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Jaary 31,2002 % Co ; To Whom It May Concern:, Please find enclosed an updated copyofthe Telomer Research Program presentation `submitted to the A ow hidon became 15,2001 The CBI claim forteinformationonpags 3 and a6d3diesdwittophadgraewsn.37Tahneds6ep3atgoeclsacroinftyatihannttoheCpBrIoapnosdsehdotuilmedlbieneisnacrleudseudbjienctthteopcuhbalnigcer.eOctohredr.wTiesxet,htahsebseeen ee the previousivertsiaonn(tARn23o6-n10v4erinatnhs.puTbhleicnroenc.oCrdBI version of ts document mended 0 p`aadgdeistidono,naottydpiofgfrearpihniacnalyoetrrhoerrownaypafgreo3m1t,hreepdloaccuimnegntthsetwhoartdwe"rLievperro"viwidtehdtohneDweocredm"bKeird1n8e,y"20h0a1s.alIsno Pleas contact me iyouhaveanyquestionsregathrissdubimisnsiogn. 2 `Best regards, PutC.bk RobertC. Buck,Ph.D. PTeastsa Sr. Technology Consultant `Emil: robert buck @usa.dupontcom Wm 63020000012/0 T= =Z =33 = w kd hd | b2ooeco0 | Telomer Research Program Update and Status Report United States Environmental Protection Agency 18 December 2001 Ep JE Agenda =e Se "= + TRP General Update; TRP Meetings * Radio-label Update + Pharmacokinetics + Toxicology & Descriptive Biology * Environmental Fate & Effects + Summary Discussion and Path Forward -- Com tnt orm cn@OMpENY SANIIZES, fe skp , x TRP Review with US. EPA -- 21 Feb. 2001 + Toxicology Program Status & Timing + Environmental Fate & Effects Program, Protocols, & Timeline + Radiolabel Material Status, Timeline ime corr src b Telomer Research Program (TRP): 2001 Key Events ~ January9, 2001: Enviconmental Fat&e Effcts Research Team Mecing ~ Februar21y,2000: US. EPA = Ma9,r200c1:MhETI = March 20.22, 2001: TRP Msting, Osaka = April 19, 2001: Environment Canada ~ May 16.17, 2001+EnvironmentalFate & EffectsResearch Team Meeting ~ May 18,2001 + UK. Environment Agency ~ JuneSeptember 200: Subtsm meting snd Confrence Calls me e~ Oncto31beNorw. 2, 2001: com TRMeeting, Frankdurt tg etn . 5 2 TRP Osaka Meeting Highlights 20-22 March 2001 Updates on 8-2 Alcohol Starting Material and Quality + Radio-label Synthesis Strategic Plan and Path Forward + TRP Database Status * Review and Upgrades to Toxicology and Pharmacokinetics Plans * Review and Upgrades to EF&E Work Plans: Tier I, II, III + Communications Team Work Plan tamerom corp ssserra f TRP Frankfurt Meeting Highlights 31 October - 2 November 2001 + Toxicology Data Review and Subsequent Upgrades to Overall `Tox Plans; ReviewData to Date and Scheduling. + Radio-label Synthesis Review, Sourcing Plan, and Timing + Pharmacokinetics Plans due to Radio-label Schedule * Analytical Effort Overview and Challenges + EDaFt&aEtoTDiaetrIe aanndd ISIchWeodruklpilnagn Updates and Revisions; Review + Workplan for Compounds Beyond 8-2 Alcohol + TRP SponsorshipofOutside Research + Communication Srategy and Path Forward + Next Meeting(s): ConferenceCallsand In Person rietare comer a,nto . Kk 3 GBI has been redacted ee. Comeymtoe corn 1-C,F,,CH,CH,0H Analysis Profile + Purity > 99% by G.C. ~ 99.29% n-CyF,,CH,CH,0H ~ no other C,F,,,,CH,CH,0H species ~ 0.8% impurity BI has been redacted rometecearem cory tn, arton , . 4 n-C4F;CH,CH,OH Selection Criteria + SReelaadciyonChCarracetaeriIzneclduded: Simpl, Single, Pre, Representative, and + Most Common and Representative from EaofcMajho Producer--s Includes Both Type and Chain Length + T~elBoemeArb8o2oCAlrcaorhaoclierFiz(CSFoClFe)-CCoHmp,oCuHnydvOerHsu-sW3CasomChpoesePnroTdo Mitr ~ Eowen)tbhRelseaoch TeamtoSuc Netaotes nh PrarmacakiWnotrks ~ ~ nSatoheDeuTgreaadmayttioMonesPurre CoranacLorcyascitcoantlsPiesnrh EnDvaitoanmrial Fae Suds = EErnarbolnmheeTneaaFmatoeRSaudieosabe a Sng KeyCompoundfor he Todogyans a Comey rng.etc . n-CyF,,CH,CH,0H Selection Criteria CDoTumeseptton0guPhnradoCwooacmssplsheHentdOylay0nbVdieNaDolonevGiAaospredoaB nmd hVaaala Hietldeh.PvFBryooDoreo opcihoee0mnGisf ,caasnl3sS,SNnoumenroausarnd reretas ResorfCommon Vai ~The iMoirsAsiDtoyvtohAneRayszoowPorondTuoca,BoyaraSco,Rt apresa anaset nWdosAce tuae,Loos wDaeteF, crtoiodnut + PFraonduoctmsaronmth afrProduearsDoSveSome SartesButar or hes PoeryoktToACcPoolmspaDaronmvoyoukrspoondbOyftheCToAmPpRoeusnedas4c5hdTPeaumWsil oHfaTvhe aBroCahdoAcpapndiRcealfebovraUinsyte BI has been redacted rim rs coy rsttartcra 0 6 5 Radiolabeled 8-2 Telomer B Alcohol F(CF,), CF, -CH,CH,-OH Neca for Pharmacoksv 3 4s sommental Fate Studies Status + Synthetic Route Demonstrate&d Reproducible: can put "C "in" + Necessary Documentatio&n Samples being finalized + Parner identified to accomplish hot synthesis + Timingtocompletion: March 2002 ime ms en Comey rst a tc uw Synthetic Strategies for Radiolabeled Fluorotelomers CF FF OH CR FFN December 2001 -- eT u 7 6 General Synthetic Strategy SK N or wr ! FT Grete TT eRe aN RF Chon] TFEnot avaasisoulrceaofbradilolaebel ~ pracical sy no demos ns SHE sus + M=uset.usCeOr,ea(deix.lByaavCaOil,abNlaeCs,oucrcc.es of "C mpc ersteprecedent oxconversion of C=O noCF, ~ typical reagents: ESF, (DAST) (MOCH,CH,NSF, (DeoxoFlur) ramets ropm coreyStnoar on i CBI has boon redacted raereaamn. CoryStncart orn 2 u 7 CBI has ben redacted race temar eT G81 has been redacted recone Como Sr,oatont 9 " 8 CB hasbeenredacted Tice howe eg 7-- vl GB has been redacted tech eT 10 u| 9 CB hasbeanredacted -- ComprSn. oo Gon u) (CBIhasbeenredacted tions eg ComprSent,oa oC i | 10 (CBIhasbeenredacted tion ep CorrSit,oa corn a (CBI hasbeen redacted Tico how en ComprSt,oa Con 12 n n GB hasbeanredacted tone gn Corser Sms, ooCoin | CBI hasbeon redacted [---- Cons St,GoneCoin 13 a 12 Radiolabel Path Forward F(CF,),"CF, -CH,CH,-OH TT [[ACnoadytSctaanlMcaertehsods ||[[ mel || ([1143CMSattuedryiMaaltaserSitaaDnodiavredry||| |[|0[]7]| onan comer rt,grin TRP Toxicology Studies Repeated-Dose Pilot Study - Rats 8-2 Alcohol Oblate: To dentermnivnievtoesrecsopnocnesenruion for 0-Day fii sy 3) Aisinscady-si blood forin eels Brosedue Do2seTGeamrer Aoolfohuoils wpiths0,5*,25 or 125mg/daoyf 5A)) TMootnailtloroldsfucorionbseearnvaaltyisoinss,weweekliygths 0wck * 10male, females group -- comp et tn 14 13 TRP Toxicology Studies Repeated-Dose Pilot Study - Rats 8-2 Alcohol `Results - ClinicalObservations + 125 mg/kg/day = Males: stripedteeth (7/10),teethclipped (4/10) ~ Females: striped teeth (4/5) + NoEff :5e -25c mg/t kg/s day reemerenarpm. a TRP Toxicology Studies Repeated-Dose Pilot Study - Rats 8-2 Alcohol f-- ght Ga Dose Level (mgkglday) Males [Females 0 297 80 5 288 ne 25 275 11s 125 238% 110 -- *p<0.05 eT z| Is 14 ZlMean | Body Weight Gar for Males (Day 0 - 81) Eee] i i aa fw fer 00 0 ameter TTT TTYE TESSSR5EY omggroan TRP Toxicology Studies Repeated-Dose Pilot Study - Rats 8-2 Alcohol RW esulte s- Lii ver ghRat tios Dose Level Liver Weight (g) (mghkg/day) 0 5 25 125 ME 234 103 21 11 27 13 279 127 Liver/Body Weight 8/100g M E 39 32 37 32 al 34 55% 36+ ime m+ 005 Comp Sts.mcr ) 16 1s TRP Toxicology Studies | Repeated-Dose Pilot Study - Rats 8-2 Alcohol Results-KidneyWeight/ Ratios Dose Level Liver Weight (g) Kidney/Body Weight 2/100 (mghkg/day) M FE M E 0 45 22 0.76 0.70 5 43 24 0.76 0.71 25 4.1 24 075 0.73 125 44 27+ 0.87 0.78% etme +5005corp es nrc " Total Blood Fluorine Analysis in Male Rats .- Dosed with: Telomer 8-2 Alcohol _ ToTigimy,e oT or E 33.l Y J gs | a sprees |- `oo rear @ cmrw eeoarrswmenom we mw - 17 1 Total Blood Fluorine Analysis in Female Rats Dosed with Telomer 8-2 Alcohol = | -- I I ~sT--oameptrgrauaay ~issmotony Zo s o rE y--------t x oe 0 wm ow ow anterorn com sal osrtcone ey ww Repeated-Dose Pilot Study AnalysisofP(oPoFlOAe,d PPalraesnmtaCSoammppoluesndO,btnaidnetdoatt SfltueoardiyneStleavteels()test day 84) or f"eTmhaelleesv.elTohfe pfaorleontwidnetgepcltaedsmiadlenvoetlseoxfcePeFdO0A.0w74epepdmeitneccitteeidnrmmaalleessand femalesdosedwith 0,5, 25, and 125 mg/kg/dayof 8-2TelomesAlcohol PaReO | Dose comertad Forala| FPoFrOsAe PFOA |conver] Largan] gom| ogo|F ton | gam)| 0 om| fom 0 |oor| oss 00| oo 5 |e] 1s 00s| 00s 5 |e| sm 0s | oar vrsine roontemarorn. i[eoseW]ikioasToer Compa "mean ooesaots|Nvnz sas, Sorin ed u Sa 12 1 TRP Toxicology Studies Repeated-Dose Pilot Study - Rats 8-2 Alcohol 125 m++gP/Brklogod/ouddcaeFysuo8i-in2ncTlleelvfeoelmcertressAchlbecododhp yowleighds tafyis5t0a s-80 + Degreofresponsecompa with ads survival 5-25 mykgday Telomer Alcohol + + NBloocdlnfeolrmsiegnesvoer wreciagchhtesffpcatcsa day 40-560 + Nosignsofadverse response 90-D+ay1T0es5t-L2e5vel2sS(msukgpgiesdtaeyd) ruoctomaren. Comeysg.oat con 5 TRP Toxicology Studies Repeated-Dose Pilot Study Conclusions * Analysis limited tobloodonly - Significant male/female differences - Results confirm earlier studies results - Other metabolitaerse present & predominaitne females - There is a significant amount of fluorinated organic material eliminated or elsewhere + Validates need to conduct pharmacokinetic studies as planned with radiolabeled study material tim msen corSonoar orn x 19 18 TRP Toxicology and Descriptive Biology Studies: Timeline* += WorkContracted oPeakeohso [ [Zodwsomn TlTdoTddibdTdTdd"aiduaoel] [RangeFindingOm Togety TI T1111[|| to| re [ E|a T THTH EoT nc rTovhe sion || TI [1 |Joos] Fimtoniet [TTITTTT "isis. proposedtimelineoduc o chan. -- Gory sin nr on TRP Pharmacokinetics Studies: Timeline + = Work Contracted J -- [6-2 Alcohol pre [EER [imcsoma|rI [7/ADMEMassBalance | THT [|| |Fasko|l + Only HasLabkbiedonlentlirepackage andwil conductth work + Start ofstudies delayed 6+ month due 0radio-label synthesis rmeteamen TE ---- ul 0 19 TRP Pharmacokinetics Study Radiolabeled Fiuorotelomer Alcohol HC Label in per uoro-chan (C #3) F(CF,),"CF, -CH,CH,-OH oe es en GorySt oar oe TRP Pharmacokinetics Study * Toxicokinetics of Telomer 8-2 Alcohol in the Rat ~The objectivesofthis study are to determine the Absorption, Distribution, Metabolism and Excretion (ADME)of Telomer 8-2 Alcohol in male and female rats following oral and dermal dosing. ime rsem Gory Stn,oaron al TRP Pharmacokinetics Study `Toxicokinetics ofTelomer 8-2 Alcohol (TBA) in the Rat ``AOlbclohaotlei:n mDae aend fiheeaabnmssorpafteoiollnl,owediin saltiannddmemedhesianngd excroeftTeiloomenr 8.2 Met*hoCodnduct ics experimen ++= 2Radciohsbneed2dafnedcloltdsTBA usd sts materi! ++++DdDeeitteoerbrmmeiilnneeeedpxlTacsBemiAaoknsinndsmefshollielfaosolilngowlweiiinghnScggrlaedhoisgehorfTlBdAos of + ConductTisoortpesitomn eexpleriments ++++ S4imngllee laonwdanfdesimnaglleeisgh ora dose ++++ SSiinngglellloowwianntdavsienngoleusidgohsedealexposure (3s) race toca+r+erFnollowplasmaconCceonariyonSsoonts,omaertion " TRP Pharmacokinetics Study ToxicokineticsofTelomer 8-2 Alcohol (TBA) in the Rat (Continued) +DirbtioR n cperismee seTOmA wet er + Excr2sEoeCdvtmoeinbaoeoltsinuneacadmpberaeimremnsxoopfsnoostrl Tr nd Tra2e 2PepSro iteowrat nTimhAgoo hadoemsres ==2DiSailtgdeylocwoorsfoTieOngAhwseivsahr eedossbbinpg rtoslleTBdA Be+Qseusatie osndtGaoirnsoaA descriptionof odiriionofTBA =SDDCea eepari TooAmpnir eounTtcAlae oanc:neirgys sinTc OA e ndbeen en ses. ramet rom cory Stncarton a 22 21 TRP Pharmacokinetics Study * In Vitro Microsomal Metabolism Study ~ The objective ofthis study i to determine th rate of metabolism of atest compound in microsomes prepared from livers ofa numofbspeecires (vomally rat, rabbi, dog, moriey, and human) and to ide the metabolites produced in cach species. + Metabolismof Telomer 8-2 Alcohol by Mammalian Hepatocytes ~ The objective ofthis study to determine the atofmetabolism ofa est . compound in cultured ivr cell prepared rom a umberofspecies (normally ra, rabbi, dog, morikey, and human) and to iden the metabolites produced in cach specie. time msem eT o TRP Pharmacokinetics Study MetabolismofTelomer 8.2 Alcohol by Mammalian Microsomes `ieObanc: sDsekpemhedifonrsesveelmastaatoiasn.d bl rot enfin St++SaMasmpelearhassdey HrmPomLaeC,Aasbitp,doegmperandebadn *Dee=noRtevaccotodofsmssccdpioanponttea4u1endNwAnrDoPrr cdincte opm7c4,3s7r iyonei , ofoc,misions +=RDeesmcoinc:rRitouofcocommpeounodl st teri cocodt cost + Tinton mealby mies vid BeatLstieomfomifcmroes atmrotts of ostcompo bycchpisstd Einofevtmer Mfc iro adn cece tame msen com Sonoar orm of a3 2 TRP Pharmacokinetics Study Metabolismof Telomer 8-2 Alcohol by Mammalian Hepatocytes `Obcluesrieved: iTvoeeveallsafrtotmh eavteeosf mmeatmambaolliiasnmssnpedciid.eniistion ofmetbolic products in MethoPdrepare hepatocytes rom a, mouse, abit, monkey,dogandhan ++ NHegeaipvet(ohaicncdceyoamtnpdoepuosnstdiivnec(ubcatehd oa x7Cycfoo2hcursomnasriniclnde)d + Samples analyzebdy HPLC.MSfor etcompound metaolits Beat+s:Quaiiveandquanitativedescriptionofmcabolic sctiiy toward est materi + iDn seesvecnrspiofipemsetabioloisnm in mesbolcally "comple" sysem + Idndiyoftet material metabolites na ete cll system [-- eT TRP Pharmacokinetics Study Development of a Biologically-Based Kinetic Model: + Objective: ~ Quantitatively Relate Biologically-based Exposure to Internal Dose Using a Kinetic Model + Critical Information Requirements: ~ Partitioning in Biological Tissue Qualitative and Quantitative Aspects of Biotransformation ~ Mass Balance and Biodistribution ~ Uptake and Elimination Kinetics timc os en a 2H 2 TRP Toxicology Studies Developmental Toxicity - Rats Status: Initiate 3Q 20028-2 Alcohol + Pregnant rats + Dose days 6-19ofgestation + Doses from 90-day study (project 1<-->10, 10<-->50, 50<-- >125 mg/kg) + Matemal parameters ~ clinical signs, body weighs, liver weight + Fetal parameters ~ extemal weight, examination, internal skeletal examination organ examination, liver + Compare maternal/feta response tam osen eT " TRP Toxicology Studies Acute Toxicity - Rats Status: Completed 8-2 Alcohol Rat - Male and Female - Slsex/group -- RSeisnuglltesoral doseof 2,000 mg/kg (0.5% aqueous methylcellulose) + No mortality + No clinical signs including body weight * Lethal dose >2,000 mg/kg ---- en " 28 2 TRP Toxicology Studies 90-Day Toxicity Study - Rats 8-2 Alcohol AddittoiProotnocsol 1. Testlevels (4 instead of 3) 1, 5,25, and 125 mg/kg 2. Extendrecovery period - 90 days 3. Add measureofperoxisome proliferation - B-oxidation 4. Add thyroid weights, plasma and urinary [F] mechs en a ---- A TRP Toxicology Studies Genetic Toxicity 8-2 Alcohol Status: Draft Reports + Salmonella/EschecorliiAcshsiaay * TA 98, TA 100, TA 1535, TA 1537 WP2uvrA. * With/without S9 activation + To 5,000 pg/plate + Negative (draft report o issue 12/01) rece etsrm eT -- x ac 25 TRP Toxicology Studies Genetic Toxicity 8-2 Alcohol +10I,n5V0i0v,o R1a,t00i0,cr2o,n00u0clmeugs Susdinygledoseoralgavage ++ 660mmalaekreaic/ygcrloouppho(sepxhaammiidnee)pdos-ihtiavercvonetartso2lt4 and 48 hours + MicronDucoeccllllu2e0s0ka0st)aneimdal 24hn dibn c0ps 030140 00077 82"1A0l0c0ohol 500 00014s 000099 "2000 010 009 recone r+opCmoncl(uddrea:ft rNeoporitnCcarvoeaairsleiaybnlwemii1ct2r/o5n0u1c)laeratteod cnells 5 TRP Toxicology Studies Reproductive Toxicity - Rats Multigeneration Reproduction - 8-2 Alcohol Status: Pending Outcomeof 90-Day Study/Developmental Toxicity + Ra-t dosing levels/control - treat 70 days pre-mating. - 2nd generation from F1 offspring + Parameters - estrous cycling/sperm assessment -gfeesrttaitliitoyn/arlelparcotdautcitoinvael fpunecrtfioornmance - pup growth/survival/structural integrity enatetopm ~ PI/F1 pCaroemntparlSpatthnoloogyt(foocnuseon reproductive system) - 27 2% TRP Environmental Fate & Effects Studies + Physica-l Chemical Properties + Environmental Fate + Environmental Effects + Bioconcentration oe es en ConnSioa cor 5 Physical - Chemical Properties 1-CgF ;;CH,CH,OH + UV/Visible Absorption Spectrum + Vapor Pressure + Sorption + Water Solubility + Henry's Law Constant + LogK,, (Oc-WatterPaasilon) Tone ars Como tn.ocr " 28 7 UV-Visible Spectra : n-CyF,;CH,CH,OH |\ 1A \ ri vt "+Direct INondaebsrporhPbhoaonttclieycsiindsvei[sOigbFlreRlaaidgihdtcnaraolatnwtegoxeri,pke3oc5ut0nen-dd8e0r0anmy ese osaero N Pom TT] Vapor Pressure : n-CgF ;CH,CH,0H wl mm. mom 1] E | rr rr fe j= REESSEEEEEE Ee TR Re eee merooe2m2Teorrrnst 2vC cma Sen Temperature (C) o 29 28 Physical - Chemical Properties : Sorption n-C4F,,CH,CH,OH + rapid sorption fom saturated aqueous solution ~ glass, silanized glas, plastic, PTFE, sinless scl + evidenceoftime-dependent adsorption with decreasingabil 0 recover material from surface(s) + specific recovery methods had t be developed and validated = weeksforcach sample0 esc eqilrm withcontinous nays ~ $1020 samples replicated sablish method andanalysisconfidence + makes wate solubilios measurement much more complicatedand mass. balances dificult 0 achieve mts on a = Physical - Chemical Properties:Water Solubility n-CqF ,CH,CH,OH pH3,7,9;T=12,25,37,60C + see no differences in solubility versus pH + material is adsorbed 10 the container, not in the water, when excess material is no longerpresent ~ sorbed othecontainersurfaces 81 has been redacted rac roarson er A 30 29 Physical - Chemical Properties:Water Solubility n-CgF,,CH,CH,0H (CaFCH.CH:OH 0.13420.029 0.1=50 0.005 0.3218 0.176) [2 [owowe 7] bros Te|] + De-ionized water measurements comets pn eT 5 Physical - Chemical Properties: Henry's Law Constant -C4F,,CH,CH,0H + Computed from Water Solubility and Vapor Pressure + Non-linearity and Non-traditional behavior + Surface Tension Driving Behavior? + Measure utilizing Static Headspace Method time esen comeStn, artonan 31 30 Physical - Che1m-iCcyaFl,PCrHop,eCrHti,e0sH: Conclusions + Water Solubility varies with T but not pH and si the 100ofpb + dHiifgfhicluyltstooprievmeovoneto many surfaces and may remain highly sorbed nd + Preliminary VPdatado not extibit nomlies + Novisvl light absorbance + cThhaelsleenpgreospegrotiiensg pfroersweanrtdsiagnndifwiiclalnteqmueithodusdeeovfelroapdimoelnatbealnedd maantaelryisiasl for more studies than expected metorts pm eT " EnvironmentalFate & Effects Work Plan 1-CyF,CH,CH,0H PhysicalProperties ++ WUaVtIeVirsSioblluebiSlipteyctnm + AdsorpttoGiaosns + Ai-Wuatte Pation E+ HnydvroliysrisonFmatee:nAtbiaotlic + Adsorption; Desorption * + Indirect Phoolyss in Ar +EAnnaveriobricoBinodmeFgaerteadn:atBtiiooantlic + Acthobidc BdiodYegarardation rimctaarerm. Env+ iBriooncomnecnentiarlatEifofn eFcatctsor + 90DayEarly Life Stage Stud--y Rainbow Trout Comersg + n21rDayoInvercbrate Daphia Study 32 31 "TRP Environmental Fate & Effects Studies : Timeline* | EEE eR F =FateStudy ; =EffectsStudy EE ie 0 |gr pre fa p e marme ma , r m ----e pC+ mrTH t EH ELTT E I E a e Ems e e t nee e e [EfAcuteinvertebrateOaphoismagna |[RET m Smmee oe TH tere A A . TRP Path Forward Items + Toxicology & Descriptive Biology + Pharmacokinetics + Radiolabel + Environmental Fate + Environmental Effects + Mass Balance Effort cet AEE . 33 2 Discussion and Path Forward racetearm Comey mtottcrn 3 33