Document YDBZqz3kZjk3576LOyXpJa2eN

ARRRG | |02 Study Title 2E6xt-eWnedeekdCRaepcsouvleeryToSxitcuidtyy SFotluldoywiwnigtha SPaelrtfi(uPoFrOoSoc;tTa-n6e2S9u5i)foinnicCyAncoidmoPlogtuasssium Monkeys Author Peter J. Thomford, PhD Sponsor am St. Paul, Minnesota Test Facility Covance Laboratories Inc. M3a3d0i1soKni,nsWmiascnoBnosuilnev5a3r7d04-2585 Laboratory Study Identification _Covance 6320-268 Sponsor Study Identification 3M T-6295.22 Report Issued 04 December 2001 Page Number 1of23 g= gz 3No 3B3S = E< ii ~8 i Crrmamn NO CBI 000032 -_-- CovaInMcTeT66e32299m-5226a28 `COMPLIANCE STATEMENT ExwtietnhdePderRfelcuoorvoeorcytaSnteudSyulFfoolnliocwAicnigdaP2ot6a-sWseieukm CSaalptsu(lPeFOToSx;icTi6t2y9S5t)udy ` in Cynomolgus Monkeys GAolloadspLeacbtosroafttohriysPsrtacutdiycweerSteainndaarcdcso,r4d0aCncFeRwi7t9h2t.heEnvironmentalProtection Agency , Study Director PhD, Covance Laboratories Inc. 7 MW)Seidl 'M. Seacat, PhD 3M `Toxicology Services Od0e 0 Date JR 10/30 t Date i i i { i 2. 000033 - CoSvmiSeMseT63e2w59:22628 `QUALITY ASSURANCESTATEMENT . `Thisreporthasbeen reviewedbytheQualityAssurance Unitof Covance Laboratories ` Inc.,inaccordance with the Environmental Protection Agency (EPA) GoodLaboratory rPerpaocrtitceedSttoatnhdeasrtdus,dy4d0irCeFctRo7ra92n.d`sTthuedfyodlilroewcitonrgminasnpaegcetmioennstw.ereconductedandfindings Inspection Dates. From To Phase 02Mar00 02Mar00 ProtocolReview 03 Apr00 03 Apr00 Protocol Amendment Review 04May00 04May00 Analytical Laboratory 05Jul00 03Jul00 20Sep00 26Sep00 27Dec00 Inspection 05Jul00 Body Weight 03Jul00 DataReview 20Sep00 *AnimalObservation 26Scp00 DataReview 28Dec00 Data Review 27Feb01 27Feb0l Protocol Amendment Review 09Mar01 09Mar01 Postlife 30Mar01 03 Apr0l DataReview 24 AprOl 24AprOl ReportReview 11Jun01 11Jun01 Protocol AmendmentReview 15Nov01 16 NovO0l ReportReview Date Reportetdo StudyDirector and StudyDirector Management 02 Mar 00 03Apr00 04 May00 05 Jul 00 06 Jul00 20Sep00 28Sep00 28 Dec 00 27Feb 01 09Mar01 03Apr 01 24Apr 01 11 Jun 01 19 Nov 01 Aidiku--bdd padecembaror Representative "Date QualityAssurance Unit ii ii | 000024 = eeei e m-------------- eeCeo-- vaS3nMcAeT66R-- 32299E5-22E628 KEY PERSONNEL . ExtwietnhdePderRfelcuoorvoeorcytaSnteudSyulFfoolnliocwAicnigdaP-o2t6a-sWseieukm CSaalptsu(lPeFOToSx;icTi-t6y29S5t)udy : in Cynomolgus Monkeys Study Monitor: Andrew M. Seacat, PhD : Study Director: 3M Peter J. Thomford, PhD Study Toxicologist: Study Coordinator: Dale Aldridge, BS Elizabeth A. Disch, BA AsSuspoecrivaitsoerD,irLeacrtgoer-,ALnabiomraaltToorxyicAonliomgay:l ~~DCoynnntahiaJ.AC. lWebeerm, DAoSV,nML,sAMT,SG Medicine: Anatomic Pathologist: Diplomate, ACLAM Robert A. Leedle, DVM, PhD Supervisor, Anatomic Pathology: Diplomate, ACVP Laurie J. Schuller, BA, LAT `Principal Investigator: Kris J. Hansen, PhD 0 | |i 1 i } 000035 a ConIeMsT66329952628 PURPOSE n `Thepurposeof thisstudywasto continueassessmentof thetoxicokinetics and ` fodlilstorwiibuntgidoaniolftyhaedmitensitstmraatteiroinalbydurcianpgsaunleteoxtceynndoemdo(lagpupsromxoinmkateeylsyfo1 ryeaatrl)earsetc2ov6erwyeeks. andat least 52 weeks of recovery. The subject studywasconduatcCotvaencde. `LTahbiosradtoocruimesenItncs.u,mimnaMraidziessotnh,eWmiasjcoornfsiinnd,inf gsfr o0r8to Mheasrm tcuhdy2.00A0lltahrosugph o0ef9tMhcairscstthu2sd0y01. `weredoneinaccordancewith theEnvironmentalProtection AgencyGoodLaboratory Practice Standards, 40 CFR 792. PROCEDURES `Theanimalsusedforthisstudy (male andfemalecynomolgus monkeys; tthwios sapnoimnaslosr/s[e3xM)wTe-r62e9p5r.e7v,ioCuosvlayncases6i3g2ne9d-t2o2t3h,e"r2e6c-oWveereykpChaapsseuolefTaocxoicmiptlyetSetdudsytuwdiythfor Perfluorooctane Sulfonic Acid Potassium Salt (PFO; T-6295) in Cynomolgus Masoinnkgelyes"da)i.lyDcuarpisnugleCdoovsaencfeor6a3t2l9e-a2st232,6twheeeaknsimfaollslorweecdeibvyeda05.21-5wmege/kkgre/cdoavyeroyf.PFAtOSthaes. `end of theinitialrecovery, apartial hepatectomy was conductedonthe animals,they `wereallowedtorecoverfromthe surgical procedure,then were transferred to the subject fnootlltorwe-atuepdsitntudhye(sCuobvjaecntcest6u3dy2.9-268)forevaluationofextendedrecovery. Animals were Animalswere obtainedfromCovance ResearchProducts Inc. (Denver, Pennsylvania) on 30June 1998.Atstudyinitiation, the animalswereyoungadulttoadultand weighed 2i.n8ditvoi4du.a1lklgy.inEsatcahinalnesism-astleweal scaigdeesnt(iefxiceedpwtitwhheancoplaliarr-thaogu.sTedhefoa r en nvii rownm meerna etahloluss ed enrichment),andcertified primate diet [#8726C,Harlan Teklad(through 22 23 January January 2001)] 2001)] and was Teklad Global provided once Diet [#2055, Harlan Teklad(beginning or twice daily. Waterwasprovidedad libitum. `The animals were observed twice daily (a.m. and p.m.)for mortality andmoribundityand once daily for signsofpoorhealth or abnormal behavior; findings wererecordedas they i { inwdeirceatoibosnetrhveadtt.hIenanaiddmiatlionw,asanniomramlaslwwearesroebcsoerrdveedd(osneceePwreoetkolcyo,laDnedviaantyionfisfndoirngs or an exceptions). Individual body weight data were recorded monthly (sce Protocol : Deviations for exceptions). Blood samples for serum PFOS level determination were c samoplleslawfee treercc2o,t l4l,eec6t,ed8d,fo1r0,PaFnOdS1l2emvoelntdehtsefrmionatliol nsato futdeyrw4i,nii8t,in aatnidg on1.2Umroinntehasndfoflelcowailng. i study initiaandtwiitohinn oneday of theserum PFOScollections. During Week 53, animalsthat werefasted overnightwereaneswt ithh kete amit neaindz xyle azid ne, i `weighed, exsanguinated, and necropsied. At the scheduled sacrifice, macroscopic observations were recorded, and selected tissues were collanedpcretserevedd. = 000036 ComMesT63a29m-2s68 Please see Protocol Deviationsonpage 11for a descriptionof all deviations from the protocol. . `StudySTtiumdeytaIbniltei:ation Date: 28 February 2000 : Inlife (Experimental) Start Date: 08 March 2000 `IEnlxipfeerTiemrenmtianlatTieornmiDnaattei:on Date: 09 March 2001 30 November 2001 All rawdata, resouftlhits documentation, study generated records, protocol, specimens, and final report generated by Covance will be archivedinthe storage facilitics of as a CSpoovnasnocre. Aftoalreapste onr eoyfeiaatro laefad tsetr1suybemairsfsoilolnoowfintghesufbinmailsrseipoonrotf,tahlleoffitnhael arfeoproermteotntthieoned `materialswillbesenttothe Sponsor,and areturnfeewillbecharged. The Sponsormay etliemcet,toanhdavCeovtahnecmeatweirlilaclhsarregteaianesdtoirnatgheefeCeo.vaIfnctheeaSrpcohnivseosrfochroaonseasddtiotihoanvael Cpoerviaondceof dispooftshee materials, adisposal fee will be charged. All rawdata storedon`magnetic `media will be retained by Covance. `The Sponsor is responsibleforretention of all raw data, documentation, records, specimens, and final reports generatedas aresouf lthitsstudybythe Sponsor. RESULTS AND DISCUSSION OClbisneircvaaltOibosnesrovfatAinoinsmals ; Clinical observations are presented in Table 1. oAblslearnviamtaiolnssstuhrrvoiuvgehdotuottthheeesntdudoyf wtheeresttuydpyicaanldowfecryenosamcorligfiucsedmoonnkDeayys 3i6n7a.rCelcionviecrayl phase, with no evidenceoftest material effect. Body Weights Bodyweightdataare summarized in Figure 1andpresentedin Table 2. Body weights for the animals remained normal throughout this extended recovery phase. IInnddiivviidduuaallaAnnataotmoimcipcaPtahotlhooglyogdyatDaaatrae presented in Table 3. `There were no macroscopic observations noted at necropsy. SReeprourtmiPngFoOfSthLeerveeslulDtestiesrtmhienraetspioonnsibility of the sponsor. i i} . 000037 -_-- URerpionretainngdofFtehceesrePsuFlOtsSiLtehveerl Deesteprmoinnastioiofnbthieslpoinstory. Reporting ofthe resultsistheresponsibility ofthesponsor. AdditionalTissue andSerumAnalysis Reportingoftheresultsistheresponsibility of thesponsor. TComvaMnrcTe6e62392s95-22z628 . CONCLUSIONS Afterthe completion of apreviousstudywith 26weeks oftreaantd5m2weeenkstof recovery, two male and twofemale cynomolgus monkeys that underwentapproximately 52weeks ofextendedrecoveryhadno clinicalobservationsor macroscopicfindings that indicated any residual test material effects. i i a. 000038 _-- . izabed] A. Disch, B; Cove Labor SIGNATURES . { Dae I Date `StudyDireSfor Covance Laboratorlinecs. Cones 329.265 Tenn | ) |i i i ! . 000039 -_-- urCoevaMnewsT63s2e9-n2s68 ANATOMIC PATHOLOGY REPORT . SUMMARY Foreucrovceyrnyosmtouldygu(s5m2ownekeeksy)s,,tfowlolomwailnegsaa2n6d-tWweoefkemCaalpessu,lewTeorxeiucsietdyiSntaudnyexwtitehnded exPteerfnldueodrroeocctoavneeryS,utlfhoenm ic Acoid Pn wotearseksfiausmteeSadlotvye(rPnFiOs gSh;t,T-a62n95e).sOtnwDhiatyehk3et6t7aoimfiztnheeeandd xsyclhaezdiunlee,dwseaicgrihfeidc,e.eTxhseanrgeuwienarteedn,oamnadcnreocsrcooppsiiccdo.bsAlelrvaantimiaolnasstsnuercvriovpesdy.untSilamtpheles of lciovlelre,ctleudn,g,laksihd-nefyF,ozsepnlienenl,iqtuhiyrdoniidt,rborgaeinn,, aanbddosmhiinppaeldfatto, thheearstp,oannsdobrilfoeraanndaslyesriusmowrere storage. METHODS Froeucorvceyrnyo(m5o2lwgeuesksmo)rsitkuedyys.,t"wThoemaanlimeaslasndwetrweporfeevmiaoluessl,yawsesriegunseedditontahnereexctoevnedreyd phase oCafapsucloempTloextiecditsytuSdtyudfyorwtihtihs Pseprofnlsuoorro[o3cMtaTn-e62S9ul5f.o7n,iCcoAvcaindcPeo6t3a2s9s-i2u2m3,Sal"t2(6P-FWOeSe;k T0.-16529m5g)/king/CdyanyoomfoPlgFuOsSMaosnakesyisng"l]e.daDiulryicnagpsthuilsesdtousdey,ftorheatalneiamsatls26rewceeeikvesdfollowed by ca 5o2-wneedkornuectohcveeartnyi.meAatldst,hteheeyndwoefrtehaelilnoitwieadlrteocroevceorvye,rafrpaormttiahlehseupragtieccaltpormoycwedausre,and tevhaelnutahteiyonwoefreexttreannsdfeedrrreedcotvoetrhye. subject follow-up study (Covance 6329-268) for OwnitDhakyeta3m6i7oneftahndeexxytleaznidneed, wreeciogvheerdy,, etxhseamngounikneaytesdw,earnedfnaesctreodposvieerdn.igAhts,aamnpelsethleitviezred (maaipnptraoixnim-a6t0eltyo -1800g)C,waansdfslhasihp-pferdozteontihnelsipqounidsonritfroorgeanna,lysstiosr.edSianmaplfreesezoefrlsuentg,tokidney, anspdleseenr,utmhyr(ociadc,habrsaimn,iacbhdaosmipnosaslibflae,)hweaerrte, c(oalplpecrtoexdiamnadtefl3lyasgh-efarcohz,einfipnoslsiqiubilde)n,itarnodgebnile andstoredin afreezer,set to maintain -60to -80C,unlshipped tothesponsor. RESULTS AND DISCUSSION i Mortality All animals survived to the scheduled sacrifice at Day 367. | `MTahcerreoswceorpeincoOmbascerrovsactoipoincsobservations. i : "o- 000040 em ee e Lo i Scaogymeme2s10 "RobertA. Leedle, DVM, PhD Date Diplomate,ACVP {i no 000041 - CSovMieTr62o9e-2m6n8 Protocol Deviations Protocol Husbandry. Environment. "Environmental controlsfortheanimalroomwill be set to v `maintain cycle." 18 to 29C, arelativehumidity of 30to 70%, and a 12-hour light/12-hourdark AOcntuDaalysPr3o5c2edaundre366 the light cycle was inadvertently interrupted. Protocol ObservofaAtniimaolsn. Clinical Observations. "Once `weekly,eachanimal will be observed;abnormalfindings,oranindicationthattheanimal isnormalwillberecorded." Actual Procedure During Week1,onemaleandeachfemalehadanobservation ofnormalrecordedmore than once. On Day `was not 28 the weekly observations recorded when appropriate, were made by exception, and an indicationofnormal : During Week29, therequiredobservationofnormalorabnormalwasnotrecorded "weekly"forAnimal No. immediately followed the 105552. previous The obserwvaasrteciorodend on Day week's scheduled normal observation 197, day. which The observation should have been recorded on Day 203. Observation ofAnimals. Body Weights."Monthly" Actual Procedure `The animals wereweigohn eDady 1 andagainon Day7, inordertoaccommodate the `weighing schedule of the remainderof the stockcolony. Protocol SerumPFOS Level Determination. `Sample Handling. "Samples will be centrifuged `within 1 hour after collection, andserumwill be harvested. Serum samples will be stored in a freezersetto maintain-60to-80C." Actual Procedure `Samples collected on Day 114 were centrifuged several minutes after 1hour had clapsed from the time of collection. On Day 226, documentation was not made`regardingthestorageofserumsamplpreiosr to centrifugation and after harvest. i 000042 : -u- - SremCs onMes e329s268 Protocol cUboerliflnaeescttaeendd;douFvreeircnneeisg(hPatpF.pO"rSoxLiemvaetellDyet2emrmLi)naatnidonf.eceMset(ahpopdrooxfiCmoaltleecltyi5ong.ra"mAsn)iwmialllsbewillnot .. Actual Procedure `TheamountofurinecolleocntDeady 113 cabnen vero ifit ed. "The documentationforfecal collectoinoDnays 113 indicates "at least" rather than "approximately" 5 grams were collected. Protocol 1 PoKisdtnmeoy,rtsepimcPcrn,octehdyurorieds,.brAadnd,itaibodnoamliTniaslsufeat,anhdeaSre,r(uamppSraomxpilmeast.ely"S3ampelaecsho,iffpluonsgs,ible), asncdhbeidluleeadnadnsderuunmsc(heeadcuhlaedssmaucrcihfaicsepso."ssible) willbecollected fromanimalsat AScetruuamlwParsocneotducrolelected from three ofth four monkeys at the necropsy. Thesedeviationsarenotexpectedto haveaffectedtheresults of thstudy. i; un 000043 i eee _-- ------------------------------ CTomeensier9a2s6s8n Frat Conca 020288 MeanBodyWeightData(kg) -MalesandFemales E SEO RECC O C ST AFL ToONoO EnMA eePWOsETAEGKSCCaMrG SCETPorRoOaTTYa o_O 5 vas --aFamos -f-------- 2 pr--- | -_ essen rgene RS -- eee asgd --_-- TOr S To -- N15 -- 02 2-- 027 -- HH m-- w @ a--4e d tow? Wook ne - 00044 -- ives-------------- ( _-- Comino ee uremsn "Table 1:IndividualClinicalObservations Sn Fimsssns murs Gt BO tnt ue 000045 EE { -_-- ------ ER ---- [ etla-- nsi po er CEE, on or 330 cto em es po, ise 000046 | aei tn t! -_-- am wiremm | FUER LEEeeMU ST oe Fhe agarose I Br Tl Bt oe 000047 --_-- em || ec---------------------------- I~ 000028 - - titti i----e -- s | -_-- 000 [m--Se--eEnRa | es tv en nis E CiW t IL e BE eT TE il iI7 (EXTENOED XECOURNYS105 POLLING A 26-wemKCAVEULSvoETCITY Bis i we CINE a" 000049 . | ete--------------------------.. comuenan -_-- TShesin eons soy i es 0 || | i. 200050 oe | = oem ammenities orema | | Table:Tn Ano PalosDut a A-- fi 900051 : Sa s m--------Ao-- A AA -- AI-- TAI-- Ss : | _-- Conuanre3e8s8 a 000052 we Te || : a teagei gs | EYEBOE SEER Smee a 00053 - [ ke (Es Rrr IE" en REE ST RT We SETI a. "00054 |