Document RpgeMmZmM7xYBe26q13Ed4QGn

M226 1499 - -- Towmu TRADE SECRET Study Title Perfluorooctanoic Acid: Toxicokinetics in the Rat Laboratory Project ID: DuPont-7473 8 2SpSgTR= a= z3=3 25 8 > TEST GUIDELINES: OU.PSP.TESPA87H0e.a7l4t8h5,EfMfeetcatbsoTleisstmGauinddePlhianersmacokinetics 1998) `SeOcEtCioDnG4u:idTeolxiinceoskifnoerttihces,TeNsot.in4g17of(C1h9e8m4i)cals AurHoR: Raymond A. Kemper, Ph.D. STUDY COMPLETED ON: April 2, 2003 SPONSOR: Association of Plastics Manufacturers of Europe (APME) FAlvueonruoepoEl.yVmearnsNCioemumwietntheueyse 4 Box 3, B-1160 Brussels Belgium PERFORMING LABORATORY: E.L du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkion Road, P.O. Box 50 Newark, Delaware 19714-0050 WORK REQUEST NUMBER: 13697 SERVICE CODE NUMBER: 1389 - Page oral 000002 Pecfluorooctanoc Acid: Toricokinetic inthe Rat DuPon.7473 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT This study was conducted in compliance with U.S. EPA TSCA (40 CFR part 792) Good Laboratory Practice Standards, whichareconsistent with the OECD Principlesof Good Laboratory Practice (as revised in 1997) published in ENV/MC/CHEM(98)17 and MAFF Japan GoodLaboratory Practice Standards (59 NohSan No. 3850) except for the item documented below. The item listed does not impact the validity ofthe study. The test substance is commercially available and was characterized by the supplier prior to the initiation of this study. A certificate of analysis was provided. Although the characterization was not performed under Good Laboratory Practice Standards, based on our `monitoring, we have no reason to doubt the validity ofthe analysis. Study Director: ond A. Kemper, Ph.D. Research Toxicologist 02:0pc200 Espey 2 000003 Pefloroccanci Acid: ToseokiinnttheiRaet `QUALITY ASSURANCE STATEMENT Dupont7473 Haskell Sample Number(s): 25028, 22705-48, 22705-49, 22705-50, 22705-51, 22705-52, 22705-53, 2705-54, 22705-55 Dates of Inspections: Protocol: August 31,2001 Conduct: September 28, 2001; October 1, 5, 2001; November 5, 2001; January 7, 2002; February 4, 2002; April 5, 2002; July 17, 25, 2002; August 2, 2002 Records, Reports: February 4-6, 10-14, 19, 20, 24, 25, 2003 Dates Findings Reported to: `Study Director: February 25, 2003 Management: April 1, 2003 Reported by: plot C Boe fp ICH Joseph C. Hamill Staff Quality Assurance Auditor 62-AP4-2003 Date fant 3 000004 Pervorooctanci Acid: Toxicokineis intheRat Dupom7473 CERTIFICATION `We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. IssueDdibryecSttourd:y `Raymond A. Kemper/Ph.D. Research Toxicologist 02-A, pr 2003 ate Approved by: [e1t- -- `Gary W. Jepson, Ph.D. Principal Research Toxicologist and Manager 024-2003 Date Approved by: = Matthew S. Bogdanff$, Ph.D, (BY. Research Manager and Director oz-Apr-2003 Date --_-- Sg 000005 Perfluorooctanoic Acid: Toxieokinetics intheRat DuPont7473 TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT wr 2 QUALITY ASSURANCE STATEMENT corse [053ToT012 -------------------------- POT LIST OF FIGURES cours: 10 LIST OF APPENDICES ccc 12 STUDYINFORMATIONccm: 13 STUDYPERSONNEL crrsmmssmmsssmsssssmmssssmssssssns 14 SUMMARYcosmos18 INTRODUCTION rss11 MATERIALS AND METHODS css 11 J S B. TES SUBSIANCE rss lt C. RadiolTEaStbSUeBSlIAeNCEdS rrr: 18 Dr Te SPRER cmmememmmmmm------------------18 EE --------| F. Animal Health MOMOMNG cr. 19 G. Dose Preparation, ANalsis and RAIES...........rmmmssmsmssssssns 20 T DURNSIHES mmmmmmmmmmm------sn3 1. Plasma kineticsfollowing Oral Dosing with Non-Radiolabeled PFOA... 21 2. Excretion and Material Balance following Oral Dosing with Radiolabeled PROB cnnmmmmmmmmmmmmmm---------------- 1. Excretion/Material Balance Experiments (EXPETIments 1-4) rn:22 2. Pharmacokinetic Experiments (EXPERIMEN 5-9).....cr.urvvrnrn2s3 3. Distribution Experiments(EXPEriments 10-12)... 24 Shi 00a0006 PerfivorooctaAncoicd Toricokinetics intheRat DuPont7473 K. Sample Processing and Quantitation of Radioactive RESIdUES vrs 25 Te WRB mmmmmmmmmm----_0 ; 2. UC.rcrersssssnssmenssomssmsssmsinsmssssmsmssmssnnnn 36 Be Blibmmmmmmmmmsesmm--------_1 do Ticnmmmmmenmmimsmmpmsm------_ 51 ED AR 2D . Vol CEgit mmmmmimmmmmmmmm------_. To. CHEERIE errereemmmeemmemmmsmmmemsmsmrmssmmesrennn 38 I -- L. Extraction of PFOA from Plasma for LC/MS ANBISIS........crvssrmrrsts 21 WM, MUHABREA mmmmmssmmmmssmmmmmmmmm----l B, STAYS MN cocmmmemmmmmmmmmmmmm------] 2. Chromosraphlie MRM mmmmemmmmmwm------------------ O. Clinical ObSErvations and MOMIY rvs 3. 3 --:S Fo -- RESULTS AND DISCUSSION cvs 35 A PHOUBKDERMENS nr: 33 1. Pharmacokinetics in Male and Female Rats following Oral Gavage with VILEPROM, mmm 2. Excretion and Material Balance in Male and Female Rats following Oral B. MEDGaSva0geRWimthm25mg/kg YOP wenB cmuO nunA unnmmmmnumunmmnmmmniion 3s5l 1. Excretion/Material Balance of ""C-PFOA in Male and Female Rats... 36 2. Plasma Pharmacokinetics of PFOA in Male and Female RAS... 39 3. Tissue Distribution of C-PFOA at Plasma Tix and Trsuz in Male and TATE RAS wummrmmmsmmmmsmmm----------4% CONCLUSIONS cvs 43 RECORDS AND SAMPLE STORAGE wooo 83 BEEERENCES mmissiondd TABLES mmmsrsommmmmmsmsmonsorsssmssmssmosmssmsrsmsommsAnS TC ---- |} APPENDICES conve 124 0 Tau EZ 000007 Perfisorooctanoic Aci Toricokinetcs in the Rat DuPon7473 LIST OF TABLES Page 1. Pilot Study ~ Dosing information for male and female Fats... 41 2. Pilot Study -- Pa harmacokinetic parameter-- s in male and fe-- male rats followi-- ng oral 3. oPirlaoltgSatvuadgye--wPietrhc2e5ntMoEf dEos"eCr-ecPoEveOrAed inr urine in male anm d female rats fos llowing 49 4. PoirlaoltgSatvuadgye--wiPtehrc2e5ntMoEfkdgos"eCr-ePcFovOeArec d in fecee s in maler and feman le rats fs ollowing: 50 5. PraitlsotfSoltluodwyi--ngPoerraclengtavoafgdeoWsietrhec2o5vMerEeKdgat"1C6-8PhFouOrAs v in tissuesr in male as nd female: S| 6. PoriallotgSatvuadgye-WiCtohnc2e5ntMrEa/tKiEon"(Cu-gPeFquOiAv/r g) in tissues ins male and fems ale rats follo: wing 52 7. mPialloet aStnuddfye-mPaleercreantstofofldloosweinrgeocroavlergeadvaagte1W6i8thho2u5rsmign/ckagge"Cw-asPhFOaAndw residr ual fe eed inn 53 8. PWiiltoht2S5tuMdZyK--EOv"eCra-lPlFmOaAssw balance inr male and fe emale ratsn followings oral gavag: e 54 9. Material Balance ~ Dosing information for male and female rats i 55 10. Percent of dose recovered in TIGRE "CPFOA corer urine in male and female rats following rrr oral gavage with 36 11. PFerceAntofE doseyrecoS vered in feces in male andE female rats following oral-- gavage wit_ h 12. Percentofdose recovered in tissues in male and female rats following oral gavage 13. Concentration (ug equiv/g) Ss= Su in tissues in male and female rats following oral gavage: ------------------._ 14. Percentofdose recovered in following oral gavage With 1 cage wash and residual feed in male and female rats ME/KE "C-PFOA crv: 60 15. Overall mass FCPFOA r balarncseroinemmamlsemaenmdefmemmmamlemsramtsssfsolslsoswsinsgsors al gavaa ge withs 1 mg/kgs 61 16. SPeIrcGeKntEof"dCo-sPeFrOeAcoc vered in urine in s male and female rr ats following oral: gavage with 62 17. P5eMrcPenGtof"dCo-sPeFrOeAcowvereod inrfectes in male and females rats folls owing oras l gavage: with 63 wa - Ep 000008 Perfivorooctanoic Acid: Tosicokintics inthe Rat Dupont7473 18. Percentofdose recovered in tissues in male and female rats following oral gavage With S MERE "CPFOA rere snes 64 19. Concentration (ug equiv/g) in tissues in male and female rats following oral gavage With S MERE "C-PFOA woven 65 20. Percent of dose recovered in cage wash and residual feed in male and female rats following oral gavage with 5 ME/KE "C-PFOA vss: 66 21. OBveOrTalTl OmaMss balmancme inmmanle amndmfemmalemratsifomllowmingmoraml gamvagme w--ith--5 m--g/k--g ""1 22. P2e5rMceInKtEof"dCos-ePFreOcAovc ered in urino e in male anr d female ras ts followingo oral gavag: e with 68 23. PBeErcMePnUtEof"doCseTrOecRovec red in feces in mar le and female ratsfm ollowingoral gav) age with 24. Percent of dose recovered in tissues in male and female rats following oral gavage With 25 mg/kg "C-PFOA ....occovvrrnssssssssssssss ersersormermmmmsmmmmJnO 25. Concentration (ug equiv/g) in tissues in male and female rats following oral gavage With 25 mg/kg "C-PFOA w.occvvvvrnssnssssssssssses werwermenwirsmrmisssmrwssnTrH 26. Percent of dose recovered in cage wash and residual feed in male and female rats following oral gavage With 25 g/kg "C-PFOA vrs:T2 27. Overall mass balance in male and female rats following oral gavage with 25 mg/kg LA 28. Percentofdose recovered in urine in male and female rats after 14-day repeated aCdRmYinistrcatioon onf 1mmge/kgmPmFOAm, mfolmlowmed mby ma 1mmgm/kgschsallseng--e d--ose--of--"C---P--FOA--Th 29. Percentofdose recovered in feces AIEEETEOA CUPRA imnmmamlemamndofmemnalsematmsmfomllsowminmgomrael rgasvmagse mwimthusm1n3 30. PWeirtchen1tKofgdose"Cr-ecPoFvOerAed(PinERtiLssO ues in male aS nd female raE ts following) oral gavage:16 31. Concentration (ug equivig) in tissues in male and female rats following oral gavage With 1 MEK "C-PFOA (FEPEAL dOSE)...rrornrrisssssssssssns TT 32. Percent of dose recovered in cage wash and residual feed in male and female rats following oral gavage with | mg/kg "C-PFOA (TEPC GOSE)....crrrcn: 18 33. Overall mass balance in male and female rats following oral gavage with 1 mg/kg HC-PFOA (TEPEat GSE)... nmin19 34. Pharmacokinetics -- Dosing information for male and female fats ...........cv.oururove 80 35. Pharmacokinetic parameters in male and female rats following oral gavage with OA TIIGTTON recension Sh 36. Pharmacokinetic parameters in male and female rats following oral gavage with TIGBGITOR commas Sl Tiied 000009 Perfluorooctanoic Acid: Toriokingtics in the Rat Dupo.7473 37. WPihtahrm1acMokiKneEtPicFOpaArao metersv in malee and fer male rs ats folle owing ie ntraver nous ins jection: 83 38. SPhMaGrmKaEcokPiOneAticw parameto ers in malr e and fes male rats e followingn oral gavs age with sion 84 39. 2Ph5aMrmEacKokiPnFetOiAc r perametere s in malev and femae le rats for llowing os ral gavage e with s 85 40. 0P.h1armmga/ckogkiPneFtOicAp(arXa(mEeNteerdsHiInMEmaCleOanUd SfemEal)e r.ats.fovllrowirngrorvalvgavvagnerwitrh ssss 86 41. Tissue Distribution --Dosing information for male and female Fats... 81 42. 8PeArVcAeEnEtWoiftdho1seMrEecEove"rCe-dPatROT,R.,win teissuers innmaleeandrfemale rats following oral 88 43. BPeArVcAeRnEtWoiftdho1seIrEecEove"rCe-dPatFOT,A.,, einntsisvsusesvirnnmarlnenarndsfiemmarlrerraitsnfiolrlsowsisngeosrarlsnses 89 44. Concentration 8agE With 1 M(uEg eEqu"iv/Cg)-atPTF,,,OinAtissueos inrmalne and female ats following oral 90 45. gCoanvcaegnetrwaittihon1 m(1gg/kegqu"ivC/-g)PFatOTA,TM...,.in..tissues in rmalemandefem--ale--rats--foll--owin--g or--al 51 46. APeVrcAeEntoWiftdho5seIrEecEove"rCe-dPatFTO,A,,c in tissuesr in male ao nd femaler rats folloe wing orals 92 47. Percent of doseA recovew red at T,,, in tissues in malR e and female rats following o--ral ---- 48. CEoAnVcAeEnEtrWaittiho5n M(uPgKeEqui"vC/-gP)FaOt AT.,w ,in tissuer s in malee and femaln e rats fols lowing ora: l 94 49. CSoAnVcAeEnEtrWaittiho5n(MuPgKeqEui"vC/g-)PFatOTA.dr ,,in tissues inr male and femar le rats followi: ng oral 95 50. PSAeVArEEcoWfietdhnos2te5 MreEcIoKvEer"edC-atPTF,,O,Ainc tissues r in maleo and femr ale ratse follows ing oral: 6 51. Percent of dose recovered at T..,, in tissues in male and female rats following oral ZAVAgE With 25 MPKG PCPROA cvseremmumemmessmemenesesssessesmmsesmmsssasiesssess 9 52. ECoAnVcAeEnEtWraittiho2n5(M1gEeRqEuiv"/gC) aPt TF..O, iAn tissc ues in mr ale ano d femalr e rats fe ollowins g oral : 08 53. ECoAnVcAeEnEtWraittiho2n5(1MgEeKqEuiv"/Cg-)PatFOT,A..,vinrtcissrueos irn mvalrevanrd nfemralverratrs frolnloswisngsorsalsss 99 Heth 49: 000010 Perfloroonanoic Aci: Tosicokintis inthRat Dupon7473 LIST OF FIGURES Page 1. Pilot Study -- PFOA concentration in serial plasma samples from male and female rats following oral gavage With 1 MZKEPFOA ......ccrvmmmmsmmsssssssssssssnisssssnsns 102 2. Pilot Study -- Cumulative recovery of "C in urine and feces in male and female rats following oral gavage with 25 mg/kg "C-PFOA ........co.vvvvven sisermmmmmrmisrmner 103 3. Cumulative recovery of "C in urine and feces in male and female rats following oral i avage With 1 MEE "C-PFOA...oocrrersremssssmssssssssssssssssssnsosssnss 108 4. Terminal tissue:blood concentration ratio in male and female rats following oral avage With 1 MEE "C-PFOA..cocrrmrsrissisimsmmsssmssssssssssssssssssesssns 105 5. Cumulative recovery of "C in urine and feces in male and female rats following oral avage With ME/kg "C-RFOA ...cccrvimrirsimrsssssssssssssssssssssssssss snes 106 6. Terminal tissue:blood concentration ratio in male and female rats following oral aVage With 5 IGG "CPROA cevnmumimssmsssmsssssssssssesmsesmess sessessesssessesorss 101 7. Cumulative recovery of "C in urine and feces in male and female rats following oral gavage With 25 MEK "C-POA .....cccrrerrsmrsssssssssssssssssssssssssssssssssssssssssssss 108 8. Terminal tissue:blood concentration ratio in male and female rats following oral gavage with 25 mg/kg FOPBOA conmnmmmmssmesssmssmesesmssasss son ---- {1 9. Cumulative recovery of "C in urine and feces of male and female rats after 14-day repeated oral gavage with 1 mg/kg PFOA, followed by a 1 mg/kg challenge dose of MC-PFOA (GY 15) ccvurvenrssmssssrsssmsmsssesssssssssssssssssssssssssssssssssssssesssssssssssssesssssssss 110 10. Terminal tissue:blood concentration ratio in male and female rats following 14-day repeated oral gavage With 1 MEKE "C-PFOA .....ccccrmmmsmsmssmsmmsssmsssssssssssenes 111 11. PFOA concentration in serial plasma samples from male and female rats following. oral gavage ith 0.1 ME/KE PFOA...cocrvimrrimrssisissssssmsssssssmsssssssnss 112 12. PFOA concentration in serial plasma samples from male and female rats following Hl Gage NHR L MEAG PFOA connssrummanersmmurmmsmmnnssssssesmomonnmions 18 13. PFOA concentration in serial plasma samples from male and female rats following intravenous injection With 1 ME/KE PROA....c..cruwmwrsmmmmsssmssssssssssssessssssssesss 14 14. PFOA concentration in serial plasma samples from male and female rats following oral gavage with S mg/kg PFOA.......cocmerrervre sisson 11S 15. PFOA concentration in serial plasma samples from male and female rats following oral gavage With 25 MEE PFOA ..ccrvcrrvmrssmssimsmsssssssssssssssssssmssssssseserss 116 16. PFOA concentration in serial plasma samples from male and female rats following oral gavage with 0.1 mg/kg PFOA (extended ime COUTSe) ........vmurvresessssrsssnssnsees 117 Ream wo 000011 Perfivoroactanoc Acid: Toriokinetcs in the Rat DuPont.7473 17. Tissue distribution of "C at T,,, and T,,,, in male and female rats following oral gavage With 1 MEKE "C-PFOA ..ccovmmnmnrsisinssssisssssisssssssssssssssss 118 18. Tissue:blood concentration ratio at T,,, and T,,, in male and female rats following oral gavageWith 1 MZKg "C-PFOA ocr 119 19. Tissue distriJ bution of0 "Cat T,,,NUand T,.., in male and female rats fo-- llowi-- ng or-- al --. 20. Tissue:blood concentration ratio at T,,, oral gavage With 5 Mg "C-PEOA and T,.., in male and female rats following cms 121 21. TgiasvsaugeedWiisttrhi2bu5tiMoEnIoKfE""CCaPtFT,O,A, avndcrT,..e,minrmtalneramnsd mfemmarlmesrastssfsolslsowsinngsorsasl ssnns 122 22. Tissueiblood concentration ratio at T,,, and T..., in male and female rats following oral gavage With 25 MEK "C-PFOA ...ovrvmmsnssssssitsmssissmssssssssmsmssnss 123 ------------------------------------er Live o -4- 000012 Perfluorooctanic Acid: Toxicokinetic in the Rat DuPon7473 LIST OF APPENDICES Page J B. Pilot Pharmacokinetics in Male and Female Rats Following Oral Gavage with 1 MEIKE PFOA wcrc 128 C. Pilot Excretion and Material Balance in Male and Female Rats Following Oral Gavage With 25 MEK ""C-PFOA ccmsss 132 D. Material Balance in Male and Female Rats Following Oral Gavage with 1 mg/kg HCIEROA nme simian J E. Material Balance in Male and Female Rats Following Oral Gavage with 5 mg/kg. F. Material Balance in Male and Female Rats FollowingOral Gavage with 25 mg/kg BOPIOA cnmmmmemssssmmemsmmensssmsarnsmssmsmesesssasmss 185 G. Material Balance in Male and Female Rats Following Oral Gavage with 1 mg/kg HC-PFOA (14 G2Y-TEPEREABOSE)cress 162 H. Pharmacokinetics in Male and Female Rats Following Oral Gavage with 0.1 mg/kg BEDS erento V9 1. Pharmacokinetics in Male and Female Rats Following Oral Gavage with 1 mg/kg PTO sss V8 J. Pharmacokinetics in Male and Female Rats Following Intravenous Injection with IMEKE PFOA worms 111 K. Pharmacokinetics in Male and Female Rats Following Oral Gavage with 5 mg/kg BEOR ress 18 L. Pharmacokinetics in Male and Female Rats Following Oral Gavage with 25 mg/kg THOR rrrerstssssmsmm--------------o 188 M. Pharmacokinetics in Male and Female Rats Following Oral Gavage with 0.1 mg/kg PFOA (eXtended HME COUTSE) rrr: 189 N. Tissue Distribution at T,,, and T,,,, in Male and Female Rats Following Oral Gavage With 1 GRE "C-PFOA crc isis: 194 . Tissue Distribution at T,,, and T,,,, in Male and Female Rats Following Oral Gavage With S MEIKE "C-PFOA snr: 200 P. Tissue Distribution at T,,, and T,,,, in Male and Female Rats Following Oral Gavage With 25 DPKG "C-PEOA coms: 206 PS ra "12 000013 Periorooctanic Acid: Toxicokineics intheRat Duront7473 STUDY INFORMATION 9th Collective Nomenclature: Pentadecafluorooctanoic acid Synonyms/Codes: + + + + + Pentadecafluoro-n-octanoic acid Perfluorocaprylic acid Perfluoroheptanecarboxylic acid Perfluorooctanoic acid PFOA 08316DO (Aldrich Chemical Co., Inc) (Lot No.) HaskellNumber: 25028 (CAS Registry Number: 335-67-1 Purity: 100.4% (titration with NaOH) 99.9% (gas liquid chromatography) Known Impurities: None identified Physical Characteristics: White powder Stability: The test substance appeared to be stable under the conditions of the study; no evidence of instability was observed. Sponsor: Association of Plastics Manufacturers of Europe (APME) Fluoropolymers Committee `Avenue E. Van Nieuwenhuyse 4 Box 3, B-1160 Brussels Belgium Study Initiated/Completed: August 3, 2001 / (see report cover page) fre on 000014 Peforsocunoic Ac: ToicokinnthteeRast Dupon7473 STUDY PERSONNEL Study Director: Raymond A. Kemper, Ph.D. Management: Matthew S. Bogdanffy, Ph.D., D.A.B.T. Primary Technician: Benjamin Robinson, B.A. Analytical Associate: Julia N. Wang, Ph.D. Toxicology Report Preparation: Lisa G. Burchfield, A.A. Management: Nancy S. Selzer, M.S. Laboratory Veterinarian: Thomas W. Mayer, D.V.M., A.CLAM. `William Singleton, D.V.M., ACLAM. Ar 000015 Perfluorooctanoic Acid: ToxicokineticsintheRat DuPon.7473 SUMMARY Perfluorooctanoic acid (PFOA) is a fluorinated fatty acid analogue used as a surfactant in industrial applications. The purposeof the current study was to characterize the absorption, distribution, elimination and pharmacokinetic behavior of PFOA in male and female rats. Male and female CD rats were administered '/C-PFOA (carbonyl label) by oral gavage at dose levels of 1, 5, and 25 mg/kg. Urine and feces were collected for 28 days in males and 7 days in females, and tissues were analyzed for residual radioactivity at sacrifice. Urine was the primary routeofelimination for '"C in both sexes. In males, urinary excretion accounted for approximately 43-62% of the administered dose. In females, the extent of urinary elimination was greater, accounting for approximately 76-84% of the administered dose. In males, fecal excretion of **C accounted forapproximately 6-14% of the administered dose, while in females, `approximately 2-6% of the dose was recovered in feces. Pilot experiments demonstrated that "`C wsaacsrinfiocte,elaipmpirnoaxtiemdaatseleyit1he3r-2"4C%O;ofotrhveodloatsieleroermgaainniecdcionmtphoeutnisdssueisno'f`mCa-lPeFOrAa-tst,rewahtielde rfaetms.aleAst retained less than 0.25%ofthe dose at any dose level. The highest concentrationsofresidual "*C were found in the blood, liver and kidney. Overall mean recovery of radioactivity ranged from 83.8 t0 91.6% in males and 81.3 t0 93.3% in females. Pretreatment of rats with 1 mg/kg PFOA for 14 days had litle or no effect on excretion or terminal tissue distribution ofa challenge dose of 1 mgkg "C. `The pharmacokinetic behavior of PFOA was investigated following oral administration of PFOA at dose rates of 0.1, 1, 5, and 25 mg/kg PFOA, and after intravenous administration of 1 mg/kg PFOA. Plasma was collected for 22 days after dosing in males and 5 days in females. `Concentration vs. time data were analyzed by non-compartmental pharmacokinetic methods Comparison of AUC for the oral and intravenous | mg/kg doses indicated that oral bioavailabilityofPFOA was approximately 100%. Plasma elimination curves were linear with respect to time in male rats at ll dose levels, while elimination kinetics were biphasic in females at the 5 mg/kg and 25 mg/kg dose levels. In males, plasma elimination half-lives were independent of dose level and ranged from approximately 138 hours 0 202 hours. In females, terminal elimination half-lives ranged from approximately 2.8 hours at the lowest dose to approximately 16 hours at the high dose. To further characterize plasma elimination kinetics, particularly in male rats, animals were given oral PFOA at a rateof0.1 mg/kg, and plasma samples were collected until PFOA concentrations fell below quantitation limits (24 hours and 2016 hours in females and males, respectively). Estimated plasma elimination half-lives in this experiment were approximately 277 hours in males and 3.4 hours in females. The tissue (Toss) and distribution of 'C at the time at the time corresponding to a corresponding retum to 50% to of maximum maximum plasma plasma concentrations concentration following attainment of maximum concentrations (Taz) was investigated following `administration after dosing in of 1, male 5, and 25 mg/kg "C-PFOA. rats and at 1.25 and 4 hours Tissues were collected at after dosing jn female rats 10F.o5rabnodth17s1exheosuarnsd at both sampling times, the major tissues for distribution of 'C were liver, kidney and blood. In Ar 000016 Peflvorooctanoc Acid: Tosicokinetics inthe Rat DuPoni.7473 omraldeesc,rtehaesefdraicntiootnheorfitshseudeos.seIfnofuenmdaliensl,ivtehreifnrcarcetiaosnedoffrtohem dToasue ptroeTsrewnxtzi,nbaultl rtiesmsauiesnerdemcaoinnsteadnt constant in males or decreased were greater betwee than 1, n a To nd ss and Tous. increased be t Live ween r:blo True od concentration and Touxz. Kidn ratios for ey:blood '"C at Tau concentration ratios at Tus in females were approximately 2 at all dose levels and remained relatively constant between Tue and Tsu. Overall, the results of this study demonstrated significant sex differences in excretion, pharmacokinetics, and tissue distribution of PFOA. in rats. BE ot Te a00s 0017 Perfluorooctanoic Acid: Toxicokinctics in the Rat DuPon7473 INTRODUCTION Perfluorooctanoic acid (PFOA) is a synthetic perfluorinated fatty acid analogue, used as a surfactant in industrial applications. In rat metabolism studies with PFOA, elimination following oral administration was found to be much more rapid in females compared to males. The dramatic gender differences elimination rate observed for PROA may be unique to rats. For example, in rabbits and mice treated with '"C-ammonium perfluorooctanoate, no sex differences in eliminationratesof '*C were observed, while in hamsters, elimination was more rapid in `males comparetod females. In dogs, a relatively minor (2-fold) sex difference in urinary elimination of PFOA was reported. A comprehensive comparison of PFOA elimination rates and tissue distribution between male and female rats will provide a foundation for conducting `mechanistic studies to elucidate the basis for the observed sex differences in PFOA elimination Kinetics `The objectives of this study were determine the absorption, distribution, excretion and `metabolism of PFOA in male and female rats following oral dosing. MATERIALS AND METHODS A. Regulatory Test Guidelines `This study was designed to meet the testing requirements of OECD Guidelines for Testing of Chemicals, Toxicokinetics, 417 (April 1984), and U.S. EPA Health Effects Test Guidelines, OPPTS 870.7485, Metabolism and Pharmacokinetics. B. Test Substance Industrial grade PFOA contains various proportions of branched chain isomers in addition to the linear form. For consistency, the current study was conducted using only the linear isomer. Unlabeled PFOA was obtained from Aldrich Chemicals (Milwaukee, Wisconsin). CAS Registry Number: ~~ 335-67-1 Molecular Weight: 4141 Molecular Formula: CiFisOH `Haskell Number H25028 rn2g4, , 000018 Perfivorooctanoie Acid: Toxicokinetcs inthe Rat. DuPont7473 Strcucrtourree:: Purity: CEAFR_IFE_F IE Fl FL F OH FF F F 100.4% Titration 99.9% Gas Liquid Chromatography C. Radiolabeled Test Substances [Carbonyl-"*C]Ammonium Perfluorooctanoate (`C-PFOA) was synthesized and characterized bSoyluAtmieonrswihtahmaPrhaadrimocahceimaiBciaolteccohnc(ePnitsrcaattiaownaoyf, aNpJp).ro"xiCm-aPtFelOyA,50a6nCd isugpplainedd cahseamnicaaqlueous concentration of approximately 4.0 mg/g. Specific Activity: 125.4 uCilmg Molecular Weight 329 `Haskell Numbers 2270548, 22705-49, 2705-50, 2705-51, 22705-52, 22705-53, 22705-54, 2705-55 Radiochemical Purity: >95% Pe(rC*f*l)uoArmomocotnainuoamte eR FAR_F_AR F AR be FL Fl F 0" NH; FF FF [#] denotes the positionofthe radiolabel D. Test Species Male and female Crl:CD*(SD)IGS BR rats were obtained from Charles River Laboratories, Inc., Raleigh, North Carolin. The Sprague-Dawley rat was chosen for this study because of the extensive experience with this strain and its suitability with respect to longevity, sensitivity, and low incidence of spontaneous diseases. Furthermore, the Sprague-Dawley rat has been used previously for pharmacokinetic and toxicity testing of PFOA and other fluorinated test materials. At the time of dosing, male rats weighed 193.3-280.0 gand female rats weighed 155.1-231.5 g. `Atthe time of dosing, rats were sexually mature and the weight variation did not exceed + 20% of the mean weight by dose group. Each animal was assigned a unique identification number SRO "18 000019 Perflvorooctanoie Acid: Toxicokinetics in the Rat DuPont7473 that was used throughout the study. The last 3 digits of the animal idenification number were `marked on the tail of each animal in indelible ink. E. Animal Husbandry Upon arrival at Haskell Laboratory, rats were removed from shipping cartons and housed in `appropriate cages, according to Standard Operating Procedures LA003-P-006 unless specified in the study records. Animals were maintained under quarantine for at least six days unless approved otherwise by the site veterinarian, had three recorded weight gains and no abnormalities detected.Afterthe quarantine period, rats were selected for study. Animal rooms were targeted at a temperature of 231C and arelative humidityof 40-60%. | Animal rooms are artificially illuminated (fluorescent light) on an approximate 12-hour light/dark cycle. `Throughout the dosing period with test compound, the rats were housed individually in appropriate cages according 10 the SOP. All animals were provided tap water and fed PMI Nutrition International, LLC Certified Rodent LacacbeDsisettof5o0o0d2aapdprloixbiimtuamt.elAyn2i4mahlosurwsaefrteefradsotseidngo.verTnhigehtacptruiaolrdtuoradtoisoinngofanfadstwienrgeisadlloocwuemdented in the study records. F. Animal Health Monitoring As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that wouldbe expected to impact the scientific integrity of the study: + Water samples are analyzed for total bacterial counts, and the presence of coliforms, lead, and other contaminants. + Feed samples are analyzed for total bacterial, spore, and fungal counts. + Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The. presence of these contaminants below the maximum concentration stated by the manufacturer `would not be expected to impact the integrity of the study. TTY "19 000020 Perfivorooctanoc Acid: Toxicokinetcs inthe Rat DuPon7473 Tlahbeoraantiomraylahneiamlatlh vaentdereinnavriiraonn.meEnvtaalluamtoinointoofritnhgesperdoagtraadmiidsnaodtmiinnidisctaetreedanbyyctohnediattitoenndsitnhgat affected the validity of the study. G. Dose Preparation, Analysis and Rates Trehqeuepsrtimoafrtyherosuptoensoofrt.eFstosruobnsetanecxepeardimmiennits,trPatFiOonAwwaassoardalmignaivsatgeer.edTbhyiisnrtoruatveewnaousscihnojseecntiaotn tthoe arelqluoiwreesdttiomaatcihoine of ve tohrealtabrigoeatvadiolasbeilciotnyc.entPrFatOioAnsa.ndT/hore `C-PFOA pH of the was dose msoilxuetdiownistwhawsataedjruassted to approsimately 60 with ammonium hydroside to ensure complete dissolution of the tst material. ex4cCre_tPiFoOnAmawtaesridaillubtaeldanwciethanPdFtOisAsuteo dtihsetraipbpurtoipornieatxepesrpiemceinftics,acdtoisveitysoflourtieoancshwdeorsee tlaervgeel.tedFotro daeplpirvoexriampaptreolxyi4mamtLe/lykg20b-o3d0yCweiig'h*tCpwearsaunsiemda.l F.orFoirntorraavlednoosuisngd,osaindgo,sea vdoosleumveoloufme of approximatel2y mL/kg was used. Dose solutions were prepared as follows: DoseAlebvseolrption/PlasmaDoPshearVmoalcuokmienetic ECxhpeemriicmaelntCsoncentration mek) lg Gegml) 0110 +4 000225s0 5100Gw 12 0152050 250 4 6250 Dose Dose MRaatdeiroicahleBmailcaanlce/STpiescsiufeicDistributiCohneEmxipcearilments Level Volume Dose Activity Concentration _(mghg)(mlkg) (Ck) (uCimg) (mghml) 500 44 112200 122000 012255 50 4 20 8 625 - RCaodnicoecnhtermaitciaoln (Climb) 3300 30 DProespearlaetvieolns wanedredadteatemramniangeedmbeanstedfoornrpardieovaicotuisvetodxoisceoksionleuttiiconasndwatosxiccairtryiesdtuoduitesuswiintgh PFOA. the DprEepBaRraAtSionlsabfoorrattoherysiinngfloermdaotsieonexmpaenraimgeenmtesntwesryestpreemp(aLraebdlporgiiccrLtToDt.h,e dShaeyffoifeluds,eUaKn)d.stDooresdeat approximately 4C until used. Dose solution for the repeat dose experiments was prepared in bulk, stored at approximately 4C, and used as needed. - EF Rane, 000021 Perflvorooctanoic Acid: Toxicokinetics in the Rat Dupon7473 'HPLC-MS wesused to analyze dose solutions for chemical concentration. Dose solutions csocinnttaiilnlaitnigon"cCo-unPtFiOnAg (wLeSrCe),asasnadyerdadiinotcrhiepmliiccaatle fpourrirtaydiwoaasctdievteecromnicneendtrbaytHioPnLbCy liquid using radiometric detection. H. Sacrifice Rats were sacrificed by CO; asphyxiation and exsanguinated by cardiac puncture. 1. Pilot Studies TchhaerafcotlelroiwzienPgFpiOlAotesltiumdiineastwieonreractoensdfuocltleodwitnogdoertaelramdimnienitshterpatliaosnm.aTkhineetdiactsaoffrPomFOthAesaend to experiments were used in setting the whole blood serial collection time-points and determining the principal routes and ratesofelimination. 1. Plasma kinetics following Oral Dosing with Non-Radiolabeled PFOA Tfrwoom mthaeleveannddotrwaondfeamlalloeweradttsorwietchovsuerrgifcoarlaltyliemapstlaonnteeddajuygaufltaerrvseuirngecraynnbuelfoarsewdeorseinogb.taRiantesd were administered PFOA ata dose level of 1 mg/kg bytheoral route and housed in metabolism cages. iFnotloltouwbiensgcdoonstianign,isnegriEaDlTbAl.oodInsacmapsleesswwheerree rpeatmeonvceydoffrtohme ctahennjuulgauslabrevceaimnecacnonmuplraomainsdepdl,aced w1h2,ol1e6,balnodod24wahsoucrosllpeocstteddofsreo,matnhdeattai2l4v-ehionu.rSainmtpelrveaslswethreerecaofltleerctuepdtpore1d6o8seh,ouarnsd. at 0.5,2, 4,8, Wcehnotrliefubglaotioodn.saPmlplaessmawewraesmsationrteadifnreodzeonnawte<t~i1ce0.CPluanstimlapwraocsessespeadrfaotredanfarloysmisr.ed cells by 2. Excretion and Material Balance following Oral Dosing with Radiolabeled PFOA tThweo25mamlge/kangddtowseo lfeevmealbleyorartaslwegarveaagdem.inFiosltleorweidntghdeotseisntgm,atraetrsiawlerfeorhmouulsaeteddiwniditvhid'u`aCll-yPiFnOAglaatss metabolism units suitable for the collection of urine, feces, expired air and volatile organics. Urine and feces were collected on dry ice at approximately 4, 8, 12, and 24 hours post-dose, and every 24 hours thereafter until sacrifice. Expired air was passed through two scrubbing towers, one containing 2 N NaOH to trap expired 1to4w0e0r,sawnedrtehreespelcaocendd ecvoenrtyai2n4inhgouerthsyploesnte-gdloysceolunttoiltrsaacprivfoilcaet.ile organic compounds. Scrubbing. Animals were sacrificed after 168 hours post-dosing. LoJ e ----- I --" 000022 Perflvorooctanoc Acid: Toxcokinetics in the Rat DuPont.7473 `Atthe conclusionofthe radiolabeled dose experiments, cages were rinsed with detergent and `water (50:50 v/v), followed by water, and finally with acetone. "The following tissues were collected at sacrifice: KBildonoedy LuUtnergus SpGlLe.ernactand contents FMauscle TBeosntees PArdoresnaels LHievaerr BOrvaairnies TSkhiynmseasmple: After collection, tissue samples were stored at <-10C until processing and analysis. The remaining carcass was homogenized and assayed so that total material balance could be determined. J. Main Study 1. Excretion/Material Balance Experiments (Experiments 1-4) `The objectivesof the excretion/material balance experiments were to: determine the rates and routes for elimination of PFOA. determine the material balance for total radioactivity administered. determineif repeated (daily) low oral dose exposure alters the excretion kinetics of PFOA. Dose Routes and Frequency The excretion/material balance experiments were comprised of four dose groups. Experiment 21 h3 DoseGrowp S1 mmgkye,,ssiinngglleeoorraall ddoossee. 25mmg/kkg,,4s-idngalyeroerpaleadtoesdedose (labeled) 1 mg/kg C-PFOA challenge dose (day 15) Each dose group (single dose) was composed of4 male rats and 4 female rats. Each dose group received dose formulated with '`C-PFOA. For the daily (repeat) low-dose oral gavage experiment, four male and four female rats were administered non-radiolabeled test compound at the low dose rate once per day for = BR 000023 Perfluorooctanoie Acid: Toxicokintics in the Rat DuPon.7473 14consecutive days. Rats were administered a challenge doseofthe test material formulated `with C-PFOA on day 15. Experimental Design Following administration of the radiolabeled dose, urine and feces of male rats were collected on dry ice at approximately 4, 8, 12, and 24 hours following dosing, and at 24-hour intervals thereafter through 336 hours (14 days). Excreta were collected at 48-hour intervals from 336 hours until sacrifice at 672 hours (28 days). For female rats, excreta was collected ondry ice at4, 8, 12 and 24 hours following dosing and at 24-hour intervals thereafter until sacrifice at 168 hours (7 days). As specified in OECD and OPPTS guidelines, since less than 19% of the administered dose was eliminataeds expired CO and volatile organic compounds in the pilot study, CO; and volatile organics werenotcollected in the main study experiments. Moreover, since less than 209% of the administered dose was recovered in the feces in the pilot experiment, bile was not collected in the main study experiments. `The following tissues were collected at sacrifice: BKildonoedy LUtuenrgus SG1p.leetnract and contents Fat TeMsustcelse AdBroenneals PLriovseurte HOevaarrites BSrkaiinnsample TThhyyrmouisd After collection, tissue samples were stored at <-10C until processing and analysis. The remaining carcass was homogenized and assayed so that total material balance couldbe determined. Atthe conclusion of the radiolabeled dose experiments, cages were rinsed with detergent and water (50:50 v/v), followed by water, and finally with acetone. Cage wash was stored at room temperature. 2. Pharmacokinetic Experiments (Experiments 5-9) `The principal objective of the pharmacokinetic experiments was to determine the extent of absorption of PFOA following oral dosing and to characterize ratesofeliminationofPFOA from plasma using plasma pharmacokinetic methods. = R _-- n 000024 Perflorooctanoic Acid: Toxicokineic in the Rat Dose Routes and Frequency `The pharmacokinetic experiments were comprised of ive dose groups. DuPont7473 TT Eaperiment oseGroup_ 6s 01 .memgk,,oraolral 1 mg/kg, inravenous 57 S25mmygk/ek,g.oroarlal 9 0.1 me/kg. ora, extended ime course rEaadciholdaobseelegdrtoeuspt cwoamspcooumnpdo.seTdheoif4ntmraavleenoaunsdd4osfeemparloeviradtesd. aEraefcehrdeonscee gfrorouepstriemcaetiivnegd nonbioavailability of PFOA by the oral exposure routes. Experimental Design tRoatrsecwoivtehrsfuorrgiatcallelaystimapdldiatnitoendaljuognueladravyeaifntecranarnruilvaasl bweefroereobdtoasiinnge.d fFroolmlothweinvgenddoosirnag,ndsearliallowed EwhDoTlAe.blIonodsosmaempclaessesw,ewrheodlreabwlnoofdrowmasthceocllaencntueldafarnodmptlhaecteidlivnetion.MicFroortamianleerrattsu,bebslocoodntaining samples were collected pre-dose, and at 0.25, 0.5, 1, 2,4, 8, 12, 16, and 24 hours post-dose, at F24o-rhfoeumrailneterratvsa,lsbltohordousgahmp1l9e2shwoeurrse,ctohlelnecatte4d8p-rheo-udrosien,tearnvdalastf0r.o25m,10.952,h1o,u2r,s4t,h8r,ou1g2,h 5126,82h4o,ur3s6., a4n8d,7s2e,xawnads9i6nfhuosuerdsipnotsot-tedsotsea.niImnalssovmieactahseejs,ugwuhloarlevebilnocoadnfnruolma dfoolnloorwainngimsaalmspolfetrheemsoavmale taoge prevent volume depletion, as per Haskell Animal Welfare Committee guidelines. Rats were ssaecprairfaitceedd bayftcerentthreiffuignaaltisoanmapnldinfgrotziemne.atW<h-o1l0eCbluonotidlwaansalpylzaedc.ed on wet ice, and plasma was rTaotsfpuertrhseerxchwaarsacatdemriizneisttheerpeodtePnFtiOaAl paetrsairsatteencoef aofppPrFoxOiAmaitnelrayt0p.l1amsmga/,kag bsayteolrlaitleggarvoaugpe,ofanfdour plasma samples were obtained overamore extended sampling period than used in previous tpooxsitcdooksien,etwihcisleexpinermiamleenst,s.samInplfeesmawleereratosb,tpailnaesdmathsraomupglhes20w1e6rehooubrtsai(n8e4ddtahysr)o.ugSha3m1p2lehsouwresre analyzed by LC-MS using multiple reaction monitoring (MRM, Section N). 3. Distribution Experiments (Experiments 10-12) `The principal objective of the distribution experiments was to determine the concentration and ccloenacreanntcreatoifonPsF(OTiAmai)nasnedleacttetdhetitsismueescaonrdreosrpgoanndsinagt tthoeatriemteurcnotrore5s0po%ndoifnmgatxoimmauxmimpluamsmpalasma concentration following attainment of maximum concentrations (Tpmyz) selected based upon previous toxicology data and the results of the pilot for PFOA. Tissues excretion/material were Jaun n - 000025 Perfluorooctancic Acid: Toricolinetic in the Rat DuPont7473 balance experiment. Sampling times were determined based on the resultsofthe plasma `pharmacokinetic experiments. Dose Routes and Frequency `The distribution experiments were comprised of the following six dose groups. _Egerimet__Do_scLewd 10 11 mmeeeg u 35 mmegf/kkgg 2 2255 mmpegg Sacrifice Time TTouor TTaorn TTuoun Each dose group was composed o4f male and 4 female rats. Each dose group received dose formulated with "C-PFOA. Experimental Design Male and female rats were administered '`C-PFOAbyoral gavage at the nominal dose rates indicated (Section G). Male rats were sacrificed approximately 10.5 hours (Tuas) and 171 hours (Tuas) after dosing. Females rats were sacrificed approximately 1.25 hours (Ter) and 4 hours (Tau) after dosing "The following tissues were collected at sacrifice: BKildonoedy FMuascle LuUtnegrus BoTensetes SpGlleeanct and contents AdPrroesntaatles Thyroid Carcass LHievaerrt OBrvaairnies TSkhiynmsuasmple After collection, tissue samples were stored at <-10C until processing and analysis. Total radioactivity in tissues will be determined by oxidation/LSC. K. Sample Processing and Quantitation of Radioactive Residues Solid samples were oxidized using a Packard Model 307 Oxidizer (Perkin-ElLmiefre Sciences, Boston, MA). LSC was carried out usinag Packard Tricarb liquid scintillation analyzer (PerkinElmerLife Sciences, Boston, MA). L Pra o v ES 000026 Perfluorooctanoic Acid: Toxicokineticsinthe Rat DuPont7473 1. Whole Blood . AWlhioqlueotbsloofodwhsoalmeplbelsoowderweermeaianptpaliineeddtooncowmebtusicteioanndcostnoerseadnadt approximately allowed to dry 4C until at room analysis. temperature. Dried samples were combusted and analyzed by LSC. Analyses were carried out in triplicate 2. Urine bUryivnoertseaxmipnlgesbriferfloym. eaAclhiqaunoatlsysoifsewaecrheutrhinaewesdamaptlreowoemrteeamnpaelryazteudreinantrdipmliicxaetde bpyriLoSrCt.o analysis 3. Feces TFehcaewsefdrofemceesacwhercoelmleicxteiodnwiinttheravanlawpperroeprtihaatweevdoalturmoeoomftdeimstpielrlaetduwraeteprriaonrdtohpormoocgeessniinzge.d using aalhlaonwdedhetloddhroymaotgreoniozmetre.mpAelriaqtuuortes. oDfrtiheedhhoommooggeennaatteeswewreereapcpolmibeudsttoecdo,mabnudstainoanlyczoendesbyanLdSC. 4. Tissues Ttiissssuueewsawserdeivtihdaewdeidntaot trwoooomrttehmrpeeeraaltiuqrueotpsriaonrdtoappprloiceedsstiongc.omFbourstsimoanllceornetsi.ssuTesi,sstuhee aenltiiqrueots were combusted and analyzed by LSC. 5. CO: Aliquots of CO; trap solution were analyzed in triplicate by LSC. 6. Volatile Organics `Aliquots of volatile organics trap solution were analyzed in triplicate by LSC. 7. Cage Rinse Aliquots of cage rinse were analyzed in triplicate by LSC. 8. Residual Feed Residual feed was separated from feces, stored at <-10 C and thawed at room temperature prior `1w0aptrerocaensdsihngo.moSgaemnpilzeesdoufsirnegsiaduhaalnfdeehdelwdehroemmoigxeenidzweirt.h Aalniqapuportosporfiattheevhoolmuomgeenoaftdeiswtielrleed applied to combustion cones and allowed to dry at room temperature. Dried homogenates were `combusted and analyzed by LSC. S:RA "%- 000027 Perflvorooctancic Acid: Toxicokinctis in the Rat DuPont.7473 9. Carcass Frozen carcasses were chopped into smaller pieces, mixed with an appropriate volume of distilled water, and homogenized using an electric blender. Aliquotsofthe homogenate were applied to combustion cones and allowed to dry at room temperature. Dried homogenates were: combusted, and analyzed by LSC. L. Extraction of PFOA from Plasma for LC/MS Analysis Plasma samples were processed by solid phase extraction (SPE) using 96-well Isolute array protein precipitation columns (Jones Chromatography, Lakewood, CO). In the pilot experiment, perfluoroheptanoic acid (Aldrich Chemicals, MilwaukeWeI,) was used as an intemal standard for quantitationof PFOA. In all main study experiments, perfluorononanoic acid (Aldrich Chemicals, Milwaukee, WI) was used as the intemal standard. Plasma samples were thawed, anda 75 uL aliquot was applied to the SPE array. Intemal standard was added (10 uL ofa 3 pg/mL solution in water), followed by 0.215 mL of ACN. The SPE array was eluted slowly under vacuum into a96-well receiver plate, and the extracts were analyzed by LC/MS. All samples were extracted and analyzed in duplicate. M. Material Balance `aTdomtianlirsetceorveedr.y for rats receiving "C-PFOA was expected to be 100 + 10% of the amount N. Analytical Methods 1. Instrumentation System 1: Detector: `Hpeuwmlpe,ttc-oPlaucmknarhdeaSteerri,easn1d10a0utLoisqaumipdleCrhromatograph, equipped with quaternary Packard SO0TR Flow Scintillation Analyzer, with CaF solid flow cel System 2: b`eWaatteerr,sa2n7d90auLtioqusiadmpClherromatograph, equipped with quarternary pump, column Detector: Quatro Ulima Mass Spectrometer Mode: SIR and Full Scan ASpouarlcyez:er Conditions: HLMM II RReessoolluuttiioonn:: EnTtornaennceer:gy 1: Coliion: Ne1g0a0tive Electrospray 11000 050 weno. wm oooozs Perfluorooctanoic Acid: MS Method 1: MSMethod 2: MS Method3: MS Method 4: MS Method 5: System 3: Detector ToxicokiintehteRcast DuPont7473 Exit 50 LHMM22 rreessoolluuttioino:n 112200 IMuolnteinpleiregry(2V:): 26500 SIR dwell time(s): 025 Mode: MRM SoAunracleyz:er Conditions: LHMM I1RReessoolluuttiioonn:: Ton energy 1: Entrance: ExCoiltli:sion: LHMM22rersesoolluuttiioonn: TMuolnteinpleiregry(2V:): N1e4g0ative Electrospray 01450-10 2-50 51-05-013 115500 61500 MToidmee:: S0I1R6,02 mmaisnses cChh:: 441633..0000 MToidmee:: S0I1R61,0 mmaisns Ch: 413.00 MToidmee:: S0.I7R.2,0mmiansses ch: 413.00 C2 363.00 TMiomdee:: Mass Range: Scan Time: F0u1ll0S0eamnin 300-700 Da 08s Mode: Time: cchhia: Dwell Time: MR2 mM assp,ais 0-120 min ((446219--303.261880..69000)) 0255 ``Hpeuwmlpe,tcto-lPuacmknahredaSteerri,easn1d10a0utLoisqaumipdlCehrromatograph, equipped with quaternary `Quattro LC Mass Spectrometer Mode: Full Scan Analyzer Conditions: iis 28: 000029 Perfluoroocianoic Acid: Toxicokinetics intheRat Dupont 7473 SoLuMrc1eR:esolution: HToMn e1neRregsyol1u:tion: EExnivatnce: LHMM22 rreessoolluuttiioonn: Mounliepnleiregry(2V:): N1e5g0ative Electrospray 0150 5500 112200 61500 MS Method 6: MToidmee:: MScaasnsTRiamneg:e: F0u1ll0S0camnin 11700s.500 Da System 4: H`peuwmlpe,ttc-oPlaucmknarhdeaSteerri,easn1d10a0utLoisqaumipdlCehrromatograph, equipped with quaternary Detector: Finnigan LCQ Mass Spectrometer Mode: MRM MS Method 7: SAonuarlcyezer Conditions: Scan Events Sean! N1egative Elecospray 44112.48.8 ((336688..337700)) [[""CC-PPFFOOAA oonnllyy)] (@13.5413.8) - (368-370) [CIC Misture] MS Method 8: SoSucracneE:vents Sean: Sean: N2egative Electrospray 4128 (368:370) 4630- (418.420) Mode: SIR MS Method 9: SSocuarnceEvents Sean 1: N1egative Electrospray SR @119-4159) 2. Chromatographic Methods Method 1: Insrumen CCoolluummnn temperature: Mobile phases: Dose radiochemical purity analysis (all "C experiments) `SWaytsetrse1mSymmetry C18, 21 x 30mm, 3.5 ym A`A:mb5ie0nmtM Ammonium Acetate B: Acetonitrile Timetable: Cow T7200 7] 0aSa ES 000030 Perfluorooctaoic Acid: Tosicokinetics inthe Rat Dion.7473 [70 T7770 7] Coo 100 | SFtloopwtnim:e: Injection volume: 0125.500mmLiinmin lL Method 2: eDxopseerciomnecnetn)tration and plasma concentration analysis (pilot pharmacokinetics MIsn:seument CCoolluummnn:temperature: Mobile phases: MSySstMeemt?hod 3 AWmbaietnxteTremsa MS C18, 2.1 x30mm3,.5 im BA: 5A0ccmioMniAimlemonium Acetate Timetable: [o TT o 00 --] [seo Two] [so T7700 C70 T7200 FSltoopwtriamee:: njection volume: 073000mmLiinmin SL Method 3: Dose concentration analysis plot material balance experiment) TMnss:ument CCoolluummnn:temperature: Mobile phases MSySstMeemthod 6 APmhbeineonmtenes Synergi MaxRP, 20x 20 mm. 2 jm BA:: A50ccmonMiiAlmemonium Acca Timetable: [Tmem |-- &B | [owTwo] [oTTswo 0-- ] [20Teo [30Two 7] [wT 00 ] CTTo %0 7] SFtloopwirmee: Injection volume: 0130000mmLiinmin SL Method 4: Dose concentration analysis (main study experiments 1,4, 6,9, and 10) wnsstument Column: MSySstMeemt4hod 7 Zorbax SB.CI8 Rapid Resolution, 4.6 75 mm, 3.5 pm. wee ee 000031 PerfloroocaAncki: ToicokiintehiRast CoNlobuimleneprpsee; AAmSbiOenmte Amorim Aces 3: Acconiie -- [mmom w so wm]) -- --2eo0---- swoo || [Few Tso FSliopw ime 7100m0Umnin Injection volume: Sul Method : Doseconcaenalynsist(rairnsuadytexpieriomennt5 vesames CoCloulummnn:tonpersture: Mobile phases: S3ySsMtie4tmho7d ZAomtbolaesSr3.C18RapidResolution, 46x75mm,3.5 im 5: 5A0cmcotnAimlmeonium Ace Dupon 7473 Timetable: [CC Timemny | & ____] [oo T7501 [20 i-- w T-- 50 -- w0 o-- 1 | Ceo Tso FSloopw rimaee: 1Loo6m0Umminn Treenvolume: Sul. Method 6: oissmens CoClouomnntempest: Vibe prc Plasma concentration analysis (main study experiment $ [females]) S8ysMeetmhods ZAomrbbiaesntSB.C18Rapid Resoltion 675 mm. 3.5 im A5750 AccmoMriAamimeoniumAcetic Timetable (moawm so wm]] oe 50 so sw Coo T5011 SPtoopwieme:: 1Lo0m0U0mminn Tnwion volume: Sit + En 000032 aT Perfluorooctanoie Acid: Toxicokinetic in the Rat DuPont7473 Method 7: Doseconcentration analysis (main study experiment 12) Instrument Ms: C`oCloulummnn:temperature: Mobile phases: Systema ZoMrSbaMxetShBo-dC9I8RapidResolution,4.6 x75ram, 3.5 pm `A:Amb5i0enmtM Ammonium Acetate B: Acetonitrile Timetable: [Tme@mnm [ &8 | [oo--T "50 ] e1501] [soo e507] Coo eso 7] SFtloopwtriamee:: Injection volume: 11.000m0Ummiinn SHL Method 8: Doseconcenantalyrsisa(mtaiinsotundy experiment 5) IMnsst:rument Column: MoCboilulmenphtaesmepesr;ature: SMySsMteet4mhod 7 Waters x Terra MS C182.0 x30mm, 2.5 pm AA:mb5i0enmtMAmmonium Acetate B: Acetonitrile Timetable: [Tme [--G&m B m1] [oe 771350 7] Co Two 7] FStloopwtriamtee:: Injection volume: 01300m0Ummiinn SL Method 9: D`aonsaleysciosn(cmenatirnasttiuodnyaneaxlpyesriism(emnatisnSs[tmuadlyese]x,paenrdim6e-n8t) 7) and plasma concentration IMnsst:rument Column; Column temperature: Mobile phases SMySstMeemthod 1 (plasma analysis) PMhSenMoemtehnoedx2Sy(ndeorsgeianMaalyxsRisP), 2.0 Ambient AB:: 5Ac0cmtoMniAvmilmeonium Acetate: x 20 mm,2 um Timetable: [ow100] oso 1 00 7} Co s00 7] P. oe Ta = 000033 PefuroocunAcoidi: Toviotieis ntheRat Powra Sutpionne:volume: 0T12o050m0mUmmniininn0(00.50.510m0inm)i) Sut Method 10: CNonisl.ouumment Column mpertue: Mobilephases: Doseconcentration analysis(mainstudy experiments 2 and 11) PSMhysesnVeammh2enoedn4SyergMssRP, 20 20mm, 2 pm Aen, 5A:: Aceon 50 mMAmmonium Acetate Timetable: Flow: Spine: [Timemn)| &B 1] [o 1 o oo | [oso 1 00 1 [Coo 1 800 0IL2o05ommomiminna0(0050.51m0i0nm)in Injection volume: Method 11: Josyumens CoCVlouemmn:mpeasnets, Sul Plasmaconcanaely nmltnsaadydexpoerimnent8) MSEyMseem2od5 hPA57:5h0eAnmocmmeeMneoAxmnSyonerrgii mMaAxc-RePt,e2.0 x 20 mm, 2 ym Timetable: [Timemn| &B ] [ow--T 00 ] [oso 1 00 1] [wo T1800 1] [oor 1 i001} [moe Ti00--] CC moTw Flow rate: Sorpiiomne:volume: Method 12: Co rumen: pi CVoemmpehmapetrtre: 1.0mL/min (0.0-0.5min) 10S2.u205l0mLm/imnin (0.5-12.0min) Doseconcenration analy mlnsudyexperiment) DSMoSyrsoMenmeSCoI Raid Reso46nx,75 mm 5.5 pm AA75m0biemnMAmmonium Aco 5: Acoonitie Duron 7473 L--- n 000034 Perfluorooctancic Acid: Toricokinetics inthe Rat Dupont7473 `Timetable: %B [oe --T 50 7] [20 1 50] Cao Two] Se Two 7] 50 SFtloopwtriamtee:: Injection volume: L10O0m0 iminn Sul 0. Clinical Observations and Mortality Cage-site examinations to detect moribund or dead rats and abnormal behavior and/or appearance among rats was conducted at least once daily throughout the study. Moribund rats were sacrificed. P. Measurement of Radioactivity Radioactivity in selected liquid samples was assayed by LSC. Total radioactive residues in solid `samples were determined by combustion, trapping liberated 'CO; followed by LSC. Samples for LSC were analyzed for 10 minutes, or until 160,000 disintegrations (0.5% 20) was accumulated, whichever came first. Q. Data Analyses Group data is represented as a mean SD. Non-compartmental pharmacokinetic analysis of plasma PFOA time course data was accomplished using WinNonlin (Pharsight, Mountain View, CA) using models 200 (single oral bolus) and 201 (single IV bolus). Values for Tray and Truuz across dose levels were analyzed by one-way ANOVA using Microsoft Excel. Bey ye 000035 Perfivorooctancic Acid: Toxicokinetics n the Rat Dupont7473 RESULTS AND DISCUSSION A. Pilot Experiments 1. Pharmacokinetics in Male and Female Rats following Oral Gavage with 1 mg/kg PFOA (Appendix B, Tables 1-2, Figure 1). Analysis of the dose solution indicated an actual concentration of 0.206 mg/mL, compared to a target concentration of 0.25 mg/mL. Thus, the actual dose rates for male and female rats were 0.78: 0.05 mg/kg and 0.80 +0.01 mg/kg, respectively. In male rats, mean plasma concentrations reached a peak of approximately 26 pg/mL after approximately 7 hours (Tes), and declined slowly thereafter throughout the observation period (168 hours). The plasma half-life for male rats observed in this experiment was approximately 103 hours. The peak plasma concentrations of PFOA observed in females rats (~25 ug/ml) was similar to that seen in male rats. However, peak plasma concentrations of PFOA were achieved within 0.5 hours of dosing in female rats, and plasma concentrations dropped rapidly thereafter. In female rats, PFOA was no longer detectable by 96 hours post-dose. The apparent half-life of PFOA in female rats in this experiment was approximately 3 hours. Furthermore, plasma. clearance of PFOA was approximately 32 times greater in female rats compared to male rats. Based on these data, the observation periods for toxicokinetic experiments in the main study were set at 528 hours and 96 hours in male and female rats, respectively. Furthermore, an additional time point was added at 0.25 hours to more accurately define Tru for PFOA in female ats. 2. Excretion and Material Balance in Maleand Female Rats following Oral Gavage with 25 mg/kg "C-PFOA (Appendix C, Tables 1, 3-8, Figure 2) `Upon analysis, the concentration of test substance in the dose solution was determined to be approximately 6.37 mg/g, compared with atarget value of 6.25 mg/g. Based on the volume of dose solution administered, male and female rats received PFOA doses of approximately 18.1 and 18.3 mg/kg, respectively. The radiochemical dose rate was approximately 77 uCifkg for both males and females Faonrd bfoetmhalseesxeesl,imuirniantairnygexacprpertoixoinmawtaeslyth3e0parnidma9ry2%rouotfethfoeraedlmiimniinsatteiroendodfos'e`Cb-yPtFhOiAs,rowuitteh, males r2e4spheocutrisv.elyI.n cUorntirnaasrty, euxrcirneatriyoenloifmi'n/atCi-oPnFoOfAraidnifoaecmtailveistywiansmraalpeids,waansd virtually complete within gradual and essentially linear throughout the observation period. `The other significant route of climination for r4aCdi-oPacFtOivAitwyabsyitnhitsherofuetcees,.whMilaelefsemeaxlcersetoendlyapeplriomxiinmaatteedlayp8pr.o5x%imoafttehleya0d.mi5n%isotfetrheeddose in the feces. No radioactivity was detected in either the CO, trap or the volatile organics trap at any timepoint, confirming that exhalation is not a significant route of elimination for PFOA (Table 8). = Sng = 000036 Perfluorooctanoic Acid: Toxicokineis in the Rat DuPont473 At sacrifice (168 hours) approximately 54% of the administered radioactivity remained in the body of male rats, while less than 0.2% of the dose remained in females (Table 5). For both sexes, the highest amounts of residual radioactivity were found in the liver, followed by the Kidney. In males, significant amounts of radioactivity were also found in the carcass and whole blood. Mean terminal tissue concentration of PFOA in males ranged from 0.57 ig cquiv/g in brain to 57.38 ig equiv/g in liver (Table 6). In female rats, mean terminal liver and kidney concentrations of PFOA were 0.030 jig equivig and 0.023 ig equiv/g, respectively. Overall, mean recovery of radioactivity in male and female rats was 93.93% and 93.90%, respectively (Table 8). Since no radioactivity was recovered in either the CO; or the volatile organic fraction, these | fractions were not collected in the main study experiments. Furthermore, since less than 209% of the administered dose was recovered in the fecesofeithersex, bile was not collected in main study experiments. B. Main Study 1. Excretion/Material Balance of /C-PFOA in Male and Female Rats (Tables 9-33, Figures 3-10, Appendices D-G) `The objective of the excretion/material balance experiments was to characterize the rates and dose dependence of fecal and urinary excretion of "C-PFOA, and to determine the terminal tissue distribution of residual '*C-PFOA in male and female rats. In addition, experiments were performed to determine potential effects of repeated exposure to PFOA on the excretion and disposition of *C-PFOA. Dosing (Table 9, Appendices D-G) Excretion and material balance of '/C-PFOA following oral administration were investigated in `male and female rats at nominal dose rates of 1, 5 and 25 mg/kg body weight. Actual dose rates were calculated based on analysis of the dose solutions and are presented in Table9. For all experiments, actual dose rates fell within + 15% of target dose rates. Animals received approximately 21-28 uCi of '"C-PFOA in the single dose experiments and approximately 29- 40 pCi of unlabeled P'*FCO-APFuOsAedfofrorthtehere1p4eadtaeydrdeopseeateexdpdeorsiimnegntwa(sTaabplper9o)x.imTahteelayct0u.a9l3dmogs/ekrga,teboafsed on analysisof the dose solution and the volume administered. Experiment 1: Excretion and terminal disposition of '*Cfollowing administration of1mg/kg 1C.PFOA by oral gavage (Tables 10-15, Figures 3-4, Appendix D). Urinary excretion was the primary route of elimination for "C in both males and females (Table 10). Within 28 days, male rats excreted approximately 43% of the administered dose in the urine. Urinary excretion of '"C was gradual in males throughout the observation period, and cumulative recovery of '*C in the urine was still increasing at 28 days (Figure 3). Female rats excreted approximat7e6l%y of the administered dose of '*C in the urine ove7r days. In female rats, urinary excretion of '`C was rapid, and nearly complete within 72 hours after dosing. ALS TT 000037 Perflaorooctancic Acid: Toxicakineic in the Rat DuPont7473 Significant amounts of C were also detected in feces of both male and female rats over their `respective observation periods (Table 11). The extent of fecal excretion of 'C was greater in males than in females. In both sexes, the majority of fecal elimination of "C occurred within the first 72 hoursafterdosing (Figure 3). At the termination of the experiment, approximately 24% of the dose remained in the tissues in male rats, compared to only 0.23% in females (Table 12). In both sexes, liver contained the hriagnhgeesdt fcrooncme0n.t0ra0t8ipongseoqfui"v*/Cg(iTnabblreain13t).o aIpnpmraolxeism,at'eClyw2asjigdeetqeucitve/dgiinn allilvetri.ssuIensfeexmaalmeisn,ed',Cand twhaasn d0e.t0e0c3tepdgineqluiivevr/,gkfiodrnealyl,twishsouelse. blFooord,maalned rsaktisn,,thaendtermmeiannalctoinscseunetbrlatoioodncsoonfce'nCtrawteiroen lreastsio for C in liver was nearly 6 (Figure 4). Tissue:blood concentration ratios were approximately 1 or less in all other tissues in males. In females, tissue:blood concentration ratios greater than 1 were observed in liver and kidney. Approximately 3%ofthe dose was recovered in the cage wash and residual feed fractions (Table: 14). Total radioactivity recovered from excreta, tissues, cage wash and residual feed amounted 10 approximately 84% and 81% of the administereddose in male and female rats, respectively (Table 15). Experiment 2: Excretion and terminal disposition of '"fC ollowing administration of5mg/kg C-PFOA by oral gavage (Tables 9, 16-21, Figures 5-6, Appendix E). Over the course of the experiment, urinary excretion accounted for approximately 62% and 78% of the administered dose of PFOA in male and female rats, respectively (Table 16). Cumulative resesceonvteiraylloyfc"o"mCplientteheinurfienmealiencsrweiatsheidngtrhaedufiarlslty7t2hrhoouugrhsoaufttetrhedoesxipnegri(mFeignutrien5m).ale rats, but was Idnostehiisnebxoptehrimmaelnet,afnedcafleemxaclreetraitosn(oTfab"l*eC a17c).couCnutmeudlafotrivapepfreocxailmeaxtcerleyti5o-n6o%f orafdtihoeacatdimviintyiswtaesred `more gradual at this dose level compared to the 1 mg/kg dose level, and continued to increase: throughout the observation period in both sexes (Figure 5). Atthe conclusion of the experiment, approximately 20% and 0.1% of the administered dose was recovered from the tissues of male and female rats, respectively (Table 18). In male rats, highest concentrationsof '*C were found in liver, kidney and whole blood (Table 19). In males, tissue concentrations of *C ranged from 0.027 pg equiv/g in brain to 5.33 pg equiv/g in liver. `Tissue:blood concentration ratios were 1 or less in all tissues of male rats except liver, for which atissue:bloodratioofapproximately 5 was observed (Figure 6). In females, only liver, kidney and carcass contained detectable concentrations of '*C. Tissue concentrations of Cin female rfaetmsawleerreatlse,stsitshsauneb0l.o0o2ducgonecqeunitvr/agtiinonalrlattiisossuceso.uldSinnocteb'e"Ccawlacuslantoetd.detected in whole blood of Approximately 3-4% of the dose was recovered in the cage wash and residual feed for both sexes f(eTmaballee 2r0a)ts. rTehspeecotvievreallyl (mTaatebrlieal21b).alance for "C-PFOA was 91.6% and 86.8% in male and TE ER 000038 Perfuorooctanoic Acid: Toxicokineics n the Rat DuPont7473 Experiment 3: Excretion and terminal disposition of "/C following administrationof 25 mg/kg *C-PFOA by oral gavage (Tables 9, 22-27, Figures 7-8, Appendix F). As seen for the 1 and 5 mg/kg dose levels, urinary excretion was the primary route of elimination orafts Celifmoilnlaotweidngapoprraloxaidmmaitneilsytr5at3i%onooffth'e"aCd-mPiFnOisAtaetretdhed2o5semign/tkhge duorisnee.ratCeum(uTalbalteiv22e).uriMnaalrey elimination in males was more rapid over the first 96 hours following dose administration, but slowed thereafter and appearedtobe approaching a plateau after 10-11 days (Figure 7). Female rats eliminated approximately 84%ofthe dose in the urine, primarily in the first 72 hours after dosing. Fecal excretion accounted for elimination of approximately 12.5 and 1.9%ofthe administered dose in male and female rats respectively (Table 23). In females, cumulative fecal excretion of 14C was essentially complete within 48 hours after dose administration (Figure 7). In males, fecal excretion of *C continued throughout the observation period. At sacrifice, approximately 13% of the administered dose was recovered from tissuesofmale rats (Table 24). In females, approximately 0.2% of the dose was recovered from the tissues. As skeiednnefyoranthdewthwoolelobwleoroddoosfemgarloeuprsa,ts,thaenhdiignhetshte cloinvceernatnrdatkiiodnnseoyfo'f"fCewmearlee fraotusn(dTianbltehe25l)i.verF,or both sexes, the highest tissue concentrations were observed in the liver. In males, a tissue:blood ratio of approximately 3 was observed in the liver, while ths ratio was close 10 or less than 1 in all other tissues (Figure 8). Radioactivity was not detected in the whole bloodoffemale rats in this experiment, so tissue:blood ratios could not be calculated. In this experiment, the cage wash and residual feed contained approximately 57% of the `8a3d.m9in%isftoerrmedalreadriaotasctainvdit9y3(.T3a%blfeo2r6f)e.mTahlee orvaetsra(lTlambalteer27i)a.l balance of '"C in this experiment was Experiment 4: Excretion and terminal disposition of '"Cfollowing administration o1f mg/kg C-PFOA by oral gavage following 14-day repeated dosing with 1 mg/kg PFOA (Tables 9, 28- 33, Figures 9-10, Appendix G). Overall, approximately 52% and 68%ofthe administered radioactivity was recovered in the urineofmale and female rats, respectively (Table 28). Similar to the single gavage dose e`mxapleeriramtesn,tbsu,tuwrainsarnyeaerxlcyrectoimopnleofte'"wCitchoinnt7in2uheodugrrsadfuoralfleymtahlreoruagthso(uFtitghuereob9)s.erTvhautsio,nrpeepreiaotdedin administration of PFOA for 14 days prior to challenge with "/C-PFOA did not have significant effects on either the rateorextent of urinary "*C excretion in male or female rats. Fecal excretion accounted for approximately 20% and 12% of the administered dose in male and female rats respectively (Table 29). However, the variability associated with the female feces is Very high, possibly due to contamination of the fecal samples with urine. Thus, the high mean vexaclrueetfioorn riencmoavelreyaonfd"f*eCmianlefermaatslewefreecessimmialyarbien atrhtiisfaecxtpuaelr.imAepnptar(Feingturraet9e)s.of fecal "C Ofiurn DD Te 000039 Perfivorooctanoic Acid: Toxicokineics in the Rat DuPont7473 Approximately 13% and 0.319%ofthe dose Was recovered in the tissues of male and female rats respectively (Table 30). For both males and females, the highest concentrations of '`C were. detected repeated in liver and exposure is kidney (Table 31). lowerthan after sin In gle males, expos the ure concentration of (0.94 ug equiv/g ""C vs. retained in liver 1.99 ug equivig). a fter In wotehreer lteissssutehsanin0m.a0l1ejs,g "e"qCuicvo/ngcefnotrrbaottihonssinwgelreeasnidmirlearp.eatIendfeexmpaolseurtiesssu(eTsa,b"l"eCs c1o2ncaenndtr3a1)t.ions Tissue:blood concentration ratios were greater than 1 in the liver of male rats (~3.5), and in both liver (~ 7.5) and kidney (~ 6) of female rats (Figure 10). Combined, the cage wash and residual feed accounted for approximately 2.5% and 8.4% of the administered radioactivity in male and female rats respectively (Table 32). In this experiment, the mean overall recovery of radioactivity was approximately 88.0% in males and 89.6% in females (Table 33). 2. Plasma Pharmacokinetics of PFOA in Male and Female Rats (Tables 34-40, Figures 11-16, Appendices H-M) `pThhaermobajceocktiinveetsiocfptahreapmheatrermsacoofkiPnFeOtiAcienxpmearliemaenntdsfweemarleetroacthsafroalcltoerwiiznegtshiengplleaosrmaal and intravenous administration and to estimate oral bioavailability of PFOA. Dosing (Table 34, Appendices H-M) Non-compartmental pharmacokinetic parameters were estimated after oral dosing at four nnoommiinnaall ddoossee rraatteeso(f0.11m,g1/.k0g,.5.0Doasned 2s5o.lu0tmiogn/skgw)eraendpraefptaerreidntarnadveannoaulsyzaeddmibnyisLtCra/tMioSnaast a adreescsruimbmedaruinzdeedr MiantTearbilaels34a.ndAMcettuhaolddso.seArcattueaslfedlolsweitrhaitens fo1r5al%l opfhatramrgaectodkionseetriacteesxfpoerrialmlents experiments. Experiment 5: Plasma pharmacokinetics of PFOA in maleandfemale ratsfollowing `administration of0.1 mg/kg PFOA by oral gavage (Table 35, Figure 11, Appendix H). Non-compartmental pharmacokinetic parameters for 0.1 mg/kg PFOA are presented in Table 35. `While similar peak plasma concentrations were observed in males and females, the time required etoliamcihniaetvieonthoefpPlFaOsmAawpaesakeswsaesntimaulclyhllinoenagrerwiitnhmraelsepsectthatno tinimfeemfaollelorwaitsn.g aInchbioetvhemseexnets,of peak `pmlaalsemraatlsevceolmsp(aFriegdurteo1f1e)m.alHeosw.evSiemri,latrhley,elpilmaisnamtaicolnehaarlafncliefew(aTsym)ucwahsmnoeraerlryap6i3dt(i~me3s4Xl)onigner in female rats compared to males. Experiment 6: administration Plasma pharmacokineticsof PFOA in of1mg/kg PFOA byoral gavage and male andfemale ratsfollowing by intravenous injection (Tables 36-37, Figures 12-13, Appendix I-J). Non-compartmentl pharmacokinetic parameters for | mg/kg PFOA following oral administration are presented in Table 36. Peak plasma concentrations of PFOA in male and Rons Te 000040 Perfluoroactansc Aci: Toxeokinetic in the Rat DuPon7473 feotmhaelreprhaatrsmawceorkeinceotmipcarpaabrlaem,ettehrosugarheseovmideewnhta,tanhdigahreersiinmimlaalresi.n mSaiggnniiftiucdaenttostehxodsieffoebrseenrcvesedinat tthheou0g.1h msgo/mkegtdheorseeirsatse.omPeleavsimdaenecliemfionratbiiopnhacsuircvbeeshwaevrioersitnilfeesmsaelnetsiaaltlylaltienreatrimien bpooitnhtsse(xFeisg,ure c12o)m.poOunned-mraelleatreadt winasthaftounnoddsiegands oofnmdoarybi9diotfythwiesreexpoebrsiemrevnetd. inThoithseervaennitmdaolcssinnotthiasppear to be experiment or in the other pharmacokinetic experiments. 3P7h,aramnadcopkliansemtaicelpiamrianmaettioenrscufrovreisntarraevperneosuesnatdemdiinnisFtirgautrieon1o3.fPVFalOuAesafroerscuommmmaroinzed in Table: wPihtahrimnaceoakcihnestexi,capnadrasmiemtielrars sweexredisfifmeirleanrcebsetinwepelnasomraalealnimdiinnattriaovnernaotuess wroeurteesoobfseardvmeidnfiostrrbaottiohn trohueteAs.UCOrfaolr biinotarvaavielnaobiulsiatdymciannibstereastitoinm.atCeodmapsartihesorantioofovfaltuheesAfUorCorfaolraonradliandtmrianviesntoruastiAonUtCo tshueggsepsitksetihnatploraaslmbaioPaFvaOiAlablielvietlysoifn PfeFmOaAlewraatsseastse1n2tihaolulrys1i0s 0u%nk(n9o5.w5n-,11a4n.d9%m)a.y Tbheearotriifgacitnuaolf, since it was not observed in either sex dosedorallyor in males dosed intravenously. aEdxmpienriismternattio7:n oPlfasmmga/pkhgaPrmFaOcoAkibnyeotriaclsgoafvPagFeO(ATaibnlema3l8,eFaingdufreem1a4l,eAraptpsefnodlilxowKi)n.g NAotnt-hceo5mpmagr/tkmgendtoasle plehvaerlm,asciogkniinfiectainct psaerxadmieftfeerrsenfcoerswmegr/ekogbsPeFrOveAd faorre aplrlepsheanrtmeadcionkTianbeltiec38. apanrdaamsetweirtshclaolwcuelradteods.e lMeavleelss,eexlhiimbiintaetdiohnigohfePrFpeOaAk fprloamsmpalaPsFmOaAiscmounccehntmroartieonrsaptihdainnffeemmaallese,s compared to males. In and kinetic parameters amraelessi,mtihleatporlatshmoaseeloibmsienravteidonatculrovweerisdolisneesa.r at this dose level (Figure However, the plasma 14) elimination curve is biphasic in females, resulting in an increased elimination half-life compared tolower doses. aEdxmpienriismterantti8o:noPfl2a5smmagp/hkagrmPaFcOokAinbeytoircaslogfaPvaFgOeA(Tianblmeal3e9,aFnidgfuermea1l5e, rAaptpsefnoldlioxwLi)n.g `NWoint-hctohmepaexrctempetnitoanlopfhtahrempaecaokkipnleatsimcapcaornacmeentterrastifoonr,2t5hemgm/akrgkePdFsOeAx are presented differences in in Table 39. W`phhialremapcloaksinmeatieclipmairnaamteiotnerwsaosblsienrevaerdwiatthlorwesepredcotsteostairmeeailnsomasleeenraattstahte 2h5igmhge/stkgd,ospelalsevmeal. einlitmeirnmaitniaolnpolfaPsFmaOeAliimninfaetmiaolnehraaltfs-lwiafesccolmeapralryebdipthoasliocwe(rFidgousree l1e5v)e,lsw.ith a consequent increase aEdxmpienriismterantti9o:noPfl0a.s1mmagp/hkagrmPaFcoOkAinbeytiocrsalofgaPvFagOeAwiinthmeaxlteeanndeddfeobmsaelrevartaitsonfoilnltoewrivanlg(Table 40, Figure 16, Appendix M). Texopefurritmheenrtchwaarsacctaerrriizeedpoluatsamtatehlei0m.i1namtgi/okngkidnoesteiclseovfelPsFusOiAngina mmaolreeasnednsfiteimvaelaenaraltyst,icaalsemceotnhdod. R--eo--m--, ----------------------"--------------eee0r0e00e4e1 Perflorooctanoie Acid: Toxicokinetics in the Rat DuPont7473 Plasma samples were collected and analyzed until the PFOA concentration dropped below quantifiable levels. `Inmatlheisraetxpplearsimmeancto,nPtaFiOneAdwqauasntdieftieacbtleedlienveflesmoaflePrFatOpAltahsrmoautghhr2o0ug1h6 2h4ouhrosur(s84afdiaeyrs)d.osiAnnga,lywshiisle tohfetihneitpilalas0m.1a melgi/mkignapthiaornmdaactoakifnreotmictheisxpeexrpiemreinmten(tTaybileeld4e0d).reTsuhletspsriimmialrarytdoiftfheorseencoebsiabientewdeeinn sexopmeerwihmaenttgsrewaetrere,saenedn twhiethvamlauleessf,ofroprlwahsimcahctlheeareasntciemactoenssfeoqrueenltilmiynlaotwieorn.haAlfs-liinfethweefrierst 0.1 `mg/kg experiment, plasma elimination curves were linear with respect to time for both sexes (Figure 16). 3. Tissue Distribution of "*C-PFOA at Plasma Tox and Tmax: in Male and Female Rats (Tables 41-53, Figures 17-22, Appendices N-P) `The tissue distribution experiments were carried out to characterize the tissue burden of H4C.PFOA and to investigate the kineticsof elimination and accumulation of PFOA in various tissues of male and female rats. Dosing and Sampling Times (Table 41, Appendices N-P) Tmiaslseueanddisfterimbaulteiornatosfat*nComatinTaralxdaonsde Traamtaewszoffo1l,l5owainndg o2r5almagd/mkignibsotdraytiweoinghwta.s investigated Actual dose in rates ewxepreericmalecnutlsa,teacdtbuaalseddosoen raantaelsysfeilsl owfitthhiend+os1e5s%oloutfitoanrsgeatnddoasreerparteess.enAtendimianlTsabrleece4i1v.edForall approximately 21-28 uCi of '"C-PFOA in these experiments(Table 41). eVxapleureismefnortsT.reTsoaunudz TWraasszcaflocrulmaatleedaasndTofuesma+lTeira.tsFwOerrceadseesteirnmwinheidchfrboipmhpahsiacrmealciomkiinnaettioinc was evident, the rapid phase Ty2 was used for calculation of Tua. Values for Tass and Tasuz were eaancahlydzoesdeblyevoenle. -AwaNyOAVNAOaVnAalytsoisesitnadbilciasthewdhtehtahtetrhedrieffweerrenet nsoamspiglniinfgictainmtedsifwfeerreenrceeqsuiinreTduafosror Tua across dose levels within each sex. For this reason, mean values for Tru and Tawa were csaalmcpulliantegdtaicmreosssfoarllmadloeseraltesvewlesrteo 1es0t.a5bhloiushrssaamnpdli1n71g thoiumress. foSratmipssluiendgisttirmiebsutfioorn.feTmhaelerreastusltant were 1.25 hours and 4 hous. fEoxlpleorwiimnegnotra1l0:admTiinsissuterdaitsitorniboutf1ionmgo/fk"gC"a"tCp-lPaFsOmAa(TTeabxleasnd42T-4e5,xFiingumraelse1a7-n1d8f,emale rats Appendix N) `The overall body burden approximately 85% and of ' 51% "C of following administration the administered dose in of ma 1 l mg/kg '`C-PFOA was e and female rats, respectively w(Thaoblleeb4l2o)o.d,Inlimvaerl,esrkaitns,atnhdemhuisgchelset(pFeirgcuerneta1g7)e.s oIfn tfheemaaldemsi,nitshetelraerdgedsotsferaacttTioanxs oWfetrheepdroessee:nt in rweecroevefroeudndininthteheboGdIycaotntTeantvss, GdIectrreaacts,edlitvoeraapnpdrowxhiomalteebllyo5od7.%Tahnedt2ot9al%aomfotuhnetadomfirnaidsitoearcteidvity 000042 Perfluorooctanoic Acid: Toxicokineic in the Rat DuPont.7473 dfoosuendininmathleesliavnerdifnecmraelaesse,draetsTpercstuizveTleyla(tTiaveblteo4T3o)u.s,Ibnumtapleercreantst,agtehes pienroctehnetratgiesosufetshdeedcorseaesed. In females, the tissue burden of 1*C at Taz either decreased or remained constant relative to Tous IbnlomoadleanrdatksiadtnTeayss(,Tatbhleeh4i4g)h.esItntifsesmuaelceosnactenTtursa,titohnes GoIf c'o*nCtwenetrse afnoduntdracitn cliovnetr,aifnoeldltohweedhibgyhest ccsooinnmccieleannrttrraaatttbiioootnnhss ootfifm1Ce*Cp,odifenoctlrsleo(awTsaeebddlbreye4l5akt)ii.dvneeInyt,ofTleiamvaselr,eaernxadctseb,plttoioisdns.uleisIvnecromnwachleeensrteraattthTieoanczson,wceetrnitesrssauietmiiolnasrwere between sampling times for all tissues, except GI contents, where the concentration of He decreased. To further calculated cahnadraacrteeprriezesetnitsesdueindiFsitgriubrueti1o8.n of In 'mCaloeverartst,imtei,sstuiesbslueo:obdloroatdicosongcreenattrearttihoannra1twioesrweere. oTobusseravnedd Toonslye.in Ilnivfeer,maalned rtahtes,ltiivsesru:eb:lboloodocdornacteinotsragrteiaotnerratthiaonin1cwreearseedobssiegnrivfeidcainntltyhebeGtIween craotnitoesntesithaenrddkeicdrneeay.sedInoortrheemrtaiisnseudesc,onrsattainost were close to between Trax 1, and in all and Tru tissues, concentration fEoxlpleorwiimnegnotra1l1:admTiinsissuterdaitsitorniboutfi5onmgo/fk"g"C'a*tCp-lPaFsOmAa (TTaabxleasnd46T-4u9a,nFiingumraelse1a9-n2d0f,emale rats `Appendix 0) Taphperobxoidmyatbeulryde8no8%f a"nCd a3t7T%ouosfftohleloawdimnigniosrtaelraeddmidnoissetriantmiaonleofan5dmfge/mkagle'r*aCts-,PrFeOsApewctaisvely (Table 46). observed at tThhee1tmisgs/ukegddiostsreibulteiveoln,oefxc'eCptatthTartatxheinprmoaploertainodn female of the rats dose wraesmsaiimniilnagrtinotthheatGI contents in females was somewhat lower (Figure 19). A decrease in total body radioactivity sCihmainlgarestoitnhtahteotbissesrueveddisftorlilbuotwiionngo1fm"g"/Ckagt T'rCwu-zPFweOrAe waalssoosbismeirlavredtoatthToasaexozb(sTearbvleed4a7t).the 1 `mg/kg dose level, except that a clear decrease in liver 14C burden was evident in female rats in this experiment. For both male and female rats, the highest concentrations of *"C were found in liver, Kidney and 1roat0ths0eardttaTitsosTosusesswxeianrnemdagTlreeaasuterzre(mtTahaiabnnlee1d,sca4on8nd-s4ti9an)nc.treLoaivsveeerdrt:bhbeiltsowioendteen"rv*TaClu.csonLacienvndetrTr:aabstlsiozoo.ndrTraiattsiiososuse(i:Fnbilmgouaorldee2rra0at)tisoisn fmoarle following 5 mg/kg PFOA were generally lower than were observed at the 1 mg/kg dose level. In females, tissue-blood C concentration ratios were similar to those observed at 1 mg/kg, with the exception of the GI contents. JSS" Bio, "a 000043 Perflsorooctanoic Acid: Tovicokineis in the Rat DuPont7473 Experiment 12: Tissue distribution of '"C at plasma Tax and Tmax: in male andfemale rats following oral administrationof 25 mg/kg "C-PFOA (Tables 50-53, Figures 21-22, Appendix P) In general, body "*C burdens in male and female rats at Trax and Tay? following administration oMfor2e5ovmegr/,kgth"eCti-sPsuFeOdAistwreirbeutsiiomniolfarthteo trheomsaeinoibnsgerdvoesdeaatt lboowtehrsdaomspelilnevgetlism(eTsabwlaess s5i0m-i5l1a)r.to lower dose groups for both sexes (Figure 21). For both 100d at TmiasalxeaannddTfaemeale(Traabtls,esth5e2-h5i3g)h.esTt hceondceecnrteraastieoinns toifss"ueCcownecreenifroautnidonininlifveerm,akliedrnaetys and bSeetwOefeTnisTsos2s1adnTdoTnayv{a0WeastsimsaotmeeTwghuautz.loTwheirstmheatnheoxdpeucntdeedr.esTthiimsatmeadyThaave fboerenfetmhaeledureattsoatthet.he: 2si5gnmigf/ickagntdloysgerelaetveelr.thLainve1r,:abnldooidnc'r"eCacsoendcbeenttrwaeteinonTruaxtiaosnd(FTiagauurze.22T)isisnume:ablleooradtsraattioTsafyorWoetrheer tKiisdsnueeys:ibnlomoadlersatwioerweaslessisgtnhiafinca1natlnydgrreeamtaeirntehdacnon1,staanndtroevmearitnheids irnetleartviavle.lyIcnofnesmtaalnetsb,etthweeen Tix and True. For other tissues, the ratio was approximately 1 or less and did not change appreciably between sampling times. CONCLUSIONS `eTlhiemirneastuilotnso,fatnhdepsheasrtmuadcioeksidneemtoincsbterhaatveisoirgnoiffPicaOntAseixn draitfsf.erUernicnesariynetxicsrseuetsiodniswtarisbutthieonp,rimary r`moiuntoerorfoleel.imEilniamtiinonatoifonPFofOPAFiOnAbobtyh bmoatlhesroauntdesfwemaasler,apwihdialnedfenceaalrleyxccroemtpiloentpelainyefdemaalreesl.ativInely `males, elimination was much slower than in females, and up to 20% of the dose remained in the `cboomdpyoaufntedrs2.8 Sdeaxys.difPfFeOreAn-cdeesriinveexdcr'e"tCiownaosfnPotFeOlAimwienrateerdefalse"ctCeOd ;inoprlaassmvoalapthialremoarcgoankiicn:etic `Pplaarsammeateelrsimiinnamtailoen awnadsfselmoawleinramtas.leOrraatls,baionadvaniolaebviilditeyncoef PofFdOoAsew-adespeanpdpernoxtiemlaitmeilnyat1i0on0%w.as ohbisgehrevreddo.seInlefveelmsa.lesI,n pboltahsmmaaleelsimainnadtfieomnawleass,rtahpeidmaainnd tdiissspuleasyfeodrbdiipshtarsiibcutbioenhaovfiPorFaOtAthweere the blood, over time, liver, and kidney. The blood:liver concentration ratio of PFOA in suggesting that this tissue may serve as a depot for PFOA in male males increased rats. The results of these studies constitute a comprehensive description of PFOA toxicokinetics in male and female ats. RECORDS AND SAMPLE STORAGE `NSepweacrikm,enDse(liafwapaprlei,caobrlaet),IrroanwModautnat,aainndRtehceofridnaslMraenpoargtewmielntb,eWrieltmaiinnegdtoatn,HaDseklealwlarLea.boratory, SE wo -- 000044 Perflsorooctanoic Acid: Tovicokinetics n the Rat DuPont7473 REFERENCES 1. DuPont Haskell Laboratory.(1997). Hazard Characterization for Human Health C8 `Exposure. Unpublished report. 2. VDiasntdriebnutHioenu,vMaelt,abJ.oP.l,iKsums,liakinsd,EBl.iLm,inVaatnioRnaoffePlegrhfelmu,orMo.oJc.taannodiPceAtecrisdoni,n RMEa.le (a1n9d9F1e)maTlies:sue Rats. J. Biochem. Toxicol. 6(2): 83-92. 3..- DuPont Haskell Labor `perfluorooctanoate in atory male (19 and 82). Excretion and disposit female rats, mice, hamsters ion of '*C-ammonium and rabbits. Unpublis h ed report, HLR 62-82. 4. Hpaenrhfiljuaorrvoio,ctHa.noi(c19a8c8i)d iAn tphreopboeasgeldesdpeocgieasnddirfatf.ereInn:ceBseiynnetnhe,rAe.naClaenxdcrSeotliloenveolfd, H.A. (Eds) New Developments in Biosciences: Their Implication forLaboratory Animals Science. MartinusNijhoffPublishers. Dordrecht, Netherlands. _ EO ha 000045 Pefonocanic Acid: Toiokinees nthe Rt Dwron7473 TABLES Faeteed "45 000046 Perfluorooctanoie Acid: Toxicokineics in the Rat DuPon7473 TABLES EXPLANATORY NOTES ABBREVIATIONS: AUChe AUCKN#D Aux cl Cou equiv hrorh LambdaZ #Ci m NA ND sD Tu Tox Tose area under the plasma concentration vs. time curve, extrapolated to infinity AUC, normalized to dose auxiliary plasma clearance `maximum plasma concentration equivalent hour(s) terminal elimination constant `microcurie, 2.22x10 dpm mnoitnuatpep(lsic)able: not detected standard deviation terminal elimination half-life me 10 Cus time 0 % Cos following attainment of maximum concentrations Cree 46 000047 Perflvorooctanoic Acid: ToxicokininettheiRcast Table1: Pilot Study - Dosing information for male and female rats T Tot TNominal mmiawagm | DwcmVto)wme | Subsnce Dose Sec "Mean SD Som S50 Pharmacokinetics Fron img FMeimei 228377 2470 `Material Balance 00%% o0o0n UCPROA mpi FMeamiee 21550112 12294 oosns oooon RAadtwe(mnigDhmge) Mean SD o[k ETool 2wis 00s3 DuPont7473 ReRcsiavedd(:eC) Mean SD N MN M 292280 01332606 T--_-- RG a 000048 Perflvorooctanoic Acid: Toxicokinetic in the Rat DuPont7473 Table2: Pilot Study - Pharmacokinetic parameters in male and female rats following oral gavage with 1 mg/kg PFOA Parameter Units Toe hr Coy (gm) Lambdaz (ho) Tn 2) AUCos (hrugiml) AUCWD (brpgmlmgke) a, (Lg) Males Mean SD 0 107 298 53 00068 0.0006 0330 1330 364775 61171 468866 56727 021 om Females Men sD 050 000 2530 146 02 on 20 03 2335 3066 15099 37.19 66 159 [Er EN 000043 Perluorooctanoic Acid: Toricokinecs in the Rat DuPon7473 Table 3: Pilot Study -- Percentof dose recoveredin urine in maleand female rats following oral gavage with 25 mg/kg 'C-PFOA J Timepoint Mean ale 5 --Mean--Fema-- le SD asnh owasr 0012084s 1h ns 030 2i49e3 0952m8 mss 53 a2s0h 2s5o0 o03s0s 70 saz 1278 2os5e0s 0226911 ose 0081 92%0h 4asaso 000088 lune 091 o0xs6 0o0o16 ou 0000 leh aime 0106 or 00 Tout 30310 25% nu 189 oun wee fon avd a da =z Toe 000050 Perfluorooctanoie Acid: Toxicokinetis inthe Rat DuPon7473 Tabled: Pilot Study - Percentofdose recovered in feces in male and female rats following oral gavage with 25 mg/kg "C-PFOA TTTimepToint Mean Wee SD a8nh 0[0r2e8 NnAA 122hh aos4o aoss a2shh 0L43e4 0o08ms 2%0hh 0osaom 00338%0 laehh 0o3s3 0l2o9n Tour B42 2057 To recales uliedfom ivi smal daw. n= Sean Fem 5 NNaA NNAA o01r3 o01e09 0o0u3s0 oNoase 00001ss 0N0A6 o001s2 0N00As [ET 2 Lg Sa m ooos 000i 051 Perfluorooctancie Acid: Toxicokinetics intheRat Dupo.7473 Table 5: Pilot Study - Percent of dose recovered at 168 hours in tissues in `male and female rats following oral gavage with 25 mg/kg "C-PFOA I --Mean TS52 --Mean CT-- 5 pcraorsctaastse so6o19 02600036 Swkhionleblood o57s6s1 o11a9n4 fbruain o00m6ss o00z00 [hieart 004010s 0000064s slpilveeren 20506468 00020569 KGiLdneuyst oLsiee 00011x3 tnGylmeuosmems 00208s 00001038 osvaersies 0N2A3 0N03a3 Sderreanasls oNoAs oNoAr mbuosncel.e oomm oooonm 0N26A8 NNAA NNAA NNaA NNAa NNaA NNaA NNAA oNAs 0N00A1 0N0A2 0N00A1 NNAA NNAA NNAA NNAA NNaa NNAA NNAA NNAa Tour sams 363 0154 0am Toul wecaleusedfom dvd mm do a2 es oI s2 `o PerfvoroocancicAcid: ToxicokiinnheeiRast e Difonies Table 6: Pit Study - Concentration (ug equi) i tissues in male and female rats following oral gavage with 25 mg/kg 14C.PFOA I Mean ale SD. Mean Female SD. prCaorscaasisc aas9s 00133% Jig 0589 0N0A60 NNAA NA NA Wskhionleblood brain 2o5s5408 00060779 ese oes NNAA NNAA NA NA fheuart lungs eag sr 0o2uml spleen 309 0210 NNAA NNAA NA 0N0A0 sivdenrey GL wat saasms am 3071406 0s oogso oon NA NNAA tGhlymouoswems 0305649 estes ess 00000040 0.66 NNAA NA NNAA NA NA oavdrreineasls werus aNAs 0N3A4 NA NA NNAA NNaA NA NA bmounscele a33u0s4 0130s5t8 NA NA . wT - Fg "sz 000053 Perfluorooctanoe Acid: Toxicokineics in the Rat Dupont.7473 Table 7: Pilot Study -Percentof dose recovered at 168 hours in cage wash and residual feed in male and female rats following oral gavage with 25 mg/kg C-PFOA TTT Mme Mean SD Fem Mean SD raeswidauaslhfeed 0N8A20 0N2A74 ooussst 00530036 Tour 0s0 om 1055 0809 Toul we cloud fom dvd sm i a2 0 0 54 Perfivorooctancic Acid: Toxiokinetcs inthe Rat DuPon7473 Table 8: Pilot Study --Overall mass balance in male and female rats following oral gavage with 25 mg/kg ""C-PFOA Percent of AdministeredeDoese M Seanme 5 MeanFem 5 wfiecnese 3w1a0 225097 sax 360 sosus 01481099 oss 0202 i Csaugeeswash & residual fod vCoO,lweaoprAganics NoDm 102)4 ND No NosDs 0N8D No ND : Troet.al.. 93929 3.422 93.902 2.581 lia - Perfisorooctanoic Acid: Toxicokinetics intheRat Table 9: Material Bala-nDoscineg information for male and female rats --_-- ShTteatsee NoDumean Sa MariaBaise Moron lax FMiee oro sms FMeimei mon mms FMiek rN mpg RMoiwee ER ETO WmemPws a 3145 6829 21063 3742 m8e5 5632 326625 mWaO Re DoSiewAd@ mi0n [os ET00s wono oomo [os TTow o6n oomn RaFtei(mbg/sg) Tie 50 ouss oomm aPmEoTs Ewos oomm 00ms oomm Dupont7473 ReTcaadivweadc(i:iCy) Mes sp mmams omss mms os aasmm oosse mBeoms 01%s - SEG -5- 000056 ------------------ perfuoroocianoic Acid: Toxicokietics in theRat DuPon7473 Table 10: Percent of dose recovered in rine in male and female rats following oral gavage with 1 mg/kg "`C-PFOA Timepoint w Mean e i) asnh 12h ocago oss 00028320 019 824h0 72h 2S1m4o Jo o02s9% 020 B96ohn lean 22:000 ass 0011866 038 Dleussn Dayo dlomls les 003408 08 DmDiiylon 1l7d0s la 0Ol363 0278 DDyia Dayle 2aLo0e1000334835 DDaayyios Dayz 22405m7 22m 0028438 078 DDDaaoyyy2a2sds 21040%2 ies 00814460 031 Tour 428 3015 Teae n mEe ) Wsoesw 5s9o%n lleooms 33028% 3s11s9 oLaxz oomas 00105% ooaNmAe 00202%0 NA NNAA NNAA NNAA NNAA NNAA NNAA NNAA NA NNAA NA NNAA NA NNNAAA NA Na sem 4066 "Totals are calculated from `individual animal data. ned "Png Ed 000057 Pesfluoroocunoic Acid: ToxicokineiisintheRat DuPont.7473 Table 11: Percentofdose recovered in feces in male and female rats following oral gavage with 1 mg/kg "C-PFOA Timepoint Mean Male 5) Mean Female SD. a8hn 2N2a69 NNaA NNAA NNAA 2102hh 25545303 23652757 0125389 01899484 a2hh 0082328 0o5z1s7 0o1m0s8 0000902s | 1%2h0h 0o2n3e8 0020sd 00100s6 00009228 114648h4 00116900 0010234 000303 o00i1s7 DDaayyo 0022595 00229678 NNaA NNAa DDeiyylllo 0021004 00210747 NNAA NNaA DDiyyll23 0002%5 000136s5 NNAA NNAA DDaayyllse 0023287 00.21539 NNAA NNAA DDeiyyi2s0 0022:82 0011588 NNAA NNAa DDiayy2za 00340597 00139133 NNAA NNAA DDaayy22ss 001292% 00019565 NNAA NNaA Tow! laos 4003 2160 2023 Totals are calculated from individual animal at net Sova Bl 000058 Pecfiorooctanoic Acid: Toricokietic ntheRat DuPont7473 Table 12: Percent ofdose recovered in tissues in male: and female rats following oral gavage with 1 mg/kg "C-PFOA Cpraorsctaastse Hhionlebood fbarain hluenagrst spleeren KiGdlneuyt Gthlyorooidwems tehsytmesus osvdrrieeasls wmuescsle bone Tour! Seanua2l8e SD o73m8 010400 o126m5 00308%7 ooosm 00000;7 0o0iss 00001i46 Boo4is0 02040647 ooss 0o1o%m 0o06z1 00001021 o0o0n 0o00o4 oNAz 0N0A1 oNAs 0N0A2s oo ool uses aoe eFeme ale Mean168 Hours)so onuAs oNiAs 0o00o1 oNoAo NNAA NNAA NNAA NNAA oNoAis 0N0A0 oNoA oNoAl 0N0A03 NNAA NNAA NNAA NNAa NNAA NNAA NNAA NA NA om ons "Totalsare calculated from individual animal data. ned iy = 000053 Perfluorooctanoic Acid: Tosicokinetics in the Rat DuPon7473 Table 13: Concentration (ug equiv/g) in tissues in male and female rats following oral gavage with 1 mg/kg "C-PFOA a Male Female "Wes Ss MeSm D pcraorsctaastse skin 00005601 00001156 ons 0029 0N00A2 0N00A1 0001 NA bWrhaoilneblood 00300587 00009092 fat 0014 0007 N00A01 0N00A0 NA NA | hleunagrst spleen 0o12m1 0000436s ogs 0014 NNAA NNAA NA NA ! lKiivdenrey 01395877 00.045247 Glact ost 0016 00002 00000010 NA NA thGylrcoiodmems 00.006068 00000334 thymus 0047 0014 0N0A0 NNAA NA NA oveasrtieess adrenals 0N09A2 0N03As 0056 0024 NNAA NNAA NA NA wmeursculse N00a3s 0N0A08 bone 00st oon NNAA NNAA NA NA _w-ee ee tre miei oe 000060 Perfuoroocunolc Acid: Toriokinetis inthe Rat DuPom473 Table 14: Percenotf dose recovered in cage wash and residual feed in male and female rats following oral gavage with 1 mg/kg "C-PFOA Sake28) S Female y 168 Hours) Sean SD Mean 5 cfegnedwwslnfed 2072326 0045580 2o8u5s6 o12o8l7 Toul" 2948 0732 3.052 1311 I i Toi are cleat from ddl rial Gas. ned Yip 00OUET Perfluoroocianoe Acid: Toriookineis in theRat Dupom.7473 Table 15: Overall mass balance inmale and female rats following oral gavage with 1 mg/kg *"C-PFOA ee -- r ------ Hien-- Makee e-- > ---- --F--Me ea-- gn mm-- 5e fuericnees csaugeewsash & residual feed Toul a14m05s5 43000s3 n20s8 aoem B80 4006 s2e00m 42006236 30o5m2 o1n3s1 ams oases "el 00006 _ Pesivorooctnoie Acid: ToricokianteetRact DuPom7473 Table 16: Pgearvcaegnetowfitdhose.mgre/ckogv`erCe-dPiFn OurAine in male and female rats following oral Timepoi-- nt Meanwwe 5 a8nh 2h oOeim lo 00038119 0468 Jfnh Pn adassss se oosss 078 fJonn Yan d3a8m aa 00861Ms ois blewasn Duo s2e0sss 26 00m21 02 DDoilol Don 22a6m1 22a 00214%8 028 DDooylte Dols aaosse 321 00228% 0306 DDoowx Dy: 3saems 2m 0032%6 03M DDoozzee Duk a2mss ass 0012s8 02 Tear 20 365% TA net SieanFem En 2ne1s3s 13054476 Tliasee a61s8e9 Slooes oz oosmm 0209 ooesr os 0043890 on NNAA NA NNAA NA NNAA NNAA NNAA NA NNAA NA NNAA NA NNAA NA NNAA NA NNAA NA nee 60M bung * a 000063 Duron 7473 Pertorsocunci Acid: Tokai 2 he Rat ecovered in feces in TE and female rats following oral aV2E rable 17; PTerhcesntmgoflkfgos`rCPFOA ,-- a_-- i EE Cm NA NA [NA3 NNAA oe asnn 12h TNoAr oro 1NA8 92 240 038 hSoaa bie sOuSe 03 i as7hb oCsieo 0a 0314 0355 S% Sa 0S.i14e6 0o0.11a6391 Shoe ' o9m6hhh wh oomwe om O0S 0 0% tNnAe oaNA NA NA wDDeohtt oomm ow 00%% Sn ows NNAA NNAA NA NA NA ppoll Do oowo om O0000) 0% NNAA NA NNAA NA mDoEle pelt ooaed om 0O0n% OF pol 0% NNAA NA NNAA NA A warE pwr oomm oonws 00%% 0% NNA NA NNAA 5.387 1719 5.886 a eToaule sm5e.568oma! Sal amt 000064 fa - C63 Perflvorooctancic Ack: Toricokinetics in the Rat DuPon7473 Table 18: Percofednoste recovered in tissues in `male and female rats following oral gavage with 5 mg/kg "/C-PFOA. aSya2l8e) oFeme ale (168 Hours) ean > ean 3 Cparrocsatsaste sin o66sm 01201m4 ows 00i6 oNtA 0N0As NA Na i bVrhaoilneblood oL1s83 fa os 00200011 oo NNAA NNAA NA NA bengasn spleen ooosos o00o0 oo 000 NNAA NNAA NA NA Kviednrey 1o0s90s6 o1o3l% Gl uact 029 oot oooolm 0000002 NA NA thGylreoiodwems 0o0o5m5 thymus ool 0o0oItS oom NNAA Na NNAA NA oewrsises adrenals 0N0A ooNA 00s 0% NNAA NNAA NA NA emusscsle bone oNsAs 0N0A8 os os NNAA NNAA Na NA Tou oe woe 275 __ 009 oom "Totals arc calculated from individual animal data. ned tp + 000065 Perflonooctance Acid: Toxicokineics in the Rat DuPont7473 `Table 19: Concentration (xg equiv/g) in tissues in male and female rats following oral gavage with 5 mg/kg "C-PFOA prcoasricaatses sVihonleblood fbwrn hneagrs splveeren iGdloeuyt Gthlyerooimd ens etehymsus Sodvraeriaelss vmuesrcslee bone. =e Sean Male > oozm o0o0ns o11s0s3 00.01671 o0o0m2 000001s o0s2s 000068l1 s01ms ooonn o0%1ss o00o3m1 0o0r2e8 000101 o0u2s4 o00o8n2 oNdAs oNsAm oNAz oNoAn os os Mean Female 5) 0N0A7 0N0A03 NNAA NNAA NNAa NNAA NNAA NNAA oNmae 0N00A3 0N01A0 0N00A1 NNAA NNAA NNAA NNAA NNAA NNAA NNAA NNAA NA NA - 5 sas 000066 Perfivoroccianoic Acid: Tosicokineics intheRat Dupo 7473 Table 20: Percoefdnoste recovered in cage rats following oral gavage with 5 wash and residual mg/kg "C.PFOA feed in male and female ale Feme ale y Hiean (Day 28) SD ean(168 5 Hours) adgeiwaeshd 3036127 0149364 2osaaml 008465d0 T_ otalal ae Al_ ca3z93f5rom di-- du2a3l62aml G-- s. 2958 -- 0845 | nes we 000 Perflonooctanoic Acid: Teriokingtis inthe Rat DuPont7473 Table 21: Overall mass balance in male and female rats following oral gavage with 5 mg/kg "C-PFOA wfiecnees ducaegeswash & residual feed Toul ean me 5 2s0s1 3165m6 ao0s1 2273505 se 25m Mean Fema 5) mssase 53os8s 0210089 0o8o4rs2 81 sie TA - 000068 Pecfluoroocianoie Acid Toxicokinetics n he Rat `DuPont 473 Table 22: Percentofdose recovered in urine in male and female rats following oral gavage with 25 mg/kg "C-PFOA I Timepolnt MesHsaleSD MemFemale 3) sahn 12h o02mst 0014%0 130 068 2265086 1810.3400 lao 4310823 ; a2s4h0 72h esassoss den o1s 914 is oSgses 09%6 ijsom o0szss2 p%onh lan aammse 3a 0137681 06 0o7a6 00311936 oars 0266 Dlesah Days 225006 less 00s57 Loss NNAA NNAA NA NA DDwaiilo Diz 1a8m6s 1s 00346k2 0489 NNAA NNAA NA NA DDaayyilse Duis LLg40o8l 14s 0357 043 NNAa NNaA NA NA DDaayyi2so Dayz L2i2sdi 19% 00324% iso 0108 NNAA NNAA Na NA DDiayyazse Doy2s s12z87 0053991 NNAA NNAa Tour S325 8490 sas 208 oFe o re caleroum tvaidueal ail Gsa- net . =83- 000063 Perflvorooctanoie Acid: Toxicokinetics in the Rat DuPont7473 Table 23: Percoefdnoste recovered in feces in male and female rats following oral gavage with 25 mg/kg "`C-PFOA T TimepoinT t MeT anMme SD FeMem an m0e ) a8hn 000120 0N2A0 2142hh o16n6s7 01617 2ahn 0osxs o10o1n8 o%hn oouss 002221 1l4hh 0054097s 00132m DDaayyso 00m627 0044l%4 DDayylllo 0039s3 o04u1d8 DDyyilnz 0034199 00a267 DDayyllas 0072918 003328 DDayys 0113901 0003533 DDyy2 0023907 0ol2s DDa2ys 0023620 0o1o3m9 0o0o0r2? NNaa o07s4e9 01718837 0o2m0 00230584 ooso ooam 0010360 00016636 NNAA NNAA NNAA NNAA NNAA NNAA NNAA NNAA NNAA NNAA NNAA NNAA NNaA NnAA Tour 1240 41s 1868 2566 Foalswe cleaned fom dvd animal da ned wtf CH 000070 Peafivoroocianoic Acid: Tosicokinetc in the Rat DuPon.7473 Table 24: Percofednoste recoveredin tissues in male and female rats following oral gavage with 25 mg/kg `C-PFOA aSyak2e8) eFeemale (168 Hours) Mean S Mean SD Cparrcoasses Sin oso is 200603s ost 009 oNiAs 0N0As ooo 00 Cbrhsdilneblood 0o7w6s0 0o3o6m6 ool 07 NNAA NA NNAA NA luhenagrts spleen oooosms 00002s8 om 0010 NNAA NNAa NA NA kiivdenrey Glut osomie os 016m% 0m o0o0i0s3 0000008 NA NA Glrociodmems o00z86 00000314 thymus [rR NNAA NNAa NA NA oevxaersies oNosAs 0N03A1 adrenals oos oo NNAA NNAA NA NA umeusscle bone oNoA 0N01A6 ome 0006 NNAA NNAA NA NA Tour" ns 5008 oe 0102 Foals are cloued from GR_GuAl arial dat ned ee Cn 000071 PerflsorooctnotcAcid: Toxicokineics intheRat Dupont7473 Table 25: Concentration gavage with 25 (m1gg/ekqgu"i/vC/-igPn)FOtiAssues in male and female rats following oral Caprrcoasses. sWihnolebiood barain huenagts siveeern KiGdlneuyt tGhlyreooidmens ethxyemsus Sodvvaernieasls muescrlse bone 7 "SMae le $n 5 0o%m 0o5a9n S1777%1 2089208s 00211 0o1s5e6 sLeses 1170s9 e12w68 s09e03 6Li2es 0275m5 0L1i5e% o01e0r0 OLsszi 0os0m sNAo oNsAe oNAa oNmA 07 oz " Me Female m 6_ oNsAs oNoA oNmae 0N0A16 NNAA NNAA NNaA NNAa oNmas 0N04a1 oNAm oNAo NNaA NNAA NNaA NNAA NNaA NNAA NNAA NNAA NA Na Foo i 000072 Perfivoroocianoic Acid: Toxicokineic in the Rat DuPon7473 Table 26: Preatrscefnotlloofwdiongseorraelcgoavevraegde iwnictahg2e5wmags/hkagn"dCr-ePsiFdOuaAl feed in male and female cTegseidvuaaslfheed Seansyal2e9 52 31939477 11681540 eFemaele Mean(168 Hours)5 suo ss 71530196 Total" 5.344 3336 6852 8360 ! . Horl al re called from TdiGual arial deta. ned " 000073 Perfluorooctancc Acid: Toxicokinetic inthe Ret DuPont7473 Table 27: Overall mass balance in male and female rats following oral gavage with 25 mg/kg "C-PFOA TT wfeicnees csaegeeswash & residual food Toul Fiean me 5% $224605 a8l4s% sS3s4 s3o3o%s Bow 34m Fiean ems 5 s1a8s68s n25o4n6 061802 08130620 9260 3554 AFr ne mT 0000u7a4 Pecluorootanoie Aci: Toieokineics intheRat DuPone7473 Table 28: Preeperatceodfeaddnomsitenisrtercaotvieornedofin1 u`rmign/ekginP`FmOaAle,afnodllfoewmeadlberyaats1af`mtge/rk1g4c-hdaalylenge dose of "C-PFOA (day 15) Timepoint Mean Saale s Mean Female ED) isnh oosms home 0o1x6 0d maosen 1s4m13 oss 288 awunn s28im name 0i8md Low 0s0os0 42351m9 1s oss osenn 2246898 1L2aDw lan 26 LIE o2sme 0os2 oss ode Dlyhs 2i2m8e 0040a3 Diys isis 042 oNAm 0N25A3 NA NA DDaiyiol Diz 1138601 len 0064%8 0&0 NNAA NNAA NA NA DDaoyyilse Diyle 2121%9 ain 00463 023% NNAA NNAA NA NA DDoulos 22308s1 Dz 20s 00o3s 4S NNAA NNAA NA NA DDiyyas Dos 1Ar8e0e lea 0042s6 04s nNAA NNAA NA NA FoTaolustwe caeui2ne4d0rom _Tod7a9]9wal Gas. sm 1661 ned - Ton 000075 Pecflonooctanic Acid: Toicokinetics in he Rat DuPont7473 Table 29: Percent of dose recovered in feces in male and female rats following oral gavage `with 1 mg/kg '"C-PFOA (repeat dose) Timepoint Mean Male 3) Sean Female 5 ashn 0Na3 oNAs 3N50A9 4N5A30 122h 6w15n2 314s60 oasmso o74s0e6 a72n0 o12s5 0o4asns 2o8r8s3 3o0s7s2 i 29061h 0Lxo6s 00270m7 o01m60 0010294 1w68h owme 0o3s1ms oouos o00o1m9 DDaayyso Lnss 0o7a1n4 NNAA NNAA DDyaiylo 1o0m620 0LI8TSO NNaA NNAA DDiiyyll2s 004365s 0044030 NNAA NNAA DDaayyllse 0003926 00023965 NNAA NNaA DDayyle 00x225 00028530 NNAA NNAA DDiyy22e 003290 002222 NNAA NNAA DDiiyy22ss 001608 00002911 NNaA NNAA Tout 19841 660 nsw sms Tol ae clculed from individual smal da n= PT ~75. 000076 Perflvorooctanoic Acid: ToxicokineticsintheRat DuPont7473 | Table 30: P`gaevargecowfietdhnos1temgr/eckogve"r"eCd-iPnFtOiAss(ureespienatmadloseea)nd female rats following oral ee Viale ee Sean ay 28) sD ---- Female ee Sean168 Hours)sD Cparrosctaastse osomse o1o8o% Sin ome 003s oNAx 0N07As 00 0000 bWrhaoilnebiood 0o97o7 0o5o7 fu ool 0006 0N0As 0N00A1 Na Na heoanrts spleen ooo ms 0000106 oz 006 0N0A00 NNAA NA NA Kivdenrey Gl act 0613163 oL6l8e4 om 00s oowos 0000026 NA NA thGylrLooiodmens 0o0o4l1 00002011 thymus ooiz 0006 NNAA NA NNAA NA eovsatreises oNosAs oNoAl sdrenals oo 0001 NNAA NNaA NA NA mwuesrcusle oNoAs2 oNao bone oo 0007 NNAA NNAa NA NA 0 Toolurssre calncafursolm andtideu4ad4l%smal Ga oxo oom---- n= J ---------- Ei -16- 000077 Perfluorooctanoic Acid: Toxicokinetics in the Rat DuPont7473 Table 31: Concentration (ug equivig) in tissues in male and female rats following oral gavage with 1 mg/kg "C-PFOA (repeat dose) a Mean Male S Mean Female ED pcraorsctaastse skin oooo 0o0o1n6 0083 0032 0N00A3 0N00A1 0002 0001 bhradienblood 00020973 00.010437 fa 0009 0003 0N00A1 0N00A0 NA NA bnegast spleen 0001821s 000s32 00% 00Is 0N00A1 NNAA NA NA Kivdenrey Gl. wact ooomd 0o28a3 0038 oois 00000086 00000011 NA NA tGhlyreociodmens 000046 0000083 thymus oo 0021 NNAA NNAA NA NA oevsariises N00A52 N00A24 adrenals oou oor NNAA NNAA NA NA meurscsle bone 0N0A2s 0N0A10 og oon NNAA NNAA NA NA A Eg ------- > 7 000078 Peruorooctanic Acid: Toxicokintis in the Rat DuPont7473 Table 32: Percoefdnoste recovered in cage wash and residual feed in male and female rats following oral gavage with 1 mg/kg "C-PFOA (repeat dose) J Male Female Meanow SD (Me6 an Hs) D rceasgieduvaalsfheed 02226653 0L314790 3766463 81691852 Toul 2528 L465 8.409 8329 _Toul ar calclaied rom individual animal dua ned ---- T Te 000079 ---- Perfloroocianoic Acid: Toxicokinetis inthe Rat DuPon 1473 Table 33: Overall mass balance in male and female rats following oral gavage with 1 mg/kg "C-PFOA (repeat dose) J MMeaa n k PerSceDne tof AdminiFsterMeeedaDnomse alED) e wifencees slos u 679690 Basi 4430 wLiss 11676S1 0x9 008 scaugee swash& residual feed des 1465 sap 83 Toul sos9 1651 ses 338 ..... | pony oe 000080 Peruoroocincic Ack: Toxcokingcs n heRat Dupon7473 `Table 34: Pharmacokin-eDtoisicnsg information for male and female rats SoTente NoDmoisneal Pharmacokinetics ron Olmpks pos mag maT ag Se Hem ' Sp mMiee 2M16643 1826 pMaisee 2l7o 9l7s DospealVoslume Men Sp 0oms 0o0m4 o1m0 o00x ARcahtuealemDgoesse Men SD 0o1u23 000000 i10a1 0oo% PFOA 1 mg/kg" pr Male 2M4o8e3 2973 0o5s0 0o0o2 1i1u1 oo0.01 pros smh fMoace mW033634 ooFm ooomn 5ss o0m PFOA 25mg/kg PMialee Tg225.0 w37a o09m0 000016 22667%6 003019 pron Olmgk fMriee 2M205 1558 0L8O1 000ms 0o09o7 0000002 a So raernno secon J - ra 000081 | I------ Perfisoroociancic Acid Toicokinetcs in the Rat DuPont7473 Table 35: Pharmacokinetic parameters in male and female rats following oral gavage with 0.1 mg/kg PFOA Parameter Units Males Mem SD Female es y Men SD Tan Ww Cou (ml) 025 645 0598 0.27 0s 031 [A Lambdaz (ho) Tin 0) 004 0001 017 37.489 021 0066 3206 0905 AUCor AUChy/D (engl) (hygimlmghg 326 35476 1096811 310491 358 0666 am 5880 a, (mg) ose 0240 23s 605 a TTT - 000052 Perflvorooctanoie Acid: Toxicokineis in the Rat DuPont 7473 | Table 36: Pharmacokinetic parameters in male and female rats following oral gavage with 1 mg/kg PFOA - Males Females Parameter Units Mean SD Mean SD Tou CLoaumrbdsz Tn AUCs AUChD a, --- We (gl) (1h) TM (wupiml) (wugmUmgke (mg) 90 38 saa LG 000s 0001 13830 31972 losses 21s 1176009 206316 osm ois uw 08 am Lue 0213 0053 sas Lm 9072 10472 38635 10093 nat 7159 - To - 000083 PeruorocunAocike: Torok ntheRat Dupon7473 | Table 37: Pharmacokinetic parameters in male and female rats following intravenous injection with 1 mg /kgP. FOA J Maes Females Parameter Units Mem SD Men Lambaz an Tia oot 0000 sss oss 02s oon ase osu AUCoe ACD rgb) (eygmmgk ssn sie 123384 1048 nes 1601 3077 6759 a, gt) ome oom M00 9230 --e--ee------------------------ r--BT un--Hg---------------- #- --------------0-- 000--84 Perfluorooctanoic Acid: Toxicokinetcs inthe Rat DuPon7473 Table 38: Pharmacokinetic parameters in male and female rats following oral gavage with 5 mg/kg PFOA Parameter Units Taw CLoinmebdaz Tia ACh AUC a, - be ((1n0l) ) on) (wpgiml) (hwygmimgkg (meh) MeanMales SD 150 10s 0w0a0r4s1 614 00007 mate 2892 e370 139283 122189 25028 oss oz Females Men SD 150 058 03 01s 158 002 a6 06 nase ns 008 201 sas ase ee Tas 000085 Perfivorooctancc Acid: Tocokinetic in the Ret DuPon7473 Table 39: Pharmacokinetic parameters in male and female rats following oral gavage with 25 mg/kg PFOA Parameter nits Te CLaombdaz Tin ACh AUD a, - be ((Mg0i)n) (epgiml) (wpgmlmgks (mUkghn) Males Men SD 7s 62 0160000i0 010109152 15747 3839 2515561 7769 94265 28467 moa Females Men SD 125 081 13265 00s 4595 0031 2 9% 19576 18151 58 692 306 688 Th ---- -8s- 000086 Perflurooctanoie Acid: Toxicokineis inthe Ret DuPon7473 Table 40: Pharmacokinetic parameters in male and female rats following oral gavage with 0.1 mg/kg PFOA (extended time course) Parameter Units Males Mem SD Females Men SD Ta Ww 55 70 125 050 Can (nL) Lambdaz (10) 108 0a 00026 0.0007 02 008 om om Ti [2 m0 see 34 126 AUCH (rug) 0638 5903 3 ox AUChD (wppmmghs 211128 58677 a, (meh) ost ox 339 329 30 306 JSS. - 86: 000087 Perfluorooctanoic Acid: Toxicokinetics intheRat DuPont7473 Table dl: Tissue Distribution~ Dosing information for male and female rats SubTsetatnce Tem NCPROA vorRoA Merron Tew UCPROA WePrOA cPrOA NoDmoisneal imghg Smghe 2smgxy imghg Smgks sme Se TMagb WeiSgDh.t FMeimiee 2192224 2324 FMeamiee 2199312 56)4 FMoaiee 21196023 3680 FMoiiee 210825 6244 FMeamei 1m9S2)3 9768 FMoiiee 21198332 4116 = TMoesmenVio) mS.D. o[CmI on o0n2 oomm ooms oooo o0m1 oomx o0ns oooo oorss o0m0 RFaetea(tmgDo/sge) T RTeacdeiiA oveadciv(i:Cy) Shean SD Men SD o[s ETool aasn oomm mu0w oomm anmass ooma Bmsomoser nomm oomme o os onom amnososn u us oon nnso 0osa nneme o12m1 2 nos o0u0 - Tens 87- 000088 Pefluorooctanoie Acid: Toxicokinetcs inthe Rat DuPont 7473 Table 42: Percentof dose recovered at Tay in tissues in male and female rats following oral gavage with 1 mg/kg *C-PFOA -- Male Mean10h30m 0) 1hFem1a5lme) Mean prsoksinttate uoosms 021038 wholeblood 22.148 062 0N4A3 0N1A62 5740 1507 fbaratin heat 20208711 00041687 0451 119 00103347 00000302 ois oom supnlgesen 007006 0010417 0040s63 00104287 sliivdenrey Gluact 2190680 5046022 29% 0929 73026808 01924686 1069 9066 thGylrcoiodmems o208s3 0o6o2o5 thymus ooss 0008 209005 103040737 02 oon ovesatreises arenals 0N1A5 0N0A7 0019 0004 0N04A7 0N0A19 0014 0005 mwuesrculse" 12N0A25 0N6A8 bone* ss osm 0o2r6o3 oosotm 0101 0017 Toul sss 6426 ses 16485 a rrr PKeirncee1nt9%r,ecowvheorlyeslcoaoledd=t7o.4w%ho,leata=n7im%a,lmausssculmei=n4g0t.h4%F,olbloonwein=g1:.3% of body weight. * Totals are calculsed from individual animal data. ned -i _ Te 000059 PerfsorooctaAnccidi: Tosicokintensthe Rat Dupon7473 Table d3: Percent of dose recovered at Tmax in tissues in male and female rats following oral gavage with 1 mg/kg C-PFOA e Sean Vgaigmakige) 55e SemFeamanle Saphnrotoiseebood sooos 822 00201 1218 oNuAs 0N0A% doses hebIraarin c05osz o01o36 ols ood oootme 0000078 05 00% splnegesn iver ooins 00000s6 nen se 0osss o00o0m6 eon 1s KiGdlnoewy s Glcomens 0T9e0o 0289 a03l0s0 0025 2 Gio eosmoe se 2 tthhyyrmouisd ees ocoost 036 0o0i0s3 0087 oosos ooool NA NA Soivarrieess cle' oNoAl 0N00A1 Sou ons ooool 00000046 oss 008 boenres 2NA 0N0A% ooiw o020o7 T oul" Per ce rresrovr5y7c.o0e2d6 5 Foe, whale load? W4h%o,l 3319 eaaTna,l suring h2e8.l77o2winrg:e10r97e6 mscle=d0 4%, bone=T.35 of ? body weigh. *Totals are calculated from individual animal data. amt oe he 000030 ---------------- Perfivorooctancie Acid: Toricokinetics in the Rat DuPon7473 Table 44: Concentration (4g equiv/g) at Tass in tissues in male and female rats following oral gavage with 1 mg/kg "C-PFOA J 0h3al0em aFneimaslem Mean sD Mean 53 prsoisntate oasss 0010%0 bWrhaoilneblood c25o6s7 0o02o4 hfeaarrt 0o28o1 0oi065l0 sphlunegesn 0L3s9 0010sst KTiidenrey a01 o0mme GGlloumscetms o02s1s8 0010s2t5 tihhyyrmouisd 00320 00008389 oveastreises No0Asi0 0N05A1 avdireensals 0N53A1 0N13A0 bmounsecle 0023567 00000583 - aed 0N2A08 oNnAe 01071373 00506098 00.140420 00105614 00270011 00109625 3109m38 00825620 29.118740 52198150 00318755 o00mss 0N42A2 0N16A7 00243180 00023716 0o11m9 000035s3 ---- o - 000091 Perfluorooctancic Aci: Tovicokintcs intheRat DuPon7473 Table 45: Concentration (ug equiv/g) at Topaz in tissues in male and female rats following oral gavage with 1 mg/kg *C-PFOA I ean aanle SD ----Me-- an Fe--amha)le--5)-- Spirnose ooixso o00osl Whleblood 0976 0143 oNaars 0N0A73 us oar barain hear ooos 0o0o0n1 om oom 0c1o5s1 000000 os: 008 sJpulnegesn iver ooantss 000ss si 063 ooszs3 o0m0s% 206 053 KiGdlnueyck o01m0 Glcomens 0025 o00s1t0 0002 2156607 0L18504 Yew 10% thtyyomid testes 0o2l8 0010837 oz om 022199 02100094 Na NA aodwrreineasls ews oNrAs oNoAn NA NA oodews 00006%3 oses 0228 mbuosncele ooiss o001o6 ooiis o000I8s .E-.D-. or ---- 000092 i ee Pesfivorooctanoic Acid: Toxicokinetics in the Rat DuPon7473 Table 46: Percent of dose recovered at Tos; in tissues in male and female rats following oral gavage with mg/kg "C-PFOA - Male aon30m 1Fh1em5alme) Shean Sb Mean SD psrkoisnttate: 1o5o5n65 0008495 0N6A2 0N1A22 bwrhaoilneblood 204095119 01092812 far 2815 0225 oSo0e8s 20008109 0220 onl henagrst spleen 00458933 00033776 0096 0017 00388287 00015072 0101 0021 Kidvenrey Gl vact 128177500 02433544 2508 0713 n42w9o3 2o1m% 7102 2594 thGylrLociodmems o2o6l32 0090306 thymus 0085 002 2080908 20300052 0.105 0030 oveasrtieess sdrenals 0N69A3 0N.1A50 0022 0004 N00A71 0N0A12 0026 0005 wmiuesrcusle" 1N35A6s 0N5A76 bone 3047 [x 0033s25t 00004106 ome 00st ToPuerlcenFtEreEcTovery8se0a3le3dT10 WE hole1Cr4i2T0alTassutT6hLmeT f8oillonwT ingg: T3187" bWoidnye1w9e%ig,htwhole blood=7.4%, at=1%, muscle=40.45%, bone=7 3% of Totalsar calculated from individual animal daa ned - N - 000093 -- Perfuoroocianolc Acid: Toeokineis intheRat DuPon7473 Table 47: Percent of dose recovered at Tua: in tissues in male and female rats following oral gavage with 5 mg/kg C-PFOA Shean VaiamleySD eFeemale Mean a 52 prSoisntate oToasm7 Wholeviood 1110 0040300 0624 0N7A oNmA san 1466 bfraarin heart oogsi 00020085 022 000 0os1s0 00001809 0x6 0051 | slpulnegesn er o034os 00109047 231 1289 ooo so o0rm012 a6 0s; kGidlneayct Gleowens 1l22oaomus 0270 002 2sa6s5s 0897667 si01 6165 thtyryrmouisd testes coososs o00o0m3 om 0% 0oo0sss 0o0o0t2 NA NA oSvdarreineasls muscle" oNwAs 0N%A 620 068 ocoolrs o00o04 0x9 om bwoenreus wNAs 0N1A 0o2i4e7 0o0o8n8 Toul 56.031 1.025 31.200 12.626 J eFaomr,resowvhereyblooedd 04W%h,olefaa=ni7m%a,lmsuusrclien=g40t.4e%,oblloonwei=nE1:3% of body weight Totals are calculated from individual animal data. ned re 000094 Perflsorooctancic Acid: Toicokinetcs in the Rat DuPon.473 `Table 48: Concentration (ug:equivig) at Trex in tissues in male and female rats following oral gavage with mg/kg "*C-PFOA ee gMalre ---------- rpFemaleer MeanG0h30m) > Meanahism 0 psrkoisntate 20se0s 012278 bVrhaoilneblood 10831806 01022278 hefrart s19i6 0013368 spnlegesn 6290046 007464 siivdenrey naosie 327088 GGllcuomeems 2177580 006029 tthhyyrmouisd s1o 922 0o8s6e eovsatreises 2N7A8 0N15A4 mSuasrcelaels s15a8 o00m6a9 boenreas 1N9a66 0N3A% 2N7A8 oNatAs J0Ex0 007 ao so om 078 6im2s 00827693 s169o3 S3445079 7ag9e8 2a4l0a8 2te 39 0o25a6 3N0A8 0N4A42 2a98s0s o15s6 t13o6e0 o02m59 wT .- : oa 000095 Pesflvorooctanoic Acid: Toxicokinetics in the Rat DuPont7473 Table 49: Concentration (4g equiv/g) at Tew in tissues in male and female rats following oral gavage with mg/kg '/C-PFOA J Mean aMnale SD Mean Feamha)le SD prsoksitnate 11703922 0o1n5e7 bhroailne blood 7o.i08s5 o0o3a93l fheaart o2g02i 00211338 slpulnegesn 3o1s0e1s 0005631 sliivdenrey 1a8d22o2 01561614 GGllL.cwoamtens 0o.1o75 00102241 tthhyyrmoaisd 1L65a2 00.24435 oevsatreises 1N2A4 NoaAn admruesnclaels o11n1ss 0010873 boernues 0N88A6 0N1A10 - wed 2NA5 0N7A86 092.40615 01047086 0288688 00528030 a11s9o9 01222615 1527035 210964 192920040 112166589 112304 002a88 N28a80 0N7A56 a2s07583 01.306%5 007607 00232620 Te ose ---- 000096 Perflurooctancic Acid: Toxicokinetic in the Rat DuPont7473 Table 50: Percent of dose recovered at To in tissues in male and female rats following oral gavage with 25 mg/kg "*C-PFOA 10Mha3l0em) Mean sD 1Fhe1ma5lme) Mean 5 pskrionse 10036876 000916s9 wbrhaoilne blood" 202096035 0L010777 hfeaatrt 2016513 00403503 spnlegesn 005i6036 0o1i0s3 Kliivdenrey s229s3 0029806 GGll ucsocmtens 24718846 0136889 thtyyrmouisd o01o2o0 0o0o25 oveasrtieess 0N62A3 0N0A58 amdursecnlaels s00s6s 00s040l4 wbioenreus' 3N00A2 0N4A38 0N3A8 0N16A6 7001s58 20020%8 00134177 00005335 00607981 00006077 o58s6s7 01574263 62949213 L1854486 00009019 00000323 oNoAn 0N01A2 0s0a3l1 00010156 0031s5t7 0o1o2n4 Toul o3 3680 sss 255 Pkeirncee1nt9%re,cowvheorlyesbclaoloedd=01.w4h%a,lefaatn=i7m%a,lmausssculmei=n4g0t.h4e%f,oblloonwei=ng7:.3% of body weight. * Toatrecaalclulastedfrom individual animal da. = - 7 6 000097 PerflvorosoccctannooiccAAccid::TTooxxicokkinneiticssiinnthveeRRett ooo Dow Table 51: Percent of dose recovered at Touyz in tissues in male and female rats following. oral gavage with 25 mg/kg `C-PFOA a Mean aanlen 51) MeanFe@mhale SD prsoisnuate sooazls9 0002172 "holeblood 7.904 1032 0N4A15 0N17A5 6407 1.406 bfraein heart 0o01s9 0001002 oie 002 0001588 00001685 021 008 spTlaengesn Tier 0030023 00005s7 20045 3098 0o7o7o5 0o20o4 9080 0895 KiGdlnueayct o1.s00s3 0011282 Gleomens 0210 0084 a35r4e7 01339036 L121 1010 thiyyrmouisd 000040ss 00000110 estes oni 00 0o0o0m7 0000002 NA NA oavdarreinaelss muscle" oNoAy N00A03 4253 035% 0o0o2r1 0o00o1 0304 00% bwoenreu's 0N5A06 0N1A00 ozs 0181 00 0050 Toul au 40 mes 256 ee FeSreeienne1tor%e,cowvheorlyeSbclaoleodd=17.W4h%o,lfeaa=m1m%,amausssculmei=n4g0t.h4e%F,oblloonwei=ngT:.3% of body weight. * Totals are calculated from individual animal dts. net wv -. 000098 Perflurooctanoie Acid: Toxicokineies in the Rat DuPont7473 Table 52: Concentration (4g equiv/g) at Toss in tissues in male and female rats following oral gavage with 25 mg/kg "C-PFOA. sprkoisntate bwrhaoilneblood fbaean splluenegsn Kliidvenrey GGlleuomtems tthhyymruoisd oveasrtieess maudsrcenlaels bwonees = 10Viha3l0em) Mean sD Bn2o2s 3122888 717.540670 40114870 22076004 1155620 i0e2 o2e 41 1s0e4s84s1 66250438 1l4e3a6s1 23394416 B958i2 13776927 1N4A3 1NA3 n796m4 0e54n6 1N0A08 1N5A3 1hFem1a5lme) Mean SD nNoAse 2N8a1 B14r75 a01m79 a84m2e8 21793089 a0.o83e5 0380808 125591265 1150015918 33992158 1192241806 1a535 2547095 NA130 2N02A1 B158762 26018 s654a6 o04e78 . "se. 000099 Perflsoroocanoic Acid: Toxicokineics in the Rat DuPont7473 | Table 53: Concentration (ug equiv/g) at Tosyz in tissues in male and female rats following oral gavage with 25 mg/kg "C-PFOA prosuste skWihonleblood bfraain bTeonagns spllieveern KiGdlneuysct thGylrcoiodmens theystmeuss ovaadrrieenasls mvuescrlse bone - = Male u MeanmSm D 400 7114 00380820 2065634%7 03046% 282139%2 01319520 1s0o61m4 015205 S0710s4 5290809 30564560 00.6876 m34261 30436634 NiAm oNsAe 4266661 00527186 3N09A5 0N34A1 Female G Mean m sD N16A653 2N9A% c1o5l5d1s 50346517 B611577 03550480 e83n85 s04e6s9 1T3a43n18 68088828 2n5e26l5 119264766 maa3s S03619 1sNA 2N8A02 n24s19 3L8es 5628997 01663371 --_ 000100 Peruorooctanoic Acid: Toxicokinetics in the Rat DuPon7473 FIGURES - 100+ 000101 Perfluorooctanoic Acid: ToxicokineicsintheRat | DuPon7473 FIGURES EXPLANATORY NOTES ABBREVIATIONS: %AD percent of administered dose Coun maximum plasma concentration F female he hour(s) Tous Tous ime ime 10 10 Cras % Coy following attainment of maximum concentrations. _ --.------io-- n ------ 000102 Pertvoroocunic Acid: Tosicokinetcinthe Rat Dupon7473 Figure 1: fPielmoatlSe rtatsufoPldlFoOywAingcoonraclengtarvaatgieonwiinthse1rimalg/pklgasPmFaOsAamples from male and Pa -- a i-- z 5 i23 oa 3\ Nr an EIE EREIEE AEE Time(Hs) A :` Tis 000103 PerivorooctaAnccidi: ToxicokiinnteheiRcast DuPont1473 Figure 2: Pilot Study - Cumulative recovery of "*C in urine and feces in male and female rats following oral gavagewith25 mg/kg "/C-PFOA Urine 5 3% i i 2 I S TE Ee we mw ww Time 0) Feces gi w Eo. --| : S dss IE IEEEE] me9) ---_ on Tio: vans RH 000104 Perflsorooctanic Acid: Tosicokinetcsin the Rat DuPont7473 Figure 3: Cumulative recovery of 14 in urine and feces in male and female ratsfollowing oral gavage with 1 mg/kg "`C-PFOA Urine gw]Hp i= 3= ETE Tiweme0)ew ew Feces 5: iH i Hf mt 3 2z 0TTi LhTE ew WwW Timeto) J T Tio: 000105 Perfuoroactanoie Acid: Toricokineics in he Rat DuPont7473 | Figured: Terminal tissue:blood concentration ratio in male and female rats following, oral gavage with 1 mg/kg C-PFOA ~ Sm Pin = -- neo Conca Rao FE Tios- ---- | 000106 Perfuorooctanoic Acid: Tosicokinetics intheRat Duo 7473 Figure 5: Cumulative recoveryof MC in urine and feces in male and female rats following oral gavage with mg/kg */C-PFOA Urine Ep esti ge il il 10. 7 Ww me EE Ea TiXeme0)@ W@W EI Feces I 1. mn S' TTR mmTimew tw) w 0m + Animal 1w0as4citFed because of an extreme valufoe24 hou fecal excreon, possibly due to contamination ith urine. v eee e 000107 Persone Act: Tsctnees heRat Dwain Figure 6: Torearlmignaavlagteiswsiuteh:b5lomogd/ckognc"eCn-trPaFtiOoAn ratio in male and female rats following. == b== a-- Wpellisohneddconeraion in fmls vs below he tion fo i sy. Se Tle 1 or se FE 'F -107- 000108 Figure7: Cumulative recoveryof TMC in urine and feces in male and female rats following. oral gavage with 25 mg/kg ""C-PFOA Urine . Ear Sm Eg eflf ll ignw HH Ex TE RB a Ww Time0) ww Feces a5 wo Ce ome a oo TLEl Re ew Time (4) ee oe 000109 Perfluoroocanoie Acid: Toxicokinetes in the Rat DuPon7473 | Figure8: Terminal tissue:blood concentration ratio in male and female rats following oral gavage with 25 mg/kg C-PFOA - (peer oe= =s am wo = -- Tis BlotConcetta *Whole blood concentration in females was below the detection limits for the assay. -- . BCH 000110 Perfivorooctansi Acid: Toxicokineics in the Rat DuPont7473 Figure: Cduamyurleapteiavteedreocroalvegrayvoafge14wCitinh u1rminge/kagndPFfeOcAes,offomlalolweeadnbdyfaem1amlge/rkagtscahfatlelren1g4e- dose of "'C-PFOA (day 15) Urine Fl g = IT i5 nl HH LE CE Feces . I naan i Te Wm ew ww Tine06) -7 Tio: 000111 PerfivorooctanAcide: Tosicokinetics ntheRat DuPon7473 Figure 10: Terminal tissue:blood concentration ratio in male and female rats following 14- day repeated oral gavage with 1 mg/kg `C-PFOA Z = ooem ewem = Thane BondConca Rio --- Sr Ths 000142 pertoaoi Aci: Toxokiesinbeot -- Figure 11: PfoFlOloAwicnogncoreanltrgaatviaogneiwnistehri0a.l1 pmlga/skmga samples PFOA from male and female rats Males 5 Nn i3$i. hh |i i Son Males. ty Females rr Semmes 5. NN g 3 Sig oi. Stn ee- ors 000113 Pesorooeanoic Acid: Toscokineics inthe Rat Dupon473 Figure 12: PFOA concentration in serial plasma samples from male and female rats following oral gavage with 1 mg/kg PFOA Males o ae zP is PegT a L ~H- i : i a i Tnetn Females Fem 7 tz fa . &Zon i TE hkinke)e mom mw --- BTR te 000114 Perfisoroocianoic Acid: Toxicokinetics inthe Rat DuPont7473 Figure 13: PfoFlOloAwicnognicnetnrtarvateinoonusininsjeercit)iopnlwaistmha1smagmp/lkegsPrFoOmAmale and female rats Males 3 {ms 3E . TN Ea 3 8 ow i Tw mm @ Time te) Females . Fens 7 2 3 g8o rsTime0)wa Tae 000115 - Perfuorooctanoc Acid: ToxiokineicintheRat DuPom 473 Figure 14: PFOA concentration in serial plasma samples from male and female rats following oral gavage with mg/kg PFOA Males ie 2Sw Bg i Thy i2 TTR mks mw Time 0) Females oe gHD) $on y-- 2 TR hTs ime0)sE sme EE iss SA ------ 000116 Prtuorosaeie Aid Toseokints nth a Dupona7s Figure 15: PFOA concentration in serial plasma samples from male and female rats following oral gavage with 25 mg/kg PFOA Males 3 Pes i3z . Hy 4ysHye i i i "% wo mw Ti0m0 e "0 00 "0 Females . ose i i i -- iBa Th Bh hohntem em a Te 000117 FetuAsct: Tooke neRa p-- Figure 16: PFOA concentration in serial plasma samples from `male and female rats following oral gavage with 0.1 mg/kg PFOA (extended time course) Males : a 22: a iyS 5 t ' g2 1a. Ew Females : Females :2 2LY i f > 5 wo nieswt = El EE 000118 Perfivoroocianoic Acid: Tosicokinetics in the Rat DuPoni1473 Figure 17: Tissue distribution of14 at Typaz 80d Tisazz in male and female rats following. oral gavage with 1 mg/kg 'C-PFOA Males 2 aSmee Uwem = m--l % Adinisierd Dose Females = =a ffelst erm Y--e = TTR % ATEdmiiEseBrDeosde: es rT Te- 000119 Peflvorooctanci Aci: Toxicokineis in the Rat DuPont7473 Figure 18: Tissue:blood concentration ratio at Toes and Taz in male and female rats following oral gavage with 1 mg/kg "C-PFOA Males romi a -= Females TT iso:BT loodConcern Rio 5s orroo as irPo = "- ThsueBloodConcentration Rao rr Tie: -- 000120 Perfluorooctanoic Acid: Toxicokinetics in the Rat DuPont1473 `Figure 19: oTriaslsugeadviasgteriwbiutthionomfg/"kCg a`tCT-oPxFO2A0d Toma in male and female rats following Males Zz = ot arm = = wi % Adminisred Dose: Females = Eat Sire h-ed = ` 7 = 5 Admiisred Dose > Ti20- 000121 Perfluorooctanoie Acid: Toxicokinetic intheRat DuPon7473 Figure 20: Tfioslsluoew:ibnlgooordalcognacveangterawtiitohnramtgi/okgat. Tyna and Tonaz MC-PFOA in male and female rats Males =or am a = : ThueTBlood ConcenraionT Ro 3 Females sr ppJeeoatt ron eoa-! = Thue Blond Concentration Ra e = Tme 000122 Perfuoroocianoic Acid: Tosicokinecs nthe Ret Dupon7473 Figure 21: Toiraslsugeavdiasgteriwbiutthio2n5omfg1/4kCgtCT-ipPexFaOnAd Tau in male and female rats following Males 2g E=l armm | k= om TTR E55 % Administered Dose Females =-- fo ooma hew4m = : =f1r:3 7 = % % Adminieed Dose T Tims 000123 Pesfuoroocancic Aci: Tosicokinetes intheRi Dupon7473 | Figure 22: Tfioslsluowei:nbglooordalcognacveangterawtiitohn2r5atmigo/aktgT"oCa-aPnFdOTAoaxz in male and female rats ! Males = fet Geo=m = - on ie Blood Coes Ri Females = = pot ET Tine Blond Cmemsent 5 J " ~ = 000124 APPENDICES C-- e= . ---- er--BT-- R-------- ---- -- 000125 peuoroocunoic Acid: ToxconeisinbeRe | Dion' APPENDICES EXPLANATORY NOTES ABBREVIATIONS: AUCH: AUCoD cl, Cou equiv F GL hrorh LambdaZ LoD L0Q M uCi m NA NS SD Ts TTrouasn area under the plasma concentration vs. time curve, extrapolatetod infinity AUCpir, normalized to dose. p`lmaasxmiamuclmeaprlaanscmea concentration equivalent female gastrointestinal htoeurrm(isn)al elimination constant limit of detection limit of quantitation male `microcurie, 2.22x10 dpm minute(s) not applicable nstoasnadamrpdledeviation terminal elimination half-life itimmee 1t00 C4onaCn.us following attainment of maximum concentrations oiree Tse -- 000126 Perfluorooctanoic Acid: Toxicokineticsin theRat DuPon7473 Appendix A Certificates of Analysis Tie: ed 000127 PerfvorooctaAnccidc ToriokineesintheRat Sigma AlsichCatictofAnsys Dupon7473 Page 10f1 @ ALDRICH TertificatesAnalysis T-- est spPeecmnoaAdTohNctioscca56n% Loroet1600) RESULTS -- -- s4e8n0s rJ -- om r rUcTrEaTcOOoFnWNTEPOWDER WHTEPOWDER semper CPoSnSTrOSTToRURCe TUYREASND Se gionnuernrouareuoTso W--EE. s[ onopma-- n -- wSoonnexoun rn Jp-- 1peogran. SARE nezoon e Re s pat. omg ing.cg Apo COIAIfo RamCOIA ouoraons J vs : Ee --000128 Petuorocunci Aci: Toxicokinics ntheRat Don 1e73 | Appendix B Pilot Pharmacokinetics in Male and Female Rats Following Oral Gavage with 1 mg/kgP. FOA ys pra . 000129 `Perflvorooctanoie Acid: Toxicokinetics in the Rat Dosing information for male and female rats Dose Concentration (mg/ml): Nominal Dose Volume (mL/kg): 0206 4.0 Nominal Dose Rate (mg/kg): 10 Male Animal 651159 65161 M`eStaanndard Deviation oe "Animal Weight @ 239.0 2683 2250377 Female Animal 656151116632 MSetaanndard Deviation "AnimalWeight 225185 24807 DuPont7473 Dose Volume. (mL) 094 097 000926 "Actual DoseTRaate (mg/kg) 0810 0745 00707486 Dos(emVLo)lume 008889 o0o8r9 ---- "ActualeDosT e Rate (mg/kg) 00759023 00.709088 Ts Ts 000130 -- Perfivorooctanoic Acid: Toxicokinetics in the Rat DuPontT473 Concentration (g/mL) in serial plasma in male and female rats folowing oral gavage with 1 mg/kg PFOA Male E imal Nammbey r Time) GSS) 651161 Mean SD 02s a a0e7 nssas BleEr Za ww 00 I8l7 24 28 16 227048 aise n20a8s8 20% D2I3B 2138 2104 01 2a n 2Jaso elasge 21900s0 less 1278 1482 0654 26 9p%o leo iases nse 11020S9 pas 740 1037 010s a2 168 ee Te 192 01 ec Female J Time) Gn1im6al Num(b51e1r63 Mem SD 0s2 4 mle0x 006 3soas 1336 2157200 LIL 176S 29 28 16 a1o7s6 og a13m1 om a1s5s3 03 00s3 02 r2y 7 o00ps 0o0m1 or 00 001003 004 0000 00 192%0 144 ooow 001 0000 00000 00 0m 0000 00 168 0 00 0% 00 -- i Tio: 000131 Peruoreoctanoic Acid: Toxicokineics intheRat Dupom 473 Pharmacokinetic parameters in male and female rats following oral gavage with 1 mg/kg PFOA Male J Animal#_ Tou Br) (Caomrl) La(mMbni)nz T(r) (hArpegirml) GrpAgmUliGmgke)(nlCkye/) gChies B20o0 7m8i o00e6 I9%e mannn aSmBs o0n2 MEYan 27000 2s59w8 o00n0e6s 11033%% eeanans 3d6es9s2e7s a00l3 > =- - Female J Animal# Tour) _CGgoml) Le(mUbhi)az Typ) (bArUuCg) (hrpAp/UmbiDmgle) (nlO-Ck,ehn uGee 0oss mmaa 0o2m 231m9 sllme 8 186 a59m2 Mam 005000 21543s0 002042 2039% m30366 31740999 c15o9 z Ta -- 000132 Perfivoroocianoic Acid: Toxicokinetcs in the Rat DuPon:7473 Pilot Excretion and MateriAaplpeBnadlianxcCe in Male and Female Rats Following Oral Gavage with 25 mg/kg 'C-PFOA Fe Te ---- 000133 `PerfluorooctaAncoidc: Toricokintisinthe Rat Dosing information for male and female rats Dupont7473 `DNoosmeinCaolncDeonsteraVtoilonum(emg()mL:kg): 6369 4.0 Nominal Dose Rate (mghke): 250 Male Animal 11002Mm MSetaanndard Deviston .- imalWeight 28138 2152041 Dose Administered 001658 o00n5 Actus(]mgD/oksee)Rate 117883683 013881124 RadioactivCitly Received 2108234262 11936218 Female Animal 110020F8 MSetaanndard Deviation .- imalWeight DoseAdmi@nistered _ Actua(lmDeoske)Rate 11555912 004464 1188316541 125972 0040s1 108125507 RadioactivkitGy Received 1121..494800 102322160 ; BER --------- 000134 Perflvoroostanic Acid: TosicokiinntehteRcast Dupo.7473 Percent recovery of radioactivity in urine in male and female rats following oral gavage with 25 mg/kg "*C-PFOA Male -- Timeepeoint 10M -- 103M uwriinnee sahn 0uxn0 oouos wuirninee 1224hm 310350 20191243 wuirinnee 782hh s41a0i2 336s8008 wiwinnee 1%2h0h asa6 aasn2s1 urwiinnee llasnh 3422639 4499 Tow 32105 28515 ei------eee Mean 5 o11a76 00120845 21517350 00360a0 39aa1n6 01322708 a45180 00.008038 43619%1 00319016 30310 2539 eetemer Female e Timepoinl___I0IF e T02F eeMeaneeSDe uruirinnee a8hn 2w0e1n9n5 2se9s1) snaises 909290)8 uurriinnee urine 2142hh 1s3a29s3 211i3ssB 1996s8 25239%1 sn 2126 2993 2560 0613 uurriinnee %2hh o03a4t1s 0063007 03034561 00001837 ururiinnee 1l2a0hn 0o2l1e7 o01l9y5 00210469 00001060 wine 168 21 os oa 0037 Toul S347 08 92140 1849 - - Te 000135 Perflvorooctanoic Acid: Toxicokinetics in the Rat DuPont7473 Percentrecovery of radioactivity in feces in male and female rats following oral gavage with 25 mg/kg `C-PFOA Male - Timepant 10M 10M Mean ED ffeecceess feces asnh 2h N0s0s 10s 0N0ss os 00002s8 osr nNaA 0705 ffeecceess feces awahh Th oasze oss jaaess oz 4L2e0 04% 40178 00% ffeecceess feces psonh ln momso ise o0l2s ozo 00sa0m ose 003304 Lon feces len os oie ows 02% Toa 700 ose sa; 209 - Female a TT impom 0 J0F Mem SD ffeecceess feces asnh Dh nNss xnss oa oo NNAA os nNaa 0109 ffeeeess feces TaGnnh oomm oooem om <d0Q ooaund 000 o0i0e% Na feces %h Ooms ows 0014 00% fffeeeccceeesss. 1ll2e0hh0 00o002o%5 <<o00zQQ o00.m0022E5 0NN0AA08 Tol Os 0231 058 041 a " Te iS 4 000136 Perfivorooctanoic Acid: Toricokinetc intheRat Duon7473 Percent recovery of radioactivity in tissues in male and female rats following oral gavage with 25 mg/kg "*C-PFOA Male a Tipo To Ey vie = Tposne Vhiye oss aTlaenn fred eooammn omaoasn on as owosenss pert oSaooas Tio ton toonp iaJeann ian oaawimss a3 Saa0o22s aapzmesd aia ous oadoo0a Goes Sihe=eeny Soa iilaaannn ImrTimo ian ass maVia0osn ion s0T0ei4es6 oom aaaoo2sn ai yC=oens Some lijiaasn ian oaG3omiiss paoezm a0a02m ra Sas ous aoaowonsn fr =ce iiaann aSiox apoed aiamm oSoonu rw mm sew sas 260 te Female a TT j=arseom Tmeem waanr ew aaa0o dor Mes aooosnn oWWnmn WnWwww . [--4= ngs iTwaohn a9am8 aproewp IWMW an am aon MW aaIN W Rfaimeeyn Gra iaiaaynn ian aooooonr 5owi6r0 am on oamaor Ww oaIwoNn Nn pCaootsmes Sos iaiaannn Wa oaapmm ppprrreey dm on "WWww NM aNWMM a Sose -- aaWann aGawmm aa5@&5 NWWMnW WAW oat om a6 ose om = - Tie: 000137 Prunes Ac: ToonnthesRt Dupo e73 Percent recovery of radioactivity in cage wash and residual feed in male and female rats following oral gavage with 25 mg/kg 1C-PFOA Malei TEWN es crwwern lsh 0G loSw E ome oRmYe m rooms e dow om om Female Fiimegpoeinni 1G01 ____1I0G2FF oagwuna Adwhn Gome aoms MMeeamn ooses SSDD oodms J rw um t ows oss ome -- oY EE-- E 000138 Perfivorooctancc Acid: Toxeokineics in the Rat Dupont7473 Percent recoveryofradioactivity in CO; trap in male and female rats folowing oral gavage i with 25 mg/kg ''C-PFOA Male Timepoint 101M 103M Mean SD CCOOmmppAA 4284hh OLODD OODD NNaA NNAA CCOoujsuppAA T%hh OODD <<LLOODD NNAA NNAA CCOOjamppAA 11420hh O<DOD L<OLODD NNAA NNAA COjupA 68h <OD <OD NA NA Toul NA Na NA nA Female --_-- Timepoini___10IF TGF Mean 3 CCoO,uApA 2468hh <O4ODD <<LLOODD NNAA CojupA Th OD <OD Na NnAA NA CCOojjmuppAA 1S0hh O<ODD <<LLOODD NNAA NNAA CCOOujsuppAA 11844hh AOODD <LLOODD NNAA NNAA Toul NA NA NA NA J Thee | 000139 Perfluorooctanoic Acid: Toricokineics intheRat DuPont7473 Percent recovery of radioactivity as volatile organics (VO) in male and female rats following oral gavage with 25 mg/kg `C-PFOA Male ESS Timepoinl 100M 10M Mean SD vvoo vo a2shh ddoopb OdODD NNAA NNAA mn 40D <OD NA NA vvoo vo 0shh OdODD <OLODD NNAA l4h OD <LOD NA NNAA NA vo lh OD OD NA Na Toul Na NA NA NA J Female - TT umepomt JIE 102F Mean SD vvoo vo 2smh 4d0oDp o40DD NNAA 7h dop 0D NA NNAA NA vvoo vo 09hh OODD <<LOODD NNAA le4n OD <LOD NA NNAA NA vo lh 40D <LOD NA NA Toul NA NA NA NA FE --- rT Tis 000140 Perfluorooctanoic Acid: Toxiokineis in the Rat DuPont7473 Concentration (ug equiv/g) in tissues in male and female rats following oral gavage with 25 mg/kg C-PFOA Male ei ------TimTeproirnt ee101MSr pCrarocasses jleeshh 3aa 6 Wsihnolebood 1Je8shh 26570638 fabrtain ljehh oLsoils enagns llehh ATalms spileeren lleeghh o3s9 KGildn.ecy t lleehh mssmes tGhlycmuosmems Jle6s8hh 035406 aedsreinsals lJeosshh aasmss bmounsec.le Jlesshh aiusze 1i0MgMee an 5 42001m2 33070s9 0ou3n% 2a6s0a8 27514596 006SM o19s7s8 olsaso 0O0s0e7 us7osns useos o01a8 s2a%n00 $33089 03271406 mdoase a31e 00132s9 035000 030 s 0000004 d40e8m 4a3s8s 0031564 226%s 3235% 0L3O5S1E Female A TT Tmo JF ciarncass llhh <4d00DQ brnadilneblood 6l8hh OLOQD fheoar l8hh o40DD spnlgeesn l8hh o40pD kiivdenrey llsehh 0o0g0 GGllcuosmctens 11868hh 4<0LODD thovyamruiess l18hh Od4DoD avderernsals l8hh dd4oopD bmounsecle 8lshh d440oDD --OF---- Me-- n --Sb L00O6D0 0N0A60 NNaA <OLODD NNAA NNAa O40DD NNAA NNAA <<OoDD NNAa NNAa 0o0mss 0o0o3 0oo0n0 <<OLODD NNAa NNaa OODD NNAA NNAA O<oDD NNAA NNAA 4o0DD NNAA NNaA - v Tio: 000141 Perfluorooctancie Acid: ToxicokineicintheRat DuPon7473 | Material BalancAeppinenMdailxeDand Female Rats Following Oral Gavage with 1 mg/kg '"C-PFOA ----- TT Te 000142 Perfuorooctanoic Acid: Toxicokinetis in the Rat Dosing information for male and female rats DuPont 7473 Male Dose Concentration (mglg): Female Dose Concentration (mg/g): 0289 0214 Nominal Dose Volume (mLkg): Nominal Dose Rate (mike): 40 10 Male Ey Animal AnimalWeight Dost Administered Actu(amleDoks)eRate Radioacti4viCy Received 10M 110032MM 2609 259 093 090 1119 Liss 28301 2.392 2226 093 1157 28240 100M 2343 095 1170 28786 MSetaanndard Deviation 26324 000923 0110520 208517890 J Female Animal "Avimal@Weight Dose Administered Actua(lmgD/oksge)Rate Radio-- activity Received Ch) 110002FF 103F 1167300 006700 00885426 2210967932 1822 070 0858 23446 104F 1810 070 0837 2110 MSetaanndard Deviation 187946 000658 00804089 212127055 J - Taz: . 000143 Perflucroocianoic Acid: Toxicokineis inthe Rat DuPon 7473 Percent recovery of radioactivity in urine in male and female rats following oral gavage with 1 mg/kg *C-PFOA Male Tipe 0 To To Tour Ve 5 w---e-- j"0s aoasmees 2350 ooTnsow tae aoaineao 19 aJitosneo 20 oouaiassne jan 0aa0i30s axe ------ = 2aEoN piemd so pi SsSoimomst Sts S2i76m0 Sr5ils 5iimm Zoo fr fro oaoasino ais i=--. -- t2ia0hnh foaSol Dw 12 T1h7oo6 i iZioman 1 o11a5e0 1 3i1s7iss Vas a5ou3n a3 --en---ee DDFweaitsot Boi VVJe iieen Ta 11r3 3d8 10 Jf15o5de2 fra1s5s V1vi7%s 1 duis jr 3ooi m ri --=ne = DDooitlsts FH zijena pi1on70ys iu 12s3i258 wuTomar 20 Son ii1sssto rd oaadsmes ass ii--nnee -- bDBonzm a1fr30e6d Dos Te 11Ti3ss0s ed f11r53e36) Vie Ii1nmi fe oZroma i Dbauridds osm -- oa oa 15 ame am em wes em 2018 Female i-- or To or View = wi--neee i@0n 2Bl0oEs6s pre MWanme Won w1h0w1n5e6 0 aw27mm5 pr wnoaams sSSooosmnt 3% ------ ne 2mon ai1s so oaseia Sia32a08r95 aoTuoi3n ao alos S2aommu a5iTs9s I) oi soteiaus G00 ------ na0anhn oozms aass 505% oomm G5io aasz Tout sas mes mae mes me nso Tr Tie 000144 `Pefivorooctancic Acid: Toicokinetic in the Rat DuPon7473 Percent recovery of radioactivity in feces in male and female rats following oral gavage with 1 mg/kg "C-PFOA Male ffe=eesr eesa lpfeeeces feeeeearr ace fecae fffoeesaa aceerr pPee Pe Tonge To Toi To To View a = i@0d 2m XoNzsss 10313 2xca2sne9 163 xxs s2o0 xNss So2m5 2a260 S2sat na 320ms aEny sen foaea0n oo0ii166 oaoasnmo non om aoe ams o001s6m73 oooszzss ous ai ao02sz4iss fr DJiuandn ars 0ot2e1ms3s a0os1smst ao0i1i2ss os 0363 ow 00o13o5505 000 10021655s00 0259 oaimn aaxizs ooDwuoitio2 Dis ooosurse om oooowmms ouoaorsmses ous0 ass ooaurewss aio aooiaomo ozs oaozumos ois DDDuyuyliies osooeum:s Dm ous 0oo0nr6z6 a00i3215o59 oDsoaisee ao am a0 oo03z8m7 Gam 0aa15si9 aise DDDyazt aoossstme aaazmmo oa oles oi oooesms o0os36ts1 oa oa 00a3u%0s5t aise o0ai3s1ss ae Toul nm 12s nm nas aos a ee - Female J Tipo TOF Tor --Toor Tor Siew = ffeee face aa z2n XNss as NNss ozs 0220 one xNss ass xNss 0261 Ls ass aa o12s% aa a1m5e4 ffaeeccaeers cer sominnn roaonds! om oorms oz ootuiz o0u0s2 oor oun aon oom 0a1o0e8 0010046s aoums mao2s fceceas ea Jmeaanhn oouuss oouuss prrd 0d0o1s0 oaomo daon e ont oss oss s esi oars 216 2m epre e PerivoroocuancicAT cidsoxcokinctcsinbeRatDuo 7als Percent recovery of radioactivity in tissues in male and female rats following oral gavage with 1 mg/kg *C-PFOA Male a Tamper TO To To To View = Erpoesse pSeycboot obwahs oDwya;s oeomn ons oaao ois ou08s6 012s os To 1502 o6o2n0 oo on73o88 oo asi ais orues aomso ih"nainn jou bDDyyoaams ooosoms oaaommnes oomomoe bya oom ai a0 oaass0s aodooonst 0101 oi roao oir ais phees SiGneey pDhoai owas uood 0am 1o2n55 Dus ows os asst aemo oouos 1o0o4n55 0ist aao0s oszz az 03 o2ua6n7 oamm Gpltdmews ~~ DDoymm pems bbyywa ooomn ooomme roim aaomsn oonews aaonne oouos oom froo aon 0080 010s oooot oooomm S[a=aase bDyoam Dam oooonm om ooi us oon a01o0s1 ous taooo ome oozs oo ramys oot To nen B30 am 136 ns aon = Female Fp 0 Tor Ta Toi pr = abfyrnon min oioonn 1166 ainsg Gog os0s0 ry Soaaosst ao Sop ao aaomqq Soo oazors QWon ooNiams a ib"en j=e]n 116666s0 166m aoop oo aoopn pr aaom ax aooon won II A 166 Sop aon pre Soo Na NNaA NNAA edeyy GSlicnoamers 116666mm 166m Iroon aon ooourz aon roiot a0 ouoon aon 105 ao a0 ous ao aao0s oaws oouotns aI peyot pre 11666600 1660 aaoon ao ao0 op aGoonn Gon Gaoonn oo NxA na 1680 aon op aon oo na INM aa . Saeaw s Tcee 1f6e80 ion aaomn pr prpree x waoonn pred aaoonn pr INN"Aa aa IN Tour one oun om ozs 0232 ois ee a Ties 000146 Perfivorooctanoic Acid: Toxicokineics in the Rat DuPont7473 Percent recoo fravdioe actr iviy ty in cage wash and residual feed in male and female rats following oral gavage with 1 mg/kg C-PFOA Male L Timepoii TOT 10M o 16M 10M Mean ED adwualshfed DDayya2s8 0158133 02499m0 018934 2Tmn o22m2e 00s4:0 Toul 236 342 ams 3m 298 072 J Female Timepan__101F___10F TOF je Mean a 5D chgweswisfhed lleshh aois 2o0m3e a02s3o 0a2s 20s8 0120837 Tow 336s 230 41 1m 30% 13m a aon gre 000147 Perflaorooetancic Acid: Tosicokinetics intheRat DuPont7473 Concentration (ug equiv/g) in tissues in male and female rats following oral gavage with 1mgkg "C-PFOA Male a Tip 10 To To To Siew = Cbpuoye oDbhonzn ooouoosm 0255 aoootisns7 ou aooanm oul ooons 0a0xm otoa0ansls0 0357 oo0niss oowms Jooe kt " DDDuuzas han ow oottse oom ooomo ais aoouns aso aaoinr om 020 aise ars oooomn oormi aoww oamoss hsnueern Kiney DDbuuossm Dz oojome o2u328 0324 om 02510 an ojoene 030 006 aoa d1o9s8t 0003s7 oaumn oaoas Cloomsaes roa ~~ DDyynm Dy: Wn Dos o0ums ooumse aGms oosmse ooauo0so oSoonmnsee asoaooeas aes oo: oouts aGmosn oseactses j= DDDaoozzze ban ooononamsl aoa0uiss oo om o001m03 oouasr aoss a0 Gaaoomsssst Ooaooomnns .-. - Female a Timp T0F Tor Ta Tor View 5 rSioeetiosd 116 h ian aomx ao o<mq owe ooomn a0 re ao oo am aoz0 Laoone ooom aNoAn oiwn oNAm bT-eaann ow ia1i6on8n0 pGorooyn praoemp pGroo)oo SLoonp ao op aon aon Sop AMW NNaa aNa naa aoie Siinoeye iiioonnn por m 166 "op auomzm aaow0w oo ou Sa2ou00n2 oouuazz Lop aor oaNouaa Na Claem oryes 1l0o6th 110666 oope aon aomn aLoo aon on Lop aaoonn aon aon aa aA aa aa jSays Tmooee 1p6e6 iroeny aaoonn paorn aoon om aamo am aoe pre SZoopn "oo AA M nNao a e ae ve 00 S01 e J N Tia 000148 Perfluorooctanoie Acid: Toxicokineics inthe Rat DuPont7473 Material BalancAepipnenMdailxeEand Female Rats Following Oral Gavage with 5 mg/kg J4C.PFOA Tian ---- 000149 Perfluorooctanoic Acid: Toxicokinetcs in the Rat Dosing information for male and female rats DuPon7473 DNoomsienCaolncDeonsteraVtoilonum(emg()m:Likg): 1211 40 Nominal Dose Rate (mghe): 5.0 Male AJ nimal AnimalWeighE t Dose Administered Actua(lmDpogs)S e Rate RadioactivWiCty)Received 11002MM 103M 119978.07 070798 44788017 2012 080 4795 2254%7 2878 108M 1933 or 4497 20611 MSetaanndard Deviation 319276 0o0r4 4017520 214.02255 Female nial Weight Dose Administered Actual Dose Rate Radioae ctivite y Received Animal (mgs) uC 11000F8 103F 11997289 00779 a45031 2105 085 865 2216.9760 24285 104F 2001 080 4810 2821 MSetaanndard Deviation 270043 005030 4002289 20997%5 J I Has -----.- : 000150 Perfivoroocianoic Acid: Toxicokngtic in the Rat Dupo:7473 Percent recoveryof radioactivity in urine in male and female rats following oral gavage with mg/kg "C-PFOA Male wW ine a os oonwese w W aos2s0 W aNmW s oaWiaesn aaoowxne enee ronee aiinh ao2smmo an Go 2aum9e 28G1211n30 svoasr pr io Ga 2uT5o9sn5 Io ooaususi orm noooeee ne s1me0nnh pae9m] Jaan an M25sems 2395m5 pae Sm Sua Sao ssnn SSuasue ojers 0o1rsst iinnee -- owuIstts 32o70u6 oo Zu 2226ao9 5 227 o6m9 5 2sZom o1s 2m 2Zp0e2t8 oaeanr ais orrneee iwee DoDavinizs 25a5 2 Dayi iow Iia 16 STioamot Z2am im Vass isa 2s a209 2is0es oaozzms a3 r=e ne DDaiyss Da 3r5e5 s5a9a 3336010 2 sJiaes 306 25a 265 n25e6 275 sSamn soos 20 am ooasossn priesee -- DbDoaszytz Doz 95m 00 iaomn is 2psdt im 2pmd im pipTnotsts aoiss oz Tout os gam ase ew am suse Female pon TOF TE Tor Tor Vie = winnee ine aon ih wwaaazn BTna7se2 Tao 5120068099688 saeossnosr 31f5a1%]3 7168 1056 13365 1S350s5a8 ped wnenee roe 2iznn0 Snoimm sen our s13o5 ose i525562 tie 20005150 03 SJoooss de ois om a6 oosssm o0xu5i iiee oe T1u0ahn in p0r219 03 oVosuss 0467 aam3s 0021661 oouite 0a31ms Tour sean wes mam na mae one Ton Perforooctancic Ack: Tonicokinetis intheRat DuPom473 Percent recovery of radioactivity in feces in male and female rats following oral gavage with 5 mg/kg "C-PFOA Male Timea To fom To Toa Vien 5 P==. io0h pxxsy oxm3s tom or xXaosse amo aNxssw oi Jwaown ano 10Mw5 ane fp=ems P= EFaYnY son ooaia6n jaittiso 0 0aa3xni0es aaainom a0a553% am ax om oawmh fr Paaay a Yi0aahnn os aaoinoe oom ooaimhs aoioiises ain oo ooaiimss aahii dn ois aim aoommm am ffoaeoa P= bojoool]o aoaoos0m Diz aon aaansae ai aaomumss aon oaooine pre boah nnss oom oaasoni om fa=eaa = DDbuoiits Diyie apourast aon aiapoe aoaiis2 ai ai oaasixmn aoiaziei oss ois oaaooome oa fPaeay fea feDDtyiynd ooaomwm ooius boi oom pias oooitmso aiaooiness a3oii)ns an aor a a0o0om5m on - oa aos oa 2350 a am um ssa 1m Female i-- Tor Tor Tor Sia 5 pwaods aa0oh NxNsss oNTossss xNnssn 03% an xX3ss om iy 13s Son ww aSviees -== feo a2nnh son 3w000i56 00s aasss o00m59 aa038mm6 om aoLtiasen onl 20o3i%0s ans 60a5i07e aia oo-mm ljiiaynn Gaw000s ooosn apirst aoosd aainse aomn Tom ans 299 20 nee sa Pe ERT) TE 000152 Perflvoroocunoic Acid: Toricokineic in the Rat Dupom.7473 Percent recovery of radioactivity in tissues in male and female rats following oral gavage with 5 mg/kg *`C-PFOA Male Tao Tom To To WViaon 5 Spferee ekved wbDoozmm osowmms Dymo SoDoaoesns 150 o5au3n5ss4 fSrooenns acSonms 12% Vou je) sa1ao3nse oaaonr tt4oo n on bbbooonnn Don oooowwn aa000n0s asaooosr ows 02 am o0au0ms%e on doooossne as joaoron 0 foKneeny Ta bDDoyunsx 0oonw8 bys om oa53mi9n ax lo0o3o5w0e faruomyse aooonsw ans 30 ax oo1um5s aon Srnhisaims Dbbuoommm ooommme pei bon om aooomons om aoooomsn alos aGaoen a aoosoomsn oom Gos aooooor Goo Smoareae bbtohomm somoosmme fjorrmed aaoomm ooaoomroo aosos aaoss eoaet won - pss mms mao -- 1s as Female Tioga TOF To or Tor WViaew = a-rnsvs Ton 1ia0r aoanm] ian pre ao0mxg aopome aLSoonpn Pe we 5 aNMaWm I onWsws Wn tiooean iiiganhn ar aaommp am GiipHp Lop adammm W0oop INNMWa op Sop Nn WMMW Na aw PSSeooa Clemens aaiannn dn aoom om am araoodsn parobimn Go ao oooxnn aSoN0a2 oo I o mNWyM NM ppfeeoet prey aaan auummw a ao oGGppp aaammm prSeoopd in dm op NaJA Mw WMNawn ----ne aaannn uuaooo a a@&5 prooeppd Wooopp N"~a WWAMM oar am oso om ams os om - == Tie 000153 PerfivorooctancicAcid: ToricokiinnttheRcast DuPont7473 Percent recovery of radioactivity in cage wash and residual feed in male and female rats following oral gavage with 5 mg/kg `C-PFOA Male Timepoint TOT ____10M Jo Mem 5 pweivafshe DDiioy2ss 2030198 6028603 40205538 J19O6D7 0s63572 01493646 Tow 2397 723 asm 1967 3935 2362 Female 7S cTegnedwuaalsfhecd l1s6hh 1L1S5T9 Toa 277 SU STR_-- -- 30150120 32a199 01078668 20544117 00.846540 3612 628 1854 2058 084s Te lan 000154 ---------- Perflvorooctanoie Acid: Toxicokinetics intheRat Dupon7473 Concentration (ug equiv/g) in tissues in male and female rats following oral gavage with 5 mg/kg C-PFOA J Male Topo To wo To To ----Vie-- w --"= pprreosye poy oowhnm Dom oomo oa oansss a oomn aie aai sm kts Dymo ao J jt ooem o1s103 aam0s a016m1 i4an hheonp obDwooan:s ooooomz Dyn oas 0Im30ds3 doouuosst ous ais oaascus o0003m5425 050 tisz oa0uo0sn oon peern sSineay DDyunm Dom ossmo om aiiso 104 aaimns he oi5me pri 0S1as 0538 oooa oure Dum ois or 0206 am aes ou Cyilsaie ~~ ODowonama ooaommn oolaueszss er bya om 20 oha2oru aooiluses oooairse osis oz 0268 oaaooonss 00a fTorneeye DoBhoomzm oo1ew ooosmm oooznz iaaon2n toiet ain oprsien oa Le. Female Ta T eeewWE we der dr Mas ow aohconestioad tan 11166880 aacoosqe oaaooo0e aooomn ao aoonn aon ih Pn oo an pr aNnr aa oNua aa h4er negesn 1i166s5n0 SGoooopo en "op aaommp aGoompp apSromyo aon aon Son NaNMa Na aNWan Na NhCineiemy a aohn ion a0o0u1oss oooon am aaon0 aon oazs ao 5 conens ian aon 0 op aop farieo NaM aouurs aNa yrsoa opirien Jann in aaaooonnn pre0d 0 paGrooep SSSooonnp NNNaaA re aon pre Sop ao0 Na NNNMaa NA oSneeie iiionnn pwwroon)n ppprrree: Gooopno paoronn) NNaa Na Aa WM Le. == - ise 000155 Perflaorooctanoie Acid: Toxicokinsics inthe Rat DuPon7473 | Appendix F Material Balance in Male and Female Rats Following Oral Gavage with 25 mg/kg "`C-PFOA TT ie -- 000156 Perfsorooctanoic Acid: Toxicokintics in the Rat Dosing information for male and female rats Duont7473 Dose Concentration (mg/g): 6.447 `Nominal Dose Volume (ml/kg): 4.0 NominalDoseRate (mg/kg): 250 Male JE Avimal 300mm 3s0amm SMuenadnard Deviation ---- ArialWeight 2021683 2103801 m63s DoseAdmimiered [0831 o[s3s 0os0ss Actua(lmDgo/sg)e Rate 2529580135 2253220 20688052 RadioSactRiviSty RTeceived 4 2243911656 22592817 204936240 E Female nial Weight Dose Administy ered Actual Dose Rate RadioactivitoygTRecoeived Avimal mehke) ne) s3o0f8 309% 1193670 1872 oonn 2525360251 015 25831 220193%4 20503 04F 1872 074 25452 200188 StMnedanardDeviation 185825 0010s2 25051794 201541398 a -----=--.--Tis: : --.G:m" 000157 Perflucrooctanic Acid: Toricokintcsinthe Rat Duron.7473 Percent recovery of radioactivity in urine in male and female rats following oral gavage with 25 mg/kg "*C-PFOA `Male Timea ot To Ey i = w----e i0n wn oT1smse pr o1hainss oa ao5sust sn aoissta pre oo1zsm 12% abaisioe aime | ------ == imoann on SwSoomo SiGonsn as ir SoSianns pit isahanen on priiisioo pi fd wi1aa0n oss pe==ed -- Djiurasn oSiosnus oo fret pZirne) j= Sihromm ii0hmo oie feid HSiodae 15 aoYsoesm ase --=--- -- bobooolhmo Bi 2iimm Las iSSiiaon iaVo n ioe aoTonn Jiiaaan isa Ji1nds tia baaiisas om ==--- -- DbDooylins Da ovoemm vom eiidm orem i0n Soinn T1po2e i aViiiaan i ao0si5ss as T----o - oDbzay [EI 1iimm TH1aonk a1Vi7m6 11i5m IHj=eis t0ried3s oa ous wom oss ame nas 0 Female ane To ai B0o or wmoeom Ea mEwm or mmmmo i nmsme = usYoomnu --=-- fepedd aiinh a SSaoe i FWSeomds fr pBHiarae in Sdaawws aos wShiwes 5Tos ibaonsis os ----= jjfroyy ian p1arn}e aoSeaan ax oi parsaei aooszm on a arvnisee 0aa3iehe -- a ww asm wen sme wm er oe wr 158 Perfivorooctansi Acid: Tosiokinetcs n the Rat DuPon7473 Percent recoveryof radioactivity n feces in male and female rats folowing oral gavage with 25 mg/kg *C-PFOA Male e ew M WW WM Wes Pca ca aoon zn ouNss oom axs5 Ns oNa s ou nNss axis oaiom 012s aNzao ans eccaaw Ea2n 00o33z6s toh22im0s o23s57e0 a0065u5677 osVots7 033 iTeon am faer a s12e0n ooims Jaan 5 0510540 our osriez 05s aosss ost oosaz2 aso azmz om a= es jorws oo 0a35s4s oan oVsart i opmd Bh 0011960 oi doaiasmts orGazdss aer ea DDwaiilo Duyiz o00a5n1s oaaYa5nr ooTro6mi1 oooruoin 0o03352i58s 0aa2ii0sn7 eeamw oDDwiisee 0077215 osm o05a0ns Vas ou01r0s6 osu ooi m oa ooasts om aoa5 ase faee fees Dywai Dz oViisee ous 0117s2t8 0 0o2n6s5 oan ainms azo 0o133n200 ooaumkss3 ffeecaes [ DoDs2t Daze onozt ass ioosrms 0o37ms ors oaa0r one 0os2 ax ooomm om Toul sss2 15816 102 sss nao as Female ew Ser ww Www Wes Pa. a n i xxs Ns Xxss nnss nn Ns oooonr oooonm ome os Nnaa ams aa a iann mn ooim orm o25x20 aim ooile 005 0002819 003 oarzis om o13584 om ffeicaa fea 12se0n0 yan a0oi1us5se6 aaammoss ooonsoss oo0u0mss 0r00e1s 0oo0m6m3 fees a aon asi one oot a0 ole Toul oss sem om outs 1868 2546 Tise- Perfvorooctanoc Acid: Toricokineis intheRat DuPom7473 Percent recoveryofradioactivity in tissues in male and female rats following oral gavage with 25 mg/kg "C-PFOA Male Tiago oo So oar View = pp-aney bDDooynmn osoommme om aaSoo0s ous proiosst ase o5am1ms is a$eo3nt5 we o2om6uems ass TYa es Yon DDDooommm bos aoaomoe a00or0% aoaomsn ow aos br caaoosne aaoaoosns ois won oaaoourn ams t--hoeken bey bbbooonnn aume bya oowms aioosss one 0iSh0se IGo5rl5s aasosxa osm oi a3 SaT0a1is0 on fSlrtem)mes yydn DOowmn DDuomm oodmmme aaco00s1 ojraus om ao a6 orooin aaDoo05n6 aio oo Gooooomsn am peosaky - Dbbooomnn Dom odoomme aSamo2n o0Smos aoaoass Goaaeomsns 0oa0o1m6 oat sass 057 neo mas sons Female Tip WiE Sar Sor Ea vie = J -Yom oct iwann an paarycm an am aooomno Gop S0dio6oa aioaadmre as am Sooaosn kN SooNuonsn ia toboYen np lalaarhn ian aaammm ao ooonnn prGieopp Saaosnme on Gp aon IIa Nn xNaM om hNeeay ina iiraennd aawowm parwoions Soma en aop 0 Souomnp Saoam i a oaNomnns WWMa SoWayM I prSao ones Sms aaanrn an aaamwm pr0o:n ao op iionn Gp uaommn INNa am WM a a NMa j--a=e iaaannn oaapmw IWonnn Gio pre aamm x I"N I"N Toul aon ass ax on aio am Tn Tis 000160 Perflvoroocanoie Acid: Toxicokinetics inthe Rat Dupon.7473 Percent recoveryof radioactivity incage `wash and residual feed in male and female rats following oral gavage with 25 mg/kg "C-PFOA Male : Timepoint 301M 302M 303M 304M Mean_ SD cfogdeuwwiafheed DDinyy28 0a0s2 204726 6490 4035s8L9 3194%7 1168104 Tow a7 M28 1018 4540 534 33% Female TT Tim SF SF GF SWF Mem pTsedwwiiseed 1166hh 03666%1 lueson 020825 0027091 4I9s9s6 7135166 Toal 43s 1926 288 090 682 8360 Tieo- 000161 Pervorooctanoic Acid: Toxicokinetic inthe Rat Dupo 7473 Concentration (ug equivig) in tissues in male and female rats following oral gavagewith 25 mg/kg "*C-PFOA Male Sw ot w om w Ey wToowr wSieew ow= proane fy obbwoonmn oo1mumes ooinehsse oaisnss Son 1i3516 Ss Sim5s2 sm 0oasss Sis TBboYevow bwDoodmm oaoims [SE] asaisess Yar aoVnano 33aa9mo%ss aoiViasa a ped ootessd 13% j=-- = fio DDDoyumnm bon eoasmmess jnosrm os aes fry TIfron]w Sen nraaagne 1 eiaasw Tie o3Saohn ass NSSiniearms ys DDDoyomnn bom oaosmmms aoiosies om ain aSToamne cass aiinieeo Sow aahissest i aoaiosnom 30 Soyeemrsa oe Dbbooomnm Dyn oaommm os aoa6mn os a1s1095 oi parnh}os 01a437% oaonsns js Female or or wn ac ass or amo oir WVem =Bm oamnee arsds oone J joyroo Tan rleeihd iaann aaonmm oo aaosmnso aaoo0eo on on a0o0p ao akINN a WWWnw " j==ee lmlaaon ian aaGwmm am aaowmp pprroep an on 0m0s as aWAoWn ao rWMewnl aos NGerrye Sime iadaanns an aoaumm am pdareeep on S2oo0pn0 on pprr6ee0 Lo iWWw Ww aWWMM Ww oamnsse Sia ilioaanyn pdaramo an am Sa5om8n prWoeop aon pr aaSo050 a IIaNN NM WWWMw M j--itte laan Gamo aown Woeo @% ww IA T Ties 000162 Pervoroocianoic Acid: Toxicokinetcs intheRat DuPon7473 | Material BalancAeppinenMdailxeGand Female Rats Following Or(a1l4 Gdaavya-greepweiatthed1 mg/kg dose) ""C-PFOA . Ties ------ ' 000163 Perfvoroocanec Acid: Toricokinetcs inthe Rat Dosing information for male and female rats Dupon7473 NoDNmoisenoaColnDDcmoeosnstereiVaRtoailtoneunm((megga(/gg)L:)lk 042036 10 Male Anima raWeigh Dose Adrinitered Actuagl Dsos)e Rate Radioacte ivuiCty)Rece eived ssoomm som 314299 3492 112296 13 00550067 ase 33804158s6 pec So 358 ia 09s ee MSaenadnard Devision n03i2 Go13s4 oo09n2?0 3r09e9 e Bmoadeybwodey wgeigahtmsveereof2S8m0.i2a5r4ation of "CTFOR chale lenge dose. AL he Atonof he 14-y repeat dosnt Female Anima ArimaTWeigh T Dose AdmiE nistered TActTuamlTeDoese)RTate TRT adioactiGviOty)TReecaeived sSoos6r So m25975 270 01901% 095 o095m4 a9s 13010879 28326 soeF 2466 099 0950 26m MSetaanndard Devision 2101305 00907s 0090624 009466 ofdemyalvbeodiynweaigihs veorfem2i45S.y25a5Gon Of "CPFOR halen dose AL he ion of the 1442ErEepeat dong. -- Ta te 000164 Perflvorooctancic Acid: Toricokincics intheRat Dupo 7473 Percent recoveryofradioactivity in urine in male and female rats following oral gavage with 1 mg/kg *C-PFOA (repeated dose) Male A ipo Ey Ti Eo Vie = w=inoee --- i0h oTnoasut aaases uoisnes a0tie0sm0s oaaiss oo0eaas 2h 26 20 so S50 2 aon ===e pisadn Soheess i2iiaasn SSakimns Spehea on SSoom 26 Tiou i ----= -- ifJrooennd 1iJ0eosd 1Liaas pTSoitnn ShSisoe fprrZa oi1uiaams ous osm jet im a 1 oi --=one -- Db5iystl Doi a2f3rm0e 1a 1T13o1es io oiannss pel aZ1umi3s us i11a0 im aaaiein ago --=ne -- DDDaiylsee Dy aZia nme we or1% end im oTionn im STiamas 25k ii15ms ns ooomaa iu pr--iinse B[oyootn iaermm 5Zaa oo5en0 j1i3od Soo15ns0 GaGsaisss --- Dyine jr193 iim froees 1h6h eTar vaisess ------oa ---- no --a-- m --mm--e sa ee s200 --2-- m Female =r wor or or aw L= y wi==ne i0oh fiosa us snHaimse 51assss pwexsi m5255m0 dsma fr --== nm. Ea2N a2m5ms 2 ITiae parsSaisssa SfSoroenn fSJoutr bp5ast9e sen ans im am Sm 1a fet -ead. aa10ym oOaomsset aaassness aaa7isssos oSiosus ap3ses 0ta3issa ee -- oateeeueseovee mAaTs ems eeeesmeeeeeeatwremeea166r _ Tiers Perflvorooctanic Acid: Toxicokinetis in the Rat DuPont7473 Percent recovery of radioactivity in feces in male and female rats following oral gavage with 1 mg/kg "C-PFOA (repeated dose) Male Son ESwn To RTWn WSiean 52 ffeeceess asn 126 oNosn oo [n2s sen oNosm oa onss o3ss oNAm a10nm onaan s12a45 ffeeceess fefeeess a2bn mn 0o8s2e0 1501 1n2a6n ost 31012590 ose s10e62 oss oan oat o12a5n4 Lou oaosat ome ffeeeess feces s1o2n08 aJanen s22s0a T1o2n0s6 0017622 ooess o02d4 oem ososu3s 1890 0o76s9 r1o1m8e0 00321051 oonse ffeessss ffeeesss DDaayyss Diyio 0130929 os o13m68 orn oosst o03omm 2130426 i219 s Tmos om o1amn ons ffeecees fees DDaiyy t12 Diy13 0o3m6 0201 Day 14 oes 0r32e5 o0%s 0011ss)t oss oouos 006s o40e3ss 006 032 o04u3n3 00209%5 tfeeess ffeosss DDaayylee Diy o01st ool oo02as5nt o0i3s odes 0o18m9 ost 0161 oe o02z0s2 0319 00205803 022 ffeeceess fos DDiy22 Diyas 00302616 o0o0s500 o0i1sst 00209 ooons oon o0s08e7 0036 00027260 oloe 0o2o0n2 0091 3 Dy Tou 1000 20645 nose nsw osu se Female Ed wEeT wW r w or e Sess 5 ffeecsess feces anw 12h osnss. 0003 onnso oan nasm 0303 Nossm pr) 15356 3A599 osmm asnn 7o4i0e6 ffeeesss = aunn nh 0o3z% oon o00n14 061s 212108 1s 0216 0055 aam 018s o23r8t oral 0s8o2m4 0083 fefeese fees 12s0h0 eaann o0o0r oon 0o1o6m 009 oo 0002637) 006s 0031s67 o0cs [0a1ra oo 0o1o2 oo1s fs Toul ose 229 nan son nau 157s 165+ 000166 Perfsoroocanoic Acid: Toxicokinetcs n the Rat Dupon7473 percent recovery of radioactivity in tissues in male and female rats following oral gavage with 1 mg/kg '"C-PFOA (repeated dose) Male Ew Ew Ww Bw We bSorynre bbbooymm oo4mm ooawsss oSammns oa23mm9 Soaauos jr a5 am aaeoodss sn tiBaonevoos han DbDyyynam Dyn oo0o6mn0 um oaimos ass a0a00o51s aoooomms aos aon aoaonuo om oaaoosnn ao aheepn Kner Dbbooosnn Dom oosmmm om SrSoh=ne aio ajeaso oan aaSoiaes oo aaGimns an oaTtooenus Goss Eames mtsd bbD booomsmymoooommm oaoomlr oon SoGoomsns am aaamooss am ooaoon0n Qos ooaoomns oo Sfaamyes j= DDDooynmn ooomome Dyn om o0Gi0r6 wo ooauoomn oroiyns oaae0o oaoooomm Tout now ew mes 250 nas I w FJemale won 0x0w om Waoymg e SaWoxwoins Woweaans aooas =oenwe i 1la0hn0 lan aGGoomri pprrSeosp am op SGioopp apaoroens oo op ooaam IN Soon WWww Jbo=rnd be ilaaannn ian daoemp pre Sap omp rS}oo So ri aadmooion aos aowman Qs oNNMam aor CGKheriyemes roa iidaabnn an aaasmse aw a GGopn aa5ne 0 pre 5 0o0o INNWnh pre a iMWnw Ww oyovmena fry jaiaannn ar aaGooo am ai imp prWaeme Sop ao Saoownp on JWAw WM akNNM IN T-ae S lan T ao Tout ams GSono prIee ass oa We os WM 09 WM ous Ties 000167 Perfivorooctanoic Acid Toxieokinetic in the Rat DuPon7473 Percent recoveryofradioactivity in cage wash and residual feed in male and female rats following oral gavage with 1 mg/kg "*C-PFOA (repeated dose) Male ----------impeponnt SSOOMM S SOM M S 503M M S S0iM M MMeeanm SSDD cageewasdh DDny2ss 03795152 0a2s6e8 0220796 o1m5i6 2022635 0113740 Toul 4667 162 2285 1s 2s La6s a Female ipa SF ENF WF SF Mes SD gowhea JJeesshh oLrSoE 312g3 i20r0e8 6002097 346786 81968S2 tow mE So 20566 6266 84 839 JS E E - ' 000168 _ Perfloroocunoic Acid: Toricokineics in he Rat Dupo 7473 Concentration (ig equiv) in tissues in male and female rats following oral gavage with 1 mg/kg C-PFOA (repeated dose) Male ww Ww WW wm We or-en DDoooymn ooooomm a0oio0sn5 x0 0oo0om5m6 aouonosom oun om aoooums om oaoonmne ale TSioenvess jo DDboyyannt bya oooomom ajron oo oi aaooionn D159 aGoooonwm 0s aa2o00s0 am araoodnn oe oeepren Yn bbbooynm oooommn bon oa aaji o a G0Too3s oaoiloens aosomim Gost aon ri a0oom2s am loiaesns yn bbwoomnn bom oooomow ome ooa0us Sa0o0 Goes aouus oaaomn apaoissno om oat oaoomo aon Satenraen bbbyoosnn thn ooommo oo aaammnos om aaaommss ooaaonns aoooons aaao0o je w Female an omw om oWnr e waoes oWou mm oGouonn cbaoTyrsees Jus ai16on8n1 an aaao0mr ao aaSa0pn aaS0mm 08 on oaSieomn on oaNoAo Na oWNowao WM jti=on at llaaanr aaamxo ian oo 5 S0p wa0ocw Sos pret aG0oomn aam ows aaooss aIImN Soon eKSeroya Sod. idlaaannn lan aaaimm aon aaamems a0 prQ4u0e a0 aparne) pr} NWhMny a N(IraNe Na yvamanes San iliaaannn ay aaammm am aWoopnn ao Woopnn op piraoeod op IWNWMn A MNWnaM WM T--oete aWno aaom 2opo Goop aomo WM I Ties 000169 Perfivorooctancic Acid: ToricokineticsintheRat DuPont7473 PharmacokineticAsppiennMdailxeHand Female Rats Following Oral Gavage with 0.1 mg/kg PFOA J Ties: Todi 000170 Perfivoraoctanoic Acid: Toxicokineis in the Rat Dosing information for male and female rats `NDoomsienCaolnDcoesnevaVtoolnum(meg(/mmLLJ)k:g): 0.028 40 Nominal Dose Rote (mph): 0.1 Male Animal 6522009932 6e52200956 MSeuanndard Deviation Se------ nialWeight 22833 2005795 2n1623 Female Animal 66522110010 65522110025 MSetaanndard Deviation o----- ima)Weight 11674958 11874656 18664 DuPon7473 ose(mVLo)lume 008991 008823 [030 Actuae l DoseR Rate (mg/kg) 0o11z2 0o11z2 00101020 osenVLo)lume o0r66 o07n4 o00n3 "AP ctual DosR e Rate (mg) o01n1s3 0o11n3 001030 ---- ee i0- ' 000171 Perluorooctanoic Acid: Toxicokinetics ntheRat Dupon7473 Concentration (g/mL) in serial plasma in male and female rats folowing oral gavage with 0.1 mg/kg PFOA Male re EToG iGws Gwe Mes FY ooz ws obeq oa aomg Nk om domm oGwm 4G0a0 eomws onm oomme ooNimaee om izv 5 0ooss ow 0he om oGmaes oosom ooOmmhe Gs ooommw osm ooonmmse oes in 52 o0oomsh oooGmameyn oomwes om ooasnm Ge oosw oomm oasnss 0o0ms 7@ I5] boomru ow Uoammms Mm ooomwm om ooomwme om ooommm ooaoows ose 1j6r8 Ooomhi aowmee om one na ooww ooma oamss 0om oomm oomm oowms oe a0 E6l oooehe GbGmwm oop ooommme oom ooommw ois ooolmms Oo oooomosez o =0 EA Sohwss Ne aMrs Gome oGimt oowm ooomm ome. = Female e HoG iGee Ges Men = ey G 0o3 aecst aoocseese dooemme 4oNm0A ownuaos ooaamts as| :2 oomz Somn oooemm oosme om oeorms oa apy om ooassese om oooaautssss 00% wi 5u G0Sorag G06 daompweee Ge aaex am daome am 0a% NA pr] Na aNA ana 7a% Gaoq Ge aanse ag wNNesSe 3a0m0 IIA NNaa - 000172 Perfvoroocianoic Acid: Tonicokinetics inthe Rat DuPom7473 Pharmacokinetic parameters in male and female rats following oral gavage with 0.1 mg/kg PFOA Male Animal Tom, Or) Co Lambanz (hr) Typ (or) (Ahrpeg/rml) (brUCD (LCghe) GGaHsr B12o0 Jeo 0oSaTd ome o00m mmsase Ssedes oo ms; mews EBRdL 12s LLEI 006856 Gass No oa om aes mas 15207 vem s 1i02s5 oosms 0oo0ls iamla 1s2al2e6 93604S 0029460 Female T animal Tou w br) _Gugml) i (hn) Tip) e"Mn0o Ga 002ss ooeess 0o3n0o3 2a2m1s 050 O70 010 3860 Ge loo on 020 25% IMe)an 0o3s1e ooeo o00m66 30256 (hArpUgiCml) (ur AUG 428386 sJse9s 3398% 25801066 0356864 a58m80 (LCghe) a260m82 23815677 260325 7 ! Te 000173 Perfluorooctancic Acid: Toxicokinetics in the Rat DuPon7473 Appendix 1 Pharmacokinetics in Male and Female Rats . Following Oral Gavage with 1 mg/kg PFOA -_ - BH 000174 Perflvoroociancic Acid: Toxicokinetics intheRat Dosing information for male and female rats NDoosmeinCaolncDeonstreaVtioolnum(meg(/nmiL)k:e): 0253 40 `Nominal Dose Rate (mg/kg): 10 Male Animal es53a74s6 e6s33714479 SMteaanndard Deviation Rnimal Weight 2256040 2249867 21867 Female Animal 6533776509 e6s5367621 MSetaanndard Devision awe 2200143 0183256 137) 0 DuPon 1473 osemVLo)lume 019090 019090 o1o0r0 ckual Dose Rate 1100118 r10o0s9 01000144 DonvLo)wm 008801 o07n3 oomo | AdwlDeRac 1100108 j1e 007 010000s To Te 000175 `Perflvorooctanoic Acid: Toxicokinetics intheRat DuPont7473 Concentration (g/mL) in serial plasma in male and female rats following oral gavage with 1 mg/kg PFOA Male ------ Timer Ee rr) Gwe Gwe Man 02os os 2a0o8e 30% a21p0e8 Taeose 2m 2252 aS0o1e6 sto 2768 ea 2n7m3 3samss 1N5A38 11943999 T2 h8 auws ois 39S02506 298 3393m soa 2910 S30 62347168 ss7s00e con 2360 21331720 onz x21 scoamn s6a39u0 574 70 spssn am 5031104 en 72202696 2121258 a6 oso sos6 06 os 30 9n% 4a2m3 2 250 aasse a35m0 3900 200 s1a2s 4s2a9n 3402 som pret sam oossss os 1i2a0 168 32018% 1610 3219a% 3s s3m2e% 2746 23069 20m 325098 0oa2n2 2788 0921 2044 29% oa w0 F5E 6 n2s% nnss 31963s 1507 1s3e58 oan Tso os 1L1as 113s 1p2a1s1e 1208 00134600 ous =wu "0 NNss Ns 0L13a02sm oosms 10071536 os oas 0v1e0 ome 00300851 0263 0397 ose oo ReIeENS GSTwanssTov_G_ed_oons_6Gyt_i_k 03 Female J mew OH wwe Tima Gna Gye Mes 3 02os 030 a32c6e0 sen aapsg an 4S901q4 6315 42000 3m as7 390 anine aasms 1n3a45 L1iao 12 h5 an3n0 a16m0 4pe3rst Soot 314a0m4 aasmms 3a3n9y9 0788 p330y1 Laz 00951203 osis 11 2 0026149s 0253 ooise o1a108 woe 00006336 o05n1s0 [02336 o0o g ooo is 0012371 00103s6 36= 9n% awo0e wg a4e ae oom ac aoom1e3 NS Nosst ooo 0o03y6 ors oNoa 0007 oo ia 17s- 000176 PecfluonooctaAncoicd: Toseokineics in theRat DuPont7473 Pharmacokinetic parameters in male and female rats following oral gavage with 1 mg/kg PFOA Male Animal To On) Cor Ggml) La(mhbni)nzTip Gn) OhArppCml) (raAgUimGlwimDghs) onLGkC,ghe ee3a4s6 14200 So4.184 000047 19680052 1S4a26s25 194042s s 017102 ee7v4e9 18200 9G3H8D0 00000055 113266670 1112095823707 110291249314 0079816 Mean sp 900 3 BLaine 00000015 1S3m3 1S94S4E63 127066301069 008116 Female T AvimaTl TTo On) ee3e59 2L0o0o eeywe 015000 sMepan 036 CGmm)Lam(Mbn)anrTyp (or) 44330%7 00262 22882% 36S4T 001239 3Sums 4L7u2 o0m03s dLamm (AruCg) GegAmUbGmgwgD) (mCiych) 4317284 046420 321206808 0o3s5s0 241124998 3204138130 o10m0m m10e09s3 270128896 re Tie 000177 Perfiorooctanoic Acid: ToxicokiinteheiRcast DuPon7473 Appendix J FolloPwhianrgmaIcnotkrianveetniocuss iInnjMeactlieonanwditFhe1mamlge/kRgatPsFOA --- ime Cie 000178 ------------------------------------ Perfluorooctanoic Acid: Toxicokinstis intheRat Dosing information for male and female rats Dose Concentration (mg/mL): 0.554 Nominal Dose Volume (mLkg): 2.0 `Nominal Dose Rate (mg/kg): 10 Male Animal 665533774420 653743 653744 MSteaanndard Deviation - Female Animal 656533775524 653758 653763 M`eStaanndard Deviation - "Animal Weight ) 2532 22355624 285 294833 "Animal Weight @) 2018 22002172 1967 2006 27 DuPon-473 Dose Volume (mL) ost 003417 050 000520 "Actual Dose Rate (mg/kg) L116 11.110082 1s 01010170 Dose Volume (mL) 040 004410 039 040 001 e "Actuale Dose Rate (mg/kg) 1.099 11112012 1.099 110s ool . Ts 0001%9 Peruorootanci Acid: Toxicokinetics intheRat DuPon7473 Concentration (4g/mL) in serial plasma in male and female rats following intravenous injection with 1 mg/kg PFOA Male J ey EGE ail GE GyE Mes oos os mamqs 5S2a0o2 nanagm eam amee ses Soo ssa 4a0m0 Taw nnmae 1am na 9m snhme 21825568 i|3 : UGe6 Sen maea temm essoee ssaw aseae uomm o7a m 11amm Timo 1113660 i 3u fteass Semm oommee dm wsmee am dasme am sasmewe dm wm ame a1Vizo0nn om a7 jo*) Tlueo sMmh dim Jdwme dsem ae sasae am aamm 2ams oodme a02046 Vimaa 0 11is 6m pe Trootk keeYaon 2298 Vis lw adYomeu ue aimmeo ooozimse SB2uy6 fy1r o0n3 Los 1BH3em8 1S on amme naLuiee oes os YB0aeo ose ooommx am 2xEg oouets Otem oomwe oosms oosmm oonmo oe. Female meen Gem Tomar Eee Men FY ozos 0570 aace GSua aSmg aasm aimq aimo osemn am oam: ped am 350 aNmae 0o6u1n2 i2 2S256505 oss soins im 3540 Wb SWaso ooms asmoe aomm saemse aomm ooems o1s2e5s8 x1 5% Gon6t GG6oqa oomw daoae aomw aamme aoocmme 40 oobiormnd Na oINurAs NA a5n 4G6068 ambse oomey waooe oNao oNuAsz oo. - - Te 000180 Perfluorooctanoic Acid: Toxicokinetcs inthe Rat DuPon7473 Pharmacokinetic parameters in male and female rats following intravenous injection with 1 mg/kg PFOA Male -- Lambdaz AUChs _ AUChalD a, Animal (Uhr) Typ (he) _(hrpg/mL) (hr-pg/mbImg/ke) (mL/kg) 65370 e372 00D 0004 19633 200779 1374590 1263389 121313 11IS808 081 0851 6e537a43 00000044 11506294708 1112037848017 190997.2676541 01.901052 Mean sD 0004 0000 1854 19558 1249817 113167 13384 100488 089% 0082 ------------------------------eree Female ere Lambdaz eeeAUTCery AUCHeeea, Animal (Uh) Tyo (hr) _(hrugml) Grpg/mLimg/kg) (ml kgrhr) eeswsse2 00226186 23528u4 339.75548 3535234290 2288337103 eeswyeisss 00320088 3223511 3234.s0788 3120493870 731686150 Mean sD 020 0047 2844 0514 33998 7601 30747 6759 34.040 9230 J -------- - Ta Tos 000151 Perfivorooctanoic Acid: Toxicokinetics n the Rat DuPont7473 | PharmacokineticAsppiennMdailxeKand Female Rats Following Oral Gavage with 5 mg/kg PFOA --- TEL heh 000182 Perfuorooctanoic Acid: Toxicokineics intheRat Dosing information for male and female rats Dupon7473 NDoomsienCaolncDeonsteraVtoiolnum(emg(/mmLL/)k;g): 1380 40 `Nominal Dose Rate (mghg): 50 Male Animal imalWeight ose(mVlo)lume Actuael Doese Rate (mg/kg) 665544660012 654603 2126300 2160 008869 086 55459069 5456 estes 270 08 5535 MSetaanndard Devistion 213840 o0o87l 05500s0 e-_-- J-- EFemale -- nial -- Weight Do-- se Volume -- "Actus Dose TRartee Animal mL) (mg/kg) 665544660056 654608 11888400 007754 55550572 1920 or 5536 654610 1850 074 S522 MSetaunndard Deviation 138673 000715 05051299 oo - Tie ta 000153 Perfvoroocianoie Acid: Toxicokineics in heRat Dupon7473 Concentration (g/mL) in serial plasma in male and female rats following oral gavage with S mg/kg PFOA Male ey ee mm wen oom aweoemee adSom0nae aSamoisme i:y NBSyTwSe adDiaaem dneemnne hWoo mdBioeim Summamers dhdeaews 7uo edlwem wmNeees hkJaomnm W w5o msWSiese mmdeeenww seaewee wBoo smfmaSes Bmsaaewwe wmWosm EBMAe odaeSmme hwdswee dsWeawwm mS=ooo ddheeee Sdismm dsNmwe mass 4dsm ms00mnoeem aakse manewmms mwbeeem adaeams apwammw wwweemnn oacoem wmbeemw mbmaman lsaoemo dndeeessne ondeesm adhmmm wuSome aanmme sdrteoes sadwwm mohmmeo ddWmeh sodmwee oGBRy emud Female e Ten) eG aw n wm mass aGoo Mwdemoes aelooss assecmso asaomneoe wbwaoasm saNme i2} WnDasEw wsGmesee smeeamsss ndneaeoss phleeessns dasumme i2: waYmseo Toammme Gdoawmmo 4doemew Soraaeo oademms @p5 aaGnne ooameme ooonmmse ooaoommn oooomwm dooowow =% aGse aaos aab0e a asa oNma >" Ties cot 000154 Perflvorooctancic Acid: ToricokineticintheRat Dupont7473 Pharmacokinetic parameters in male and female rats following oral gavage with mg/kg PFOA Male TAviTmal To 0) Cmlm) La(hme)i: Tip Oe) gAUmG)w (hrpgA/UmGbWimDge) (GmCh,) esol BO 302 0000 196 ams 85926 116 s660a3 24400 4S018S1 0O000368 2109047012 7G5E05T93 11326524418 001530 G04 240 902 00063 lela 706 141041 on Mseoan 5050 467145 0000m0 m2481%9 e19m28 122510828 oozs1s Female Animal Ton) mClo) LaOMb) iaTyp: n) (ArUaGg) OeAspUmGUMmgDks) (mGLiCgh,e 564006s 1100 211947500 00116296 4S512013 11010148087 2108423% 4498SaT) 664661008 2200 218148005 001156 a42s6i1 1s2e15s0s2 221796408 4435953653 Mean 150 20% 015 40 14% 2078 84s 0 ose 15% om os nz 200 as6 - Te 2 fre 0001:5 `Perfioorooctanic Acid: Toxicokineics intheRat DuPont7473 | Appendix L FPohlalromwaicnogkOirnaeltiGcasviangMeawliethan2d5 Fmegm/aklgePRFaOtsA JN Ties . 000156 Perflvorooctanoic Acid: Toxicokinetcs inthe Rat Dosing information for male and female rats Dose Concentration (mg/mL): 6.726 Nominal Dose Volume (mL/kg): 4.0 Nominal Dose Rate (mgkg): 25.0 Male -- Animal 665555116689 655170 655172 sMeDan TT @AvimalWeight 221500 240 2300 23570 Female C AnimT al 656555117765 656555117787 sMeDan AvimaiWeght 11883200 22014000 1194448 Dose Volume (mL) 008580 050 090 000910 Dose Volume (mL) 00773 00882 007086 DuPont7473 Actual DoscRate (mg/kg) 22667980 2267302 2063716 AcusiDoseRate (mg/kg) 22668938 2276.9004 2060994 -- we 5 -- 00018 Perfivorooctanoic Acid: Tosicokineics in the Rat Dupont7473 Concentration (g/mLi)n serial plasmain male and female rats following oral gavage with 25 mg/kg PFOA Male - nme EEG GGyr) GW Em Mes = os vsV gacegm lms waswe gam aaome mes q4o00s mss sael mee Wm Dees ese mee mew dNsam Busm i2 n` NlBeawsws 1% dmdaasmmmse mae lmemmss lamesa ddeoeos smmsss ipmemnes dbaeme Bsss: dlows u1 i7" TBoemsso Soi adsavamess ease bboaanss mam smamss Dams ddeomss doxs dEeet nd BN woo cae tem mew 198 5MT%oo SBGaammms Gh Gssmmms Wms amsasamsms owes mmWammw mss e0 smess sen nndeaetw nes a2ie0n FA BS5a5s i 3 hDseaasmm Bm mnseemwm aw eosuemsse eso ne maew lo nneea mas Bas S=a =io oBaRs TSwhee oRwE lleoww shmss aeemso mnoes mmaeow mwnme dsaese owes 1a0m3% oo. =a Female ee ime EEGit GE Ge Mes oog 0i% sdoaomgwo doaoscdemo smaeaqoo Teme mame sane dwoeeone mmooaras em mes 01n9as% wa i2 n5 mWhoe Siomee mwes dsamew mwawe msoeww daomes sqomz mma omosms 31s we 230 u3% a3 a03a4n9 ourseed 0G38m1 Gomwee oauose ooowu oLmo oovee o2mm oomsa ca1osr3oo oo %= ou0sst dob aoop aapo o0w0s oNmA sr I----.---- Lous Se 000158 Perflvorooctanoic Acid: Toxicokinetcs in the Rat DuPont7473 Pharmacokinetic parameters in male and female rats following oral gavage with 25 mg/kg PFOA Male Animal Ta On) esis Gi 40 20 sit Gs 160 80 MseDan 7625 co _(Csognml) La(mhnb)a: Tip (n) (rAaUgCmols) GraAgmUlinDgks)a (nlcis,ho 156875 ITS 00047 00042 147100 165499 22156S9T808A8S 150825 00062 112365 1EM208 8066S 9E51551163 1240 1104487) 1S4TIS 0003 20472 3510232 133367 0750 116109050 0000024 135873497 27SI2S6S6%l 9248246657 113 031 Female Con Lambinz AUCps__ AUCoeD a a, Avimal Tou 0) (gl) (Gb) Ty) (rugiml) (hrpgml/mg/ie) (ml/kgho) eGssii7s6 0055 2J000L2M700 0000275 8911S%T 1E0M633%6 20 1m240 00% 20366 1234 2349674180 20967 25.183 035577516 GGasm 20 106950 0105 6625 69803 2581S 38737 Mean EY 125 om 16s 4s9s 005 om l962%2 7198517s6 2695524 3658086 i -------- ar Tie- 000159 Perfluorooctanoic Acid: Toxicokinetics in the Rat DuPont7473 PharmacokinetiAcpspiennMdailxeMand Female Rats Following Oral Gavage with 0.1 mg/kg PFOA (extended time course) - roe BCH 000190 Perfluorooctanoic Acid: Toxicokinetics in the Rat Dosing information for male and female rats Dose Concentation (mg/mL): 0.024 `Nominal Dose Volume (mL/kg): 40 `Nominal Dose Rate (mg/kg): 0.1 Male Animal 665599227187. 665599228709 sMeDan - "Animal Weight ) 22764700 2600 2690 m8s DuPont7473 os(emVLo)rume 111100 110 110 010100 "S ActualL Dose RaE te (mg/kg) 00.009979 0095 0.099 00.009072 Female Animal 665599228653 665599228868 MseDan "Animal Weight ) 21089400 22009200 201.0 ng Dose Volume (mL) "ActualDoseeRaete (mg/kg) 007844 00.009977 008814 00009977 081 005 0.007 0000 -- _ T1%0000191 Perflucrooctanole Acid: Tosicokinctic inthe Rat DuPom 473 CPoFnOceAnt(reaxttieonnde(dutgi/mmel)coiunrsseer)ial plasma in male rats following oral gavage with 0.1 mg/kg. re EETGam Ew -------- Mes o33 aw9eq oMtm%m MR adGamgss as dow eme eoomoe oem ow oonwme oo 2i: 1 oG See MEbMmM 0 Mh Ooommm om ooonmme om oooewesss oes ooonwmee oi i=1 5 o0oe%e oh 0Momee om doOimna ows ooosemes om ooommme om ooonmm om %Vwioao in Soommmo fUMmRm oGfemm Gl ow om ooowmm om aoommm oooomm om 0 =wmo no0e oRos SMMnRh 0m aaommws Sm oooommm am owommme om ooaomxs om =@ 5 MaGee UL MfBeke ooommme fk om woasmm om ooomnm oooaou ome oo a@eo oMEn moWm f GGem fsaamm ke oom omomwm owe ooowmes omy oopoommo om Wiono wo ooheme ow fbohawe ooooown te om ooooowmne oom pooommwy ooowmmss oom oom 2Im%ee Jo o00m%%e 0 OG0mW Gm ooooommm ape eoommmse ome ooommm omo oooooonn 00% umweee M0omDm G0bam%n fea Gooowmes om ooooommm em ooommm oom oooomon oon nRMeeoo us 00Se%m See 0GGmGe Wm ooowmme ow oooommne ome eoommmsee oon ooooozhh aol wBleem 1 0o0me S%e oGGmmm fh aaaGpoepee oooooonn om oooomanz ow ooowomn om m mm E 0 4 Gee BE 0% aGgmmess Gow aaasnoeee aoe ooommee os oooommnee ome 0o00om% ome m 2 R Je He SR ow om oo ome ew Tore Bey 000182 Perfiuorooctanoic Acid: Torcokineics in the Rat Depon7473 Concentration (ug equivig) in serial plasma in female rats following oral gavage with 0.1 mg/kg PFOA (extended time course) -- ee -- ee -------- ---------- Ten) Gm om GO Gm Men s 2o1 092g Om aocme osm aomcee oso 4o0em0 omy onsnm oad oNoam ows ni: ooxsmu ooowiwss ooosmms oooasmn oaums dw oomoyn ows 1u 5 Gas ag ooood ae ooone ae odaaoxe ooasm ooawo 7@ % a a a) aaaxx, aaxx ax a ax ax NNAA a nNna NM jnwm 6 G9ao8g waweoxee aa awm aaasmwe naaa aANnA 0m on GGoogg W@W wawoewea aaaemx aaaome NNaAa nNInM -_ Blakley Tos 000193 Pesfluorooetancic Acid: Toxicokinetis inthe Rat DuPons7473 Pharmacokinetic parameters in male and female rats following oral gavage with 0.1 mg/kg PFOA (extended time course) Male a Animal Tour) Cm _Ggml) Lambdaz (hn) Tipe) (AwUCappe) GraAgnUliCmHgks) (lai,sh) eso GGoorso 20 20 160 0912 000042 23994s8 218937760 160 om 0006 1937 12628 216919564682 132928 003580 075 Gorse 20 1004 003 3005 24787 25037 040 Mean EY ss 70 108 oe ome oo 2s7e7.e0 25096308 28162778 0o5n1 Female Animal 59283 Geoosss esos EMYean Tpuhr) Con Gugml) Lombdaz (hn) Tip(or) AUChs__AUCoalD a a, (ug/ml) Grgg/mlimg/ke (nl/ghe) 10 10 oa osm 02 013 340 sa 28 3s8 10 oss 030 231 348 2957 33568879 38 227719 20 oa 025 282 342 3524 84 o1s25o 0o0ss2 ooomr 312M6 033%2 3432399 2390360 153 Bab 000194 Perfluorooctanoie Acid: Tosicokinetics in the Rat DuPon7473 | Tissue Distribution at Appendix N Tass and Tauz in Male and Female Rats Following Oral Gavage with 1 mg/kg *C-PFOA Tee ---- 0001S5 Pervorooctanoic Acid: Toricokineics in the Rat Dosing information for male and female rats `DNoosmeinCaolnDcoesnteaVtoilounm(em(ym:Lkg): 0220 40 Nominal Dose Rate (make): 10 DuPont7473 Male Avia T"amomn aanm M`eSwona Devan Te"oosom oonm vSeanneud Doviasen ee ew e mm22 m22 052 0ma6is4 ms m2z4 DutAdmaered oamm oonr ooonr os0ots% om oonn AenmDaohe ate ooswme ooms oosue oosmteo 0os1m6 ooums TadoncivpiTey FeTedT esso D0e0e6r Boases Be24sn08 Bas Boosa Female Friar Wah Dose Adel Ach DosFate eTredosciiyReceed psi) 0 w mena) =) T"ewmaorr ar 1193312 1942 0o0n or oosme ome 2 22s wr 2 om os 236s MSeinnt Devin 120224 oorn asasoo aamms Tenar aasre 11082018 1985 oo7r3s 078 oossss om 0850 Bnoeso nZess as je om SMientaandDevan 61193 oou76 oasoen 23s -- - 195+ o . 000156 | Perfiuorooctanoic Acid: Tonicokietcs intheRat DuPom.473 Percent recoveryofradioactivity at Tu in tissues in male and female rats following oral gavage with 1 mg/kg *C-PFOA Male Times go or on va 5 oThtrve e Mnhobooiommm lo;eomemew mnoeomw amonise anwnees muamwm o2i0om%n bwiew.n hTTooonnoommm o0105u61s pT2eo56s0 a2o5ie0s a2W30o0e8 o2oosn aaoiotnse f-- ier llToohhndiooommm maoiommo soousesew no5leomro omoimms naaooso ooSoenin) joCTloiema lllooohhvuaimnn 11I7sa8e ro lohiom dol Totondm sprToeio Gos oon T3Taaass dios iYto0ew aos raaerss aes Sa--rmoa a lllooonnnoommm aadooies aaaomsno asoams aaaocess o0a5osss aoSouoosmn ohm nen nee ue Na nos oes pes london zo EEN pres re im os E E eeETVTwR TmSmsRT Oeom ITTOARmVesE RHoR te 4wT %ieeT T pS OsasTE R BerwasT oy we Female Tioga Br or mE or via 5 wVonenttoes iIibshisnmm o7dw5osn0 bY him ai o0eaee rt ooomxo S0ao0mm aaSihni oi as ais d0toiom pre Y--ooon ihhiimnm aadiomem 0io3as ooGorsi oi0os3a)7n ao0iu0sst aaohmoas fNToooesn hhhisimnm oSa7m0m6 iGboe Snpieeesn fSrooes] sfSa0r60) aSV0o62e6 Cpyliendmens hIIhhsilsmsmm 2oo1so3% 5aou3ii3o aBTooarews ou0om0r7s maoeosns noooaen Sreyness iInhbiiisssmmm oo0mwm aomiiss aaaooone oooaotm aaaoonnno 0or0e1s5 feyet ihhsmm aamms oam aGese ooiro aolzor oaomn Te wee mem ess sam sen eas E Toor e ET 5%: Perfuorooctanoic Aci: Toxicokineic inthe Rat DuPon7473 Percent recovery of radioactivity at Tmax in tissues in male and female rats following oral gavage with 1 mg/kg ""C-PFOA Male Tipp oar Foy ww Vie w ptrrToasrguetev.or mmRheh 1o6m04S03a0 G0Sa0s8 am 0SSo0h3oe2 oms 003o3m20 a Go0i0a30 Go acs as 0ooi0o0xam2 ane | joaan mnmhnh mh oaabume 0Gra5i5s aooszms ows as ous o0asosin soe 0aa1s09as ue 0oGo0un5e San YiSi=noeya ims m nnnn M asTesa mn om m1Tames 2a oViwaoasses ano am0Tsia a0sT2ao9 a6 toot aaam50s ou fbrireod om nnihn mh aarmoesr om aaamossr oon roaasdm a0s% oan roea] oeSu0t10 on aooooonmo ares fjreeegd n[in prHe] Gio=s LTaona to id ao rw sme sas sow son sow ams TFooewi. ABE TTR eSTR meSe Female Tima gira a wer View = jwrutneba "o Sdoiozsn paoeiesd oral aa0iss%s oie frsoasyes eed Losimoyo oer asfrmoesse oom ob--een op"y o aoomsm 0050 jaaronee a0as0z6 Son je aoaisisn pnt a0ouis35s an aoosossm 15 poKreyya G1Goons oao a iZfsaenn) oSan i Si00 faiar mm Dons iSiooos StSiohan S008 aos ap3e5rr5m)8 rs paorno a ros o"ao "o doaa00ms am ojoormo am oGaoommi oi 0aa0om6as a6 oaaomsss 02st aoaoosar ou jwp=ol pipaie a0ii2m6e2 aa oornasl o03s0s4 aaasn aazoos To wr was mew mse mm ome J Taye TT I 7s 000158 Perfivorooctancic Acid: Toicokinetics in the Rat DuPon7473 Concentration (1g quiv/g) at Tax in tissues in male and female rats following oral gavage with 1 mg/kg "C-PFOA Male ptionsae bWrhaoilnebiood fbaean slpuingesn Kliivdenrey GGllLcuosniens tthhyyrmouisd eesmteis s bmounsecle Timepoinl__AOIM___daM 1100nh3300mm 00477630 0053367 l1o0nh330mm 0203588 20600671 100nh3300mm 00927480 0os2s83 0108h330mm 01301749 o1.x1:2s8 00hn3300mm 41850182 1as7i3a9 1100nh33oomm 00139917 [0r2y3 1loonh33oomm 00342159 0022195 1l0ohh3o0mm 00458728 0o5s5e8 11008h3300mm 00235572 003206 4M dam 0oess 0o4m6es o26o0s1s 2050563 o12s0 0o2sse1 o13a79 01.20488 3L5a8e9 2521926 o02m0 002s09 o04y8 00243100 0037650 00.445625 0042661 0023520 EE Mean 5 5) [06Am 0019170 c25o8s7 o00o2n4 0025871 00106510 01315379 00105s1 a17610 00732092 00522188 00105218 0032%m 00003898 00533410 0001s3!0 0023567 00005038 Female e Timepoini___409F ET e iF ar Mean 5 Vskhionleblood I1hhiIsSmm 02303460 brain Ihism 0082 2[355 0038 01120828 os 01222381 0026 01279187 0033 0o5n6e9 0.008 heftart longs IThhiissmm 00418449 Ihism 087 00262385 0855 00038114 0521 00130206 0551 0014402 0701 001056)4 0152 spilveeern Kidney TInhhiiisssmmm 301529846568 02226947 387 01175828 2863 01173087 1967 01290318 3073 00026650 0852 GGllcoumens 1Ihhilssmm 70.76580 017s5 thyroid Ihism 0256 03710 15536051 0540 p1.a86s9 0376 0241780 0385 25198150 on thovyamriuess Sewls nIhiissmm 00241378 hism 0319 0o6z5s2 0287 00311643 01m 00121843 017 00147252 0238 00106s7 0076 muesrcasle bone IIhhiissmm 00714M 00316814 Thism 0160 0245 0010 0002911 00411190 0020331s 0162 ons oun 0083 oe I To Ti, o 000159 Perfluorooctanoic Aci: Toricokinetics inthe Rat DuPont7473 Concentration (4g quiv/g) at Tawa in tissues in male and female rats following oral gavage with 1 mg/kg "C-PFOA Male a Timpani AOS 06M 40M ____doBM Mem 52 Spironstate Tminh bod Ih oomm Ol oopwe LUE 0ox1m0s 094 0o2me4 087 0o1xso o09m% 0o0o3l5 000M01 bforn hear MTihh Mh Ooomss oa oomoo oss ooom ooaxn oomo oouxs 0003%m 046 00000 00 spnlgesen liver MMhh Dh ooma sSoewn oowpss o3smms 4on6s osm oJme os oAilso 0B 0006% ois) Gdlreuact TMihh Shewe ITiMh oomosd 0:6 ooimer ows ooums oss ooim omy 000m 08 000100 01 tthyyrmous aedsrteensals h ihomGowe Mh oe ooasms oi oonzs oi oomm owe oolal ors 000089 o00mi6 mbuosncele MTihh Oowms oowm ooime ooimr 0o1i0s8 oon o-.- Female TT YE TESM 1 JC 5 5) siWhnoleblood 4anh brain in o1a9r0 con oimso oom 0ne3s oo 0asme og 0l4i1ss 00a o00a723 0005 01s 000 hieart Jungs aann an 9Os9i12 03s oowe loo oomse; Oo8z0s ooi a 00m3 00583S% 02 00006%7 00% spilveeren sidney aanb ah o1n9 o2wse o1e91s s2iss aasmso os 2as3s 260 2208078 1567 0058003 Lisa GGlleuomeens 4ahn thyroid aann oosmm 24s 0m 021 oo 0T2o4e 0s a02s4o oI e12w89 2100%% os 0109 towyrimees vSderernssls aa4hhn 00O9sd6s ooowsdssa 0o032a3s o0028s470 0o03d306e8ss 00000002686%33 bmounscele aann o0l0 oolal o0i3s6 o03i1 0o1i8s 00S .-.-. ---- TI: an 000200 Perflorooctanoie Acid: Toniokinetes in theRat DuPon7473 Appendix O Tissue Distribution at Tuy and Tauyz in Male and Female Rats Following Oral Gavage with 5 mg/kg `C-PFOA we : 000201 Perflvorooctancie Acid: Toxicokinetics in theRat Dosing information for male and female rats NDoomsienCaolncDeonsteraVtoiolnum(meg/(gm)L:/kg): 1171 4.0 `Nominal Dose Rate (mgkg): 50 DuPont7473 Male Animal T"eam piom om MSaunndar Deviation T"ear m a am am MSetatnodud Deviation va r one REated e Aewa&lT Dose ote R Taoace iicyh Re eed m2021 224 oosse 093 waeer asa 2w9o7u 2a1s6s0 208 095 an E6o 0o9m2 aoonsee os3s0 136425 24 o09n4 08 a"e0o sess w267m30 42959 264 092 am E7X6 000530 4o20o8 n092e2 Female r Avimal w e AmaD h) Reseyid T"ease aasre 119706 1945 0017s6 078 aaeosn am 22514008 p20e0t5 ar Mean 201 09 wo 1952 on a0o 033 2010814 Standard Deviation 54 oo Te"wsG:or peodr 21004497 1843 oosn 078 aamme 4360 223858651 22331000 ost or Men 1948 on 1923 oomo aonme eEmX Sudd Deviion 9 IE] 208 000202 Perfivorooctancic Acid: Toxcokinctics in the Rat DuPoni1473 Percent recovery of radioactivity at Tus in tissues in male and female rats following oral gavage with mg/kg "C-PFOA Male Timp pGirorokcvoot iOloohnvoimmn tbooynn lllooohvhiiionmm tpoheepn llloohnhiioommm Cdilemoyamas lllooonhbooommm yna er lllooohhhaoanmn Sa at fey lllooohhniiiooommm Toul ee y weigh.S A py 2e02a004m n1oaoss 00so0ais 29oe1r9 ois 20o705n83 TOoosaimsss 11189638m Z1Vo3orz ooomn 06s oGoms as a osaos a1n2551 Sa wie 50150 TSBe alow, wo Fy View = 1m6o7em6r6 21o5371o072 asoens 2 oas9s isa o[2umms ao2im5s o2o0rs ous oouzis ai 1oor7im5 nooommme jooosoems oo2ox4n 2Tsoomln 253su60s I25m08 pre 0o3ms 0530 ou0ot7u5es5 oaom0 oars oaouoesns oGaos oo 1002s8 ri oBae ha 1a5m6s fred o05o7n6 osu TTR,wosk Bh5dwmGTR, Tewor4nT mte 5raT Female Tops w= Frid 3 View = aSotevkat tn hIbsimsm hhiimm 9oazms oomo oaufmess]t o1s0o3ms81 01% ome oo0sa0ro6s0 oDe005869 038 azo 0o20ao80 om Y4epnr en iiibhsiissmmm oowss oo na 0a3i0s8 Sasmt 0ou5s23 am aasmse ois oasw10e1 10 9296 1150 oouis o2u1i2 Oemnreya hhhiiimmm 3ses j7ea Gltomas Dm om ainoss oae Tass E$s3h0a a piirz Ze ows a0 oon oShmou t23o0os yyvaannes Saeon ihiihhsiiigsmmmm oooomwne om oaaomse s o0ou0ossl o00u01ss7t ois 0551 ooauosn ooamsoo ed 000 a em Te nnihiiisssmmm 0033% oles oo0su3s0t0 ooime 0a2ms 0o3nsa aaunsi? eo Toul am EE VHT S106 egaleve, Sas I Fe Wh Vo sean 4 TR reE n58d974%. BT one 3a%m by. 02. * ad 000203 Perflsorooctanoie Acid: Toxicokineic intheRat DuPont7473 `Percent recovery of radioactivity at Taz in tissues in male and female rats following oral gavage with 5 mg/kg "C-PFOA Male Tipp py w= wo Va w peSroyse e MmnnhL odxus)e om moSmmmo as ampoesnie 000 an5oas0s on ouljsee? am oaom0a aos bi9onn -- mmwhhh aases mh aooosm aiamss ou aaosi6s aes oo1m0i1:i pr) asazae a0 ooaimmse oun prbKoeey roa hmnhhh nh Taosst fM1t5e fwr05wy5e1 ozs pe] a0 mVLaaiaw mTiamo om om aaVonaosin Svioaem -- wmnhhho aporiueost ooGuooms ny aon jr aaosooor aus Dawoomnss oom Gooomamt a0 aao0oo aaos Seaayms [ia fSio)m toan o1m sijrn a5% oie re ssw sms se sew seen ros T [Sy To TB R OB TR, ORwe Female Top mor oF = view = a---evi opny GoP5se0s a"oossso pi aso om Saonmns oGGauisot Ss0aaxi0ns7 oom he ano ormy o0rsa6 biaene fa pi""on oaos nuss Toi aaoiozmo Sion a05Sla4iess Se aotoxas amaSe7o im 7 oaamom ame fibEoeay piad 1 Coens a" isomss os priiems wor 2fe5ia1s rt LStihisone i5TSe5aos5n Gon 00s woGroeers oe ppiaeatd Se o"pid pGaeoons oz ooauo0 aie aanoouson an Doa0oms am aoa00on1ss 02 o oookmo aos p=r--o-t oa iom Fuen 0a3s6s0 o03m84 a0i3a7 om re mms wm eo nus am ne T Toy wight T ee TE TI ha TTR BO So TT Te 000204 Pesuomoacancic Acid: Tonicokinees i heRat Dupon7473 Concentration (ug equiv/g) at Tox in tissues in male and female rats following oral gavage with 5 mg/kg *C-PFOA .-Male T -- T --SO--T-- S m=e Het foonndoomm Joniom 0S310 MES ums eass Poames saomms aosme asmeee l0es%s sa aess zzoLmaem omo 00% juass bneeasn oohhmm ohm Shemew ohm e%e soewm bem stssew cao saeme s2nmo smwee cemose o0i 0o7e e oNer Noohm dom adawn sow io lohlom Tas msemen aosmye aemn m2aamo 2a4mmo ses Dlaosws ame 320m8 0o6s9e CCleolnemsue red oo00hhommm dTieows ims london 3% adown aasmse aasme 2amms 2aadmimse sm d1aomse oomxe 01s pwdeimaes one OOh Nmm hm STeen He slaaws som slaemw dom 4dsss Lam dasas 136 o0m0e8 03 See ee = - Female W -- wHi-- innn et I Inhiimsmm BaGaimsen n2oemnn T Iaosemmls d3oammmee BaoETwS 0Le 4m 00m epSan ngs hisem f03h% IhiSm STime GSeee sbems sloans adses aimsos mumee a1sam eimms ooaonm 002m8 on Maee iIMhEmm hsm owles hm Woe mdeasw eas dsenss soe p0amm ososm 2le0sms oaswl 3sd4s0)9 2L4i0e SClemhenswe dred hIMeimm im Ziasnme dew Gms Sm Sma ddaoee dseews 2daam ale0es 2mee0 dow 1lams 08 0o2n% ode oem--e ww tMhiemm Mm W3mR Jim sdsms oTmosm saoms uaem aoa0 lsee 2a8s0s daee 01ss o02m9 epoe hm om 1% = I So = ---- 0002065 PerfvoroocanAcicd: Toricokinetics intheRat Dupon473 | Concentration (4g equiv/g) at Tray: in tissues in male and female rats following oral gavage with 5 mg/kg "C-PFOA Male Timepuint AIM EM Siprnose imne Seebiood Ih saess een n1asm cs bIran heart MTiinn oasmo oomme Tin ams ae snegesn or DTiinn Din aoasas msm zoes mse KidnePya Tminh Olimwe Mh o3s0s oie 4oam oie yisd ches TTiinn otsise daoseas Tin dee ass smaursecnlaels bone TPiinn cdcesn oaeas Tih a os ee ee----e EMM Me o5e0 lloens Tse oissas Tako llmg ss o01nse 039% oolsees ae ooiees 24 ooiess 242 oOIoE 03 sossas wee aosa pan aogsos ise 00506m sn adsos ow osdwuosss d0dss os 00se1s oon awmase os 21226% um lLee 124 0042s6 oan oosms ose olsawe oon olums ose o01o8m oo eet ------eete Female Timon GF or dF RF Men a = sin boot a4h bran ih 2oadms ome 2besms oss 7aeas oi daod0es 0x9 2osss oa 0L7a8s6 OOK fheaart Tongs ainh ho OSsase osams 2o0e0w dm sew som mLem ss a0mse amo 005280 1268 spoleeern Kidney Gihh Ih dTeiew sre Nsiswe dase oosau asm anaws ew udmwss 13 o10a6 2948 GOlluit n B4oh tyioid Gh Woemm oom ldoase ams moasms aM 2coawm las aosmm 1s n12e6s5s9 038 omvarsies Sireals iinh Gh o2s3e0 2m zrseeeszs orsss dew slaxoes 206 21ma;0 203 00278%8 0330 esrcse hove iGhh n oGwee Tas aosww va oamss ose osswe it 0a7s6 Loo 0L0262S 0360 o.-. oT So ' 000266 Pecfiuorooctanic Acid: Toxicokinetics in the Rat `DePon 7473 | | Tissue Distribution at Appendix P Tass and Tass in Male and Female Rats Following Oral Gavage with 25 mg/kg. MUC.PFOA 26- Pat 000287 Perflvorooctanoic Acid: Toxicokinetics in the Rat Dosing information for male and female rats DNoomsienCaolncDeonsteraVtoiolnum(meg(/gm):k): 6.166 40 Nominal Dose Rate (mg/kg): 25.0 Male Avimal Te" a oSamn jo ---- T"ouGot mm oomn Saannia Deviion See wWag 2a6e3 2210219 n(eaz 22i1s63s p2id3 2736 Female Ain aw e Teaarr 110447 waarr h1os MStanard Devin 195003 Te"sssrr 12941 warr 19196449 MSeannt Devinn a2o -- Do Adamired o05m2 oonx oIrse oons 0a5s3s oouss AunmDgoae Re Z25o00o6 2prsa o0 us: u0s0e Zaom uosnaer Dos Adel Acin]DgoaeFate o0or7n6 p22i5a2d9m0 076 pr ooonl uosm 0o7768 079 224570s 25026 079 as ooma 2000513 -- DuPon7473 Taa escivxiT yRecived u3ms DBisos Bammo BBaeo 2i4s5s n0o5u0s TadeaciveiCya Received 2a w0an0 oe noeas e22n0 anwa 2sa1s - 207% 3m 000208 " perfuoroostanoic Acid: Tonicokinetics intheRat DuPont7473 Percent recovery of radioactivity at Tou; in tissues in male and female rats following oral gavage with 25 mg/kg "`C-PFOA Male Tipo Fr wo war Vm = TrDaorrteoos nlMoo0vbim0omm 2iozose fo12 5rt0s% nroosmss fr 3aeosas o12u3r605 aso Tow 0auo5ns6 our Ybnaainn os ollooonhiimoomm o2oao0nm4 lonom om assmo oi 0Tsot u ooroe cyumz oss 2o1s5e as i ois oouo o0n1s0 KhSionekeey Sima lllooohnnrjdooommn 1o26i4 26vasmn loom 20 55 1ZT5ao5w% an2sa5em9 sm n22ms2msw dine Saasazos 13 S-- olitosmens llJoonohdbiooommm o2omoi proaior aa lonoom 0s 066 oaaot0ma 0520 oaoom ome odoms oes a oduosn oaooa SajTrooeinae lllooonnndirooonmm 13o3m35e066 SBoims f1oru2ys6 no2auamse S2o55rs ooseu Tout nse wo sass as om 2680 oJ yweigh. LT Female Tipo ar wo wr Siew En Saihteboos rn ii1sbiiesmm oo8a1w poeax0 oo oie IS0ri3a0n3 oom oouossss am o7au5sm8t air 0G21o26s26 ous bjhYoen ken hhiisimmm ooms aassii0 ibis om o52s5s oooozmms 1002 o0oi5es oosats om 106 1053 00007 oiamn Sbelrnoeye Cleon nihbssiseem nism o5e3wm0s 2m ipsea 329 iS3e02 566 sseat0ss ams So2i0mr0 aon aa 01r554d:6 oom yira Senss ii[hhiigiImm STooowms Ihign oo aoaousnss aos aoo0ome ous 0oo10u3s0 ooownt ou os oaamozsn one oeme Te hiIhhiiissmmm oomeem oom a0i3o0 oie o0031s26s6 aa0s2ssi aasss Ooroans Tout ss260 sao 0260 ass as03 ass brotyeweight TS TOR SRE TRIO wh Dent 4 BT mABo So 208 : 000209 Perfivorooctanoic Acid: Toxicokinetics inthe Rat DuPon7473 Percent recovery of radioactivity at Trey: in tissues in male and female rats following oral gavage with 25 mg/kg "*C-PFOA Male a impo 5 Fo) won Er = riVhogoseeteatt mmha 708 me o$u304 Eon aSoiteo Sans oosons E500 osms 9 osuasis 7500 he om oor aos 00s oamz ojorm ihgs hnegn mmyh En ao0m3m67 nn oo oaassuian otorzamsee oasorzi3e0 ome Ir ao o0ol3ee0 o0z aarueissot ons jKiodkneeny Gia mnhe my waVimss 0287 mT1o0ss8s a1as0a6en7 o16ou7i9sr9 ai am oi 1oV0soosy 0210 aSaioms aos pColemens yess Mmbe me ooumse mh 0252 oauosst 020 pro02m07 aow0s oi oop tan ows oriesd aouzs oaoam aooo Sepndt immHah 0ix01mds pir assnas oiess pr0e506 aissmt emo TTEout AR TansB Saovs,SRSORaWIzoohs4%s, aT mnE cead0n0%T ,Sooo 3T w%nof bay weg Female aF -- -- whonltebo" a"o-- --o7z0s7 -- oGs0ns 0Taxt2e -- o6s7e0 oi-- uosr oTniss brYin rer aWw a o0u09s1 oz ao ows 0o02u30s696 afrmed oz 1020 0753 aaamx9s aoeimts ain oms oadeoos ee negn Sinneey aon o82n5 i pre] dS0o7n6 ise 1000363 oes 0Ea0n hd Gs 201 206 oSoos0 pSida aaisms 3193 1mcoamers peae ao 25oa5u00 o0os1u0ss8 oasae0r oeu0yn2 aaaomn a0ss ooss ous once oo a10210 aammo oeSwaewrss jet) aPoH aou0s o0u1i55 0021150 PH 0338 oss 032 0a2m5o1 036 oos m 0365 aoms om 030s ois ois ois ow ne a 010 eee ou RE VER son sem a0 ue ie Novi ST, OR Horde A aT,mas mas0%, bT one 32T %56of9 ey with. -Foro ETH . PesuomoacanAcsied: Tosicokineis intheRat Dupon2473 Concentration ue equiv/g) at Tou in tissues in male and female rats following oral gavage with 25 mg/kg '"C-PFOA .-Male pe mbye WO od doohnmm ohlom lJeeasns Toms aaim heat oohhmm ohm D2ew Xow MneEs or loohhdmom Ohm BgoIoEn be bMoee Glu lehme ohm Sdiws dame CFlemoens -- JM bm lve=w ohiom 0% wwowes one MONm0m ohm Baws SW Soe eR BP GM olomsee Gms msasnws mis amme mow eumm mas Toesaem loin sessdw sole eswme hes smooss wes t dseaasn C omemw ewans nso moeor ose Gi EMeEm Ww mSEsse Tex mdeasm TE 2Lams dl 6dMm ssa 1sw mow o1w0 lm mjoesws Isa moime ois 2oc4h 6d e15s2o% am sleeass wa 0236 390 pms dos maN m3 S 3131 m7a6o Sse m1am 104s 0bws 15 .-.Female ----w-- ------ Winn-- ot T hniismsmm Tt2eeesss _ a1Nsgem mloeesmsT 0maomwsse m1Lo0am%s 2481m4 orm hwaeant je hphiismm phism Stlee BER oswees Bieos awame aseasm moesss soesiss msaans oossss a1m0e9 o3s0s9 seorn bawee iihhiissmm hiehmm NWikTe wGlma mAommy ew essoee mew mmsuss mar imssies mam ome mam l0o) nwake GClemlensue grod MIMiimm INEM MER dispm sMaee somnos enns mmaemn wosee nsmeo nie 1nsesnh dan a248 2 howmess Jrmade MihIisRm IniSm eBeS 9% susmm ioe asemm sae ewsaes eu nless sew ems caw ess 2e0w8 o0aanm fy ow Ihism SWE - Te: -- 000231 Perfivorooctancie Acid: Tosicokinetics in the Rat `Dupont7473 Concentration (1g equiv/g) at Tau in tissues in male and female rats following oral gavage with 25 mg/kg "C-PFOA Male = Timepomt GTM adam aM Mean > spkroisnuate mmhh Wholeblood I71h 4720s8 30200 s6omn6 25.120 37462850 28758 23206014 2510 470140 26647 o03s0o2 34% brfaain bean mmhh mh o2s7e esa 021s75 341 02514696 sas [L83A8 70% 2052336 8192 00036940 1192 spnlegesn iver mVihn Mih uas seal 130341 $9199 1301080% $125 2B6a7n 4s8E 13006017 S474 01250354 5989 sGildnaecy e mPhh Glcomems 171h 2400300s5 0629 231.20066 0598 148165505 0507 126641498 0.466 139514563 oeso 20609%7 08s tthhyymrouisd ses mmihn mh 3o3m7e aes n39s2e0 3S5a 79 aa 3820 52821957 si 73747216 som 03436643 0663 smcursecnlaels bone. mmhh mh a29 on an a23s59s6 Sua9 a24s5l5 37259156 2639 3078 2662661 3.005 00527186 0341 a Female ee TT imepoimi aaSF asf 47k 448F Men SD skwihnoleblood a4nh brain an 6B2e2a c19o71s3 s18e60d5 m14391 o1l66d5s3 1.488 L437 2384 1095 1551 S2396% 04s? ihneart lungs aann an 85874183 27805040 l58a1s7s l6a00s8h 1681567A 36513 sell ae 38s me 03.564008 Se spvleeren Kidney aann Gh @8a5s29s e81s0a8 T89S7O7 17592243 T83U8L5 6040629 uma08 13498 141409 121609 14318 88S GGllucaocntens 44hh thyroid an 537053 ;s1e4m1 165662106 93380448 26 5265 1192647663 N70 24s leds des 1409 5319 tovyamriaess adrenals 4ahn n n2.a01e0 12a 2s7s8 108 1757660d dase 260720739 Nem 1780732 12419 0268)0 Lado mvuesrcale bone. a4nh J1o68n3o i6190758 2s72i8 2a0o00n2 2512S973 30865341 ah 6286 8955 7238 soa 6m 1631 - 180 ON NIVINOO -FT ne 000212