Document dn4X71dj0Z1aM7xVaL0VMEvM6
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A
T-2253
"AL ORIGINAL
ARG -- 0965
w*ihUKEH, - 0800 - 37>
anaAabtTseiorerspAutedimoDniinsiatnsdrtirBbaiutotitioronannosfafnoKdr-mEEtalhtiyimloinnFaOotfSiEoN-n-IEAotCfhCyialncbFOoeSneE-d14 Sanaary 19, 1983
gel 0 uo lh
Conducted Att
During: Conducted By:
R3ikeCrentLearboratories, Inc. St. Paul, Minnesota 55144 October 1980 to February 1981
5. 3. Gibson and 3. D. Johnson
Report By:
Sf Gloory 1/27/73 S5.en3i.orGiLbasboonratory TechniciDaante
R/57 3R.esDe.alsfhohSnpseonc,ia4lsist Date
Reviewed By:
2 ( Row 1J21]83
MRaEna.gerO,berD,rugPhMDetabolism Date
Hig
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03477
TaofbConltenets
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INEEOCEION +veeverssessersessnsrnsssessessensnerens 1 Materials and Methods +oeveeusersersnersessesseesneres 1
Carbon-14 Labeled N-Ehyl FOSE veeuvessessnssnesnns 1
Preparation of Dose/Feed MIXLUE vveversessseres 2 Adninistration Of DOSE .eesseeseersesserreeseeres 2 Sample COLLEGELON +evverserseeseessessassesnesness 3 Radiometric ANalYBes ..veerreeseeisiereeeisieseens 3 Sample Preparation for Radiometric Analyses oo... 3 Analyses Of SERPLES -vervreseeriiisenrenieiseenes 4 Isolation and Identification of Metabolites ........ 4 EXLFACEION +ovvvensenreersennenneranernnnennenes 4 Column CHEGRBLOGEBBRY +evvevserveessessneessseses 4 Thin-Leyer Chromatogeaphy of Column Fractions .... 5 Results and DISCUSSION veevreseersessasessenssesees 5 ExtDeBnLtEAaBnUdLIROoNute+vovferEvxrcsrveetrisosnssnannsdrsTnissssnusesessensseres 5 Isolation and Identification of Metabolites ........ 8 References ouvveusersreseesessnesnesssssaeseessesnes 10 List of Tables, Figures and Appendices +eseessesserses 11
cosas
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Summary Asfutlefroneanisdiongleethaonroall) do(sneeaonfdNos-es,thy1l0.1F3OSmEg-/Tk4gC)_(2i-nN-feetehdyltopefrafslteudorcroacttsane~ cv(eagrrryboounsp=lso1w4o;f4sf3)r,oambsaot0r-b3le2eda.dsatysE7,l0%imonialnnydatip6ro3%onbaoobfflycthamerobrodneo-s1et4haivnsiae70l%uirmiionfneattehaden.dtofteFacelecsal is eoflimtihneatdiiosnmpoefarcaanrcbeon-f1r4omipslaabmoautof20-c3a0rbofno-l1d4thfartomofdayuri1net.o dTahye1h6alifs-l7i.f5e da1an9yo-stM.hMerRAmaemnteaatlbyaosbliosiltietasefortfohmeN-pleeitrvhefyrlluohFarOsoSocEbteaeinnseostluealntfteodatniafvtreeolmyanliiiovdnee.rntwiafIsniedaidddaesinttipioefnri,felduobryooctanesulfonmide. Introduction mIendiaadtdeitiionnthteo pberiondguctaioprnodoufctothseorldprboydu3c,ts.N-etNh-yElthFyOlSPEOSiEs iaskeiympoirnttaenrt PihnostphehatsetuedsyteorfsFCof-8N0-7etmheytlabPoOlSiEsmanbdecanuseaddtihetiotnhrPeCe-8e0s7tercsontoafiFnsC-8a07traacree m0e.t8ab4o)liotfesNo-cectuhrylfFrOoSmE.PC-8I0t7waonudldN-bestheyxlpeFctOeSdE vthiaatdipfofsesriebnlte pcaotmhmwoanys or btihoattraanfstferorphmoasoptnhaotfe Ne-settehrylhydPrOoSlEysainsd FoCf-8P0C7-80f7oll(oswysstiemniiclarandp/aotrhwagyust.) the TNh-uest,hylthPeOSaEbsworeprteioinn,vetsitisgsauteedd.istrTihbeutrieosnu,ltsandarebidoitsrcaunsssfeodrmaitnitohneofcontext sofulfootnhaetre.fluorochenical metabolism data from FC-807 and perfluorooctaneMaterials and Methods
Carbon-14 Labeled -Ethyl OSE
cats ere1stcvroaycsn0orn * Denotes Position of Carbon-14 Label N-Ethyl POSE is 2-N-ethyl perfluorooctanesulfonsmido ethanol. Tshterucctaurrbeo)n.-14Onlabtehle biassiast tofhethcearbsopneci@fitco tahcetivsiutlyfurdetaetrommin(asteieona,bove Chemical characterization, and radiochemical purity reported separately Ts(ht1eu),siseptsheeci(NfR-iiecktehraycltIisPvoOitStoEyp-e'o4fICnvthewenastolrjoytudNgouefmdbN-eserutiht4y6al8b)lFeOiSsfEo-r0'.m44eC8t3au+bsoeld0i.s0i2mn0stthueCdsiie/ensg.. The radiochemical purity deternination vas repeated on the N-ethyl FPiOgSuEr-e1s4C 1-d5o)sinagndstohleutNi-ocnth(ysleeFOASpEp-e1n4dCixva1s-fToaubnldeto1, beandstAplpeeansdtix96%1 = pure.
C0349
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Animate WianldeivCihdaurallesmetRailvemredtCabbolriatssa,ceaiggehstfworeek4s8 ohlodu,rsveprreiorcontdoidtoisoinnegd. toThe Fats were fasted with free access to water for 24 hours prior to deboorsdeiyngwd.eoisgeThdhtesinobfgordoryuaptwsseiwogfihtths3i;nrainengadecidhvidgfurraaolmup2ro2a0fts3tvoewre3sr2e9sgew,lietcmhteieandn21s27o7grtagh.mast oRtfahtes Cchaocwh oatnhderw.aterTheatFeartsdowseirneg.alloved free access to Purine Ground Dosing Preparation ofDose Peed Mixture An N-gthy) POSE-14C" solution vas prepared by weighing N-ethyl NvFooOelStuEhm-ye1l4CvPiOtiShnEt-so1b4gacol1ustolelitueteritohCnanlovalas,ss Aacnrdavnomlsiufxmeeirtnrrgeidcbytofliaansvke4,rtliiantdgej:rustbiTenhagkeertoand PVuarsinsatiGrrroeudndfoCrhoonwewahsouraddtehde.n tTrhaensNf-eerrtehdyl tPoOSaE-g'l4aCs/sfeterdaymiaxndturtehe meitxhtanuorle wwaass edveatpeorrianteedd. byThceombcuasrbtoino-n14(sceoenAtpepnetndoifxth2eanddose/feed
Appendix 2 - Table 1).
Administration of Dose
EaVaniccehinftdoaisvtithdeuedalriantmseitdweaalsofwmeeitegaahcbheodlicasigmmemceatdgoiea.theollAyd bftehefeeodrsceiunpgbleeviansgoratalrtatndaoscsfheee.drrweidTthheto Some vas a veighed mount of Purina Ground Chow containing 0.531 53 Nh1-o,eu2rt,hyplearniFdoOdS4.E-d1a4yFCso/rgp.roasttAsdlolssaecofrciofntishcueemderdaattsthe8i,ndot1sh6,ee aagnrddomuipn3si2stdseaarycserdipfoiiscnteddaostaetw,o a aTointgheorughpeHrOiSoEd ooff tthienefvaasstedallraotweedatteo tchoensfueesd/tdhoesdsosiemme(d1i3atheoluyrs.) ASnuybtGroasctee/dfeefdranmitxhtueretotnoatl dcoosnes/ufmeeeddvamsixtvuerieghegdiveanndtotheeacwheigrhatt. By tIhnespercattsi.on, Thiet adpopseearaeddmintihastterveedryealcihttlreatofvasthecalfceeudlavtaesd sfpriolmietdheby
weight of feed consumed. The mean dose was 10.13 mg/kg (see Appendix 3).
E CpuhrairnleesLRaibveChrowB,reeRdailnsgtonLabPourraitnoariCeosm,panWyi,lsiSntg.toLno,sisM,assMaicshsuosureit.ts.
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Sample Collection Urine and feces were collected at 24 hour intervals for each rat
sacrificed at 1, 2, 4, and 8 days postdose (groups of 3). Urine and feces were collected at intervals and respectively pooled for
eNVEaicehn1,ra2al,teths4syalcr8,ietfhi1ec6r,esdabnaldtoo31d26 avdnaadsysd3p2roesdntaaycsFereposomstFtdahoteseedewse(crgeernodauinpnsegsotfhmeotr3)it.ezedand vLaasnepdrieaptaerleydtprraonmspfetrlryedbytcoenatrhiefpuagraitniiosne.d VaThceutariantesrewetruebes.acrPifliacsemda L=y wehxoslaenguoirgnaantsi.on BaonndeLmiaverrr,owspwlaeseno;btaKiidnneedysf,romantdhelunfgesmuwresreandcollected
tibias by splitting the bones and collecting the marrow on pieces of
mFtaaat'r,ediannctdoesmmtbiuunssectsli)eonvapenarddest=ch.eollreSecamtmsepidln.eisngDoficgaersscuatbsicsvuetvaentrereoaucstcola(lnedescotapehbdadgoumfsir,noamlstroamtasch, acrificed at | and 2 days postacse. Radiometric Analyses Sample Preparation for Radiometric Analyses
FhBeoacmseotsgieonanindzsiomnneagejso3.rndoraRgloaimnqosugoetwnieinrageingparweaapmsaprldeeodneofforitnhcWeaarrbhioonnmg-o1g4elneaantndeaelryissnitsobybcyomPatohdemdoigncgeonneantienasendwpeaarrdetdisnwgeofig1hw.ea0dtegriOnfttootochonemebhopumasorttgieononaftceob.nieoslCoagirinecadvluapsmlaitcteaartkieeanlb.ytotmTaihrxieng 2tnhde hToedmsgbelnoaodtecebleltsweweenresawpeliignhgesd. intSoapcloemsbusotfiobnonecommeasr.row,Carfeatwas datrayTkiaencngk.atrodwHeMoiomgdoheglentah3t0e6esseoxsaniadmdpilszeaesmrpplreoRsmepcwtoelviyegrhyetdoOfadviorcieadcrtblolyno-s1sw4eroeffrowcmeoimgbbhuitsotleobdgyiwciatlh Samples vas deternined by combusting suitable blank homogenates Rs(lofdleauclteeis,,on:alinvdtehree,snedkoirfdenfeetyrh,eenmceuexspceslraeim,npelenastnadwlesrpselaemecpnol)mebusssepttiekde(dsaewtitAthphpeNe-nbedetighxiynln4i)n.FgO,SE-ldc U@irzienceticyoslldeucptliiocnastveer1e:0smm1plaeldiquboetfsoroefferaecehzinsgampalned wveerres cpoiupnettetded directly ints scintiliation vials and 15 ml Adussels vas seed.
Plasma was sampled before freezing and counted directly; duplicate
dS1ai.mr0pelcmetlslyalveiirqneutootcsoslcodirntani0dl.5ldaamtrlikonalaidvqaiupeoltetesdaprbdleufos1r5e0m.1c5omAuldnutiwsnasgte.eirs waedrdeed.pipAeLtLted
2 pIaickiatrsd.Instrument Company, Tnc., 2200 Warrenville Road, Downers Groves
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Analyses of Samples ALL radicmetirc measurenents were done using Packard Model 3380 and u3r3i6n5eTrsim-pClaersb LcioquunitdedSdciirnetcitlllya,titonheSpceocutnrtoimnegteerfsf.iciePnorcyplfaosrmaeacahnd tsoamepalcehvassampdleeteranmdinerdecobuyntaidndgi.ng Aaftkenrowneacahmousnmtploef wianstecronrarlecstteadndafrodr bthaeckcgarrobuonnd-w1i4tchonttheentapopfroperaichatesambpllaenkwsasandcalfcorulactoeudn.tingForeffciocmibeunsctye,d osfamptlhees,AEcSou(nMtuitnogmaetifcfiEcxiteenrcnyalforStaenadcahrds)amprlaetivoasmetdheotde.rminTeodcablyibursaete t2h8ededextteornsaellecstteadndasradm,pleasknionwntheamgoruonutpof(tihnreteerwniatlhstlaonwdaAErSd vraatsios caonmdbutshtreede swaimtphlehsi,gharcaotirorse)ctaionnd wtahsesmeadseampfloerstwheererecroecvoeurnytefdr.om For ctohmebuosxtieddizewri.th Tehaecshesrmepcloeversieets (wseereeApbpaesneddixon4re~fTearbelnecse s1a-4m)p.les Isolation and Identification of Metabolites Extraction Adlaiyqsuoatfsterofdotshieng9:1wehroemopgooelneadt.es oTfheliavleirquoftosr r(abtyswesiagchrti)ficcoendtaaitne2d gaentaottaelvaosf e1x,t0r52actvgedeqthurievealetnitnsesofwitN-hetdhiyelthFyOlSEe-t1h4ecr.withhebhacokmo-exE1r,a5c0t0iomn1sanOdf tthhee feitnhaelr vviotlhumweatoefr.wateTrhevafsina1l,20v0olmulm.e ofTheetheetrhervaswas Tehveapwoartaetredlaanydertvheasreasciidduiefiweadsvirtehdi2s5s0olmvLedofin1m0e8thHaCnLoland(Fsrtaicrtrieodn 1). dfoirethaynlhoeutrh.er.ThTehewateetrherlavyaesr weavsapotrhaentedextanrdacttehde rtweosidtuienewsaswitrhe tdhiessoflilvteedr icnakmeetwhaasnolext(rFarcatcetdiotnwo2).tinTehsewiwtahterchvlaosroffoirlmt-ermeedthaannodl w1:a1s r(evd/vi)s.solTvheed cihnlomreothfaonronl-ne(tFhraancotliownas3).evaporated a.nd the residue Column Chromatography Thrge 2.0 cn in diameter columns were packed to 40 cm with silica eextiracitnioanchoflorloifvoerrmwesrleurrcyh.romTahtoegrtahprheeedfrbyacptlioancsingfrtohmetheextract on cthhelorcooflourmnn. anEdacwhashcionlgumnitvaisnteoluttheedbweidthwit5h00 amlsmoafllCHaCmloyunt(Eolfuate A5)0,0 m5100ofmlmeotfhacnholloro(fEolruna-teneCt)h.anoTlhe1:1nin(ev/vf)rac(tEilounastewBe)r,e eavnadporated tcaordbrony-n1e4sscoanntdenrte.dissolved in methanol and then analyzed for
2 CUnotmepialn,y, acIntci.v,atWeidllsiialmiscpiocrta,ciPden1n0s0y/l1v2a0nimae.sh, Clarkson Chemical
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:
Thin-Layer Chromatography of Column Practions
mBaecthhanoofltheelutsiioxn)colvuemrne afsrsaacyteidonsbythtahtin-cloanytearinecdhicoamrabtoogne-a1p4hy(.notSmall
liquogs of the materisl vere straskea on pre-adsorbent silica gel
pSIonlltaovteenstscinsayntsdit1eitnah.teipo`lnTahvteieapsllsawtecreoesntwdaeeivrneeilnotgpheedmnetsthcoarna1cp5hedcmanidnin70t..55hemcinselsofeecgtmaeednts
mstciotodiniviivetidaylsepceirvnetrsee1g1mc1eoannuttnEteedxvparsaensadsdedtedhde.sadatpTaehceoweecnrotenteocnfatlsctuooltfaalttehcdearabnsaocnitnfita4idliolon-a-the
Plate.
Results and piscusston
Extent and Route of Excretion and Tissue Distribution The results indicate that at least 708 of an oral dose of N-sthyl FTTaOhbSelEe-d1a4t1Ca, aftdhrmeoimndiaastntaaelryfseoerdsiuonrfinfeefeedcaensatolyfposrreesviinaodcueisvlsiydhuoafmlasrtieandtTsarbaaltrsee s2i,hsowaann.bdsoirntbheed. dTahteasefdoratatotaarle esxrcprreetsisoend s(efeccuesmulpaltuisveuripneer)cenAtreofshdovonmeienxTcarbetleed.3. (The dPaetraiodareinlAipspteenddiaxs y5g- eTqaubilveaslen1tsanNd-e2t)h.ylAPsOSsEh-o1w4nCienxTcarbelteed2,perexctriemetion
034. 83
cao$rf5.b0to0onteoa1fl4ctah1rsebo2dno0-s-1e34013fvioaledliumnroiirnneeateeidxstvneionatsiuevrxeitnetenh.sainveeh;leinbyifneac32talidoaneylvsiimapionsauttrdiionosenes,of sFohroeuvter6,08thoef texhteendto.neofbcyar3b2edn-a1y4s peolsitmdionnaet.ionThveiagafesctersoinistesSttiinlallonly atfrfaencstitthtieneratien fofasteexdcrertaitoenfeodf faecneosnsbiasor<b3e0dhocuormspou(n3d).whiTchhe dfoeecsslnot excretion rate of rats in this study 1s normal and does not seem to be
affected by the N-ethyl FOSE-4C (see Appendix 7 and Appendix 7 -
Td4a6abyhl,oeura1sn).dpo8Tshtdaeaoynsmeeapnofosrtcduomtshueelatvgiarvsoeup3sp8e.ro1fcen31t4.f4ao,ftsdaonsdsaecr1ei5.xf2ci,creedtreedsatpveic2atidvfaeeelc,ye.s4by SSiinncgelecaorrbaoln-d1o4seLeivsemlosstfoulnidkeliyn ftoecersepratese4n8thomuaetserioarllattheart ahafsterbeean Cuubmeiolrabteidveandpectoheennteoxfcrdeotseed erxactrheertedthvainaunfaebcseosrbferdoncotmipnoeunodf, dotsheing to 4p6echoaunrsofoseddoosese.not(4s1b4e-o38r0b)ed.18 Tthhues,uppaetrleLaisntit7o0fpethrecenetstiomfattehefdorose
Of N-ethyl POSE-14C was absorbed.
TaGhrneoauldpyissgeeodfstfiorvraetscatrrsbaacoctnrs-i1f4i(ceecsdoonpthaeatgnut3s4,faornstdoim4na8dcihhv,oiudruasanldporisantttdeeosstiein.neesa)Tchhveeofrreestuhelts NT(oapebetlrhecyeln| tPfOooSfrEtdoehsqeeum)ievaa6ireernattssah/oowanroefinrteTipasebsaluteeed4i.ninApT(paTebhnledeidax4.ta6.)TshceePemecexeapsnredtsaostteaadl4f5rom3 GGcfair"bttohhnee-1dG4iogseecsotnaittveen2.4trohfaocutrfssecpeaosestp4dl8oussheo,udrisgeHsobtwoeiavvteedro,steratchcteonwttiaitishnsuceaosnmteaeanndntsocfonits1e1n.3t48s0.3% Gf the dose, and since the tranait time of rats is faster than 48
2B Aondaiittieechd,m7s5:Blu2e5.H2e9n DFrroi.ve,1.N01ewaskD,imeDtehlyalwarPeo.ROP, and 3.8 1 toluene.
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hToaubrlse w1)i,th 1ntor4m8aplrorbaatbelseofthaetxcrtehetio1n1.4(%seoefAptpheenddioxse7obasnedrAvpepdenadtix487 -
hours is not unabsorbed N-ethyl FOSE-14C; the 11.4% of the dose
ltiiskaeuleyscoofmprtihseesdigceasrtbiovne-14tralcatbelaendd mcaatrebroina-l14aslsaobeclieadtemdawtiertihalthein the feelciensinaastioanrveisaultbiloef. absItorpftoilolnowosftNh-aetthsyolmeFOofSE-t1h4eCcwairtbhon-s1u4bseiqnuefnetces Nbeeeftohryel 4T8OBhEourdseriivsedlimkaetleyriaabls.orbTehdusN,-etthhyel aPbOsSoEr-p't4iConanodf Nt-heetnhyelxcreted
PosE-14C is probably greater than 70%.
Tbhleoodrecseullltss offorancaalrybsoens-1o4fcolnivteern,t sbypleceonm,busktiidonenysa,ndlufnogrs,carabndon-r1e4d in p8il1na1cslmguardoeubdpysi.dniTrae(bcTltheecod5autnaatreinagrreesaureelxtpsrsehoosfwsnedanianalsTyaspbeeslrceefno5trfocorfardbioonsnde-i)1v.4iducaoAlnltseornattsofin aigestive tract and carcass of rats sacrificed at 24 and 48 hours psToeusdbtcdbuoltsaoeno.edoucseTlhlefsa,td,aptlasahsdfnoraom,minbaaolnnaelfaytms,aersraoonwfd, mlduiivsgecrel,setiasvpreleeentnro,amcatkl,iidznceeayrdsc,atsosl,ungs, e1i0qnumAigpv/pakelgenndtdisox/sge8.aofndtiasrseues.hown[Thien Tsaabmleeda6taas (ungotN-neotrhmyallizFeOdS)E-la4rce listed Maenadn48tohtoaulrsrec[osvuenryofofsmoruandtioaicntitviistsyuefr(oTmablreats5) saancdrifmiocuendtaetxc2r4ethoeudrs
(Table 3)] was 86%. Since a correction for recovery from the combustion
analyses was made, these results seem low. It is probable that some
OpTfroeoptnahtereamNtp-ieeortnahtyoulfrePt)Oh.SeE-s1aP4mrCpolmeaTsnadb/(loNer-e5it,thsylimteFtOiaSsbEo-al1pi4ptCaerseisnwtesrlteihgahtltolsayts dvwuoirtlhiantgPiCl-e80a7t o3c)t,anpooattaess(i5)un8pesrifglnuiofriocoacnttanpeosrutiifoonna(teean(,4),9.5a4n)d omfpotnhieundopseerfofluoroGCfarbtohen-1l4abeilsedrectoamipnoeudndi.n tThheelmievaenr latog3c2ardbaoyns-1a4ftelrevealssin(gnloermoarlailzeddosteo
a 10 ma/kg dose) in liver and plasma are plotted versus time in Figure 1
Gfaorrbgonr-o1u4psloefvelrsatsare(3plroattst/egdrovuepr)s.us TthiemeraitniFoig(uLrieve2r./plPasrmoam)Foifgure 2, eiqtuiilsibarpipuarmenits tnohtatestthaeblliisvheerd/pluanstmial r1a6tdiaoysisponsottdocsoen.stanSteleacndtivtehe Fetention of a biotransformstion product in the liver with more rapid PcolsesairbalneceeoxfplNa-neatthiyoln PfOoSrE-t1h4iCs apantdt/eorrn.otheArt m3e2tadbayoslitaefsterwoualdsinbgelea oral bdoonsee mofarNr-oeut/hpyllasFnOaSEc-a1r4bCo,n-1t4helemveealn rliavteiro/splvaesrmea,11s.8p,lee0n./4,plaasnmda,0.4a,nd
respectively. At 124 days after a single iv dose of FC-807-'4c, the
mTeeavnellirvaetri/opslawsemrae, 22s.p1l,een2/0p2l.a8s,maa,ndan4d8.1b,oneremsaprerctoiwv/epllya.smaThcuasr,bont-h1e4
pattern of distribution of carbon-14 after PC-807-14C administration
is so different from the pattern after N-ethyl POSE-'4C administra-
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Page 7
vteirroosnmudstohsaitiv)ngdaentsaopitsthaeecrtidhfieifccteew)or,ednicifetfeiirsnedpnrtuocbrtaoibuoltneesotfhoaftthaeFdCm-ie6nx0ip7setrrbiamiteointotrnsans((ftooriranlemahftyiodorrnmoaltiyissominosroefofcthotehneplrpeehxloesatpshheaodnruaasl-csooirhmyopglleenacsobNno-vneedtrwhsiyitlohnFOtsSouEb.Ns-eeqtuheynlt PbOiSoEtrabnys-
TslhueelvfelomneaartnaetLioi(sv6)ecr/aaplrlceausl9ma.at3,,ed 0s.pf2lr,eoemna/ndpdalta0as.n2ra,e,proearsntpdeedcbtofinoverelmpyao,rtraoastws/ip6ul9nadpseamryafalcuaaoccrtboeoronc-t1&4anesingle intravenous dose. Thus, in contrast to the issue carbon-14 drfaaatttaii.oo ddAaaltttaahoafurrgeohmspFiCen-ri8lf0al7ru,ortootohtcehteapneNer-sfeultluhfoyorlncaoFtcOetSaEni-se1s4usClhfoowtnniasttseou-e'b/4epCl8atmimasestuarbeao/tlpiilotaesma osfimNiileatrhiytliesFOSsEhou(lsdeenobtelobev., itnhtiesrprreeptoerdt)a,s tehveisdeencteisstuhea/tpltahsemscarrbaotni-o1d Plearbfelleudoromoacttearnicaalulattonlaattee.r tines (32 days) in liver is due only to Tdahadeyminh1iaslttfor-aldtiaifyoen1.o6f (HtFohiwegeuvdreeirs,a1)ppaefiatsrera7n.c5deadyafyr1so6mtahptelearsdmlNas-aepotfpheycalarrabFnOocSneE--1iI4s4mcfurcahm Stlhoewemreansinlceeveltsheomneadnayca1r6bo(n2-.124bgleevqelusivaolnendtasy o5n2 daarye a16b,ou2t.1the4gsame as ecthaqarutbiovnar-le1ep4notrstaecdtoenrfodNraeyecta3hr2y)b.lonF-TO1S4hEe-a1fp4tleCarsomoraraahllalafda-mdliminifinesitsrtvaratalituoeinoonfiosf7.t5pheotdsaaaysnsseiufmo4rs pdaafeytrefrl6)uoar(cf)oe.cwtdaAanayesswuil(tf5ho6nNdaa-tysest-)h1y4lCthFteoOSrmaEat-leieCo,fradtLsitsa{(pnepsestapirpmaaarnteecndetoffrthoasmtardabsyoonm-e11t4itsoefrom PSloaasmmaucahftelroveardairanties.tration of perfluorooctanesulfonate-14c decreases
Ohvaelcfa-llli,fetvhaelipeasttefronr for N-othyl FOSE-14c
tofhecaFribroant-1f4evddiasytsripbousttioonrailn dtoissasguee aanrde sthiemilar and potassium perfluorooctfoanantee-sHucl.
cInarbsodnai-t1i4ons,eenfortobodtehcrceoamspeousnodsth,atthleatecratpelsasomfadivaslsupepseatfaonrcecarofbon-14
LTeevveellss aanrde tShoemewhhaaltf-lhiigfheervaltuheasn.voTuhludsbeforpretdhiecsteedcomfproomundtsheienarrlaitesr
t(iannedsLbiakseeldy oonthehralfs-pelciifees)e,stipnraetdeicstioofnseloifmipnlaatsimoan inaccurate and should not be attempted.
flreavmelpslaastmalaatreer
2 Tnhoet nchiaqnugee tion Nra-teethoyf FeOlSiEn-iTmAaCtioanndopfetroftlavlorcaorobcotna-n14esfurlafmonpla1atsecm-a iits is quite common for other compounds.
03485
Page 8
Isolation and Identification of Metabolites aTthe48Livheorurshomafotgeernataespionoglle (o9r:a1,l dwaotseer/otfisHs-ueet)hylfrPoOmSEr-a1t4sCsvaacsrifeixc-ed Garfatcertedfiwlittrhatieotnh,erth(eFrfaiclttieorn c1)akethewanswietxhtraacctiedd-evthietrh c(hPiraocrtoifoonrn2); mTheethaLnivoelr 1h11omo(gFernaactteionfor3).eachThefrpaecrtcieonntvaosf:carFbroanc-t1idonex1,tra3c0.t1e8d1 from Fraction 2, 25.187 and Praction 3, 11.08. The vater layer separated b1y0i5i2tfeir4lgtcraeaktqeiuoicnvoanblteeafniotnrseedoftnhNoe-ed1te:h1tyelccthPalOboSlrEeo-fTocAracmr-bmpoernt-e1hs4aennto(l01i)ne.xtthrTeahcutfsie,ocneosfopfotohtleh,e 705 4g equivalents (670) vas extracted. nThde t3hefraccoltuimonnss wweerree eclhurtoemdatsougcrcaepshseidveolnysveiptahracthelosriolfiocarnge(llucsotleumAn)s: w1a41s cvehrlyorJoiftotrl-enectahrabnoonl-14(ErleumsotveeBd)fraonmdamneythoafnotlh(eFcloulutmensC)b.y meTthhearneol c@hlruoamtaetoCg)r.aphFeodroneacahsioflictahegeLlivecroluhmonm,ogetnhaetree eaxretratcwotiocnoslumtnhateluwaetrees BAluaatnedsB)A aconndtbainfionrgeacacrhbofnr-a1c4t.ionThaerersehloawtniveincaTrabbolne17d. content of tThhien-slixayecrolucmhnromfartaocgtriaopnhsy.(ElRuaadtiesocAhroannadtoB)grawsesrefcrhormomtahtiong-rlaapyehredchbyroma`cSth'orsgomrmmaaoptnhotyugnroafhpyhtdehrdeosxeiindseit)xhe f(rsPaaincgetuiroesnsoslv3-ea5nr)te, sshtyohsewtnetm ihne(1eP0i0gcuocrlheulsmonro3f-eo1lr2um.a,teWs3h5e(mn3e'tsh)anol, from the three extractions (ether, acid-ether, 1:1 chloroforn-nethanol) F`Seruaagccghteishotansve2tohna(etacmeiaadjc-oherthceopren)atka,EilnuaanttdheecBosamwmpaeasrmiecsthoarnboomolfaittotegh.eraprThahededioecixhntraroamacstteoicgoornnadms Saondlveinnt8sytshtiernd s(o1l00vebnuttasnyoslt,em10(1a0c0ecthilcoraocfiod,rn,101w0a0temre)tha(nFoilg,oreand6 2 Ealcuesttiec Baciidn)dic(aPtlegutrheat7).theThreaditohcrheeemircaadliopcuhrriotsyatoofgratmhse mofetFarbaoclittieonis2 "ose. VTahse eLxatbrelaecdtimoentParbaoclittieonPr2ac(taicoind-eIthaenrd) suEblumsitteteBd t(ochSl.orPoaftohrrn-emeotfhatnhoel) CKe-nt1r0alaAnndalKLy-t2i0c0alSpLeacbtorroamteotreyrsf,or T1h9ePr-eRsulatnsalyasriesroenporttheedVairnian Aspuplefnodniaxte9;anitohne.metabolite vas identified as the perfluorooctane-
03486
Page 9
.
From the percent of total carbon-14 extracted from the liver homogienna1t:1e cpholoolro(f6o74r)m-amnedthtahneoltoatnadltchaerbpoenr-c1e4ntrceocmopvoesreidtiofnroomftthheecsoelumns eluates by thin-layer chromatography (95%) it can be estimated that at least 228 Of the carbon-14 in liver at 48 hours after a single dItoseisofquNi-teethlyilkeFlOySEt-h1a4tCduies dtuoelotsospedrurfilnugoroeoxcttraancetsiuolnfoannadtet-ol4lco,ss during chromatography that the actual amount of perfluorooctanesulfonate is somewhat greater than 22%.
The chloroform column chromatographed using
telhuiant-elsayefrracmhrtohmeattohgrreeapheyxtriancttihoensafmreactsioolnvsentwere
systen As with
(100 the
cchhlloorrooffoorrmm,-me3t5hmaentohlaneollu,ate5s,amcmoomnpiaurmihsyodnrooxfidteh)e
t(hFriegeurecsolu8m-n10).
eluates suggests that most of the carbon-14 is the same metabolite.
The extraction Fraction 1 (ether) Eluate A was chromatographed in a
second solvent system (100 butanol, 10 acetic acid, 10 water) (Figure 11)
and in a third solvent system (100 chloroform, 100 methanol, and 2
acetic acid) (Figure 12).
The extraction Fraction 1 (ether) Eluate A (chloroform) was labeled metabolite Fraction II and submitted to S. Pathre of the Central AXLn-a2l0y0tiScpaelctLraobmoertaetrosr.y fTorhe 'r4ePs-uNlMtRsanaarleysriespoortnedtheinVAaprpieanndiXxL-19.00 Tahned metabolite was tentatively identified as perfluorooctanesulfonamide. Similar to the calculation for perfluorooctanesulfonate, it can be estimated that at least 328 of the carbon-14 present in liver at 48 hours after a single oral dose of N-ethyl POSE-14C is metabolite Fraction II.
Further refinement of these extractions and separations would likely
froensautlet ainndathheigmheertabeosltiitmeatteenOtfattihevelpeyrciednetnatgiefieodf apserpfelrufolruooorcotoacnteasnuel--
sulfonanide since these
weistthimarteesspecetstatbolitshhe
ttohtaatl tchearbtowon-m1e4tapbreosleintte.s
aHroewepvreers,ent
in substantial quantities, further refinement of the extraction and
separation is not planned. The presence of other peaks in radio-
chhormoomgaetnoagtreantshat(Fwiagsurensot 8e-1x0t)raacntdabtlhee by33%thoefsethceoncdairtbioonns-14indiincatthee
liver that
other unidentified metabolites are present.
Cosas;
'
_--
Page 10
.
References
1. FJoOhsnEs-oTn4,C I(DReapnodrt)B,ehrD,eceFEm:berSy1n1,the1s9i8s0. and Characterization of N-Ethyl 2. TThroamcptsoonf, thReC Raantd HboyllIinsg,estOLe:d RuItrhreandiiuamt-i1o0n6.of AtmheJGaPshtyrsoiionlte1s9t4i,nal
308-312, 1958.
3. Johnson, JD: Absorption of FC-807-14C in Rats After a Single
Oral Dose (Report), July 10, 1979.
4. OJorhanlsoDno,seJD(:RepAobrts)o,rpOtcitoonbeorf F2C6,-951-91794.C in Rats After a Single 5. JOorhanlsoDno,seJD(:RepAobrst)o,rptDieocnemboefrPC2-8,1431-91754.C in Rats After a Single 6. JofohTnsootna,l CJDa:rbonE-x1t4ent4naRnadtsRoAuftteerofaExSicnrgelteionInatnrdavTeinsosusueDoDsiestorfibution
FC-95-14c (Report), December 28, 1979.
7. MAlatrmyalna,nd,PLFeandderaDtititomnero,f ADSm:ericBalnoosdocanidetOitehserfoBroEdvypeFlruiimdesn.talBeBtihoelsodgay,, 1971, p.5.
02488
rage 11
List of Tables, Figures, and Appendices
Table 1: Cumulative Excretion of Total Casbon=14 in Feces After an Oral Dose of N-Ethyl FOSE-14C in Feed to Rats (Mean Dose,
Table 2 Table 3:
10.13 mg/kg)
Cumulative Excretion of Togal Carbon=14 in Urine After an
Oral Dose of N-Ethyl FOSE-14C in Feed to Rats (Mean Dose,
10.13 mg/kg)
Cumulative Excretion of Total Carbon-14 in Urine and Feces
After an Oral Dose of N-Ethyl FOSE-14C in Feed to Rats (Mean
Dose, 10.13 mg/kg)
Table 4+ Carbon-14 Content in Digestive Tract (plus contents) and Feces After an Oral Dose of N-Ethyl FOSE-14C in Feed to Rats (Mean Dose, 10.13 mg/kg) at 24 and 48 Hours Postdose
Table 5: Carbon-14 Content in Tissues After an Oral bose of K-EEhy) POSE-T4C in Feed to Rats (Mean Dose, 10.13 mg/kg)
Table 6 Carbo1n4 Content in Tissues After an Oral Dose of N-Zehyl FOSE-14C in Peed to Rats (Mean Dose, 10.13 mg/kg)
Table 7: FRrealcattiiovnesCa1r,bo2,n-1a4ndCo3ntent of Flustes A and B for Extraction Figure 1+ MeinanLiLvoegr CaanrdboPnl-a1s4maLeovfelRsats(o(rGmraoluipzsedofto3) 81.01,mo/2k,y4sDos5e,) 16,
Na-nd5331202D-a4y3s-4P4o,stWO3r-a3l65D3o1s5e of N-Ethyl FOSE-14C in Feed
Figure 2:
Figure 3: Figure 4: Figure 5:
Figure 6:
RRaattaio (oGfroCuapsrboofn-13)4 Laetvle,l 2i,n L4,ive9,r/C1a6,rboannd-1432LDeavyesl PionsPtlOacsamla of
Dose of N-Ethyl POSE-'4C in Peed NB-53102-43-44, NB-56531-5
EThliuns-lta3eyer(1R11adCihoicohrroofmoartmomgettehaonfolE)xtraNbc-t5i1o5n75P-r3a6ction 1 (ether) EThlians-lta3eyer(1R11aaCiholcohrroefnoartmosmteetnhaonfolE)xtraNcbt-i5o1n57P9r-a3c6tion 2 (acid-ether) T[Chheilnnod-riloafcoyhreanrn-pReatdhiaoncohlr)onaBlteoagtrean3of(1E1x1trcahcltoiroonfoFrrmamcettihoanno3l)(131 TEhliuna-tleey3er(1R11adiCohcihoeraomfsotrongmeeatmhaonfolE)xtrNaBc-t5i1o3n7P5r-a3c5tion 2 (acid-ether)
(03459
Page 12
List of Tables, Figures, and Appendices (Con't)
Figure 7: TEhliuns-LtaBeyer(1R:1adicholcohrroofmosrtno-gmreatmhaonfolE)xtraNcBt-i5o1n57F9r-a3c5tion 2 (acid-sther) Figure 8: TEhliuns-tLeaAyer(cRhaldoiroofcohrrme)matKoBg-r5a1m57o5f-E3x6traction Fraction 1 (ether) Pigure 9: TEhliuns-tLeeAyer(cRhaldoiroofcohrrma)matNoBg-r5a1m57o5f-E3x6traction Fraction 2 (acid-ether) Figure 10: Tchhlionr-oLfaoyrenr-nReatdhiaoncohlr)amEatlougaratAmeof(cEhxltorraofcotrimo)n PrNaBc-t5i1o5n79-336(1:1 Figure 11: EThliuna-LtaAeyer(cRheldoiroocfohrrma)matNoBg-r5a1m57o5f-3Ex5traction Fraction 1 (ether) Figure 12: EThliuna-LtaAeyer(cRhaldoiroocfohrrna)matoNgBr-a5m157o5f-3Ex5traction Praction 1 (sther)
Appendix I-Table 1: roTshEi-n-4LacyermC-h5r1o8m0a6t-o4g1raphy Systems for N-Ethyl
Appendix 1-Pigure 1: Thin-Layer Radiochromatogrem of N-Ethyl FOSE-14c Dosing Solution, Plate No. 1 MB-51806-42
Appendix 1-Figure 2: TDhoisni-nLgaySeorlutRiaodni,ocPhlraotmestNoog.ram2 oMfBN--5E1t8h0y6l-4P2OSE-14c
Appendix 1-Pigure 3: TDohsiinn-gLaSyoelrutRiaodni,ocPhlraotmeatNoog.ra3m oKfB-N-5E1t8h0y6l-42FOSE-ldc
Appendix 1-Figure 4: DTohsiinn-gLaSyoelrutRiaodnl,ochPrloamtaetNoog.ram4 oKfB-N-5E1t8h0y6l-4F2OSE-1C
Appendix 1-Figure 5: Thin-Layer Radiochromatogram of N-Ethyl FOSE-14c
Dosing Solution, Plate No. 5 NB-51806-42
Appendix 2:
DPeOtseEr-m1i4nCatDioosne/oFfeeCdaMribxotnu-r1e4 Content of N-Ethyl
Appendix 2-Table 1: MCiaxrtbuorne-14 Content of N-Ethyl POSE-14C Dose/Peed
Appendix 3:
DRaotseW/eFiegehdtMsixatnudreAmAodumnitniosfteNr-eEdthytlo EFaOcshE-RTadtc
C0390
Page 13
List of Tables, Figures, and Appendices (Cont)
Appendix 4: Appendix 4-Table 1: Appendix 4-Table 2: Appendix 4-Table 3: Appendix 4-Table 4:
DPreotnerBaliannaktiBoinoloofgiRceaclovSearmyploefsToStpailkedCaWribtohn-K1-4Bthyl
rose-T4c
Recovery of Total Carbon-14 Prom Blank Biological SSeatmpNloers S1 piked With N-Ethyl FOSE-'4c, Combustion SRaemcpolveesrySopfikTeodtNailtCharN-bEotnh-y1l4 FPOrSoEm-1B4lCa,nkCoBimobluosgtiicoanl Sever 2 Recovery of Total Carbon-14 From Blank Biological SSaemrpvleers S3piked With N-Ethyl POSE-'4c, Combustion Recovery of Total Carbon-14 From Blank Biological SSaemtploe.s 4Spiked With N-Ethyl POSE-l4c, Combustion
Appendix 5-Table 1:
Appendix S-Table 2:
10013 maka) Total Carbon-14 in Feces After an Oral Dose of
N-Ethyl POSE-14C in Feed to Rats (Mean Dose,
Total Carbon-14 in Urine After an Oral Dose of
N-Ethyl FOSE-14C in Feed to Rats (Mean Dose,
10.13 mg/kg)
Appendix 6:
Appencix 7: Appendix 7-Table 1: Appenaix 6:
Appendix 9:
Carbon-14 Content in Digestive Tract (plus contents)
and Feces After an Oral Dose of N-Ethyl POSE-14c
in Peed to Rats (10.13 mg/kg)
CRoamtpsarative Data Shoving Normal Fecal Excretion for CRoamtpearative Data Shoving Normal Fecal Excretion for
Carbon-14 Content. in Tissues After an Oral Dose o7f0.N1-3Etmhoykla)POSE-14C in Peed to Rats (Mean Dose,
oRfepMoerttaboofliCteentrFarlactAinoanlsyticaalndLaITboratory Analysis
003431
Page 14
.
able 1
in FeCcuemsulAafttievre EaxncrOreatlionDosofe TooftNal-ECtahrybonF-O1S4E-Mc
in Feed to Rats (Mean Dose, 10.13 mg/kg)
Pecroitotdectaiyons)
ot 021 02-1 E3H 01-12 p33y pers "e 0-16 106--1362
x Rat Tge5ntification Tenis.
29.98 1 aTy AGroup 1.99 2 paTy15G60roup EC 1 7.74 4 Daytacrovp 2wo0e aiem 2s 2s 2.36 8 DayTaGroup sSre eamms Q7.e41 awsam aseus ssaies 56 ses 66.27 16 ba6y63Gsroup Ge 32 paay eGrowp Gm. ses
2.5 2.653 6.02 2M0005 215.046%+ 22.1610 60.583 U7u1zsE 22..341 2260.7040 2109..0805%% 11..9895 132.70 1a5.s16s% 120.m98 206003125 23.3090%% 59.2117 2392.02572 044..4047%% 1100..1386 337s s4i1s1% 10s.a0t0 1 6.151 2.9 5S63.762 s56n.o0r7x4 8s.1o5
2 pcaotlalecatrieonexpperreisosde.d as percent of dose excreted during Notebook Reference: N-55673-37 and 38
03492
Page 15
i
abe 2
Cumulative Excretion of Total Carbon-14
4n Urine After an Oral Dose of N-Ethyl FOSE-l4c
in Feed to Rats (Mean Dose, 10.13 mg/kg)
CPoetrtioedctiDaoyns) x Rat sen5tiication T Mean sso.
ot
0.138 1 ayToGgroup on oazso0
0-1
0.14 2 bay50G9row 0.11 0.114 0.03
2
0023 017
020 020% 0.03
ot
0.11 4 DayaGroup 0.1 01s 0.01
225
00123s6 001:3244
003232 002344%% 000022
fH
0l5 ola
043 ols 300s
01
0.10 8 bay50G6roup 0.09 0.084 0.02
32
o01l3y0 001288
002514 o0.3s1% o0.0z3
poos
oollees 006316
oousds o06r7E% ootse
<=re
019076 o0.e7r2
oolml oolesos0
"8
herd om olen os ois
[=
245 16 DaytGsroup Lio sexo.
0-32
1.85 32 DayTeGroup 162 2.052 0.56
2 Dcaotlalecatrieoenxpperreisosde:d as percent of dose excreted during Notebook Reference: NB-55673-38
03432
Page 16
Tabie 3 Cumulative Excretion of Total Carbon-14
in Urine and Feces After an Oral Dose of N-Ethyl FOSE-l4c
in Feed to Rats (Mean Dose, 10.13 mg/kg)
cPoernieocdtiDoayns) x Rat Tgen5tisication T ments.
0-1
30.12 + DaTy12G8r3oup. 2.66 21.774 8.2
0-1
was 2DaTyotGesroup Her sss 3.61
=
se asts ws mE 702
ot
7.05 4 payicrop see 762s 2
p2y
2w0a3s 1er2es 2T.N07 2w1e9s%E 213908
pt
006 2m 051 250% 1.83
01
2.48 8 bayiGlroup a0 48ss 2.60
a23
0S7e amraisa 212006961 1250..3401%% 105.1948
fots
waions wlem 226s.i505 3461..4161%% 150..1296
<Zre
wstinm 5553..5282 3361.534 a47e.9s%4 1100..4046
e
We sin 3058 S09F sae
0-16
s12 16 DaTyisGsroup EXTER
032
ose 32 DasyheGsroup 60.98 63.0+6 4.83
2 Dcaotla laerecfotnexpperreisosde.d as percent of dose excreted during Notebook Reference: NB-55673-39 and 40
03494
Page 17
-
Table 4
Carbon-14 Content in bigestive Tract (plus contents) and Feces After an Oral Dose of N-Ethyl FOSE-ldc
in Feedatto2R4atasna (4M8eaBnoDuorsse,Fos1t0d.o1s3emg/kg)
IdentRiaftication DToisnee (PHoosutrs-) D(ipgleussticvoenteTnrtasc)t Feces
n Mea+n 5.0.
2
12.08 2.98
2
2.40
12.40
2
14.60
2.55
16.61 5.09 21.65 1 0.82
2 x Mean 3 5.0.
no
um
"
13.03
20.98
"
10.10
20.59
A149 26.00 70
2 Date are expressed as percent of dose. Notebook Reference: KB-51806-45-51
03495
pase 10
:
Table 5
.
Cafbon-o1t4NCoonmtee`nWtaPsniOnBHoRsaeEs,uei1sn0.AT1te5ts2as9rt/o2s5n)ROatchal Dose
sentniteication Liver spleen xigners Langs [erCell mame |DigFeaneesth carcams?
ni
1wWSa.shoooose omUemh ooodehs ecvheaee adaasmes mdmeeeee dwwaaees
enn mas en om oa ne zm we mas
=2a
wT Whn eondee oWme E eose Bsam damm Wwhe WwETle]
P. met om em ous se am ma ma
ia"e
21WW.5eo9 oeoonud w0e.7sn 0oo.d4le3 Sos4hw4ee 2aa.m6s7 -==2 -=-
aan was en em aa se am. -- -
"=
mBaee eooe ownx aenae aama naass --= -=
H
Wi es ese one da ode = =
Pe.
ws eos eae am ae ae
=
0aie
wWP li oeee E oowine ooeh otse ohme = =~=
osm es ee ew am es am -- -
aimin
aTGoEmi eosol ooiae aemw eewm ewem == -==
Po.
as ee em eo oe oes -- -
B36pD0autk3aa RairrieengeerpibrioemdsyssteewndeiaogsfhtpPue0rr0cc+eenntt ooff dmosee pirnesteinstsvei.n red blood cells. Tad blood cell volime =
&
Dwauiltaseshreveasarntienstceasreno.f perount of done present in plas.
Plaeas volume = 31.3 mig body
Notebook References: KB-56531-8 and 5, M-51806-43, and 1B-52102-43
rage 19
Tie SepiagCharFtRo1n4RConitnanFte.edintoFiBaanksee.s GAcatnasDaons,Ora1l0.D15os2e9o/f9) aentniateiontton Livert spree Kitoers Lange nedCHBIlLcgEs Plamet masorneeo,nt DigFersatcitzhe Corcamst sTdeaykt. NPoaackg. masciel ie eWsleeroCS6ohme wwGmsE ouGmmoe amZlaueoowinea mdBieasn ddNoiaan X2dne3o aaGmie osssno eoosia wn 2 6s 0 0 29 Ge me mes a en ne on =aa WBaoesTlEe ewewmwe633 mBmiaae SG5Ax8 Wd0uE0s oWewnee a1Lnse addsne dWdaeas ooofmx J <s BGals deTesos wmeessowwsnems aWwiSae0ovmneem wnseem Z o--2-Z ooBauafssas oGwmeRs 1unsade Hew a0 GB ne wi mas Le Le = = am Le La Ho B1Mee aamemos EnNawEs aIammoaedsw SaeWs MI38mm C Z -- C Z= 8o0hm ooobmn ooobnn Hew ans am a a sa nm ns = = Lom es os i@e fIHldms Voolsee aaLmse auLame 3aawm daLa;m oeweses C -= Z= ooonme oaonor oooaes Nem ae om aa am a am Le -- = an os on sFFeAN WwBeereoLnleBn awLeen aVnmem oaelmne Vatsme eetsew T ----. C== ooolmm ooomee ooolmms Mem 3 00 aM Mm Le 20 es ~~ el oe on B2 oDatma ia mraesiiatedrco a 10 aig dose and expresseda 33 Neethy FORE-MC squivatene/s. Notebook References: F-56515 and 6, W-53102-03 and 44
rage 20
Table 7 Relative Carbon-14 Content of Eluates A and B
for Extraction Fractions 1, 2 and 3
Eluate A (ehloroform)
Fraction 1 (ether) 93%
Fraction 2 (acid-ether)
23
Fraction 3 (1:1 chloroforn-methanol)
on
Eluate B
19%
61
20
(111metchhalnoorlo)forn-
Total +
1128
sas
a3
recovered
Notebook Reference: NB-51579-34
C03498
rage Figuee 1
MT(oeoarmnoanrLpeeosgotCboanrseybrona-bi1n41sLiLve3e0vrel4sra'n8d(,NFoidremeoagnlraiazoefd32trDoaotgsas
- 100-
. N_.
3
Liver
L ow
8
z
8
1: 0 2 4 6 6 1012 14 16 18 20 22 2 28 28 0 RN
DAYS POSTDOSE
C0439
Page 22
Toss
Figure 2 LReavteilo oifn PCalrabsomna-1o4f LReavtesl (iGnroLupisveorf/Ca3)rboant-114, W2o,e4t,hy)8,FO1S6,E-Tg1dC i3n2 FDeaeyds Post Oral Dose of
z
4 10-
x
3 Zz
g5
x
0 0 2 4 668 1012141610 024232%R DAYS POSTDOSE
03500
Page 23 8 Ts
LJ
Figure 3
I(heitnhe-rL)ayeErluaRtaediBoch(r1o11maSthogiroarnofoofrmEmxettrhaacntcito)n Fraction 1 Pre-adsorbent SGP Uniplate: 10305 mcehtlhoarnocftorm
3 Srmoniun hydroxide
Total CPM on Plate = 1,125
0:
g0
aE 30
B Ed
.
"1 DIST4 AN0 5 CE 6 FRO7M1 8 ORI9 GI1N2 0(1C1M)1213 31415 C3501
hee 2
Figure +
T(haicni-aLaeyteherr)RadEiluosctheioBmat(o1g:r1acnhoiforEoxftorramcnteitohnanFcrla)ction 2
Pre-adsorbent SGP Uniplate: 10305 cmehtlhoarnocftorn 5 ammonium hydroxide
Total Cou on Plate = 4,363
=
g
E=
g@
10 0109019003030040.058 6 7 P00.080100010100102010301040105
DISTANCE FROM ORIGIN (CM)
Co3502
Page 25
t LJ
Figure 5 TFhrianc-tLiaoyner3 R(a1d61iocchhlroormoaftoorgmramnetohfanEoxlt)racEtliuosnte B
(1:1 chlofoform-methanol)
Pre-adsorbent SGF Uniplate: 10305 mcehtlhoarnoofsorn s ammonium hydroxide
Total CPM on Plate = 664
50:
zw
2E 0:
B
-
10
"101 2D3 ISTA4N5 CE F86ROM7 O8RIG9IN10(1CM1)12131415
03502
Pre-adsorbent SGF Uniplate: 100 butanol
80 50:
40
3E EJ
B=
10:
"101
23 456 7 8 9 101112131415
DISTANCE FROM ORIGIN (CM)
03509
LL
.-
.
rage 27 .
$07
Figure 7 TFrhaicnt-iLoanyer2 R(aadciiod-cehtrhoemra)togErlaunatoefBEx(t1r:a1ction chloroform-methanol) Pre-adsorbent SGF Uniplate: 110000 cmehtlhoarnooflorm
2 acetic acid Total CPM on Plate = 1,474
n
g
?
Ew
2 E
B
=
10 01-92907690905090009092904 8000 1012345678 91011121315
DISTANCE FROM ORIGIN (CM)
02505
. te
Page 20
Figure 8
TFhrianc-tLiaoyner3 R(aedthieorc)hroBmlautsotegrAan (ocfhlEorxotfroarcnt)ion Pre-adsorbent SGP Uniplate: 10305 cnehtihoarnoofrorn
3 Shmonion hydroxide Total CoH on Plate = 4,983
80:
0
40
EEl
g
$
10
@
0d Sop2
59000000000000000
"101 2D3 ISTA4NC5E 6FROM7 O8RIG9I1N0(1C1M1) 2131415
03506
sage 29 ST uin-tayer KattoshromstE ogean of Bessaction Sre-aducebent SGP tniplate: 1030 cooohtmleoeereotnfsorhmydroride
80
50.
g0
E5
6
g
10
"101 23 456 7 8 9 101112131415
DISTANCE FROM ORIGIN (CM)
C03507
Page 3
Figure 10
T0h:i1n-cLhalyoerrofRoardmiomcehtrhoamnaotlo)grEalmuoafteEAxtr(acchtiiooronfoFrrna)ction 3
Pre-adsorbent GF Uniplate: 10305 mcehltohraonfoorm 5 ammonium hydroxide
Total CPM on Plate = 1,216
=
g
E=
i
.
1 0-9 8dg1o3g3ed456760Se10000010e125T10040105
DISTANCE FROM ORIGIN (CM)
03508
rage 31 Coe
Figure 11 TFhrianc-tLiaoyner1 R(aedthieorc)hroEmlautaotgecaAn (ocfhlEoxrtofroarcmt)ion Pre-adsorbent SGF Uniplate: 100 butanol
1200 waacteetric acid Total CPM on Plate = 2,879
g 2E =
i
10
01--0000009000900002 101234526788
286000000 101112131415
DISTANCE FROM ORIGIN (CM)
C0509
2 page 3 .
Figure 12
TFhrianc-tLiaoyner1 R(aedthieorc)hroBlmuasttoegrAan(ocfhiEoxrotfroarcnt)ion Pre-adsorbent SGP Uniplate: 110000 mcehtlhoarnocftorm
2 acetic acid Total CoH on Plate = 2,882
0
Ew
i
Ea
b
wo
&
0T4+0--010020030004008060970-925 0 onSeeapon te DISTANCE FROM ORIGIN (CM)
EE
03510
. Appendix 1 = Table 1
Thin-Layer Chromatography Systems for N-Ethyl FOSE-ldc
mNaore
SSoylsvteenntt
Re. of N-zehyi rose-Tc
1
110000 eahcteosroonteorn
0.70
2
110000 mcehtthoarnootlo.rn
0.50
2 soutic acta
s
15500 mcehtlhoarnooflorm
0.50
s Smponion hydroxide
.
13050 meehtihoarnootlorn
1.00
+ Smmonin hydroxide
s
10100 wbauttearnol
0m
10 acetic acta
& solvents vere prepared volue:volumes a 100 x1 aliquot of p RcSgorlavinepnotfplmmaitaxejt,ourre (w>asS84a)ddepdeaktoonthtehechrtohmiantioegyrearphcyhrtoannka.to Neti acid and ammonium hydroxide vere concentrated. Notebook Reference: B-51806-41-42
C0511 .
Tow
Appendix 1 - Figure 1
hFions-el-q1vCerposRiandgioScohlruotmiaotno,grPalnatoef NNo-.Eth1yl Pre-adsorbent SGF Uniplate: 110000 cahcleotronoeforn Total CP on Plate = 5,393
Ia
Tw
Ew Eeo
Ew
B 2
10
10123 458678 9101112131415
DISTANCE FROM ORIGIN (CM)
COLHLn
Appendix 1 - Figure 2
FThOiSnE--l'a'vCerDosRiandgioScohlruotmiaotno,grPalmatoef
N-Ethyl No. 2
Pre-adsorbent SGF Uniplate: 100 chloroform 100 methanol 2 acetic acid
. 90: Total CPM on Plate = 5,310
.
bE
g 80:
50
E 0:
=
2
10 04-9090909090969000 400000000 59 "1 450 86 71 8 912 0111213 51415
DISTANCE FROM ORIGIN (CM)
03513
Appendix 1 - Figure 3 TFhoiSnE--j1g1verDosRiandgioScohlruotmiaotno,grPalnatoef NNo-.Eth3yl Pre-adsorbent SGF Uniplate: 15500 mcehtlhoarnooflorn - Total CPM on Plate = 5,356 5 ammonium hydroxide
0
0:
.
[
5 so
E
20
2
10:
ER EEE NEE EE
DISTANCE FROM ORIGIN (CM)
Cois514
Appendix 1 - Figure 4 Thin-Lgver Radiochromatogram of N-Ethyl FOSE-"'C Dosing Solution, Plate No. 4 Pre-adsorbent SGF Uniplate: 100 chloroform
35 methanol 5 ammonium hydroxide . 90: Total CPM on Plate = 5,154
0:
.
7
g0
50
E
i2
2
10
04--90000000909090009000009000009 "10123 4567869 101112151415 DISTANCE FROM ORIGIN (CM)
(03515
Appendix 1 - Figure 5 FTOhSiEn--"g'vCerbosRiandgioScohlruotmiaotno,grPalmatoef NNo-.Bth5yl Pre-adsorbent SGF Uniplate: 100 butanol
10 water 10 acetic acid Total CPM on Plate = 5,258
.
7
gL 5=
g
Ed 10 o "10123 456 7 8 8 101112131415
DISTANCE FROM ORIGIN (CM)
Coss26
Appendix 2
Determination of Carbon-14 Content of
N-Ethyl POSE-'4C Dose/Feed Mixture
CPFcaoiocnvnkteeaesrnadtlaniMdqooufdpoeattlsdhesoX3fd06oosntOehex/aEdedfieoizdsveeer/a-.fipeileqaduRceoectmoeiavxnetwarualyrsyetidofcewatelercraencbiabwlnoeaenind-gc1he4eb.dyvacisTonhmtebdosutscteatarrirenobdinonnwec1ido4tmhbtousatbieon uC8on0ri.r1f8eocrta(elsdyeeluAsopivpnegtnhedtoihuxigsh4oroeatn.cdovtAehprepyecnofdamicbtxuosrt4:io=nTaSbalzeple1).set,Thitshusretchoeverdyatavawsere
2 pDaocmkeacrsd GIrnosvtee,uneTn1tliCnootmsp.any, Inc., 2200 Warrenville Road,
--
Cos537 .
Appendix 2 = Table 1 Carbon-14 CDoonstee/nFte.eodfMiNx-tEtuhryel FOSE-14c
vg N-Bthyl POSE-MC equivalents/g
overall =
523.69 535.61 17.61 517.37 559.24 530.7 3 17.58
Notebook Reference: NB-51806-45
C03518
:
Appenaix 3
RDoasteW/eFiegehdtMsixatnudreAmAodumnitniosftNe-rEetdhytlo FBaOcShE-lR4act
e-- ee------------------ IdentRiaftication at TWiemieghtof (D3)ose FAemeoduMnitxt(u9)reoCfonDsousmee/d Dmogs/ekgin
1n
22316
1c
202
=2
23210
x
237
a
33219s
327
atee
1100..1087
361
7.92
a4:206
1100..2206
pe
10.05
6.6.1317
1100..3206
6.34
10.29
aoa
227609
a
260
55..6213
1100..3206
5.58
10.28
116688
226609
16c
276
F3o
30397
2c
301
s5.a6z1
1100..2370
5.35
10.29
6.5.1959
1100..3290
pt
10.30
r-- e ---------------- 5.--= 10a .13 3t 0.56 Notebook Reference: NB-56531-16b-s and NB-51806-46
03519 a
Appendix 4 BlaDnekteBrinoilnoagtiicoanlofSaRmepcloevseSrpyikoefdTWoittahl CN-aErtbhoynl-1F4OFSEr-o14c
aF50olriqulue,oatcehadndowfi1tt0h0heculafloouifrbrdasiteletudsteomdficrNso-apemtiphplyeeltstFocOroSsmEb-uds'it4reCedc,dtolsyfiinvigentsoroelspucltiiicnoatntielwslearotefion10 ul,
ovFialssi.x rAetplitchaetessaneofti1n0eulu,sin5g0 utlh,e into combustion cones containing 1
sanadme1s00oluultiwoenreandalpiiqpueottse,d ediitrheecrtlyfive g blank biological material (Fecels
Paienvldelret,thsenspvlepereeelnl,ceotomibrzuesmdutswecidltehanhd5omctohnegeanssahotlleevsse)sn.tsficTlothleelreccoptamepbdeurs.tiinoBtnlhaecnoknveisaflislwteertreo wdphraiipceehdr
ct5o0hmebuuFl,sCt-e9ad5nd-1at41C0t0hheaudlbKeb-geeientnnhiyanldgd,PeOdSmiEdd-id'rl4eeCc,tlsypa.inkdeOednndepelooflfeteesaacchhwerosefetrtohofeutsi1an0meplulyle,s.
Abvfuatssetricoanlc.courlrTaehtceetdiornebycofcovroemrpybaadrcaikntggaroumfnoedranafonruedrsuclostuestnstifonrfgomeadfmifprilececistenctayhd,astiptieworenrceenatnadnarlecycosomevdery
Aaopnrpedein8fd4.fi1xe8r,4en5-t2T.d7aa8by,lses9f3o.r13-14t,.otaaTlnhdeca9m5re.b0ao0nn.-1r4eTcho(evNe-rreietehcsyolvefrFoiOrSeEst-h1ve4eCrf)eouruarnseiafsmohprolmweynselitonsw
tthheroaupghporuotpritahteecormebcuosvetriyonfsaactmoprlse. sets, so the data were corrected using
--
Cos520
Appentix 4 - Table 1 BioloRgeiccoavlerSyamofplTeostaSlpiCkaerdbWoint-h14N-PErtohmylBlaFnOkSE-14c,
Combustion Set No. 1
Conbusted Spiked Biological Samples
Feces Feces Peces Liver Liver Liver andofFeLcievser
10m se tee 1682 1750 1s 173 1680
S01 ems e329 76 e219 60s Is 79s 10051 16381 S05 15581 15724 15693 14438 15464
Direct Addition Samples
x
10 1917 1907 1912 ies 1962
1929
SW 957 9558 9609 9605 9819
9628
1001 18543 18415 18654 19154 18741
19781
10m 11698249 x 100 = 67.30
50 SI692594 x 100 = 62.6%
100 1 ITSa4r6n4 5 100 = 62.38
Osvaemrpallels = +54.51.D.+ 2r.e0c8o.very used for correction of oxidized
22 ADmaotuantareofeNx-psrtehsysledPaOs aSpnE. spiking solution added. Notebook Reference: NB-51806-44
--
COSGRE
Appendix 4 - Table 2
BioloRgeiccoavlerySamofplTeostSaplikCeadrbWoint-h14N-PzrtonnylBlFaonskE-14c, Combustion Set No. 2
e------------------e------------------------ Combusted Spiked Biological Samples
r -- r-------- re --------
Spleen Spleen Muscle Muscle Liver STploefen MaFsocfle
M%usocfleS,pleaennd, Liver
10m8 1eso sz 101 te22 198s 1M tes 1806
Sou sa Tea s:97 sar ems sets sam 8927
100 ul 18645 18613 16306 --S 19135 18629 16306 18023
Direct Addition Samples
x
1000 1933 1938 113 1925 1919
1886
Sou sen sea sess seer 9331
9876
1004 1973 19735 19546 19523 19338
19577
10m 1Te8s 06x 100 = 35.768
50m
100 11
S597627x 100 = 90.364 119859772x3 100 = 92.068
Osvwemrpallels = +325..70.+ r2e.c0%o.very used for correction of oxidized
S2 DAsapmitokuainntagroefereNrxo-prer:tehsyssleadmPpOlasesE-vd1pam4s.Cnostpikuisendg.solution added. Notebook Reference: NB-53102-46
03522 -
Appendix 4 - Table 3 Recovery of Total Carbon-14 From Blank Biological SaCmopmlbeusstiSopinkesdetWiNot.h 3N-Ethyl PosE-l4c,
ree ers esee ee e eeeConbusteae Spiked BiologicealeSaemples e stiertetet seems
10m
Som 1051
Spleen Spleen Feces Feces Feces SpXloefen XFeocfes
1972 207 2084 202 197 2005 2038
90S 037 10061 t004s 8530 10152 18332 18070 teses 19641 19798 e201 194s
Xaonfg sSopelceeen
2032
sear vsszs
Direct Addition Samples
x
10m 2080 255 es 2087 2105
2076
SOW 10624 10664 10609 10525 1046s
10578
100 21668 20617 21263 20810 21253
2122
0 2200692. 100 = 57.9%
sou
100
STo8s741x 100 x 53.00 12928284 100 gota
Osvaemrpallels %= +338..3D4. r4e-c4o8very used for correction of oxidized
-- am-- oun--t--of--K-- -sth-- y)tpr-- osE--- 4c s-- pikin--g so-- luti-- on ad-- ced.--------
2 sDpaitkainagreererxoprrsessseadmplaes cvpams.not used. Notebook Reference: NB-53102-53
CO3523
I"1p
Appendix 4 - Table 4 BioloRgeiccoavlerSyaCmoofpmlbTeuossttSailpoinCkSaeerdtbWoNinot-.h14K4-PErtohmylBlFaOnskE-ldc, eer --------------
Combusted Spiked Biological Samples
Kidney Kidney Kidney Feces Feces anodf KPeicdensey
10m 220% 2386 210 2341 2310 2333
S0uL Mes2 1187 eke 116s T0782 11596 10000 22569 22444 22622 22067 21963 22430
Direct Adaition Samples
%
10 2412 2384 2384 2013 U2 206 soul mass 12222 1232 122M wana 2009
1041 24816 20405 20269 2673 WIE 24627
10m 20230363 x 100 = 96.970
su
100 1
1T12509169 x 100 = 96.48% 2220642974 x 100 = 91.34%
Osvmeprlaelsl = +355..00+. r3.e1c8o.very used for correction of oxidized
2 DmaotuantacoefeNx-pertehsysledP2Os SdpEm. spiking solution added. Notebook Reference: KB-56531-10
03524 -
Total
_--m Croerlilceact(idoanys) --_--
01 01--21 01--12 32--43
Appendix 5 - Table 1 Carbon-14 in Feces After an Oral N-EthyelaFnOSDEo-s1e4,C 1in0.F1e3endg/tkog)Rats
x Rat IdeBntification T
72.68 1 DTa7y753Group 2.1
451.5
2 Day Group
352.8
201.2
3744 30216
209.5
251.0 4 D1a7y8.G0roup 320.6
204.2 19404
238.5 184.7
2078 163.2
ae 159.0
M60
Dose of
mean ts.0. 7471 218.9 326915..855% 8825..57 223409..29%4 273..30 113890..88%% 21260.90
0=1
6950..63
8D2a2y5.G6roup 579.0
214287..37
3W05o.9 F+ 24892.84
23--34
3525390.15 312894..06
212752..77 232761..84%% 18730..69
= 5-6
150.4 119.6
142.8 99.4
9926:.32 112085..51%% 3121.67
76--87
7957..35
w68.z7
896..05 6888..18%% 1226..18
0-16
1906.0 167D5a7y.6Group 1762.6 1828.8 + 67.3
106--1326 -_--
208953..00
32 Day croup T2i035..88 178517..76 1718565..85 +% 218260..65
Dcaotlalecatrieonexpperreisosde.d as ug N-ethyl FOSE-'4C equivalents/sample
Notebook References: NB-51806-50, NB-55673-30-33
CO3525
-- ec caii
Appendix 5 - Table 2
Total CN-aErtbhoynl-1F4OSiEn-1U4rCineinAFfteeerd taon ROartasl Dose of Olean Dose, 10.13 ng/kg)
--_--
CPoelrlieodctiDaoyns) -_--
x Rat Ide5ntification T Meant s.0.
01
3.52 1 ba3y G7roup. 211 2.664 0.52
02-1
3.30 2Day2G.1r1oup
2.6
nn
22..1685 22.0692%+ 00..2670
0-1
3.72 4 Day3.3G1roup 3.76 3.60 + 0.25
2 23
".e 3.72
ve 331
33.766 34.36003% 00.5295
34
wn
32s
322 373% oles
01--12
22.8360
8Day2.G0r5oup iss
34..9028 23..4668%4 00..5976
32--43
41.0.2402 2.33610
43.5836 4si1s22%3 04.2718
5a-s6
82.04465
81..3845
23..4172 26..2664%% 03..3055
6778
2.1.6738
11.3571
22.9821 21..3959%% 0o.7n4
0-16
7.34 16 Da3y5.4Gr6oup. 31.27 45.69 + 21.45
0-32
60.36 32 Da8y5.G44roup 50.07 65.2+9 18.19
2 Dcaotlalecarteioenxpperreisosde.d as ug N-ethyl POSE-14C equivalents/sample Notebook Reference: NB-51806-52-55
Cois2e
--------
:
Appendix 6
CarabndonF-e1c4eCsoAnftteenrt
in an
Digestive Oral Dose
oTrfaNc-tEt(hpyllusPOcSoEn-telndtcs)
in Feed to Rats (Mean Dose, 10.13 mg/kg)
_--
Rat Identification EE
"
Tine Post Dose (Hours)
2
Digestive Tract (Plus contents)
1.852
Feces --
64.04
1
2
31.98
105.79
Mean + 5.0.
2
8.54
57.38
17.46 + 12.69 75.74 + 25.24
a
4
8.51
91.79
3
4
12.37
15.74
ES
I
8.12
44.15
Mean + 5.0. EE
9.67 + 2.35 83.89 + 36.44
* Data are expressed as ug N-ethyl POsE-'4C equivalents/g.
Notebook Reference: NB-51806-49-50
COis27 --------------------------------
Appendix 7 Comparative Data Showing Normal Fecal Excretion for Rats
Appendix for rats.
7
- Table Grams of
1
fescheoswsecxocmrpeatreadtibvyeradtastaatsho24winhgournorimnatlervfaelcsal feorxcraet7ion
dcoanytrpoolstdgroosuepsperiinodpreavreiougsivesntudfioersra(tFsC-iEnxptehriismensttsudy8 aanndd 9f)o.r rTahtesseuseddataas
tsohowthethaetxcrtehetiofnecarlateesxcorfetiroantsruasteesd
of as
croanttsroiln
gtrhoiuspsstuidny2 aortehecrompstaurdaibelse.
C0G528
--------------------
Appendix 7 = Table 1 Comparative Data Showing Normal Pecal Excretion for Rats
_--
PeCroiloldect(iDoayns) _--
01
PY
23
4 .s
se -_-- 7
3 4ra5ts.0fr.omotfhe present study
8.0 +2602
9.47 + 2908
10.79 + 1.14 1.614 0.918 0.9+2 2.008 9.78 + 2.17 10.69 + 1.23
coFnt1ro8l0r.atsoffr5am rE. 6
10.294 3.68
7191s
10.27 + 2.00 10.33 + 2.22 0.514 2.63 9.014 1.79 8.6+5 1.93
coTnt+r5o.l0r.atoeffr5om rep. 9
7.00+ 4.38
5.008 2.21
0.3+0 1.20 5.708 125 9.15 + 0.86 5.574 1.54 8.624 1.07
2 TDhaitsa adraetaexisprefsrsoemdthaes g2raDmasy Gorfoufpecoefs tehxicsretsteuddyp,er collectionperiod.
This data is from the 8 Day Group of this study.
Notebook References: NXBB--5563513012--1269u--1269v5aanndd 1462dgd-16hh, and
Cosis29
--_--
ete
oemintieontion iw Mem xaa Mem a Mw =a
Ee
pr CarbonS=e14eCronetasWnataTr1ODRoHsiAeRze,aue1Ts8n.FA15atvtasarreoaenpOarrsal Dose
timed spleen sianers tne ne"aGmu1l.ieE promt Raoamer_,iot Di"gHenItE" cuccnnst eGPlsEOLgwTw weeenn weetmne 3 Dae3s wneshx emWamR deOeGseE MaGEma B38 61M LB Dae ko mer mae na
oGI ams aane wemeo sdwn wBai 5e3s WdoGw wWnN MrEe MSG Wm a was nas me ser ues
wwWeaeeernen awetmmm doasnne aBouwaen Faoen wWeeHn Z Z2o ZLC0E
G22 aa we 206 3 no
wHweEss dveemo aaeneM eaLnen owTwhee aasame kaowse Z Z =Z I ~
[RE----E--E LL
IeLnwa
oeLseneo
om am
es ass re
SoRw eaenovne en ae nes
a ym
animenogavee
ase ner rae
e4Shspooa0snBe ooeemwm
soiiae EmFLre ew TxEe R im HYen Mew as es a3 we ae
i=Sne EWmERInEouS0mR% R aLwsw eaLsA e Hd0em Mem aes em 0 we nae
B ER re
--
ins v+e am nm aS Lem rw0ms nM os
e D0 RTo0. Aon ow = on oe om
~ Ce Z R ~I ----
+oooi Joemmo om are ows or
Notebook References: MB-S1006-47-43, MB-S3102-43-44, 47-52, and 50,NB-36531011012
C05530
Pence
Appendix 9
ens
TECHNICAL REPORT SUMMARY
70: TECHNICAL COMMUNICATIONS CENTER = 201.20N
ene 3. 1901
portent --If reportisprinted on both sidesof paper,sendtwo copiesto TCC.)
GENTIAL RESEARCH LABORATORIES, Analytical and Properties Research Laboratory] 0507
j
e
"
0007
8 No, 7476+ = PerfluoriotoecotfanTeH-S3u1l2f5oni=cJAucneid9,- 1981 A Rat-Liver
aAR
.
J
= 262
v._ pashee
223931250
sTNrowmoOntoveR:h rDmDO CosRmiNtT GRB8CCol:osn. nin |PAEIMOICSAL > Tom ees Request No. C7427
3
EveChemicals ereRepdortad.
CARnLaAlPytical Repore| PPreoGjSeecsttoNro.- 9S.15J0.502Gi6bson, J. D. Johnson Cheatcal Analysts
TT 0Fe Tn ma Sond To Common Soe
A rat-liver metabolite is identified as perfluorooctane sulfonic acid by 'r-nm.
Pr. IA
03531
CONFIDENTIAL
hbad ad
CENTRAL ANALYTICAL LABORATORY
Report No. coe 826e ooee none .n
Date...du.ne .5: .10.00..
Sobject: Pexf+luoJ.rooctGaibnsoen Sulfonic Actd - A Rat-Liver Matabolite of FN-3422
Requestor: JL. Da JShADD.
Dept. Name ._.RU...... Proj. No2l305026.
Request No. . 57427...
Dated .Ressrber 100JB0.
Report:
vT4ew-ro3e4m2el2taabvbeeolreleditesassubmiIis-toCtlHea;dtCeld-fHoefrOrEsopmeelctuthtereodslciovapenirdcoIfIa-nCaaHlyyrsaitesl.uatdemdTi.hniessteertewdo m`eCt-albaobleilteeds (Hac
(CF4CP3~CF3 (CF2)3CP CP,N-CHy~CHyOF
m2
Experimental Bsoamtphlessamvpelrees vobetraeinreedconosntitthuetVeadriiannCDXyLO-D1.00 Tahned X!L*-P2-0N0MRMMsRpecstpreactroonmettheersse.
Metabolite I !*F MMR 13875N
Metabolite II 17 MMR 30190X
Results
.
Tshpeectcrhaemaircealgsihviefntsbel(opwp.m 81.0 ppm.
uTphfeielpdeakfrofmreqCFuCeLnyc)iesofartehe nmoarjmoarlizpeeadksto i6n (tChFse)
f=luorine
1 8.0 1143 1204 1215 1224 126.0 Im 80 129 120.2 121.8 122.8 126.2 Discussion
BmoetthaboslpietcetraI by comparing
wvteaherseirdetefynpetiricecanalcleoft'oFppeMerMrfRflluuo(or1ro1oo2oc52ctXta)anneeofsuslutflhofenoynlliacttdeearrciiwvdiattahisvedtseh.taternToihfneeId.
CFs -- CF; -- CF; -- (CFa)3 -- CF; -- CP) -- SO3H 81.0 126.0 122.4 121.5 120.4 114.3
[$3]
Tochbheseenrisvcpeaedlctarstuhim1f1t2o.f9oftphpetmhmAenetfIalTb,uoo1lr.io4tmeeptphImTyulpewfnaieselvadelrpfhyraosmittmohialttahreinstIuo.lftohTnahytelo1fg1r2oI.u5pe.xpcpempIttpetiashke,
Cosa
ge
.
AJuRneNo.9, 71497681 Page 2
aoflthtoheughsunloftonaumniadmebig(u-oSu0s;lNyH,;)cagrnoubpe:assigned to the alpha fluoromethylene
CF--s Cfa-- Fy -- (CPa)s -- CFs -- CFs -- SOME:
.
12.9
an
Concluston
TshuelfolniivceracmiedtaaboodlittehatlablealbeedledI-1CHIC-lCsH-CH)eOHis1ssugigdeesntteidfiaeds sulfanantde.
apesrfpleurofrlouoocrtoaoncet.ane
5. V. Pathre svP/re
0:533
-