Document ba2v9b9peqRR0nE3xbO2J9Kq3

Attachments to Letter to C. Auer dated May 4, 2000 R126 oI 3 Perfluoroctane Sulfonate Studies H h A R >3 NO Ongoing Research/Study Protocols ~ 1) 104-week Dietary Chronic Study and Carcinogenicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS: T-6295) in Rats, Covance Laboratories Inc. Study Number 6329-183. In progress. Interim data provided. J 26-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS: T-6295) in Cynomolgus Monkeys, Covance Laboratories Inc., Study Number 6329-223. In progress. Interim data provided. 3) Protocol for Study: Low Level PFOS Dose versus Rat Serum and Liver PFOS, 3M Medical Department, Corporate Toxicology, Study No. T-6295.16 DT31, October 29, 1998. (Study in progress.) 4) Protocol for Study: Pharmacokinetic Study of POS in Rats, 3M Medical Department, Corporate Toxicology, Protocol for Study No. T-7098.1, January 7, 1999. (Study in Progress). 5) Study Plan, ST-43: Standard Procedure for Liver Subellular Fractionation, undated, 3M Toxicology Laboratory 6) PAlbasnorfpotrioSntuSdtyudNyoso.f TTh-e6o2p9h5y.l2l3i;neS,TS4al6i,cyElixcplAocriadt,orPyerIfnl-uVoirtorooctPyelrsvuultfoannaetoeu,sand Ammonium Perfluorooctanoate in SkinEthic Reconstituted Epidermis Model, May 4,2000, 3M Toxicology Laboratory 7) Study Plan, Luebker, Perfluorooctane Sulfonic Acid Induced HMG-CoA Reductase Inhibition in Pregnant Rats and Rat Pups, January 21, 2000 04411 . T4295.16;10D2T9/3918 Low Level PFOS , 3M MEDICAL DEPARTMENT, CORPORATE TOXICOLOGY Protocol for Study No. T-6295.16 DT-31 La Lvs`FPrEojDecSteBd rStearet Drate: aOcttSobeearma29,n19L9i8v PEOS oR 3 Study Objective: `The objectiveofthis study is to obtain data from which to construct standard curves of single oral dose versus serum and liver PFOS concentration in male and female rats. These curves will be used to interpret future oral absorption, distribution, metabolism and excretion (ADME) studies on POSF-based polymeric fluorochemicals (FCs) which may contain low-level contamination with PFOS. These curves will be used to compare serum PFOS concentration after a single oral dose of POSF-based polymeric FCs containing known quantities of PFOS 10 expected serum level and liver level increases predicted by thestandardcurvebased onanequimolar oseoftheresidual.Thesecurveswillhelp evaluate whether an increase in serum and liver concentrationof PFOS is a result of metabolic degradation of the polymer or absorptionofresiduals. Research Client: 3M Specialty Chemicals Division 3M Center, Building 236 Saint Paul MN 55133-3220 Sponsor: 3M Specialty Chemicals Division 3M Center, Building 236 SaintPaul MN 55133-3220 Study Location: 3M Strategic Altemative Toxicology Laboratory 3M Center, Building 270-SB-181 Saint Paul, MN 55133-3220 Study Director: Andrew M. Seacat PhD. Sr. Research Toxicologist 3M Medical Dept. / Corporate Toxicology 3M Center Building 220-202 Saint Paul, MN 55133-3220 Ph.: 651-575-3161, FAX: 651-733-1773 Study Toxicologist: Deanna Nabbefeld, MS Advanced Research Toxicologist 3M Medical Dept. / Corporate Toxicology 3M Center Building 220-2E-02 Saint Paul, MN 55133-3220 Ph: 651-737-1374, FAX: 6517331773 ProposedStudy Timeline: In-Life Start Date: October 29th, 1998 C In-Life End Date: November 19th, 1998 004412 T6295.161, 0D273918 Low Level FOS Regulatory Compliance: `This is a rangefinder study and thus non-GLP. TmTaehtseetrsiMpaaoltnewsrioilrlalbw:iellthperorveispdoeansisbaimltpyloeoftfhPeFsOpSo.nsoArn.alyAticchaelmdioccaulmceonmtpaotsiiotnioon tsfhpecsitfairctaitnigon sheet will be kept on ile Identification: Name: Perfluorooctane Sulfonic Acid, LMootleNcuumlbarerF:orTmhuleal:ot CnyuFmb1e;r0sS0wi,lKl"be Potassium maintained Salt; CAS in the raw # 2795-39-3 data. Purity:Documentation will be kept in on file Stability: Documentation will be kept on fle. StorageUpCoonndirtecieoinpst:, test material will be stored tightly sealed at room temperature. CharactdIeenrfifisontreimcatsth:ieotnesotnmastyenrtihaelsiwsilmletbheokdesp,tcoonmpfols.ition or other characteristics that Animals: Species: Rat SStoruaricne:: HSaprrlaagnueLaDbaorwalteoyries, Inc. Age at initiationoftreatment: 6.8 `Weight at initiationoftreatment: weeks old approximately Number and sex: 75 males, 75 females 150-200g Identification: GROUP GROUP 1: 2: control 3ughkg ~~ 15 male, 15 female ~~ 15 male, 15 female `GGRROOUUPP 43:: 3100p0gp/gk/gke-- 1155 mmaallee,, 1155 ffeemmaallee GROUP 5: 300pg/kg - 15 male, 15 female ear tag. Husbandry: Al Housing: ats will be group housed in standard cages Diet/Water: soy 004413 ASltleirlatzsabwlilelDbieetpr(oHvairdleadn Ttaepklwaadt,erMaadnidsoHna,rlW an TaeIdklliadb) iLtMu-m4t8h5roMuoguhosuet/Rtahet 2 : T4295.161;0D29T53918 ; Environment: Low Level PFOS otEfenmvrpioeroroamntmaueirnretopaeflr c7ho2onut+rro3alnsFd,foahru1tm2hiedhioatnuyirmolafilg3hr0to-/od7am0r%kw,icyalclmbeie.nsietmutom moafin1t0aienxcahanges dDfooosiisnmegag.n/dmSLeDriosastloicdnkiglsuPotlriuoontcsieoodnfoutrfehsP:RsOtSockinso2lu%tiTowneweilnlb8e0 pweirlflobremperdeptaorreedaichmmediately prior to 2c3-o75ndcooennsdtirnaagytzsieoonlruoftooirfotenahckehgsdbtouosddyey.lewvTeeilh.gehtA, wsiilnlglbeedaodsmeionifsctoemrepdovuindo,raulsignagvaagdetohtseoearvpaotpslrouipnmregiraootuef5ps control rats will receive no treatment. DThoesedoSseelsecsteiloenctJeudsftoirftihciatsiolno:w PROS levels that are at or near tdhoesleiPmiFtoOfSquastnutdiyfiacraetidoensi(g1n5edpptbo).yield serum pblroeovdi.ousThdearteaf,or1em,guosifnignlgiensetaerdexPtFraOpSolyaiteilodns, a3ppprgo/xkigmawitlellyth5eopreptmicaPlBFlayOsySeideilnodntahbeout M1i5xpipnbgPpFrOocSedinurtehe: blood. Three ug/kg was thus selected as the low doge. PwAiFlLlObSmegip/nemr10fsotmrolmce2kd%sbuasTspweeednesonino8nto0hfeusfPioFnlOglSowi1wn5iglmclablegclupalrasetsiptoanirsse:sduebgyrihnodmero.geAnizseirniagl 1d0ilmutgion * Assumea dosingvolumeof 03 mg/Kg dose group: (Sml/kg) (0.3 kg) = 1.5 mlrat (0.3mg/kg dose)(0. 3 kg 2% Tween 80 needed. rat) 1.5 ml rat = 0.06 mg/ml PFO solution in * D0.i1lumteg/6kmglodofstehegr|oumpg:/m solution to 100 mlin 2% Tween 80. (T0w.e1 emng/8k0gn)ee(d0e.3d.kgrat)1.5mlrat =0.02mg/mlPFOSsolutionin2% D0i.l0u3tmeg3/3k.3g3d3omsleogfr0o.u0p6 mg/m! solution up to 100 mlin2% Tween 80. (0.03mg/kg) (0.3 Tween 80 needed. kg)/ 1.5 mrat = 0.006 mg/ml PFOS solution in 2% 0D.i0l0u3tem3g0/kmglodfotsehgero0u.02pmg/ml solution up to 100 ml in 2% Tween 80, (0.003) (0.3 80 needed. kg)/15 mi / rat = 0.0006 mg/m PFOS solution in 2 % Tween Dose Dilute 10 miofthe Verification: 0.006 mg/m! solution up to 100 ml in 2% Tween 80. w0Sia.lmlpmbleaeksaneoaftldyhozseeedcgobrnyocLuepnCt)rMaaSntdefdtohr1edm0og.s/0e2mvlmergPi/fRmicOlaStsitosontcobkcyk(K,frtrithsehH0ea.n00.6s1emnmg,g//3mklgsdtoocske(fgorrotuhp)e Lsaobl.utioItnswialndnosttilblequpaonstsiifbylethteo PsuFfOfSi.cienEtxltyrdaiploultaettihoen0t.o0t0h6ealnodwe0r.0dM0o0s6Eenmlvgeiv/remolnlsmwdeionlslteal 04414 3 . . T4L2o9w5.L1ev6e1;l0D2P9TR/3O91S8 therefore,beperformed based on the quantification ofthe more concentrated dose psoelruftoiornmse.dbAyllDrd.oseVsenwtiallkaaslswoabrelucoPnoftihramperdabgaydtaot(aDrl.orVg.)a,ni3cMflSuoCriDneLaanba.lysis Observationof Animals: Clinical Observations: Eafcihanniwmidalllbwiielrnlebceogrodbessde.rveWdedeakillyy,fcoarchmaorntiamliatlywainlldbmeorrbeimdoitvyedafnrdnoomtaitbsle Acdadgietiaonndalafriencdoirndgoswfialblnboerrmeaclorfdineddiansgsthoerynaorremaolbisteyrwvieldl.be made. Body Weights: E`aancdhimamneidmiaaltweilylpbreiowretiogheeudthianmamseidai.ately prior to dosing, weekly thereafter Sample Collection: Frequ`eSncchyedaunldedN sacru ifim coesf:b Anie malr s: Five males and five 4 and 14 post dose. females from See Table 1 each group - schedule. willbeeuthanized on days 1, 04415 4 T46295.16;10D2T903918 Low Level PFOS / TABLE 1 - SCHEDULE ddaBy 0| dayO1atpost omDaOeS3E|| ecmraondronye Novz 2eac8h,3g0ps. Novs| Nove dNaeycRdopdPooSssYte gmDdsOaS,yE|04|| Ndaeycr1dopoorssyet SMSF 5] SMSF 2ea8ch3,0g0rp)s. (90)| eacLh,3g8p5s Novo Nov iz 0 dayd4opsoset Necrorsy posdtadyos1e4 NecRorsY ' SMSF SM,SF eac1h,3g8rp5s 50 2ca8ch3, gap0s Nov 17 Nov io day 14 "pcosrtodorsee. SM,SF cacLh,igersps a0 Method of Sample Collection: nAetcalrlopdessyipgenraftoerdmteidm.esD,uarniinmgalnsewcirlolpbsye,esyustetmichbblaoyoCndO(;i= a5nzmdige)rwoidsllsbe wcoiltlheocuttedanvtiiacotahgeulaabndto.miAnlallbaloorotda asnamdptlreasnswfielrlrbeed taollbolwoeoddtcoolclleocttfioorn atubes dpoewrinodoinfa1c5enttor3i0fumiganetut1es 1atxr0gofo0omrtemmpienruatteusr.eTahndestehreucmlwotilwillblebe spun tXr1an0sfrerermeodvteoalnabyerleemda1i.n5imnlgrmeidcbrolfouogdectelulbse.sTahndescenterifwurigleldatuhgeanimbnaet 2000 ltirqaunisdfenrirterdogteon.labLeilveedrspowlilylprboepryelmenoevemdi,crwoefiuggheedt,ubpelsaacnedd ifnldaisvhi-dfuraolzleyniinnto labeled tubes and lash frozen in liquid nitrogen. Sample Handling: `80SaCm.pleFsowrilalntaleymspiosr,atrhielsyebseamstpolreesdwiinllabferepeazecrkseedtitnodrmyaiincteaainnd-6s0hitpope-d to 004416 5 . T4L2o9w5L.e1ve61l0,2DP9TR/3O91S8 K3rMisEHnavnisreonn,mePnht.aD.l Technology and Safety Services 935 Bush Avenue St. Paul, MN 55133-3331 Telephone No.: 651-778-6081, Facsimile No.: 651-778-6176. The number, type and dateofsamples to be generated for analysis are as follows: TABLE 2 - SAMPLES [Sem 12077720 "T3030 J20 [30 [iso| (Live 120 720 30 30 Joo 30 [150 | A`nSaalmyplseiss:will provided for bineclaunsailoynzeindbtyhe 3fiMnalErnevpiorrto.nmental for PFOS concentration. Results wil be RBeespto-rftit: curves will be obtained bylinearregression based on mean serum and liver PFOS concentrations for each group. AndrDeeawnMn.a NSaeabcbaetf:elSdtuadnydDAinredcrteorw,SDeeaacantnaarNeabrebsepfoenlsdi:blSetufodrydToosxiincgoltohgeisatnimals, performingthenecropsy and collecting and sending tissue samples for analysis. A*ndrew bKerfiosrHeaanSsfeeiannac,la3rtwaMiflElnidvsriiarsfsoutneamde.rnetpaolr,tawinldlebnesruerseptonhstibilterefcoreitvhee.saapnaplryotpircailataneal3yMsirs.eview Signatures: 4 DSre.riAonrdRreesewaSrecahcTaotxicologist Study Director 10/29, Date Meisels f DeAdavnannaceNdabTboexfieclodl,ogMisSt Study Toxicologist 1087/5F Date 004417 s o T:6295.16,1D1T/5-/3918 Low Level PROS. Protocol Amendmen#t 1 LowLevel PFOSStDudoysNeov.erTs-u6s2R95a.t1S6,erDuTm-a3n1dLiver PFOS Sponsor: 3M Specialty Chemicals Division SSStttuuudddyyyDDLiiorrceeacctttiooorrn:::___M3ApnMddrSrteerwawtMeM.giScSeAalectaetmacPthi.vDue. To.xicology Laboratory "This amendment modifies the following portionsofthe protocol: Effective November S, 1998 1 Page 2.ToAnsitmraelnsgt,hNenutmhbeelrowa-nddosSeexp:ortionofthe dose response curve, Dose. Group $ was replaced with a now be as follows: 10 ug/kg dose group. The dosegroupswill GROUP I: control - 15 male, 15 female GROUP GROUP 23:: 330uugghhkkg g -- 1155 mmaallee,, 1155 ffeemmaallee GROUP 4: 100ug/kg - 15 male, 15 female GROUP 5: 10 pg/kg - 15 male, 15 female 2. Page 3.`MThiex0i.n0g10Prmogc/ekdgurdeo:sing solution will be made by makinag 10 fold dilution oPfFtOhSe 0s.o1lmugt/ikoignd2o%siTngwesoelnuti8o0n.wiTlhlebreedfiolruet,ed1t0oml1o0f0tmhle i0n.202%mTgw/melen 80 10 yield the 0.002 mg/ml PFOS solution in 2 % Tween 80 needed. 3. Page 4. Dose Verification: `toTthael0o.r0g0a2nimcgf/lumolriPnFe OanSalsyosliustpioenrfionr2me%d TbyweDer.n V8e0nwtialklebsewacrolnufirmedby Pothapragada (Dr. V.), 3M SCDLab. 4. Page. Analysis: PSeFrOuSmcaonndcelnitvreartsiaonm.pleRseswuilltlsbweilal bne aprolbviyydBezadttfeeolrdliencLlaubsoiroantionritehse ffionral report. Shipping Address: Battelle Laboratories Attention: Angela Capers 505 King Avenue Columbus, Ohio 43201 Phone: (614) 424-5588, Fax: (614) 424 -3268 004418 7 . AmendmentApproval: Signatures: Dr. Andrew Seacat Senior Research Toxicologist Study Director 7/5/99 Date Miedo] U/L2f Deanna Nabbefld, MS Date Advanced Toxicologist Study Toxicologist a11/5/98 ) 04419 . - T46295.160,4D2T0-9391 Low Level PFOS Amendment #2 Protocol Amendment #2 Study No. T-6295.16, DT-31 LowLevel PFOSDoseversusRatSerum andLiverPROS. Sponsor: 3M Specialty Chemicals Division Study Location: 3M Strategic Altemative Toxicology Laboratory FR oStudy Director: ___Andi rew M. Seacat Ph.DS . -- Effective April 26", 1999 TgrhoeuppuorfpoSsmego/fktghibsoadymewnedimgehtntanids taonreecflreocptstyhedadteecoifsi2o8nodfatyhsepoSsptondsoosrettoo atdhedoavedroaslel s#1t.udyThdeesimgond.ifiAclaltimoondsifairceaatsiofnoslalrowesa:dditions to the original protocol and Amendment 1. Page 1 Protocol, Proposed Study Timeline: `Additional Proposed Timeline specific to Amendment #2: In-Life Start Date: 3/2/99 In-Life End Date: 5/24/99 2. Page`Th2ePfrooltloocwoilng/ 2Padgoese1gArmouepnsdwmilelnbte #a1d,deAdntiomatlhes,prNoutomcbole:r and Sex: GROUP 6: vehicle control - 12 male, 12 female GROUP 7: Smg/kg -20 male, 20 female 3. Page 3 Protocol /Page 1 Amendment #1, Mixing Procedure: `gsArionugplse7Somng/dakyg zdeorsoeoofftchoemsptouduyn.dTwhiellcboempadomuinndiswtielrlebdevipareopraalregdavasagae1t%o r(a1ts in vmogl/ummLe)ounf5ifmoirmsussupsepnesnisoino/n king2b%odTywweeeingh8t0wiulslibnegaadm1i5nimslteirsesdu.eRgrei-nsduesr.peAnsion ofsolids will be performed with S strokesof the tissue grinder pestle before each sdaomspeldewiistdhr5awmnl-/kugpi2n%thTewseyerning8e0f(ovrehdiocsliengc.onTtrhoel1).0control rats (group 6) will be 4. Pag4e Protocol / Page 1 Amendment #1, `The vehicle control sample (2% Tween Dose Verification: 80) and the 1 mg/mi PFOS solution in 2 %VenTtwaekeasnw8ar0lwuilPlboetchoanpfriramgea(dDdbray. tVo.t)a,l 3orMgaSniCcDflLuaobr.ineanalysisperformedbyDr. S. PageFr4ePqruoetnoccyola.nSdaNmpulmebeCorlolefcAtniionm,alFsr:equency and Numberof Animals: ScFihveedumalleedssaacnrdiffiicvees:femalesfromgroup 7and 3malesand 3 females from \ group 6willbeeuthaonndiayzs1e,4d, 14and28post dose. SeeTable 1 : schedule Page 10f3 04420 . TABLE 1 - SCHEDULE Csre oez"= day0| day I post co | ov rt 04/20/99 ST I.= day 4 post ii ppYooeyastwl2 ar Sr [Mavic] May17] May8] Mayi5|Ways] Mayai| Mays] ` \ sats 04421 ' AmendmentApproval: - - Low Lev PFO Ameind 04120199 Signatures: Liss IV. Soi? `Andrew M. Seacat, Ph.D. Senior Research Toxicologist Study Director Morssgtlapt DAdevaannncaeNdabTboexfieclodl,ogMisSt Study Toxicologist 4/43/22 Date ese Date Pagers 04422