Document 8R58ZGYpw7yZ3v2d41nME35wB

107 f AR 26 _ 1126 REVISED DRAFT HAZARD ASSESSMENT OF PERFLUOROOCTANOIC ACID AND ITS SALTS s ._. = =2 x 25 = a U.S. Environmental Protection Agency Office of Pollution Prevention and Toxics Risk Assessment Division November 4, 2002 000001 PREFACE a"Tshsiosciisataepdrweiltihmienxaproysausrseetsosmpeenrtfolufotrhoeocptoatneonitciaalcihdaz(aPrFdsOAt)o haundmaitns hseaasl.th Tahned tmhaejoernivtiyorofntmheent tinocxliucdoelsogayrienvfioerwmoafttihoneisstfuodrieasmtmhoatnwieurmepaevrafilluaobrloeoacstoafnoOicctaocbiedr,(A2P0F0O2).. This assessment 000002 `Tableof Contents Executive Summary 1 10 Chemical Identity 7 11 Physicochemical Properties 7 20 Production of PFOA and is Salts 21 Uses ofPFOA and its Salts 9 i 22 Environmental Fate 12 22.1 Photolysis 2 222 Volatility 223 Biodegradation 224 Hydrolysis 13 13 225 Bioaccumulation 14 22:6 Soil Adsorption 1s 23 Environmental Exposure 15 23.1 Discharge to Air 232 Discharge to Water i1s5 233 DischtaorLagned 16 234 Environmental Monitoring 16 24 Human Biomonitoring 18 30 Human Health Hazards 3.1. Metabolism and Pharmacokinetics 23 2 3.11 Half-life in Humans 3.12 Absorption StudiesinAnimals 23 2 3.13 Distribution Studies in Animals 25 3.14 Metabolism Studies in Animals. 28 3.15 Elimination Studies in Animals 28 32 Epidemiology Studies 32 32.1 Medical Surveillance Studies from Antwerp and Decatur Plants 32 322 Medical Surveillance Studies from Cottage Grove Plant 34 323 Morality Studies 36 324 Homone Study 3.2.5 Studyon EpisodesofCare (Morbidity) 39 40 3.3 Acute Toxicity Studies in Animals a2 33.1 Oral Studies 2 332 Inhalation Studies a 333 Dermal Studies a3 334 Eye Imitation Studies a 33.5 Skin Imitation Studies a 34 Mutagenicity Studies 4 35 Subchronic Toxicity Studies in Animals 4" 36 Developmental Toxicity Studies in Animals 6 37 Reproductive Toxicity Studiesin Animals 64 000003 38 Carcinogenicity Studies in Animals 7 38.1 Cancer Bioassays 7 3.82 Modeof Action Studies 75 3.82.1Liver Tumors 76 3.82.2 Leydig Cell Tumors 7% 3.82.3 Mammary Gland Tumors 7 3.8.2.4 Pancreatic Tumors 7 3.9 Immunotoxicology Studies in Animals 78 40 Hazards to the Environment 80 41 Introduction 80 42 Acute Toxicity to Freshwater Species 81 50 References 87 ANNEX I - Robust Summaries 104 000004 Introduction EXECUTIVE SUMMARY pPerrofdluucoerdooscytnatnhoetiiccaaclildy o(rPtFhOrAo)ugahndthiesdseaglrtasdaarteiofnulolry mfelutoarbionlatiesdmoorfgaontihcercfolmupooroucnhdesmitchaalt can be pprroodcuecstssi.ngPaFidOsAinisthperipmraordiulcytuiosnedofasfalrueoarcotpiovleymienrtseramneddifaltueo,rwoheillasetiotmsesraslasanrdeiunsoetdhearssurfactant. u`smeasn.ufIanctruerceedntinyetahres,UnlietssedthSatnat6e0s0ormeitmrpiocrtteodn.speMroysetaorfotfhePtFoOxiAcoalnodgyitsstsudaiseshhaavveebbeeeenn conducted this report. with the ammonium salt of perfluorooctanoic acid, which i referred to as APFO in `EnviroFnatmeaendnEtffaeclts PFOA is persistent in the environment. environmental conditions. It does not hydrolyze, photolyze or biodegrade under `peGrrfoluunodrwiantaetredssaumrpflaecstatnatskehnadneealrefviartee-drPaiFniOnAg acroenacsentthratatuisoends fmiaren-yfiygehatrinsgaffotarmtshecofnotaaimnuisneg. Tthheissudrefmaoctnasnttrsa,t(e2s)tPhFe OfoAlloorwiintsg:pr(e1c)uPrsForOsAmieigtrhaetreetxhirsoteudghint-h-eorsowial,safnodrm(3e)dPvFiaOdAegprearsdiasttisoninof: groundwater. Several wildlife species have been sampled around the world to determine levelsof PFOA. PNoFrOthAPhaacsifriacreOlcyebaenenanfdouAnntdairnctfiicshlsocaamtpilonesd, forroimntfhseh-U.cSa.t,incgerbtiaridnsEaumrpolpeesacnolcloeucntteridefs,rotmhethe cUo.aSs.t,s.inPclFuOdiAngwaMsidfwoaunydaitnolal,ftehwe mBailntkicliavnedrsMferdoimteMrarsasnaecahnusSeetatss,,abnudtJnaoptanfeosuendainndmKionrkeafnrom WLoausihsiinangat,onSoauntdhOCraergoloinnaStaantedsIwlleirnoeisl.essPtFhOanAtchoenqcueannttriaftiicoantsioinn lriimvietrooftt3e6r lnigv/egr,s wfertomwt. PFOA. wGasuonoftMldeexteifcctoeodfattqhueanUt.iSf.iacobalset.concentrations in oysters collected in the Chesapeake Bay and "The concentrationsof PFOA in surface water, sediments, clams, and fish collected from locations upstream and downstreamofthe 3M manufacturing facility at Decatur AL have been determined. Of the three downstream water and sediment sampling locations, the two closest to tsihteesf;actihleittyhhreaeddPoFwnOsAtrseurafmucleocwaattieonrscaolnscoenhtardatsieodnismseingtnicfoinccaennttlryagtrieoantsersitghnainfitchaenttlwyogruepastterretahman tbhoeduypPstFrOeAamcsointceesn.trTahteiosnmsa.llThsaemapvleerasigzeePpFreOvAenctoendcdeentterramtiinoantiinoncloafsmisgnwiafsicnaotncseigfnoirfifciashntwlhyole different between the upstream and downstream locations. Based on available laboratory data, APFO does not appear to bioaccumulate in fish. In a study of fathead minnows, the calculated BCF for APFO was 1.8. Inastudyof carp, the BCF ranged 1 000005 from 3.1 109.1. Smeivnenroalw s(pPeicmieesphwaelreestpersotmeedltaos)a,ssbelsusegtihlelascuuntfeisthox(iLcietpyoomfisAPmaFcOh;rotchheisreusi)nc,lwuadteedrtfhleeafa(tDhaepadhnia maraegnpar)o,blaenmadtaicgrfeoernseavlegraael (rSeealsoennsa.strTuhmecsatpurdiicesorwmeurteumc)o.nCdoucmtpeadriwsiotnhsdoiffftehreendtitffeesresnutbssttaundcieess. G`meanteerriaalllyistahemaajmomrocnoincuemrnsalatndorwtahse tnoettrsaufbfuitcyielnatmlmyocnhiaurmacstaelrtiwzaedsiensttheeds.ePteustrs.yoIfntshoemteesttests it a2p7p1e0ar8e5d%)thawtas10u0se%d.tesWtactheerm,iacaslolwvaesntu(siesdo,pororpaontohle)rosra achceommibcianlaotfiolneosfsebroptuhriwtyas(aupsperdoxiinmoattheelry rteesptosr,tfeodr; ntoheoabcvtiuoaulscsotnacteendtrraetaisoonns. wFeirnaellnyo,tornelpoyrtneodm.inal test chemical concentrations were r`Tawneglevdeftresotms 7w0erteo c8o4n3dmugc/tLe.d wIittihs ufnactlheeaadr mwihnynothwiss;ra9n6g-eh iLsCsSo0wviadel.uesAs(sbuamseidngonthmeosretasltiutdyi)es are: tvawloida,cauntedvdauleuetso fthoer blliumeigtialtliosnusnfdiisshcuaslsseodiandbiocvaet,etlhoewsetotxoixciictiyty(v9a6l-uheLsCi5n0discoafte>4lo2w0,toaxnicdit5y6.9The mg/L). Nrianngeeadcuftreomte3st9s1w0e>r1e0c0o0ndmugc/tLe.d Twihtehldoawpehrnivdalsuaensdar4e8-ihndEicCaSt0ivevaolfuemsod(ebraasteed toonxiicmimtyo,bibluitztahteion) wide range makes interpretation difficult. dSeenvseitny,tecsetlslwceoruentcso,nadnudctderdywwietihghgtrse)enraanlggeaed;f9r6o-mh 1E.C2 S(00>v6al6u6esmg(/baLse(tdhoenEgCrSo0wtcehllradte,nscietlly value 0to1xi,c0it0y0, bmags/eLd oisnetxhceluadceutdefcrroitmertihai.sTdhiseculsoswieorn)v.alTuheewloouwledravlasloubeeinidnidciactaetsivheoigfhmtoodemroadteer.ate mtogx/iLci,tyb,asbeadseodnocneltlhceocuhnrtosn,ifcormogdreereantaelgcarietweraisona(ls0o.1c<a1lc0umlga/tLe)d.in Aon1e4s-tdudEyC. S0Thviasliuseoinfdi4c3ative tohfelmoowscthsreonnsiictitvoexitceistty,spbeacsieeds oinntthhee4c4hr%onAiPc FcrOitteersitonsa(m1p0lmeg,/dLa)p.hnGirdesewnearlegateheapnepxetarmeodstto be sensitive, and fathead minnows were the least sensitive. Human Health Effects and Biomonitoring oLintgtoleinignf5o-rymeaatri,ohnalifs-alivfaeilsatbuldeycionn9cerrentiinregdtwhoerpkhearrsmahcaosksiungegteisctseodfaAmPeFaOn sinerhuummaPnFs.OAAhnal life 0f 4.37 years (range, 1.50 ~ 13.49 years). bioaccumulate PFOA in humans. These data provide evidence ofthe potential to aAnndimtoa.l slteusdsieersehxtaevnetsfhoollwonwitnhagtdAerPmFaOl eisxpwoeslulraeb.soIrnbtehdefpoalstl,owCihnegmoorlailtaenwdoriknhearlsathiaovneexbpeoesnure, esixgpnoisfeicdantto rloalregeindethremaalbsdoorspetsioonfoPfFPOAF.OAItinaptpheeasreswtohraktedrse.rmaUlpoexnproescuorgenimtaioynhtahvaet PplFaOyeAdcaould. 2 000008 rbeedaubcseodrdbeerdmdaelrmeaxlploys,urweso.rk practices were changed and engineering controls were adopted that PofFtOheAbdoisdtyriibnuctleusdpirnigmtahreiltyesttoistahendliovvera,ryp.laIst md,oeasnndoktipdanretyi,tiaonndtotothaelleispsiedrferxatcetino,nootrhearditpiosssuees atinsdsuteh.erPeFisOeAvibdienndcsetoofmeanctreor-omhoeplaetciuclecsiricnultahteiotniosfsutehselicstoemdpaobuonvde.. PFOA is not metabolized The urine s the major route ofexcretion of PFOA excretion in male rats. iTnhtehreefaermeamleajroatr,gwehnidleetrhdeiuffreirneencaensdinfetcheesealriemibnoatthiomnajoofrPrFoOutAesionfrats. In f1e0m5ahleinratths,e tsheerhuamlfa-lnidfe2i1s02h4ihn itnhethleivsere.ruTmhaenrdap6i0dhexicnrtehteiolnivoefr;PiFnOmAalbyraftes,matlheehraalts-ilsidfeueits o active renal tubular secretion (organic acid transport system); this renal tubular secretion is believed to be hormonally controlled, since castrated male rats treated with estradiol have neoxtcraeptpieoanrrattoecsohfanPgFeOtAhe rsaitmeiolafreltiomtihnoasteioofnfeinmaralte. raTths.isHgoernmdoenradlifcfhearenngceeshdausrinnogt pbreeegnnancy do observed in primates and humans. `"TOhcecruepaatrieonlaimlidtaetdadfatraomonplPanFtOsAinstehreuUm.Sl.evaenlsdiBnewlogrikuemrstheatndmatnhuefgaecnteurrael poorpuusleatPioFnO.A indicate trheaptorttheedmionsatwroecreknetrmiena1n99s7erwuamsl8e1v.el3spipnmw.orIknenrosnr-aoncgceupfartoimon0a.l84potpoul6a.t4iponpsm,.seTrhuemhPigFhOesAt level sleevreulsmwPeFrOeAmulcevhellsowrearn.geIdnfbrootmh3potool1e7dpbplbo.odTbhaenkhisghaemsptlesseraunmd PinFiOnAdivliedveulasl wseamrpelreesp,omrteeadnin a sampleofchildren from different geographic regions in the U.S. (range, 1.9 -- 56.1 ppb). Epidemiological studies on the effectsof PFOA in humans have been conducted on workers. eTnwdoocmroirntealsiytsytesmt,udaiensd, laipmiodrmbeitdaibtoylsitsumd,y,haanvde sbteuedniecsoenxdaumcitneidntgo edfafteec.tsInonadtdhietiloinv,era, pcarnocssr-eas, sectional as well as a longitudinal studyofthe worker surveillance data have recently been stuhbomuigthterde.cenHtowPeFvOeAr,ltehveesles alrateesstim2ilsatrud1i0esorfhoicguhseprritmhaarniPlyFoOnSPlFevOeSlsrianthweorrtkhearnsPatFOthAe,seepvleannts. (It should be noted PFOA levels). that PFOS levels in the sampled general population are much higher than aAssroectiraotsipoenctbievtewceoehnorptromsotrattaelictayncsetrudmyordteamlointsytarnadteedmpalwoeyamke,natltdhuroautgihosntaitnitsthiecaclhleymsiicganilfifaccainltity sopfeacipflicanextphoatsumraenumfeaacstuurreesswPeFrOeAu.sedH,owaesviegnri,fiicnaantraescseonctiautpidoantefotroptrhoisstsatteudcyanicnewrhwiachs nmootre dobusreartvieodn.s sIoungahmtocrabriedimtoyrestoufdtye,nwfoorrkperrosstwaittehctahnecheirgthreesattPmeFnOtAtheaxnpwoosrukreerssfowritthhelloownegrest exposures. lAenvoetlsh;erhoswteuvdeyrr,epnoornteeodfatnheinoctrheeasrehionremsotnraediloelvellesvealnsalinyzweodrkienrdiscwatietdh atnhey haidgvheersstePefFfOecAts.seSruomme 5 000007 ochfotlheecyssatmoekienmipnl(oCyCeeKs) wlhevoelpsarintiecmipplaotyedeeisn.theNohopromsoitnievestaussdoycailastoiownewraesninoctleuddebdeitnwaeesntuCdCyKo.f ivnalwuoerskearnsd. PTFhOeAr.e dTihdenootthaeprpaevaariltaobblee satnuydsyigenxiafmiciannetddcihfofleersetnecreoslaamnodnogthweorrkseerrsuomfdciofmfpeorneenntts eIoxnpgoistuurdeinlaelveslts.udieAstfpoluanntdspwoshietrievetshiegsniefriucamnPt FasOsoAcilaetvieolnsswbeertewleoewnerP,FcOroAssa-nsdeccthioolneasltaernodl and triglyceride levels. In addition, a positive, significant association was reported between PFOA and T3 hormone and a negative association with HDL in the cross-sectional study. There are many limitations to these studies, and therefore, allof these results must be interpreted carefully. In acute toxicity studies in animals, the oral LDSO valuesforCD rats were >500 mg/kg for males and 250-500 mg/kg for females, and <1000 mg/kg for male and female Wistar ras. There was no mortality following inhalation exposure of 18.6 mg/L for one hour in rats. The dermal LDS0 in rabbits was determinedtobe greater than 2000 mg/kg. APFO is a primary ocular irritant in rabbits, while the data regarding potential skin iritancy are conflicting. AtePstFeOd eiisthneortwmiutthagoernwiict.hoAuPtFmOamdmiadlnioatniancdtuicvaetimount.atiAoPnFiOn ediitdhenroSt.itnydpuhciemguernieummuotratE.iocnolwihwehnen tested with or without metabolic activation in the K-1 lineof Chinese hamster ovary (CHO) cells in culture. APFO did not induce chromosomal aberrations in human lymphocytes when tested with and without metabolic activation upto eytotoxic concentrations. APFO was tested twice: for its ability to induce chromosomal aberrations in CHO cell. In the first assay, APFO induced both chromosomal aberrations and polyploidy in both the presence and absence ofmetabolic activation. In the second assay, no significant increases in chromosomal aberrations were observed without activation. However, when tested with metabolic activation, APFO induced significant increases inchromosomal aberrations and in polyploidy. APFO was negative in a cell transformation assay in CsH 10T,; mouse embryo fibroblasts and in the mouse micronucleus. assay. Subchronic studies in rats and mice with 28 and 90-daysofexposure have demonstrated that the liver is the primarytarget organ. In rat studies, males are far more sensitive than females. Dietary exposure to APFO for 90 days resulted in significant increases in liver weight and hepatocellular hypertrophy in female rats at 1000 ppm (76.5 mg/kg/day) and in male rats at doses as low as 100 ppm (5 mg/kg/day). Analysesof serum and liver levels ofPFOA showed a `marked gender difference that accounts for the difference in sensitivity. Chronic dietary erxesppoescutrievoeflyr)atfsort2o y3e0a0rsprpemsuAltPeFd Oin(i1n4c.r2eaasnedd 1l6i.v1ermagn/dkgk/iddnaeyyfwoerimgahltess, haenmdatfeomlaolgeisc,al effects and liver lesions in males and females. In addition, testicular masses were observed in males at 300 ppm and ovarian tubular hyperplasia was observed in females after exposure to 30 ppm (1.6 me/kg/day), the lowest dose tested. Ina 90-day study with rhesus monkeys, exposure to dosesof 30 mg/kg/day or higher resulted 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, analyses ofthe 4 000008 serum and liver levels did not reveal a gender difference in monkeys, but the sample size was. very small (N=2). Ina 6-month studyofmale cynomolgus monkeys, dosingofanimals in the 30 mg/kg/day dose group was stopped from days 11-21 because of toxicity. 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 treatmentwasalso 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 evidence ofperoxisome proliferation, there was evidenceofmitochondrial proliferation suggesting a different mode of action than observed in rats. The serum levels were highly variable and shouldbetreated 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 pg/mL in the 3 mg/kg/day group and 51.5 + 77.6 pg/mLinthe 30120 mg/kg/day group. The LOAEL for this study was 3 mg/kg/day and a NOAEL was not established. PFOA is immunotoxic in mice. Feeding CS7BU/G mice a diet containing 0.02% PFOA resulted in adverse effects 10 both the thymus and spleen. Inaddition, this feeding regimen resulted in suppression of the specific humoral immune response to horse red blood cells, and suppression of splenic lymphocyte proliferation in response to LPS and ConA. The suppressed mice recovered thei ability to generate a humoral immune response when they were fed a diet devoid of PFOA. Studies using transgenic mice showed that the peroxisome proliferator-activated receptor alpha was involved in causing the adverse effets to the immune system. Prenatal developmental toxicity studies in rats 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 inhalation exposutroe 25 mg/m' resulted in reduced fetal body weights. In a rabbit oral developmental toxicity study there was a significant increase in skeletal variations after exposure to 50 mg/kg/day APFO. There was no evidence of maternal toxicity at 50 mg/kg/day, the highest dose tested. AInPaFOtw,o-sgigenniefriactaintoninrcerperaosdeusctinivaebstoolxuitcietaynsdturdeylaitnivreatlsiveexrpaonsdedkitdon0e,y1w,e3i,g1h0t,sawnedre30obmsge/rkvge/ddainy 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 levelsofthe 10 and 30 mg/kg/day groups were measuredforFO males after `mating and FO females at weaning ofthe F1 pups. In FO males, the serum levels were 51.119.30 and 45.3212.6 ug/l, respectively for the 10 and 30 mg/kg/day groups, and in FO females, the. serum levels were 0.3740.0805 and 1.020.425 ug/l, respectively for the 10 and 30 mg/kg/day groups. In F1 females, there was a significant increase in post weaning morality, 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 andbody weight gains, and significant changes in absolute liver and spleen weights and in the ratiosofliver, kidney, and spleen weights-to- s 000009 dbrealianywienisgehxtusalwemrateuorbasteironvewdaisnaallsotrneoatteedd girnoFuIps.maTlehseaitnc3r0eamsge/ikngp/odsayt.weRaenpirnogdmuocrttialvietyinadincdesthe were not affected in the Fl animals. The LOAELforthe FI females was 30 mg/kg/day, and the dNeOteArEmiLnewda.sT1h0emdgi/fkfge/rdeanyce; itnheseLnsOitAiEviLtyfoirs pFrIesmuamleesd twoasbe1rmegla/tkegd/tdoatyheangdenadNerOdAiEffLerewnacse niont eliminationofAPFO. No treatment-related effects were observed in the F2 generation. However, it should be noted that the F2 pups were sacrificed at weaning, and thus it was not possible fo ascertain the potential post-weaning effects that were noted in the FI generation. Carcinogenicity studies in Sprague-Dawley (CD) rats show that APFO is weakly carcinogenic, inducing Leydig cell adenomas in the male rats and mammary fibroadenomas in the females following dietary exposure to 300 ppm for 2 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 pancreasofmale CD rats at 300 ppm. `The mechanism(s)of APFO tumorigenesis is not clearly understood. Available data appear to indicate that the inductionoftumors by APFO is due to a non-genotoxic mechanism, involving activationofreceptors and perturbationsofthe endocrine system. There is sufficient evidence to suggest that APFO is a PPARa-agonist and that the liver carcinogenicity/toxicity ofAPFO is `mediated by binding to PPAR in the liver. Recently, IARC (1995) concluded that the liver tumors induced in rodents by PPARa-agonists are unlikely to be operative in humans based on `our current understanding of the animal modeofaction. The Agency is curently examining the scientific knowledge associated with PPARa-agonist-induced liver tumors in rodents and the relevantcoe humans. Available data suggest tht the induction of Leydig cell tumors (LCT) and mammary gland neoplasms by APFO may be due to hormonal imbalance resulting from activationofthe PPAR and induction ofthe cytochrome P450 enzyme, aromatase. Preliminary data suggest that the pancreatic acinar cell tumors are related to an increase in serum levelof the `growth factor, cholecystokinin. 6 000010 1.0 Chemical Identity Chemical Name: Perfluorooctanoic Acid Molecular formula: C8 H F15 02 Structural formula: F-CF2-CF2-CF2-CF2-CE2-CF2-CF2-C(=0)-X, TThhee pferereflaucoirdoaocntdasnooamtee canoimomnodnoedserniovtahtiavvees ahasvpeecitfhiecfColAlSowmiunmgbCeAr.S numbers: Free Acid (X=OM5M=H) [35-67-11 Ammonium Salt Sodium Salt Potassium Salt Silver Salt (X=OM#M=NHe) (X=OM+ M=Na) (X= OM+; M=K) (X=OM+ M=Ag) [3825-26-1] [335-95-5) [2395-00-8] [335-933] Acid Fluoride X=F) [3356-0] Methyl Ester Ethyl Ester (X= CH) (X= CH2-CH3) 376272) [3108-24-5) Synonyms: 1-Octanoic acid, 2.2,3,3.4,4,5,5,6,6,7,7,8,8,8-pentadecatluoroPFOA 1.1 Physicochemical Properties For this report, perfluorooctanoic acid is consistently referred to as PFOA. Mostofthe toxicology studies have been conducted with the ammonium saltofperfluorooctanoic acid, `which willbereferred to as APFO in this report. PFOA is a completely fluorinated organic acid. "The typical structure has a linear chainofeight carbon atoms. The physical chemical properties pneontteaddbecealfolwuoarroeocftoarntohiecfarceiedac[i3d3,5-u6n7l-e1s)s,oitshtehrewimsoeststactoemd.plTethee.dTahtaefroerpotrhteefdreveapacoirdp,ressure of 10 mm Hg appears high for a low melting solid when compared to other low melting solids. (NeIhOlSorHo)a,cebfuitc aiscicdo:nssiosltied;ntMwPit=h o61t.hetro 6pe3rflCu;orBiPna=ted18c9omCp;ouVnPds= w0.i1thkPsiami(l0a.r75bomilminHgep)oi@nt2s0 C; (perfluorobutanoic acid BP = 120 C, VP 10 mm Hg@ 20 C; Beilstein IV 2 p. 811). Another explanation may be that the 10 mim vapor pressure was measured at an elevated temperature (but the temperature inadvertently omitted), as perfluorooctanoic acid is typically handled as a liquid at 65 C (3M data sheet for FC-26). The free acid is expected to completely dissociate in water, leaving the anionic carboxylate in the water and the perfluoroalkyl chain on the surface. In aqueous solutions, individual molecules of PFOA anion loosely associate on the water surface and partition between the air/ water 7 000011 itnhteeyrfdaicse.perSseevaernadlmriecpeolrltessnfootremthaatthPigFhOerAcsoanlctesnstlrfa-tiaosnsso.ci(aStiemiastttehre, s1u9r9f2a;ceC,ablufotuwrist,h1a9g8i5t;ation Evadlwuaersdsar,ef1o9r97a).miWcartoedirsspoelrusbiiolinotyfhmaiscebleleens,rerpatohretredthfaonr PtrFuOeAso,lubbui!liittyi.s uDnucleeatrotwhheestehesramtehese PsuFrOfaAce-isacatnitviecippraotpeedrttioesfoorfmPmFuOltAi,plaendlatyheersteisntopcrtoatnooclo/lwaftoerr,thmeuOcEhClDikeshthaokseefolbasskermveetdhofdo,r PFOS. Therefore, an n-octanolwater partition coefficient cannot be determined. `The available physicochemical properties for the PFOA free acid are: MMPW:: 4451-4 5(BeiCls(tBeeiinl,ste1i9n7,5)1975) BP: 189 192 /7C36 mmHg (Beilstein, 1975) VP: 10 mm He @ 25 C (approx.) (Exfluor MSDS) Sol. - Water: 3.4gL (telomeric [MP = 34 Merck, Fischer, and Chinameilan Internet C ref. sites) 0.01 - 0.02mol/L ~4 - pKa: 2.5 (USEPA AR226- 0473) pH (1gL): 2.6 (MSDS Merck) g/L) (MSDS from `(TAhPeFPO)F,OA38d2e5r-i2v6a-t1i1v)eo.fTghriesatseusbtsctaonncceewraasntdhmeotsesttwinigdesusbpsrteaandceusfoeristhtehetoaximcmitoyntieustminsgalt performed and has the P-Chem data provided in the Table below. `wTahteerwastoelurbsiolliutbyioliftAyoPfFOAPtFoObeh>as1b0e%e.nIitnwcoanssinsotteendtliynraenpoeratreldi.er sOtnuedy3tMhatstatudcyonrceepnotrrtaetditohnes of 20 g/L, the solution "gelled" (3M, 1979). These numbers seem surprising low foar salt, in light of Apollo Scientific selling a 31%aq. solutionof APFO. One author reported the APFO "pTahritsitviaolnuceomefifgihctiennottlboeg aPcocwura=teS.duAentoothtehereasuttihmoartrieopnomretetdhoadn eussteidma(tHeadnsAcPhFaOndloLgePoo1w97=9)-.0.9. `Again, the anticipated interface would make dfeotremramtiinoantoifonanofelmouglsKiofiwedimapyoessribbleet.ween the octanol and water surface Dveatpeorrmpirneastsiuorneooftf7hex v1a0p-o5rmprmesHsgureaot f20AEPFCO, whisiccohmpsleiecmastetdo.o lAoPwFfOohraamdatreecreinatlltyhartespuobrltiemadates sasubtlhiemaatmemaotn1i3u0msCal(t.US(E3PMAEAnRv-i2ro2n6me47n3t)a.lALsabtohreattoermyp,er1a9t9u3)r.e inTchreeaasemsmfornoimuwmhseanltAbPegFiOns to dbeognionts dteomsounbsltirmaattee,si2mi0l%arofwetihgehstalmopslseunwtieli2g3h7isClosotrbhyigh1e6r9.(CL.ineOst,he1r98s4a)i.s (DCesc,omKp,oAsgi,tiPobn, oLfi) datif3f2er0entCsfaorstphreosdoudceisumpesralftluaonrdohatep2t5e0n-e2(9l0ossCoffomretthaelsfilluvoerrisdaeltan(dBecialrsbteoinndi1o9x7i5d)e,). This occurs `The 1 physicochemical properties of PFOA and its common derivatives are summarized in Table s 000012 ialFedPO PO PO OY [RECO2H a[Loeg[ Lo 1 1] NH4+ [335671 |55C [189C 3825-26-1_| (sub) rr |iommMg [34gL | | mm Hg gels 2.0 Production of PFOA and its Salts PFOA has been commercially manufactured by two major alternative processes: 1) the Simons 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 `UwnhiitcehdiSstualtteismaitne1l9y99c.onvTehretyedptroedPoFmOiAn.antlDyatuasefdorthteheEFCCF-2p6ro(c9es7s%tCo8p) rsugogedsatusPFtchOiseApuprriefciuerdsor In the ECF process to make PFOA, an electric current is passed through a solutionofanhydrous `hydrogen fluoride and an organic feedstock, typically an octanoic acid derivative. The ECF process replaces the carbon-hydrogen bonds on moleculesofthe organic feedstock with carbonfluorine bonds, in an identicalmannerused to make PFOS. Perfluorination occurs when all the between 30-45 percent straight chain (normal) perfluorooctanoyl fluoride (PFOF), along with a variable mixtureofbyproducts 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 impuritiesofthe crude reaction mixture, the initially formed acid fluoride is base hydrolyzed in batch reactors and acidified to ultimately yield PFOA. The PFOA salts are synthesized by base neutralization of the kg per year in the US, and its importation at less than 100,000 kg (3M Company, 2000a). (These : `fcigounrseusmmedayinotvheersmtaantueftahcettuorteaol fptrohdeucatmimononvioluummoeroofthPeFrOmAetaslilnicce stahletsv.)asItndmuasjtorryitsyouorfcPesFOhAaveis characterized 3M as the dominant global producer of PFOA-related chemicals, manufacturing 000013 M(oErMeG,pr2e0c0i1s)e.pUroSdEucPtAiohnavsonloutmleoscoatfedPFinOfAoramnatditohnetahamtmwoonuiludmcoanntdrasdoicdtiuthmissaclltasimh.ave been prerpeovretnetdintgodUiSscElPosAurbeyin3Mth,isbruetpohratv.e Sbienecnec1l9a8i5m,edUSasETPSAChAascronefciedievnetdiaaltbotuaslionfesaspipnrfooxrimmaattieolny, I2n5vennottiofriyc.atMioosnstfoofrtPhFeOsAe-nroetlifaitceadticohnesmwiecraelsftrhoamt cwoemrpeannoitesproetvhieorustlhyanon3Mt.heITnSmCosAtCchaesemsi,ctahle vnootliufimceatlieosnsstqhuaanli1f0iemdeftorricthteonLsopwerVyoelaur.me Exemption for new chemicals with a production bCuyrirnednutstprryo,dnuoctriiosnitvaovlauimlaeblienfionrUmaStEiPonA'fosrCmhaenumfiaccatlurUeprdsatoethSeyrsttheamn (3wMhihcahscnoonttabienesn provided iinnfvoorlmuamteisonaobnovneon4-,p5o2l5ykmge)r.iFcuorrtghaenrimcorceh,emtihcearlesismnaonuifnafcotrumraetdioinn otnhetUhenittoetadl Sctuamtueslaotriviemported pinrocdoumctmieonntvsotloutmheesdorfafPt FhaOzAarsdianscseisnistmiealntcoomfmePrFciOaAliz3aMtiohna.s stIanttedertmhsaotfthoeni-rgMoaiyng1p6,ro2d0u0ct0ion, parnondouucntcseimnecnltuodefstPhFeOphAasaen-douitsosfatlhtse. prTohdiuscctoimonmoiftspe3rfMlutooraooccotmapnlyeltcehpehmaisset-royuatondfrPelFaOteAd and ePnFdOAo-fr2e0l0a2t.edIcnhaedmdiictaiolns,itdheentFilcaulortooptohleypmhearseMaonuutfoafctPuFreOrSsaGnrdouPpFO(S3-rMcllaartgeedstchceumsitcoamlesr bfoyrthe. `PmFaOnuAfapcrtoudruicntgs,30s0p,ec0i0f0ickagl/lyyrtthoemaememtotnhie uinmdsuaslttr,yAdPeFmOa)ndhafsorinAfPoFrmOedthtahte3EMPAhatshnatotitmweitll(bFeMG. 2002 AR226-1094). The FMG manufacturing process is based on telomerization. "(Tshuechtealsompeernitzaafltuioornopertohcyelssi,odaicdec.o.r.d)iwnigtthoa3pMo'lsymBeurlitzmabalneaentdhyPlieknei,c*coismtphoeurnedac(tisouncohfasa telogen tetrafluoroethylene) to form `telomers'. In this process the resultant telomer iodides are then reacted with ethylene, via free radical addition. This forms a mixtureofiodides that can be reacted subsequently to form a varietyofuseful materials..."". Dupont uses an analogous telomerization process. Either process yields predominantly pure straight-chain acids with an even numberofcarbon atoms. Commercial products manufictured through the telomerization (prRoecnensesr,ar2e00g1e)n.erDailsltyilmliatxitounrceasonfbpeeursfleudotroinoabtieadincopmurpeoucnomdpsownietnhtrsa(ngEeCsT,of1e9v9e4n) carbon numbers Aside from the United States, OECD Member countries that reportedly have production capacity include France, Germany, Haly, and Japan. There may also be some production in non-OECD countries such as China. Following are companies that may manufacture PFOA and is salts (3M Company, 2000; Directory ofWorld Chemical Producers, 1998; Dynax, 2000; Renner, 2001; SEMI, 2001): OECD + 3M Company (United States) + DuPont (United States) + Exfluor Research Corporation (United States) 10 000014 + PCRInc. (United States) .+- CCliabraiaSnptec(iGaelrtmyaCnhye)micals (Germany) + DHoyencehosnt (AGkteiremnagnesye)llschaft (Germany) + EniChem Synthesis Sp.A. (taly) + Miteni SpA. (Italy) + DAasiakhiinGl(Jaaspsa(nJ)apan) + Dainippon (Japan) + Tohkem Products Corporation (Japan) Non-OECD "+ Chenguang Research Instituteofthe Chemical Industry (China) + Shanhai 3F New Materials Co, Ltd. (China) 2.1 UsesofPFOA and its Salts PFOA is used mainly as a chemical intermediate, and its salts are used in emulsifier and surfactant applications According to 3M, the vast majority ofPFOA is consumed to make the ammonium or sodium salts. 3M also uses PFOA as a reactive intermediate in the industrial synthesis ofa fluoroscrylic ester. The fluoroacrylic ester is used in an industrial coating application (3M Company, 2000a). "The salts of PFOA have include the following: additional uses, mostly in surfactant and emulsifier applications. These pPorloycteestsrianfgluaoirdoeinthtyhleeniendausntdripaollysyvnitnhyelsiidseonfe fflluuoorriodpeolwyitmherasvaanridetfyluoofroinedluassttroimaelrasnsducchonassumer uses (3M Company, 20002; DuPont, 2000; Daikin, 2001). Pfolsuto-rpooellaysmteormiezrastipornioprrtoocefsustihnegraiinddsusitnrtiahle psrtaobcielsisziatnigo(no3fMsuCsopmepnasniyo,ns2o0f00f2l)u.oropolymers and Processing aid for factory-applied fluoropolymer coatings on fabrics, metal surfaces, and fabricated or molded parts (3M Company, 20004). Extraction agent in ion-pair reversed-phased liquid chromatography (Pettis, 1999). Bsuarsfeadctoannttohre epmhuylssiicfoiecrheumsiecsaalsparoppheorttoigersaopfthihcecshaelmtsicoaflPoFrOiAn,thtehemyanmuafyacatlusroeohafveeloetchtreornrieclated components such as semiconductors. These same properties may lead indusiry to explore PFOA n 000015 asa replacement chemical for PFOS in other applications in which PFOA is not currently used. 22 Environmental Fate 22.1 Photolysis Direct photolysis ofAPFO 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 mg/l APFO in 2. litersofdistilled water was exposed to simulated sunlight ai 22:2 C. `Spectral energy was characterized from 290-600 nm witah max output at ~360nm. Direct photolysisofthe test 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 potential for direct photolysis, APFO was dissolved in pH 7 buffered water and exposed to simulated sunlight (Scrano, 1999; Nubbe, 1995). For indirect photolysis, APFO was dissolved in 3 separate matrices and exposedtosimulated 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 pH 7 buffered aqueous solution containing H202 as a well-characterized sourceofOH radicals `(TOhgeatsae,co1n9d83m;atLruinxakc,on1t9a9i2n)e.d TFhei2s0t3esitnedwattheerptrhoaptenhsaistbyeoefnAsPhFowOnttoougnedneerrgaoteinhdyidrreoctxyplhortaodliycsaliss via a Fenton-type reaction in the presence of natural and arificiel sunlight (Kachanova, 1973; Behar, 1966). The third matrix contaistnanedardd solutionofhumic material. Neither direct nor indirect photolysis ofAPFO was observed based on lossofstarting material. Predicted degradation products were not detected above their limitsofquantitation. There was no conclusive evidenceofdirect or indirect photolysis whose ratesofdegradation are highly dependent on the experimental conditions. Using the iron oxide (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 volatilityofAPFO and PFOS. Solutions of APFO or PFOS containing ammonium acetate inwater I-propanol (50:50) or phase transfer wageernetsb,leo.gw.n wni-tahlk2y8l0dilimteertsohyflabiernaztyalafmlmoownriautme ochflo|rLi/dmein(.3M(3EMnvEinrvoinrmoennmteanltLaalboLraabtoorrayt,ory1,993) 1993). The results indicate there is some lossof APFOand PFOS, but most of the solutions. retained over 80% or moreofthe fluorochemicals. The average retention was 92% for both APFO and PEOS. This indicates that there is loss from the solutions. However, someofthe aslollutthieonfsl,uopraorcthiceumliacrallys.theThne-saelkryesludlitmsewtehryelbreenvziyelwaemdmboyniDur.m cEhdlwoirindeTuscokluetrioofn,thapepCehaermtiosrtertyain Dept. at the Universityof Oklahoma (3M Environmental Laboratory, 1993). He concluded that itis very unlikely that these fluorochemicals were removed by bubbling air through water due to 2 000016 sthoeliurtivoenryphlaoswe vias pcoorncpernetsrsuarteiso.noHftehesusgugrefsatcetdantthsatina fmooarme apnldausloisbslefrmoemchtahenibsumbbfloerdlsososluftrioonmstahse foam or micro-droplets tInhrtohuegsheacotnradinpaorftiomftphinegeerxspecroinmteanitn,inagirtwheasampmasosneiduomvearcetthaetfelsuoolruoticohne.micItalwsasanedxpbeucbtbeldedthat if aanmymoflnuiouromchaecemtiactaelsswoleurtieopnr.esHeonwtevinerth,enaoirftlhueoyrowcohuelmidcbaeltsrwanesrfeerprreesdeanntdinrectiatihneerdthbeyftihrset or second impinge. 10 E-07 mim Hg. The report concludes that the vapor pressureofboth compounds is less than vAacpcoorrdpirnesgsutoret.heQsueaenxtpietartiimveentcso,ncAlPusFiOonasnrdePgaFrOdiSng(proatteasssoifuvmolsaatlti)lihzaatvieonvefrryomlowwatveolratoirliHteynarnyd's ALlaswo,ctohnestlaonstsaorfe tnhoetfpuoosrsoibclhee.micHaolwsevmeary, hAaPveFObeaenndasPFthOeSfraeree accaipdas,blneootfttrheanssalptorftoromust.ofAPwaFteOr. vsaulbildiimtyeosfatth1e3t0esCt m(seetehPohdysfiorcodcehteemrimcianlinPgrovpoelarttiileistySoefcttihoente1s.1t).subTshtearncee.is nToheinsftourdmyatailosnoolancktsh.e characterizationofthe purityofthe tet substance. 2.2.3 Biodegradation Using an acclimated sludge inoculum, the biodegradationofAPFO was investigated using a shake culture study modeled aftr the Soap and Detergent Association's presumptive test for degradation (Reiner, 1978). Both thin-layer and liquid chromatography did not detect the presenceofany metabolic products over the course of2 1/2 months indicating that PFOA does not readily undergo biodegradation. Ina related study, 2.645 mg/L APFO was not measurably degraded in activated sludge inoculum (Pace Analytical, 2001). Test flasks were prepared using. aa HmiPnLerCa/lMsaSltDs smyesdteimu.m,S|evmerLalmeotthhaenroslt,udaineds c5o0nmdLucsteetdtlbeedtwsleuednge1.97A7n-a1ly9s8i7sawlsaosdciodnndoutctoebsderwviet.h APFO biodegradation using what probably were standard COD and BOD methods, however, the `methods used in these studies were either insufficiently described (i.. no description of reexspuelrtismweenrtea,ltphreorteofcoorles,)doeretmheedreuwnreerleiaibnldeicbaytitohnessoubfamihtitgehr (de3gMreCeoomfpeaxnpye,ri1m9e7n7t;al3eMrroCro.mpTahney, 1950; 3M Company, 1985b; Pace Analytical, 1997). 22.4 Hydrolysis `The 3M Environmental Laboratory (2001) performed a study of the hydrolysis of PFOA. The study procedures were based on EPA's OPPTS Guideline Document 835.2110 (EPA 1998); although the procedures do not fulfill al the requirements of the guideline, they were more than adequate for these studies. Results werebasedon the observed concentrationsof PFOA in buffered aqueous solutions as a functionof ime. The chosen analytical technique was high performance liquid chromatography with mass spectromery detection (HPLC/MS). Bn 000017 During the study, samples were 11.0overa period of 109 days. prepared and Experiments examined at six were performed different pH levels from at 50C and the results 1.5 to eobxjtercatpiovleataenddtowe2r5eCr.ejeDcatetda. frAolmsotwreojoefcttehdewpeHreltehveeldsa(t3a.o0balnadine11d)ffoarilpeHd t1o.5mebeectatuhseediaotnapqauiarliintgy pleHd tloevaerltsif(i5c.i0a,ll7y.0l,oawncdon9c.e0)ntirnadtiicoantsedfonroalclletahredienpceubnadteinocneopefritohdes.deTgrhaedartesiuolntsraftoerotfhePrFeOmaAinoinng, `pH. From the data pooled over the three pH levels, it was estimated that the hydrolytic half-life O`mfePanFOvaAluaet a2n5dCpriescgirseiaotneorfthPaFnO9A2 yceoanrcse,ntwriatthitohnse,miot swtaslieksetliymvaatleudetohfe2h3y5dryoelayrtsi.cFharlof-mlitfheeof PFOA to be greater than 97 years. 225 Bioaccumulation `Three studies have been conducted to determine the potential for bioaccumulationofAPFO. Howell etal. (1995) exposed Fathead minnows to 25 mg/l APFO for 13 days. After 13 days exposure, the fish were then removed from APFO contaminated water and analyzed for depuration over 15 days. After 192and312 hours exposure to APFO contaminated water, the average concentration ofAPFO in fish tissue was 44.7 and 46.7 g/g wet weight (ww), respectively. At this point, APFO appeared to reach steady state. Twenty-four hours aftr being transferred to clean water, the concentrationof APFO decreased 10 19.9 g/gwiv and by 96 hours post-exposure, the concentration had decreased to approximately 8 ug/g wi and remained relatively should be cnoontsetdantthautnqiulestteistontserhmaivneatbieoennatra3i6s0edhaoburosu.t hTihse sctauldcyulraetgeadrdBiCnFg tfhoer aAnaPlFytOicwaals 18. It techniques, high-test chemical concentration, and short test duration. Ina bioaccumulation study ofcarp (Cyprinus carpio), 28 carp were exposed to two concentrationsofPFOA, 5 and 50 1g /L respectively for 28 days in a flow through system (Kurume Laboratory, 2001). The chemical was prepared for exposure by using a dispersant `made upofhydrogenated castor oland mixed in acetone. The purity of PFOA was 100%. `PWFatOeAr qwuaasliftyouwnadstmoobneitloorw.edThdaeilcyartphreoxupgohsoeudt1t0he5dgur/aLtiorne.suTlhteedbiinoaacBcCumFuolfat3i.o1nwphoitleenttihael coafrp exposed 10 50 yg/L showed a BCFof <5.1-9.1. Vraspir (1979) conducted a study to determineif bluegill sunfish bioaccumulate fluorochemicals from the 3MDecaturplant. Two lotsof 30 fish were used. One lot was exposedto Decatur plant effluent for 21 days and the other to iver water only for 23 days. Expose fish, both living and dead, as well ss the control fish were homogenized and analyzed for fluorochemicals by GC. TLC, and GC/MS. There were no detectable amounts of APFO in the ethyl acetateortoluene extracts of the tissues. No fluorochemicals were detected in the river water exposed fish. However, interpretationofthis study is problematic for several reasons. Effluent concentrations of subject fluorochemicals were not characterized and the specific protocol for exposure of the feifsfhluweantsunsoetdfionuntdh.e sTthudeyr.ewAadsdiatlisoonanlloy,iniftowramastniootn oknnoawnnailyfstihseorfetwhaesTeannnyeospspeoertRuinvietrywfaotretrheor depurationofthe ish prior 10 sacrifice. No explanation was attempted as to what was the cause 4 000018 obfettwheeetnwetlhveebdieoaacdcfuimsuhliantithoeneoffftlhueenttes-texcpoomspedougrnodupa.ndThtehesstourdpytiaolnsoodnitdo ntohte sdiufrffearceentoiftateh fish. 2.2.6 Soil Adsorption `diTshteilaldesdorwpattieorn-wdietshorpgtiBorniollfsAanPdFyOlowaamsssotiuldfioerd2i4n 2h5oumrls asoaluttieomnpseroaft1u4rCe-olfab1e6l-e1d9ACP.FOThien sstaunddyy rleopaomrstoeiald (KWdelosfh0.129178a).nTdaheKoKcocofv1a4liuned,ihcoatwienvgetrh,aits PquFeOstAiohnaasblheigdhucmotboilthietyilanckBroifll accurate information on the purityofthe 14C-Tabeled test substance (Boyd 1993,6). Mtoo3odmeytearnsdbFeiellodw(t1h9e99so)ilcosnurdfuaccteedinscalmopsleipnrgoaxinmdiatnyaltoystiwsooffisrae-mtprlaeisnitngakaerncafsrwoimtghraouhinsdtwoartyeorf1 aqueous film forming foam use. Perfluorooctanoate was detected at maximum concentrations rdiasncgoinntginfureodm. 1T1h6etsoe6r7es5u0ltusgs/uLggatestthethtawtoAsPitFesOmmaanyyhyaevaersthaeftpeortietnstuisale tao tmhiogsreatseittehsrhoaudghbesoeinls to relatively shallow groundwater where it persists. 2.3 Environmental Exposure 23.1 Discharge to Air FitosrCo1t9t9a7g,e3GMroevset,imMatNedlo1c9a5t0ioInbsa.nodfaPnFotOhAe-rc4o5m0p0obusn.df(roPmFOCoAttaangderGerlaotveed sinacli)nesrtaatcekd roeflfseiatsees at (in3cMi,ne2r0a0t0e)d.offI-nsi1te9;98i,nc7in0e%raotfitohneisfnlouowritdhee-cpornitmaairnyindgiswpaosstaelsmaett3hMo'dsfDoerctahteuser lmoactaetriioanlsw(e3rMe, 2W0o0r0k)s., FWoVr 1l9o9c9a,tiDonu,Poplnutseasntoitmhaetred16s,t0a0c0k rIbesl.eafsreosomfWa2s4h,i0n0g0tIobsn.WAoPrFkOs aitnciitnseWraatsehdinofgfstioten: (DuPont, 2000). "The above data may not account for allofthe sourcesofai releasesof PFOA. Other potential sToouwrcteesmpaedrdarteusrseoedfisnutbhleimlaitteiroantu(re~1i3nc5lCu)dethtahtewrmooullydsiysioelfdfPluFoOroApoflryommedrrsyi(Enlgl,iaskeat asli,n2te0r0i1n)g;, tohfe fFlbuoornodp(oNlaypmoelri,maetdea,wi1t9h84P;FTaOyAloars, aetpralo,ce1s9s9i0n;gTasiadn;gt,heettahle,r1ma9l9l8y) rtehfartawctoiuvledchraerqaucitreerovefrtyhheiCghtemperature incineration as & meansof destructionofthis molecule. 232 Discharge to Water BpayrtaincaullaotgeymtaottPeFrOaSn,dPseFdOimAendti,scahnadr/goerdbteo awsastiemrilmaateydrbeymaoirngatnhiesrme,s.beFcoorme19a9d9,so3rbMedesttoimated PitFs OCAot-tcaogmepGoruonvde MwaNterlorcealteiaosnes(3ofM<C3o0m,p0a0n0yI,bs.20a0t0iat,sbD)e.caFtourr1A9L99,loDcautPioonn,taensdti<m1a5t,e0d0t0helbs. at following APFO water releases per location: Washington Works WY, 55,000 Ibs; Parlin NJ, 300 15 000013 Ibs; Spruance VA, 150 Ibs.; Chambers Works NJ, 9500 Ibs. (DuPont, 2000). fDruoPmonat1m9e9a9sdurriendkianngAwPatFeOr scaomncpelnetroabttiaoinneadt ftrsosmitGe EWaPslhaistnigctsoinmWmoedrikast,eWlyVdoswitnesotfre0a.m55o2nutgh/el cOohnicoenRtirvaetr.ionMoodfel0e.4d23 1u9g9,6 wAiPtFhOA-PcoFmOpocounncdenrterlaetaisoensisnldiikcelaytetodaenxcaeveedra1guegaCn-nu8a/laPboFuOtA50% of the time year during the year, and likely to exceed 10 ug APFO/L about 2.2%of the time during the 233 Discharge to Land 3M reported that land treatment ofsludge from wastewater treatment at their Decatur, AL location ended in mid-1998; less than 500 Ibs. weredisposedto land at that ste in 1997. Sludge from the Decatur site is now transportedtoan offsite landfill; sludge from 3M's Cottage Grove, 3M,N900faIcbisl.itoyfisAsPeFntOoslaundgiendluasntdriiiallleldaondnfsililte(3iMn 1C9o9m9paatntyh,ei2r0C0h0a.m5b).erDsuWPoornkts,(2N0J00f)aceilsittyi.mated DuPont estimated 2,600 Washington Works, WV Ifbasc.ilAitPyF. O transferred offsite 0 a hazardous waste landfill rom their Prior operations resulted in ground- and surface water concentrations of APFO monitored at three landfills operated by DuPont's Washington Works WV facility. Average surface water `concentrations for two landSills were 1392 ug/L and 18.5 ug/L, respectively. A third landfill had a maximum concentrationof 33 ug/L in the permitted outfall. Average groundwater concentrations for two landfills were 2537 ug/L and 8.83 ug/L, respectively. A third landfill had `2 maximum groundwater concentration of 15 ug/L (DuPont, 2000). DuPont also reported the following APFO concentrations, measured January 2000, in three drinking water wells of the Lubeck Public Service District, downstreamof DuPont's Washington Works WV site: 0.8 ug/L, 0.44 ug/L, and 0.313 ug/L (DuPont, 2000). AsofAugust 2000, the Lubeck Public Service District (LPSD) reported APFO concentrationsof 0.2 ppb in drinking `water at DuPont's Washington Works facility, and 0.2, 0.5, and 0.1 ppbinthe three LPSDwells (LPSD, 2000). 2.3.4 Environmental Monitoring 3M' Mult-City Study reported on PFOA concentrations from water, sludge, sediment, POTW. effluent, and landfill leachate samples taken in six cities (3M, 2001a). Four of the cities (Decatur, AL; Mobile, AL; Columbus, GA; Pensacola, FL) were "supply" cities that have `manufacturing or industrial useoffluorochemicals; twoofthe cities (Cleveland, TN; Port St. Lucie, FL) were "control" cities that do not have significant fluorochemical activities. Across all cities, POTW effluent concentrations ranged from 0.040 to 2.42 ppb. The POTW sludge (dry wt) range was non-detect to 244 ppb; the drinking water range was non-detect (0 0.029 ppb; the landfill leachate range was non-detect to 48.1 ppb; the surface water range was non-detect to 0.083; the sediment range was non-detect to 1.75 ppb (dry wt.); andthe quiet water range was 16 000020 naobno-vdeetreacntge1s0,0e.x0c9e7ptppfbo.r tThheeP"OcTonWtroeflf"lcuietnitesasnadmsplluedsgegefnienrdailnlgysifnohraCblietveedltahned,lowwheircehnwdoefrethe intermediate in their ranges. 2`T0h0e sMualmtpil-eCsittyakSetnufdryoamlsgoreiennclbuedaends,aampaprlkees,t pboarskkemtussaclmep,licnogwofmiPlFk,OAchircekseindumeuisnclaet,otcahliocfkoevner ergagnsg,inbgreuapd,toho2t.3d5ognsg,/gc,atwfeisrhe, faonudngdrionutndwboegerfo(u3ndMb,e2e0f0s1a)m.pleMsea(scuornarbollecqiutiaenst)i,titewsoofbrPeaFdOA, ssaammppllees((scuopnptlryolciatyn)d. supply cities), two apple samples (supply cities), and one green bean sGiaemspylerdepforrotmedthtehaUt.PS,F,OcAertwaaisn Eraurreolpyefaonuncdouinntifiessh,atnhde fNiosrht-hcaPtaicnigfwiactOecrebainr,ds.andFiAsnhtawrecrteic IMoicdatwiaoynsa(toGlile,styh,e2B0a0l1tai)c. anFdisMhe-dcaittienrgrabniredansaSmepasl,esJawpearneesceolalnecdtKedorferaonm ctohaestUs.S(.Giienscyl,u2d0in0g1b) Giesy reported on PFOA inminkand river otter livers from the U.S. (Giesy, 2001c). PFOA was found ina few mink livers from Massachusetts at a concentration range of <18 to 108 ng/g, dry. rwitv.erboutenrotlifvoerusndfrionmmWianskhfirnogmtoLnouainsdiaOnra,egSoonutShtCataersolwienraealnedssItlhlainnoitsh.e PquFanOtAificcoantcieonntrlaitmiitonosfin 36 ng, wet wt. Giesy reported that PFOA was not detected at quantifiable concentrations in oysters collected in the Chesapeake Bay and GuoflMexficoof the U.S. coast (Giesy, 2001). Giesy reported on the concentrationsof PFOA in surface water, sediments, clams, and fish collected from locations upstream and downstreamofthe 3M facility at Decatur, AL (Giesy, 320M01fa)c.ilOiftythhaedtPhFreOeAdoswunrfsitcreewaamtewratceorncaenndtrsaetdiiomnesnstigsnaimfpilcainntglylogcraetaitoenrs,thtahne tthweotcwloosuepststtroetahme sites (meansof 1900ug/L and 1024 ug/L, vs. 0.008 (est) and 0.028 ug/L); the three downstream locations also had sediment concentrations significantly greater than the upstream sites (wet wt. means 1855 ug/ke, 892 ug/kg, 238 uglkg vs. 0.08(est) and 0.09(est). The average fish whole body PFOA concentration for the upstream location was 11.7 ug'kg (wet w.), while that for the downstream location was 106.4 ug/kg; the small sample size prevented determination of significance. The average PFOA concentration in clams at the upstream location was 4.38 ugk; that for the downstream location was 8.42 ug'kg. These differences were not significant. Hansen (2002) reported concentrations of PFOA measured from surface water samples taken from the Tennessee River up- and downstream of the outfall rom the fluorochemical manufacturing facility at Decatur AL (the 3M facility mentioned above). There were 20 sampling sites above and 20 sites below the outfall location, spaced at approximately 2 mile ciontnecrevnatlrsa.tiNoonnseooffPtFhOeA.samTphleesdtoawknesntfrreoammucposntcernetarmaotfitohnseoffacPilFitOyAhawdermeeaosbusrearbvleed to increase at a point approximately six miles below the outfall the average PFOA concentration from that " 000021 pcooinnctendtorwatnisotnrsewaimthwianst3he9s4e=tw1o28renggi/oLn.s sTuhggeesretpsotrhtestaabtseesntcheaotftehietchoenrsimsatjeonrcyenovftihroenmPeFntOaAl sinks or additional sources of PFOA in the areas sampled. uMposotdreyamreapnordtdeodwtnhestcroencaemntorfaatisopnilsl ooffPfiFreO-Afigihntsiunrgffaoceamwattheatr cfornotmaisnterdeapmerlfolcuaotriionnastesdampled surfactants, including PFOA (Moody et al, 2002). Upstream surface water samples taken over the three week period post-spill had PFOA levels of 0.008-0.033 ug/L; corresponding. downstream levels ranged from 0.035-10.6 ug/L. Statistical significance was not evaluated for these measurements. 2.4 Human Biomonitoring Table2 provides serum PFOA levels in both occupational cohorts and in the general population. "The highest levels reported to date in the general population are similar to some ofthe lowest Tevels in workers exposed to PFOA occupationally. The data are currently limited to those discussed below. 3M has been offering voluntary medical surveillance to workers at plants that produce or use perfluorinated compounds since 1976. Serum PFOA levels have been measured and reported since 1993. Prior to this time, only total organic fluorine was measured. The results of biomonitoring for PFOA have been reported for 3 plants: Cottage Grove, MN; Decatur, AL and Antwerp, Belgium. Surveillance years include 1993, 1995, 1997, 1998, and 2000, although not allofthe plants offered surveillanceinall ofthese years. The 1998 data reported for the Decatur plant consist ofa random sampleofemployees; however, volunteers participated in allofthe other sampling periods for allofthe plants. Mean serum PFOA levels have increased slightly at both the Cottage Grove and Decatur plans since 1993. Workers at the Cottage Grove plant, where PFOA exposuresare highest, have the highest PFOA serum levels. The latest sample was in 1997 (Olsen, et al, 19980). The mean serum PFOA level was 6.4 ppm (range = 0.1 ~ 81.3 ppm). Only 74 employees participated in the 1997 surveillance. The eligible voluntary participation retes ranged from approximately 50% in 1997 10 70% in 1993. At the Decatur plant, 263 of 500 employees participated in 2000 (Olsen, eta, 2001a). The `mean serum PFOA level was 1.78 ppm. It was higher in males (n = 215) than females (n = 48), 1.90 and 1.23 ppm, respectively. In addition, male production employees had higher mean Serum levels (2.34 ppm). Five employees had serum levels greater than 5 ppm, the Biological Limit Value established by the 3M Exposure Guideline Committee. Cell operators had the largest increase in serum PFOA between 1998 and 2000. The highest level was in a chemical operator on the Scotchgard team (12.70 ppm). The mean level for the restof the membersofthe t3eMamrwepaosrt5s.0t6hapt pthmis(irsadngueeSto-i9ncprpema)s.edOPtFheOrAjopbrocdautcetgioroineastdtihdenDoetceaxthuirbiptlasnutchbeagilnanrgienginicnrease. 1999. 18 000022 dSeecrruemasPedFOslAighltelvyelssinfocret1h9e9A5n(tOwlesrenp,peltaanlt,ar2e00l1obw)e.r tPhaartniactipDaetciaotnuirnomredCioctatlagseurGvreoivlela,nacendathtahvee "ATnhtewmeerapnplsaenrtuwmaPsFtOheAhilegvheelstwaitsh0a.d8e4vpeprmb,eeanndinth2e00h0ig(h2es5t8 sveorluunmteleervesloruetopofrt3e4d0wwaosrk7e.r0s4).ppm. fAesmailnetsh(eaD=ec4a9t,u0r.p0l7anptp,mm)a.leTshr(ene=e2m0p9l)oyheaedshihgahderlemveealsngsreeartuemr tPhaFnO5Aplpemve.ls (1.03 ppm) than f3lMu'osroScpheecmiiaclatly rMeasteearricahls(BMuainludfiancgt2u3r6i)n,gcDoinvdiuscitoendLvaobolruanttoarriyebs,iowmhoenrietoermipnlgooyfe4e5s epemrpfloorymees in 2000 (Olsen, etal, 2001). The mean PFOA serum level was 0.106 ppm (range 0.008 --0.668 ppm). o`cSceurpuamtPioFnOalAelxepvoeslsurien tcoorPpForOaAtessthaofufladnndotmahnaavgeeorcscuartraed3,MweprleanrtepinorStte.dP(au3lM, MReNp,orwth,e1r9e99). Four of 31 employees had mean for these employees serum PFOA levels was 12.5 ppb. greater than the detection limit of 10 ppb. The tDraetnadsonovPerFOtiAmelecvaenlnsoitnbteheesgteanbelriaslhepdo.puTlhateimoneaarnesveerruymliPmiFtOedA. lTevheelys aarree lvoewreyrreicnetnhtesgoentehartal `population than in workers exposed to PFOA. `PCooomlpeadnbyl,ooFedb.sa5m,pl1e9s99f;r3omMUC.oS.mpbalnooyd,bMaankys2i6n,di1c9a9t9e).meTahnePhFigOheAstlepvoeolsloedfs3atmopl1e7 rpeppbor(t3edMwas 2le2veplpsb.areSagemnpelreasliwzearbleectoolltehceteUd.Si.n p1o9p9u8laatnidon19f9or9.sevHeorwaelvreera,sointsc:an1n)obtlboeodasdsounomresdatrheatatuhneiseque b`garnokusp othraitgidnoaellsyncootnnteaccetsesdarfiolryporesfsliebcltetihnecUl.uSs.iopnoipnultahteisotnudasy adewchloilnee,d 2to) pmaarntiycoipfatthe,e3b)loonoldy a asgmea,llsenxu,mobreorthoefrsdaemmpolgersahpahviecaicntfuoarlmlyatbieoennaraenaalvyazieladblfoeroPnFtOhAe,doannodrs4.) no other data such as oItnhdeirvifdluuaolrbolcohoemdiscaamlpsluessinfgrohmig3h-dpirfefsesruenrtealgiqeuipdopcuhlraotmiaotnosgwrearpheyr/eccleencttlryoasnparlayyzteadndfeorrnPmFaOsAs and sipnecclutdreodmeatdruylt(bHlPoLodC/doEnSoMrsS,MaSn)e(ldOelrsleyn,poeptuall.at2io0n02p2a,rt2ic0i0p2at,in2g00i2na).proTshpeecsttiuvdeiesst'updayrtiincSiepaatnttlse, m`WeAa,nsanwdercehislidmrielnarfraocrmo2ss3 astlat3espoppaurltiactiipoantsin(g4.i6npapcbl,in4i.c2alpptrbi,ala. nOdv4e.r9alplp,bt,herePspFeOctAivgeleyo)m.etTrhiec f`goeuonmde)traincdmtehaeinrsuapnpder9b5o%untdoslewreanrceecloimmiptasr(atbhleeparcorpoosrstiaolnl 3oftsthuediepso.pulHaotwieovneerx,ptehceteudppteorber:anges wfohretthheerchtihlidsriesntahendreasduullttosfwgeeroegrmaupchhichdiigfhfeerretnhcaensfionr PthFeOeAldelrelvyelpsopourlsaotimoen.otIhteirsfnaocttorc.leaItr ashnodurld=.b7e5n)oatnedd tthhaatt PPFFOOSAadnidd nPoFtOmAeweetrtehehicrgihtleryiacofrorrealaltoegd nionramllalthdriesetrsitbuudtiieosn(bra=se6d3,on=the70, Shapiro-Wilk test in anyofthe studies. The authors suggest that it may be due to the greater 19 000023 proportionofsubjects with values < LLOQ; detailsofeach study are provided below. however, oly geometric means were reported. The oBblioaoidnesdamfprloemssfixroAmme6r4i5cUa.nS.ReaddulCtrobslsoobdlodoodnobrasnk(s33l2ocmaatleeds,in:31L3ofsemAanlgeesl)e,sa,gCeAs;20-69, were: Minneapolis/St. Paul, MN; Charlotte, NC; Boston, MA; Portland, OR, and Hagerstown,MD (Olsen, etal., 2002a). Each blood bank was requested to provide approximately 10 samples per 10-yearage intervals (20-29, 30-39, tc.) for each sex. The only demographic factors known for ach donor were age, gender, and location. "(T1h.e9)gte0om5e2t.r3ipcpbm.eaMnalseesruhmadPFsiOgnAifliecvaenltlwyahsig4h.e6rp(ppb.< T.h05e)rgaenogmeetwraisc <mleoawnerPlFiOmiAtolfevqeulasnttihtaantion females (37.8 ppb vs. 32.1 ppb). Age wasnotan important predictorof adult serum mfleuaonrofcohrePmiFcOalAcwonacsenitnratthieonssa.mplWehsernosmtraCthiafrileodttbey,gNeoCgr(a6.p3hipcpbl,ocraatnigoen:, t2h.e1h2ig9h.e0st)gaenodmetthreic lowest from Portland (3.6 Hagerstown (52.3 ppb). ppb, range: 2.1 ~ 16.7). The highest individual value was reported in `Serum PFOA levels were reported for 238 (118 males and 120 females) elderly volunteers in Seattle participating in a study designed to examine cognitive function in aduls aged 65-96 (Olsen, etal, 2002b). Age, gender and numberofyears' residence in Seattle were the only data available on the participants. Mostofthe participants were under the ageof 85 and had lived in the Seattle area for over 50 years. `The geometric meanofPFOA for all samples was 4.2 ppb (95% CI, 3.9.~ 4.5). The range was 1.4 16.7 ppb. There was no significant (p < .05) difference in geometric means for males and females. In simple linear regression analyses, agewasnegatively (p < 05) associated with PFOA in elderly men and women. In bootstrap analyses, the meanof the 95% tolerance limit for PFOA was 9.7 ppb with an upper 95% confidence limit of 11.3 ppb. PFOS and PFOA were highly correlated (r = 75) in thi study. A sample of 598 children, ages 2-12 years old, participating in a studyofgroup A streptococcal infections, was analyzed for serum PFOA levels (Olsen,et al, 2002). The samples were collected in 1994-1995 from children residing in 23 states and the District of Columbia. PFOA did not meet the criteria for a log normal distribution based on the Shapiro-Wilk est. The authors suggest that it may be du to the greater proportionofsubjects with values < LLOQ for PFOA. However, only geometric means were reported. The geometric meanof PFOA for all of the participants was 4.9 ppb (95% CI, 4.75.1). The range was 1.9 to 56.1 ppb. Male children 4h.a7dpspibg,nirfeiscpaencttliyve(lpy<.01I)n hsiigmhpelregleionemaertrreigcrmesesainonsaenraulmysPesF,OaAgelwevaeslsstihganniffiemcaalnets(l:py 5<.205p)pb and negatively associated with PFOA in both males and females. When stratified by age, the. `geometric meanofPFOA was highest at age 4 (5.7 ppb) and lowest at age 12 (3.5 ppb). `Although the data were not reported,a graphical presentationoflog PFOA levels for each state by gender looked similar acrossthestates; however, itis difficult to interpret these data without 2 000024 tahnealdyasteas,anthdegmieveannothfethleimi9t5ed%staomlpelraensciezelifmoirtfeoarchPFgeOnAderw/alsoca10t.i1onppsubbwgirtohuap.n In bootstrap upper 95% cPoFnOfiAdeanncdePliFmHitSo(fper11f.l0upoprbo.hePxaFnOesSulafnodnaPtFe)OwAerweearleshoigcholryrecloartreedl(arte=d (4r8)=..70) in this study. Tadhueltas,bocvhield3resnt,udainedsainndiecladteerlsyimpiolpaurlagteioomn.etrHicowmeeavnesraa,nndurnaenxgpeesctoefdPfFiOndAinagmwoansgtsheamlpevleeldof PFHS and M570 (N-methyl perfluorooctanesulfonamidoacetate) in children. These serum levels were much higher in the sampled children than in the sampled adults or elderly. It is not clear why this occurred, but it is probably due to a different exposure pattern in children. eItnala.n,ot2h0e0r1s)t.udyT,hitrhteyP-FonOeA.docnoonrcesnatmrpalteiosnwwearse aobniaaliynzeedd finrohmum16anmasleeras aanndd l1i5vefresmaamlpelseosve(rOlasnen 18-month period from the International Institute for the Advancement of Medicine (IAM). The average ageofthe male donors was 50 years (SD 15.6, range 5-69) and the average ageofthe: female donors was 45 years (SD 18.5, range 13-74). The causesofdeath were intracranial hemorrhage (n = 16 or 52%), motor vehicle accident (n= 7 or 239%), head trauma (n = 4 or 13%),braintumor (n = 2 or 6%), drug overdose (n= 1 or 3%)and respiratory arrest (n = 1 or 3%). Both serum and liver tissue were obtained from 23 donors; 7 donors contributed liver tissue only and 1 donor contributed serum only. Serum samples were obtained from 5 mlofblood; liver samples consisted of 10gof tissue. Samples were frozen at IAM and shipped frozen to 3M for analysis. Samples were extracted using an ion-pairing extraction procedure and were quantitatively assayed using HPLC-ESMSMS and evaluated versus an unextracted curve. Extensive matrix spike studies were performed to evaluate the precision and accuracyof the extraction procedure. Serum values for PFOA ranged from < LOQ (<3.0) ~ 7.0 ng/mL. Assuming the midpoint value between zero and LOQ serum value for samples <LOQ, the mean Serum PFOA level was 3.1 ng/mL with a geometric mean of 2.5 ng/mL. No liver to serum ratios were provided because more than 90%ofthe individual liver samples were <LOQ. 2 000025 1997 (n =74) 1995 (n =80) `Table 2. Serum PFOA Levels in Human Populations & 64 0.1-81.3 68 0.0-114.1 Eek F T EPE >EWe a =R 1995 (n=93) L13 000-132 * F mRL e p lloew |] Er fe LfooeeJe es] gm Jo Jee |] *Geometric mean and 95% confidence intervals were not included in the reports. **PFOA detected in about 1/3 of the pooled samples but quantifiable in only 2 . 000026 3.0 Human Health Hazards 3.1. Metabolism and Pharmacokinetics 3.1.1 Half-life in Humans ``Twhheirceh atroetavleorrygalniimcitfeldudoaritnaeonintbhleoohadlfs-elrifuemofwaPsFmOeAa.suWrietdhinthoeneexcweoprtkieorn, onofaot1h9e8r0dasttaudwyeirne aavnadilCaobtlteagunetiGlrJouvnee32M00p0la(nUtbselwaest auln,,de1r9t8a0k)e.n,Ainhwalhfi-clihfesestruudmysoanmp2l7ersetwierreeesdfrraowmntehveeDreyc6atur s`muobnmtihtsteodve(rBaurr5-seyetaarlp,er2i0o0d.0;TBwuorrisnteetrailm,r2e0p0o2r)t.s dTehscerifibrisntginttheerriemsurletpsortthussugfgareshtaevde2bmeeendian serum half-life of PFOAof 344 days, with a range of 109 0 1308 days. The two highest haltlife calculations were for the 2 female retirees who participated in this study (654 and 1308 days). `There were several limitations to this first analysis including: 1) the limited data available and the rangeofserum PFOA levels measured; 2) serum was analyzed after each collection period with only one measurement per time period on different days using slightly different analytical theacdhnbieqeunesa;naalnydze3d).thAenreeffefroertncweamsatmeardiaeltpoumriitnyimwiazseneoxtpdeertiemremntianlederurnotri,l ianfctlrudtihnegfisrysstt3emsaatmipcles and random error in the analytical method, involvin9g of the original 27 subjects. Serum samples were collected from eachofthe subjects over 4 time periods spanning 180 days, measured in triplicate with all time points from each subject analyzed in the same analytical run. "This would allow for statistical evaluationofthe precision of the measurement and assure that all systematic error inherent in the assay equally affected each sample used forhallife determination. Oplfantt.he T9hreetaivreeersaignecalguedoedfitnhheirsetainreaelsyswias,st6h1eryeewaresr,et7hemmaelaesnannudm2befreomfalyeesa,rasllwforrokmedthaetDecatur Decatur was 27.7 years, and the average number ofmonths retired was 18.9. Average BMI of this group was 27.9. The mean PFOA value at study initiation was 0.72 ppm (range 0.06 -- 1.84 ppm, SD = 0.64). `The mean serum half-life for PFOA was 4.37 years (range 1.50 -- 13.49 years, SD = 3.53). Only 1 employee had a half-life value that exceeded 4.3 years. The 2 females had valuesof3.1 and 3.9 years. Age, BMI, numberofyears worked or years since retirement were not significant predictorsofserum half-lives in multivariable regression analyses. "This analysis has attempted to reduce experimental error in the determination ofa halflife for PFOA. However, several sues should be noted. First, the effectof continued nonoccocnutpaaitnieodnaclo,ncleonwt-rlaetvieolnsexopfofsluuroeroocnhtehmeichaallsf-tlhiafte ivsaruinekdnboywna.faScetcoroonfd,3b0,ectahuesdeatsaubcjaenctnso'tbbleood pooled or averaged unless the serum concentration decay curve shows first-order kinetics. 000027 "Third, it is not knownifthere are interactions between PFOA and other fluorochemicals in the body. Fourth, this estimate is much higher than that reported in lab animals. Fifth, systematic errorofthe analytical method could be as high as +- 20% and still satisfy the data quality criteria 3.1.2 Absorption Studies in Animals APFO is well absorbed following oral and inhalation exposure, and toa lesser extent following dermal exposure. The liver and serum levels have been measured in several subchronic and reproductive toxicity studies. These resultsarepresented in the relevant studies summarized in subsequent sections. Other studies are summarized here. In female rats, an averageof 749 ug or 37%ofthe fluorine in the administered dose was recovered in the urine within 4.5 hr after PFOA dose (by stomach intubation 2 ml ofan aqueous solution containing 2 mg PFOA) (Ophaug and Singer, 1980). The quantity ofnonionic fluorine recovered in the urine increased to 61%ofthe dose at 8 hr, 76% at 24 hr, and 89% at 96 hr. After asingle oral dose of "C-PFOA (mean dose, 11.0 mg/kg) in solution to groupsofthree `male rats, at least 93%ofthe total carbon-14 was absorbed at 24 hours (Gibson and Johnson, 1979). The half-life for eliminationoftotal carbon-14 from plasma was 4.8 days. Following APFO head-only inhalation exposure in male rats 6 h/day, 5 dayswi/ for 2 wk to 0, 1,8 or 84 mg/m3) concentrationsoforganofluoride in the blood showed a dose relationship with initial levels of 108 ppm in rats treated at 84 mg/m3 (Kennedy etal, 1986). Immediately after tphpemteinnththeexp1,os8,uraendpe8r4iomd,gthme mdeoasne ogrrgoaunposf.luoride blood levels were 13 ppm, 47 ppm, and 108 Subchronic dermal APFO treatment in rats and rabbits (10 applications, doses, 2 rest days, 5 doses) with either 0, 20, 200, or 2000 mgkg resulted in elevated blood organofiuorine levels which increased in a dose-related manner (Kennedy, 1985). O'Malley and Ebbins (1981)conducted a range finding study which indicates significant dermal absorption of PFOA in male and female rabbits. PFOA (100 mg/kg, 1000 mg/kg, and 2000 `wmhyi/ckhg wien rsealtihneenslfuirttreyd) wwiatsh aapppllaisetdictocoalplaprr,oxainmdattheelytr4u0nk%owfatshwerasphpaevdedwtirtuhnikomfpterhveioaunsimpallass,tic sheeting. The exposure period was 24 hr, days/week over 14 days. Mortality was 100% (44) in the 2000 mg/kg group, 75% (3/4) in the 1000 mg/kg group and 0% (0/4) in the 100 mg/kg group. A tetrabutyl ammonium saltofperfluorooctanoate in the formoftreated fabric and as liquid formulation was applied dermally to rabbits (Johnson, 199Sb). Liver samples were analyzed at 28 days post dose for total organic fluorine. `The results from treated animals were the same as control values. All total organic values were below the practical quantitation limit. Serum levels were also below the practical quantitation limits ofthe analysis for samples u 000028 cpohlalremcatceodkaitndeatiyc1satunddy2(aJfothenrsaodnm,in1i9s9t5raa)t,ioitnowofutlhdebmeixutnulriekeolrytthheattraenayteedxtfeabnrtioc.faFbsroormpttihoen could have been detected in this study. 3.1.3 Distribution Studies in Animals PofFtOhAe bdoidsyt.ribIuttedsoepsrinmoatriplayrttiotitohnetloivtehre, lppliadsmfar,acatnidonkoirdnaedyi,poasnedttiossauel,esbsuetrdeoxteesntb,inodthteor issues `macromolecules in the tissues. There is evidence ofenterohepatic circulationofthe compound. Stoexricuimtyasntduldiyve(rGrciofnfciethntarnadtiLoonnsgo,f1P9F80O)A. wIenrmeodnekteeyrsmiantetdhein3rmhge/suksg/mdoanykdeoysse,inmaea9n0 sdearyuomral PfeFmOalAeswa7sp5p0mpipn mlivienrmsaalmepslaens.d 58 At p10pmmgi/nkfge/mdaaleys.dosAest,tmhealseammeondkoseey,smhaaldesa had 3 mean ppm and serum PreFspOeActoifvel5y8,pmpemasaunrdefdeamsaloersga7ni5cpfplmuo.ridLei.ver levels were 9 and 10 ppm formalesand females, OfoplhlaouwignagntdheSiandmgienri(s1t9ra8t0i)onmeoafsPuFreOdAonbiycsftloumoarcidheianntudbtaottiaolnf(l2uomriinoe iafnn thaequseeoruusmsooflufteimoanle rats cnoonntiaoinniicnfgl2uomrignePlFeOvAe)l.13.S6eprpummfarnodmvirarttsua4l.l5y harlaoffttehritshewaadsmibnoiusntrdattoiocnoomfpoPnFeOnAtshiandtahe serum aflnudorniodteulletvrealltreermaablien.edDevesrpyitleotwhe(0.l0a3rgpepimn)c.reaPsreioirntnooinnitounbiactifolnuoorfinPeFiOnAt,hethseeriuomn,ictahnedionic nleovneiloninicthfelusoerrinuemldeevcerlseaisnesdetroum1w1.e2rpep0m.0a3t2ahnrd,00..0357 ppppmm,atre2s4pebcrt,ivaenldy.0.T08heppnomniaotn9i6c hfrl. uoTrihnee acluetahroerds cfornocmltuhdeestehrautmP.FOA is rapidly absorbed from the gastrointestinal tract and rapidly `sTtwoemnatcyh-fionutrubhaotuirons)a,ftfeermaorlaelaatdsmihnaidstaramteiaonnosfeArPumFnOon(i2omnigcAflPuForOinienl2evmell oaqfue0o.3u5sppsoml,utwihoinlbey male rats had was bound to aasmiemialnarseerxtuemntnoinnitohneicplfalsuomraionfe mleavleeloafn4d4.fe0mpalpemra(tHsan(h9i7j.a5rv%ibeotunald.).1982). APFO Itnhemcaolneceanntdrafteimoanloefra"t"sCa-dPmFiOnAi-sdteerriedve"dCr-adPiFoaOcAtiivnitpyrionpytlheenbelogolydcwola/swahtiegrhe(r9.a4nudmcolli/mkign,ati.epd), mmaolree rsalso,wltyheinlimvearlehsad(tt1h/e2h=i9gdhaeysst,PmFaOleAsvcson4cehnrt,rafteimoanle(s2,1V%aonfddeonsHeeautve2lhrc,t2al%, o1f99d1o).seIant 2th8e dhaeyasr), fteosltliso,wefda,bayntdhegapsltarsomcaneamniduskimdunsecy.le.FaIrnlfoewmearlePsFaOtA2 hcronpcoesnttrdaotsieo,ntshewehrieghfeosutnd in the cthoantceonrtdrera.tioTnhseofavPerFaOgAe tw1e/2refofroeulnidmiinnatthieonploafsPmFaOfoAllforwoemdtbhye tlihveerkiidnnmeya,lelirvaertawnadsov11ardiaeyssin celoimmpianrateidontowaansaavpeprraogxeimoaft9eldyay3shfr.or extrahepatic tissues. In females, the average t1/2 for tissue 2 000023 ee VApapnrdoexnimHaetuevleyl 1et1a%lo.f(1t9h9e1)cuimnuvleasttiivgaetdedosteheodfisp"oCs-iPtiFoOnAoifnPfFusOeAd (i0n.0p8erufmuosle/dmmianlex 4r8a lmiivner,. 3.84 uPmFoOlAtoetxatlr)awcatesdbexyttrahceteldivbeyr atthe2lmiivenr(d3u3ri%n)gwaafsirssutbpsatsasn.tiaIlnlaydgdrietaitoenr, tthheancuthmautlasteievneapfeerrc4en8tmoifn (11%) indicating that first-pass hepatic uptake ofPFOA may be saturable. dYilsitnreinbuettioanl.a(n1d99a0c)cusmtuuldaitediotnheofdiPfFfeOreAncaeftbeertwseiennglmeaalnedasnudbcfhermoanliecWaidsmtianrisrtartastiinont.heThe single dadomsieonifstPeFreOdAin(tr0apmegri/tkogneianllpyrotopy1l0enweegelkycoolld-awtaste(r2m0ixmtaulree,,210:1f,emvoall.e)0..2S5umblc/h1r0o0ngi)c was amdlm/i1n0i0sgt)rattoinoneowflyPwFeOaAnecdonrsaitsst(e1d8omfa3l,e,101,8anfedma3l0e)m.g/Akfgt/edratyhebysignagvleagdeos(ei,n s0a.m9p%leNsaCwle,re0.5 caodlmliencitsetdraftoironP,FaOnAd idnettehermsiunbacthiroonni12c,t2es4t-o1n68th(aet2284thhrdaiyn.terTvhales)s,e2r4u4m awnads3c3o6llhecotuerdsbayftcerartdhie.ac `sppulnecetnu,reo;vaarfyt,rtdesetciasp,iatnatdiaodnitphoesebrtaiisnsuaendweartenceoclrloepcstyedsaanmdplfersozferno.mTthhee lbiivoelro,gkiicdanlehya,lfl-ulnigf,e of PPFFOOAA cinontcheentsreartuimonanindtthiesssueemsiwlaogsadreitthemrimcinpelodt.frIonmtthheesliinngelaer-rdeolsaetisotnusdhyi,pcboentcweneternattiiomneoafnd PouFrOsAafintetrhtehse eardumminaisntdrtaitsisounesofwaPsFhOiAghaebrouint m1a0l%eosftthahne fdeomsaelewsaast faolluindmein ptehreiosdcs.rumTwoeflve freemmaaliense,dwihnetrheeassearbuomu.t 4In0f%emwaalsesi,nPthFeOsAercuomnocefnmtarlaetiso.n Ainfttheres1e4rudmay,slaivbeoru,ta3nd.5k%iodfntehyeocdcousre.red inain dthiescfoenmtailneusouasndfamshailoens,,irnedsipceacttiivneglyd.istiInnctthpehafseemsa.lesT,hea hhaallff--lliiffeeoifn t6h0ehsrewrausm ewsatsim2a4teadndin1t0h5e lrievtearindeudribnygtthheelfiivresrt,wietewka.s Innotthfeoumnaldeisn,tthhehliaplidlfirfaectiinonl.iveIrnwtahesk2i1d0nebyr., tAhlethhaolu-glihfePFwaOsA1w4a5shr ainndfe1m3a0lehsrainndfemmaalleess, arensdpemcatlievse,lyr.esPpeFctOiAvelwya.sIanltsohefosupnledienn,brthaeinhaltfi-slsiufee. wPaFsO7A3 hwraasnndot170 hr dsiegtneicftiacbalnetliyn haidgihpeorsePtFiOssAue.conIncetnhterastuibocnhsroinnitchestsuedry,umsaamnpdletisstsaukesenofomnaltehes2v8etrhsudsayfeimnadliecsatiendall tdihsrtereidbuotseed lienvetlhse. sAefrtuemrosfurbacthsr.onHiic,ghascowneclelntasrastiinognlseo-fdoPseFOadAminwiesrteraatlisoon,foPuFndOAin wtahes lmiaveirn,ly kmiadlneesy,exahnibdilteudn,gorfesmpaeclteisvealyn,dsfeermaulmesc.oncAetnttrhaethiiognhs doofs1e3.l9ev2ealn(d3051m.g6/5kgu/gd/amyl),,lifveemrales and concentrations of 6.64 and 49.77 ug/g, kidney concentrationsof 12.54 and 39.81 ug/g, spleen ccoonncceennttrraattiioonnssooff01..05494anadnd4.01.071u0g/ugg,/gl.unTghceonocveanrtyractoinotnasoifne0d.17.516anudg/2g3.a7n1d utgh/egt,easntsdcbornatianined 7.22 ug/g. A significant positive correlation existed between the administered dose and the concentrationofPFOA in the liv, kidney, spleen, and lungoffemales. On the contrary, no significant correlation between the administered dose and the concentration of PFOA was oorbgsaenrsvetdhainn t3h0emmga/lkegs/,daasy.10Hmogw/ekvge/rd,ayinpmraoldeusc,etdhehicgohnecrenPtFraOtAiocnoinncetnhtersaptlieoenns,itnestthise,saenrdubmraainnd comelsted positively with the concentration in the serum. 2 000030 Vplaansdmea,n aHneduvteeslteestoafl.ra(t1s9.92C)adrebmoonn-s1t4r-laatbeedltehdatPPFFOOAAwacosvaaldemnitnliysbtienrdesdttoo spiroxt-ewieneskionltdhemalliveer, HuamrollakngS,pirpa. guNeo-Dtaiwmlee-yderpaetsndiennptrocphyalnegnees gilnyeciotlhiewraatbesro(l1u:t1e, ovr/vr;el|atmilv/ekcgo)ncatenatrdaotsieonosf o9.f4 covalently bound PFOA-derived ""C were found at 2 h, 1 and 4 days post-treatment. Covalently c`obnocuenndtPraFtOioAnowfacsorveaplreenstelnytebdoubnyd0.P1FtOoA0.w3a%sosfitghneifitciasnstuley'hCigchoenrteinntt.heTphleaasbmsaoltuhtaen inthe liver. `The testes had the highest relative concentration ofPFOA-derived radioactivity covalently. binocurneda.seIdninteastlsi,nceoarvaflaesnhtiobninwdiitnhgionfcr"e"asCi-nPgFPOFAOtoAaccooncnesnttarnattcioonn.cenTthreatcioovnaolfenatlbbuimndiinng(8oufM) tPhFatOpArottoeihnemsuolgflhoybdirynlwgarsoudpismimnaiyshbeed binyvtolhveeadd.ditionof cysteine but not methionine, suggesting dHaunrhiinjgasruvbicehtroaln.i(c1a9d8m7i)nicsotrmaptairone.d tPheFOdiAspwosaistiaodnmoinfiPstFeOrAedbbeytgwaeveangmealtoe4a8ndnefwelmya-leweWainsetdar rats awnaismacollslaetct0e,d3o, n10t,hean7dth3a0nmdg2/8ktgh (dianyo0f.t9h%eNsatCuldy,(0d.i5smcJu/s1s0e0gd)bfeolrow2)8. consecutive At the end days. ofthe Urine study, bthleoopdlawsamsaocofltlheectemdalveiaractasrdwiearcepusnicgtnuirfei.cantAltyehaicghhedrotsheanletvehlo,setoheftmheeanfePmFalOeAatcso.nceTnhteramteioanns in p24l.a7smuagPiFmO(A10cmogn/ckegn)t,raatniodn5s3f.o4r+t-h1e1.m2alueg/rmalts(w3e0rmey4/8k.g6)+.-2T6h.e5 cuogr/rmelsp(odnodsiendgatfi3gumrge/skfgo)r,f8e3m.a1l+e- PraFtsOwAerceon2c.e4n3t+r-a5t.io9n6suign/mtlh,e p1l1a.3s+m-a8o.f5t9hueg/mmall,eaanndim9.a0l6+s-8s.u80gguegst/edmlthaitntthheebsianmdienogrsdietre.s oTfhPeFOA `cmoanycebnetrcaotmieonssawteurraetesdigantitfhiceacnhtrloynhiicghdeariliyndtohseemlaelveelroatfs3, 0nomgs/igkngi.ficAalntthhoiusgtohptahtehoplloagsicmaalPFOA differences between the sexes were observed at necropsy. "aTdhmeindiisstproastiitoionnaosfwPelFlOaAs iwnaisntsatcutdmiaeldeisn amnadlefeWmiaslteasr(rYalsinaeftneertcaaslt,ra1t98i9o)n.anTdheestmraadlieolrats (N=20) owpeerreatceadstarantded10atitnhteacatgmeaolfes28wedraeysadamnidniasftteerre5dweesetrkasdiwoelrvealuesreadteinsutbhceutteasntse.ouHsallyfo50f0thueg/kg pvuenrctyursee.coAntdtdhaeyednudorfintghe14tdesaty(s9b6ehfno)r,etthheectoenstc.enBtlroaotidosnaomfplPeFsOwAerien ctohlelseectreudmobyficnatradcitacmales wstaastisctoincsalildyersaigbnliyfhiicgahnterdi(f1f7er-e4n0cetiimnest)hethsaenruimtchoencseenrturmatoifoontshbeertgwreoeunpst.heTohtehreer gwraosupnso. PFOA was similarly bound to the proteins in the serumofmales and females. Jcloihmnisnoantieotnalo.f(A1P9F84O).inSvienscteigAatPeFdOtheexeifsftescatsoafnfaenediionngacthpohlyessitoylroagmiicnpeHt,o irtawtsoounldthbeefeexcpaelcted to acdommipnliesxtewrietdhacmhmoloenstiyurmam'i"nCe-.peTreflnumoraoloectCahnaoraltees (R2i.1vemrgC/mDl)radtsis(s1o2lvweedekins0o.ld9,%3N0a0C-l34a2s gas)iwnegrlee cihnotlreavsetnyoruasmidnoesein(2femeda.tU,rianveeraangdefAecPeFsOsadmopslees13wemrge/kcgo)l.lecFtievdeartatisntweervraelsgifvoern144 %days, at which time the animals were sacrificed and liver samples were collected. At 14 days post dose, " 000031 5t.h5e)mweaasn9p.e8r-cfoelndtatgheeomfePaFnOpAercdeonsteageeloimfidnoasteedeilnitmhienafteecdesionffcehcoelsebsytyurnatmrienaetedtrreaattsed(4.r4at+s-1(.403)..2+lEixvcerrerteiporneisnenutreidne1w2a.1s+-421.1%ufgoreqt/regaatenddr2at2s.a3n+d6.627u%g feoqr/ugnitnretarteaetderdatasn.dCuanrtbroeant-e1d4rpatrse,sentinthe arensdpe1c4t.i7v+e-l6y.(84u%g aenqd/m8l%ionftrdeoastee,d arnesdpuecnttirveealtye)d. rIant,plraesspmeac,titvheelyl.eveIlnsrweedrbelo5.o1d+c-e1l.l7s,utgheeqle/vlels hwiegrhec1o.n8c4e-n0t.r7atuigoneqof/m""aCn-dA4P.F2O+-i2n.4liuvegreatq/2lweienktsraatfetedradnodsiunngtraenadtetdheratfsa,ctretshpaetcctihvoelleys.tyTrahmeine etnrteeartomheenptaetnichacnicrecuslafteciaolnoefliPmiFnOaAti.onofcarbon-14 nearly 10-fold suggests that there is b"Teheendriesppoorstiteido(noJofhtnhseont,et1r9a9b5u3t)y.l aImndmiovindiuualmrsaablbtiotfspweerrfleugoirvoeonctianntoriacveancoiudsidnofseemsalate0r,ab4b,it16s,haansd l2e4vemlgd/ikegdawnidthaipnp5eamriendutneosmoifaldotshirnogu)g.hoSuetrtuhme sstaumdpyle(sthweearneimaanlaltyrzeeatdefdoartttohteal4o0rgmagn/ikcgflduooser:ine a16t,2,a4n,d62,48,mg12/,k2g4d,oasnedd 4r8abhbiotusrsweproest 1d.o2s5e.ppAm,t24.h0r9s,pspemr,um14o.r9gpanpimc,falnuodr4in1e.0lepvpemls, irnestpheect0i,v4e,ly. 4`T8hehrr.e wTahseabiroalpoigdidcaelcrheaalsf-eliifneswearsumonletvheeloofrtdoetraol fo4rghaonurisc.flTuohreinteotwalitohrgtainmie,c fnlouno-rdienteecitnawbhleolaet liver were a2t04u8gh,r4p3osutg,d6o6seugf,oracnodnt5r4oluga.nimals4, mg/kg, 16 mg/kg, and 24 mg/kg intravenous doses 3.1.4 Metabolism Studies in Animals P`VFaOndAen(9H.e4uuvmeolllektgal,. .(p1)9.91P)oionlveedstdiagialtyedurtihneemseatmapbloelsis(0m-o4fdPayFsOpAositn-trraetsatamdemnitn)iastnedrebidle"Ccexotmrpaocutsnda.nalTyizsesduebsywHePreLCtackoenntfarionemdraatssitnrgelaeterdad4i,oa1c4t,iavnedp2e8akdealyustipnrgeviidoeuntsilcyalwliythto"tChe-PpaFrOenAt to dperetseernmtinine athtetpirsseuseesn;cneoofPFPOFAO-Ac-ocnotnatianiinnignghylbirpiiddcloinpjiudgsawteesr.e dOentelcytetdh.e pFalrueonrtidceocmopnocuenntdrawtaisons in plasma and urine before and afier PFOA treatment were unchanged, indicating that PFOA does not undergo defluorination. OfoplhlaouwignagnodraSliandgmeirn(i1st9r8a0t)ioanlosoffPoFunOdAnotocfheamnagleeirnatsi.oniYcliflnueonriedteall.ev(e1l98i9n)thfeosunedrunmooerviurdiennece of phase Il metabolism of PFOA following a single intraperitoneal PFOA dose (50 mg/kg) in male and female rats. 3.15 Elimination Studies in Animals OTfhePrFeOaAreimnamjaolregerantdseirs dmiafnfeyretnicmeessignrtehaeteerlitmhiannatthiaotnoinffPeFmaOlAe riantsraatsn.d Tthhies dbiifofleorgeinccael ihsalf-life dpuriematroialcytidvueerteonallotwubreunlaalr cselceraertainocne(ionrmgaanliecraatcsi.d Ttrhaensrpaopritdseyxsctreemt)i;ontohifs rPeFnaOlAtubbyulfaermsaelcerertaitosnis x 000032 iesxcbreeltiieovnedrattoesbeofhPorFmOoAnalsilmyilcaornttrooltlheodsesoifnfceemcaaslterartatesd. maHloermroansatlrecahtaedngweisthduerstirnagdiporlehganvanecy do noobtsaeprpveeadritnoprcihmaantgees tahnedrhautemoafnse.liTmhineatsitoundiiensadtesm.onTshtirsatgienngdetrhidsiafrfeerdeensccerihbaesdnboetlboew.en "bTohtehumraijnoerisrotuhetemsaojforexrcoruetteioofnoefxcPreFtOioAnoinfmPaFlOeAratisn(tVhaenfdeemnalHeeuravta,lw,hi1l99e1)t.he uMrailnee aanndd ffeecmeaslaere realtismwinearteedadPmFiOnAi-stdeerreidve'd*Cr-adPiFoOacAtiivniptryorpaypliednlye ignlytchoeluirwianteerwi(9t.h49u1m%ol/ofktgh,ei.pd.o).seFbeemianlgeexractrseted irnadtihoeacftiirsvtit2y4whar,s wrheicloevemraeldeirnattsheexfcerceetseodfofnelmya6le%raotsf. thIendmoasleeinratthsadtutriimnegptehreio2d8. -dNaeyglcioglilebclteion rpeesrpieocdtitvheelyc.umTulhaetifveemaelxecrreatiroentoafinPedFOlAes-sdtehrainve1d0%"oCftinheuraidnmeiannidstfeerceedsdwoasse 3af6t.e4r%24anhrd,3w5h.i1l%e, thahlef-mlailfeeirnatfsermeatlaeisnewda3s0l%essofthtahneoandemidnaiys,tearneddidnomsaelaefsteirt2w8asday15s.daTysh.e wIhnorleena-lb-oldigyateeldimriantastion ienxjcercetteedd ii.pn. twhietbhil"eCa-ftPeFrO6Ah,r a(pVparnodxeinmaHteeulvye0l.e3t%oa.f, t1h9e91P)F.OAN-odesrexi-vreedlartaeddidoiacftfievrietnycewainsthe biliary excretion ofPFOA was observed when the Kidneys were ligated. Jcaorhbnosno-n1a4nbdetGwiebesonnm(a1l9e8a0)ndobfseemravleedraatsseaxfidrifafesrienngclee iinvedxotseent(amnedanradtoesoef:exfcermealtei,on1o6f.7tomtga/lkg; mhoaulres1w3h.i1lmega/tktgh)e osfam"eC-tPimFeOApe.riFodemmaalleerraattsseexxccrreetteeddeosnsleynt2ia0llpyeraclenotftohfethdeosdoesvei;amuarlieneraitns24 einxctriestseueds8o3f%fevmiaaluerirantesaantd175.d4a%ysvipaosftecdeosseb;ym3a6ledaryastsphoasdt d2o.s8e%.oNfothreaddioosaectiinviltiyvewraasnddet1e.c1t%edin plasma at 36 days post dose with lower levels (< 0.5% of the dose) in other organs. OAnpihmaaulgsawnedigShiingnegra(p1p9r8o0x)imiantveelstyi2ga5t0edgtwheermeetaadbmoilniicstfearteedobfyPsFtOoAmaicnhfienmtaulbeatHioonlt2zmmlaonfraatns. `aanqdueporuosvisdoleudtriaotn cchonotwaiannidngta2p mwagtePrFOfoAr.4.5T,h8e,a2n4i,moarls52w.e5rher.thIenn apdldaicteidoni,nfmoeutrarbaotsliwsemrecapgleasced. hirn. meAttatbhoeliesnmd cofatghees aenxdpefreidmeanltoalw pfelruoiroiddeth(e<u0r.i5nep,pfme)cedsieatnadnsdedriustmilwleerdewactolelrecftoerd.a pWeiritohdionf4.956 hrrecaofvteerrePdFiOnAthdeousrei,nea.n aTvheeraqugaeontfit7y4o9fnuognoiron3i7c%offlutohrieneflrueocroivneeriendtihnetahdemuirniinseteirnecdredaosseed wtoas 6th1e%PoFfOtAheddoosseedaatni8mharl,s7w6a%santo2t4sihgrn,iafincdan8t9ly%daitff9e6rehnrt. thUarnintahartyofetxchreetcioonntooflioanniicmafllsu.oriFdeecailn excretion `The urine offronomnuinondiocsefdluaonriinmealwsacso4n.ta5i%neodf ntohedaedtmeicntaibslteerneodnidoonsiecaftl5uo2r.i5neh.r and 14.3% at 96 hr. `aTnhde suirxinfaermyaleexcHroetlitosnmoafnAraPtFs Owerineraadtsmiwnaisstienrveedst2igmagtedAbPyFOHanibni2jamrlviaeqtuaelo.u(s19so8l2u)t.ioFnobuyr male santiommaalcshwienrtuebatthieonn.plaSceevdeninfmeemtaalbeorlaitssmwecrageeasdwmiintihsrtaercehdo2wmainddisttaipllweadtwear.terUarsinceonwtarsolsc.ollTehcteed 2 ee 000033 uanntdiltoatnailmfallusorwienreecosnatcreinftoicfedsaetr2u4mhbanyd ucrairndeiawcaspudnectteurrem.ineSde,raunmdwnaosnicoonlliecctfeldu.orilnoeniwcasfluoride acnaelsctulhaetteidzeadswtihtehdIinfafcetrienn.ce.ThFeofrecmloeraarlanacretesrtyuwdiaessocfanAnuPlFatOedanfdoricnuolnitni,ntuhoeusratisnfwuesrieonof 5% "mTahneniutroinlairnyibsloatdodneirc wsaalsinaelsaondcatnhneuflaetmeodraflorarsteerriaylwcaosllceacntinounlsatoefdurfionred.raIwnitrnagvbenloouosdpsramipmliensg. dtroisteiasotefd i5n.u2l-i5n.6(mmegth[o1x-y1-4C3]H),asmpmaoctni1u14mupCeir/flmugo)rowoecrteangoiavteen(tsopaecatc0h.a5niumCali./mgT)heanrdad8i.o8laubg.led aindudliitnioannadl A0.P42F-O0.i6n35m%g/mhan'ni`tCo-lAiPnFiOsoatnodni9c.6saulgin/ehrwtaistattheedn iinnufluisnedwaatsairnaftuesoefd0d.u2r1inmgl/tmhein. An perxpoebreinmeecnitds.waWshaedmnintihsetuerriende(a6n5d-6s8ermugm/kcgo,lliepc)tiaonnds afdodritthieoncalleacrlaenacreanscteudteystwsewreerceopmeprleftoer,med. 2In0t%h)eacnudmuulnaltaibveeleedxcArPetFiOon(s8t0u-d9y0,%r)a.ts wFeivreepdeorsceedntivmawnintihtaolmiixntiusroetoofnircasdailoilnaebwealesdiAnPfuFseOd(a1t0arpartoeboefn0e.c0i8d1wamsl/amsisnesasnedd ubryiandemsipneicstiemreinnsgw6e5r-e68comlgle/cktgedipovaetrle3a0s-tm3i0nmiintnerpvrailos.r toThtheeeffect of aedxmcirneitsetdr7at6i+o-n2o.f7%AoPfFOt.he Tdowseentiyn-tfhoeuurrhioneurasnadftheardoraalmeadamninsiesrturamtnioonnioofniAcPfFlOu,orifneemalelveelraotsfhad 0n.o3n5i+o-n0i.c1f1lupoprmi,newlheivleleomfa4l4e.r0a+t-s1h.a7dpepxmc.retAePdFoOnlways9b.2o+u-n3.d5%tooaf stihmeidloasreexatnednthiandthaempelaanssmearoufm. dmiaflfeeraenndcefsebmeatlewereantst(h9e7s.e5x+e-s0i.n2r5a%tsb.ouTnhd)e.APTFheOcclleeaarraanncceesitnudfieesmadlemroanlsstwraastesdevmearjaolrtimes agcrteiavteersetchraentitohneoifnuolrignacnliecaraacnicdes., rAeddmuicneidstArPaFtOi/oinonuflpirnobcelneeacriadnc,ewrhaiticohisntfreomngallyesinfhriobimts14t.h5e troenal r0.e4d6u.ceAdPfFroOm4c.le6ar1a0n0c.e1w3ausg/rmeidnu/c1e0d0gf.romIn5m.8al1e0 r0a.t1s1, hmolwiemvienr/1,0t0hge.APNFeOt/AinPuFlOienxcclreeatriaonncwe arastio calnedartahencneetwaesxc0r.e1t7iomnol/fmiAnP/F10O0gw,erAePFvOi/ritunaullliynuncalfefaercatnecdebryatporowbaesne0c.i2d2., aInndtnheetmaAlPeFs,OAePxcFrOetion wdoasse,0.w1h7iluegmmailne/smge.xcrIentetdheoncluymu7l.a8ti%ovefetxhceredtoisoenosvtuedrieas7,-fhermpaelreiorda.ts Perxocbreenteedci7d6a%domfintihsetraAtPioFnO modified the cumulative excretion curve for males only slightly. However, in females `probenecid markedly reduced APFO elimination to 11.8%. The authors concluded that the bfoedmya.leTrhaitspossescersesteorsyamneacchtaivneissemcriestloarcykimnegcohranisirsemlawthiiveclhy rianpaicdtliyveeilnimmianlaetersatAsPaFndOafcrcoomuntthse for the greater toxicity of APFO in male rats. HWainshtiajraarvtis edtuarli.n(g1s9u8b7c)hcroonmipcarademdintihsetruartiinoanr.y eAlPimFiOnatwiaosnoafdmPiFniOsAterbeedtwbeyegnamvaalgeeatond48fenmeawlleyUwreianneewdaasnicmoalllescatted0,o3n,t1h0e,7atnhda3n0d m28gt/hkgda(yionf0t.h9e%sNtauCdly., 0A.l5mtlhe/1e0n0dgo)ftfohre28stcuodny,sebcluotoidvewdaasys. collected via cardiac puncture. At necropsy, tissue specimens for histopathologic examination wseevreentcholdlaecytoefdtfhreomsttuhdeycpoenrtiroodl,s tahnedffermoalmethraetsgrionutpherelcoewievsitngdo3s0emggr/okugp/d(3aymgP/FkOgA/d.aOy)netxhhei.bited significantly greater urinary PFOA excretion than the males (3.12+-0.30 vs 1.50+0.57 50 000034 mexgc/r2e4theid/ksgi)g.nifUinclaintkleytlheessfPemFaOleArtathsa,notnhetihred7atilhyddaoyosfetohfePFstOuAd,y awlhlitchhreseuggrgeosutpesdotfhmaatltehermatasles PhaFdOnAoteqrueaalcthoeatdhesirtedaadiylystdaotsee.by seven days. Onthe 26th day, the males excreted an amount of HIaabnohriajtaorrvyiberteadl.b(e1a9g8l8e)diongvses(t3igmaatleed,3thefeemxaclree)tiwoenrkeinaenteisctsoheftiPzFedOAwitihnmtehethboexaygflleudroagn.e aSnidx caanthientterrasvewneorues pdloasceedofin30bomtgh/ukreeotefrsPaFfOerA lfaoplalroowteodtobmyycaonndticnyusotuostoimnfyu.siTohnewiatnhim5a%lsmwaenrneitgoilven ssoalmuptlieonwaats1c.7olmlle/cmteidn.inUtrhienmeiwdadsleocoflleeacctheduartin1e0smaimnpultienginpteerrivoadl.s fPorro6b0enmiicni.d (A30Smmgl/kbgloiovd) cwlaesartahnecneoadfmiPnFisOtAerewda,sacnadlcuurlianteedanfdorbtlhoeobdesfaormeplaensdwaefrteerapgraoibnecnoelcliedctiendjeacstiboenfopreer.iodRse.naFlour akdedpittiionnmaeltdaobgosli(s2mmaclaeg,es2,faenmdalbel)oowderseamgpilveesnw3e0rmegc/oklglePctFeOd Aintienrtmriatvteennotulsylyf.or T3h0edsaeysd.ogRsewnearle cclleeaarraannccee riantbeowtahsseaxpepsr,oixnidmiactaetliyng0a.0n3acmtli/vmeins/ekcgr.etiPornombeecnehcaindissimgnfiofriPcaFnOtlAy.reTdhuecepdlathsemaPFhaOlfAl3i0fe5o)f.PFOA was longer in the male dogs (473 h and 541 h) than in the female dogs (202h and. a`dThmeinuirsitnraartyioexncarsetwieonloalsf PinFiOnAtacwtamsalsetusdaineddifnemmaalleesW(iYsltianrenreat aalf.t,er19c8a9s)t.ratTihoneamnadleesrtartasdi(oNl=20) wopeerreatceadstarantded10atintthaecatgmeaolfes28wedraeysadamnidniasfteerre5dweesetrkasdiwoelrvealuesreadteinsutbhceutteasntse.ouHsallyfo50f0thueg'kg vduerriyngs9e6chonrdafdatyradusriinnggle14indtaraypserbietfoonreealthPeFtOestA. dUorsien(e5w0amsg/ckogl)l.ectBeldoiondmseatmapbloelsiswmerceagceosllected bstyicmaurldaitaocrypeufnfcetcutreo.n tChaesturraitniaornyaenxdcraedtmiionnoisftrPaFtiOoAn.ofeDsutrriandgiotlhetofitrhset 2m4alheourrast,s hfaedmaalesirgantisficant ethxecreestterdad7io2l+t-r5e%at(meNn=t6,)obfotthhtehedoisnet,acwthaenrdeacsastthraetiendtamcatlmeasleexscerxectreedtPedFoOnAlyin9a+m-o4u%nt(Ns=s6i)m.ilaArftteor efxecmraelteesd(P6F1+O-A19in%uarnidne6f8a-st1e4r %th,anretshpeecitnitvaeclty)m.alTeshe(5c0a+s-t1ra3t9e%d),mabluteslewsistthhoaunttehsetrfaedmioalletsreaantmdentth.e eisnttarcotgmeanlterseawtaedsmcaolnessi.deArtabtlhey ehnigdhoefrt(h1e7t-e4s0tt(i9m6eshr)),thtahne icnontcheensterartuimoonfoofthPeFrOAgroiunpst.heTsheerruemwoafs nPoFsOtAatiwsatiscaslilmyisliagrnliyfibcoaunntddibfyfetrheencperoitneitnhse sinerthuemsceorncuemontframtailoenss baentdwfeeemnaltehse. other groups. mVaarnkdeednsHeexu-vdeiflfeetreanl.ce(s19in92t4h)e iunrviensatriygeaxtecdrewthieonthoefrPaFnOdAro.geCnasstorrateisotnroogfemnaslaerse igrnevaotllvyedinicnretahesed (p>ro1d-ufcoledd)btyhetheelitmeisntiastiisonreosfpo'nCs-ibPlFeOfAor(t9h.e4sulmoowlleklgi,miinpa.t)ioinnoufriPneF,OdAemoinnsmtarlaetirnatgs.thaCtaastrfaacttioorn ptleusstos1t7eBr-oensetrraedpiloalcheamednntoatfutrhteheprhyesfifoecltogoincaPlFlOevAelerleimdiuncaetdioPnFwOhAereelaismicnaasttriaotnitoon pthleussame level as rats with intact testis. Thus,inmale rats, testosterone exerts an inhibitory effect on renal 3 000035 aefxfcercetteidonthoefuPrFinOaAr.y eIxncrfeetmiaolnoefratPsF, OneAi,thdeermoovnasrtireacttionmgythoartotvhaeriincheitboitmoyryplcufsfetcetstofotsetsetroosnteerone: tornanPsFpoOrAt sryesntaelme,xdcercetrieoanseids athmealhei-gshpreactiefiocfrPeFspOoAnsree.naPlroebxecrnectciiodn,iwnhciacshtriantheidbimtasltehsebruetnahlad no effect on male rats with intact testi. oHforCmonaaftlercohraanlgaedsmdinuirsitnrgaptiroengnoafnacysidngolenodtoaspeopefaarmtomocanuisuema c"h"aCn-gPeFiOnAt(heGiabtseoonfealnidmJionhantsioonn, d1o98s3e)d. (mAeta8nodros9ed,a1y5smagf/tkrgc)onacnedptiinodni,vifdouuarlpurreignneasnatmprlaessawnder2encoonlplrecetgendanatt 1f2e,m2a4l,e3r6a,tsawnedr4e8 hours post dose within 24 hours afonrdbaontahlygzreodupfsoorf"raCtsc.ontent. Essentially allofthe C was eliminated via urine (F1e9e8d4i)n.gMoaflcehorlaetsstwyerraemiandemitnoisattesreednhAaPncFeOd (t2h.e1fmegca/lmell)idmiinsastoilovneodfinA0P.F9O% N(JaoChlnsaosnaestianlg.le: pinetrrcaevnetnaoguesofdoAsPeF(O2 mdloaste,elaivmeirnaagteedAPinFtOhedfoescees1o3fmcgh/oklge)s.tyArtam1i4ned-atyrseaptoesdt rdaotsse,(4t3h.e2+m-e5a.5n) was 9.8-fold the mean percentageofdose in urine was 41% for treated rats and 6el7i%mifnoarteudntnreafteecdesrabtys.untreated ras (4.4+-1.0). Excretion tKhuedroeneatlaml.R(2N0A02l)evdeelmsoonfstsrpaetceifdicinomrgaalneicanadnifoenmatlreanrsaptosrttehrast renal clearance (CLy)of PFOA are markedly affected by sex. and hfoermmaloenersa.ts aTnhdetbhiioslodgiifcfaelrehnaclef-ilsifdeueofpPriFmOarAiliyntmoalloewraCtsLwaisn mfaoluendrattso.beCa7s0trtaitmieosnloofnmgaelrethraantsin rceaduusceeddab1y4-tfroeladtiinngctrheaesmewiintChLtxestoofsPteFrOonAe.. TTrheeatelmeevnattoefd mPaFlOeAraCtsLwitinhceassttrraadtieodl males was increased the. wCaLs roefdPuFceOdA.byIenstfreadmiaolletrraeta,tmoenvta.rieTcrteoamtymecnatussoefdfaesmiagnlifriactasntwiitnhcrteeassteositneCroLnye roefdPuFcOedA,thwehCiLcyh. orfedPuFcOeAd.the`TCrLeyatomefnPtFwOitAh ipnrombaelneecriadt,,acaksntroawtnedimnhailbeitroartos,faonrdgafneimcaalniroant.trTanospiodretnetrisf,ymtahrekedly ltervaenlsspoorftsepremcoilfeiccuolregsantihcataanrieonretsrpaonnsspiobrlteerfsowrePrFeOdAetterramnisnpeordtiinnmtahleeraatnkdidfneemya,lerernaatls umnRdeNrA mvaarlieoursathsowramsonoanllyst1at3e%s athnadtcionmfpeamraeledrwaitts.h tChaestCrLatyioonfoPrFeOsAtr.adiTohletlreevaetlmeonftOiAnTcr2eamseRdNthAe lienvel OOfvaOrAieTc2tommRyoNfAfewmhaelreearsatstrseiagtnmiefnitcaonftclaysitnrcarteeadsemdalteherlaetsvewliotfh OteAsTto3stmerRoNneA.redMuucletdipitl. e rreegsrpeosnssiiobnleanfaolryusriisonafrytheelidmaitnaatsiuogngoefstPedFOthAationrtghaenircat.anion transporter 2 (OAT2) and OATS are 32 Epidemiology Studies 32.1 Medical Surveillance Studies from the Antwerp and Decatur Plants A cross-sectional analysis of the data from the 2000 medical surveillance program at the Decatur 2 000036 ee ``aanndd hAenmtawteorlpogpyl,anctlsinwiacsalucnhdeemristtarkieens,toadnedtheorrmimnoeniaflthpearreamweetreresaonfyvoalsusonctieaetrioenmspbleotyweeeesn(POFlsOeAn., setearl.u,m2l0e0v1el)s.weTrhee1d.a0t3apwpemrefoarnaalllyzmeadlefoermapllloeymepelsoyaetetshefArnotmwbeortph ppllaanntt aloncdat1i.on9s0.ppMmeafnorPalFlOA s`miaglneifeimcapnltolyyeheisghaetrt(hpe D<e.c0a5t)umrepalannts.erMuamlelepverlosdu(c2t.i3o4npepmmp)lotyhaenesthaotstehaetDtehceaAtnurtwpelarnptphlaadnt (s1e.r2u8mplpemv)e.ls Nwoenr-ephriogdhuecrtitohnanetmhpeloPyFeOeSs saterboutmhvpallaunetsshaatdbomtehapnlanltesv,elesspbeecliaolwly1 tphpemD.ecPaFtuOrAplant hwihgehreerstehranumthleevPeFlsOaArelehvieglsh.er overall. In addition, values for total organic fluorine were even aMfufletcitvtahreiarbelseulrtesgorfetshsieonclainniaclaylsceshewmeirsetrcyontedsutsc.teTdhteofaodljulsotwifnogr vpeorsisaibblleescwoenrfeouinndcelrusdetdh:at may yperaordsucwtoiroknejdobat(ytehse oplrannot.),Aplapnots,itaigvee,sbiogdniyfimcaasnst aisnsdoecxia(tBiMonI)w,ascirgaerpeotrtteesd/dbaey,twdereinnkPs/FdOayAaanndd achnoalleyssteesr.olAl(cpo=ho0l5c)oannsduPmeFdOpAeranddaytrwiaglsycseirgindiefsic(apnt=i0n0t2h)e.chAolgeestwearoslamloodesli,gnwihfiiclaentBiMnIboatnhd icingcalruadtetdesinsmthoekeandalpyesreds,aynewtahsersirgeniafcihceadntstfaotriswtiigclaylcseirgindeisf.icaWncheeinn tbhoethchPolFeOstAeraonldmoPdFeOlS, wwheirlee wPiFthOAPFreOmAai(npe=d.s0i4g)niafincdanrtem(pai=ne0d2s)iignntihfeitcrai(ngptly=cer0i4d)eswmhoednelb.otHhDPLFOwAasannedgaPtFiOveSlyweasrseociated ionbcsleurdveeddianntdheremmoadieln.ed Astaptoisstiitciavlelyasssiogcniifaitciaonnt(p(p== 0.105))bwehtewenePnFTO3SawnadsPiFnOclAudweadsinaltshoe model. cBhMeIm,isctirgya,rtehtyerso/iddayo,rahlecmoahtolo/ldoagyywmeeraesuarlseos swiegrniefisciagnntifiincatnhtelmyoadseslo.ciaNtoend ewiotfthhPeFoOtAherinctlhineical regression model, pAerlfonogrimteudditnoaldeatnearlmysiinseowfhtehtehearboovcecudpaattaioannadlperxepvoisouursemteodifcluaolrsoucrhveemiilclaalnsceovreesrulttismweaiss related to (cOhlasnegne,stinalc.lin2i0c0a1l1)c.hemTihsetrclyianincdallicphiedmriessturlitessiinnecmlupdleody:eecshoolfetstheeroAln,tHwDeLrp, atnridglDyeccearitduers,facilities aallkaanliinneeapmhionsopthraatnassfee,ragsaem(mALaTg)l,uttotaamlyatnrdandsifreerctasbeil(iGruGbTin)., aMsepdairtcaatle saumrivneoitlrlaannscfeedraatsaef(rAoSmT)1,995, s1u9b97c,ohaonrdt2t0h0at0iwnecrleudaendaltyhzoseed uwshiongpamrutlitciivpaartieadbilne2reogrremssoiroen.meTdihceaplleanxtasmwsebreetawneaelnyz1e9d9u5sainndg 3 l2e0a0s0t.onAe tootthaelr.ofO1n7l5ym4a1leemepmlpolyoeyeeseswevroelupnatratriicliypapnatrstiicnipaallte3dsiunrtvheeil2l0an0c0espuerrvioedisl.lance and at e`WmhpelnoymeeeasnpasretricuimpaPtFinOgAinlmeevedliscawlerseurcvoeimlplaarneced abytsheurAvneitlwlearncpepyleanr,iPncFrOeaAseldevbeelstwienetnhe1994/95 sanedru1m9l9e7vealnsddtehcerneadseecdrebaesteudveselnig1h9t9ly4/b9e5twaenedn11999977aannddt2h0e0n0.incArteatsheedDbeectawteuernpl1a9n9t7, PanFdO2A000. `DeWchaetnuarneamlpylzoeydeuessi,ngthmeirexewdasmoadsetlatimsutlitciavllayrisaibglneifriecgarnetspsoisointiavnedacsosomcbiiantiionngbAenttwweeernpPaFndOA and 5 000037 asnedruamlscohoblyesstuebrcoolho(rpt=, t0h0e0s8e)asasnodcitartiigolnyscewreidreesl(ipmi=te0d0t0o2t)heovAenrttwiemre.p eWmhpelonyaeneasly(pze=d.b0y05p)laanntd, iHnowpaervteicru,latrh,etahseso2c1iaAtnitownebreptweemepnloPyFeeOsAwahnod ptarritgilcyicpeartieddesiwn aalsl a3lssoursvteaitilsltainccaellyyesairgsni(fpic=an.t00(1p).= T1h02e)refowratshe1s0utbagsriogunpifiincawnhtiacshsoecmipaltiooyneebsetpwaerteinciPpFatOeAd iannbdiotrmiognliytcoerriidnegsianm1o9n9g4/D9e5caatnudr200. walokrakleirnse. phTohseprheatwaesree, nGoGTsi,gnAiSfiTc,anAtLaTss,octiotaatliboinlsirbuebtiwne,aenndPFdiOreActabnidlicrhuabinng.es over time in HDL, Tsheerruem aPrFeOseAvelreavlellsimwietrateiosnisgntiofitchaent2l0y0h0igchreosrsa-tsetchteioDneaclataunrdplloanngtittuhdainnaalt stthuedAinestwiencrlpudpilnagn:t, 21)) palrlofpialretsicainpdandtesmwoegrreapvholiucnstebeertsw,e3e)ntehmeprelowyeereesosefvterhael DceocnsaitsutrenatnddiAfnfetrweenrcepspilnanctlsin(icAanltcwheermpistry elomwpelroyBeMesI,aswcoorkmepdafreetwdeoryDeeacrast,uhraedmphliogyheeresalhcaodhollocwoenrsPumFpOtAiosne,rhuimghleervemlse,awnerHeDyLouanngder, had bmielairnubtihnyrvoailduehso,rlmoowneremvaelaunestrtiegnldyceedritdoeb,ealhkiaglhienre),ph4)osPpFhaOtSasaen,dGoGtTh,erApSerTf,luaonrdinAatLeTd cvhaelmueisc,alasnd caroempalasroepdrebseecnatusien tthheesyewpelranetsp,la3c)eidnitnhteocqruoasrst-isleecstbiaosnaeldsotnudPyF, OplSansteproupmuldaitsitroinbsutciaonnnsootnbley awhciercthaiwnerpoeidnitffinerteinmtefowraesaccohllseucbtgerdofuopr aenadchnocltianipcpalliccahbelmeistotrPyFtOesAt,, a6n)do7n)lyPoFnOeAmesaesruurmelmeevneltsat oovnelryalalshmaavlle nbueemnbeirnocrfeaesmipnlgooyveeerstpiamretiicnitpahteesde einmpallloy3esesa.mplIinnagdpdietriioond,si(n2t4h%e),lodnigfifteurdeinntallasbtsudy and analytical techniques for PFOA were used each year, and female employees could not be: analyzed becauseofthe small numberofparticipants 322 Medical Surveillance Studies from the Cottage Grove Plant MAinvnoleusnottaaryplmaendtiicnal19s9u3r,ve1i9l9l5a,ncaenpdro1g99r7am(wna=s1o1f1f,e8re0datnode7m4pleomypeleosyoefetsh,ereCsoptetctaigveelGyr)o(vOel,sen, et aal.n, d 1l9i9po8pbr,otOelisnenleevtelasl),u2s0e0d0)i.n Tthheelcolnigniitcuadlincahlemainsdtrcryopssa-rsaemcettieornsal(cshtouldeisetseoroflt,hheeApanttiwceernpzaynmeds, wDaecsaatlusropmleanatssurweedreataltshoe uCsoetdtaignetGhirsosvteudpyl.antI.n aCddCiKtiolne,veilns 1w9e9r7eoonblsye,rcvheodlebceycsatuoskeinciernt-a3i3n(CCK) rtheeseraerscuhlthoafsinsucgrgeeassteeddCthCaKt plaenvcerlsea(sOabcoiunamr,ceetllala,de1n99o7m)a.s seen in rats exposed to PFOA may be eOmnpllyomyaelees ewmeprleocyeoemsmionnvotlovtehdei1n9P9F3OaAndpr1o9d9u5ctsiaomnplwienrgepienrcilodusd,ed21inwtehreestcuodym.moSnixbtye-tcwiegehtn r1a9n9g5esanadre1p9r9o7v,iadnedd i1n7Tpaarbtlice2iopaftetdheinBailomtohnrieteosruirnvgeiSlelcatnicoenyoefatrhsi.sMreepaonrts.erItusmhoPuFlOdAbelenvoetlesdand that Cottage Grove has the highest serum PFOA levelsofthe 3 plants studied. Employees' serum PFOA levels were stratified into 3 categories (<1, 1- <10, and 210 ppm), 4 000038 c`mheoasnensetro upmroPvFidOeAa lgerveealtserinncuremabseerdo,nfoesmtpaltiosyteiceaslliyn stihgeni>fi1c0anpt pambncoartmeagolryl.iveAr sfuenmcptiloonyeteesst"s, hreygproelsispiiodnemainaa,lyosreschcoolnetsrtoalsliisngwefroer poobtseenrtivaeldcionnafnoyuondfetrhse(saagme,plailncgohyoelarcso.nsMuumlpttiivoanr,iaBblMeI,and cgilguacroestet,esansdmohkeemda)toylioegldyemdesaismuirlaersrweseurletsn.otThasesoacuitahtoerds wailtsho sreeprourmtePdFthOaAt rleenvaellsf;uhncotwieovne,rb,lotohedse data were not provided in the paper. `mTehaenmseianntCheC2Ksevarluumecraetpeogrotreidesfo<r the 1997 sample was 28.5 10 ppm were at least 50% pg/ml (range 8.8 - 86.7 pg/ml). higher than in the > 10 ppm. The ctahtee3goPryF.OAAssetartuismticcaatlelgyosriigensiwfiacsantob(spe=rv0ed3.) nAegsacattitveerapslsootcoiafttihoennbaettuwraelenlomgeoafnCCCKCKanldevePlFsOaAnd sthheoswesetmhpaltoaylelebsut(2CCCKCKvalvuaelsuoesf8a0r.e5wiatnhidn8t6h.e7apsgs/amyl')s hraefdesreenrcuemrPanFgOeAolf0eve-l8s0lpegss/mtlh.anB1o0thppomf (s0e.r6u.manPd F5.O6Applemv,elrsescpoencttiivneuleyd).toAdismpullatyipalenergeagtrievsesiaosnsomcoidateiloonftafhteernaadtjuursatlinlgogfoofr pCoCtKentiaanld confounders. `The cross-sectional sampling years. In design is addition, taheimmietdaitciaolnosfurtvheiisllsatnudcye.prOonglryam17issaubvjoelcutnstwareyreonce.omTmhoen to all 3 p1a0r.t5i0c%ipaitni1o9n9r7a.teAolfesloi,gtihbelelapbroordautcortyiroenfeermepnlcoeyreaensgdeeccrheaansgeeddfsruobmstaapnptriaolxliymaftorelAyL7T0i%n i1n99179.93 Fdientaelrlmy,indeidffbeyreentleacntarloystpircaayl hmiegthh-opdesrfwoerrmeanucseedlitqouimdeacshurroemsaetrougmrapPhFyO/Am.assSespreucmtrPoFmeOtArywians1997, but by thermospray in 1993 and 1995. cAonndeuarcltieedr matedtihceaClotsutravgeeilGlraonvceesptluandty;ohnowweovrekre,rstowtahlosweerruem eflmupolroinyeedwaisn tmheeas1u9r8e0'dsiwnsatsead of PtoFPOFAO(AGidlelvilealnodpahnedpaMtaonmdeegla,ly19a96n)d.alBtaesraetdioonns ainnilmipaild smteutdaibesoltihsatm,reapcorrotsesd-stehcattiaonnialm,als exposed o10ccPuFpOatAi.onaIlnastPudFyOwAasprpoedrufcotriomnedfatcoildietyt,er1m1i5newiofrkseirmsilwarereeffsetctusdiaerdetporedseetnetrmininweorwkheertsheerxpsoesreudm PweFrOeAexapfofescetdedtothPeFirOcAholfersotmero1l9,85li-p1o9p8r9otewienrse, ainncdlhuedpeadtiinc tehnezystmuedsy.(F9o6r%typ-acritgihctipwaotrikonerrsatwe)ho Suinxetxyp-ofisveedegmrpoluopy.eeTshewsheoemciptlhoeyreveosluwnetreeeraesdsourmweedrteo ahsakveed ltiottplearotricniopaPteF,OwAereexpionsculrudeebdaisnetdhoen twhoerikrejrosbhdeasdcrPiFptOioAn.levHeolwsemvuecrh, wgrheeantersetrhuanm tlheeveglesnwerearlepaonpaullyazteido,n.it wThaesrenfootreed,tihnastttehaidsogfrjooub.p of categories, total serum fluorine was used to classify workers into exposure groups T`moetaaslurseedr,umdufelutooritnhee wcoasst uosfeadnaaslyazisnugrrtohgeatseammpeleass.ureBlfoorodPFsaOmAp.leSsewreurmePaFnOalAyzweadsfonrottotal spyerruuvmicflturoarinnsea,misnearsuem(gSlGuPtTamoyr oAxLaTl)oa,cgeatrimcitmaragnhsiatmaimnya!setr(aSnsGfOerTasoer (AGSGTT)),,scehroluemstgelruotla,mlyolw- 3s 000039 ~-- eeee ---- r -------------------- dpelnascietdyilnitpoofpirvoeteciantseg(oLrDiLe)s,ofantodtahligshe-rduemnsfiltuyorliinpeoplreovetlesi:ns<(1HpDpLm),. All 1-3 ofthe participants ppm, 3 - 10 ppm, were >10- p1p5mp).pm,Apapnrdox>im15atpeplmy.halTfheofrathnegewoofrtkheressfeerllumintfolutohrein>e 1va-lu3epspwmasca0tetgoo2r6y,pwphmil(em2e3anha3d.3serum levels < I ppm and 11 hadlevels > 10ppm. `Tuhneirvaeriwaetreeannaolyssiegnsiffoircacnhtoldeisftfeerroeln,ceLsDbLe,twaenednHeDxLp.osuIrntehceatmeuglotriiveasriwahteenanaanlaysliysz,edthuesrienwgas not a aslicgnoihfoilcacnotnsasusmopctiiaotni,onabgee,twBeMeIn,toatnadl sciegraurmetftelusomroiknienagn.d cThhoelreestwereorleonroLsDtaLtisatfitcearllaydjsuisgtniifnigcfaonrt dHiofwfeevreenrc,esinacmroeansgesthien AexSpTosaunrde cAaLteTgoorciceusrorfedtowtialthseinrcurmeafsliunogritnoetaflosreArSuTm,fAluLorTinaendleGveGlTs.in odibreescetlwyoirnkesresru(mBoMfIw=or3k5erksg/imn')1.993T,hi1s99re5s,ulotrw1a9s9n7osturovbesielrlvaendcewdhaetanoPfFeOmpAlowyaesemsoeafstuhreed Cottage Grove plant (Olsen, et a, 2000), SeimnpcleoyPeFeOsA(wega.slennogtthmofeeasmuprleodymdeirnetcetlxypaonsdurtehe)r,e tishenroeseuxlptososufrtehiensftourdmyatpiroonvipdreovliidmeidteodn the ibnefeonrmoabtsieornv.edThinetahuetsheoersmpsltoatyeeethsa;thnooweavdeverr,siet cislinnoitcaclloeaurtcthoamtetsherreelahtaesd tboeePnFfOoAlleoxwp-ouspuorfe have `fwoirdmeefroermmpalonyyeoefs.theIneaxdpdoistuirone,ctatheegroarniegse,ofinrdeiscualttisngrevpaoriratbeidliftoyrtinhethleivreersueltnsz.ymGeisvewnertehaftaoirnllyy `one sample vas taken from each employee, this is not surprising. It would be much more helpful 10 have several samples taken over time to ensure thir reliability. Italso would have been interesting to compare the resultsofthe workers who were known to be exposed to PFOA to tthheoseemwplhooyeweesreinortihgeisnealglryoutphso.ugThhtenroetwtoerbeemeoxrpeoosefdthteo s"eueneiftxhpeorseedw"eermepalnoyyedeifsf(enre=nc6e5s)among participating in the study than those who worked in PFOA production (n = 48). 3.2.3 Mortality Studies AplarnettrwohsipcechtpivreodcuocheosrtAmPorFtOali(Gtiylslitluadnydwaansd pMearnfdoerlm,ed19o9n3)e.mpAltotyheiessplaatntt,heACPoFttOagperoGdruocvtei,onMwNas lthiemiptleadnttoftorheatChleeamsitc6almoDnitvihssiobne.twTeheen cJoahnouratryco1n9s4is7taednodfDweocrekmebresrw1h9o83.hadDebaetehn ecemrplilfoiycaetdesatof allofthe workers were obtained to determine causeof death. There was almost `complete follow-up (99.5%)ofallofthe study participants. The exposure statusof the workers was categorized based on theirjob histories. If they had been employed for atleast | month in the Chemical Division, they were considered exposed. All others were considerteod be not exposed to PFOA. The number ofmonths employed in the Chemical Division provided the cumulative exposure measurements. Ofthe 3537 (2788 men and 749 women) employees who participated in this study, 398 (348 men and 50 women) were deceased. Eleven of the 50 women aexnpdo1s4e8dotfotPhFeO3A4.8 men worked in the Chemical Division, and therefore, were considered 3 000040 cSotamnpdaarreddizteodUM.So.raalnidtyMiRnantieossot(aSwMhRi)t,e daedajtuhstreadtefsorfoargem,ense.x,Faonrdwroamceenw,eroenlcyalsctuatleataetdeasnwdere apveariiloadbsleo.fduTrhaetiSoMnRosfefmoprlmoaylemsenwter(e5,st1r0a,tiafniedd2f0orye3arlsa)t,ency periods (10, 15, and 20 years) and 3 Feloervaaltledfe(maalltehoeumgphlonoyteessi,gntihfiecSanMt)RsSMfoRr awlalscafuosreIsyamnpdhofpooriaelticcacnacnecresr,wearnedlwesasstbhaasned1. oTnhoenloynl3y dweeartehss.ignWihfiecnanetlxypolsouwreerstthaatnusewxpaesctceodn,sibdaesreedd,oSnMthResU.foSr. arlaltecsa,usfoersobfotdheatthehCahnedmifocralallDicvainscieorns workers and the other employeesofthe plant. IcnomlplamraeldetwoobroktehrtshaetUt.hSe. palanndt,thteheMiSnMnRessotwaerdeeactlhosreatteos.1 for mostofthe causesofdeath When latency and duration of when e`CmhpelmoiycamlenDtivwiesiroencwoensriedecroemdp,atrheedretoweMriennneoseolteavadteeadthSMraRtses., tWhheeSnMeRmpfolropyroestdaetaethcsanicnetrhefor w(1o.r9k7eresxpiencttehde)C.heTmhiecraelwaDisvialssiooan wsatasti2s.ti0c3al(l9y5s%ignCiIfic5a5nt-a4s.s5o9)c.iatTihoinswwiatsh bleansgetdhoofne4mdpelaotyhsment ihanztahredCmhoedmeilcsa,ltDhievriesliaotnivaenrdispkrofsotraate1c-ayenacrerinmcorretaalsietyi.n eBmapsleodymoennttheinretshueltCshoefmpircoaplorDtiivoinsailon Cwhaesmi1c1a3l(D9i5vi%siCoIn1f0o1r 1100 y1e.a2r7)s.wIhternosceo1m0p3a.r3ed(9t5o%thCeIot1h.e0r2 e-m10p.l6o)yefoerswionrktheersplaenmt.ploTyheedSinMtRhe 5fo9r).workers not employed in the Chemical Division was less than expected for prostate cancer A1n99u7p(dAalteexoafntdheirs, s2t0u0d1ya)w.asThceoncdouhcotretdcotonsiinsctleuddoefth3e99d2eawtohrekxepresr.ieTnhceeoefliegmibpilliotyyereesqutihrreomuegnht wwearseicnhcraenagseedd t1o0b1eymeaorreofspeemcpifliocy.meWnotrkaetrtsheweCortetpalgaecGedroivnteop3laenx,poasnudrethgereoxuppossbuarseecdatoengjoroibes shhiistpopriynginafnodrmpaatcikona:gidnegfoifnitPeFPOFAOoAcceuxrproesdurtehr(onug=h4o9u2t,tjhoebhsiswthoerryoefctelhlegpelnaenrta)t;iponr,obdarbyliengP, FOA eTxopwoesruorret(rann=si1en6t85e,xpootshuerresc)h;emaincdalnodtiveixspioonsejodbtsowfhleuroreoecxhpemoiscuarlest(onP=FO13A15w,apsripmoasrsiilbylenobnu-t with chemical divisionjobs) Ignrotuhpi,s n26e7w icnohtohret,pr6o0b7abdleeatehxspowseurreegirdeonutpi,fiaend:d4269o4fitnhtehseendoena-tehxspwoesreed ignrotuhpe.PFWOheAnexalplosure ehimgphleoryefoersawlleorfetcheomcpaaurseesdotfodtehaetshtaatneamloyrzteadl.itNyornateeos,fSthMeRSMweRrewleerssetshtaatnis1tiocralolnylsyigsnliifgihctalnyt at PFi=ve.0d5e.atThhsewehirgeheosbtseSrMveRd r(3e.p8o3rteexdpwecatsfedo)rbladdercancer (SMR = 1.31,95% C1 = 042- 3.05), AcanfceewroSfMthRe wlaerrgee einlteevsattiendef(orSMeRmp=l1o.y67e,ie9ns5t%heCIde=fin0i.t0e2P~F6O.0A2)e,xp1 ofsruormepgarnocurpe:at2icdceaantchesrfrom wn 000041 ee (SMR = 1.34,95% CI = 0.03 ~7.42), and 1 from prostate cancer (SMR = 1.30, 95% C1 = 0.03 7.20). In addition, employees in the definite PFOA exposure group were 2.5 times more likely to die from cerebrovascular disease (5 deaths observed, 1.94 expected; 95% CI = 0.84 ~ 6.03). In the probable exposure group, 3 SMR shouldbenoted: cancerofthe testis and other male `genital organs (SMR = 2.75, 95% C1 = 0.07 -- 15.3); pancreatic cancer (SMR = 1.24, 95% CI = 0.45 -2.70); and malignant melanomaofthe skin (SMR = 1.42, 95% CI = 0.17 - 5.11). Only 1, 6(,95a%ndC21c=0ase2s w8er-e 2obs0e(rn2ve=d)),.respectively. The SMR for prostate cancerin this group was 0.86 `There were no notable excesses in SMR in the non-exposed group, except for cancerofthe bladder and other urinary organs. Four cases were observed and only 1.89 were expected (95% CI=0.58 ~ 5.40). tis difficult to interpret the resultsofthe prostate cancer deaths between the firs study and the update because the exposure categories were modifiedin the update. Only 1 death was reported in the definite exposure group and wereobserved in the probable exposure group. All of these deaths would have been placed in the chemical plant employees exposure group in the first study. The numberofyears that these employees worked atthe plant and/or were exposed to PFOA was not reported. This is important because even 1 prostate cancer death in the definite PFOA exposure group resulted in an elevated SMR for the group. Therefore, ifany ofthe. employees' exposures were misclassified, the resultsof the analysis could be altered significantly. "The excess morality in cerebrovascular disease noted in employees in the definite exposure `group was further analyzed based on numberofyearsofemployment at the plant. Threeofthe 5 deaths occurred in workers who were employed injobs with definite PFOA exposure for more. than 5 years but lessthan 10 years (SMR = 15.03, 95% CI = 3.02 -- 43.91). The othe2r occurred in employees with less than I yearofdefinite exposure. The SMR was 6.9 (95% CI = 1.39 -- 20.24) for employees with greater than $ yearsofdefinite PFOA exposure. Inorder to confirm that the results regarding cerebrovascular disease were not an artifactof death certificate coding, regional mortality ates were used for the reference population. The results did not change. `When these deaths were further analyzed by cumulative exposure (time-weighted according to exposure category), workers with 27 yearsof exposure in probable PFOA exposedjobs or those with 9 yearsofdefinite PFOA exposure were 3.3 times more likely to die of cerebrovascular disease than the general population. A dose-response relationship was not observed with years of exposure. Its difficult to compare the results ofthe first and second mortality studies at the Cottage Grove. plant since the exposure categories were modified. Although the potential for exposure. misclassification was certainly more likely in the fist study, it may sill have occurred in the update as well. Its difficult to judge the reliabilityofthe exposure categories that were defined. without measured exposures. Although serum PFOA measurements were considered in the exposure matrix developed for the update, they were not directly used. In the second study, the 38 000042 chemical plant employees were sub-divided into PFOA-exposed groups,and the film plant employees essentially remained in the "non-exposed" group. Thiswasan effort to more aecxcpuorsautreelyorcllaesnsgitfhyoefxpeomspulreosy;mehnotw.eveArn,otthheerselnimeiwtactiaotnegtoortiheissdsotundoyt itsaktehaitnt1o7 adcecaothuncterdtuirfaitciatoensof winecrleusniootnloorcaetxecdlufsoirodneocfetahseesdeedmepaltohyseceosuladndchtahnergeefotrheewaenarleysneost ifnorcltuhdeecdaiunsetshoefstdueday.thTthhaet had acosnmtianlule.numAbletrhooufcgahstehse.re Fwoelrleowmourpeofthwaonr2k0e0ramdodrittailointayladteCaotthtsaigneclGurdoevdei(natnhidsDaencaaltyusirs),nieteidssato small number and the cohort is still relatively young. Given the resultsofstudies on fluorochemicals in both animals and humans, farther analysis is warranted. 32.4 Hormone Study Endocrine effects have been associated with PFOA exposure in animals; therefore, medical surveillance data, including hormone testing, from employeesofthe Coftage Grove, Minnesota plant were analyzed (Olsen, etal, 1998). PFOA serum levels were obiained for volunteer workers in 1993 (n = 111) and 1995 (n = 80). Sixty-cight employees were common to both sampling periods. In 1993, the rangeofPFOA was 0-50 ppm (although 80 ppm was the limit of detection that year, so it could have been higher) and 0-115 ppm in 1995 using thermospray mass spectrophotometry assay. Eleven hormones were assayed from the serum samples. They were: cortisol, dehydroepiandrosterone sulfate (DHEAS), estradiol, FSH, 17 gammahydroxyprogesterone (17-HP), free testosterone, total testosterone, LH, prolactin, thyroid stimulating hormone (TSH) and sex hormone-binding globulin (SHBG). Employees were p<l3a0cepdpimn,toa4ndex>p3o0suprpem.catSetgaotriisteiscablasmeedthoondtsheuisresdetroucmoPmFpaOrAe lPeFveOlsA: 0l-e1velpspamn,d1h-<orm1o0npepmv,alu1e0-s included: multivariable regression analysis, ANOVA, and Pearson correlation coeflicients. PFOA was not highly correlated with anyofthe hormones or with the following covariates: age, alcohol consumption, BMI, or cigarettes. Mostofthe employees had PFOA serum levels less than10 ppm. In 1993, only 12 employees had serum level>s 10 ppm, and 15 in 1995. Hemopwleovyeere,stihnestehele>v3e0lsprpamngPedFfOrAomgraopupproixnim1a9t9e3lyan1d0opnplym5toinov1e99r5.114Thpeprme.forTeh,eriteswelirkeeloynlthya4t there was not enough power to detect differences in eitherofthe highest categories. The mean age of the employees in the highest exposure category was the lowest in both 1993 and 1995 (33.3 years and 38.2 years, respectively). Although not significantly different from the other categories, BMI was slightly higher in the highest PFOA category. Estradiol was highlycorrelatedwith BMI (+ = 41, p < 001 in 1993, and r = 30, p< 01 in 1995). In 1995, all 5 employees with PFOA levels > 30 ppm had BMIs > 28, although this effect was not observed in 1993. Estradiol levels in the >30 ppm group in both years were 10% higher than the other PFOA groups; however, the difference was not statistically significant, The authors postulate that the study may not have been sensitive enough to detect an association between PFOA and estradiol because measured serum PFOA levels were likely below the observable effect levels suggested in anima studies (55 ppm PFOA in the CD rat). Only 3 3 000043 eesmtprlaodiyoelesleivenltshiisn stthuedhyighhaedstPeFxOpAossureerucmatleegvoerlsy tchoiuslhdigshu.ggeTshtey tahlrseosshuoglgdersetltahtaitontshheiphibgehtewreen PFOA and estradiol Frerpeoertteastnoesgtaetriovneeawsassochiiagthiloyn bcoertrweeleatnedPFwiOtAh asgeeruimn bloetvehls19a9n3datnesdto1s9t9e5r.oneT.heThaeurtehowresrdeidnonot statistically significant trends noted for 17-HP, a precursoroftestosterone, was PFOA and either bound highest in the >30 ppm or free testosterone. PFOA group in both However, 1993 and 1995. Tn 1995, PFOA was significantly associated with 17-HP in regression models adjusted for o`fpoosnsiebleemcpolnofoyuenede(rdsa.ta wHeorweevneort,prtohveiaduetdhoirnstshaetreeptorhta)t.thiTsheasrseowciearteionnowsaisgnbiafisceadntonastshoeciraetsiuoltnss between PFOA and cortisol, DHEAS, FSH, LH, and SHBG. TFihrestr,eaalrtehsoeuvgehratlhedreeswiegrneis2susetsudtyhaytesahrosu(l1d9b9e3 naontded19w9h5)e,ntehveaploupautliantgitohnesrweseurletsonofttihnidsespteunddye.nt. Spairxttiyc-icpiagthetdeimnptlhoeyseteusdypairnti1c9i9p5a,tetdhiunsbroetdhucyieanrgs.theSpecoownedr,otfhtehree wsteurdye.31Tfheewreerweemrpelaolyseoevsewryhofew employees in cither year with serum PFOA levels greater than 10 ppm. Third, the crossstheecthiaolnfa-llidfeesoifgnPoFfOtAheisstautdlyeadsote1syneoatr,altlhoewauftohroarnsalsyusgigsesotf ttheamtpoitraisliptoysosfibalne tahsastoctihaetrieonm.aySibnece saocmhehboirolmoogniecalfoarcecaocmhmoofdtahteisotnudtoy tyheearesf.fecItnsoorfdePrFtOoAg.etFmoourrteha,cocnulryatoenmeesaasmuprleemewnatsstfaokresnofmore ofthe hormones, pooled blood taken in a short time period should have been used for cach ptahretirceispualnttso. fFainfthe,arsloiemreopafptehrethaastsolciinakteidonPsFtOhaAt wwietrheimnecarseausreeddeisntrtahdiisosltaunddy wdeecrreedasoende based on PteFsOtoAs,temraonkeilnegveiltsd.iffHiocwuletvetor,cotmotpaalrseerthuemroersgualnti.cFfilnuaolrliyn,etwhaersemmeaaysuhraevdeibnetehnatssotmuedy instead of `measurement errorofsomeofthe confounding variables. 3.2.5 Study on EpisodesofCare (Morbidity) Tn an order to gain additional insight "episode of care" analysis was ito the effectsof undertaken at the luorochemical exposure on workers' Decatur plant t0 screen for morbidity health, o20u0t1c2o)m.esAtnha"tempiasyodbeeoafscsaorcei"ateisdawistehrielsoonfg-hteearlmt,hhciagrheesxeprovsiucerseptroofvliudoerdocfhreommictahlesst(aOrltsoenfa.et al., particular disease or condition until solution or resolutionofthat problem. Episodesof care were identified in employees' health claims records using Clinical Care Groups (CCG) software. All inpatient and outpatient visits to health care providers, procedures, ancillary services and prescription drugs used in the diagnosis, treatment, and management ofover400 discases or conditions were tracked. Episodesof care were analyzed for 652 chemical employees and 659 film plant employees who worked at the Decatur plant for a least 1 year between January 1, 1993 and December 31, 1998. Based on work history records, employees were placed into different comparison groups: "0 000044 GworrokuepdAincoenistihesrtetdhoeffailllm foirlcmhaenmdiccahlempilacnatl; pGlraontupwoCrkceornss;isGtreoduopfeBmphaldoyeemepslwohyoeswowrhkoedonliyn.jobs wcihtehmihciaglhpPlOanStFfoerxp1o0syueraerss; oarndmoGrreouprpioDr htoadtheemopnlsoeytoeefstwhehostwudoyr.keFdilimn hpliagnhteexmppolsouyreeessinwethree ascsonusmiededrteod thoahvaevtehelihtilgehoerstnoexfplousourroecsh.emical exposure, while chemical plant employees were nRuatmiboesrosfowbesreerbvaesdedtooenxp3eMc'tsedemeppilsooydeeesopfopcualraetiwoenreexcpaelrciuelnacteedusfionrgeaincdhirpelacntt.staEnxdpaerdcitzeadtion tpleacnhtn'isquoebss.eArverdattioooefxtpehcetecdheemxipcearliepnlcaentw'assobcsaelrcuvleadtetdo teoxppercotveiddeexapreerliaetnicveerdiisvkirdaetdiobyfotrheeafcihlm oefpicsaordeeothfatcwareere(oRfRgErpeCa)t.est9i5n%terceosntfwiedernectehionsteerwvhailcshwehraedcbaelecnulraetpeodrtfoerdciancahniRmRaElpoCr. Episodes einpviodlevmiinoglotghiecthliytreoriadtugrleaonnd PanFdOSlipainddmePtFaObAol:islmi,vedriasnorddberlsaodfdetrhecanlicveerr,aennddobcirliianrey dtiascotr,daernsd reproductive disorders. `tThheemoanlley rienpcrroedauscetdivreisskoysfteepmisaonddesforfotrhtehoevseercaolnldciattieognosroyofafcparnicoerrisntaenrdesbtewneirgen fgorronwetohpsl(awshmischof ithneclouvdeerdalclacnacnecreorfctahteegmoarlyefroerparlold4ucctoimvpeasryisstoemn)g.roTuhpesr.eTwhaesrainskirnactrieoawseadsrgirsekoatfesetpiinsotdheesgrfoorup o=f1e2m-p2l1o1y)e.esIwnictrheatsheedhriigshkesotfeapnidsoldoensgeisnt eloxnpgo-stuirmees, thoigfhl-ueoxrpoochseumrieceamlpsl(oRyReeEsPCals=o1w.a6,s9r5ep%orCt1ed fcoornfmiadleencreepirnotdeurvcatlivies vcearnycewrisd(eRfRorEpmaCl=e 9r.e7p,ro9d5u%ctiCvle=ca1n.c1er- s45a8n)d. tIhtesshuobu-lcdabteegnoortyoedfptrhoastttahtee. cancer. Five episodesofcare were observed for reproductive cancers in chemical plant eobmspelrovyeedesin(1f.i8lmexppleacntteedm)p,loofyweheisc(h3.44weexrpeectperdos)t.atTehciasncfeirnsd.ingOnsheouelpdisboedenootfepdrbosetcaatuesceaanncer was excess in prostate cancer mortality was observed in the Cottage Grove plant mortality study `dwivhiesniotnheermepwleoyreeeosn)l.yT2heexpuopsduarteeocfattehgeorsiteusd(ycshuebm-idciavliddeidvitshieoncheemmpilcoayleeplsaantndemnpolno-yceheesmiacnadl did enxotpocsoendfiermmpltohiyseefsi.nding when exposures were divided into definitely exposed and probably `eTxhpeorseuwraesgraonuipnc(rReRasEePdCri=sko1.f8,ep9i5s%odCeIs =for1.n2e-o3p.l0)asamnsdoftthehleongags-ttreorimnteemstpilnoaylmternactt,inhitghhe high ebexnpiogsnurceolgornoiucpp(olRyRpsE.PCSi=mi2l9a,r9nu5m%beCrIs=of1e.p7i5s.o2d)e.s wMeorsetroefpotrhteeedpiinsofdielsm awnedrechatetmriicbaultapbllaentto employees. Ibnlatdhdeeernctairnececroh(o1r.t5, eoxnpleycte1 de)p.isBoodetohfoccacruerrweadsinrefpiolrmtpeldanftorelmipvleroyceaensc.erO(0n.6leyx2peccasteesdo)facinrdrh1osfoirs oTfotwheer ulrivienrarwyertreacotbsinefrevcetdio(n0s.9ienxcpheecmtiecda)l,pbloatnht ienmpthleoyceheesm,icbault ptlhaenyt.weTrheermeoswtalsy adugerefaoterrecruirsrkinogf. a 000045 oebpsiesrovdaetsioofnsc,agreivbeyn tthhee ssamamlelenmupmlobyeereosf. epItissoddiefsfirceuplotrtteodd.raw any conclusions about these Cmhoermeilciaklelpyltaontseecmkplcoaryeeefsoridnitshoerdheirgsohfetxphoesubriel,ialryontgr-acttertmhaenmtphleiorycmoeunnttegrrpoaurtpswienrtehe2 f%iltmipmleasnt (emRpRlEoPyeCe=s 2a.n6d, 9145%inCfIil=m p1l.a2n-t5w.o3r).kerEsi.ghtTeheenseupbi-scoadteesgoofriceasrtehawteirnefloubesnecrevdedtihins cobhseemrivcaatliopnlant wunesrpeeceipfiiseoddecshoolfeccyhsotlietliist.hiMasoisstwoiftthhaecuotbesechrovleedcycsatsietsisocacnudrcrheodleilnitchhieamsiiscawlitphlacnhtreomnpilcooyrees. dRiissekasrea,tidoisoabfeteeps,ishoydpeesrolfipciadreemifao,r aennddooctrhienreednidsoocrdreirnse,owrhniucthriitinocnlauldedidssourbd-ercsa,tewgeorrieensootfetlheyvraotiedd innultlhehycpoomtphaesriissoinn tghreou9p5s.% Ccoonndfiitdieonncsewihntiecrhvawlefroer tnhoethdiegnhiefxipeodsaurper,iloornbgu-ttewrhmiecmhpelxocylmuednedt the `group included: disordersof the pancreas, cystits, and lower urinary tract infections. "cTahree rdeessuilgtsnofaltlhoiwsesdtfuodryaondilryecsthocuolmdpabreiussoendoffowrohrykpeortshewsiitshgseinmeirlaatriodne.moAglrtahpohuigchstbhuetedpiifsfoerdeentof earxeporseuproerst,edt,henroet adriesemaasenyinlciimdietnactei,on2s)ttohethdiastdaesairgen.difTfihceultli0mitianttieornpsreitncbleucdae:use1a) elpairgseodReRsoEfpCcare `empaiysondoetsonfecceasrsearhilaydivnedriycawtiedheigchonrfisikdeonfcienicnitdeernvcaleso,ftdhiesreeabsye,pr3o)vmidainnygoufntshtaeblreisrkesrualttiso,s 4f)orthe analysis was limited 10 6 years, 3) the utilization ofhealth care services may reflect local medical practice patiers, 6) individuals maybe counted more than once in the database becausetheycan bseamceatiengdoirviizdeudalunsdeeverrallartgiemreosr, sm)anlolteraldliesemapsleoycleaesssiwfiecraetiionnsc,lu7d)eedpiinsotdheesodaftacbaarsee,masuychinacslutdheostehe ominsclloansgs-itfeyrmepdiissoabdielsiotfy,ca9r)et,he1a0)natlhyesissofmtawyarbeemlaiymiatsesdibgyn 2thdeisffoefrtewnatrdeiuasgendo,sewshitcohthmeasyame episode, database. and 11) certain services, such as lab procedures may not have been reported in the 3.3 Acute Toxicity Studies in Animals 33.1 Oral Studies The acute oral toxicityof APFO was tested in male and female rats in three studies. Death oucpcounrrneedcraotpcsoync(eknitdrnaetyi,onssto2m4a6ch4,mugt/ekrugs)(Iwnetremeaot'b|seRrevsedan(dGlDazeav, C1o9r9p.7,) at195780)0. mAgb/nkogr(mhailghfeirndings concentrations were not tested). Clinical signs oftoxicity observed in these three studies hiynpcolaucdteidvitthye,fhoullnocwhiendg:porsetdu-rset,aisnteadggfeacree,dsgtaaiit,needxucreosgseinvietaslalairveaat,iown,etptuorsoigse,npiitlaoleraereetai,on, decreased limb tone, ataxia, comeal opacity, and hypothermic to touch. In one study (Internat'l Res and Dev Corp., 1978), the oral LDS0 values for Charles River CD 2 000046 `ramtgs/kwger9e56%8c0omnfgi/dkegnc(e39l9im--it)11f5o7r fmegm/aklegs;95an%dc5o4nf0imdgen/ckeel(i3m8it9)-fo7r4m9almegs/;k4g3905m%g/ckognf(i2d9e5nce626 mligm/ik)gffoorrmmaallees Canrdl:fCemDa(lSeDs.)BTRheratrse,maanidni2n5g0t-w5o00stmugd/ieksgpfroorvfiedmeadlLeDCSrOl:vCaDlu(eSsDo)fB(R1)ra>ts500 (1G9l7a6zba),. 1997); and (2) <1000 mg/kg for male and femaleSherman-Wistar rats (3M Company, 3.3.2 Inhalation Studies d`Tohseealceuvteel ionfha1l8a.t6iomngt/oLxi(cniotymoifnaAlPcoFnOcenwtarsattieosnt)e,diannmdaelxepoasnudrefedmuarlateiSopnorfaogunee-Dhaouwrl.eySiragtnss, aotfa staolxiivcaittiyodn,ureixncgesasnidveuplatcori1m4atdiaoyns, daefctrretahseeedxapcotisvuirtey,pleraiboodr,edinbcrelautdheidngt,hegafsopllionwgi,ncgl:oesxecdeesyseisv,e amnuocgoeinidtnaalsfaulr,didsrcyhaarngde,moiirsretgruallaers,breeadthmiantge,riraeldanraosaulndditshcehaerygees,, ayenldlboowdsytatirneimnogrosf.thUpeon Bneacsreodpsoyn, tlhuensgtduidsycorlesourlattsi,onthweatsestobssuebrsvteadncien waahsignhoetrftathaalntnoorramtsalatiancniodmeinnceaolfexaptossu(r8e/.10). concentration of 18.6 mg/Landexposure durationof one hour (Bio/dynamics, Inc. 1979). 3.3.3 Dermal Studies d`Tohseealceuvteelodfer2m0a0l0tomxgi/ckitgy,oafnAdPaF2O4-hwoausrteexspteodsuirnempaelreioadn.dAflelmaanliemaHlrsaa(pNpZeWa)reSdPFnorrambabiltsa,ndat a dexuhriibnigttehdebfoirdsyt wweeeikg.htDgeairnmatlhriorurgithaotuiotntchoenssitsudtye,d owfistlhitghhetetxocmeopdteiornaotfeoenryetmheamlse,tehdatemlaos,t awnedight uatpoonnian;esclriogphstyd.esTqhueamdaetrimoanl; LcoDrSiOaceinoursanbebsitss; waands fdiestseurrimnign.edNtoobveisgirbelaetleerstihoansnw2e0r0e0ombsge/rkvged (Glaza, 1995). 3.3.4 Eye Irritation Studies "The wo oefytehrienietasttiuodniepso,tAenPtiFaOlowfaAsPdFeOterwmaisnetdesttoedbeinaaplbriinmoarryabobciutsl,aratimaitdaonst.e level of 0.1 gram. In the studies in In 7whdiacyhs,AtPheFnOriwnassed,foournndottorbineseadp.riImiatraytioocnulsacrorieistavnatr,ieAdPdFurOinwgatsheleoftbsienrcvoanttiaocntpweirtihodt.he eye for IInnci.ta1t9io7n6)scaonrdesofrfotmh2e-c1o0nijunntchteivoat,heirriss,tuadnyd(c3oMmeCsomrpaangneyd,f1r9o7m622).4Ininbootnhessttuduideys,(Biiroristeaatricohn, irnemwahiincehdAePviFdeOntwafsordtehteedrumrianteidontoofbethaenoobns-eirrviattainotn(pGeabrriioedl)(,7-tdhaeytsepstosstu-besxtpaonscureew).as Ilnetthien study contact with the eye for 5 or 30 seconds, and then the eyes were rinsed. In this study, positive scores were reported for conjunctivac irritation for up to 7-days post-exposure, so the author's negative conclusion for ocular irritancy is problematic. a 000047 3.3.5 Skin Irritation Studies f`T0h.e 5skgirnaimrsi,tautnidonerpootcecnltiuadledofteAstPcFoOndiwtaisontse.sItend in albino rabbits one study (Riker in two studies, Laboratories, ata Inc. dose level 1983), -AhPoFuOr pcronotdaucctedpeirriroedv.erMsiobdleertaitsesueerdyatmhaegmaeainndfeedmealmea,rababsiwtse,llfoalslcohweimngicaal3-bmuirnnu,tee,sch1-ahro,uarn,dand ntheicsrosstiusd,ywdeureetoobesxetrrveemdefoirliltoawtiinogn aflolltlhorweiencgoenatcahctcpoenrtiaocdts.perAinod.endIpnocionnttrwaasst innotthaechsieecvoendd isntudy h(oGuarbsri,elb)a,seAdPoFnOprwiamsarreypoirrtrietdaatisonascnoorne-soiftazenrtoo.fskinaferan exposure periodof24 or 72 3.4 Mutagenicity Studies ~AEP.FcOolwia/smtaemsmtaelditawni-cmei(cLraowsloomre, r1e9v9e5r;se19m9u6t)atfioorniasssaabyi.litTyhteotiensdtsucweermeutpaetrifoonrimnedthbeoStahlwmiotnhelalnad wtiytphhoiumtumreituamboTlAi1c5a3c7tivwahtieonn.teAstseidnwgiltehpoousttmievtearbeoslpiocnascetisveactnioant wonaesdnoosterelperveolduicnibSl.e. APFO did `nmotamimnadluicaenmuacttaitviaotnioinn. eAiPthFerOSd.itdynpohtimiunrduicuemcohrrEo.mcoosliomwahleanbetresrtaetdioenisthienr whiutmhaonrlwyimtphhouotcytes N`wOhTenOtXe,ste2d00w0i)t.h aSnaddhwuit(h2o0u0t2)merteacbeonltilcy racetpiovratteidonthuatpAtoPcFyOtodtioxdincoctoinncdeuncteragteionnesm(uMtuartliio,n19w9h6en; tested with in culture. or without metabolic activation in the K-1 lineof Chinese hamster ovary (CHO) cells cMeulrlsl.iI(n19th9e60fi)rsttesatsesdayA,PAFPOFOtwiicnedufcoerditbsoatbhilcihtyrtoomoisndoumcaelcahbrerormaotsioonmsalanadbeprorlaytpiloonisdiyniCnHboOth the prcehsreonmcoesoamnadlaabbseernrcateioofnsmewtearbeoloibcsearcvtievdatwiiotn.houInt atchteisvaetcioonnd. Hasoswaeyv,enro,swighneinfitceasntteidnwcirteahses in pmoeltyapblooliidcyac(tMiuvart,ion1,99A6Pb)F.O induced significant increases in chromosomal aberrations and in AemPbFrOyowafisbrtoebslatsetds.in aThceellcetlrlatnrsafnosrfmoartmiaotniaonndwacystodteotxeicrimtiynaessaasybcootnhdcuocltoendyitnrCan5sHfo1r0mTa;t;iomnouansde foci transformation potential. tested in either the colony or fTohcieraesswaaysmneotheovdisde(nGcaerorfyt&ranNseflosornm,at1i9o8n1)at. anyofthe dose levels AinPcrFeOaswesasintmeistcerdontuwcilceeiianntdhewmaosucsoensmiidcerroenducnelgeautsivasesuany.derAPthFeOcodnidditniootnsionfdtuhceisanaysssaiygn(iMfuirclain,t 19963) 3.5 Subehronic Toxicity Studies in Animals Smounbkcehyrso.nieTtwoxoicuintpyusbtluidsiheesdh2a8v-edbaeyefnecedoinndgucstteuddiiens rwaetsr,empiecref,orrhmeesdusatmIonndkusetyrsiaalnBdioc-yTneosmtolgus " 000048 Laboratories, and mice the Inc. liver (Metrick and Marias, was the target organ. 1I9n7r7atas,ndmaClhersishtaodphmeorraenpdrMoanroiuansc,ed197h7e)p.atoTtnoxbioctihtyraatsnd hciosntdoupcattehdoliongircatesf(fGeoctlsdetnhtahnalf,em1a9l7e8s.3,TPharlaezez9ol0o-,da1y99s3u)bcahnrdonrihcestuosximcoitnyksetyusdi(eGsohladvenetbheael,n c1y9n78o)m.olTghuosmmfoonrkdey(s2.001Ian,abd)drietcioenn,tlcyhcroonndiuc/cctaerdcainroagngeen-cfiiyndsitnudgiaesndhaav6e-bmeoennthcotnoxdiuccitteydStwuhdiychin amroerdeepscrroinboeudncinedsehcetpiaotno3t.o8x.icIintyalalnsdpehciisetso,patthheolliovgeircies ftfheectmsatihnantafregmetaloersg,anp.reIsnumraatbsl, ymableecsauhsaed of the gender difference in elimination ofAPFO, Ifnemaal2e8s-dwaeyrestsutduydoifedC(hMRet-rCiDckaalnbidnMoarraita,s,ei1g9h7t7r).anAdfotmelryraastssiwgenreed aglrloouwpesdoftiovaceclmiamlaetse afonrdafive w10e,e0k00i,noirnd3i0v,i0d0u0alpcpamgeAsPthFeOy tfhoren28redcaeyisv.edTshiemialnairmfaelesdwceornteaoibnsiengrv0e,d30d,ail1y00a,n3d00b,od1y00w0e,ig3h0t0s0, afonrdgfrooosds cpoatnhsoulmopgtyi,oanswweerreerseucrovridveidngweaenkilmya.lsAanti2m8adlasyst.hatIdiisedstdautreidntghatthethsetusdtyudwyeirnecleuxdaemdianed c`eoxmapmlienteed,exbautmitnhaetsipoencoiffigcrlosstsipsantohtosluopgpyliaendd. aLciovemrpslewteeresetwoefigthisesduetso adentdeorrmgiannesrwelearteive organ weight then stained for histopathologic examination. Awlelreanniomaplrsemianttuhree1d0e,a0t0h0saonrdot3h0e,r0c0l0i-nipcpaml sgirgonusopsfdtioexdicbietfyorine tthheeoetnhderofgtrhoeupfsi.rstBwoedeyk.weTihgehrte ``ggaaiinnswweerreearlseoduocbesderivnetdheingmraoluepss reexcpeoisveidngto1030000oprpmmoraendppmma.lesSlaingdhtferemdaulcetsiofnesd i1n0b0opdpym.weight RReeldautciveedlfiovoerdwienitgahkteswawesroebsinecrrveeadseidn rinatmafleeds1f0e0d03p0ppmpomrohrigmhoerreinanaddofseem-arleelsatfeeddm3a0n0neprp.m or more. organs Gbreosisdsepsaltihvoelrso.gicFaolcaelxtaommduildtinfootcarlevceyatlotprleaastmmiecnte.nrlealragteedmeenftfoecftsheinpaktiodcnyetyessowraosthneorted in faendim1a0l0s0fpedp3m0o0rphpigmh,era.ndThmeusletieffofceacltstowdeirfefumsoereenlparrogneomuenncteodfihnempaalteoscy(tMeestwriacsknaontdedMainraasni.mals 1977). mInaale2s8a-nddayfisvteudfyeomaflCehsarwleerse Rstiuvdeire-dC(DCahlrbiinsotmoipcahe,nedreigMhatrirsaan,do19m7l7y).asAsfitgenredmigcroeuwpesroeffailvleowed 10 acclimate for 300, 1000, 3000, days in 10,000, oirnd3i0v,i0d0u0alpcpamgeosftAhePyFtOhefnorre2c8eidvaeyds.siTmihlearanfiemeadlcsonwtearienionbgse0,rv3e0d, 100, daily astnuddbyowdeyreweeixgahmtisnaenddffoorogdrocsosnspautmhpotlioogny,wearsewerreecosrudrevdivwienegklayn.imAensimaatl2s8tdhaaytsd.ied idsusrtiantgedthtehe sotrugdaynsinwcelruedeedxaamcionmepdl,ebteuetxhaemispneactiifoicnolfigstriossnsotpasutphpollioegdy. aLnidvearrsewpererseenwteaitgivheedsettoofdteitsesrumeisneand relative organ weight then stained for histopathologic examination. `Aglrouapnidmiaeldswiinthtihne 21600d0a-ysppemxcaenpdth1igmhaelre.grOonupesadniiemdalbeifnoreeacthhoefetnhdoef3d0aaynd9. 1T0h0e-epnptmirgero3u0p0s-ppm a 000049 PdiFeOdAp.remAatt1ur0e0lpy.pmClsinoimcealasniigmnaslwseerxehiobbisteerdvceydainnomiscoiensedxapyosse1d0taon1d0101popftmesatnidngh,igbhuetradpopseeasreodf mnuosrcmuallatrhwreoaugkhnoeuststahsewreesltloafsthsiegnsstoudfy.cyaAnnoismiaslsaffteeerd 3d0a0yspopfmtreexahtimbeintt.ed Aronuigmhaelds ffuerda1n0d00 ppm eefxfheicbtisteadftserim4ildaaryse.ffects ater 6 days and those receiving 3000 ppm or greater doses exhibited Ainllmimciecefefded30A,P1F00O,loorst3w0e0igphptm.. RAedduocstei-orneslaitnebdopdayttwerenigwhatsgsaeienniwenrtehefodlelporweesdsebdybwoediyghwteilgohstsess. pRaetlhaotliovgeiacnald eaxbsaomliuntaetiliovnerofwkeiidgnhetsyswoerreotihnecrreoarsgeadnsinbemsiicdeesfeldiv3e0rspipsmnootrdmisocruessAePd.FOT.reaGtrmoesnsterenllaatregdecmheanntgaensdw/oerrediosbcsoleorrvaetdioinnofth1e loirvemrsoraemolinvgeralllobAesP.FOHitsrteoaptaetdhoalnoigmiaclsexianmcilnudaitnigonofall (ApPaFnOlotbruelaatrehdympiecretrroepvheya)leadccdoifmfpuasneiceydtobpylafsomcialc teonlmualrtgiefmoecnatl ocfythoepplaatsomciyctevsactuhorloeusg.hout the liver mDeigceenweirtahtiinonallangdro/uoprsne(cCrhorsiisstoofphheepraatnodcyMtaersasa,nd19f7o7c)a.l bile duct proliferation were also noted in (`TGhorledeen9t0h-adla,y1s9u7b8c3h)r,oonniec wtoaxsicciotyndsutcudtieedsihnarvheesbuesenmocnonkdeuycste(dG.oldOennethwaals, 1co9n7d8ubc)taendditnhreattshird was conducted in male rats (Palazzolo, 1993). 3In,1t0h,e 3m0onorke1y00stmugd/yk,gG/odladyenptehrafllu(o1r9oo7c8t)anaodimcianciisdte(rFeCd-r1h4e3s)usinm0o.n5k%eyMset(h2soecxe/lgrboyupg)avdaosgeesfoorf70, bdaasyesd/wuepeoknftohre9w0edeakylsy. bAoldlydwoesiegshtwse.reAgniivmeanlsinwaecroenosbtasnetrvveodlutmweic;eidnadiilvyidfuoarlgdeanielryaldopsheyssiwcearle papeprefaorramnecdedaunridnbgethhaevicoorntarnodl ppehrairomdacaontdomxoinctshilgnys.durGienngertahle spthuydsyicpaelrieoxda.miInnadtiviiodnusalwebroedy `wpeeirgihodtsanwderaet r1 eacnodrd3edmownetehklsyo.ftBhleoostduadyndfourrihneemastaomlpolgeys,wcelrineiccaolllcehcetmeidsotnrcyeadnudruirnignatlhyesicso.ntrol Monkeys were fasted overnight prior to the collectionofblood and urine samples. Organs and tissues from animals that were sacrificed at the endofthe study and from animals that died during the treatment periodwere weighed, examined for gross pathology and samples taken for choinsttrooplatahnodlotgrye.atHmiesnttogpraotuhposl:ogaydrweanaslsp,eraofrotram,ebdonoen,tbhreaifno,lleoswoipnhgagoursg,anesyefsr,ogmalalllblmaoddnekre,yhseairntthe s(kwiint,hmceosreoantaerryicvelsysemlpsh),ndoudeo,derneutrmo,phialreyunm,gejaeljulnyummp,hcneocduem,,mcaomlomna,rryecgtluamn,d,kindenrevyes,(wliivtehr, lung, smpuisncalle)c,orsdp,lepeitnu,itpaarnyc,rseatso,mapcrohs,ttaetset/eustoevraursi,ersi,b jtuhnycrotiido,n p(abroantehymraorird,owt)h,ymsualsi,vatrryacghleaan,dt,onlsuiml,bar tongue, urinary bladder, vagina, identifying tattoo, and any tissues(s) with lesions. wAlelemko2n;kaellysaniinmathles w1e0r0e-mdge/akdg/bdyaywegeroku5p.s Sdiiegdnsduarnidngsytmheptsotumdsy.whTihcehffiirrssttdaepapteharoecdcudrurreidndguring " 000050 w`geuemsk, 1swionlclluednefdaacneoarnexdieay,efsr,osthlyiegmhoetsissevwehriecdhecwraesasseodmeacttiimvietsy,brproowsntrianticoonloarn,dpbaloedyfatcreeambnlding. `7Tahrnedetmhoentkweoysfefmraolemstdheie3d0d-umrgi/nkgg/wdeaeyksgr1o2upanddie1d3.duBreignigntnhiensgtuidnyw;eoenke4m,aallel dfoiuerdadnuirmianlgsweek asnhdowaetadxisal,igshwtotlolemnodfearcea,teeyaensdasnodmevutlivmae,s-assewveelrleadsepcarlelaosroefdtahcteifviatcye.aOnndegmuomsn.keByeghiandnienmegsiins wpteoesikso6,ftthweo meyoenlikdesy.s had black stools and one monkey had slight to moderate dehydration and N`mog/mkogn/dkaeyy-sdoisnetghreo3uporoc1c0amsigo/nkagl/ldyahyagdrsooufptsstdoioelds dourrminogdetrhaetsetutdoym.aArnkiemdadlisarirnhetah;e f3r-othy eanmoerseixsiwcadsurailnsgo woceceaksi4o,nhalaldyanpoatleedainndthsiwsoglrloeunp.facOenienmwoenekke7yainndthhead10blmagc/kksgt/odoalsy fgorrosuepvewraasl days in week or symptoms. 12. The other animals in the 10-mg/kg/day groups did not show any unusual signs dCohsaenggerosupisn.boMdoynwkeeiygshtfwreormethsei3m0ilaan0dr 1th0e0cmogn/trkogl/sdafoyrgarnoiumpaslslofstrobmotdhyew3eiagnhdt1a0ftmerg/wkege/kda1y. ``Amtg/thkeg/ednadyogfrotuhep s(t2u.d3y0,ktghsvslo3s.s78waksgsftoartitshteiccaolnltyrsoilg)nificant for the one surviving male in the 30- tHheem3ataonldog10y mvgal/ukegs/dataythgereonupdos.ftAhte3I0amngd/k3g/mdoanyt,hstoheftsruervaitvmienngtmwaelreehsaidmidleacrrfeoarsethdencuomnbtreorlsaonfd etriymteharoncdytaecst,ivdaetcerdeparsoetdhhreommobgilnobtiinm,e dweecrreeaalsseodihnecmraetaoscedr.itT,haensdeiinnccrreeaasseedspwleatreeletasp.paPrreontthartom1bin `month but were much more marked at three months. F(1o1l7lovw5in8g9 omnge/1m0o0ntmhlofinttrheeatcmoenntrto,l)g.lucTohsee awuathsosrisognfitfihceanrtelpyoerlteavtattreidbuitne tthheis3t-omag/skigng/ldeayhiggrhoup `vgarlouuepsfohramdalleeve#l7s3o6f61w12h,o1h0a5,daanvdal1u2e0o-fmg1/311.00Tmhle. oGtlhuecrotshereleemveolnskienytshein10thaen3d-3mg0/mkge//kdga/yday ``gmroonutphsswoefrtere1a0t4meannt,d g1l2u2c-omsge/l1e0v0elmslw,erreesp8e1c,ti9v6e,ly$,8,afatnedro6n6e-mmgo/n1t0h0ofmltreinattmheencto.ntArtolt,hr3,ce10 and 30 mg/kg/day groups respectively. `iTnhtehree cwoanstraold)eactreoanseemionnatlhk,alwihneicphhopseprhsaisttaesdeilnevtehlesoinnetshuer3v0i-vimngg/kmga/ldea(y3g6r0ovusp8(53165IvUs 5i9n7th1eU/ c`omnotnrtohls)waetr3em7o8n3thasn.d 7A4lk3alIUi/nlesphhooswpihnagtaasdeoslee-vreleslaitnetdhetre3n-datnodwa1r0dmdge/ckrge/adsaeydglrevoeulps.s at three ScoGntOrTol)leavnedlsiwnetrhee orneeduscuerdviivnitnhgem3a0l-emagt/k3gm/odnaythgsro(u8p8svast4o5neImUonitnhth(e59covntsro2l9).TUS/lGPinTtwheas elevated in both the 10 and 30 mg/kg/day dose groups at 1 month; the levels were 15, 34, and 44 IU in the control, 10 and 30 mg/kg/day groups, respectively. SGOT levels in the 10-mg/kg/day a 000051 `eglreovuaptewderinetchoemopnaerasbulrevitvointghemcaolnetrionlsthaet330m-omngt/hkgs/(d3a4yvdsos3e1 gIrUo/upin(t4h6eTcUon)trol) but were stil Cmhgo/l1e0s0temrlo)lainndthteotoalneprsoutreviinvainngd maallbeuimninthien 3th0ismagn/ikmga/ldawyergeroruedpucweads. eTloetvaaltepdro(t2e4i0nvwsas1655.52 vs a control level of 8.21 /100 ml and total albuminwas2.00vs acontrol level of 4.52 g/100 ml. There were no treatment related changes in urinalysis studies at any time period studied. `sTthuedryeowrerwheincohmwaecrreosscacorpiifcicleedsaitontshenoetneddofatthgreostsrenaetcmreonptspyeorfioadn. y animals which died during the r"eTlhaetfivoellwoewiignhgtochfatnhgeesheianrtasbsionlufteemaalneds rferloatmivteheor1g0amngw/ekigg/hdtaychgarnoguepswweerreedneocterde:asaebds;oalbustoelaunted bwreaiignhtwoefigthhteopfitfueimtaalryesinfmraolmetshifsrsoammtehegr3omugp/wkegr/edaaylsgordoeucprweaassedinacnrdearseelda.tiTvheegrsiogunpifmiecaannce of cthhaensgeewse.ight changes is difficult to assess, a they were not accompanied by morphologic ``gOrnoeupmahlaedamnadrktewdo fdiefmfaulseeslifpriodmdetphlee3t0iomngi/nktgh/edaadyregnraolusp. aAlnldmaalllaensiamnadlsfefmraolmetshfer1o0m0tmheg/3k0ga/dnady `1m0o0demrga/tkega/tdraoyphgyroofuplsyamlpshoohiaddfsolliligchltestoinmotdheersaptleeenh.ypoOcneellfuelamrailteyforftohmethbeo3n0e-mmagr/krgo/wdaayndgroup athned lalylmapnhinmoadlessi.n Ntoheo1th0e0r-mcgo/mkpgo/duanyd grreolautpedhaldesmioondserwaetree asternophiny aotftthhee 3l0ymapnhdo1i0d0fomlgl/icklge/sdiany `groups. No treatment related lesions were seen in the organsof animals from the 3 and 10 mg/kg/day groups. `pTrheeselnetveeldssooftPheFrOeAareindtohueblseereuntmraiensdfloirvemrosartedporseeselnetveelds.below in Table 3. Individual values are Table 3. Levels ofPFOA in the Serum and Liver Dose Serum (ppm) Liver (ppm) Liver total (ug) [I Males Females 308 6 38 50 0 4s 7 won 030 1N4D5 NNDD 100 ND ND M0a0l5es Fe0m0a7les Mal3 es Fs emales 37 250 350 ND ND ND ND 9 ND 600 ND ND 10 ND 750 2650 18205 84000000 79500000 100 325 6000 20000 a 000052 I1n0,t3h0e,fi1r0st0,ra3t0s0t,udayn,dG1o0ld0e0npthpaml p(e1r9f7l8u4o)roaodcmtianniositcearceidd.CDThreastse (dSo/sseexl/egvreoluspa)rediaeptparryoxliemvaeltseolfy0, meqgu/ikvga/ldenaty0in 0f.e6m,al1e.s7., 5.A6n,i1m7a.l9s, awnedre63h.o5usmegd/kign/ddiaviyduianlmlayliens,wiarnedm0e.7s,h2c3a,ge7s.a7,n2d2h.a4danfdre7e6.5 maocrcteaslsittyo. fDoeotdaialneddweaxtaemri.naAtniiomnaslwsewreerpeeorbfsoerrmveeddotnwcieceadwaeielky.foIrndsiivgindsoufaltobxoidcyitwyeiagnhdtfaonrd food consumption samples were wceorlleercteecdordduerdinwgeethkelyprdeutresitngpetrhieopdraetnedstatan1datnrde3atmmoenntthpseorifotdsh.e Blood study and for urine ahenmdasthoilpopgeyd atondthcelisnpiocanlsocrhefmoirsatnraylyasinsd.urOirnaglaynssisa.nAdttiwsesueeks 1f3r,omthaensiemraulsm tshaamtpwleersewsearceriffrioczeednat ethxeaemnidnoefdtfhoregsrtousdsypaantdhoflroogmytawnod fseammaplleesstthaaktedniefdordhuirsitnogpatthheoltorgeya.tmHeintstpoepraitohdolwoegryewwaesighed, pgreorufposr:mebdraoinn wtihtehfocelrlvoiwcianlgcoorrgda,nlsufmrboamr rsaptisnaflrcoomrdt,hepceornitprhoelr,al10n0e,rv3e0,0e,yaesn,dp1it0u0i0tapryp,mthdyorsoeid nwoidteh,patrhaytmhuysr,oibdo,naedrweintahlsm,alrurnog,w h(esatretrwnuimt)h,csoarloinvaarryy gvleasnsdel,ss,maaolrltai,ntsepslteienne,s m(edsueondteerniucm,lymph jsekjiunn(umm,amimlaeurmy) gcloalnodn),,paannycrteiasss,uelsiv)erw,iktihdgnreoysss, luersiinoanrsy. bLliavdedresr,frtoesmtersa,tsovfarroiems,thpero1s0taatne,du3t0e-rupsp,m dose groups were frozen andsentto atlhseosepxoanmsionrefdormaincarloyssciosp.ically and liver samples from all dose groups were TOhneesefedmeaaltehsinwtehree1n0o0t canodnsoinedefretmeoadlebeintrtehaet3me0n0t-rpeplamtegdr.ouAplldioetdhedrurainnigmaclosllseucrtviiovneodfubnltoiold. scheduled sacrifice. vTshe4r6e6gwasinathseigcnoinftircoalntgrreoduupc)t.ioFnoiondmceoannsubmopdtyiowneiwgahstriendmuacleedsiinnmtahlee1s0i0n0t-hpep1m00g,ro3u0p0(a3nd6.2 & 1000-ppm groups, but the differences were not statistically significant. eMrayltehsroicnyttehse a3t0,th1e0e0,nd3o0f0tahnedt1r0ea0t0m-epnptmpegrriooud.psThhaedvsailguneifsiwcaenrtely7r.9e5d,uc7.e0d5,nu7m.b16e,r6s.o72f, and 6.94. vianltuheescconotmrpoal,re3d0,to10t0h,e 3c0on0taronlds 1i0n 0al0l-dpopsme ggrroouuppss,, rbeustpewcetriveelsyt.atiMstailcealslyhsaidgnriefdiucacnetdaltetuhkeoc3y0t0e ppm group only; 30, 100, 300 and leukocyte 1000 ppm vgarlouuepss,werersepe1c0t.i6v4e,ly8..88A, s9i.m3i3l,a9r.p35h,en7.o6m3e,naonnd w8a.0s6sienetnhweictohntrol, 10, dhoesmeogllevoeblionnlvya.lueHse,mwohgilcohbiwenrvealrueedsucweedreat1a6l.l2d,o1s4e.7l,ev1e5l.s0,bu1t5.w4e,r1e4.s9i,gn1i3f.i1ciannttahtetchoent1r0o-l,pp1m0, 30, h1e0m0,at3o0l0ogaincdal1p0a0r0ampeptmergsrooufpfse,marelsepercattisvienlyt.heTshteurdye.was no similar effect upon the wMhailcehs waterthees3ta0t,is1t0i0c,al3ly00s,igannidfic1a0n0t0a-tpapllmbduotstehele1ve0l0s-hpapdmidnocsreealseevedl.glRuecpoosretleedvegllsu(comsge/1le0v0elmsl.), were 121,120, 136, 134, 143 and 135mg/100 mlforthe0, 10, 30 100, 300 and 1000 ppm Wo 000053 lgervoeulpss;,mreesapnecvtailvueleys.atB9.0UdNa.yslewveerlesw2e0r.4e,e2l3e.v9a-taenddi3n5m.1almegs/a1t0t0hemi10f0o,r3t0h0e,tahrnede1d0o0s0e pgrpomupdso,se. riensmpaeclteisveilny,thceo1m0p0a,r3e0d0,toan1d6.210m0g0/-1p0p0mmglrfoourpts;hethceonltervoellss. weArleka1l4i7n,e 2p0ho4sapnhdat2a1s2e IwaUs eflorevtahteed cthhraenegegrsoiunpsb,iorcehspeemcitciavlelmye,acsoumrpeamrenetdst.o 104 IU/L for the controls. Females showed no similar aNelitthhoeurghmafleemsalneosrffreommalalelsgsrhoouwpsedshanoywetdreaathmiegnhterreflraetqeduecnhcayongfesocicnuulrtibnalloyosdisinpathreamuertienresthan did males, `aTnhiemaolnslyhgardoesnslnaercgreodplsiyveorbsstehravtastihoonwewdasvanroytiendgidnemgarleeessoaftstuhrefa1c0e00d-ispcpomlodroastieonle.vNele.itThheerse females from such effects. the 1000-ppm dose level nor males or females from the lower dos levels showed B1o0t0h0-apbspomlugtreouapnsd arneldatiinvoenleivfeermwaelieghitnsthweer1e00si0g-npifpimcagnrtoluyp.inCcormeapsoeudndin-rmeallaetseidn ltihveer30l,es3i0on0sand tooccmuurlrtiefdocianla,llvmearyleslriaghst-itnot-shleig1h0t0,hy3p0e0rtarnodph1y0o0f0-hpeppamtogcroyutpess. inThceensterilleosbiuolnasrctoonsmiisdtzeodonafl focal riengciroenassoedftahmeouanftfeocftedyellilveorwilosbhu-lebsr.ownInpsigommeentinrsteasnecmebslithnegsleiploefsuiosncsinwienrethaecccyotmoppalnaisemdobfy an wheapsatmoocryetepsraonndouonccceadsiaonmaolnlygimnaslienursatosidaatltlhieni1n0g0c0el-lps.pmThdieetianrcyidleevnecle.and severityofthe lesions `oAbsceormvpeadriisnotnhoefmatlheessethraunmilnevtehlesfoefmaPlFesOAis idsusehtoowtnhebeglenodweirndTiafbfleere4n.ceTihneelgirmeiatneartitoonxiacsity demonstrated by the differences in serum PFOA levels. `Table 4. Comparison of Male and Female PFOA Serum Levels Dose PFOA in Serum (ppm) 0 Male0s 10 21 30 34 100 36 300 38 1000 49 Fema0les ND 01s ND 025 0.65 ND = Not Determined. Ignrotuhpe,sdeocsoensdorfat1,st1u0d,y,30P,aolraz1z0o0lop(p1m99(3a)ppardomxiinmisatteermeeda4n5-c5o5mmpaoluenSdpcroangsuuem-pDtaiwolneyatrwatesepker13 of 0 000054 `0g.r0o5u,p0s,(4a7,no1n.p4a4,ira-nfded4.co9n7tmrgol/kggr/oduapy)anAdPaFcOoantdrolligbirtouumpipnaitrh-efdeidettofothre1310w0eepkps.m dTowseogcroonutpr)ol w`gerroeupawlseoreexfpeodsbeadsadlurdiinetgftohraatnpeardidoidt.ioFnoalll8o-wwienegktshepo1s3t--twreeeaktmeexnptosaunrdeopbesreirovde,d1f0oraanniymaslisgnpesrof rAlelcoavneirmya.lsAlwletreestodbiseetrsvweedrtewaicsesadyaeidlyanfodremvoarltuaalitteyd,fmoorrtiebsutnmdaitteyr,iaalnhdogmeongeernaleictlyinaicnadl sstiagbinlsitoy.f pteoxriicoidt,y.anBdotdhyenweoinghthtes dwaeyreofrneeccorrodpesdy.oncFeoobdefcoroenseuxmppotsiuorneswbaesgarne,cowredeekdlwyedeukrliyngfotrhaelltrgeraotumpesn,t tihneclaundiimnagltshreentoanipnaeidrf-ofredthceorntercoolvegrryoupphsasdeaoilfytfhoer tsthuedyp.airA-fetdotaalnoifm1al5s,aannidmatlhsenpewregerkoluypfworeralel of swaecerkifsoicfedtrfeoaltlmoewnitnga4n,d7f,oolrlo1w3inwgee8kwseoeftkrsoeaftmneonn-tt;re1a0tmaennitm.alsSepreurmgrsoaumpplweesrceoslalcercitfeidcefdroafmte1r013 adunriimnaglsrepceorvgerroyuwpeartecaancahlsyzcehdedfuolreedstsraacdriiofli,cetodtuarlitnegsttorsetaetrmoenen,t aluntdeifnriozimng$ haonrimmaolnsesp,erangdrofuopr test mwaatserainaallryezseiddufer.omThaeselcetvieolnofopfallimviertotyha!tCwaos oobxtiadianseed, afnroimnd5icaantiomroalfsppeerroxgriosuopmeatpreoalcihferation, swecihgehdeudl:edbrsaacirni,filcieve.r,Tlhuengfso,ltleoswtiisng(oonreg)a,nssemfirnoamlalvlesaincilem,alpsroasttaetaec,hcosacghueldautliendgsgalcarnidfi,caenwdere fuorertmharlai.n Tahned efxolalmoiwniendgtimsascureossiconpitchaelsleys:aemxetearnnialmaslusrfwaecreoefptrheseerbvoeddy,inll10or%ifpicheoss,pthhaetec-rbaunifaflered ctahveitthyo,rtahceice,xatbedmoamlinsaurlf,aacensdofpetlhveicbcraaviintiaensdasnpdinvailscceorrad;,atnhde nalassoalecxaavmiitnyeadndmipcarroasncaospailcaslilnyu:seasn;y oabnsdeurrveetdhrlae.siIonnsa,ddbirtaiionn,,litvheer,folulnlgosw,intgesttiesss(uoensew),erseempirneaslervveesdicilne,gplruotsatraatle,dechoyadgeulfaortienlgecgtlraonnd, microscopic examination: brain, liver, lungs, testes (one), seminal vesicle, and prostate. cInomthpearaenadlytositsohefctohnetrdoaltaa,niamnailmsalisn itnhegrnoonuppasierx-fpeodsegdrotuop,1,w1h0i,le30t,haenddat1a0f0rpopmmthAePpaFiOr-fweedre ccoonntsriodleraendimtaolbsewheormeocgoemnpeaoruesd atnodanstiamballesuenxdpeorstehde (e0x1p0e0ripmpenmtaAlPcFoOn.ditAilonlst.estAldlieatnsiwmearles sthuartviwvaesdstaocrsicfhiecdeudloend wsaecerikfi4ced,uweittohstehveeerxecneepctkiosnoorefsonuenrealnaitmeadltionttrheeat1m0en0t-.ppTmwidcoes-edda-iglryoup ewxeaimgihntastwieornes osfeaelnlcaonmipmaarlesdwetorethuenpraeimra-rfkeadblceon.troAltg1r0o0upppdmur,isniggnwiefeickan1tarneddutchteionnosnpianibro-fdeyd croendturcotliognrsouinpbdoudryinwgewigehetksswIe-r1e3 a(pipca.retnht.roBuoghdoyutwetriegahttmendta)t.a iDnutrhienogtrheecrodvoersye,d-hgorwoeuvpesr,wenroe cpaoimrp-afredabcloenttroolcognrtrooulps.duArting10w0epepkm,1 amnedasnigbnoidfiycawnetilgyhltogwaeirnsthwaenrtehesingonnipfiaciarn-tfleydhciognhterrolthgarnouthpe dtuherinnognpwaeierk-fsed1-c1o3n.trAotl 1g0roaunpda3t 0wepepkm,2.meTahnesbeoddiyffweeriegnhctesgaininbsowdeyrweesiigghntifgiaciannstlwyelroewenortthan o21bs1a0r0vepdpdmurdiunrigntghewereekcosve1raynpder2ioodn.ly,Siwghniefniccaonmtpdairffeedretnoctehseinnofnopoadirc-ofnesducmopnttiroolngwreoruep;obnsoerved oditfhfeerrseingcneisfiacmanotndgiftfheergerncoeuspsinfofrooadnycoofnstuhmephtoiromnowneerseenvoatleuda.teTdheinrethweesreerunmo. siLginkiefwiciasnet, serum st 000055 atrneaaltymseinsto.f tSetsattimsattiecarlilaylsriegsniidfuiecasnthohwigehdernoheipnactriecaspealimnistoeyrlumCAoAPFoOxildeavseelsacotvievirttyhweacsouorbsseerovfed apter3i0oda.ndAt10100 ppppmm;, hstoawteivsteirc,alltyhissiegfniffeiccarnetthuimgehdertolecvoenltsroolfhleepvaetliscbypatlhmeiteonydloCftohAe orxeicdoasvee.ry activity animais were observed exposed to 10, at week 30, and 510o0nlpy.pm.MeSaingneifnizcyanmteiancctrievaisteiessiwnearbesohliugtheesatnddurreilnagtiwveeelikver for w1e0i0g0htpspamngdrhoeuppast.ocTehlleulaaurthhoyrpsesrutgrgoepshtyewdetrheaotbhseesrevcehdaantgweesemkisgh4,t7b,eoarss13ociinattehdew1i0t,h30 and pweerroexailssoomoebpsreorlviefedraattitohni,sedsopseecilaelvleylsdiunrcienigntcrreeaatsmeesnti.n hDeupartiincgpraelcmoivteoryyl,ChoowAevoexri,dansoenaectoifvitthye liver effects were observed, indicating that these treatment-related liver effects were reversible. TLhOerAeEfoLroef, u1n0deprptmhe(0c.o4n7dimtgi/okngs/odfatyh)isarsetuidnyd,icaatNeOd AbaEsLedoonfre1.d0upcptmio(n0s.0i5nmbgo/dkyg/wdeaiyg)htanadndabody hwyepiegrhttrogpahiyn., and on increases in absolute and relative liver weights with hepatocellular `cTyhnoommfoolrgdu(s2m00o1nak,eby)sr.ecIennttlhye croanndgue-cftienddianrgasntgued-yf,inTdhionmgfaonrdda(62-0m0o1an)thadtmoixniciisttyersetdudmyailne cThyenroemowlegrues3mmoonnkkeeyyssainnotrhael 2caapnsdul2e0cmogn/takign/idnagy0g,r2o,uoprs2a0ndmgo/nkeg/mdoanykAeyPFinOthfeorc4onwteroelksg.roup. `fTohremomrotnaklietyysawnedimgohreidbu2.n1ditt0y3a.6nkdegwaetretheexsatmairtnoefdtartealtemasetnto.ncAenidmaiallysfworerseigonbsosefrvpeodortwhiecaeltdhaiolry abnormal behavior. Food consumption was assessed qualitatively. Body weight data were recorded before the startoftreatment, on day Ioftreatment and weekly thercafier. The mthoenskteuydsy waenrdeonfadstaeyd3o0vefronricglhitniacnaldhbelmoaotdoslaomgpyleasndweclrieniccoalllecchteemdisotnreywaenaelkyspersi,oratondthhoersmtaornteof `(aanpdpProFxOimAatleevleyl.24Bhloouordsfaofrtecrlitnhiecafliscthedmosies)t.rySwaamsplaelssowceorleleacntaeldyfzreodmfeoarcehstarandiimoall, eosntrdoanye,2 estriol, thyroid stimulating hormone, total and free triiodothyronine, and fotal and free thyroxin. aAnuismcahleadnuldeadnnaelcyrzoepdsyfo,rspaamlpmlietsooy!ftChoeAriogxhitdalasteeraacltilvoibtey.oftRehperelsievnertawteirvee csoalmlpelcetseodfrliovmere,arcihght ausnidnglefptrotleistfeesr,atainodn cpealnlcnruecalsewaerraentcioglelne.ctBeidlefrwoamsecaoclhleacntiemdaflrfoomrecaeclhparnoliimfaelraftoironbielveaalcuiadtion daneatleyrsmiisn.atTihone. foA.llsoawmipnlgeotifslsiuevser(wwhaesncporlelseecntte)d ofrrroempreeascehntaantiimvaelsfaomrpPleFsOwAerceonccoelnltercatteidoannd preserved in 10% neutral-buffered formalin, unless otherwise specified, for possible future examination: adrenal (2), aorta, brain, cecum, colon, duodenum, epididymis (2), esophagus, eyes [preserved in Davidson's fixative (2), femur with one marrow (articular surfaceofthe distal end), gallbladder, heart, ileum, jejunum, kidaey (2), lesions, liver, hig, lymph node (mesenteric) mammary gland, muscle (thigh), pancreas, pituitary, prostate, rectum, salivary gland [mandibular (s2t)e,rnsucmiatwiicthnebroven,esmeamrirnoawl,vesstiocmlaec(h2,)tseksitins, (s2pi)nalthcyomruds(,cetrhvyircoaild, (t2h)orwaictich,paanradthlyurmobiadr,),trsapclheeean,, 2 000056 aenmdbeudridneadryinblpaadrdaefrf.inT,hseecatdiroenneadl,s,stlaiivneer,d pwaintchrehaesm,atsoplxeyelni,naannddtceostseisnfarnodmeexaacmhinaneidmal were `microscopically. Atrlelaatendimgarlosupssuravnidvetdhetroe swcahsednuoleedffseacctriofinceb.odTyheweriegwhte.reLnoowcloirnincoalfsoiogdnscoofntsouxmipctiitoyniwn atshe oobnsdearyve1d2faorndonleowanfiomoadlcgoinvseunm2p0timogn/kwga/sdanyo.teNdoonfdoaoydsco5,ns7u,m1p1t,i1o4n 1w7a,sanndot2e4d,froersptehcitsiavenliym.al FTohretrheiswaenriemanlo,edfefeccrtesaosendefstoroaddicool,nseustmrpiotli,otnhyisroiindasltilmiuklealtiihnogodhorerlmaotnede,totoAtaPlFaOndadfmrieneistration. t2raiinoddo2t0hymrgo/nkinge/,daayndAtPoFtaOl.anTdhferreeewtahsyrnooxine.viEdsetnrcoenoeflpeevreolsxiwseormeenoprtoalbilfyerlaotwieonr foorrcemlalles given periotlhiefregrraotisosnorinctlhienicliavlerp,attehsotleosgoyrsptaundicerse.asoftreated monkeys. No adverse effects were noted in dIonstehse o2f6-we0,3e, k10sotrudy3,0mmagl/ekgc/ydnaoymoflorgu2s6 mwoenekksey(sThwoemrfeoradd,mi2n0i0s1tebr;eBduAtPenFhOofbfyetorala.l,c2a0p0s2u)l.e aAtt s`gtruoduypiannidtia6timoonntkheeymsoninkecyacshowefitghheedot3h.e2rtgoro4u.p5s.ke.DoTshienrgeowf anei4mamlrosnikneeythse i3n0tmhge/3kgm/gd/akyg/ddoasye `agnriomuaplwsarsecsetiovpepde2d0fmrgo/mkdga/ydsay1a1n-2d1tbhiescagursoeuopfwtaoxsidceistiyg.nWatheedntdheos3i0n/g20wamsg/rkegs/udmaeydgornoudpa.y A22t, the endof the observed for a 2163--wweeeekktrreecaotvmeernyt ppeerriioodd., 2 animals in the control and 10 mg/kg/day groups were Aonnciemadlasilwyefroer soibgsnesrovfepdotowricheeadlatihlyofroarbmnoorrtamlailtybeahnadvimoorr,ifbouonddictoynasnudmpwteiroenewxaasmiasnseedssaetdleast qualitatively. weeks 26 and Ophthalmic examinations were done 40. Body weight data were recorded before initiation of treatment and during weekly before the start oftreatment, on day 1 ofhetmraetaotlmoegnyt, aclnidniwceaelkclhyemtihsetrreayf,tearn.d Burlionoadlyasnidsubreifnoerestahmepslteasrtowfetrreecaotlmleenctteadnfdorocnlidnaiycsal11, 31, 6s3a,m9p1l,es1w82e,re21a7n,al2y4z5edanfdor27es5t.raBdiloolo,desstarmonpel,eseswtreiroel,atlhsyorotiadkesntifmourlhatoirnmgohnoermdeotneer,mitnoatatlioannsd; free tdruiriiondgotwheyerokni2nea,ndtoetavleraynd2wfreeeektshytrhoexriena,ftaenrddtuersitnogstterreoantem.enBtloaondd,ruercionveerayndfofrecPeFsOwAere collected concentration analyses. The animals were not fasted before collections. Alattesrcalheldoubleeodfntehcerolpivseyr,wlaisvercoslalmepclteeds fwreorme etaackhenanfoirmadletfeorrmpianlamtiitoonyo]fCPoFAOoAxildevaesles.actTihveitryight afnraolmysceasc,haanndirmeaplrefsoernctealtlipvreosliafmeprlaetisoonfevliavleura,triiognhtusainndglpertoltiefsetresa,tiaonndceplalnncurcelaesarwearnteicgoelnl.ecAtleld asvcahieldaublleedbialnedwuansscchoelldeuclteeddsfaocrribfiilceeas;cipdaidreetderomrignaantsiowne.reThweeifgohlelodwsienpgeroartgealyn:s waedrreenawlei(2g)h,ebdraaitn, ebpoiddyidwyemiigsht(2p)e,rkciednnteayge(s2)a,nldivoerr,gapnantcorebarsa,intwesetiigh(t2),raatniodstwheyrroeicdal(c2u)lawtietdh. paTrhatehyfroolildo.wiOnrggtainsstuoes 5 000057 ewpeirdeicdoylmliesct(e2d),feosrohpihsatgoupsa,theoyleosgy[:praedsreernvaeld(i2n),Daavoritdas,obnr'asinf,ixcaetciuvem,(2c)o],lofne,mduurowdietnhubmo,ne marrow l(aurntgi,cumleasresnutrefraicceolfytmhpehdinsotdael, emnad)m,mgaarllyblgaldadnedr,,phaenacrrte,aisl,epuimt,uijteajruy,nupmr,osktiatden,eyrsec(t2u),m,lessailoinvsa,ryliver, oglradnd(c[emravnidcailb,ulthaorra(c2i)c,,sacnidatilcumnbearrv)e,, sspelmeienna,lsvteesrinculem (w2i)t,hskbeolneetamlamrursocwl,e s(tthoimgahc)h,,sktiens,tssp(i(n2a)l preserved in Bouin's solution, thymus, thyroid (2) with parathyroid, trachea and urinary bladder. mTgw/okga/ndimaayldso,soengermoaupl,ewferroemstahceri3f0i/c2e0d ming/mkogr/idbauynddocsoendgirtoiuopn daunrdiongnethmealsteudfyr.oTmhtehem3ale in the h3y0p2oa0ctmigv/iktyg,/dwaeyigdhotselogsr,oufpewwaorsnsoacfreicfeisc,edloonw odrayno29f.ooTdhicsonasnuimmpaltieoxnhiabnidtetdhesiegnntsiroefbody was ionlddica10titvheeoftoaunchinbjeufroyrethdaetaotch.curNreecdrodpursiynrgedvoesailnegd easnodplhiavgeerallesainodnsgatshtartiwcelreesipornsestuhamtewdetroebe treatment related. The animal showed clinical animal from the signsoflimited 3usmega/nkdg/pdaaraylydsoisseofgrtohuephwiands lsiamcbrsif,iacteadxoina adnady 137. This dheytpeoramcitnievde,bbeuhtavAioPrF,Ofetwrefaetcmeesntancdounlodfnoootdbceornusluemdptouito.n. The causeofdeath was not cMoanlseusmgpitvieonn3a0ndmgt/hkegy/ldoastywferiogmhtdadyusriIn-g11weheakd c1olifnticraelatsimgennsto.ffBeawsedfeocnestahensdelsoiwgnsf,ootdreatment dwoasseswtaosppleodwoenreddayto1210amngd/kwga/sdanyo;t rtheissugmreodupunwiialsdtahye2n2.desWihgneantetdrethaetm3e0n/t2w0amsgr/eksgu/mdeady,gtrohuep. wOefetkhseorfetmraeiantimnengta.niTmraelastimnehnitosfgtrhoruep,e monallyes2gtiovleernat3e0d/2th0ismgd/oksge/ldeavyelwfaosr hthaeltreedmoanindianygs2433 t(hwieneakpp7)e,ar6a6nc(ew,eefkew10o)r,naondfe8c1es(,wleoewko1r2n)orefsopoedctciovnelsyu.mpCtliionni,caalnsdigwnesiginhtthleossse. anTihmealasniimnacllsuded appeared to recover from compound-related effects within 3 weeks after cessationoftreatment. mMge/akng/bdoady.y wDeuirgihntgcwheanegke2s,wtehirsecnhoatnagbelywlaoswsetratdiusrtiicnagllwyeseikgnsif1icaanndt.2Tfroeramtamleenstrweacseisvtinogpp3e0d on sdiagyni1f1icaanntdlywhloewnerittwhaasn rcoensturmoeldsadtur2i0ngmgw/ekegk/sda7,y9onandday242.1,Omveeraanllbmoedaynwebiogdhytwcehiagnhgteschwaenrgees tihnrcroeuagshedweienckid2e7nwceeroefnlootwabolrynloofwoeordfcorontsheummpatlieosnifnotrhaen3i0m/e20s ming/tkheg/3d0a/y20grmogu/p.kg/Tdhaeyregrwoausp.an that was considered to be treatment related. sTthiemruelawteirneg hnoorcmoonnseis,toenrtteosrtcolsetaerrloynedotshea-trweelarteedseeefnfeicntsaonny tersetraotnmee,ntesgtrraoduipolo,veesrtrtiiomle,.thyInroid m`gge/nekrga/l,datyhygrrooiudphs.orTmroinieosdowtehryerodneicnreeraesmedaibneegdindneipnrgesosneddatyhr3o5ugihn danaiyma1l8s3 iinn tthhee 3100/o2r03m0g//2k0g mgrgo/ukpg. ATPoFtaOl.thTyhreoxeifnfewcatsodnetchryeraosxeidnbweagsinmnoisntgpornodnaoyun3c5edinaatndiamyal3s3aidnmianniismtaelrseaddm1i0noirst3e0r/e2d0 10 mg/kg/day and day 66 in animals administered 30/20 mg/kg/day. Thereafter, the effect began El 000058 0recdoivmeirnyisphhaasnedorfetchoeveerxypewraismeonbts.erNvoedcehiatnhegresininthceholalsetc3ysmtooknitnhisnocfodnocsenitnrgatoirodnusrwienrgethseeen over time in either dose group. Ttrweoatmmeanlteswafsrosmtotphpee3d0b/e2c0amugs/eokgf/pdoaoyrghreoaulpt,h,thheaodnmeodsaecrraitfeicteod moanrdkaeyd2i9ncarnedasoendesfeorruwmheonmzyme cdoenhcyednrtorgaetniaosnes,(iacn.dacsrpeaarttiantee kaimniansoet)raannsdfearamsiel,dlaylainnicnreeaasmeidnosterraunsmfbeirlaesea,cisdorcbointcoelntration. At 3de0c/r2e0asmegskgin/daabsyo,luttheerneeuwterroephsilligchotuinntc,rteoatsaelspirnotteriinglcyocnecreindtercaotnicoenntarnadtiaolnbsuamnidn mcoinlcdenttoramtoidoenr.ate `miTlwdolayniinmcarlesasiendthseer3u0m/2b0ilmega/ckigd/cdoanycegnrtoruatpihonasd.maArtke3dmlgy/ikngc/rdeaasyeodrs1e0rummg/ekngz/ydamye,aActPivFitOiehsaadnd nofopeerffseicsttsenotnohredmealtaoyleodgyt,oxciocagefufleacttisono,ncclliinniiccaallcphaetmhiosltoryg,y otersturriensaullytsissd.urTihnegrtehewarsecnooveervyipdeernicode. Aretlatteirvmeinliavlersawceriigfhictesaitn2a6llwdeoeskes,grtohueprse.weTrheesatbatsiosltuitcealllyivseirgwniefiigcahnst wiencrreeaisnecsreiansaebdsbolyut35e,a3n8d ainncdre5a0se%dibnyth2e0,3,2010anadnd6300%/2i0n mtghe/k3g,/1d0ayangdro3u0p/s2,0rmegsp/ekcgt/idvealyy;grroeulpatsi,vreelsipveecrtiwveeilgy.htsInwearddeition, minecarnealsievderl-itvoe-rbwreaiinghwtesigwhetrewacsonssiigdneirfiecdanttrleyatimnecnrtearseeladteidn. thTehe10rmegw/ekrge/ndoaytrgeraotumpe.nt-Trheelated madarcernoasl,cosppilceeonr,mpiacnrcoresacso,piacndchtaesntgies.s iWnhialney tohregraenwsaast tnhoe etveirmdiennaclesoafecrnihfiacne,ceindclceuldlinpgrolliivfeer,ration iwnastheevtiedsetensceoorfpamnictroecahsoonfdrtihael tprreoaltiefdermaotniokneyins,thtehelifvienrsdoifngtsrienatthede mloivnekrewyesre(eBquutievonciaol.feftTahle,re 2002), Aabtstohleutreeocrovreerlyatsiavceriofrigcaen, twheeirgehwtseare nreocorveaetrmyesnatc-rrieflicaeteidndeifcfaetcitnsgotnhattertmhienlailvebrowdeyigwhetigchhtasnogreson seen at terminal sacrifice were reversible over time. There were no treatment.related macroscopic or microscopic changes at the recovery sacrifice. "5T-h8e, rreesspuelcttiofvtehlye(a3nMalyEsnevsiroofnPmeFnOtAaliLnatbhoerasteorruym,,2l0i0ve1r6,)u.riLnoewanldevfeelcsesofarPeFpOrAesewnetreed oifntTeanbles dweetreectseidgniinfitchaentsleyrah,ilgihveerr,tuhrainnethaonsde fseeceensoinftthheeccoonnttrroolls.anIinmaglesn.eraTlh,ePlFeOveAlslienvetlrseaitnetdhaensiemraalosf ttersetatamneinmta,lsthienscererausmedlewvietlhs wdeosree b1u2t6dec3r6e.a1sepdgo/vmeLritnimtheed3urmign/gktgr/edaatymegntr,ouOpnadnady1959o7f2392 nngg//mmLL iinn tthhee 330m/g2/0kmgg//dkagy/gdraoyugpraonupd,5a1n.5d du7r7i.n6guwge/ekmsl 2i6n/t2h7e,3t0h/e2s0emrgu/mklge/vdealsywgerrouep5.2.P5F+O9A.14 Ttehveel1s0 imngs/ekrg/udmadyecgrreoauspedasovceormptairmeeddutroi0n.g0r7e3c8o+ve0r.y0u0n2t5il6tihnetyhreecaocnhterdol1s.d1u8r+in0g.w82e7ekpg40/.ml in A similar trend was seen in the urine. On day 9, the levels in the urine were 73.5 38.1, 221 & ss 000059 w12e4e,ka2n6d,9th0e9l+ev2e0l9s wge/rme L5i1.n6t=he133.,7,101a0n9d+3705/.220, magn/dk1g9/.d2a+y 2g7r.o0upusg,/rge,spreecstpievcetliyv,ealyn,dinduthreisneg sthaemceongtrrouoplsa.nimDaulrsi,nagnwde7e.k432,%th6e.5l4e,ve1l5s.4in=th1e0.f2ecaensdw5e6r.e6 l+es7s3t.h7aungt/hgeilnitmhieto3f, q1u0a,natnitdat3i0o/n20in mg2/0k.g8/dgayggrinoutphse,3r,e1s0p,ecatnivdel3y0;/2d0urmign/gkwg/edeaky2g6rotuhpesl,evreelsspewcteirveel2y..92Th1e.r3e5,is4n3o.0e%xp3l6a.n9atainodn 10.3 for trheecohviegrhylpeevreilosdo,fPPFFOOAA lesveeelnsiinntbhoethfeucreisonfetahned fceocnetsroflelalntiomlaelvseldsurtihnatgwweereekc2o2m.paDruarbilnegttohe control levels. Under the mortality) caonnddiatNioOnsAoEfLthweasstundoyt,etshteabLliOsAheEd.L was 3 mg/kg/day (liver toxicity and possibly 56 000060 Table 5 Average PFOA Concentrations in the Serum (ng/mL)ofTreated = Animals [imepom -- [Week12 10.123 00507[7962259 [9062245 [1402775 | [Week2a T<100___"[0T 097 %2120 2[e:276 27483 8| [Week30 To1s200238[NS [Week32 T0.1i0200216[NS [1i3esi [Ns [760390 [ns | | REE ee 0.0256 : 0.0324 0.00256 standard fortified deviation associated with that sample recovery. The average group. Data are fortified sample accurate recovery to within was 94% one SDofthe average with an SD of 11%. . a 000061 Table 6 Average PFOA Concentrations in the Liver (ug/g) ofTreated Animals 0 mg/kg/day 3 mg/kg/day 10 mg/kg/day | m30g//2k0g/day 0.117%0.0730. 0.114%0.0441 RLeOsuQlt=s aLriemietxopfreQsusaendtiatsatgiroonu;pNaSve=raNgoesS+amtphelestandard deviation associated with that group. Dfoarttaifaierdesaaccmuprlaetere0cowvietrhyinwaosne9S0D%owfitthheanavSeDraogfe 2fo6r%t.ified sample recovery. The average ss 000062 ee [Week2 [Weeks Week 8 frWeek 10 rG e lJr prJe Week 12 T<100 ___ [75e31 1015220337 [5492462 [oidJo0os3e0 [1902916 [40161 | | 0.0587 = 128+ 50.0 272% 140 0.0716 00161 = 180109 0.0177% 175923 359%449 0.014] 488188 20192.7 Hg111 0.0299 + 5022210 139%57.0 502679 [re pJ r aen 0.00688 00.0265 [Week3s--T<100 INS Toi2i=00305[Ns | 0.00841 0.0166 LOQ = Limit ofQuantitation; NS = No Sample; Results are expressed as group averages = the `standard deviation associated with that group. Data are accurate to within one SDofthe average . CL 000063 Average PFOA ConcentrationsTainbltehe3Feces (ug/g) ofTreated Animals Omgkgday |3mgkgday | 10 mgkgday [3020 mg/kg/day [TimePoint-- ------------------------------------ A Week 4 F00214S 1045120 [242106 [2202623 000192 [Week18 00894 00762 [025820654 [5722715 [1732133 [22i+317 | 000892 Weeks 36-40 [00..000160384= 0000331336 + NS R'eTsOuQlt--s aLriemietxporfeQsusaendtiatsatgiroonu;pNaSve=raNgeosSamthpelestandard deviation associated with that group. Dfoarttaifairede saaccmuprlaeteretcoowvietrhyinwaosne1S17Do%fwitthhe aavneSraDgoeff2or2t%if.ied sample recovery. The average 3.6 Developmental Toxicity Studies in Animals "wThoreoeraplresntautdailesd.evelopmental toxicity studies ofAPFO have been conducted, one inhalation and "oTnhethfeirrstesoufltthsoefseasrtaundgiees-fwiansdianng sotruadlyd,eavneluopppmeerntdaolsetolxeivceiltyofst1u5d0ymign/rkagts/d(aGoyrwtnaesr,st198o1r).theBased d0e,f0i0ni5t,iv1e.5s,tu5,dyanindw1h5i0chmgf/ikvge/gdraoyupAsoPfFO22intidimset-ilmlaetdewdaStperrabgyueg-avDaagweleoynrgaesstwaetiroenaddamyisni(sGtDer)e6dc1l5.iniDcaolsses iweorfgetaodnxjiucissttye.d aIcncdoirvdidiunagltboobdoydywewiegihgthst.weDraemrsecwoerrdeedmoonniGtoDre3d, o6,n9,GD12,3-1250,afnodr20. 000064 AwenriemaelxsamwienreedsafcorritfhiecenduomnbeGrDof2c0obrypocrearvliuctaela,dinsulmocbaetrioonfvainadbtlheeaonvdarnioens-,vuitaebril,eafnedtucsoens,tennutmsber osufbrjeescotrepdtitoonesxitteesm,aalngdronsusmnbeecrroofpismy.plaAnptpartoixoinmasitteels.y Foneet-utsheisrdweorftehweeifegthuesdesawnedrseexfiexdedanidn rBeomuaiinn'sinsgolfuettiuosnesawnedreexasumbijneecdtefdortovisskceelreatlalaebxnoarmmianlaittiioens ubsyinfgreael-ihzaarnidnsreecd.tioning. The wSeiiggnshtosfomnatGerDna9l, t1o2x,icaintdy c1o5nastisttheedohifgsht-atdiossteicgarloluypsiogfni1f5i0camngt/rkegd/udcatyi.onsMeinamnemaantemrantaelrnbaoldybody wsteaitgishtticoanllyGsDig2ni0ficcoanntt.inuOetdhetro sriegmnasionflmoawteerrntahlantocxoinctirtoylst,haatlotchocuugrhretdheondliyffaetrtehnecehiwgahs-dnooste gArdomiunpiisntcrlautdieodnoaftaAxiPaFaOnddudreiantgh giensttharteieonradtiddanmost. apNpoeaorthteoraeffffeecctttshweeorvearrieepsorotredr.eproductive t1r5a0ctmogf/kthge/ddaamys.forUmnadteermathletcooxnidciittyiownesoreftinhdeicsattueddy., a NOAEL of mg/kg/day and a LOAEL of Adosseiggnirfoiucpanotfly1h5i0ghmegr/kign/cdiadye;ncheoiwnefveetrustehsiswisktehloetnael mviarsisaitnigonstaelrsnoeobcraccurwraesd oinbstehrevceodntartotlhseahnidghtthheeroetfhoerretwharseendootsceongsriodueprsed(attosbimeiltarreaitnmecnitd-ernecleatbeudt.loNwoerstihganinfitchaenthidigfhf-edroesnecegsrobuept)waenedn treated annudmbceonrtorfolmaglroeuspasnwderfeemnaloetse,d oftoarlotahnedrddeeavdelfoeptumseenst,atlhepamreaamnetnerusmbtehartoifnrcelsuodrepdttihoen msietaesn, diemspclraintbaetdiaosnasivtaers,iectoyorpfoarbanlourtemaaalnmdomrephaonlofgetiucsalwecihgahntsg.esLilkoecwailiszee,datofetthael laerneasoffitndhiengeminbirtyiaolnlyal `tnhuecrleefuosr,ewnaost claotnesriddeetreerdmtionebde ttorebaetmaennta-rrteilfaetcteodf.thUnedferreet-hehacnodndsietcitoinosnoinfgttheechstnuidqyu,eaanNdOAEL for developmental toxicity of 150 mg/kg/day (highest dose group) was indicated. ABasseecdoonnd otrhaelrepsruelntastaolfadervaenlgoep-mfeinndtianlgtsotxuidciyt,yasntuudpypewrasdocsoenldeuvcetloedfi5n0rmabgb/iktgs/(dGaoyrtwnears,s1e9t82f)o.r tahdemidneifsitnietrievde0s,tu1.d5y,i5n,wahnidc5h0fmogur/kggr/oduapys oAfP1F8OpriengdniastnitllNeed wwaZteearlbayndgaWvhaigteeornabgbeisttsawtieornedays (piGtDui)ta6r-y18l.utePnriezginnganhcoyrmwoanseesitnaobrldiesrhetdoiinnedaucche osveuxluaatliloyn,maftoulrleowfeedmablyeabrtyifii.vc.ialinijnescetimoinnaotfion awsitdha0y.05 moflogefsptaotoiolne.d sAemcoennstcaonltledcotseed fvroolmummealoefr|abmbli/tks;gtwhaesdaadymoifniisntseermedi.natIinodnivwiadusaldebsoigdnyated w3e-i2g9hftosrwaebrneormmeaalsuclriendicoalnsGigDns.3, O6,n9,G1D2,291,5,th1e8,daonesd w29e.reTehuethdaoneiszewderaendobtsheerovveadrideasi,lyutoenruGsD aimnpdlcaonnttaetnitosn esixtaesm.inFeetdufsoerstwheerneuemxbaemrionfecdorfpororgarolsusteaab,nolirvmealaintdiedseaadndfeptluascese,driensaor3pt7ioCns and ivinsccuebraatloarnfdorskae2le4t-ahloaubrnosurrmvailviatliecsh.eckA. blPouopdswsaemrpelseubwsaesquteaknetnlyfreoumthsainxidzoecdsapnrdioerxatomidnoseidnfgorand twheerneosnenGt Dto 1th8easnpdo2n9s;orafloirvearnaslaymsipsl.e w"Tahsistiankfeonrmfartoimonthweassaumneaavnaiimlaalbsleoan tGhDe t2i9m.eoAfllthsiasmples a 000065 --e -------- ----------------o aa-- review. wSeiiggnhsotfgamianteornnaGlDto6x-i9ciwthyeconnsciosmtpeadorfedsttaoticsotnitcraolllsy;sbigondiyfiwceanitghttragnasiiennstrreetduurcnteidotnos cionnbtorodlylevels roenpGroDduc1t2i-2v9e.traAcdtmiconnitsetnrtastoifontohfeAdoPesF.ONduorcilnignigceasltaotriootnhdeirdtnroetatampepnte-arreltoataefdfescitgntshewoevraeries or froerpomratteed.rnaUlndtoexrictihteycwoansdiitnidoincsaotfedt.he study, a NOAEL of 50 mg/kg/day, the highest dose tested, Nmaolessiganinfdicfaenmtaldeisf,fedreenacdesorwleirvee nfoettuesdesb,eatnwdeefnetaclonwterioglshsa.ndLtirkeeawtiesdeg,rtohueprse fwoerrtehenonusimgbneirfiocafnt dciofnfceerpetnicoens irnecpiodretnecde,foarbtohretinounmrbateer,oofrrtehseo2rp4t-ihoonuranmdoritmaplliatnytaitnicoindesnicteeos,fctohrepofreatulsuetse.a,Gtrhoess dneevcerlooppsmyeanntdalskteolxeitcailt/yvicsocnesriaslteexdoafmianadtoisoen-srewlearteeduinnrcermeaarskeabilnea.skTelheetaolnvlayrisaitginono,fextra ribs or m1e3/kigb/,dawyi,th20st%atiastti1c.a5lmsgigkngi/fdicaayn,ceaantdt1he6 h%igaht-d0omsge ggr/oduapy)(.38A% astta5ti0stmigca/lklgy/sdiagyn,if3ic0a%ntaitn5crease isnig1n3i%ficrainbcse-osfpturhriesd oefcfceucrtrieduinncetrhteaminids-idnoceseingrbootuhp othfeShmiggh/-kga/nddayl;owh-odwoesveergr,otupes,bitohliosgeifcfaelct o`Tchceurrerfoerdea,tutnhdeesratmhee croantediatnidonwsaosftnhoet ssttautdiyst,icaaLllOy AsiEgnLiffiocrandtelvyedliofpfmereennttaflrtoomxiccointtyroofls50 mg/kg/day (highest dose group) was indicated. cSotnaspilsetseedtoafl.a(n19in8h4a)laatlisoonaconnddaucnteordaal dpeorvteiloonp,meeancthalwittohxitcwitoytsitauldsoyorfexApPerFiOm.entTsh.e sTthuedyfdiresstitgrinal wthaesstehceotnedratrtaoll,ogtyhepodratmiosnowfetrheealsltouwdye,d tino wlhitiecrhatnhdetdhaempsupwserweerseacsraicfriicfeidceodnoGnDda2y1;35w-hpiolsetin partum. For the inhalation portionofthe study, the two trials consisted of 12 pregnant SpragueD15a.wlIenythreatosrpaelrgporrotiuopnoefxtphoesesdtutdoy,0,205.1a,nd1, 1120,Sparnadg2u5e-mDga/wml'eyAPraFtsOfofrorth6ehfoiursrts/adnady,seocnonGd.D 6t6r-i1a5ls., rFeosrpebcottihverloyu,tweseorfeaaddmmiinniissttrearteidon0, afnedma1l0e0s wmge/rkegm/adtaeydAoPnaFnO ains-cnoemedoeidl bbaysigsaavnadgewohnenGtDhe ansusmibgenredo(f0mgartoeudpsfebmyalreostawtiaosn birneodn,dtehreoyfwrearnke.raFniknaeldlyw,itthion abdrdeietdoinngaldagryosubpys b(soidxyawmeisghpterand group) were added to each tial that was pair-fed to the 10 and 25 mg/m' groups F21oratnhdeotbesreartovleodgydapiolrytifoornoafbtnhoermsatludcyli(ntirciaall osingen)s,.daOmnsGwDer2e1,wetiheghdeadmosnwGerDe s1,ac6r,i9f,ice13d,b1y6, and ctheervriecparloddiuscltoicvaetisoantaunsod fexeaamchinaendimfaorl awnaysgervoaslsuaatbendo.rmaTlhietioevsa,rileisv,eruwteeriugshtasndwecroentreenctosrwdeerdeand esixteasm. inPeudpsfo(rlitvheeannudmdbeeardo)fwceorrepocoruanltuetde,a,wleiivgehaenddadnedadsefxeteudseasn,dreesxoarmpitnioendsfaonrdexitmepmlaaln,tation `veisxcaemrianl,edanfodrsvkieslceetraallaalltetreartaitoinosn.s Tashweehlelaadssmoafaclrlo-coanntdromliacnrdoshciogphi-cdoevsaelduagtrioounpoffetthuesescywees.re 000066 For trial rial one two, in which up to GD 21. tThweodadmasyswbeerfeoraelltohweeedxpteocltietedr,datyhoefppraorcteudruirteiown,aseatchhe dsaammewaassthhaotusfoerd in awneiignhdeivdidaunadlecxaagem.inTehdefodratceloinfipcaalrtsuirgintsioonnwDaasysno1t,e7d,a1n4d, daensdig2n2atPPe.dODanyD1aPyP.23DPaPmasllwedraems `wwearsessuabcsreifqiuceendt.lyPwuepisgwheerdeacnodunitnesdp,ecwteeidgfhoerda,davnedrseexcalmiininceadl sfiogrnesxotnemDaalyaslt4e,ra7t,io1n4s,.anEdac2h pPuPp. `DTahyesey2e7saonfdt3h1e pPuPpsfowretrhee aglasvoaegxeapmoirntieodnoonftDhaeysstu1d5y.anPdu1p7sPwPerfeorsatchreiifnihcaeldaotnioDnapyor3t5ioPnPanadndon examined for visceral and skeletal alterations. Inhalation Exposure "Trial One: T2r5ematgm/emn'-raenldactoendscilsitneidcoalfswiegtasoabfdmoamteensm,alchtrooximcoidtaycfroyrotrirahleao,nech(rtoemrotrohliongoy)rrohcecau,rraegdenaetr1a0l and unkempt appearance, and concentration group only). lethargyin Three out four dams at the of 12 dams died endof theexposure during treatment at period (high25 mg/m' (on GD 12, 13, and signific 17). Food ant differe consumption was nces were noted b estiwgeniefnictarnetaltyedreadnudcepadiart-fbeodtghro1u0pasn.d 25 mg/m'; Significant however, no reductions in b`ocdonycewnetiragthitonwoenrley.alsLoikoebwsiesrev,esdtaattistthiecsaellcyosnicgennitfriactainotnsi,ncwrietahsesstaitnismtiecaaln sliigvneirfwieciangchetsatwtehreehsiegehn- amtattheernhailght-oxciocnicteynotrIfatiaonndg1r0oumpg./mU'n,derrestpheectciovnedliyt,iwonesreofitnhdeicastteudd.y, a NOAEL and LOAEL for No effects were observed on the maintenanceofpregnancy o the incidenceofresorptions. Mean fetal body weights were significantly decreased in the 25-mg/m' groups and in the control `ngortourpeypeaailr-afneyd t2r5eamtgm/emnt'-.reAlatdeedtaeiflfeedctmsi;chroowsecovpeircivnistcheercaolnatrnodlegyreouepxatmhiantawtaisonpaoifrt-hfeedfe2t5uses did mwga/smo'b,saervsetadt.istUicnadlelyrstihgenicfoincdainttiionncsorfeatsheed isntcuiddye,naceNoOfAfEetLuseasndwiLthOApaErtLialfloyr odsesvieflioepdmsetnetmaelbrac toxicity of 10 and 25 mg/m', respectively, were indicated. "Trial Two: Clinical signsofmaternal toxicity seen at 10and 25 mg/m' were similar in type and incidence to tthhoasnecdonetsrcorlisb,eadlftohroutrgihaltohneed.ifMfaetreernncealwabsodnyotwestiagthisttgicaailnlydsuirginnigfitcraneta.tmeInntadadti2t5iomn,g2/omutwoafs 1l2ess dwearmesadniyedaddvuerrisneg tefrfeeacttmsenntotaetd2f5ormga/nmyo'f.thNeo moethaesrutrreemaetnmtesnotfrerleaptreodduecffteicvtes wpeerrfeorrempaonrctee.d,Unnodrer the conditionsofthe study, a respectively, were indicated. NOAEL and LOAEL for maternal toxicity of1 and 10 mg/m', @ 000067 pSiugpnsboofddyewveeilgohptmoenntDaalyto1xiPcPit(y6.i1n gthiast 2gr5omugp/cmo'nsviss.te6d.o8fg stinatciosnttircoallsl)y.siOgnnifDicaant4yraednsudcti2o2nsPPi,n pup body weights continued to remain lower than coro, although the difference was not statistically significant (D4aPPy: 9.7 gat 25 mg/m' vs.10.3 in controls; Day 22 PP: 49.0 gat 25 o`fmtg/hme'pvus.ps5o0r.1wiitnhcoonpthrtolhsa)l.moNsocospiigcniefxiacamnitnaetffieocntosfwtehree eryeepso.rteUdndfeorlltohweincgonedxitteironnasl oefxtahmeinsattuidoy,n ainNdiOcaAteEd.L and LOAEL for developmental toxicity of 10 and 25 mg/m', respectively, were Oral Exposure "Trial One: TGhDre1e1;outtwoofo2n5GdDams12)d.ieCdlidnuircailngsitgrnesaotfmemnattoefrn1a0l0tmogxi/ckigtyAiPn FthOe dduarmisngthgaetstdaiteidonwe(roenesidmeialtahrotno ttrheoasteedseaennimwailtsh cionhmaplaarteiodnteoxpcoosnturroel.s.FNooodacdovenrssuempstiignosnoaftnodxbiocdiytywweeigrhetsnotweedreforreadnuycoedftihne rLeipkreowdiuscet,inveopsairgnaimfeitcearnts sdiufcfheraesnmceasinbteetnwaenecneotrfeparteedgannadnccyonotrroilncgirdoeunpcsewoefrreesnoortpetdiofnosr. fetal wfeoilglhotwsi,ngormiicnrtohsecoinpciicdeexncaemsionfatmiaolnfoofrtmhaetieoyness.and variations; nor were there any effects noted "Trial Two: aSdivmeilrasreoebfsfeecrtvsatoinonrsepfroordculcitniivcealpseirgfnosrwmearnecenoorteidn faonryothfetdhaemfsetaasl ionbsteriravlaotnieo.nsLwiekreewinsoet,edn.o 3.7 Reproductive Toxicity Studies in Animals 3`Y0oSrkpr(a2g00u2e)-Dcaownldeuyctreadtsaptewros-egxenpeerradtoisoen rgerporuopduwcetrieveadtmoxiinciisttyesrteuddAyoPfFAOPbFyO.gavFaigvee gatrodouspessooff 0ra,t1s,c3o,nt1i0,nuaenddun3t0ilmgm/aktgin/gdawyassixcownefeikrsmepdr,ioarntdotarnedatdmuernitnogftmahteinFgO. fTermeaaltemreanttsofctonhteinFuOedmale throughout gestation, parturition, and lactation. "aTnhde dFeOatahnsi.maBlosdwyewreeiegxhtasmionfeFdOtmwiacleedraaitlsywfeorrecrlienciocradlesdigwnes,ekalbyordtuiornisn,g ptrheemdaotsuargeedpeelrivieordieasn,d ptrhee-naonndtchoehdaabiyotaftisaocnripfeircieo.dsBoanddytwheeinghotnsogefstFaOtifoenmdaalyesr(atGsDw)er0,e7r,ec10o,rd1e4d, w1e8,ek2l1,yadnurdi2n5g (tihef. nceocnessusmaprtyi)oanndvoalnuelsacitnaFtiOonmadlaeysra(tLsDw)er1e, 5r,e8c,or1d1e,d1w5,eeaknldy2d2ur(itenrgmtihnealtrbeoadtymewnetigphetr)i.od,Fowohidle in F14,O18,fema2l1,e raantsd, 2va5launeds woenrLeDrsec1o,r5d,ed8,w1e1e, kalnyddu15r.ing the precoabitation period, on GDs 0,7, 10, o 000068 Ebesftorroeusthceycslcihnegdwualesdecvoahlaubaitteadtidoanilpyerbiyodexaanmdincaotnitoinnoufivngaguintniallcocnyftiorlmoagtyiboenogifnmnaintgin2g1 bdyaytshe psrcehseednucleeodfsascpriefricme,inthaevsatgaigneaolfstmheearesotrrocuosnfciyrcmlaetwiaonsoasafsescsoepdu.latory plug. On the day of dFaoyrs.matFienmga,loenreatmsawliethratevainddenocneeoffesmapleermraitnpaervaggrionuapl wsemreearcoohracboiptualtaedtofroyr palmugaxweirmeudmeosifg1n4a.ted 2`5gesGtDatio0n,anfdertaislsitiygnienddetxo, ignedsitvaitdiuoanlihnoduesxi,ngn.umPbaerrenatnadl sfeexmoafloefsfwseprreinegvapleuratletdt,fornulemnbgetrh ooff isimzpelaanntdatviioabnilsiitteys,,vgieanbielriatlycionnddeixt,iloancotafttihone dinadmex,anpderlcitetnetr dsuurrviinvgalt,heapnodsstepxarrattuimo.peMraiotde,mlailtter behaviorofthe dams was recorded on LDs 1,5, 8, 15, and 22. FstOudgyenfeorratmiaolnearnaitsm,al.s,weafrteersaccormipfliceetdiobnyofcatrhbeoncodhiaobxiitdaetiaosnphpeyrxiioadt;ioann(ddLayD12026ftoor 1f1e0maolfethraets), nsuercfraocpessieadn,daonrdifeicxeasm,iansewdelfloragsrionstselmeaslioenxs.amiGnraotsisonnoecfrotpisssyueisncalnuddeodrgeanxsa.minIantdiivoindoufaelxotregmaansl `brwaeirne,wkeiidgnheeysd,asnpdleoerng,aonv-atroi-ebso,dtyeswteesi,ghtthyamnuds,orlgiavner-,toa-dbrreanianl wgelaingdhst,rpaittiuoistawreyr,eutcearlucsulwaittehd for the ovevsiidculeetss, a(wnidtchecrovaigx,ullaetftinegpigdliadnydmsiasn(dwwhiotlheaannddwciatuhdoau)t, rfliugihdt).epTiidsidsyumeissr,etparionsteadtienannedutsrealminal b`vuafgfienra,edut1er0u%s,fwoirtmhaloivnifdourcpto,scseirbvliexhiasntdoloovgairciaels,evrailguhatttieosntii,ncsleumdiendalthveespiictlueist,arryi,gahtdreepniadlidgylmainsd,s, apenrd sperxofstraotem.thHeisctoonltorgoilcaalnedxhaimgihnadtoisoangewagsropupesr.foArlmlegdroosnstliesssuieosnsfwreorme1e0xraamnidnoemdlhyissteolleocgtiecdalrlayt.s Al FO generation rats that died or appeared moribund were also examined. Hciosntdoulcotgeicdailnerxaatsmitnhaattieoxnhiobfittehde rreedpruocdeudctfeirvteiloitrygbanyseiinthtehrefaliolwi-ngatnodmmaitde-,dcoosnecegirvoeu,pssirwea,sor dmeolripvherolhoeaglytwhyeroeffaslptreirnegd;.oSrpfeorrmwhniucmhbeerst,rmooutsileiytcyl,icaintydomrosrppehromlonguymbweerr,emeovtailluiatyt,edorin the left cinautdhea elepfitdtiesdtyism.isoThfeFnOugmebneerraatnidondimsatlreibruattiso;ntoefstiimcupllaarntsapteiromnatsiitdescownecreentrreactoirodnsedwienreFOevaluated `fgoernperraetginoannfceymsatlaetursa.t.UteRraitosftahpatpadriednntolty dnoenlpirveegarnalinttterrawserweerseacerixfaimciedneodntGoDco2n5fiarnmdtehexaambisnenecde opefrifmoprlmaendt.atiFoenmasiltees.raAtsgwriotshsountecarocposnyfoifrmtedemtahtoirancgicd,ataebdthoamtidniadlnaontddpeleilvveirc avilsictteerrawwearse sacrificed on an estimated day 25ofgestation. AintFsOchfeedmualleedrsaatsc,ribfliocoedafstaemrpcloemsp(l1e0timoanloefsthaendc1o0hafbeitmaatlieosnepaecrhiofdorinthFeO1m0aalnedra3t0smagn/dkogn/dLaDy 22 danoasleysgisr.oupTsh;e3mmeatlheosdsansdec3tifoenmacilteess ftohratthleivceornstaromlplgersouwpe)rewearlesoccoolllleecctteedd,anbdutfrnoozeonthfeorr dfeuttauirle.s were provided and the results did not appear to be available at the timeofthe report. C 000069 v`TahreiaFt1iognesnferroatmieoxnppeucptsedinlaccatcathilointtbeerhwaevrieorcoaunndtgerdoossnceextdearinlayl. pPhhyyssiiccaallasniogmnasli(eisn)clwuedirneg LreDco1r2d,edaflloFrIthgeenpeurpastieoancmhadlaey.puPpuspwbeordeyewxeaimgihntesdwfeorrethreecporredseedncoenofLnDispp1l,e5s,.8,Pu1p5satnhdat22d.ieOd n PbuefposrefoeuxnadmidneaatdioonnoLftDsh2ltitote2r2fowrepruepexviaambiilnietdy ofonrLgrDos1swleersieoensvaalnudatfeodrftohrevciatualsesotaftduesaathb.irtAhl,l FI generation rats wereweanedon LD 22 basedon observed growth and viabilityof these pups. pAutpwsepaenrignrgo(upL)Dw2e2r),etsweloecFtIedgefnoerrcaotnitoinnpuuepdsevpaelruasteixonp,erlriestuelrtpiengrignro6u0p0 t(o6t0almraaltse(a3n0d06r0atfsepmearle wsehxe)naspossisginbelde,towtehreefsievleedctoesda.geF1grgouepnse.ratAitonlepausptstwnootmsaelleecptuedpsfoarncdotntwionfueedmaolbesepruvpastipoenr floitrter, sNeexcuarlopmsaytuirnactliuodnedwearseinsgaclreicfircoesds.-seTchtrieoenopfutphsepheerasdexatpethrellietveerlwoeftreheexfarmointnaeld-pfaoriregtraolsssutleusrieons. tahnydmeuxsamfirnoamtioonneoofftthhee ctrhorsese-sseelcetcitoendedpubrpasipnefrosreaxpppaerrenlitttheyr dwreorceepwheailgyh.edThaendbrtahien,brsapilne,esnplaenedn, eavnadlutahtiyomnu.s Aflrlomretmhaeitnhirnege pseulpesctweedrpeudpisscpaerrdseedxwpietrholuittefruwrtehreer erextaamiinneadtifoorn.possible histological m`aTnheneFrI agsentehreartiroenspreacttsiwveerFeOggievneenratthieosnasmieredsoasnadgdealmesv.eloDfotshaegetsestwesruebsgtiavnecneoanncdeidnatihley,same wbeegrienenxinagmiantewdeafnorinaggeaonfd vcaognitnianluipnagteunnctyil, tbheegidnanyibnegfoonredsaaycr2i8ficpeo.stFp1argteunmer(aLtDio2n8)f.emFa1le rats p`goesntepraartitounmm(aLlDe 3ra9t)s. wBeoredyevwaeliugahttesd wfeorreagreeocforpdreedpuwthiaelnsreaptasrarteiaocnh,ebdesgeixnunailngmaotnurdaatiyo3n.9 bEesftorroeusthceycslcihnegdwulaesdecvoahlaubaitteadtidoanilpyerbiyodexaanmdincaotnitoinnoufinvgagniinlalcocnyftiorlmoagtyiboenogifnmnaitnign2g1 bdyaytshe sprcehseednucleeodfsascpriefricme,inthaevsatgaigneaolfstmheearesotrrocuosnfciyrcmlaetwiaonsaossf2escsoepdu.latory plug. On the day of fAemtaablleeroatf. raIfnrdaonmduonmitasswsaisgnumseendtttoo acsoshiagbnitFa1tigoennreersautlitoendriantsthteopceoihraibnigtaotfioFn1, goenneermaatlieonrat per siblings, 14 days. an alternate assignment was made. The cohabitation period consisted ofa maximum of pBeordiyodwaenigdhotnsotfhethdeayFoIfgseancreirfaitcieo.n BmaoldeyrwaetsigwhetrseofretchoerdFe1dgweeneekraltyiodnurfienmgatlheerpaotsstwweeraenirencgorded weekly during necessary) and the on postweaning period to cohabitation, and on DGs 0, 7, LDs 1,5, , 11, 15 and 22. Food consumption values 10, for 14, the 18, 21 and 25 F1 generation (if `mgaelneerraattisonwefreemarleecorartdsewdewreeekrlecyodrudreidnwgetehkeldyodsuargienpgertihoed.posFtowoedancionngsupmerpitoidontovcaolhuaebsitfaotritohne, FoIn GDs0,7, 10, 14,18, 21 and 25 and on LD 1,5, 8, 11 and 15. Because pups begin to consume & 000070 matemal food on or about LD 15, food consumption values were not tabulated afier LD 15. `Awtersechweediuglheeddsaacnrdifeixcea,mtihneedF1hiasntiomlaogliscawlelryeasudbejseccrtiebdetdoagbroovses nfeorcrtohpesFy,Oaannidmsaellse.ctSedpeorrgmans analyses were also conducted as described for the FO animals. Fst2ilgbeintchrsa,tiloinvelbiitretrhsswaenrdegerxosasmianlteedraatfitoenrs.deElaicvherylittoeridweanstiefvyatlhueatneudmbfoerrviaanbdilsietyxoatflpeuapsts,twice: cfarcohm dtaheyonfestthieng22bo-xd.ayApnoosgtepnairttaulmdpiesrtiaondc.e DweaasdmpeuapssuroebdsefrovreadllaltitvheeFs2e tgiemneesrawteiroen pruepmsovoendLDs Land 22. Parental Males (FO) One FO adverse mclailneicraaltsiingntshe(e3m0acmiga/tkigo/nd,acyolddo-soe-tgoruocuhp,waansd sacrificed on day decreased motor 45ofthe activity). study due to Necroscopic `meaxlaemirnaatstisounrviinvtehdattoansicmhaeldurleevdeaslaecdriafipcae.leSatnatdisttaincallilvyers,iagnnidfirceadntteisntcesr.eaAslels ointhcelrinFicOalgesniegrnastwieonre aalbsdoomoibnsearlvfeudr,inanmdaluengrartosoimnetdhecohaitg.h-dose group that included dehydration, urine-stained pSeirgniiofdicaanndtcroendtuicntuiionngs uinntiblodteyrmwieniagthitonaonfdtbhoedystwuediygihnttghaei3n,w1e0r,earnedp3or0temdg/fkorg/mdoasytodfotsehegrdoouspasge m`gA/bksgo/lduatyfdooosdecgornosuupm,pwthiiolnevsailguneisfiwceanrteianlcsroeassiegsniifnicraenltaltyivreedfouocdedcdounrsiunmgptthieosnevpaelruieosdsweatrethe 30 observed in the 3, 10, and 30 mg/kg/day within those same periods. Npaoratmreetaetrmsenats-sreeslsaetde,d eifnfcelcutdsiwngerneumrbepeorrsteodfdaatyasnytodoisnseelmeivnealtef,ornaunmyboefrsthoefrmaattsinthgatanmdatfeedrt,ility fceorhtaibliittyatiinodne,x,anndumnbuemrbserosfroaftpsrweigtnhacnotnaftisrmpeedr mraatsiinngcdoahtaebsitdautiroinn.g tAhte fniercstroapnsdy,sencoonnedowfetehke of saptearnmy pdaorsaemleetveelr,s evaluated (sperm number, motility, or morphology) were affected by treatment A3t0nmegc/rkogp/sdya,y.staAtbisstoilcualtley wseigingihftiscoafntthreedulcetftioannsdirnigthetrmeipniadlidbyomdiydewse,iglehfttscwaeurdea seepeidniadtym3,is1,0, and stehmyimnuaslwveersieclaelsso(wsiigtnhiafincdanwtiltyhroeudtufcleudid)a,t p3r0osmtga/tek,g/pditauyi.tarTyh,eleafbtsaonldutreigwhetiagdhrteonfaltsh,esspleemeinn,aland vweesiigchlteos fwtihtheoulitvefrluwiadswasisgnsiifginciafnitclayntilnycrreeadsuecdedinianllthdeos1e0-gmrgo/ukpgs/.daKyiddonseey gwreoiugph.tsTwheeraebsolute stihgen3if0icmagn/tklyg/idnacyregarsoeudp.in tAlhle oI,rg3,ananwdei1g0htm-gt/o-ktge/rdmaiynadlosbeodgyrowuepisg,hbtuatnsdigrnaitfiiocsanwtelryedseicgrneiafsiecadntilny ifonrcsreoamseeoirngaalnlstrateattheed hgirgouhpsd.oseOgrrgoaunp,weaingdhts-itgon-ibfriacainntwlyeiignhctreraasteidosfworerotehseirgonirfgiacnasntalymornedguacleld & 000071 treated groups. Nreoprtordeuacttmievnetorreglaantse,d weifftehcttsheweexrceespeteinonatofneicnrcroepassyeodrtuhipcoknnemsiscaronsdcporpoicmienxeanmcienoafttihoneofzotnha.e `glomerulosa and vacuolationofte cells ofthe adrenal cortex i the 10and 30 mg/kg/day dose groups. PSeFrOuAm wanaaslypsriessfeonrttihnealFlOsagemnpelreastiteosntemda,leinscsluadmipnlgecdonattrtohles.enCodontfroclohmaablietasthiaond sahnoawveedratgheat cugo/nmcle,ntrreastpieocntoifv0el.y0f3or4t4he0.1001a4n8du3g0/mlgP/kFgO/Ad.ayTdroesaetegdromuaplse.s had 51.149.30 and 45.3+12.6 Parental Females (FO) dNoosetrleeavetlm.entN-oretlrateeadtmdeenatt-hrslaotreaddvefefrescetsclwienricealrespiogrntsewdefroer breopdoyrtweedigihntpsa,rebnotdayl wfeeimgalhetsgaatinasn,yand absolute and relative food consumption values. NThoenreeowfetrheennoatturreaaltdmeelnitv-erreylaatnedd elftfteecrtosbosnerevsattrioounsscwycelrieciatfy,femcattedinbgyotrrefearttmielnitty,ptahrtamiest,etrhse. pneurmbdeelrisvoefrdedalmitserd,etlhievegreisntgatliitotneris,ndtehxe d(unruamtbieonrooffgdeasmtastiwoint,htoheneavoerrmaogersefloirviebmoprlnanptuatpiso/nusmitbeesr o`fanpdrsetginllabnotrnraptus)p,stvhieabniulmitbyeirnsodefx,dapmusp sweixthrastitoisl,lbaonrndpmuepas,ndbairmtsh wwietihghatllspwueprse dcyoimnpga,rlaibvleebotron controls among all treated groups. oNregcarnopwseyigahntsd,hainstdopoartghaonl-otgoi-ctaelrmeivnaalluabtoidoyn wweeirgehatlsroatuionsrewmearrekacbolmep.arTaebrlmeintoalcobnotdroylwveailguhetss,for aalnldttrehaetreadtgiorsooufpst,heesxeceoprtgfaonrwkeiidgnhetys-atnod-tleirvmeirnwaeligbhotdsy. wTeihgehtwse,igahntdsofoftthheelleeffttkainddneryigwhetikgihdtn-etyo,bwreaiignhtwse-itgoh-ttewrmeirnealsibgonidfyicwaenitlgyhtrewdausceadlsaotstihgenihfiigchaensttlydorseeduocfe3d0atmg3/akng/dda1y0.mgT/hkge/rdaatyi.o of liver wReassulptrseosfetntheinsalelrsuammapnlaelsystiesstiend,FOexgceenpetrainticoonntfreomlaslweshesraemptlheedleovnelLwDas22beslhoowwethdetlhiamtiPtsFoOfA q1u.a0n2t:i0ta.t4i2o5nu(g0/.m0l0,52r8eusgpneyct1i)v.elyTrfeoarttehdef1e0maalneds3h0admga/nkagv/edraaygedocsoencgernoturpast.ion of 0.37+0.0805 and F1 Generatio-n Males Nbeotwefefeencttsrweaetreed arnepdorctoentdraotlagnryoudpossewelreveelnoftoerdthfeorvitahbeilniutmybaenrdsolafcptautpiosnsiunrdviicvesi.ngNpoerdiitfefre,retnhcees pweericgehnttoagneaopfemrallietteprubpass,isli(tseerxseiszecoamnbdianveedr)awgeaspuspigbniofdiycawnetliyghrtedpuecreldtienrtahteb3ir0thm.g/Pkugp/dbaoydy os 000072 s`iggrnoiufpicoanntd,atyrsea1t,m5e,natnrdel8atoefdldaictfafteiroenn.ceOsfwtehreepoubpssernveecrdofposritchdeawtewiegahntisonfg,thnoesbtraatiins,tiscpallleyen and thymus and the ratiosofthese organ weights o the terminal body weight and brain weight. tShiegnhiifgihcadntosiencgrreoauspesofin3r0eamtgm/ekngt/-draeyl.ateOdnederaatthwsa(s7 manoirmiablusndtotsaalc)riwfeirceedroenpodratyed3i9n pFoIsmtawleaensiinng afnoudnadndotehaedrownadsafyosu2n-d4dpeoasdtowenandianyg.107 postweaning, but the majorityof the FI male rats were dStuartiinsgtimcaolslty osfiegnnitfiirceanptoisntcwreeaanseisnginpecrliinoidc.alTshiegsnes sofitgonxsiicnictlyuwdeedreanalisnocroebasseerdveidnciindFe1ncemaolfes mangn/uklga/rdacyon;satrsiicgtniiofnicoafntthienctarielaasteaaltl d1o0saesn,dw3i0thmgs/taktgis/tdiacayl isnigtnhiefnicuamnbceeraotfthmeal1,e1r0a,tsantdhat30were `emmoatcoiratacetdi;viatny,daansdiganbidfoicmainntailndcirsetaesnetiinonthaet 3in0cmidge/nkcge/odfayu.rine-stained abdominal fur, decreased cBoohdaybiwteatiigohntsanadnddubroidnyg twheeigehnttigraeidnossiwnegrepesrtiatoidstiincaallllytsriegantiefdigcarnotulpys.reSdtuacteisdtpicrailolrytsoigannidfidcuarnitng 3r6e,du4c3t-i5o0n,s ainndbo5d0y-5w7epiogshttwsewaenrinego.bsBeorvdeydwaeti1g0htagnadin3s0wmegr/ekga/ldsoaysidgunriifnicgandtalyysr8e-d1u5c,e2d2i-n29t,he293-0 `smiggn/ikfgi/cadnaty,gdroosue-proelnatdeadysre1d-u8c,ti1o5n-s22i,n3b6o4d3y,W5e7i-g6h4t,gaanidns6w4-e7r0e opobsstewrevaendinfogr.thSetaetnitsitriecadlolysage apter1i0odan(dda3y0s m1g-/1k13g/pdoasytwdeuarniinngg)th.e Aebntsiorleuptreecfoohoadbictoantsiuomnppteiroinodva(lduaeyssw1e-r7e0 psiogsntiwfeiacnaintnlgy),rewdhuicleed relative food consumption values were significantly increased sSteaptairsattiicoanll)ywseirgeniofibcsaenrtv(epd<in0.h0i1g)hd-edloasyesainnimseaxlusavlemrastuusrcaotnicounr(rtehnetacvoenrtaroglesd(a5y2o.f2 pdraeypsuotfiaalge. versus 48.5 daysofage, respectively). aNnodapprpeagrneantnceyffiencdtiscweser(enuombbseerrovefdproengannanyocfitehsepemrantuinmgbeorrofferrtaitlistythpaatrammaetteedrsanidncrlautdsiinng fertility ctohheanbiutmabteiorno,frreastpsecwtiitvhelcy)o,nftihremneudmmbaetrionfgddaaytesstdouirnisnegmtihneatfei,rstthweeenku.mbNeroosftartaisstitchaaltlymated, and csiognnciefnitcraantti,otnr,eaotrmmeonrt-prheollaotgeyd)e.ffects ere observed on any ofthe sperm parameters (motility, 3Ne0cmrgo/skcgo/pdiacyexraamnigniangtifornormetvaenalaerdeasstaitnistthiecallaltyesrailgnainfdicmanetditraenatlmoebnets-orfeltahteedlievfefrecttos maot d3e,r1a0t,eatnod slight dilationofthe pelvisofone or both kidneys. wStearteisotibcsaelrlvyesdi.gniTfhiecanatb,sodloustee-rweeliagthetdsdoefctrehaeselsivienr wteerrmeinsailgnbiofidcyanwtelyiginhcsroefapsaedreanntdalthFe1abmsaolleuste weightsofthe spleen were significantly decreased at all treated groups. The absolute weights of 000073 athnedlseiftgnainfdi/coanrtrliygdhteckriedanseeydsiwnetrhee s3i0gnmigf/ickagn/tdlyayindcorseeasgerdouipn.thTeh1eaanbdso3lumtge/wkegi/gdhatyodfotsheegtrhoyumpsus twhaesparolsstoastieg,nbirfaiciannatlnyddleecftreaadsreendailngtlhaend10waenrde 3si0gnmigf/ikcagn/tdlayydedcorseeagsreodupisn.thTeh3e0ambsgo/lkugt/edwaeyight of ldeofstaagnedgrrioguhpt.kiTdhneeyrastitoosotfhttheermwieniaglhbtsoodfy twheeigshetmsinwaelrevessiigcnliefsi,cwainttlhyainndcrweiatsheoduitnflalulidt,reiavteerd and `rgirgohutpts.esTthsetoratthieostoefrmtihnealwebiogdhytswoefitghhte, wleefretessitgsn,ifwiictahntalnydiwnicrtehaosuetdtahte3tumngi/ckaga/ldbauygianneda haingdhetrh.e 1`0Thtehreatteiorsmoifnatlhbeowdeyigwhetisgohfttwheerelefstigenpiifdiicdaynmtliys,inlcefrtecasaeuddaatep1i0dmigdy/mkigs/,dariyghatndephiidgihdeyr.miTshaenrdatbiroasin ofthe weightofthe seminal mg/kg/day and higher, with vesicles with fluid to the statistical significance at brain 1 and weight were increased at 1 10 mg/kg/day. The ratiosof the liver `wgerioguhpts-,taon-bdrathien rwaetiigoshtoftwehreelseiftgnainfidcraingthlty kiindcnreeaysweediignhttsh-eto1-mbgra/ikng/wdeaiyghatnwdehrieghseirgndiofsicaagnetly dienccrreeaasseedd iant a1llmtgr/ekagte/ddagyroaunpsd.hTighheerr,atainodsotfhethreatsipolseoefnthweeitghhyttmou-sbrweaiignhwt-etiog-hbtrawienrewesiigghntifwicearnetly brsaiginnifwieciangthlty wdeecrreeaisnecdreaatse1d0ianntdhe303 mmgg//kkgg//ddaayy. aTnhdehriagthieosrodfostahegelegfroaunpds.riTghhesteesrtaetsiwoseiwgehrte-to- significantly increased at 10 mg/kg/day (right testis only) and 30 mg/kg/day. Hreilsattoepdamthioclroogsiccopeixcamcihnaantgieosnowferteheobrseeprrvoedudcitnivteheoragdraennsawlagslaunndrseomfahrikgahb-led;osheowaenviemra,lstreatmenta(nciymtoapllsatsrmeiactehdypweirtthr3o,ph1y0,aannddv3a0cumogl/aktigo/ndoafy(thheepacteollcseolfltuhlaer ahdyrpeenratlrocpohryt)ex.) Nanodoitnhetrhetrleiavtemreonftrelated effects were reported. FI Generation ~ Females Nbeotwefefeencttsrewaetreed raenpdorcotnetdraotlagnryoudpossewelreveelnoftoerdthfeorvitahbeilniutmybaenrdsolafcptautpiosnsiunrdvicievsi.ngNpoerdliiftfteerr,etnhcees percentage male pups, liter size and average pup body weight pr liter at birth. Pup body `gwreoiugphtoonndaaypser1,li5t,tearnbdas8iosf(lascetxaetsicono.mbined) was significantly reduced in the 30 mg/kg/day `AAtdd3i0timogn/alklgy/,doany,laocnteatpiounpdfaryosm6oannedd8a,mstdaitiesdtipcrailolrytsoigwneiafincianngt ionncrleaacsteastiionntdhaeyn1um(bDe1r)s.of pups cfoonusnidddereeaddtwoebreetorbesaetrmveendt artel3ataenddb3e0camugs/ekgt/hdeayyd.idAncoctoorcdciunrgitnoathdeosset-urdeylaatuetdhomras,nntehirsawnadsdniodt pneort aliptpeeraarntdolaifvfeecltitatenrysiozteheart mweeiagshuirnegs.ofApnupinvdieapbeinlidteyntthsattatiinsctliucadleda,nanluymsbiserwsaosfcsounrdvuicvtiendg bpyups US EPA (20020). significant trend. No significant differences were noted between dose groups and there was no "0 000074 oObfsathrevepdupfsorntehcerowpesiigehdtsaotfwtehaneibnrga,inn,ossptlaeteinstaicnadlltyhsyigmnuisfiacnandt,thtereraattmieosnot.frtehleatseedodrigfafnerweenicgehstwsetroe the terminal body weight and brain weight. pAonstiwnecarenaisnegidnatyrsea2t-m8enatt-trheelahtiegdhemsotrtdaolsietoyf(63a0nmigm/aklgs/tdoaayl.) wNaos aodbvseerrsveedcliinniFc1elfseimganlsesofon treatment.elated toxicity were reported for any dose level during any timeof the study period. dStoasteisatniciamlallyssiognnidfaiycsan8t,de15c,re2a2s,e2s9,in5b0o,dayndwe5i7ghptosstawnedanbiondgy,wdeuirgihntg pgraeicnoshwaebirteaotibosner(vreedcoirndehdigohngtehsetdaatiyoncoahnadbiltaacttiatoinonb.egaDne,crwehaesnesFi1ngaebnseorlauttieofnoroadtscwoenrseum9p2t-i1o0n6wdearyesoobfsaegrev),edadnudrdiunrgindga.ys 1-8, w8i-t1h5 3p0osmtgw/ekagn/idnagy.durRienlgatpirveecofhoaobditcaotnisounmapntdiodnurvianlguegseswtearteiocnoamnpdarlaabctlaetiaocnroisnsanalilmtarlesatterdeated groups pStaatteinsctiyc)alwleyrseigonbisfeircavnetd(ipnsh0i.g0h1-)dodseleaaynsiimnalssexvuearlsumsatcuornactuirornen(tthceonatvreorlasg(e3d6a.6yodfayvsagoifanagle versus 34.9 daysofage, respectively). oPfreiosrtrtooumsatsitnagge,stpheers2t1uddyaayusthionrhsingoht-deodsaesatnaitimsatliscal(l5y.4sivgenrisfuisca4n.t7iinncrceoantsreolins)t.heFoarvetrhaisge numbers dcaeltceurlmaitnieodn,. tThehinsutmybpeerooffcailncduelpaetnidonenctanocbceururseendceass oafsecsrtereunsfionrtehfefe2c1tsdoaynsothfe eosbtsreoruvsatciyocnlew,absut 3`aMmoCroemdpetaanilyed(2a0n0a2l)ysriescesnhtoluyldcotmhpelnebteedcoanndauncatleydsitso tdheattesrhmionweedwhtehtehreerwethreerenoisetfrfuelcytsaonneftfhecet. 2es4trdouasyscoyfcldei;estthreures wien rtehencoodnitrfofleraenndcehsiignh tdhoesneugmrboueprs.of Afneamlaylseesswictohnd>uc3tdeadybsoyftheestUrSusEoPrAw.ith a(2n0d0h2i4g)hadlsoosedegmroonuspts.ratTehde tchyactltehserweerweereevanlouadtiefdfearsenhcaevsining tehietheesrtrroeugsulcayre4l-e5admaoyncgyctlhees,counnterovlen acsyc4l-i6ngda(ydedfiiesnterdusaspberriieofdpse)reixotdesnwdietdhesitrrruesgu(ldaerfpiantetderans)3oorrpe4rdiaoydssooffpcroomliofnigeeddsdmieeasrtsr)u,s p(doesfsiinbeldy gprseeautdeorpdraeygsnoanft,co(mdielffiineeddsamseaGr-sg)r.eatTehredatywsoogfrloeuupksocwyetrees)nootr dpiefrfseirsetnetnitneasntryuos f(dtehfeinpeadraamse5t-eorrs smetausduyraeudt.hoTrhsuiss,dtuheetiontchreeawseayininthwehniucmhbtehre ocfaelsctulraotuisonstwaagsesdpoenre2,1anddayissntohtatbwioalsognioctaeldlyby the `meaningful. nNuomebfefrescotsfroantasntyhoafttmhaetemda,tfienrtgilaintydifnedretixl,itryatpsarwaimtehtceornsf(inrummebdemrastoifndgadyasteisndcuorhiabnigttahteiofni,rst week ofcohabitation and numberofrats pregnant per rats in cohabitation). dAlalmsnadteurlailvedreilnigvelrityeorsb,setrhveadtuiroantsiwoneorfeguensatfafteicotne,dabvyertargeeastmfeorntimatplaannytadtoisoen lseivteels. peNrudmebleirvesreodf n ~--------------------------------------------------,-- 000075 ihi 1li1tt)e,r, tthhee ngeusmtbaetrioson fidndaemxs(nwuimtbhesrtoilfldboarmnspuwpist,hdoanmesowritmhoralel lpiuvpesbodrynipngupasn/dmulmivbeebroronfparnedgnant sillbom pups were comparable among treated and contol groups. tNhoe ptirteuaittmaernyt.arnedlattheedreaftfieocsotfstwhereepiotbusietrarvyedweoinghtte-rtmoi-ntaelrmbiondayl wbeoidghytsw.eigThhteaanbdsotlouttheewberiagihnt of rweesipgohntsew.erNeosiogtnhiefricdainftfleyredneccerseawseerdearte3pomrgt/ekdgf/odratyheanadbshoilguhteer,webiugthdtisdonrortatsihooswfoar dootshee-r organs eevxaalmuiantaetdi.onsN.o treatment-related effects were reported following necroscopic and histopathologic: F2 Generation Offspring trNeoattmreeanttmreenlta-treedlaetfefdeacdtsvewresreecrlienpiocratlesdifgonsllwoewriengonbescerrovsecdopaticaneyxadmoisneatlieovenl,. wiLtihketwhieseex,cneoption of 0stilmliblokmidnisdtnoomtaschhoiwn pduopsset-hraetswpeornesefo(u3/n2d8,de6a/d2.8,T1h0e/2n8u,m1b0e/r2s8,ofapndup6s/2f8oiunn0d, ei1,th3e,r1d0e,aadnodr30 `mg/kg/day dose groups, respectively) and therefore were unlikely related to treatment. Nbeotwefefeencttsrewaetreed arnepdorctoentdraotlagnryoudpossewelreveelnoftoerdthfeorvitahbeilniutmybaenrdsolafcptautpisonsiunrdviicvesi.ngNpoerdliiftfeerr,etnhcees pLeDrsce1n,t5a,ge8,of1m5,a0lre22p.upAsn,olgiettneirtsailzediasntdanacveesramgeeaspuurpedbfoodryFw2eimgahltepaerndliftteemrawlheepnupmseaosnuLreDdso1nand 22 were also comparable among the five dosage groups and did not differ significantly. lStaacttiasttiiocnaldlayysi1gantiftihcean3tainndcre1a0smesg/(kpg</0d.a0y1)doinsatghee gnruomubpes.roAfcpcuoprsdifnogutnodtdheeasdtwuedyreauotbhsoersr,vetdhiosn awnadsdniodt ncootnsaipdpeeraerd1t0oabfefetctreaantymeonttherrelmaeteadsubreecsaoufseptuhpeyvidaibdilniotty tochcauirnicnluaddeods,en-uremlbaetresd mofanner scuornvdiuvcitnegdpbuypsUSperElPitAte(r2a0n02d6i).ve Ntoersisgniizfeiactanwteidgifhfienrge.ncAesnwienrdeepoebnsdeernvtedsbteattiwsteiecanldaonsaleysgirsowupass and there was no significant trend. `wTeeirgmhitnsaolfbtohdeybwreaiing,htssplieneFn2anpduptshywmeurse anontdstihgenirfaitciaonsotflythdeifsfeeroerngafnrowmeicgohnttsr-otlos-.teArbmsionlaulteb.ody weight and to brain Weight were aiso comparable among treated and control groups Conclusions mDaolseinagndwiftehmAalPeFFO1 aotf3fs0prmign/gk.gT/dhaeyaaupthpoerasroefdtthoedesltauydythceonotnseentdotfhsatextuhealdemlaatyusraitnisoenxuinalboth mfaactturthaattiotnhe(spereapnuitmiaallssehpaavreataidonecorreavsaegidngaelstpaattieonncayl)aogbe,searvveardiianblheigwhh-idcohsethaenyimhaalvse adreefidnueed taosthe the time in days from evidence ofmating in the FO generation until evidenceof sexual n 000076 `imnahtiugraht-idoonseinanthiemaFl1sgaetnethreattiiomne. oTfhaecqauuitshiotrisonst(attheetthiamtegweshteatniosneaxluaalgemaatpupreaatrieodn twoabserdeeaccrheeda)s,ed cwohnitcrholtghreoyubpe,liinevwehmiecahntthetrhee waanismnaolssiginnitfhiactagnrtoduipffweerreencyeoiunngseexruaanldmamtourreatiiomnm.aturethanthe iInn goersdteartitoontaelstagtheiswihtyhpotthheesdiesl,aytsheinaustehxouraslcmoavtaurriaetdiosnepianraotredleyrtthoeddeetcerremaisneeswihnebtohdeyr woreingohttbaonddy wwietihghtthseatnidmegetsotsaetxiounaallmaagteurwaetiroen,a ctohnettriimbeuttiongsefxauctaolr.maWtuhreatniotnhesbhoodwyedweaidgohstewraeslactoevdadreileady wthaast wpaarstlsytarteilsattiecadlltyo bsiogdnyifwiceaingthta,t bthuetpnost0e.n0t5i.relTyh.isWhsuegngegsetsstatthiaotntahleadgeelawyasincsoevxaurailedmawtiutrhattiheon `tmiamteurtaotsieoxnubaeltmwaeteunractoinotnr,oltshearnedwhaisghn-odossigeniafniicmaanlts.difTfheirsenicnediicnattehse tthiamtetohef eofnfseecttooffsdeexluaayled sexual maturation could possibly be attributed to decreased gestational age. a`fWfheicltetihteistikmneotwonsaenxudaclommamtuornaltiyona,ccwehpettehdetrhaotrcnhoatnggeesstaitniotnhaelbaogdey, awseidgehftisnoedfobfyftshperianugthcoarns, palrsooviadffeedctbsytthheetaiumteohofrsatcoqusiuspiptoirotn tishipsurreellaytisopneschuilpa.tiAvded,ietsipoencailallyl,ycsoivnacreytihnegregewsatsatnioonadlataage swiigtnhiftiicmaenttochsaenxugaelimnatthueraltenigotnhiosfprgoebstlaetmiaotnicatf3r0ommga/sktga/tdisatyi,calbasstaenddpoonintth.e aSuitnhcorest'hdeerfeiwniatsionnoof t"igemsetattoisoenxaluaalgem'a,tutrhaetdieocnr.eaTsheesreifnogrees,tasteixounaallmaagteurwaotuilodn hisaevsesetnotbiealdlyuebemionsgtlcyovtaorciehdanwgietshiintself mSetrile,lyevoeffnerisfaanreelxaptlioannsahtiiponbeftowretehne ogbessteartvieodnadlealgaeysainndsteixmuealtomasteuxruaatlimoantiunrahtiigohn-dwoesreeasnhimoawlns,,it but does not diminish its significance. bTheerIemfgo/rke,g/udnadye,rtthheelcoownedsittidoonsseoftetshteed,stbuadsye,dthoenLsiOgAniEfiLcafnotriFncOrpeaarseenstianl tmhaelleisveirs aconndskiidderneedy to oweuilghdtsn-ottob-etedremtienramlibnoeddysiwneciegthrteaatnmdentotrberlaaitnewdeiefgfhetctrsatwioesr.eAseeNnOaAt EalLlfdoorstesheteFstOedp.arental males `rTehsepeNctOivAeElyL, baansdcdLOonAEsiLgniffoircFanOtpraedruecnttiofnsemianlkeisdanreeycwoenisgihdteraenddtokibdene1y0 waenidgh3t0-tmog-/tkegr/mdianyal, bodyweightand to brain weight ratios observe at the highest dose. d`TehcereLaOseAsEiLn bfoodryF1wegiegnhetrsatainodnbmoadlyesweisigcohntsgiadienrse,datnodibnet1ermmgi/nkagl/dbaoyd,ybwaesiegdhotsn;saignndifsiicgannitficant scwheaingghetss-itno-abbrsaoilnuwteeilgihvtesr;aannddsbpalseeedn owenisgihgtnsifaincadintn,tdhoeser-arteiloastoedf rlievdeurc,tkiiodnnseyin, baonddyspwleeiegnhts and bAoNdyOwAeEigLhtfgoaritnhse oFbIsemravleeds pcroiuolrdtonoatndbedduertinegrmcionheadbistiantcieontraenadtmdeunrti-nrgelttheedenetfifreectdsowseinrge pseereinoda.t all doses tested. 260677 r`TehsepeNctOivAeElyL, baansdeLd OonAEstLatifsotricFa1llygesniegnriaftiicoanntfeimnacrleeassaerseincopnossitdweeraednitnogbmeor1t0alaintdy,3d0emlagy/skgi/nday, saenxdudalecmraetausreastiinonab(stoilmuetetofvoaogdincaolnspuamtpentciyo)n,,daellcroebasseersviendbaotdtyhewheiigghhetstanddosbeodteystwede.ight gains, rTehleatNedOeAffEecLtsfworertheeoFb2segrevneedraattiaonnyofdfosspersintgeswtaeds icnonthseidsetrudeyd. toHboewe3v0emrg,/kitgs/hdoauyl.d bNeontorteeadtmtehnattpthoestFw2epaunpisngweerfefescatscrtihfaitcewderatewneoatneidngin,tahnedFt1hugsenietrwaatsionno.t possible o ascertain the potential 3.8 Carcinogenicity Studies in Animals 3.8.1 Cancer Bioassays (`T3hMe,ca1r98c7i)n.ogIennithcipsostteundtyi,algorfouApPsoFfO5h0asmableeenanidnv5es0tfigeamtaeldeiSnparatwgou-ey-eDaarwlfeeeyd(inCgrs:tCuDdyBiRn)rartasts wseexrewefreed dfieedts0,coonrt3a0in0ipngp0m,A3P0ForO3a0n0dpepvamluAaPteFdOatfotrhetwooney-eyaersa.r iGnrtoeurpimssoafcr1if3icaed.diTthioenamleaatns per actual test `mg/kg/day afrotrictlheecloonwsuamnpdtihoinghw-adso:semaglreosu,ps1,.3reasnpedct1i4v.e2lym.g/kg/day; females, 1.6 and 16.1 tThheerfeemwaalse raadtsosaes-rceolmapteadreddectroeatshee cionnbtroodlys;wtehieghdtecgraeianseisn wtheeremaslteatrisattiscaalnldy stoiganliefsisceanrteixntetnhte, in choignhs-udmopsteiognrowuapss oafcbtouatlhlyseixnecsr.eaTsheed (broadthyerwetihgahntdcechreaansegd)ea.rseThterreeatwmeenrterneoladtiefdfseirnecnecefseiend t`mhoerctaolnittryolb,eltowwe-e,natnhdehtirgehat-eddosaendgruonutprseawteerdeg:rmoaulpes,; 7th0e%s,ur7v2iv%alanradte8s8a%t;thfeemeanldeso,f5100%4,w4ee8k%safnodr i5n8c%i.deTnhceesoinnlythcelicnoinctarlols,iglnowo-bsaenrdvehdigwha-sdoasedogsreo-urpelsatweerdei:nc4r%e,ase18in%aatnaxdia30i%n.theSifgenmiaflicearnatts; the odebcsreeravseedisnitnhreehdibglho-oddocseellmacoluentasn,dhefmemoaglleobriant caosnccoenmtpraarteidontsoacnodnthreomlavtaolcureist.vaClluineiscawlere (chAeLmTi)s,trayspcahrtaantgeeasmiinndoitcraatnisvfeoefrlasieve(rAStoTx)icaintyd ianlcklaulidneed pihnocsrepahsaetsasine a(lAaPn)inien abmoitnhotrreaantsefdermasael:e `lgivreorupasndfrkoimdn3e-y18wemiognhtthss,webrute onnoltyedininthbeothhighhi-gdho-sdeosmealmeasleata2n4d mfoenmtahlse.raIsn.creSaigsneisfiincarnetlantiovne nienocpildaesntciecolfesliiovenrs mwaesrseess,eehnypperripmlaarsitliycinnotdhuelelsivaerndanfdoctie,stains;d tihnetreestwiecrulearinmcarsesaseessiinntthhee.highddiofsfeusmeahleepgartooumpe.galOotchyetrosliivse,r ctyosxtiociedffdeecgtesneirnactliuodne,daosned-rpeolratatledmionncorneuacselseianrtcheelliinncfiidlternacteioonfin dbootshe mmaallees.anAd fsetamtailsetitcralelaytesdiggnriofuipcasn;t,thdeossee-irneclraetaesdesinwcerreeassetaitnistthiecailnlcyisdiegnnciefoicfaonvtianrtihane thuibguhl-ar dhoypseergplraosuipas wwaassf0o%u,nd1i4n%,feamnadle3r2a%ts,; rtehsepeicntciivdeelnyc.e Boaftsheidsolnestihoenseinttohxeiccoenftfrecotls,, ltohew,hiagnhddhoisgehselected in this study appears to have reached the Maximum Tolerated Dose (MTD). Based on " 000078 adencdrheeapsaetdicbosdysytweemis,ghtthegaLinO,AiEncLrefaosremdallievearnadndfekmiadlneeyratwseiisgh3t0s0apnpdmt.ox[iBcaistyedinotnheinhcermeaatseosloignitchael incidenceofataxia and ovarian tubular hyperplasia, the LOAEL for female rats is 30 ppm.) oAftthtehe ltveerrm,intaesttiios,notfhtyrhoeid,stauddrye,naalslainghdtmiancmrmeaasreyingltahnedsi,nceitdce.)ncweaosfvsaerenioiunsthneeotprelaatsemdsan(itmuamlosr.s mAamloenrgatst,haenm,dotfhemianmcmreaarseyd finicbirdoeandceensoomfateisntibcoutlhagrr(oLuepysdoifg)fceemlallaedreantsomwaesreinsttahteishtiigcahl-ldyose. tsiugmnoirfsic(anLtC(TP)<i0n.t0h5e)caosntcrooml,palroew-d atondthheicgohn-cduorsreemnatlceosntwroalss.0/T5h0e(0i%n)c,id2e/n5c0eo(f4t%h)eaLnedy7d/i5g0cell (w1e4r9e%),11r/e5s0pe(c2t2i%v)el,y;21t/h5e0r(es4p2e%c)tiavendin2c4i/d5e0nc(e4s8o%)f.maTmhmeairncyrefaisbersoaardeeanlosmossitnattihseticfaelmlaylseiggnriofuicpasnt oasbsceormvpeadriend1t,o34t0hemhailsetoarincdal1c,o3n2t9roflemianlceidSepnrcaesgu(eL-CDTa,wl0.e8y29c%o;ntmroalmrmaatsruysefdibirnoa1d7enoma, 19.0%) Scaprrcaignuoege-nDiacwilteyystruadtiseisn (oCthhaenrdsrtaudeiteasl.w,a1s99r2e)p.ortTehdetsopboentaapnperoouxsimiantceildyen5ce%(ocfiLteCdT ini:n C2l-eygegareotlald., a1t9s9,7)i.nTdhuecrienfgoLree,yduingdecreltlhteucmoonrdsitiinotnhseomftahliesrsattsudayn,dAmPaFmOmaisrcyarfciibnroogaedneincoimnaSspirnatghueef-eDmaawlleey rats. P"TFheOAindiuncmtaiolneoSfpLreaygduieg-Dcaelwllteuym(oCrDs)warastscoatnafidrimeetdariynlaevfeollolfow3-0u0pp2-pymea(rCmoeockhcatnai.s,m1s9t9u4d;y of (B8i/c7g6e,l1et1a%l.) a2s00c1o)m.paArsiegdnitofitchaenctolnytirnoclrse(a0s/e8d0,L0C%T).inIcniaddednicteiowna,sPoFbOseArvalesdoicnatuhseedtrseiagtneidfriactasntly aindcerneoamseadsiinncithdeenccoenstorfollainvedrttruematoerdsgarnoduppsanwcerreaeti2c/8a0ci(n3a%r)cealnldtu1m0o/r7s6. (1T3h%e),inrceisdpeenccteisvoelfy,liver ownheerpeaanscrtehaotsiecfaocrintahre cpealnlccreaartiiccinaocimnaairnce7l6lofatdheneomreaastwederreas0/a8n0d(n0o%n)eainnd870/c7o6nt(r9o%l)s.. TThheere was winacsidaelnsocesoifgncifoimcbaintnleydipnacnrceraesaetdiacsaccoinmapracreelldatodetnhoemcaolnctraorlcsi(n0o/m5a0,in0%t)h.e treated rats (8/76, 11%) NPiFlOssAonhaestaal.l,so1b9e91e)n shown to promote liver carcinogenesis in rodents (Abdellaticft al,1991; 3.8.2 Mode of Action Studies P`TFheOmAecwhaasninostm(msu)toafgteonxiiccoinlotghiecAalmceasrctiensotguesniincg afcitvieosntroafinPsoFfOSAalismonontelclleaartlyyphuinmduerristuomo,do.f in an aapspsaeyarwitothsuSgagcecshtatrhoamtyPcFeOsAc.erisevniostiaaeD(NGAr-ifrfeiathctainvdeLcoonmgp,ou19n8d0.). Short-term genotoxicity assays However, when tested with pmoeltyapblooliidcyacitniCvaHtiOonc,ePllFsO(AMuirnlid,uc1e9d96s)i.gniTfhiceasntiginnicfriecaasnecse ionfcthhersoemogseonmoatolxaibcerefrfaetcitosnsisaunndclienar. `Avmaeiclhaabnliesmd,atianvaoplpveianrg taoctiinvdaitciaotne otfhartectehpetionrdsucatnidonpeorfttuurbmaotrisonbsoyfPtFheOAenidsodcureinteo saysntoenm-.geTnohteoxic 7s 000079 ee Asgumemnacryieisscaurrerennottlymeeaxnatmitnoibnegathdeesteaiploesdturleavtieedwomfotdheesolfitaecrtatiuorne,ibnudtetsaiilm.plTyhseumfomlalroiwziengthe current scientific evidence. 38.2.1 Liver Tumors tpehraosxibseoemnewperlollidfoecrautmieonntiendthtehaltivAeProFfOraitss2apnodtemnitcpee(reo.2x.i,sIokmeedaprcotliafl.e,ra1t9o8r,5;inPdausctionogr etal, p1r9o8l7i;feSroahtiloennieuxissetts ailn.,r1a9s92()K.awAassheix-mraeleattaeld,di1f9f8e9r)e,ncbeutinnottheininmdiucceti(oSnoobfleinvieurs peetralo,xi1s9o9m2e). `dTehpeehnidgehnetroinndtuhcetsieoxnohforlimveornepetreosxtoisstoemreonpero(lKiafewraasthioinmainemtaalle, r1a9t8s9w).asLsihkeowmnantoyboethsetrrongly opfepreorxoisxoimseomperoplriofleriafteorrast,orAhPeFpaOtohcaasrcailnsoogbeeneesniss)hoiwnnrattos c(aTuaksaeghi,epeattaolm,e1g9a9l2y;(Caonoeka,rly19b9i4o)maanrdker m"Tihceeto(tKaelintnyeodfyt,he1s9e87d)a,taanadppienadruscetooxsiudgagteisvtetDhaNt Athedalimvaergetoixnicliitvyeraonfdracatrsc(iTnoagkeangiiciettyalo.f 1A9P91F).O mpraoymobteerehleaptaetdoctoaricnidnuocgteinoensoifspienrroaxtiss(oYmaegeprroalnifderYaatgioenr., Meanwhile, estrogen 1980; Cameron et aL, has been shown 1982); an to ihnecpraetaoscearicniensotgreongeesnisleivnelrsasa.fteRreAcPenFtOly,exIpAosRuCre(1(9d9i5s)cucsosnecdlbuedleodw)thmatatyheallsioveprltauyamorrosleinidnuced in urnoddeenrtsstabnydiPnPgoAfRtahlephaaniamgaolnimsotdsearoefaucntliiokne.ly tobeoperative in humans based onour current 3.8.2.2 Leydig Cell Tumors Ato lianrdguecenuLmebyedriogfcenlolnt-ugmeonrosto(xLiCcTc)oimnproautsn,dmsiocfe,diovredrosges.cheAmirceavlieswtorufcttuhreesavhaaivleabbleeeinnfroerpmoartteidon ogrnoLupCsTbainsdeudcotinonthieniramniomdaelssolfeadcatiwoonr(kCslheogpgpeatnaell.,to19c9l7a)s.sifTyhtehecsoemcmoomnpotuhnedmseiinntothseemvoende of `agcrtoiwotnhfborymdoisstrucptoimnpgotuhnedhsypiostthhealtamtihce-speitcuoimtparoyu-ntdesstiacfuflecatr tahxeishaormvaorniaoluscopnotirnotlsotfhaLteryedsuilgtcienll tioncsrteiamsuilnagtitnhge tsheerpurmoldeuvcetlisoonfolfutteesitnoisztienrgohneo,rLmoHnema(yLHa)l.soItplhaaysabemeintopgoesntiuclartoeldetihnatthienLaedydidtiigon c`eglrlosw;tah-ssutsitmauilnaetdinigncmreedaisaetoinrscisruccuhlaatsinIgGFL-H1,leTvGeFls-Ba,ndlecuhkrootnriicensetsimaunldatviaornioofusLferyedeirgadcieclallssbcyan lead to LCT development (rev. in: Clegg eta, 1997). AmalseeriSepsroafgusteu-dDiaeswlheayve(CbDe)enractosnedxupcotseeddtotoiAnvPesFtOiga(tCeotohke emteaclh,a1n9i9s2m;oBfiteugemloretaflo,r,ma1t9i9o5n; iLniu et al, 1996). No significant various dose levels for 14 increases in LH days. However, were seen serum and in the rats testicular aftr treatmentof levelsofestradiol APFO were at sthiagtnitfhiecaenltelvyatiendcreesatsreaddiaonldletveesltsosmtaeryonceaulseveelLseywdeirgecseilglnhifyipcearnptllaysdieacarenadsetdu.moIrt fwoarsmaptoisotnulbayted acting as a mitogen and/or enhancing growth fector secretion; the transforming growth factor a. Ed 000080 p(rTolGiFfeur)a,tiwohni,cfhorbiinnsdtsantcoet,hheaespbiedeernmdaeltegcrtoewdthinfLaectyodri(gEcGelFl)s (reTceeeprtdosreatnad.,st1i9m9u0l)a.teSducbesllequent Pex4p5e0riXmIeXnt(sarhoamvaetassheo)w,nwhthiacthAcPonFvOeritnsctreesatsoesdtetrhoeneletvoelesstorfeadsitorla.dPieorlobxyisionmdeucpirnoglicfyetraotcohrrsoamree: pkenroowxnistoomiendpruocleifpe-roaxtiidoantaicotnivaantdiocnyrteoccehprtoormeaP(-P4P50ARmoan;oaosxuybgfeanmaisleyosfbsytbeironiddinhgotromothnee arencdepatcotrisv)a.tiIngistbheelPiePvAedRt.hat APFO induces cytochrome P450 XIX (aromatase) by binding to AAlPtFhOouginhtshiegn1i4fidcaayn-tsitnucdrieeass,eist ainppLeHarwsetrheatniontcrseeaesneininSLpHralgeuveel-sDacawnlneoytrbatesrauflteedr torueatttomebnet of sitnuvdoilevs,edsi(ginniafdicdainttioinnctroeianscerienasheedpaetsitcraadrioolmalteavesle) (iwnhtihcehicnodnuvcetritosnotfesLtoCsTterboyneAPtoFOes.traIdnitohl)ese oacbtsievritvieeds iansstohceiattreeadtewditrhatd.ecTreesatsoesdtesreornuemistsesytnotshteesriozneedlaenvedlsseacnrdetiendcbreyatsheed Lesetyrdaidgioclelllesv,elasnwdeirse orredgeurlattoedmabiyntLaHi;n taedsetqousatteerotneesatonsdteLrHonefoprlmasamcalloesveedl-s,loroepdufeceeddbtaecsktossytsetreonmeilnevtheelsH(PcaTusaxeids.byIn finecerdebaascekdmaercohmaantiassem.acIttihvaitsy)beaeren epxopiencttededotuo tlheaatditnocirnecasreesasiendLLHHmlaevyelnsottharlowuagyhstbhee nseegeantiinveall cstoumdpieensosaftichoenmmicaaylshafvoer wohciccurhrtehdetporroepsotosreedhmoomdeoesotfaascitsiaonndcianlasppfroorperlieavtaetetdimLiHn,g oafndsatmhpalting are someofthe explanations for failing to detect changes in LH levels (Clegg et al., 1997). 3.8.2.3 Mammary Gland Tumors aEsntdratdhieolovhearsexaplrseosbseieonnosfhoTwGnFtao shtaismubleaetne stuheggseesctreedtiaosnoofneTGpoFssibbleyfmaactmomrainrypreopdiutcheilnigal cells nsuesotpalianseida c(eLlilupcrtolail.f,er1a9t8i7o)no. fHmeancmem,airt iys tpuosmsoirblceeltlhsatantdhetAhePFsOub-sienqduuecnetddeelveevlaotpimoennotfoesftradiol DleavwellseymaryatsalisnoabdedirteisopnotnosiLbCleTf(orditshceusdseevdelaboopvmee)n.tIonffmacatm, mthaisriys cfoinbsriosatdeentnowmiatshitnheSpmreacghuaenism rbayts.whIit chhassbpeonetnadneemoounssmtraamtmeadrtyhatnethoepleaarslmysawpepreeardaenvceelaopneddhiinghagsipnogntfaenmeaoluesSipnrcaigdueencDeaowfley e`xmpaomsmuarreytogleannddotguemnooruss iensturnotrgeeanteadn,dapgrionlgacftienmazlseaSrpersualgtuoef-aDnawalcecyelreartastiisngdueeffetcotioncnrneoasremdal, age-related perturbationsofthe etal, 1996) estrous cycle in this strainof rat (Cutts and Noble, 1964; Chapin 3.8.2.4 Pancreatic Tumors o`TthheermpeecrhoaxniissommebyprwohiifecrhatAoPrsFaOlsiondpurcoedducpeanpcarnecarteiactiacciancairnacerlcleltlumtourmsoriss uinnkrnato.wnA.vaAilanbulmebdeartaof (suCgCgKes)tltehvaetltsheecpoanndcarreyattiochaecpiantaircccehlolletsutmaosriss (arCeooreklaetteadl,to1a9n94i;ncOrbeaosuerinnestearl.u,m1c9h97o)l.ecCysCtKokiisnian " 000081 gparnocwrtehatfiacctaocrintahratchealssbienernatssh(oLwonngtnoecsktiemru,la1t9e87n)o.rmHaolw,eavdearpt,ivdea,taanodn ntehoeprloalsetiocfgCrCoKwthinof pancreatic tumor formation are conflicting. 3.9 Immunotoxicology Studies in Animals Fwoausraifmemeudniontgoxstiucdiytyinsmtuidciees(oYfanPgFeOtAalh.a2v0e00b).eenFocronidnuvcestteidgaitnimoinocef.thTeheefffeicrtssofotfhese studies perfluorooctanoic acid (PFOA), and other PFOA was administered to male CS7BY6 peroxisome prolferators, mice in the dict for 2, 5, 7, on or lymphoid organs, 0.02 10 days. At the end of % twheeigfheeedd.ingThpeerieofdf,ecmtiocfePwFeOrAe saadcmriinfiiscterdaatnidontohenltihveerc,elslpulleaerni,tya,ncdltlhsyumrufsacweeprheendoitsyspeect,eadnodutcealnld ctyhcylmeocofyttehsymaoncdystpelsenaoncdytsepsletnooPcyFtOesAwiansvidtertoewrmeirneede.xaImninaedddi.tion, effectsofexposure of Tsihgenirfiecsauntsisnhcroewaesed,trhealtaatidvmeintiosctornattrioolns,oifn l0i.v0e2r%wPeiFgOhtA, feovre2n,a5f,t7h,eoerar1l0iedsatyismreespuolitnet.d inAlaso, a ddeacyreSaasdemiinnibsotdraytiwoenigphetricoad,usseidgnbiyfiPcaFntOdAecardemaisneisstirnattihoynmwuassanobdsseprlveeedn. weSiugbhsteqwueernetldye,tebcytetd.he Arefstpeerctaidvmeilnyi)stirnattihoentootfal0n.u0m2b%ePrFoOfAthfyomro7cydtaeyss,asnidgnsipfliecnaonctydteecsrewaesreeso(b8se5r%veadn.d 8T0h%e,results also snhuomwbeedr tehxaptretshseinnugmbboetrh oCfDth4ymaondcyCtDeSs edxepcrreesassiendgbbyot5h7C%;D4anadntdhCe DnuSmdbeecrreeaxsperdesbsyin9g5ei%thterhe CanDd4BorceCllDsS(CdDe1cr9e)asdeedcrbeyas6e4db%yan7d57%2a%n,dr8es6p%ec,tirveeslpye.ctiFvoerlyt.heAslpsloe,nosciygtneifsi,cbanotthdeTcrceealslses(CinD3b)oth CPDF4OAhetlopemricaendfoCrD7Sdacyyst,ottohxyimcoscpylteenipcroTlicfeelrlastwioenrewaosbsaelrsvoedi.nhiUbiptoend,aadsmidneitsetcrtaetdiboyn ocfel0l.c0yc2l%e ifnloswplceyntoocmyettersyaanndaltyhsyesm.ocyItnevsitarfoesrtudioers2s4hhoowuerdsotfhatcutlhteurreinwgaisnstphoenptraenseeonucseoapfopvtaorsyiisngoccurring concentrations (50, 100, or 200 M) of PFOA. cell cycle under these conditions. However, PFOA did not significantly alter the IInn oorrddeerr ttoo esxtuadmyinmeecthheandiossme (deYpaenngdeetnacly.o2f0t0h1e),efafneocttsh,erCmSo7uBsUeSfmeiecdeinrgescetiuvdeydwdaisetpsecrofnosrimsetdi.ng 0 0.001%-0.05% PFOA (w/w) for 10 days. For examining the time-course, a diet containing 0st.u0di2e%d.PFOA was given for 2,5, 7 or 10 days. Effects ofwithdrawal of PFOA were also "wTehieghretsuwlatss sobhsoewrevdedt,haatl,tahtohuigghhenrodootsheesr,aappsairgneinfticsaingtnsdoefctroexaisec,itryelsauticvheatsoscoornetsr,ollse,thianrgbyo,daynd pobosoerrvgerdo.omMiincgewreerceeinvoitincgedd.ietHaroywePvFeOr,Aasfiogrn1i0fidcaaynst decrease in experienced total water significant intake was increases in liver wleaiugrhotyla-nCdoApoerropxailsmoimteopyrlo-lCifoeAraastiosnu,bsatsramtee.asuTrheedsebyinicnrdeauscetsiosntaorftaecd yalt -tCheoAloowxeisdtadsoesweitahnd 000082 srpelaecehnedantdheitrhmyamxuismbaelgavnalauteas ahtigahdeorsdeoosfe0(.00.0031-%0).0w1it%h. nIonmcoanxtriamstu,mthreeawcehiegdhtwidtehcrtehaesdeososefsthe wgievreen.evTidheenttiamtethceouerarsleiessttudtiiemsesphooinwtedextahmatiniendc.reaIsnecdonltirvearstw,esiigghntisfiacnandtptehryomxuissoamnedpsrpolleifeenration twheeigshptledeencrweeaisgehstrreeqmuaiirendedPcFoOnsAtaandtmiwnhiislteratthieonthfyomruaspweeriigohdotfcaotnlteiasntu5teddoaydse,crfeoalsle.owiHnogwwehviecrh, w`ueproen opbrsoelrovnegde.d Itnreaantomtehnetrfsoertoofneexmpoenrtihm,enntos,fuarnthiemraldsecrreecaesievseidn0t.h0y2m%usPFanOdAsfpolree7ndwaeyisg,hatnsd tthhaetntthheeaynriemcaelisverdapniodrlmyarleccohvoewrefdotrhaepbeordiyodwoefig1h0tdtahyes.secTohnedsedaryecaofvteerrywietxhpderraiwmeanltosfsPhFoOwAe.d rHeocwoevveerry,sttahreteldivoernwdeaiygh2tadniddwnaotsrceotmuprnlettoendobrymadlayev1e0n. a`fTtheer s1p0ldeaeynswoefirgehcsovrereyt.umeTdhytomunosrmal tbryedatamyen2tpaonsdt-wwiitthhddrraawwaall. pIanraaldldeilteidont,hethcehacnhgaensgeisniontatlhytmhuysmoacnydtespalnedenswpeleingohctyutepocnouPnFtsOA `Fnuurmtbheerrmcoarues,edflboyw PcyFtOomAettrryeactemlelnctyicsldeueexpmeariinmleynttos isnhhoibwietdiotnohafttthhyemdoeccryetaeseprionlitfehryamtioocny.teIn contrast, PFOA treatment caused no changes in the cell eyeleofsplenocytes. tAhethpierrdofxeiesdoimneg psrtouldiyfe(rYaatonrg-aecttailv.at2e0d0r2ec)epwtaosrdaelspihgan(edPtPoAeRxaminintheetihmempuosnsoimboldeuilnavtoilovnemeexnetrtoefd breygParFdOsAt.o aTfhuinsctsitoundaylmmaudtaetuisoenoifnttrhaensPgPeAniRc:PgPeAneR.:Tnhuellsemimciec,ewdhoicnhotaerexhhiboimtopzeyrgooxuissowmieth pprroolliiffeerraattoirosn.orThheespeatmoimceegwaelryeanfeddhaepdaiteotccaorncsiinsotgienngeosifs e0v.0e2n% aPfFteOrAex(powsiu)reftoro 7pedraoysx.isoAmtethe aennddowfetihgheedf.eedTihneg peefrfieocdt,ofmiPcFeOwAeroenspaecrriofxiicsedomaendprtohleifleirvaetri,osnp,lceeelnl,cyacnlde,thaynmdus were removed Iymphoproliferation was ascertained. iTnhneoressiuglntisfischaontwededctrheaats,einincobnotdryastwetioghwti.ld-Htoypweevmeirc,e,ifnecreedaisnegsPiPn AivRe:r wmuelilgmhticweePreFsOiAlrseeseunltiend PPARo: null mice, suggesting that this is notaPPAR dependent process. As expected, `npulelromxiicseo.meAplrsooliifnercaotnitorna,stastomewaisludrteydpebymifcaet,tyfaeceidding- oPxPidAaRt(ionm,ulwlamsictoetaPlFlyOlAacrkeisnugltiendPiPnAnRoo: tsihgendifeiccraenatsdeeicnrewaesieghitn athnedwceelilguhltaroifttyohfetshpeletehnyomrutshweansumabtteernoufatesdp,lebnuotcyntoets.totAaltlytheelismaimneatteidmei,n tthheymPuPsARce(llnsuallndmitchee.nuImnbaeddriotfiotnh,ytmhuedseccerlelassiensithne tSheansdizGeo2f/tMhephCaDse4so+CfDth8e+cpelolpuclyactlei,onwhofich lreesfsleecxtsteinnshiivbeitiinonPoPfApRro(linfuelrlatmiiocne,.oFbisnearlvley,d iinn cwiolndttryapstetomwiicledatdympienimsitceer,ePdFPOFAOAtrweeatrmeenmtuch mciacues.ed no significant change in splenocyte proliferation in response to mitogens in PPAR( null sApefcoiufritchhfuemeodrianlg sitmumduyn(eYarnesgpeotnasle.s2i0n0m2ibc)e.waFsodrehsiisgnsetdudtyo,e0x.a0m2i%nePtFheOeAffwecatss aodfmPinFiOsAteroend to ------------------------ 000083 amnadleseCrSu7mBaYn6timbiocdeyfaosrsa1y0s,dafyosr.thTeihreanbitlhietyantoimgaelnserwaetreeaenxiammimnuende, rveiasppolnasqeuteofhoorrmsienrgecdelbllo(oPdFC) cells (HRBCS). performed. Ex vivo and in vitro splenic lymphocyte proliferation assays were also s`Tthreonrgeshuuitmsorsahlowreesdpotnhaste,miascemefaedsunroerdmablycthheowPFreCsapsosnadye.dItno ccohnatlrlaestn,gemiwcitehfHedRwBiCtsh PwiFtOhAa urensipmomnudneidzteodHcRonBtrColsi.mmHuonwizeavteiro,niwnietxhpneroiimnecnrtesaswehienreHRPBFCO-sAp-etcriefatiecdPmFiCcse,rreecleaitvieved tnoormal PcFhCosw sftoilmluolwaitnegd.HRThBeCsuipmpmruensisziaotnioofn,thtehehruemwoarsala isimgmnuifniecarntesrpeocnosveerbyyofPtFhOeAnwuambsecrosnoffirsmpeedcibfyic caonnatlryoslisomifcteheresseprounmdeadnttoib-oHtRhBCCornesApoannsde.LPISn weixthvilvyomepxhpoecryitmeenptrso,lisfpelraetnioocny,teass miseoalsautrededfrboym ptrhoylmiifedrianteioinn.coIrnporasettioonf.inHoviwtervoeerx,petrriemaetnintgs,miPcFeOwAit(h1P-2F0O0A M(0).0a2d9d%edfotro7tdheaycsu)ltautrteenmueadteidutmheof isnplreensopcoyntseestcoulLtPuSroedrfCroonmAu.ntreated mice did not cause an alteration of lymphocyte proliferation 4.0 Hazards to the Environment 4.1 Introduction `mTahdeeaqmuoartiecdtiofxfiiccuiittybayndsehvaezraarldporfoAblPeFmsOdtioscauqsuasteidcboerlogwa.nisTmhsesweaspraosbselsesmesd.coTmhpilsictaatsekdwtahse task oFfudrettheerrmmoirnei,ngtihfetshe epreocboltoexmisciltiymitteesdtsthweerceonvfaildiednacnedthcaotulcdoubledubseepdliancethdeoansstehsestmoexnitc.ity test tvhaeluiensh,earenndttthouxsiciintytuamndlhoawzearreddotfheAcPoFnfOidteonacqeuoafticcoonrcglaunsiisomnss.that couldbedrawn in assessing G1e)nAeravalrliye,tytohefadimfmfeorneintumAPsFalOt Sorwtihteh tveatrryaibngutdyelsaimgnmaotniiounms saanltd wlaotsntuemstbeedr. sThweereexatecsttecdo.mposition and identification ofimpurities, which may affect toxicity, in ach lot number used is not known. 2f)roAmvaaprpireotxyoimfatteesltyin1g97la4b-o1r9a9t6o.rieTshicsonsdituucatteidontsheerAvePdFtOo itonxcirceiatsyesotvuedriaelslovteestrvaarpiearbiiolidtoyfatnidmtehus `made inter-laboratory comparisons more difficult. m3a)jPourrictoyonfcetrhne. tPeusrtietdymwaatesrinaolt,sourffpiecriceennttlytceshtarmaactteerriialzeadnidnptehrecseenttesottsh.eIrnmsatoemreialt(ess)s, iwt aasppaeared uthsaetd.10P0ur%ittyeostfctheestmimcaatlerwiaals duoseeds;afifneoctthteorxsicaictyheamnidcaslhooufldlebsesetrapkuernitiynt(oapapcrcooxuinmtawtehleyn$p5o%ss)ibwlaes, by expressing toxicity on the same purity basis. 4) Water, an isopropanol solvent, or a combinationofboth were used with the test material in 50 000084 ee ``mmaatneyrioafltthoemtaokxeiciittymitsesctisb,lfeorwintohotbhveitoeustsdiinlduitciaotnewdarteearsobne.foSroeltvheenttsesatries mbeigxuend.wiStohlvtehnettsesatre uasmeodunintotefsttesswthmearteertihaelcmounsctenbteraatdidonesdotfotthhee tteesstt cmahtaemrbiearls.areItexwtarsemneoltyclleoawrafnrdomatvheersyusmmmaalrlies osfutmhmeasreizsteuddiceaschwhteystaasnodlvsetnattewda"sDuasteadomarywnaosteavcecnurfaoteulnydtroeblaete nteocxeiscsiatryoyf.thIneftaecstt,s3aMm.ple with tthoaxticoiftythvealtueestsshuabdsttaonbcee.a"djTuhsutse,d itno tthaokseeitnetsotsacwchoeurnet t1h0e0p%ertceestntmastoelrvieantl(ws)a,sannodttuoseedx,prtehses the values on a 100% test chemical basis, so that the tests could be compared. 5c)heImniaclalthceosnecteonxitcriatytiteaosrtnsesoinnlsytenaodmianlawlayesstrecchoemmimceanldecodncseontthraattioonnescwaenreacucsuerda.telMyeadsetuerremdinteest tdheetearctmuianledtetshtacthtehmeincoalmicnoanlcecnotnrcaetnitornattioownhsiacrhe otnhleyt,esftoorregxaanmipslmes5ar0e%eoxfptohseed.meaIfsurietisd `cmonecaesnutrreamteinotnsso, fthcehteomxiiccaitlycvoanlcueenstrwaitlilohnasvheotuoldachcaovredibnegelny tbaekaednjourstmeaddbeya5v0ai%l.ablAen.alTyhteinc,al vroelcaoivletryy)rattheastcmoiuglhdthlaovweerbetehne adcettuearlmcionnecde,ntarnadtipohnyssitcoowchhiecmihctalhptresotceosrsgeasn(ics.gm.shwyedrreoleyxspioss,ed otaukledn ahnadvethbeeerenlattaikoennshiinptooafbccootuhnt.is kNnoomwinn.als may be used when measured concentrations are Itnheosredteersttolipmriotcateieodnswiatnhdatnoyassosrutmoefetnhvaitrtohnemneonmtianlalhaczoanrcdenrreavtiieownist wwaesreneacne"sasdaerqyutaotei"gnore etoxxpirceistsyiaorneofbatsheedmoenasweulrle-destteastblcihsehmeidcvaalluceosnc(elnotrwaitsio>n1s0.0Cmrgit/eLr;iamfeodriaussmesosrimnogddeergarteeeoisf>a1c<u1t0e0 mg/L; high is <I mg/L). 4.2 Acute Toxicity to Freshwater Species S`emvienrnaolws(pPeicimeesphwaelrees tpersotmeedltaos)a,ssbelsusegtihlel ascuuntfeisthox(iLceitpyoomfisAPmaFcOh;rotchheisreusi)n,clwuadteedrtfhleeafa(tDhaepahdnia madajgunsat)e,datnod1a00gr%eteenstalcghaem(iSceallenaansdtrtuesmtcraepsruiltcsoranruetpurme)s.enTtheed tinoxTicitay t9bes(toelrngdapenoiiznsetsd hbayvteesbteen substance) reference. and 10 (organized by test species). Each value is related toa testing facility and `rTawneglevdeftreostms7w0erteo c8o4n3dmugc/tLe.d wIittsh ufnactlheeaard mwihnynothwiss;ra9n6g-ehiLsCsSo0wivdael.ueAss(sbuamseidngonthmeosretasltiutdyi)es are vtawloida,caunted vdauleuetso tfhore blliumeigtialtliosnusnfdiisshcuaslsseodianbdoicvaet,etlhoewsetotxoixciictiyty(v9a6l-uheLsCi5n0discoatfe>l4o2w0,toaxincdit5y.69The mg/L) rNainngeeadcfutreomte3st9stw0e>r1e0c0o0ndmugc/tLe.d wTihtehldoawpehrnviadlsueasnadr4e8-ihndEicCaSti0vevoalfumeosd(ebraasteed otonxiicmimtyo,bibluitzathtei.on) 8 000085 wide range makes interpretation difficult, dSeenvseitny,tecsetlslwceoruentcso,nadnudctderdywwietihghgtrse)enraanlggeaed;f9r6o-mh 1E.C2Sto0>va6l6uesmg(/baLse(tdhoenErg5r0owctelhlrdaeten,sicteyllvalue 0to1xi,c0it0y0, bmags/eLd oisnexthceluadceudtefcrroitmertiha.isTdhiseculsoswioenr).valTuheewloouwledravlasloubeeiinnddiiccaatteishveigohftmoodmeordaetreate tmogx/iLci,tyb,absaesdeodnocneltlhecocuhnrtosn,ifcormogdreereantaelgcareitweraisona(ls0o.1ca<l1c0ulmagt/eLd).in oAne14s-tdudEy.CST0hivsaliuseinodfic4a3tive otfhelmowoscthsreonnsiictitvoexitceistty,spbeacsieeds oinntthhee4c4hr%onAiPcFcrOitteersitonsa(m1p0lemg,/dLa).phnGirdesewnearlegateheanpepxetarmeodstfo be sensitive, and fathead minnows were the leas sensitive. 000086 -- Ee SE [a `athead minnow (Pimephalespromelas)[96:-h LCS0_[70 [3M Company, 1974a [9L6-Ch S0_[7[36M 6 Company, 1980a___| [96-1LCS0[301 3M Company, 1987c I96-[h74L0 C[SWa0rd et al., 1995 [mBalcuhcrgiolclhisruunsf)ish (Lepomis. | L(Green algac (Selenastrum leapricornutum) [IEC Laboratory, 1982 1000 fLabtor`aEtnorvyi,ronm1e9n8t2al [8-h[22E1 CS 3WMar0d etalC,ompany1, 99159875. [06-hECS0 3[10Ward etal, 1995 [96h ECS0 [1000 [Wardetal 1995 | phosphoreum) EC50 EC50 Laboratory, 1996s (OFC EC50 1000 3M Company, 1987d Fathead minnow (Pimephales promelas)[96-hLCS0_440 est Sample: APFO ammoniumsaltin[9560h%LwCaSt0er[343 [Fathead minnow (Pimephales promelas)| phosphoreun) [EC50 [3MCompany, 1974b___| [3M Company, 1985 19w9i0roSystems, Inc., J [11E9n9v0i8roSystems, Inc, 11990 Laboratory, 19902 [ECS0 Laboratory. 1990 5 000087 (Test Sample: APFO ammonium salt in 80% water [F(aWattheerafdlmeia(nDnaopwh(nPiiammeapghnaal)espromelas)4068-hhLECC5S00[[429440 [Wardetal, 19962 [Wardetal. 199%c | | reen algac (Selenastrium [Ward etal, 1996b leapricornutum) [9E6-hCS06_ 66 [[Wa>rd et al. 1996b. [pBhaoctseprhioar(ePuhmo)tobacterium BECoSm0a 60 h[wLabo`raEtnovryironm1e9nt9a6l ho5m0 [0M`Environmental Laboratory, 1996 [EC50 Test Sample: APFO in 50% isopropanol {[Fathead minnow (Pimephales promelas)p| eRLcs0 io Laboratory, 19964 "R. Wilbury | Laboratories, Inc., 1996 Laboratories, Inc., 1996b. p ia r ad al apricornutun, aboratories, Inc., 1995 [Laboratories Inc., 1995 [Laboratories, Inc., 1995 Waterflea(Daphniamagna) ~~WSHECS0 141 [Wardetal 1995 | [Water flea(Daphniamagna) W8-hECS039 [Wardetal 1995 | apricornutum) apricornutun | apricornutun) *Values were adjusted to represent 100% active ingredient. These values may be inconsistent due to different diets tested. " 000088 [Table 10. Summary [Test Organism of EcologicalToxicity Datafor APFO (grouped [Value [Reference byspecies [Duration (mg/L) Fpartohmeealdasm)innow (Pimephales [96hLC50_70 [3M Company, 19742 | [96:1LC50 [440 [3MCompany, 1974b. | id OA itn 9L 6hCS050_ 0 | [Envir> oSystems, Inc., 1990a | | 19968 | oy INOAEL [[TEoxGi&coGlBoigoynoLmaibocrsatoAryq,uati1c978 PREC oI" TT19R95Wilbury Laboratories, Inc., peRECSD[aT IT1R99.5`Wilbury Laboratories, Inc.| Blues sunfish (Lepomis imachrochirus) Water flea (Daplmia magna) | | | ad ll1982Favironmental Laboratory, RRECD| t `Environmental Laboratory, 100% [1982 [48-hECS0 [221 [3M Company, 1987b [48-hECS0_292" [EnviroSystems, Inc., 1990b I 19"R9.6bWilbury Laboratories, Inc., INOEC INOEC [48-0ECS0[417 Wardetal, 1995 ] [48-[3h9% E[C War5det0al. 1995 | 5 000089 [Test Organism (Green algac (Selenastrum |eapricormatam) | [Duration alue (mg/L) [Reference | pe r w PREC 0" C50 T19R95 Wilbury Laboratories, Inc., ard ot al, 1995 | [Bacteria (Photobacteriunt phosphoreum) | 96hECS0 [127 [Wardetal 1995 | Er rlall [ECS0 "Company, 19872 1 Ea [EC50 1996E1nvironmental Laboratory, | [ECS0 al 1990Eanvironmental Laboratory, EC50 [139M96Eb.nvironmental Laboratory, ECs0 | 1996 [Activated sludge e OEC l `Company, 1980b [EC50 fom [EC50 [500 f19t90E5nvironmental Laboratory, r EC50 l1996Eanvironmental Laboratory, | Values were adjusted to represent 100% active ingredient, These values may be inconsistent due to different diets tested. PTested substance was APFO ammonium salt PTeesstteedd ssuubbssttaannccee wwaass AAPPFFOO ammonium sal in 50% water FTested substance was APFO ammonium salt in 80% war. FTested substance was APFO in 50% isopropanol. Test Sample: APFO (44%) in 27.9% water and 27.2% isopropanol 56 000090 5.0 References 3M Company. 1976a. Primary Eye Iritation Study-Rabbits. 3M Company. 1976b. Acute Oral Toxicity in Rats-T-1585. L3aMborCaotmopray.ny.St. 1P9a7u7l., MRNe.ady Biodegradationof FC-143 (BOD/COD/TOC). Environmental 3FlMuoCroocmhpeamnicyaIlnFteCr-n1a4ti3onAacluRteesOeraarlchToaxnidciDteyv(eLlDospom)eSnttuCdoyrpinorRaattiso.nS.tu1d9y78Nbo.. Fluorad 137-091, 3M Company. 1979. Technical (USEPA AR-226 528) Report Summar-y Final Comprehensive Report: FC-143. 3M Company. Environmental 1L9a8b0ocr.atoRreya.dyStB.iPoaduelg,rMadNa.tionof FC-143(BOD/COD). Lab Request No. 56255. 3M Company. Laboratory. St. 1981. Paul, Water, MN. Acetoneand Toluene Solubility Estimates. Environmental 3M Company. 1984. Chronic toxicity to freshwater invertebrates. 3EnMviCroomnpmaennyt.al L1a9b8o5raa.to9r6y,-hSotu.rPaauclu,teMsNt.aticLtaobxiRceiqtyuetsotfaNtuhmebadermC1i006n.~nFFeXbo-r1u0aw0r1y 2. 3NoM.CC1o0m0p6a.nyE.nvi1r9o8n5mbe.ntRaeladLayboBriaotdoergyr.adaStt.ioPanoulf, FMXN-.10F0e1br(uBaOrDy/1C4O. D). Lab Request 3LaMbCRoemqupeasnty.Num19b8e7.r EA1c2t8i2v.ateSdt.SPlauudlg,eMRNe.spiration Inhibition Test. Environmental Laboratory; s3uMlfoCnoamtep:anCyu.rre1n9t9s9u.m"mTahreySocfihenucmeaonfseOrrg,anhiecalFtlh,uoarnodchteomxiiscotlroyg"yadnadta""P.erFfelburouraoorcyt5a,ne1999. (SEHQ-0299-373). 3M Company. 1999b. SEHQ-0699-373. Supplement. May 26, 1999. 3M Company. 2000a. Voluntary Use and Exposure Information Profile for Perfluorooctanesulfonic Acid and Various Salt Forms. 3M Company submission to USEPA, dated April 27, 2000. A3cMidCoanmdpaSnalyts.. 230M00C.oVmoplaunnytasruybUmsiessainodn EtoxpUoSsEuPreA,IndfaotremdatJiuonneP8r,of2i0l0e0.for Perfluorooctanoic 5 000091 3hiMtp:C/ovemvpeaw.ny3,M.2c0o0m0/ca.boAubt3omu/two3rMldWwoirdled/wriedlee:as3e.MhPthmalsing Out Someof Its Specialty Materials 3LaMboCraotmoprayn,yJ.un2e00215a..InEnUv.iSr.oEnmPeAntAadlmiMnoinsittroartiinvge -ReMcuolrtd-CAiRt2y2S6t-u1d0y3,03A.M Environmental 3M Company, 2002. Submission dated September 17, 2002 to USEPA, AR 226. 3M Environmental Laboratory. Lab request number G2882. 1990a. Microbics Microtox Toxicity Test. St. Paul, Minnesota. M3iMnnEensvoitrao.nLmaenbtRaelquLaebsotrantuomrby.er1G99208b8.2.Activated Sludge Respiration Inhibition. St. Paul, P3aMul,EnMvNi.ron3mMenLtaablorLaatboroireast.ory.3M199L3a.bIRmepqiunegsetrNSutumdbieesroLf3V3o0l6atilityofFC-95 and FC-143. St. 3LMabERnevqiureosntmennutmableLrabPo1r6a2to6r.y.St. 1P9a9u6la,. MMiincnreosboiteas Microtox Toxicity Testof FC-143. R3eMquEensvtirnounmmbeenrtaPl16L2a6b.oraStt.oryP.aul,19M9i6nb.nesMoitcarobics Microtox Toxicity TestofFC-118. Lab 3M Environmental Laboratory. 1996. Microbics Microtox Toxicity Testof FC-1015-X. Lab Request number P1626. St. Paul, Minnesota. L3aMb ERnevqiureosntmNenutmableLrabEo0r0a-t1or8y5.1.20M0a1rac.hH3y0d.rolysis ReactionsofPerfluorooctanoic Acid (PFOA). 3StManEdnavridr~onTmeesnttCaolntLarboolrRateofreyr.en2c0e0#1T.CRC-h9a9ra0c3t0e-r0i3z0at.ioPnhaSsteu:dySoolfubPiFliOtAy D(eltoetr#m3i3n2a)t,ioPnr.im3aMry Laboratories, St. Paul, MN. 3M Environmental Laboratory 2001c. 26-Week Capsule Toxicity Study with Ammonium Perfluorooctanoate (APFO) in Cynomolgus Monkeys Amended Analytical Laboratory Report Title Determinationofthe Presence and Concentration of Perfluorooctanoate Fluorochemical in LAinvaelry,seSse,ru3mM, UErnivnieroannmdenFteaclesLaSbaomrpaletso.r.iesP,eSrtf.oPramuiln,gMLNab,orFaetcoersieAsn,aLliyvseer,s SCeenrturmeaAnnadlUytriicnael Laboratories, Inc. State College, PA. Analytical Phase Completion Date, June 11, 2001, 408 pp. cAabrdceilnloagtefn,eAsi.sG.byPrpeeartf,lVu.o,roToacptearn,oiH.cS.aciadn,daRpoebrerofxriosiodm,eMp.rol1i9f9e1r.atTorh.eTmooxidcuolla.tiAopnpol.frPahtarlmiavecrol. 111: 530-537. 58 000092 FAilneaxlanRdeepro,rtB..HD.iv2i0s0i1oan.ofMoErntvailriotnymsetnutdayolfawnodrOkcecruspaetmiopnlaolyeHdeaalttht,heS3chMooClootftaPgueblGircovHeealfatchi,lity. UniversityofMinnesota, April 26, 2001. RAelpeoxratn.deDri,vBisHi.ono2f00E1nbv.irMoonrtmaelnittaylsatnuddyOocfcwuopratkieornsalemHpelalotyhe,dSacthtohoel3ofMPDuebcliactuHreaflactihl,ity. Final University of Minnesota, April 26, 2001. BeharB,; Stein, G. Science 1966, Vol. 154, p.1012. JSBuyelsaytceh2m,6.. S. 31M99C5ao.mpIannhyib,itEonrvyirEfofnemcetnotfaLl-1La3b4o9ra2totroyM,iSctroPbaiucls,'MMNi,crLoatboxReTMqTuoexsitcintuymbAenarlNy2z1e6r9. EBnevaicrho,nSm.en1t9a9l5bL.abIonrhaitboirtyo,ryStE.ffPeacutlo,fMLN-,13L4a9b2RoenquAecsttivNa2t1e6d9S,luJdugley.263. M Company pBeirctgeilu,orLooBc,taLniaut,e oRnCLMey.digHucretltl,fMunEc.tiaonn,d Caonodk,exJ.vCi.vo19s9t5u.dieEsf.feTctsoofaxmAmpioplnc.iPuhomarmlaco.l. 134: 1825. Beixetgrealh,epLatBi.c tHuumrotr,iMnEdu,ctFiroanmbey,pSerRo.xiOs'oCmoenpnroorli,fe1.rCa.t,orasnidnJm.aC.leCoCoDk.rai2.001T.oxiMceoclhoagniciaslms of Sciences. 60: 44-55. SBti.oP/aduyln,aMmiNc.s IPnrc.ojec19t7N9.o.A7n8-A7c1u8t4.e Inhalation StudyofT-2305 CoCin the Rat. 3M Company, BSito.sPeaaurlc,h,MNIn.c. 1976. Primary Eye Iitation Study-- Rabbits. Philadelphia, PA. 3M Company. MBaoegrnia,.R,,TRM.agWaizlub,urIy, LWaaborrda,torT.ies1,99I5n2c.., 3AcMutCeotmopxiacnityyLoafbLR-e1q3u4e9s2t ntoutmhbeearpNh23i3d2,,DJualpyhn1i3.a PBioemreip,hRa,t,esMpargoamzeul,asJ., TW.aRr.d,WilT.bu1r9y95Lba.borAactuotrieesT,oxIincci,ty3oMf LC-o1m3p4a9n2ytoLathbeRFeaqtuheesatdnMuimnbneorw, N2332, uly 13, aBonedrit,heR,F,reMsahgwaatzeur, AIl,gaW,aSredl,enTa.st1r9u9m5cc.apGrricoowrtnhutaunnd. reTp.rRo.dWuicltibounryToLxaibcoirtaytoTreisets,wiItnhc.L, -31M3492 Company Lab Request number N2332. August 3. Boeri, R, Kowalski, P., Ward, T. 19954. Acute ToxicityofN2803-2 to the Fathead Minnow, 000093 Pimephalespromelas. T N2803-2. November 16. R. Wilbury Laboratories, Inc., 3M Company, Lab Request number BPoiemreip,hRa.l,esKopwraolmseklia,s.P.,TRWa.rWdi,lbTu. ry19L9a5beo.ratAocruitees,TIonxci.c,i3tyMofCoNm2p8a03n-y4LtaobthReeqFuaetshteanduMmibenrnow, N2803-4. November 21. NBo2e8r0i3,-R2,,anKdowtahlesFkrie,shPw.a,tWerarAdl,gaeT,. S1e9l95efn.asiGrruomwtchapaicnodrnRuetpurmo.ducTt.iRo.nWTiolxbiucrityyLTaebsotrawtiotrhies, Inc., 3MCompanyLab Request number N2803-2. November 28. 4Boaenrid,tRh.e,FKroewsahlwsaktie,r AP.l,gaW,arSedl,enTa.st1r9u9m6c.apGicroorwntuhtuamn.d TR.eRp.roWdiulcbtuiroyn LTaobxoircaittoyriTeess,tIwnict.,h 3N2M03Company Lab Request number N2803-4. March 7. BMoaegrnia,.R.,TRK.owaWlislkbiu,ryP.L,abWoarradto,riTe.s,1I9n9c.6,b.3MAcCuotmepTaonxiyciLtaybofReNq2u8e0s3t-n4umtobethreND2a8p0h3n-i4d., DMaaprhcnhia 2s. mBaoegrnia,.R,,TRKo.waWlislkbiu,ryP.L,abWoarradto,riTe.s,1I9n9c6.c,.3MAcCuotmepTaoxniyciLtaybofReNq2ue8s0t3N-utmo2btehre ND2a8p0hn3i-d2,.DMaaprhcnhia 2s. BSooily.d,MSi.ch1i9g9a3na.StRateeviUneiwvoefrsTietcyh.niMcaayl R19e.port Summary: Adsorption of FC 95 and FC 143 in Boyd, S.A. 48277, p30. 1M9i9c3hbi.gRaenvSiteawtoe fUnTiveecrhsniitcya.l Notebook. Soil Thin Layer Chromatography. Number Bultman, D. http:/home haannmdiPri.kceo,mM/.~hoafh3nMw/"nTehwse/U3smeohfimF]luorochemical Surfactants in Floor Polish", Burris, JM; Olsen, G; Simpson, C; Mandel, J. 2000 Determinationofserum half-livesof several Cfloumopraocnhye.micals. Interim Report #1, Corporate Occupational Medicine Department, 3M Burs, JM, Lundberg, JK, Olsen, GW, Simpson, C, Mandel,J. 2002. Determinationofserum half-livesof several fluorochemicals. Interim Report #2. 3M Medical Department. BP,utOelnsheonf,f,G,J,aCnodstTah,omGf,oErldc,omP.be2,00C2,. FTaorxriarc,itDy,ofHaanmsmeno,nKi,uImwapie,rfHl,uoJruonogc,tRa,noKaetneniendmya,leG, Lieder, cynomolgus monkeys after oral dosing for 6 months. Toxicol. Sei. 69: 244-257 Cameron, R.G., Imaida, K., Tsuda, H. and ItoN,. 1982. Promotive effects ofsteroids and bile 0 000094 acidson hepatocarcinogenesis initiated by diethylnitrosamine. Cancer Res. 42:2426-2428, Calfors, J. etal. Colloid Interface Sci. 103, 332 -336.(1985) Chandra, M,, Riley, M.G.1. and dawley rats. Arch. Toxiocol. 66: J4o9h6n-s5o0n2,.D.E. 1992. Spontaneous neoplasms in aged sprague- C`hSaypmipno,siRuEm,ovSetrevvieenws:, Je.nT.d,ocHriungehmeosdu,laC.tL.,iKoenlocfe,reWp.rRo.du,cHteiosns., FRu.nA.d.aAnpdplD.asTtooxni,coGl..P.29:119-9167,. CMhaejmogruBarreda,kt2h0r0o0u.ghChinemAgFuFaFrdFiIrnecF,igPhrteisnsgRFeloeaamseTeRec:hnCohleogmyg,uaJrundeI3n0c,or2p0o0r0a.ted Announces CMhircies,toFpihnearl,RBe.poarntd, MInadruisatsr,iaAl.JB.io-1T9e7s7t. L2a8bo-rDaatyorOireas,l TInocx.icSittuydSytNuod.y8w5i3t2h-F1C0-61554,3 3inMAlRebfienroence No. T-1742CoC, Lot 269. Chylpeegrgp,laE.sDi.a,aCnodoakd,e1n.oC.m,aCfhoarpmiant,ioRn.:Em,ecFohsatneri,smPs.Ma.nDd.raenldevDaanscteotno,hGuPma.ns1.99R7.eprLoedyudcit.g cTeolxlicol. 10: 107-121. CInLfOoGrPm(avt4i.on71S)yst~eCmasl,cuInlca.tiwowno.fdhayydlriogphhto.bciocmity as Log P(o/w). 2001. Daylight Chemical Cinodoukc,tiJo.nC.b, yHupretrt,oxLisEo,meFprraomleif,erSa.tRo.r,sainndCBrile:gCelD,BLR.B(.CD1)99r4a.ts.MeTocxhiacnoliosgmissot,f1e4x:t3r0a1h,epaabtsitcratcut m#or 1169. Cbuethtasv,iJorHo.fatnudmoNrosb.leC,anR.cLe.r R1e9s6.4.24E:s1t1r1o6n-e-1i1n2d3u.ced mammary tumors in the rat, I. Induction and Daikin, 2001. Nobuhiko Tsuda, Daikin Industries Ltd., "Fluoropolymer Emulsion for HighPerformance Coatings" in Paint & Coating Industry Magazine, June 2001, p. 36-66. DCP, 1998. Directoryof Services. Dallas, TX. World Chemical Producers: 1998 Edition. Chemical Information DuPont, 2000. Voluntary Use USEPA, dated June 23, 200. and Exposure Information Profile. DuPont submission to D3yMnAaF,F2F00A0g.enLtest,tedratferdomAuEgduusatrd2,K2l0e0i0n.e (Dynax) to Charlie Auer (USEPA), Re: Phase-Out of Edwards, PJB et.al. LANGMUIR 13(10), 2665-2669 (1997) 0 000095 7E8G.0&3GonBihoantcohmaibcilsitAyqoufateigcgTsoaxnidcoglroogwythLaabnordatsourrvyi.val1o9f78f.ryTohfefeaftfheecatdsomficnonnotwin(uPoiumseepxhpaolseusre to promelas). Report #BW-78-6-175. Research report submitted to 3M Company, St. Paul, MN. EalslaispDo.teAn.t,iaSl. sAo.urMcaeboufhrayl,oJg. eWn.atMeadrtoirngaannidc Da.ciCd.s iGn.tMhueiernv2i0r01o.nmeTnht.ermNoaltyusries:o4f12f,lupopr.o3p2o1-l3y2m4e.rs AEllgnaalbaArsaswayy,TMe.sTt.Me1t9h81o.d.3RMepToercthnNiucmableRrep0o0r6.t SPurmomjeacrtyN,uMmubletr-P9h9a7s0e03E0x0p0o0s.urOec/tRoebcoevre1r6y. PEinmveirpohSaylsetsepmrso,meInlca.s.19H90aam.ptSotant,icNAH.cutSetuTdoyxincuimtybeorfFwXa-s19000134-t3o the Fathead Minnow, HEnavmiprtooSny,stNeHm.s,EInnvc.ir1o9S9y0sbt.emSstastitcudAycuntuembTeoxri9ci0t1y3-o3f.FX-1003 to the Daphnid, Daphnia magna. ES&T, 2000. Cheryl Moody and Jennifer Field, "Perfluorinated Surfactanantds the TEencvhinroolnomgeyn,taVlolI.mp3l4i,caItsisouneso18f,Tph.e3i8r64U-s3e87i0n.Fire-Fighting Foams" in Environmental Science & PFlMasGt,ics20I0n1d.ustVreyr.baFlMcGo/mEmePnAtsmbeeyttihnge,FMlaurocrhop7o,l2y0m0e1r Manufacturers Groupofthe Societyofthe GFrMoGupFPlrueosreoncthaetmiiocnaSlliMdeasn)u.facturers Group AR226-1094 2002 (Fluoropolymer Manufacturers G`aSburbimeilt,tKeadrtlo.3SMumCmoamrpaynoyf,: 3PrMimCaernyteSr,kiSnt.IrPraiutla,tiMonNS.tudy Rabbits. Performed by: Biosearch. `Gabriel, Karl, Summary of: Submitted to 3M Company, 3PMriCmeanrtyerE,ySet.IiPatualt,ioMnN.Study ~ Rabbits. Performed by: Bioscarch. Gary, V.F., and R.L. Nelson. 1981. AnAssy of Cell Transformation and Cytotoxicity in C3H 10% Clonal Cell Line for the Test Chemical T-2042 CoC. 3M Company, St. Paul, MN. AGemimsyo,nJi.uP,mDPr.erf1l9u9o5ro.oc3tManoraetqeu:esSttaetdiecxFpiesrht Toevsetr"v.ieGweoisfy"EBciootaocxciucmoulloagtyi,vIencP.ropMearrtciehs2o0f. Giesy J. P. and K. Kannan, 2001a. Accumulationofperfluorooctanesulfonate and related fluorochemicals in ish issues. Prepared for 3M, St. Paul MN. June 20. In U.S. EPA Administrative Record AR226-1030A Giesy J.P. and K. Kannan, 2001b. Perfluorooctanesulfonateandrelated fluorochemicals in fish2 000096 eating water birds. AR226-1030A Prepared for 3M, St. Paul MN. June 20. In U.S. EPA Administrative Record. GfileusoyrJoc.heP.miacnadlsK.inKmainnnkana,nd20r0iv1e.r oAtctecrusm.uPlraetpiaorneodffpoerr3fMlu,oSrto.ocPtaaunleMsuNl.foJnuantee a20n.dIrnelUa.tSe.d EPA Administrative Record AR226-1030A oGyisetseyr,J.CrP.asasnosdtKr.eaKvainrngianni,ca2,0f0r1o4.m tPheerfGluoruooofcMlteanxeifscuolfoannadteChaensdarpeelaakteedBfalyu.orPorcehpearrmiecdalfsori3nM, St. Paul MN. June 20. In U.S. EPA Administrative Record AR226-1030A Giesy J. P. and J. Prepared for 3M, L. St. Newsted, 2001. Selected Paul MN, Project 178401. fluorochemicals in June. In U.S. EPA the Decatur, Alabama area Administrative Record AR226-1030A GDiosbes.onR,iSk.eJr,LaanbodrJaotohrniseosn,,I1n.cD.,. S1u9b7s9i.dAiabrsyoorpft3ioMn,oSft.FPCa-u1l4,3M-i1nn4eCsoItnaR.ats Afiear Single Oral TGoitbaslonC,arSb.Jo,n-a1n4diJnoMhanlseona,nd1.DF. e1m9a8l0.e REaxttseAnfttaenrdaRSoiuntgeleofIEVxDcroesteioofnFaCn-d1T4i3s-s1u4eCD.isRtirkieburtion of Laboratories, Inc. Subsidiaryof 3M, St. Paul, Minnesota. PGriebgsnoann,tSR.Ja,tsanAfdtJeorhansSoinn,glJe.DO.ra1l98D3o.seEoxtfenAtmamnodnRiouumteo14fEC-xPcerreftliuoornooofctTaontoaalteC.arRbiokne-r14 in Laboratories, Inc, Subsidiary of 3M, St. Paul, Minnesota. Gillett, James. 1993. University. March. 3Merequested expert reviewof "Bioaccumulation Studies". Cornell GDiolcltiolraandl,tFh.esi1s9,92D.iviFsliuoonroocfhEenmviicerlosnmaenndtaHluamnadnOcHecaulptaht:ioSntauldiHeesalitnha,nUOncicvueprsaittiyoonaflMCionhnoersto.ta. pGirloldiulcatnid,onF.pDl.anta.ndJMOaMn.de3l5,(91)S:.915909-39.54M.ortality among employeesofaperfluorooctanoic acid lGiilploiplraontde,inFs,DaannddcMhoalnedsteelr,olJ:S.a s1t99u6d.yoSfeorcucumpPaetrifolnuaolrloyocetxapnoosiecdacmiedn.andAhmepJatIincdeMnezdym2e9s:,560568. Glaza, 5. 1995. Acute dermal toxicity studyofT-6342 in rabbits. Coming Hazelton, Inc. Madison, WI. Project ID: HWI 50800374. 3M Company. St. Paul, MN. Glaza, SM. 1997. Acute Oral Toxicity Studyof T-6669 in Rats. Corning Hazleton Inc. CHW 61001760. January 10. Sponsored by 3M, St. Paul, Minnesota. 0 000097 SGtolPdaeunlt,hMail,nnEe.s.ot1a9,78bay.INnitneemtaytiDoanaylSRuebsaecaurtcehRaantdTDoexivceiltoypSmteundty.CoFripnoarlaRteiopno,rtStP.rPeapualr,ed for 3M, Minnesota, November 6, 1978. P`Groelpdaernetdhaflo,rE3.LM.,1S9t78Pba.ulN,inMientnyeDsoatya,SubbyacIuntteemRahtieosnuaslMRoensekaerychToaxnidciDteyvSetluodpy.meFnitnaClorRpeoproarttion, St. Paul, Minnesota, November 10, 197. Gorner, E.G. 1981. Oral Teratology StudyofT-2998CoC in Rats. Safety Evaluation Laboratory and Riker Laboratories, Inc. Experiment Number: 0681TRO110, December 1981 LGoarbtonreart,orEy.Ga.nd1R9i82k.erOrLaabloTraetroartioelso,gyncS.tudEyxopefrTim-e3n1t4N1uCmobCeirn:R0a6bb8i1tTsB.03Sa9f8e,tyFeEbvrauluaartyio19n52. Griffith, Am. Ind. F.D.,andLong Hyg. Assoc. J. 4J.1E(.8)1:95870.6-5A8n3i.mal toxicity studies with ammonium perluorooctanoate. Hanhijarvi, H., Ophaug, R H., and Singer, L. 1982. The sex-related difference in perfluorooctanoate excretion in the rat. Proc. Soc. Exp. Biol. Med. 171:50-55. pHaenrhfiljuaorrvoio,ctHa.n,oiMc.aYcliidnednu,riAn.g Ksoujboc,haronndiVc.adKmoinsimsat.rat1i98o7n.inEtlhiemiWniasttiaornaatn.dPhtoaxrimcaictoylo.fToxicol 61: 66-68. Hanhijarvi, H. etal. 1988. Aproposed species difference in the renal excretion of perfluorooctanoic acid in the beagle dog and rat In: Beynen, A.C. and HLA. Solleveld (Eds). New Developments in Biosciences: TheirImplicationsfor Laboratory AnimalScience. Martinus Nijhoff Publishers. Dordrecht, Netherlands. CHoaenfsfcihci,enCtsa.ndSuLbesot,itAue(nEtdsC.o)n.st1a97n9t.s fCohraCpotrerrelIaVt,ioTnheAnFarlyasgimsenatndMeChtehmoidsotfryCaanldculBaitoeldogPya.rtiJtoihonn Wiley and Sons, Inc. HchaanrsaectnerKi.zaJt,ioHn.ofOt.raJcoehnlseovne,lsJ.oSf.PEFlOdrSidagned, PJ. FLO.ABuitnetnhheofTfe,nannedssLe.eA.RivDeirc.k,En2v0i0ro2n,.QuSacnit.itative Technol. 2002, 36, 1681-1685. Hatfield, T. 2001. Screening Studies on the Aqueous Photolytic Degradation of Perfluorooctanoic Acid (PFOA). 3M Environmental Laboratory. Lab request number E002192. St. Paul, MN. Henwood, S. 1997. 5 Daily Dose Oral Toxicity Study with T-6669 in Rats. Coming Hazleton, Inc., Madison, WI. Laboratory Project Identification: CHW 6329-197. 3M Company, St. Paul, 0 000098 MN. pHeerufvleulo,roLocPt.anoeitcala.cid19i91n.malTiesasnueddfiesmtarilbeutaitosn., mJ.etBaibooclhiesmm., Taonxdiceolliomgiyn.ati6o(n2)o:f83-92. eHfefuevcetol,ftLePs.tVo.steetraoln.e.19J.92B.ioRcehneaml.eTxocxriectoiolnoogfy.per7(f1l)u:or3o1o-3c6t.anoic acid in male rats: inhibitory PHleausvmeal,, JLiPv.eVr., aetndal.Te1s9t9e2.sofCoRvaatlse.nCthBeimn-dBiingoolfInPteerrfalcutoironisn.at8e2d:3F1a7t-t3y2A5c,ids to Proteins in the BHioowaeclclumR.uDl.a,tiJvoehPnrsoopne,rt1i.eDs.,oDfrAamkem,o1nB.i, umYoPuenrgflbuloormoo,cRt.aDn.oate19:95S.tatiAc.sse3sMsmTeencthnoiftchale Report. May 31. IARC, No. 24. 1I9n9t5.emaPteiroonxailsAomgeenPcroyliffoerrRateisoenaarcnhd its on Role in Carcinogenesis. Cancer, Lyon, France. IARC Technical Report Tinkerdaat,liTv,erAbiybap,erKf.l,uForuiknuadtae,d Kf.aaynadciTdasn,akmaet,aMb.oli1c9a8l5l.yTihneertidnedruicvtaitoinovefspoefrfoaxttiysoacmiedsp.roJ.liferation Biochem. 98:475-482 Industrial Bio-Test Study with FC-143 LianbAolrbationroiMesi,ceI.nc.IB1T97N7ao.. 8R5e3p2o-r1t06t5o53. M Company: 28-Day Oral Toxicity Industrial Bio-Test Study with FC-143 LianbAolrbationroieRsa,tsI.nc.IB1T9N7o7.b.85R3e2p-o1r0t6t5o4.3M Company: 28-Day Oral Toxicity JSothundsyoonf, T1.-D6.061799i5na.RabFbiintasl. ReSptourdty,NAunamlbyetric:alAMSDtTu-dy1,20S6i9n4gl.e1-.Dos3eMInEtnrvaivreonnomusenPthaalrmTaeccohknionleotgiyc & Services, St. Paul, MN. JTo-h6n0s6o7n,,TJ-.6D.0681,99a5bn.d TF-i6n0al69ReipnoRratb,bAitnsa.lytSitcuadlySNtuudmyb,eSri:nAglMeD-TD-o0s1e1A0b9s5or.p1t.ion3/MToExincviitryonSmteundtyalof Technology & Services, St. Paul, MN. Jcoahrnbsoonn-,14J.iDn.,raGtisbasfotner,aSd.mJi,niasntdraOtbieorn,ofR.aEm.m1o98n4i.uCmho[l1e4sCt]yprearfmliunoer-oeonchtaanncoeadtefeocralpoetlaismisniautmion of [14C]perfluorooctanesulfonate. Fund. Appl. Toxicol. 4:972-976. Kachanova, Z. P.; Koslov, J. N. Zh. Fiz. Khim. 1973, Vol. 47, p2107. pKearwfalsuohriom-ao,ctYa.,noiUcy-acYiud,oNf.pearnodxiKsoozmukeaB,-oH.xid1a9t8i9o.n,Semxi-crreolsatoemdaldif1f-earceynlcgelyicnetrhoelipnhdouscpthioocnhsolbiyne 95 000099 a60c0y.ltransferase and cytosolic long-chain acyl-CoA hydrolase in rat liver. Biochem. J. 261: 595- KPheanrnmeadcyo,l.GL$1.(21)9:8354.8-D35e5r.mal toxicityofammonium perfluorooctanoate. Toxicol. Appl. pKeernfnleudoyro,oGc.tLa.noa1t9e87a.nIdnrcerleaatseed ifnlumooruoscheemliicvearlsw.eiTgohxticfooll.loLewtitn.g 3f9e:e2d9i5n-go30f0a. mmonium tKoexninceitdyyo,fGa.Lm.,moHnaillu,mG.pTe.,rflBuroirtioeolcltia,nMoaRte,. BFaomoeds,ChIeRm,,aTnodxiCchoel.n,24H(.1C2.):11938265.-1I3n2h9a.lation Kidde, 2000. Manufacture, Kidde Fire Fighting, May 30, 2000. Press Release Re: 3M Withdraws from Fire Fighting Foam OKrigrakn-iOcrh(mHeirg,he1r99A4c.id"sF)l"uoirniKniartked-OHtihgmheerr ECnacrybcolxoypleidciAaocifdCsheumnidcearl"FTleucohrnionleogCyo,mp4ouend.d, s,Vol. 11, pp. SS1-558. Kudo, N., Katakura, M,, Sato, Y., Kawashima, Y. 2002. Sex hormone-regulated renal transport ofperfluorooctanoic acid. Chem. Biol. Interact. 139: 301-316. Kurume Laboratory, 2001. Bioaccumulation testof Perfluoroalkylcarboxylic acid (C=7-13) ["TTehsitsNtoe.st5i1s5p1e9.r,foCrhmeemdicusailnsgEPvearlfulautoiroonocatnadnoRiecseaacricdh(TIenssttitsuutbes,tJaanpcaen.n,uDmebceermKb-e1r51198),]20i0n1c,arp. pages 1-26. LCaowllio/rM,aTm.mEa.li1a9n9-6m.icMruotsaogemneiRceivteyrTseestMuwtiatthiTo-n6A5s6s4ayinwtihtehSaalCmoonnfeilrlmaat--oErsycAhsesraiyc.hiaCorning Hazleton Inc. Final Report. CHV Study No: 17750-0-409R. September 13. Lawlor, T. 1995. Mutagenicity test with T-6342 in the Salmonella-Escherichia colifmammalian-microsome reverse mutation assay. Laboratory Number: 17073-0-409. Coming Hazleton Inc. Vienna, VA. 3M Company. St. Paul, MN. Lines, D. and Sutcliffe, H, Journalof Fluorine Chemistry, 25, 505 - 512 (1984). Liu, RC.M., Hutt, M.E., Cook, J.C. and Biegel, L.B. 1996. Effect of the peroxisome proliferator, ammonium perfluorooctanoate (C8), on hepatic aromatase activity in adult male Crl:CD BR (CD) rats. Fund. Appl. Toxicol. 30: 220-228, Liu, S.C, Sanfilippo, B., Perroteau, I, Derynck, R., Salomon, D.S. and Kidwell, W.R. 1987. Expressionoftransforming growth factor & (TGF) in differentiated rat mammary tumors: estrogen inductionof TGF production. Mol. Endocrinol. I: 683-692. % 000100 Longnecker, D.S. 1987. Interface between adaptive and neoplatic growth in the pancreas. Gut, 28253258. LPSD, 2000. wwwwlpsd.zzzip.netprojectshtm LPuhnoatko,ch$e,m;.SePdhioatko,biPo.l.PhAo.toCihneiima.te1d99R2e,acVtoil.on6so8,fpHp.yd1r-o33g.en Peroxide i the Liquid Phase. J. M3eMndTeelc,hnAi.ca1l97N8o.teSbooiolkT.hiOnctLoabyeerr C13h,ro19m7a8t.ogNruampbheyr--F4C8-27975,,pF3C0.-1P4r3o,jeFcMt-N3u4m22b.erEx9c9e7r0p6t1f2r6o00m. MFientarlicRke,poMr.t,anIndduMsatrriiaasl,BAi.oJ-.Te1s9t77L.abo2r8a-tDoariyesO,raIlncT.oSxitcuidtyyNSot.ud8y53w2i-t1h0F65C4-,1433MinReAflebriennoceRaNtos,. T1742C0C, Lot 269, September 29, 1977. MImopoadcyteCd.bAy.Fairned-fJ.igAh.tiFnigelAdc,ti1v9i9t9y.. EDnevtierromni.naStcii.onToefcPhenrofll.u1o9r9o9c,ar3b3o,x2y8l0at0e-s28i0n6G.roundwater MPeorotdluyo,riCn.aAt.e,dJSWur.faMcatratnitns,iWn.BCi.otKawaannd,SuDr.fCi.cGe.WMautierr, SS.aAm.plMeasbuFroyl.lo2w0i0n2g. anMoAncictiodreinntgal Release ofFire-Fighting Foam into Etobiocoke Creek. Environ. Sci. Technol. 2002, 36(4), 545-551 Murli, H. 1995. Mutagenicity test on T-6342 in an mouse micronucleus assay. Coming Hazleton Inc., Vienna, VA. 3M Company. St. Paul, MN. Muri, H. 1996a. 17750-0-455. 3M Mutagenicity Company, St. tPeasutl,onMNT-.6564 in an mouse micronucleus assay. Study number Murl, H. 1996b. Mutagenicity Test on T-6564 Measuring Chromosomal Aberrations in Chinese Hamster Ovary (CHO) Cells: with a Confirmatory Assay with Multiple Harvests. Final Report. Coming Hazleton Inc. CHV Study No. 17750-04370. September 16. MBluoro,d LHy.m1p9h9o6cc.ytMeustaWgietnhicaiCtoynTfeisrtmaotnoTr-y6A3s4s2a,yMWeaistuhrMiunlgtiCphlreoHmaorvseosmtas.l ACboemrirnagt-iHoanzseilntWonh,olInec. (CHV). Vienna, VA. CHV Study No. 17073-0-449C0. MHaumrs,teHr. O1v9a9r6y4.(CMHutOa)geCneilclsi:tywiTtehstaoCnonTf-i6r3m4a2t,oMryeaAssusraiyngwiCthhrMoumlotispolmeaHlaArbveersrta.tiCoonmsiinngC-hinese Hazelton, Inc. (CHV). Vienna, VA. CHV Study No. 17073-0437C0. NPearpfolluiorMo.a,lkFarnaecscualrfoonCy.l, FSlcuiopriidoensi:A,ThaendPyrAorlmyeslilsoifR.Pe1r9f8l4u.oroT-hne-romcatlanDee-1c-osmuplofsointylioFnluoofride. Journalof Fluorine Chemistry,24, 377-385. on 000101 Nhielpsastoonc,arRc.i,nBoegiejnei,ciBt.,yoPfrepaet,roVx.,isEormixeopnr,olKi.fearantdorRsa.mCehle,mC..Bi19o9l1.. On the Interact. mechanismofthe 78:235-250. NCuOlTtuOrXe.d Pe2r0i0p0h.erEavlaHluuamtaionnoLfymtphheocAbyitleist.y oNfOT-T7O52X4PtroojIencdtuNceumCbherrom2o9s20o6m2e.AbHeerrrtaotgieonnbsosinch, `The Netherlands. N(MOaTxiOmXis.ati2o0n0-1.TestA)s.sesNsOmeTnOtoXfPCroonjtecatctnuHympbeerrse2n9s2it0i2v7i.tyHteortTo7g5en2b4osicnht,heThAelbNientoheGrulianndesa.Pig NHeuxbabceh,loMr.ocEy;clAodpaemntsa,diVe.nDe,;WMaoto.rRee,s.W.19M9.5,TVhoel.Di2r9e,cNtoa.nd5,Spepnlsi2t8i7z-ed Ph1o2t93o.- oxidation of `MOebcohuarnni,smJ.sD,fForratmhee.paSn.cRr.e,aBteilcl,onRcHo.geJnri,cLeofnfgecntescokferth,eD.pSe,r,oExlilsiootmte, Gpr.oSl.ifaenrdatCorooWky,eJt.hC.141,969473.. `Toxicol. Appl. Pharmacol. 145: 425-436. Di`rOeEcCtDaGnudidIenldiinreectfoPrhoTteosltyisnigs,of(DCrhaefmticDaolcsu,mePnhott)o;tOraEnCsDfo,rm2a0t0i0o,noppf1-C5h9e.micals in Water- Ogata, Y.; Tomizawa, K.; Furuta, K. Chemistryof Peroxides, in S. Patai (ed), The of Peroxides 1983, p.720 Chemistry OwlistehnO,cGc.upWa.tieotnala.l 1E9x9p8oa.suArentEopPiedrefmliuoolroogoicctaInnoviecstAicgiadt.ioJnoOEfMR.ep4r0o(d7u):c6t1i4v-e62H2o.rmones in Men cOhlosleenc,yGst.oWk.i,nient,al.hep1a9t9i8c.fun3cMtioFninaanldRsepeorrutm:pAenrfelpuoirdoeomcitoalnoogiiccaicnivdeslteivgealtsiionnporfopdlucatsimoan workers. 3M Company, St. Paul. Sept 4. Ohlespaetni,cGe.nWz.y,meBusr,ricsh,olJeMs.te,roBluralnedw,liMpo.pMr.o,teMinasndienla,m1mHo.ni2u00m0.perPfllausormoaoccthaonloeactyestporkoidnuicntainond workers. Drug Chem Tox. 23(4):603-620. O20l0s1ean., GDWes,crLiopgtainv,e PsWum,mSairmyposfons,eCruAm,fBlururoirso,cJhMe,miBcuarlleevwe,lsMaMm,onLgunedmbpelrogy,eJeK.paMratincdiepla,ntJsH.of t2h0e01year 2000 Decatur fluorochemical medical surveillance program. Final Report. March 19, Olsen, GW, Schmickler, M, Tierens, JM, Logan, PW, Burris, JM, Burlew, MM, Lundberg, JK, Mpaarntdiecilp,anJtHs.of2t0h0e1by.eaDre2sc0r0i0ptAinvtewseurmpmfalruyoorofcsheemriucmalflmueodrioccahlemsiucrvaelilllevaenlcse apmroognrgame.mpFlionyaele Report. March 19, 2001 58 000102 Ofllsueonr,ocGheWm,icMaaldlseevnel,sDaCm,onBugrr2i3s6, JbuMi,ldMianngdeelmp,lJoHy.ee2s.00F1i.nalDeRsecproirptt.ivMeasrucmhma19r,y2o0f01s.erum OFllsueonr,oGcWhe,mHiacnasilensn,HCulmeamnenT,isLsAu,e.BFuirnrails,RIepMo,rtM.anEdpeild,emJiHo.lo2g0y0,1d2.2I0d-e3nWti-f0i5c,atMioendiocfal Department, 3M Company, St. Paul, MN 55144. pOelrsfelnucGrWoo,ctBaunrcsluelwfoMnMat,e B(uPrFrOisS)JMa,ndMapenrdfelluoJrHo.oct2a0n0o1at.eA(crPoFsOsA-)seicntrieolnaatilonantaolyclsiinsoicfalserum cpahretmiicsitprayn,tstohfyrtohied 2h0o0r0moAnnet,wheermpaatnodloDgeycaatnudrufrilnuaolryoscihsermeiscualltsmefdriocmamlasluervaenidllfaenmcaelperoegmrpalmo.yee Final report. 3M Medical Department. OSlesreunm, GPe.rWf.l,uoBruorolcetwa,neMsuMlf,onBautreri(sP,FJO.SM).,aMnadnPdeerlf,luJoHr.ooc2t0a0n1o.ateA(LPoFnOgAit)udLienvaellsAnianlRyesliastioofn to L1i9p9i4d/9a5n,d 1H9e9p7a,taicndCl2i0n0i0calFlCuhoermoicshtermyicTaelstMeRdeisuclatls SfurrovmeiMlalalneceEPmrpolgoryaeme. Pa3rMticFiipnaanltsRoefptorhte.: Oelpsiedne,miGoWlo,giBcuralnealwy,siMsMo,fepHioscokdiensgo,fBcBa,reSokrfat3t,MJCD,ecBaurtruirs,chJeMm,icMaalndaenld,fJiHl.m p2l0an0t1ge.mpAlnoyes, 1993-1998, Final Report. May 18, 2001. OIdlesnetni,fiGcaWt,ionBuorfrifsl,uJoMro,chLeumnidcbaelrsg,inJhKu,mHaannsseenra,.KJI., MAamnedreilc,anJHR,eZdobCerlo,ssLRad.ul2t0b0l2o.od donors. Final report. 3M Medical Department. Olsen, GW, Burris, JM, Lundberg, JK, Hansen, KJ, Mandel, JH, Zobel, LR. 2002b. `ITdehnotuigfhitcaSttiuodnyo,fSfealtutolreo,chWeamsihcianlgstoinn.huFmiananlsRereap.ort11.. 3ElMdeMreldyipcaarltiDceippaanrttsmoefntth.e Adult Changes in OIdlesnetni,fiGcaWt,ionBourfrifsl,uJorMo,chLeumnidcbaelrsg,iJn Kh,umHaannsseenra,.KJ11,1.MaPneddiealt,riJcH,paZrotbiceilp,anLtRs.i2n0a02Gcr.oup A Streptococci clinical trial investigation. Final Report. 3M Medical Department. OS'tMuadlylweiyt,hKT.-D2.,61a8ndCoECbbiennAsl,bKi.nLo.Ra19b8b1i.ts.ReRpiekaetrALpapbloircaatotriioens,28StD. aPyauPle,rMcNut.aneous Absorption Ophaug, Soc Exp RH. and L. Singer. 1980. Biol Med. 163:19-23. Metabolic HandlingofPerfluorooctanoic Acid in Rats. Proc PReaqcueeAsntalNyoti.caEl1.2821.997M.inRneeaapdoyliBsi,odMeNgr.adMataiyon2o9.f FC-126(BOD/COD). 3M Company Lab 9 000103 BPaacseedAnCahleymtiicsatlr.ie2s0.013. MThCeom1p8a-nDayyRAeeqrueosbti,c CBoinotdreagcrtadAnaatliyotniScatludPyroojfePcetrIfDl:uorCoAo0c9ta7n,esulfonylMinneapolis, MN. February 23, PPaelrafzlzuoolroo,ocMt.aJn.oa1t9e93(.CATShiNrot.ee3n8-2W5e-e2k6-D1i)etianrMyaTloexiRcaitst.y SFtiundayl wRieptohrTt.-51L8a0b,orAamtomroynPiruojmect Idenification HWI 6329-100. Hazleton Wisconsin, Inc. Pstausdtioeosro,fTa.Pm.,moLenei,uK.mP.perPfelrurio,roMo.cAt.anaonatdeG-iilnldiusc,edP.hJe.p1a9t8o7m.eBgiaolcyhaenmidcpaelraonxdismoomrephproolloigfiecraatlion. Exp. Mol. Pathol. 47:98-109. Pettis, 1999. K. Pettis, et al. "lon-pair reversed-phase liquid chromatography for pdaeitreirnmginaagteinotn"oifnpJo.lCahrruonmdaetroivgartaipzheyd Aa,miVnolo.ac$i3d3s,u1s9i9n9g,ppepr.fl1u4o7r-i1n5a5t.ed carboxylic acids as ion R3eiMneCro,mEp.Aa.ny,19E7n8.virFoantmeeonftaFlluLoarboocrhaetmoircya.lsJuilnyth1e9.Environment. Project Number 9970612613. Reiner, E.A. 1981. 3M Company Environmental Laboratory, St. Paul, Minnesota, Dec. 7. Renner, 2001. "Growing Concer Over Perfluorinated Chemicals in Environmental Science and Technology, Vol. 35, Issue 7, pp. 154A-160A, April 1, 2001. Riker Laboratories, Inc., Safety Evaluation Laboratory. 1979. Repeat Application 28-Day Percutaneous Absorption Study with T-261CoC in Albino Rabbits. St. Paul, Minnesota. Experiment Number: 09790ABO48S TRi3k3e7r1LaibnorAaltboirnioesRaIbnbc.itsS.afeStt.yPEavuall,uMatNi.onELxapboerraitmoernyt. #1093883.3EPBr0i0m7a9r.y Skin Irritation Test with Sadhu, D. 2002 CHO/HGPRT forward mutation assay ~ ISO (T6.889.7) Toxicon Corporation, Bedford, MA, Toxicon Final Report: 01-7019-G1 Submitted to: 3M, St. Paul Minnesota 551441000. Scrano, L.; Bufo, S.A; Perucc, Rimsulfuron, Pestic. Sci. 1999, VP.o;l.M5e5a,llpipe.r9,5P5;-9M6a1.nsour, M. Photolysis and Hydrolysis of Simister, E. etal. J. Chem. Soc. Faraday Trans. 88(20), 3033-41 (1992) Sohlenius, AK. Anderson, K. and DePierre, J. 1992. The effectsofperfluorooctanoic acid on hepatic peroxisome proliferation and related parameters show no sex-related differences in mice. Biochem. J. 265:779-783. 100 000104 TSetarpalteosg,enR.iEc.,PoBtuerntgieasls,ofB.AAm.,moanndiKuemmPse,rfWl.uDo.roo1c9t8a4n.oatTehe(AEPmFbOry)oi-nFetthealRaTto.xiFcuintdy.aAnpdpl. Tor. 4, 429-440. t`oTatkhaegip,eAr.,oSxaiiso,mKe., pUromlmifeemrautorras,,pTer,flHuaosreogoactwaan,oiR.c aacnidd aKnudropkearwfalu,oYr.ode1c9a9n1o.icShaocritd,-tcearumseesxposure significant increasesof$-hydroxydeoxyguanosine in liver DNAofrats. Cancer Lett. $7:55-60. c`Taarklaygib,ioAm.,arSkaei,rKf.o,r hUempmaetomcuarrcai,noT.g, enHeassiesgianwdau,ceRd.bayndpeKruorxoiksaowmae,prY.oli1f9e9r2a.toHre.pJa.tEonmveigraoln.y is an Toxicol. Pathol. 11: 145-149. oTfayHlaozraPr.,doDuesllOirnggaenriBc.CoanmdpoLueendC.-CI.n,ci1n9e9r0a.biliDteyv.elEonpvmiernotnmoenfataTlheScrimeanlcSet&abiTlietychBansoeldoRga2yn4k,,ing 316328. t`Treaenrsdfso,rKm.iJn.,g Rgormowmtehrtfsa,ctFo.rG-.a iannLdeDyodrirgincgetllond,urJ.iHn.g t1h99e0d.evIemlmoupnmoehnitstofotchheemiractatlesdtiest.ecMtoiloenc.ofCell Endocrinol. 69:R1-R6, (`TAhPoFmOfo)rdi,n CPJy.n2om0o0l1g.u2s6M-oWnekeekysC.apSstuuldeyTpoexrifciotrymeSdtubdyyCwoivtahnAcmemLoabnoirautmorPieersflIunco.r,ooMcatdaniosaotne: CWiosvcaonncsein6352397-0243-12,5C9o2mpfolretAiPonMEDatAed-DheocceAmbPeFrO13T,ox2i0c0o1l,o4g6y3Wpopr.king Group. Study No. (`TAhPoFmOfo)ridnPCJ.yn2o0m0o1l.gu4s-WMeonekkeCyasp.suSlteudTyoxpiecriftoyrSmteuddbyywiCtohvaAnmcmeoLnaibourmatPoerrifelsuIonrco.o,cMtaadnoiastoen `WCiosvcaonncsein6352397-0243-0,25C9o2mpfloretAiPonMEDatAed-DheocceAmbPeFrO18T,ox2i0c0o1l,o1g5y9Wpopr.king Group. Study No. 3ToMddC,oJmWp.any19T7e9c.hnFiCc-a1l4R3epPohrottoNloys.i0s02S.tudFyebUrsuianrgyS2.imulated Sunlight. Project 9776750202, aTnRd. tWheilFbruersyhwLaatbeorraAtlograi,esS,eIlnec.nas19t9r5u.m GcarporwitchorannudtuRme.prMoadrubclteihoenadT,osMiAci.tySTteusdty wniutmhbNe2rB0933--3TH. PTiRm.epWhiallbeusrpyrLoambeolraast.orMiaesr,blIenhc.ea1d9,96MaA..AcSuttuedytonxuicmibteyrof8N9218T0H3.-3 to the Fathead Minnow, mTaRg.naW.ilMbaurrbyleLhaeboarda,toMrAi.es,StInucd.y1n9u9m6bb.erAc8u9t2e-TTHo.xicity of N2803-3 to the Daphnid, Daphnia TOsraganngicW.,ComBuproguensdss.D.RC.o,mabnudstBiaobnusSchioekncV.e,&19T9e8c.hnOonlotghye,I1nc9i9n8e,r1ab3i9l,ity38o5f-4H0i2g.hly Fluorinated 101 000105 fUlbueolroFcAh,emSiocraelns-s-oanpSrDe,liRmoinaacrhyDrEep.ort.198A0mHeIanldthHystgatAussosfocplJa4n1t:5w8o4r-k5e8r9s.exposed to PUhSotEoPlyAsi1s9S9c8rFeaetnei,nTgrTaensstp;orEtPAa7n1d2T-rCa-n9s8f-o0r9ma9t;iUonniTteesdtSGtuaitdeesliEnnevsi,roOnPmPenTtSal83P5ro.t5e2c7t0ioInndAigreecntcy, USS. Govemment Printing Office: Washington, DC, 1998, ppl-22. F"uUnScEtPiAon1o9f98p,H;FaEteP,AT7r1a2n-sCp-o9r8t-a0n5d7;TrUannistfeodrmSattaitoesnETnevsitrGounimdeenltianelsP:ro8t3e5c.t2i1o1n0:AgHeyndcryol,yUs.iSs.as a Government Printing Office: Washington, DC. "USEPA October 20023. Memorandum 2, 2002. from Dr. Ralph Cooper, NHEERL, to Dr. Jennifer Sed, dated USEPA October 2002. Memorandum 21, 2002. from Dr. Elizabeth Margosches to Dr. Katherine Anitole, dated Vanden Heuvel, J.P, Davis, JW., Sommers, R., and Peterson, RE. 1992. Renal excretion of perfluorooctanoic acid in male rats: Inhibitory effectoftestosterone. J. Biochem, Toxicol. (1):31-36. p`eVrafnldueonriHneatuevdefla,ttyJ.Pa,cKiudssltkoipsr,oBt.eiLn,sainndthPeetpelrassomn,a,REli.ver19a9n1da.tesCtoesvoafleantts.biCnhdeimn.g of -Biol. Interact. 82317328. Vanden Heuvel, J.P, Kuslkis, B.1,, Van Rafelghem, M.L. and Peterson, R.E. 19910, Tissue distribution, metabolism, and elimination of perfluorooctanoic acid in male and female rats. J. Biochem. Toxicol. 62):83-92. Vraspir, G.A., Mendel, Arthur. 1979. Analysis for Fluorochemicals in Bluegill Fish. Project 9970612600: FateofFluorochemicals. 3M Technical Report Report Number 14. May 1 `Ward, T, Nevius, J. and R. Boeri. 1996a. Acute toxicity ofFC-1015 to the fathead minnow, Pimephales promelas. T.R. Wilbury Laboratories, Inc. Lab Request number P1624. 3M Company, St. Paul, MN. a`Wnadrdt,heT.,freNsehvwiatuesrJ,a.lagna,dSRe.leBonearsi.tru1m9c96abp.ricGorronwuttuhma.ndTRre.prWoidlubcutriyonLatboxoircaittoyriteesst,wIinct.h FLCa-b1015 Request number P1624, 3M Company, St. Paul, MN. mWaagrnad.T,.,T.NRe.viWuisl,bJu,ryanLdabRo.raBtooerriie.s, 1I9nc9.6c.LaAbcruetqeuetsotxinciutmyboefrFPC1-612041.5 3toMDCaophmnpiadn,yD,aSpt.hnPiaual, MN 102 000106 WEnevlisrho,nSmKen.ta1l9L7a8b.orTaetcohryn.ica3lMReCpoormtpaSnuymmPraojre-yctA9d9s7o0r6pt1i2o6n3o3f: FFCa-te9o5fanFlduFoCro-c1h4e3miocnalssoi,l.Report Number 1. St. Paul, MN. February 27. `hYeapgaetro,cJa.rDc.inJro.geannedsiYsagienrf,eRm.al1e98S0p.raOgruale-cDoanwtrlaecyeprattisv. esCtaenrcoeirdsRaess.p4r0o:m3o6t8e0r-s36o8f5. Yspalnege,nQa.n,dXmiiec,eY..,Calnidn.DEepxipe.rrIem,muWn.ol2.0001.22:E2f1f9e-c2t2so6.fperoxisome proliferators in the thymus of Yfoarntgh,eQi.nvXoilev,emY.e,ntEorfickinshsiobni,tiAoMn,ofceNlellsporno,liBf.eDr.ataionndanDdePdieevrerel,opJ.meWn.t 2i0n01t.hymFiucrtahnedrsepvliedneincce aPthraorpmhaycoiln.du6c2e:d1b1y33t-h1e14p0e.roxisome proliferator perfluoroctanoic acid in mice. Biochem. `thYeanpge,rQo.x,iXsioem,eY.p,rolAilfeexrsaotonr,-aSc.tEi.vHa.t,edNerlescoenp,toBr.Da.l,phaanidnDtehPeieirmrmeu,nJo.mWo.du2l0a0t2iao.nIcnavuoslevdebmyent of peroxisome proliferators in mice. Biochem. Pharmacol. 63: 1893-1900. Y20a0n2g5,.Q.P,otAebnetdis-uVpaplruegsesridoin,ofM.t,heXiaed,apYt.ivZehaiom,mXu.,neMorlelsepro,nsGe.,inNmeilcsoenu,pBo.nD.d,ieatnadryDeexPipeorsruer,eJ.toW. 2t,he38p9o-t3e9n7t.peroxisome proliferator, perfluorooctanoic acid. International Immunopharmacology luriinneanr,y eMx.c,reHtainohniojafrpveir,flHu.,orJoaoacktoannaohioc,aIc,idanidn tPheeurmaa,leP. ra1t9.89P.haSrtmiamcuolla.tiToonxibcyole.st6r5ad:i2o7l4-o2f7t7h.e lthienerant,aMf.e,r Ksionjgol,eAa.n,dHsaunbhcijhdrrovnii,cHa.dmainnidstPreautriao,n..Bu1l9l9.0.EnDviisrpoons.itCioonntoafmp.erTfolxuiocroolo.c4t4a:n4o6i-c53a.cid in YSotrukd,yoRf.GA.mm20o0n2.iuOmraPler(fGlauvoargoeoc)tTanwooi-cGe(nAePrFaOt)ioinn (RaOtnse. LAitrtgeursPeRresGeeanrecrhatLiaobno)raRteoprrioedsu,cItnic.on Protocol Number: 418-020, Sponsor Study Number: T-6889.6, March 26, 2002 103 000107