Document 2BKvvqEMKRwxjrrdxN3x7m67

.. 3M StLaafrfryViRc.eZParbeels,enMtD, MPH and Medica Director 3M Medical Department AR226-0002 P3OMBCeonxte3r3,2B2u0ilding 220-2502 S6t5.1P7a3u3l 5M1N815O5f1f3i3c-e3220 April 20, 2000 Dr. Oscar Hemandez U40S1 EMPASt/rOeePtP, TS/WCCD (7405) Room E615B Washington, DC 20460 PCeeCET 0 Miho Dear Dr. Hernandez. sLtaumdyworintpiongtatsosciluamripfeyrifnlufoorromoacttiaonnescuolnftoanianteed. inAthreeptowrot-ogfetnheirsatsitoundyrewparsodsuucbtmiiotnted oThnaFtenbortuiacreyh1a5d, b2e0e0n0faislead smuipdpwlaeymetnhtrotuogthhethTeSsCtuAdySewchteionnw8e(eb)eNcoatmiceeaowfar9/e14o/f98F.I sptuupdymowrataslictoyndatucttheedhiwgihtehstpetrwfloudoorsooecstiannetshuelsftoundayte(1g.i6veanndby3.o2ramlg/gkagv/adg).e atThfeour daonsdes3,.20.m1g,/0k4g,/d1a.y6 daonsde3g.r2omugp/sk,go/dn.ly tFhoell0o.1wianngdt0h.e4pmugp/kmogr/tdaalyitdyosseeesngirnotuhpes 1w.e6re continued into the second generation. Lmga/nkggu/adgaeyidnotshee grreopuopr.t iTnhdiiscaitsendotthtahteFc2aspe.upAvtiatbaiclhietyd wisasanaaffmeecntdededinrtehpeor0t.4from the laboratory performing language clearly states the study, that there Pwreirmeedniocat,oxAircogluosgiDciavlilsyioinm.porTthaentamefefnedctesdon pup sEu2r0vifvoarl yoorugrrroewfterhenactet.heIht isghhoeswtsdnoosasiggenitfeisctaendt0d.i4ffmegr/ekngc/edsayb.etw1 eheanvethaettvaehcihceldetable control and 0.5 g+r/-ou0p.9)a,ndputphevi0a.b4ilmigt/yk(e9/7.d1ay%doasned g9r6o.u2p%)foorrnnuummbbeerrooffstpiulplbsorsnur(v0i.v3i+/n-g 0.6 per litter, preculling, on day 4 (13.7 +- 3.3 and 13.8 +/-2.4). RDra.yMmaornvd CYaosrek,oDfiPrercitmoerdoifcTaoxAircgoulsopgryepaatr3edMaapnadpeDrr.fMorilpdurbelidcCahtrioinsttihaantarnefdleDcrt.s tfhoirsmienrtleyrporfetEatPioAn.an`dThnisowpaapecronissuslttilalntunidneTroixnitceorlnaolgyr,evhiaesw.alsDor.reJvoihenwe(Jdactkhe) fMuollore, report and agrees with this interpretation. Iwirlelqnuoetset tthhaatt ythoeusttrueadtytrheepoartttascuhbemditrtepeodrtasafsoslulpoewrcuepdtiongthtehe8eahralideronrlepyorstu,mmYaoruy data tables. summary. The enclosed report includes allofthe data tables, individual as well as 000002 ee Dr. Oscar Hemandez April 20, 2000 Page2 Also enclosed is an analytic report that gives the perfluorooctanesulfonate concentrations in liver and serum samples collected from selected animals in the two-generation reproduction study. The serum and liver analytical data included in the report offer a limited understanding, becauseofthe timing and limited number of samples,of the pharmacokinetics ofperfluorooctanesulfonate. Two additional studies have been undertaken to develop an understandingof the dispositionofperfluorooctanesulfonate during gestation and lactation. In the first of these studies, potassium perfluorooctanesulfonate was administered by gavage up to the point of mating, and disposition of the body burden in dams to pups was followed during gestation. In the second study, dosing continued through gestation and lactation, and disposition was followed through lactation. The in-ife aspects of these studies are complete, and reports are enclosed. Protocols for the analytical work associated with these two studies is enclosed. Final analytical reports should be available within three months. A complete cross fostering study was also done. This study was done with only two groups, a control and a group dosed at 1.6 mg/kg/day. This dose level had minimal effect on the dams but produced neonatal mortality in the original two. generation study. The cross-fostering study shows that neonatal pup mortality is rceolnattreidbuttoioenxptoostuhreeomofrptualpistyinfrutoemrtohdeutrrienagtegdesdtaatmisoinf, paultphsowueghrethaelrseoaepxppeoasresdtoinbe a utero. A copyofthe final report is enclosed. Tsewroumanpceirlfllauryorroeopcotratnsaesruelafsosnoactiealteevdelwsiitnh dtahemscraonssd-fpousptserwiengrestmuodyn.itoIrnetdheatfrlsatc,tation d`caaynsbe14exapnods2e1d ovria22m.ilkT.hisLirtetperosrtwidtehmoenxsptorsautreesitnhauttepruopsanadrevieaxpmoislekdfirnomutterreoataendd foors2t2ero-fdalamcstahtaiovne. seLirtutmervsawlhuiecshapwperroexibmoartnionfgunftorsteeart-eddadmasmcsrubmutvacrlousess-ofonstdearyesd2t1o ttrheeaetenddodfamlsacthaativoen.serLiutmtecrosnbcoenrtnroafttiroenastreodudgahlmys obnuet-tchriorsds-offosftoesrteedr-todaumntvraelauteesd at dams have serum valuesofapproximatelyhalf lactation. The untreated foster dams are found their birth to acquire dams at the single-digit end of ppm levels of perfluorooctanesulfonate and feces. in their serum, presumably from exposure to pup urine 000003 Dr. Oscar Hemandez April 20, 2000 Page3 Tmihcersoesccoonpdy acnocnidlulacrtyedreopnortlutnogtahnedcrloisvse-rfiosssteureinogfsptuupdsycruelllaetdesshtooretlleyctafrtoenr birth pLuulnmgotniasrsyueswurafsacetxaantmipnroedducftoiropno.ssTibhleereefwfeacstsnoofdpiefrffelruenocreoobcettawneeseunlfcoonnattreoloannd exposed pups with regard to lung `Type I pneumocytes. Surfactant architecture and the presence production appeared normal. of lamellar Since bodies in pwearsfleuxoarmoiocnteadnefsourltfhoenaptreesceanucseesofppeerrooxxiissoommeesp.rolPifueprsateixonpoisnerdodienntust,erloivweerrteisfsoueund to have a enclosed two to three fold increase in peroxisomes. Copiesofboth reports are Adencraedadsietsioinnalchfoollelstoewr-oulpasttbuidrythisabseainmgecplhaannniesdmtfooerxrpeldourceetdhepupposvsiiabbilleitryo.le Iotfhas abceteinvistyhoprwinor(tLoevbiinrthet.foall.l, o1w9e8d9b)ythaatperraitopduopfs muuncdehrgroedaucbeudrsstoynfthsetseirsoifdolslyonwtihnegs.is birth CoA (perhaps due to the presenceofexogenous cholesterol during lactation). reductase and HMG CoA synthase mRNAs are highest during late fetal HMG life and undergo showed that a precipitous reduction immediately fluvastatin, an HMG CoA reductase after parturition. Harb et. al inhibitor marketed as Lescol for mhoyrptearlcihtyo.lesTthereolmoermtiaal,iitfyawdmaisnipsrteveernetdepdriboyrctoo-aadnmdindiusrtirnagtigeosntoaftimoenv,aclaounsaetse,netohneatal productofthe reaction catalyzed Perfluorooctanesulfonate reduces by HMG CoA reductase. serum cholesterol in laboratory animals and is r1e99p2o)r.tedOtuorrpeldauncneedacstitvuidtyy woofuHlMdGtestCothAe rheydpuoctthaesseis(tHhaatugthheomneaonnadtaSlpymdoervtoalldit,y ostbusdeyrviesdduine tthoethhiegrhedduocsteiognroiunpcshoolfesttheertowlos-ygnetnheersaitsidonuepetrofrleudourcooecdtHanMesGulfCoonaAte reductase activity. This would be the fluvastatin study. We will also done by attempt attempting rescue with mevalonate cholesterol. rescue, similar to `wTowuoldadbdeittioonmaolroebjpercetciivseeslyardeefbienienga NdeOsEigLneadndintLoOtEheLpfloarnnpeudp smtourdtya.litTyhebyfitresstting doses between 0.4 and 1.6 mg/kg/day. pharmacokinetic data. The second is to obtain additional 000004 Dr. Oscar Hernandez April 20, 2000 Human infants do not undergo a similar precipitous drop in cholesterol synthesis at birth (Levin et. al., 1989). Establishing reduced cholesterol synthesis as a mechanism of action would have significant implications when assessing risk associated with the findings in the two-generation study. The planned study is and expected completion date with you when they are available. `We are looking forward to discussions between our scientists and agency scientists about the information we have submitted and continue to submit on perfluorooctanesulfonate. Sincerely, o2 n MDS Larry R. Zobel, MD MPH StaffVice President & Medical Director c: Dr. Charles Auer, Director Chemical Control Division (no attachments) References: Harb, R.V., Hartman, H.A., and Cox, R.H. (1994), Preventionoffluvastatin induced toxicity, mortality, and cardiac myopathy in pregnant rats by mevalonic acid supplementation. Teratology, 50, 19-26 Haughom, B. and Spydevold, O. (1992), The mechanism underlying the hyperlipemic effectofperfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOS) and clofibric acid. Biochimica etBiophysica Acta, 1128, 65-72. Levin, M.S,, Pitt, AJA, Schwartz, A L., Edwards, P.A. and Gordon, J.1. (1989), Developmental changes in the expressionofgenes involved in cholesterol biosynthesis and lipid transport in human and rat fetal and neonatal livers. Biochimica et Biophysica Acta, 1003, 293-300. 000005 Eb To TSCA SeconbnT [AO cess ub ssacmenss ( froube J wT F Ha-0yso= 0333) Protocol 418-008 Combined oral (gavage) fertility, developmental and . perinatal/postnatal reproduction toxicity studyof PFOS in rats (Sponsors study number: 6295.9), Table E20, 1-3. Hianrdbu,ceRd.Vto,x,icHiatry,tmmaonr,talHiAty,, aanndd cCaorxd,iaRcHm.yo(p1a9t9h4y),iPnrperveegnntainotnorfafslubvyasmteavtailnonic acid supplementation. Teratology, 50, 19-26 Haughom, B. and Spydevold, O. (1992), The mechanism underlying the hyperlipemic effectofperfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOS) and clofibric acid. Biochimica et Biophysica Acta, 1128, 65-72. Levin, M.S., Pitt, AJA, Schwartz, A L., Edwards, P.A. and Gordon, J.I. (1989), Developmental changes in the expressionofgenes involved in cholesterol biosynthesis and lipid transport in human and rat fetal and neonatal livers. Biochimica et Biophysica Acta, 1003, 293-300. Final Report Protocol 418-013 Oral (Gavage) Pharmacokinetic Studyof PFOS in Rats (Sponsor's study number: T-6295.12), June 24, 1999 Protocol FACT-TOX-110 Oral (Gavage) Pharmacokinetic Studyof PFOS in Rats, Protocol, June 8, 1999 Final Report Protocol 418-015 Oral (Gavage) Pharmacokinetic Recovery Study of PFOS in Rats (Sponsor's study number: T-6295.14), July 23, 1999 Protocol FACT-TOX-111 Oral (Gavage) Pharmacokinetic Recovery Study of PIFOS in Rats, Protocol, June 8, 1999 Summary PFOS Rat Two-Generation Reproduction Study (Study numbers: 3M T-6295.9, Argus 418-008 [in-lifc), FACT-TOX-012 [analytical]) Report Amendment I, 13 April 2000, Protocol 418-008 (Sponsors study number. 6295.9) Combined Oral (Gavage) Fertility, Developmental and Perinatal/Postnatal Reproduction Toxicity Study of PFOS in Rats, Final Report Analytical Laboratory Report on the Determinationofthe Presence and Concentration of Potassium Perfluorooctanesulfonate (CAS Number: 2759-393) in the Serum and Liverof Sprague-Dawley Rats Exposed to PFOS via Gavage, Laboratory Report No. <U2006>, Requestor Project No. <3M TOX 6295.9>, October 27, 1999 000006 Interoffice Memo from Tom Kestner to Leo Gehlhoff, "Fluorochemical Isomer Distribution by "'F-NMR Spectroscopy, December 1, 1997 aFinndalPeRreipnaotratl/PProosttoncaotlal41R8e-p0ro0d8uCcotimobninTeoxdicOirtayl S(tGuadvyagoef)PFFerOtSiliitny,RaDtesve(lSopopnmseonrt'asl study number 6295.9, June 10, 1999 `Summary PFOS Rat Cross-Fostering (Study numbers: 3M T-6295.13, Argus 418014) Final Report Protocol 418-014, Oral (Gavage) Cross-Fostering Study of PFOS in Rats (Sponsor's study number: T-6295.13), July 23, 1999 CAnoanlcyetnitcraaltiLoanboorfaPteorrfyl uRoerpooorcttaonnestuhlefDoentaetrem(iPnaFtOiSo)no(fCtAhSe NPurmebseern:ce and 2759- 39 -3 ) in * the Serum of Sprague-Dawley Rats Exposed to Potassium Perfluorooctanesulfonate via Gavage, Laboratory Report No. U2779, Requestor Project No. 3M Tox 6295.13, June 10, 1999 000007