Document zbv4p7KvD6R9nYQBQJLe6xQ7z

Attachments to Letter to C. Auer dated May 4, 2000 AR2G-ol 92, Perfluoroctane Sulfonate Studies Planned Studies 1) Preliminary Study Outline, One Generation Reproduction Study of PFOS in Rats, Pharmacokinetic Analysis, May 3, 2000 2) Preliminary Study Outline, One Generation Reproduction Study of PFOS in Rats, Mevalonic Acid/Cholesterol Challenge and NOEL Investigation in Rats, April 27, 2000 04589 Argus PK Outline 5103/2000 ' in Rats-- OneGeneration ReproductSionStudvof0PESInRats= $=) `Study Outline `Study Objectives: This study will serve as a follow-up study to CombOrialn(gaevagde) Risattso g(aAirnguadsdPirtoiotnoaclolph4a1r8m-a0c0o8,ki3neMtcst(uPdKy)nduamtbaeornTP-6F2O9S5.i9n).prTeghneanobtjreacttsivaenodftthheiersptuupsd.y GLP Status: A GLP study with appropriate QA audits; a signed QUA statement to be included in the final report. Animals: Female Harlan CD rats. Dose Groups: Six: Vehicle Control; 0.1 mg/kg PFOS; 0.4 mg/kg PFOS; 0.8 mg/kg PFOS; and 1.6 mg/kg PFOS. Number Per Group: 36 per group = 150 total Test Article: Compound will be furnished by the Sponsor who is responsible for `compound identity and purity. Reserve sample to be retained. TChoempveohuicnlde A(0d.m5i%nisTtwreaetino8n0:iFnedmeailoensizoendlyw,adtaeirl)ywoirlallbientpurbeaptairone,ddwoeseeklvyo.luPmFeOSSmlw/ilkl.be padrmeipnairsetdrdaatiiloyn awsilal sstuasrpte6nswieoenkisnprdieoirontiozemdatwiantgeranwidtcho0n.t5in%ueTtwhereoungh80d.aCyo2m1poofund lactation. `Samples of dosingpreparationswill be collected once duringthesix weeks prior to mthaetsiengs,amopnlceesdwuirlilngbegefsrtoazteinonanadndshoinpcpeeddurtiontghtehSepopnosstonraftoarl ppoesrsiiobd.le Aanaployrstiiso.noAfcbaacchkuopf sample of cach will be retained by the testing facility. Records will be maintained on how dosing preparations were made. Clinical Observations: Twice daily - approximately one hour after dosing and again 4-6 hours later. Body Weights: Weekly except when females are cohabiting with males during mating. Food Consumption: Weekly except when females are cohabiting with males during mating. Mwialtlibnegc:o-Aifnihearb6itweedekwisothfecaochmpfoemuanlde.adAminfiesmtarlaetiwoinl,lboenedemtaelrem(iAnregduassbmraetedeedur pcoolnotnyh)e presence of sperm of gestation. positive vaginal smear. The day of mating shall be considered day 0 04590 Page 1 of 4 DJ. Luebker Argus PK Outline 5/03/2000 DpraeygnZaenrtofoefmaGleesstainticoanchSagcrroiufpicweilalnbdeEsxaacrmiifniacetdiboyn:COOn, dasapyhyzxeiraotioofn.gestAattieornm,i6nal body wgreoisgshtlefsoironesacwhildlabmewdielslcbriebeodbtaanidnerdecaonrdderde.coSredredu.m aAnndimlaivlesr wsialmlpbleesnewcirllopbseictdakaenndfarnoym each dam. All specimens will be frozen (-20C) and shipped on dry ice to Kris J. HBuainlsdeinn,gP2h-.D3.-,093,MStE.nvPiaurlo,nmMeNnta5l51T3e3c-h3n3o3l1o.gyUpaonnd rSeacfeeitpyt,Sesrervaicweisl,l9b3e5aBnualsyhzeAdvefnoure, PFOS and livers will be stored for possible future analysis. Day 15of females in GceascthagtrioounpSawiclrlifbiecesaacnridfiEcxeadmbiynaCtOi,ona:spOhynxidaatyio1n5aonfdgceesstaatricoann,-s6ecptrieognnawniltl be paecrhfolrimtetder.wiAlltbeermoibntaalibnoeddyanwdeirgehctorfdoerde.acDhadmasmwialnldbaepnoeoclreodpstieerdmiannadl abnoydygrwoesisglhetsifoonrs will be described and recorded. Serum, liver and milk samples will be taken from each dtoamK.riDJsa.mHasenrsae,nl,ivPehr,.Dm.i,l3k ManEdnwvhiorolnempeunptsalwiTlelcbhenoflroozgeyna(n-d20SaCf)etaynSdesrvhiicpepse,d9o3n5dBruysihce Apuvpesnuwei,llBbueiladnianlgyz2e-d36f-o0r9P, FSOtSPaaunld, lMivNers55w1i3ll3-b3e33s1t.oreUdpfoonr proescseiipbtl,esfeurtau,rmeialnkalaynsids.whole gPerset-aBtiiront)h6SapcrreigfniacnetafnedmaElxeasmiinnaeatcihong:roJuusptwpirlilobretosadcerliifviecreyd (bmyoCrnOi,nagsopfhydxaiyat2i1onofand cteersmairneaaln-bseocdtyiowneiwgilhltfboercpearcfhorlmietdt.er wAitlelrbmeinoabltabinoeddyawnedigrhetcofrodredc.achAndiammalasndwiallpboeoled nweilclrobpesitcadkeannfdraonmyegarcohssdalemsiaonnds whielrlbpuepdses(cpruipbseadmapnldesrepcooorldeedd.bySelirtuemr).anMdillkivseramspalmepsles `willbecollected dry ice to KriJs. fromeach dam. Hansen, Ph.D. All specimens will be frozen (-20C) and 3M Environmental Technology and Safety shipped on Services, 935 BwiulslhbAevaennauley,zeBdufiolrdiPnRgO3S-3aEn-d09l,ivSetr.sPwaiulll,bMeNsto5r5e1d3f3o-r33po3s1s.ibUlpeofnutruerceeiapnta,lysseirs.a aMndAmYilk ACDAND BADEDEIXTAIMOINNAELDDOARMSMIANYSSOAMVEEDROESMEAGIRNODUEPRSOSFO EWAHCOHLEPUPPUAPFPTFEORSLLIEVVEERLS AND SERA ARE COLLECTED. Female Parturition: Remaining rats will be allowed to deliver their litters. `PmuopriEbuxnadmiitny/amtoirotnasli:tPyuopnspwoisltlnabtealcoduanytsed0,, s1e,x2e,d3, awnedig4h,e7d, a1n4daonbds2e1r.ved for cRoantdsitFioounnodr aDbeoartdioonrwMiollrbiebuenxda:miRnaetdstfhoartcdaiueseoorfadreesaatchriofricmeodribbecuanudsceoonfdimtoironibounndthe dexatyentthepoosbssiebrlvea.tWiohneins mpaosdsei.blAeb,otrhteefdofleltouwsiensgasnpde/ocrimienn-ustweirlolpbuepscowlillelctbeedeaxnadmiannaeldystiosthe performed: Rats will be necropsied and any gross lesions will be described and recorded. Serum and lbiyvelritstearm).plMeislkwislalmbpeletsakweinll(ibnedicvoildlueacltleyd fforroemacehacdhadmama.ndAhlelrsppuepcsim--epnsupwislalmbpelefsropzoeonle(-d Page 20f 4 DJ. Luebker 04591 Argus PK Outline. 5/03/2000 2`a0ndCS)afaentdy sSheirpvpiceeds,on93d5ryBiuschteo AvKreinsueJ.,HBaunisledni,ngPh2.-D3.-,039,M SEtn.vPiaruoln,mMenNta5l5T1e3c3-h3n3o3l1o.gy Upon receipt, sera and milk willbeanalyzed for PFOS and livers will be stored for possible future analysis. Lthaecitraptuiposn wDiallyb7eSsaaccrriiffiicceedabnydCEOx,amaisnphaytxiioant:ioSnioxndalamcstaitnioenadcahydo7.seAgrtoeurmpiannald baloldoyf waenidgrhetcofrodreeda.chAdniammalasndwiallpoboelneedctreorpmsiineadlabnoddaynwyeigrgohstsfloerseiaoncshwliiltlebrewdiellscbreiobbetdaiannedd rseacmoprldeesd.poSoelreudmbaynsdelxifveorr scaamcphlleisttewri)l.lMbielktaskaemnplfersomwiclalcbhedcaomllaecntdedhefrrpoumpesa(cphudpam. E`AnlvisrpoencmiemnetnaslwTiellchbneoflroogzyenan(-d2S0afCe)tyanSdersvhiicpeps,ed93o5n BdruyshiceAvteonKurei,s BJ.uiHladnisnegn,2-P3hE.-D0.9,,3SMt. Paul, MN 55133-3331. Upon receipt, sera and milk will be analyzed for PFOS and livers will be stored for possible future analysis. Lthaecitraptuiposn wDiallybe14sSaaccrriifficiecdebaynCdOE,xaamsiphnyaxtiiaotni:onSoinx dlaacmtsaitinoneadcahy d14o.seAgrtoeurpmiannald baloldoyf waenidgrhetcofrodreed.achAndiammalasndwialploboelenedctreorpmsiineadlabnoddaynwyeigrgohstsfloerseiaoncsh wliilttlerbewidllesbceriobbetdaiannedd rseacmoprldeesd.poSoelreudmbaynsdelxivfeorr scaamcphlleisttewri)l.lMbieltkaksaemnplfersomwielalcbhedcaomllaecntdedhefrrpoumpesac(hpudpam. EAlnlvisrpoencmiemnetnaslwTiellchbneoflroogzyenan(d-2S0afCe)taynSdersvhiicpeps,ed93o5n dBruyshicAevteonKurei,s BJ.uiHladnisnegn,2-P3hE.-D0.9,,3StM. Paul, MN 55133-3331. Upon receipt,seraand milk will be analyzed for PFOS and livers will be stored for possible future analysis. tLhaecitraptuiposnwDiallyb2e1sSaacrcirfiifciecdebaynCdOE,xaamsiphnyaxtiiaotni:onSoinx ldaacmtastiinoneadcahy 2d1o.seAgrtoeurmpiannadlabloldoyf waenidgrhetcofrordeeda.chAndiammalasndwaiplol obleendectreorpmsiineadlabnoddyanwyegirgohstsfloerscioancshwliiltlerbewidllesbceriobbetdaiannedd rSeacmoprldeesd.poSoelreudmbaynsdelxfivoerrcsaacmhplleisttewr)i.lMbielktaskaemnplfersomwiclalcbhedcaomllaecntdedhefrropumpesac(hpudpam. EAlnlvisrpoencmiemnetnaslwTiellchbneoflroogzyenan(d20SafCe)tyanSdersvhiicpeps,ed93o5n dBruyshicAevteonKurei,s BJ.uiHladnisnegn,2-P3h6.-D0.9,,3StM. Paul, MN 55133-3331. Upon receipt, sera and milk will be analyzed for PFOS and livers will be stored for possible future analysis. 04592 Page3 of 4 DJ. Luebker i Argus PK Outline 5/03/2000 Table 1 -Scheduled Sacrifices (N dams/group/sacrifice) nEa C l CO BERCO k Fr ever [|e 1 oo[1m e] [v v| [So Emmmm [J[6o [Jf5oe [ eJooJT vr oT[e 5o]]| [[Fo1m 50Ta 50t 15n 0 1r 350 e 15e 0 ] Study Director: Deanna J. Luebker, M.S. 3M Corporate Toxicology 3M Medical Department 3M Center Bldg. 220-2E-02 Saint Paul, MN 55144-1000 "Telephone 651/737.1374 FAX 651/733.1773 Alternative Study Director: John Butenhoff, Ph.D., DABT, CIH 3M Corporate Toxicology 3M Medical Department 3M Center Bldg. 220-2E-02 Saint Paul, MN 55144-1000 Telephone 651/733.1962 FAX 651/733.1773 Ao In-Life Phase Investigator: Analytical Phase Investigator: Kris J. Hansen, Ph.D., 3M Environmental Technology and Safety Services, Bldg. 02-3E-09 935 Bush Avenue, Building 2-3E-09, St. Paul, MN 55133-3331 Telephone 651/778.6018 FAX 651/778.6176 04593 Page 4 of 4 D.J. Luebker