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sf CAORM2P2AN6Y-1SA0N4I4TIZED Telomer Research Program Update and Status Report United States Environmental Protection Agency 18 December 2001 2 8 on z 33 z 3 s 33 = rime tre Comyn rrr \ Agenda + TRP General Update; TRP Meetings Radio-label Update + Pharmacokinetics Toxicology & Descriptive Biology Environmental Fat&e Effects + Summary Discussion and Path Forward teetarpm comp rtsgto g 2 SR o ZZ a8 5 2 Company Sanitize.. i TRP Review with U.S. EPA -- 21 Feb. 2001 + Toxicology Program Status & Timing Environmental Fate & Effects Program, Protocols, & Timeline * Radiolabel Material Status, Timeline recat ge ComprSs ocr s Telomer Research Program (TRP) : 2001 Key Events ~ January 9, 2001 : Environmental Fate& Effects Research Team Meeting ~February21, 2001:US. EPA ~March 9, 2001 : METI ~ March 20.22, 2001:TRPMesting, Osaka ~ April 19, 2001: Environment Canada ~ May 16-17, 2001 : Environmental Fate & EffectsReseaTrecamh Meeting ~ May 18, 2001 : UK. Environment Agency ~ June-September 2001: Sub-team meeatndiConnfegrensce Calls ~ Octo31b-Neovr. 2, 2001: TRPMecting, Frankfurt ar cspoe Cononen.ow crn . 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 Upgradteos Toxicology and Pharmacokinetics Plans + Review and Upgradetso EF&E Work Plans: Tier I, I1 11 + Communications Team Work Plan metc en Comyn rrr 5 TRP Frankfurt Meeting Highlights 31 October - 2 November 2001 + TTooxxicPolalnosg;yRDeavtiaeRweDvaiteawtaoDnadtSeuabsnedquSecnhtedUuplgirnagdes to Overall + Radiorlabel Synthesis Review, Sourcing Plan, and Timing ++ APnhaalrymtaiccoaklinEefftoirctsOPvlearnvsideuweatnodRaCdhiaol-lleanbgeelsSchedule + EF&E TieIr and I WorkplanUpdatesand Revisions; Review + DWaotrakptloaDnatfeoraCnodmSpcohuednudlsinBgeyond 8-2 Alcohol + TRP SponsorshipofOutside Research ++ NCeoxmtmuMneistciantgi(osn):SCtroantfeegryeanncde Path Forward Calls and In Perso n [-- Comer rns.on tr . 3 G81 has boan redacted ToeRas en cornSin. ot oni CF;CH,CH,OH Analysis Profile Purity > 99% by G.C. ~ 99.29 n-CyF};,CH,CH,0H ~ 10 other C,Fa,.CH;CH,OH species ~ 0.8% impurity GBI has boen redacted TheKaason Conny in on econ ) \ 4 CF7CH,CH,OH Selection Criteria SeRleeacdtiliyonChCarriatecrtieariIznecdlude: Simple, Sil, Puro, Reprosentative, and + Most Common and Representative from Each of Major Producers Includes Both Type and Chain Length + Talomer 8.2 Alcohol - F(GF,GF,) CH,CH,OH - Was Chosen To ~~EnBaobAlbelethteo RCahsaaraacrtcahrTiezaaemStiogSltouCdoymMpeoaubnodlvterssuns haeCPohmaprlmeacPorokdiunctasMWoourrka ~S(uxodue)heDegradationProductsandLocations i he EnvicrmentlFat Stes ~~EnaabblleatnhoaTTeeaammtooRMaecaisoulraesGe raSalPhysKicyalCPormoppeorutynDdaftoar Toxicologyand Enronmental aio Studs rao tna open a-- o CF7CH,CH,OH Selection Criteria + DTeuseitnogP1r0oCtoomcopslHeaxdiat0nbydeNDoenv-eClloapsesdiaBnedVhaladaovtfedh.eBPyioDreevcihno,miaSisnNugmarous CInotmrppotuantdiowaRsesthuelOtonsflCoVimambloenAVlaeimaie hat Hed Prospects fo GainSgniantand + TLhiosAbDirtovleoAhnealRyezseeaPrrcohcuTcesa,rByo-aPrSodiucntso,ReMperloasboonlteast,veanMdolAcaulno,LNoowtDaePcotcounct Mire + PPanrDioferrdeonmuihcetMajsor ProducersDoShareSome SiresButar fotheMost + EPryotToAcPolMseDmebveerlsopoendbGyhtehreCToAnPpoRtesredasracnhdToPraomducitlsHoafTvheeBrrCoardoAcpepacnadbRietlyevfoarnUtsloe arCompany 81 has been redacted recto rm corySei,oert on w 5 Radiolabeled 8-2 Telomer B Alcohol F(CF,);"CF, -CH,CH,-OH Needed for Pharmacokinetics & Environmental Fate Studies Status + Synthetic Route Demonsraed & Reproducible can put 4C "in" + Necessary Documentation & Samples being finalized + Partner identified accomhpotlsynithseshis + Timing to completion: March 2002 race esrm corySem,ort on u Synthetic Strategies for Radiolabeled Fluorotelomers FFoF n orcFFi December 2001 Tmt en com Sr.oton | 6 General Synthetic Strategy CRF F a FF 7 } ~~ k oreo F~Eprmaotcaasyvnbesais3sniostodureacmeoobfnrsaldtirSolHaeaEbtieelsdo:s + Mu=st5u.s.eCrOe,ad(eixlyBa1vCaiOla,blNeACHs,otuc.rocfe"sC =~ aympplce Hreiagerntas: pEreNceSde,ns(foDxcAoSnv)er(sMioenOoCfHG,=C0HnNoSFCF,;(DeosoFlort) tame es en Cory stnoar onan u CBIhasbeen redacted em a en comer onsston w 7 CB hasbeenredacted resents ope Cornts,oa crn i (CBIhasbeenredacted recor pn Compan rt,oe crn w 8 (CBI hasbeenredacted recontaarepe coment,oa crn " GBIhasbeanredacted -- Pr u) 9 (08 has boon redacted rasantora mgm ComprSs.oa corn w C8 has boon redacted -- coment, owes ona | 10 CB hasbean redacted econ ge companySng. cnc a GB hasbeanredacted -- Gomer rs, eeeGren 2 n (CBIhasboonrodacted Thomo ee a n [-- -- a ---- a 12 Radiolabel Path Forward F(CF,);"CF,-CH,CH,-OH peoyy TT [T SCoatanser[r isoys ml ||| [(1w143CCaMSattoetorialeasSrtanadarid |D| o|i| v[eSri[f7y]|] -- compar portman x TRP Toxicology Studies Repeated-Dose Pilot Study - Rats 8-2 Alcohol Objective: To deABt))erAmIintnaveiinvteosstrteecasodpnyoc-nessntetartaetbiloonofdorl9o0-iDnaylteovxeilcsity study Procedure: D8.o2seTeGlroomueprsAloofrbaotls with 0, 5, 25 or 125 mg/kg/day of BA)) TMootnailtbolrocoldinuicralionbesearnvaaltyisoinss,weweekilgyh as week 10males, emlegsro/up rtm tomtom omer rs gurrcnan u 13 TRP Toxicology Studies Repeated-Dose Pilot Study - Rats 8-2 Alcohol Results- ClinicalObservations + 1~25Mamlges/:kgs/rdpaeyd teeth (7/10, tecth clipped (4110) ~ Females:stripedteeth(415) + No Effect:s 5 - 25 mg/kg/day Tm csen corrSn.ont core TRP Toxicology Studies Repeated-Dose Pilot Study - Rats 8-2 Alcohol `R-eBosdy WueilghttGaisns Dose Level (me/kglday) Males Eemales 0 297 80 5 288 119 25 275 1s 125 238% 110 mbes en *p<0.05 cornytr,cartconn n 14 Mean Body Weight for Males (Day 0 - 81) - OmeGogh wo -- wo GNm Boh eG V3nna aGeV8ove ey !HE / 200| - = - PEE LLL TRP Toxicology Studies Repeated-Dose Pilot Study - Rats 8-2 Alcohol RW esulte s-Lii ver gh/Rat tios Dose Level (mgkg/day) 0 5 25 125 Liver Weight (g) M _E 234 103 201 11 227 13 279 127 Liver/Body Weight 8/1008 M E 39 32 37 32 4.1 34 55% 36+ eres m+ 00S CoronSram.secon ) 1s TRP Toxicology Studies Repeated-Dose Pilot Study - Rats 8-2 Alcohol Results-KidneyWeight / Ratios Dose Level (mekglday) 0 5 25 125 Liver Weight (g) ME 45 22 43 24 4.1 24 44 27+ Liver/Body Weight 2/100g ME 076 070 0.76 071 0.75 0.73 087 0.78% mete # P05 Caronrms.seen Total Blood Fluorine Analysis in Male Rats Dosed with Telomer 8-2 Alcohol " = 0: -- rTiartoan =TSinineer, i= fo [a | . et, | ` 20 time msen "0 ConnJ.Dayosm100 120 conan 140 160 180 x 16 Total Blood Fluorine Analysis in Female Rats Dosed with Telomer 8-2 Alcohol =r ee _-- 1 sasiinaen sor licen i 2 Sof 1-- oer atoerm 6[oaw wm -- ow om . ww Repeated-Dose Pilot Study Analysis of(PPoFoOlAe,d PPalraesnmtaCSoammppoleusndO,btaanidnetdotaatl fSltueoardiyneStlaevteels()test day 84) Thelevel ofparentdetecteddid notexceed 0.074ppminthe males or femfaelmeasl.esTdhoesefdowliltohwin0g,p5l,a2s5,maanldeve1l2s5omfg/PkFgO/Adwayeorfed8e2teTcetleodmienrmAallceoshaonld ParOeA Fama| FPorrona converted PFOA |comverod ghgiday) | pom) |to pom F | (px pom) |10 ppm | F (ppm) 007| oos | we | 00 | oo | ww 219| 1st | wa | ooe| oos | wm sar | sm | an [ose| oa | ses trod isnsgoW]ikhladsTsoerch|measnaozfe |spvaetse|a 1N2-1mt|esssrm d. rene tt ro cory rs,Saton Ml 17 TRP Toxicology Studies Repeated-Dose Pilot Study - Rats 8-2 Alcohol 125 mgkg/day 8-2 Telomer Alcohol + Producesclinicaleffects /body weight effets ++ BDloeodgFolfurorreisenpeoneesveecormepaacthiebdlpe witah ddatoySg0ss<-s>yur8v0ival 5-25+ mNgokcgl/ndiacyl TseliomogerrwAneilgcshothfoflcts + Blood fluorineeve reachespaca day 40<->60 + Nosignsofadverse respons 90-D+ay1T-es5t 2Le5vel1s25(mgpeksgtieady) ime es gn Conor tin Sn conan | TRP Toxicology Studies Repeated-Dose Pilot Study Conclusions + Analysis limited to bloodonly - Significant male/female differences - Results confirm earlier studies results - Other metabolites are presen&t predominate in females - There is a significant amountoffluorinated organic material eliminated or elsewhere + Validatesneedto conduct pharmacokinetic studies as planned with radiolabeled study material teesteam comorySrss. oascoran x 18 TRP Toxicology and Descriptive Biology Studies: Timeline G81 has boan rdacted remtonsrm eT-- ) TRP Pharmacokinetics Studies: Timeline + = Work Contracted ho2 Rsecehers ee [[A|DE sswseanacs J -- | ||decd dEeRcEaE"wTeTe"E| + Only Haskell Lab bid on entire package and will conduct the work + Startofstudies delayed 6+ months due to radio-label synthesis 19 TRP Pharmacokinetics Study Radiolabeled Fluorotslomer Alcohol 14C Label in perfluoro-chain (C #3) F(CF,),"CF, -CH,CH,-OH riontosrarmem. CornySin carton TRP Pharmacokinetics Study Toxicokinetics of Telomer 8-2 Alcohol in the Rat ~The objectives ofthis study are to determine the Absorption, Distribution, Metabolism and Excretion (ADME)ofTelomer 8-2 Alcohol in male and female rats following oral and dermal dosing. rime tsoe coro ctori " 20 TRP Pharmacokinetics Study Toxicokinetics ofTelomer 8-2 Alcohol (TBA) in the Rat O`Abljceochtoilvei:n mDaeltenrmdinee ltheeabrsoarspftoilolno,wdiinsgtrribsutsinond,dmerematl daoibanngodlexcirestimonofTelomer 8-2 Met*hoCdo:nd+u+ctRiadcitoleaxbpeelreidmnendtsold TBA usstemstesrisl +++ 2Demtaelremisnned2plafsemmaalkeinrcuttises followsiinnglge high oraldos ofTBA ++ D dobbee edexTcrOm eAtionani dmetbn olisn ollowaisinngge igh orl dose of + Con+d+oTsBbAortpesitomnateexrpiearliments +=+= 4Singlmealnowdaa4nfdlesimngaleeleisgh orldose ++++ SSiinnggllee lloowwainnadvsienngoleushdiogshedealexpose (8 hs) ++ Follow plasma concenrations ots terial TRP Pharmacokinetics Study Toxicokinetics ofTelom8e-r2 Alcohol (TBA) intheRat (Continued) re --R m-- aenadTeoAest cil *Excep5tC E meo otu lrenxddpt sen ationxfpootsseal Tnsnd Tour ++ a SaigenidTehoes gmnhiloromdorwest +2=DSHuelnytdeogxenficdTBirgeArhideelrmttnodidmdwvoesningrotlsbeled TBA BeQsiueaetimic pndoquotafnTteao decripionof disrbionof TBA ++ DSDceecnrrkiipiisnhTfoBaAfrrpmeeianbTcoOalAnmacevrdesnaoifTicosAncernssdbw ses ------ come ras.gtco " 21 TRP Pharmacokinetics Study * In Vitro Microsomal Metabolism Study ~The objective ofthis study i todettehernteomfmietabnoliesm ofa test compounidnmicrosomesprepared from liversofa umberofspecies m(entoarbmoalliltyersap,roradbubcite,didongc,amchospencsak,ndehuyma,n) and to identify the * MetabolismofTelomer 8-2 Alcohol by Mammalian Hepatocytes . ~Tchoemopbojuencdtiivnecoufltthuirsedsltivdeyr cieloldeprteeparrmedintfhreomraatemoufmmbeetrabofolsipsecmieosf atest (rormally a, rabbi, dog, monkey, and huanmd 0aidenntify)the metabolites produced in each species. iene wim cornSnins.Storin " TRP Pharmacokinetics Study `MetabolismofTelomer 8-2 Alcohol by Mammalian Microsomes belte:rDoemsipnehee dreFofossevse]eslme bolirosn bol prods esis MaersoneSsumpsrereeprHrPmLsC,NSts,dog, okey ndhan DemiRncetocenyom ofemscti doppnetoseo tsadeuAeEis nrentdrcpoi Hcae74nn.i3yos 7neCn, colors, mcrsons, +=+DReamcaonrsaKeedeotofccoomampls econ rin oncnmion nd contin + Tiecoe mebyi mornes lsd BeRsdtceofoifmcroesaltmrcbaoltisfscompoundby xhspecies sed tes ft nt lf iro atc cha rime rsrn comesrt. arto " 22 TRP Pharmacokinetics Study Metabolismof Telomer 8-2 Alcohol by Mammalian Hepatocytes Objceocltuivree:d iTvoerecvaelluafteotmherseavteeor]fmmaemtmabaolliiasnm sapnecdieisd.entificationofmetabolic products in Metho+d:Prepare hepatocytes fom rt, mous, rabbit, monkey, dog and human + + NHeegpaattiovceyt(esvaned hcsoimdpcopuolsntdeivi)encu(bcahteodxsycc3o7uCmafiorn2 orsnl inclded + Samplesalyzed by HPLC.MS forest compound snd metabolites: Reus+ :Qualmiveandquantiativedescription ofmetal scvity toward st material +Deisncsriepvtieonsopefcimeestabli inametbalically"complete" ssi + Ideiyof estmateria metabolic in whole cll syste LL. comer sms orc us TRP Pharmacokinetics Study Development of a Biologically-Based Kinetic Model: + Objective: ~ Quantitatively Relate Exposutroe Internal Dose Usinag Biologically-based Kinetic Model + Critical Information Requirements: ~ Partitioning in Biological Tissue ~ Qualitative and Quantitative Aspects of Biotransformation ~ Mass Balance and Biodistribution ~ Uptake and Elimination Kinetics taste ropm com ets.otcon 23 TRP Toxicology Studies Developmental Toxicity - Rats 8-2 Alcohol Status: Initiate 3Q 2002 + Pregnant rats Dosedays 6-19ofgestation >+ 1D2o5smegs/fkrgo)m 90-day study (project 1<->10, 10<-->50, 50<-- + Maternal parameters ~ clinical signs, body weights, iver weight + Fetal parameters --external examination, internal organ examination, iver weight, skeletal examination + Compare maternal/fetal response receos pe com Svo,aton rl TRP Toxicology Studies Acute Toxicity - Rats 8-2 Alcohol Status: Completed Rat - Male and Female - Slsex/group -- RSeisnuglltesoral dose of 2,000 mg/kg (0.5% aqueous methylcellulose) + No mortality + No clinical signs including body weight + Lethal dose >2,000 mg/kg Toba ren Coney nn.ccna al 2 TRP Toxicology Studies 90-Day Toxicity Study - Rats 8-2 Alcohol AddittoiProotnocsol 1. Test levels (4 instead of3) 1,5,25,and 125 mg/kg 2. Extend recovery period - 90 days 3. Add measureofperoxisome proliferation - B-oxidation 4. Add thyroid weights, plasma and urinary [F] rime rtee a " TRP Toxicology Studies Genetic Toxicity 8-2 Alcohol Status: Draft Reports + Salmonella/Eschceorlii Acshsiaay + TA 98, TA 100, TA 1535, TA 1537 WP2uvrA + With/without $9 activation + To 5,000 pglplate + Negative (draft report to issue 12/01) time rs en a 5 25 TRP Toxicology Studies Genetic Toxicity 8-2 Alcohol *+ I0n,5Vi0v0o, R1a,t00M0i,c2r.o0n0u0clmeuks Stsuidnygle dos ora gavage ++ 660mamlyfekrgcaytcglroopuhpo(sepxhaammiindede5p)os-thiavrevecsotraal24and 48 hours + Micronacleatedcells2000/animal 0 Dose(mg/kg) c8p2.6A0lcohol 500 "21000000 2040h4rs4080h7es 030140 007089 001105 000099 ime cs+eCeonclu(ddrea:ft rNeoporitnSacvroaeiraloaisbenlSemi1oc2r/io5n0u1rc)leeastedncells 5 TRP Toxicology Studies Reproductive Toxicity - Rats Multigeneration Reproduction - 8-2 Alcohol Status: Pending Outcome of 90-Day Study/Developmental Toxicity Rat -dtorseaitn7g0ldeaveylss/pcroen-tmroalting - 2nd generation from FI offspring + Parameters - estrous cycling/sperm assessment -fertility/reproductive function - gestational/lactational performance - pup growth/survival/structural integrity ke es pn - PL/FI [parientmal pathology (focus on reproductive system) a 2 ! TRP Environmental Fate & Effects Studies + Phy-ChsemiicalcProapertlies Environmental Fate + Environmental Effects + Bioconcentration rece ws gn Corry ang.onc 5) Physical - Chemical Properties 1-C4Fy,CH,CH,OH + UV/Visible Absorption Spectrum + VaporPressure Sorption + WaterSolubility + HenLarwCyon'stasnt + LogKy, (OcWatterParioln) racer rg companys oa crn 27 2 UV-Visible Spectra : n-CqF ;;CH,CH,OH |\A | oN ND oSori an e debglenls g raontgee ,re3n9e0d00 -- + ep IndirectPhotolysis [OHRadical) workunderway . Vapor Pressure:n-CyF;;CH,CH,OH wl mem me 1] Ero BZZ=SEEce omrmoernaare [Gornn d u 28 Physical - Chemical Properties : Sorption 1-CyF ;CH,CH,OH + rapid sorption from sanrated aqueous solution ~ plas silanized gas, plastic, PTFE, sinless scel evidenceoftime-dependentadsorption ith decreasing ability 0 recover materrioam suface(s) + specific recovery methods had tobe developed and validated = weeks foreach sample oresch quilbri with continuous analysis ~ $1020 samples epee to eblih method nd analysis confidence + makeswate solubility measurement much more complicanadtmeasds balancesdificult 10 achieve ome tt pom Comey ons.mtn 5) Physical - Chemical Properties : Water Solubility 1-CyF ;CH,CH,OH + pH3,7,9;T=12,25,37,60C see no differences in solubility versus pH + material is adsorbed to the container, not in the water, when excess material is no longer present ~ sorbed to the container surfces CBI has boon redacted itai comer ms.gmton 5 2 29 Physical - ChemCicaFl P,r;oCpeHr,tCieHs,O: HWater Solubilty Solubility 7m (ppm) [w | sc [e ac[wc (CoPvCH.CHOH_|0.134 0020 0.1505 0005031850.176|__| pero Towoww[1] + De-ionized water measurements metas cor ngpo tc Physical - Chemicanl-PCrgopFe;rCtiHe,sC:HH,eOnHry's Law Constant + Computed from Water Solubility and Vapor Pressure + Nonlinearity and Non-traditional behavior + Surface Tension Driving Behavior? + Measure utilizing Static Headspace Method romctmmarre [ry ---- wl 30 Physical - Che1m-iCcyaFl;CPrHo,peCrHti,eOs:H Conclusions + WaterSolubilityvaries witTh but ot pif andi inthe 100's ofppb + Highly sorpive onto many surandfmayaremcainehigshlysorbedand difficult o remove + PrelimViPndaatardyonot exhibit anomalies + Novisbl lightsbsorbance + These propetespresentagaicaamethod develoanpdmanealnystis challenges going forward and will equi use of radiolabeled material for more studies than expected rinetmarem Comey rt oe crn a Environmental Fate & Effects Work Plan n-CyF,CH,CH,0H Ph+ysUiVcIVailsPirbloepeSrpteictersum ++ AWdastoerrpStoilounbtiolGiltyas + Air-Water Parton Coefficient E+ HnydvroliysrisonFmatee;nAtbiaotlic + Adsorption Desorption * + Indirect PhotolyinsAiisr +EAnnaevroibricoBinodmFegaretaedn;atBtiiooant*ilc. + Actobic Biodegradation A Redubtetot ars enetwarom Env+ iBriooncmonesnetnatlaEifofneFcatcsor +90 Day Ealy Life Stage Study Rainbow Trout Comeyaigp2t1 Dcaoy Ioverebrate Daphnia Study " 31 "TRP Environmental Fate & Effects Studies : Timeline BI has been redacted ome tts og Comper rn ort o TRP Path Forward Items Toxicology & Descriptive Biology + Pharmacokinetics + Radiolabel * Environmental Fate * Environmental Effects + Mass Balance Effort rims ts comer rstportman " 32 Discussion and Path Forward [------ Comyn oeetre 33