Document N2zk7yvdxRyGnax8Ryd4aQX0p

vo NOTE TO FILE - OPPTS 50639 AR 226 _ 0946 Vy DATE: October 23, 2000 FROM: Karen Lannon SUBJECT: Revised PFOS Hazard Assessment ---- e-- ee ----re-------- by these changes. Attached is a revised PFOS Hazard Assessment. Minor changes from the text in the original version (August 31, 2000) are found on pages 6, 7, and 26, and concern the corrected 1974 reference to Biesemeier and Harris. The conclusions were not affected 2 ex ZR Z2z 3552 2 Contain NO CB! I HazoanrdPeArsfsleusosrmoeoncttaannedSuBlifoomnoantiet-orPiFnOgSData I Executive Summary p[ohpuulmatainonbsloinodthseapmpplmest,o PpFpbOSrahngaes.be[enntdheetUe.cSt.edriencetnhte sbleoroudmosfeorcucmuplaevteilosnoaflPaFnOdSgeinneral smearnuufmaccotlulreicntgedemfprolmoybeleosodhabvaenkbseeanndaschoimgmheracsi1a2l.8s3ouprpcmes, while in the general have indicated mean population, PFOS levels of 30-44 ppb. levelof 5 Levels ppb. ina very small sample of children yielded even higher results, with a mean wSiadmepslpirnegadofdissetvreirbaultiwoinldolfifPeFsOpSe.cieIsnfrreocemnat avanraileytsyeos,fsPiFteOsSacwraosssdettheectUenditiendtShteaptepsbhraasngsehoinwnthe pbleaesnmdaetoefctseevderinalthsepepcpibesroafngeeagilnest,hewililvderbsirodfs.unaendxpfoisshe.d Erantdsougseendoiunstloexvieclistoy fstFudOieSs, have also which presumably occurred through exposure to a dietary source (fishmeal), Studies show that PFOS No further metabolism is is well-absorbed orally expected. Elimination and distributes from the body mainly is slow in the serum and the liver. and occurs via the urine and five feces. Serum PFOS and ahalfyears and levels in 3 retired male 3M suggest a mean elimination chemical half-life workers have been followed for (1.,) of 1,428 days (approximately + years). Based on female monkeys, a the pharmacokinetic data obtained from volumeofdistribution (V.) of 0.19L/kg a 28-cay oral was reported; study in male and no sex differences in the pharmcokinetic parameters ware noted. hPoFuOrSLChaSs0osfhown5.2 mmogd/elrianteratascuhtaestboexeicnitryepboyrtetdh.e orPaFlOrSoutweaswiftohuandrattoLbDeSm0ilodfly25i1rrimtga/tikngg.toAthoe.ne- eyes and non-irritating to strainsofsalmonella and the did skin of rabbits. PFOS not induce micronuclei was negative in an in vivo in mutagenicity studies mouse bone marrow in five micronucleus assay. ANduvmeerrsoeussigrnespeoaftto-dxoisceitoyraolbtsoexrivcietdyisntruadtiesstuodniePsFiOncSluhdaevdeibnecerneacsoesndiuncltievderiennrzaytsmeasn,d hperpiatmiecs. `vaabcnuoorlmiazlaittiieosn,awnedighehptatlooscse.llcuolnavrulhsyipoenrst,roapnhdy,degaatsht.roTinhteessetienfaflecetfsfewctass, hreempoarttoeldogaitcdaolses of2 me'kg/day and above. Adverse signs of toxicity observed in Rhesus monkey studies included aannodretxhieap.aenmcerseiass,, dmiaarrkrheeda,dehcyrpeoaascetisviintys.erpruomstcrhaotlieosnt.ercooln.vualnsdiolnispi,dadterpolpehtyioonfitnhethsealaidvraernyalgs,lanTdhse dose range for these effects was reported benween 1.5-300 mykg/day. No monkeys survived 1 i absey4o.5ndmg3/kwge/edkays.intAottdroesaetmseanst laotw1a0sm0g.7k5g/mdga/ykgo/rdabye,yocnydno7mwoelezkuss imnotonktereyastmeexnhtibaittdeodsleoswasfoloodw aconndshuemppattioocnel,leuxlacreshsyipveertsarloipvhayt.iosni,gnliafbiocraendt brreedautchtiinogn,shiynposaecrtuimvicthyo,leatsatxeirao,l hleepvaetsi.cavnadcudoelaitzha.tion gPeonsetrnaattailondecaetphrsodauncdtiovtehetroxdiecivteylosptmudeyntianlraetfs.fectAst wteheretwroephoirgtheedsatt dlooswesdoOsfes1.6inaonfdfs3pr2imnagriknea/d2a-y, Pup survival in the frst generation was pups) at the highest dose died within a significantly decreased. All day after birth while close to first 30% generation offspring (FI of the F1 pups ia the w1.o6 mtgo/pkdgo/sdeaygrdoouspes,gornoluyp tdhieedtwwoitlhoiwne+s:ddaoysseafgtreorupbisr,th0..1Aasnad r0e.s4ulmtgof/ktgh/edapyu,pwmeorretaclointtyininuetdhe piuntpos)thweesreeco0.n1dmggen/ekrga/tidoany. anTdhe0.N4 OmgA/EkgL/daanyd.LreOsApeEcLiivfeolry.thbeasseecdoonnd rgeednuecrtaitoinosn ionffpsuppribnogd(yF2 rwaeiisgihntg. coRenvceermssibalbeoduetlathyes pionternetfilaelx afnordepvheylsiocpamlednetvaellnoepumreonttoxwiecriteyifsoolloobwsienrgveexdpoinsutrhiestsotudy. PFOS. aDnedverlaobbpimte,natlatlhoeuffgehctats swleirgehtlaylshoigrhepeorrdtoedseinlepvr-lesn.ataSligdnesveolfodpemveenltoaplmetonxtiaciltytosxtiucdkiyeswienretheevriadcent datecdroesaesseosf i$n fmegta/lkbgo/ddyaywaeingdhatbaonvde siingnraitfsicaadnmtiniinsctreearseeds PinFeOxStedmuarlinagngdesvtiastcieorna.l aSniogmnailfiiecsan,t wdeelraeyaeldsoosrsiefpiocratteidona,t adnodsesskealsetlaolwvaasria| tmigon/skgw:er{eayobisneornveed.rat Apbrennoartmaalldietveesloofptmheentlaelnsstoufdtyh.ebeuyte could not be repeated significant reductions in in afestaelcobnoddystwuediygohftsainmcilsairgndiefsiicgann.t iAntcrdeoasseessoifn2d.e5lamyge/dkogssdiafiycaatnidonabwoevree, observed in rabbits administered PFOS during gestation. rTehperroeduacrteisveevetroaxilciutnycesrttuadnytideossiendtthheedaFtOa-mbaalsee.s fFoorronelxyamspilxew,eseiknsceprtihoerttwoo-mgaetnienrgatainodndid not fionrclmuadleearneypreovdaulcuattiivoentsooxfiscipteyrisminncuommbpelre,tem.otiAilctyh.ou2gnhd mbolropohdocloongcye,ntaantainoanlsysoifs PfoFrOtSheinpotential wanaismaalsssahyaevdeinbetehneseestaniamlaytseeds.basMeodreoonvelri,mittheed =pxhiaernmtaocfokpionteenttiicaldaitnat.eritspiescuinecseartnadininhtroawspPecFiOcsS variabilis in the ascertained with tphheartmwaoc-goeknienreattiiconhatnodxliicintgyofstFudOy Salonise.notThweerlle understood and presently exists cannot be fully uncertainties Fwiotrhoctcheuphautimoannalexepxopossuurreedsa,toanalsywleilmli.teDdadtaataononextphoessuarmepplaetdhwwoarykserfosriasilavpaoiplualbalteiaonnsd ihsummiassning, esxeprousmurleesveclsomweerefrnoomt pmoeoalseudresedraovaenrdtmiumsetinbethientsearmpreetienddiwviitduhalcsa.utioDna.taIonnadgdeinteiroanl,pdoupeultaottihoen PloFnOgShailn-tlhiefeboofdyP.FOitSis iunnctehrecabiondywhaentdhegrivbeondythebulridmietnediskandoewqluaetdegley rreegfalredcitendg btyhesdeirsutrmibluetvieolns of Several on-going mechanistic and other studies may help address some of these data needs. 3 IL. Hazard Assessment Metabolism and Pharmacokinetics Absorption 4P.F2OmSg/iksgw)eliln asbosluotriboendtfooglrloouwpisnogfitngherseteionm.aleAfrtaetrs,aasilnegalset o9r5al%odfotseheoftPotFalOSca-r1b4oCn-(1m4eiasn dose. systemically absorbed contents contained on at 24 hours (Johnson. average, 3.45% of the Gdoisbe.sonThaendmOebaenr,fe1c9a7l9ae,x)c.retTihoen digestive is 1.55% tract and ofthe dose 2dtig2e4sthiovuertsraacntdpl3u.s2c4o%ntaetn4ts8 ihsou5r%so. fAtthe24dohsoeu.rs,Sothmeemoefatnhissu5m%oflitkoetlayl rceaprrbeosne.at1s4 siynsfteecmeiscaalnldy a2bcseosrulbtedofceaxrcbroetni-o1n4. prTehseendtaetizthferromintthhee4d3igheosutrivpeotsrtacdtostiessgureosuoproifnrtahtes dairgeecsotnisviesttreanctt wciotnhtetnhtes2a4s hour post dose administration data. Thus, at to non-fasted least rats 95%ofthe PFOS-14C dose was absorbed from solution after Distribution Aof1t2h4e10rad4i8oahcotiuvristyafrteecroavesriengdlewaorsalfoduonsde ionftPheFOcSar-c1as4sC((J4o.h2nmsogn/,kG)ibisnornatas,ndapOpbreorx,im1a9t7e9lay).36T%he cnaercceassssardyataandarehonmootgaesnereiltiyaobflesaasmtphleeotahleirqutoitssswuadsatdaifsfiicnuclet large volume homogenates were to assure. There is some excretion of owtearlecanaarlybzoe1dn4foirn tuortianlec(a1-r2%b/od1an4y)c.ontTehnet,saplnedentshefpreormcetnhteo2ft4hheoudrosaendin48thehowuhroploestordgoasnewraatss 0m.e2a%n.ratTiohoefrcoendcebnltoraotdicoenlslo1f0 tpoltaalsmcaarcboonnc-e1n4triantiroendabtl2o4odacnedll4s8anhoduprlsaissm0a.2w5eraendco0m.p3a9,red. The rreestpeencttiiovneolfy.caTrhbuosn,-1a4t 2i4n raenddb4l8oohdoucrelslsafter a single oral dose of FC-95-14C. there is no selective A14t8co9ncdeanytsraatftieornsa asibnogvlee oinnterauvgeenqouuisvdaolesnetosf/gPwFeOrSe-a1s4fCol(l4o.w2s:mel/ivkegr), 2i0n.6m:alpelarsatmsa,.m2e.a2;nktiidsnseuye,C- m1.a1r;raonwd, launndg,sp1l.e1e(nJohhandsocno,ncGeintbrsaotnioannsdtOabnegri,ng1f97r9obm).0.2Otthoe0r.6tiusgs/uge.s sTuhcehreaswmausscaldei,ffskeirne,ncbeoinne C14 contentofsubcutaneous was found in whole eye (0.16 fat (0.2 ug/g) ug/g) and no and abdominal detectable C-14 fat (<= 0.08 ug/g). was found in brain. Very litle C-14 Only liver and prelsapsecmtaivceolnyt.aiTnehdealosuwbslteavnetlisoalfpreardcieonatctaigveitoyf dfoosuendatfo8r9kdiadynseyp,osltundgo,sete,st2e5s,.2a1nd% sapnldee2n.8a1re%,due in part 10 blood still contained in these organs when nomogenized. wPlearceengtiavlentaonrsatledroosfesPFofOSPFhOaSs been (0.1, d0e4m.on1s.6t.raorte3d.2(Amreg/ukse/Rdeasyeairnc0h.L5a%boTrwateoernies80,).199M9a),le FO FO rats Y animals were administered treated 42 days PFOS daily 42 dparyisorptroiomrattoimnagtainngd,tthhrroouugghhmgaetsitnatgiopne,riaond;d female FO animals were up to 20 days following 2lnidethdeeilrivoefrfys.priLnigve(rF1a)ndwesrereaasnaamlpylzeesd cfoorlltehcetepdrersoenmcetohefiPnFitOaSl.poTpuhleatFiOonroesfuldtossbeydaarneimpraelsse(nFtOe)d below, by dose group: Dose group Average PFOS conc. (mgkg/day) 0.0, in serum (ug/ml) female 0.0307 ol male 0.0244 female 5.28 04: male 10.5 female 13.9 16 male 45.4 female 82 male 152 32 female NR* male 273 "samples not received Average PFOS conc. in liver (ug/g) female 0.171 male 0.665 female 14.8 male 84.9 female 58.0 male 176 female 184 male 323 female NR* male 1360 A0v.e0r5a1g1e,P6F.1O9S,57c.o6,ncaenndtr7a0t.i4ounsg/ignipnotohleed0.li0v,e0r.1s.am0p.4l,easnfdro1.6 m F1 animals my'kg/day shortly after birth dose groups, were respectively. Elimination UinrglrnaavreynoeuxscrdeotsioenoifsPtFheOSpr-i1m4aCry(4r.o2utmeogf/kegl)imiinnamtailoenraftosr, PmFeOaSn. urBiynar3y9edxacyrsetaifotnerwaassi3ng0l.e2+-1.5% oefxctroettailoCn-w1a4sad1m2i.n6i+s-t1e.r2e%d.(JRoahdnisooanc,tiGviebscoonnt,eantndinObfeecse,s1w9a79sb)0.0 Mloewantocmuemausluatrievaeffeorca6l4 days, Tmgh/ekhga)lfi-nlimfealfeorreatlsimiisn7a.t5iodnaoyfsto(tJoahlasPoFnO.SGicbasrboonna-n1d4 Ofbreorm,p1l9a7s92m)a.afTehrias dseintgelremionraaltidoonsewa(4s.2 b1a4s4ehdouuprsonafatnearltyhseissionfglpelaorsamladsoasme.ples from groupsofthree rats at 1, 2, 6, 12, 24, 48, 96, and Twheeartmeeinste,vtihdeenmceeaonfpeenrtceernothaegpeatoifc circulation PFOS-14C of PFOS. After dose eliminated 21 daysofcholestyramine via feces (75.8 = 5.0) was 9.5- fGoilbdsothneamnedaOnbepre,rce19n8t4a)g.e oAfftdeorsaedejluismtimneanttedfovriathfeecaemsobuyntcoonftrcoalrbroants- 1(34.0ex~c-re0t.8e,d Jionhunrsionne,(13% efxorcrceotnetdroalrsea1n9d%5fo%rfcohroclheoslteysrtaymrianmei-nter-etarteeatderda)t,s tahneda7m4ou%ntfosrocfonctraorlbcaot1sn.4 rAefmtearinPiFnOgSt-o1b4eC 4 s faodrmicnhiosltersattyiroanm,inthee-tmreeaatnedliavnerdccaornbtoronl-1r4atcs,onrteesnpetctaitv2e1ly.dayMseraenprepsleanstmsa1a1n%d raenddb4l0oo%docfeltlhe dose acuatrhboorns-1c4onccolnucdeenttrhaattitohnes hairgehscigonnicfeinctarnattliyolnoowfePrFaOftSe-r 1214Cdaiynsloifvecrhaol2esttyr3awmeineeksTraefattemrecnots,inTghe 2fonldd tshueggfeacstttthhaattcthhoelreesitsyaracmoinnseidterreaabtlmeen2tnteenrhoahnepcaetsicfecciarlceullaitmiionnaotfioPnoFfOcSa-r1b4oCn.-14 by nearly 10Acute Toxicity, oFroaulrsrteupdoiretsos forfaatcsu,taensdtuodnieesdoefrmPaFlOaSndhavyee birereintatsiuobnmistttueddy,oofnreabibnihtaslation toxicity of rats, two P[nFaOSstduudsyttoindaeitre0rmiSnperatgheuem-eDdaiwalneyletrahtasl. c5o/nsceewn/tgrraotuipo.nl(eLvCe.lys),ofRus1.c89htoeta4l5..9(719m7g9/)laPdEmiOnSisttoeeriegdht test groups. minute was uAsedWrtiogahdtmdiunsits-tfeeretdhmeePcFhOaSnidsumstw.itRhatdsryweairreaetxapofsloewd rate for of 12 to | hour. 16 The liters per test group rats iwneiitigahteiodn.20T1h-e29t9estggartosutpudryatisniwteirateioenx.pTohseedco(n0tr1o.l99g.r2o.u8p6.r4a.t8s8.we6i.g4h9e.d7.20053.-2136.39,22a4t.s09nodr 45.97 p#1r.otoTchoelscwoenrteolthreatssawmeereasetxhpeosteesdt gtoroduryp raaitrs.at T2hleorwatsrawteeroefo1b2selirtveresdpfeorrmaibnnutoer,malAlsliogtnhseprrior chaemxbpeorsu,rheo,uartly13f-omrifnouutrehoinutresrvaafltserduerxipnogsutrhee, 1a-nhdoudraielxypothseurreea,ftaetrrfeomro1v4aldafyrso.mItnhdeiveixdpuoaslurbeody iwseirgephotrstewdertehatreaclloradneidmaolnsDdayyin0g(spproinortatnoeeoxupsolsyurwee)r.eDnaeycr1o,psDiaeyd 2a,5Dsa0y0n42, Dpaoyss7i.balendafDearyde14a.thIt pBrloovoiddesd.ampTlhees LweCre0cfol5l.e2ctmegd/lonaDnady951+%4 fcroonmriadilenscuervliivmiintsg oanfima4.l4 sa,ndbu6t.4anmagl/ylsewserweercealncoutlated using the method ofLitchfield and Wilcoxon DThaey h2i.ghAecstthdaotspeoignrto,uopn,l4y5.59a7nimgm/all,s wsausrvniovtedusaendd ibnlothoed LsaCm,plceaslcwulearteiotnaskeanndattteerrmmiinnaattieodn.on The 13.9 mg/l exposure. group These was also animals terminated early (Day !) were also not used in the because of2 mechanical LC. determination. problem during [n the 24.09 mg/l exposure group, 80% mortality. At4.88, 2.86, and all animals died by 1.89 mg/l there was Day 6. 20%, At 10%, 7.05 and and 0% 6.40 mg morality, there was respectively. The rats in material around the nose all or these other groups showed nasal discharge. signs of yellow toxicity material including emaciaion, around the anogenital red region. dry ralesor other breathing observations were reported (d0isbteurlbeasnscferse.qaunendtgiennetrhaellopwoeorrecxopndoistuirone. Abnormal groups. inlife At necropsy, the Discolorationof most common abnormality the lung was also observed iwnacsondtirsoclolroartastainondotfhetrheefolrievemr aayndnoltunbge weatment 5 6 deilsacteodl.oraTthieornefoofret,hetlhievemro.stAmsiognnigfiacnaintmatlrseatthmaetndtieredlaptreedmaatbunroerlym,alidteycrweaassedvabroyidnygwdeeiggrhete,s of discoloration observed. of the lung, and discoloration and distention of the small intestine were also d{onsaesstoufd0y,to10d0e,t2e1r5m,in4e64t,heaancdut1e00or0almgL/D,k,g,PDFeOaSn ebtyal.gav(a1g9e7.8)TahdemipnoiswtdeerreeddCtDestramtas,terSi/aslexw/agrsotp, svuoslpuemnedseodfin10am2U0k%g abcoedtyonweei/g8h0t%. cTohmeoirlatsmiwxetiugreh.edAl1l72d-o2s1e2lgevaetlsthweerbeegaidnmniinnigstoefrtehdeasstudy oibmsmeerdvieadtefloyr aprbinoorrtmoadlossiignngsadnudriwnegigthhetsfwoeurrehoruercsoradfetedraetxDpoasyur7e,anadndDadyail1y4.thTehreeafrtatesr wfeorre14 days. Its reported ats that survived to that the all animals dying end of the 14 day spontaneously study. were grossly necropsied, as weil as all Amgc/uktge),oraflemLalDes v(a2l7u1es(2a0n0d-39659)%mcgo/nkfgid)eancned lciommibtsinweedremcaallecualnadtefdemfoarlemarlatess((225313 [[119690--331389]] mg/kg). Ainllthaets21f5n mthge/4k6g4garnoudp1d0i0e0dmpgre/mkagtudroesley.grou[pasppdeiaerdsbseifgonrseofthetoexnidciotyf mthoeststufdrye.queTnhtrleyeoabnsiemravlesd iynecllluodwe-ds:iahiynpeodacutriovgiernyi,tadlecrreegiaosne,d sltiommbatcohned,isatnedntaitoanxiaan.d Astignnescorfopisryri,taotbisoenorfvtathieongslainncdluuldaerd: `mucosa, and lung congestion. In 2 second oral Sherman-Wistar study, albino Gabriel rats (5 (1978; cited in /sex/group) two DdeoasneseotfalP,F1O9S78b)yagdmaivnaigseteinrewdattewr.o groups of The rats weighed between 200 -300 grams. mg/kg and less than 1500 mike, & was determined the acute oral LD, was greater than 50 AthlelolfatsthreatrdatesadadomninDiastyer9.edN1o5n0e0 omfg/thkegrdatisedadbmeifnoirsetetrheed1540-dmayg/okbgsedriveadtiboenfopreeritohde eennddedo,ftwhieth study. Tis stated that rats were observed how frequently they were observed and no for signsof individual toxicity and mortality but animal data was provided. it is ot clear [ts stated that stheemih-icgohmdaotsoeseg"robuyp2r4athsowuersr;es"adyeiprnegssinedt"hiasts2t-at3e hunotuirlsdaefattehr dococsuirnrgeda.ndN"oseivnedrievliydudaelprpeastsheodloogry data were provided. remarkable." The author states: "Gross pathologic examination revealed nothing SBiixesaelmbeiinoerraanbbdiHsarhraids,th1e9i7rh4aierxacmliipnpeedd tthreopmottehnetiiralbafcokrsPaFnOdSfltaonkcsa.usaendskiitnapapnedaresvefiivmeittaetnitohns. of one gram (0.5 g; the procedure states either 0.5 g or 0.5 ml and the test material as supplied by 6 7 3M was covered a solid)ofthe test material with gauze patches. After was placed on abraded: or 24 hours and 72 hours the intact prepared coverings were test sites, removed then and the pdreogvriedeeodffeorrymtehetmhaoadnodr secdoerminagowfarsesruelctos.rdeCdoanccceonrtdriantgiotnooarsttoatanldadrodsiezeodfstceaslte.matNeoriarlefwearesncneotis ipnrdoivciadteeds.no[nraeldldseinxinrgabobris,weitllisinrgepdoertteectdedt.he primary skin irritation scores were 0; which a the could eye not riunbittahseiiornesytesu.dy.[tsiaxppaelabrisnoonNeewtenZtehaolafandgWrhaimte(0.c1abgb;ittsheweprreocpeldaucreed in collars so they sates either 0.1 g or 0.1 one ml was used and T117 eye, the other eye was was left a solid as untreated supplied by as a control. 3M)ofthe test substance was instilled The concentration or total dose of the in test 2susbcsatlaenocfe dwaemraegneottoprtohveicdoedm.ea[,tiisisr,epaonrdtetdhethbautlbtaher arenadctpiaolnpetbortahlectoenstjumnatcetriivaal awta1s, r2e4a,d48a,gaainnsdt w7e2rheousrcsoraefdt,erantyreaatcmceunmtu.laTtheed sdciaslcehacrrigteeroira rweesrieduneootfptreesstenmatteedroiralrewfaesrenfcleuds.heEdafcohmtitmhetehyee,eyes 2T4hehroeurissnaofterrefterreeantcmeenptrotvhiedneddefcorretahseedmeotvheord.theItreasptpoefartshethsattudsyco(rBeisewseemreeimearxainmdalHarartis| ,ho19u7r4)a,nd Mutagenicity aPnFdOiSn wthaesDt4estsetdrafionorfitsSaabciclihtayrtoomyincdeuscecemruevtiastiizoen(LinittthoenABmioensetiScasl,mo[nnce.l,l1a9/7M9i)c.roItsowmaes Paliastoe Test ested in: (Mech. (1) a Salmonella ~ Escherichia 1999): (2) an in vio assay for cchorloim/oMsaommmaalliaabne-rrmaitciroonssoimnehruemvearnsewhmuotlaetbiioonoadssay lymphocytes primary cell (Murli, cultures 1999): and (3) (Cifone, 1999). an assay It was for unscheduled DNA synthesis negative in all assays in which it (UDS) in rat iver was tested. PFOS dlooceussnooftEi.ndcoulciewrheevenrsteesmtuetdawtiitohnoart wtihethhoiusttimdienteabloolciucsoafctSi.vattiyopn.hiImtudroieusmnoortaitndthueceTryptophan acchtriovamtoisoonmaanldadboeersrantoitonisndinucheuUmaDnSliynmpprhiomcayrtyesculwthuernestoesftreadt whietphatoorcywtiest.houPtFmOeStawbaolsiaclso tested in an bone in vivo marmow mouse micronucleus assay of Crl:CD-1 BR mice and (Murli, 1996). is negative in PFOS did not the mouse bone induce micronuclei in marrow micronucleus the assay. pTe-r2t2l4u7orCooocCtawnhesiuclhfoins aate50in%wbatyewrewiagshttsesoileudtifoonr of is the diethanolammoniurn salt of ability to induce gene mutasion in strains of (S.Sitmympohri.mu1r9i7u8m).anTdhaelscohefmoirciatslawbialsitnyetgoatiinvdeucien arlelc5omsbtiraniantsioofn SianlSm. ocneerlelvaisainade sinaSi.nCeD5r.ovisiae eDy3phwihmeunrituesmtesdtrwaiintshTaAnd98wiatnhdouTtAm1e0t0aboinliacdaecstiicvcataitoonr.asTs-a2y24fo7rCthoeCdewtaescttieosntoefd vwoiltahtiS.le compounds. It was nonmutagenic when tested under these conditions. g Repeat-Dose Toxicity Three 90-day monkeys and subchronic one dietary studiesof POS study in ras. [n have been addition. 2 conducted, four week two and gavage studies in a 26 week capsule rhesus study in eynomolgus this review. monkeys have been conducted. In addition, a two-year cancer Both reports were bioassay is currently unaudited drafts at the time of being conducted, but was not available at the timeofthis review. 2IUnstehxeigfrirosutpr,hdeossuessmoofn0k,ey10,st3u0d,y,10G0olodren3t0h0almye/tkalg./d(a19y79P)FOadSmi(nFiCs-t9e5r)edinrhdiesstuisllmedonwkaetyesr,by gavage. kg. The The males weighed 3.05-3.30 monkeys were observed daily kg for at study general initiation and clinical signs the and females weighed 2.75.10 body weights were recorded wbeeegkilnyn.ingHoefmatthoelostguidcy.al Tanhde csltiundiycawlacshetmeirsmtirnyataendalayfsteers 2a0nddauyrsindaluyesitso wtheeredecaotnhdoufcttheed matontkheeys. Awetignheecdr.opsTyhtehethhyeraoritd,/lpiavrear,thaydrroeindalwse,rseplweeein.ghpeidtuiattatrey.fkiixadtnieoyns., Ttiesstseuse/sovwaerrieesparnedsebrrvaeidniwnere obrugfafenrsefdrnoemurcaolntr1o0l%anfdoramlallwine;attehde geryoeusswsewresrpereesxearmviendeidn mRiucsrsoeslclo'psicfailxaltyi:ve.adrTehnaelsf,olaloortwai,ngbrain, esophagus, eyes, gallbladder, colon, rectum, kidneys, liver, heart lung, (with skin. coronary vessels). mesenteric lymph duodenum. ileum, jejunum, cecum, node, retropharyngeal iymph code, mammary junction), sgallainvda.rynegrlvaned(,wlituhmbmaurscslpei)n,alspcloeredn.,ppitaunictraerays,,Stproomsatcaht,e/uttesetreuss/,obvoarnieesb.otnheyrmoiadr.row (ib parathyroid. thymus, trachea, tonsil. tongue, urinary bladder and vagina. 4Alltoheftmhoenktereyastedinmtohnek1e0y0smdgi/edk.g/dTahye gmroonukpedyisedinbtehtewe3s0n0 dmaey/ske3/-d5.aythgermoounpkdeiyesd binettwheee3n0days 2- mbeyrkwge/ednadyaygsro1u1p-d2i0eodfwbeeattwmeeenntd.ayTshe7-1m0o.naknedysthefomomnkalely'thseignrtohueps10smhgo/wkegd/dsiamyilgarrosuipgndsieodf toxicity including decreased activity, emesis wembling, twitching, weakness, convulsions with and some diarrhea, prosiration. At body stiffening, general necropsy, severalofthe body monkeys in the 100 and 300 mg/kg/day groups histologic examination showed no microscopic lheasdio2nsy.elCloonwgiessht-iborno,whnedmiosrcrolhoargaetiaonndofltiphied liver; depletionofthe adrenal cortex was noted in all treated groups. No other lesions were noted. In the second 00,0.5, 1.5 study, Goldenthal etal. or 4.5 mg/kg/day PFOS (1973) (FC-95) administered thesus in distilled water by monkey's. /sex/group, doses gavage for 90 days. The mmaolnekseywseiwgrheedo2b.s5e5r-v3e.d55dakiglyatfsortugdeyneirnailticatliionnicaalndsitghnes faenmdalbeosdywewiegihgehdts2.w7e3r.e7r5eckgo,rdeTdheweekly. tHheemasttuodlyogaincdalafatnerd 3cl0ianincdal9c0hdeamyissotfrtyraenaatlmyesnets.anTdheurimnoanlykseiysswewreerecosnacdruicftieceddaatftiehre 9b0egdianynsinogfof weatment and a gross necrospy was conducted. At necropsy the heart, liver, adrenals, spleen, 3 9 paifttueirtfairxya,tikoind.neTysi,sstueesstewse/rovearpireessearnvdedbrianinbuwfefreerewdeineguhterda.l The 10% thyroid/sarathy roid were weighed formalin; the eyes were preserved minicRruosssceolpli'csalfliyx:atiaved.renTalhse, faoolalo,wibnrgaion.rgeasnosphfargoums.co2nvterso.l gaanldlballalddterre,atheedagrtro(uwpisthwceorreoenxaarmyined vessels), duodenum, ileum, jejunum, cecum. colon, rectum. lymph node, retropharyngeal lymph node, mammary gland. kidneys. liver, lung, nerve (with muscle), skin, mesenteric spleen, ppiatnucirtearays,, sptroosmtaacthe,/utteesrtuess,/obvoanreie/sb,ontheyrmoaird.ropwar(astihbyjruonicdt.iotnh)y.musasl,ivwaarcyheglaa,ndto,nsliul,mbtaorngsupei,naulricnoarrdy, bladder and vagina. A7lolfmtohneksetuydsy.inBtehgei4n.n5inmgg/okng/tdheayfigrsrtoourpsdeiceodnodrdwaeyreofstahcerisftiucdeyd,intheexstermemoinskebyetsweexehnibwieteedk s5igannsd otfhegamsotnrokienytessthiandaldtercarcetatsoexdicaicttyiviintcylaudnidnjgusatnoprreixoira,toedmeeastihs.sbhioawcekdsmtoaorlkaendd dehydration. All to severe rigidity, of c3o.n4v4uklgsiaotnst,hegbeenegrianlniiznegdobfotdhye wsetumdbylitnog2.a7ndkgpraotswtreaetkion5.. ATfhteerm3e0andabyosdoyfwweeiagthmtendte,crtehaesreedwfasoma ascitginviiftiyc.anAttrendeuccrtoiposny.inmseearnumorcghaonlewsetiergohltsanwderae 3c0o%mpraerdaubclteioanmionnsgertuhem caolnktarloilneapnhdotsrpehaatteadse fmeomnakleeyss.hadHimsatrolkoegdicdiefxfaumsienlaitpiidondesphloetwieodn sienvtehrealadtrreenaatlsm.entOrneelamteadleleasinodnst.woAlflemthaelemsalheadand mzoydmeorgaetne dgriafnfuulsees.atrTowphoy moafltehseapnadncorneaetifcemeaxloecrhiandemcoeldlesrwaittehddiefcfurseeasaemdocpehlly soiftzehaendselroosussof alveolar cells characterized by decreased cell size and loss of cytoplasmic granuies wAlelekmoonfktehyesstiundtyh,eth1e.5mmogn/kkegy/sdahyadgrdoeucpresausrevdivaectdivuintty.il the end Signs of of the study. During the first gastrointestinal tract toxicity awnedreblnoootdeyd osctocoals;ioatnatlhleyednudrionfgtthheessttuduyd.y aannodreixnical.uddeehdybdlraactkiosntooolr.gdeinaerrrahleab.omduycToeumsblinintghewsetroeol dnortoepdp.edAlftrhoomu3g.h15stkatgisattictahlesbigengiifnincianngcoefwtahsensottudaychi1ev2e.d9.3 tkhge amtetahne ebnoddoyfwthee istgoudfhyt,htaendmatlhees tmheeafnembaoldeyshwaeidgahstigonfitfhiecafnetmarleedsucdtrioopnpiendsferroumm 3a.l2k2alkignetpoh2o.s7p5haktga.seAfatcetriv9it0ydaanyds soferwurmeatment, potassium reduction levels. One in inorganic pohfostphheatfee.maNleescrhoapdsyverreyvelaolwedsenroutmrecahtomleenstterreollataendd another lesions. had 2 All monkeys in gaswointestinal the 0.5 mg/kg/day tract toxicity were group noted survived unil the end of the occasionally during the study study. and Signs of included diarrhea, soft stools. anorexia and emesis. After 90 daysofweaument. a Occasionally. decreased slight decrease in serum activity alkaline was noted in phosphatase three of the was noted. monkeys Necropsy revealed no treatment related lesions. in the rat subchronic study, Goldenthal etal. (1978) administered CD rats. Sisex. group. dietary 9 16 2fe3v2elgs aonfd0,th3e0,fe1m0a0l,e3s0w0,ei1g0h0e0do1r6350-02006pgpmatPstFuOdSy i(nFitCi-a9ti5o)n.forTh9e0 ddiaeyst.aryTlheevemlaslweesreweeiqguhievdale1n9t6- s0igdnos;sebsoodfy0,we2i,g6h,ts18a,nd60foaondd c2o0n0smumgpktziodnayw.ereThreecroartsdewderweeeoklbys.ervHeedmadatiollyogfoircaglenaenrdalclcilniinciaclal 9ch0emdiasytsoryfatnraealtymseenst.andThureinraatlsyswiesrweesraecrciofnidcuedctaettderat9t0hedabyesgionfntirnegaotmfetnhteasntdud2ygarnodssafnteecrr3o0spaynd awnads bcroanidnucwteerde.weAilgnheecdr.opTshyetthheyhreoaird,/plairvaetr,hyardoriednawlesr,espwleeiegnh,epditaufittearryf,ixkaitdionne.ys,Ttiessstueessowvearriees preserved following in buffered neutral 10% organs from control and formalin: the eyes all weated groups were wer preserved examined in Russells fixative. The microscopically: adrenals, aorta, brain, esophagus, Jejunum, cecum, colon, reeycets,umg,alKlibdlnaedydse.r,lihveearr,tl(unwgi,thskcionr,omneasreynvteesrsieclsl),ymdpuhodneonduer,n, ileum. prreotsrtoapthe/aurtyenrguesa,l bloynmep/hbonnoedem,armraomwma(rribyjgulnactnido,n)n.ersvaeli(vwairtyhgmluasncd.lel),umsbpalreesnp,inpaalnccroerads,,pinsiary, stomach, vagina testes/ovaries, thyroid, parathyroid. thymus. trachea. tonsil tongue, urinary bladder and aAnlldodfaytshe1r8a-ts28infotrheth3e00m,al1e0s00anadndfe3m0al0e0s.ppremspgecrtoiuvpelsy,dieidn.thDeea3t0h0 opcpcmurrgreodupb.erwAeten10d0a0yspo1m3,-25 Tdehaethraotcsciunrarleldgbreoutpwseesnhodawyesd8s-i1g4n,soafndtoaxti3ci0t0y0ionpclmu,ditnhge eramtascidaiteidobn,etcwoenevnuldsaiyosns7-f8oolflowrienegment. rheagnidolni,ngi,nchruenacshededsebnascitki.virteyd tmoateexrtieamlaalrsotuinmdultih.ereeyduecsedvealcltoivwitmyataenrdiamloairsoturneddtmhaetearnioaglenairtoaulnd the mouth or nose. Three males males and two females in and the two females died the 100 ppm during week group died prior to 5 and the third male scheduled sacrifice. died during week 11 Twoofthe oftre astnuddyf.emAaclestgurdoyuptse,rmreisnpaetcitoinv,elmy.eanAvbeordaygewefiogohdtscownesruemprtediuocneudrbiyng16t.h7e%enatnidre1s6t.u3dy% pienrtihoedmale. w(ge/artamvednety.)hweamsatsoilgonigfiiccavnatlluyersewdeurceedcofmorpamraalbelseaanmdofnegmatlheescaotnt1r0o0lpapnmd. 10A0ftperpm30grdoauypss.ofClinical ucrheeaminsittrryogaennalvyasleusesatinonmealmeosnatnhdsfheomwaeleds.a asingdnicfriecaatnitniinnecrpehaossepihnokmienaanseglauncdosaelkianlimnaeles. blood hphaodsspihgantiafisceanvtallyuersedfuocrefdemearlyetsh.rocAyfttee,rh9e0modgalyosboifn.trehaetmmateonetraitt 1a0n0d plpemuk,octyhetetwcoounstusr:vitvhiengtrmeaeles ssluirgvhitvliylngowfeermaelreysthhraodcystieg,nihfeimcaanttolcyrirteadnucdedlehuekmoocygtleobciounntasn.d rTewtiocoulfotchyteescuoruvnitvsi,ngasfweemlalleass aschtiovwiedidess.liUgrhtintaolymsoidserreastueltisncwreeraesecsominpaprlaabslmea agmluotnagmitcreoaxtaeldacaentdiccoanntdroplyrgurvoiucpstratan3s0amainndas9e0 dlaiyvse.r weRieglahttisvewelrievesriwgeniifgihctanwtlaysisnicgrniefaisceadntilnytihencdreemaasleeds.in Rtehleamtaivleeskiadnndeyabwseoilugthetsanwderreelative significantly increased in both sexes, A 1 bAloldyratwseiignhtthse w3e0rpeprmedgurcoeudpbsyur8.v7ivaenddun$t%il itnhetheenmdaolfesthaensdtufdye.maleAst,srteusdpyecttievremliyn.atiAonv,ermaegaenfood c3o0npspumm.ptiHoenmadtuorlionggitchevaelnutiersewsetruedycopmepriaordab(lg/eraatmdoanyg) wthaescsoingtnrioflicaanndtly30repdpumce2drfoourptahte 3m0alaensdat i9n0cdraeyass.edOalnkealfienmeaplheossphhoawteadsealselvieglhtalty 3e0ledvaayts.ed gAltu9co0sdeaylsev,elonaendmaolneesmhaolweesdhmoowdeedraatselightly hinacdresaisgensifiincagnltucioncsree,abselsooidn uarbesaolnuitteroagnednraenladtiyv-eglliuvaermyw|eiaghntssp.epTthiedamsaeleacstihvaitdy.sigTnhifeicfaenmtales decreases in absolute and absolute pituitary weight. relative adrenal The biological swiegingihftisc.anacbesoolfuttehetchhyraonigde/spairnatmhaylreoiodrgwaenigwhetigahntds is unclear since similar changes were not noted in higher dose groups. vAatrnyeicnrgodpesgyr,eterseoaftdmiesnctolreolraatteidognraonsds/loersieonnlsarwgeermeenprteosfetntheinlialvlertraenadteddisgcrooluoprsatainodnoifntclhueded ggrloaunpdsu.larCemnuucriolsoabuolfatrhetosmtiodmzaochn.al Hsiysttooplloagsimciecxhaympienrattrioopnhyaolfsohesphaotwoecdytleessiaonnsdifnocalall tnreecartoesdis awdadsitoibons,erevsepdeciinaltlhyealmivoern;gthreatisnicnidtehenc3e00a.nd10re0l0atainved s3e0v0er0itpypwmergerogurpesa.tetrreianttmheentmarleleast.ed.ln mhiessteonltoegriiccllesyimopnshwneordeesn)otleydmpihnotihde oprrgiamnasr.y s(ttohmyamcuhs,.ibnotensetimneasr,rmouws)calnedansedcsoknidn.ary[n(stphleestah,ymus. mthairs rcoonwsihsytpeodcoelflduelparliettyiownasinntohteedn. umTbheersapnldeesnizweaosftslhieghllyympathrooipdhifeoldliwciltehsaancdorirnetshpeonbdoinneg idnectrheeamseesiennttehreiscizleyamnpdhnnuodmebse.roMfulcyomspahlohiydpefroklelricalteossiasndancde/lolsraancdan2thsoismiislawradsepolbesteirovnewdaisn ntoheted Dfeocrreesatsoemsacthraonpdhymuicnotshaelhheiegmhotrrahnadgtehsicwkenreessonfottehdeinvitlhlie wgelarnedunloatredpoirnttihoen somfalthleisntteosmtaicneh.. Atrophy of the skeletal was noted in the skin. muscle was noted. as well as epidermal hyperkeratosis andor acanthosis [1a99o8r)decrontodudcetteedrmain4e-wteheekdorsaengrea-nfgiendfionrgasstiuxd-ymionntcaynsotmudoyl,gTuhsommoinokredyse.t al. (unaudited drat, Male and female cmygn/omdoalgyus(Umsoenxk/aeryosupw)erPeFaOdSmiinnisctaepsrteidledsopsleascoefd0di(r2ec/tslye girntooupt)h,e 0s.t0o2ma(c3h/.sexT/hgeroumpo)n,koery2s.0 weighed 2.1- 2.4 kg general clinical signs at study initiation. and body weights It appears the were recorded monkeys were twice weekly. observed at leas: daily for Hematological and olinical c~h7(ebmaissetlriyneanvaallyuesse)s wanedredacyon2d9u.ctAedddiotniosnaamlplbelsoocdolslaemcpteldesbeffoorrcelitnhiecablecghienmniisntgroyftwheerestcuodlylecattedday on study days +7.2.3.7. 14. 2.7. and and 29. 14. Blood In addition. samples samples for serum from day POS -7and concentrations were taken day 29 were analyzed for on days leveolfs aesntirmaadilosl.weersterotneer.mienstartieold.atshsycrohiedduslteidmualtat3i0ngdahyso.morAe.netcrrioiposdyothsaymrpolneianonefd.fitvheyrrowxaisn.cTolhleecsteududy from each animal for palmitoyl CoA oxidase activity analyses. Samples of liver, testes, and A 12 aplasnocrceoalslewcteerde fcroollmeectaecdh faonripmraolliffoerraPtFioOnSceclolnncuecnlteraartiaonntiagnealnyseivsa.luaTthioen.folAloswaimnpgloerogafnlsivferrowmas control and all treated groups were examined microscopically: adrenals. eye. kidney. liver, lung. spleen, pancreas. femoral bone marrow. testes, and thymus. Noneof the monkeys died before the study was ended. There were no test-related effects on c`lmiancircoalscoobpsiecrvoartimoincsr.osbcoodpyicwepiagthhto,lofgoyodficnodninsgusm.ptNioon,tebsto-dryelatteemdpeerffaetcutrsesw,erheemnaottoeldoginy,thoerlevels of estrone, estriol, thyroid stimulating hormone. and thyroxin. Cell proliferation, as measured by immunohistochemical detection of proliferating cell nuclear antigen, was not increased in the liver, testes, or pancreas of monkeys. Both the male and female monkey that received 2.0 mg/kg/day showed reductions in serum cholesterol. Serum cholesterol levels for the male dropped froma baseline value of 150 mg/dl to 91 mg/dl at day 29. Serum cholesterol levels for the female dropped from a baseline value of s1a4m1pmlge/sdflrtoom6d2aymg7/dfloratthdeahyig29h.-doTsheeandiemcarlesa.seTshienmsoenrkuemycshoilnesttheer2o.l0wemrge/kfzir/sdt aeyvigdreonutpinboth showed estradiol levels Similarly, the monkeys that were in the 2.0 less than their prestudy mg/kg/day group both values and controls at day 29. showed miiodotayronine levels that wer lessthantheir prestudy values and controls at day 29. However, pre-treatment, the high dose monkeys also had triiodothyronine values lower than controls in baseline samples as well. cHloewaerivfetrh,esseincheorthmeonaeumlbeeverlscohftaensgtesedaraenitmraelatsmeanret-srmeallalteadnedffbeacstse.line levels are variable, it is not In by the final study, oral capsule at Thomford doses of0 (u (6 naudited draft, monkeys per s 2000) administered POS ex). 0.03 (+ monkeys per s to ex) cynom . 0.15 olgus monkeys (6 monkeys per sex), or 0.75 mg/kg/day (6 monkeys per sex) for 26 weeks. Two animals from the control, 0.15 and 0.75 mg/kg/day groups were assigned to a recovery group and were not weated for at least 52 weeks following the last administration ofPFOS. Animals were observed twice daily for morality and toxicity; food moribundity and were examined at least consumption was assessed qualitatively. once daily for abnormalities and signs Ophthalmic examinations were done of before initiation of treatment and during weeks 26 and 52. Body weight data were recorded weekly before the startof treatment, on Days -1 and | and weekly thereafter. Blood and urine osfamtprieeatsmwenetreancdolaltecstpeedcfiofriceldininitcearlvahlesmdautroilnoggytr.ecaltimneinctalacnhdemriescotvreyr,y.andBluoroidnalsyasmipslebesfworeerethaelssotart taken for hormone determinations. The following organs were weighed at scheduled and. unscheduled sacrifices; paired organs were weighed separately: adrenal (2), brain. epididymis (2). kidney (2). liver, ovary (2), pancreas. testis (2). following issues were collected for histopathology: and thyroid (2) with adrenals (2), aorta. parathyroid. The brain, cecum. cervix, colon, duodenum. epididymis (2). esophagus. eyes (2). femur with bone marrow. gallbladder. heart. ileum. jejunum. kidneys (2). lesions. liver, lung, mammary gland. mesenteric lymph node, ovary (2). pancreas. pituitary, prostate, rectum. salivary gland [mandibular (2)], sciatic nerve, pe 13 sspelmeienna.lsvteesimculme (w2i)t,hskbeolnetealmamrursocwl,e s(tthoimgahc).h.sktiens.tissp(i2n)a,ltchoyrmdus(,certvhiycraoli,dt(h2o)rawciitch, apanrdatlhuymrboaird),, trachea, urinary bladder. uterus, and vagina eMnadleOsf w26eiwgeheekds3o.f3t-r3e.a4tkmgenatn,dmfaelmeaslewseiwgehiegdhe3d.72,.83.-82,.93.k5,g aatndth3e.3bekgginfnoirntghoef0t,h0e.0s3t,ud0y..15Acantdhe 00..705.0m3,g/0k.g1/5daanydt0r.e7a5tmmengt/kggr/oduapys wreesaptemcteinvtelgy.rouFpesmarleespsecwtievielgyh.eTdhe3.1,d3i.f1f,er3e.1ncaenbdet2.w8eekngftohrethe ocfotnhtreolreacnodvetrhye 0pe.r7i5odm,g/dkifgf/edraeyncfeesmianlewetirgehattmbeenttwgereonupthsewcaosntsrtoaltiasntidcatlrleyastiegdniafniicmanatl.s Awterteheneond longer obvious. dTiueod amfatleresdofsrionmg tohne D0.a7y5 1m5g5/k(gW/edeaky g23r).ouCplidniidcanlotsisgunrsvinvoetetod tihnetshicsheadnuilmeadl sianccrliufdiceed.: Ocnoensatnriicmteadl phuyppiolasc,tipvailtey,gulmasb,orfeedwr,esmpuicroatiido,n,lidqeuhiyddraantdiobnl,acakn-dzorleocruemdbfeenctes,polsiocwiofn.ood[acaodndsiutimopnt,iotnhe, animal dweatsecromlidne1d0 ttohebetopuuchl.moAnnareyalnaercgreodsilsivweirtwhassevdeerteecatceudtebyinpfallapamtmiaotni.onC.auOsneodafyde1a7t9h, wthaessecond. male was sacrificed in a consumption, excessive moribund salivation, condition. Clinical signs noted included low labored respiration, hypoactivity and ataxia. food Causeofdeath was not determined Males and females in females the 0.15 in the 0.75 ma/kg/day dose-group had and 0.75 me/kg/day groups had lower lower total cholesterol and males and high density lipoprotein cholesterol during reatment. The effect on high density elfifpeocptrootneitnotcahloileoslteesrtoelrowlaswarsevreervseerdsweidtwhiitnh9inweewkesekosf of recovery recovery. and the oEfsviarradiiaotliovnalounelsywtehreedalyowe1r82invamlauleeswagsivseingn0if.i7c5anmtg./Eksgt/rdoanye ovnalduaeysswe62r,e9g1,enearnadll1y82hibguhterbeincatuhes,e evaalsueesd wfeermealseisgnoinfidcaanytsly37d,if6f2eraenntd f9r1ombutthaegcaoinntrbolesc.auTsreioifodvoatrhiyartoinoinnien vtahleuedsatwaenroenenootfabtlhyesleower oinnstdaanycses91inawnhdic18h2hionrmmaolneesvaanlduefseminalterseagtiedvegnro1u0p.s15waenrde d0i.f7f5ermegn'tkgE/odamy.thoTsheeorfe cwoenrterooltshebrut tahnedsediddiznfoetreanpcpeesarwetroebenortelcaotnesdisttoenttheovademrintiismteraotriboentowfetehnesteexsetsm.atweerriealn.otApcplaearrelnytddoisfef-erreeinacteesd in the the sexual maturityof hormone data. both males and females used in the study complicates the interpretation of Awetitgehrtm,ilniavlersa-ctr0i-fbiocdey, fweemiaglhetspienrctehnet0ag.e7s5,magn/dkgl/idveary-tdoo-sbrea-ignrowuepighhatdraitniocsr.ea[saedmaalbesso,lultievelriv-eorbody wlieviegrshtweperrecoenbtsaegrevsedweinretwionchriegashe-ddoisnetmhaelheisgha-nddosien ognreouhpigcho-mdpoasreefdemtoalt.heOcoFnttrhoelst,wo"mMaoltetslendo"t PE " the high-dose group. surviving until the scheduled terminal sacrifice, one had a "mottled" and large liver. Three of4 `high-dose males (including those that did not survive to scheduled sacrifice) had centrilobuloarr diffuse hepatocellular hypertrophy which was also observed in all high-dose females. Centrilobular or diffuse hepatocellular vacuolation occurred in 2of 4 females and 2of 4 malesin No PFOS related lesions were observed either macroscopically or microscopically at recovery sacrifice indicating that the effects seen at terminal sacrifice may be reversible. Developmental Toxisity `Three prenatal developmental toxicity studiesof PFOS have been conducted, two studies in rats. and one study in rabbits. The first study administered mg/kg/day PFOS in com oil four groups of 22 time-mated Sprague-Dawley rats 0, 1, by gavage on gestation days (GD) 6-15 (Gortner, 1980). 5, and Doses 10 were adjusted according to body weight. Dams were monitored on GD 3-20 for clinical signs of toxicity. sacrificed Individual on GD 20 body weights were recorded on by cervical dislocation and the GD 3, 6, 9, 12, 15, and 20. ovaries, uteri and contents Animals were were examined for the numberofcorpora lutea, numberofviable and non-viable fetuses, number of resorption sites. and number of implantation sites. Fetuses were gross necropsy. Approximately one-thirdof the weighed and fetuses were sexed fixed and subjected to external in Bouin's solution and examined for visceral abnormalities by free-hand sectioning. The remaining fetuses were subjected toaskeletal examination using alizarin red. Signsofmatemal toxicity consisted of significant reductions in mean body 12-20 at the high-dose group of 10 mg/kg/day. No other signs of matemal weights toxicity during were GD reported. Underthe conditionsof the study, a NOAEL of 5 mg/kg/day and a LOAEL of 10 mg/kg/day for maternal toxicity were indicated. Developmental toxicity evident at 10 mg/kg/day implantation sites, corpora lutea, resorption sites consisted of reductions in the mean number of and the mean numbersofviable male, female, and total fetuses, but the incidences of unossified, differences were not statistically significant. In addition. unusually assymetrical, bipartite, and missing sternebrae were observed in all high dose groups; however, these skeletal variations were also observed in control fetuses at the same rate daenvdetlhoeprmeefnotraelthteosxeiceiftfyecotbssweervreedniont aclolndsoisdeergerdoutopsbecornesaitsmteendto-fraeblantoerdm.aliTthieesmoosfttnheotlaebnlseofstighneof eye, which was not seen in controls. The proportion of fetuses with the lens abnormality in one or both lenses was significantly higher in the high dose group. All eve abnormalities appeared to be localized to the areaofthe embryonal lens nucleus, although a varietyof morphological appearances were present within that location. According to the authors, this abnormality appeared (0 be an arrest in development ofthe primary lens fibers forming the embryonal lens J Ie nucleus. Secondary lens the abnormal embryonal nfuicbleeruds.eveUlnodpemrentthepcroongdrietsisoendsonfotrhmaellsytuedyx,ceaptLiOmAmEedLiaftoerly surounding developmental established. toxicity of| mg/kg/day was indicated; a developmental NOAEL could not be SApsreacgouned-Daprwelneaytarlatdsev0,el1o,p5m,eanntdal10tomxigc/iktyg/sdtauydyPaFdOmSiniinstceoremdofiolubryggroauvpasgeofon25gepsrteagtniaonntdays p(aGiDr)ed6u-n1i5il(cWoentfzeilr,mat19i8o3n).ofSmeaxtuianlglyormaunttuirletSwporwaegeuke-sDhaawdleelyaprsatesd,. onMeatpienrgsewxaspecrocnafgier,mweedrbey daily plug. vaginal examinations fof The dayofconfirmation the presence and viabilityof of mating was designated as sperm day 0 or of the presence ofa gestation. Doses copulatory were oadbjsuesrtveeddatcwciocredidnaiglytoftohresimgonsstofremcoerntallyirteycaornddemdobroidbyunwdeiitgyhatnmdeaosnucreemdaeinltysf.orcDlainmiscawlesriegns of 2to0x.iciAtny.imaIlnsdiwviedruealsabcoridfyicweediognhtGsDan2d0fboyodCcOo,nsausmpphytxiioantiwoenreanrdectoherdfeedtuosnesGwDer6e, d8,el1i2v,er1e6d, baynd cfeesmaarleeawnassecetxicoinseodn, GwDeig20h.edAangdroesxsanmeicnreodpsfyorwtahse pneurmfboerrmeadndonplalalcdeammesn.tofTihmepultaenrtuastifornomsieteasc,h annudmbtehernawnediogfhleidveagaanidndaeftaedrftehteusceosn,teanutmsbweerroefreeamrolvyead.nd Tlahtee roevsaorripetsiownesr,eanedxaamniyneabdnoforrmatlhieties wneuimgbheerdo,facnodrpeoxraamilnuteeda.exEtaemcahllfye.maAleppwraosxiemxaatmeilnyeodnbe-ythgirrodsosfntehceropfestyu.seEsawcehrefeftiusxewdaisn sBeoxueidn.'s astoelunttiioonna(n0dtehexaemyeisn,edpalfaotre,viasncedrablraaibnn.orTmhaelirteimesaibnyintghefeWtiulssesonwetrecehsnuibqjueec,tweidttho paarstkieclueltaarl examination exemities, that included evaluationofthe and pectoral and pelvic girdles skull, using long bones, alizarin red; vertebral column, ib cage, bone alignment and degres of ossification were also evaluated. dEuvriidnegncaendoffmoaltleorwniangl ttroxeiactimteyn,ttahantdwcaosnsoibdseerrevdetdoabtethtere5atamnednt-1r0elmagt/ekd,g/cdoanysidsotsedeogfrohuupnschbeotdh eprousstt.ureS,iganniofriecxainat,dbelcoroeadsyevsaigninmaeladnisbcohdarygew,eiugthetrignaeisntsaidnusr,ianlgopGecDia6,-8r,ou6g-1h6h,aairncdoa0t-,2a0nwderbleoaoldsyo torbesaeurnveendt-arteltahtee5d asinndce10memagn/kbgo/ddyaywdeoigshetggroauipnss.weTrheesgreearteedructthiaonnscownetrroelscodnusriidnegretdhetopobset- exposure observed period on GD (GD 16-20). Significant decreases in mean 17-20 in thel0 mg/kg/day dose group. and total food consumption on GD 7-16 and 0-20 in were both the 5 wanads s1i0gnmigf/ikcagn/tdlayyldoowseer wgrhoeupns.comTphaermedeawnitghracvointdroultse.rinTehweeimgehatnitnetrhmein1a0lmbgo/dkyg/wdeaigyhdtossmeignruosup the gravid mg/kg/day. uterine weights were High-dose animals lower in all reated groups, also exhibited an increased with significant decreases at incidence in gastrointestinal 5 and 10 lesions. No significant differences were observed in number and placementofimplantation sites pregnancy rates, number of corpora among treated and control groups. lutea, and Two dams in the 10 mg/kg/day dose group were found dead on GD 17. Under the conditionsofthe snudy, a pre 6 NOAEL of | mg/kg/day and a LOAEL of 5 my kz/day for maternal toxicity ers indicated. lSaikgenrsoefsodrepvieolnso,pmteotnatlarlestoorxpirciiotnys.innculmubdeedr3ofdodseea-drelfeattuesdest.reannddtfoewcaalrdlosasn, ianlctrheoausgehd, innocniedeonfctehoefse waeffiegchttsswfeorrebsoutthismtaiclaelslyansidgnfiefmiaclaenstlwyedrieffoebresnetrvfeodmincotnhtero5lsa.ndSi1g0nimfaikcagn/tddaeycrdaoasseesgrionumpse.anThfeetal cpeormcpeanrteodf1m0a4le4%fetiunsceosntwraolss.52S%t,at5is4t%i,calalnyds6ig0ri%fifcoarnt1. in5,craenadses10inmythkee/idncaiyd,enrceesspeicntitvheelyn,umber owfelriettoebrssecrovnetdaiinnintghefehtiugshesdowsiethgrvoisucperoafl 1a0nommaglikezs/.dayd.elaTyheedsoessiinfcilcuatdieodn,exatnedrnsaklelaentdalvivsacreiraatlions oasnsoimfailcaiteisonoofftthheeclsekfutllp,alpaetce,rosrualbcguitrdalnee.oiusb ecdageem.a,vearntedbrearlypcroolrucmhni,smpealsviwceigliradsled,ealnaydsliinmbskseletal Skeletal study, a variations in NOAEL of | the ribs and stemebrac were mg/kg/day and a LOAELof also observed. 5 mg/kg/day Under the conditionsofthe. for developmental toxicity were indicated. aTohteodbesveerlvoepdmeinnttahel e1y9e83abdneovremlaolpimteienstatlhattoxwiecriteysseteundyinetvheenprtehvoiuoguhstshteusdtyu(dyGodretseirg,n 1a9n8d0d)owseesre rweeartemetnhce-sraemlea.tedFibnudtitnhgeson flaatebrnosrumgagleisttieedsaisnbeevi2ngdeavretilfoapctmsoenftsweecrtieoniinintgi.alTlyhethAogueznhcytoisbeaware of the conoversy surrounding these findings and the matte is currently under review Christian 0F0.0.1, et al. (19992) administered 10,25 or 3.75 mgkg/day pregnant New PFOS in 0.5% Zealand White rabbits. Tween-30 by gavageon 22 per group. doses gestation Gays 7-20 A dose volume of5 ml/kg was administered. weights. The does were observed twice daily 2djusted daily on for viability. and the basis of individual body clinical observations were proescto-rtdreedauImehnoturpeprriiorotdo (i.ae ngdesatfatetriodnosdianygs d2u0r-2i9n)g.thMearteerantamlenbtodpyeriwoedigahntds ownecreedraeiclyordduerdionng the gzeessttaattiioonn ddaayys209,atnhde6d-o2e9s; wfeoroed ecuotnhsaunmizpetdi:on2 gwraosssrenceocrrdoepdsydaoilfythtehrtohuograhcoiuct. athbedosemuicyn.alOannd upteelrvticwevissceexraamwiansecdonfodrucntuemdbearndantdhednisuimrbibeurtioofncoofripmoprlaanltuatteaioinns,ealcihveoavanrdydewaads freetcuosredse,d.andThe acbanrolrymaalnidtileast.e reAslolrpftetiuosne.s wTehreefeextuasmeisnweedrefowreviigscheerda,l saenxdedskaelnedtaelxaabmnionremdalfiotrieesxiaenrndalthe brain of one-half of the fetuses were free-hand cross-sectioned and examined in site In addition. a administered satellite the same study doses was conducted as in the main in which pregnant New Zealand study. The numberofdoes was White 3. 3. 3. rabbits 3 and were. in the conwol. 0.1, gestation day 1.0. 21. 2.5 and 3.75 my/kg/day groups. respectively. blood samples were collected. and the liver The does were was weighed and euthanized sectioned. on The fenuses were removed and examined for external abnormalities. Fetwses and placentae were J 17 pooled per litter. All samples were not available at the time of OPPT's sent to review the Sponsor of the data. (3M) for analysis and final reports were Matemal toxicity mg/kg/day group was and evident at doses nine does in the of 1.) mya day and above. 3.75 mykg day aborted. All One doe abortions in the 2.5 occurred on gestation days 22-28 and significant increase in the wienrceidceonncseiodfersecdanttrefaetcmeesntf-nrtehleat3e.d75bymt'hkegstduadyy authors. 2roup. There was Scant fecas a wmaetreernaalslobnoodtyedweiin gohntegaanidnstwhreereedsoiegsniifnictahnetl1y.0raednudce2d.5 imn etkheg/3d.7a5y mger/okuep/s.daryesgprecotuipveolyn. gesMteaatinon dwaeyastm1e0n-t13p,er1i3o-d16(,da1y6s-179-2a1n)d. p2o1s-2t4-.treMatemaennt body weight period (days g2a1i-n2s9w)earnedadlusoractailocnuloafttehde for the study (days 7-29). period There in the was 1.0, a significant 2.5 and 3.75 reduction mg/kg/day in. mean groups. matemal body weight gain during the Mean body weight gain for the entire ceatment study period was also significantly reduced in the 2.5 mg kg/day group. Mean food consumption (agn/dkg2i1d-a2y4), wasasweslilganififcoarnttlhye reentdiurceesdtuindythpeer2i.o5dm(gdaygs/d7a-2y9)s. ouMpeaonn fgoeostdactioonnsudmapystio15n-1w9a,s19-21 s2i4g,naisfiwcealntllaysrtehdeucenetdirien ttrheea3t.m7e5ntmpge/rikogd.dayThgeroLuOpAoEnLgefsotratmiaocnedmaayls t1o3x-i1c6i.ty1w6-a1s9,1.109m-2g1kga/ndda2y1- and the NOAEL was 0.1 mg/kg/day. Developmental toxicitywasevident corpora lutea, cesorprions, live/dead at doses fetuses. of 2.5 mg/kg/day liter size and sex and ratio above. `were The number of comparable among wsiegantiefdicaanntdlycornetdruolcegdroiunpst.he 2M.e5aanndfe3ta.l75bmoday kwgeridgahyt g(rmoaulpes..feTmhaelreeawnadssaelxseosacosimgbniinfiecda)ntwas grreoduupcst.ioannidnathseigonsisfiifciacnattiroenduocfttihoensitn ethmeumoss(iltifiecrataivoenroafgtehs)eihnyotihde 2l.i5fearndav3e.r7a5gems)e.kmye/tdaacyarpal (lirter averages) and pubis for developmental toxicity (liner and fetal averages) in was 2.5 mg/kg/day and the the 3.75 NOAEL mz kg/day group. was 1.0 mg kz day The LOAEL Reproductive Toxicity Areptrwood-ugcetnievreatfiuoncntrieonproinduacdtuilvteantoixmiaclitsyasntdudoyn, ddeevseilgonpemden(0tatle.stlfeoarrntihneg,toexincderfefperctosduocftiPvFeOeSffeocnts in 35 trhaetsofpfesrprsienxg.pewradsosceongdruocutpedweirneSpardmaignuies-tDearweldePyFrOatSs (Christian by gavage 2 at al. 19995). doses 00. Five groups 0.1. 0.4, 1.6, of and o3.n2emdea/ykbgeffdoarye fsoarcrsiifxicwee(eakpsprporxiiorma1t0ealynd2d2urdianygs mtaottailn)g:.feTmraelaetfmaeisntweinrematlreeatceatdstchornotuignhuoeudtuntil gestation. parturition. and lacatio, EGOeneration: Parental animals (FO) were observed twice daily for clinical signs. Body weights and food Fe 1g dcuornisnugmpmtaitoinngvaalnudesthweenrdeairleycodrudreidngwgeeesktlaytiodnu.rianngd the on treatment lactation period das 1. in 4. male 7, 10. rats: 14, and and weekly at sacrifice in consistedof female rats. the first ten Efaemcahldeorsaatgs ewigtrhoucponcfoinrsmiasttieodnoofftmwaotisnegts; of female rats, this group was One set dosed until cgoesmtpartiisoenddatyhe(sGeDc)on1d0saetndwhdielcihvedreeldivveiraedCaneastaurraelalny-.secDtuiroinnigngt.heT2h1e-draeymaliacntiantgiofnepmearlieosd. the dliartmerswwaesreeveavlaulautaetdedaftoleracsltintiwciaclesdiaginlsy dfuorrisnigzepaarnmdurpituiponviaanbdililteyngatthbiorfthg.estPautpioon,bsaenrdvatthieonnsexch dsuurrfiancgetrhiegh2t1i-ndgaryefllaecxt,atpiionnnpaeurnifoodldiinncgl,udeevdepohpyesniicanlg,siagcnosu.stbiocdsytawretileghrtess,ponnusresianngdbaeihravriiogrh,ting rreafnledxo.mlPyupciulllceodnsttorifcotuiromnawlaesaenvdalfuoautrefdeomnallyeopnupsl.actTahtieonredmaayin21i.ngOpnuplsacwteartieonsadcariyf4i,celdivaenrds were onfecpraorptsuireidt.ionT(hleacFtaOtimoanldearyat1s).weTrheestaecsrtiefsi,ceedpiadniddynmeiccreosp,siperdosatfatteer. tahnedensedmoifnadlosviensgiclatesthweetrieme weighed. protocol. TEhvaeluFaOtigoennseroaftisopnerfmemnaulmesbetrh,atmdoetliliivteyr.edanbdy mCoarcpsahroelaong-ysescetiroennwoteriencslaucdriefdiciendtohen GD 10 and necropsied. and distributionof coPrrpeogrnaanlcutyeas,tairmpslwanatsatcioonnfisrimteesd.wetrhee odveatreiremsinweedr.eaenxdaemmibnreydofsorwethree number elaxcatmatiinoenddafoyr(vLiaDb)ili2t1y.anTdhneecFrOopgseineedr.atOivonarfieemsalweesretheaxtadmeilniveedreads naabrouvraellayndwetshes nsuacmrbifeirceadnodn dwiesitgrhibeudtiaonnod fainmaplylzaendt.atiBolnoosditessamwpalsesrewceorrdeedc.ollTehcteedlifverromfr3ommaelaechraptasretnhattalherdat mwaatsedreamnodvefdr.om $ female rats on these five dams wLeDre2a1lsfoorcoplhlaercmtaecdofkoirneantailcysaisn.alysTihse: livers om final result the of pups these trom analy the ses liziers of were aot available at the time ofthis review. El Generation; Sgrionucpes.FLongleynetrhaet0i.o1n apnudp 0v.i4abmilgit/y dwaasysidgonsiefigcranotulpysrweadruececdarirnietdhein1t.o6 tahneds3e.c2omndggkegn/edraatyiodr.ose Tdowseenssoy-fd0i.ve0.F1.1 agnedne0r.a4timogn/kragt/sdpaeyrbseegxipnenrindgosoen gLrDou2p2waenrde caodnmtiinniusitnegretdhrPoFuOghStbhve dgaayvabgeefoarte sacrifice. avoidance At 24 days paradigm. of age, On LD one 28, rat per sex per lifer in each females were evaluated for dose group was tested in 2 the ageofvagina patency passive and on wLeDre34e.vamlaulaeterdatisnwaerwaeteerv-afliulalteeddMfeomrathzeeaogreoLfDpr7e0.putiAaslsisgepnamreanttiotno. coOhnaebirtaattpieorn sweixthpienrclaictherdose group began on LD 90. assigned 10 individual Females with housing for the reevmiadienncdeeorfomfatthiendgoswienrgepecroinosdi.dered to be 21 GD 0 and TinhteheFIFOgegneenreartaitoinonm.alAellraFtIs wgeerneersaatciroinfifceemdaalfetserwmearteinagi.lonweecdrotposdieeldivaenrdneatvuarlaullayt.ed Dasamdessctrhiatbed delivered lizers were sacrificed and necropsied on LD 21. All F2 generation pups were 8 9 sacrificed, necropsied, and examined on LD 21 as previously descrived for the Fl generation pups. maortthaeliFtyO,gaenndernaotieofnfemcatlseonratmsa,ttihnegreorweorneannoytorfeatthmeenfetr-trieliltaytepdarcalmineitcearlsseivgansluoafte`doxiicnitayn,y ndoose grerloautpivetefstoeodd. cRoenpsourmtpetdioefnfeatcttsheinc1.l6udaenddr3e.d2ucmtyiokngs/fdnaybodtohsbeogdryouwpesigdhutrignagintsheanpdrei-nmaabtsionlgute and pmegr/iokdg./daFyoldloosweinggromuapst.ingT,erfmoiodnaclonbsoudmypwteiiognhtwsaswesrigeniafliscoanstilgynifriecdaunctelyd in the 0.4. reduced in and the 1.6 1.6 and a3t.2thmegh/ikggh/edsatyddoosseegrgroouupposf. 3S.i2gmngs/okfg/rdeparyodauncdtiivnecltuodxiecditsyiginniftihceanFtOrgeednuecrtaitoinosninmatlheesabwseorleutseeen weights aumber of the seminal vesicles (with ofmales with brown liver at fluid) and 3.2 mgkg the day prostate. A dose group significant increase was also reported. in the. GInDth1e0FfOorgeCnaeersaatrieoann-fseemcatlieonriantg., ntohedreeadtihds nwoetraeprpeepaorriteodbaetaannyyedfofsecetsleovenl.estIrnodusamcsyclsiancgr,ifmicaetdinogn and fertility parameters. the numbers of viable or non-viable embryos. The only corpora lutea and findings reported implantations. or in the number of in the FO dams occurred in the 0.2, 1 6, alancdta3t.i2onm;ga/nkdg/rdeadyuctdioosnesgirnobuposdyanwdeiignhctluadneddflooocdalcizoendsualmoppteicoina vdaulruiensgopbrsee-rmvaetidndgu.rgiensgtatthioenp.rea.nd mating period and continuing throughout gestation and lactation. Reversible offspring. Tdheleayabsiliintyretfolesxurafnadcephryisgihcawladsevsieglnoipfimceannttlwyedreelaoybesderivnetdhein1t.6heanFId generation 3.2 mg/kg/day dose groups which there on LD were no 3-10 (delays in surviving pups the 3.2 mg remaining ka/day dose group ware for further observation). observed on LD 1, By the end of the ader obsseurrvfaatcieornigphet.rioTdh,ehroewewveerre,naolldseulravyisvoibngsepruvpesd in in the the 1.6 mg'ka/day dose group had ability co surface righ in dose the abiliyy group<s 0t-h4ermsgwkezr/edatyra.nsiSeinmtidlealraryessspeoennsewsitwhertehesseeasnifgosrpoifnnpahysuincfaollddienvgelaonpdmeeynetoapcernoisnsg.all Adlotsheouugphs. dbeyvtehleoepnmdeonftotfhtehoebsaecrovuasttiiocnstpaerrtileodrerfelsepxo2nnsedsthine pabuiplsitywetroeaisrimriilghats twoercoentbrootlhs.sigTnhiefitcainmtelyof droesdeucgerdouinptohef1.0.61 mmgg//kkgg//ddaayyadnodseonglryouap.traNnosieenftfedcerlsaoyn(otnhesLeDre1f6leoxnelsy)weirnethOebsabeirlviteyd tion atihreilgohwt was seen in the 0.4 groups (0.0.1. 0.4, mg/kg/day group. At the end and 1.6 mg'kg/day) had pupil of lactation constriction (LD 21), al response. live pups in all dose The most significant bighest cose groups. finding reported The reductions in in the pup offspring was that viability began to ofreduced pup appear on LD + viability at postculling the ia two the 1:6 mg kmea//dkagy/ddaoysedogsreougpro4up3,%woifththoevpeurp2s6w%erosf the pups found dead found dead on LD: between LD 2-4. 10 pups survived [n the 3.2 beyond LD | As acest, the viability index was greatly reduced in these dose groups (0% at 3.2 mgkg/day 19 40 and L6 66% dose at 1.6 group. mg/kg/day). In addition. gTehsetaltaicotnatlieonngtihndweaxswsaisgnaiifsiocasnitglnyifriecdauntcleyd reduced (54.6%) in the high-dose in the group caonndctohmeirzeaanltsorewdausct2iosniginnifliictaenrtsirzee.ducStciaocnistiinctalhley numberof implantation sites significant reductions fn pup followed by 1 body weights were allesveoloabssseorcvieadteadtwtihtehtrweoduhcitgihoensst dinospeupgrvoiuapbsil.itOytahnedr maadtveerrnsaelsciagrnes iinnctlhuede3d.2limttgers2w/idtahypduopssethat cwaenrneibnaoltiznautrisoinngoforpuwphsothhaatdwneoreevsitidlelnbcoernoofrmfiolukndin the stomach, dead as well as matsrmal Sgrionucpes,F1ogneynetrhaeti0.o1n apnudp 0v.i4abmilgi/tkygw/adsaysidgonsiefigcarnotulpysrweedruececdarirnitehdein1t.o6 tahneds3e.c2omndg'gkegn/edraatyiodnose Clinical observations in the elated deaths were reported F1 generation male and no statistically rats appeared unremarkable. significant differences were No zeatmentreported for any of vtahelufeosllfoorwilnegarpnairnag,mestheorrst:-tbeordmyrewteeingthiotns.bloodnyg-wteeirgmhtretgeainntsi,onaovrerraegsepodnasyeoifnhpirbeiptuitoinalasseepvaarlautaitoend: pbayrapmeertfeorrsm:annceecrionscaoppaiscsievxeamaivnoaitdiaonncse; oarbswoalutteermoarzreefpaetirvfeorwemiagnhctespfaorradthiegms;igmhtatoirnlgefotr ferilicy erespiosr.tesdemeiffneacltsvewseircleess,igraiigfhitcaenptidrieddyumcitsi.onosr ipnroasdtsaotleu:teanfdootdercmoinnaslumbpotdiyonweoinghtpso,stwTehaenionnglydays 1-8 occurring at the 0.1 and 0.4 mg/kg/day cose levels. Cthlein0i.c4almgob/skegr/vdaatyiodnossfeorgrtohuepF1ingcelnuederda.tiroendufcetmiaolnessiwnebroedylikweewiigshetsunornemdaarykab| lpeo.stwOebasneirnvga,tions at dsaigynsif1i-c8anptoslotswseeasniinngboadnydwdeuirgihntg olnactLaDtison.[-4T,haenrdeswiegrniefincoanstutriesdtuicctailloynssiignniffoiocdanctdoniseurmepntcioens on reporied rexention for or raensypoofntsheeinfhoilbliotiwoinngaspaervaamleutaetresd: values for leaming, by performance in a short-term retention. passive avoidancs or long-term wfaatiese;ramnadzenepcerrofsocrompaincceexpamairnaadtiigomn:s.mating and fertility parameters: gestation index: pregnancy Evidence Pup body of weatment-related effects in weights (on 2 per litter basis) otbhseeFr2vegdenacer0a. tiomng/pkugp/sdcaoynsoinsiLeDd of reductions ix 4 and 7. Body mean weights were comparable to control levels by reductions in mean pup body weights LD 14. At 0.4 wers observed mekg/day, statistically significant on LDs 7-14. Mean body weights on LD21 (c3o6n.t5ingueidn 0t.o4cmegm/akign/ldoawyerdotsheangrcoonutprovls.s.5a0itghoinugchontthreoldsi)f.feCrleinnciecawlaasnndotnescurtoisstciocpailclyobssiegnrivfaitciaonnts ofthe F2 ceported. generation pups were unremarkable. No other toxicologically significant effects were : Under male the conditoifotnhse and female parents are study. the NOAEL 0.1 mykgiday and and 0.4 LOAEL for me kg day, oth the 0 and F1 respectively, based generation on reductions So Al toihnfefbsnopurdimynbgweeariorgefh0t.i4gmapmilgna/naktngadt/idfoaonyosdaitncedos,n1sl.ui6mtepmrreiksoiynz/e.,dapTyuh,pevrieNasbOpieAlcitEtiyLv.elgayrn,odwbtLahsOeaAdnEdoLnsusfriovgrinvitafhli.ecaFnITthgereenNdeurOcattEiiooLnns ainnd oLnOsAiEgnLififcoarntthereFd2ucgteinoenrsaitniopnupofgfrsporwitnhg ar: 0.1 mg k/day and 0.4meka/day, respectively. bases UL Human Data PFoFrOSm.an[yt wyeaasrsa,lsPoFrOecSenhtalsy bdeeetnecmteedasiunrtehde isnerthuemosfetrhuem ogfenweorrakleprospuolcactuipoant,iobnuatllayt meuxpcohseldowteor sleuvmelmsa.riTzheedriensTualsbolfet|.he gost recent analysesofblood samples are described below and Occupational exposures apPneFrdOtslSuurosfreaorcceuhmepmrlioectvaeelcltssiaohnnadvpertohbdeeuecpntrsom.ceeasBssiiuonrmgeodnoifitntohwreoisnregkcedorasmrpaionauvroneldavsveadiinlitanoblbpeortofhdruotchmet,mmaasnnuuucffhaaccatstuufrriiirnenggprpoolftaencttsiionn Alabama and Belgium, and a processing facility in Japan. Fluorochemical Manfacturing fTuwooro3chMempilacnatlss, lthoactatmeadyintDreacnastfuorr,m Alabama and metabolically Annwerp, to PFOS. BSelegriuumm,PFprOoSdulceeveclsewrenre measured liinqmuaidnuctharcotmuartionggraplpahnyt/emmapslsosypeeecstrionm1e9t9r5y a= (3M R1e7p5o)ras,nd191999)9.7 (n = The 1P4E9)OSuslienvgelhsigihn performance workers alcorwoesrsabtotthhepAlnatntwserinp 1p9l9an5traacnrgoesds fbootmh s0a.m1p0lpinogmpteori1o2d.s3.3 Tphpe.faTnghseosfePruFmOSlevleelvselwsoerfewsoirgkhelrys in 1997 periods was had 0.10 PFOS 9.93 ppm. Mosofthe serum levels that were employes <6 pom. at both facilities and during both sampling mTohneitpoarrtiincgippartioognraramtefroofmthwehtiocthal tnhuesmebedartoafwpeorteendteiraillvyedexwpaossenodtepmrpolvoiydeede.s in [t the was medical expressed that atchteuealmlpylpoayrteiscipwaetrede.ofIfneraedddi2timoend,iacgael omfontihteoermipnlgopyreoegsraamn.d bduutraittiiosnnootf eclmepalrohyomwenmtanwyeroefntohtem Tcehpeorretfeodr.e.anitdsihtoiusludncbleeanrotheodwthmatanthyesoefdtahteaootnallynpurmobveicroe fa senmapplsohyoeteosfwtohrekseedruatmslaecvhelsploafnt participating workers during each sampling period. snamoprldeero1f0eamdpdlroeysesetshervoomluntthearDyecnaattuurrepolfantshewamsoncihtoosreinngtoprmoegarsaumreatsetvheen3dMifpflearnetnst, a random fuorochemicals in employees blood (Olsen 2. AL. 1999). Limited job information. years > 2 worked, and building location were collected offluorochemical serum levels in employees. to provide a heer understanding The srandom sample consisted of of the 137 distribution chemical pclaanndtowmolrykcehross(e1n26anrdan1d6ovmollyunctheoersse)n. wTohrekelresv=alnsdin51thveosleunetmepelrosy)eaensd. 7w6hofiwlmerpelasnatmwpolrekderins (60 late 1998, were 10.600) for similar to those reported above. the random sample, 1.259 ppea Mean for the PFOS leveis were 1.505 ppm (range, 0.091volunteers. and 1.424 pom for all participants cSailnccuelattheed.PFTOhSeylewveerles a0p.p9e4a4rpedpmto(b9e5l%ogCIno0r.m7a3l7l-y1.d1i2s6tr)ibfuortecdh,egmeiocmaeltrpilcanmteeamnpslowyeereesaalnsod 0.136 Pp (95% workers in CLO.114-0.161) for film plant the chemical plant had higher emplovess. PFOS levels When compared than workers in by the job description. film plant. PFOS tlheeveclsheimnimcaallepslawnetr.eAplotshitoiuvgehlyt,hiasltchrooussg-hsemcotdieosntallys.tausdsyoctriiaetdedtowaidtdhrensusmbteherovofluynetaerserwboiraksed in associated with the previous worker participation. stud, there are still many limitations regarding exposures and Fluorockemical Processing Biomonitoring fire protection data were submitted products and surface on workers in Japan products (ures at. processing AL. 1999). perfluorinated chemicals into [n 1999, PFOS. PFOA and PFHS Serum (perfluorohexanesulfonate) were was drawn from both production measur: empio; in employees" 22s (n = 32) who serum at the Sagamihara regularly handle plant. duorochemicals also drawn from and management employees (+ = management employees (n = 30) 32) who are at the Head rot regularly exposed. Otfice in Tokyo. The Serum highest was `PTFheOShiglheeveslt iPnF3O2Sprleovdeulctiinoenitehmeprolfotyeheesmwaansag0e.3m2e8ntppgmr.ouwpisthwaasn a0r.i0t9h6m7etpipcmm.ewahniolfe 0t.he13a3veprpamg.e Sleavgealmwiahsaraappprloanxtimiantdeiclayte0.l0o4weprpml.eveTlsheofrePsuOltSsofthatane biomonitoring at eitherofthe performed at the manufacturing facilites cited above. APlFtOhSoulgehvetlhseienxcpoorspuorreastewostualfdfmnoatnangeecresssaatrialy3MSepcloannstiidnerSet.d P"aouclc.uMpiatninoensaolt"afworereeitsheirmiglraorutpo, tnhoonseeorfewpohrotemd ihnadthweocrokrpeodraitneflmuaonraogcehresmiicnalJappraondu(c3tMioRneoprorrse,se1a9r9c9h).anTdhdiervye-loonpemeenmtp,lowyeerees, ssearmupml.edTihne1m99e8a.n APlFlOoSftlheeveplarwtaisci0p.a0ti4n7gpepmmp.lowyietehs2hraadngmeeaosfu0r.a0b2l8etioev0e.l0s9o6fPppFm.OSIninthtihseigrroup Of 3M employees, age was significantly these workers were provided. associated with increased serum PFOS. Noother data on Non-occupational exposures . numberPsFoOfShihsatosribceaelnsmaempalseusre(ddaitnintgheassfear rboafcukthmaes general U.S. 1957) from population and in sources throughout small the world. > 43 Ipnpb19a9n8d.2P6F-O4S5lpevpebls(3inMpRoeoploerdt,se1r9u99m).froTmhe2recowmemreerczipaprlosxoiumracteestyin3t0h0e dLoSn.orrsaningetdheffriorsmt 4s3o-ur4c5e athneddaonnoersst,imwaetreed p2r0o0viddoendo.rs3iMn tahlesoseacnoanldy.zedNotohtirhteyr-fdiavtea,lotssucohf iansdi3veiodguraalphoricpoloolceatdiohnuomraangseeroaf samples samples from U.S. yielded an chemical or biological supply companies average of 35 ppb POS, ranging from 5 in to 1999 (3M 35 ppb. Lerter, 1999), These Sera pooled from 18 regional blood banks in various geographic regionsofthe U.S. were adonnaolrysz.edTfhoer PovFeOraSllinme1a99n8P(F3OMSRseeprourtm,le1v9e9l9)a.crTohssertehewpeoroel6s8waposo2l9s.a7npdpba.n eTshteimPatFeOdS34l0ev-e6l8s0 vleavreilesdaqcuriotses2gbeiotgdreappehnicdirneggioonnsthweagse9og1r0ap3h6icpplbo.cawthiiolneotfhtehreanbgleooofdtbhaenk.aveTrhaegersawngaeso1f4t1h0e 52 pob. pVielroty sltiumdiytemdedaantta thoavveerirfeycetnhtelyanbaelyctoimceteavcahinliaqbuleeuosnedPFonOSsmlaelvlelvsoiinumU.eSs. ocfhisledrruemn.. b[lnoaod1s9a9m9ples oafnaclhyizleddreuns6i-ng12hiygeha-rpsroelsdsuwreerleiqauniadlyczherdomfaotroPgFraOpShy(e3lMecRterpoosrptr,ay19t9a9)n.demTemnasssamsppleecstrwoemreetry (PlFimOiStofindettheesceisoanmpils e3spwpab)s. 54PFppObS,wwaisthdaetreacntegdeoffna3l1l-o1f1t5heppsba.mpTiehse.se Tihnedivaivdeuraalgelelveevlesl aorfe hthieghsemraltlhannutmhboesreorfespaomrtpeldesin,pfoeowleidnfsearmepnlceessciannadbueltmsaidnetaheboguetnetrhaelrpeospuultlsaotifotnh:esheowdeavcae.rA, gisvteundy analyzing over 600 pediatric serum samples is ongoing. These daw are useful in they must be interpreted providing carefully. preliminary levels of PFOS in It cannot be assumed that the the general U.S. raporied PFOS population, levels are but rinecplruessieonnatiinvtehoeftsthuedyU.dSe.clpionpeudltaotipoanr.ticMipaantey.otfhutsheinbtlrooodducbianngkspoosrsiigbilnealnloync-ornetsapcoinesde fboirasp.osOsinbllye aqusimtaelalbaitumdbeepernodfinsgamopnlegseohgarvaephaicctuallolcyatbioenenofantahleybzleododfobraPnkF.OS.Alsaon.dnsoomotehoefrtdhatea,lesvueclsh v2asraigeed. sbeex,coonrsoitdheerreddermeporgersaepnthaitcivvearoifabtlhees,U.aSr.e apvoapiullaabtlieononasthaewdhoonloe.rs. Blood donors 2s a group cannot A summaryof Table 1 the occupational and general population exposure daw are presented below in pd 24 TABLE 1 MEANPFOS SERUM LEVELS [N HUMAN POPULATIONS Decatur, Alabama 1595 1997 (a=380) Antwerp, Belgium 1995 1997 (a = 65) Sagamihara, Japan (1999) (processing PFOS) n = 52 Range (pom) 244 025.128 196 010-995 L1i93g 001.0--493983 0.135 00475-0628 Non-occupational (n = 31) | (corporate stafor managers) St Paul,Minnesota(1998) a7 | (Npolna-notcmcaupnaatgieomneanlt,(1J9a9p9a)n) Sagamibara n=32 03 Tokyo n=30 523 Commercial Intergen po n= ~300 donors 23-96 519-566 53-967 Hea Snig=m~a200 donors 1| 33 26-45 | Other Commercial Sources ~~ n=35 lots | 35 5-85 Blood Banks = ~340-630 donors 29.7 ESaY a=mplee s in children t|---- sa -- | --so-- us ) 2 Human Hazard Data Epidemiologicdataon the health effects associated with fluorochemical exposure are limited. There are two studies that specifically analyzed possible effectsof PFOS on workers. `1T9h9e5saanmde g19r9o7upaotftheemDpelcoayteuer,s (Amlaalbeasmoanlpyl)anwthwoerheadstbuedeinedmtoonidettoerremdifnoer iPftFheOrSesweerruemalneyvels in associations between PFOS levels and hematology. clinical chemistries, and hormonal parameters proliferator (Olsen in rats et. AL, 1998, 1999). Animal studies had reported and that it reduces cholesterol in rhesus monkeys. that PFOS When the is a peroxisome data from both palnadnttshewehreemactoomlboignyeda,ndtohtehreerwcelrienincoalcconhseimsitsetnrtyapsasroacimaettieornss fboertewietehenrPtFimOeSpelreivoelds. iMnetahenwsoerrkuemrs cholesterol levels remained constant or increased with increasing PFOS serum levels depending on the year; however, those employees with the highest PFOS levels had lower HDL mean values." [t should be noted that age was significantly associated with higher PFOS levels. In addition, levels in there were workers. no associations between clinical hepatic enzyme tests and serum PFOS Eleven hormone values were collected from 38of the employees who 1995. The employees who participated in the hormone portion of the participated in the study study were significantly in different fom higher WBC). the non-participants a both locations (younger, After adjusting for confounders, thers were no higher PFOS levels, smokers, and significant associations between PFOS and the hormones analyzed, except estradiol; however, it seems that one employes with hRiegmhovPaFlOSofmtehaissuermepmleonytese(f1r2o.m33thpepamn)aiaynsdesa rleasrugleteBdMiIn nmoaysighnaivfeiciannftlausesnocceidattihoensse wriestuhltesswadiol. `There were several differences between the employees at the two plants. such as body mass ithnede1x,99a5lcaonhdol1c9o9n7scuomhpotritond.ueantdo aaghei.ghInraatdediotfiotnu.motvheerreawtebroetaonpllyan6t1s eFmopmlo1y9e9e6s-1c9o97m.moSnotmoebootfh bthieomfoinnidtionrgsinwgerweasnovtercyonlsioswteanttthoeveDrecthaetu2r tpilmaentpe(r3i5o-d4s0.%)T. he(npaardtdiictiipoant,iotnheraetmepilnotyheies svoaltubntoatry wsietrese u1s.e5d7 pPpFmO)A. aTshaesnuurmfabcetraonfty(emaerasn tPhFasOeAacshegrruomulpevweolrskiend1a9t95thewe2repla1n.t4s6 (pepxpmosaunrde)inwe1r99e7not Aplrsoov,idneidneitny-tfhievaenpaleyrsceesn,toafltthhoeuegmhptlhoeyyeoeusngaecrsotsesmbpoltohypeleasnthsaadntdheboltohwetsi:melepveerlisoodfs sheardusmePrFumOS. PFOS reflect levels body less than 6 ppm. burden because There is also the concern that PFOS primarily concentrates in serum the rat PFOS liver. may no accurately These limitations. indicate that the resultsofths study should be interpreted carefully A retrospective cohort morality study was aiso performed on Decatur employees to determine whether plant employees had significantly different death experiences fom the general 26 population one year at (Mandel and Johnson, 1995). There the Decarur plant between 1961 and were 1991. 1957 employees who Seventy-four deaths had worked at least were recorded. and `tcheormepawreirseonnpoospiuglnaitfiiocanntulsyedel(eAvlataebdamSaMsRiaste,forUSal,l omrajAolrabcaaumsaescooufntdieeast)h. rWeghaerdnletshseodfattahe.were analyzed by statistically job description (chemical department us. film plant significant deficit for all causes ofdeath in both job employees), categories. there was a H"Tohwisevsetrud,yshinacdeatlhmeoswtorckofmoprlceetewafsolrleolwat-iuvpeolfytyhoeuncgo,hoorntlyan7d4 adsecaetrhtsaiwnemreentreopforctaeudsefsoorf1d,e9a5t1h. employees. aumberof Also, women PFOS in the serum study levels were not examined was very small (+ deaths). in relation to mortality. In addition, Therefore, the cohort needs to be the. followed for many these workers. additional years to provide a meaningful pictureof the mortality experience of IV. References C3uMrrReenptortSsu:mm"aThreyoSfciHenucmeaonf OSrergaa,niHceaFllthu.oraoncdheTmoixsiicroyl"oagyndDa*rPae"r,tdlautoerdooFcetbarnueaSruylf5o,na19t9e9:. (3EHQ-0299-373). Biesemeier, J.A. and Harris, D.L. 1974. Eve and Skin Report. Project No. 4102871, WARF Instirute Inc. Irtation Report on Sample T-1117. Burris J, Olsen G.W., Mandel J.H., Schumperr. J.C. 1999. Determinationof Serum Fluorochemical Levels in Sumitomo 3M employees. Final Department, Epidemiology, 220-3W-05. FYI-0500-01578. Report. 3M Company, 3M Medical TChorxiisctiitayn,StMu.dS.yo, fHoPbFeOrSmainn,RAabMbi.ts.anAdrYgoursk,ReRs.eGa.rch19L9a9b2o.raOtrorailes(.StIoncm.acPhroTtuocboel)NDuemvbeelrop:m4en1t3al 012. January 1999. FYT-0500-01378. 04/21/00 Submission. Christian, M.S. Developmental Hoberman, AM., and and Perinatal/Postnatal York. R.G. 1999. Combined Oral (Gavage) Reproduction Toxicity Study of PFOS in Rats. Fertility, Argus Research Laboratories, nc. 1999.(8EHQ-0200-00374) Protocol Number: 418-008, Sponsor Study Number: 6295.9, June 10, CFiifnaolneR,epMo.rtA.. C1o99v9a.ncUensScthueddyuNloe.d D20N7A840Sy4n4t7h.esCiosvainncReatLaLbiovreartPorriiemsarIync.C.elVlieCnunltau.reVsirwgiitnhiaPFOS. 2182 Dean. W.P., Jessup. D.C.. Thompson G.. Romig, G.. and Powell. D. 1978. Fluorad Fluorochemical Surfactant FC-95 Acute Oral Toxicity (LD) Study in Rats. Study No. 137-083, oF 27 Intemational Research Rats with T-2297 CoC and Development Corporation. (Includes . Project No. 78-1433, Biosearch, Inc.) Acute Oral Toxicity Study in Goldenthal, EI, Jessup, `Monkey Toxicity Study. D.C., Study Geil, No. R.G. and 137-092, Mehring, 1.5. Intemational 19782. Ninety-day Subacute Research and Development Rhesus Corporation, Mattawan, MI. # FY1-0500-1378. 05/04/00 Submission. Repeated-Dose Toxicity GSoulbdaecnuthtaelR,aEtLL,StuJdey.ssuSpt,udD.yC.N,o.Ge1i3l7,-R0.8G5.,, IJnetfefmerastoino,naNl.RDe.seaanrdcAhracneod, DRe.Jv.el1o97p8mbe.ntNiCnoertpyo~rdataiyon, Matawan, MI. FY1-0500-1378. 05/04/00 Submission. Repeated-Dose Toxicity #2. Goldeathal, EL, Jessup, Monkey Toxicity Study. D.C., Study Geil, No. R.G. and 137-087, Mehing, 5. International 1979. Ninety-day Subacute Research and Development Rhesus `Corporation, #ib. Mattawan, MI. FY1-0500-1378. 05/04/00 Submission. Repeated-Dose Toxicity Gormer, E.G. 1980. Riker Laboratories, Oral Inc. Teratology Experiment Study of Number: FC-95 in Rats. 0680TR0008, Safety Evaluation Laboratory and. December, 1980. FY1-0500-01378. 04/21/00 Submission. Johnson, 1.., Gibson, S.J. and Ober, R.F. Single Oral Dose. Riker Laboratories, Inc., 1979. Absorption of FC-95-14C Subsidiaryof 3M. St. Paul, MN. in Rats aftear Project No. 890310200. JDioshtnrsiobnu,tiJo.nDo.,fGTiobtsaolnC,aSr.bJ.o,na-n1d4 OibneRra,tsR.aEt.e,r 1a97S9ibn.glEexItnetnrtaavenndouRsouDtoesoefoEfxcFrCe-t9i5o-n14aCn.d TRiiskseure Laboratories, [ac., Subsidiaryof 3M, St. Paul, MN. oJfohCanrsboonn,J-. 1D4.,inGiRbastosna,ftSe.rJA,damnidniOsbterra,tiRoEn.of(A19m8m4)o. nCihuolmes[t1y4Cr]aPmeirnfel-uEonrhoaonccteadnoFaetcealorEPliommisnsaituiomn (14C]Perfluorovctanesulfonate. Fundamental and Applied Toxicology 4: 972-976. Lion Bionetics, [nc., 1979. Mutagenicity Evaluationof T-2014 Salmonella/Microsome Plate Test. Final Report. LBI Project No. CoC in 20838. the Ames Mecchi, M.S. 1999. Salmonella Assay with PFOS. Final Report. - Escherichia coli/-Mammalian-Microsome Covance Study No.: 20784-0-209. Covance Reverse Mutation Laboratories, Vienna, Virginia 22182. : MReuprolrit,. H.CH19V96.StuMduytaNgoe.:nic1i7t4y03T-e0s-t4o5n5.T-C6o2r9n5inign Haanzl/netoinvoIncM.ou(sCeHVM)icVrioennuncal,euVsirAgsisnaiya. 22F1i8n2al. a 4 MFiunralli,ReHp.or1t9.99C.ovCahnrcoemoSstoumdyalNoA.b:er2r7a8t4i-on0s44i9n.HuFimnaalnRWehpoorlte. CBloovoadncLeymLpabhoorcayttoreiseswiItnhc.,PFVOiSe.nna, Virginia 22182. OMlasnednelG.JWH..,ALuogguasnt, 1P1.,W.1,99S9i.mpFslouno,roCc.hAe.m,icHaalnsEexnp,osBuurrreisAsJs.Me.s,smBeunrtloefwDeMc.aM.t,urScChhuemmpiecratl JaCn,d Film Plant Employees. Final Report, 3M Medical Department. FYI-0500-01378. Rusch, G.M., 2306 CoC in Rinehart, W.E. the Rat. Project and No. Bozak, C.A. 1979. An Acute 78-7185, Bio/dynamics Inc. Inhalation Toxicity Stuodf Ty- Simon, V. T-2247 CoC Fa.nd19T7-82.[2V4n8iCmooC.MFiicnraolbiRoelpoogritc.aSlRMIutPargojeencitc:itLySCA-s4s4a4y2s-o0f163.M company Compounds SRI Intemational Menlo Park, California 94025. TPohtoamsfsoirudm,SPa.lJt. (1P99F8O.S;4-TW-e62e9k5C)aipnsCulyenoTmoxoilcgiutsy SMtoundkyeywsit.hUPnearufdliutoerodcDtraanfet.SuSltfuodnyicNoA.ci6d329-222 1f3o7r8.3M0,5/S0t4./P0a0ulS,uMbmNi,ssbiyonC.ovRaenpceeatLeadb-oDroatsoeriTeosxiIcnict.,y Madison, #4. WI. SEHQ-RDT. FY1.0500- TPohtoamsfsoirudm,SPa.lJ.t (2P0F00O.S;26T-6W2e95e)k CinapCsyunloemToolxgiucistMyoSntkuedyysw.itUhnaPuedriftleuodrDoroacfttanFeinSaullfRoenpiocrtAcid P2r5e9p5a.reSdtfuodry3NMu,mSbtePrau6l3,29M-i2n2n3e.soAtparibly 1C2o,v2a0n0c0e. L5a0b2orpapt.oriFeYsI,-0I5nc0.0,-M1a3d7i8s.on05W/i0s4c/o0n0sin 53704Submission. Repeated-Dose Toxicity #5. AWmetezreilc,a,L.ITn.e. 19P8r3o.jecRtatNuTmebreatro:lo1g5y4-S1t6u0d,y,DTe-c3e3m5b1e,rFi1n9a,l1R98e3p.ort(.TSHCaAzeSletcotniLoanb8o(ra)tosruibemsission 8EHQ-0399-374. 04/21/00 Submission. oYfortkh,e PRrGe,seHnacneseann,d KC,onacnedntCrlaetmieonno,fPL.o,t1a9s99s.iuAmnaPleyrtfilcuaolrLoaocbtoarnaetsourlyfoRneaptoert(CoAnSthNeuDmebteerr:mi2n7a9t5i-on 3R9e-s3e)aricnhthLeabSoerartuomriaens,d ILnicv.e,roHofrsShparma,guPeA-.DaLwalbeoyraRtaotrsyERxeppoosretdNtoo.PUF2O0S06v,iaReGqauvaegset.or PArrogjuesct No. 3M TOX 6295.9, 3M Environmental Laboratory Report No. FACT Tox-012. 28