerausmacPiFnaOrAcellelvealdse.nComCaKs slecveenlsinwerartes exposed a1l0l PthFrOeeAsmaampylibnegtpheerrieosduslt(o1f99i3n,cr1e9a9s5e,daCnCdK19l9e7v)e.ls.ThSeevseanmteeesntoatfisttihcealsumbejtehctosdswewreerecousmemdoinn to this study same period as used in 1993 and 1995, and the four PFOA exposure categories were also the. `The mean (range 0.1 PFOA - 81.3 serum ppm). TlehveelmienaenmpClCoKyeevaslpuaerwtiacsip2a8t.in5gpign/tmhle 1997 study (range 8.8 - period was 6.4 ppm 86.7 pg/ml). The. highest CCK values were 50% higher in were these reported in the 2 2 categories than exposure categories less in the categories greater than than 10 10 ppm. ppm The (p = means 06). nWehgeatnivaedjaussstaecdiaftoironpobteenttwieaelncoCnCfoKunadnedrsP,FmOuAlt;ivhaorwieavbeler,retghreedsastiaonwmeordeenlost iinndcilcuadteedd ainwtehaekreport, o`Tfhtehesasmteudmyeatshowdeolll.ogical issues that applied 10 the study in 1993 and 1995 apply to this portion 3.2.4 Cholesterol Study aBnadseadltoenraatinoinmsailn tleisptiidngmewthaibcohlirsemp,oratecdrotshsa-tseacntiimoanlals,eoxcpcouspeadtitoonaPlFsOtAudydewvaesloppehrefpoartmoemdetgoaly dfaectielirtmyi,n1e15ifwsoimriklearrsefwfeercetssatruediperdesteondteitnerwmoirnkeerwsheetxhpeorsesdertuomPFPOFAO.A aInffaecPtFedOtAhepirrocdhuoclteistoenrol, elixppoopsroetdeitnosP, FanOdAhfepraotmic1e98n5z-y1m9e8s9(wGielrleilianncdluadneddMianntdheel,stu19d9y6)(.96F%orptayr-tciicgihptatwioonrkreatres).whSioxtwye-re ufinveexepmopsleodygereosupw.hoThceistheeermvpollounyteeeesrewderore waesrseumaesdketdothoavpaertliictilpeaotre,nwoePreFOinAcleuxdpeodsuinrethbe.ased on wthoerikrejrosbhdaesdcrPiFptOioAn.levHeolwsemvuecr,h wgrheeantersetrhuanm tlheeveglesnwerearlepaonpaullyazteido,n.it Twhaesrenfootreed,tihnastttehaidsogfrjooub.p of categories, total serum fluorine was used to classify workers into exposure groups. Tmoetaaslurseedr,umdufclu0oritnhee cwoasstoufsaendaalsyzaisnugrrtohgeatseammpelaessu.reBlfoorodPFsOaAmp.leSsewreurmePaFnaOlAyzweadsfonrottotal tsrearnusmamfilnuoarsiene(,SGsPeTr)u,m gluatmammay!glouxtaalmoyaclettriacnstfrearnassaem(iGnaGsTe),(ScGhOolTe)s.tersoelr,umlogwl-duetnasmiytlyplyirpuovpircoteins (LDL). and high-density lipoproteins (HDL). Allofthe participants were placed into five 000043 pcaptme.gorTiheesorfatnogtealofstehreumsefrluumorifnleuolreivneels:val<u1esppwma,s 1-3 ppm, =3 0 0 26 ppm - 10 ppm, (mean 3.3 >10ppm). 15 ppm, and > 15 Approximately half had of the levels workers fol > 10 ppm. into the > 1 - 3 ppm category, while 23 had serum levels < 1 ppm and 11 uTnhievraeriwaetreeannaolyssigensiffiocracnhtoldeisftfeerroeln,ceLsDbLe,tawenednHeDxLp.osuIrnetcheatmeuglotriiveasriwahteenanaanlaylsiysz,edthuesrienwgas not a asilgcnoihfoilcacnotnassusmopctiiaotnio,nabgee,twBeMeIn,taotnadl csiegrauremttfelusomroikneinagn.d cThhoelresetwereorleonroLsDtaLtiastfitcearllaydjsuisgtniinfigcafonrt dHiofwfeevreenrc,esinacmroeansgesthine SexGpOosTuraendcaSteGgPorTieoscocfurtroetadlwsietrhuimncfrleuaosriinnge tfootralSGseOrTu,mSfGluPoTr,ineanldevGelGsTi.n obese workers (BMI = 35 kg/m'). eSimnpcleoyPeFeOsA(cgw.alsenngotthmoefaseumrpleoddyimreenctt/leyxpanodsutrhee)r,e tishenroeseuxlptososufrethiensftourdmyatpiroonvipdreovliidmeidteodn the binefeonrmoabtsieonr.vedThinetahuetsheoersmpsltoatyeeethsa;thnooweavdeverr,siet cislinnoitcaclloeaurtcthoamtetsherreelahtaesd btoeePnFfOoAlleoxwp-oupsuorfe have wfiodrmeefroermmpalonyyeoefs.theInexadpdoistuiroen,ctahteegroarniegse,oifndriescualttisngrevpaorritabeidliftoyr itnhethleivreersuelntsz.ymGeisvewnertehaftaiornllyy 1o0nehasvaempsleveewraalsstaamkpelnesfrtoamkeenacohveermptlimoeyeteo,enthsiusreis tnhoitrsurerlpiraibsiilnitgy.. It would be much more helpful It also would have been tihnotesreeswthinogwteorceomorpiagrienatlhley trehsouulgthstonfotthetowoberkeexrpsowsehdotwoesreee kifntohwernetwoebreeeaxnpyosdiefdfetroePncFeOsAamtoong the employees participating in in these groups. There were more the study than those who worked oinf PthFeO"Aunperxopdouscteido"ne(mnpl=o4y8e).es (n = 65) 3.25 Study on Episodes of Care (Morbidity) In an order to gain additional insight "episodeof care" analysis was into the effects of undertaken at the Dleucoartoucrheplmainctalto esxcproeseunrfeoor nmosrwboirdkeirtsy" health, 2ou0t0c1o)m.esAtnha"tempiasyodbeeoafsscoacriea"teisdawisterhielsonogf-hteearlmt,hhciagrheesxeprovsicuerseptroofvliudoerdocfhreommictahlesst(aOrltsoenfact al., particular identified diniseemapsleooyreecson"dihetailotnhucntlialimsoslruetcioornodsrruessionlguCtliionniocfalthCaatreprGorboluepms. Episodesof care (CCG) software. were All pirnepsactriienpttiaonnddrouutgpsatuiseendt ivnistihtes doiahgenaolstihs,catrreeaptrmoevnitd,erasn,dpmroacneadgueremse,natncoifolvlaerry s4e0r0vidciesscaasneds or conditions were tracked. wEpoirskoeddesatotfhceaDreecwaetruerapnlaanltyzfeodr aftorle6a5st2 1chyeemaircbaeltewmepelnoJyaeneusaraynd1,651999f3ilamndplDanetceemmpbleorye31e,s 1w9h95o. GBraosuepd Aoncownosrikstheidsotforaylrefciolrmdsa,ndemcphleomyieceasl pwlearnet pwlorakceersi;ntGordoiuffperBenhtacdoemmpaprliosyoenesgrwohuopso:nly wwiotrhkehdigihn PeOitSheFr etxhpeofsiulrmeso;r acnhedmGircaolupplDanth;adGreomupploCyeceosnswishtoedwoofrkeemdplionyheiegsh wehxpooswuorreksedinitnhej.obs "0 000044 ccohnesmiidcearledpltaonthfaovre 1li0ttyleeaorrsnoor mflouroeropcrhieomritcoaltheexopnosseutreo,fwthheilsetucdhy.emiFciallmppllaanntteemmppllooyyeeeesswweerree assumed to have the highest exposures. nRuatmiboesrosfwoebrseerbvaesdedtooenx3peMc'tsedemeppilsooydeeesopfocpualraetiwoenreexcpaelrciuelnacteedusfionrgeaincdhirpelcantt.staEnxdapredcitzeadtion tpelcahnnti'qsuoebss.erAvreadtitoooefxptehcetecdheemxipcearliepnlcaentw'assobcsaelrcuvleadtetdo etoxppercotveiddeexapreerliaetnicvee rdiisvkirdaetdiobyfotrhceafcihlm oefpciasroedeothfatcwareere(RoRfEgPreCa)t.est95in%terceosntfwiedreenctehoinsteerwvhailcshwehraedcbaelcnulraetpeodrtfeordciancahniRmRaElPoCr. Episodes ienpviodlevmiinoglotghiecthliytreoriadtugrleaonnd PanFdOSlipainddmePtFaObAol:islmi,vedriasnorddebrlsaodfdterhecanlicveerr,aennddobcirliianreydtirascotr,daernsd reproductive disorders. "tThheemoanlleyrienpcrroedauscetdivriesksyosfteepmiasonddesforfotrhtehoevseeraclolndciattieognosroyofafcparnicoerrisntaenrdesbtewneirgen fgorronwtehosp(lwahiscomhsf tihneclouvdeerdalclacnacnecreorfctahteegmoarlye froerparlold4ucctoimvpeasryisstoemn).groTuhpesr.eTwhaes rainskirnactrioeawsaes rgirsekaotfeesptiisnotdheesgrfoorup o=f1e.m2p2l.o1y)e.esIwnictrheatsheedhriigshkeosft acnpdisloodnegsesint leoxnpgo-stuirmees, thoigfhl-ueoxrpoocshuemrieceamlspl(oRyReeEsPCals=o 1w.a6,s9r5ep%orCtIed cfoornfmiadleencreepirnotdeurvcatlivies vcearnycewrisd(eRfRoEr pmCal=e 9r.e7p,ro9d5u%ctiCv1e=ca1n.c1e-rs45a8n)d. tIhtesshuobu-lcdatbeegnoortyoedfptrhoatsttahtee ceamnpclero.yeeFsiv(e1.e8piesxopdeecstoedf)c,aorfewwheirche o4bsweerrveedprfoosrtarteeprcoandcuecrtsi.veOcnaenceerspinicohsefmpoircoasdltaeptleanctancer was eoxbcseesrsveidn pinrofsitlamteplcaanntceermpmloortyaeleisty(3w.a4sexopbescetrevde)d. iTnhtihsefCiontdtianggeshGoruolvdebpelnaonttemodrbtaelciatuysestaundy when there employees). weTrheeounpldya2teeoxfptohseursetucdaytesguobri-edsiv(icdheedmithcealchpelamnitcaelmpplloanyteeesmpalnodyefeilsm plant and did not cemopnlfoiyremest.his finding when exposures were divided into definitely exposed and probably exposed e`Txhpeorseuwraesgraonuipnc(rReRasEePdCri=sko1.f8,e9p5is%odCe1s=for1.n2-eo3p.l0)asamnsdotfhtehleognags-ttreorimnteemstpilnoaylmternactt,ihnitghhe high ebxepnoisgunrceolgornoiucpp(olRyRpsE.PCSi=mi2l.9a,r9n5um%beC1rso=f1e.p7i-so5.d2e).s wMeorsetorefptohretecdpiinsofdielms awnedrechaetimriicbaultapblleantto employees. bInlatdhdeerenctiarnececroh(o1r.t5,eoxnpleycte1de)p.isBoodetohfocccaurerrweadsinrefpiolrmtpeldanftorelmipvleoryceaensc.erO(n0.l6ye2xpceacsteesod)facinrdrh1osfiosr Tofowtehre ulrivienrarwyertreacotbsinefrevcetdio(n0s.9inecxhpeecmtiecda)l,pbloatnht einmptlheoyceheesm,icbault ptlhaenyt.weTrheermeoswtalsy adugeretaoterrecruirsrkionfg episodesofcare by observations, given the the same small employees. numberof epIitsioddiefsfirceuplotrtteodd.raw any conclusions about these. a 000045 Cmhoermeilciaklelpylatontseecmkplcoayreefeosridnitshoerdheirgshofextphoesubriel,iarlyontgra-cttertmhaenmtphleoiymcoeunnttegrrpoaurtpswienrtehe2 f%iltmipmleasnt (emRpRlEoPyeCes= 2an.d6,1945i%nCfIil=m p1l.a2nt- 5w.o5)r.kerEsi.ghtTeheenseupbi-scoadteesgoorficeasrtehawteirnefloubesnecrevdedthiisn cobhseemrivcaatliopnlant uwnesrpeeceipfiiseoddecshoolfeccyhstoilteilsi.thiMasoisstwoiftthhaecuotbesecrhovleedcycsatsietsisoaccnudcrhroeldeliinthcihaesmiiscwalitphlacnhtreomnpilcooyrees. dRiissckasrea,tidoisoabfeetpesi,sohdypeesrolfipciadreemifao,r eannddooctrhienreednidsoocrrdeirnse,owrhniucthriitniocnlauldedidssourbd-ercsa,tewgeorrieesnootfetlheyvraotiedd ninultlhehycpoomtphaesriissoinn tghreou9p5s.% Ccoonndfiitdieonncse winhtiecrvhalwefroer tnhoethiidgehnieixfpieodsaurepr,iolroinbgu-ttewrhmiecmhpelxocylmuednedt the group included: disorders of the pancreas, cysiits, and lower urinary tract infections. c"Tahreerdeessuilgtsn oaflltohiwsedstfuodryaodnilryecsthocuolmdpabreiussoenod ffowrohrykpeortshewsiitshgseinmeirlaatriodne.moAglrtahpohuigchstbhuetedpiifsfoerdeentof earxeporseuproerst,edt,henroetadriesemaasenyinlciimdietnactei,on2s)ttohethdiastdaesairgen.difTfihceultlitmoitianttieornpsreitnbcleucdaeu:se1a) elpairgseodReRsoEfpcCare: mepaiysondoetsonfececsasraerihlaydivnedriycawtiedheigchonrfiiskdoenfcienicnitdeernvcaleso,ftdhiesreeabsye,pr3o)vmidainnygoufntshtaeblreisrkersaulttiso,s 4f)orthe aprnaacltyiscies pwaatsterlnism,it6e)ditnodi6vyiedaurasl,s5m)atyhebeutciloiuznatteiodnomfohreealtthahncoanrceeseirnvtihceesdamtaaybarseeflbeectcaluoscealtmheedyiccaanl sbeamceatiengdoirviizdeudalunsdeveerrallartgiemreosr, s8m)anlolteraldliescmapsleoycleaesssiwfiecraetioinnsc,lu7d)eedpiinsotdheesodaftcabaarsee,masuychinacslutdhoeset:he omnisclloansgs-itfeyrmepdiissoabdielsoitfy,ca9)ret,he1a0)natlhyesissofmtawyarbeemlaiymiatsesdibgyn t2hdeisffoefrtewnatrdeiuasgendo,sewshitcohthmeasyame episode, and database. 1) certain services, such as lab procedures may not have been reported in the 33 Acute Toxicity Studies in Animals 33.1 Oral Studies "oTchceurarceudteatorcaolncteoxnitcriattyioofnsA2P4F6O4 mwga/sktges(tIendtienrnmaatleRaesndanfdemDaelev rCaotrspi.n, t1h9r7e8e).stuAdbienso.rmDaelatfhindings cuopnocnenntercartoiposnys w(keirdenenyo,tsttesotmead)c.h,Cluitneircuasl)swiegrnes oobfsteorxviceidty(Golbaszear,v1e9d97i)n tahte5s0e0thmrge/eksgtu(dhiiegsher hiynpcolaucdteidvitthye,fholulnocwhinegd; porsetdu-rset,aisnteadggfeacree,dsgtaaiitn,eedxcureosgseinvietaslalairveaat,iowne,tptuorsoigse,npiitlaoleraercetai,on, docreased limb tone, ataxia, comeal opacity, and hypothermic to touch. Iantsonweesrteud68y0(Imngt/ekmagt'(l3R9e9s-- a1n1d57Dmegv/Ckorgp.9,5%19c7o8n)f,itdheencorealliLmDi)S0forvamlauleess;fo4r3C0hmagrl/eksgRi(v2e9r5 C--D626 mligm/itk)go9r5m%alceosnfainddenfceemalliemsit.)Tfhoer freemmaaliensi;nagntdw5o4s0tumdgi/eskgpr(o3v8i9de--d7L4D9SOm0g/vkaglu9es5o%fc(o1n)f>i5d0en0ce 000046 m(Ggl/akzga, f1o9r9m7)a:leanCdrl(2:)C<D1(0S0D0)BmRg/rkatgs,faorndma2l5e0-a5n0d0fmegm/akleg Sfhorerfmeamna-lWeiCsrtlar:CrDat(sS(D3)MBRCoramtps any, 19760). 33.2 Inhalation Studies d`oThseealceuvteel ionfha1l8a.t6iomng/tLo.xi(cniotymoinfaAl PcoFnOcenwtarsattieosnt)e,dainndmaelxepoasnudrefedmuraalteioSnproafgounee-Dhaouwrl,eySiragtnss, aotfa staolxiivcaittiyodn,ureixncgesasnidveupla1c0ri1m4atdiaoyns, adfetcrretahseedexapcotisvuirtey,plearbioodr,edinbcrelautdheidngt,hegafsopllionwgi,ncgl:oesxecdeesyseisv.e a`nmougceoniidtnaalsafulr,didsrcyhaarngde,moiirsretgaullaers,breeadthmiantge,riraeldanraosualndditshcehaerygees,, ayenldlboowdsytatirneimnogrso.fthUep:on Bneacsreodpsoyn, tlhuensgtduidsycorlesourlattsi,onthweatsestobssuebrsvteadncien w2ahsignhoetrftahtaan tnoorramtsalatiancniodmeinncaeolferxaptossu(8r/e10). concentration of 18.6 mg/L and exposure durationof one hou (Bio/dynamics, Inc. 1979). 333 Dermal Studies d"Tohseealceuvteel doefr2m0a0l0tomxgi/ckitgy,oafndAPaFO24-hwoausrteexspteodsuirnemapelreioadn.dAfllemaanliemaHlrsaa(pNpZeWar)eSdPFnorrambablitsa,ndat a deuxrhiibnigttehdebfoirdsyt wweeeikg.ht Dgeairnmatlhriorutgahtoiuotntchoensstiusdtye,dowfitshlitghhetetxocmeopdteiornatoefeornyethmeamlae,tehdatemloas,t awnedight autpoonnia;nescirogphsty.desTqhueamdaetrimoanl; LcoDrSiOaceinoursanbebsitss; waands fdiestseurrimnig.nedNtoovbiesigbrleeatleersitohnasnw2e0r0e0obmsge/rkvged (Glaza, 1995). 3.3.4 Eye Irritation Studies w"Tohe oefytehrieietasttiuodnicpso,tAenPtiFaOlowfaAsPdFetOerwmaisnetdes{t0edbienaaplbriinmoarryabobcitusl,aratiraridtaonst.e Ilenvtelheosft0u.d1iegsrianm. In w7hdiacyhs,AtPheFnOriwnassedf,oournndottorbinesaed.priImrrairtyatoiconulsacrorierrsitvaanrt,ieAdPdFurOinwgastheleotbsienrcvoanttiaocnt with the period. eye for IInmci.ta1t9io7n6)scaonrdesforfotmhe2-c1o0njuinnctihievaoet,heirrss,tuadnyd(c3oMmeCaomrpaangneyd,f1r9o7m6a2).-- 4Ininbootnhessttuduideys,(Biiroistcaatriconh, irnemwahiincehdAePviFdeOntwafsodtehteedrumrianteidontoobfethae noobns-eirrviattainotn(pGearbriioedl)(,7-tdhaeytsesptossutb-sctxapnocseurwea)s Ilneftthien study sccoonrteasctwweirteh rtehpeoretyeed ffoor5rcoonrj3u0ncsteicovnadis,itaantdiotnhefnortuhep etyoe7s-dwaeyrse proisnste-de.xpIonsuthries, sstoudtyh,e paoustithiovres negative conclusion for ocular iritancy is problematic. 3.3.5 Skin Irritation Studies 0"T7h0e.s5kginraimrsr,itautnidonerpootcecnltiuadleodfteAstPFcoOndiwtaisontse.steIdn ionealsbtiundoyr(aRbbiiktesriLnatbowroatsotruideisc,s,Inac.ta 1d9o8s3e),level a 000047 4A-PhFouOrpcronotdaucctedperiirorde.verMsiobdleertaitsseueerdyatmhaegmae ainndfeemdaelmea,rababsitwse,llfoalslcohweimngicaal3-bmuinmu,tee,sch1a-rh,ouarn,dand inheicsrosstiusd,ywderuetoobesxetrrveemdefoimliltoawtiinogn aflolltlhorweiengcoenatcahctcpoenrtiaocdts.perAinod.endIpnocionnttrwaastsinnotthaecsheicevoendd sintudy h(Goaubrrsi,elb)a,seAdPoFnOprwiamsarryepiorritteadtiaosnascnoorne-siorfitzaenrtoo.fskin afer an exposure periodof24 or 72. 34 Mutagenicity Studies A~ PE.FcOolwia/smatemsmtaelditawni-cmei(cLraowsloomre, r1e9v9e5r;se19m9u6t)atfioornitasssaabyi.litTyhteotienstdsucweermeutpaetrifoonrimnedthbeoStahlwmiotnhelalnad wtiytphhoiumturmietuambTolAi1c5a3c7tivwahtieonn.tAestseidnwgilethpoousttmievtearbeoslpiocnascetisveaetnioant one was dose level in S. not reproducible. APFO did mnoatmminadluicaenmuacttaitviaotinoni.n eAitPhFerOSd.itdynpohtimiundruicuemcohrrEo.mcoosloimwahleanbetresrtaetdioenisthienr hwiutmhaonrlwyimthpohuotcytes NwhOeTnOtXe,ste2d00w0i)t.h aSnaddhwuit(h2o0u0t2)merteacbeonltilcy racetpiovratteidonthuatp AtoPcFyOtotdoixdincotcoinncdeunctreagteionnesm(uMtuartiio,n19w9h6e;n tested with in culture. or without metabolic activation in the K-1 lineof Chincse hamster ovary (CHO) cells MuIrnltihe(1f9ir9st60a)sstaeys,teAdPAFPOFOindtuwciecde bfoorthitschabriolmitoys0omianldaubceercrahtrioomnsosaonmdaplolaybperlroaitdiyonisn ibnotChHtOhecells presence and chromosomal aabbseernracteioonfsmweetarbeoloibcsearcvtievdatwiiotn.houInt tachteivsaetcioonn.d aHsoswaeyv,enro, swighneinfictaenstteidnwcirteahses in `metabolic activation, APFO polyploidy (Muri, 1996b). induced significant increases in chromosomal aberrations and in eAmPbFrOyowafisbrtoebsltaestds.in aThceellcetlrlatnrsafnosrfmoartmiaotniaonndwacystodteotseircmiitnyeadssaasybcootnhdcuocltoendyitnrCanssHfo1r0mTa,t;iomnoaunsde tfeocsitetdriannsefiotrhmerattihoencpooltoenntyiaolr. fTohcieraesswaaysmneotheovdisde(nGcaeorrfyt&raNneslfsoornm,at1i9o8n1)a.t anyofthe dose levels. iAnPcrFeOasewsasintmeistcerdontuwcilceeiianntdhewamsoucosnesimdiecrreodnuncelgeautsivaessuany.derAtPheFOconddiidtniootnsinodfutcheisaansysasyig(nMiufriclain,t 1996) 3.5 Subchronic Toxicity Studies in Animals mSounbkcehyrso.nicTtwooxicuintpyusbtluidsiheesdh2a8v-edbaeyefnecedoinndgucstteuddieins rwaetsr,empiecre,forrhmeesdusatmIonndkusetyrsiaalnBdioc-yTneosmtolgus Laboratories, and mice the Inc. liver (wMaestrtihcektaarngdetMaorrgiaans., 1I9n7a7tsa,ndmaClhersishtaodphmeorraenpdrMoanroiuansc,ed197h7e)p.atoItnoxbioctihtyraatsnd `hciosntdoupcattehdoliongiractsef(fGeoctlsdetnhtahnalf,ema1l9e7s8.4, TPharlaezez9o0lo-,da1y99s3u)bcahnrdonrihcestuosximcoitnyksetyusdi(eCsiholadveentbheael,n " 000048 c1y9n7o8)m.olTghuosmmfoonrkdey(s2.00I1n.6ad)dirteicoenn,tlcyhrcoonnidcu/cctaerdcianorgaenngiec-iftiyndsitnudgiaesndhaav6e-bmeoennthcotnodxiuccitteydstwuhdiychin maroeredepsrcroinboeudncinedsehcetpiaotno3t.o8x.icityalalnsdpehciisetso,ptathheolliovgeirciseftfheectmsatihnantafregemtaloersg,anp.reIsnumaatbs,lymableecsauhsaed ofthe gender difference in eliminationofAPFO. fInemaal2e8s-dwaeyrestsutduydoifedC(hMRet-rCiDckaalnbidnoMarraitas,s,ei1g9h7t7)r.andAfotmelryraastssiwgenreed aglrloouwpesodftofiavceclmiamlaetse afnodarfive w1e0,e0k00i.noirnd3i0v.i0d0u0alpcpamgeAsPtFheOy tfhoren28redcaeyis.vedTshiemialnairmfaelesdwceornetaoibnsiengrv0e,d30da,il1y00a,n3d0b0,od1y00w0e,ig3h0t0s0, faonrdgfrooosds pcaotnhsoulmopgtyi,oanswweerreerseucrovridveidngweaenkilmya.lsAatni2m8aldasysth.at diisedsadtuerdintghatthethsetsutduydwyeirnecleuxdaemdianed ecxoampmlienteed,exbuatmitnhaetsipoenciofficgrloisstsispantohtosluopgpyliaend.d aLciovemrpslewteeresetweoifgihsesduetso daentdeorrmgiannesrewlearteive organ weight then stained for histopathologic examination. wAlelreanniomaplrseminattuhree1d0e,a0t0h0soarndot3h0e,r0c0l0i-nipcpaml sgirgonusposfdtioexdicbietfyorine tthheeoetnhdeorfgtrhoeupsf.irstBwoedeyk.weTihgehrte ggaaiinnswweerreealrseoduocbesderivnetdheingrmoaulpess erexcpeoisveidngto1030000 oprpmmoraendppmma.lesSlaingdhtferemdaulcetsiofnesd i1n00bopdpym.weight Reduced Relative food liver wienitgakhetswwaesroebsinecrrveeadseidn riantsmafleeds1f0e0d03p0ppmpomr ohrigmhoerreinanaddofseem-arleelsatfeedd manner 300 ppm or more. organs Gbreosisdsespaltihvoerlso.gicFaolcaelxtaommduiltdinfootcarlevceyatloptlraeastmmiecnte-nrlealragteemdeenftfoecftsheinpaktiodcnyetyess or other was noted in afnedim1a0l0s0fpedpm30o0rphpimgh,era.ndThmeusletieffofceacltstowedirfefumsoereenlparrogneomuennctedofinhempaalteoscy(tMeestrwiacsknaontdedMairniaansi.mals 1977), `Imnaale2s8a-nddayfisvteudfyeomafleCshawrelrees Rstiuvdeire-dC(DCharlibsitnoophmeircea,nedigMhatrirsaan,do19m7l7y).asAsfitgenredmigcroeuwpesroefaflilvoewed 13000a,cc1l0i0m0a,te30f0o0,r1d0a,y0s00i,noirnd3i0v,i0d0ua0lpcpamgeosftAhePyFtOhefnorre2c8eidvaeyds.siTmhilearanfiemeadlcsonwtearienionbgse0r,v3e0d, d1a0i0l,y s`atnuddybowdeyreweeixgahmtisnaenddffoorogdrocsosnspuatmhpotlioogny,waesrewerreecosrudrevdivwienegklayn.imaAlnsimaatl2s8tdhaayts.died idsusrtiantgedthtehe ostrugdaynsinwcelruedeedxaamcionmepdl,ebtuetetxhaemsipneactiifoicn loifgstriossnsotpsautphpollieodg.y aLnidvearsrewpererseenwteaitgivheedsettoodfettiesrumcisneand relative organ weight then stained for histopathologic examination. `gArlolupandiimadlswiinthtihne 21600d0ay-sppemxcaenpdt h1imgahleer.grOonupesadniiemdalbeifnoereacthhoefetnhdoef3d0aaynd9. 1T0h0e-pepntmirgero3u0p0s-ppm dPiFdOAp.remAattu1r0el0y.ppmClsinoimcealasniigmnaslwseerxehiobbisteerdvceydanionsmiiscoenedxapyosse1d0atond10101opfptmesatnidngh,igbhuetradpopseeasreodf nmoursmcaullatrhwroeuagkhnoeuststahse wreesltolfstshiegnsstoudfyc.yaAnnoismiaslasftfeered9 3d0ay0spopftmreeaxthmiebintte.d rAonuigmhaelds ffuerda1n0d00 ppm as 000049 eefxfheicbtisteadfesri4mildaaryse.ffects afer 6 days and those receiving 3000 ppm or greater doses exhibited All mice fed APFO lost weight. in mice fed 30, 100, or 300 ppm. RAeddouscet-iroenlsaitnedbopdayttwerenigwhatsgsaeiennwienrethfeodlelporweesdsebdybwoediyghwteilogshstess pRaetlhaotliovgeiacanld eaxbasomliuntaetiloinverofkweiidgnhetysswoerreotihnecrreoarsgeadnsinbemsiicdeesfeldiv3er0spips mnootrdmisocruessAePd.FOT.reGartomsesnt ernellaatregdecmheanntgaensdw/oerrediosbcsoleorrvaetdioinn otfhe| loirvemrsoraemolinvgeralllobAesP.FOHistrteoaptaetdhoalnoigmiaclsexianmcilnuaditnigonofall (ApaPnFlotbruelaatrehdympiecretrroepvheya)leadccdoifmfpuasneiceydtobpylafsomcailcteonlmualrtgiefmoecnatl ocfythoepplaatsomciyctevsactuhorloeusg.hout the liver `Dmeigceenweirtahtiinonalal ngdro/uoprsn(CehricstoorfphhoeerpaastnodicyMtasersasa,nd19f7o7c)a,l bile duct proliferation were also noted in (TGhorledeen9t0h-adla,y1s9u7b8c4h)r,oonniec twoaxsicciotyndsutcutdieedsihnarvheesbuesenmocnonkdeuycste(dG.olOdennethwaals, c1o9n7d8ubc)taendditnhreattshird was conducted in male rats (Palazzolo, 1993). 3In,1t0h,e 3m0onorke1y00stmugd/y,kgG/odladyenptehrafllu(o1r9o7o8cbt)anaodimcianciisdte(rFeCd-1rh4e3s)usinm0o.n5k%eyMset(2h/osceex/lgrboyupg)avdaogseesofofr07, dbaasyesd/wuepeoknftohre9w0edeakyls.y bAoldlydwoesiegshtwse.reAgniivmeanlsinwaercoenostbasnetrvveodlutmweic;eidnadiilvyidfuoarlgdeanielryaldopsheyssiwcearle appeprefaorramnecdedaunrdinbgethhaevicoorntarnold ppehrairomdacaontdomxoinctshilgnys.durGienngertahle spthuydsyicpaelrieoxd.amiInndaitviiodnusalwebroedy wpeeriigohdtsanwderaet r1 eacnodrd3edmownetehksloy.f tBhleoostduadyndfourrihneemastaomlpolgeys.wcelrieniccaolllcehcetmeidsotnrcyeandudruirnignatlhyesicso.ntrol tMiosnsukeesyfsrowmeraenifmaasltsedthoavtewmeirghetsapcrriiofritcoedthate tchoelleencdtioonfotfhbelsotouddyaannddufrrionem saanmipmlaelss.thOartgdainesd and dhiusrtionpgatthheoltorgeya.tmHeinsttpoepraitohdolwoegryewwaesigpheerdf,oremxeadmionnetdhefofroglrlooswsinpgatohroglaongsyfarnodm saallmpmloensketaykseninfotrhe c(ownittrholcoarnodnatrryeavtemsesenlts)g,roduupso:deandurmen,alisl,euamo,rtjae,jbuonnuem,,bcreaicnu,me,scooplhoang,usr,ecctyuems,, kgiadlnlebylsa,ddleirv,erh,ealrutng, smkuisnc,lem)e.sesnptleerein,c playnmcprheanso,dper,osrteattreo/puthearruysn,geraibljluynmctpihonno(dbeo,nemammarmraorw)y,gslaalnidv,arnyergvlean(dw,itlhumbar stpoinngaule,courrdi,naprityuibtlaardyd,ers,tovmaagcihna,,teisdteenst/iofvyairnigest,attthoyor,oiadn,dpaanryatthiysrsouieds,(st)hwyimtuhs,letsrioancsh.ea, tonsil, Awlelekmo2n;kaellysaniinmathles w1e0r0e-mdge/akdg/bdyaywegerkou5p.s dSiiegdnsduarnidngsytmheptsotumdsy.whTihcehffiirrssttdaepapteharoecdcudrurreidngduring wguemesk, Iswionlclluednefdaacneoarnexdieay,esf,rostlhiyghetmetosissevwehriecdhecwraesasseodmeacttiimvietsy,bprroowsntrainticoonloarn,dpbaloedyfatcreemabnlding, "7Tharnedetmhoentkweoysfofmraloemsthdeie3d0d-umrgi/nkgg/wdeaeyksgr1o2upanddie1d3.duBreinggintnhiensgtuidnyw;eoenke4m,aallel fdoiuerdadnuirmianlgsweek a I 000050 asnhdowaetadxisal,igshwtotlolemnodfearcea,teeyaensdasnodmevutlivmae,s-assewveelrleadsepcarlelaosreofdtahcteivfiatcy.eaOnndegmumosn.keByeghiandnienmgesiins week ptosis 6, two of the monkeys eyelids. had black stools and one monkey had slight to moderate dehydration and Nmgo/kmeo/ndkaeyy-sdoisnethgero3uporoc1c0asmigo/nkagl/ldyahyagdrsooufptsstdoioeldsdourrminogdetrhaetsetutdoy.marAkneidmadlisarirnhetah:e f3r-othy eanmoerseixsiwcadsurailnsgo woceceaksi4o,nhalaldyanopatleedainndthsswoglrloeunp.facOenien mwoenekke7yainndthhead10blmagc/kksgt/odoalsy fgorrosuepvewraasl days in week or symptoms, 12. The other animals in the 10-mgkg/day groups did not show any unusual signs Cdohsaenggerosupisn.boMdoynwkeeiygshtfwreormetsheim3i0laarn1d0 t10e0cmogn/tkrgo/ldafoyrgarnoiumpaslslofstrobmodtyhew3eiagnhdt 1a0ftmerg/wkege/kda|y Amgt/tkhge/ednadyogfrtohuep study. (2.30 this loss was kg vs 3.78 kg sftoartitshteiccaolnltyrosli)g.nificant for the one surviving male in the 30- tHheem3ataonldog1y0 vmagl/ukegs/dataythgereounpds.ofAtthe30| amngd/k3g/mdoanyt,hsthoefsturrevaitvmienngtmwaelreehsaidmidleacrrfeoarsethdencuomnbtreorlsaonfd etriymteharoncdytaecst,ivdaetcerdeparseodthhreommobgilnobtiinm,e wdeercreeaalsseodihnecmraetasoecdr.itT,haensdeiinnccrreeaasseedspwleatreeletasp.paPrreontthartom1bin month but were much more marked at three months. (F1o1l7lovwsin8g9 omnge/1m0o0ntmhloifn ttrheeatcomnetnrto,l)g.luTcohseeawuathsosrisgonfitfihceanrtelpyoerlteavtartiebdutine tthheis3t-omag/skigng/ldeayhiggrhoup vearlouuepsfohradmalleeve#l7s3o6f61w12h,o1h0a5,daanvdal1u2e0-omfg1/311.00Tmhle. oGtlhuecrotshereleevmeolnskienytshein10thaen3d-3mg0/mkgg//kdga/yday `mgornotuhpssowfertere1at0m4eannt,d g1l2u2c-omsge/l1e0v0elsmiw,erreesp8e1c,ti9v6e,ly8,8,afaincdr o6n6e-mmgo/n1t0h0ofmltrienattmheencto,ntArtolt,h3r,ee10 and 30 mykgday groups respectively. Tinhetrhee cwoanstraold)eactreoanseemionnatlhk,alwihneicphhopseprhsiasttaesdeilnevtehlesoinnetshuer3v0i-vimngg/kmga/ldeay(3g6r0ovusp 8(53165UvJs]5i9n7th1eU/1 cmoonnttrhols)waetr3em7o8n3thasn.d A7l4k3alUi/nlesphhoowspihnagtaasdeoslee-vreellsaitnedthtere3n-datnodw1a0rdmgd/eckrge/adsaeyd glrevoeulps.s at three cSoGntOroTl)leavnedlsiwnetrhee orneeduscuerdviivnitnhgem3a0l-emgat/k3g/mdoanythgsro(u8p8svast4o5ne[Um/o]nitnhth(e5c9onvtsro2l9).1/S1GPinTthweas eLl/eLvaitnedthiencboonttrholt,he1010aanndd3300mmgg//kkgg//ddaayygrdoouspesg,rroeusppesctaitve|lmy.ontShG;OthTe lleevveellss iwnetrhee1150,-3m4g,/akngd/d4a4y roup were elevated in comparable to the controls at the one surviving male in the 3 months (34 30-mg/kg/day vs 31 dose 1U/ in the group (46 control) 1U/). but were still Cholesterol in the one surviving male in the 30 mg/kg/day group was elevated (240 vs 165 a 000051. amgc/on1t0r0omlil)evaenldotfotal8.2p12ro/t1e0i0nmaindaanldbutomtianl ailnbtuhmisinanwiamsal2.w0e0revsreadcuocnetdr.olTolteavleloprfot4e.i8n2wga/s1050.5m2l.vs There were no treatment related changes in urinalysis studies at any time period studied. sTthuedryeowrewrheincohmwaecrreosscacorpiifcicleedsiatontshenoetneddoafttghreostsrenaetcmreonptspyeorfioad.ny animals which died during the rTehleatfivoellwoewiignhgtcohfanthgeesheianrtasbsionlfuetmeaalneds rferloatmivteheor1g0amngw/ekigg/hdtaychgarnoguepswweerreedneoctreeda:saebds;oalbustoelautned wreaiignhtwoefigthhteopfitfueimtaalryesinfmraolmetshfsrsoammtehegr3omugp/wkegr/edaaylsgordoeucprewaassedinacnredarseelda.tiTvheegsriogunpifmiecaannce of cthheasnegewse.ight changes is difficult to assess, a they were not accompanied by morphologic `Ognreoupmahlaedamnadrktewdo dfiefmfaulseeslifpriodmdetphlee3ti0omngi/nktgh/edaadyregnraolsu.p aAlnldmalalleansiamnadlsfefmraolmesthfer1o0m0tmheg/3k0ga/ndady `1m0o0demrea/tkega/tdraoypghryooufplsyamlpsohohiaddfsollilgihctletsoinmotdhee rsaptleeenh.ypOocneellfuelamrailtey forfotmhethbeo3n0e-mmga/rkreo/wdaayndgroup athned lalylmapnhinmoadless.in Ntoheo1th0e0r-cmogmkgp/oduanydgrreolautpedhaldesimoondserwaetree astcreonphinyoatftthhee 3I0ymapnhdoi10d0fmolgl/ikclge/sdiany `mggr/oukpgs./daNyogtrroeuaptsm.ent related lesions were seen in the organsofanimals from the 3 and 10 pTrheeselnetveeldssooftPheFrOeAareindtohueblseereuntmriaensdfloirvemrosatredporseeselnevteelds.below in Table 3. Individual values are 000052 "Table 3. Levels of PFOA in theSerum and Liver Dose Serum (ppm) Liver (ppm) Liver otal (ug) 0 MNalpes Females 1 ~~ Males 005 Females 007 3s 3s 6s 50 37 ND ND wo4s 07 7 9 ND ND 10 0 ND 30145 ND ND 25 80 60 125 100 ND ND 100 325 Males Females 3s 250 350 ND ND 60 ND ND 750 8000 7500 4000 9000 6000 20000 I1n0,t3h0e,fi1rs0t0,ra3t0s0t,udayn,dG1o0l0de0npthpaml p(e1r9f7l8u2o)roaodcmtianniositceraceidd.CDThreastse(dSo/sseexl/egvreoluspa)rediaeptaprryoxliemvaeltseolfy0, equivalent me/k/day 0 in 0.6, 17, females. 5.6, 17.9, Animals awnedre63h.o5usmegd/kign/ddivaiyduianlmlayliens,wiarned m0e.7s,h2.c3a,ge7s.7a,n2d2.h4adanfdre7e6.5 access to mortality. food and Detailed weaxtaemri,naAtniiomnaslwsewreerpeeorbfsoerrmveeddotnwciecea dwaeielky.foIrndsiivgindsouafl boxoidcyitwyeiagnhdt for and food scaomnpsluemsptwieornewceorlleercteecdordduerdinwgeetkhelyprdeutersitngpetrhieopdraetnedstatan|dantrde3atmmoenntthpseorifodts.he sBtluodoydfaonrd urine ahnedmasthoilpopgeyd atondthcelisnpiocanlsocrhefmoirsatnraylyasinsd. urOirnaglaynsiss.andAttiwsesueeks f13r,omthaensicmralusm tshaamtpwleersewsearceriffriocezdenat ethxeameinndeodftfhoregsrtousdsypaantdhoflroogmy tawnod sfeammaplleesstthaaktedniefdordhuirsitnogpatthheotlroegya.tmHeinsttpoepraitohdolwoegryewwaesi.ghed, `pgerrofuposr:mebdraoinn wtihtehfcoelrlvoiwcianlgcoorrgda,nlsumfbraormsrpaitnsaflrcoomrdt,hepecroinptrhoelr,al10n0e,rv3e0,0e,yaesn,dp1i0tu0i0tapryp,mthdyorsoeid nwoidteh,patrhaytmhuysr,oibdo,naedrweintahlsm,alrurnog,wh(esatrterwuimt)h,csoarloinvaarryy gvleasnsde,lss,maaolrltai,ntsepslteienne,sm(edsueondteerniucm,lymph jsekjinun(umma,mimlaeurmy) gcloalnodn),,paannycrteiasss,ucl(isv)erw,itkihdgnreoysss, luersiinoanrsy. bLliavdedresr,ftreosmtersa,tosvafrrioems,thpero1s0taatned, u3t0e-rupsp,m dose groups were frozen and sent to atlhseo sepxoanmsionrefdormaincarloyssciospically and liver samples from all dose groups were TOhneesefedmeaaltehsinwtahree 1n0o0t caonndsoidneerefdemtaolebeintrtehaet3me0n0t-rpeplmategdr.ouAplldioetdhedrurainnigmaclosllseucrtviionveodfubnltoilod. scheduled sacrifice. "vT5h4er6e6wgasinathseigcnoinftircoalntgrroeudpu)c.tioFnooindmceoannsubmopdtyiowneiwgahst rinedmuacleedsiinnmtahlees10i0n0t-hpep1m00g,ro3u0p0(a3n6d2 & 1000-ppm groups, but the differences were not statistically significant Wo 000053 eMrayltehsroicnyttehse 3at0,th1e00e,nd3o0f0tahnedt1re0a0t0m-epntpmpegrrioodu.psThhaedvsailguniefsiwcaenrtely7.r9e5d,uc7e.0d5n,u7m.b16e,rs6.o72f, and 6.94 ivnaltuheescconotmrpoal,re3d0,to10t0h,e3c0on0taronlds 1in00al0l-dpopsmeggrroouuppss,,rbeustpewcetirveelsyt.atiMstailcealslyhsaidgnriefdiucacnetdaletuhkeoc3y0t0e 3p0p,m1g00r,ou3p00onalnyd: leukocyte 1000 ppm vgarlouuepss,werersepe1c0t.i6v4e,ly8..88A, s9i.m3i3l,a9r.p35h,en7.o6m3e,naonnd w8a.0s6sienenthweictohntrol, 10, hdoesmeoglleoveblinonlvya.lueHse,mwohgilcohbiwnervealrueedsucweedreat1a6l.l2,do1s4e.7l,ev1e5l.s0,bu1t5.w4e,r1e4.s9i,gn1i3f.i1cainnttahtetchoent1r0o-l,pp1m0, 30, h1e0m0.at3o0l0ogaincdal1p0a0r0ampeptmergsorofufpes,marlesepercattisveilnyt.heTshteudrye. was no similar effect upon the. Mwhailcehs awtetrhees3t0at,is1t0i0c,al3ly00s,igannidfic1a0n0t0a-tpapllmbduotstehelev1e0l0s-hpapdmidnocsreealseveedl.glRuecpoosretleedvegllsu(comsge/1l0ev0emlsi), `wgerroeups1,21re,s1p2e0ct,iv1e3l6y,. 134, 143 B.U.N. alenvdel1s3w5emrge/e1l0e0vamtied for in the 0, males 10, 30 at the 110000,,33000,0 and and 1000 1000 ppm ppm dose rleesveplesc;timveelayn, cvaolmupeasraetd9t0od1a6y.s2wmegr/e12000.4m,i23f.9oratnhedco3n5t.r1olsm.g/A1l0k0almiinefoprhtohsephtahrteaesedowsaesgerloeuvpast,ed itnhrmeaelgersouipnst,here1s0p0e,ct3i0ve0l,y,ancdom1p0a0r0e-dpptmo g1r0o4up1Us/;1tfhoerltehveelcsonwtreorles.14F7,em2a0l4esansdh2o1w2edInUoA sfiomritlhaer changes in biochemical measurements. aNletihtohuerghmafleemsalneosrffreommalalelsgsrhoouwpesdshaonwyetdreaathmiegnhterreflraeteqduecnhcaynogfeosccinulutribnlaloyosdisinpathreamuertienresthan did males. "aTnhiemaolnslyhgardoesnslnaercgreodplsiyveorbsstehravtastihoonwwedasvanroytiendgidnemgarleeessoaft tshuerf1a0ce00d-ispcpomlodraotsieonl.eveNle,itThheerse females (rom such effects. the 1000-ppm dose level nor males or females from the lower dose levels showed B1o0t0h0-apbspomlugtreouapnsdarneldatiinvoenleivfeermwaelieghitnsthweer1e00si0g-npipfimcagnrtoluyp.inCcormeapsoeudndin-rmeallaetseidn ltihveer30l,es3i0on0sand otoccmuurlrtiefdocianla,llvemrayleslriaghst-itnot-shleig1h0t0,hy3p0e0rtarnodph1y0o0f0-hepppamtogrcoyutpess. inThceensterilleosbiuolnasrctoonsmiisdtzeodnoafl focal riengciroeanssoedfatmheouanftfeocftedyellilveorwilosbhu-lberso.wnInpsiogmmeentinrsetsanecmebslitnhgesleilpeosfiuosncsinweinrethaecccyotmoppalnaisemdobfy an hweapsatmoocryetepsraonndouonccceasdiaonmaolnlyg imnaslienurastosidaatlthleini1n0g0c0e-llps.pmTdhieetianrcyidleevnecle. and severityof the lesions oAbsceormvpeadriisnotnheofmatlheessethraunmilnevtehlesfoefmaPlFesOAis idsusehtoowtnhebeglenodweirndTiafbfleere4n.ceTihneelgirmeiantaetritoonxiacsity demonstrated by the differences in serum PFOA levels. 0 000054 `Table 4. Comparison of Male and Female PFOA Serum Levels Dose PFOA in Serum (ppm) Males Females 0 10 0 21 0 ND 30 34 100 36 01s ND 300 38 025 000 49 065 ND = Not Determined. In the group, sdeocsoensdorfat1,st1u0d,y,30P,aolraz1z0o0lop(p1m99(3a)ppardomxiinimsatteermedea4n5-c5o5mmpaoluenSdpcroangsuuem-pDtaiwolneyat rats per week 13 of g0r0o5u,p0s4(7a,no1n.p4a4,ira-nfded4.co9n7tmrogl/kggr/oduapy)anAdPa Oconatdrlolibgirtouumpipnaitrh-efdeidcttofotrhe1310w0eepkps.m dTowseogcroonutpr)ol `wgerroeupawlseoreexfpeodsbeadsadlurdiinetg ftohratapneraidoddi.tioFnoalllSo-wwienegktshepo1s3t--twreeeaktmeexnptoasnurdeopbesreirovde,d1f0oranainmyalssigpnesrof Arelcoavenriym.alsAlwleerstodbiseetrsvweedrtewaiscesadyaeidlyanfodremvoarltuaalitteyd,fmoorrtiebstunmdaitteyr,iaalnhdogmeongeernaelictlyinaicnadl sstiagbinlsitoyf. ptoexriicoidty..anBdotdhyenweoinghthtes dwaeyroefnreeccroorpdesdy.oncFeoobedfcoroenseuxmppotsiuorneswbaesgarne,cowredeekdlwyedeukrliyngfotrhaelltrgeraotumpesn,t thinecalnudiimnaglsthreentoanipnaeidrf-ofredthceorntercoolvegrryoupphsasdeaoilfytfhoer stthuedyp.airA-fetodtaalniomfal1s5,aannidmatlhsepnewregerkoluypfworeralel of wsaecerkifsoicfedtrfeoaltlmoewnitnga4n,d7f,oolrlo1w3inwgeekwseoefkstorefantomenn-tt;re1a0tmaennitm.alSsepreurmgrsoaumpplweesrecoslalcercitfeidcefdroafmte1r013 daunriimnaglsrepceorvgerroyuwpearteeaancahlysczheeddfuolreedstsraacdriiofli,cetodtuarlitnegsttorsetaetrmoennet, launtdeifnriozimngS haonrimmaolnsesp,erangdrofuopr test w`maasterainaallryezseiddufer.omThaeselcetvielonofopfallimviertotyhaltCwoasAoobxtiadianseed, fanroimnd$icaantiomraolfsppeerrgorxoiuspomeatprcoalcihferation, wsecihgehdeudl:edbsraacirni,filciev.er,Tlhuengfso,ltleoswtisng(oonreg)a,nssemfirnoamlavllesaincilme,alpsroasttactaec,hcosacghueldautliendgsgalcarnidfi,caenwdere ufroertmharal.in Tahnde efxolalmoiwniendg mtaicssruoesscoipnitchaelsley:saemxetearnnialmaslsuwrefroeafptcrheeseerbvoedds.inall1o0r%ifpicheoss,pthhaetec-rbanuifaflered ctahveitthy.ortahceice,xatbedmoamlinsaulrf,aacensdopfeltvhiecbcraaviintiaensdasnpdinvailscceorrad;,atnhde anlassoalecxaavmiitnyeadndmipcarrosacnoapsiaclalsilnyu:seasn;y aobnsdeurrveetdhrlae.siIonnsa,ddbirtaiionn,,litvheer,folulnlgosw,intgestteisss(uoensew),erseempirneaslervveesdiclien,gplruotsatraatle,dechoyadgeulfaortienlgecgtlraonnd, microscopic examination: brain, liver, lungs, teses (one), seminal vesicle, and prostate. cInomtphearaenadlytositsohefcotnhterdoaltaa,niamnailmsalisn itnhegrnoonuppasierx-fpeodsegdrotuop,1.w1h0i,le30t,heanddat1a0f0rpopmmthAe PpaFiOr-fweedre `control animals were compared to animals exposed 10100 ppm APFO. All estdiets were. si 000055 scuornvsiivdeedretdotsochbeedhuolemdogsaecnrcifoiucse,awnidthsttahbeleexucnedpetriotnhoefexopneeriamneinmtaall icnontdhieti1on0s0.-pAplmldaonsiemda-lgsroup ethxaatmwinaastisaocnrsiofficaeldloanniwmeaelks w4edrueeu1n0resmeavrekraebnlee.ck Asotr1e0s0unprpemla,tesdigtnoiftirceaanttmernetd.uctTiwoincse-idnabioldyy cwoenitgrhotlsgwreoruep sdeuernincgomwpeaerkesd1t-o13th(ei.p.a,itr-hfreodugchoonturtoltrgeartomuepntd).uriDnugrwienegkre1coavnedryt,hehonownepvaeirr,-fneod croedmupcatriaobnlseintobocodnytrowlesi.ghtAstw1e0r0epappmp,aremneta.nBbooddyy wweeiigghhtt gdaaitnasinwetrheeostihgenrifdiocasnetdl-yghrioguhpesrwtehrane the dpuairri-nfgedwecoenktsro1l-1g3r.ouApUd1u0rianngdw3e0ekpp1ma,nmdesaingnibfoidcyanwtleyiglhotwegraitnhsanwetrhee nsoignnpiafiirc-afnetdlycolnotwreorl tghraonup otbhesenrovnepdaidru-rfiendgctohnetrroelcogvreoruyp paetrwioede.k S2i.gnTihfeicsaentdidfiffefreernecnecsesininbofdoyodwceoingshtumgpatiinosnwewreerenootbserved oatth1e0r0sipgpnimfidcuarnitndgifwfeeerkensce|sainndf2ooodnlcyo,nwshumepntcioomnpwaerreedntootetdh.e nTohnepraeirw-efrede cnoontsrioglnigfriocaunpts no adniaflfyesriesnocefsteasmtomnagtetrhiealgrroeusipdsuefosrhaonwyeodfntoheihncorremaosneeisn sevearluumatAePd FinOtlheevselesruomv.erLtihkeewciosuer,sesoefrum treatment. at 30.and 10St0atpipsmti;cahlolywesviegnri,fitchainstefhfiegchterrehteupranteidc palmitoy] to control CoA levels obxyidtahseeeancdtiovfittyhwe arsecoovbesreyr.ved period. activity At 10 ppm, statistically were observed at week 5siognnliyf.icManetahnigehnezrylmeveelascotifvihteipesatwiecrpealhmiigthoeyslt CoA oxidase during week for waeniimgahltss aenxdpohseepdattooce1l0l,u3l0a,r ahnydper1t00roppphmy.weSriegnoibfsiecarnvtedinactrewaeseekssin4,ab7,soolrut1e3 ainndthreela1t0,iv3e0liavnedr p1e0r0o0xpispommegrporuoplsi.ferTahtieona,utehsoprescisalulgygessitnecde tihnactretahseesseicnhahnepgaetsicmipgahltmibteoaylssCocoiAatoexdidwaisteh activity lwievreer eaflfseoctosbsweerrveeodbasterthviesd,doisnedilceavteilngdutrhiantgthterseaettmerneta.tmeDnutr-rienlgatreedcloivveerrye,ffheocwtesvewre,renorneveeorsfibtlhee. "LTOheAreEfLoreo,fu1n0deprptmhe(0c.o4n7dimtgi/okngso/dfatyh)isarsetuidnyd,icaatNeOd AbaEsLedoofn1.r0edpupctmio(n0s.0i5n mbgo/dkyg/wdeaiyg)htaandndabody weight gain, hypertrophy. and on increases in absolute and relative liver weights with hepatocellular eTyhnoommfoolrgdu(s2m00o1nak.eby)s.recIennttlhye croanndgue-cftienddianrgasntgued-yf,inTdhionmgfaonrdda(62-0m01oan)thadtmoixniicisttyersetdudmyailne Tchyenroemowlegrues3mmoonnkkeeyyssainnotrhael 2caapnsdul2e0cmogn/takign/idnagy0,gr2o,uoprs2a0ndmgo/nkeg/mdoanykeAyPFinOthfeorc4onwtereoklsg.roup. fTohremomrotnaklietyysawnedimghoerdi2b.1un10d3a.6ndkgweart etheexsatmairtnoefd tartealteamsetnto.ncAenidmaiallysfowresreiobgsoefrnpvoesodrtwhieacletdhaiolry arbecnoorrdmeadlbbeefhaovriotrh.e sFtoarotdofctornesautmmpetnito,nownadsayass1 eosfsetdreqautamleintattiavnedlyw.eeBkoldyythweeriegahftterd.ataThweere tmhoenskteuydsy awenrdeonfadstaeyd3o0vefronrigclhitniacnald hbelmoaodtoslaomgpyleasndwecrlieniccoalllecchteemdisotnreywaenaelkyspersi,ora1n0dthhoersmtaornteof (aanpdprPoFxOimAatleevleyl.24Bhloouordsfaofrtecrlitnhiecaflircsthedmosies)t.rySwaamsplaelssowceorleleacntaeldyfzreodmfeoarcehstarandiimoall, eosntrdoanye,2 02 000056 estriol, thyroid stimulating hormone, total and free triodothyronine, and total and free thyroxin. Aantismcahleadnudleadnanelcyrzoepdsyfo,rspaamlpmlietsooylfCtoheAriogxhitdlaasteeraacltilvoitbye.ofRtehperelsievnertawteirvee csoalmlpelcetseodfflriovmere,arcihght aunsidnglepfrotleisfteesr,atainond cpealnlcnruecalseawreraentcioglelne.ctBeidlefrwoamsecaoclhleacntiemdaflrfoomrecaelclhparnoilimfaelraftoironbielveaalcuiadtion daneatleyrsmiis.natTihone.foAllsoawmipnlgeotifslsiucvser(wwhaesncporlelseecntte)d ofrroremprceascehntaantiimvaelsafomrplPeFsOwAerceonccoelnltercatteidoannd epxraemsienravteidoinn: 1a0dr%enanleu(t2r)a,l-aobrutfaf,erberdaifn,orcmeacliunm,,ucnolleosns,odtuhoerdweinsuems,peecpiifdiiedd,ymfiosr p(2o)s,siebsloephfautguurse,. eyes e[npdr)e.segravleldblianddDearv,ihdesaorn,'silfeiuxmat,ijveej(u2n)]u,m,fekmiudrnewyit(h2)o, nleesmioanrsr, olwive(ra,rtliucnugl,arlsyumrpfhacneoofdteh(emdeissetnatleric) (m2a)m,msaciratyicglnaenrdv,e,msuesmcilnea(lthviegshi)c,lepa(n2c)rsekaisn,,psiptiuniatlarcy,orpdro(scteartvei,carle,cttuhomr,acsiacl,ivaanrdy glluamnbadr)[,masnpdliebcunl,ar santdemuurimnawriythblbadodneer.maTrhreowa,drsentaolmsa,chl,iveers,tpsan(c2r)e,as,thsypmluesen,,tahnyrdoiteds(te2s) wfirtohm peaarcahthaynriomiadl, wtrearcehea. embedded in paraffin, microscopically, sectioned, stained with hematoxylin and cosin and examined Atrlelaatendimgarlosupssuravnidvetdhetroeswcahsednuoleedffseacctriofinceb.odTyhewerieghwte.reLnoowcloirnincoalfsoiogdnscoofnstuomxpictiitoyninwathse oobnsdearyve1d2faonrdonleowanfiomoadlcgoinvseunm2p0timogn/kwga/sdanyo.tedNoonfdoaodysco5n,7s,um1p1t,i1o4n 1w7a,sanndot2e4d,froersptehcitsiavenliym.al FTohretrheisweanriemanlo,edfefeccrtesasoendesftoroaddicool,nseustmrpiotli,onthyi roiindalsltilmiuklealtiihnogodhroerlmaotnede,totoAtaPlFaOndadfmrieneistration. 2traiinoddo2t0hymrgo/nkinge/,daayndAtPoFtaOl.anTdhefrreeewtahysronxoine.viEdsetnrcoenoeflpeevreolsxiwseormeenoptroalbilfyerlaotwieonr ofrorcemlalles given cpirtohleirfegrraotsisonorincltihneiclailverp,attehsotleosgoyrsptaundicerse.asoftreated monkeys. No adverse effects were noted in dInostehseo26f-we0,3e, k10stourdy3,0mmagl/ekgc/ydnaoymoflorgu2s6 mwoenekkesy(sThwoemrfeoradd,mi2n0i0s1tbe)r.edAAtPsFtOudybyinoirtailatciaonpstuhlee at mmoonnkkeeyyss iwneicagchheodf3t.h2e0ot4h.e5rkger.ouTpsh,ereDowseirneg4ofmaonnikmeaylssiinntthhee330mgm/gk/gk/gd/adyaygrdoouspeagnrdou6p was rsetcoepipveeddf2r0ommgd/akygs/d1a1-y2a1ndbetchaisusgerooufptowxaicsitdye.siWghneatneddotshien3g0w/2a0smrge/skugm/eddaoyngrdoauyp.22,Atantihmeaelsnd of tfhoera261-3w-eweekektrreeactomveenrtyppeerriioodd,. 2 animals in the control and 10 mg/kg/day groups were observed oAnnciemadlasilywafroer osibgsnesrvoefdpotowircheeadlatihlyorfoarbmnoorrtamlailtybeahnadvimoorr;ifbouonddictoynsaunmdpwteiroen ewxaasmaisnseedssaetdleast qwueaeliktsat2iv6elayn.d 4O0p.hthBaoldiyniwceiegxhatmidnaattaiownesrewerreecodrodneed wbeeefkolryinbietfioarteiotnohfetsrtaerattofmternetatamnedndtu,roinngday 1 oftreatment and weekly thereafter. Blood and urine samples were collectedforclinical 5 000057 h63e,m9a1t,olo18g2y,,2c1l7i,nic2a4l5cahnemdi2s7t5r.y,aBnldooudrisnaamlpylsiessbweefroerealtshoe tstaakretnofftorrehaotrmmeonnteadnedteornmidnaaytsio1n1s,;31, satrmipilodeosthwyerorneinaen,atloytzaeldafnodrferseteratdhiyorlo,xeisnt,roanned,teessttriooslt,ertohnyer.oidBlsotoidm,uluartiinnegahnodrmfeocnees,woetrael caonldlefcrteeed dcounrcienngtwraeteikon2aananldyseevse.ryT2heweaenkismatlhserweeafrteernodturfiansgtetdrbeeaftomreentcoalnldecrteiocnosv.ery for PFOA Alattesrcalheadbuleoefd tnhecerolpivseyr,wlaivsercoslalmepctleeds fwreorme etaackhenanfiormadletfeorrmpianlamtiitoonyolfCPoFAOoAxildevaesles.actTihveitryight afnraolmyseeasc,haanndimreaplrefsoernctealtlivperosliafmeprlaetisoonfleivvaelru,atriiognhtusainndglpefrtoltiefsetreas,tiaonndceplalnncurcelaesarwearnteigceonl,lecAtleld asvcahieldaublleedbialnedwuansscchoeldleuclteeddsfaocrribfiilceesa;cipdaidreetderomrignaantsiowne.reThweeifgohleldowsienpgaroartgealnys: waedrreenawlei(2g)h,ebdraaitn, ebpoiddyidwyemiigsht(2p)e,rkciednnteagye(s2)a,nldivoerr,gapnantcorebarsa,intewsetiisgh(t2),raatniodstwheyrreoicdal(c2u)lawtietdh. paTrhatehyfroolildo.wiOnrggtainsstuoes wepeirdeicdoylmliesct(e2)d,feosrohpihsatgoupsat,heolyoegsy:[praedsreernvaeld (i2n),Daaovritdas,obnr'asinf,ixcaetciuvme,(2c)o],lofne,mduurowdietnhubmo,ne marrow (laurntgi,cumleasresnutrefraicceolfymtphhe dniosdteal, emnad)m,mgaarllyblgaldadnedr,,phaenacrrt,eaisl,eupmit,ujiteajruyn,upmr,osktiatden,eyrsec(t2u),m,lessailoinvsa,ryiver, golradnd(c[emravnicdailb,ulthaorra(c2i)c,,sacniadtilcumnbearrv)e,, sspelmeienna,lsvteesrinculem (w2i)t.hskbeolnetealmamrursocwl,es(ttohimgahc)h,,sktiesnt,issp(i(n2a)l preserved in Bouin's solution, thymus, thyroid (2) with parathyroid, trachea and urinary bladder. `mTew/okga/ndiamaylds,osoengermouapl,e from were the 30/20 sacrificed imng/mkogr/idbauynddocsoendgirtoiuopn daunrdionngethmealsteudfyr.oTmhtehem3ale in the 3hy0p2oa0ctmiaviktgy/,dwaeyigdhotselogssr,oufpewwaorsnsoacrfeicfeisc,edloonw odrayno29.fooTdhicsonasnuimmpatlieoxnhiabnidtetdhesiegnntsiroefbody was oinlddicatotitvheoeftoaunchinbjeufroyrethdaetatohc.curNreecdroduprsiyngredvoesailendg easnodplhiavgeerallesainodnsgatshtartiwcelreesipornsestuhamtedwetroebe tarneiamtamlensthorewleatdedc.linTihcael asniigmnasloffrloimmittehde 3usmega/nkdg/pdaayrdaolseyofsgtrihosuephwiands slaicmrbisf,iacteadxoian adnady 137. This dyeptoearcmtiinevde,bbeuhtavAioPrF,Ofetwrefaetcmeesntancdounlodfnoootdbceornusluemdptouito.n. The causeofdeath was not c`Moanlseusmgpitvieonn3a0ndmgt/hkegy/ldoastywferiogmhtdadyusri1n-g11wheaedk c1loifnitcraelatsmiegnntso.fBfaeswedfeocnestahensdelsoiwgnsf,ootdreatment dwoasseswtaosppleodwoenreddayto 1210amngd/kwga/sdanyot; rtheissugmreodupunwtialsdathyen22.desWihgneantetdrethaetm3e0n/t2w0amsg/rkegsu/mdeady,rtohuep. OweFetkhseorfetmraeiantimnengta.niTmraelastimnenthtiosfgrtohurpe,e omnallyes2gtiovleernat3e0d/2th0ismgd/oksge/ldeavyelwfaosr thhaeltreedmoanindianygs2433 (thwieneakpp7e)a.r6a6nc(ew,eefkew10o)r,naondfe8c1es(,wleoewko1r2n)orefsopoedctcivoenlsyu.mpCtliionni,caalnsdigwnesigihntthleossse. anTihmealasniimnacllsuded appeared to recover from compound-related effects within 3 weeks afer cessation of treatment, st 000058 mMee/akng/dbaoyd.y wDeuirgihntgcwheanegke2s,wtehrisecnhoatnagbelywlaoswestratdiusrtiicnagllwyeseikgnsifi1 caanntd. 2Tfroeramtamleenstrweacseisvtiongpp3e0d on dsiagyni1f1icaanntdlywhleowneirt twhaasn rcoensturmoelsd datur2i0ngmgw/ekegk/sda7,y9aonndday24.21,Ovmeeraanllbmoedaynwebiogdhytwcehiagnhgteschwaenrgees tinhcrroeuagshedweiencki2de7ncweeroef nlootwabolrynloofwoeordfcorontsheummpatlieosninfotrhaen3i0m/a2l0s ming/tkhge/3d0a/y20grmogu/p.kg/Tdhaeyregrwoauspan that was considered to be treatment related. `sTthiemruelawteirnge hnoorcmoonnsei,stoenttoesrtcolsetaerrloynedotshea-trweelarteedseeefnfeicntsanoyn etsrteraotnmee,ntesgtrraoduipolo,veesrtrtiiomle,.thIynroid `mgge/nekrga/l,datyhygrrooiudphs.orTmroinieosdowtehryerodneicnreeraseemdaibneegdindneipnrgesosneddatyhr3o5ugihn animals day 183 in in the the 10 or 30/20 30/20 mg/kg. group. mg/kg Total APFO. thTyhreoxeifnfewcatsodnetchryeraosxeidn beginning was most opnrodnaoyun3c5edinaatndiamyal3s5 aidnmianniismtaelrseaddm1i0noirst3e0r/e2d0 010dmiem/iknigs/hdaayndanrdecdoavyer6y6wiansanoibmsaelrsveaddmeiintihserteirnetdh3e0l/a2st03mgm/okngt/hdasyo.f dTohseirncagfoterrd,urthiengeftfheect began rtiemceovienreyipthhearsdeoosfetghreoeuxpperiment. No changes in cholecystokinin concentrations were scen over "trTewaotmmeanlteswafsrosmtotphpee3d0/be2c0amugs/ekogf/pdoaoyrghreoaulpt,h,thheaodnmeosdaecrraitfiecetod moanrdkaeyd2i9ncarnedasoendesfeorruwmheonmzyme cdoenhcyednrtorgaetniaosnes,(ai.ndacsrpeaarttianteekaimniansoet)raannsdfearamsiel,dlaylainnicnreeaasmeidnosterraunsmfboirlaesea,cisdorcbointcoelntration. At d3e0c2r2e0amsegs/kign/adbasyo,luttheerneeuwterroephsilligchotunitn,crteoatsaelspirnotteriinglcyocnecreindtercaotnicoenntarnadtiaolnbsumainnd mcoinlcdenttoramtoidoenr.ate "miTlwdolayniinmcarlesasiendthseer3u0m/2b0ilmega/ckigd/cdoanycegnrtoruatpiohnasd.maArtke3dmlgy/ikngc/rdeaasyeodrse10rummg/ekngz/ydamye,aActPivFitOiehsaadnd o1f0peerffseicsttsenotnohredmealtaoyleodgyt,oxciocaegfufleacttisono,ncclliinniiccaallcphaetmhiosltoryg,y otersturriensaullytssisd.urTihnegrtehewarsecnooveervyipdeernicoed. rAetltaetirvmeinliavlersawceriigfihctesaitn2a6llwdeoeskes,grtohueprse.weTrhee satbastoisltuitcealllyivseirgwneifiigchatnst wiencrreeaisnecsreiansaebdsbolyut35e,a3n8d ainncdre5a0se%dibnyth2e0,3,2010anadnd6300%/2i0n mthge/k3g,/1d0ayangdro3u0p/s2,0rmegs/pekcgt/idvealyy;grroeulpatsi,verelsipveecrtiwveeilgy.htsInwearded.ition, minecarnealsveedrl-itvoe-rbrwaeiinghwtesigwhetrewacsonssiigdneifriecdanttrleyatimnecnrtearseeladteidn. thTeh1e0remgw/ekrge/ndoaytrgeraotumpe.nt-Trheelated `admraecnraols,cosppilceeonf, mpiacncrroesacso,piacndchtaesntgise.s iWnhialney othregraenswaastnthoeetveirdmiennacleosfacreinfhicaen,ciendclcueldlinpgrolliivfeerr,ation iwnastheevtiedsetensceoorfpmaintcroecahsoonfdtrihaeltprreoaltiefdermaotniokneyins,thtehelifveirnsdoifntgsreianttehdemloivnekrewyesre(Bequutievnohcaolf., pTehresroneal communication) Aabtsotlhuetreeocrovreerlyatsiavceroifrigcaen, twheeirgehtwseraet nreocotrveeartymesnactr-irfeilcaeteidndeifcfaetcitnsgotnhattertmhienlailvebrowdeyigwhetigchhasnogreson ss 000059 smeaacnroastctoeprimcinoarlmsiaccrriofsiccoepwiecrcehraenvgeerssiabtlethoevreerctoivmeer.y Tsahcerrifeiwceere notreatment.related T5-h8e, rreessupletcstoifvtehlye(a3nMalyEsnevsiorfonPmeFnOtAalinLatbhoerasteorruym,,2l0iv0e1r),.uriLneowanldevfeelcsesofarPeFpOrAewseenrteedofinteTnables dweetreectseidgniinfitchaentsleyrah,ilgihveerr,tuhrainnethaonsde sfeeceensoinftthheeccoonnttrorlosl.anIinmaglesne.raTlh,ePlFeOveAlslienvetlrseaitnetdhaensiemraalosf ttersetatamneinmta,lsthienscererausmedlewvietlsh wdeosree b1u2t6d+ec3r6e.a1segd/omveLritnitmheed3urmign/gktgr/edaatmyengtr.ouOpnadnady1959o7f+ 2392 ng/mL pg/mL in in the the 330m7g2/0kmgg//dkagy/gdraoyugpraonupd,Sa1n.d5 during + 77.6 weeks pg/mL 26/27, in the the serum levels 30/20 mg/kg/day were 52.5 + 9.14 group. PFOA ltheevel1s0 imngs/ekrgu/mdadyecgrreoauspedasocvoermptairmeeddutroi0n.g0r7e3c8ove0r.y0u0n2i5l6tihnetyherecaocnhterdols1.d1u8r+in0g.w82e7ekpg40/.mL in A124s,imainldar9t0r9end 2w0a9s psege/nmLinitnhethueri3n,e.10Oanndda3y0/92,0tmheg/lkegve/ldsayingtrhoeupusri,nreewspeecrti7v3e.l5y, a3n8d.1d,ur2i2n1g+ week same 26. the groups. levels were 51.6 During week 2, the13l.e7v,el1s09in+t7h5e.f2e,caesndwe1r9e.2le=ss27t.h0anugt/hge,lriemsitpoecftiqvuealnyt,itianttihoensien tmhge/kcogn/tdraoyl garnoiumpasls,,raesnpdec7t.i4v3el&y;6.d5u4r,in1g5.w4eek102.62 tahnedl5e6ve.l6s+we7r3e.72u.g9/2g1in.3t5h,e433,.100,+a3n6d.93-0a7n2d0103 +th2e0.hi8ghugl/egveilnstohfeP3,FO10A, asneden30in/2th0emfge/ckegs/odfaythgercoounptsr,olreasnpiemctailvseldyu.riTnhgewreeeiks n22o.exDpulrainnagtitohnefor recovery period, control fevels. PFOA levels in both urine and feces fell to levels that were comparable to tis difficult there is only otonedrtaiwmeapneyrifoidr,mwceoenckl2u7s,iofnosr awbhoiucthcdoamtpaafroartilviveerleavnedlssienrulimvecraanbndesceormupmarseindc.e At tshtiastepmoienntt,hloevweelvseirn bseccrauumseaopnpleayrttoonebetihmieghpeorintthawnatshaovsaeilinabtlhee floirverc.omTphairsisisonnoatnaddbeefcianuistei.ve daonsdilnigovefr tlehvreeles ainnitmhael3s0i/n2t0hemg3/0k/g2/0dmagy/gkrgougprowueprehasdimsitloaprped by week 12. At week 27, serum Umonrdtearlitthye) caonnddiatNioOnsAoEfLthweasstundoyt,etshtaebLliOshAedE.L was 3 mg/kg/day (liver toxicity and possibly s6 000060 ee Average PFOA Concentrations in the Serum (ug/mL) ofTreated Animals [Tmepoim-- ---------------- [Weeks 1100 [0472273 [9762235 [lesz080 | Co 000061 Table 6 Average PFOA Concentrations in the Liver (ug/g)of Treated Animals Omgkg/day | 3 mgkgiday | 10 mg/kg/day | 30720 mg/kg/day Week 20 Week 40 0.177500730 [1535502 [soo ns [1405755 [428563 Toniazoomr LReOsuQlt=s aLriemietxpofreQsusaendtiatsatgiroonu;pNaSve=raNgeosS+amthpelestandard deviation associated with that group. fDoarttaifairede saaccmuprlaeteretcoowvietrhyinwaosne9S0D%ofwitthheanavSeDroagfe 2f6or%t.ified sample recovery. The average 5 000062 Table 7. Average PFOA Concentrations in the Urine (g/mL) ofTreated Animals [Mimepoine 7 Week 6 0.0587 + Week 8 0.0161 + NF a 272% 140 1802109 0.0339 Week20 0.0248 0.0211 + 44.0599 Week 22 fr r T Week24 00231 + 0.0125% 4638.52 98.54134 56.0772 [[WWeeeekk332o--T1<110000----IINNSS---- Toserzoiis [Ns | Toil4z00608 [Ns] FreE Ie LOQ = Limitof Quantitation; NS = No Sample; Results arc expressed as group averages = the . 000063 Average PFOA Concentrations in the Feces (ug/g) of Treated Animals [MimePoine 77 ---- [Week10 0.00192 T<100-- T596:368 [260%174 [aso0=380 | Week 16 6.88262 3145233 1825288 PRE PT 0.00892 292135 43.0369 1032208 0.0.05, 1.5, 5, and 150 mg/kg/day APFO in :distilled water by gavage on gestation days (GD) 6- 000064 AwenriemaelxsawmeirneedsafcorriftihceenduomnbGerDof20cobrypocreravliuctaela,dinsulmocbaetrioonfavnidabtlheeaonvdarnioesn,-vuitaerbil,eafnedtucsoens,tennutmsber osufbrjeescotrepdtitoonesxitteesm,aalngdronsusmnbeecrroopfsiym.plAapnptratoixoinmasitteesl.y oFentues-estwhoefirterhwdeeifgethuesdesawnedrseexfiexdedanidn Broeumiani'nsinsgolfuettiuosnesanwedreexsaumbijneecdtefdortovisskceelreatlalaebxnoarmmianlaittiioensubsyinfgreacl-ihzaarnidnsreecdt.ioning. The Signsof maternal weights on GD 9, toxicity 12, and c1o5nastisttheedohifghs-tadtoissetigcarloluypsiogfni1f5i0camngt/rkegd/udcatyi.onsMeinamnemaantemrantaelmbaoldybody wsteaitgishtticoanllyGsDign2i0ficcaonntt.inuOetdhetro sriegmnasionflmoawteermtahlantocxoinctirtoylst,haatltohcocuugrhretdheondliyffaetrethnecehiwgahs-dnooste `Agdrmoiunpisitnrcaltuidoend aotfaAxiPaFaOndddueraitnhg ginesttharteieonradtiddanmost.apNpoeaorthteoraeffffeecctttshweeorvearrieepsorotredr.eproductive tractof the dams. 150 mg/kg/day for Under the maternal tcooxnidciittyiownesorfetihndeicsattuedd.y, a NOAEL of5 mg/kg/day and a LOAEL of dAosseiggnirfoiucpanotfly1h5i0ghmegr/kign/cdiadye;ncheoiwnefveetrustehsiswisktehleotnael mviarsisaitnigonstaelsmoeborcaccurwraesd oinbstehrevceodntartoltsheahnidgh tthheeroetfhoerre twharseendotosceongsriodueprse(dattosbimeiltareraitmnecnitd.ernecleatbeudt. loNwoersitghnainfitchaenthidgihff-edroesnecegsrobuept)weaennd treated annducomntorbfolmeaglrreouspasnwderfeemanloetse,dtfootralotahnedrddeeavdelfoeptumseenst,atlhepamreaamnetnerusmbtheart oifncrleusdoerdpttihoen msietaesn, diemspclrainbteatdiaosn asivtaers,iectoyropforaabnluotremaaalndmomrpehaonlofgeitucsalwecihghatnsg.esLilkoecwailiszee,datofetthale laernesaoffintdhiengeminbirtyiaolnlyal nthuecrleefuosr,ewnaost claotnesriddeetreerdmtionebde ttorebaetmaennta-rrteilfaatcetdo.ftUhndferreteh-ehacnodndsietcitoinosnionfgttheechstnuidqyu,eaanNdOAEL for developmental toxicity of 150 mg/kg/day (highest dose group) was indicated. ABasseecdoonnd otrhaelrepsruelntastaolfadervaenlgoep-mfeinntdainlgtsotxuicdiyt,yasntuudpypewrasdocsoenldeuvcetloedfi5n0rambgb/iktsg/(dGaoyrtwnears,s1e9t82f)o,r tahdemidneifsitneitrievde0s,tu1d.5y,i5n,wahnidc5h0fmougr/kggr/oduapys oAfP1F8OpriengdniastnitllNedewwaZteearlbayndgaWvhaigteeornabgbeisttsawtieornedays (piGtDui)ta6r-y18l.utePnriezginnganhcoyrmwoanseesitnaobrldiesrhetdoiinnedaucche soveuxluaatliloyn,maftoulrleowfeedmablyeabrtyifiivc.ialinijnescetimoinnaotfion awsitdha0y.05 omfigoefstpatoioolne.d sAemcoennstcaonltledcotsede fvroolmummealoef r|ambbUiktgs twhaesdaadyomifnisitnesreemdi.natIinodnivwiadusaldebsoigdnyated 3w-e2i9ghftosrwaebrneormmeaalsculriendicoalnsGigDns3.,6O,n9,GD12,291,5,th1e8,daoneds w29e.reTehuethdaoneiszewderaendobtsheerovveadrideasi,lyutoenruGs D aimnpdlacnotnatteintosn esixteasm.inFeedtufsoerstwheerneuemxbaemrionfecdorfpororgraolsusteaab,nolrivmealaintdiedseaadndfeptluascese,d riensaor3pt7ioCns and ivinsccuebraatloarnfdorsake2le4t-ahloaubrnosurrmvailviatliecsh.eckA. blPouopdsswaemrpelesuwbasseqtuaeknetnlyfrcoumthsainxidzoeedsanprdioerxtaomdionseidnfgorand wtheerneosnenGt Dto 1t8heasnpdo2n9s;oar floirvearnaslaymsipsl.e wTahisstiankfeonrmfartoimonthweassamuneaavaniilmaabllseoant GthDe t2i9m.eoAfllthsiasmples o 000065 review. oSwniegiGngshDtofg1a2m-ia2n9t.oenmAaGdlmDiton6xi-is9ctirwtayhtecinoonncsoiofsmtpAeadPorFefOdsttadotuicrsoitnnitgcraogllelsys;tsabitgoindoinyfidwcieadnitgnohtttraagnpaspiieennsatrrrteeotduuanfcfteeidcotntsothcieonnobtvoraodrliyclsevoerls rrfeoeprpormrotadetude.crtniaUvlendttoerxariccttihcteoyncwtoaennsdtisitonidfoinctsoahtfeetdd.hoees.stuNdoy,clainNicOaAloEoLthoefr50remagt/mkegn/td-arye,lattheedhsiigghnesstwdeorsee tested, mNaolessiganinfdicfaenmtaldeisf,fedreenacdesorwleirvee fneottuesdesb,eatnwdeefnetcalonwterioglhssa.ndLtirkaetweidseg,rtohueprse fwoerrtehenonusimgbneifricoafnt dciofnfceerpetnicoens rinecpiodretnecde,foarbtohretinounmrbaeer,oofrrethseor2p4t-ihoonuranmdoritmaplliatnytiantciiodnesnictees,ofctohrepofreatulsuetse.a,Gtrhoess dneevcerlooppsmyeanntdalskteolxeitcailt/yvicsocnesriaslteedxaomifanadtoisoen-srewlearteeduinnrcermeaarskeaibnlea.skTelheetaolnvlayrisaitginono,fextra ribs or mi1ny3/"1k3gr"iibd,raiwybis,t-h2sp0sutr%artieasdttio1cca5clumsrgir/gekndigf/iidncaatyhn,eceamnaitddt-h1de6os%heigaghtr-o0duompsgeolkgfgriodmuapgy)(/.3d8aA%ysa;ttaSthiOoswtmiegcv/aelklrgy,/sdtiahgyen.ibfi3ioc0laon%gtiacntael5rease oscicgnuirfriecdanacteothfe sthaimseefrfaetecainsdunwcaesrtnaoitn sstiantciestiincablolythsitghneifhiicgahn-tlaynddiflfoewr-endtosferogmrocuopnsr,otlhsis effect "mTgh/ekrgef/odraey, u(nhidgehrestthedocosnedgirtoiounps)owfatsheinsdtiucdayt,eda. LOAEL for developmental toxiityof$0 `Sctoanpsliesstecdtoafla. n(19i8nh4a)laatlisooncaonndduacnteodraa dpeorvteiloonp,meeancthalwittohxitcwitoytsitauldsyoorfeAxpPeFrOi.menTthse. sTthuedyfidrestsirginal twhaesstehceontderatrtioall,ogtyhepodratmisonowefrtehealsltouwdey,d itno wihtiecrhatnhdetdhaempsupwserweerseacsraicfiicfeidceodnoGnDda2y1;35w-hpiolsetin partum. For the inhalation portionofthe study, the two tials consisted of 12 pregnant SpragucDr1i5a.awll,Ienrytehsrepaetoscrtapilevreplogyrr,toiwuoepnroeefxtapdhomesiensditsutdtoye,r0e,2d50.0a1,annd1d,112100,S0pamrngad/g2ku5ge/-mdDgaa/ywmlA'ePyAEPrOaFtiOsnfcoforort6rhneohffoliusrbtsy/adgnadayv,saeogcneonoGdnDG6Dn6a-su1sm5i.bgenerFdoorf0bmogatrthoeudrposuftebemysaloreofastdamwtiiaonsnisbitrrenda,toitohrneo,ydffrweeaemnrarkel.ersaFniwkneearldelywm,iattthweiond abodrndeieatdniioannsgad-lnageyresodbuepdysbb(assoiidxsydawanemdisgwhhpteeranntdhe rou) were added to each trial that was pair-fed to the 10.and 25 mg/m' groups 2F1oratnhdeotbesreatrovleodgydapiolrytifoonroafbntohermsatludcyli(ntiricaal soingen)s,.dOamnsGwDer2e1,wetiheghdeadmosnwGerDe s1,ac6r,i9f,ice1d3,b1y6, and ctehrevriecaplroddiuscltoicvaetisotnataunsdocfxeaamcihnaendimfaorl awnaysgervoaslsuaatbendo.rmaTlhietioevsa,rileisv,eruwteeriugshtasndwecroentreenctosrwdeedreand seixteasm. inPeudpsfo(ritvheeannudmdbeeardo)fcwoerrpeocroaunltuetde,a,wleiivgehaenddadnedadsefxeetudseasn,dreesxoarmpitnioendsfaonrdexitmeprlnaanlt,ation veixsacmerianle,danfdorsvkieslceetraallaalltetreartiaotnis.oanTsshewehlelaadssmoafcarllo-coanntdromliacnrdoshciogphi-cdoevsaelduagtrioounop ffettuheseseywees.re @ 000066 ee tFroiarltorinael tuwpo,toiGn Dwh2i1c.h tThweodadmasyswbeerfeoraelltoheweedxpteocltietedr,datyhoefppraorcteudruirteiown,aseatchhe sdaammewaassthhaotusfoerd in awneiignhdeivdidaunadlecxagaem.inTehdefodratceloinfipcaalrtsuirgintsioonnwDaasysno1t,e7d,a1n4d,daensdig2n2atPPe.d DOany D1 aPyP.23DPaPmsallwderaems wwaersessuabcsreifqiuceend.tlyPwuepisgwheerdeacnodunitnesdp,ecwteeidgfhoerda,davnedrseexcalmiininceadl sfiogrnesxotnemDaalyaslt4e,ra7t,io1n4s,. anEdac2h2pPuPp.. "DTahyesey2e7soanfdth3e1 pPuPpsfowretrhee aglasvoaegexapmoirntieodnoonfDthaeysstu1d5y.andPu1p7sPwPerfeorsatchreifiincheadlaotnioDnapyor3t5ionPPanadnd.on examined for visceral and skeletal alterations. Inhalation Exposure "Trial One: T2r5ematgm/emn't-arenldactoendscilsitneidcaolfswiegntsoabfdomamteenrsn,alchtrooximcoidtaycrfoyrortrrihaleso,nech(rtoemraotrohliongoyr)rohcecau,raregdenater1a0l and cuonnkceemnptrtataipopneagrraonucpe,onalnyd).leTthhraregeyoiunt four dams at the of 12 dams died end of the exposure during treatment at period (high25 mg/m' (on GD 12, s1i3g,naifnidca1n7t).diFfofeordenccoensswuemrpteinoontewdasbestiwgneiefnictarnetaltyedreadnudcepadiart-fbeodthgro1u0psa.ndS2i5gnmigfi/cma'n;t hreodwuecvteiro,nsnoin bcoondcyenwteriagthitonwoenrley.alsLoikoebwsiesrev,esdaaitsttihceaslelcyosnicgennitfriactainotnsi,ncwrietahsesstaitnismtiecaaln sliigvneirfwieciagnchetsatwtehreehsiegehn- amtattehrenhailght-oxciocnicteyntorfat1 iaonndgr1o0umpg./mU'n,derrestpheectciovnedliyt,iwoenrseofintdhiecastteudd.y, a NOAEL and LOAEL for No effects were observed on the maintenance ofpregnancy or the incidenceofresorptions. gMreoaunp fpeatiarl-fbeodd2y5wemgi/gmh't.s weAredestiaginliefdimcainctrloysdceocpriecavsiesdceirnatlhaen2d5e-ymeg/emx'amgirnoautpisonanodf tihnetfheetcuosnetsrdoild nmogt/mr'ey,eaalsatantyisttirceaaltlmyesnitg-nriefliactaendteifnfcerctesa;sehdowinecviedrenicnetohef fceotnutsreosl wgirtohuppatrhtaitalwlyasospsaiifri-efdesdt2e5mebrac was observed. toxicity of 10 anUdnd2e5rmtgh/einc'o,ndrietsipeocntsiovefltyh,ewsetruedyi,ndaicNaOteAd.EL and LOAEL for developmental "Trial Two: tChlionsiecadlesscirginbseodffmoratteriranlaolnet.oxiMciattyesmeaelnbatod1y0 waenidg2h5t gmagi/nmd'urwienrgetsriemaitlmaerntinatty2p5e magnd/mi'ncwiadesnlceessto tdhaamnscdoniterddolusr,ianlgthtoruegahtmtehnetdaitff2e5remngc/em'w.asNnootostthaetristtriceaaltlmyensitg.nriefliacatnetd.effInecatdsdiwteiroen,r2epoourtteod,f n1o2r wtheerecoanndiytaidovnesorsfetehfefescttusdyn,otaeNd OfoArEanLyoafntdhLeOmAeEasLurfoermemnattseomfalretporxoidciutcytiovfe1paernfdor1m0anmcge/.m',Under respectively, were indicated. 000067 pSuigpnsboofdydewveeilgohptmoenntDaalyto|xiPcPit(y6.i1n this ga group consisted of 25 mg/m' vs. 6.8g statistically significant in controls). On Days reductions in 4 and 22 PP, pstuaptibstoidcayllwyesiigghntisficcoanntti(nDuaeydt4orPeP:ma9i.7ngloatwe2r5tmhgan/mc'onvtsr.o1l0.s3, alitnhcooungthrotlhse;dDiaffyer2e2ncPeP:wa4s9.n0otg at 25 mofg/thme'pvusp.s50o.r1wiitnhcoonpthrtolhsa)l.moNsocospiigcniefxicaamnitnaeftfieocntsofwtehree eryeepso.rteUdndfeorlltohweincgonedxitteimonasl oefxatmheinsattuidoy,n a NOAEL indicated. and LOAEL for developmental toxicity of 10 and 25 mg/m', respectively, were Onl Exposure "Trial One: GThDre1e1;outtwoofo2n5GdaDms12)d.ieCdlidnuircailngsitgrnesaotmfemnattoefrn1a0l0tmogxi/ckigtyAiPn FthOe dduarmisngthgaetstdaiteidonwe(roenesdimeialtahrotno those seen with treated animals inhalation compared exposure. to controls. FNooodacdovnesrsuempstiignosnofantdoxbiocidtyywweeirgehtnsowteedreforreadnuycoedf in the rLeipkreowdiuscet,ivneo psaigrnaimfeitcearnts dsiufcfheraesncmeasinbteetnwaenecneotrfeparteedgannadnccyonotrroilncgirdoeunpcseowferreesnoortpteidonfso.r fetal wfeoilglhotwsi,ngormiicnrtohsecoinpciicdeexncaemsinoaftmiaolnoffortmhaetieoyness.and variations; nor were there any effects noted "Trial Two: Saidmvielrasre oebfsfeecrtvsatoinonrsepfroordculcitniivcealpseirgfnosrwmearnecenoorteidn faonryotfhethdaemfseatasl ionbsteiravlaotnieo.nsLwiekreewinsoet,edn.o 3.7 Reproductive Toxicity Studies in Animals `3Y0orSkpr(2a0g0u2e)-Dcaownldeuyctreadtsaptewros-egxenpeerratdioosne rgerporuopduwcetrieveadtmoxiinciisttyesrteuddAyoPfFOAPbFyOg.avFaigvee agtrdoouspessooff 0ra.ts13co,nt1i0n,uaenddu3nt0ilmgm/aktgin/gdawyassixcownefeikrsmepdr,ioarndto and during treatmentof mating. the FO fTermeaaltemeranttsocfontthienFuOedmale. throughout gestation, parturition, and lactation. a"TnhdedFeOathasn.imaBlosdwyewreeiegxhtasmionfeFdOtmwaicleedraaitslywfeorreclrienciocradlesdiwgense,kalbyodrutiroinnsg, ptrheemdaotsuargeedpeelirvieordieasn,d tprhee-n aonndtchoehdabaiyotaftsiaocnripfeircieo.dsBoanddy twheeinghotnsgoestfFaOtifoenmdaalyesr(atGsDw)e0r,e7r,ec10o,rd1e4d, w1e8,ek2l1,y adnudri2n5g Gthie cnoecnessusmaprtyi)oanndvaolnuelsacitnaFtiOonmadlaeysra(tLsDw)er1e, 5r,e8c,or1d1e,d1w5,eeaknldy2d2ur(itenrgmtihnaeltbreoadtymewnetigphetr)i.od,Fowhoidle in FO female 14,18,21, rats, and values 25 and wonereLDrse1c,or5d,e8d,we1, eaknlyddu1r5.ing the precohabitation period, on GDs 0, 7, 10, " 000068 bEesftorroeusthceycslcihnegduwlaesdecvoahlaubaitteadtidoanilpyerbiyodexaanmdincaotniionnuoifnvgagunitniallcocnyftiorlmoagtyiboenogifnnmiantgin2g1 bdyaytshe psrcehseednucleedofsascrpiefrimce,intahevsatgaignealofsmtehearesotrrocuosnfciyrcmlaetwioansoasafsascsoepdu.latory plug. On the day of cWoihtahbiintaetaiconh,doonseagmealgreoruapt,pceornfseemcaultievreato.rTdherewcaoshaubisteadttioonaspseirginodpacroennstiasltegdenoerfa2tmioanxiramtsutmoof 14 d4asyGs.DF0eamnadleasrsaitsgnweidthtoeviinddievnicdeuoalfhsopuesirnmg.in aPavraegnitnaallfsemmeaalresowrecroepuelvaatlouraytepdlufgorwelernegtdhesoifgnated giemsptlaatnitoant,ifoenrtsiiltietsy,ignedneexr,algecsotnadtiitoinoinondfetxh,enudmabmeranadndlistetxe doufroifnfgsptrhienpgopsetrpalritteurm, npeurmiboed,rloiftter sbiezheavainodrvoifabtihleitdy,amvisabwialistyreicndoerxd,edlaocnatLiDosn i1n,d5e.x,,pe15r,ceanntdsu22r.vival, and sex ratio. Maternal FstOudgyenfeorratmiaolnearnaitsm,ail.sc.,waafrteersaccormipfliecetdiobnyocfarthbeoncodhiaobxiitdaetiaosnphpyexriioadt;ioannd(dLayD12026f0or 1f1e0maolfetrhaets), nsuercfraocpessieadn,daonrdifeixceasm,iansewdelfloragsroinstserlneaslioensx.amiGnraotsisonnoefctroipsssyueisncalnuddeodrgeanxsa.minIantdiiovindoufaelxotregrannasl bwrearien.wkeiidgnheeyds,asnpdleoerng,aonv-atroi-bso,deystweesi,ghtthyamnuds,orlgiavner-,toa-dbrreanianlwgeliangdhst,rpaittiuoistawreyr,eutcearlucsulwaittehd for the ovevsiidculcetss, a(wnidthcacrvoiaxg,ullaetftinegpigdliadnydmsiasn(dwwhiotlhe aanndd wciatuhdoau)t, rfilugihdt).epiTdiisdsyumeissr,etparionsteadtienannedutsreamlinal bvaugfifnear,edut1er0u%s,fwoirtmhaloivnidfourctp,oscseirbvliexhiasntdoloovgairciaels,evrailguhatttieostnisi,ncsleumdiendalthveespiictlueist,arryi,ghatdreepniadlidgylmaindss,, apenrdsperxostfartoe.m tHhiesctoonltorgoilcaalnedxhaimgihnadtoisoangewagsropupesr.foArlmlegdroosnstliesssuieosnsfwreorme1e0xraamnidnoemdlyhissteolleocgtiecdalrlayt.s All FO generation rats that died or appeared moribund were also examined. `Hciosntdoulcogtiecdalinerxaasmitnhaattieoxnhoibfittehde rreedpurocdeudctfeirvteiloitrygbaynseiithtehrefaliolwi-ngatnodmmaitdc-,dcoosnecegirvoeu,pssirwea,sor dmeolripvherolhoegalytwhyeroeffaslptreirnegd;. oSrpfeorrmwhniucmhbeerst,romuotsicliytcyl,iaitnyd or sperm number, morphology were motility, or evaluated in the left cinautdhae elepfitdtiesdtyism.isTohfeFOnugmebneerraatnidondimsatlreibruattiso;ntoefstiimcupllaarntsapteiromnatsiitdescownecreentrreactoirodnesdwienreFOevaluated gfoerneprraetginoannfceymasalteusr.ats.UteRraitosftahaptpadriednntoltydneolnipvreerganalnitterr awserweerseacerixfaimciedneodn tGo Dco2n5fiarnmdtehexaambisneencde opferifmoprlmaendt.atiFoenmasiltees.raAtsgwriotshsounteacrocposnyfiorfmethdemtahtoirancgicd,ataebdthoamtidniadlnaontddpeleilvveirc avilsictteerrawwearse sacrificed on an estimated day 25 of gestation. AintFsOchfeedmualleedrsaatcs,ribflicoeo,dafstaemrpcloemsp(l1e0timoanloefs tahnedco1h0afbeitmaatlieosnepaecrhiofdorinthFeO1m0aalnedra3t0smagn/dkogn/dLaDy 22 dose groups: 3 males and 3 females for the control group) were collected and frozen for future. os 000069 awnearlyesipsr.oviTdheedmaentdhtohdesrseescutlitsondicditnesotthaaptpleiavrertosabmepalveasilwaebrlee aatlstohecotlilmeecotefd,thbeutrenpoorto,ther details "vTahreiaFtIiongsenferroamtieoxnppeucptsedinlaecatcahtiolinttbeerhwaevrieorcoaunndtgerdoossnceextdearinlayl. pPhhyyssiiccaallasniogmnasli(eisn)clwuedirneg rLeDco1r2d.edallfoFrIthgeenpeurpasticoancmhadlaye.puPpuspwbeordeyexwaeimgihntesdwfeorrethreecporredseedncoenoLfDnsipp1l,e5s,.8,Pu1p5santhdat22d.iedOn bPeufposrefoeuxnadmidneaatdioonnoLfDthse2l0itte2r2fworerpeupexviaambiilnietdy ofonrLgrDos1swleersieoncsvaalnudatfeodr ftohrevciatualsesotaftudseaatthb,irtAhl,l FI generation rats were weaned on LD 22 based on observed growth and viabilityofthese pups Aputpwsepaenrignrgo(upL)D w2e2r),e tsweloeFctIedgefnoerrcaotnitoinnpuuepdsevpaelruasteixonp,errelsiutletripnegrignr6o0u0p t(o6ta0lmraaltse (a3n0d06r0atsfepmearle swehxe)naspsoissginbelde,towethreefsievleecdtoesd.ageFIgrgoeunpesr.atAitonlepausptstnwootmsaelleecpteudpsfoarncdotntwionufeedmaolbesepruvpastipoenr fliotrter, sNeexcuarlopmsaytuirnactliuodnedwearseinsgalcericfriocesds.-seTchtrieoen opfutphsepehreasdexatpethreliltetveerlwoefrteheexfarmointnaeld-pafroiregtraolsssutluersieons. atnhdymeuxsamfirnoamtioonneooffththe ctrhorsese-sseclcetcitoendedpubprasinpefrorseaxpppaerrenltthrydwreorceepwheailgy.hedThaendbrtahien,brsapilne,esnplaenedn, `eavnadlutahtiyomnu.s Aflrlomretmhaeitnhirnege psuelpesctweedrpeudpisscpaerrdseedxwpietrholuitttefruwrtehreer reextaamiinneadtfioornpossible histological mTahneneFrI agsentehreartiroenspreacttsiwveerFeOggievneenratthieosnasmieresdoasnadgdealmesv.el Doofstahgeetseswesruebsgtiavnecne oanncdeidnatlhye,same wbeergienenxinagmiant ewdeafnorinaggeanodf vcaognitnianluipnagteunnctyil, btheegidnanyinbgefoonredsaaycr2if8icpe.ostFp1argteunmer(aLtiDon28)f.emFa1le rats `generation male postpartum (LD rats 39). were evaluated Body weights wfeorreagreeocforpdreedpuwthiaelnsreaptasrarteiaocnh,edbesgeixnunailngmaotnuradtaiyon3,9 A table oatf.ra1ndroamnduonimtsaswsaisgnumseendtttooacsoshiagbnitFaItigoennerreastuilotnedrianstthoecpoahiarbiintgatoifonF,1 ogneenemraatlieornatsipbelrinfges,maalne alternate assignment was made. The cohabitation period consisted ofa maximum of 14days. BpeordiyodwaenidghotnsotfhtehdeayFoIfgseancreirfaitcieo.n BmaoldeyawtesigwhetrseorfetchoerdFeIdgweeneckraltyidonurfienmgatlheerpaotsstwweeraenriencgorded weekly during necessary) and the on pLoDsstw1e,a5n,i8n,g1p1,er1i5odantod c2o2h.abiFtoaotdiocn,onasnudmpotniDonGsva0l,ue7s, 10, for 14, the 18, 21 and 25 F1 generation (if mgeanleerartatisonwefreemarleecorartdsedwewreeekrleycodrudreidnwgetehkeldyodsuargienpgetrhieodp.osFtouvoedancionngsupmerpitoidontovcaolhuaebsitfaotritohne, FoIn GmaDtSer0n.a7l,fo10o,d 1o4n,1o8r,ab21ouatnLdD2515a,ndfooond cLoDnsu1m,p5t,i8o,n11vaalnueds1w5.ereBencoatutsaebupluaptsedbeagftienrtLoDco1n5,sume Aftemsaclheerdausl,edblsoaocrdifsiacme,plaeftser(1c0ommpalleetsiaonnodf10thfeecmoahlaebsiteaatcihonfoprertihoed1i0nanmadle30ramtgs/akngd/doanyLdDos2e2 in 3 000070 agnraoluypssi:s,3bmuatloenslyantdhe3sfeermuamleasnafloyrstehse fcoornttrhoelFgOrogeunpe)rwateiroencwoellreectperdesaenndtefdroiznetnheforrepfourttu.re The amnedthtohdesresseuctlitondicditneosttahpatpelairvetrosbaempalveasilwaeblreeaatltshoectolilmeeoctfetd,hebutrepnoorto.ther details were provided sFt2ilglbeinrethrsa,tiloivnelbiitretrhsswaenrdegerxoassmianlteedraatifoenrs.deElaicvehrylitttoeriwdeanstiefvyatlhueatneudmfboerrviaanbdilsietyxoaft lpeuapsts,twice afrcohm dthaeyonfestthieng2b2o-x.d"ayApnoosgtepnairttaulmdipsertiaondc.e DweaasdmpeuapssuroebdsfeorrveadllaltitvheeFs2e tgiemneesrawteirone pruepmsovoendLDs Tand 22 Parental Males (FO) One FO adverse male rat clinical siingntshe(e3m0acmiga/tkigo/n,dacyolddo-steo-gtrooucuhp,waansd sacrificed on day decreased motor 45ofthe activity). study due to Necroscopic mexaalmeirnaattsisounrviinvtehdattoansicmhaeldurleevdeaslaecdriafipcae.leSatnatdisttaincallilvyers,iagnnidfirceadntteistnecsr.easAelsl ionthcelrinFicOalgesniegrnastwioenre aalbsdoomobisncarlvfeudr,iannmdaluengrartosoimnetdhecohaitg.h-dose group that included dehydration, urine-stained pSeirginiofdiacanndtcroendtuicntuiionngs uinntiblodteyrwmieniagthitonanodftbhoedystwuediygihnttghaei3n,w1e0r,eanredpo3r0temdg/fkorg/mdoasytodfostehegrdouopssa.ge mAubskogldutaeyfdooosdecgornosuupm,ptwhiiolnevsailguneisfiwceanrteianlcsroeassiegsniifnicraenltaltyivreedfuocodedcdounrsiunmgpttiheosnevpaelruieosdsweartethe 30 observed in the 3, 10, and 30 mg/kg/day within those same periods. pNaortarmeeattemresnatsrseelsastede,d iefnfcelcutdsiwngerneumrbepeorrstoefddaatyasnytodoisnseelmeivnealtef,ornaunmyboefrsthofermaattsitnhgatanmdatfeedrt,ility `fcerothialbiittyatiinodne,x,anndumnbuemrbserosf oraftsprweigtnhacnotnrfaitrsmpeedr rmaattsiinngcdoahtaebsitdautriionng. tAhte nfiercstroapnsdy,sencoonnedowfetehke of sperm at any dpoasreamleetveelr,s evaluated (sperm number, motility, or morphology) were affected by treatment A3t0nmegc/rkogp/sdya,y.staAtbisstoilcualtley wseigingihftiscaonftthreedulcefttioannsdirnigthetrmeipniadlidbyomdiydewse,igohfttscwaeurdea seepeindiadtym3,is1,0, and tshemyimnuaslweverseicallesso(wsiigtnhifaincdanwtiltyhroeudtufcleudid)a,t 3pr0osmtga/tkeg,/pdiatyu.itarTyh,eleafbtsaonldutreigwhetiagdhrteonfaltsh,esspleemeinn,aland wveesiigchlteosfwitthheoulitvefrluwiadswasisgnsiifginciafnitclayntilnycrreeadsuecdedinianllthdeos1e0-gmrgo/ukpgs./daKyiddonseey gwreoiugph.tsTwheereabsolute tshiegn3if0icmagn/tklyg/idnacyregarsoeudp.in Athle o1,rg3,ananwdeig1h0tm-eto/-ktge/rdmaiynadlobseodgyrowuepisg,hbtuatnsdigrnaitfiiocsawntelryedseicgrneiafsiecadntilny fionrcrseoamseedoirngaalnlstarteattheed hgirgohupdso.seOgrrgoaunp,weaingdhts-itgon-ibfricaainntlwyeiignhctreraasteidosfworerotehseirgonirfgiacnasntalymornedguacleld treated groups. @ 000071 `rNgeolportmoredenuauctltmoiesvnaetaornredglaavntaescd,uwoeiflftaehtcittoshnewoeefxrcteehespetcieeonlnlastooffnteihcnrceorepaadssryeedonratluhipccookrnnteemsxisciarnontsdhceporp1oi0cmaiennxdeanm3ci0enomafgt/itokhngeo/zfdoatnyh.edose groups. cPSoeFnrcOueAnmtwarnaaatsliyopsnriesoseffnotr0it.nh0e3a4lF4l:Os0ag.em0np1el4re8astuitgoe/sntmemlda,PleiFnsOcAsl.uadmipTnlrgeecdaotnaetdrtomhlae.leeCnsodonhtfardocl5oh1ma.ab1lie9tsa.t3hi0aondansadhno4aw5ve.e3dr4a1tg2he.at ug/ml, respectively for the 10 and 30 mg/kg/day dose groups. Parental Females (FO) adNboossoetlruleteavetelma.enndtNrroetellraaettaievtdemefdnoetoadtrhceslooanrtseuadmdevpfeftreiscoetnscwvlaielnruiecesa.lrespiogrntsewdefroer breopdoyrtweedigihntpsa,rebnotdayl wfeeimgalhetsgaatinasn,yand nNTuhomenrbeeeorfwsetorhfeednnaoamttusrreadaletldmieevlneitrv.iernregylalatinetddereslf,iftteehcretosdbousrneartevisaottrniooounsfsgeweysectlraietciiaoyfn,f,emctatheetdianvbgeyroatrrgefeeasrttmfieolnirttyi,mptpahlraaatnmtiesat,tetrihsoe.n sites aopfenrpdrdseetglinlialvbneortrendraptlusi)pt,esrt,vhietahbneiulgmietbsyetaritnsiodoefnx,diapnmdusepx sw(einxtuhrmabtsietoirslo,lfbaodnrndampmusepasw,nitdbhairmotsnh ewweioitrghmhaotlrsl epwuelprisveedbcyooirmnnpgap,rulapibsvlemebuo1mr0bn er controls among al treated groups. aoNlrelgcrarenoaptwseeyidgaghnrtosd,uhpaisns,tdoeopxarctgehapontl-otfgooir-ctkaeilrdmenivenayalluaabntdoidoiynvewwreeriwgeehiagtlhstraost.uionsrTehwmeearrwekeaciboglhmetp.saorTfaebtrlhmeeintIoaelcoabnontdrdoylriwvgehaitlgukheissd,nfeoyr, wbarenaidignhhtewse-ritagot-hittoeswormefirtnehalessibgeonoidfryigcwaaennitwlgeyhitrgehwdtausscteoad-lstaoetrstmihigennaihfliigcbhaoensdttlyydworeseiedgouhcfte3da0nadtmog3f/katgnh/deda1lye0.fmkgTi/hdnedearyaytwi.eoiogfhtlitvoe.r wReassulptrsesoefntthiensaellrsuammapnlaelsystiesstiend,F0exgceenepraitnicoonntfreomlaslewshesraemptlheedleovnelLwDas22beslhoowwethdetihamt sPFoOfA `1q.ua0n2t0i.ta4t2i5onu(g0/.m0l0.5r2e8supgencyt)iv.elyTrfeoartethdef1e0maalneds 3h0admga/nkagv/edraaygedocsoencgernoturpast.ion of 0.37:+0.0805 and Fl Generation - Males pbNeeortcweeefnfetenactgtseroewafetremedaarlenepdpoructopenstd,raoltliatgneryosuidzpoessaewneldreveaevlneofrtoaergdethfpeourvpitahbbeiolndiuytmywbaeenirdgshltoafcpteparutiplosinttsieurnrdavitciebvsii.rntgh.NpoePrudlipiftftbeeorr,detynhcees 8weoifghltactoantioan.perOflitttherebpauspiss wneacsrospigsniicfdicaatnwtleyanriendgu,cendoisntatthiest3i0camllgy/skigg/ndifaiycagnrto,utpreoantmdeanytsre1l,a3t,edand a -------- Re ----m 000072 differences were organ weights to tohbesetrevremidnfaolr btohdeywewiegihgthstofantdhberbarianinw,eisgphleten and thymus and the ratiosof these tShiegnhiifgihcadnotsiencgrreoauspesoifn3t0remagt/mkegn/td-aryc.latOednederaatthwsa(s7 manoirmiablusndtotsaalc)riwfeirceedroenpodrateyd3i9npFo1stmwaelaensiinng afnodunadnodtehaedrownasdafyosu2n-d4dpeoasdtwoenandianyg,107 postweaning, but the majorityofthe FI male rats were dSutartiinsgtimcaolsltyosfigennitfiirceanptoisntcwreeaanseisnginpcelriinoidc.alTshesieosfgigtnonsxiicnsictlyuwdeedreanalisnocorebasseerdveidnciindeFn1cemaolfes mangn/uklga/rdacyo;nsatrsiicgtniiofnoicfanttheintcarielaaste all at doses, 10 and w3i0thmgs/taktgis/tdiacayl isnigtnhiefnicuamnbcee raot ftmheaIl, 10, and 30 rats that were `emaciated; and motor activity, a significant increase in the and abdominaldistention at 3in0cmidgekngc/edoafy.urine-stined abdominal fur, decreased cBoohdaybitwaetiigohntsanadnddubroidnyg twheeigehnttigreaidnossiwnegrepesrtiatoidstiincaallllytsriegantiefdigcraontulpys.redStuacteidstipcrailolrytsoigannidfidcuarnitng 3re6d,u4c3t-i5o0n,s ainndbo5d0y-5w7epiogshttwsewaenrinego.bsBeorvdeydwaetig1h0tagnadin3s0wmegr/ekga/ldoaysidgunrifiincgadntalyysr$e-d1u5c,e2d2i-n29t,he293-0 smigg/nikfgi/cdanaty,gdrooseu-preolnatdeadysre1d-u8c,ti1o5n-2s2i,n3b6o-d4y3,w5e7i-g6h4t,gaanidns6w4e-r7e0 opobsstewrevaendifnogr.thSetaetnisttriecadlolysage apter1i0odan(dda3y0s m1g-/1k1g3/pdoasytwdeuarniinngg)t.he eAnbtsiorleuptreecfoohoadbictoantsiuomnppteiroinodva(lduaeyssw1e-r7e0 spiogsntiwfeiacnanitnlgy),rewdhuicleed relative food consumption values were significantly increased. sSetaptairsattiicoanll)ywseirgenifoibcsaenrtv(epd<in0.h0i1g)hd-edloasyesainnimsaelxusavlemrastuusrcaotnicounrr(ethnet acvoenrtraoglesd(a5y2o.f2pdraeypsuotfiaalge versus 48.5 daysofage, respectively). aNnodapprpeagrneanntceyffiencdtiscweser(e onbseurvoefmdprobengannaeyncoirfesthpeemrantuinmgbeorr offerrtaitlistythpaatrmamaetteedrsanidncrlausdiinng fertility tchoehanbuitmabteiorno,frreastpsecwtiitvhelcyo),nftihremnedumamtiobngfeddaatryesstdouriinsnegmtihneatfci,rstthweeenku.mbNeor ostfatriatsstitchaaltlymated, and csoignnciefnitcraantti,otnr,eaotrmmeonrtp-hreollaotgeyd).effects were observed on anyofthe sperm parameters (motility, 3Ne0cmrgo/skcogp/idcayexraamnigniangtifornormevtaenalaerdeasstaitnistthiecallaltyesrailgnainfidcamnetdtiraenatlmeonbte.sorfeltahteedleifvfeercttos maot d3e,ra10t,eatnod slight dilation of the pelvis ofone or both kidneys. wStearteistoibcsaelrlvyeds.igniTfhiceanatb,sodloustee-rweeliagthetdsodefcrtehaeselsiveirn wteerrmeinsailgnbifoidcyanwtelyigihntcsroefaspeadreanntdalthFeIabmsaolleuste twheeiglhefttsaonfdt/hoer rsipglhetenkiwdenreeyssiwgenriefisciagnntilfyidceanctrleyasiendcraetasaleldtirneattheed 1graonudps3. mTg/hkega/bdsaoyludtoesewegirgohutpssof 000073 awnadsaslisgnoifsiicgannitfliycadnetclryedaescerdeainsetdhein3t0hmeg1/0kga/ndda3y0domsge/kggr/odupa.y dTohsee agbrsouoplsu.teTwheeigahbtsoolfuttehewetihgyhmtusof tdhoesapgroestgartoeu,p.brTaihnearnadtiolesoftfadtrheenwaleigglhatnsodfwtehree ssiegmniinfailcavnetsliycldeesc,rewaistehdainndtwhiet3h0oumtgf/lkugid/,daliyver and egrfotuapsn.d Trihgehtraktiidonsoeyfsthtoetwheeitgehrtmsinoaflthbeodlyefweteisgtihst,swwiethreansdigwniiftihcoaunttltyheintcurneiacsaedalibnuaglilnteraeaatnedd the Tighhetrtaetsitoissotfo tthheewteeirgmhintaslobfotdhye lweeifgehpti,diwdeyrmeiss,igeniffticcaanutdlay ienpcirdeiadsyemdisa,t r3igmhgt/ekpgi/ddiadyymainsdahnidghebrr.ain to the ofthe terminal body weight of the weight seminal were significantly vesicles with fluid increased at to the brain w1e0imggh/tkwga/rdeayinacnrdeahsieghdeart. |The ratios `wmegi/gkhtg-/tdoa-ybaranidnhwiegihgerh,t wwietrhestsaitginsitfiiccalanstilgyniifniccraenacseedatin| and the | 10 mg/kg/day. Theratiosofthe mg/kg/day and higher dosage liver girnocurpesa,seadnidntahlel trraetaitoesodfgtrohuepsl.etThanedrartiigohstokfidtnheeyspwleeieghntwse-itgoh-tb-rtaoi-nbwraeiinghwteiwgehrtewseirgneifsiicgannitfliycantly dSiegcnriefaisceandtalty d1 emcgr/ekags/eddaayt a1n0dahnidgh3e0r,mga/nkdg/tdhaeyr.atTiohseorfattihoesotfhtyhmueslwefetiagnhdttroi-gbhrtatienstweseiwgehitghwte-rtoe- sbirganiinfwiceaingthlty winecrreeaisnecdreaats1e0d imng/tkheg/3damyg/(krgig/hdtaytesatnisdohnilgyh)eranddos3a0gemgg/rkougp/sd.ayT.hese ratios were Hreilsattoepdatmhioclroogsiccopeixcamcihnaantgieosnowferteheobrseeprrvodeudcitnivteheoradgraennsalwagslaunndrseomfahrikgahbl-ed;osheowaenviemra,lstreatment{acnyitmoapllsatsrmeiactehdypweirtthr3o,ph1y0,aannddv3a0cumogla/tkigo/ndoafy t(hheepcaetlolscoeflltuhlearahdyrpeenratlrocpohryt)e.x) Nanodoitnhetrhetrleiavetrmeonftrelated effects were reported. FI Generation -- Females bNeotwefefeencttsrweaetreed raenpdorcotnetdraotlagnryoudpossewelreveelnoftoerdthfeorvitahbeilniutmybaenrdsolafcptautpiosnsiunrdviicevsi.ngNpoerdliiftfeerr,etnhcees pweericgehnttoagneampaelrelpiuteprs,balsiitsewrassizaelasnodsaivgneirfaigceanptulyp body weight per reduced in the 30 liter at birth. Pup mg/kg/day group body on days 1, 5re,l.aatnedd8doiffflearcteantcieosn.werOeFtohbesepruvpesd nfeocrrtohpeswieediagthtwseoafnitnheg,brnaoins,tastpilseteicnalalnydsitghnyifmiucsanat,ndtrtehaetrmaetnio-s of these organ weights to the terminal body weight and brain weight. Aponstiwnceraenaisnegidnatyrsea2t-m8enatt-trheelahtiegdhemsotrtdaolsietoyf(63a0nmigm/aklgs/tdoatya.l) wNaos oabdsveerrvseedcliinniFc1alfseimganlseosfon treatmentrelated toxicity were reported for any dose level during any timeofthe study period. Sotsateisatinciamlallyssiognnidfaiycasn8t,de15c,re2a2s,e2s9i,n5b0o,dayndwe5i7ghptosstawnedanbiondgy,wdeuirgihntg gpariencsohwaebriteaotibosner(vreedcoirndehidgohnhgeestdaatiyoncoahnadbiltaacttiaotniobne.gaDne,crwehaesnesFi1ngaebnseorlauttieonforoadtscwoenrseum9p2t-i1o0n6wdearyesoofbsaegrev),edadnudrdiunrgidnagys 1-8, -15 postweaning during precohabitation and during gestation and lactation in animals treated 0 000074 with 30 mg/kg/day. Relative food consumption values were comparable across all treated groups. pStaatteinsctiyc)alwleyrseigonbisfeicravnetd(ipnsh0i.g0h1-)dodseleaaynsiimnalssexvuearlsumsatcuornactuirornen(tthceonatvreorlasge(3d6a.6yodfayvsaogfinaagle versus 34.9 daysofage, respectively). oPfrieosrtrtuosmsattaignegs,ptehre2s1tuddayyasutinhohrisghn-odtoesdeaasntiamtaisltsic(a5l.l4y sviegrnsiufisc4an.t7 iinnccroenatsreolsin).thFeoarvteirsage numbers Calculation, determined. tThheinsutmybpeeorfocfailncduleapteinodnenctanocbceururseendceasosafsecsrtereuns in the 21 daysofobservation was for effects on th estrus cycle, but a m3oMreCodemtpaailneyd a(n2a0l0y2s)isrescheonutlldy cthoemnplbeetceodnadnucatneadlytsoisdetthaetrmsihnoewwehdetthheerretwheerree insotreuflfyecatns eofnfectth.e 4esdtrauyssocyfcdliee;stthreurseiwnetrhee ncoondtirfoflearenndcehsigihn dtohesenugrmobuepsr.ofAnfeamlaylseesswciotnhdu>c3teddyabsyotfheesUtSrusEoPrAwith = a(2n0d0h2i)gahldsoosdeemgornousptsr.ateTdhethcaytctlheesrewewreereevnaoludaitfefderaesncheasviinngtheeitehsetrrursegcuylcalre4a-m5odnagy tchyeclceosn,truonlcven acsyc4l-i6ngda(ydedfiiensetrduassbpreireifodpse)reixotdesnwdietdhesitmreugsul(adrefpiantetderans)3ororp4eridoadyssooffprcoomliofnigeeddsdmieeasrtsr)u,s (pdoesfsiinbeldy gprseeautdeorpdraeygsnoanft,co(mdieffiiendedsamsea6r-sg)r.eatTehredatywsoogfrloeuupksocwyetrees)nootr dpiefrfseirsetnetntinesatnryuos f(dtehfeinpeadraasmeSt-eorrs smetausduyraeudt.hoTrshuiss,dtuheetiontchreeawseayinitnhwehniucmhbtehreocfalecsutlrautsiosntawgaesspdeorne2,1 adnadysisthnaottwbaioslongoitceadllbyy the meaningful nNuombefefresctosfornatasntyhaotfmtahteemda,tfienrtgilaintydifnedrteixl,itryatpsarwaimtehtceornsf(inrummebdemrasotifndgadyasteisndcuorhianbigttahteiofni,rst week of cohabitation and numberofrats pregnant per rats in cohabitation). ANllumnbateurrsalofddelaimvesrydeolbisveerrviantgiolnitserwse,rtehealdsuoraatpipoanreonftlgyesutnataifofne,ctaevderbaygetsrefaotrmeinmtplaatntaantyiodnosseitleesveple.r pderleigvnearnetdrlaist)e.r,tthheenguemsbtaetrisonofinddaemxs(nwiutmhbestrilolfbodranmpsupwsi,thdaomnse woritmhoarlel pluipvsebdoyminpgupasnd/nluimvbeebroromf and stillbom pups were comparable among treated and control groups. tNhoe ptirteuaittmaernytarnedlattheedreaftfieocstosfwtehreepoitbusietravryedweoinghtte-rtmoi-ntaelrbmiondaylwbeoidghytsw.eigThhteaanbdsotlouttheewberiagihnt of rweesipgohntsew.erNeosoitghneirfidciafnftelyredneccerseawseerdearte3pomrgt/ekdgf/odratyheanadbshoilguhteer,webiugthdtisdonrortatsihooswfoardootshee-r organs evaluated. No treatment-related effects were reported following necroscopic and histopathologic examinations, F2 Generation Offspring n 000075 tNroetartemaenttm-ernetlarteeldateefdfeactdsvewresreeclrienpiocratlesdifgonlslwoewriengonbescerrovsecdopaticaneyxadmoisneatlieovenl,.wiLtihketwhiesee,xcneoption of sntoilmliblorknidnisdtnoomtaschhoiwn apudposset-hrateswpeornesefo(u31n2d8,de6a/d2.8,T1h0e/2n8u,m1b0e/r2s8,ofapndup6s/2f8oiunn0d,e1it,h3e,r1d0e,aadnodr30 bmeo/dkyew/ediagyhtdsosien gFr2ouppusp,srweespreectniovtelsyi)gnainfidcatnhtelryefdoirfefewreenrtefurnolmikceolnytrroellsa.tedAbtsootlruetaetmweenti.ghTseormfitnhael bbrraaiinn,wsepilgehetn waenrdetahlysmoucsoamnpdartahbelreataimosoonfgtthreesaeteodrgaannd wceointgrhosl-tgor-otueprsminal bod weight and to bNeotwefefeencttsrewaetreed arenpdorctoentdraotlagnryoudpossewelreveelnoftoerdthfeorvitahbeilniutmybaenrdsolafctpautpiosnsiunrdvicievsi.ngNpoerdliiftfteer,etnhcees pLeDrsce1n,t5a.ge8,of15m,a0le22p.upAsn,olgteenritsailzediasntdanacveesramgeeaspuurpedbofdoyr Fw2eimgahltepaerndltfteermawlheepnupmseaosnurLeDdso1nand 22 were also comparable among the five dosage groups and did not differ significantly. Conclusions mDoaslienagndwiftehmAalPeFFOI aotff3s0prmign/gk.gT/dhaeyaaupthpoerasroefd ttohedesltauydythceonotnseentdotfhastetxhuealdemlaatyusraitnisoenxuianlboth `fmacattutrhaattiotnhe(spereapnuitmiaallssehpaavreataidonecorreavsageidngaelstpaattieonncayl)aogbe,searvvaerdiainblheigwhh-idcohsethaenyimhaalvse adreefidnueed taosthe tmhaetutriamteioinn dinaytshefFrIomgeenveirdaetnicone.ofTmhaetianugthionrsthseaFteO tgheantergaesttiaotniounntaillaegveidaepnpceeaorfedsetxoubaeldecreased winhihcighht-hdeoysebealniiemvaelmseaatntthethteimaeniomfalacsquiinstihtaitongr(otuhep twiemree wyhoeunngseerxuaanldmmaoturreatiimomnatwuarsertehaacnhetdh)e, control group, in which there was no significant difference in sexual maturation. In order to gestational test age this hypothesis, with the delays the authors covaried in sexual maturation the decreases in body in order to determine weight and in whether or not body wweeirgehctosvaanrdiegdeswtiatthiotnhaelsaiggneifwiecraentalcyornetdruicbuetdibnogdfyacwtoeri.ghWtahenthethteidmeeloafysaciqnuisseixtuiaoln,matthueration Sdiefxfuearlenmcaetuwraastisotnillwsaisgnpiafritclayntr,elbauttedatttobheodp<yw0e.i0g5htv,ersbuust pn=ot0e.0n1t.irelTyh.isWhinednicattheesdtehlaatytshien dseelxauyalin smeaxtuuarlatmiaotnuroabtsieornv,etdheatrethweahsingho sdiogsneifgircoanutpdwiefrfeerceoncveeriendthweitthimgeesotfatoinosneatloafgseexatutahlemtaitmueraotfion mbaettuwreaetniocnonctoruollds paonsdsihbilgyh-bdeosatetarnibiumtaelds.toTdheicsreiansdeicdagteessttahtaitontahle aegfef.ectofdelayed sexual s"iTghneiafuitcahnotrsinaclrseoacsoevsairnietdhetahevedreacgreeansuemsbienroboftehsbtoroduyswsetiagghets apenrd2i1n gdeasytsattihoantalwaargeeowbistehrtvheed at the high dose of 30 mg/kg/day and found that the difference between treated and control animals. was still significant While it is known and commonly accepted that changes in the body weightsofoffspring can n 000076 aaflfseoctaftfheecttsitmheettoismeeoxufaalcmqautiusriattiioonn,iswphuertehleyrsopercnuoltatgievset,aetisopneacliaalgley,saisncdeeftihneered wbaysthneoaduatthaors, `mpartouvriadteidobnywithteh aguetsthaotrisontaolsuapgporistptrhoibslreemlaattiiocnsfhriopm.aAdsdtaittiisotnicaalllys,tacnodvpoairnitn.g tShiencdeeltahyerien sweaxsuanlo "siggensitfaitciaonntalcahgaen'g,ethine tdheecrleeansgetshoifnggeessttaattiioonnalata3g0e wmog/uklgd/dhaayv,eb1a0sbeeddounetmhoesatultyhotros'chdaenfgineistiionn of iSmtiell,toevseenxuiafla mraetluartaitoinosnh.ip Tbheetrweefoerne,gessteaxtuiaolnamlataugreatainodn tiismeessteontsieaxlulaylbmeaitnugractoivoanriweedrweitshhoiwtsnel,f.it `merely offers an explanation for the observed delays in sexual maturation in high-dose animals, but docs not diminish ts significance. Tbheer|emfogrkei,duanyde,rtthheelcoownedsittidoonsseotfesttheed,stbuadsye,dtohenLsiOgAniEfiLcafnotriFncOrepaarseenstainl tmhaelelisveirs aconndskiidderneedy to oweuilgdhtsn-ottob-etdeertmienramlibnoeddyswienicghttreaantmdetnot-brrealiantewdeiefgfhetctrsatwieosr.e AseeNnOaAt EalLl dfoosretshteesFtOedp.arental males rTehsepeNctOivAeElyL, baansdedLOonAEsiLgniffoircFanOtpraerdeuncttailofnsemianleksidanreeycwoenisigdhetraenddtokibdene1y0 waenidgh3t0-tmog-/tkegr/mdianayl, body weight and to brain weight ratios observed at the highest dose d"TehcereLaOseAsEiLn bfoodryFIwegiegnhetrsatainodn bmoadlyesweisicgohntsgiadienrse,datnodbien |temrgm/ikngal/dbaoyd,ybawesiegdhotsn;saignndifsiicgannitficant wcehiagnhgtess-tion-abbrasionluwteeilgihvtesr;aannddsbpaleseend woenisgihgtnsifaincadnti,n dtohseer-arteiloasotefdlrievdeu,ctkiiodnnseyi,n baonddyspwleeiegnhts and bAodNyOwAeEigLhtfgoaritnhse oFb1semravleeds pcroiuolrdtonoatnbdedudreitnegrmcionheadbistiantcieontraenadtmdeunrti-nrgeltahteedenetfifreectdsoswienrge pseereinoda.t all doses tested. "rTehsepeNctOivAeElyL, baansdedLOonAEstLatifsotricFaIllygesniegrniaftiicoanntfeimnaclreeassaerseicnopnossitdewreeadnitnogbmeor1t0alaintdy,3d0emlyay/skgi/nday, asenxduadlecmraetausreastiinonab(stoilmueteoffvoaogdicnaolnspuamtpetnicyo)n,,daelcroebasseersveindbaotdtyhewheiigghhetstanddosbeotdeystewde.ight gains, rTehleateNdOeAffEecLtsfowrertheeoFb2segrevneedraattiaonnyofdfosspersintgeswtaedsicnotnhseidsetrudeyd.toHboewe3v0emrg,/kitgs/hdoauyl.dNboe ntorteeadtmtehnatt- pthoesFtw2epaunpisngweerfefescatcsrtihfaitcewderate weaning, noted in tahnedFtIhugsenietrwaatsionno.t possible to ascertain the potential 3.8 Carcinogenicity Studies in Animals 38.1 Cancer Bioassays ("T3hMe.ca1r98c7i)n.ogIennitchipsostteundtyi,algorfouApPsoFfO5h0asmableeenanidnve5s0tifgeamtaeldeiSnpartawgou-ey-eDaarwlfeeeyd(inCgrls:wCdDyBiRn)rartasts n 000077 wSeexrewefreed dfieedts0,coonrt3a0in0ipngpm0,A30PForO3a0n0dpepvamluAaPteFdOafotrhetwooney-eyaerasr. Ginrtoeurpimssoafcr1if5icaed.diTthioenamleraants per amcgt/ukagl/tdesatyafrotrictlheecloonswuamnpdtihoinghw-adso:semaglreosu,ps1,.3reasnpedct1i4v.e2lym.g/kg/day; females, 1.6 and 16.1 Tthheerfeemwaalseraatdsoasse-rceolmatpeadrededctroeatshee cionnbtroodlys;wethieghdtecgraeianseisn twheermeaslteatirsattiscaalnldy tsoiagnilfeiscsaenrteixnttehne, in hciognhs-udmopsteiogrnowuapssoafcbtouatlhlyseixnecsr.eaTsheed (broadthyerwetihgahntdcechraenagseesd)a.reThterreeatwmeenrterneoladtiefdfseirnecnecefseeind `tmhoerctaolnittryolb,eltowwe-e,natnhde htirgeaht-eddosaendgruonutprseawteerde:gromuaplse;, t7h0e%s,ur7v2iv%alanadte8s8a%t;thfeemeanldeso,f5100%4,w4e8ek%safnodr 5i8n9c%i.deTnhceesoinnlythcelicnoinctarlols,iglnowo-bsaenrdvehdigwha-sdoasedogsreo-ureplsawteerdei:nc4r%e,ase18in%aatanxdia30i%n.theSifgenmiafliceanratts; the doebcsreeravseedsiinntrheedhbilgoho-ddocseellmcaoluentasn,dhefmeomaglleobriatnscaosncceonmtpraarteiodnstoacnodnthreomlatvaolcureist. vaClliuneiscawlere c(hAeLmTi)s,trayspcahrtaantgeeasmiinndoitcraatnisvfeeorfasieve(rAStoTx)icaintydianlcklauldineed pihnocsrepahsaetsasien a(lAaPn)inienabmoitnhottrraenastfeedramsael.e `Trvoeurpasnfdrkoimdn3e-y18wemiognhtthss,sbruet onnoltyedininthbeothhighhi-gdho-sdeosmealmeasleata2n4dmfoenmtahlse. raItsn.creSaisgensifiincarnetlantiovne-. nienocpildaesntciecoflelsiivoenrs mwaesrseess,cehnypperripmlaarsitliycinnotdhuelelsivaerndanfdocti,esatsn;dtihnetreestwiecruelarinmcarsesaseessiinntthheehigh- ddiofsfeusmealheepgartooumpe.galOotchyetrosliivse,r ytosxtiociedffdeecgtesneirnactluidoen,daosned-rpeolrtaatledmoinncorneuacselseainrtcheleliinncfiidlternacteioonfin bdootshe mmaallees.andAfsetamtailsetitcraellaytesdiggnriofuicpasn;t,thdeossee-irneclraetaesdesinwcerreeassetaitnistthiecailnlycisdiegnncifeiocafnotvianritahne htuibguhl-ar hdyopseerpglraosuipaswwaassf0o%u,nd1i4n%,feamnadle32ra%t,s; rtehsepeicntciivdeelnyc.e Boafstehdisolnestihoenseinttohxeiccoenftfreoctls,,lthoewhiagnhddhoisgeh- sdeelcercetaesdedinbtohdisyswteuidgyhatpgpaeianr,sitnochreaavseedrelaicvehredantdhekiMdanxeyimwueimghTtoslearnadtetdoxDiocistey (iMnTtDh)e.hemBaatsoeldogoincal ainncdidheepnacteiocfsaytsatxeimas,antdheovLaOriAaEnLtufbourlamrahlyepearnpdlafseimaa,lteheraLtsOiAs 3E0L0 fpoprm.fem[aBlaeseradtos nis increases 30 ppm.] in the Aofttthhee ltievrerm,intaetsitio,notfhtyrhoeids,tauddry,eanalslainghdtmiancmrmeaasreyingltahnedsi,nceitdce.)ncweoasfsveaernioiunstnheotprleaatsemdsa(ntimuamlosr.s `maAlmeonrgatst,haemn,dotfhemianmcrmeaasreyd fiibnrocadiendoomefatneisnctbiacetulhsagrr(oLuepysdiogf)fceemlallaedreantosmwaesreinsttahteishtiicgahl-ldyose Stiugmnoirfisc(anLtC(TP)<i0n.t0h5e)caosntcrooml,palroew-d atondthheicgohn-cduorsreenmtalceosntrwoalss.0/T5h0e(0i%n)c,id2e/n5c0eo(f4t%h)eaLnedy7d/i5g0cell (w1e4r9e%),11r/e5s0pe(c2t2i9v%e)l,y;21t/h5e0re(s4p2e9c%t)iavendin2c4i/d5e0nc(e4s8%of).maTmhmeairncyrefaisbersoaardeanlsoomsitnattihseticfaelmlaylseiggnriofuicpasnt aosbsceormvpeadriend1t.o34t0hemhailsetoarincdal1c,o3n2t9roflemianlceidSepnrcaesgu(eL-CDTa,wl0e.y82c%o;ntmroalmrmaatsruysefdibirnoa17denoma, 19.0%) cSaprrcaignuoege-nDiacwilteyystrautdsiisn(oCthhaenrdsrtaudeitesal.w,a1s99r2e)p.ortTehdetsopboentaapnperoouxsimiantceildyen5ce%o(fciLtCedTini:n C2l-eygegaertoladl., " 000078 r1t9s97,).inTdhuecrienfgorLee,yduingdecrelthteucmoonrdsitiinotnhseomftahliesrsatsudayn,dAmPaFmOmaisrcyarfciibnroogaendiecnoimnaSspirnatghuee-feDmaawlleey nas. "PTFheOiAndiunctmiaolneoSfpLreaygduieg-Dcaelwllteuym(oCrsD)warastscoatnfaidrimeetdariynlevfeollolfow3-0u0p p2-pymea(rCmaeockheatnail.s,m1s9t9u4d;y of (Bi8e7g6e,l 1et1a%l.) a2s00c1o)m.pAaresidgntiofitchaenctolnytrionlcsre(a0s/e8d0,L0C%T).inIcniaddednicteiowna,sPoFbOseArvalesdoicnatuhseetdresaitgendifriactasntly aindcerneoamseadsiinnctihdeenccoenstorofllaivnedrttruemaoterdsgarnoduppsanweerreaeti2c/8a0ci(n3a%r)cealnldtu1m0o/r7s.6 (1`T3h%e),inrceisdpeenccteisveolfy,liver whereas those one pancreatic for the acinar cpealnlcrceaartiiccinaocminaarince7l6loafdtehneomtraesatwederreat0s/a8n0d(n0o%n)eainnd870/c7o6nt(r9o%l)s.. There The was iwnacsidaelnscoeosifgnciofimcbaintnleydipnacnrceraesaetdiacsaccoinmapracreelldatodtehneomcaoynctraorlcsi(n0o/m8a0,in0%t)h.e treated rats (8/76, 11%) PFOA has also been shown to promote liver carcinogenesis in rodents (Abdellatif etal, 1991 Nilsson etal, 1991). 3.8.2 Mode of Action Studies "PTFheOmAecwhaasninsomt(msu)taogfeonxiiccoilnotghiecaAl/mcsarctiesntoguesniincgafcitvieosnotafinPsFofOASailsmnoontelclleaartlyyphuinmdeurrsituomo,d.or in an aaspspaeyarwittohsuSgagcecshtatrhoamtyPcFesOAcerisevniostiaaeD(NGAr-ifrfeiatchtainvdeLcoonmgp,ou19n8d0.). HSohwoervte-rt,erwmhgeennotteosxtiecdiwtyitahssays pmoeltyapblooliicdyacintiCvaHtiOonc,elPlFs O(AMuirnlid,uc1e9d96s)i.gniTfhiecanstiginnicfriecaasnecse ionfcthhreosem_ogseonmoatloxaibcerefrfaetcitosnsisaunndclienar. AIvnaeiclhaabnliesmd,atianvaoplpveianrg taoctiinvdaitciaotne otfhartetcheeptionrdsucatnidonpeofrttuumrorbsabtoyifoPtnFhsOe Aenidsoderuinteo s2ysntoenm-.genotoxic 382.1 Liver Tumors IpehraosxibseoemnewperlollidfoecrautmieonntiendthtehaltivAeProFfOriastsaapnodtemnitcpee(ro.gx.i,sIokmeedapreotliafle.ra1t9or8,5;inPdausctionogr etal., p1r9o8l7i;feSroahtiloennieuxissettsal.i,n ra1t9s92()K.awAassheix-mraeleatteadl,di1f9f8e9r)e,ncbeutinnottheininmdiuccti(oSnoholfeinvieurs eptera.o,xi1s9o9m2e). dTehpeenhidgehnetroinndtuhcetisoenxohfolrimveornepetreosxtoisstoemreonper(olKiafweraasthioinmianemtaal.,e r1a9t8s9w)a.sLsihkeowmnantoyboethsetrrongly opfepreorxoixsoimseomperolpirfoelriafteorrast,orAhPeFpaOtohcaasrcailnsoogbeeneesniss)hoiwnnrattos c(aTuaskeaghie,peattaol.meg1a99l2y;(Caonoeka,rly19b9i4o)maanrdker "mTihceeto(tKaelnitnyedofy,th1e9s8e7d)a,taanadppienadruscetooxsiudgagteisvtetDhaNt Athedalimvaergetoixnicliitvyeranodf actarsc(iTnoagkeangiiciettayl.of A19P91F),O mpraoymobteerehleaptaetdotcoaricnidnuocgteinoenosifspeinroraxtiss(oYmaegeprroalinfderYaatigoenr., Meanwhile, estrogen 1980; Cameron et al. has been shown 1982); an to crease in estrogen levels afier APFO exposure (discussed below) may also play a role in 7 000079 hroedpeanttoscabryciPnPoAgeRn-easlipshianargatosn.istRsecaernetulnyl,ikIeAlyRCto(b1e99o5p)ercaotnicvleuidnehdutmhaatntshebalsievderotnumoourrsciurnrdeuncted in understandingof the animal modeofaction. 3.8.2.2 Leydig Cell Tumors AIo lianrdguecenuLmebyedrigofcenllont-ugmeonrosto(xLiCcTc)oimnproautsn,dmsiocfe,diovredrosges.cheAmirceavlieswtroufcttuhreesavhaaivleabbleeeinnrfeopromratteidon ognroLupCsTbainsdeudctoinonthieniramniomdaelssofleadctaiwoonr(kCslheogpgpeatneall.,to19c9l7a)s.sifTyhtehecsoemcmoomnpotuhnedmse iinnttohseemveonde of ``arcotiwotnhfobrymdoisstrucptoimnpgotuhnedhsypiostthhaaltamtihce-speictuoimtparoyu-ntdesstiacfuflecatr tahxeishaotrmvaorniaoluscopnotirnotlsotfhaLteryedsiulgtceilnl tioncsrteiamsuilnagtitnhge tsheerpurmodleuvcetlisoonfolfutteesitnoisztienrgohneo,rmLoHnema(LyH)a.lsoItplhaaysabemeintopgoesntiuclartoelde tihnatthien Laeddyidtiigon cgerlolws,tah-sstuismtuailnaetdinigncmreedaisaetoinrscisruccuhlaatsinIgGLF-H1,leTvGeFls-fa,ndlecuhkrootnriicensestaindmvuarloioafutsLeifyredoeingradcieclalslsbcyan lead to LCT development (rev. in: Cleg etal. 1997). AmasleeriSepsroafgusteu-dDiaewslheayve(CbDe)enractosnedxupcotseeddtotoiAnvPesFtOiga(tCeotohke emteacl.,han19i9s2m;oBfietguemloretfaolr,ma1t9i9o5n; iLniu et avl.ari1o9u9s6)d.osNeolesvieglnsiffoirca1nt4 idnaycsr.eaHseosweinveLrH, sweerreumseaennditnestthiecurlaatrs laefvteelrstorfeeasttmreandtioolf AwePrFeO at shiagtnitfhiecaenltelvyatiendcreesatsreaddiaonldletveesltsosmtaeryonceaulseveelLseywdeirgecseilglnihfyipcearnptllaysdieacarneadstedu.moIrt fwoarsmaptoisotnulbayted a(cTtGiEng)a,s awhmiicthogbeinndasntdootrhceaehpaindceirnmgalgrgorwotwhthfafcatcotrorse(cEreGtFi)onr;etcheepttorraannsfdosrtmiimnuglgatreodwtchellfactor perxopleirfiermaetnitosn,hfaovreinsshtoawncne,thhaatsAbPeFenOdientcercetaesdedintLheeyldeivgelcsoelflses(tTreaedridosl ebtya.i,nd1u9c9i0n)g. cyStuobcsheqruoemnet 4Kn5o0wnXItoXi(nadruocmeatBa-soex)i,dawthiiocnhacnodncveyrttoschtresotmoestPe-r4on5e0tmooensotroaxdyiogle.nPaesreosxibsyobmiendpironlgifteortahteors are. peroxisome proliferation receptors). I is believed activation that APFO receptoar (PPAR a; induces cylochrome a subfamilyofsteroid P450 XIX (aromatase) hormone by binding to and activating the PPARG. A'lAtPhEoOuginhtshiegn1i4fidcaayn-tsitnucdricesa,seist ainppLeHarswetrheatniontcrseeaesneiinnSLpHralgeuveel-sDacwanlneoytbraetsrauflteerdtoruetattomebnet of iStnuvdoilevse,dsi(ginniafdicdainttioinnctroeianscereinasheedpaetsitcraadrioolmalteavesle)(iwnhtihcehicnodnuvcetritosnotfesLtoCsTterboyneAtPo FOes.traIdnitohle)se: aocbtsievirtvieeds aisnstohceiattreedatweidtrhatds.ecTreesatsoestdesreonreu,mwtheistcohstiesrsoynnetlheevseilzsedanadndinscerceraesteeddebsytrtahdeioLlelyedvielgscwelelrse,: iosrdreergutloatmeadinbtyaiLnHa;dteeqsutaotsetetreosnteosatnedroLneHpfloarsmmaa lcelvoesles,d-rleodoupcefdeetdebsatcokstseyrsonteemleivneltshe(cHaPusTedaxibsy. In ifnecerdebaascekdmaercohmaantiassme.acIttihviatsy)baereenepxopienctteeddou(0t ltehaatd itnocirnecarseeassiendLLHHmlaevyelnsottharlowuagyhstbhee nseegeantiinveall 7 000080 Sctoumdpieensosaftichoenmmicaaylshafvorewohciccurhrtehde tporeosptoosreed hmoomdeoestofasaicstiaonndcailnlasppfroorperlieavtaetetdimLiHn,goafndsatmhpalting `are some of the explanations for failing to detect changes in LH levels (Clegg et al. 1997). 3.8.2.3 Mammary Gland Tumors EasntdratdhieolovhearsexaplrsoesbseieonnosfhToGwnFtao shtaismubleaetne stuheggseesctreedtiaosnoofneTpGoFssibbley fmaactmomrainrypreopdiutchielnigal cells S`huesotpalianseidac(eLlilupetraol,l1i98f7)e.orfHmaeantcmemi,aoirtnyis tpousmsoirblceeltlhsatantdhethAePFsOub-sienqduuecnetddeelveevlaotpimoenontfeosftradiol lDeavwellseymaryatsalisnoabdedirteisopnontosiLblCeTf(orditshceusdseevdelaboopvmee)n.toInffmacat,mmthaisryis fcoinbsriosatdeentnowmiatsh itnheSpmreacghuaenism brayt.whIit chhasspboenetnadnecmoounssmtraamtmedartyhatnctahepleaasrlmysawpepreeardaenvceeloapneddhiinghagsipnogntfaenmeaoleusSipnrcaigdueencDeaowfley `exmpaomsmuarreytogleannddotguemnooruss iensturnotrgeeanteadn,dapgrionlgacfteinmaalseaSrpersaulgtuoef-Daanwalcecyelreartastiisngdeuffteoctinocnrenaosremdal, `age-related perturbationsofthe estrous eyele in this strain of rat (Cutts and Noble, 1964; Chapin etal. 1996). 3.8.2.4 Pancreatic Tumors oTthheermpeecrhoaxniissommebyprwohliifcehraAtoPrFs Oalsiondpurcoedducpeanpcarnecarteiactiacciancairnacerllcemllotrumsoriss uinnkrnatosw.nA.vaAilnabulmebedartao.f S(uCgCgKes)tltehvaetltsheecpoanndcarreyattiochaecpiantaircccehlolletsutmaosriss a(rCeoroeklaetteadlt,o1a9n94i;ncOrbeoasuerninestaelr.um1c9h97o)l.ecCysCtKokiisnian `pgarnocwrtehatfiacctaocrintahartchealssbienernatssh(oLwonngtnoecsktiemru,la1t9e87n)o.rmHaol,weavdearpt,ivdea,taanodn ntehoeprloalsetoifc gCrCoKwthinof pancreatic tumor formation are conflicting. 4.0 Hazards to the Environment 4.1 Introduction "`Tmhaedeaqmuoatriecdtiofxfiicciultty bayndsehvaezraarldporfobAlPeFmsOdtioscauqsusaetidcboelrogwa.nisTmhsesweaspraossbelsesmesd.coTmhpilsictaatsekdwtahse ask oFfurdtehteerrmmoirnei,ngthieftsheeprcocboltoexmisciltiymitteesdtstwheerceonvfaildiednacnedthcaotulcdoubledubseedpliancethdeoansstehsesmtoexnitc.ity test values, and the inherent tthouxsiciintytuarnndlohawzearreddotfheAcPoFnOfidteonacqeuoafticcoonrcglaunsiisomnss.that could be drawn in assessing G1e)nAervaalrliye,tytohefadimfmfeornenituAmPsFalOtsorwithtehtveatrryainbgutdyelsaimgnmaotniiounms saanltdwloatsntuemstbeed.rsThweereexatcesttecdo.mposition and identificationof impurities, which may affect toxicity, in cach lot number used is not known. " 000081 2f)roAmvaaprpireotyxiomfatteesltyin1g9l7a4b-o1r9a9t6o.rieTshicsonsdituucatteidontsheerAvePdFtOo itonxcirceiatsyesotvuedriaelslotevstevararpiearbiiolidotyfaindmethus made interlaboratory comparisons more difficult `3)maPjuorrictoyonfctemh.e tPeusrtietdymwataesrinaolt,sourffpiecriceennttlyecshtarmaactteerriiazleadnidnptehrecseenttesost.heIrnmsatoemreialt(ess)s, iwtaasppaeared tuhsaetd.10P0ur%ittyeostfctheesmtimcaatlerwiaals duoseeds;afinfeoctthteorxsicaictyheamnidcaslhooufldlebsesetrapkuernitiynt(oapapcrcooxuinmtawtehleyn8p5o%ss)ibwlaes, by expressing toxicity on the sam purity basis. 4m)aWnayteorf,thaentiosxoipcritoypatneostls,soflovrennto,oobrviaocuosmbiindniactaitoendorfebasootnh. wSeorleveunstesdawrietmhitxheedtewsittmhattheeritaelstin umasteedriianltetsotsmawkheeriet mtihsecciobnlceewntirtahttihoenstoesfttdhielutteisotnmwaattereiralbeafrocreextthreetmeesltyislboewguann.d aSovlevreyntssmaalrle o`afmtohuensteosfttuedsitesmawtheyriaalsomluvsetntbewaasdduesdedtoorthweatsesetvcehnamfboeurnsd.toItbweansecneostsacrlye.ar fInrofmactt,he3sMummaries `thSautmomfartihzeetdesctascuhbstetsatnacen.d"stTahtuesd,"iDnattahomseaytesntostwahcecrureat1e0ly0%retleasttemtaotxeirciiatlyowfatshenottesutsseda,mptlhee with vtoaxliuceistyonvaalu1es00h%adtetsotbceheamdijcuastlebdastiost,a5k0e tihnattotahcecoteusntts ctoheulpdebrececnotmspoalrveendi.(s), and to express the c5)hemiaclallthceosnecetnotxriactitiyontsesatrseoninlsytenaodmianlawlaytsesrtecchoemmimceanldceodnscoentthraattioonnes cwaenreacucsuerda.telMyeadseuterremdinteest dtheetearctmuianledtetshtacthtehmeicnaolmicnoanlcecnotnrcaetnitornattioownhsiacrhe otnhleyt,esftoorregxaanmipslmes 5ar0c%eoxfptohseed.meaIfsuriesd cmoenacseunrtreamteinotnsso, fthcehteomxiiccaitlycvoanlcueenstrwaitlliohnasvheotuoldachcaovredibnegelnybteaakednjuosrtmeaddbey a5v0a%il.ablAen.alTyhteinc,al Vroelcaotvileirtyy)rattheast cmoiuglhdthlaovweerbetehen adcettuearlmiconnecde,natrnadtipohnyssitcoowchhiecmihctahleptreostceosrsgeasn(ies.gm.s wheyrdreoelyxspioss,ed tcaokuelnd ahnadvethbeeerneltaatikoennshiinptoofacbcootunht.is kNnoomwinn,als may be used when measured concentrations are tInheosredteersttolipmriotcaetieodnswiatnhdatnoyassosrutmoeftehnavtitrhoenmneonmtianlalhaczoanrcdenrtervaiteinwonist wwearseneacne"sasdaerqyutaotei"gnore teoxxpirceistsyiaorneofbatsheedmoenasweulrle-destteastblcihsehmeidcvaalluceosnc(elnotrwaitsio>n1s0.0Cmrgit/eLr;iamfeodriaussmesosrimnogddeergarteeeiosf>a1c<u1te00 mg/L;highis <1 mg/L). 42 Acute Toxicity to Freshwater Species `iSenvenraol s(pPeicimeesphwaelreestpersotmeedltaos)a,ssbelsusegtihlelascuuntfeisthox(iLcietpyoomfisAPmaFcOh;rotchheisreusi)nc,lwuadtederthfeieafa(tDhaepadhnia m`aadgjnuast)e.d taond1a00gr%eteenstalcghaem(iSceallenaansdirtuesmtcraepsruiltcsoranruetpurme)s.enTtehdeitnoxTiacbilteyste9st(oerngdapnoiiznetds bhyavteesbteen ES 000082 substance) reference. and 10 (organized by test species). Each value is related toa testing facility and `rTawneglevdeftreostms 7w0erteo 8c4o3ndmugc/tLe.d wIittihs ufnactlheeaard wmihnynothwiss;ra9n6g-eh iLsCsSo0wivdael.uesAs(sbuasmeidngonthmeosretasltiutdyi)es are valid, and two acute dueto values the for limitations discussed above, bluegill sunfish also indicate these toxicity values indicate low toxicity (96-h LCS0sof low toxicity. 420, and 569 The mg/L). Nrainngeeadcuftreomte3st9stwoe>r1e0c0o0ndmugc/tLe.d wTihtehldoawpehrnivdasluaensda4re8-ihndEiCcaSt5i0vevoafluemsod(ebraastede otonxiicmimtyo,bibluitzathteion) wide range makes interpretation difficult. Sdeenvseinty,tecsetlslwceoruentcso,nadnudcdtredywweiitghhgtrse)enraanlggaeed;f9r6o-mh 1E.C2S100>v6al6u6esmg(/baLse(tdhoenErgSr0owctelhlrdaetne,sicteyllvalue otofxi1c,i0t0y,0 bmags/eLd iosnexthceluadceudtefcrroitmertiah.isTdhiseculsoswieorn)v.alTuheewolouwledravlasloubeeiinnddiiccaatteisvheiogfhmtoodmeordaetreate mtogx/iLci.tyb.asbeadseodnocneltlhceocuhnrtosn,ifcormogdreeernataelcgraitewraisona(ls0o.c1a1lc0ulmagt/eLd)i.n oAne14s-tdudyE.CST0hivsaliuseoinfdi4ca3tive othfelmoowscthsreonnsiictitvoexitceistty,spbeacsieeds oinntthhee4c4hr%onAiPc FcrOitteersitonsa(m1p0lemg,/dLa).phnGirdesewnearlegateheapnepxetarmeodstto be sensitive, and fathead minnows were the least sensitive. 000083 able 9. Summary phages of AcC ute Ecol7 ogical To7 xicty DataCforC APFO (grouped ee by fest | Test Organism [ES APFO ammonium ait [Duration [Vmagl/uLe)" [Reference 1 |Fatheadminnow (Pimepprohmaella e996-s0 LLCCSS00 [[77066 T3MMCCoommppaannyy,: 11998704s | _ [9b6e:0hLcCsSo0 J[301 o[W3MadCeomrpsany1.09t5ose | BIlmuaecghirlolchsiurnufsi)sh (Lepomis 196-h LC50_|>420 3M Company, 1978 | Water Nea (Dapiimia magna) F4SoEEoCCS0 [126 1000 [La3bMoEFrnatvroirryoa.nm1me9n5ta2al [44S8HhEECCSS00_ 2[12210 5WLaMaCrboodrmapttaaorlny,y,,119998152 987||1 Green algae Selenastram (capricornutum) Ward etal. 1995 Bacteria (Photobacterium SO-min 870 5M Company,1987 osphoreum) f [ECS0 |_ _ 3C0-mi0n |1730 [[L3MaEbnvoirronmoebnteanl ~ | Activated shudge min [1000 3M Company, 19806 | lL[Test Sample: APFO pm INOEC pepio ComC p 7 eso [| [TTTj [r p[TFeaosttheSeaadmmmpilne:noAwP(FPOimaempmhoalneisupmrosmiaetlas3)09%6P-Ewhe haLLtCeCr3S0O 843 3[3MM CCoommppaannyy,, 11998754b | PGR NOEC 500 19904 [EnviroSysiems, Tne, fo_ r lca_ (Daph_ nia mag_ na) [8f HECS0 l [592 o [EnviroSe ystems, Is nc. | p Bacteria (Pe horobacteriam hosphoreun; [0-_min [500 3iMsEsnvoironmental | [Ecso Laboratory. 1990a [T(AecsttiSvaatmepdsliea:dAgePF~O~ammonium sait inB500m%inwater, [c5o0nt0inueSdM Enviconmental -- [cso wo [Laboratory 19900 000084 [[TFeasttheSaadmpmlien:nAowPF(OPiammepmhoanliesumprsomaellas)i9n6-h80L % wateC r [4S 94 0 [Ward etal. 199Ga (Water flea (Daphnia magna) [Green algac (Selenastrum [8-HECS0 1240 [Ward etal. 1996 capricormutum) [96 ECS0 > 666 [Ward etal., 19961 Bahcotseprhioar(ePuhmo)tobacterium { E30 msin o|630 [30min [390 3[LMaboErnavtoirryo,nm1e9n9t6a0l [3M Environmental [Activated sludge ECs0 [30-min 5662 Laboratory. 1996 3M Environmental | I Test Sample: APFO _ in 50% isopropanol [ECs ----Itaboratory,1996 | Fathead minnow (Pimephales promelas)[96h LCS0 [140 [[TL.aRb.orWatiolrbieusr,yInc., 19%6a Waterflea (Daphnia magna) 8h ECS0 [360 [LTa.bRo.raWtiolrbieusr,y Inc., 1996b. carpernicaolrgnae (Selenasirum 96H ECS0 Pe Wilbury Laboratories, Inc. 1995 [Fathead minnow (Pimephalespromelas)96-h C30Pr R Wilbury [Fathead minnow (Pimephales promelas) aal Laboratories, Inc., 1995 R. Wilbury [TestSample: APFO (44%) in 27.9% water and Laboratories, 27.2% isopropanol Inc., 1995 (Water flea (Daphnia magna) FSHhECS0[aW1 ardet199a5 l.| (leGarpereincaolrnguateu(mS)elenastrum (cGareperniaclgoaren()Selenastrum raepernicaolrgnaucnu(mSelenasirum 96-h ECS0 96-h ECS0 G6 ECS0 *Values were adjusted to represent 100% active ingredient. These values may be inconsistent due to different diets tested. 5 000085 [Table10._ Summary [Test Organism of EecoologicalToxicity DaVtaalfuoer AP[FReOferenc(egrouped by species [Duration (mg/L) 4 [ minnow (Pimephales |96-hLC50 [707 3M Company, 1974 \promelas) 196-1LC50_[766" [3MCompany,1980a. 19S6o-hnLiCcSsO_ [[4340017 [33MCMCoompamny,p1199a877c4n5 y, } [96-hLCS0_843 96-h LCSO_T> 500 3M Company, 1985 [EnviroSystems, Inc., 1990a | 96:1 NOEC 500 W_|oErnvdirtoSays.tem1s9,86In0c., 1990a | | [06h LCS" 1407 [1T9.R9.6aWilbury Laboratories, Inc.| Soday Fo [EG&G Bionomics Aquatic | | L-- Busi sunfoh (Eepoms machrochirus) -I hECS0 [391 |lTo.Ro.sWilbury Laboratorics, Inc.| BOHECSD [i227 TR. Wilbur Laboratories, ne. = loos -- BLES = 20" JCompany, 1978 [96h LC50_[569" [3MCompany, 1978 Water lea (Daphnia magna) | | || [48-1 ECS0 126" [139M52Environmental Laboratory, 4SHECS0 [> 3M Environmental Laboratory, | L 48h EoCS0 2l2o1o"l[3o M Coms pany,s19876 -h ECS0 8-0 ECS0 202" [240 W[EnavierrotSadyl.stem19s9,6In.c., 19905 | [4}8-0 EC50" [3607 [1T9.R9.6W)ilburyLaboratories,Inc 2[2i1d-daayy C5043" 22" [3[M3CMoCmopmapnanyy., 11998844 IBNOlEeCy 2 I 5M Company, 1984 lIiNsOhECbso are Im war ShECS039 Wardetal. 1995 | cb apria corn()Selenasir~am~ [P96GhHEECC5S00[3696667 Ward etal, 1998 [Ward etal. 1996 1 1 0 000056 |[Table10.Summoafry [Test Organism | Ecological Toxicity Data for APFO (grouped by species) | -- a NE [Value [Reference 7 [EC50. [96-[2.h17EWCarSd e0 tal, 1995 [B96e-Rh EECC5S00 31.62"7 \WWaanrddeetraal.l, i1090955 A | | " 000087 I (Boacstpertioar(cPuhmorobacierium 1 fBSO0e--emmsiinn [[08070% P[M3MeCEomneparnnyo, 1n95L7abor, prEeCsoSo0nn r7 imef19o9n6 Tabor,~ 3l0cmsi)n [630 100s 3M Environmental Laboratory, | [EC50 I 1996 | Reva side cm3FN0aoiimmroienen 51|1"00000000"7" 5V[i1FN CECnoovmmippraaonnmyym,,en09a85l70o85 boe | Ecso | ooo, Lo eso {30-min |> fost 664" 3M Environmental alias wre 5d 0 epee 1009 2 "hese values may be inconsistent duc todifferent dicts tested. "Tested substance was APFO ammonium salt Tested substance was APFO PTested substance was APFO ammonium salt in 50% water. "Tested substance was APFO ammonium salt in 80% water. "TTeesstteSdasmupblset:anAcPeFwOas(A44P%F)Oinin2570.%9i%sowpartoepraannodl.27.2% isopropanol | Laboratory, | w 000088 5.0 References 3M Company. 1976a. Primary Eye Iritation Study-Rabbits. 3M Company. 1976. Acute Oral Toxicity in Rats-T-1585. 3M Company. Laboratory. St. 1P9a7ul7,. MRNe.ady Biodegradationof FC-143 (BOD/COD/TOC). Environmental 3FlMuoCroacmhpeamnicyalInFteCr-n1a4ti3onAacluRteesOeraarlcThoxaincdiDteyve(lLoDp)menSttuCdoyrpinorRaattis.onS.tu1d9y78Nbo.. Fluorad 137-091, 3M Company. 1979. Technical (USEPA AR-226 528) Report Summary - Final Comprehensive Report: FC-143. 3M Company. Environmental 1La9b8o0rca.toRrey.adySt.BiPoaduelg,rMadNationof FC-143(BOD/COD). Lab Request No. 5625S. 3M Company. Laboratory. St. 1981. Paul, Water, MN. Acetone and Toluene Solubility Estimates. Environmental 3M Company. 1984. Chronictoxicitytofreshwaterinvertebrates. 3M Company. Environmental L1a9b8o5raa.to9r6y-,hSot.urPaauclu,teMsNa.ticLatobxiRceiqtyuetsotfNatuhmebadermiCn10n0o6w. -- FX-1001 February 2. N3oM.CC1o0m0p6a.nyE.nvi1r9o8n5mbe.ntRaeladLayboBriaotdoergyr.adaStt.ioPnauol,f MFXN-.10F0e1br(uBaOrDy/1C4.OD). Lab Request 3LaMb CRoemqpuaensyt.Num1b98e7.r Activated E1252. St. Sludge Respiration Paul, MN. Inhibition Test. Environmental Laboratory; s3uMlfoCnoatmep:anCyu.rre1n9t99s0u. m"mTahrey Sofchuimaoenf Osnerrgaca, nheiecalFthl,uoarnadchteomxiicsotlroyg"yadnadt"aP.erFfelburouraoroyct$a,ne1999. (SEHQ-0299-373). 3M Company. 1999b. SEHQ-0699-373. Supplement. May 26, 1999. 3PeMrfCluoomrpoaoncyta.ne2s0u0l0fao.niVcolAucnitdaarnydUVsaeraionudsESxaplotsFuorremsI.nf3orMmaCtoiomnpParnoyfisleubfmoirssion to USEPA, dated April 27, 2000. 3AcMidCoanmdpaSnalyts.. 230M00C.oVmoplaunnytasruybUmissesainodn tEoxpUoSsEuPrAe,IndfaotremdatJiuonnePr,of2i0l0e0.for Perfluorooetanoic 5 000089 h3uMtpCi/owmwpwwa.ny3, M200.0c.cAobomut/3wMoarWlbodrwloiddweuirdeetl:ea3s3eM.mmP/lha.sing Out Some ofIts Specialty Materials. L3aMboCraotmoprayn,yJ.un2e00251.. InEnUv.Si.roEnmPeAntAadlmiMniostnratiivte-oRMeurclotirid-nCAiRtgy22S6t-ud1y0,330M. Environmental 3M Company, 2002. Submission dated September 17, 2002 to USEPA, AR 226, L3iMb ErnevqiuersotnmneunmtbaelrLGa2bo8r8a2t.ory. 1990a. MicrobicsMicrotox Toxicity Test. St. Paul, Minnesota. 3MiMnnEensvoitrao.nLmuenbtRaelqLuaebsotrantuomryb.er1G99208b8.2.Activated Sludge Respiration Inhibition. St. Paul, P3aMul,EnMvNi.ron3mMenLtaablorLaatboorriaetso.ry.3M199L3a.bIRmepqiunegsetrNSutumdbieesroLf33V0o6.latoiflFiC-t9y5 and FC-143. St. 3LMabERnevqiureosntmennutmableLrabPo1r6a2t6o.ry.St.1P9a9u6l3,.MiMincnreosboitcas Microtox Toxicity Test of FC-143. R3eMquEensvtirnounmmbeenrtaPl16L2a6b.oraStt.orPya.ul,19M9i6nbn.esoMtiac.tobiesMicrotox ToxTiesctofiFCt-11y8. Lab R3eMquEensvtirnounmmbeenrtaPl16L2a6b.oraStt.orPya.ul,19M9i6ncn.eMsioctr.obics Microtox Toxicity Test ofFC-1015-X. Lab L3aMb ERnevqiureosntmeNnutmableLrab0o0r-a1to8r5y1.. 20M0a1rac.hH3y0d.rolysis Reactionsof PerfluorooctanoicAcid (PFOA). S3tManEdanrvdi-ronTmeesnttCaolntLraoblorRaetofreyr.en2c0e01#bT.CRC-h9a9ra0c3t0e-r0i3za0t.ioPnhaSsteu:dySoolfubPilFiOtyAD(eltoter#m3i3n2a)t,ioPnr.im3aMry Laboratories, St. Paul, MN. P3eMrflEunovrioroocntmaennotaatle (LaAbPoFrOa)toirnyC2y0n01ocm.ol2g6u-sWeMeoknkCeapyssuAlemeTonxdiecdityAnSatluytdiycwalitLhaAbomrmatoonriyuRmeport "LTiivleer.DeSteerrummi,naUtriionneoafntdheFePcreessSenacmeplaensd.CoPnecrefnotrrmaitnigonLoafboPreartfolruioers,ooLcitvaenr,oaSteerFulmuoarnodchUermiinecal in LAanbaolryasteosr,ie3sM, IEncn.viSrtoantemeCnotlalelgLea,bPorAa.toArniaelsy,tiSct.alPaPuhla,sMeNC,omFpelceetsioAnnaDlaytsee,sJCuennetr11e,A2n0a0l1y,ti4c0al8 pp. cAabrdeclilnaotgiefn,esAi.sG.byPrpeeart,flVu.,orToaopcetran,oiH.cS.aciadn,daRpoebreorfxriosiodm,eMp.rol1i9f9e1ra.toTrh.eTmooxidcuolla.tiAopnpolf. rPahtarlmiavecrol. 111: 530-537 56 000090 AFilneaxlanRdeeporr,t.BH.Div2i0s0i1oan.ofMoErntvailriotnymsetnutdaylofanwdorOkcecrupsaetmiopnlaolyeHedaalttht,heSc3hMooClootftaPgueblGircoHveealftachi,lity. UniversityofMinnesota, April 26, 2001. RAelpeoxratn.derD,ivBi.sHi.on 2o0f0E1nbv.irMoorntmaelnittaylsatnuddyOocfcuwpoartkieornsalemHpelalotyhe,dSacthothoel3ofMPDueblciactuHreaflatcihl,ity. Final UniversityofMinnesota, April 26, 2001 BehB.aSterin,,G. Science 1966, Val. 154, p.1012. SByesatcehm..S. 31M995Cao.mpIannhyi,bitEonrvyiErfofnemcetnotfalL-L1a3bo4r9a2totroyM,iSctroPbaiucls,'MMNi,crLoatboRxeTMquTeoxsitcnituymbAenarlNy2z1e6r9. July 26. BEenavcihr,onSm. en1t99a5lb.LabIonrhaitboirtyo,ryStE.ffPeacutl,ofMLN-,13L4a9b2RoenquAecsttivNa2t1e6d9S,luJduglye.263.M Company Bpiecrgfellu,orLooBc,tanLaitue, Ron.CL.eMy.d,igHucreltl,fMu.ncEt.ioan,ndaCnoodk,ex.Cv.ivo19s9t5u.dieEsf.feTcotxsicoofl.amAmpopln.iPuhmarmacol, 134: 18.25, eBxitcrgaehl,epLa.tB.i,cHtuurmtotr,iMnEdu.c,tiFornabmye,peS.rRo.x,i0s'oCmoenpnroorli,fe1.rCa.,toarsnindmaJ.Cl. eCoCoDk.rat2s0.01T.oxiMceoclhoaginciaslms of Sciences. 60: 44-55. Bio/dynamics St. Paul. MN. IPnrc.ojec1t97N9o.. A78n-7A1c8u4t.e Inhalation Studyof T-2305 CoC in the Rat. 3M Company, Biosearch, Inc. St. Paul, MN. 1976. Primary Eye Iritation Stud~y Rabbis. Philadelphia, PA. 3M Company. MBoaegrnia,.R.,TRM.agWialzbuu,ryJ, LWabaorrda,torT.ies1,99In5c.., 3AcMutCeotmopxiacnityyLoafbLR-e1q3u4e9s2t tnoutmhbeeDraNp2hn3i3d2,,DJaulpyhn1i3.a PBioemreip,haR.l,esMpargoamzeul.asJ.., TW.aR.rd,WilT.bu1r9y95Lba.borAactuortieesT,oxIincci.,ty3oMf L-13492 to the Company Lab RFeaqtuheesatdnMuimnbneorw, N2332,July 13. aBonedrit,heR.F,reMsahgwaatzeur.AJl.,gaW,aSredl,enTa.st1r9u9m5cc.aprGircoowrtnhutaunm.d rTe.pRr.odWuictlibounryToLxaibcoirtaytoTreisets,wiItnhc.,L-31M3492 Company Lab Request number N2332. August 3. Boeri, R., Kowalski, P., Ward, T. 19954. Acute Toxicity of N2803-2 to the Fathead Minnow, 5 000091 NP2i8m0e3p-h2a.lesNoprvoemmeblaesr. 1T6..R. Wilbury Laboratories, Inc., 3M Company, Lab Request number PBoiemreip,hRal.esKopwraolmseklias,. P.T,.WRa.rWdi,lbT.ury19L9a5beo.ratAocruitees,TIonxci.c,i3tyMofCoNm2p8a03n-y4LtaobthReeqFuaetshteandumMbienrnow, N2803-4. November 21. NBo2e8r0i3,-R2..anKdowtahlesFkrie,shPw.a,teWrarAdl,gacT,. S1e9l9e5fn.asiGrruomwtcahpiacnodrRmuetpurmo.ducTt.iR.onWTiolxbiucrityyLTaebsotrawtiotrhies, Inc., 3M Company Lab Request number N2803-2. November 28. 4Boaenrid,tRh.e,FKroewsahlwsaktie,r APl.,gaW,aSredl,enTa.st1r9u9m60c.apiGcroorwmtuhtuamn.d TR.eRp.roWdiulcbtuiroyn LTaobxoircaittoyriTcess,t Iwnict.,h3NM2803Company Lab Request number N2803-4. March 7. MBoaegrnia..R., TK.oR.waWlislkbiu,ryP.L,abWoarradto,riTe.s,1I9n9c6.b,.3MAcCuotempTaoxniyciLtaybofReNq2u8e0s3t-n4utmobethreND2a8p0h3n-i4d., DMaaprhcnhia 25. mBaoegrnia,.R.,TRK.owWalislkbiu,ryPL.,abWoarradto,riTe.s,1I9n9c6.e,.3MAcCuotmepTaonxiyciLtayboRfeNq2u8e0s3t-N2u0mbtehre ND2a8p0h3n-i2d., DMaaprhcnhia 25 SBooily.d,MSi. ch1i9g9a3an.StaRteeviUneiwvoefrsTietcyh.niMcaayl R19e.port Summary: Adsorption of FC 95 and FC 143 in 4B8o2y77d,.p3$.0A.. 1M9i9c3bh.igRaenvSiteawtoe fUnTievecrhsniitcya.l Notebook.Soil ThinLayer Chromatography. Number hBuutlpt:m/ahno.mDe. haanndmiPri.kec,omM/.~ohfah3nMw/"nTehwes/U3sme.ohftmFlluorochemical Surfactants in Floor Polish' fBulruroirso,chJeMm;icaOllss.en,InGt:erSiimmpRseopno,rtC#;1M,aCnodreplo,raJ.te20Oc0c0uDpaettieornmailnaMteidonicoifnseerDuemparhatlmfe-nlti,ves3oMf several Company. hBuarlrfi-sl.ivJesMo,fsLeuvnedrbaelrgl,uoJrKo,chOelmsiecn,alGs.W,ISnitemrpismonR,epCo,rtMa#n2.del3,MJ.Me2d0i0c2.al DDeetpearrmtimneantti.on ofserum aCcaimdesroonn,heRp.aGt.ocmaaricidnso,gKe.n,esTissudinai,tiHa.teadnbdyIdti,etNh.yI1n9i8t2r.osParmoinmeo.riCvaencefefrecRtess.of42s:e2r4o2i6d.s2a42n5d,bile CarlfoJ.resta,l. Colloid Interface Sci. 103, 332 -336.(1985) 5 a -------------------------------- 000092 dCahwanlderyar,atsM., RAriclhe.y,ToMx.iGo.e1o.l.an66d:J4o9h6n-so5n0,2 D.E. 1992. Spontancous neoplasms in aged spraguc- CShyamppions,iRuEm.oSvterevvieewn:s,enLdTo.cHruignheemso,duC.lLa.,tioKneolefer,epWrRod.uctHieosns., RFu.nAd..aAnpdplD.asTtooxni,coGl..P.20:119-9176. CMhaejmogruBarreda.kt2h0r0o0.ughChineAmgFuFaFrdFirInec,FPigrhetsisngRFeloeaamseTeRec:hnCohleomgyg,uaJrudneI3n0c,or2p0o0r0a.ted Announces CMhircies,toFpihnearl,RBe.poarntd, IMnadruisatsr,iaAl.JB.io-1T9e77s.t No. T-1742CoC, Lot 269. L2a8bo-rDaatyorOireas,l TInocx.icSittuydyStNuod.y 8w5i3t2h-F10C6-5154,3 in Albino 3M Reference 1CI1ylpe0eg7rg-p,l1aE2sD1ia,.aCndaoakde.nLoC.maChfaoprmiant,ioRn:Em.,ecFohsatneri,smPsM.anDd.raenldevDaanscteotno,hGu.mPa.ns1.99R7.eprLoedyudcitg, cTeolxlicol. `InCfLoOrGmRat(ivo4n7S1y)steCmasl,cuInlca.twiownosfedhaydyrloipghhobti.cciotmy as Log P(o/w). 2001. Daylight Chemical Ci1n1o6do9uk.c.tiJo.nC,byHupretr,orMi.sEo.m,eFprraomleif,erSa.tRo.r,sainndCBrileg:eCl,BLR.B(.CD1)99r4a,ts.MTeocxhiaconliosgmissot,f1e4x:t3r0a1h,epaabtsitcratctumor Cbeuhtatvsi,orJHo.fatnudmoNrosb.leC,anRc.Le.r R1e9s6.4,24E:s1t1r1on6e--1i1n2d3u,ced mammary tumors in the ra. I. Induction and DPearkfionr,ma20n0c1e. CoNaotbiunhgsi"koinTsPauidnat,&DaCiokaitniInngduIsntdruisetsryLiMda.ga"zFilnueo,roJpuonley2m0e0r1E,mpu.l3s6i-o6n6,for HighSDeCrPvi.ce1s9.98D.allDaisr,eTcXt.oryofWorld Chemical Producers: 1998 Edition. Chemical Information DuPont. USEPA. 2000. dated JVuonleun2t3,ar2y00U0s.e and Exposure Information Profile. DuPont submission to D3yMnaAxF,F2F00A0g.entLest,tedratferdomAuEgduusatrd2,Kl2e00i0n.er (Dynax) to Charlic Auer (USEPA), Re: Phase-Out of Edwards, PIB etal. LANGMUIR 13(10), 2665-2669 (1997) pE7r8oG.m0&e3lGaosnB).ihoatnRcoehmpaibocirlstitA#yqBouWfa-t7ai8gc.eT6so-ax1ni7dc5o.glrooRgweytsheLaaabrnocrdhastruoerrpvyoi.rvtals1u9o7bf8m.ifrtytTeohdfetfeoaft3fheMecatdsCoomfmicpnoannnotyiw,n(uSPto.iumsePapeuixlhp,aolMseNusr.e to 000093 ee aEsllaispoDt.enAt.ialS. sAo.urMcae boufrhyal,Jo.gWe.natMeadrtoirngaannidc Da.ciCd.s G. i tMhueiernv2i0r0o1n.meTnht.ermNoaltyusries: o4f12f,lupopr2op1o.l3ym2e4rs AEllgnaalbaArsaswayy,TMesTt.Me1t9h8o1.d. 3RMepToercthnNiucmableRrep0o0r6t.SPurmomjaecrtyN,uMmubletir-9Ph7a0s0e3E0x0p0o0s.urOecRteocboevre1r6y. PEinmveiprohSaylsetsepmrso,meInlca.s.19H9a0ma.ptSotant,icNAH.cutSetuTdoyxincituy ofmwFaXbs-9100e1043-r3to.the Fathead Minnow, HEnavmiprtooSny,stNeHm.s,EInnvci.ro19S9y0sbt.emStsatsitcudAycuntuembTeoxri9c0i1t3y-3o.f FX-1003 to the Daphnid, Daphnia magna. EEnSv&iTr,on2m0e0n0t.alCIhmeprlyilcaMtoioondsoyfaTnhdeJiernnUisfeeriFniFeildr,e-"FPiegrhftliunogriFnoaatmeds"SuirnfaEcntvainrtosnamnednttahle Science & Technology, Vol. 34, Issue 13, p. 3864-3870. PElMasGt.ics20I01n.dustVreyr.baFlMcGo/mEmePnAtsmebtyintghe,FMlaurocrhop7o,l2y0m0e1r Manufacturers Groupofthe Societyofthe GErMoGupFPlrueosreoncthaetmiiocnaSlliMdaesn)u.facturers Group AR226-1094 2002 (Fluoropolymer Manufacturers GSaubbrmieilt,teKdarlt.o 3SMumCmoamrpaynoyf,: 3PrMimCaernyteSrk,iSnt. IPriatualt,ioMnN.Study- Rabbits. Performed by: Bioscarch SGaubbrmiietlt,eKdartlo. 3SMuCmommapraynyof,: 3PMriCmeanrtyerE,ySet.IrPraiutlat,ioMnXS.tudy Rabbits, Performed by: Bioscarch. G1a0rr%y.ClVo.nFa.,l aCenldlRL.iLn.eNfeolrsotnh.e Te1s9t81C.heAmnicAaslsaTy-o2f94C2elCloCTr.a3nsMfoCrommatpiaonnya,nSdt.CyPtaoutl,oxMicNi.ty in C3H GAemimsoyn.i1u.P.m, DPr.erf1l9u9o5r.ooc3taMncraetqeu:esSttaetdicexFpiesrht Toest"v. Geeoisfyr"BEicvooatcoxciiucmouelloagtywi,veIncP.ropMearrtciehs2o0.f GNuioersoJyc.hePm. iacnadlsKi.n Kfainshnatnis,u2cs0.01Pr.epAacrceudmfuolra3tMi,onoSt.fpPearuflluMoNr.ooJcutannee2s0u,lfIonnaU.tSe. aEnPdAr.elated Administrative Record AR226-1030A cGaiteinsgJyw.aPt.eranbdirdKs.. KParnenpaanre,d2f0o0r13.M,PeStr.flPuaourlooMcNt.aneJsuunlefo20n.ateInaUn.dS.reElaPtAedAfdlmuionrioscthreamtiicvaelsReicnofridsh AR226-1030A Giesy J.P. and K. Kannan, 2001. Accumulation ofperfluorooctanesulfonate and related 0 000094 AfdlmuionrioscthreamtiicvaelsRiencomridnkARa2nd26r-iv1e0r3ot0tAers. Prepared for 3M, St. Paul MN. June 20. In U.S, EPA Goyisteesr,yJ.CrPa. sasonsdtrK.eaKvainrngainni,ca2,0f0r1om. tPheerfGluoruooofclMtaenxeifscuolfaonndatCehaensdapreelaakteedBfalyu.orPorcehpeamriecdalfsori3nM, St. Paul MN. June 20. In U.S. EPA Administrative Record AR226-1030A GPrieepasrJye.dPf.oar n3MdJ,. L. St. NPeawusltMedN,,2P0r0o1j.ectSe1l7e8c4t0e1d.fJluunoer.ocIhneUm.iSc.alEsPiAn tAhdemiDneicsatturra,tiAvlegRbeacmoardarea. AR226-1030A GDoisbes.onR,iSk.eJ,raLanbdorJaothorniseosn,,I1ncD.,.Su1b9s79i.diAabrsyoorpft3ioMn,oSft.FPCa-u1l4,3M-i1n4neCsoItnaR.ats Aftear Single Oral GToitbaslonC,ar5b.o1.n-a1n4diJnohMnasloen,an1dD.Fe1m9a8l0.e REaxttsenAtfatneadrRSoiuntgeleofIVExDcorseetoiofn FaCn-d14T3is-s1u4eC.DisRtirkibeurtion of Laboratories, Inc, Subsidiofa3rMy, St. Paul, Minnesota. GPriebgsnoannt,RSa.Jt.sanAdftJeoahrnSsionngl,e .OD.ra1l98D3.oseEoxfteAntmmanodnRiouumteo14fECx-PcerreftliuoonroofoctTaontoaaltCe.arRibkoenr-1i4n Laboratories, Inc., Subsidiaryof3M. St. Paul, Minnesota. Gillet, James. 1993. University. March 8. 3M-requested expert review of "Bioaccumulation Studies". Comell GDiolcltiolraanld,tFh.esi1s9,92D.iviFsliuoonroocfhEenmviicraolnsmaenndtaHluamnadnOcHceualptaht:ioSntauldiHeesalintha,nUOncicvueprsaittiyoonfalMCinonheosrotta, Gpirloldkuacntdi,onF.pDl.anta.ndJMOaMn.del35,(91).:5.915909-39.54.Mortality among employees ofa perfluorooctanoic acid Gliilploiplraontde.inFs,DaannddcMhaolnedsetler,olJS:.a s1t99u6d.yoSfeorcucmupPaetrifolnuaolrloyocetxapnoosiecdacmiedn.andAmhepJatIincd eMnezdym2e9s:,560568. GMlaadzias.oSn., W1I9.95.ProAjceuctteIDd:erHmaWlIto5x0i8c0i0t3y7s4. t3oMufTCd-o6m3py4a2nyi.n raStb.biPtasu.l,CMoXm.ing Hazelton, Inc G6l1a0z0a1,76S0..M. Ja1n9u9a7r.y A1c0.uteSpOornaslorTeoxdibcyit3yMS,tuStd.yoPfauTl,-6M6i6n9neisnoRtaats. Corning Hazleton Inc. CHW GStolPdaeunlt,hMail,nnEe.s.ot1a9,78b4y. Ninety Day Intemational Subscute Research RaantdTDoexivceiltoypSmteundty.CoFripnoarlaRteiopno,rtStP. rPeapualr,ed for 3M, Minnesota, November 6, 1978. 9 000095 SGPtor. ledpPeaanurlte,hdaMlfi,onrn3e1M.so,t1Sa9t7,8PNba.ouvlN,eimMnbientenyreDs1oa0t,ya1,S9u7bb5y.acIuntteemRahtieosnuasl MRoesreearychToaxnidciDteyvSetluodpy.meFnitnaClorRpeoproarttion, GLoarbtonreart,orEy.Ga.nd19R8i1k.erOLraabloTraetroartioelso,gyIncS.tuEdxyopefrTim-e2n9t98NuCmobCeirn:R0at6s8.1TSRaOfe1t1y0,EvDaleucaetmiboner 1981 GLoabronreart,orEy.Ga.nd19R8i2k.erOrLaabloTreatroartioelso,gyInSc.tuEdxyopefrTim-e3n1t4N1uCmobCeirn:R0a6bb8i1tTs.BO3Sa9f8e,tyFeEbvraulauratyio1n952. Griffith, Am. Ind. F.D., Hyg. aAnsdsLoco.Jn.g41J.(E.8)1:95870.6-5A8n3i.mal toxicity studies with ammonium perfluorooctanoate. pHearnfhlijuaorrvoio,ctHa.n,oaOtpehaeuxcgr,etRiHo.n inanthdeSriantg.erP,roLc.. 1982. The Soc. Exp. sex-related Biol. Med. difference 171:50-55, in pHearfnlhuoirojoactHra.vn,oiMic,.aYcildidnuerniAn,.g sKoujboc,hraonndiVc.adKmoinsimsat.rat1i9o8n7.inEtlhiemiWniasttiaornraatn.dPhtaoxrimcaictoyl.ofToxicol, 61:66:68. pHearnfhliuojraorovcHit,a.noeitcaal.cid1i98n8.theAbperaogploesdeodgsapnecdireastdIifnf:erBeencyeniennt,heA.rC.enaanldeHxLcAr.etSioolnleovfeld (Eds). MNaerwtiDneuvseNliojphmoefnftsPuibnliBsihoesrcsi.encDeosr:dreTchheti,rNIemtphleirclaatnidosn.s for Laboratory Animal Science. CHoaenfsfcichi,enCtsa.ndSuLbesot,itAue(nEtdCso.n.st1a97n9t.s Wiley and Sons, Inc. fCohraCpotmerrelIaVt,ioTnheAnFalryasgimsenatndMeChtehmoidsotfryCaalncdulBaitoeldogPya.rtiJtoihonn cHhaanrsacetnerKiz.aJti.oH,no.fO.trJacoehlnevseloJsn.o,fS.PEFlOdSriadngdeJ,P.FL.OABuitnenthheofTte,nannedsLs.eeAR.iDvierc.k,En2v0i0r2o,n,QuSaenititative Technol. 2002,36, 1681-1685 PHaetrffileulodr,oTo.cta2n0o0i1c.AcSicrde(ePnFinOgA)S.tud3ieMs EonnvtihreonAmqeunetoaulsLaPbhoortaotloyrtyi.c DLeagrbardeaqtuieosnt onfumber E002192. St. Paul, MN. IHnec.nwMoaodd,isS.on1W9,I97.. L5abDoarialtyoDryosPeroOjrecatl ITdoexniticfiitcyatSitonu:dyCwHitWh T-6669 in 6329-197. Rats. 3M CCoomrpnainnyg,HSatz. lePtaouln,, MN pHeerufvleulo,roLoPc.tVa.noeitcaal.cid19i9n1.malTiesasnude dfiesmtarilbeutraitosn., mJ.etBaibooclhiesmm., Taonxdiceolliomgiyn.ati6o(n2)o:f83-92. 2 000096 Heuvel, LP.V. etal. 1992. Renal excretionofperfluorooctanoic acid in male rats: inhibitory effectof testosterone. J. Biochem. Toxicology. 7(1): 31-36. Heuvel, LP.V. etal. 1992. Covalent BinofPderfiluorninagted Fatty Acids to Proteins in the Plasma, Liver, and TestesofRats. Chem-Biol Interactions. 82:317-328, Howell R.D., Johnson, J.0., Drake, J.B., Youngblom, R.D. 1995. Assessment of the Bioaccumulative Properties ofAmmonium Perfluorooctanoate: Static. 3M Technical Report. May 31 IARC. 1995. Peroxisome Proliferation and ts Role in Carcinogenesis. IARC Technical Report No. 24. Intemational Agency for Research on Cancer, Lyon, France. Iinkerdaat,lTi.v,erAbiybap,erKf.l.uoFruiknuadtae,d Kf.attayndacTidasn,akmaet,abMo.li1c9a8l5l.yTihneertinddeuricvtaitoinvoefspeofrofaxtitysoacmiedsp.rJo.liferation Biochem. 98:475-482 Industrial Bio-Test Laboratories, Inc. 1977a. Report to 3M Company: 28-Day Oral Toxicity Study with FC-143 in Albino Mice. IB No. 8532-10655. Industrial Bio-Test Laboratories, Inc. 1977b. Report to 3M Company: 28-Day Oral Toxicity Study with FC-143 in Albino Rats. IBT No. 8532-10654. Johnson, J.D. 1995a. Final Report, Analytical Study, Single-Dose Intravenous Pharmacokinetic. S&tuSdeyrvoifceTs-,6S0t.67Paiunl,RaMbNbi.ts. Study Number: AMDT-120694.1. 3M Environmental Technology Johnson, 1.0. 1995b. Final Report, Analytical Study, Single-Dose Absorption Toxicity Study of T6067, T-6068, and T-6069 in Rabbits. Study Number: AMDT-011095.1. 3M Environmental Technology & Services, St. Paul, MN. Jcaorhbnosno-n14, i.Dn., raGtisbasfotner,Sa.dJm.inaisntdrOabteiorn,ofR.Ea.mm1o98n4i, uCmho[l1e4sCt}yprearfmliunoer-oeonchtaanncoeadtefeocralpoetlaismsiiunmatioofn (14C]perfluorooctanesulfonate. Fund. Appl. Toxicol. 4972-976. Kachanova, Z. P.: Koslow,J. N. Zh. Fiz. Khim. 1973, Vol. 47, p2107. Kawashima, Y., Uy-Yu, N. and Kozuka, H. 1989. Sex-related difference in the inductions by perfluoro-octanoic acid ofperoxisome p-oxidation, microsomal 1-acylglycerolphosphochaline acylransferase and cytosolic long-chain acyl-CoA hydrolase in ra liver. Biochem. J. 261: 595 60 Kennedy, GL. 1985. Dermal toxicityof ammonium perfluorooctanoate. Toxicol. Appl. 5 000097 Pharmacol. $1(2):348-355. pKeernfnleudoyr,ooGctLa.noa19t8e7a. ndInrcerleaatseed ifnlumooruoscheemliicvearlsw.eiTgohxticfolo.lloLwetitn. g 3f9e:e2d9i5n-g3o0f0.ammonium Ktoexnincietdyyo,fGa.Lm.,moHnaillu,mG.pTe.r,flBuroirtoiollcit,anMoRat,e.BaFomoedsC,h1eRm..,aTnoxdicCohle.2n4,(12H.C). :11938265.-13In2h9a.lation Kidde, 2000. Manufacture, MKiadyde30F,i2r0e0F0i.ghting, Press Release Re: 3M Withdraws from Fire Fighting Foam OKrigrakn-iOcth(mHeirg,he1r99A4.cid"sF)l"uoinriKniartekd-OHtihgmheerr ECnacrybcolxoypleidciAacoifdsC"heumnidcearl"FTleucohrnionleoCgoy,mp4ouendd.,s,Vol 1, pp. 551-558. K[TuhriusmteestLaisbopreartfoorrym,e2d00u1s.ingBiPoearfclcuuomruoloacttiaonnoitcesatcoifdP(eTrefsltuosruobasltkaynlcceanrbuomxbyelricKa-c1i5d19()C]=7i-n1c3a)rp. "Test No. 51519., pages 1-26, Chemicals Evaluation and Research Institute, Japan., December 18, 2001, CLoawllio/rM,amT.mEa.li1a9n9-6m.icMruotsaogmeneiRceivteyrTseestMuwtiatthiTon-6A5s6s4ayinwtihtehSaalCmoonnfeilrlmaat-orEyscAhsesraiyc.hiaComing Hazleton Inc. Final Report. CHV Study No: 17750-0-409R. September 13. cLoalwliofrm,amT.mal1i9a95n.-miMcurtoagseonmieciretvyetresset mwuittahtTi-on63a4s2sayi.n tLheabSoarlamtoonreyllNau-mEbsecrhe:ri1c7h0i7a3-0-409. Coming Hazleton Inc.Vienna, VA. 3M Company. St.Paul, MN. Lines. D. and Sutcliffe, H., Journal of Fluorine Chemistry, 25, 505 - S12 (1984). Lprioul,ifRe.rCa.toMr.,,aHmumtot,niM.uEm.,peCrofoluko,rJo.oCc.taannodatBeie(gCe8l),,Lo.nB.he1p9a9t6i.c Eafrfoemcatotafsethaectpievritoyxiisnoamdeult male Crl:CD BR (CD) rats. Eund. Appl. Toxicol. 30: 220-225. LEixup,reSs.Cs.i,onSoafnfitlriapnpsof,orB.m,inPgergrrootweatuh, I, Derynck, R.. factoar (TGF) Salomon, D.S. and in differentiated rat Kidwell, W.R. 1987. mammary tumors: estrogen induction of TGFa production. Mol. Endocrinol. I: 683-692. Longnecker, 28253258, D.S. 1987. Interface between adaptive and ncoplatic growth in the pancreas. Gut, LPSD, 2000. www.Ipsd.zzzip netprojehcitms os 709098 PLhuontaokc,heS.;m.SePdhioatko,biPo.l.PhA.o:toCihnietmi.ate1d99R2e,acVtoilo.n6s8o,fppH.yd1r-o3g3.en Peroxide in the Liquid Phase. J. 3MeMndTeelc,hnAi.ca1l97N8o.teSbooiolkT.hiOnctLoabyeerr 1C3h,ro19m7a8.togNruampbheyr--F4C8-27975,,pF3C0.-1P4r3o,jeFcMt-N3u4m2b2.erEx9c9e7r0p6t12f6r0o0m. FMientarlicRke,poMr.t,anIndduMsatrriiaasl,BAio.-JTe1s9t77L.abo2r8a-tDoraiyesO,raIlncT.oSxticuidtyyNSo.tud$y53w2i-t1h06F5C4-,1433MinReAflebriennoceRaNtos., T1742CoC, Lot 269, September 29, 1977. IMmopaocdteCyd.bAy.Fairne-dJf.igAh.tiFnigelAdc,ti1v9i9t9y.. EDnevtierromni.naStcii.onToefchnPoelr.flu1o9r9o9c,ar3b3,ox2y8l0a0t-es28i0n6G.roundwater Moody, C.A., Perfluorinated J.W.Martin, Surfactants inW.BCi.otaKwaannd,SuDr.fCa.cGe. Muir, Water SS.aAm.plMeasbuFroyl.lo2w0i0n2.g anMoAncictiodreinntagl Release ofFire-Fighting Foam into Etobiocoke Creek. Environ. Sci. Technol. 2002, 36(4), 345-551 HMauzrlleti1o,n.In1c9.9.5.VieMnuntaa,geVnAi.cit3yMtesCtoomnpaTn-y6.342St.inPaaunl,mMoNu.se micronucleus assay. Coming M1u7r7l5i0,-0H4.551.9963aM. CMoumptaangy,enSt.itcPeasiutlto,ynMNT-.6564 in anmousemicronucleusassay. Study number CMhuirnle,seH.Ha1m9s9t6eb.r OMvuatrayge(nCiHciOt)yCTeelslts:onwiTt-h65a6C4onMfeiarsmuartionrgy CAhsrsaoymowsiothmaMlulAtbieprlreatHiarovnesstisn. Final Report. Coming Hazleton Inc. CHV Study No.: 17750-0-437CO. September 16. Muri, Blood LHy.m1p9h9o6cc.ytMeustaWgietnhicaiCtoynTfeisrtmaotnoTr-y6A3s4s2a,yMeWaistuhrMiunlgtiCphlreoHmaorsveosmtas.l CAobrenrriantgi-oHnaszeilntWohn,olIenc. (CHV). Vienna, VA. CHV Study No.: 17073-0-449C0. HMuarmlsit,eHr. O1va9r9y6.(CMHutOa)geCnelilcsi:tywiTtehsta oCnonTf-i6r3m4a2t,orMyeaAssusraiyngwiCthhrMoumlotispolmeaHlarAvbeesrtrsa.tiCoonmsiinngC.hinese. Hazelton, Inc. (CHV). Vienna, VA. CHV Study No.: 17073-0-437C0. PNearpfolluioMr.oa,lkFarnaecscualrfoonCy.l, FlSuocriideps:iA.o,TahnenPidyroAlrymsieslolRfi.Per1f98l4u.oroT-hne-romcatalneD-e1c-osmuplofsointylioFnluoofride. Journal ofFluorine Chemistry, 24, 377-385. hNielspsoan,toR.c, aBerijce,iBn.,ooPgfrpeeaetnr,oiVx.ci,iEsortmiyexpornoKl,i.fearantdorRsa.meClhe,mC..-B1i9o9l1.. On the Interact. mechanoifsthme 78:235-250. NOTOX. Cultured Pe2r0i0p0h.eraElvaHluuamtainonLoyfmtphheocAbyitleist.yofNOT-T7O5X2P4rtoojeIncdtuNceumCbherrom2o9s20o6m2e. Aberrations in Hertogenbosch, os 000099 The Netherlands. (NMOaTxiOmXi.sati2o0n0-1T.estA)s.sesNsOmeTnOtoXfPCroonjetcatctnuHympbeerrse2n9s2i0t2i7v.ityHteortTo-g7e5n2b4osicnht,heThAlebNientoheGruliannedas.Pig. HNeuxbabceh,loMr.ocEy;clAodpaenmtsa,diVe.nDe.;,MWoato.reRe,s.W.19M9.5,TVhoel.Di2r9e,ctNoa.nd5,Spepnsli2t8i7z-ed Ph1o2t9o3-. oxidation of OMbeocuhrann,isJ.mDs,foFrratmhee.paSn.cRr.e,aBteilcl,onRcHo.geJnri,cLeofnfegcntescokfert,heDp.Se.r,oxElilsiootmte, Gp.rSo.lifaenrdatCorooWky,eJt.hC.141,99674.3. Toxicol. Appl. Pharmacol. 145: 425-436. OECD Direct aGnudidIenldiirneectfoPrhToetsotliynsgi,of(DCrhaefmticDaolcsu,mePnhto)t;otOraEnCsDfo,rm2a0t0i0o,noppfl-C5h9e.micals in Water- Ogata, Y.; Tomizawa, K.; of Peroxides 1983, p.720 Furuta, K. Chemistry of Peroxides, in S. Patai (ed), The Chemistry Olsen, G.W. etal. with Occupational 1998. An Exposure tEopPiedrefmliuoolroogoicctaInnoviecstAicgiad.tioJnOoEfMR.ep4r0o(d7)u:c6t1i4v-e62H2o.rmones in Men cOhlosleenc,yGstWo.kineitna,l.hep1a9t9i8cb.fun3cMtioFninaanldRsepeorrutm: pAenrfleupoirdoeomcitoalnoogiiccaicnivdeslteivgealtsiionn porfpolduacstmioan workers. 3M Company, St. Paul. Sept . Olsen, 2001. GW, Logan, Descriptive PW, Simpson, CA, summary of serum fBlururoirso,cJhMe,icBaulrlleevwe,lsMaMm,onLgunedmbpelrogy,eJeK,paMratnicdiepla,ntJsH.of the year 2001 2000 Decatur fluorochemical medical surveillance program. Final Report. March 19, Olsen, GW, Mandel, JH. S2c0h0m1icbk.leDre,scMr,ipTtiievreenssu,mJmMa,ryLoogfsane,ruPWm,flBuurorriosc,hJemMi,caBlurlleevewl,s MM, Lundberg, JK, among employee participantsofthe year 2000 Report. March 19,2001 Antwerp fluorochemical medical surveillance program. Final Ofllsueonr,ocGheWm,icMaaldlseevnel,saDmC,onBgur2i3s6,bJuiMl,dMianngdeemlp,lJoHy.ees2.001Fci.nalDeRsecproirpt.tivMeasrcuh m19,m2o0fa0s1er.ruym OFllsueonr,ocGhWem,icHaalnsseinn,HCulmeamnenT,isLsAue,.BFuirnrasl,ReJpMo,rtM.anEdpeild,emJiH.olo2g0y0,142.2I0d-e3nWi-f0ic5a,tiMoendiocfal Department, 3M Company, St. Paul, MN 55144. OpelrsfelnuoGrWoo,ctBaunresluelwfoMnMat,e B(uPrFiOsS)JMa,ndMpaenrdfelluoJrHo.oct2a0n0o1at.eA(PcFrOoAss)-siencetiloantailonatno calilniocyfaslscirusm % 000100 pcahretmiicsitprayn,tsthoyfrtohied 2h0o0r0moAnnet,wheermpaatnodloDgeycaatnudrufrlinuaolryoscihsemreiscualltsmefdriocmamlasluervaenidllfaencmealperoegmrpalmo.yee Final report. 3M Medical Department. OSlesreunm, GP.erWf.l,uoBruorolcetwa,neMs.ulMf,onBautrer(iPsF,OJS.M.), MaannddPeelr,flLuHo.roo2c0t0a1nfo.ateA(LPoFnOgAit)udLienvaellsAnianlRyesliastioofn to L1i9p9i4d/9a5n,d1H9e9p7a,taincdCl2i0n0ic0alFlCuhoermoicshtermyicTaelstMeRdesiuclatlsSfurrovmeiMllaalneceEmPrpolgoryaem.e Pa3rMticFiipnaanltsRoefpotrhte. eOlpsiedne,miGoWlo,giBcuranlaelwy,siMsoMf,epHioscokdiensgo,fBBca,reSkoraftt3,MJCD,ecBautrruirs,chJeMm.icMaalndaenld,fJiHl.m p2l0a0n1tge.mpAlnoyees, 1993-1998. Final Report. May 18, 2001 OIldesnetni,fiGcWat,ionBuorfrilsu,oJrMo,chLeumnidcbaelrsg,inJhKu,mHaannsseerna,. KJ1., AMmaendreilc,anJHR,eZdobCerlo,ssLRad.ul2t0b0l2o2o.d doors. Final report. 3M Medical Department OIdlesnetni,fiGcaWt,ionBuorfrifsl,uJoMro,chLeumnidcbaelrsg,inJhKu,mHaannsseenra,.KJ11.. MEalnddeerlly, pJaHr,tiZcoibpealn,tsLoRf. th2e0A0d2u.lt Changes in "Thought Study, Seattle, Washington. Final Report. 3M Medical Department, OIldesnetni,fiGcWat,ionBuorfrifsl,uoJrMo,chLeumnidcbaelrsg,inJKh,umHaannsseerna,. KJ, 111. Mandel, JH, Zobel, LR. Pediatric participants 2002c. in a Group A Streptococei clinical trial investigation. Final Report. 3M Medical Department O'Malley, Study with KT.D-.2, 61a8ndCoECbbiennAsl,bKi.nL.o. 1981. Repeat Rabbits. Riker ALpapbloircaattoirioens2,8StD.aPyauPle,rMcuNt.aneous Absorption Ophaug, Soc Exp R.H. Biol Maendd. L.16S3i:n1ge9r-.23.1980. Metabolic Handling of Perfluorooctanoic Acid in Rats. Proc RPeaqcueeAsntalNyot.icaEl1.2821.997M.inRneeaapdoyliBsi,odMeNg.radMataiyon2o9.f FC-126(BOD/COD). 3M Company Lab BPaacseedAnCahleymtiisctarli.c2s.0013.MThCeom1p8a-nDayyRAeequreosbti,c CBoinotdreagcrtadAantaliyotniScatludPyroofjPecetrfIlDu: orCoAo0ct9a7n,esulfonylMinneapolis, MN. February 23. PPaelrafzlzuoolroo,ocMt.aJn.oa1t9e93(.CATShiNrot.ee3n8-2W5e-e2k6-D1i)etianrMyaTloexiRcaitts.y SFtiundayl wRieptohrtT.-51L5a0b,orAamtomroynPiruojmect Identification HWI 6329-100. Hazleton Wisconsin, Inc. sPtausdtioeosr,oTf.aP.m,mLoenei,uKm.P.p,erPfelrruio,roMo.cAt.anaonatdeG-iilnldiusc,edP.Jh.ep1a9t8o7m.eBgiaolcyhaenmdicpaelraonxdismoomrephporolloigfiercaatlion. 9 9200101 Exp. Mol. Pathol. 47:98-109. dPeettreirtmsi,na1t9i9o9n. ofK.poPleatrriutsn,deertialv.ati"zleodn-apmaiinroreavceirdssedus-ipnhgaspeerlfilquuoirdicnahtreodmacatrobgorxayplhiyc afocrids s ion paiting agent"in J.Chromatography A, Vol. 833, 1999, pp. 147-155, R3eiMneCro.mEp.aAn.y,19E78n.virFoantmeoenftaFlluLoarboocrhaetmoircya.lsJuilnyth1e9.Environment. Project Number 9970612613. Reiner, E.A. 1981. 3M Company Environmental Laboratory, St. Paul, Minnesota, Dec. 7. aRnendneTre,chn20o0l1o.gy,"GVorlo.wi3n5,gICsosunec7e.rppO.ve1r54PAe-rf1l6u0oAr,inaAtpreidlCh1,em2i00c1a.ls" in Environmental Science RPiekrecrutLaanbeooruastoArbiseos,rpItnci.,onSStaufdeytywEivtahluTat-i2o6n1L8aCboorCationrAy.lbi1n9o79R.abRbeiptse.atStA.ppPlaiucla,tMiionnne2s8o-tDaa.y Experiment Number: 09790AB04SS. TRi3k3e7r1LaibnorAaltboirnioesRaIbnbci.t,sS.afSett.y Evaluation Paul, MN. Laboratory. Experiment 1983. Primary #0883EBO0T9. Skin Irritation Test with BSeaddfhour,d,D.M2A0,02ToCxHiOco/nHFGiPnaRlTRefpoorrwta:r0d1m-u7t0a1t9i-oGn1asSsuayb-miItStOteo(dT:63.8M8,9.St7.) TPaouxlicMoinnnCeosroptoara5t5i1on4,41000. SReirmasnuol,fuLr;oBnu,fPoes,ti$c..A.S;ciP.er1u9c9c9i,, P.; Mealler,P.; Mansour, VoL55,pp.955-961. M. Photolysis and Hydrolysis of Simister, E. etal.J. Chem. Soc, Faraday Trans. 88(20), 3033-41 (1992) Sheophalteinciupse,rAo.xKi.s,omAendperrosliofne,raKt.ioannadndDerPeilearterd,pJa.ra19m9e2t.erTshseheofwfenctossoefx-preerlfaltueodrodoicftfaenroenicceasciind moince. Biochem. J. 265:779-783, STtearpalteosg,eRn.iEc.,PoBtuerngtieaslso,fB.AA.m, maonndiuKemmPse,rfWl.uDo.roo1c9t8a4n.oatTehe(AEPmFbOry)o-inFetthealRaTto.xiFcuintdy.anAdppl. Tox. 4, 429-440. Ttoaktahgeip,eAr.,oxSiasio,mKe.,prUolmimfeermatuorrsa,,pTe.r,flHuaosreogoactwaan,aiRc.aacnidd Kaunrdopkearwfal,uoYr.ode1c9a91n.oicShaocritd-,tcearumseesx.posure significant increasesof 8-hydroxydeoxyguanosine in liver DNAofrats. Cancer Lett, $7:55-60. "Takagi. A., Sei, carly biomarker K., for hUempmaetomcuarrcai,noTg,enHeassiesgianwdau,ceRd. bayndpeKruorxoiksaowmae,prY.oli1f9e9r2a.torHse.pJa.tEonmveigroanl.y is an 9% ~n0102 Toxicol. Pathol. 11: 145-149. ToafyHlaozraPr.d,oDuesllOirnggaenriBc.CoanmdpoLueendC.~CI.n,ci1ne9r9a0b.iliDteyv.elEonpvmiernotnmoenfataTlheSrcimeanlcSeta&biTlietychBansoeldoRga2yn4k,,ing 316328. `tTreaenrsdfso,rKm.iJn.g, Rgroomwmtehrfta,ctFo.rG-.a iannLdeDyodrirgicneglltodnu,riJn.Hg. t1h99e0d.evIemlmoupnmoehnitstofotchheemiactatlesdteist.ecMtoiloenc.ofCell Endocrinol. 69:R 1-R6. (TAhoPmFfOo)rdi,n CPJy.n2o0m0o1lbg.u2s6M-oWnekeekysC.apSstuuldeyTpoexrifciotrymeSdtubdyyCwoivtahnAcmemLoabnoirautmorPieersfIlnuco.r,oMoactdainsooante CWoisvcaonncsein6352397-0243-12,5C9o2mpfloretAiPonMEDatAed-DheocceAmbPeFrO18T,ox2i0c01o,lo4g6y3Wpopr. king Group. Study No. (TAhPoFmOfo)ridn PCJ.yn2o0m0o1lb.gu4s-WMeoenkkeCyasp.suSlteudTyoxpiecriftoyrSmteuddbyywiCtohvaAnmcmeoLnaibourmatPoerrifelsuIonrco.o,cMtaadnoiastoen CWoisvcaonncsein6352397-0243-0,25C9o2mpfloretAiPonMEDatAed-DheocceAmbPeFrO18T,ox2i0c01o,lo1g5y9Wpopr.king Group. Study No. T3oMddC,o1m.pW.any19T7e9c.hnFiCc-a1l4R3epPohrottoNloy.si0s0S2t.udFyebUrsuianrgyS2.imulated Sunlight. Project 9776750202, aTnRd. tWheilFbruersyhwLaatbeorraAtlograi,esS,elInecn.as1t99r5u.m GcarporwitchorannudtuRme.prMoadrubclteihoenadT,oxMiAc.itySTteusdtywniutmhbNe2r8B0933--3TH, TPiRm.epWhiallbeusrpyroLmaebolraast.orMiaesr,blIenhc.ea1d9,96MaA..AcSuttuedytonxuicmibteyrof$N912-8T0H3.-3 to the Fathead Minnow, TmaRg.naW.ilMbaurrbyleLhaebaodra,toMrAi.es,StInucd.y 1n9u9m6bb.erAc8u92t-eTTHo,xicity of N2803-3 to the Daphnid, Daphnia O`TrsgaanngicW.C,oBmuproguensdss.DR.C,ombaunsdtBiaobnusSchioekncV.e..&19T9e8c.hnOonlotghye,In1c9i9n8e,ra1b3i9l,ity3o8f5-H4i0g2.hly Fluorinated Ubel FA, Sorenson fluorochemicals--a SD, Roach preliminary DreEp.ort.198A0mHeIanldthHysagtuAssosfocplJan4t1:w5o8r4-k3e8r9s. exposed to PUhSotEoPlyAsi1s9S9c8reFaetnei,nTgrTaensstp;orEtPAa7n1d2T-rCa-n9s8f-o0rm9a9t;ioUnniTteesdt SGtuaitdeesliEnnevsi,roOnPmPenTtSal83P5r.ot5e2c7t0ioInndAigreecntcy, U.S. Government Printing Office: Washington, DC. 1998, ppl-22. FUuSnEctPiAono19f98p.H;FaEteP,A7T1ra2n-sCp-o9r8t-a0n5d7;TrUannistfeodrmSattaitoesn ETnevstirGounimdeelnitnaels:Pr8o3t5e.c2ti1o1n0:AgHeyndcryo,lyUs.iSs, as a 9 ~en10a Government Printing Office: Washington, DC. USEPA October 2002. Memorandum 2, 2002. from Dr. Ralph Cooper, NHEERL, to Dr. Jennifer Seed, dated pVearnfdleuonrHoeoucvtaenlo,iJc.aPc,iDdaivn imsal,eJ.rWa.s,:SoImnhmiebristo,ryRe.,fafencdtPoeftteerstsoosnt,eRr.oEn.e. 1J9. 9B2.iocRheenma.leTxocxriectoilo.nof (131-36. VpearnfdlueonriHneatuevdefla,ttyJ.Pa,cKiudssltio kipsr,otB.eLi,nas nindtPheetpelrassomn,a,R.lEi.ver1a99n1da.tesCtoesvaolfernatts.biCnhdeimn.g of -Biol. Interact, $2:317-326. dViasntrdiebnutiHoenu,vemle,taLbPol,isKmus,laiknids,elB.iL,mVinaatinonoRaffpeelrgfhleumor,oMo.cLt..anaonidc aPceitderisnonm,alRe.Ea.nd19f9e1bm.alTeirsastu.eJ. Biochem. Toxicol. 6(2):83-92 V9r9a7s0p6i1r2,6G0.0A:., FMaetnedoefl,FlAurotrhourc.hem1i9c7a9l.s.An3aMlysTiescfhonricFalluRoerpoocrhtemRiecpaolrstiNnuBmlubeegrill14F.iMsha.yPr1o.ject WPiamredp,hTa.l,eNsepvroimueslJ,a.sa.ndT.RR.. BWoierlib.ury199L6aab.oraAtcoruitees,toIxnicc.ityLoafb FReCq-u1e0s1t5ntuomtbheerfPa1t6h2e4ad. mi3nMnow, Company, St.Paul, MN. aWnadrtdheT,.f, NreveiussJ,a.lhgaanw,dSRe.aleBtnoaesreiir.rum199c6abp.ricGorromwutuhm.andT.rR.eprWoidlubcutriyonLtaobxoircaittoyriteesst, with Inc. FC-1015 Lab Request number P1624. 3M Company. St. Paul, MX. Wmaagrnda,.T.,TN.Re.viWuisl,bJu,ryanLdaboRr.aBtooerriie.s, 1I9n9c.6c.LaAbcruetqeuetsotxincuitmyboefrFPC1-61240.153toMDCaophmnpiadn,yD,aSpt.hnPiaual, MN. WEnevlisrho,nSmKe.ntal19L7a8b.orTaetcohryn.ica3lMReCpoormtpaSnuymmParrojyec-tA9d9s7o0r6p1t2i6o3n3o:f FFCa-te9o5faFnlduoFrCo-c1h4e3miocnalssoi,l.Report Number I. St. Paul, MN. February 27. hYeapgaetorc,ar1cD.inJro.geannedsiYsaignefreR,m.al1e98S0p.raOgraule-cDoanwtrlaecyeprtatisv.eCsatnercoeirdsRaessp.r4o0m:o3t68e0r-s36o8f5. uVrliinnaerny, eMx.c,reHtainohniojfarpveir,fHl.u,orJoaoacktoannaohioc,aLc.,iadnidn tPheeurmaa,leP.ra1t.989P.haSrtmiamcuolla.tiToonxibcyole.st6r5a:d2io7l4-o2f71t.he Vthieinreant,afMt.e,rKsoijngol,e anA.d, HsaunbhcihjrodnrivciH,a.dmainnidstPreautriao,n.P. Bu1l9l9.0.EnDviisrpoons.itCioonntoafmp.eTrofxilcuolo.r4o4o:4c6t-5a3cn.iodicn 100 000104 York, Study RG. 2002. Oral (Gavage) Two-Generation of Ammonium Perfluorooctanoic (APFO) in (One Rats. Litter Per Generation) Reproduction Argus Research Laboratories, Inc Protocol Number: 418-020, Sponsor Study Number: T-6889.6, March 26, 2002 0 000105