Document zdq5NzVkOmE40jag3YDk5bmJz

HH9o no0r5shSahme,ehPPyAADri1Cvb9e,H0i4LdA0 Tekfax: (215) 43.8567 AR Q26- 1206 ~~ CharAleRsGRiUyvSerRLaEbSorEaAtoRrCieHs Discovery and Development Services Deanna J. Lucbker, M.S. 3M 3M MCoerdpiocraalteDeTpoaxritcmoelnotgy S3tM. PCaeunlt,eMri,nBnueislodtian.g52521404--2100020 Telephone: Telefax: ((665511))773373--11377743. 4 November 2002 _ s=ank Ted& 1 V1 RE: Protocol 418-018 Dear Ms. Leubker: AOcnied/GCehnoelreasttieornolRCehparloldeuncgteioannSdtNudOyEoLf PInFvOesSti-gaMteivoanlionniRacts Sponsor's Study Number: T-6295.25 CertificEanticolnosoefdAuatrheetnhteicoirtiygifnralomGoEoxdygLeanboSrtguodryy02P3ra-c0t6i9c.e Compliance Please sign tShteasteedmoenctumaenndts and return them to Argus. If you have any questions, please do not hesitate to contact me. Sincerely, plunge oc Raymond G. York, Ph.D., DABT aAsnsdocSitautdey DDiirreeccttoorrof Research BL z 38 we E 20 ARGuY;jf = Apsdez 418-018:PAGE I-1 TITLE: ONE GENERATION REPRODUCTION STUDY OF NPFOOESL-IMNEVVEASLTIOGNAITCIOANCIIDN/RCAHTOSLESTEROL CHALLENGE AND ARGUS RESEARCH PROTOCOL NUMBER: 418-018 SPONSOR'S STUDY NUMBER: T-6295.25 I. SUMMARY AND CONCLUSION `The purposes of this study were to determine whether the co-administration of mevalonic acidor cholesterol could prevent or antagonize the adverse maternal and fetal effects (reduced matemnal body weight gain, increased incidence of stillborn, decreased birth RweeisgehatrcahndPrdoetcocroelas4e1d8-p0u0p8,sur3vMivaSlt)udoybsNeurvmebdeirnTa-6p2re9v5i.o9u)sasntdudtyo wbietttherPdFeOfSine(Atrhgeunsoobserved-effect-level (NOEL). A. Methods' rFeecmeailveedCirnlt:wCoDs(hSipDm)enItGsSdBesRigVnAaFte/dPlasusReplraitcsatweer|eaunsde2d,froersptehcetisvteuldyy.. The rats were The rats were rreapnldicoamtleyfaorssGirgonuepdsto1,123,d4ostahgreouggrho7u,ps12(Garnodup1s3, |1t4hrraotusgfhor13G)r,o1u4pr3atrseppelircgatreou1p, p1e5rrats for Group 3, replicate 2, and 10 rats per group per replicate for Groups 8 through 11. The cfiornstfieirgmhetdfdeamtaeloefrmatastpienrg dwoesraegeasgsriogunepdintoGCraoeuspasrea| nt-os7e,ct1i2onainndg 1o3nodfaRyep2l1icoaftgees|twatiitohna (DG 21). The remaining female rats article was perfluorooctane sulfonic were permitted to acid potassium salt naturally (PFOS) deliver and the liters. conirol The test articles `woesrmeosmiesvmaelomnbircaanceidpraoncdescshoeldesdteeirooln.izeTdhweatveehri(clReOsDwIerHe;00)..5% Tween 80 and reverse a. pDreotaviildeedddienstchreipatpipornosporfiaatlel spercotcieodnusreosf tuhsiesdreipnotrhteacnodndiuncAtPoPfEthNiDs IstXudCy are (PROTOCOL AND AMENDMENTS). 000003 418-018:PAGE 1-2 `The dosage groups and dosing schedule were as follows: Dest Grogsnd on St 12h <1y mints |p Shea oe na] [NTIumTbeE|r| EcVIedeeEtntntifeticCaotniosnol |I_RSOmDaIhHgse0 | I 05af5teTr I--swt donsag30 | rn2nod dbolsagin] IEI Terr TRTe | emes IE Sms EE 2 mg/kg PFOS + I 500 mg/kg. EE 500 mg/kg [[ ETra rgrrerenTT CeSoooeto, 0_5|_%16TmueepearpoR03s0-| Norgpleaic [IFETGE nasT 705 [0 rhepFos Forappcaoc| GCaimmpgihegFPrrooss|Narmpicane | |Nouaptcstc| 1mpiaPFs|Forappicane | [TT Tamgkerros | Noite |m3pkg|pNroramoicnse | `The dosages, concentrations and dosage volumes were as follows: rrel or T----R FR [0R5%OTDweEenO8[ 0| 0 0-- 1 |-- fp ----T------------ 6 |----5 [| MevCahloloensiecrAolig[|50T0 oo[joo joo [|5+ 5 [ [PPrO oS s T --T oa0 |8 o0s 0 | | 5 5 1 -- --] ] [pros 11 [pros 117 0p | 5s --] 0p [5] [pros -- eT Leos 1 16 Tom 2 1ow 1 5 15] Dosages were approximately adjusted for the the same times most each recently day. recorded body weight and given at 000004 418-018:PAGE 1-3 The rats were given the test article, control article and/or vehicle daily beginning 42 days before cohabitation (maximum of 14 days) and continuing through DG 20 (rats assigned to Caesarean-sectioning), DG 24 (rats assigned to natural delivery that did not delivear litter) or day 4 of lactation (DL 4, rats that delivered a litter). F1 generation pups were not directly given the test article, control article and/or vehicle, but were possibly exposed to the test article or control articles during maternal gestation or via maternal `milk during the lactation period. Rats were observed for viability at least twice each day of the study. Observations for clinical signs of effectsof the test article and deaths were made daily prior to dosage administration, approximately one hour after the second dosage and at the end of the working day. These observations were also recorded on the day of sacrifice. Body weights were recorded weekly to cohabitation, daily during presumed gestation, on DL1 (rats assigned to natural delivery) and at sacrifice. Feed consumption values were recorded weekly to cohabitation, on DGs 0, 7, 14, 21 and 25 (if necessary) and DLs 1 and 5 (rats assigned to natural delivery). Mating was evaluated daily during the cohabitation period and confirmed by observation of spermatozoa in a smear of the vaginal contents and/or a copulatory plug observed in situ The rats assigned to natural delivery were observed for adverse clinical signs during parturition, duration of gestation and pup viability at birth. The rats were also observed for fertility index, gestation index, number of offspring per litter, number of implantation sites, general condition of the dam and litter during the postpartum period and viability index. Maternal behavior was recorded on DLs 1 and 5. Litters were examined after delivery to identify the number and sex of pups, stillborns, live births and gross extemal alterations. Each litter was evaluated for viability at least twice each day of the 5-day postpartum period. F1 generation pups in each litter were counted once daily. Physical signs were recorded each day. Pooled litter weights were recorded on DLs 1 (birth, liveborn pups), 2, 3,4 and 5. Eight rats from dosage groups 1 t0 7, 12 and 13 (Replicate 1) were sacrificed on DG 21 Blood and liver samples were collected from these rats. The rats were Caesareansectioned and a gross necropsy of the thoracic, abdominal and pelvic viscera was performed. `The numberof corpora lutea in each ovary was recorded. The uterus of cach rat was excised and examined for pregnancy, number and distribution of implantation sites, live and dead fetuses and early and late resorptions. Placenta were examined for size, color and shape. Blood samples were collected from the rats assigned to Caesarean-sectioning. Following collection of blood samples, the liver of each rat was excised and the liver weight was recorded. A portionofeach liver sample (right lateral lobe) was flash frozen and - 8400S 418-018:PAGE 14 pmoaritnitoaninoefdthferolzievne.r wTahsefmiexeddiainn glliuvteerrlaolbdeehwyades.frTozheen.reAmasiencitnigonpofrrtoimonthoef trheemaliinveirngwas frozen. Fetuses were pooled by liter and litter body weights collected from each fetus. The liver from cach fetus were recorded. was collected. Blood samples were One fetal liver from eliatctehr lwiettreer wdiavsidreedmoinvteodtharnede fsiaxmepdliensgolfuteeqruaalldenhuymdbee.r.ThTewroemoafinthiengsafmetpallelsivweerrseinfreoazcehn. `The remaining samples were flash frozen in liquid nitrogen and maintained frozen. OthnorDacLicS, atbhedormatisnaalssaingndepdeltovincatvuirsaclerdaelwiavserpyewrefroremseadc.rifBilcoeodda,nmdilak,grhoesasrtneacnrdoplisvyeorf the sblaomopdlessamwpelrees,cotlhleechteeadrtfarnodm lmiavteremofalearcahtsdoanmDwLer5.e cFoolllelcotweidn.gTcholelelcitvieronwoeifmghitlkwaasnd rmeacionrtdaeid.nedAfrpoozretn.ionTohfeemacehdilainvelrisvaermplolbee(wriagshtstlaotreerdalfrloozbeen). waTsheflhaesahrtfraonzdenaasnedction pforrotmiotnheofretmhaeilniivnergwpaosrtfiroonzoenf.the liver were fixed in gluteraldehyde. The remaining sOinngDleLScr,ospsu-psesctwieorne osfactrhiefhiceeaddaantdtheexalemvienleodfftohre gfrroosnstalle-spiaornise.talNescutruorpesaynidncelxuadmeidnaation of the cross-sectioned brain for apparent hydrocephaly. from each pup. Blood samples were collected For Replicate 1, pups combined. blood samples For Replicate were pooled per 2, blood samples litter, were samples from male and female pooled (two litters per sample `liwtittehri)naenadchthdeopsoaogleedgrwouepi)g.htTrheceorldievder. frOonmeelaicvherpfurpomwaesaccholllietctteredp,ooploowlaesd r(ebymosveexdpearnd `fsiaxmepdleinsgolfueteqruaalldneuhymdbee.r.ThTewroemoafitnhiengsalmipvelressiwneeraechstloirtteedr fprooozlenw.erTehdeivriedmeadiniinntog three tsawmopmlaelweaasndfltaswhoffreomzaenleapnudpmsaifnrtoamineeadchfrloizteenr.(pTohoelehdebarytssewxerpeercoliltlteerc)teadndfrwoemrethfeifxierdst in gluteraldehyde. retained. Thyroids were excised from each pup, pooled (by sex per litter) and MfiecmraolsecFoIpigceneexraamtiinoantpiounp wfarosmmdaadmesooffteheachheaorfttahnedvtehhyircloeidcofnrtormolon(eGrmoaulpe1a)nadnodne 2 mg/kg/day PFOS groups (Group 13). B. Results N(moevdaelaotnhiscwaecriedactotnrtirboult)a,bl3e(t1o.6thmegt/ekstgoPrFcOonStr+olmaervtaiclloens.icOanceid)raatnidn e5a(cchhooflesGtreoruolps 2 csounrtvriovle)ddtioedscahsetdhuelerdessualctriofficien.tubation accidents or natural causes. All other rats 000008 418-018:PAGE 15 d`Tuhreinngumgebsetrastioofn rwaetsrewistihgneixfciceasnstlsyaliinvcatrieoans,eda ipnerGiroroaulpsSub(smteavnacleoannidc cahcirdomcoornhtrionlo)rrashea t`hceomtpaastreedoftomeGvraoluopni|c(avceihdi;cltehecoinntcroild)e.nceThoefsteheisnecroebasseersvawteiroensatwtarisbuctoemdptaoraanblaevearmsioonngto dthueritnhgretehemepvraelcoohnaibcitaactiidong,roguesptsat(iGornouapnsd 2, 3 and lactation 4p).eriAoldlsotwheerreccloinnisciadleorbesdeurnvraetliaotnesd to the test or control articles. test or control articles. All necropsy observations were considered unrelated to the iTnerGmrionuaplsb6odayndw7ei(g1h.t6saonfdr2atmsgC/akesgarPeFaOn-Sse+ctchioolneesdteornolD, Gres2p1ecwtievreelys)i.gniTfhiecawnteliyghrtedoufctehde ilnivGerrowuapsss6iganinfdic7anatnldy tihnecrienacsreedasiendGlrioveurpw7e.igAhst ainrGesruoltupof7,thtehererdatuicoesdotfetrhmeinlailvewrewiegihgthst t0ertmhienatlerbmoidnaylwbeoigdhytsw,eilgihvterwweerieghstisgnainfidcraenltaltyivienclrievaesrewdeiinghtthsesoeftrwatosgCraoeuspas.reaAnl-l other sectioned on DG 21 were unaffected by PFOS or mevalonic acid, Terminal (2 mg/kg bPoFdOySwaeliognhet)saonfdniantuGrraolluypsde6liavnerde7d rats (1.6 waenrde2simggn/ikfigcaPnFtlOySre+duchcoeldesitnerGorlo,up 13 sriegsnpeicftiicvaenltyl)y.inTchreearsaetdioisn oGfrothuepsli9v,er1w1eiagnhdts13to(0t.h8e, t1e.r2mainnadl2bmogd/ykwgeiPgFhtOsSwaelroene, rienslpievcetrivweeliyg)h,trsefilnetchteisneg sglrioguhpts.redTuhcetiloinvserinwetiergmhitnawlasbosdiygniwfeiicgahnttlsyainndc/roerassleidghitn iGnrcorueapse3s w(1e.i6ghmtg/wkegrePsFiOgnSif+icmaentvlayloinncirceaasciedd).inTGhreourpatsio3saonfdth4e(l1i.v6eranwdei2ghmtg/tokgthPeFteOrSmi+nal body mevalonic acid, respectively) cholesterol, respectively). and in Groups 6 and 7 (1.6 and 2 mg/kg PFOS + GBrooduypwe1i3g(h2tmgga/iknsgfPoFr OthSe aenltoinree)parnedcoGhraobiutpasti6onanpder7io(d1.w6earneds2igmnigf/ikcagntPlFyOrSe+duced in Gchrooluesptser6ola,ndre7speocntiDveSlsy)2.2 tD0ur2i9nagntdhi2s9petroi3o6d;, agnaidnisnwGerroeuspig1n3ifoincaDntSlsy r2e9dutoce3d6.in rAdeddiutcieodnaolnlyD,Sbsod2y9 1w0ei3g6htangdaibnosdfyorweGirgohutplo1s2s(o1c.c6umrrge/dkginPtFhiOsSgraoluonpeo)nweDrSess3i6gntiofi4c2a.ntly oAns DaSrses2ul9t,o3f6tahnedse4c2h.anBgoeds,ybwoedigyhwtegiagihntss fwoerrtehesiegnntiifriecapnrtelcyohraebdiutcaetdioinnpGerroiuodpsin6 and 7 bGordoyupwe5ig(chhtolgeasitnesrowlercoenturnoalf)fewcetreed sbiygnmiefvicaalnotnliycinaccriedasaend.d dPorseamgaetsionfgPbFoOdSy waesihgihgthsaasnd 12 mfg. GBrooduypswe6igahntdg7ai(n1s.6foarndth2e emngt/irkeggPesFtOatSio+ncpheorlieosdtewreolr,erseisgpneicftiicvaenltyl)y.rGedruocuepdso3nlayndin4 (1.6 and 2 mg/kg 2 mg/kg PFOS + PFOS + mevalonic acid, cholesterol, respectively) respectively), Groups and Groups 9, 11, 12 6 and 7 (1.6 and 13 (0.8, and 1.2, 1.6 and f2irmstg/wkegekPoFfOtShealgoenset,atrieosnpepcetriivoed.ly)Thhaedresiwgenrifeicnaontsliygnriefdiucacnetddbiofdfeyrewneciegshtamgoainngs afnorytohfe these dosage groups during the second week of gestation. Group 13 had a significant bean 418-018:PAGE 1-6 increase in body weight gain during the third week of gestation. Body weights were significantly reduced in Group 12 (1.6 mg/kg PFOS alone) on DGs 2 through 16, and in Group 13 (2 mg/kg PFOS alone) on DG 0 through 19. When PFOS was administered along with mevalonic acid, the effect on body weight was less severe and appeared over a shorter period than PFOS administered alone. Body weights were significantly reduced in Group 3 (1.6 mg/kg PFOS + mevalonic acid) on DGs 4 through 13, and in Grou4p (2 mg/kg PFOS + mevalonic acid) on DGs 7 through 10. The effect on body weight was more severe and appeared over a longer period when PFOS was administered along with cholesterol. Body weights were significantly reduced in Groups 6 and 7 (1.6 and 2 mg/kg PFOS +cholesterol, respectively) on DGs 0 through 21. Gestation body weights were significantly increased in the cholesterol control group (Group 5) on DGs S, 8 through 17 and 21. Despite this effect of cholesterol alone, body weights in the groups administered PFOS with cholesterol (Groups 6 and 7) had significant reductions in gestation body weights Body weight gains during the first five days of the lactation period were significantly reduced in Groups 9, 10, 12 and 13 (0.8, 1, 1.6 and 2 mg/kg PFOS alone, respectively). `The average body weight on DL 5 was significantly reduced in Group 13. When PFOS was administered along with mevalonic acid, the effect on body weight was less severe than PFOS administered alone. Body weight gains were significantly reduced on DLs | 15 in Group 3, but average body weights on DL 1 and S were comparable among Groups 2, 3 and 4 (mevalonic acid control, 1.6 and 2 mg/kg PFOS + mevalonic acid, rweesipgehcttivwealsy).morWehesenverPeF. OSBowdays waedimgihntisstoenreDdLaslo|nganwdit5hwcehroelesstiegrniofli,catnhteleyfrfeecdtuocendbiondy Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively) and a significant body weight loss occurred on DL 110 5 in Group 7. Absolute and relative feed consumption values were significantly reduced in Group 13 (2 mg/kg PFOS alone)forthe entire premating period and within this period on DSs 8 to 15 relative only), 22 t0 29, 29 to 36 and 36 to 42. Absolute and relative feed consumption values were also significantly reduced in Group 12 (1.6 mg/kg PFOS alone) during the last week of the premating period. Absolute feed consumption values were significantly reduced in Groups 3 and 4 (1.6 and 2 mg/kg PFOS + mevalonic acid, respectively) on DSs 22 t0 29 and 36 to 42. Relative feed consumption values were significantly reduced in Groups 3 and 4 on DSs 8 to 15, 15 10 22, 22 t0 29 and 36 t0 42 (Group 4 only). This effect of PFOS and mevalonic acid was reflected in the significantly reduced absolute and relative feed consumption values for the entire: premating period in both groups. When PFOS was administered along with cholesterol, the effect on feed consumption values was more severe. Absolute and relative feed consumption values were significantly reduced in Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively) on DSs 22 t0 29, 29 to 36 and 36 to 42. This effect of PFOS and cholesterol was reflected in the significantly reduced absolute and relative feed `consumption values for the entire premating period in both groups. Relative feed consumption values on DSs to 15, 15 t0 22,2210 29 and 1 to 42 were significantly increased in the mevalonic acid control group (Group 2). Absolute and relative feed consumption values were significantly increased on DSs 29 to 36 and absolute feed 208003 418-018:PAGE 1.7 consumption (Group 5). was significantly increased on DSs 36 to 42 in the cholesterol control group wAbeseokluotfegeasntdatrieolnatiinveGrfeoeudpcso9nstuhmrpoutgihon12va(l0u.e8s, were significantly reduced during the 1, 1.2, 1.6 and 2 mg/kg PFOS alone, first Grersopuecpti1v3eloyn).DGAbsso7l1u0te14f,eeadndcornelsautmipvetifoenedcconotnisnuumepdtitoonbewasisgnsiifginciafnitclayntrleydiunccerdeaisned in pGerroiuopd (1D2Gosn0DG10s211)41w0er21e. siAgnbisfoilcuatnetlyfereeddcuocnesduimnpGtrioounpvsal1u2esanfdor1t3he(1e.n6tiarnedge2stmagt/ikogn. ePfFfeOcStsaolnonfee,erdescpoencstuivmepltyi).onWvhaleunesPwFeOrSe cwoamspaadrmaibnliestteortehdeaelfofnecgtswoifthadmmeivnailsotnriactiaocnido,f aPnFdO4S(a1l.o6nea.ndA2bsmogl/ukteg fPeFeOdSco+nsmuemvpatlioonnicvaalcuied,s rweesrpeecstiigvneilfyi)caonntlDyGrsed0u1ce0d7,in7Gtroo1u4psan3d 00100D21G.s0R1e0la7tiavnedf7eetdoc1o4n.suWmhpetnioPnFvOalSuewsawseardemisniginsitfeirceadntallyornegdwuictehd cihnolGersotuerposl,3eafnfedct4s PonFOfeSedalcoonne.sumAbpstoilountevafleueeds cwoenrseuamlpstoicoonmvpaalruaebslweetroetshiegenfiffeicctasntolfy ardemdiunciesdtriantiGornouofps 6 and 21. 7Re(l1a.t6ivaendfe2edmgc/onksguPmpFtOiSon+cvhaollueesstwereorle, sriegsnpiefcitciavnetllyy)roenduDcGeds 010 7, 7 to in Groups 6 14, and 0 and 7 on to DGs 0107 cholesterol, and significantly respectively) on increased in Groups DG 14 to 21. 6 and 7 (1.6 and 2 mg/kg PFOS + sAibgsnoilfuictaentfleyedrecdouncseudmpintiGornouvpaslue1s2 daunrdin1g3 t(h1e.6fiarsntdf2ivemgd/akygsoPfFtOhSe laalcotnaet,iornesppeercitoidvewlye)r.e R1e3l,arteiavcehifenegdstcaotnisstuicmapltsiiognnivfailcuaenscefoirn the same period were Groups 9, 10, 11 and reduced 12 (03, in I, Groups 1.2 and 9 through 1.6 mg/kg aPcFidO,Sefafleocntes,ornesfpeeecdticvoenlsy)umvpatluieosn. vWalhueens wPeFrOeSalwsaoscoamdpmainriasbtleeretod tahleonegffweicttshomfevalonic saidgmniinfiisctarnattliyorneodfucPeFdOiSn Galroonuep.sA3bsaonldu4te(1a.n6darnedla2timveg/fkeegdPcFoOnsSum+pmteivoanlvoanliucesacwide,re erfefsepcetcstiovnelfye)eodncoDnLssum1pttoio5.n When values PweFrOeScowmapsaardambilneisttoetrheed along effects with cholesterol, of administration of iPnFGOrSouaplosn6e.anAdbs7ol(1u.t6eaanndd2remlgat/ikveg fPeFedOSco+ncshuomlpetstieornolv,alrueesspewcetriveelsyi)gnoifnicDaLntsly1 roed5u.ced r`aTthsewniutmhbceornfoifrdmaeydsmiantcionhgabdiattaetsiodnu,ritnhge ftehretifliirtsyt aanndd psreecgonnadnwcyeeikndoifcecsohaanbdittahteionnumwbeerer of `cwoemrpeabraasbeldeoinn etihgehtthiprrteegennadnotsdaagmesgrionupesa.chCoafesGarroeuapns-s1ectthiroonuignhg7o,bs1e2ravnadtio13n.s on DG 21 PNFoOCSaeaslaorneeano-rsaedcmtiinoinsitnegroerd ltr with peaitrhaemrectheorlseswteerreolaofrfemcetevdalboyndiocsaacgide.s up to 2 mg/kg. gTortoaulpss.ofTh17etdour2a0tiroatnsowfegreestparteigonnawntasansdigdaiefliicvaenrteldy lrietdeursceidn einacGhrooufptshe91t3hdroosugahge13 (0.8, P1,FO1.S2, +1.m6eavnadlo2nimcg/akcigd,PrFeOspSecatliovneel,y)r,esapnedctGirveoluyp),s G6raonudps7 3(1a.n6da4nd(12.6mga/nkdg2PmFgO/Skg+ cholesterol, respectively). The number of dams with all pups dying on DLs 1 to 5 was 000009 418-018:PAGE 1-8 increased in Groups 13, 3,4, 6 and 7; the increase was significant in Groups 13,4 and 7. `The pup viability index was significantly reduced in Groups 12 and 13 (1.6 and 2 mg/kg PFOS alone, respectively), Groups 3 and 4 (1.6 and 2 mg/kg PFOS + mevalonic acid, respectively), and Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively). `The numbers of pups that died or were presumed cannibalized on DL | and DLs 20 5 was significantly increased in Groups 12, 13, 4, 6 and 7. The numbers of surviving pups. per liter were significantly reduced on DLs 2,3,4 and 5 in Groups 12, 13, 3,4, 6 and 7. A dosage-dependent pattem of reduced pup body weight was evident on DLs 1,2, 3,4, 5 and/or 110 5 in cach group administered the test article. Groups 11, 12.and 13 (1.2, 1.6 and 2 mg/kg PFOS alone, respectively), Groups 3 an4d (1.6 and 2 mg/kg PFOS + mreesvpaelcotinvieclya)cihda,dressipgencitfiivcealntyl)yarnedduGcreoduppsup6 baonddy7w(e1i.g6hatsndo2n mmogs/tkgwePiFgOhSing+ dcahyosle.stWerhoel,n average pup weight was normalized for litter size, Groups 3 and 4 (1.6 and 2 mg/kg PFOS + mevalonic acid, respectively), Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively) and Groups 8, 9, 10, 11, 12and 13 (0.4, 08, 1, 1.2, 1.6 and 2 mg/kg/day PFOS, respectively) were also significantly reduced from Group 2 (mevalonic acid control, Group 5 (cholesterol control) and Group 1 (Vehicle Control), respectively, over the same days of lactation. Adverse clinical and necropsy observations associated with reduced pup viability and potential reduction in maternal care occurred in Groups 11, 12 and 13 (1.2, 1.6 and 2 mg/kg PFOS alone, respectively), Groups 3 and 4 (1.6 and 2 mg/kg PFOS + mevalonic acid, respectively), and Groups 6 and 7 (1.6 and 2 mg/kg PFOS +cholesterol). Increased numbers of and 7. The litters with pups number oflitters that were cold with pups not to touch occurred in Groups 11, nursing was increased in Groups 12, 12, 13, 4,6 13, 3, 4, 6nd 7; the increase was significant in Group 7. Necropsy observations in pups that were stillborn or found dead included increases in the numbersofpups with no milk in the stomach in Groups 9, 10, 11, 12 and 13 (0.8, 1, 1.2, 1.6 and 2 mg/kg PFOS alone, raensdpeGcrtoivueplsy)6, Ganrdou7p(s13.6aanndd42(m1.g6/akngdP2FOmgS/+kcghoPlFeOstSer+olm,evreaslpoenctiicvealcyi)d., rTehspeecitnicviedley)n,ce of this observation was significantly increased in Group 6. All other clinical and necropsy observations in the FI generation pups were considered unrelated to the test article. Clinical chemistry parameters were generally unaffected in the DG 21 dams that were treated with or without cholesterol and 1.6 or2 mg/kg PFOS. Total and free T; and Ty in dams administered 1.6 or 2 mg/kg PFOS with or without mevalonic acid or cholesterol were significantly reduced. The LDL was significantly increased in the dams that were `administered mevalonic acid and PFOS. Liver cholesterol levels were significantly reduced in DG 21 dams administered 1.6or 2 mg/kg PFOS and in DG 21 dams sciogandimfiinciansttleyrerdedmuecveadloinniDcGac2i1d daandms1.c6oaodrm2inmigs/tkegrePdFmOeSv.aloLniviecratcriidgolryccehriodleeslteevreollsawnedre 1.6 or 2 mg/kg PFOS. LiverLDLand HDL levels were increased or significantly increased in dams coadministered cholesterol or mevalonic acid and 1.6 or 2 mg/kg PFOS. 000010 418-018:PAGE 19 Cholesterol and LDL were significantly increased in the fetuses from dams that were treated with 1.6 or 2 mg/kg PFOS. Free Ti was significantly reduced in the fetuses from dams that were treated with or without cholesterol or mevalonic acid and 1.6 or 2 mg/kg PFOS. Cholesterol and LDL were significantly increased and triglycerides were significantly decreased in the fetuses from dams that were treated with mevalonic acid and 1.6 and/o2r mg/kg PFOS. The clinical chemistry parameters of cholesterol, LDL and HDL were significantly increased in the fetuses from dams that were treated with cholesterol and 1.6 or 2 mg/kg PFOS. Liver cholesterol and triglyceride levels were increased or significantly increased in DG 21 fetuses from dams coadministered mevalonic acid or cholesterol and 1.6 or 2 mg/kg PFOS. Liver HDL levels were significantly increased in DG 21 fetuses from dams administered 1.6 or 2 mg/kg PFOS aloneorcoadministered mevalonic acid and 1.6 or 2 mg/kg PFOS. Serum cholesterol was significantly decreased in the lactating dams that were treated with 04,08, 1, 1.2, 1.6 or2mg/kg PFOS. The glucose was significantly increased in the DL 5 dams that were treated with 2 mg/kg PFOS alone and triglycerides were significantly decreased in lactating dams treated with 1.6 or 2 mg/kg PFOS alone. Total and free T. levels in lactating dams administered 0.4 (free Ts only), 0.8, 1, 1.2, 1.6 or 2 mg/kg PFOS were significantly reduced and total and free Ts levels in lactating dams administered 1.2, 1.6 or 2 mg/kg PFOS were significantly reduced. Serum cholesterol was significantly decreased in the lactating dams that were treated with mevalonic acid and 1.6 or 2 mg/kg PFOS and cholesterol in the milk was significantly increased in the. lactating dams that were treated with mevalonic acid and 2 mg/kg PFOS. Total and free Ta were significantly reduced in the lactating dams that were treated with mevalonic acid or cholesterol and 1.6 or 2 mg/kg PFOS. Cholesterol in the blood and triglycerides were. significantly decreased in lactating dams that were treated with cholesterol and 1.6 or 2 mg/kg PFOS and glucose was significantly increased in lactating dams that were treated with cholesterol and 2 mg/kg PFOS. Liver triglyceride levels were increased or significantly increased in DL5 dams administered 1.6 or 2 mg/kg PFOS alone and in DL 5 dams coadministered mevalonic acid or cholesterol and 1.6 or 2 mg/kg PFOS. Clinical chemistry parameters were not significantly different in the DL $ pups from lactating dams that were treated with 0.4, 0.8, 1, 1.2, 1.6 or 2 mg/kg PFOS. Free Ta levels in the FI generation pups from lactating dams administered 0.4, 0.8, 1, 1.2, 1.6 or 2 mg/kg PFOS were significantly reduced. Free Ts levels in pups from lactating dams administered 0.4, 0.8 or | mg/kg PFOS were significantly reduced, however, levels were significantly increased, in pups from lactating dams administered 1.6 mg/kg PFOS. Total Ta levels in pups from lactating dams administered 0.4, 0.8 or | mg/kg PFOS were significantly reduced. TSH was significantly increased at 1 mg/kg PFOS. Liver triglyceride levels were reduced or significantly reduced in DL 5 male and female pups from dams administered 1, 1.2, 1.6 and 2 mg/kg PFOS alone and in DL 5 male pups from dams coadministered cholesterol and 1.6 or 2 mg/kg PFOS. Cholesterol, LDL and triglycerides in the blood were significantly increased in pups from lactating dams that were treated with mevalonic acid and 1.6 mg/kg PFOS. Total Ts were significantly decreased in pups from lactating dams that were treated with mevalonic acid and 1.6 mg/kg PFOS. LDL and HDL were significantly increased in the pups from e121 418-018:PAGE I-10 lactating dams that were treated with cholesterol triglycerides were significantly decreased in the and pups 1.6 or 2 mg/kg PFOS from dams that were and treated with cholesterol and 2 mg/kg from lactating dams that PFOS. Total were treated Ts and free T: were with cholesterol and significantly 1.6 and/or 2 decreased in mg/kg PFOS. pups No microscopic changes were seen in the heart or thyroid of the male and female pups `whose dam was exposed to 2 mg/kg/day PFOS (Group 13). C. Conclusion On the basis of cholesterol can these data, prevent or it does not antagonize appear that the adverse coadministration matemal or fetal of mevalonic acid or effects observed in a previous study with PFOS (Argus Research protocol 418-008; 3M study number T-6295.9). 0T.h8emmga/tkegrnaanldnoh-iogbhseerrvdaobslaeg-eesffoefctP-FleOvSelc(auNsOeEdLa)n for this study is increased liver 0.4 mg/kg PFOS (the weight to terminal body weight ratio, absolute and rdeelcarteiavesefdeebdocdoynwseuimgphttioganidnudruirnignggesgteasttiaotnioannadndlacltaacttiaotinoonnadnadysd)e.creased `The reproductive NOEL in the dams is also 0.4 mg/kg (the 0.8 mg/kg dosage decreased the duration of gestation). 0`T.h4emNgO/kEgLafnodrhviigabhielritcyauasneddgdreocwrtehasiendthpeupofbfsopdryinwgeiisghltessswthheann0n.o4rmmagl/ikzged(dfoosralgiettserof size). L' e FaSlealed) Geor . Dearlove, Ph.D., DABT Associate Director of Research Dee Date x) vod A Wo SD2E 00 ond G. York{Ph.)., DABT Date Associate Director of Research and Study Director soamtz 418-018:PAGE II-1 IL DESCRIPTION OF TEST PROCEDURES A. ConductofStudy Al Sponsor 3M Corporate Toxicology, 3M Center, Building 220-2E-02, St. Paul, Minnesota 55144-1000 A2. Testing Facility Argus Research, 905 Sheehy Drive, Building A, Horsham, Pennsylvania. 19044-1297 AJ. Study Number 418.018 Ad. Sponsor's Study Number T-6295.25 AS. Purpose of the Study "The purposes of this study were: 1) to determine whether or not co-administration of mevalonic acid or cholesterol can prevent or antagonize the adverse maternal and fetal effects (reduced matemal body weight gain, increased percent stillborn, decreased bith weight and decreased pup survival) observed in a previous study (Argus Research Protocol 418-008, 3M study number T-6295.9); and 2) to better define the no observed effect level (NOEL). A6. Study Design `The requirements of the U.S. Food and Drug Administration (FDA) were used as the basis for the study design. A. Regulatory Compliance `The requirements of the U.S. Food and Drug Administration (FDA) were used as the basis for the study design. "The study was conducted in compliance with Good Laboratory Practice (GLP) regulations of the U.S. Food and Drug Administration (FDA), the Japanese Ministry of Health and Welfare (MHW) and the European Economic Community (EEC). There were no deviations from the GLP regulations that affected the quality or integrity of the study. Quality Assurance Unit findings derived from the inspections during the conduct of this study are documented and have been provided to the Study Director and the Testing Facility Management. 088813 418-018:PAGE 11-2 AS. Ownership of the Study `The Sponsor owns the study. All raw data, analyses, reports and preserved tissues are the property of the Sponsor. AS. Study Monitor DeannaJ. Luebker, M.S. A.10. Alternate Study Monitor John Butenhoff, Ph.D., DABT, CIH AJL Study Director Raymond G. York, Ph.D., DABT A12. Technical Performance John F. Bamet, B.S. (Director of Laboratory Operations) `Todd J. Killino, B.S. (Research Associate) Alaine L. Casey, A.S. (Laboratory Technician) Brian K. Kelsch (Necropsy Laboratory Technician) Christopher K. Ruppert, B.S. (Formulation Laboratory Technician) A.13. Report Preparation Raymond G. York, Ph.D., DABT Jo Ann Frazee, M.S. (Study Coordinator) Pamela J. Shufelt, B.S. (Data Management Team Leader) Cristina Petrescu (Report Administrator) A.14. Report Review Valerie A. Sharper, M.S. (Directorof Study Management) A.15. Date Protocol Signed 21 August 2000 08814 A16. Dates of Technical Performance A.16.a. Replicate 1 Rat Arrival Dosage Period Ra(t4s2 Adsasyisgnbeedfotroe Ccaoehsaabriteaatni-oSnecatnidoncionngtinuing through DG* 20) Rats Assigned to Natural Delivery [t4h2roduagyhsDbGefo2r4e(croahtsabtihtaattdiiodn naontddceolnitvienruainlgiter) or DL" 4 (rats that delivered a litier)] Cohabitation Period Male Male 1 2 (7 (7 days days maximum) maximum) Scheduled Sacrifice DG 25 Sacrifice (DG 21 Caesarean-sectioning) No Confirmed Date of Mating Sacrifice DeSlcihevdeurlyedPeSraicordif(iDcLe (1D)L 5) A.16). Replicate 2 Rat Arrival Dosage Period Rats Assigned to Natural Delivery t[h4r2oduagyhsDbGefo2r4e(croahtsabtihtaattdiiodn naontddceolnitvienruainlgiter) or DL4 (rats that delivered a lite)] Cohabitation Period Male Male I 2 (7 (6 days days maximum) maximum) DOG 25 Sacrifice SDcehlievdeurlyedPeSraicordif(icDeL(1D)L 5) 413-018:PAGE 11-3 22 AUG 00 29 AUG 00-02 NOV 00 29 AUG 00- 18 NOV 00 09 OCT 00 PM - 16OCT00 AM 16 OCT 00 PM - 23 OCT 00 AM 31 0CT 00-03 NOV 00 05 NOV 00-09 NOV 00 17NOV 00 310CT0004 NOV 00- 15NOV00 19NOV 00 05 SEP 00 14 SEP 00 - 02 DEC 00 25 OCT 00PM - 01 NOV 00 AM 01 NOV 00 PM - 07 NOV 00 AM 20NOV 00-23 NOV 00 2160 NNOOVV 0000 -- 2003 NDOECV0000 a. b. DDLGiissaann aabbbbrreevviiaattiioonn ffoorrddaayyooffl(apcrteastiuomne/dp)osgtepsatrattuimo.n. 000815 418-018:PAGE 114 A17. Records Maintained Tvehheicolreigcionamlporenpeonrtt,sraarwe rdeattaainaenddirnetsheervaercshaimvpelseosoffAeragcushRleostcoafrcthh.e coAnntyrolpraersteicrlveedand idrsasfutesfinaarle rreeptoaritn,eadfitnertwhhe iacrhchtiivmeesotfhethSepoTnessotirnwgilFlacdielcitiydefotrheoinrefiyneaal rdaifstpeorsimtaiiolni.ngAltlhe unused prepared formulations were discarded at the Testing Facility. Unused bulk test article was returned to the Sponsor. B. Test Article Information BL. Description Perfluorooctane Sulfonic Acid Potassium Salt (PFOS) - light-colored powder B2. Lot Number 217 B3. Date Received and Storage Conditions The test article was received on 25 August 2000, and stored at room temperature. Bd. Special Handling Instructions `Standard safety precautions `mask and safety goggles or (use of protective safety glasses and clothing, gloves, dust-misVHEPA-filtered a face-shield) were taken when handling the test article. B.S. Analysis of Activity oInnfofirlmeawtiitohntrheegaSrpdoinnsgort.heTihdeentpiutryi,tcyoimsp9o8s.i9t%i.on,AstCreerntgitfhi,caatnedopfuArniatlyyosfisthies taevsatilaratbilceleinis APPENDIX E. C. Control Articles Information C.L. Descriptions Mevalonic Acid - white with a yellow cast, semisolid Cholesterol- white powder C2. Lot Numbers Mevalonic Acid - 070K26603and080K2618 Cholesterol- 119H0218 000816 418-018:PAGE 11-5 C3. Dates Received and Storage Conditions `The mevalonic acid was received from Sigma Chemical Company, St. Louis, Missouri, on 1 August 2000 (lot 070K26603) and 21 September 2000 (lot 080K2618), and stored frozen. The cholesterol was received from Sigma Chemical Company, St. Louis, Missouri, on 20 July 2000, and stored at room temperature. C4. Special Handling Instructions `Standard safety precautions (use of protective clothing, gloves, dust-misVHEPA-filtered mask and safety goggles or safety glasses and a face-shield) were taken when handling the control articles. C5. Analysis of Purity Neither the Sponsor nor the Study Director was aware ofany potential contaminants likely to have been present in the control articles that would have interfered with the results of this study. "The purity of the mevalonic acid is approximately 97%. The purity of the cholesterol is 95%. The expiration dates for the mevalonic acid are August 2004 (lot 070K26603) and September 2004 (lot 080K2618). The expiration date for the cholesterol is July 2004. D. Vehicle Information D.L. Description 0.5% Tween 80 prepared using Tween 80, a yellow liquid, and reverse osmosis membrane processed deionized water (RODI HzO). Reverse osmosis membrane processed deionized water (RODI HO). D2. Lot Number N32477 D3. Dates Received and Storage Conditions `The Tween 80 was received from J.T. Baker, Phillipsburg, New Jersey, on 7 March 2000, and stored at room temperature. Reverse osmosis membrane processed deionized water is availablefrom a continuous source at the Testing Facility and is maintained at room temperature. D4. Special Handling Instructions Standard safety precautions (use of protective clothing, gloves, dust-misVHEPA-filtered `mask and safety goggles or safety glasses and a face-shield) were taken when handling the vehicles 88017 418-018:PAGE 11-6 D5. Analysis of Purity Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the vehicles that would have interfered with the results of this study. The expiration date for the Tween 80 is March 2004. E. Test Article Preparation and Storage Conditions PFOS suspensions and the 0.5% Tween 80 were prepared weekly at the Testing Facility. Mevalonic acid was prepared twice daily in reverse osmosis membrane `processed deionized water. Cholesterol was prepared as a suspension once daily in 0.5% Tween 80. The prepared vehicle (0.5% Tween 80) was stored at room temperature. The prepared test article formulations were stored frozen (-20C). -- El. Sample Information 27 SEP00 _ | Frozen (-20C) po m-- 27 SEP00 5 008013 418-018:PAGE 11-7 E2. Analytical Results Sleavmepllseisn twheereDasyen0t taondEx1y0gsetnabRielisteyaracnhd,cSotnacteentCroaltlieogne,saPmenpnlseyslvbarancikae,tfionrgatnhaelyrsaisn.ge PoFfOS c1o4ncFeenbtrruaatriyon2s00a2ndtcoo1n5diFteibornusaorfyt2h0is02stsuhdyowweedreandeatveerrmiangeed.perAcennatlyrseicsovoefrsyampslteasndoanrd deviation for PFOS in when compared to the the dosing solutions as 93% assigned concentration, which 7w%asannodtrcaonngseiddefrreodmt8o3b5e.% to 105% significant. Results of the stability and concentration analyses are available in APPENDIX F. F. TestSystem Fl Species Rat F2. Strain Crl:CD@(SD) IGS BR VAF/Plus F3. Supplier (Source Charles River Laboratories, Inc.. Raleigh, North Carolina Fd. Sex Female (Note: Male rats were used only for the purpose of breeding and are not considered part of the Test System). FS. Rationale for Test System T1)hethCisrslt:rCaiDno(fSrDa)t hIaGsSbBeeRnVdAemFo/nPsltursaterdattowabse sseenlseicttievdea1s trheepTroedsutcStiyvseteamndbecause: ddeevveellooppmmeennttaall ttooxxiicnistyanedvahlausatbieonesn;w2i)dheilsytoursiecadltdhartoaugahnoduetxipnedruisetnrcyefeoxrisrtepartotdhuectTievsetianngd 4F)actihliistsytr"a;in3h)atshebeteesnt uasrteidclienipsrpehvairomuascorelporgoidcuacltliyonacsttiuvdeieins othfePsFpOeSc.ies and strain; and 000013 418-018:PAGE II- F.6. Test System Data Number of Rats Approximate DateofBirth Approximate Age at Arrival Weight (g) the Day after Arrival Weight (g) at Study Assignment Replicate | 180 27JUN 00 57 days 167-204 196-224 Replicate 2 179 10JUL 00 58 days 170-228 199-247 FJ7. Breeder Male Rat Data Number of Rats AApppprrooxxiimmaattee ADagtee of Birth at Arrival Weight (g) the Day after Arrival WWeeiigghhtt ((gg)) aatt Cohabitation Cohabitation - Replicate Replicate | 2 Shipment | 150 29FEBOO Tldays 245-339 473.767 452-773 Shipment 2 150 20 MAR 00 72days 286-344 537-748 593-791 F38. Method of Randomization FweamsadleesirgatnsatweedreasrReecpeliivceadtein1tawnodsthhiepmseenctosn,dssehpiarpamteendtbwyastwdoeswiegenkast.edTahseRefiprlsticsahtiep2m.ent Upon arrival, the male and female rats were assigned to individual housing on the basis of computer-generated random units. After acclimation, female rats were selected for s`Tthuedyraotsn wteherebaassissigonfepdhytsoic13aldaopspaegaeragnrocuepasn(dGbrooduypswe1itghhrtosurgehco13r)d.edThduerrienwgearcecli1m4atraitosn. per group per replicate for Groups 1,2, 4 through 7, 12 and 13, 14 rats for Group 3, replicate 1, 15 rats for Group 3, replicate 2, and 10 rats per group per replicate for Groups 8 through 11. Computer-generated (weight-ordered) randomization procedures were used to assign rats to groups. The first eight female rats per dosage group in Groups 1107, 12 and 13 of Replicate 1 with a confirmed date of mating were assigned to Caesarean-sectioning on DG 21. The remaining female rats (including those with no confirmed mating date) were permitted to naturally deliver liters F.9. System of Identification Male rats were given unique permanent identification numbers upon assignment to the Testing Facility's breeder male rat population. Female rats were assigned temporary `numbers at receipt and given unique permanent identification numbers when assigned to the study. Each rat was individually identified with a Monel self-piercing car tag (Gey Band and Tag Co, Inc., No. MSPT 20101) inscribed with the rat's designated a See APPENDIX D (DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY), item 1 000820 418-018:PAGE 11-9 nunuimqbueer,pesremx,anteesnttarntuimclbeerid.enCtiafgiecattiaogns were marked with and dosage level. the study number, permanent rat Pups were not individually idenified during lactation, all parameters were evaluated in terms of the litter. G. Husbandry G.1. Research Facility Registration USDA Registration No. 23-R-099 under the Animal Welfare Act, 7 U.S.C. 2131 et seq. G2. Study Rooms Thahlelswtauydaynrdoionmdsepweenrdeenmtaliyntsauipnpeldieudnwdietrhcaonmdiitniiomnsumofopfotseinticvheaanigrefslopwerrehlaotuirveofto a a1n0d0%hufmriedsihtyairwethraetmhoandibteoreendpcaosnssetdantthlryoutghhro9u9g.h9ou7t%tHheEsPtAudyf.ilteRrso. omRotoemmpetreamtpuerreatWuarse {argeted at 64F to 79F (18C to 26C); relative humidity was targeted at 30% 10 70%" G3. Housing cRoahtasbiwtearteioinndainvdidpuoalsltypahrotuusmedperiinosdtsa.inlDeusrsisntgeelc,ohwaibriet-atbiootnt,omaecdhcapgaiers,ofexractespwadusrhinogused ainsstihgenmeadlteo nraatt'usraclagdee.liBveergyinwneirneginnodilvaitdeuratlhlaynhDouGse2d0,inFnoegsteinnegrabtoixoens.femEaalcehrdatasm and dcealgievesriezedslaitnedr hwoaussihnogusceodndiintiaocnsomwemroeninnecsotmipnlgibaonxceduwriitnhgtthheeGpuoisdtepafrotrutmhepeCrairode.aAnldl Useof Laboratory AnimalsTM. G4. Lighting A12n-haouutromsadtaircka,llwyi-tchonetarcohlldeadrkflpueorrieosdcebnetgliingnhtincgycalte1w9a0s0 maintained hours EST. at 12-hours light: G5. Sanitization Cchaagnegpeadnalpipnreorxsiwmearteelcyheavnegreyd oatphperrowxeiemka.telByedthdrienegtwiamesscehaacnhgewedeaks. Cages often as were necessary to keep the rats clean and dry. 2 Sec APPENDIX G (TEMPERATURE AND RELATIVE HUMIDITY REPORTS). 000021 418-018:PAGETI-10 G6. Feed Rats were givenadlibitum access International, St. Louis, Missouri) to in Certified Rodent Diet individual feeders. #5002 (PMI Nutrition G7. Feed Analysis eAxncaeleydsiensgwtehreemraouxtiinmeulmy pceonrcfeonrtmreadtiboyntfhoer fceeretdifsiuepdplfieere.d oNrodecvoinattaimonisnafnrtosmaetxlpeevcetlsed nutritional requirements were detected by these analyses. Copies of the results of the feed analyses are available in the raw data. lNiekietlhyetrothhaevSepobnesenorprneosretnhteiSnttuhdeyfeDeidretchtaotrwwoausldawhaarvee oifntaenryfeproetdenwtiitahl tchoenrteasmuilntsanotfsthis study. G8. Water (LoRcOa.l wwaatteerr)twhaatshaavdaibleaebnleptrooctehsesreadtsbaydplaisbsiatguem tfhrroomugahn aaurteovmeartseicoswmaotesriisnmgesmybstreamne and/or individual water bottles attached to the cages. Chlorine was added to the processed water as a bacteriostat. G9. Water Analysis T(LhaencparsotceerssLeadbowraattoerriiess,anLaalnyczaesdtetrw,iPceenannsnyulavlalnyiaf)orapnodssmiobnltehclhyemfoircaploscsoinbtlaembiancatetriioanl contamination (Analytical Laboratories, Inc., Chalfont, Pennsylvania). Copies of the results of the water analyses are available in the raw data lNiekietlhyetrothhaevSepobneseonrpnroesretnhteiSnttuhdeywDaitreerctthoartwwaosuladwahraevoefiannteyrfpeorteedntwiiatlhctohnetaremsiunlatnstosf this study. G.10. Nesting Material Bed-0'cobs bedding (The Andersons Industrial Products Group, Maumee, Ohio) was used as the nesting material. G.11. Bedding Analysis Analyses for possible contamination are conducted semi-annually. Copies of the results of the bedding analyses are available in the raw data. NliekietlhyetrothheavSepobnesenorpnroesretnhteiSnttuhdeybDeidrdeicntgorthwaatswoauwladrehoafveaniyntpeortfeenrteidawlictohntthaemirnesaunlttss of this study. 000822 H. Methods HI. Dosage Administration The dosage groups and dosing schedule were as follows". 418-018:PAGE [I-11 me 0 |Semcon| Number Identification somnig | woemases| after 1st dosage sono after 2nd dos | Ee RFP Bam RT Tern [mms | {om oTroenmers||oommmeionse||mosmausmnon e| rwwae}} ae|s omonm e|a ranargr ron |o ems i] a See APPENDIX D, items 2 through 4. 208023 418-018:PAGEII-12 The dosages, concentrations and dosage volumes were as follows': FoT e T eTaw TTTe "The rats were assigned to groups as follows: [i]: ne [+[vewecow So [To [angel 2mg/kg PFOS + Epph ger [5 |0empkgPFOS [Jos PFOS [10 tmphgPros oowmor | | on | | 20 T--20 | 20 o[rmomTETT| oam) 10901 -10905, 10907. |10906, 10909,10911, 10908, 10010. 10912_| 10913, 10914 | ion torn tosu | oBotEosEpsss | 1o544-n1557 10945-10947, 10949-|10043, 10944, 10948, [iissaussr_| o[A tBp | =SRR| |Notappiicable |Novapplicable |Notspplicsble pp |tooo ios |T1600 11609 [11009-11018 |now tiozs |1161011619} | 11620-11629. [71029-11038 11630-11639 [+] J-- [=] EE Toes. Hoo. Hoes. ee |110% : a. See APPENDIX D, items 5 through 7. 000024 418-018:PAGE 1-13 H2. Rationale for Dosage Selection Dosages were test article. selected by the Sponsor on the basis of previous studies conducted with the H3. Route and Rationale for Route of Administration Trohueteo,ratlhe(gexaavcatged)osraougteecwaansbseealceccuterdatfeolry uasdemibneicsatuseer:ed; 12))init cios mopnaeriosfotnhewipotshstihbeledireotuatreys of human exposure; and 3) it is the route used in previous reproduction studies on PFOS. Hd. Method and Frequencyof Administration aDpopsraogxeismawteerleyatdhjeusstaemdeftorimtehse emaocshtdraeyc.enDtloysargeceosrwdeedreboaddmyinwiesitgehrteadnadcgciovredninagtto the previous table. for each rat. The mevalonic acid dosing needle was wiped clean before administration 4F2emdaalyes rbaetfsowreerceohgaibvietnattihoent(esmtaaxrtiicmlue,mcoofnt1r4oldaarytsi)claenadndc/oonrtivneuhiincglethdraioluyghbeDgGinn2i0ng(rats adsesliigvneeadr ltiotCear)esoarreDanL-4se(crtaitosntihnagt)d,eDliGver2e4d(araltisttears).sigRnaetdstionntahteurparlocdeelsisvoefrydetlhiavterdiindg.not were daily not given dosages) test/control article; such on the dayofparturition. rats may not have received any or all of their Fbultgweenreeraptoisosnipbluypsexwpeorseednottodtihreecttelsyt garitviecnletdhuertiensgt amrattieclren,aclognetsrtoaltairotnic(lienauntde/roorevxephoisculer,e) or via matemal milk during the lactation period. HS. Method of Study Performance H.S.a. Fo Generation Rats mWailtheirnatepaecrh fdeomsaalgeergart.ouTp,hecocnosheacbuittiavteioonrdpeerriwoadscounsseidstteodaossfaignmaraxtsitmoucmohoafbi1t4atdiaoyns,.one cFoepmuallaetorraytspwliutghosbpseerrvmeadtoiznosaitoubsweerrveedcoinnsiadsemreedartoofbethaet vDaGgin0alancdonatsesnitgsnaenddt/oor a iwnedrieviadsusailgnheodusailntge.rnaFteemmaalleerartastsntohtatmahtaeddmwaittehdinantdherfeimrsatisnevdenindcaoyhsaboiftactoihoanbiftoartiaon maximum of seven additional days. Rfoartsclwineircealoobbsseerrvveadtifoonrsvaianbdilgietnyeartalleaasptpetawricaenceeacath ldeaaystoofntcheedsutruidny.g tRhaetsacwcelirmeaetixoanmined period. Observations for clinical signs of effects of the test article and deaths were made 4a. See APPENDIX D, items 8 and 9. sans 418-018:PAGE 1-14 daily prior to dosage administration, approximately one hour after the second dosage and at the end of the working day (approximately one hour after the third dosage)". These observations were also recorded on the day of sacrifice. Body weights were recorded at least once during the acclimation period, weekly to cohabitation, daily during presumed gestation, on DL 1 (rats assigned to natural delivery) and at sacrifice". Feed consumption values were recorded weekly to cohabitation, on DGs 0,7, 14, 21 and 25 (if necessary) and DLS 1 and 5 (rats assigned to naral rdeelpilveenriy)s"h.menDturoifnfgecdohjaabristwataisondowchuemnenttweod,ratbsutocicnudipviiedduatlhevaslaumees cwaegree wniotthroencoerfdeeeddojrar, tabulated. Mating was evaluated daily during the cohabitation period and confirmed by observation of spermatozoa in a smear of the vaginal contents and/oar copulatory plug observed init "The rats assigned to natural delivery were observed for adverse clinical signs during parturition, duration ofgestation (DG 0 to the day the first pup was observed) and pup. viability at birth. The rats were also observed for fertility index (percentage of matings that result in pregnancy), gestation index (percentage of pregnancies that result in birth of live liters), numofobffseprirng per litter live and dead pups), number of implantation sites, general condition of the dam and litter during the postpartum period and viability index (percentage of pups bom that survived five days). Maternal behavior was recorded on DLs 1 and 5. Deviations from expected maternal behavior were recorded, when and if observed, on all other days of the postpartum period. H.5.b. FI Generation Pups Litters were examined after delivery to identify the number and sex of pups, tillboms, live births and gross extemal alterations. Day 1 of lactation (postpartum) was defined 2s the day of birth and was also the first day on which all pups in a ltter were weighed (pup body weights were recorded after all pups in a liter were delivered and groomed by the dam). Each litter was evaluated for viability at least twice each dayofthe 5-day postpartum period. Dead pups observed at these times were removed from the nesting box. F1 generation pups in each litter were counted once daily. Physical signs (including variations from expected lactation behavior and gross extemal alerations) were recorded cach day. Pooled lier weights were recorded on DL 1 (birth, liveborn pups), 2, 3, 4 ands. a See APPENDIX D, items 8 and 9. b. See APPENDIX D, item 10. Cc. See APPENDIX D, item 11. 000026 418-018:PAGE 11-15 HG. Gross Necropsy" H.6.a. Fo Generation Rats Assigned to Caesarean-Sectioning Eight rats from Groups 1107, 12 and 13 (Replicate 1) were sacrificed by carbon dioxide arastpshywxeiraetiCoanesoanrcDanG-s21e.ctiBolnoeoddaannddalgirveorsssanmepclreospswyeorfe tchoelltehcotreadcifc,roambdtohmesienaraltsa"n.dTpheelvic viscera was performed. Gross lesions were retained in neutral buffered possible future evaluation. Representative photographs of gross lesions 10% formalin for are available in the raw data. Uteri of apparently nonpregnant rats were stained with 10% ammonium sulfide to confirm 10% formalin for the absenceof possible future implantation evaluation. sites and retained in neutral buffered e`Txhceisneudmabnedreoxfacmoirnpeodrafolrutperaeignnaenaccyh,onvaurmybewrasanrdecdoirsdterdi.butTihone oufteirmupslaonfteaatciohnrastitwesa,slive and dead in which fetuses and early and late resorptions. organogenesis was not grossly evident. An A early resorption was defined as one late resorption was defined as one in wtehrimchfetthues otchacturrreesnpcoendoefdortgoasntoigmuelnie.siNsownraessgproonsdsilyngevfiedteunste.sAwerleivceofnestiudsewraeds tdoefbienededada.s a Dmaerakdefdettuoseexstarnedmelaateutroelsyosripstiionndsicwaeterde tdhiaftfetrheentfieatutsedwbays taheladtegrreesoerpotfioanu.tolPylsaicsepnrteaseenwte;re examined for size, color and shape. sBelcotoidonsianmgpvlieast(haetilnefaesrti4ormvLeneaaccahv)awaenrde sceoplalrecatteedd finrtoomttwhoe araptpsraosxsiimganteedlytoeqCuaaelsaalriequaonts. "tTrhaensffierrstreadliiqnutootswearsumplsaecpeadraitnotrotEuDbeTsA.-cTohaetseadmtpulbeesswaenrdetshpeusnecinonadceanltiqruioftugweaasnd the resulting serum (divided into labeled polypropylene tubes. two All aliquots) and samples were plasma (one aliquot) were transferred immediately frozen on dry ice and into. maintained frozen (<-20 C). wFoelilgohwtiwnagscorlelceocrtdieodn".ofAblpooordtisoanompfleeas,chthleivleirvesraomfpelaec(hrirgahttwlaastereaxlcilosbeed)awnadsthfelalsihvefrrozen finrolzieqnui(d-n2i0trCo)g.en Aandsemctaiionnta(ianpepdrofxriomzaetnel(y<-07.03C()0.0.T5heemmewdidiea)n flrivoemr lthoeberewmaasinsitonrged portion of remaining the liver was fixed in gluteraldehyde for possible portion of the liver was stored frozen (<-20C) electron microscopy. The Fetuses were pooled by litter and litter weights were recorded". a ACabeslareeaonf-sreacntdioomniunngitfsrowmaswhuiscedh talolsteilsescutesoneexacomnitnreodl gatronuepcrroaptsaysswiegrneedrettoained, in of order gross to provide lesions. control tissues for any possible histopathological evaluations b. See APPENDIX D, item 12. c. Sec APPENDIX D, item 13 d. See APPENDIX D, item 14. 000027 418-018:PAGE 11-16 Caps and labeled (empty) and after tubes were weighed retentionofpooled (combined weight, to the nearest fetus samples for subsequent use 001 in gram) before ipdheanrtmiaficcoaktiinone,tidcataenaolfycsoelsl.ectSiaomnp,lsetutduybedsayw,esraemlpalbeelieddenwtiitfhictahtieosntaunddy cnoulmlbeecrti,onlitter timepoint Baplporoodxismaamtpelleysowneer-ehacloflloefcttheed ffertoumseesaicnhefaecthuslvitieardwecaaspiptlaatcioend.intBoloEoDdTAf-rcomoated tubes wanedrethsepurnemianianicnegntfreitfalugbelaoondd twhaesrtersaunlstfienrgrsederiunmto(sdeirviudmedseipnatroattowrotaelsiq.uotTsh)eansdamppllaessma i(omnmeedailaitqueolty)fwreorzeentroannsdfreyrriecdeianntdo mlaabienlteadinpeodlyfprroozpeynl(e<n-e20tuCb)es,. All samples were. `fTihxeedliivnerglfurtoemraeladcehhyfdeetufsorwapossscoilblleecteelde.ctrOonnemifcetraolslciovpeyr.frTohmeeraecmhaliinttienrgwafestarl elmivoevres dinand seaacmhplleitstewrewreersetdoirevdidferdoziennto(t2h0reeCs)a.mpTlhese orfemeaqiuanlinngusmabmeprle(swhweenrepofslsaisbhlef)r.ozTenwoin olfiqtuhied nitrogen and evaluation. maintained frozen (<-70C). Fetal carcasses were discarded without further H.6.b. Fo Generation Rats Assigned to Natural Delivery tOhne tDhLorSacitch,earbatdsomwienraelsaacnrdifpieclevdibcyvicsacrebroanwdaisoxpiedrefoarsmpehdy.xiaBtliooond,anmdilak,grhoesasrtnaecnrdolpisvyerof sneaumtprlaelsbuwfefreerecdol1le0c%tefdofrmraolminmaftoerrpnoaslsriabtlseofnutDurLe e5*v.aluGartoisons.lesRieopnrsesweentratrievteained in photographs of gross lesions are available in the raw data. `OanppDroLxi5m,aetaelcyh fdoaumr hwoaurss.reTmhoeveddamfrowmasthienjneecstteidnginbtorxavaenndouisnldyivwiidtuhalolnyehuonuisteodffooxrytocin caoplplreocxteidm.atTehley fsiavmepmliensuwteesrebeifmomreedmiialtkelsyamfprolzeesn(oatnlderaystic1e00anudLpmaeirntsaaimnpelde)frwoezreen (20C). fForlolmotwhiengramtsilvkiastahmepilnefecroilolrecvteinona,cbalvoaoadnsdamspeplaersat(aetdlienatsot t4wmoLapeparcohx)imwaetreelycoelqluecatled walaisqutortasn.sfTehrreedfirisnttoalsieqruoutmwsaespaprlaatcoredtuibnetso.ETDhTeA-scaomaptleeds twuebreessapnudntihneasceecnotnrdifaulgiequaontd tinhteorleasubletliendgpsoelryuprmo(pdyilveindeedtuibnetso.twAlolasliaqmupoltess) awnedrepliamsmmedai(aotneelyalfirqouozte)n woenrderytriacnesfaenrdred maintained frozen (<.20C). cFoollllecotweidn.g Tcohlelelcitvieornowefimgihltkwaansdrebclooroddeds.amAplepso,rttihoenhoefarctacahndlilvievrersoafmpelaech(rdigahmt lwaeterreal lobe) was flash frozen in liquid nitrogen and maintained frozen (70C). The median a Sec APPENDIX D, item 12. 0000238 418-018:PAGE [1-17 liver lobe was stored frozen (20C). The heart was excised and two cuts were made to allow proper fixation. The first cut started to the right of the ventral midline surface at the apex and extended anteriorly and ventrally to the pulmonary artery. The second cut was made starting to the left ofthe ventral midline surface at the apex and extended through the left ventricle to the ascending aorta. The cut heart and a section (approximately 0.3 to 0.5 cm wide) from the remaining portion of the liver were fixed in gluteraldehyde. The remaining portion of the liver was stored frozen (20C). Rats that did not deliver a litter were sacrificed on DG 25 and examined for gross lesions. Blood and tissue samples were not collected. Uteri were stained with 10% ammonium s1u0lf%idfeortmoacloinnfiforrm ptohsesiabblseenfcuteuoref eivmaplluaanttiaotnion sites and retained in neutral buffered Dams with no surviving pups were sacrificed after the last pup was found dead, missing or presumed cannibalized. Blood and tissue samples (serum, plasma, heart and liver) were collected as previously described. A gross necropsy of the thoracic, abdominal and pelvic viscera was performed. Rats that died or were sacrificed because of moribund condition were examined for the cause of death or moribund condition on the day the observation was made. The rats were examined for gross lesions. Representative photographs of gross lesions are available in the raw data. When possible (ot precluded by autolysis). serum, plasma, heart and liver samples were retained as previously described for rats assigned to natural delivery. Pregnancy status and uterine contents of female rats were recorded. H.6.c. F1 Generation Pups Pups that died before examination of the litter for pup viability were evaluated for vital status at birth. The lungs were removed and immersed in water. Pups with lungs that sank were identified as stillborn; pups with lungs that floated were identified as liveborn, and to have died shortly after birth. Pups with gross lesions were preserved in Bouin's solution for possible future evaluation. When postmortem autolysis precluded these evaluations, it was noted on the liter observation data sheets. Pups found dead or sacrificed due to moribund condition on DLs 2 to were examined for gross lesions and for the cause of the moribund condition or death. When postmortem autolysis precluded these evaluations it was noted on the litter observation data sheets. On DL 5, pups were sacrificed and examined for gross lesions. Gross lesions were preserved in neutral buffered 10% formalin. Necropsy included a single cross-section of the head at the level of the frontal-parietal suture and examinationof the cross-sectioned brain for apparent hydrocephaly. Caps and labeled tbes were weighed (combined weight, to the nearest 001 gram) before (empty) and after retention of samples for subsequent use in pharmacokinetic analyses. a See APPENDIX D, item 15. 000029 418-018:PAGE TI-18 `Sample tubes were labeled with study day, sample identification the and sctouldlyecntuimonbetri,merpaotiindte.ntification, date of collection, Bblloooodd ssaammpplleess wweerree pcooollleecdtepderviliattcear,rdsiaamcppluensctfurroem fmraolme eaancdhfpeumpa.leFporupRsepcloimcbaitneed1., bAlpopordoxwiamsatterlanysf1emrrLedofintboloEoDdTAw-acsotartaensdfetrurbeesd. inTtohesesraummplseespawraetroerstpuubnes;in aancyenrtermiafiungieng aapnpdrtohxeimraetsuelltyin3g0s0emruLmowfassedriuvmi,daenddinsttoortewdofraloizqeunot(s7o0faCp)p.roxAinmyatreelsyul2ti0n0g mplLasamnad was transferred into one aliquot and stored frozen (70C). gFroorupR)e.pliAcpaptreo2x,ibmlaotoedlysa0.m3plmeLs woefrbelopoodolweads(ttrwaonslfietrerresdpeinrtsoaEmDpTlAe-wciotahtinedeawcbhedso.saTghee remaining centrifuge ablnodotdhewarsesutlrtainnsgfesrererduminwtoassedriuvmidseedpairnatototrwtoubaelsi.quoTthseasnadmsptloersedwefrroezsenpun in a (570C). Resulting plasma was transferred into one aliquot and stored frozen (<-70C). r`Tehceorldievde"r.frOonmeelaicvherpfurpowmaesaccholllietctteerdp,ooploowlaesd r(beymosveexdpearndlitfeirx)edanind gtlheutpeoroallededhwyediegfhotr tphorseseibslaemeplleecstroofn emqiucarlosncuompbye.r T(hwehernempaosisniibnleg).livTerws oinoefatchhe lsiattmepr lpeosolwewreerestdoirveiddefdroiznetno f(r5o2z0enC().70ThCe).remTahienihnegarstsamwpelreewcaosllfelcatsehd ffrroozmenthien lfrisqtuitdwnoitmraolgeenaannddtmwaoinfteamianleedpups wferroem eexaccihselditefrro(pmoeoalcehd pbuyp,sepxopoelredli(tbery)saenxdpewrerleittefri)x.edTihnyrgoliutdesrawledreehyrdeet.ainTehdyrionindesutral buffered 10% evaluation formalin. The remaining carcasses were discarded without further a. Sec APPENDIX D, item 16. 000030 418-018:PAGE II-19 H.6.d. Sample Shipment and Analyses [i [ore [EComnionms e [ee [ew [SSeerummsahbauuo7l ]Te2a5Cc TSApnoymiocrs "pTrootscholeser | SS13h,T1o3)H.. L(oOGlrLo&wAfse.1:e1 Ts wieerides [Livermedmiobe [30 1 La 2amd 1) T Spoor hro] [EiLviveerr:sreecmtaiionnder 30 |Gluteraldchyde |E ASpnonnsoer E| PLosBsLibbletB.Mat | F Poded se om -am lqsot|To3rFCe Toimret Tol hese Fc13o1uH9s,.Do(Guirlo&wHsDfL1.e1, ieeriaes 123061112 and 5) [Liver Thiver |Gluteraldchyde |Sponsor PossibleBM | [Lier Vsposed vers [3076 [ Spoorpros] chloral. ngyerdes [PSeimkdquo TTaermee TT aASpwnouemo ser usrTooue tschon les ]| SS1h3Tc1o9Hs,eLt(oGorlLo&wHsLf1.e-1T17, m malee s Worcee iar |Mv|iepvessoeindsessc Grourpsy [I Cirigh robe[70C | Spomor --c |oi-- ebodhemial | JTS choleqerol gyerides fTroe TitTpraonrdtTySwHasIaveas yThTeorhodlph rioryewasansnsdyJsa!scfoor LTDhLe SFoDnLdonad noppeaomntcosr aT 000831 418-018:PAGE 11-20 Condiions [PSopesmReapbionrietr TeS7av6ec [SAonmLyeiers TOTouSl cheesral || ghcToSsH. w(Girlou&psre1e1Ts. 13.13) LDL HDL, =e Frmedes Wareenar | wML iegvlsylcoea nriideess"a1a(nGdro1u) [Sa eSreuamm h sigur?au TSC oc[p1 AoniLmyies--_JT TotP al c0 hResS ]e ] lcTaS,H (oGurlou&psre1e1T.o 13.13). LoL HbL. sve Framed Woreesar | MwLiegvAlayclLeornicdeas7dnGrodu1ps [iver V3poled vers[7l0iCon [ivLieverr.V133ppoooolleedd vveerrss|[s2260C Toemaarlss perwialaest307 | Clierldohyds [ST SppoomsoForr out| Poisseebocht emialn| [SApnoyoiers JPLORL.SFOL. wil | cPhoosliEsnMiesnbgdhlylcisgeshitdes mieroseop Sales of ersfweerrempernonaed slows: CR Sherioes Ft 4nd iw PROS mes. 5. Tano 5t0t0 TpyroTenaynwdaTsSaHmaevsessforTahlthicrhdolpreisotrriotly wanadsaancaol,yfoTheLsDaLcoHndDLp.riaornidtyhwgayscfeorrodtsal oHniestfopeamtahlolFoLgygewnaesrapteirofnoprumpedfboymRsesaecarocfhfPoaurthWleosryrSoemvteh.e VIenh.icolne Choentnroalngorfouopn (Gmraoluepan1Dd) 4 aaFnniddsat2ononpmde2ughf/moekilmgoaklsPeeyFPFwOlaESsGggeSprngeoerrurfoapotu(ripGmonre(doGpurubpopyu1fRp3)eo.s1me3a)ercchhPoafthfooltogry Sservifcoesm,tIhce.VoehitclhetChoyrnoivdoogfroounpm(aGlreoup Results of these analyses are available in APPENDICES H and I. H.7. Data Collection and Statistical Analyses Data generated during the course of this study were recorded either by hand or using the Primedica Argus Automated Data Collection and Management System and the Vivarium Temperature and Relative Humidity Monitoring System. All data were tabulated, `summarized and/or statistically analyzed using the Primedica Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, Microsoft Excel [part of Microsoft Office 97 (version SR-2)] and/or The SAS System (version 6.12). 00032 418-018:PAGE 11:21 The following schematic represents the statistical analyses of the data: 1. Parametric: A. Bartlett Test TyofpTeest II. Nonparametric" A. Kruskal-Wallis Test (75% tes) Significant aTM Not Significant Significant at T 05 Not Significant Nonparametric AnalofyVasriiansce Dunn's Test Significant aps0.05 Not Significant B. Fisher's Exact Test (75% tes) Dunnett Test TI. TPesrtfoorportiDoatna oVfartihaenBcienToemsitalfoDriHstormiobguteinoenity a. b. SPtraotpiostritciaolnlydsaitganiafriecnaontt pirnocblaubdielditiinesthairsecraetpeogorrtye.d as eitherp<0.05 orp<0.01. e. Test for homogeneity of variance. 000833 413-018:PAGE 11-22 aGcrioducpon1tr(ovle)hiacnlde cGornotruopl)S d(acthaolweestreeroflirsctonsttraotils)tidcaatlal.y cGormopuapreId(vteohGicrloeucpon2tr(omle)vadaltoaniwcere PthFeOnScoamlopnaer)e.dGtrooGurpou2p(sme8v,a9l,on10i,c 1a1c,id12coanntdrol1)3 d(a0.t4a,w0e.r8,e c1.o0,mp1a.2r,ed1.6toaGnrdo2u.p0sm3g/akngd 4 c(o1m6paanrded2.t0omGgr/okugpsP6ROaSnd+7m(e1v.a6laonndic2.a0cimdg)/akngdPGFrOouSp+5ch(oclheoslteesrtoelro,lrcesopnetcrtoilv)eldya)t.a were Clinical observations and other proportion data were analyzed using the Variance Test for wHeoimgohgtse,nebiotdyyowfeithgehtBicnhaonmgieasl,Dfiesetdricbountsiuomnp"t.ioCnonvtailuneuso,ulsitdtaertaav(ee.rga.g,emsatfoerrnpaelrcbeondtymale Pups, pup body weights, pup morality data) were analyzed using Bartets Test of BHaormtloegtet'nseTietsyt owfasVanroitasnicgneisf"icaanntd(tph>e0.A0n0a1l)y).sisIoffthVeaArniaalnycsei's,ofwVhaerniaanpcperowpraisatseig[nii.fc.i,cant i(npd<i0v.i0d5u)a,lDgurnonueptst.'sITfethsetA"nawlayssiusseodf tVoariidaenntciefywathse nsottatiasptpircoaplrsiiagtneifii.cc.a,ncBearotfletthte's Test 1w0a.s7s5i%gntiifeiscwanetre(pp<r0e.s0e0n1t).),InthceasKersuswkhaelr-eWatlhleisKrTuesskta"l-)WawlalsisusTeeds,twwhaesnslteastsistthicaanlloyr equal sstiagtniisftiiccaalntsi(gpn<i0f.i0c5a)n,ceDuonfnt'hseMiendtihvoidduoalf gMruolutpisp.le ICfothmeprearwierseong'rs*e)awtearstuhsaend7t5o%idteinetsi,fy the Fisher's Exact Test" was used to analyze the data. Count data obtained at Caesarean-sectioning of the dams were evaluated using the procedures described above for the Kruskal-Wallis Test"? 208034 418-018:PAGE III-1 HL RESULTS A. Mortality (Summary - Table 1; Individual Data - Table 23) No deaths were attributable to the test or control articles. One rat in each of Groups 2 (mevalonic acid control), 3 (1.6 mg/kg PFOS + mevalonic acid) and 5 (cholesterol control) died as the result of intubation accidents or natural causes. Observations in these rats arc described below. All other rats survived to scheduled sacrifice. Dam 10926 in Group 2 (mevalonic acid control) was moribund sacrificed on gestation day 12 (DG 12). Adverse clinical observations included excess salivation and soft or liquid feces on DG 11, and decreased motor activity, chromorhinorrhea, chromodacryorhea and a red perioral substance on DG 12. This rat lost weight after DG 11. Feed consumption values were unremarkable. Necropsy revealed a perforation in the esophagus and tan discoloration of the left axillary area; all other tissues appeared normal. The litter consisted of 14 live embryos that appeared normal for their developmental ages. The death was attributed to an intubation accident. Rat 10936 in Group 3 (1.6 mg/kg PFOS + mevalonic acid) was found dead on DS 2. There were no adverse clinical observations before death. Necropsy revealed a dark red clotted material in the thoracic cavity; all other tissues appeared normal. The death was attributed to an intubation accident. Rat 11562 in Group 5 (cholesterol control) was moribund sacrificed on DS 16. Adverse clinical observations included decreased motor activity, pale appearance and coldness to touch on DS 16. Body weight was reduced on DS 15 compared to other rats in this dosage group. Feed consumption values were unremarkable. Necropsy revealed the small intestines were twisted and constricted at the jejunum and the jejunum contained a dark red fluid; all other tissues appeared normal. The death was atiributed to natural causes. B. Clinical Observations (Summary - Table 1; Individual Data - Table 23) `The numbers of rats with excess salivation, a perioral substance and chromorhinorrhea during gestation were significantly increased (p<0.01) in Group (mevalonic acid control) as compared to Group 1 (vehicle control). These increases were attributed to an aversion 10 the taste of mevalonic acid; the incidence of these observations was comparable among the three mevalonic acid groups (Groups 2, 3 and 4). All other clinical observations during the precohabitation, gestation and lactation periods were considered unrelated to the test or control articles because: 1) the incidences were not dosage-dependent; and/or 2) the observation occurred in one o four rats in a group. `These observations included localized alopecia, dental problems (missing, broken or misaligned incisors), chromodacryorrhea, scabs on paws and limbs, bent tail, missing or swollen digit, swollen snout, red perivaginal substance, lacrimation, scab on mouth, tip of tail missing, ptosis, soft or liquid feces, rales, red substance in cage, labored breathing, scant feces, swollen ear, dehydration, emaciation, decreased motor activity, pale in appearance, cold to touch, and ulceration or scab on chest or limb. The significant increase 000035 418-018:PAGE IL-2 (Gpr<o0u.p011)1i(n1t.h2emign/ckigdePncFeOoSf alloocnael)izaesd caolomppeacrieadontotGherobuapck1,duwraisngcotnhseigdeesrteadtiuonnrepleartieodd tion the test article because it was not dosage dependent. C. Necropsy Observations (Summary - Table 2; Individual Data - Table 24) A1)llthneecirnocpisdeynocbessewrvearteionnost wdoesraegeco-ndseipdeenrdeedntu;nraenldat2e)dtthoetohbesteersvtaotriocnonotcrcoulrarretdicilnesonbelcyaousnee: roaftbiontah gkriodunpe.ys,Thaecsaelcoublsuesrvianttihoensbliandcdleurdeadndmitshsihckaepneendkbildandedyesr, wsalilglhstidniloanteioGnroofutphe2pelvis ++(cmheovlaelsotneircola)cirdatcotnhattrowla)srastaacrnidfipcuepd btiescsauuesien itthheasdtnoomascuhrvoifvionngepGurposuopn7d(a2ym2go/fkglacPtFatOiSon (DL 2). Necropsy observations in rats that were found dead were described previously. D. `TTeerrmmiinnaall BBooddyy WWeeiigghhttss a(nSdumOmragrayn -WTeaibglhets3;anInddiRvaitdiuoasloDfaOtrag-aTnaWbelieg2h5t)s to D.L Caesarean-Sectioned Rats T(peSr0m.i0n5alorbpo<d0y.w0e1i)gihntsGorforuaptss6Caacnsdar7e(a1n.-6seacntdio2nmedg/okngDPGFO2S1 were significantly reduced + cholesterol, respectively) asisgcniofmipcaanrteldy tioncGrreoasuepd 5(pv<a0l.u0e5s)(icnhoGlresotuepro7l. coAnstroal)r.esuTltheofwtehieghrtedoufcethdetleirvmeirnawlasweights in Gthreouteprsmi6naalndbo7dayndwetihgehtinwcreeraesesdiglniivfeircawnetilgyhitncirneGarseodup(p7<,0t.h0e5roartipo<s0o.f01t)heilnitvheersweetigwhot to groups, as compared to the cholesterol control. All other sectioned toenrmDinGal2b1owdeyreweuingahftfse,cltievderbwyePigOhtSs aorndmervelaaltoinveicliavceird.weiTghhetsraotfiooraftlsiCvaeerswaeriegahnt t+omteevramlinoanlicboacdiyd)weaisgchotmwpaasresdigtnoiftihceanGtrlyouipnc2revaasleude((pm<e0v.a0l5o)niincGarcoiudpco3nt(r1o.l6),mbgu/tkwgaPsFOS. considered dependent. unrelated to the test or control articles because the increase was not dosage D2. Naturally Delivered Rats P`<Te0r.m0i1n)alinbGordoyuwpei1g3ht(s2 omfg/naktgurPaFllOySdealliovneer)edasractosmwpearreedsigtoniGfricoaunptly| r(evedhuiccelde (cpon<t0r.o0l5),orand GinroGuropu5psva6luaensd(7ch(o1l.e6staenrdol2comngt/roklg).PFOS +cholesterol, respectively) as compared to `(T0he.0ra5tioosropf<t0h.e0l)ivienrGwreoiguhptss9t,o1t1heantedrm1i3na(0l.b8,o1d.y2 awneidg2htmsgw/ekrgePsiOgnSifiaclaonntel,yrienspcercetaisveedly), compared to Group 1 weights and/or slight i(nvcerheiacsleescionntlriovle)r,wreeifglhetctsinign slight these reductions in terminal groups as compared to body the Group 1 values. The liver weight was significantly increased (p<0.01) in Group 3 (1.6 mg/kg PFOS 000836 418-018:PAGE Il-3 + mevalonic acid) as compared to Group 2 (mevalonic acid control). The ratios of the liver weightto the terminal body weight were significantly increased (p<0.05 or p<0.01), in Groups 3 and 4 (1.6 and 2 mg/kg PFOS + mevalonic acid, respectively) as compared to Group 2 (mevalonic acid control), and in Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively), as compared to Group 5 (cholesterol control). E. Body Weights and Body Weight Changes (Figures 1 through 3; Summaries - `Tables 4 through 9; Individual Data - Tables 26 through 28) El Precohabitation Body weight gains for the entire precohabitation period (DSs 1 t0 42) were significantly reduced (p<0.05 orp<0.01) in Group 13 (2 mg/kg PFOS alone) as compared to Group | (vehicle control), and Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively), as compared to Group (cholesterol control). During this period, gains were significantly reduced (p<0.05 orp<0.01) in Groups 6 and 7 on DSs 22 to 29 and 29 to 36; and in Group 13 on DSs 29 to 36, as compared with the corresponding control group value. Additionally, body weight gains for Group 12 (1.6 mg/kg PFOS alone) were significantly reduced (p<0.05) on DSs 29 to 36 and body weight loss occurred in this group on DSs 36 1042. Asa resultof these changes, body weights were significantly reduced (p<0.01) in Groups 6 and 7 on DSs 29, 36 and 42, as compared with Group 5. Body weight gains for the entire precohabitation period (DSs 1 t0 42) in Group 5 (cholesterol control) were significantly increased (<0.05) as compared to Group | (vehicle control). Premating body weights and body weight gains were unaffected by mevalonic acid and dosages of PFOS as high as 1.2 mg/kg. Significant increases or reductions (50.05 or pS0.01) in body weight gains in Group 8 (0.4 mg/kg PFOS alone) on DSs 1 to 8 and 11042, Group 12 (1.6 mg/kg PFOS alone) on DSs 1 t0'8, Group 3 (1.6 mg/kg PFOS + `mevalonic acid) on DSs 22 to 29 and 29 to 36, and Group 4 (2 mg/kg PFOS + mevalonic acid) on DSs 1 to 8 and 29 to 36 were not considered an effect of the test or control articles because they were not dosage-dependent and did not persist. E2. Gestation Body weight gains for the entire gestation period (DGs 0 to 21) were significantly reduced (S005) only in Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol). Groups 3 and 4 (1.6 and 2 mg/kg PFOS + mevalonic acid, respectively), Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively) and Groups 9, 11, 12 and 13 (038, 1.2, 1.6 and 2 mg/kg PFOS alone, respectively) had significantly reduced (p<0.05 or p<0.01) body weight gains, compared to their corresponding control groups, for the first week of the gestation period (DGs 010 7). There were no significant differences among any of these dosage groups during the second week of gestation (DG 7 to 14). Group 13 hada 000037 418-018:PAGE Ill-4 significant increase (p<0.05) in body weight gain during the third week of gestation (DGs 141021). Body weights were significantly reduced (p<0.05 or p<0.01) in Group 12 (1.6 mg/kg PFOS alone) on DG 2 through 16, and in Group 13 (2 mg/kg PFOS alone) on DGs 0 through 19, compared to Group I (vehicle control). When PFOS was administered along with `mevalonic acid, the effect on body weight was less severe and appearedover a shorter period than PFOS administered alone. Body weights were significantly reduced (p<0.05 or Pp<0.01) in Group 3 (1.6 mg/kg PFOS + mevalonic acid) on DGs 4 through 13, and in Grou4p (2 mg/kg PFOS + mevalonic acid) on DGs 7 through 10, compared to Group 2 (mevalonic acid control). The effect on body weight was more severe and appeared over a longer period when PFOS was administered along with cholesterol. Body weights were significantly reduced (p<0.01) in Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively) on DGs 0 through 21, compared to Group 5 (cholesterol control). Gestation body weights were significantly increased (p<0.05) in the cholesterol control group (Group 5) on DGs 5, 8 through 17 and 21, as compared to the vehicle control group. (Group 1). Despite this effect of cholesterol alone, body weights in the groups administered PFOS with cholesterol (Groups 6 and 7) had significant reductions in gestation body weights. E3. Lactation Body weight gains during the first five days of the lactation period (DLs 1 to 5) were. significantly reduced (p<0.05 orp<0.01) in Groups 9, 10, 12 and 13 (08, 1, 1.6 and. 2 mg/kg PFOS alone, respectively). The average body weight on DL was significantly reduced (p<0.05) in Group 13, compared to the vehicle control group value `When PFOS was administered along with mevalonic acid, the effect on body weight was less severe than PFOS administered alone. Body weight gains were significantly reduced (p<0.05) on DLs 1 to 5 in Group 3, but average body weights on DLs | and 5 were comparable among Groups 2, 3 and 4 (mevalonic acid control, 1.6 and 2 mg/kg PFOS + `mevalonic acid, respectively). `When PFOS was administered along with cholesterol, the effect on body weight was more severe. Body weights on DLs 1 and 5 were significantly reduced (p<0.05 orp<0.01) in Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively), compared to Group 5 (cholesterol control), and a significant (p<0.05) body weight loss occurred on DLs 1 t0'S in Group 7. 000038 418.018:PAGE IIl-5 F. Absolute (g/day) and (Summaries - Tables 1R0eltahtrivoeug(hg/1k5g;/dIanyd)ivFiedeudalCoDnatsaum-pTtaibolnesVa2l9utehsrough 31) F.1. Precohabitation pA<b0s.o0l1u)teinanGdroruelpat1i3ve(f2emed ckonsPuRmOptSioanlovnael)ufeosrwtehreeenstiigrneifpirceamnatltyinrgedpuecreidod((p<D0.S05| o(r042) canodmpwairtehidnttohitshepevreihoidcloencoDnStsro8l gtroou1p5.(reAlbastiovleutonelay)n,d2r2elta0ti2v9e,f2e9ed1c0o3n6suamnpdt3i6ont0va4l2,ues were also last week osfigtnhiefipcraentmlaytirnegdupceerdio(dp<(0D.S0s5)36in(G0r4o2u)p 12 (1.6 mg/kg PFOS alone) during the aAsbshoilguhteasa1n.d2rmegl/atkigv.e fAebesdoclountseufmepetdicoonnsvaulmupetsiownerweausnasifgfneicftiecdanbtylydionscargeeasseodf(P<F0O.S05a)loinne cGaolrononsueup)mop8nt(i0Do.Sn4smvag1l/5uke1gs0 2Pw2eF.rOeTShsiaeglsnoeinfeii)nccaornnetlaDysSeissnci2nr9efaetsoeedd36c(;opn<as0nu.d0ma5pb)tsiioonlnuGtvreaolauunpeds1rw0eel(ar1teimvnego/tfkecgeodnPsFiOdeSred related to treatment because they were not dosage dependent and did not persist. WVahleuens PwFaOsScowmapsaraadbmlienitsotetrhaetd oafloPnFgOwSitahlomnee.valAobnsiocluatceidf,etehdeceofnfescutmpotnifoenedvaclounessuwmeprteion `simgenviafliocnainctlaycirde,durecsepdec(tpi<v0e.l0y5) or on p<0.01) DSs 22 in to Groups 3 29 and 36 and 4 t0 42, (1.6 and 2 compared mg/kg PFOS to Group 2 + (9(<me0v.a0l5oonircpac<id 0conit.nroGl0)r.ou1Rpes)l3atiavenf4eeoddncDonSssum8ptto io15n,v1a5l1u0e.s2w2e,r2e2s1i0g2ni9faincdand3y6troed4u2ced r(eGdruocuepd4(opn<l0y.).05 Tohrips<0ef.f0e1c)t aobfsPolFuOtSe aannddrmeelvatailvoenfiecedacciodnwsausmprteifolenctveadluienstfhoerstihgeniefnitciarnetly premating period (DSs 1t0 42) in both groups. VWahleuens PwFaOsSmowraessaedvmerien.istAebrseodlaultoenagnwdirtehlacthiovleesfteeerdolc,otnhseumefpfteictononvafleueedscwoenrseumsipgtniiofincantly rDeSdsuc2e2dt(0p2<90,.0219) tion3G6roaunpds366 a0nd427,(a1s.6coamnpda2remdg/tkogGrPoFuOpS5+(cchhoolleesstteerrooll,cornetsrpoelc)t.ivTehlyi)son pef<f0e.c0t1o)faPbFsoOlSutaenadncdhroelleasttievreolfeweadscorenfsluemcptetdioinn tvhaeluseisgnfiofrictahnetleyntrreedupcreedm(apt<i0n.g0p5eorriod (DSs 1 10.42) in both groups. sRieglnaitfiivceanfteleydicnocnresausmepdti(op<n0v.a0l5ueosr po<n0D.0S1)8intoth1e5,me1v5a1l0on2i2c,2a2ci1d0c2on9traonldg1rotoup42(Gwreoruep 2), as compared consumption to the vehicle control group (Group values were significantly increased 1). Absolute and relative (p<O.01) on DSs 29 to 36 feed and absolute cfoenetdrcolongsruomuppti(oGnrowuaps5s)iagsnicfiocmapnatlryedintcoretahseevde(hpic<l0e.0c5o)ntornolDgSrsou3p6 (t0Gr4o2upin1t)h.e cholesterol 000039 418-018:PAGE 1-6 F2. Gestation <Ab0s.o0l1u)te2duamrngid/nkgregtlaPhtiFvfOierSsfteaweldeoneceko,norsfeusgmpepestcttiaiotvnieolnvya)(l.uDeAsGbsw0oelr1ue0t7es)ifgienniefdGirccoaonuntpslsuym9rpettdihuorcnoeudcgoh(npt1<i20n.(u00e58d,otro1b, e1.2, csio6gnnsaiufnimdcpatnitolyndweacsresaisgendif(ipc<an0t.l0y5)inicnreGarsoeudp(p1<30.o0n5)DGinsG7ro10up141,2aonnd DrelGativ1e4 fte0e2d1, compared gtoestthae1t3ivoe(nh1i.p6celraeinocddon2(tDrmoGgls/gk0rgotPuopF2O1va)Sluwaeeslr.oneesA,ibrgsenosilpfueitcctaeinvftelelyeydr),ecdocunocsmeupdmap(rtpei<do0n.t0ov5atohleruevpse<h0fio.cr0l1te)hceioennntGtriroroleugprsoup1.2 nd WvahleuensPwFerOeScwoamspaardambilneisttoertehed eaflfoencgtswoifthadmmeivnailsotrnaitcioanciod,f PefFfeOcStsaolonnef.eedAbcsoonlsuutmeptfeieodn c2coomnmsypuakmrgpetdPiFotonOGSvra+oluumepsev2wae(lrmoeenvisacilgaoncniifidic,caarncetisldpyeccrotenidtvrueoclley)d). o(RnpeSlD0a.Gt0is1v)e01ifn0eGe7dr,oc7uo1pn0ssu31m4paatnniddo4n0(1v1a0.l62u1ae,sndwere Significantly reduced (p<0.05or p<0.01) in Groups 3 and 4 on DGs 010 7 and 14 10.21. wWehreenalPsRoOcSomwpaasraabdlmeintiosttheereedffaelcotsngofwiatdhmicnhiosltersatteirooln,oeffPfeFcOtsSoanlofneee.d cAobnssoulmuptteifoenedvalues c2omngs/ukmpgtPiFonOSva+lucehsolweesrteersoilg,nriefiscpaencttliyverleyd)uocnedD(Gps<00.1010)7.in7G1r0ou14p,sa6ndan0d1072(11,.6caonmdpared troedGurcoeudp(5p<(0c.h0o1l)esitnerGorlocuopnstr6ol)a.ndR7eloantiDveGsfee0dtoco7nsaundmpstiigoninfivcaalnutelsy were significantly increased (p<0.05 or Pp<0.01) in Groups 6 and 7 on DGs 14 t0 21. F3. Lactation 1Ab0s5o)lwuetreefesiegdncifoincsauntmlpytrieodnuvcaeldue(sp<d0u.r0i1n)g the first five in Groups 12 days and of 13 the lactation period (DLs (1.6 and 2 mg/kg PFOS | ai1ln0o,Gnre1,o1 urapenssdpe9c1tt2ihv(re0lo8yu),g.h1,1R31e,.l2arteaianvcdehi1fn.eg6 dmstgca/toiknsgstiucPmalFptOsiiSognnailvfoaincleau,necsreefs(oppreSctt0hi.ev0es5layom)r,epc<po0emr.pi0oa1dr)ewiden rtGeoroGruredpousucp9e,d| (vehicle control) values. vWahleuensPwFerOeSawlsaoscaodmmpianriastbelree1d atlhoengefwfiectthsmoefvaadlmoinniicstarcaitdi,oenffoefctPsFoOnSfaeleodnec.onAsbusmopltuitoenand (re1l.a6tiavnedf2eemdgc/okngsuPmFpOtSio+n mveavluaelsonwiecreacsiidg,nriefsipcaencttliyverleyd)uocnedD(Lps<01.0t1o)5,incGormopuaprsed3toatnhde4 Group 2 (mevalonic acid control) value. When PFOS was were comparable administered to the effects aolfoandgmiwniitshtrcahotlieosnteorfoPl,FeOfSfecatlsonoen. fAebesdoclountseuamnpdtiroelnatviavleues 2femedg/ckognsPuFmOptSio+nchvoalleusetserwoelr,eressipgencitfiivcaenltyl)yornedDuLcsed| (tp0<50,.0a1s)cionmGpraoruepdsto6 Garnodu7p(51.6 and (cholesterol control). oeoadp 418-018:PAGE III-7 G. Mating and Fertility (Summary - Table 16; Individual Data - Table 32) Tprheegnnaunmcbieesr poefrdnayusmbienrcoohfabaittsattihoant,mtahteefderatinlditryaatsndinpcroehganbaitnactyioinn,dirceesspe(cntuivmebleyr),oafnd the cnouhmabbeitratoifornatwsewriethcocmopnafriarbmleed imnatthiengthdiartteeesndduorsianggethgerofuiprsst. and second week of T(1h.e6 nmugm/bkegrPoFfOdSay+scihnolceoshtaebriotla)t,iaosn cwoamspsairgendifitcoaGntrloyurped$u(ccehdol(eps<t0er.o0l1)cofnotrroGl)r.ouTphi6s finding was not considered treatment-related because it was not dosage-dependent. H. Caesarean-Sectioning and Litter Observations (Summaries - Tables 17 and 18; Individual Data - Tables 33 through 35) Caesarean-sectioning observations on DG 21 were based on eight pregnant dams in each of Groups I through 7, 12 and 13. No Caesarean-sectioning or PFOS alone or administered ltter with parameters were affected by dosages either cholesterol or mevalonic acid. up to 2 There mg/kg were no bliivoeloagnidcadlelyadimfpeotursteasn,tedairflfyearenndcelsateinrtehsoerlpittitoernsa,vepreargceesntfdoreacdoroprorraeslourtbeea,d icmopnlcaenptuautsieosn,s, wpeerrceenntolliivveemfaelteusfeestaunsedsaollr pploaocleendtafeetaalppbeoadryedweniogrhmtasl.. No dam had a liter in which there rTehseorapvteiroangseannudmtbheerpeorfcerenstoargpetioofndse(atdotaolrarnedsoerabreldy)c,otnhceenptuumsbeesrpoefrdliattmesr wweirteh saingynificantly r(evedhuiccelde (cpon<t0r.o0l5) ovralpu<e0s..01T)hefsoreGfrinoduipng1s3w(e2remgn/oktgcoPnFsiOdSeraeldonter)e,actmoemnpta-rreeldatteodGbreocuapus|e an increase, toxicant. rTahtheerpetrhcaennatadgeecroefadsee,adinorthreeisnocribdeednccoenocfeprteussorepstpioenrliistttehre expected effect of was significantly a tihnecrreaansgeed o(bps<e0r.0v5e)d ihnisGtroroiucpall7y(a2tmthgi/skTgesPtFinOgS+Facchiollietys"t,etrhoel)v;alauletihsocugohmptahirsabvalleuteoitshaebove concurrent vehicle control group (Group 1) and reflects the low value in the cholesterol control group. I Natural Delivery and Litter Observations (Summaries - Tables 19 and 20; Individual Data - Tables 36 through 38) Totals of 17 10 20 rats were pregnant and delivered litters in cach of the 13 dosage groups. tThhreoudgurhat1i3o(n0.o8f,g1e,st1a.t2,io1n.6waasndsi2gnmigf/ickagntPlyFOreSduacloende(,pr<e0s.p0ec5tiovrepl<y)0,.0G1r)ouinpsGr3oaunpds 49 2(1m.6g/akngd 2PFmOgS/+kg cPhFolOeSste+romle,varelsopneicctiavceildy,),reasspcecotmipvealrye)d, atondthGercoourprses6poannddi7ng(1c.o6ntarnodl a Sec APPENDIXK (HISTORICAL CONTROL DATA). 000041" 418.018:PAGE IlI- values. Groups The number of dams 13,3, 4, 6 and 7: the with all increase pups dying on DLs I t0 5 was significant at pO. was increased in in Groups 13,4 and 7 "DTLhe 1puwpavsiasbiiglniitfyiicanndtelxy (rneudGmurcboeedurp(ospf<3l0i.av0ne5dpou4rp(sp1<.o6nOa1Dn)dLS2inmpGegrr/oknugupmsPbFe1O2rSaonf+dlmi1ev3vea(bl1o.om6niapcnudpasc2iodm,ng/kg TrPehFsepOeSactuaimlvboeneleyr),s,roaefsnpdpeucGptrsiovetulhpayst),d6ineddor7w(e1r.6eapnrdes2ummge/dkcganPnFibOaSli+zecdhoolnesDteLrol1,arnedspDeLctsiv2el0y)3 was Ssiugrnviifviicnagntpluypisncpreeralsietder(pw<e0r.e05siogrnipf<i0c.a0nt1l)y in Groups 12, 13,4, reduced (p<0.05 or 6 and 7. pS0.01) The numbers on DLs 2,3, of and Sin Groups 12,13,3, 4,6and 7. aAnddloosramg1ge1/-0kdgeSpiPennFdeOeaSncthalpgoarntoetu,eprrneasodpfmeicrnteiidsvutecleeyrd)e,dpGutrhpoebutopesdsty3arwtaeincildge.h4t(Gw1r.ao6suaepnvsdid21e1n,mtg1o/2nkagnDdLPsF1O31S,(12+.,23,.14.6 5 2rmenesdvpae2lcotnivieclya)cihd,adressipgencitfiivcealntyl)yarnedduGcreodup(sp<60.a0n1d)7pu(1p.6boadnyd w2emiggh/tksgoPnFmOoSst+wcehioglehsitnegrodla,ys, 4(D(L1s61 atnhdPrF2oOumgSgh/+5k)gc.hoPWlFhesOetSner+oalv,meerrveaasgpleeocpntuiipcveawlceyii)dg,ahnrtedswGpaerscotunivoperslmya8),l,9iG,zre1od0u,fpo1sr1,l6 t1a2rn.dasni7dze(,11.3G6r(ao0nu4dp,s083.an1.d 2(17.m<2g.01/..0k65gaonrdp<20m.g0/1k)gf/rdoamyGPrFoOuSp a2l(onmee,varleospneicctiavceildy)cownetrroel)a,lsGorosiugpni5fi(ccahnotlleystreerdoulcecodntrol) and Group 1 (Vehicle Control), respectively, over the same days of lactation. ThAlihlgehoatavhsee2rramngaget/unkruaglmabddeemlriinoviefsritymeaprnleaddntalilatottenireopnoasrriatiemnse,ctotemhrbesigwneaestrtiaetouinnonawfiiftnehdcetmxeedvaabnldyontdhioecsanagucemisdbeoofrrsPchFoofOlieSsveearsboolr.n SanGdllsbtoimllpbuopmspuwpasswseigrneifciocmanptalryabinlcereaacsreodss(pal<lO.1031d)oisnaGgerogurpou8ps(.0.T8hmegn/ukmgbPeFrOoSf daalomnse)wiatnhd Sailgonnief,icraenstpleycirveedluy)c.ed T(hp<e0s.e05s)igninifGircaonutpdsif1f0e,re1n1c,es12waenrde n1o3t(c1,on1s.i2,de1r6edatnrdea2tmmegn/tkrgelPaFteOdS pbeerccaeunsteatgheeoyfwmearleenpoutpdsosoangeD-Lde3peinndGenrto. uTp4hewassigrneilfaitceadnttroetdhuectiinocnre(apsSeOd.p01u)p in the mortality in this dosage group and nota direct effect of PFOS with mevalonic acid. J. OClbisneircvalatOibosnesrv(aStuimomnasrfireosm- BTiarbtlhesto21Daaynd5 2P2o;stIpndairvtiudmuaalnDdaNteac-ropsy `Tables 39 and 40) 3p`oAtmdevene/trkisaeel cPrleFidnOuiSccatlailoaonnndien,nmreeacstrpoeepmcstayilvoecblaysr)ee,rvoGacrtcoiuuorpnrsseda3sisanoncGdira4otue(pdLs6wi1at1nh,d1r2e2damungcde/dk1e3puP(p1F.O2v,iSab1i+.l6imateynvdaanldonic 3a"cmidb".Teheresspmeuocmftbilveietrleyros)f,wliaittnthderpsGurwpiostuhtphspaut6pwsaenrndoet7cno(ul1r.ds6tiaonngtdowu2acshmgion/cckcrgueraPrseFeddOiSinn +GGrrcohououlppessst1e11r2,o,l1)12.3,,13I3,n,c4r4,e,a66saeandndd 7; the increase was significant at pS0.01 in Group 7. 000042 418-018:PAGE II-9 nN1eu.c6m.rbaoenprdss2yomofbgps/uekprgvsaPwtFiitoOhnSsnaionlompniuelp,ksrietnshptaethcewtiesvrteeolmys)at,cilhGlrbioonrunGprosoru3fpoasunn9d,d41d0(e,1a.d161ia,nnc1d2lu2adnemddg/i1kn3cgr(eP0a8Fs,eOsS1,i+n1.t2h,e Tmehveailnocniidcenaccied,ofrtehsipsecotbisveerlvy)a,tiaonndwGarsousipgsni6fiacnandtl7y(i1n.c6raenadse2d m(pg</0k.g01P)FiOnSGr+ocuhpol6e,staesrol), compared with Group 5 (cholesterol control). 2uA)nlrlteohletahtoeebrdscetlroivntaihtceialotneastnocdacrnuteirccrlreedobpeisncyaoounbslseye:rovn1ae)titlohitenesri.nicnCitldhieennicFce1aslgwoeebnrseeerranvtoaittoindoopnssuapgisen-cwdleeurpdeeedncdodenensctir;deeaorsreedd pmrootbolreamcsti(vimtioysf,sipgnragos.tpripunodgri,tnilgoantboomnriegsduseibnrwgeaaastnhsdiingtgni,ipfnbiolctaacnnkte)lsytairnnegdd,nueocxeomdpi(hlptk<h0ian.l0ms1ot)osm,ianscGwhro.loluTephnsel8in.me9bc,,rot1ap0i,sly11, o1b2searnvdat1i3o,nreflecting (Group 1). A single the pup single in the occurrence mevalonic aocfidthciosnotbrsolergvraotiuopn(iGnrtohuep vehicle 2) had control no oral group. opening, no eyes and Significantly reduced displaced ears; as a (p<0.01) in Groups result, the incidence 3 and 4. One pup in of tis Group observation was 8 (0.4 mg/kg PFOS alone) had a tan area on the median lobe of the liver at necropsy on DL 5. All other pups appeared normal at necropsy on DLS. K. Blood and Tissue Analyses (See APPENDICES H, I, J and K) No significant difference between control groups (Groups 1,2 and 5) for any of the parameters K1. Gestation Day 21 Kila Dams Clinical chemistry parameters were generally unaffected in the DG 21 dams that were treated with 1.6 or2mg/kg PFOS alone. [FaClsSisntiecyealr|C|heCm6 hisotorysesV|alGueuscao)(smeg/|dL)oLfDPLFDOrS|aa loWnOe LD |Toghice[Tng des |MewloniicAdd| [ol op [Tg11e05[| oT8a978 |wwel [omelh|aPTaoeiggslT|]M oWe=rl 3T | 2Thme tgotalPaFnOdSfraeelotnheyrwoeirdehsoirgnmiofniecasntlleyverlesdfuocreTds(apSn0d.T01i),incdoammpsaraeddmtionitshteerveedhi1c.l6eocrontrol group. 000043" 418.018:PAGE TI-10 `Thyroid Hormone Values of PEOS alone I ya i oid pon. in. ogi (vehicle) 16mg a a 2m Fi) a Laidvmeinricshtoelreesdte1r.o6l olrev2elmsgw/ekrgePsFiOgnSi,firceasnptelcytdievcelrye,asceodmp(paSr0e.d0510otrhpe<v0e.h0i1c)leincoDntGro2l1 gdroaump.s Other liver clinical chemistry parameters were generally unaffected in the dams that were treated with 1.6 or 2 mg/kg PFOS alone. [PaLmiver Cl|inicaClhCoheesmiestryTV_aluIeDs L(Dmgc/gm| ) of PFWOoSLaDlosne|Tophenss | Vehicle [om16it[mem |oer [wee| Tg | 2m Tinhcerecalisneidca(lp<c0h.e0m5isotrrpy<p0a.r0a1m)e,taelrbeoift lnootwddoesnasgitey-dleippeonpdreotneti,ni(nLtDhLe)DwGas21sidganimfsictahnattlywere coadministered mevalonic acid and PFOS. [PasimCeleinric|alChCohleemtirsotlry|GlVuaclousees|(mg/LdDLL) of PROS plus |HOLD M|evTraglhoeneircdeAsc[idMevioricAdd| EMe7vii0on)|l ) TOR =r 154 8) l TILT l 9 BT| B0830lTl Co2m Ta [a a [Tar ar] | Tmheveatlootnalicanadcifdreaendthy1.r6oiod rh2omrgm/okngesPlFeOveSlswfeorreTssigannidfiTcaanitnlyDrGed2u1cedda(mps0c.o0a5dmoirnpi<s0t.e0r1e)d, compared to the vehicle control group. * * SSiiggnniiffiiccaannttllyy ddiiffffeerreenntt ffrroomm ccoonnttrroollggrroouupp;;pp0<0..0015. 00p044 418-018:PAGE I-11 Fe d Ale l a iTl aLieedTl aid Thyroid Hormone Values of PFOS plus. Mevalonic Acid Liver cholesterol and triglyceride levels were significantly 1.6 or 2 mg/kg. PFOS. reduced (p<0.01) in dams Liver LDL and HDL levels were cSoigandimfiinciasnttleyreidncmreevaaseldoniincdaacmisd and coadministered mevalonic acid and | 6or 2 mg/kg PFOS. CaE eeal eeT al ls dl Liver Clinical Chemistry pe ie 1 Chooser V[ aluo es o (mgn /gm) | of PFOSWoplLusbMreva| loniTcaAhciednds | Clinical chemistry parameters were generally unaffected in the DG 21 dams that were treated with cholesterol and PFOS. Clinical Chemistry Ce TrdTed aa aaA al [Famer |Chole Values (mgo/f PdFLOS) | Glocose | COLD plusCholesterol | WOLD: [Trgheends | The total and free thyroid hormones levels cholesterol and 1.6 or 2 mg/kg PFOS were for Ts and Tq significantly in DG 21 dams coadministered reduced (p<0.01), compared to the. vehicle control group. + Significantly Significantly different different from from control control group; group: p<0.05. p<0.01. 000045 418-018:PAGE I-12 pThmyroid Hormone Valuesof PTFoOSdI ,plus CholeFsrteeer,ol IiTA (Cholesterol Vomene or 0035 | S03 91| 0=0O5 TT | 14225080| 010x oss nGorkp T0000| OB ETI | 060TH| T0808| o0u 10E cLSionvneedrremaitsnreiidsgtloyercreseridigdnceihfolilecevasentlteslrywoleirnaecnrdseiag1sn.e6idfoiircna2dntamlmgys/rkcegodauPdcFmeOidnS(i.spt0Le.ir0ve1ed)rciLhnoDlDeLsGtaen2rd1olHdaaDnmLds1l.e6veolrs 2wemrge/kg tPrReOaSte.d wLiitvher1.c6hoolres2temrgo/lkpgarPaFmOetSerpsluwseCrheolgeesnteerraolll.y unaffected in the dams that were [LiPvaermCeleinric| al CheCmihstoryse V| aluesLD(mLgD/:gm)|of PHFOOLSD:pl| us CholeTsotgehreoelrdes | (Cholesterol a ar | & i Ceaahs Tm a | a&r| a | aPdFmOiSnisctoenrceendtr1.a6tioorn2s wmegr/ekgsiPgnFiOfiScaanntldyiinndcraemassecdoa(dpm<i0n.0i5s)teirnedthCehsoelreastoefrDolGof21 dams iMnecvraelaosneidc(pa=c<i0d.0a5n)din1.t6heorli2vemrgs/okfgdPaFmOsSa.dmPinFiOsStecroendce1n.6troarti2omnsg/wkegrePFsiOgSn.ificantly "= Significantly different from control group; p<0.01. 000046 PFOS Levels in aTE DG 21 Dam Sera and Liver 418-018:PAGE ITI-13 [Tm K.Lb. DG 21 Fetuses `The clinical chemistry parametersofcholesterol and low density lipoprotein (LDL) were significantly increased (p<0.05 or p<0.01) in the DG 21 fetuses from dams that were treated with 1.6 or2 mg/kg PFOS alone. * Significantly different from control group; p<0.05. 000047 418-018:PAGE I1I-14 d Bl at l i idB= Clinical Chemistry Values (mg/dL) of PFOS alone The level of free Ts was significantly reduced (p<0.01) in the DG 21 fetuses from dams that were treated with 1.6 or 2 mg/kg PFOS alone. oI er0Tl l oCeToIr Trad l ll1lll 2lTBl r]ll Thyroid Hormone Values ofPFOS alone Liver HDL clinical chemistry parameters were significantly increased (p<0.01) in DG 21 fetuses from dams administered 1.6 or 2 mg/kg PFOS alone. Other liver clinical chemistry `mg/kg PFOS alone. LiverClinical Chemistry Values (mg/gm) of PFOS alone [Parameter T Cholesterol |_LDLDw|HOLD | Taghecendes | 5:The clinical chemistry parameters of cholesterol and low density lipoprotein (LDL) were significantly increased (p<0.01) and triglycerides were significantly decreased (p<0.01) in the DG 21 fetuses from dams that were treated with mevalonic acid and 1.6 and/or 2 mg/kg x Significantly different from control group; p<0.05. ** Significantly different from control group; p<0.01. 000048 Clinical Chemistry 418-018:PAGE [I-15 Values (mg/dL) of PFOS plus Mevalonic Acid 3 The level of free T was significantly reduced (p<0.01) in the DG 21 fetuses from dams that were treated with mevalonic acid and 1.6 or 2 mg/kg PFOS. IP P = le llA I ma PiewP tgl]l Thyroid Hormone Values of PFOS plus Mevalonic Acid Liver cholesterol, HDL and triglyceride levels were significantly increased (p<0.0S or p=0.01) in the DG 21 fetusesofdams that were treated with 1.6 or 2 mg/kg PFOS plus Mevalonic Acid. Liver Clinical Chemistry Values (mg/gm) of PFOS plus Mevalonic Acid [ammeter Cholesterol _T__LDLDir| WDLDir| Tgiycerdes | CAE Tribe Temi wmTir] `dTehnesictlyinliicpaolpcrhoteemiinst(rHyDpLa)rawmeerteerssigonfifcihcoalnetsltyerionlc,rleaoswedde(nps<i0t.y0l5ipoorppr<ot0e.i0n1)(LiDnLt)heaDndGhi2g1h fetuses from dams that were treated with cholesterol and 1.6 or 2 mg/kg PFOS. ** Significantly different from control group; p<0.01 000949 Clinical Chemistry Values (mg/dL) of PFOS plus Cholesterol 418-018:PAGE III-16 * The level of free Ty was significantly reduced (p<0.01) in the DG 21 fetuses from dams that were treated with cholesterol and 1.6 or 2 mg/kg PFOS. I [ led l a d TTToal "Thyroid Hormone Valuesof PFOS plus Cholesterol Liver cholesterol and triglyceride levels were increased or significantly increased (p<0.01) in the DG 21 fetuses from dams coadministered cholesterol and 1.6 or2 mg/kg PFOS. Liver LDL and HDL levels were generally unaffected in the fetusesofdams that were treated with 1.6 or 2 mg/kg PFOS plus Cholesterol. CS TrellwcmlW| wolwrWi| cl Liver Clinical Chemistry Values (mg/gm) of PFOS plus Cholesterol [Parameter T Cholesterol T__LDLDx__ J HWDLDi 1Trghcendes PFOS concentrations were significantly increased (p<0.01) in the pooled sera ofDG 21 fetuses administered 1.6 or2 mg/kg PFOS and in fetuses coadministered Cholesterol or Mevalonic acid and 1.6 or 2 mg/kg PFOS. PFOS concentrations were significantly increased (p<0.05) in the livers of fetuses administered 1.6 or 2 mg/kg PFOS. * Significantly different from control group; p<0.05. ** Significantly different from control group; p<0.01. 000050 PFOS Levels in EA Pooled DG 21 Fetal Sera and Livers A (Mevalonic) (6) Na. 418-018:PAGE I-17 = CEGrousp 9 TwTw= ]1 K.2. Lactation Day 5 K2.a. Dams The clinical chemistry parameter of serum cholesterol wassignificantlydecreased (p<0.01) in the lactating dams that were treated with 0.4, 0.8, 1, 1.2, 1.6 or 2 mg/kg PFOS alone, compared to the vehicle control group. The clinical chemistry parameter of glucose was significantly increased (p<0.01) in lactating dams treated with 2 mg/kg PFOS alone and the clinical chemistry parameter of triglycerides was significantly decreased (p<0.05 or P<0.01) in lactating dams treated with 1.6 or 2 mg/kg PFOS alone, compared to the vehicle control group. * Significantly different from control group; p<0.05. ** Significantly different from control group; p<0.01. 000051 418-018:PAGE III-18 Clinical Chemistry Values (mg/dL) of PFOS alone Cholesterol | Chalesierol Taghyeenide| MevAaciidone Guup1 | T1Bl6o2o1d3]2 |967i2339 $L0o2L3D0i|| 2_2Hp2LD0i7c | 1574s2976| STOR (eh) 0:|___91) 3T T1a6s28| 10a692)37 as) as) ToaB9)I] aNo8r) 0G.r4omups | T=203) 3 20) T63a020173 [320:,27|#32a1096 20 | Eves 0G8rou1p0 | S852al n1187|l BBa2)317|I171a9l n2195|l 37a2n19| H0a=1)T0|rl 101ia2n25d27 Pe Girnouep s[|| 539+051)17%| 84as13| 172[5)2177 | T8a2s27 | 9x16 | as LI 2707 an Longs |SETanTI0T| e6a30) 4| TRaInZH0 an B3azn03 [9an2a| 9262)009 Grmougps13|| $962(91)077|TH0=4T7| Tp8r92y3 Ti[z)0s| sBosm: | Wha=ised an a9 The total and free Te levels in lactating dams administered 0.4 (free Ta only). 08, 1, 1.2, 1.6 or2 mg/kg PFOS were significantly reduced (p<0.05 or p<0.01) and total and free Ts levels in lactating dams administered 1.2, 1.6 or 2 mg/kg PFOS were significantly reduced (p=0.05 orp<0.01), compared to the vehicle control group. `Thyroid HormToanlesValoufTPeoFuOrsS7, alone Feet Parameter aL wal. 0 nIginl. Fnei c, (VGerhioculpe1| 145402)0660 a) To 1250)057 | TE13s)20 | 072ir025 Gr0o4up'mse 0. TS i=o)3T40| 020170)86 Te 2100.)11 08mp a eS a IE I OF o0l3i0 | r R=&l 187 | WOAT 2l 0% | Ta 1a 05 | 030 0TE 12 mesg OI a0nTH | FIOIaS) T| O26a2s)00 | TESi2n)07 | 0353 a2s0)067 OS a0n10 | 33+an(1700 | 0359 2107 56 | TSHa2n06 | UI2i007 2 9 15 15) is) a) Ltrievaetredtrwiigtlhyce1.6roiderl2evmelgs/kwgerPeFsOiSgn.ifAilclanottlhyeirnlcirveearsceldin(ipc<a0l.c0h1e)miinstlracytaptairnagmdetaemrss twheartewere `generally unaffected in the DL 5 dams that were treated with 1.6or 2 mg/kg PFOS alone. * Significantly different from control group; p<0.05. ** Significantly different from control group: p<0.01. 000052 418-018:PAGE ITI-19 A Il Liver Clinical Chemistry Values (mg/gm)of PFOS alone [Parameter Cholesterol| LDLDic | THDL-Dir (Venice T6207| 001a2900% TE=as0) TS 04 mas T320)05| 08c:o00 THa20010 08 my an in an my T5219)08| 0T02aa091r06 | mT%e019)7m5 12 maf as) 15) as) 16 my ra)l I an an F2 E a9 Ta19) a9 Taaz T2c2o)37 in) TaI9E as) an, Stya `The clinical chemistry parameters of serum cholesterol was significantly decreased (pS0.01) in the lactating dams that were treated with mevalonic acid and 1.6 or2 mg/kg PFOS and cholesterol in the milk was significantly increased (p<0.05) in the lactating dams that were treated with mevalonic acid and 2 mg/kg PFOS. Clinical Chemistry Values (mg/dL) of PFOS plus Mevalonic Acid Params | l[Blolod] Group 2 lTasl STE | TA32397 [L[3o7L2sD2i9||on[pGoTL=ueIbn8icT| [g1y[3cea5re6i3de8s6| ] BA1ci4d= Oevalonic) a as as) as aw | ma5s) 1G6omdg | 6[TieR| W0SaEe67 | TRaI9 E | 34as2)0|S20=9)1T | 18a3s365|| 2T02002x 15) Cmoeups? TRROZTIA6| T7a853)05 [3a7s2)31 | 50a:01 | 118a792507|| Ts8a66sadss a9) The levels of total and free T, were significantly reduced (p<0.01) in the lactating dams that were treated with mevalonic acid and 1.6 or2 mg/kg PFOS. `Thyroid Hormone Valuesof PFOS plus Mevalonic Acid [rome|SiL [anreal Tpobnt inl. Sngr. [(MCevoaonicd) [mmsa) m | r Ste5)lam | Wwmglon | mawal | wMmolsow El ar aoy l @ all a @ @ Ee@ n 5 Io Lwievreerttrreiagtleydcewriitdhe 2lemvegl/skwgePreFOsiSgnpilfuiscaMnetlvyalioncnriecasAecdid(.p<A0l.l01o)thienrtlhievelracctlaitniincagldcahmesmitshtarty `parameters were generally unaffected in the DL5 dams that were treated with 1.6 or 2 * Significantly different from control group; p<0.05. ** Significantly different from controlgroup; p<0.01. 000053 418-018:PAGE 111-20 `mg/kg PFOS plus Mevalonic Acid. Liver Clinical Chemistry Values (mg/gm) of PFOS plus Mevalonic Acid [Paameter 1Cholesterol| LOLDw |HWDLDi|Trghcendes | [|E wor Ter eTe blood level of glucose was significantly increased (p<0.05) in lactating dams that were treated with cholesterol and 2 mg/kg PFOS. A Comer |S | oh | mAel re | gol[pl r Clinical Chemistry Values (mg/dL)ofPFOS plus Cholesterol `The level of total and free T and Ts were significantly reduced (p<0.05 or p<0.01) in the lactating dams that were treated with cholesterol and 1.6 or2 mg/kg PFOS. [[eoerl [Lrriee Yl omi i omW tTo T |vTls |T rwol=o Thyroid Hormone ValuesofPFOS plus Cholesterol Liver triglyceride levels were significantly increased (p<0.05) in lactating dams coadministered cholesterol and 2 mg/kg PFOS. All other liver clinical chemistry parameters were generally unaffected in the DL 5 dams that were treated with 1.6 or 2 mg/kg PFOS plus Mevalonic Acid. * Significantly different from control group; p<0.05. ** Significantly different from controlgroup;p<0.01. 000054 418-018:PAGE 111-21 Liver Clinical Chemistry Values (mg/gm) of PFOS plus Cholesterol [Pameter TTM Cholesterol _T---- LDLDw [~~ HDLDi | Taghcendes | FOPFOS Levels in DL 5* Dam Sera and Livers al Bl * Significantly different from control group; p<0.05. 000055 418-018:PAGE 1.22 K.2b. LD 5 F1 Generation Pups "The clinical chemistry parameters FI generation pups from lactating measured dams that were were not significantly treated with 0.4, different in 08, 1, 1.2, the 1.6 or 2 mg/kg PFOS alone, compared to the vehicle control group. [PCalminmiecealrC|heCmiisoteryselV|alueGsho(msge/dL)|of PLFDOLSDaWlo|ne _WOLDY Group 1 | 11252106| 582618 | 93:87 Tassie | 26s ado|Tia2s) :| Feas: a) T7122)69 | B920 oGirmoeupne | a5) omg | 03) T0HT| saes)e |Whaaiw| ae05d| Naked a3 05) 05 1 mei Tuaes)r an FaSa Eaia |Th [ee | IEsg |Eus)l a) fir a Lome | ) @ r2ml al6 l 0 a Go TE 6 w e] The free and total Ti levels in DL 5 pups from lactating dams administered 04, 0.8, 1,12, 1.6 0r 2 mg/kg PFOS were significantly reduced (p<0.01), compared to the vehicle control group. The thyroid stimulating hormone (TSH) was significantly increased (p<0.05 or PpSO.01) at 1 and 1.6 mg/kg PFOS, but not in a dosage-dependent fashion. E0 S = `Thyroid Hormone Values of PFOS alone (Venice 04 nar 08 na mg G1r2oupmo1n2e 16 man I v3 TIp2e2rl0 Go a O05 SOOT | a o S38 796| 009ou2n0.00 | 101ny8i2n0l.166 po an an Frame] T |e we [T e ii l rl PS 0 WTSa2 78 Sa@ l lThO0w:0a2l% | 0012@ 005 T7p0i8t2 TO | 0004io2)0009 5 00ma005 & ET | rie Liver triglyceride and LDL levels were decreased or significantly decreased (<0.05 or PpS0.01) in DL female pups from lactating dams administered 04, 0.8, 1, 1.2, 1.6 or 2 mg/kg PFOS. All other liver clinical chemistry parameters were generally unaffected in the female pups of lactating dams that were treated with 0.4 to 2 mg/kg PFOS alone. * Significantly different from control group; p<0.05. ** Significantly different from control group; p0.01 000056 418-018:PAGE 1-23 Female Pups Liver Clinical Chemistry Values (mg/gm) of PFOS alone [PoGrmoupe1 |G5o20s60s [| TIODL= 0D0K857| 1H0b2L0D0r55 (GVreohuicplse 9:as0)0 T00as05 T=as00T osm 08 mei f52e0)50 an T0072o0y00007 an 00-c0o0% an [om i 0as8) 020fi.r0000 i2s0)0% B12mo |Tae| Toapn e an I Goup15 T200.67 5%d0o)0000 TT0aG0oa.1m7 2 @ @ @ 181a2)754 W0an46 TT as)560 Sana m0dao2y2T07 @ Liver iglyceride levels were decreased or significantly decreased (p<0.05 of p<0.01) in DL 5 male pups from lactating dams administered 0.4,0.8. 1, 1.2, 1.6 or 2 mg/kg PFOS. Al other liver clinical chemistry parameters were generally unaffected in the male pups whose dams were treated with 0.4 to 2 mg/kg PFOS alone. [MalPe Puaps | nLivemr CChleionliecse aelolCr hemistry Values (mg/gm) of PFOS alone [LDL FOLD: (GSVreaobkuipecs) |CTa920n8 e| o G60a25g)0000 T2a000 TTafri}e 0G4romup T6a2o,05 fe TO20,G | TAa=,6% 0Gr5omup10 T7i207 TG 2a0n0077 02in0050 in) Gi!roup IT T6a2s0)5 00i2.0600 TIis2000 052it4s50 12 in) is) as) ity I os do) a0, i do) ao, 2 me @ m@T me@ m 1Ee Levels of cholesterol, low density lipoproteins (LDL) and triglycerides in the blood were significantly increased (p<0.05 or p<0.01) in DL 5 pups from lactating dams that were treated with mevalonic acid and 1.6 mg/kg PFOS. * ++ SSiiggnniiffiiccaannttllyy ddiiffffeerreenntt ffrroomm ccoonnttrrooll ggrroouupp;: pp<=00..0051. 000057 418-018:PAGE 11-24 Clinical Chemistry Values (mgo/fPdFLO)S plus Mevalonic Acid [Parameter | Cholesterol | Glucose| LDL-Dir| HDL-Dw | Trghcenides |Mevalonic Acid | Levels of total Ts were significantly decreased (p<0.01) in DL 5 pups from lactating dams that were treated with mevalonic acid and 1.6 mg/kg PFOS. Thyroid Hormone Values of PFOS plus Mevalonic Acid I dsll ill sl Parameter ug/L ng/dL 1 pe/mL ng/ml. g/dL NOVALUESFOR THis GROUP Liver clinical chemistry parameters were generally unaffected in the DL 5 female pups of lactating dams that were treated with 1.6 PFOS plus Mevalonic Acid. There were no liver samples for female pups of lactating dams that were treated with 2 mg/kg PFOS plus Mevalonic Acid. Female Pups Liver Clinical Chemistry Values (mg/gm) of PFOS plus Mevalonic Acid Ci ATa a mNaO eVALUES F|OR THaISiGReOUP| li [Pammecr | Choleseol [| LDLDi | WOLD __[ Tnglycendes | Liver clinical chemistry parameters were generally unaffected in the DL 5 male pups of lactating dams that were treated with 1.6 PFOS plus Mevalonic Acid. There were no liver samples for male pups of lactating dams that were treated with 2 mg/kg PFOS plus * Significantly different from control group; p<0.05 ** Significantly different from control group; p<0.01 a Group 2 significantly different from Group 1; p<0.01. 000058 418-018:PAGE III-25 Male Pups Liver Clinical Chemistry Values (mg/gm) of PFOS plus Mevalonic Acid [Parmeier |Cholesterol | LDLDir [~~HOLD |Tghcerides | % NO VALUES FOR THIS GROUP ro ES ee) Levels of low (LDL) and high (HDL) density lipoproteins were significantly increased (p<0.05 or p<0.01) in the pups from lactating dams that were treated with cholesterol and (p<0.05) in the pups from dams that were treated with cholesterol and 2 mg/kg PFOS. Clinical Chemistry Values (mg/dL) of PFOS plus Cholesterol l i[i | ier[Wil hlr WwelTieirl)l [Pammeter[Cholesterol| Glucose |LDLDi | WOLD |Tagherdes | Levels of total Ts and free Ts were significantly decreased (p<0.05 or p<0.01) in pups from I cHI Thyroid Hormone Valuesof PFOS plus Cholesterol [Eh wif |woe |eo |wer] Liver clinical chemistry parameters were generally unaffected in the DL 5 female pups of lactating dams that were treated with 1.6 or 2 mg/kg PFOS plus Mevalonic Acid. FemalePupsLiver Clinical Chemis Values (mg/gm) of PFOS plus Cholesterol l 0 al l WlO0 l 1.6 mg/kg 1D). {i (an) * Significantly different from control group; p<0.05. ** Significantly different from controlgroup;p<0.01. a Group 5 significantly different from GroupI;p<0.01. 000059 418-018:PAGE 111-26 Liver triglyceride levels were significantly reduced (pS0.05 or p<0.01) in DL5 male pups of dams coadministered cholesterol and 1.6 or 2 mg/kg PFOS. All other liver clinical chemistry parameters were generally unaffected in the male pups of lactating dams that were treated with 1.6 or2 mg/kg PFOS plus Mevalonic Acid. Male Pups Liver Clinical Chemistry Values (mg/gm) of PFOS plus Cholesterol [ammeter Cholesterol |_LDLDi [| ~HDLDi | Trgheondes Er Group 7 T2073 0.000 +0.0000 00 = 00835 PFOS Levels in Pooled DL 5 Fetal Sera and Livers al2 mglkg (1) ne Group 8 73423083 1380+0.00 2452293.36*% RR Ee * Significantly different from control group; p<0.0S. ** Significantly different from control group; p<0.01 000060 418-018:PAGE 111-27 L. Histopathology of Hearts and Thyroidsof F1 Generation Pups (See APPENDIX J) `The type and incidence of the histomorphologic observations in the heart and thyroid of the male and female pups from dams of the vehicle control and 2 mg/kg/day dosage groups are shown below: ose Group T Sex M MT FT TF DNoa.mPNuop.s 1091 09 1101 59 109| 09 110i 59 TNHoY. ReOxaImDined HNEo.ARNTormal NNoo.. eNxoarmmianled No microscopic changes were observed; all sections examined were within normal histologic limits. 000061 413-018:PAGE III-28 REFERENCES I. Study Design as Modification of: U.S. Food and Drug Administration (1994). Intemational Conference on Harmonisation: Guideline on detection of toxicity to reproduction for medicinal products. Federal Register, September 22, 1994, Vol. 59, No. 183. 2. US. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. 3. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standardfor Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. 4. European Economic Community (1989). Council decision on 28 July 1989on the acceptance by the European Economic Communityof an OECD decision/recommendation on compliance with principlesofgood laboratory practice. Official Journal of the European Communities: Legislation. 32 (No. L 315; 28 October); 1-17. 5. Christian, M.S. and Voytek, P.E. (1982). In Vivo Reproductive and Mutagenicity Tests. Environmental Protection Agency, Washington, D.C. National Technical Information Service, U.S. Department of Commerce, Springfield, VA 22161. 6. Christian, MS. (1984). Reproductive toxicity and teratology evaluations of naltrexone (Proceedings of Naltrexone Symposium, New York Academy of Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10. 7. Lang, PL. (1988). EmbarndFyetoal Developmental Toxicity (Teratology) Control Data in the Charles River Crl:CDBR Rat. Charles River Laboratories, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research.) 8. Institute of Laboratory Animal Resources (1996). Guidefor the Care and Use of Laboratory Animals. National Academy Press, Washingion, D.C. 9. Salewski, E. (1964). Firbemethode zum makroskopischen Nachweis von Implantationsstellen am Uterus der Ratte. Arch. Pathol. Exp. Pharmakol. 247:367. 10. Snedecor, G.W. and Cochran, W.G. (1967). Variance test for homogeneityofthe binomial distribution. Statistical Methods, 6th Edition, lowa State University Press, Ames, pp. 240-241. 11. Sokal, RR. and Rohlf, F.J. (1969). Bartlett test of homogeneity of variances. Biometry, WH. Freeman and Co., San Francisco, pp. 370-371 12. Snedecor, G.W. and Cochran, W.G. (1967). Analysisof Variance. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 258-275. [110] FINAL REPORT PFOS - MEOVNALEOGNEINCERAACTIIDO/NCHROELPERSOTDEURCOTLICOHNASLTLUEDNYGEOFAND NOEL INVESTIGATION IN RATS | SPONSOR'S STUDY NUMBER: T-6295.25 FINAL REPORT DATE: 16 DECEMBER 2002 poss TITLE- ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACIDICHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS ARGUS STUDY NUMBER: 418-018 SPONSOR'S STUDY NUMBER: T-6295.25 TABLE OF CONTENTS SUBJECT PAGE 1 SUMMARY AND CONCLUSION 31 A. Methods 3] B. Results 4 C. Conclusion +o I. DESCRIPTION OF TEST PROCEDURES LSI A. Conduct of Study mi B. Test Anicle Information 4 C. Control Articles Information 4 D. Vehicle Information 5 E. Test Anicle Preparation and Storage Conditions 6 F. TestSysiem 7 G. Husbandry 9 H. Methods 1 mM. RESULTS m1 A. Morality m1 B. Clinical Observations m1 C. Necropsy Observations m2 % 000864 SUBJECT PAGE D. Terminal Body Weights and Organ Weights and Ratios of Organ Weights to Terminal Body Weights m2 E. Body Weights and Body Weight Changes m3 F. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values ms G. Mating and Fertility m7 H. Caesarean-Sectioning and Litter Observations m7 I Natural Delivery and Litter Observations m7 J. Clinical Observations from Birth to Day 5 Postpartum and Necropsy Observations ms K. Blood and Tissue Analyses mo L. Histopathology of Hearts and Thyroids FI Generation Pups m-27 REFERENCES m28 APPENDIX A - REPORT FIGURES Figure 1. Body Weights- Fo Generation Female Rats - Groups 1, 8 through 13 A-1 Figure 2. Body Weights - Fo Generation Female Rats - Groups 2,3 and 4 A2 Figure 3. Body Weights - Fo Generation Female Rats - Groups 5, 6 and 7 A3 APPENDIX B - REPORT TABLES Table 1. Clinical Observations - Summary - Fo Generation Female Rats Bl Table 2. Necropsy Observations - Summary - Fo Generation Female Rats B-9 Table 3. Terminal Body Weights and Organ Weights and Ratios (%) of Organ `Weight to Terminal Body Weight - Summary - Fo Generation Female Rats, B12 Table 4. Body Weights - Premating - Summary - Fo Generation Female Rats ~~ B-15 Table 5. Body Weight Changes - Premating - Summary - Fo Generation Female Rats B18 iii 000065 SUBJECT PAGE Table 6. Maternal Body Weights - Gestation - Summary - Fo Generation Female Rats B-21 Table 7. Maternal Body Weight Changes - Gestation - Summary - Fo Generation Female Rats. B-27 Table 8. Body Weights - Lactation - Summary - Fo Generation Female Rats B-30 Table 9. Body Weight Changes - Lactation - Summary - Fo Generation Female Rats B-33 Table 10. Absolute Feed Consumption Values (g/day) - Premating - Summary - Fo Generation Female Rats B-36 Table 11. Relative Feed Consumption Values (g/kg/day) - Premating - Summary - : Fo Generation Female Rats. B-39 Table 12. Maternal Absolute Feed Consumption Values (g/day) - Gestation - `Summary - Fo Generation Female Rats B-42 Table 13. Maternal Relative Feed Consumption Values (g/kg/day) - Gestation - Summary - Fo Generation Female Rats B-45 Table 14. Absolute Feed Consumption Values (g/day) - Lactation - Summary Fo Generation Female Rats B-48 Table 15. Relative Feed Consumption Values (g/kg/day) - Lactation - Summary - Fo Generation Female Rats B-51 Table 16. Mating and Fertility - Summary - Fo Generation Female Rats B-54. Table 17. Caesarean-Sectioning Observations - Summary - Fo Generation Female Rats B-57 "Table 18. Litter Observations (Caesarean-Delivered Fetuses) - Summary Fo Generation Female Rats B-60 Table 19. Natural Delivery Observations - Summary - Fo Generation Female Rats B-63 Table 20. Litter Observations (Naturally Delivered Pups) - Summary - FI Generation Litters B-66 Table 21. Clinical Observations from Birth to Day 5 Postpartum - Summary - Fl Generation Pups. B75 wv 000066 SUBJECT `Table 22. Necropsy Observations - Summary - F1 Generation Pups PAGE B78 Table 23. `Table 24. Clinical Observations - Individual Data - Fo Generation Female Rats Necropsy Observations - Individual Data - Fo Generation Female Rats B-81 B-102 Table 25. Terminal Body Weights and Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight - Individual Data - Fo Generation Female Rats Table 26. Body Weights - Premating - Individual Data - Fo Generation Female Rats `Table 27. Maternal Body Weights - Presumed Gestation - Individual Data Fo Generation Female Rats `Table 28. Maternal Body Weights - Lactation - Individual Data - Fo Generation Female Rats Table 29. Feed Consumption Values - Premating - Individual Data- Fo Generation Female Rats Table 30. Maternal Feed Consumption Values - Presumed Gestation - Individual Data - Fo Generation Female Rats B-122 B-135 B-148 B-174 B-187 B-200 Table 31. Maternal Feed Consumption Values - Lactation - Individual Data Fo Generation Female Rats Table 32. Mating and Fertility and Days in Cohabitation - Individual Data - Fo Generation Female Rats B-213 B-226 Table 33. Caesarean-Sectioning Observations - Individual Data - Fo Generation Female Rats B-239 Table 34. Litter Observations (Caesarean-Delivered Fetuses) - Individual Data Fo Generation Female Rats B-242 Table 35. Fetal Vital Status - Individual Data - Fo Generation Female Rats B-245 Table 36. Natural Delivery, Implantation Sites, and Pup Viability and Sex Individual Data - Fo Generation Female Rats Table 37. Pup Body Weights Pooled by Litter from Birth to Day 5 Postpartum - Individual Data - FI Generation Litters B-248 B-261 v 000067 SUBJECT . PAGE Table 38. Pup Vital Status and Sex from Birth to Day 5 Postpartu-m Individual Data - FI Generation Pups B24 Table 39. Clinical Observations from Birth to Day 5 Postpartum - Individual Data - F1 Generation Pups B-287 Table 40. Necropsy Observations- Individual Data - F1 Generation Pups B-292 APPENDIX C- PROTOCOL AND AMENDMENTS CloC67 APPENDIX D- DEVIATIONS FROM THE PROTOCOL ANDTHE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY D-loD-6 APPENDIX E- CERTIFICATE OF ANALYSIS E-l0E2 APPENDIX F- HOMOGENEITY AND CONCENTRATION ANALYSIS F-lt0F21 APPENDIX G - TEMPERATURE REPORTS AND RELATIVE HUMIDITY G-110GS APPENDIX H- BIOANALYTICAL REPORTS (ANILYTICS) Hl to H-125 APPENDIX I- BIOANALYTICAL REPORTS (PRIMEDICA WORCESTER, SPONSOR AND SRI) to 1-444 APPENDIX J - HISTOPATHOLOGY REPORT Fo) APPENDIX K - HISTORICAL CONTROL DATA K-110K-$ APPENDIX L- STATEMENT OF THE STUDY DIRECTOR Lt APPENDIX M- QUALITY ASSURANCE STATEMENT M-1toM2 vi a0006s 418-018:PAGE 11-29 13. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatwimtheanconttrosl. J. Amer. Stat. Assoc. 50:1096-1121 14. Sokal, RR. andRohlf, F.J. (1969). Kruskal-Wallis Test. Biometry, WH. Freeman and Co., San Francisco, pp. 388-389. 15. Dunn, O.J. (1964). Multiple comparisons usingrank sums. Technometrics 6(3):241-252, 16. SiegelS,. (1956). Nonparametric Statisticsfor the Behavioral Sciences, McGraw- Hill, New York, pp. 96-104. 000069 APPENDIX A REPORT FIGURES 208070 418-018:PAGE A-1 8 E+ 3 - eo 2 = 2 [| : JEL3 il LEEi E i : f fF F s FFF REE Ts 2! EL Tevd 5! g: fo T8gs & lesRN = : Fi I.Eo NeEe :: 2 ey g 0 w 2 T EZq &3 O Wd i=3 ga 2S23E9e 5g-o0osuwes BE 0 2E gz oO 3gs 2 g 8 E :%o 2 ; = 73 8 I BRN = = hes =z Rovlien MxER =82 RSpinp C`nom rweam:NXES og h1z4b] =2=hbvoeemwoweee:rt: =Ti5 =Sbene: =: BE --- e aett p-s 2EaL Ie -->- lens 2, aw=E:Y 28 i0 e >= oe g 3 8 8 3 8 8 8% 8% + (9) LHOIIM 000071" 418-018:PAGE A-2 i] ---- 1 i 1 3% $ g i > cg03,v8g zisf 2 3 f ET hts I gi SY 3 Ey "5 i i oo - -- TEg32 3 8 ha - 3p a S ilzEe: gEETZg Y omg g6 SHz= xaEz0Sed =O wo g 8B3 o og g3h 5 ou 8 i 83 o 3 = TeS, w =: > KNeT i=- >> aae 2=2= ect 2 > ent <8 >>boeeest P-~e 8z >>oeect -a Wo= -= Voheoe -B=Y - 3, :oC 528 2 oe RS"a C8 $s 8 5 8 8 8 5 8 3 (9) HOM oosav2 418-018:PAGE A-3 i -- iii 82 3gf8g 3*8 ssEs5fsfz z 2 2% s%% 83 g 8 1 :2 - -- 8 CE g3 eeenennnsnes ae > 3 ~~ &3 "a >N i, "le, 8 Edn enH ow f: 2o3uss we oe 1050z8 - oxe 828 o = a [SY 88> E x 53d3 ~egS 53 eeneoeneeeee=8E32 -8= : 2= = ===2 <3 -2 -x8% #058 n= 8 5003 gos" 53 g 8% u 5 8 yw - woe o >x >= - > yo=m =- >= - 8 8 v> e= 3 EN 5 > <2 2 e8 S8e f Mu, X :E $ 5 2 3(9) H&OM8 8 8 & % 000073 APPENDIX B REPORT TABLES 000074 418-018:PAGE B-1 oe Demian Po i |8 | mem ave eee Polo lig foommrrnaails BE LhlE og owA ogo heiggd Dr HEREE RRREG i Pople one HEE HPeg oioTgpei"g Uomo avaiE,i so 8 g ozaidyy i {EE A I i Dob pigEs 8esdi802 30i &fF A dfFiEgggI gFRgdiiEggsg,td Hr iid SOBER fg fii ;FOoEodiBrEigEiE cfgggo ppgkEriBidzfdz 000075 418-018:PAGE B-2 Poe lemmaiiiiig i sip oC gEEEs RRsos ss osi s 8 i PL laammmaanid E : os TT :: EL lommamiiiii [I Deel Doss gpageososoaigh i582 go all By iv 3oases seers oaaih ere eeeEH 3caww EE IE IE E 580 5 iid i03dog B 23,E8 E : JgiEve wt 3 0 HE |0 Psooioapddd: 0 Gb8 B1 ORELFRGEE aig 2 BiBESE iLiioalE bcooIigEgiitgEegdf 1i sdiijiisiiaakdns PEE FOREEE Eg 000076 418-018:PAGE B-3 Poe zi i {: lp i= 8 INNS : i amsa eeeo nooo oafi Bags sass sal i ET iT 5& zaman iE aoa aout 18 gE : ig88 Bl sooomoiiinEhEE Fig i H HE ppl gBi10 ml1 s iopgil pio IEEE fo SEL Eg gig BEE 5Ps g* fis iBg or4ft%g HH; EIDE OEEg.EE 1IEidiME Riggs RR EEg 000077 418-018:PAGE B-4 io Poin ! 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L iH iaf ii i5 000385 418-018:PAGE B-312 fo HED BE phy ;EL i | , Po gig 5boa5r3 is dE o| pidr. i 83s 3 gfd:sz if gPo i a =Eap BJeRaR FCoat Poff HEL gf pbEnR gin iE: gh Pi S oog nRBEEfEeMIiRnRrEoEfIGanEEenaaeCE anmnl nEsmopiinnne i lo HE hk ERE i EEE i B IPEHd sii sHiy ihjag g2F 0 0 Hr ;Pi41p8 ti OE HEEe tin cee iEsh iE iE i igi7 ils i4h ioiE 000386 418-018:PAGE B-313 : | feo 5 ig gd : :H 2 8.3g s `EF HE i i cH H idly iy 1 eg i EEE EE of oh HH i 5 iH is 000387 418-018:PAGE B-314 i foEWEFEErEAEEE IaeREf E IETi L Eo{oiagfmedlagfehf afcPafd geiffg f ffoniE, Po EH P{o op BHEERHRE LBEaE d dfie Bte EE 5%i2 (PE 55: 8 0 i gi giIE iE FHP EN PPoiragt TTT Ths iisfs iE if nshl 22 i it i0. 000388 418-018:PAGEB-315 ; Hmipg Po Po i PRE Dg EE HER 2 FE ZF Do oniidieh Col EgsiEEeR RoE ulIEEE 2 gE gE & Blogg Bein pugi: Bd gE io oo wih AED gadidx Po slain iD Bohn PSoaai d rHge ianean faemaatn nferield 1niain a i, 8 Bim ihm ah nl lich s PE pEHELH 5 f IEu ofrf iBEsclE8 N8Eh3 FI gq EH ig wg 5 E,0 P32 ZH.E0EHR i587 = FF = = = EE ii H BEg i(13 FEE 1 fiihY! Iy 000389 oH Ti lsg E2 L1LIg(BEgE 2 PEE BE ogi gE Epp igii gil I EE gel Eo ggg pBoiopgiogBBsRd EdsL%sYil FFiEfI iEg uly gs 37 pid... $ E0 o xFi Hi iF BfEyE of: og igd ni 33 Poi de ui 3 183 FEL it f fit ey 418-018:PAGE B-316 000399 APPENDIX C PROTOCOL AND AMENDMENTS 000331 418-018:PAGE C-1 PRIMEDICA Ar Raesmo ebLaesom nic rs TAp aon PROTOCOL 418-018 STUDY TITLE: Funes PURPOSE: SPONSOR'S STUDY NUMBER: T-6295.25 One Generation Reproduction Study of PFOS - Mevalonic Acid/Cholesterol Challenge and NOEL Investigation in Rats cToh-eadpmuirmpsotsaetsioofntohifsmsetvuadlyonairec t2o6ddetoerrcmhienleeswehreatlhearnor not p{rreevdeunctedormaatnetrangaolnibzoedtyhweeaidgvhetrgsaein,matmeerrneaalseadndpoferteaelnetffects stillbom, decreased birth weight and decreased pup survival) o5th1be3s.en0ro0v8oe,bds3ienMravsepdureodvfifnoecuutsmlbsotevuerd!y1(-(NA6Or2EgL5u)s8)ReasnedatrchbaPtireortodceofline TESTING FACILITY: Argus Research Laboratories, Inc. 9Ho0r5sShhaeme,hPyanDnrisvyei,vaBruiial.din1g90A44-1257 Telephone: (215) 443-8710 Telefax: (215) 443-8587 STUDY DIRECTOR: Raymond G. York, Ph.D., DABT Associate Director of Research raymond.york @primedica.com `SPONSOR: 3M Corporate Toxicology 3M Center, Building 220-2-02 St. Paul, Minnesota 55144-1000 STUDY MONITOR: Deanna J. Luebker, M.S. 33MM CMoerdpioarlatDeeTpoaxritcmoelnotgy Telephone: (651) 737-1374 Telefax: (651) 733-1773 ALTERNATE STUDY MONITOR: John Butenhoff. Ph.D., DABT, CIH 3M Corporate Toxicology 3M Medical Department Telephone: (651) 737-1962 Telefax: (651) 733-1773 000392 418-018:PAGE C-2 REGULATORY CITATIONS: Protocol 41P8a.g0e128 ISnttuedmyatDieosniaglnCaosnfMeordeinficceatoinonHoafr:moUn.iSs.atFiooond; and Drug Guideline Aodnmidneitsetcrtaitoinonof(t1o9x8i4c)it.y to Nreop.ro1d8u3c.tion for medicinal products. Federal Register, September 22, 1994, Vol, 59, U.S. 21 CFFoRodPaartnd58D. rug Administration. Good Laboratory Practice Regulations: Final Rule. Japanese for Safety Ministry Studies of on Health Drugs, aMnHd WWeOltradriena(n1c9e87N).umGboeord21L.abMoarracthor2y6,Pra19c9t7i.ce Standard aEcucreoppteaannceEcboynothmeicEuCroompmeuanniEtcyo(n1o9m89i)c. CoCmoumnucniiltdyecoifsainonOoEnC2D8 Jduelcyis1io9n8/9roecnotmh-e tmheendEautrioopneaonn Ccoommmpulniiatniceesw:itLhepgirsilnactiipolne.s of good 32 (No. lLab3o1r5a;to2r8y Oprcatcotbiecer.): Official 1-17. Joumal of REGULATORY COMPLIANCE: Trehgiuslsattiuodnyswicliltebdeacboonvdeu.cted in compliance with the Good Laboratory Practice (GLP) DAlilrecchtaonrgaensdotrhereSvipsoinosnosr,ofdtahtisedpraontodcomlaisnhtalalinbeeddwoictuhmtehneteprdo,tocsoilg,ned by the Study aTatnhdtehtTeheTesetrsietnpigonrgtF,aFcaiaclniitldyi'twsyilQlinuiaanlcsipcteoycrAtdsacsrniuctriecaanwlicptehhaUtnshieetsS(toQfaAntUdh)aorswdeillpOoparuetdriiaottnitsnhgoefpPtrrhooetcosectodluu,dryethsceoonfrdaAuwrcgdtuaestda Research Laboratories, Inc. QShAoUulfdoranthyatpofractiilointyowfiltlhceosntduudcytbceritciocanldpuhcatesde biynsapescutbicoonnstarnacdtoaurdoirt bryestpheectSipvoenrsoers,usthe apDihnradecstreoerpi.onrstTpsehcfetoirdotanhtaertsepsootfruttdshyeapniodnrtsirpoeenpcotarictocnaosurdadiintndsgwriteolpotbrhete ssSuuObbmPmiiststsoeifdotnhbsaytwtifhlalactiblfetya.icnicSlourctpohortcahrteiteiSdctailundtyo i2nQclAusUioSntianttehmeenfitnaglerneeproartt.ed by that facilty and provided to the Testing Facilty for Tthheerfeipnoarltraecpocrutrawtilellyinrcelfuldeectas tchoemprlaiwandacteasotbattaeimneendtdsuirginnegdtbhye tpheerfSotrumdayncDiereocfttohretshattudy aShnodutlhdatsiagllniafpipclaintcadbelveiaGtLioPnsrefgruolmatGioLnPs wreegruelaftoilolnosweodcciunr,theeaccohndwiulcltbeofdtehsecrsitubdeyd. in detail. together with how the deviation might affect the quality or integrity of the study. 000393 418-018:PAGE C-3 STUDY SCHEDULE: Protocol 41P8a.g0e138 See ATTACHMENT 1 to the protocol. TEST ARTICLE AND VEHICLE: Identification: Test Article: Name: Physical Description: ~~ PLiegrhfti.ucoorlooorcetdapnoewSduelrf.onic Acid Potassium Salt (PFOS). LSpoetcBiafitcchGrNavuimtby:er: 217 06 Purity: Expiration Date: 98.9% NA wIintfhortmhaetiSopnonosnort.he identity, composition, strength and purity of the test article is on file Control Atticles Name: LPohtysNiucmableDre.scription: ~~ PuSrpietcyific Gravity: Expiration Date: WMheivtaelowniitch Acid. dark yellow cast, semisolid. 0N7A0K2603 AAuppgruosxti2ma0t0e4ly 97% Name: Physical Description: ~~ WChhoilteestpeorwodler LSpoetcNifuimcbeGrra.vity: N1A18HO218 Purity: Expiration Date: 95% July 2004 mIanfionrtmaaitnieodn ionnthteheriadwendtaittya,.composition. strength and purity of the control articles will be Vehicles: 0(R.O5D%ITHw;e0)e.nSu8p0pliinerreavnerdselotoisdmeontsiifsicmateimonbrofaTnewepernoce8s0setdo data. deionized water be documented in the raw Reverse Osmosis Membrane Processed Deionized Water (RODI H;). 000394 418-018:PAGE C4 Protocol 41P8a.g0e1s8 Neither the Sponsor nor the 10 be present in the vehicles Study Director is aware of any potential contaminants that would interfere with the results of this study. likely Therefore, no analyses other than those mentioned in this protocol will be conducted. Safety Precautions: Gcolaotveasr,edtuosbte-mwisoymHEPduAr-ifnigltfeorremdulmaatsikon, parpeppraorpartiiaotne aenyde dproostaegcteiaodnmiannidstarautniionf.ormT/lhaeb Material Safety Data Sheet (MSDS) is attached to the protocol (ATTACHMENT 2). Storage: Bulk Test Article: Control Article Components: Vehicle Components: PPrreeppaarreedd Vehicle (0.5% Test Article Tween 80): Formulations: Room temperature. Room temperature. Room temperature. Room temperature. Frozen (-20C) JAuliliteasntGuarltbiicnlseksih,iMpamneantgsertoofthFeoTremsultaitnigoFnasc,ilaittythsehopurledviboeusaldydcrietsedseadddtroetshse attention and of telephone number. Shipments should cartons should be include labeled information concerning storage conditions and appropriately. The recipient should be nofified shipping in advance of shipment. FORMULATION: Erequency of Preparation; Formulations of PFOS (suspensions) will be prepared weekly at the Testing Facilty. The vehicle (0.5% Tween 80) will be prepared weekly. Mevalonic deionized acid will water. be prepared twice daily in reverse osmosis membrane processed Cholesterol will be prepared as a suspension once daily in 0.5% Tween 80. `Ddeotcaiulmeedntparteipoanraotfifoonrmpurloacteidounrperseaprareaattitonacwhielld to be this protocol (ATTACHMENT maintained in the raw data. 3) and 000395 418-018:PAGE C-5 Adjustment for Purity: Protocol 4P1a8g0e185 cTahlecultaetsitoansn.d control articles willbe considered 100% pur for the purpose of dosage Testing Facility Reserve Samples: tahhceehcSolpuotorsnoefsotorfhewhicilolsnrtsertsoudleyra.vretiTachleseaaTmnepdsltveienh(g1icFgla)ecoicflotemyapwcoihlnleorntetsosefrutvsheeeadbusdlaukmriptnelsgett(ah1retigccoloeurru&sseemdLof)dtuohrfiisng study. Samples will be stored under the previously cited conditions, ANALYSES: tShaempcoluersseaodfdthoenstutdoyt.hose described below may be taken if deemed necessary during Bulk Test Article Sampling: CNIenorftoairfnmiaacltayitseoenosfoonAfntathlheyessibtsabuiilsitoteynstoffairltthiweciltbehuwltiklhletbeSsetpcoaorntnsidoculrecatisneddondaufcrilioenpwgyittwhhileltchbeoeuSripsnocenlsouofdre.tdhisiTnshttehudeyf.inal report. Analyses of Prepared Formulations Stability: cdSoteantbceierlnimttiyrnadetaditoadnusfroirannpgdrtehcpeoanrcdeoidtnidtouencssttoaofrfttithchilises sfstoturuddmyyu.laartTeieoosnnts afbrirlteiaccwlkieethtsiutnshgpeetShnepsoirnoansnsogrewialolnfbdewipllrenpoatrbeed weekly at the Testing Faciliy. Homogeneity Analyses cLHooopum.romsgieednodfeliethtiaysnodsftubtdohyt.ettoeAmstsofyarrtithniegceehiiwngilhlperbsetepcauorsneecddensttuorsawptieitnohsndirooannwstshwaielmlfpibrlseetsdvea(ry5ifmoifeLdprdeeuaprcaihrn)agtfitrhooen.m. the oaElnaiecquhoofts2a(3mmpmllL.ea) n(w5dilmlaLbn)ee wroiefllt3abiemnLed.divaiOtdntehedeiaTnletiosqtutoiwtnog(a2FlamicqLiul)iottwysilaalsnbdae pbslahacicpkepudepdisnfatoomrpglalneaa.slsys`ciBosan:ctaktiuhnpeeorts,her sTeasmtpilnegsFawiclillbtye usptoornedthuenrdeeqrutehset opfretvhieouSsploynsciotre.d conditions and discarded at the 000396 418-018:PAGE C-6 Concentration Analyses: Protocol 41P8a.g0e1s8 oCfontchiesntsrtuadtyi.onAofsytrhienpgreewpilalrbede tuessetdarttoicwlietshudsrpaewnssaiomnpslewsill(5bemLvereiafcihed)dfurroimngetahcehcourse concentration gestation and once during each of the postnatal. Each sample following periods (5 mL each) will of be the study: premating, divided into two aliquots and pslhaicpepdedinftoorgalnaaslysscios;nttahieneortsh,eornaeliqoufo2t m(3LmaLn)dwiollnebeofr3etmaLi.nedOantethaeliTqeusottin(2g mFaLc)ilwiitlyl absea backup sample. and discarded at BthaeckTeusptsinagmpFlaceisltwiyllupbeonsttohreerdeuqnudeestr the previously cited of the Sponsor. conditions. Shipping Instructions Samples to be analyzed will be shipped (frozen on dry ice) to: Dave Ehresman 3M Corporate Toxicology 3M Center Building 236-0C-48 TSte.lePpahuol.neM:inn(e6s5o1t)a73535-1540470 Telefax: (651) 733-1773 Both the recipient and the Study Monitor will be nofified in advance of sample shipment. DISPOSITION Prepared article will formulations be retumed twoilthbeeSdtiusdcyarMdoenditaotrtahte tTheestprienvgiFoaucsilliytyc.iteAdllardedmraeisnsi.ng bulk test TEST SYSTEM: Species/Strain and Reason for Selection: T1)hethiCsrs:tCraDi@n(oSfDr)atIhGaSs BbReeVnAdFe/mPolnusstrraattewdatso sbeelescentseidtiavsetthoerTeepsrtodSuyctsitveemabnedcause: adnevdedleovpemleonptmaelnttoaxlintsoxaincidtyheavsalbueateinonwsi:de2l)yhuissteodritcahlroduagthaoauntdinedxupsetrriyefnocrereepxirsotduactttihvee Tstersatini;nganFdac4i)ltthyiTMs;st3r)aitnhehatsesbteaeniniculeseisd pharmacologically active in previous reproduction in the species and studies of PFOS. 460397 413-018:PAGE C-7 Number: Protocl 41P8a.g0e187 Initial population acclimated: 360 virgin female rats (two shipments of 180 female rats each designated as Replicates 1 and 2). Population selected for study: 332 female rats (28 in each of Groups 110 7, 12 and 13, and 20 in each of Groups 8 to 11), aEsigshitgnmeadtetodCfaeemsaalreearnat-sseicnteiaocnhinogfoGnroduapys211 toof 7p.r1e2suamnedd1g3es(tRaetpiloni;cattehe1)rewimlalibneing female rats will be permitted to deliver litters. Body Weight and Age: Female they will rats will be ordered to be expected to be at weigh from 175 least 56 days of g to age. 225 g each at receipt, Actual body weights at will which be time recorded the day after ranges will be included receipt in the fainnadl rwielplorbte. documented in the raw data. The weight Sex: Female rats will be given the test article. Male rats of the same source and strain will be used only as breeders and are not considered part of the Test System. Source: Charles River Laboratories, Inc. The rats will be shipped in fitered cartons by air freight andlor truck from Charles River Laboratories, Inc. to the Testing Facilty. Identification: Eo Generation: Rats are permanently identified using Monel selt-piercing ear tags (Gey Band and Tag Co.. Inc.. No. MSPT 20101). Male rats are given unique permanent identification numbers upon assignment to the Testing Facilty's breeder male rat population. Female rats are assigned temporary numbers at receipt and given unique permanent identification numbers when assigned 10 the study on the basis of physical appearance and body weights recorded during acclimation. 1 Generation: Pups wil not be individually identified during lactation; all parameters will be evaluated in terms of the litter. 000398 418-018:PAGE C- ANIMAL HUSBANDRY: Protocol 4P18a.g0e1s8 All cage and Use sizes and housing conditions of Laboratory Animals". are in compliance with the Guide for the Care Housing: Fo Generation Rats/F1 Generation Litters: xoFfcoregaptestnewdriulalrtibinoegnhtrohauetssceowidhlalibnbitetahitenidominavliadenuadrlaltpy'osshctoapugasere.tduBmienpgseitrnianoiidnsln.egssnDosutrleiastn!egrwcitorhheaa-nbbidotatayttio2omn0e,dosfcaacghespair ipnrdeivsiudmuaeldlyghesotuasteiodn,inFnoesgteinnegrabtoixoesn.femEaalceh common nesting box during the postpartum rdaatsmaassnidgdneeldivteorneadtulirtatler period, dweillivbeeryhwoiulsbeed in a Nesting Material: Bdeeldivdeirny.g material (bed-0'cobs) will be supplied to female rats assigned to natural ABneadldyisnegswiflolr the raw data bpeoscshibalnegceodntaasmoifntaetnioans anreececsosnadruycttoedkeseempit-haennaunailmlaylsancdrydaoncdumcelenatne.d in Room Air, Temperature and Humidity: Tmfraheiesnhtaanaiiirnmetahdlatartoh8oa4msbiFse(ei1nn8depCpa)esnstdeoedn7t9tlhyrFosu(ug2php6lC9i)9e.da9wn7idt%hmHoatEniPlteAaosrfteidteercsno,ncshtRaaonntogleym.stpeRemropeohromautrhuourmfeid1wii0tl0yb%e will also be monitored constantly and maintained at 30% to 70% Light: Amaninatuationmeadt.icaElalcyhcodnatrrkolpleerdi1od2-whilolubrelgiighnt:a1t2-1h9o0u0rhdoaurrksfElSuoTr,escent light cycle wil be Diet: aRadtlsibwiiltlumbfergoimveinndCievritdiufailefdeeRdoedresn.t Diete #5002 (PMI Nutrition Intemational) available 000399 418-018:PAGE C-9 Protocol 4P1a8g0e1s8 Water: Water will be an automatic available watering ad libitum from access system. individual All water botties will be attached to from a local the cages or from source and passed pthrroocuegshseadrweavteerrseaossamobsacitsermioesmtbatr;apnreocbeesfosreed uwsaet.erCihsloerxipneectwieldl btoecaodndtaeidntnoothmeore than 1.2 bacterial pcopnmtacmhilnoaritnieonatatnhde time twice oafnnanuaallylsyisf.or Wpoastseirblies achneamliyczaeld cmoonnttahmliynaftoiropno.ssible Contaminants: tNoeibteheprretsheenStpionntshoerdnroirnktihneg Study water oDrirtehcetonresits ianwgamraeteorfiaalnyatpolteevnetlisatlhactonwtoaumlidnainnttesrfleirkeely awtitehxtthreemreelsyulltsowofletvheilsssitnudtyh.eTcehretiSfipeodndsieotr. isThaiwsarloew-olfeaveploctoennttiaamlincaotnitoanmiwnilalnntotpresent interfere routinely wpietrhftohremerdesublytsthoef this feed sstuupdpyl.ieTrhoerretfhoorsee, mneontainaolnyesdesin otthhiserprtohtaoncotlhowsilel be conducted. RANDOMIZATION AND COHABITATION: Eo Generation: eInacohr)desretpoarfaactieldtabtye stcwhoedwueleiknsg., fTehmealfeirsrtastshiwiplmlebnet rweilclebieveddeisnigtnwaotsehdiapsmeRnetpsli(c1a8t0e rats 1 aasnsdigthneedsetocoinnddivsihdiupalmehnotuswiilnlgboendtehseigbnaastiesdofascoRmeppulticeart-ege2.nerUaptoend arrrainvadl,omrautnsitwsi.ll Abfeter aacncdlibmoadtiyonw,eifgehmtaslreercaotrsdweidlldbuerisnegleaccctleidmaftoirosnt.udTyhoen rtahtes bwialslibseofaspshiygsinceadltaopdpoesaargaence groups based on computer-generated (weight-ordered) randomization procedures. `Wciothhaibniteataicohn,doonseagmealgeroruapt,pceornfseemcaulteivreat.ordTehrewiclolhbaebiutsateidontopaersisoidgnwirllatcsontosist of a vmaagxiniamlucmonotfen1t4sdaanysd.orFaemcaolpeularattosrywiptlhusgpoebrsmeartvoezdoian observed in a smear of situ will be considered the to be at mdaayte0dowfipthrienstuhmeefdirsgtes7tdataiyosn oafncdohaasbsiitgatnieodntwoililndbieviadsusalighnoeudsianlgt.emFaetemamlaelerartastnsotthat have mated and will remain in cohabitation for a maximum of seven addtional days. Tahceonfifrsitmeeidghdtafteemoaflemartaitsngpewirlldboesaagsesiggrnoeudpt(ogCraoeuspasr1eatno-7s,ec1t2ioannidng13o,nRedpalyic2a1teof1) with mparteisnugmdeadteg)eswtialltiboen.peTrhmiettreedmationniantgurfaelmlyaldeelriavtesr (including liters. those with no confirmed 000400 418-018:PAGE C-10 Protocol 4P1a8g-e01180 F1 Generation Pups: Day 1 of lactation (postpartum) is defined as the day of birth and is also the first day on which all pups in a litter are individually weighed (pup body weights will be recorded after all pups in a litter are delivered and groomed by the dam). ADMINISTRATION: Route and Reason for Choice: The oral (gavage) route was selected for use because: 1) in comparison with the dietary route, the exact dosage can be accurately administered: 2) it is one of the. possible routes of human exposure: and 3) itis the route used in previous reproduction studies on PFOS. Method and Frequency: Dosages will be adjusted for the most recently recorded body weight and given at `approximately the same times each day. Dosages will be administered according to the table in the Dosage Levels. Concentrations and Volumes section of the protocol. The mevalonic acid dosing needle will be wiped clean before administration for each animal. Eo Generation Female Rats: Female rats will be given the test article daily beginning 42 days before cohabitation (maximum of 14 days) and continuing through day 20 of presumed gestation (rats assigned to Caesarean-sectioning), day 24 of presumed gestation (rats assigned to natural delivery that do not deliver a litter) or day 4 postpartum (rats that deliver ltr). Rats in the process of delivering will not be given test/control article; such animals may not receive any or all of their daily dosages) on the day of parturition. 1 Generation: F1 generation pups will not be directly given the test article, but will be possibly exposed to the test article during matemal gestation (in utero exposure)orvia matemal milk during the lactation period. Rationale for Dosage Selection: Dosages were selected by the Sponsor on the basis of previous studies conducted with the test article. 000201 418-018:PAGE C-11 Dosage Levels, Concentrations and Volumes: ome T mm o [o[no|ecrvmens||20=0| vreoomno|| arceonrmass|| msonoio]| [aT = |e ammne,m | om e | o] mny, | [[omm = |apm,| ows| ome, | [R* EmaE mr [E =[moem E |EoEom |N w [|7[[mmawmmmer| ==[mmmmye || ees | mers | ow ow] [oCoo Tomomrmesenss[|| 005T T [aw Tmp ocoumms oesT| a] ] [CooTmToammmmerooss||ToT T Tw eTTTeormarmeeessTTa o] ]| CE [eoE rem |[ Te T ll e T llI e ] [DCooivmevnes[||[ oaee T e e o e [m reT e emem [CCaooem[[ [ oy[e on |[ e a e Te e oe e oe[oe [as [eee [reeT= 1 oe o | r 0 |ooonsomuemmn] 000402 418-018:PAGE C-12 TESTS, ANALYSES AND MEASUREMENTS - Fo GENERATION: Protocol 4P1a8g.e01182 Viability: All Periods: Atleast twice daily. Clinical Observations and/or General Appearance: Acclimation Period: Atleast once Dosage Period: hProiuorr attotedrotshaegeseacdominndisdtorastaigone.aanpdpratoxtihmeaetenldyoofntehe working dosage). day (approximately one hour after the third Day of Saciifce: Once. Matemal Behavior: Dbeahyasvi1o.ranwidll5bpeosrtepcaorrtduemd. daAilnyy observed abnormal CalpipnriocparlioabtseerbvyatthieonSstumdayyDbireecrteocroarndde/domroSrteudfyreMqouneinttolry. than cited above, if deemed Body Weights: Acclimation Period: Atleast once. Dosage Period: Weekly to cohabitation. Daily during presumed gestation and on natural delivery). Day 1 postpartum (rats assigned to Sacrifice: Terminal weight. Feed Consumption Values (recorded and tabulated): Dosage Period: W(ifeneekcleysstoarcyo)haobfitpartieosnu.meOdngedsatyasti0o.n7,an1d4,o2n1daanyds 25 1 and 5 postpartum (rats assigned to natural delivery). nFeeceedsscaornysutmoprteipolnenvisahlutehsemfaeeyd.beDruercinogrdceodhamboitraetiforne,quwehntelny ttwhoanractisteodccaubpoyvethifeitsiasme cage with one feed jar, replenishment of the feed jars will be documented. Individual values will not be recorded or tabulated. 000403 418-018:PAGE C-13 Mating Performance: Protocol P4a1g8e01183 Mobasteirnvgawtiilonbeofesvpaelrumataetdozdoaialyinduarsinmgeatrheocfothhaebivtaagtiinoanl pceornitoedntasndancdo/nofriarmceodpublyatory plug observed in sit Fertility Parameters: Fertiity Index (percentage of matings that result in pregnancies) Gestation Index (percentage of pregnancies that result in birth of live liters). Number of offspring per litter (ive and dead pups). Number of implantation sites. General condition of dam and liter during the postpartum period. Viability Indices (percentage of pups bom that survive 5 days) Caesarean-Sectioning Observations Eight rats sectioned from dosage on day 21 of groups 110 7. 12 and presumed gestation. 13 (Replicate 1) The fetuses will will be Caesareanbe removed from the uterus and distribution pofo:oled by liter for body weights. The rats will be examined for number and Corpora Lutea. I[mPpllaacnetnattaieonthSaittaesp.pear abnormal (size. color or shape) will be noted in the raw data). L(iAvleivaenfdetDuesaids dFeeftiunseeds.as one that responds to stimuli; 2 dead fetus is defined as daetaedrmfefteutsuessthdaetmodnosetsrantoitnrgemsapornkdedtotsoteimxutlrieamnedauthtaotlyissisnoatremacroknesdildyeraeudtotloyzbeed; late resorpions.) E(aArcloynacnedptLuasteisRdeesfoirnpetidoanss.a late resorption fits grossly evident that aorngeaanrolgyerneessoirpstihoans.)occurred if this is not the case, the conceptus is defined as 000402 418-018:PAGE C-14 Fetal Observations: Protocol P4a18g.e01186 Body Weights: Fetuses weights will be pooled of ive fetuses by wil lbieterreacnodrdleidt.er) body weighs willbe recorded. (Only body Blood and Tissue Samples (See ATTACHMENT 4 for tissue collection and processing) pCbheafapomsraecao(nkedimpnltaeybt)eilcaendadntaualbfyetsesersw.rilelteTbnheteiwsoeneiowgfehipegodhotl(secdowimflbleitbuneseddsoawcmepuilmgeehsn.tfteoordtshiunebtnsheeeaqrureeaswnttda.ut0sa0,1e iganrnadm) tdcauoybp,eiessswaiomlflptlbheeeisldaeebnweteliifeigdchawttisitohwnitlalhnebdesctioulndlcyelcuntduiemodnbewtiritm,hepltoihitneertp,daecnktiinigcaltsitopnr,iodrattoe sofhicpomlelenctt.ionS, asmtpuldey taBuplbpoerosodxaisnmadamtptelhleeysrowenimela-lhibanelifncgoolffletethcaeltebfdelftourosdoemwsielilancbeheacftehrtaulnisstfveerirawriedldecbianeptioptalstaeicroenud.misnBtelopoaEorDdaTtfAor-rocmtoubaetse,d The a`slsaiamqmpuploletesss)ww/iiplllllabbseemaism(pmouenndeiianaltaieqlucoyetn)ftrrwoiizflleungbeeoantnrddarnytshfieecrerreaesdnudlitnimtnaogilnsatebaerilunemedd(pdofilrvoyizpderenodp(iyn<lt-eo2n0tewCtou)beusnt.il All shipment for analysis. The liver removed from and feixaecdhinfegtluustweirllalbdeehcyodlleefcotredp.osOsinbelefeftuatlurleivearnaflryosmiseabcyhelleitcetrrowinll be eumnqitucilarlosshnciuoppmmybe.entrT(fhowerharenenamlapyosisinssi.inbgleTf)he.tealTrlweimovaeirosnfiitnnhgeeasscaahmmppllilteteesrwiwwililllllbbebeefldfairsvohizdfeerndoaziennntdoistnthlorireqeeudids(an<mi-tp2rl0oegsGe)nof dainsdcamradiendtawiintehdouftrofuzretnhe(r=-ev7a0luCa)tiuonnt.il shipment for possible analysis. Carcasses will be `Sample Analysis and Shipping Instructions: Abpepsrohpirpipaetdefsraomzepnleosn wdirllybiecemvaiianotvaeimneidghftromzaeinl.until shipment for analysis. Samples will gsOlanumetpelorfealetdauecbhheydapeanidwrillolifvbeserewsreeuinmgthsttaosmDpalanevdse,aEpfhrarocezkseimnnaglnilv,iesrtatswiatlmlhpeblepersie,nvcialonuudsdlelydivwceiirtteshdatmahpdedlsreeassmsfpi.lxeeTsdhisenent to Dave Ehresman. 000405 418-018:PAGE C-15 Protocol 4P1a8g.e01185 The and trreimgalyicneirnigdess.erTuhmesaendslaimvperlessamwpilllebsewislhlibpepeadnatol:yzed for LDL, HDL, total cholesterol Or. Saroj R. Das Ani Lytics, Inc. 200 Gerard Street, Suite 200 Gaithersburg, Maryland 20877 Telephone: (301)921-0168 Telefax (301) 977-0433 Plasma mevalonic acid levels will be measured. These samples will be shipped to: JPirmimJeedrisceayWorcester Laboratories 57 Union Street WTeolrecpehsotneer:, Ma(s5s0a8c)h8u3s0e-t0t1s5101608 Telefax: (508) 753-1834 Both the recipients and the Study Monitor will be notified in advance of sample shipment. Natural Delivery: Female rats will be evaluated for: Adverse Clinical Signs Observed During Parturition. Duration of Gestation (day O of presumed gestation to the time the first pup is observed). Litter Size (defined as all pups delivered). Pup Viability at Birth. METHOD OF SACRIFICE - Fo GENERATION: dReactaspiwtialtlibone.sacWrhifeincedpobsysibclaer,bornatsd.iopxuipdse aasnpdhyfxeitatuisoens.wilFlebteusseascrwiiflilcbede asancdritfiiscseudesvia collected at approximately the same time each day. 000406 418-018:PAGE C-16 NECROPSY - Fo GENERATION: Protocol P4a18g.e01186 tGeovraoGlasuesastlaierosneiao(nna-sstwaeibcllteibooefnrrfeartnoaimdnowemdhiuicnnhinteaslulwtirtlaillsbsbeuuefusfseeerxdeadm10i1ns0ee%ldecfatotromnanelecirncoofpnostrryopwloislglsribobeuleprefrtauattiuanreseds,igInned order to lesions). prUonvliedsescsopnetcrioflictailslsyuceistefdorbaenlyowp,osalsliobtlheehritsitsospuaethsowliolglibcealdeivsaclauradteido.ns of gross pBrloocoedssainngd)Tissue Sample Collection (See ATTACHMENT 4 for tissue collection and baCneaafploysrseeas(n.edmplTtahybe)eslaeednwdteuiabtgethestrswriwleiltlelbnebtiewoendioogcfhusemademn(ptcleoedmsbfiinonrteshdeuwbresaiewgqhud,eatnatt,o utahsneednicenoapprhieaesrstmoa.f0c0ot1khiegnsreeatmi)c wlsaeabimegplhletedswiwdiieltlnhtbitfehieciasntctiluounddyaenndudwmicbtoehlrlte,hcetainpoianmctakilimneigpdeoinistntitf.pirciaotriotno, sdhaitpemeofntc.ollSeactmiponl,esttuubdeysdwaiyl, be Eemale Rats Assigned to Caesarean-Sectioning: eOinghdtaryat2s1deofsipgrneastuedmefdorgCeasetastairoena,nb-lsoeocdtiaonndinlidveorssaagmeplgersouwpisll time of sample collections will be recorded in the raw data. 1b1e0co7,ll1e2ctaedndfr1o3m. the The cpBlalavocaoeddasniadnmtsopelEpeDasTrAa(ta-tecdloeaiatnstteod4ttwmuoLbaeepsapacrnho)xdiwtmihaleltebsleeycceooqnluldaelcatlaielqdiuqfoutrootwsmi.llthbTeehretartfasinrvsstifaearltriheqeduoiitnnfwteiorlilsorbeervuemna ps(odeilpvyaiprdraeotdpoiyrnltteounbetewsto.ubaeTlsih.qeuoAsltalsm)sp/alpmlepaslsemwaisl(wibolnelebsaepluiinqmumoient)daiwaicltelenbltryeiffturrgoaeznesanfneordnretddhreiynrtieocseullaatbniendlgemsdaeirnutmained frozen (:-20C) until shipment for analysis. wfFreooilzglehonwtiiwnniglllcibqouleildercneticitoorrnodgeofedn.blaAonoddpomsrataiimnopntlaeoifsn.eedatchfehrollziiveveenrr o(sf2a7em0apclChe)r(arutingtwhiitllllsabhteierpaemlxeclniotsbeef)dorwaiplnoldsbsteihbefllelaisvher faainnvaaellryywssiiilsls..beAThfsieexcemtdeiidonniga(lnauptipevrreoarxlildmoeabnteyedwleiyllf0ob.re3ptofosrso0iz.be5lnecamfnudtwuisrdteeo)arnefadrloy(smsi-ts2h0ebyCr)eelmueancittinrliosnnghmipipocmrretonisotcnofopofyr.the The remaining analysis. portion of the liver wil be frozen and stored (<-20C) until shipment for Eemale Rats Assigned to Natural Delivery: Blood. milk, postpartum. hTeairmteaonfdsalimvperlesacmopllleecstiwoinlls b(eblcoooldleacntdedmfilrko)mwmilal tbeemraelcorartdsedonindathye 5raw. data. 000407 418-018:PAGE C-17 Protocol P4a18g.e01187 hOonusdeady 5foproasptppraorxtiumma,teelaychfodurahmouwrilsl.beThreemdoavmedwilflrbome tihnejencteesdtiinngtrbaovxenaonudsliyndwiivtihduoanlley sunaimtpolfe)oxayrteoccionllaepctperdo.ximTahteelsyamfipvleemsinwiultlebsebiemfmoerdeimaitleklysafmrpozleenso(natdlreyasitce1a0n0diL per maintained frozen (s-20C) until shipment for analysis. fFroollmotwhiengramtislkvisaatmhpelienfceorliloerctvieonn,a bclaovoadasnadmpsleepsar(aatteldeaisntto4tmwoLaepapcrho)xiwimlaltbeelycoelqlueaclted waillilquboetst.raTnshfeerfrresdt aliquot will into serum be placed separator tiuntboesE.DTTAh-ecosaatmepdletsubwielsl and the be spun sien caocnedntarliifquuogte tarnadnstfheerrreedsuilnttionglasbeerleudmp(odliyvpirdeodpyilnetonetwtoubaelsi.quAoltlss)a/mplpalsemsa w(iollnebealiimqumoetd)iawitlellbyefrozen on dry ice and maintained frozen (s-20C) until shipment for analysis Following collected. cTolhleelcitvieornwoefimgihltk wainlldbbeloroedcosradmepdl.esA, the heart portion of aeancdhlilvievrerofsaemapclhed(arimghwtilllatbeeral lobe) will shipment be for fploassshifbrloezaennalinysliisq.uidTnhietrmoegdeniaanndlimvearilnotbaeinwieldl frozen (=-70C) until be frozen and stored (m5a2d0eCto)aulnltoilwpsrhoippemrefnitxaftoirona.nalTyshies.firsTthceuthewairltswtialrltbteo tehxecirsieghdtaonfdthtewovecnuttraslwimlildbliene ssuercfoancde cautttwhiellabpeexmaanddeesxttaretnidnganttoetrihoerlleyftaonfdtvheentvreanltlryaltomitdhieipnuelsmuornfaarcey aatrtterhye. apTehxe asencdtieoxnte(napdptrhorxoiumgahtetlhye0l.e3fttvoen0t.r5icclme to the wide) afrsocmentdhienrgeamoaritan.ingThpeortciuotnhoefartthealnidvearwill be fmiixcerdosicnogplyu.terTahlederheymdaeifnoirngpopsosritbiloen future of the analysis by liver willbe eflreoczternonanmdicsrtoosrceodp(y<-a2n0d/Co)r light until shipment for analysis. Sample Analysis and Shipping Instructions: bApepsrhopirpipaetdefsraomzepnleosn will dry biecemvaiiantovaeirnneidghftromzaeiln. until shipment for analysis. Samples will Omendeiaofnelaocbehs)p.aiarnodf lsieverruamnsdahmepalrets.safmrpozleensmfaixteedmianlglliuvteerrsaaldmephlyedse (wriilglhtbelasteernatl taonDdave pEancrkeisnmganis,t awtilthbeepirnecvliuoduesdlywictithetdhaedsdraemspsl.esTsheentsatompDlaevetubEenraensdmalinv.er weights and a 000408 418-018:PAGE C-18 Protocol 4P1a8g.e01188 aTnhde trreimglayicneirindgess.erMuimlkasnadmlpilveersswaimlpbleesanwaillybzeedanfaorlytozteadl cfhoorlLeDstLe,roHlD.L,Thteotsael cshaomlepslteesrol will be shipped to: AOrn.i SLayrfiocjs,A.InDc.as 2Ga0i0thGeerrsabrudrgS,trMeaert,ylSaunidte 22008077 Telephone: Telefax: ((330011)) 992717--00413638 Plasma mevalonic acid levels will be measured. These samples will be shipped to JPriimmJeedrisceayWorcester Laboratories 57 Union Street TWeolrecpehsotneer:, Ma(s5s0a8c)h8u9s0e-t0t1s5101608 Telefax: (508) 753-1834 sBhoitphmtehnet.recipients and the Study Monitor will be nolified in advance of sample. Scheduled Sacrifice - Female Rats Assianed to Caesarean-Sectioning; Oannddaaygr2o1ssofnepcrreospusmyeodfgtehsetatthioorna,cifce.maabldeormaitnsawlilalnbde psealcvriicfivciesd,ceCraaewsiallrebaen-pesrefcotrimoende.d, dBelsocordibaendd. tUitsesruie osfaamppplaersen(tbllyoondonsperreugmn/apnitasrmatas awnildlblievesrt)awiinledbewictohll1e0ct%edamasmopnreivuiomusly s1u0lf%idfeortomacloinnffiorrmptohsesiabblseefnucteuroefeivmaplluaanttiaotn.ion sites' and retained in neutral buffered Scheduled Sacrifice - Female Rats Assigned to Natural Delivery: Othnordacaiyc,5aobfdloamcitantailon,anfdempaellveicravtisswcielrlabweilslabcreifpiecrefdoramnedd.a gBrloososdnaencdrotpissysuoefstahmeples (blood serum/plasma, heart and fiver) will be collected as previously described. eRaxtasmitnhaetddfoorngortodseslilveesrioansi.teBrlwoioldlbaendsactriisfsiuceedsaomnpldeasy 2wi5llonfoptrbeescuomleledctgeeds.tatUitoerniawnidl abnedstraeitnaeidnewditihn n1e0ut%raalmbmuoffneiruedm 1su0l%fifdeortmoalcionnffiorrmpotshseiablbesefnutcuereofeviamlpulaatinotna.tion sites 000409 418-0IS:PAGE C-19 Dams with No Surviving Pups: Protocol 4P1a8g-e01189 olDirvaepmr)rsewiswlilutmbheendcooclaslnunericvbtiaevldiinazgespdp.urpesBvilwooiuolsdllbyaendsdeasctcririsifsbiueceedd.saafAmtpeglrretoshses(blnalesoctordpousppesryiusomff/otpuhlneadstmdhaoer,aadch,iecam.ritssainndg eaxbcdloumdiendalfraonmdspuemlvmiacrvyistcaebrlaesw.ill be performed. Postpartum data for these dams will be. Rats Found Dead or Moribund: emRaxadtaesm.itnhaeTtdhdefioerraottrhseawricelausbasecereioxffiacdmeeidanbtehedcoafrourmsogerrioofsbsumnoldersiciboonunsdn.idticWoohnndeoinntitpohonesosdriabaylbeotrh(tenioootnbpswreielrlcvlabuteidoend ibsy adoufetsfoclerymisaiblsee)d,rfbaotlrsorowaidtlslseabresusrmiegicnpoelrdadsetmdoa.n,aAthbueroaarrlttedaednlifdveeltriuyv.seerssPaarnmedpgllnoearsndcweyillilsvtbeaerteurdsetapaunipdnseudwtiealrlsibnpeerecevoxinaotumesinltnysed tbaoumftmfheoerneeidxut1emn0t%suploffsoisrdimebaltleoi.ncofUnotrfeiprriomsosftihbaelpeapabfrsuetenuntrcleeyevnoafolnuipamtrpieloagnnn.taanttiornatssiwtilelsbeansdtarienteadinweidthin1n0e%utral TESTS, ANALYSES AND MEASUREMENTS - F1 GENERATION: Viability Postpartum Period: TLihteterpsuwpisll ibneeaocbhselrivtteerdwfilolr bdeeacdoupnutpesdaotnlceeasdtaitlwyi.ce daily. Clinical Observations and/or General Appearance: Postpartum Period: Ciinical observations and sex will be recorded once day. CalpipnriocparlioabtseerbvyatthieonSstumdayyDibreecrteocroarnddeldomrotrhee fSrteuqduyenMtolnyittohra.n cited above, if deemed Body Weights: Postpartum Period Days 1 weights (birth). will be 2, 3, 4 and recorded. 5 postpartum. Pooled litter MMEETTHHOODDOOFFSSAACCRRIIFFIICCE-- F1 GENERATIONPPUUPPS;: tAissspureesvicooulslleyctceidteadtfaoprpFrooxgiemnaetrealtyitohnerastsa.meWthiemne epaoscshibdlaey,.pTuhpes wtiillmeboefssaacrmipfliceed and collection will be recorded. : 000410 418-018PAGE C-20 Protocol 4P1a8g.e02108 F1 Generation Pups Found Dead on Day 1 Postpartum: Pups that die before examination of the liter for pup viability wil be evaluated forvital status at birth. The lungs will be removed and immersed in water. Pups with lungs that sink will be identified as stillbom; pups with lungs that float will be identified as livebom, asonlduttioonhafovrepdoisesdibslheorfuttyuraefteevralbiuratthi.onP.upSshowuitlhdgproosstsmloerstieomnsawuitlollbyesipsrperseecrlvuedde itnhBeosuein's evaluations, it will be noted in the necropsy data. F1 Generation Pups Found Dead or Moribund on Days 2 to Postpartum: Pups found dead or sacrificed due to moribund condition will be examined for gross lesions and for the cause of the moribund condition or death. Pups with gross lesions. found on days 2 10 4 postpartum will be preserved in Bouin's solution for possible future evaluation; gross lesions of pups found on day 5 postpartum will be preserved in neutral buffered 10% formalin. Should postmortem autolysis preclude these evaluations it will be noted in the necropsy data. `Scheduled Sacrifice - F1 Generation Pups (See ATTACHMENT 4 for tissue collection and processing): On day 5 postpartum. pups wil be sacrificed and examined for gross lesions. Gross lesions will be preserved in neutral buffered 10% formalin. Necropsy will include a single cross-section of the head at the level of the frontal-parietal suture and `examination of the cross-sectioned brain for apparent hydrocephaly Cbeafposrean(edmplatbye)leadndtuabfetesrwrileltebnetiwoeniogfhseadm(pcloemsbfionresduwbesiegqhut,entto tuhseenienaprheasrtma.0c0o1kignreatmi)c analyses. These weights wil be documented in the raw data, and copies of these weights will be included with the packing list prior to shipment. Sample tubes will be labeled with the study number, animal identification, date of collection, study day. sample identification and collection timepoint. Blood samples will be collected via cardiac puncture from each pup, pooled (by sex per liter) and separated into four (two per sex) approximately equal aliquots. The first aliquot per sex will be placed into EDTA-coated tubes and the second aliquot per sex will be transferred into serum separator tubes. The samples will be Spun in a centrifuge and the resuting serum (divided into two aliquots)/plasma (one aliquot) wil be transferred into labeled polypropylene tubes. All samples will be immediately frozen on dry ice and maintained frozen (<-20C) until shipment for analysis. 000411 418-018:PAGE C21 Protocol P4a1g8e01218 `wTehieghltiverrecforrodmede.acOhnpeupliwveirlfbreomcoelalcechteldi,tepropooloeldwi(lbybseexrepmeorvleitdtera)nadnfdixtehde ipnooled glilvuetresrianledeahcyhdelitftoerr ppoooslsiwbillle bfeutduireviadneadlyisntios tbhyreeelescatmropnlemsicorfosecqoupayl.nuTmhbeerre(mwahineinng possible). analysis. Two of the samples will be frozen The remaining sample will be flash afnrodzsentoirnedliq(u<i-d2n0itCr)ougnetnilasnhdipmamiennttafionred ftrhoezfeinrst(t-w7o0mCa)leunatinldsthwiopmfeenmtalfeor ppuopsssifbrloemaneaalcyshisl.itteTr h(epohoelaerdtsbywisllexbepecrollliettcetr)edanfdrowmill blieghftimxiecdrionsgclouptye.raTlhdeehyrdeemafionripnogssciabrlceafsusteusrewiallnableysdiissbcyaredleedctwriotnhomuitcrfuorstchoerpyevaanldu/aotrion `Samples will be shipped for analysis as previously described for dams and fetuses. 000412 418-018:PAGE C-22 PRPOROPPOOSSEEDDSSTTAATTIISSTTIICCAL MMEETHTOHDSO'D*"S2! Protocol P4a16g.e02128 aApvperropargieastea.ndAdpdeirtcieonnatlagpersocweidlubreescaalncdu/loarteadn.alLyitsteesr vmaalyuebsewiplerbfeorumseedd, wfhaeprperopriate. Type of Test I. Parametric A. Bartlett's Test" | II. Nonparametric A. Krus(ka7l5-W%altliiess)Test Significant at p<0.001 Not Significant Significant at p<0.05 Not Significant Nonparametric Analysis of Variance Dunn's Test Significant a|t ps0.05 Dunnett's Test Not Significant ~~ B. Fish(e>r7's5%Extaicest) Test II. Test for Proportion Data oVfartihaenBcienoTmeisatlfoDrisHtorimbougtieonneity 2. b. Statistically significant probabilfies Proportion data are not included in are this reported category. as either p<0.05 or p<0.01. c. Test for homogeneity of variance. 000413 418-018:PAGE C-23 Protocol 4P1a8g.e02138 DATA ACQUISITION, VERIFICATION AND STORAGE: Data generated during the course of this study wil be recorded either by hand or using the Primedica Argus Automated Data Collection and Management System and the Vivarium Temperature and Relative Humidity Monitoring System. All data will be tabulated, summarized and/or statistically analyzed using the Primedica Argus Automated Data Collection and Management System. the Vivarium Temperature and Relative (version Humidity Monitoring System, Microsoft Excel [part SR-2)] andor The SAS System (version 6.12) of Microsoft Office 97 Records will be reviewed by the Study Director andor appropriate management personnel within 21 days after generation. All original records will be stored in the aalrlcrhaivwedsaotfatwhiellTbeestsiunpgplFiaceidlttyo.thAellSoproingisnoarl duaptoanwirlelqubeestb.ouPnrdesaenrdveidndteixsesdu.esAwicllopbye of stored at the Testing Facility at no charge for one year after mailing of the draft final report after which time the Sponsor will be contacted to determine the disposition of these materials RECORDS TO BE MAINTAINED: Protocol and Amendments. TAensitmaalndAcCquoinstirtoilonA.rticle, Vehicle and/or Reagent Receipt. Preparation and Use. Randomization Schedules, Mating History. Treatment (if prescribed by Staff Veterinarian). General Comments. Clinical Observations and/or General Appearance. Phamacokinetic Sample Collection, Processing and Shipment. Body Weights. Feed Consumption Values. Caesarean-Sectioning Observations. Natural Delivery Observations. Litter Observations. Gross Necropsy Observations. Organ Weights. Photographs (if required), Study Maintenance (room and environmental records). Feed. Water and Bedding Analyses. Packing and/or Shipment Lists 000414 418-018:PAGE C-24 KEY PERSONNEL: Protocol 4P1a8g.e0218 DEixreeccuttoirveofDiRreescetaorrcohf: RAelsaenarMc.h:HoMbielrdmraedn,S.PhCh.rDi.s,tiDaAn,BPTh.D. Fellow, ATS ADsirseocctioartoefDOipreerctaotrioonfsRaensedaCrocmhplainadncSet:udyBaDribreacrtaor:J. PRaattyemrosonnd, GB..A.York, Ph.D., DABT DiDriercetcotrorooff LSatbuodryatMoarnyagOpeemreanttio:nsV:alJeroihen F. A. Bamet Sharper, B.S. M.S. Manager of Animal Committee: Dena Operations and C. Lebo, V.M.D. Chairperson, Institutional Animal Care and Use Consultant, Veterinary Pathology: W. Ray Brown, D.V.M.. Ph.D., ACVP FINAL REPORT: Abecfoimnpalriezheednfsoilvloewidnrgactofnisnualltraetpioornt will wih bteheprSpeopnasroerd. onThceomrpelpeotritownilolfitnhcelusdteudtyheand wil following: `ExSpuemrmiamreyntaanldDCeosnicglnusainond.Method. AEpvapleunadtiicoens:of Test Results Figures, Summary and Individual Tables Summarizing the Above GDaLtPa,CPormoptloicoalncaendStAastseomceinatt,edReApmoertnsdmofenSutpspoarntdinDgevDiaattaio(nisf,apSptruodpyriDaitree)ctaonrd's QAU Statement. `The Sponsor will receive one copy of the draft report and two copies of the final report, IINNSSTTIITTUUTTIIOONNAALLAANNIIMMAALLCCAARREAANNDDUUSSEECCOOMMMMIITTTTEE SSTTAATTEMENT. TInhsetitpurtoiocneadluArneismadelsCcarirbeedanidn tUhsisepCroomtomciotltehea.veAbllepernorceevdiuerweesddbeysctrhiebeTdesitninthgisFapcrioltiotcyo'l tdhiastcoimnfvoorltv,e dsitsutdryesasnoirmaplasinwitlo btheecaonnimdaulcst.ed in a manner to avoid or minimize TnehceesSspiotnysoforr'csosnidguncattiunrge tbheisloswtuddoycaunmdentthse tfahcetftahcatttthhaits iisnfnoortmaatniounnnceocnecsesranriinlgythe dpurpolciecdatuirveesswteurdey mavaayilabbeleobftoarimneeedtifrnogmtthheestSaptoendsopru.rpNosoeaslotfemtahteivsetu(diyn.vitro) 000415 418-018:PAGE C-25 REFERENCES Protocol 4P1a8g-e02158 1. CThersitsst.ianE,nvMi.rSo.nmaenndtaVloyPtreokt,ecPt.iEo.n (A1g9e8n2)c.y,IWnaVsihviongRteopnr,odDu.cCt.ivNeatainodnaMluTteacghenniiccailty Information Service, U.S. Department of Commerce, Springfield, VA 22161 2. nCharlitsrteixaon,neM(.PSr.o(c1e9e8d4i)n.gsRoefprNoadlutcrteixvoenetoSxiycmitpyoasnidumt,erNateowloYgoyrekvaAlcuaatdieomnsyooff Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10. 3. CLoanntgr,olP.LD.at(a19i8n8t)h.e EChmabrrlyeos aRinvderFeCtral:DCeDvSeBlRopRmaet.ntaClhaTrolxeisciRtiyv(eTrerLaatboolroagtyo)ries, LInacb.o,rWaitolrmiiensg,toInnc,.)MA 01887-0630. (Data base provided by Argus Research 4. Insitute of Laboratory Laboratory Animal Animals. National RAecsaoduermcyesPr(e1s9s9,6)W.asGhuiindgetofno,r the Care D.C. and Use of 5. SImaplleawnstkait,ioE.nss(1t9e6l4l)e.n aFmarUbteemreusthdoedreRaztutem. maArkcrho.skPoatphiosl.chEexnp.NaPchhawremaiksolv,on 247:367. 6. tShneedbeicnoormi,alG.dWi.straibnudtioCno.chSrtaant,isWti.cGa.l M(e1t9h6o7)d.s,V6atrhiEadnicteiotne,stlofowrahSotmaotgeeUnneiivteyrsiofty Press, Ames, pp. 240-241 7. SBiookmae,trRy,R.W.aHn.dFRroehlelm,aFn.J.an(d19C6o9.)..SBaanrtFlreatntcitsecsot,ofpp.ho3m7o0g-e3n7e1i.ty of variances. 8 SMneetdheocdosr,,6tGh.WE.ditainond,CloocwharaSnt,atWe.UGn.iv(e1r9s6i7t)y.PrAensasl,ysAimseosf,Vpapr.ia2n5c8e-.275S.tatistical 9. Dunnett, CW. (1955). A treatments with a control. mJu.ltAimpelre.coSmtapta.rAisssoonc.pr5o0c:e1d0u3r6e-1fo1r2c1o.mparing several 10. WSo.kHa.l.FRreRe.maanndaRnodhClo,.,F.JS.an(1F9r6a9)n.cisKcrou,skpap.l-W3a8l8l-i3s89T.est. Biometry, 11. Dunn, O.J. (1964). 6(3):241-252. Multiple comparisons using rank sums. Technometrics 12. Siegel. S. (1956). McGraw-Hill, New YNoornkp,aprpa.me9t6r-1i0c4.Statistics for the Behavioral Sciences, 000416 PROTOCOL APPROVAL: FOR THE TESTING FACILITY 418-018:PAGE C-26 Freer sF15.k010 George Dearlove, Ph.D., DABT Associate Director of Research (2s; 4 on nd G. , #h.D.\DABT Ass&tiate Director of Research Study Director Date enBLIAYGIEO Date Dena C. Lebo, V.M.D. Chairperson, Institutional Animal Care and Use Committee FOR THE SPONSOR Date DeannJa. Luebker, M.S. `Study Monitor Foto ol. util John Butenhoff, Ph.D., DABT, CIH Altemate Study Monitor Date 23- AVG- 2000 Date 000417 418-018:PAGE C-27 ATTACHMEN1T STUDY SCHEDULE 000418 ATTACHMENT 1 418-018:PAGE C-28 ProtocPoalg4e181.00/128 SCHEDULE REPLICATE 1 22 AUG 00 ARnatism)al Receipt - Acclimation Begins (Female 29 AUG 00 - 12 NOV 00 29 AUG 00- 20 NOV 00 Dosage Period - Female Rats Assigned to Caesarean-Sectioning (42 days before cohabitation and continuing presumed gestation) through day 20 of DNaotsuaragleDPeelriivoedry- 4F2emdaalyesRbaetfsorAessciohganbeidtattoion through day 24 of presumed gestation (rats that do not deliver a litter) or ay 4 postpartum (rats that deliver a liter), 090CTO0PM-160CT00 AM Cohabitation Period (Maximum of 14 days) Male 1 (07 days) 160CT 00 PM -230CT 00 AM Male 2 (07 days) 100CT 00 230CT 00 First Possible Day 0 of Presumed Gestation Last Possible Day 0 of Presumed Gestation. 310CT 00 13 NOV 00 CFiaresstaProesasni-bsleectDiaoyni2n1g.of Presumed Gestation LCaaesstaProesasni-bsleectDiaonyi2n1g.of Presumed Gestation 310CT 00 17 NOV 00 First Possible Delivery (Day 21 of presumed gLeassttatPioosns)i.ble Delivery (Day 25 of presumed gestation). 04NOV 00 17 NOV 00 First Possible Day 25 of Presumed Gestation Female Sacrifice. Last Possible Day 25 of Presumed Gestation Female Sacrifice. a. b. TRehpelisctautdey2inwiitlilatbieonidniattieatiesdtthweodwaeyetkhse aSfttuerdythDeirsetcatrtorofsiRgenpslitchaetepro1tocol. (see Page 2 of ATTACHMENT 1). 000419 ATTACHMENT 1 418-018:PAGE C-29 ProtocPoalg4e182.001128 04 NOV 00 21 NOV 00 First Possible Day 5 Sacrifice (Dams and F1 generation pups). Last Possible Day 5 Sacrifice. REPLICATE 2 05 SEP 00 Animal Receipt- Acclimation Begins (Female Rats). 14 SEP 00 - 06 DEC 00 Dosage Period - Female Rats Assigned to Natural Delivery [42 days before cohabitation through day 24 of presumed gestation (rats that do not deliver a liter) or day 4 postpartum (rats that delivera litter). 250CT 00 PM ~01 NOVOOAM CoMhaalbeit1at(i0o7ndPaeyrsi)od (Maximum of 14 days). 01NOV 00 PM-08NOV 00 AM Male 2 (07 days) 26 OCT 00 08 NOV 00 LFiarsstt PPoossssiibbllee DDaayy 00 ooff PPrreessuummeedd GGeessttaattiioonn.. 16 NOV 00 03 DEC 00 First Possible Delivery (Day 21 of presumed gestation) Last Possible Delivery (Day 25 of presumed gestation), 20 NOV 00 03 DEC 00 First Possible Day 25 of Presumed Gestation Female Sacrifice. Last Possible Day 25 of Presumed Gestation Female Sacrifice. 20 NOV 00 07 DEC 00 First Possible Day 5 Sacrifice (Dams and F1 generation pups). Last Possible Day 5 Sacrifice. 01 MAR 01 Dratt Final Report 000420 418-018:PAGE C-30 ATTACHMENT 2 MATERIAL SAFETY DATA SHEET 000421 418-018:PAGE C-31 DATA SHEET 3St. CePanutle,r Minnesota 515-184040--1306040-3577 or (612) 737-6501 (24 hours) ACLoLpyrriigghhtt,s r19e9s8e,rveMdi.nnesCootpayinMginianngd/oarnddoMwannluofaadcitnugrinogf Cthoimspany. iisnfoarlmlaotwieodnprfoorvidtehde pthuartp:ose of properly Utilizing SM products 1) ptrheiorinafgorremeamteinotn iiss coobptiaeidnedinfrfoumll,withandno changes unless 2) ndeiistthreirbuttehde wciotphy tnhoer ithnetenotriiogninaolf ietarnriensgolda oprrofoitthertwhiesreeon. DTIRVAIDSEIONNA:ME: 3 CHEMICALS 10FGNU-M9B5ERF/LUU.OPR.CA.D B0 rand Fluorachemical Surfactant 9988.-00221017-.00180838..75 ZF.0002. 104.1 0000--5511113355.-n009903e5642-.17 9988.-00221017--30911064--15 0000-.5511113355.-0029301515..26 SIUSPSEUREDS:EDEJSa:nuaNroyve2m9b,er19058,8 1967 DOCUMENT: 10-3796. 1. INGREDIENT Cas. No. PeRcENT PPOOTTAASSSSIIUUMM PPEERRFFLLUUOORROOAALLKKYYLL SSUULLFFOONMAATTEE............ POTASSIUM PERFLUOROALKYL SULFONATE...... 2378957-319.-3929.6382 29420-45-3 3 - 86 7 PPOOTTAASSSSIIUUMM PPEERRFFLLUUOGRROOAALLKKYYLL SSUULLFFOONRAATTEE............ 630827702..552.85 .112 Te3 2. PHYSICAL DATA vBaOpIoLnINGPREPSOISNUTR:E:...1.1..1.1..1.1..1.1..1.]. vapon oewsr:. 111111 NWIaA Wa ESOVLAUPBOIRLAITTIYON1%RwAaTTEER::L1L11110111111.]] sNl/iAght SPECIFIC GAAVITY:.........1.] PERCENT VOLATILE:.............. ca(.Bul0k.)6 0% Waters: VwIeScCTOnSGIpToY:iit 1 ....... 1 oi1 i NI(D0.1% ip Aqueous) APLPiEgAhRtANCcEoloArNeDd,GDOfRr:ee flowing powder. 000422 Abbreviations: N/D - Not Determined NIA - Not Applicable GA . Approximately JMaSDnSu:aryFC-299,5 1F9L9U8ORAD Brand Fluorochemical Surfactant 418-018:PAGE C-32 PAGE 2 3. FIRE AND EXPLOSION HAZARD DATA FFLLAASMHMABPLOEINTL:I.MI.T.S....L..E.L.:....[.1.1.1.1.]. NN/oAme AFULTAOMIMGANBILTEIOLNIMTITESMPE-RAUTEULR:E.:............. N/A N/A EXWTaItNeGrU,ISHCIaNrbGonMEDdIiAo:xide, Ory chemical, Foam SPWEeCaIrALfuFlIlREprFoItGeHcTtIiNvGePRcOlCoEtDhiUnRgE,S: including helmet, self-contained, apnodsitpainvtes,prbeasnsdusrearorounpdreasrsmusr,e Wdaeimsatndanbdrealetghsi,ngfaacpeparmaatsku,s, anbdunker coat protective covering for exposed areas of the head. UNSUeSeUALHazFaIrRdEouAsNDDeEcXoPLmOpSoIsOiNtioHnAZAsReDcSt:ion for products of combustion. 4. REACTIVITY DATA STABILITY: Stable INNCoOtMPAaTppIlBiIcLaIbTlYe.- MATERIALS/CONDITIONS TO AVOID: HAZARDOUS POLYMERIZATION: Hazardous polymerization will not occur. HACZaArRbDoOnUSMoDnEoCxOiMdPeOSIaTndIOCNarPbRoOnDUCDTiSo:xide, Oxides of Sulfur, Hydrogen Fluoride, Toxic Vapors, Gases or Particulates. S. ENVIRONMENTAL INFORMATION SPIOLbLserRvEeSPOpNrSeEc:autions from other sections. Vacuum, use Wet sweeping bCeORPanOUNidgnoirtioWnatesrourtcoe.avoiCdleadnustuipngr.esCiAdUuTeIOwNi!thAwavtaecru.um cPllaecaenerincoanuld approved metal container. Seal the container. RE0C0OMMnoEtNDErDeleDaIsSePOStAoL:Waterways or sewer. Do not use in products or p1r/1o0cesosfesthethaltowecsotuldECSr0esuolrt LCiSn0 aqcuoantciecntrcaotnicoenn.tratIinocnisnergarteeateinr than an miantdeursitarli.al CoormbcuosmtmieornciaplrodfuacctislitwyillininthceludperesHFe.nceDiofspoasaclombustible alternative: Dispose of Waste product in a facility permitted to 000423 Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately MJSaDnSu:aryFG-299,5 F1L9U%ORAD Brand Fluorochemical Surfactant 418-018:PAGE C-33 PAE 3 5. ENVIRONMENTAL INFORMATION (continued) accept chemical waste. ENVS6I-RHOrN.MENATqAuLatiDcATAF:ish LCSD, Fathead Minnow(Pisephales proselas)=38 mg/l, Bgaliureagnielrls)S=u1n1fismhg/(LL;epo4n8i.Hse.macECrSoOc,hirDuasp)h=n6i8a mMga/gln,a R=ai5n0boawg/lT;rouCtO(DS=a.l0m0o4 Gig; BODZ0 = Nil. REVGoUlLaAtTiOlReY OIrNgFaORnMiAcTICOoNm:pounds: N/A. VOC Less H20 & Exempt Solvents: WIA. Sbienfcoererdeigsuploastailo.ns vU.aSr.y, EcPoAnsHualztardaopupslicWaabsltee rNuemgbuelrati=onsNonoer a(uNtothorUi.St:ies EPA Razardous.) TTShCiAs, prEIoNdEuCcSt, coCOmSpLl,iesAICWSi,thMItThIe canhdemiKcoraela.registration requirements of EPFICRREA HHAAZZAARRDD: CLNAoSS:PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: Yes 6. SUGGESTED FIRST AID EYETaCmOeNdTiAaCtTe:ly flush eyes with large amounts of ater for at least 15 minutes. Get immediate medical attention. SKIINmmCeOdNiTaAtCeTl:y flush skin with large amounts of Water. Remove ccoonnttaamsiinnaatteedd ccllootthhiinngg. beIfforierrirteuastei.on persists, call a physician. Wash INMIfALAsTiIgOnsN:symptoms occur, resove person to fresh air. If signs/syeptoms continue, call a physician. IFDrSiHnAkLLOtWoED:glasses of water. Call a physician. 7. PRECAUTIONARY INFORMATION EYAEvoPiRdOTEeCyTeIOcNo:ntact. Wear vented goggles. had 000424 Abbreviations: N/D - Not Deterained N/A - Not Applicable CA - Approximately MSDS: FC-95 FLUORAD Brand Fluorochesical Surfactant January 29, 1998 7. PRECAUTIONARY INFORMATION (continued) 418-018:PAGE C-34 PAGE 4 SKI`ANvoPiRdOTsEkCiTnIOcNo:ntact. Wear appropriate gloves when handling this mFaetceormimaeln.ded:A pabiutrylofrugblboevre.s maUdsee ofrnoemorthemorfeolloofwitnhge mfaotlelroiwailn(gs) are pCoevresroinnagl, prcoovteercatlilosn. itePmrsotaesctinveecegsasramreynttso p(roetvheerntthsakinnglcoovnetasc)t:shouhledad pobelymeatdheyloefnee/iptohleyrvionfyltihdeenfeollcohwlionrgidemat(eSrairaalnse:x). RE`CUOsMeMEwNiDtEhDaVpEpNrToIpLrAiTaItOeN:local exhaust ventilation. Use in a wellveemnitsisliaotnesdbearleoaw. recPormomviednededsufefxipcoiseunrte vliemnittisl.atioInf teoxhamuasitntavienntilation is not adequate, use appropriate respiratory protection RE`SAPvIoRiAdTObRrYeatPhRiOnTgECToIfONd:ust. Select one of the following NIOSH approved arcecsopridraantcoerswibtahsedOSoHnA ariergbuolranteioncso:ncenhtarlaft-miaosnkofdusctontaandminmaisnttsraensdpiriantor, half-mask supplied air respirator, full-face dust and mist respirator, full-face supplied air respirator. PREDoVENnToItONeatO,F AdCrCiInkDENoTrALsmoIkNeGEWShTeIOnN:using areas thoroughly With soap and water. tWhaissh prhoadnudcst.aftaesrh haenxdploisnegd and before eating. RECKOeeMpMENcDoEnDtaiSTnOeRrAGdEr:y. Keep container closed when not in use. FIRNEonAflNaDmmEaXbPlLeO.SION AVOIDANCE: OTHNEoRsPmRokEiCnAgU:TIOSNmAokRiYngINwFhOiRMlAeTIuOsNi:ng this product can result in contamination of of the hazardous tdheecomtpoboascictoionandp/roorducstmsokemenantdionleedad itnostehcetiofnorm4atoifon this MSDS. HIS HAZARD RATINGS: HPEEARLSTOHN:AL2 PROFTLEACMTMIAOBNI:LITXY:(Se0 e REACTIVITY: 0 precautions, section 7.) EXPOSURE LIMITS INGREDIENT POTASSIUM POTASSIUM PERFLUOROALKYL PERFLUOROALKYL SULFONATE... SULFONATE... POTASSIUM POTASSIUM PERFLUOROALKYL PERFLUOROALKYL SULFONATE... SULFONATE... VALUE UNIT 0.1 MG/M3 0.1 0.1 MG/M3 MG/M3 0.1 MG/M3 TYPE AUTH SKIN HA THA aM aM Y THA aM Y THA aM Y Abbreviations: N/D- Not Determined N/A - Not Applicable CA - Approxisately000425 MJSaDnSu:aryFC2-99,5 FLUORAD 1998 Brand Fluorochemical Surfactant 418-018:PAGE C-35 PAGE 5 EXPOSURE LIMITS (continued) INGREDIENT VALUE UNIT TYPE AUTH SKIN POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/M3 TA aM Y t=heSKIpNoteNnOtTiATaIlONc:ontrLiibsuttedionsubtostatnhceesoveirnadlilcateexdposwuirteh b'yY' thuendecrutaSnKeIoNusrefreourteto ibynclduidriecntg mcuocnotuasctmweimtbhranteheansdubsetyaen,cee.ithVeerhibcyleasirbcoanrnealtore,r smokrien paabrstoircputliaornly, SZOU3MR:CE OF3MEXRPeOcSoURmEmenLdIeMdITExDApToAs:ure Guidelines 8. HEALTH HAZARD DATA EYEMilCdONTEAyCeT:Irritation: signs/symptoss can include redness, swelling, pain, and tearing. SKIMNildCONSTkAiCnT:Irritation (after prolonged or repeated contact): 3igns/syaptoms can include redness, swelling, and itching Meaxytenbdeedabtsiomreb.ed through the skin and persist in the body for an INMHaAyLATbIeONh:armful if inhaled. May be tame. absorbed by inhalation and persist in the body for an extended Single overexposure, above recommended guidelines, may cause: ISorrreinteastsionof (tuhpepernosreespaindrattohrryo)a:t, sicgoungsh/isnygsptaonmdssnceaenziinngc.lude IF ISnWgAeLsLtOiWoEnD:is not a likely route of exposure to this product. Ithlilsnesmsatemraiyalr.esult from a single swallowing of a moderate quantity of May be harmful if swallowed. MUTMAuGtEaNgIeCnIiTcYi:ty assays indicate the product is not mutagenic. 000426 Abbreviations: N/O - Not Determined N/A - Not Applicable CA - Approxisately MJSaDnSu:aryFC-299,5 F1L99U8ORAD Brand Fluorochemical Surfactant 418-018:PAGE C-36 PAGE 6 8. HEALTH HAZARD DATA (continued) REPNRoOtDUtCeTrIaVtEogDeEnViEcLOiPnMEtNhTeALratTOXaItNSo:ral doses below maternally toxic Levels. OTTHhEiRsHEpArLoTdHuctHAiZsARnDotINkFnOoRwMnATItOoN:contain any substances regulated under California Proposition 65. A Product Toxicity Summary Sheet is available. SECTION CHANGE DATES HEADING SECTION CHANGED SINCE November 0S, 1987 ISSUE Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately bTehecoirnrfeocrtmataisonofinthethidsateMatiesrsiuaedl.Saf3eMtyMAKDEaStaNOSheWeAtRRA(NMTSIDESS), iEsXPbReElSiSeEvDedORTo MIEMRPLCIHEADN,TABIINLCILTUDYINOGR, FIBUTTNESNSOTFOLRIMAITEPDARTTOI,CULAANRY PIUMRPPLOISEED WORARRCAONUTRYSEOFOF wPhEeRtFhOeRrMANtChEe O3RM UprSoAdGuEctOFisTRAfDitE.forUsearpa1srtirceuslpaornsipbulreposfeoranddetesrumiitnaibnlge for user's method of use or application. Given the variety of factors that cuanniquaeflfyectWitthheinusteheanudsera'psplikcnaotwiloendgeofanad3cMonptrroodlu,ct,itsoimseesofsewnhtiicahl atrheat tphaertiucsuerlarevapluuraptoesethaend3MsuiptraobdluectfoTro duseetre'rsminmeetWhohdethoefrusiet iosr faiptplifcoartiaon. 3M provides information in electronic form as a service To its customers. Dinueertroortsh,e roemmiostseionpsossoribailltietryattihoantselinecttrhoisnicinftorramnastfieorn,may3Mhamvaekesresnoulted representations as to its completeness or accuracy. In addition, iinnffoorrmmaattiioonn oibntatihenedMSDfSromavaaildaabtlaebasdeiremcaytlynotfrobme a3Ms. current as tne 000427 re Avie SH . en4couN cr 1AMcHo asREeNT..SWHFEEy TM-vCaalTipd68y/C0R0Do O0LN TETRPOE< lAp alnl4y1S 8-m01a 8r r :r PAGE5hC-37 B sraniie a r SiTyeIe rTes swiannesa3,34 u1s71 3768 T aeEPhonRee.ss314 771 3768 fan net (Qter eroan n5. e = - = = - c-astCsHEMICAL TOBNTEFICATION - = = = << =< reotahr TeasCouroiCioavieosnteTnRoF:SATION ON INGREDIENTS + = - = = = sOneoSLrosqeees-e-s3a--02i (3-SETA)= (SGI) CHOLEST_S IN 30L (IERet + sCHeOLmESoT-tS-aCaNea-3TE-A3i5OAnL-oL 5< :6 meEE H rTR aE EL H OwL oLEsE TE s ons + oPNROVICIthNioIatRceRors3tTrseRCahtoazLLoEcnaownoELn=Ty =OY=ICHH=OoLev-rE3R+I=NE ometOnNTihoOnaT oarRvaAeCaosIvLirMaIaecIAzs, |25ImWEoDvIeArLpsEoLsYroFaLrUoSHweEaYsESuamWsI-TH<CO=PIOU=S<A<WODcN=TS-OF- EcMI OaUEnNTEsSnOOFFNWARTAE ETRERo.WcIo hrIGNaTsftseAiISWRyUi.FtWFhIIACfASEriNtSOh,KTINGBSiRRvWEOIeAVTTIHoHORIXDYNSGGOEAPNPGE.IRAVSNEODNACRIOTSPIIFCOIOUNCSSICAILOUS. E ELlL ASN ISA amen A cuommov ssroTnsoavcuest.NEASURES - -- - = = = = = = iSNfEeareEveSR sSEherhNiee.kirwE onioes:ione. pCFhHoEEcMEItuCuRAiELbSgFAOPRPDAERRATOURSAPABNDROPPRRIONTTEECTIFVOEN.CLOTHING 70 amoeEnveensErTaOnCsoenaeRnAogc.uSrtEsENPTLuHbaStSINEnKOINNSFrAaMUsADFAcREoDYwSEpSr.rrReotnesn.sE WEASURES- - - - - ~~ EE RomiE insT sareryTcootseAuisEBsa,:t AcWoveHsOLaDvoFOwRasWtA.STE DISEOSAL. enSR EE BaR rAstee ustAWASHS SPILLe SITS AFATDERSMTOARTAEGREI.AL=P=IGKUE ImS CoOMPoLEsTE. seeTIi oortmetssin 7a5lo SsseaEerCTrshIirtoynnsoca5Eoc.eaisrnssti.saoanecoNcToRvOeLsS./PERSONAL PROTEGTION- - - = = = NIOSH/MSHA-APSROVED RESPIRATOR. 000428 Tom L tin op tr tReet PRODUCCoTat4:s vm ran wi C850q3n SHEET, me VNaAlMiEd: v4CRHOL=ESoTwEesRGLeam2n0e45s10s8so-wm0ae1t8F:3eP6lA3"G6E54C-38 8/2000 - MReGmekM:tiobmatses IA 07/25/2000 35:03 Faxiosess aas7 87 ISOECSHA,NTCmAoLmeEnXWaAmUpSTEwREQEUAIRNES,. TERT AAVVOoIiDb Voie ICPNORHNOATLLAOACNTTGIEODWNI.TOHR ERYEEPSE,ATESDKINEXPAONSDURCEL.OTHING. WKSnETgEoHPReTTHIIOGnRHOTAULGYCHOLCOYLLOSAOEFRDTYERPLAHCAEN.DLING. seeming NA OO NY E Sieas ano cHewIca eROPERTIES - = = = <<< APPWEHAIRTAENCPEOWADNEDR ODOR PHBYSoIrCiAnLg PRrOomPnEtR:TIES MELTING POINT: T3c60 To sc scrSiPmrcitFonic GRAVTITTYY:L LL 1I .0l6g7taszizny amp REACTIVITY - = = = = =< co `smSatsariLIcT.Y IHANZCSAOTRMRDOPONAUGTSIBOIXCLIOI0MT:BI2UEISSNTGIONAGEONRTSDECOMPOSITION PRODUCTS HAZCZTAAoRRxBDzOcONUSoMwOFeNOsOLXYIoMDFEE:R,SZACTAIROBNON DIOXIDE SECTWIOINLLANLOTeOCClUR. + + - - TOXICOLOGICAL INFORMATION = = = = - = = = AcuVtAeG MAY E35FFEMCMTASMFUL BY INHALATION, CAUSE IRRITATION INGESTION, OR SKIN ABSORPTION. oHNOTUCSOELEOSGPIICNAGL PDRAATCATICIENSDICSAHTOEULDA 3L8OW FOORLDLOEWREDO.F TOXICITY. GENERAL GOOD- RTECCHSOLE#:STEFR2O8L400000 TARKTGIEEDTTNESCYTO,SRGAGONRNETDFEAERTR,ATILBILTAYDDE(RPOS(TBL-AIDNDPELRANTTUAMTOIROSN) MORTALITY) SSZrPOrENECGcIRiTIsIGcENOSNDCEVFEE(RLETOQIPULMIIEVTNOYTCAALL(LTAIBUTNMTOOERRRMIAGSLEIZINETI)ICESAGE(NCTRABNYIOFRATCEICASL)CRITERIA) TO(NORLNTYOECRSIS)GEELNDEICACTTEAD(ITsRUEMGOSRIRSSETSRAETYNTOESFDITETHEORXOEFI.CAPSEPEFLEFIECCAATCTSTIUOAONLF) CENHTERMYICAILN SRTUEBCSSTANFCOERS SECTICOONMPL12E.TE=IN=FOoRoMAT2IOoN.l. - SCOLOGICAL INFORMATION = = = - <= = = = = SECTI5DO2ANSTAS013LN.VOET-YOER<TMAI=XVATT=LHAE=B<LWEA.T.ER-IADLISPWOISTAHLACOCNOSMIBDUESRTAIBTLIEONSSO=LVE-NT= A=ND= =BUR=N=IN= A SECTCBIHOSENEMRI1VC4E:ALA+LIL=NCIFoNEEDERoRAATLOo,R CS1TQAUTIEZPEADNTDRAWNILTSOHPCOARLATNEANIFVNTIFERORORBNMMUAERTNNITEOARNLA-NRDE=GU-SLCAR-TUIB=OBNE~SR..= - = SECTICOONNTA1C5.E S=IGoHoA CHoEMoICA=L- CO-MPRAENGYULAFTOORRYTRAINNSFPOORRMTAATTIIOONN=IN=FO=RM=AT=IO=N:= = = = REVOIEZiWmSu,AKSTANDARDS, AND REGULATIONS IARC CANCER REVIEW:ANIMAL INADEQUATE EVIDENCE IMEMDT 10,33,1576 Su aA re coI mmune 10 sae sD ucePsasgR eof a2ur CI uriemers, Epler ni 000428 oe te wow maert siemmtn taes watt eaopuct #: C8503 we en we >wens 418-018:PAGE C-39 MAME: 8C/H2O00L0ES-TW EROLS tSaSedDsrO 40UST 4 o -- ICT nas TaaencRoi4A0z7e0s/7u/2e25s5/,/T2u2e00V00a00li1d815::00e33amg eFagxe 80m33r s26m- 5(s 3104e)82n771.8757 --- IAARRCC NoNS C1CA3CN74CR:ERE HRIEDVIBZy 0H0:EGLR:OUNNPiiss3 03;) TTuurr 1a3v2a1l;; Nwooss 1110; TTuTNsHuEEoLg13i778a,01;63T,E2E5830330 SHE-CLONAL ASSAY EHEES EEN TECEEECTTRtOoUNonsRw((0i3))s19s8COo8HN,EPMU(NIBTECLSGAICALSATTHISEIV)DNEV:ERDNERTIAOALRTYB/ASSAET,ETDYICSEoTNUSOEeTXSsY139w3ok suneont perTEE tOEhFA T1To6Con.E TiTromOaMrAiIpo.niSiHasALCnLBoEiLr2I5suEVeUESFnDEoDn7m0OraNoNiBntTaOACBNTSOUIRAORGANEECGCTURIEDaSEuU,tLTDIsONtEGoSwF,NLOOT,BYIFMWOUSLEUIGTCON,NETIO<R0 FBEOLRUCRRA aHTCow:O L19H3A O3 SAIAGMDAO-TTAh7LuDrURAAILBCoHVTDECOR.MFEAGADPNAUDPCE:RCONSCDEOEIPTIIEROSENVSEFROSROEFISSNIATDLEEER.MOAFL I USE ONLY COPYRIGHT 30) SIS MAKE ONLIMITED . Page 3 mn en A eT 000430 418-018:PAGE C-40 ol. 3 Material SafetyOOuuDiCarPatnreease. S712h81e20ea0t0 Vereen 16 Section 1 - Product and Company Information B-- Parnadct amber CCiSotrmyepeatonAdeyd,rZeps,sCountry fTeeythment Prine SNOoLamMaEasVCArLeOmNeInC ACID LACTONE S2St0g5mo3auSa,onrMecOn.S8e3m103.US S003a2srssos Emergency Phone: razr 2050sess Section 2. Composition/information on Ingredient SuBbstEancNetTameico LcToe Scasos FSoermaamns comoos sanNaosiy Section 3 Hazards identification - For assnons roman on oxery, peas ee Secon 11 Section 4- First Aid Measures IoF nowEexpso.urw s oa tmouh nwh wat sreeperson = conscious.Cal yscan nnaascti.onrEexpmoomureeen a. 1 ct eat ve atc eseaton. H rea fsGC, Gwe yen DIecremast ExSpoonmurae rmeaey wash inwi 5445 58S muofvsat EIrCeasExptonruarect mma sh yes wih 29008 mur ofaisfo at ast15meres Section 5 Fire Fighting Measures [-- as ae Aoigtion Tams: I" Fama, NA ExtWiSantgueurisasenianyg.MCeadrisaon Gonos.cychamcal power,o sparsefoam 000431 418-018:PAGE C-41 FirPtriogtheicntgive Equipment Wearsetcoraine _-- brehing paras and procecive ching o revert cortact wih ki and eyes Sec6t-Acicidoentnal Release Measureeys WPreoacradTuersep(ast)oro.fcPheermsiocnaallsaPfreetcyaGuotgigoenss.)rubber bouts. and heavy aber goves. ACMbeostomhropsdesonfoSranCdloeanvinegmUcpue andplace in ciosed conaners or dposa. Vertis ares nd wash ila afermaienal kus & _S--e--_ction 7 - Handing and Storage HonVdeienrgExponure Avo haat. Ave conact win eyes, skin, and coming, Avid rolonged of esested exposure. Sto"rSaugnesble Keep thy comma. _S-e--ction 8 - Exposure Controles/ PPeE 000 ESanfgeirnsehroiwnegrCaanmcrooives ban Mechan<al ena aurea. ParRseasmpailrPartootreyctive Equipment NIHOanSaHAMSHAapproves espero CEvaempatii chemcatrensar goves Creme suey gogges. GWeansehrCaorHsyagmiiennaeteMaesurengsbefore reuse, Wahasr h ar nancing. _S--ection 9 - Physical/ChemicalPPrrooppeerrties Aopesrance color Form Far begs rSaogkmdeeressmass or Molecur Weight 130.15AMU Property Value oBHP/BPRange 1N45A. 150C MFrPeeMzPingRaPnoginet 2nAc VVSaaatppuoorrrsPDeardneasVisatupyroer Cone. NNAA NA S`BGOudDlokarnDTaahnrraeysi.hyold NNAA NA T1 emperaortPruesrmuere 5 mig SPiaggmea2Cremer Mase? Sigmae-Aledricsh Carporstion 000432 _-- 418-018:PAGE C-42 VaVOlCstCosn.tant NaA WSaaitveerrCtoCnotnetnetnt NNAA ViEsvcpoourtsytion Rae NNAA DPeacrotmtipoonsiCotsifoinciTeenmtp. NNAA FFilnnaenh PPaointtCF 2Tsaec AEuxtpoliogsridoinoLnimTietmsp NNAA SoRleutmriancyte index NYaAra Section 10- Stwbility and Reactivity smb`iCiotnyditions of inetabitty PCrootnedcittrioomtnmsoAovouid PMroatetctefrotnmo mAvooiud, Song cxdizng sgeres. Haz`aHradzoaursdoDuescDoampcoosmiptoisotnioPrnodPurcotdsu.cts Carcan mance Carson danse Section 11 - Toxicological Information Rou`tSekionfCEaxnptoaucture EMyaeyCcoanttaaecstun rrsan IMnahyaictaiuosne eye ration MMautletraemRaoyutoeesrising to mucous membranes and upper resarany ac: May be hari by maison, ingestion, oin asserpeen TSoigns0aansdtSofymlprtKonmoswoefagEex.ponseurCreamcal. BSE, and {9XEOIOGGA IaPeTOES have ni been rou inesLgaled RTECS Number: Section 12- Ecological Information `Section 13- Disposal Considerations s`DAeipprsrvoopenriioartemaocMxeerti,heoedsatoref,nDi4s5wpdois1ha4l)CooermSvDurUbosrtmbamlneecrSecsa0rr0reepgAanrua.tUiron1 8 CRETCI IICELr 60353Wh an Eerourer an uber. Section 14 - Transport Information oPotroperShipping Name: None SPiaggmea3Crema Mas? Sigme-aa saricsh Ciarrpeornstion --_ 000433 418-018:PAGE C-43 NorHazardous for Transport; Th subsarce cormcsredto be nonhazarordfaoraupess waNporroepee ShriniangorarmAeo:TrNacomanpeoert; Nohazaeous a i rasont Section 15 Regulatory Information SARA 313 ned No ---- E Section 16 - Other Information E -- rv -- TenShorvesearcr Iohmraeaonrhaslenalore)obreavcyoaehrnedcaacnToeecsserck1hrioSseotCAo0n0Sya1ec99u3sSvce artrAswaailnes Coscegoar nnypar3egSeoe.mSarasoso eed See esor eee on SPaogmea&ramet wats? im-- e-arcnCaorntion 000434 -- 418-018:PAGE C-44 ATTACHMENT 3 TEST ARTICLE, CONTROL ARTICLE AND VEHICLE PREPARATION PROCEDURE 000435 418-018:PAGE C-45 ATTACHMENT 3 Version: 18:P0r1ot8o(c1o6lA4U18G.001081 Page 1015 TEST ARTICLE, CONTROL ARTICLE AND VEHICLE PREPARATION PROCEDURE Test Article: Control Articles: Vehicle: PFOS CMheovlaelsotneircolacid 0.5% Tween 80 in R.O. Deionized Water for PFOS and Cholesterol R.O. deionized water for Mevalonic Acid A. Purpose: oTfhedopsuargpeosfeoromfulthaitsiopnrsocofedPuFrOeSi,s tmoepvraolvoindiecaacmied,thcohodlefsortetrhoelparnedpatrhaetion A0r.g5u%sTRweeseeanrch80Lavbeohriactloerfioers,orIanlc.adSmtiundisyt4ra1t8i-o0n18t.o rats on Primedica 8. General Information: 1. All formulation containers wil be Specify the protocol number, test labeled and color coded. Each label article identification, Argus batch will number, concentration, dosage level, preparation date, expiration date and storage conditions. 2a. Suspensions __ Daily of PFOS wil X_ be prepared: Weekly ~~ _ For__daysof use 2b. FoXr_mulaOtnicoensDoafiltyhe(cchoonltersotleraorlt)icles_Xwi_ll be prepared: Twice daily (Mevalonic acid) 2c. The __ 0.5% Tween Daily 80 Vehicle will _X_ Weekly be prepared: _ For__daysofuse 3. Suspensions will be prepared at a final dosage volume of mL/kg. 4. Safety: X_ Gloves, lab coat. goggles or safety glasses and faceshield XC _ Dust-Mist Respirator Half-Face Respirator ~ Full-Face Respirator/Positive Pressure Hood TZ Tyvek SuitApron 5. Dosage formulations of the test article and control articles adjusted for Free base and % Purity Yes _X_ No (Calculations based on 100%) _ FreeBase __ Pury 000436 418-018:PAGE C-46 ATTACHMENT 3 Version: 418P:0r1o8(t1o6cAolU41G8.00108 Pagezol 5 TEST ARTICLE, CONTROL ARTICLE AND VEHICLE PREPARATION PROCEDURE 6. Sampling requirements: Cited in protocol. 7. Storage: Cited in protocol NOTE: The high test article dosage to suspensions will the low dosage. be prepared as a serial Once the final volumes dilution from are achieved, the sir pbraerpsaraarteiotno,bealiaqdudotetdintgo, tshaempclonitnaginaenrds/;ormidxoisnaggsehaodumlidniosctcruatridonu.ring C. Preparation of the 0.5% Tween 80 Vehicle: 1. Add 2985 container. mL of Heat tRh.eO.wadteeirontioz5e0dwCat=er5toC.anthaepnpraodprdia1t5elmyLlaobfeTlewdeen 80 and mix until uniform. D. Test Article Suspension Preparation: NOTE: Praipoprrotporiparteeplyarsaitzieodncoofnttheai0n.t4e0ormtghe/mdLesisruesdpevnosliuonm,e pwrietchalRi.Ob.rate an deionized water. 1. tTeostparrelpcalree(tSheee0T.4E0SmTgA/RmTLIsCuLsEpePnRsiEoPnA.RwAeiTgIhOtNheCAreLqCuiUrLeAdTaImOoNuSnt) oifnto arenquaiprperdoparmiaotuenlty swiiztehd,0.l5ab%elTewd,eeprne-c8al0ibarnadtehdecaotnttahienemri.xtuQrSe taod8t0otChe =5C for approximately 30 minutes or until the TAS dissolves. 2. Once bath, the add test article has a magnetic stir dissolved, bar to the croenmtoaivneert,heplsaucsepeonnsaiomnagfnreotmitchestiwrater spluarteetahnedremiisxauvnitislibtlheevsorutsepxe,ntshiiosnwielquaiclhiibreavteesthteo dreosoimretdemepmeurlsaitounr.e). (Be Be dSuorseagtheatgrtohuepss,usapleinqsuoitoinngi,s mdioxseadgepraionrdtoorasnadmpdiuirnign.g preparation of other 3. T0.o40prmegpa/rmeLtsheus0p.e3n2simogn/m(SLeesuTspEeSnTsiAonR.TIrCeLmEovPeRtEhePAreRqAuiTrIeOd Namount of CALCULATIONS) QS ad to the final and add required it to an volume appropriately sized with 0.5% Tween graduated cylinder. 80 (See TEST cAyRlTinIdCeLrEanPdRiEnvPeArtRsAeTvIerOaNl tCiAmLeCsUtLoAeTnIsOuNreS)p.ropSetrompipxeinrgt.heTgrraandsfueartetdhe suspension to an appropriately sized, labeled container. Add a magnetic 000437 418-018:PAGE C47 ATTACHMENT 3 Version: 18.P0r1o8t(oc1o6lA4U1G800108 Page30l5 TEST ARTICLE, CONTROL ARTICLE AND VEHICLE PREPARATION PROCEDURE `stainrdbdaurrtiongthperecpoanrtaatiineorn,ofploatcheer odnoasamgaegngertoiucpss.tiralpilqautoettainngd, mdioxspargieoratnod/or `sampling. 4. T0.o32prmegpa/rmeLtsheus0p.e2n4simognim(SLeseuTspEeSnTsiAoRn,TIrCeLmoEvPeRtEhePAreRqAuiTrIeOd Namount of CALCULATIONS) and add it to an appropriately sized graduated cylinder. AQRSTaIdCLtoEtPheREfiPnaAlRrAeqTuIiOreNd CvoAlLuCmUeLAwiTtIhO0N.S5)%.TwSteoeppner8t0he(SgereadTuEaSteTd scyulsipnednesriaonndtionavenrtapspervoeprrailatteilmyessitzoede.nsluarbeelperdocpoenrtamiinxeirn.g. AdTrdanasmfeargntehteic astnidbdaurrtiongthperecpoanrtaatiinoenr.ofploatcheerondoasamgagengertoiucpsst,iralpilqautoettainngd, mdioxspargieoratnod/or sampling. 5. 0T.o24prmegpa/rmeLtsheus0p.e2n0simogn/m(SLeseuTspEeSnsTioAnR.TIrCeLmoEvPeRtEhePAreRqAuiTrIeOd Namount of CALCULATIONS) and add it to an appropriately sized graduated cylinder. QARSTaIdCLtoEtPheREfiPnaAlRrAeqTuIirOeNd CvoAlLuCmUeLwAiTtIhO0N.S5)%.TwSteoepnper8t0he(SgereadTuEaSteTd csyulsipnednesriaonndtionavenrtapspervoeprrailatteilmyessitzoede,nsluarbeelperdocpoenrtamiinxeirn.g.ATdrdanasfmeargntehteic astnidbadrurtiongthperecpoanrtaatiinoenr,ofploatcheerondoasamgagengertoiucpsst.iralpilqautoettainngd,mdioxspargieoratnod/or sampling. 6. T0.o20prmegpa/rmeLthseus0p.e1n6simogn/m(SLeseuTspEeSnTsiAonR,TIrCeLmoEvPeRtEhePAreRqAuTirIeOdNamount of CALCULATIONS) QS ad to the final and add required it to an volume appropriately sized with 0.5% Tween graduated cylinder. 80 (See TEST AcyRlTinIdCeLrEanPdRiEnPveArtRAseTvIerOaNl tCiAmLeCsUtLo AeTnsIuOrNeS)pr.opSetrompipxeirngt.heTgrarnasdfueartetdhe Sstuisr pbeanrstiootnhteocaonntaaipnperro,prpilaatceelyosnizaedm.aglnaebetliecdsctorntpalianteer.andAdmdixapmriaogrnteotic and during preparation of other dosage groups, aliquotting, dosage and/or sampling. 7. To prepare the 0.08 mg/mL. suspension, remove the required amount of 0C.A1L6CmUgL/AmTLIOsuNsSp)enasnidonad(dSeitetTo EanSTapApRroTpIrCiaLtEelPyRsEizPeAdRgAraTdIuOatNed cylinder. QS ad to ARTICLE the final required PREPARATION vCoAlLuCmUeLwAiTtIhO0N.S5)%.TwSetoepnper8t0he(SgereadTuEaSteTd 000438 413-018:PAGE C-48 ATTACHMENT 3 Version: 18.P0r1o8t(oc1o6lA4U1G800108 Page 4015 TEST ARTICLE, CONTROL ARTICLE AND VEHICLE PREPARATION PROCEDURE cylinder and invert several times to ensure proper mixing. Transfer the sstuispbeanrstiootnhteocaonntaaipnperro,prpilaatceelyosnizaedm,aglnaebetliecdstciornptlaaitneera.ndAdmdixa pmraiogrnteotic and during aliquotting, dosage and/or sampling. 8 To prepare the 0 mg/mL suspension, add the required amount of the appropriate vehicle appropriately sized, (lRa.bOe.leddeicoonnitzaeidnewra(tSereeorT0E.S5T% ATRwTeIeCnLE 80) to an PREPARATION CALCULATIONS). Add a magnetic stibar to the container, place on a magnetic stir plate and mix prior to and during aliquotting, dosage and/or sampling. E. Preparation of Mevalonic Acid Solution 1. Wlaebieglhedtchoenrteaqiunierred(SaemeouTnEtSoTf AmeRvTaIlCoLnEic/VaEciHdICinLtEo aPnRaEpPprAoRprAiTaIteOlNy CALCULATIONS). 2. Add approximately 80% of R.O. deionized water to the container. Adda sti bar to the container, place on a magnetic stir plate and agitate until the control article has dissolved completely. 3. Transfer solution to an appropriately sized graduated cylinder and Q.S. to the final desired volume with R.O. deionized water (See TEST ARTICLE/VEHICLE PREPARATION CALCULATIONS), 4. Cover the graduatedcylinder with a glass stopper and mix by inversion. Retumn the solution to the original container. Add a magnetic stir bar to the container, place on a magnetic stir plate and mix prior to and during dosage. F. Preparation of Cholesterol Suspension: NOTE Prior to preparation of the cholesterol suspension, precalibrate an appropriately sized container to the desired volume with R.O. deionized water. 1. Weigh the required amount of cholesterol into an appropriately sized, labeled container (see TEST ARTICLE/VEHICLE PREPARATION CALCULATIONS) 000439 418-018:PAGE C-49 ATTAGHUENT 3 Ves: 1P8oeAFaan1eo5s.0a1d8 TEST ARTICLE, CONTROL ARTICLE AND VEHICLE PREPARATION PROCEDURE 2 Add a small amount cholesterol by using of 0.5% Tween a glass rod. QS 80 ad to thecontainer and wet the with the 0.5% Tween 80 to the final required volume (see TEST ARTICLE/VEHICLE PREPARATION 5 Amidxduanmiaunginfoermspirriobra0rtoantdhedvnessgeld,opslaagcee oandmaimmaagsnaettiinc.si plate and CALCULATIONS). Witen by: Approved oy, Date: esis / Clarification: No __(Yes{See attached clarification form.) ialsDate: (T2h olXeDyr ey 000440 418-018:PAGE C-50 ATTACHMEN4T TISSUE COLLECTION AND PROCESSING 000441 418-018:PAGEC-51 Tissue Collection and Processing `Blood `Pooled/itier [[2 7 spleasmma--TT3<30 TPL To Tiver Pooleder Tiiver i] [3aitiesT<20 EY) Mevalonic sad | PFOS 1 Possible ENT PFOS Blood. + mlam 1 er --rn tote. s70 wi -- er chol. ingly | ochemica [isenm Te 77%-- Toros = [m fmm rTm w:a] [medmnioh Ts Tow eros [TM Pooledsexfliner ips Te [enn Teo { L Liver Pooledsexfiver | Valier 1236 TPWL TW TAM |Mevioncas|d eros chol. ng! Teros | | { Valles |Liquid narogen. | M1 S70 Possible Biochemical 000442 418-018:PAGE C-52 r~PRIMEDICA Arg5u0s5RSehseeaerhcyhDsLrahibavoenr,a,tPBourAsiieso1,n9g0In4cA.3 Tellepehoanne 3(21155) 44441348751507 ---- PROTOCOL418.018 `ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/ CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS SPONSOR'S STUDY NUMBER: T-6295.25 Amendment | - 13 September 2000 IL Storage (page 4ofth protocol) t"Tehmepesrtaotruargee. conditions for the Mevalonic Acid should be frozen. rather than room ReaforsChoangne: "This change was made at the request of the Sponsor. 2. Shipping Instructions (page 6of the protocol: "The comect address for Dave Envesman is the following: 3DaMveCoErhproreastmeanToxicology 3M Center Building 236-0C-148 St. Paul, Minnesota 55144 Telephone: (651) 733-5070 Telefax: (651) 737-4754 000443 aAmneynrdemveinsito.ns made to this finalized amendment must be made by subsequent Reason for Change: "Ths change corrects th protocol. 418-018:PAGE C-53 J amendmPenote| dling 2 NY. `Assosate Director of Reseazch Acie DecorofR Study Director isL3:5EP 00 b0uaC.tLsebo, VMMlDl.ooled ssiDate MDeainnaJ.sLuefblriM.S.tsTaDalteeo Chairperson, Institutional Animal Care Study Monitor and Use Committee Silo. Jienktf finde JAolhtnemBautteenShtoufdfy, MPohn.Di.torDABT.CIH Date Any revisions made to this finalized amendment must be made by subsequent `amendment. 000444 rrPRIMEDICA 418-018:PAGE C-54 Shol p Benes Argus Research Laboratories. Inc. PROTOCOL 418-018 `ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/ `CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS Amsnian 2. 22 Never 1000 SPONSOR'S STUDY NUMBER: T-6295.25 1. Altemate Study Monitor (page 1 of the protocol): The telephone number for John Butenhoff. Ph.D.. DABT. CIH is (651) 733-1962. Rosen fr Chane rather than (651) 737-1962. `This change corrects the protocol. 2 `Sample Analysis and Shipping Instructions (page 14 of the protocol): The fllowingpcgraphs wil plc th pag hich ses tht ser nd ves `samples will be analyzed for LDL. HDL. total cholesterol and triglycerides: The emsiing ivesamples will nly orLDL. HDL otal cholesterol and Serum samples collected from all dams and pups will be analyzed for total asee oarn ni dg cholesterol. glucose, total and free T3, Ts and TSH levels, LDL, HDL and triglycerides. The first priority will be analysis for total cholesterol and glucose. The 000445 Any revisions to this finalized amendment must be made by subsequent amendment. 418-018:PAGE C-55 `The liver and serum samples will be shipped to: ProAwmcoelnd4m1e8.n0t182 Page Dr. Saroj R. Das Ani Lytics, Inc, 200GerardStreet, Suite 2000 Gaithersburg, Maryland 20877 Telephone: (301) 921-0168 Telefax: (301) 977-0433 Reason for Change: t"TihsissuechsaanmgpleewsaasndmatdoepraitortihteizreeqtuheesutsoefotfhseaSmppolnessorforinaonraldyesreos. include additional 3. Scheduled Sacrifice - FI Generation Pups (page 20 of the protocol): (Effective Date: 3 November 2000) For Replicate 1. blood samples wil be pooled pSearmplilteesr,wsiallmpbleeaslifqruoomtemdaale faonldlofwesm,arlaethpeurptshcaonmabsidneesdc.rirbaetdheirntphaarnapgoroalpehd3.per sex. Approximately I mL of blood will be transferred into serum separator tubes: any. remaining blood will be transferred into EDTA-coated tbes. The samples will be spun in a centrifuge and the resulting serum will be divided into two aliquots. The first aliquot (approximately 200 L) will be used for PFOS analysis. The second aliquot (approximately 300 WL of serum) will be used for analysis of total cholesterol, glucose, total and free Ts T. and TSH levels and LDL. HDL and triglyceride levels. according (0 the priorities described in tem 1, above. Any resulting plasma will be tcrhaenmsifsetrrrieedsifnitrosto(naeccaolridquiontg.1Retshuelptriinogristeiersudmewscirlibbeedpirnioirtietmize2,daabsofvoel)loawnsd: tchleinnical PFOS samples. All samples will be immediately frozen on dry ice and maintained frozen (-70C) until shipment for analysis. Reason for Change: "This change samples for was made analyses. at the requestofthe Sponsor in order to prioritize the use of 4. Scheduled Sacrifice - FI Generation Pups (page 20 of the protocol): (Effective Date: 17 November 2000] For Replicate 2, blood samples wil be pooled (ftolwloowlsi,terrascpheerr tshaamnplaes dweistchriinbeeadcihndpoasraaggeragprhou3p.).ApSparmopxliemsatweillyl 0b.e3amliLquooftebdloasod will be transferred into EDTA-coated tubes. The remaining blood will be transferred into serum separator tbes. The samples will be spun in a centrifuge and the resulting serum will be divided into two aliquots. Resulting plasma will be transferred into one aliquot. The serum will be prioritized as follows: clinical chemistries first (according 000426 Any revisions to this finalized amendment must be made by subsequent amendment. 418-018:PAGE C-56 Pro"cAomlen4d1mt8e.ne0t1s82 tothepriorities described in item 2, above) and then PFOS samples. All samples will be frozen on dry ice and maintained frozen (<-70C) until shipment for analysis. Reson for Change: "This change was made a th request of the Sponsor in ordetro prioritize the use of `samples for analyses. 5. Scheduled Sacrifice - F1 Generation Pups (page 21 of the protocol): (Effective Date: 3 November 2000] Thyroids wil be excised rom each pup. pooled (pboysisbelxepfeurtulirtetere)v.alTuahtyirooni.ds will be retained in neutral buffered 10% formalin for Reason for Change: `This change was made at the request of the Sponsor. pana Assorcgiea.te DDieraercltoovreo,fPRhe.sDe.arDcAh BT dx A Al 22d Date ARisyefilaotned DG.irectof ofhI.RhsDeaArcBh T Date Study Director Cha7iarpCe.rsLoenb,o,InVst.iMt.utDi.onal Animal Care Date DSteuadnynaMoJ.niLtuocrker. MS Due and Use Committee: Plo 2 Bellicr boty 1 foo ree JAolhtnemBautteenShtoufdfy, MPohn.Di.t,orDABT, CIH Date 000447 Any revisions to this finalized amendment must be made by subsequent amendment. 418-018:PAGE C-57 r"2 F; RIMEDICA Ar5g05RSeeseeancyhDLiavbeo:ratBoraiels,oLAgn TelephoHnoer:sh(a2m1,9) P4A43-149701404 Telefax: (215)443.8587 --_--_--mm-- PROTOCOL 418.018 ONECGHEONLEERSATTEIROONL RCEHPARLOLDEUNCGTEIOANNDSTNUODEYLOIFNVPEFSOTSI-GMATEIVOANLOINNIRCATASCID! SPONSOR'S STUDY NUMBER: T-6295.25 Amendment3 - 11 January 2001 1. ConrolAnicles (page 3ofthe protocol): "The lot number for mevalonic acid is lot number 070K26603, rather than 070K2603. Reafos rChoangne: This change corrects a typographical errr. 2 CoAntrroltic (pal ge3eofs the protocol): iFnoradmdeivtailonontiocloatcindu,mlboet rnu0m7b0eKr26068003K.2618, expiration date September 2004, was used Reason for Change: c`AodndtirtoilonaanldmPeFvOalSonpilcusamciedvawlaosnirceqauciirdedfofromrutlhaetipornesp.arationof the mevalonic acid 3. `SampleAnalsis andShippingInstructions (page 14ofthe protocol): Plasma Vehicle mCeovnatlroolni(cGarcoiudple1)v,elMsewvialllobneicmeAacsiudrCeodntforrolth(eGfroolulpow2i),ng1.d6osmaggkeggrPouFpOsS: + PMeFvOaSlo(nGircouApci1d1)(,Gr1.o6upmg3/),kg2 mg/kg PFOS (PGFrOouSp+12M)evaanldo2nimcg/AckigdP(FGOrSou(pG4r)o,u1p.213m)g,/rkatgher dthoasnagaellgdroosuapgseagfrteorupesv.aluMaetviaolnoonfitchacriedsulletvseolsfmtaheyabbeovmeeaasnualryesdesi.n tRheemlaoiwneirnPgFOS usnatmilplneostiwfiilclatbieonreftraoimnetdheatSPproinmseodricfaorWdoirscpoessitteiorn.Laboratories or the Testing Facility 000448 aAmneynrdemveinsito.ns made to this finalized amendment must be made by subsequent 418-018:PAGE C-58 Reston evens --pro-- t[evien Tis hinge wasmade a he request ofthe Sponsor 4. SampleAnalusisandShioping Instructions(page 1ofAmendme2nt othe protocol): Total and free Ts, Ta and TSH levels will be measured for the following dosage groups: Vehicle Control (Group 1), 1.2 mg/kg PFOS (Group 11), 1.6 mg/kg PFOS (frGereoTu,p, T1a2)aannddT2SmHg/lekvgelPsFmOaSy (bGermoeuaps1u3r)e,draitnhetrhethlaonwearllPdFosOaSgedogsraoguepsg.roTuoptsalafatnedr `evaluationofthe resultsof the above analyses. Reverted `This change was made at the requestofthe Sponsor. corggF. DE eariovet , PLD. e DABT r DatesRbymp dbd G. Yy ork, NnD), DeAoBlTlTD0at:e00 (ssoctate Director ofResearch te Director search and Study Director ABhtcro vtolttifonbid 117Dma.te MDeiannJas.Lud]blerF , M.St Datteo/ Cpr Irons] Art Care Say iother and Use Committee Fh 2 ET) 1" oe 01 JAlothenrnBautteenShtoufdfy, MPohr.Di.i,orDABT,CIH Date 000449 Aanmyernevdissi,ons mae to ths alized srmsadment aust be neade by svboequent ry MEDICA 418-018:PAGE C-59 A"m3i0s5RSehseeeahcryhDsLraihbvoe,,raBtuPriiAledis1n,9g0Ic4A.4 TelTeeplheofnuex:: ((221155)) 444433--88751807 PROTOCOL 418-018 ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/ CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS SPONSOR'S STUDY NUMBER: T-6295.25 Amendment 4 - 18 April 2001 I. FI Generation Pups (page 10 of the protocol): [Effective Date: 21 August 2000] Day 1 of lactation (postpartum) is defined as the dayofbirth and is also the first day on which all of the pups ina litte are weighed. The pups will not be individually weighed; pooled litter weights will be recorded. Rea forsCho angne: `This change was made to be consistent with Tests, Analyses and Measurements F1 Generation, Body Weights 2. Scheduled Sacrifice - FI Generation Pups (page 20, 21, page | ofATTACHMENT 4 and item 5 of Amendment2 to the protocol): Histopathology will be performed on the heart and thyroid of one male and one female FI generation pup from eachoffour litters from the Vehicle Control group (Group 1) and 2 mg/kg PFOS group (Group 13). Ifany difference is found, histopathology will be performed on the heart and thyroidof one male and one female F1 generation pup from eachoffour liters, when possible, from the 0.4 and 1.6 mg/kg PFOS dosage groups (Groups 8 and 12, respectively). Tissues will be shipped (ambient conditions) for evaluation to: W. Ray Brown, D.V.M,, Ph.D, ACVP Veterinary Pathologist Research Pathology Services, Inc. 438 E. Butler Avenue New Britain, Pennsylvania 18901 Telephone: (215) 345-7070 Telefax: (215) 345-4326 000450 Any revisions made to this finalized amendment must be made by subsequent amendment. ReafosrChoangne: "This change was made atth request ofthe Sponsor. 418-018:PAGE C-60 PrNocaa1c8[.0e5148 ote Geprge|. Dearlove, Ph.D, DABT ~~ Date Associate Director of Research 0= Ra G. York, ?h.D./{DABT `Associate Director of h and Study Director th601 Date donscase, duno douddisdirt! ChairpersAo.n,WIenssttu,tioDnalMA.nimal Care Date DSersyanMaJo.niLtuoerblds M.S. Dae and Use Committee loan. Geilanty Fpond 25,70 John Buteahoff, Ph.D. DABT, CH_ Date Alternate Study Monitor 000451 Aamneynrdemveinsito.ns made to this finalized amendment must be made by subsequent Toren ote 905 Sheehy Drive, Bidg. A TTeelleefpahxo:ne(:21(52)154)34-4835.887710 418-018:PAGE C-61 2 ; ~~ ARGUS RESEARCH DiscoveCrhyaralnedsDReivveelropLmaebnotraSteorvriiceess PROTOCOL 418-018 `ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/ CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS SPONSOR'S STUDY NUMBER: T-6295.25 Amendment 5 - 4 February 2002 - nnn 3 Shipping Instructions (page 6of the protocol): [Effective Date: 29 January 2002] Homogeneity and concentration samples shipped to Dave Ehresman at 3M Corporate Toxicology for analysis will be reshipped (frozen on dry ice) to: Emily R. Decker (Principal Investigator) 3E0x5y5geRnesReeasrecahrcDhrive State College, Pennsylvania 16801 Telephone: (814)272-1039 Telefax: (814) 272-1019 Email: edecker@centrelab.com The analyses will be subcontracted to Exygen Research by the Sponsor and the Quality Assurance Unit for Exygen Research will conduct critical phase inspections and audit the respective results and reports according to the Standard Operating Proceduresof that facility. Such critical phase inspection reports and audit reports will be submitted by that facility to the Study Director, Raymond G. York. The date of the inspections and report submissionswill be incorporated into a QAU statement generated by Exygen Research for inclusion in the final report for protocol 418-018. Any revisions to this finalized amendment must be made by subsequent amendment. 000452 Reason for Change: `This change was made a the requestof the Sponsor. 418-018:PAGE C-62 Poncea sniistsi Hoon Denes- e George . Dearlove, PhD, DABT Date" Associate Director ofResearch Xe 7 Rijghond G. ork, Associate Dil and Study Director R02. Ph.D, DABT Date f Research Ahtcrlsd iti. Met]iets coos Ap Theresa H. Woodard, D.V.M. Date Chairperson, Institutional Animal Care and Use Committee Deanna J. Lueber, M.S. Study Monitor Date Pl SR E deZmoii John Butenhoff, Ph.D., DABT, CIH Date Alternate Study Monitor Any revisions to this finalized amendment must be made by subsequent amendment. 000453 418-018:PAGE C-63 H9T05aoShaneehrWyh(D1r1i19v,9e,08B5i1d8g.7A10 Telefax (215) 443-8587 ~~ CharAleRsGRUi.vSerRLaEbSorEaAtoRrCi3eHs Discovery and Development Services PROTOCOL 418-018 ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/ CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS SPONSOR'S STUDY NUMBER: T-6295.25 `Amendment 6 - 9 October 2002 1 `ShippingInstructions (page 6 of the protocol and Amendment 5, item 1): {Effective Date: 14 February 2002) The samples shipto Epxyegedn Research will be analyzed using the LC/MS/MS conditions found in the attached pages. sendne m`Tehtishocdhoalnoggeywasbmeaudseedatfotrthhe reqauneasltysoifsEoxfytgheensaRmespelaer.ch to clarify the analytical 2. Shipping Instructions (pag6e of the protocol and Amendment 5, item 1): [Effective Date: 16 September 2002] The e-mail address for Emily R. Decker is emily.decker@exygen.com. Any revisions to this finalized amendment must be made by subsequent amendment. 000454 Reason for Change: a sset 418-018:PAGE C-64 `This change was made because the e-mail address was changed. J] , "lg < 0) defo / rge E. Dearlove, Ph.D., DABT sociate Director of Research yond imid Date Ray Assoc G. York, ! Director & _gaecsor. DABT Date sgarch A LO) i in DenaC. Lebo, V.M.D. Member, Institutional Animal Care Date Miacwaciplantdl DeannJa. Luebkst, M.S. `Study Monitor otto Date G2 + z=: lode softer POAT John Butenhoff, Ph.D., DABT, CIH Date Any revisionstothis finalized amendment must be made by subsequent amendment. 000455 E en PrePcriosvenRRREsesearcSh EARCH 418-018:PAGE C-65 LC/MS/MS System and Operating Conditions (Turbolonspray) Mass Spec: Interface: PE SCIEX API 3000 Biomolecular Mass Analyzer HSaCrIvEarXdTiunrfbuoslioonnpSuprmapy Liquid Introduction Interface Computer: Dell UltaScan P1110 Software: WPiEnSdcoiwexsAnNaTlyst 1.1 HPLC: HewlettHPPacQkuaartdP(uHmPp),Series 1100 HHPP AVuatcousuammpDleegrasser HP Column Oven HCoPlLuCmnCoTleummpn.::Ge3n5esiCs Cy (Tones Chromatography), 2.1 mm x 50 mm, dj IMnojbeicltieonPhVaols.e: 10 uL (A): 2 mM Ammonium Acetate in ASTM typeI water FMloobiwlReatPeh:ase (B0)3: mMLe/tmhiann.ol Ti0me %C A T%B 0 20 0 0 100 100 75 Ho 0 6 4 4 iItnsmtaruymebnet mm x 30 npeeccefsosramrayncet.o adCjuosltumthnesHwPitLhCdigfrfaedrieenntt diinmeonrsdieorntso (oep.tgi.mi2z.1e mm) and columns from different manufacturers (Keystone Betasil Cyy Obtained. etc) can be used, provided equivalent chromatography is Tons monitored: Analyte PFOS Mode negative Transi4ti9o9n 5Mo9n9itored RetenAtpipornoTxiimmaet(emin) 440 000456 X=2 oi Eo0n2co1m0 E en PrPercovReenseRRarsEsSEARCH 418-018PAGE C-66 On the abadtacyh-otfo-mdoabyilbeasipsh,asteh,e retention etc. times may vary slightly depending un TFhxeamfpollleowTiunngevaFillueesPaarreampertoveirdsed as Instrument to instrument. Also, these an example. values may be Actual values changed from may tim vary from order to optimize for greatest sensitivity. e to Sm in rTOehnpiceseattteuhdneeaisfnlnseetcriesusmtsehanertnyiustsoteeudnnesdduu,rretihnoegptoripomtuatilimniseezneasdniatpliyvasiritasym..etTerhse anreinsagvepdroacseadu"rteunmeafyileb"e Tune File Parameters CIoSn-ltorsoprlasy DPF-PD-eFcolcuusstiernignPgotPeontteinatlial ECPE--ECnotlrlainscieonPoEtneenrtigayl CXP-CollDisFi-oDnefCleelctEoxirt Potential CEM-Channel Electron Multiplier 42S0et00 51.0 2300 100 EN 5 300.0 28000 NGeabuslFizleorwGsas Set 12 Curtain Gas Collision Gas 13 4 TIS Temperature 350C Calibration Procedures 2 Isntjaencdtartdhe(psraempearvedoliunmMee(ObHet)weinetno 10 the to 20 uL) of LC/MS/MS, each calibration b. usUstsiaenngdlaitrnhedearca,upUrpvrxeospwreiaiargtehetgseeodnfestrtwaaatnrededasrydfsocrtuermev.aecshfAosnreytqucbaaynltiilbfirinceaatrionr.egrLeisnseioanr bfaelleixncglouudtesdidferom 3t0he%,calbiabsreadtioonn ciutrsvec.alcHuolwateevderc,onctehanettitrooanttaslitonanun,dmmabraedyrs oOfftchaelitbortaatlionnumstbaenrdaorfdssttahnadtamrdasyinbjeecetxedc.luded must not exceed 20% The comelation coefficient must be 20.9925 (20.985). (1) for calibration If calibration rest curves generated | outside these So Ei Bean, usa 000457 ey2en8com5 E en ProPrcovReenseRRareEchsSEARCH 418-018:PAGE C-67 limits, then appropriate steps should be taken to adjust instrument operation, and the relevant set of samples must be reanalyzed. Sample Analysis Inject the same volume used for the calibration standards (between 10 to 20 uL) obfe eaancahlyszaemdplien,dufpolritcifaitcea.tion, control, etc. into the LC/MS/MS. Each sample must a. Standards corresponding to at least six concentrations must be included in an analytical set. b. Inject inject an entire standards set of standards (six) at the beginning of interspersed about every 5-10 samples. the All run and sample injections must be bracketed by standard injections. c. dTehteermcionnceedntfrraotmiontheofsteanadcahrd sample, curve bafsoertdifoicnattiohne, control, peak area etc. of is the analyte in all standards injected during a set. The standard responses. mneucsetssabrrya,ckdeitlurteestphoensseasmpolfesthaendrersei-daunealfyozuentdo in the give a rseasmppolnesesewti.thiInf the standard curve range. Xez= Rann 000458 Bcoocon APPENDIX D DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 000459 418-018: PAGE D-1 DEVIATIONS FROM THE PROTOCOL PROCEDURES OF THE AND THE TESTING STANDARD FACILITY OPERATING 1. rReactesiptw.erTehoirsddeerveidattoiownediigdhn1o7t5adv1e0rs2e0l0y gafaftecrtectehiepto,urtactohmeretohranin1te7r5prgettaot2io2n5ogfatthe study because the rats were a sufficient weight to go on study. 2. The following dosage 60 minutes late. administrations were performed from two minutes early to Dosage NDuomwbseer Administered Group | WenViefhcicalteion |13SEP00 Day DosfS2uds" | Early 2or Le T15-105114 Conwol | 1220S0ECPT0000| DS4D3,9DG0 33 110195--11000195111144 114400CCTT0000| DS47p,sDG3s 1-4 33 1110-59-11100059111144 224000CCTT0000| DGs2D.s191-14 22 10109-9100109114 Mevalonic |1l3oNSEoPv0o0o| DBG5120 Acid Conwol | 22 SEP00 Ds 72 TISI1S0,91131517 3 1515-11528 12800SEcPT0000| DSD43S.S060 32 11150269-111019552288 114400CCTT0000|DS4D7s,D3G1s1-4 33 11150159--111019552288 t26o0NCoTv0e0e||DGs3,B96.011-14 22 10109-5121079528 TPoFmOgSk+s || 21265SEEPP00D0 BDS919 Mevalonic | 28 SEP00 S15 37 1152190-91301543 2 11529 11543 Add | 114000CCTT0O00|| DDSG4s32.-04G0 33 1100992299.1010994422 214400CCTT0000| DDGss1321.14 23 1101952299-.1101953423, m+MgevaalPonFiOcS || 2126SSEEPP0000 DDSS199 7 T0109-9130445335 3 1154411557 Acid | 1S0E0PCTO0O0| DS4D3S.SDG0 32 1H0i9s46e3. 1101955567 114400CCTT0000| DS47S,3DG1s0-4 33 101914534.4 1101955567 Cholesterol oxovoo| pDS2105 22 TI1S09512571 a DS uCsomerdola_s|an abbr1ev0iaNtoiovneo0r|day of sDtuGdy.18DG 7 uscd 5 a2n abbreviaion1f0or96d7ay oF (presumed) gestation. DL is useda an abbreviation for day of actaton. 060460 418-018: PAGE D-2 DGosraogwe | Mdemificaion 1P6FmOgSk+g || 2218SSEEPPOO0D Cholesterol | 017100CCTT0000 02I1N0oCvTe0o| 7 Zmeke FOS| 1027SNEoPv0e0o| + Cholesterol |21810SECPT0o00| 120CTO0 | sD8s DDs23:s DG2G0.3DL2 DG2S1.sDL2 DS4D4S.S0G0 DS45.0G0 200CT00| DGs9.11 o0i1NNoOvVe0o0| pDaGa6r 0127NN0OvV0000| DS 50L,7DtGs 4,5. NDuomsabgeer AEadrmliyniosrteLrueed| Rat Number 72 T1I5S7823-1111558855 22 u105s84 22 1097120,98130973 27 1138140,98151585 22 11150869-. 119019549085 2 1099100,59104592, 2 1010-99190819859, 22 1099171.59110998 2 11591-11599 2 Liss `bTehceasuesedetvhieattiiomnesddeivdiantoetdadwvaesrssemlayllafafencdttthheedoeuvtiactoimoen oorcciunrtreerpdreotnatnioonmoofrtehethsatnudfyour days of the approximately 60 to 80 day dosage period for any rat 3. Aretcloeradsetdofnoeretvheenftoolflodwoisnaggreatasd.ministration and/or postdosage observation was not DGroonupe Idenificaion Dayo Stuy [U VehicleCT onwol__|_ 28SEPO0 | [2 MevaAlciodConntriolc| _285EP00 | DSI5 DS15 |11502-1151|2 |11513-11524] Tbehceasuesdeesvuifaftiicoinesntdiddatnaotweardevearvsaeillyabalfefetcotetvhaeluoauttectohmies poarrianmteetreprr.etation of the study 4. Dosage administration was not performedforthe following rats. DoGsroaugpe Ienificaion AdmDionsiasgteeNroetd Study | NuTmabrer Tm PFO + Cholesterol | Cholesterol | 78SEP00_|DS15 | 115% [00 imgrgPFOS TT PFOS |orocT00|DSI8|11623 | `bTehceasuesedeivtiwataisonassdiindglneootcacduvrerresnecleyfaofrfeecatcthherato.utcome or interpretationofthe study. 5. OMenva1lOocntiocbeAcri2d0,0w0e,rDeSad1m8i,ntihsetefroeldlotwhienignrcaotrsreicntGvrooluupme3,o1f.6temstg/arktigclPe.FOS + 000461 418-018: PAGE D-3 Pl mL) (L) [ssa mss Te 5 CsTrTy `bTehceasuesedeovnilatyiofonusrdriadtsnowteradevaefrfseecltyedafafnecdttthheeaodudittcioomnaelovroilnutemreprweatastisomnalolf t(0h.e1sttoudy 03m). 6. OPnFO1S0 +OcMteovbaelro2n0i0c0,AcDidS,4w3eroer aDdGmi0n,israttesre1d09t4he30t.h3r2oumggh/1m0L95c6onicnenGtrroautipo4n,o2fmPFOgS, raadtmhienristthearnetdheth0e.400.0m8gm/gm/LmLat c5Sonmcle/nktgr.atiAopnporfoxPiFmOatSealty520mLmikneu.tesThleasteerdtehveiraattisonwsere did not correct daodsveargseelwyasafafedcmtintihsetoeuretdco1mealolroifnttheerprraettsa.tion of the study because the total 7. Ogrno2up0(NGorvoeumpb7e)rr2e0c0ei0v,eDd L1.39,mrLato1f1t5e8s9t airnttichlee2ramtghe/rkgthPanFO1.S5 +mLC.holTehsitserdoelvidaotsiaogne doifdexntortaavdovelrusmeelyreacfefeicvtedthweaosustmcaolmleaonrditnhtiesrpwraestaatisoinngolfetehveenstt.udy because the amount 8. Clinical observations, the following rats. body weights and dosage administration were not recorded for [GSrouop ] lgenitfoicuaion 7 T6 ekg PFOS 5 | OoTNOeV00|oDamy obsfeS65ura | sane| 1103 DDGG 1199 111002421 07Nov oD GDG2112 1111064437 DGG912 1l1e6s4s8 DGGoO 111665510 DDGG i120 111665523 TROVE DDGG1120 T11o6s5ts DDGG i1I1 1111665576 DDGG 1110 1111665589 DG 10 11660 `bTehceasuesedesvuifaftiicoinesntdiddatnaowteardevearvsaeillyabalfefetcotetvhaeluoauttectohmeeseorpairnatmeertpreertsa.tion of the study 000462 418-018: PAGE D-4 9. Data for the following rats were not collected due to a computer filing error. TGorvoiuspe Iaenificsion Rat Number [1 [V16emaekEPCRo+MneOvarloSonisl|| Acid 2008SEEPP0000 | DDS7T TiTs0IrS-iTt1s5i63z] | [cdArosa 3 os me e| These deviations did not adversely affect the outcomeor interpretation of the study because sufficient data were available for evaluation of this parameter. 10. The feed left and/or feed fed values were not recorded for the following rats. GrToouspe tdenificaion Duy of Sue 6Memvga/lokngiPcFAOcSid+ TENOVHD DG21 0939 2MmepvlgonPiOASci+d SEF TIS These deviations did not adversely affect because sufficient data were available to the outcome evaluate this or interpretation parameter. of the study 11. Matemal behavior was not recorded for the following rats TGroosupe Ideniticaion [ [2 I ie"vVClheoolnneisctcekAroceliCCdCooomnnlttrol ||0OTi9NNNOoOVVV00e00S[|__bDDLLLisT |06i23,m10i674]| 0967 TERE PROS + Mevalorie| 0272NNO0Vv0000 bDLLsT cit LTiosoer? `These deviations did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. 000463 418-018: PAGE D-5 12. =Eom The terminal blood collection data (time collected, and date) was not recorded for the following rats. volume collected, performedby [a E re |r e|] [6 T7.6 mg PFOS +Cholesterol| 03NOVO0 | [8 1 OsmghgPrOS C0 TT TmehgPrOs TT 2aNovoo| |22novo0| G21 bLs DLS |__10980| | iter | | nem] `These deviations did not adversely affect the outcome or interpretation of thestudy `because the blood was collected and available for evaluation. 13. On 31 PFOS October 2000, DG + Mevalonic Acid 21, the dosage matemal liver weight for group (Group 3) was not rat 10932 recorded. in the 1.6 mg/kg This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. 14. The pooled litter weights were not recorded for the pups of the following dams. Ls TT odmghgPROS |mNoveo| bis | tise] `These deviations did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. 15. 2Onmg1/9kgN/odvaeymPbFerOS20+00M,evDaLlo3n,itcheAcniedcrdoopssaygoebsgerrovuapti(oGnrsofuopr4r)atwe1r1e55n4otinrtehceorded. `This deviation did because sufficient not data adversely affect were available the outcome or to evaluate this interpretation parameter. of the study 000464 418.018: PAGE D6 16. Tfohlelowweiingghtdaomfs.the pooled liver samples was not recorded for the male pups of the [Sor| wewtonn |oe |ourorsuay|serene| [0TT VaeMheviapclloenCeicoAmscridl |2B5NNOOVVOOD0| DDLLsS | tTi15s97: | Tbehceasuesedesvuifaftiicoinesntdiddatnaotweardevearvsaeillyabalfefetcotetvhaeluoauttectohmies poarrianmteetreprr.etation of th study All deviations are documented in the raw data. / CAN Te ARasymsonociate DGi.reYcotrokr,ofmR6es.eaDrcAh T Date and Study Director 000465 APPENDIX E CERTIFICATE OF ANALYSIS 000488 418-018PAEG-E1 Certificate Of Analysis Ti his ow me FC-95, Lot 217 Mar 9,c 20h 00 RichM.aParyfder aHNMR, iPE ee ti2o. Tr SRCRSOR | gmp------ `Additionally,theisomerdistributionofthesamplewasdezerminedusing VP-NMR techniquesandfound t ERE CF3(CF2)-CF(CF3HCFz5)0,; K EE `wherex+yFiHsCF{CFmaijnlyr5,anSd0x7 0, y #0) 53% P [emp|C ires| (Alpha branch.where xis mainly 6) Comp EETo (butylbranch,where xismainly4) CFy-{(CF: (CFD, 50, K ismai 4,n andl x #y 0) 000467 418-018:PAGE E-2 . SIGMA: w sS nE pBS r aR a I E n DPRio-bNuECVTALORON:ICwAaCIeD CTEACRTTONIEFICATE OF ANALYSIS cas 0: 678-2610 pZFroOorRsNMsoAm: dWOirEcoLKiGaHit:desi1n3d0.1S FORA A: Cyt 00. 3 stor4.1 SA FrieszcER Pr E=EN: WeTRrIEeTeEErNeTTrTTEEIpoRRReYse eron ow2ve0o _T W __w S A SEE TBoEEYnSsR ETtRmEA wa e W Cuma me n veLoN _0 To _A0ToPRw0 emUvoenTi.wTs5s7Y0 yi soc0 oRE 00 Conrom0 s % 0 T3ITaRcAcTaIvOmNance ore ee o0 uy 2000 0 5.2% Do Zast-- REE, Ee Alon services 191720000741/XB1, SHAAER5 5 aur LTtL7 on1a 1 omD eneSSoNes1 uT mse oGe sTewtn A 000468 APPENDIX F HOMOGENEITY AND CONCENTRATION ANALYSIS REPORT 000469 418-018:PAGE F-1 STUDY TITLE One Generation Reproducti`oinndSNtuOdEyLofIPnvFeOstSig--atMieovnailnonRaitcsAcid/Cholesterol Challenge DATA REQUIREMENTS Analytical Method Requirements STUDY DIRECTOR Raymond G. York, Ph.D., DABT ANALYTICAL PORTION COMPLETED ON October 30, 2002 PERFORMING LABORATORY Exygen Research 3058 Research Drive State College, PA 16801 Phone: 14-272.1039 STUDY SPONSOR 3StM. PCaourlp,orMaNte T5o1x4i4c-ol1o0g0y PROJECT Study Protocol Number: 418-018 Exygen Study Number: 023-069 Total Pages: 21 000470 418-018:PAGE F-2 Exygen Study No.: 023-069 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT Exygen Study Number 023-069, entitled "One Generation Reproduction Study of PFOS -- Mevalonic Acid/Cholesterol 3M Corporate Toxicology, Challenge and NOEL Investigation in Rats," conducted for was performed in compliance with U.S. Food and Drug Administration Good Laboratory Practice Regulations by Exygen Research. Elk aDire Principal Instigator Exygen Research Sh \ Raynfgnd G. York,, Argus Research . DABT 4 (ea eA Deanna J. Luebker,\M.S. `Sponsor Representative 3M Corporate Toxicology DaeJf tiwovor Date a7fave Date Exygen Research 000471 Page20r2l yen sy os 418-018:PAGE F-3 QUALITY ASSURANCE STATEMENT le on anon diction Sy ofPFOS Merten AcdChlsr Exygen Research's Quality Assurance Unit reviewed Exygen Study Number 023-069, entitled, "One Generation Reproduction Study of PFOS -- MevalonicAcid/Cholesterol cProontdouccotl, aacncdordaillngaptpoliEcaxbylgeenGoRoedseLaarbcohr'astoSrtyanPdraarcdticOepeSrtaatnidnagrdsP.roceAdlulrefsi,nditnhegs Swteurdey pu DuDRcTo DDareoepmt Phase Inspected Management Sponsor Management owe usw we uum Sepmianar owe wm Lao Phe en = lis fon I. ours mwsan 418-018:PAGE F-4 Exygen Study No: 023.069 CERTIFICATION OF AUTHENTICITY `hTehisrarwepdoratt,a foorr Ethxeygsetnu.Study Number 023-069, is a true and complete representation of . `Submitted by: E30x5y8geRnesReeasrecahrcDhrive Sute Callege, PA 16501 (814) 272-1039 Principal Investigator, Exygen: SEncfiiielnytisRt. :Dgcker Exygen Research Exygen Research Facility Management: RicharAd, Grazfunc,PrRD President Exygen Research `Study Director, Argus Research: reser Raymgyld G. York, P DABT `Sponsor Representative, 3M: DeannaJ.uLucokel MS. 3M Corporate Toxicology Exygen Research Date' 2-~otr-or Due Ly-wov02 Date n Due er 000473 Pagedor21 418-018:PAGEF-5 Exygen Study No.: 023.069 STUDY IDENTIFICATION One Generation Reproduction Study of PFOS ~Mevalonic Acid/Cholesterol and NOEL Investigation in Rats Challenge. STUDY PROTOCOL NUMBER: 418-018 EXYGEN STUDY NUMBER: 023-069 TYPE OF STUDY: SAMPLE MATRIX: Analytical Dosing Solutions TEST SUBSTANCE: SPONSOR: STUDY DIRECTOR: Perfluorooctanesulfonate (PFOS) 3M Corporate Toxicology St. Paul, MN 5144-100 RaymonGd. York, Ph.D., DABT Argus Research 905 Sheehy Drive, Building A Horsham, PA 19044-1297 SPONSOR REPRESENTATIVE: TESTING FACILITY: ANALYTICAL PHASE TIMETABLE: Deanna J. Lucbker, M.S. 3M Corporate Toxicology 3M Center, Building 20-26-02 St. Paul, MN 55144-1000 Exygen Research 3058 Research Drive State College, PA 16801 Study Initiation Date: 0821/00 Analytical Start Date: 0214/02 Analytical Termination Date: 015/02 Analytical Report Completion Date: xx/xx/xx Exygen Research 000476 Page Sof 21 418-018:PAGE F-6 Exygen Study No.: 023.069 PROJECT PERSONNEL TRehseeaSrtcuh.dy TDhierefcotlolrowfionrgtpheisrspornonjeelctfrwoamsExRyagyemnonRdeseGa.rcYhorwke,rePahs.sDo.c.iaDteAdBwTithatvaArrigouuss phases of the study: Name Emily Decker Karen Risha Rickey Keller Title Scientist/Principal Investigator ScientisuPrincipal Investigator Sample Custodian Exygen Research 000475 Page 60r21 418-018:PAGE F-7 ExygenStudy No.:023.069 TABLE OF CONTENTS J GOODLABORATORY PRACTICECOMPLY IANCE STATEMENT woPag2e| CQUAELIRTYTASISUFROIAFNCACUEATSHTETANTTIEIMCEOINTTNY...eros 3 SPTRUODJYECITDPEENRTSIOFNINCEALT.I.O.N... oes 6 T L AOFBCONE L TENTE S... J LI OFFSIGT URES... 8 LO SUMMARY... 2.0 OBJECTIVE... css A 3.0 INTRODUCTION 40TEST SYSTEM... cosmos @ 5.0 6.0 RDEFEERESNCECMOARFTEARI NIAALLPY.T.IT .CAIL ON METHOD... ooo 10 66..21PErXeUpFaarCattiioonnoPrfOCSCtAaUnIdEardsandcFortrific. ation SOIUtOA NS o.oo ---- 10 6:3CHIOMOGIAPRY...o 6:4 INSUUMEDE SEASIIVILY ores s eo 11 11 66..65 QDeUscarnoiafnpIindtsEttXirAuomMaePnnItEatCnAdIiOCpUeoIraatOniNn.g.C.o..n.d..i.t.ic.o.ncsoo.r.o.oos 11 12 7.0 80 EXPERIMENTAL RESULTS DESIGN ccs 14. A 91:00C.0ONRCELUTSEIONNOTSFIDOAt TNA ANs D SAMe PLES ........cc.cocooooonso 14 oe 14 ExygenResearch 000476 Page 7of21 413-018:PAGE F-8 Exygen Study No.: 023.069 LIST OF TABLES Table Summary of PFOS in Dosing SOLution Page Samples... 17 Figure 1. Figure 2. Figure 3. LIST OF FIGURES Typical Calibration CUrVe for PFOS.....cccereccrnrinrr Page 19 Chromatogram Representing a 0.5 ng/mL Calibration Standard for PFOS... 20 CSEhLro0m2a1t4og0r2a)m Rc epresento ing Dosinn g Solutios n Samplee (Exygenr ID: 0200283,21 LIST OF APPENDICES Page Appendix A Study Protocol 418-018 (Exygen Study No. 023.069) and Amendments... 22 ExygenResearch 000477 Page 8or21 418-018:PAGE F-9 Bxygen Study No. 023.069 10 SUMMARY pEexryfgleuonrooRcetsaenacrsuclhfonaantaely(zPeRdOS)doascicnogrdisnogluttoipornotoscaomlp4l1e8s-01fo8r (AtphpeenddetierAm,ination" of R10tehcovearsiiegsnfeodr cPoFncOeSntrinattihoen.dosing solutions ranged from 83% to 105% when compared 2.0 OBJECTIVE The objective of dAomsienng dmsoelun#tti6on this study samples was to using determine levels the analytical ocfonpdeirtfilounosroodcetsacnreisbueldfoniante(PPrFoOtSo)], 3.0 INTRODUCTION hsoilsutiroenposratmdpelteasilusstihnegrtehsuasnaloyftitchaelacnoanldyistiisonfsodtehesedbeteedrmiinnPartoivooncoo]f aPmFeOnSdimnetn:h cdeosing Tnhuembsetrud4y18w-0a1s5.initTiahteedanoanlyAtiucgaulstSa2t1,da2t0e00w,aswhFeenbrtuhaerystu14d,y 2d0i0r3ec,toarrsisgneedopbrortoicosl termination date was February 15, 2002. 4.0 TEST SYSTEM TsRweaesegnateryc-hseovnenJanduoasriyng31s,ol2u0t0io2nansdamlploegsgeweinrebyreEcxeyigvaedn pferorzseonneolnadnrypliacceedatiExpoyngeern Sasasmopcliaeteldogw-iitnhatnhdischstauidny.ofSctuosrtaogdeyriencfoorrdmsatwiiloln bceanKebpet copy of the storage records is available upon request found in the raw datapackage at Exygen Research and g yey 5.0 REFERENCE MATERIAL TEnhveiraonnamleytnitcaall TsetcahnndoalrdogPyFaOndSSawfastyrSeecreviivceeds at Exygen on May 17, 2000 from 3M RavsuttReees n 000478 PagBeoosro2r! 418-018:PAGE F-10 Exygen Study No: 023.069 `The available material PFOS information for the was stored frozen. reference material is listed below. The reference Compound ExygenControlNo. PFOS SP248 TCRNo. SD00Y Purity (%) NA `The molecularstructure of the reference material is given below. PFOS Chemical Name = Molecular weight = Perfluorooctanesulfonate 499 (CaF17S057) Expiration Date 01/01/10 i CoFy T --o Ndeortiev:edT, hisepnoetuatrsasliummolpeecruflleuoaronodctsatnaensdualrfdofnoatrem [froCm1wSyhOiKcFh],PFmOolSec(ualnaironw)eiisght 538. 6.0 D DESE CRIS PTIC ONOORFAI NALP YTIT CAALI LMEOTHN OD 6.1 Extraction Procedure Each sample was diluted in methanol prior to analysis by LC/MS/MS electrospray. 6.2 Preparation of Standards and Fortification Solutions Standard standard solutions of solution was PFOS were prepared at prepared on January a concentration of 100 10, 2002. pg/mL by An individual dissolving 10 stock mg of the LO standard (corrected pg/mL fortification for purity and/or standard solution salt content) in methanol. was prepared by taking 0.1 From this solution, a mL of the stock and bringing the volume up to 10 mL with methanol. fAort0i.f1icuatgi/omnl.stfaonrdtairfdicaatniodn bsrtianngdianrgd twhaesvoprleupmaereudpbytota1k0inmgL1.w0itmhLmeotfhathneol.10 Apg0/.m01L pg/mL 10 mL standard was prepared with methanol. by taking 0.1 mL of the 0.1 pg/mL standard and bringing to ExygenRygenReRseesaearrch 000479 Page 100of 21 418-018:PAGE F-11 Exygen Study No. 023.069 cAalsiebtraotfiosntsaonlduatridosnscoinnttahienifnogllPoFwiOnSg was prepared manner: by dilution of the 0.1 pg/mL various Initia Cone. (ug/ml) or Volume (ml) 05 Dilutetdo (ml) 0 Final Cone. (ug/L) [I ol 01 02 ol 10 10 0.002 0.001 0.005 0.002 10 10 10 10 0.0005 0.0002 0.001 0.001 10 10 0s 10 0.0001 0.00005 The stock stored in standard solution and a refrigerator (4 + all fortification 2C) when not and in calibration standard solutions were use. Documentation of standard preparation can be found in the raw data associated with this report. 6.3 Chromatography Quantification of time of PFOS was PFOS was ~ 4.4 min, accomplished by LC/MS/MS electrospray. The retention 6.4 Instrument Sensitivity Tcohnecenstmraaltlieosntofs0t.a0n0d0a1rdg/ammoLunotf PFiOnjSe.cted during the chromatographic run had a 65 Description of Instrument and Operating Conditions Instrument: Computer: Software: HPLC: Micromass Quattro hima Dell UltraSean P1110 WCiOnMdPowAsQNPTr,ofveesrssiioonnal4Workstation AP200 Hewlett Packard HP Quat (HP) Series Pump 1100 HHPP VAuatcousuammpDleegrasser HP Column Oven Exygen Research 000480 Page 11021 418-018:PAGE F-12 Exygen Study No. 023.069 HPLC Column:Genesis Column Temp.: 35C Cy (Jones Chromatography), 2.1 mm x 50 mm, dj Injection Vol: 10 pL. Mobile Mobile Phase Phase (A): (B): 2 mM Ammonium Methanol Acetate in ASTM type I water Flow Rate: 0.3 mL/min Ti0me %6A0 %aB 10 0 100 70 0100 75 60 40 mo 6 40 Tons monitored: Analyte Mode Transition Monitored Approximate Retention Time (min PFOS negative 499599 44 `Tune File Parameters Controls IS-Tospray Set 42000 DP-Declustering Potential FP-Focusing Potential 510 2300 EP-Entrance Potential CE-Collision Energy 100 El CXP-Collision Cell Exit Potential DF-Deflector 5 3000 CEM-Channel Electron Multiplier 2800.0 Gas Flows set Nebulizer Gas Curtain Gas 12B Collision Gas 4 TIS Temperature 350C 6.6 Quantitation and Example Calculation T`Twheenpteyakmiacrreoaliwtaesrsmoefassuarmepdleanodr tchaelisbtraantdioanrdstcaunrdvaerwdawsegreeneirnajetcetded(uisnitnogt1h/exLfCt/wMeSi/gMhtSe.d cloinnecaerntrreagtrieossniwona)sbdyettehremiMniecdrofmraosmsthseofetqwuaarteiounssinbgelsoiwx. concentrations of standards. The Exygen Research Page 120121 000481 418-018:PAGE F-13 Exygen Study No.: 023.069 Equation 1 calculated the amount of analyte found (in ng/mL, based on peak area) using tphreogsrtaamn.dardThceunrveEq(ulaitnciaorn re2grceaslsciuolnatpeadratmheetearms)ougnetneroafteadnablyytethefoMuincdroimnaspsg/smoLftw(atrhee equations for serum are shown). `Equation Equatio2n: `Analyte found (ng/mL) = (Peak area - intercepy) slope Analyte found (ug/=m(aLna)l. found (ng/xmDFL))x Lug Where: 1000 ng DF = Dilution Factor Equation 3 calculated the percent recovery. Equatio3n: Recovery (%) = (anal. found (ug/ml) x 100 sample conc. (ug/ml) An exampleofa calculation using an actual sample follows Dosing solution sample Exygen ID 0200283 (Set 021402), where: peak area intercept slope dilution factor sample con. = 1380 = 413585 = num = 200000 = 400 pg/mL From equation 1: Analyte found (ng/ml) = [1380 = 41.3545 720773 = 185ngmL Exygen Research Page 13.0f21 000482 418-018:PAGE F-14 Exygen Study No. 023.069 From equation 2: Analyte found (ug/ml) = (1.85 ng/mL x200,000) x1ug 1000 ng = 370pgmL From equation 3: % Recovery = 347000ppgg//mmLL x 100 = 9% Nsloitgeh:tlTyhdiisffeexraenmtplferocmaltchuelavtailouneswasshodwonneinustihnegRrAouWndDeAdTnAu.mbers, and therefore may be 7.0 EXPERIMENTAL DESIGN The set of samples and throughout the crounnsainsdtetdheof2a7nsianmsptlreusm.ent blank,a st of calibrations at the beginning 8.0 RESULTS TInhdeivaivdeuraalgerepceorvceernitesrefocrovPerFyOS+ sitnantdhaerddodseivnigatsioolnutfioornPsFaOmSpleins tahreeddoestianiglesdoliuntiToanbslweasI.. 93% 7%, A typical are given calibration in Figures curve 1.3. and representative chromatograms of a standard and sample 9.0 CONCLUSIONS The concentration and results of this report. homogeneity of the dosing solutions were demonstrated by the 10.0 R RETE ENTT IONOE OFDDN ATATANI DSSAAO MMPLN ES wWihllenbethsehifpipnaeld rteopotrhteisspconosmoprl.eteT,hialsl dooreigsinnaoltpianpcelruddeatfaacgielniteyr-astpeedcifbiyc ErxaywgdeantaRessuecahrcahs instrument logs. Exact copies of all raw data, as well as a signed copy of the final Exygen Research Page 14021 000483 418-018:PAGE F-15 Exygen Study No.: 023.069 aRneasleyatriccahlarrecphoirvtesanfdoraltlheorpiegriniaold foafcitliimtye-ssppeecciiffiicerdaiwn d2a1taC,FwiRllPabret r5e8.tainReedtaiinntehdesEaxmypgleens of reference substances are archived by the sponsor. Exygen Research Page 15 of21 000484 418-018:PAGE F-16 Exygen Study No. 023-069 Exygen Research 9004385 Page 16.0f21 418-018:PAGE F-17 Exygen Study No.: 023-069 Tablel. Summaryof PFOS in Dosing SolutionSamples Exygen D Sponsor D Peak AFnoaulnytde AFnoaluydte SCaomnpel.e Rec DF __ Arca (ng/ml) (uml) (uyml) _(%) 0200283 0200284 3L0off6GTM ((0044mmyy/mmLl)) 25AAUUGOG0 200000 20000 1380 1522 185 205 371 410 00 00 oe 105 00285 0200286 5100f20(f 04mmyyi6mmLl)B )1288SAEPU.G0OO0 200000 0 1551 ND 209 ND 0200287 10f2(008 mgiml) ISSEPOO 50000 995 132 418 400 ND 661 0 105 . 0020000228898 11o0ff2(20(A062m0pmmpLl)) ISSEPOO ISSEP00 50000 200000 2156 714 293 0932 146 186 160 200 3 0 3 0200290 00091 11ooff22((00322mmyymoll)) IISSSSEEPPOO0O 0200292 10f2(040 mpiml) ISSEPOO 200000 200000 867 1079 114 144 200000 1385 186 29 288 3712 240 320 400 os op 3 0200293 020029 310off66TM((0O44mmyymmll))2277.SSEEPPOO00 200000 200000 1495 1423 201 191 0200295 S0f6B(O4mgmL)27.SEPOD 200000 1313 176 403 383 352 00 400 400 101 96 8 000296 0200297 1o1f02f(200O8mymmpmLLO)LONLONVO.V0.00O 20 91 NQ 50000 1002 13 NO 665 80 . 3 0200298 000299 1100ff22((001260mmygmmll))OOILNNOOVV..00OO S000 200000 2046 278 743 0.972 139 194 160 200 7 o7 0200300 020030 1100ff22((003224mmggi/mmlL))OOLLNNOOVV..00OO 200000 200000 863 1056 Lis 140 0200302 10f2(040mgml)OLNOV.0O 200000 132 179 228 281 358 240 30 400 os gn 49 0200303 0200304 1o1fo2f(200(8Ommgg/mmll))IISSNNOOVV.O00 20 95 Ng 50000 1001 133 NQ 665 $0 g3 0200305 0200306 1of2(016mgml) 10f2(020myml) ISNOV.0O ISNOV.00 50000 200000 2082 802 283 105 141 211 160 200 gs 15 000307 000308 1I0off22((002342mmyymmll)) IISSNNOOVV.O0O0 20000 200000 826 1145 109 153 217 306 0200309 1of2(040mgiml) ISNOV.0O 200000 1481 199 399 240 320 400 9 of 100 ND = Not Detected NQ but w=asNoltesQsuatnhtainftihaeblleow(eAstpecaonkcwenatsradteitoenctoeftd hatetchaelicborrarteisopnosntdainndgaradnsal(y0t.e1 retention ng/mL)) time Exygen Research 000436 Page 17 of 21 418-018:PAGE F-18 Exygen Study No. 023-069 Exygen Research 000487 Page 18 0f21 Figure 1. Typical Calibration Curve for PFOS `CCCooonmhtpaoaunnntd oc1f nBeaomer:Tmpa2Fn01nS:7305"8181305245 RCeseganoaen!oCer.asE.vGarnp,3Eho,a Weng 1s Ads vans: oro 7003 418-018:PAGE F-19 Exygen Study No.: 023-069 ; 00 Os to 1s 20 2s so a5 45 45 seoTM Exygen Research 000488 Page 190721 418-018:PAGE F-20 Exyaen Study Nos 023.069 Figure 2. StCahnrdoamradtofgorraPmFROeSpresenting a 0.5 ng/mL Calibration connann nas nom sus - erathoyasdsy i " | |i | TEE RR TE he Ie Tee ee re Expgen Research 000489 Page 00121 418-018:PAGE F-21 Exygen Study No: 023.069 Figure3. Chromatogram Representing Dosing Solution Sample (Exygen ID: 0200283, Set: 0214024) [rp-- eicanion me 2) er01a0n2 wo Pats, | | | an Exygen Research 000290 Page21 of21 APPENDIX G TEMEPRATURE AND RELATIVE HUMIDITY REPORTS 000491 ARGUS 418-018:PAGE G-1 TemperatureLoacnadtiRoenl:atRioveomHu1m7idity Report { Protocol Number: 418018 | Range of Dates: 22-Aug-2000 14:44 to 12-Nov-2000 08:59 | TSahregsetiRraanlge: 7ERT ro | Relaotivoe HuTmoid [---- | | TTToootttaaalll NNNuumubmemroboobfffebHDoaaaurtyrsrs:B:ains: MMoadxiamnum: 19T68o20 1b9863r20 | mo win| ws wm | 7n8s 757006 ||| MNNumberuimmbeerocoffPrFof oPitnnettss iHnT ohGr : 195d s4 90N 9I) | 1955 8(997 .9) Report Generated: 30-Nov-200a0 1402 comments: reeseeeeesessmmstmeneerree rere - nnn REVIEWED BY: ~~ oat: 3 2570) 000492 ARGUS 418-018PAGE G2 TemperLaotcuatrieoDn:evRiaotoiomns17Report Protocol Number: 418018 Range of Dates: 22-Aug-2000 14:44 to 12-Nov-2000 08:59 TSpeemcpieersa:turarte Target Range: ofrSDieaptzeao0J T0i60m0e TeGmapa.l 64F 10 79F Date Time Temp. =Valueout of ange - Hei= gmhp_eLr=aVtaluugrout ofrange Low Report Genorateds30Nov-2000 at 14:10 +These deviations did not advaeffecrtthseouetclomeyor interpretationofthestudy. Thefolowingdeviations) impactedonthe outcomeofthestudyasdescribed: StudyDirector: x 7. 7 Hi Date: 30 hed) 000493 Me ARGUS 418-018:PAGE G-3 Relative Humidity Deviations Report Location: Room 17 Protocol Number: 418018 PRr eneofDao ten 220c g200Teee d 12 Nos v-000005s Range of Dates: 22-Aug-2000 14:44 to 12-Nov-2000 08:59 HSpuemciideist:y rTaatrget Range: wll, Date Ime Time mARH. 30% to 70% Date Time RH. Report GoriaRe:viSeoero2a0E0R107R8ivee Hnuamyfros9 i oeaehotrnas tidac)kvmottoaonomt neemnrre pmrirsteine, StudyDirector: 7| x Date: 20"MAR 0" 000494 ARGUS 418-018:PAGE G-4 | Temperature and Relative Humidity Report Location: Room 18 Protocol Number: 418-018 | | Rangeof Dates: 05-Sep-2000 14:00 to 03-Dec-2000 13:59 I ven | Trenspmasse | Species: rat Total Number of Days: sTotnteroftoy: #2ulewon | msulwen | Total NumbofeDarss Bonts: | % % | | HE Maximum: | 708 702 Mfpinomimmmurm:gwamtmpnnmnener | | | 26o7mp% os Cont ta a 070 Numob fPoeinr ts Low (%): | 0 aon || am e mome 423 (0.0) 0 (0.0) ee es ee REVIEWEDBY: 4 0, bate: J 250/ 000495 ARGUS 418-018:PAGE G-5 Relative Humidity DeviationsReport Location: Room 18 Protocol Number: 418-018 Range of Dates: 05-Sep-2000 08:00 to 03-Dec-2000 13:59 Humidity Target Range: Species: rat 30% to 70% [MC Date Time RH. Date Time RH. =Value ot of pnge High = Value outof range Low Report Generated: 13.0ec:2001Ra.1H.1'4=5R7elative Humidity (%) Les vats tars sc ptm irsonct boty The folowing deviton(s) paced onth ute fhe sad as described sway one LL, -- [mec [o 8 n one: _(3-bec-0/ 000496 APPENDIX H BIOANALYTICAL REPORTS (ANILYTICS) 000497 418-018:PAHG-E1 tents ARGUS Heh AAoRNRoRIES, THC. Data Collected: INCORPORATED 301-921-0168 Fax: 301-977-0433 BEE one ote Suporte 1/10/2001 (215) 443-8710 Ajosceseiconession ggec. "Gp Go SexAgeCHOLEST GGLUtCOSE ae "Ibi-piR HBDLr-eDIR TRWIiG 000498 418-018:PAGE H-2 GYTICS INCORPORATED oes 3019210168 Fax. 200. Ganersour. 301.977.0433 MD 20877 Client: A5BR0UG5IULSDSIHNERGEEHSYAEARDCRIHVELABORATORIES, INC. DDaattee RCeoclelievcetde:d: 12/08/2000 HORSHAM, PA 15044- Date Reported: 01/16/2001 (215) 443-8710 Client No. 1028 Study: 418018 DAMS GD21 Species: RAT A NoucceSp1 esc.s|iGopSnex Age BB5000000333000233011910 111111000885613 111333 FFEF BBB 000000333000333111234 1111110808e680s 111333 F&EF BB 00003300321156 1111066636 1133 EFF Hse%a8n7 Group 13 CMHGO/LDELS_T_GMLGU/CDOLS_E_LDMGL/-DDLIR_ MDGL/-DDLI=R TRMGI/GDL 78533 777368 1573 i233 131515288 8870 152%398 138s 323564 22397069 7788 110023 iis i5s1 2ii1s 7623.3 8185.3 n31a air 28071s BBB 000000333000111588315 111000998111578 223 EF F BBB 08000033300011188887 111080983211088 322 fEFFF BB 00003300118890 116089328s 22 F* MSe8a7n Group 2 7F78e9 111302081 43& a&1s% 42534393 H88i38 ji eiists 1391 31E2d F72e01r38d i1o1e9 10814 39 7Ss 1832372 i92.e5 1t0e8.5 2S.i3e 23%274 3T0a7s.s8 Reference Rannege 86- 31T94- 0 - o9- 3104= Page 2 + 000499 418-018:PAGE H-3 AYTICS 200 Girard Sr, Sue 200, Gainersours, MO 20877 Client: ABRGEUSERIERSNECAORCRHPOLARBAOTRAETDORIES30,1-9I2N1C-.0168DBaatteeFaxRS:eotl3a0lt1s-vc9e7td7et-d'0:43312/08/2000 B2O1R5ERC0Bny d1s0ud- Date RepPorted: . 01/111861/:2001 Crtent wo. 1028 Study: 410018 DAMS GD21 Species: RAT NRoe.cession s8pac.| Gp SexAge GRMOG/LDELST GMLGU/SOILSE LMBGL/SDDLTR EHDO/LoBb.IR E&RIISEL pBBBoooaosasiidddiiiineeesrdh i1aag0e8eas8ss 3333 %%E pole ies 3} 3B 78 iiI1ng FiiSf 89 3 # $ =0m m 3i 3 BpBaedEadliEless IiiNaeN 333%%1 W a3 aa38 a $ 803 3 H sdeeag n Grow 3 H51e m ea3ia EHETE Iss BBBb oooooojaag0iillees aa1t0ee0s:s fff4 fffE BBH BoRoiHIaaNagGes ff ffoF soepan Grow 4 1334#i10 ia8as 1322o #0 i i$ fu #8F0O e3 2 Lf 88a8 iiig i34 88& 33i] s8s1 m0Be 2Se #E2a mzia Reference Range J $= mo o-oo. a. 96 319 0 o 104 Page 3+ 000500 418-018:PAHG-E4 Cltent: JHP3E68gE,UEsuLEeILEENECGOREoPOLoRARAATTEODRIES3,01-9T2H1C-.0168BDGEauEttSeeFaxRSG:eeSap3L0lo1Mer-rE9eb7Ee7e-Ssd0t4-33o1i2/01ne/raa000n0s (215) 443-8710 a Accession spec." GpSex Age CHSOOLREEST GGLeUeCOrSE LgDLe-nDIR HmDLo-nDIR TmRInG 060s01 418-018:PAGE H-5 cttents gug prINCORPORATED 301-921-0168 Fax: 301-977-0433 BEcolr SRATID SHES oveBesrepara, oreo (215) 443-8710 jijoeessiong3pa. GpS-exAge CMHGO/LDELS_T_ MGLGU/CDOLS_E LMDGL/-DpLI|R HMDGL/-DDLIR TMRGI/GbL~~ a Je 96 319 0 0 104 000582 418-018:PAHG-E6 Citents pNrEisASRITNTCAOEYRPLOP RATEDA301-9a21-0168pB2e8FaxS:R3L0I1-T6H7A7-T0433La/0n/000 (215) 443-8710 Fang fosession spec. ap Sex Age BB RR ER T4,TOTALT3,T0TALFREE T3 7o3He FfREhE a ae 7 100 o 3l41 2.5 000503 418-018:PAGE H-7 CIYTICS soos sue so ncn vo on Client: ARGUSSRRIEESNECAORBCRRHPIOLARBAOTRAETDORIES30,1-9I2N1C-.0168DBaAtEeSFaxCR:oEl3V0l1Ee-cA67tL7e-"d0:43312/08/2000 B(2O15R) E4R43-B8a71019044 Date Repaorted: . 01/16/2001 Client No. 1028 Study: 418018 DAMS GD21 Species: RAT AReossession sgpec. | Gp Sex Age BBBsoo0o003o3oe0sa2ni0t?5 MHH11oee0s8sss3 1BbI3 EEEF BB55ooo0oo0stl3ee0ann%iiindts mHHHoeobesselss IBIBEfFF ygoepan Group 13 BSiyTnOeTAL W13 TEOTAL FBRmET EhGRe RagcilgO0eea Ha0 33s.E4d7 g8fo%pr En1L.pYA3 Ga3g:ie80oe8 E 3iseEds S 808260 En 1wakm 38 #Wa0a1: 1 ls LLaBie FRREREELLEA o.o1 888:188n83 o8sms 5BBBoooggbudsd0iIIisssEiEy paIIoNnNmTes 2ffffffof BBBEoooRSdbIiEsEn IaINaEEA 111 ooff Hgeapn Grow 2 gJge8En3f9 1RR75E.ss Ggff se B17R8 20 4 8O0:.3E422 aSaeoiiFfe ea gdhsEs 8 SSaeRt 1 nLgR 8 8 8:4 aAv ERSnH Tahy dnegn aasm Reterence Range nae 3-0 mec 9. 100 0 Page 7+ - pa- 3.41 2.5 000584 418-018:PAHG-E8 Client: ARGUS BIESNECAORCREPOIRASAOTRENTDORIE3S0,1-9n21e-,0168BateFaxm:e3r01i-n97i7r-0e433 BIEL ee Date Reporeeds 01/16/2001 (218) 443-8710 Eg Accessionspec. B0030161 10930 WET RE EEE EL ap Sex Age T4,TOTAL T3,TOTAL FREE T3 TSH FREETA TE 0.00 48.86 0.06 0.03 --_ re! 9 7 100 0 34a 2.5 000505 418-018:PAGE H-9 Client: BA359R5038G,,USSRHEEREIESSNEECAAORRCRHCPHOLRABAOTREATDORIESS,oroTrHrCo.rasTMBDaatteeHaSGeoSnlRl1secStEssRds: 12/08/2000 BUELOEG By 1o0ue- Date Reported: 01/16/2001 Client No(.2151)028443-8710 Study: 418010 DAMS GD21 Species: RAT NRoo:sansion sbipec. GipSex Aas HGAGJ/IDOETALF3NTG/ODTL ALERBEoEfM.LT~3_ENEoRjML RNRoEjbELEL BgBBoooo0oos0lom3os0eni1erg7snse7i1ii1e0ese90s5se?861:p325 f2iFE BBoooooottlaeeillessstiidoeossees s:3pfof tseegarn -- F Ba$1.392E9 EEBH39E 1.EE313 0e.8B5 eoua n3.m72 naens o0a.m30 goas 6Se:hn3 esennnal oToetR Le Jgg::t25 HBie Mresl.s ETEe a3n aana oBEB5 oosocRmjie0einiEnssszls i103e72 iieseee f6 f ffff BBFooooRe0iiEsse i ese Ff `orip Group Sgg 0:1i000 y da selr dooouakRs 272 oa 388o::%m38 sgegooeess mffmdEEmr: eogeeyyh rnvghekm soooullnff W Th EmSon Eap3 LeaRm a oe Setenense nege 3s- Bso- 8gPage 5 + Shsme- B1B3- 000506 418-018:PAGEH-10 ANI Client: ASBRO0GTSULVSRSIHNREIEEESRNAEYCAORDCRRHIPVOELRABAOTREMTDORIES30,1-9I2N1C-.0168BDaatteeFaxRC:eocl30el1ie-vc9e7t7de-'d0:43312/08/2000 HORSRMRN4C . Paad1s044- Date Reported: - 01/16/2001 Client No. 1028 Study: 418018 DAMS GD21 Species: RAT ANoc.cessionS2pac.| GpPSSeexxAhgee T4B,RTEOTTALTR3A,TT0TTAL FBREERET73 TIaAS. BBB5o0ooo0ool33oo00tr1ioa3esd3: 11110000332388888525 777 7 IIF E B oo301oy 10385 7 o00a:.d808e80 3s3A3i:7E3r7 GGf0iu3fsse 2 nndisigp glee 3 oh hE BBB oo0o0e33a0ci1o5es5 111800333888839 777 aaa:oo0ee8 dssaedg 88gi%8l sa. Koepan a8 P80%2 T3ae IWoEn Group 7 FRRERE mi eoo8i:les8 88 88::8B82 on Reference Range ng 3- so. 0-19. 7 100 0 3a 2.5 ApprovedPag--e--10-o-f=-10-I--lo- page --oililfor 000507 418-018:PAGE H-11 GIYTICS ocr sm sre comes wo zn Client: BA25R6GE0USS,ERREEISSNE8EACARORCCHRH,pPsIOoLaARsBAOTRAETDORIES3,01-9I2N1C-.0168bDBaaattteeeFaxSRS:eoLpl30olI1rs-tc9Ce7t7deE-:d0:4-331042./1227//22000010 Citent No(.2151)02844a%8710 Study: 418018 DAMS 1D oP : ' Species: RAT Rheecsension Sp3ee. Gp SexAes CRHPOLEEST GLSUEUCSOSSE IRBS-EhTiR EEBNLRPIR EARMIIES, 5BBBoooooRgii3R0eeT5i4sIs7N1dae0ooe3s0ase8 1111 ppEOF Boast its: if #[Fa0IrT In 8I 33 i3B iuisa3E2 FA BogMEsiie 1k yteogan HE] WEE os hos $ L1ai a1 i89a3 Haneis Group 1 BBBBooooosesnEae Hii11l0se1y9 1IBB0 BPFE BBBBoogoooogiiiggeeeessssses liMHoiorfizr:: 8118 bb Bose Hi IF sseeagn Group 10 [n B FHE aEo ]m] 2j5: 5i#30 a2338 F 8B $ 00 o EB n] 3ii: 3i2i Ep2&iH] $1 a8 W%ee iBsNs 33 0 h2a01i8nn Retarence Range oe = 96 319 Page 1+ 0-0-3. 0 0 104 000508 418.018:PAGE H-12 CLYTICS soci san so commen vo wo Client: 2A8R8GUSSRRIESENECAORBCRRHPIEOLARBAOTRAETDORIES3,01.I5N21C-.0168BDaatteeFaRCxo5l0Al1e9c7Lt7e0d4:5 12/22/2000 O2R0ST3A8N,8"Ba 10044 Date Reported: 04/17/2001 Client Yo(.2151)028443-8710 Study: 418018 DAMS IDs species: RAT hjecscession g3pec." b55B 088g3e330338832aa30s%308 111111118g083s322e5 Bbp5b 88833300333300005e880R002! 11111118888333282 B003ERE 8% seegan Group 11 Gp Sex Age CSHeJOBLEoETST GLSEUJSCEOSSSE IRDRLUS-RTMDIR HHDLE-DUIRRETRSIG.. ii11 FF ii aF E5I0 H.316 3iT i iin Ton m238 iiiii Pffb 52i# 8 811i83%8 8888 ii i $0 aa8 iF 8 138 $ 38 a B 118lea n1ss nWda 8imA pBBB o80eo0033e00ed603:78 1i111t084e81 B1i132 FEEF eHopan Group 12 8#2s0 ania1n s i F#12H i 3s8e 3 fsdhe1s% 23 . ##833 BTaYs 5 0030603 1105 13 F Reference Range ase 2 2a 88 -78M . 8o0- 8o- to3x- rage 2 + 000503 418-018:PAGEH-13 Client: Bje deavEgsuEsBe RpnbIpesNnEBCAORoCRHuPOsLAReBAGTRAETDORIES30,1-8T2M1G-.0168v8Ba2at8te2sFaxRSC:eoEpt3H0ou1Sre-tcE6e7rR7de-Y:d0s4330142//127//22000001 client vo. 1028 (215) 443-8710 seuay: 410010 owns 105 species: mat EPr E PHoamemrnat ter ? 4uGf ponds i 4: SREB 8g a o Gm HI0SRBm T E:mr17 Wr#na8mT me #88 kB HE wwepan Group 13 gFp0&0Wmem g f LT L EBY8 BasB ppPPomaooeemnmemmtmmeiedeeslmnd f1222o:ppfop F B $ow m mmm3o4q3& 8F %oomr BBo3mme Group 2 Eeean RHoa HEeG: 3R5 OBHTG hOEeYs pfPsoaoaamommas iteesds 1C33 bf:x 882g oo0m0wmmm f333F:: # &$=5 8L8oBw croup 3 tyoopun mFoodesWs oTni oEEST OIEs Raterence Range 0M1S 380 -98 aas rage 3 000519 418-018:PAGE H-14 Client: ARGUS EISNEACROCRYPOLARBAOTRAETDORIES3,01-9m21e-0168DateFaxo:r3r0n1i-9r7e7-r0:433 FORE B,3 ---- Accession spec GpSexAge SCHOOLLEEST GGLeUeCsOSELgDLe-nDIR HDmLo-nDIR TmAIma 9 96 319 o o 104 060511 418-018:PAGE H-15 CLYTICS soe. sre soe cutnun io Client: AF RGUS r RIESNECAa ORCRHPOLARBAOTRAETDORIES3,01.I5N21C-.0168BDaatteeFaRCxol5Al0e1T6c7tE7e0d4:3912/12/2000 B(O2R13E)RAN4,437Ba872010044 Date Reppoertteeedd::. 04/17/#2001 Client No. 1028 Study: 418018 DAMS IDS Species: RAT Acfeceessionggec. Gp sex Age CRHEOPLREEST BBB50ooo0ss3ggs0e5ese6se3 i1n 10388e 3 fff FEEEF 8ig esepan !3ss Group 6 SGELUUSRCSOSSE LDRRLV-RDRIR HMDOLT-RRDTMIR TMRTISG. i33Is8E 23$23 3$85 i8H5H 8le%s iars 8033 T3he8a BpB5888o880o333j8d0oea3s5i9e3s3s 1i1100803380888925:5 777 E 7 FREAE EH Megaen Group 7 # 0a 31am 33s 332# 2778 7 & aa $2 d 2? am3 Se s H 1h, 35 s iWEi Biad BBB5 08oo033l0g8:a71egH10en9E9s9 238 OEEfFB fF BEE GE fF Reference Range 5E7I a a $i3 i20 a240820 B ss idag i3 #$ 0 i 8s9- 7a- 80- 8o0- H3n- Page 5+ 000512 418-018:PAGE H-16 CLYTICS ocr sn 0 commen vo wor Client: AORSGUSSERIEESNECAORBCRRHPEOELARBAOTRAETDORIES,301.I5N2C1.0160DBaaEtSeFaxRC:RoSl3Al0Ie16Tc7Et7Ee0Yd0:5812/22/2000 HORERAN, Ba 10044- (215) 443-8710 Datee ReRPpeeoprotretedd:: 04/11771/2001 Client No. 1028 Study: 418016 DAMS LDS species: RAT fRiecession S8pec. 5BBB80a830333g3e0e0e32rn77sl68 111111180888088d82 Bees He seeagn Group Gp Sex AgeCHSOoLtESTGSLeUCiOsSE LMDeLr-oDrIRHMEDJSRL TR -TD RARIIGIE.LA 883 F I 55aE 8 Hi8das 333 rr$ E#0 H3 IY731 8 fF di 2 3i asta BImYe Lia 38 oiunes 5BB8 000o0o0033j30003ss06ae3:d1 1111118008101%29 339 EF 8 fF B8330ses dE Bpa8d33d0es8ds diidtee 3 fF eoagn Group 9 sEB HoI i ik lse 43i$ 2# 3 #0 01 1uissse i ad 8 FH 1 $ 8 B18 ii 3 32 2 85% iBsua 3335 33 1355s Reference Rannsg!e E@H]- 7aPage 6+ 0 8 -0 8 -3doz 000513 418-018:PAGE H-17 Client: ABSRBSGERUSSSHREIEEESNLECAORBCRHPROLRABAOTREATDORIESd,o1.T6N21C-.0168BDaatteeFaSCxoRl3Al0Se16cE7tE7eYde:ms12"/12/2000 BRERA By 1o0ae- (215) 443-8710 Date Reported: - 04/17/2001 Cuient No. 1028 Study: 418018 DAMS 105 Species: FAT Reescension S8pec. apPSseexxAAgaes EBABRMOTAL R3BRMTAL BBRREEETET IESNEe RREARE BBBH 5 oeoodgae3d0es8ta1tE e7 iid1e0es3e:3er8 TE iiifff iBBYefnas ooidaueeeense Ga SS oEninaoyod 8 onLraini og 3oge:a8ees8 8 BBN IE IF setoag n ah SMa TWEugdle 3 a Tse vm nLaams og oTaye Group 1 BBBB ooooosgdnoseesso aHH110iee19 181130 bE BBBBooooilooeallssee HHHHeegen iB1188 fffF BosiEss He 18 steeparn Group 10 e 0n0.88 na B7n 9.E66 ga aE oS0o.Ese8 gE xea pBap 4oo0.nyB31 om SaGG15nd8 2 fwaae SEeSyEai vegoenmp gggukrek TaE8 g CaanrTam Luaun aann Reference range 9s 3-0 seo 7 100 Page 7+ o-oo o 3.41 s- 2.5 000514 418-018:PAGE H-18 Clients ECgurgiGyaLBLIEENYTCOERTYSPOILRAARCTCEADTS,ORISS3o,5c0105r.5Ss0eyBDeaaottessSuuSaeer20Bs0sSscaeHsrnnne1s210w/o20s0o0m Er Date Reparved. aefisfaces client vo. 1028 (215) 443-8710 study: 410010 Dass 105 species: mar TJ TOFCM pao BpI iFNo.eReOeMsa eRe1eEn HngOEfi UGgSgE /CDRfpoLT NR#dG/iE DE4Lg PG/ecoaMgEmELENE GrnL/TMEEdL rNGa /g8oDLnE3' IP I IHio oRny nEo HHHHiEEE tg$geg2ie SeBpriEFme Sg3eEEg eL pmg RHofb8a croup 11 wreyan HHEOoHHmE CEET OORLEE TThRE, P [ J SoE BMn E i We fOBBE eII geEefglue a wogeume ooonnfge LInLREae goooEHmm -- rweran BE hmeEe HCEE ThEE aTnR astotmiorse w10nm 3 7 P 3 ea A P anes ode or oh ous 12 rage 8 + 000515 418-018:PAGE H-19 (52/04 (05 I ---- Client: ABROGSUSBERIRESNTECAORBCRRHPIOELARBAOTRAETDORIES3,01-9I2N1C-.0166BDaatteeFasCReoEl2G0l0Ae-cI0t7N7e"de:ms12/12/2000 HBORSIRANNC: BTaad15044- Daattee ReRpePoprotrteedd:: - 04/2177/2 001 Client No. 1028 Study: 418018 DAMS 1D5 Species: FAT ANoc:cessionSp8ec. | 5B5b0oogaGoa3iii00ee6ess33ss3s 1jdHi1ied0gee5sll5 5 oo3ezs 11s Hoepan Group 13 GpSexAge 1B133 EfFF 1133 FfF TU4G/,DTL0_TALTN3O,1D0ETALFBROEMELT3 INSOHMI 0882383 gi3e EshiHds ged 0.76 oGe8s8 sas o98m2 aes si 6 IR 2d 77 aTs ee T8ass Tnays FRNeErEmLTi 0.25 o0Sr7E Taegs BBBB0aoo0oon0llosoaassss2:d 1e11000e30332s821 2222 %I Ba30ssE 188 3 fF Hoapne Group 2 $d#i2a0g2s s8aa1e.lia2s8 08S88%Rp3 bSgroYAEs nu1mnf; ad 3% aides 98 28 8] 31.86088 g8a.5a884 53322 1n.0e62 aaomd B8BB ogo0do0iejj000sasssissIos7 e111000e395s428:10 333: 3F Keopaen Group 3 0aa.0i088 Sis essgaee.s3sd7 08S.:68E53 8% S1p1Rd2 8 809.k300 8 eay8 TS em m ess i 1am aan Reefeereence Rang9e 33. sBoo. o8 age 9+ s57h E1R9- 000516 418.018:PAGE H-20 GIAYNTIICS scores ss cans vo om Client: A8R0SGUSSHERIRERSNYECAORDCRRHIPVOELRABAOTREATDORIES30,1-6I2N1C-.0168DBaatteeFaxCR.oOl330le1e1.cP9te7ea7d".:045152"/22/2000 H(O21R5S)HAM4,457P8A71010044 Date Reppoorrtteedd:: . 04/17/z2001 Client No. 1028 Study: 418018 DAMS 1D5 Species: RAT ANcoc:essionSbipec. | GpSexAg9e TBae,yToOETALTR3E,TDOETALFRBEeEwLT3 TNSoHpe 5pBB8ooo3aoo3g33%0eeeeiiiisddl i111088e388425d328 i14 iEF 1 80827337 SdeIdrHde ea a o2 ie onnsags Bpa83g3%eeisl 1i88e22 iiF 8So5d EasEt 88:%38 a ER soeoapn S3E efaasee oemm Lmaises Group 4 FNReEjELT4 0oog3nnfs 8B aEzR FBB o8oR%o%j3eEoeeseEeEso 10987 11883388s 5 EF 33 Bpa80g3esesi 1i8s38e8 33 fF seoagn Group 5 32H.88E0 hgh 1oaES0g8e.iny4s88 B 1N.E00 n 0L.5R2 18 diz 0.87 a87n8 nndEOWeheR 8 aE 8 8 88p 2h.0e87 eI1I.7se C1aer s3i a338) 8poosj3osszeess 110808777 FfEF Reference Rang9e 60:.8080 530:.731 0S.3i6 0u.6g2 0.21 33 - sBooo. 0 8 -7s.h 1BR9- rage 10 + 000517 418-018:PAGE H-21 Client: A30R8GUSSHERIRERSNYECAORDCRRIHPVOELARBAOTRAETDORIES30,1-8I2N1C-.0168BDaatteeFaRxC:eocl3e0lf1e-Vc9e7td7el-d"0:43312/12/2000 B(O2R15E)RAN4C43-Ba871010044- Date Reppoorrtteedd:: - 04/17//2001 Client No. 1028 Study: 418018 DAMS LDS Species: RAT fAicecsession S9pec." 5B5o0od0ol3ea0ed3ita?es 11100059878933 5 G030els 10562 K3ean Group Gp Sex Age & F fF 6 1B4BTEOTAL 7R3U.BTEOTALFBRoEiENL73 1N3ew a08.88080 e875n1.6d88 aed 9338 b60%0E ni oegs 3 G7 WTeias a Tsae FNReEjEhLTA 800.g325 3 a3n% BB5 B 00000000333100008d3s3l9e0o0s 111100003339888989s5 777 EF 7E B 0630631 10838 7 F Keegan Group 7 8 a0.000 ea s3508e:.98y80 el G80.s33 Gs na1l33f2 nd 8 o0.R9 83 8:38 say Ged id 83 Tai3 TWenEis e5w6 Lnasis oaadn BB5 B 0000030033330000885877773:1 1111113000030088:088 53 EF 3 B 003037 1603 5 F Reference Range aaD 1l.ee0ds5 Esa8R 1dg6se3 0o0.7Bp9 oie 1 gass 830.843)7 Rd a8 ss nis a 8% 33 - sBoo". 8o- E$O57N5 1.9- Page 11+ 000518 418-018:PAGE H-22 Client: A0AR2EG8USTRER"REISNECARORCRHEPOLARBAOTRAETDORIES3,01-9I2N1C-.0168DBaatteeFaRxC:eoLl3I0l1Ve-Ec9St77Ye-"d0:43312/12/2000 BBERERMS Bnad1004e- Date Reported: - 04/17/2001 Client No. 1028 Study: 418016 DNS 105 species: RAT Rhesceession s8pec. Gp Sex Ade ReAy,oReOTMTAL 1N3aImeTAL FRReEEpTS REoNhe RFRERTECEI B8B50o000003g3300i052777e888 H1g181o%t0t:0 5835 kfEFF BER 10 fF afTIa3pes ashseeesaseess gf03d8fss L1pL.aof3s5 oog0.dne60 os ese 8 BE of Nteeagr Grou a sos BTeri: gTenm Luies aage pBB eooooaojd0lsseese: Hie110eee00 533f%fEF BBBBoooooodnddlmdeee AHiHeeEere 3333 Of OF soeparn Group 3 a8E 9.i%99 SdHsEirlme 0m o048us L, p2.e23 o0 8od:me3 aa gfeg3sg hg5 heEsEt 8 28L38e0 nrnBiinhsp oooonddm a He STaete ase8s Luayy aps Ret. Range erence ae 3 so. o- so 1a[ 7 Sage N i1i00or 12 o/ 341V 2.5 000519 418-018:PAGE H-23 Client: A25RSGUSRREIESSNECAEORCLRHPLOLRABAOTREATDORIES3,01-9T2e1-.0168BDaatteeFaxSG:eOl30sL1s-c9I7e7sS-s0:43312/14/2000 HEOSRSNEAN. B_ Client No. 1028 19044 Date RepPorted: . 01{/186//2200001 Study: 418016 IDS MILK Species: maT hes EeSr P Sex Age HOLE: BBBBBo0oooB03ninn1S0is3ie7 tI1iI0eN9aee0es6 111iiokkf}F S2iiiS6 TTT Grow 1 tsoegan Ts BB5ooo0oo3mns0ieseiHH11t ae0a1st9 11de0epff 577 BBBBoooodoisgsceeee HHMHateeas e1118 ppfF 4ogs BOGS HA Bo 3 tseoan #533 Group 10 Reterence Range 8Page 1+ 00052 418-018:PAGE H-24 tient: y5gus porta amar INCORPORATED 301 TS -921-0168 BE Fax: 301-977-0433 BERERAN. $a 1004s (215) 443-8710 Date Reported: 0 i 136; J Nos 2 P 9 ReTBL -- B 0031088 11029 1F 18 oT 2 000521 418-018:PAGE H-25 ANI& AYTICS 200 Girara Set, Sue 200. Gainrsourg, MO 20877 Client: HABFORoRGESRURSTaANtR.EiIESNBECaAOR3 CRH1PsO0LRA4B4AO-TRENTDORIZS30,1-9I2N1C-.0168DBDaaaEttSeeFaxRSS:eoEpl3L0ol1Ire-tcS9e7tE7de-E:d0:4-330112//1264//22000010 Cuient No(.2151)028443-8710 Study: 418018 10S MILK Species: RAT NAocscession Spec. | Gp2 Sax Ag9e GSROOILBELST TTTTTTTTTTTIIITImem--ee-- BBBpB 0Oooo03Nee1n0Ell4i2 eR1109ss821 33333 kOffFFFF 535:$0 Hogaen f3 a Group 2 TTT pBB ooeoadtnoss7sa1g0ee9s2:8 333 foFf 138s steogan a33 Group 3 pBp8 eoaoonsnntgoaesao 10957 ieenees 2f5fBiof 28$3, HpR oFnEieEs ine 2 388 seteagnr 31s Group 5 Reference Range Hi s- 96 Page 3+ 000522 418-018:PAGE H-26 INCORPORATED B PEEr LE gros (215) 443-8710 BREE SERENE 10/10/2000 301-921-0168 Fax: 301-977-0433 pute Reported: o1/20/2 /16/ ANocscession S2pBec.| GpP Sex Ag9e GHREOJLBLE.ST TT s 000523 418-018:PAGE H-27 ANTE. Cltents psgus somos GRATED ILSEGAE HSL INCORPORATED 308SuEziy DRIVE 301-921-0168 Fax: 301-977-0433 Date Received: 12/14/2000 NAocecessionS3Bpac.| GpP Sex Age GMHGO/LDLE.ST B 0031070 11008 8F 17 TTTTTTTTTTTTTmmmsmmsmeeeeee EE Aprovred opoNL Datete -------5-tlLexZi/ 000528 418-018:PAGE H-28 ANI Client: AFRrGUS RIESNECAORCRHPOLRABAOTREMTDORIES30,1-9I2N1C-.0168BDaatteeFaxRC:ol3A0l1e-Tc9t7E7e-d0:43312/08/2000 R(O31R8E)RAN4,4sB78a71010044 - Date ReRpeoloprotretedd::. 01/16/2001 Client No. 1028 Study: 418018 PUPS GD21 Species: RAT ARecscession s#pec. 85B80880033380023313187] B 0030370 111808333808218 10s0s BBB B 88030333300333532321 883035 111880333880285 18328 JrEH Group 1 GpSex Age CHHOoLjEoST GSLeUysCcoO.SE LMDeLj-oDrIR HHDELU-EDRIR TREIRGI.S, 111 1 EImH2 28 38fr23) 58 3i58 3 frii}f i 33a i 111 i EH81 8 3&88 & Fei3 3% bBir) if 3$35 3% 36 5en 3aHte 3Fr BBB o80oe0l3300e%2ai7nd3 8 8330272 1111110888i30 itis 111B32 13 BB5 88830333300023277008 B0638%a3 11188182800i 1163 111333 13 KLoegan Group 12 aE57e 8 5ia % 3a& # 1iit6 # 3318 38 88$8 3382 55 383 El iFiiea) 33381 EH 5 8s 7H8s1 m3s 1na4s nilss Reference Range s48- M 74- 8o- 8o- hs= Page 1+ 000525 418-018:PAGE H-29 ANI Clients ERFTRETLarS BEeIENCEOASRPOPRATIED I301-9a21-0168paatteeFaxRE e:ep30oe1r-Tt9e7r7t-s0433oasserzo0n Client vo. 1028 (215) 443-8710 Study: 410016 PUPS co21 Species: mF FJaEnitor 3 PFSaoe mpuun lm n4kf OESg gFI gr hee& pavib #@5 iN#E re mne# i[[oIhongnonaannnimseeE ioHH&fo gg00588FFE#%o&H x0xi H&0n zon Group 13 rweegaen aE oBmyy EEeOETewOW PE I B ooiouai mnneE e tJomEs 23 | pon ian 1 gg ggoog ma#54 9ow 8# 50#woHu omBo0&%z #x p paat g ie f2 g 8 %085 0# o&n 0 3% awn2 wseyan Proir owY ali EreYli OER OE Retezence Range 9 @- me e- o- a. 96 319 0 125 ye 2+ 000526 418-018:PAGE H-30 INCORPORATED 301-921-0168 Fax: 301-977-0433 (215) 443-8710 ANcecsessionSip)ec. | Gp SexAge CMHGO/LDELST GLMGU/CDLO.SE LMDG/LD-LD.IR HHGDJLoE-.D.IA TRMGTsabL 9 96 31s 0 0 12s 000527 418-018:PAGE H-31 ANI @ Clients ABNGUSEBIEE NSCEOEP RYPOJRABAOTREMIDORITS30,1-9721G-.0168rBeEtsFaxS:ol30i1e-e97t7e-d0:433 LL bvbommovbuson Stems wo(n2152)078443-8710 Study: 419018 UBS GOZL Species: BAT fE ceseion TRgpe ?Se eGIT OLEST SGLCeSeE i hin R[RUDR nme PBTBFBa0iao0ot3n0nem2in4nn9 i1Nd e09n5ed8 f}:|5 5F#wR 2o4Eoo T6E #32 3Em EE T0B w1HE3BE E33B4 & 5[iRmaEtEe ClEag: ## 44 EEF EEHZ sreayn H FEEFPn OhEa hOFa OW Sp gjiBBooooimntnoiipdeenss wn lloeegnee f s 42g2 0s 0822 w %8#0m3%I 0 18B2 EBLooEtihIaaiSgil ddoossree0 qa a 05008%# 30%% 0%B vroyr HFr HmrY OPESe OPEe aHi aroup EN 9 @- mo 96 319 ase + 3-8-1: 0 o 125 000528 418-018:PAGE H-32 ctor: 2agus,passo SA rt aR rB8e2 SERSSET 00/2000 INCORPORATED 301-921-0168 Fax: 301-977-0433 (215) 443-8710 Accession spec. B0030265 10985 GpSexAge CHOLEST GLUCOSE LOL-DIR HDL-DIR TRIG 7 64 90 47 16 28 000529 418-018:PAGE H-33 co ST a i per en INCORPORATED 301-921-0168 Fax: 301-977-0433 RORSEANC Pa 10044 (215) 443-8710 Date Reported: 01/16/200: P iss: nL F--Accession Spec.| GpPSSeexxhAogee T4BU,TOTTOALTALTB3,ETNOTALFBRUERET73 TtSHoh B 0030217 10901 1 0.00 0.00 FhRhEE,14 TT 000530 418-018:PAGE H-34 Client: 5A0R2GUSSuERIEERSNYECAODRRCRIHPVOELARBAOTRAETDORIES30,1.5I2N1C..0168DBaAtEeSFaxCR.eocl30el1ie:vc9e7t7de::d0:43312/08/2000 BH(OO2R1P8SL)HOAIMN4,G7AP8A0019044- Date Reported: 01/16/2001 Client No. 1028 Study: 418018 PUPS GD21 Species: RAT RAec:cession Sbpi)ac.| 5BB oooooo33zaae%zsa:ll 1ll1ii0gg5se3e BBB o00a00333a00%33es8le8 1111i00g6sgss BB 0000330033887 111100663s Me2a0n Group 13 Gp Sex A9g%eu1o/4bTLOlTALTN3ejTbOLTAL FBRoEpE.T3 111333 088.::088088 1.16 111333 888:::888888 122.::s38e39 1133 28::8888 58::0388 52 132%8 TNSGH L 116 FNREE/EbLT4. a8.:a808 058:.:508608 &Tg8 BBB 00000033300032332357 11100099311157 323 0aa.g08e0 828.:48d30 0.07 5BBB g000000o33330000333s3%23058i 11110000833333118385 3323 33::8388 0.00 50630337 10338 2 [R2] KEeEaXn ?8 2.[R8112] 8a7 Group 2 Reference Range 33- 2so60 o5 - t5T7-1a9dPage 7 + 000531 418-018:PAGE H-35 SN abe og WI . .0 INCORPORATED 301-921-0168 Fax: 301-977-0433 BE, goose Date Reporveds 01/16/1201 (215) 443-8710 fAececessionESpSec. | GpPSSeexxAgeAe T4B,TTMOTAL TR3,BTOTALFBRUERET13 TMSHa FRRERET4 000532 418-018:PAGE H-36 CYINCTORIPORCATESD 301c821o.01i88n sFavx.e 301.6G7a7.i0t4e33rs, MO 20877 Client: BA5RU05GTULSDSIHNERGEEHSAYEADRCRHIVELABORATORIES, INC. DDaattee RCeoclelievcetde:d: 12/08/2000 H(O2R18S)HAM4,437P8A71019044- Date Reported: 01/16/2001 Client No. 1028 Study: 418018 PUPS GD21 Species: RAT . AVoc.cessionSp4)ec.| GpSexAge T4UG,/DTLO__TAL TN3G,/TDOLTALFPRGE/EMLT~3_ TNSGH/ML __FNRGE/EB.LTd BB8000000333000333455910 1oT00s33s65s08 335 900::.000000 0.00 BBB 00000033300033382343 l11o00s33e68s1 23 0o8ll:0d30e0 182.:893968 0.00 0.05 9.04 BB 00003300333865 110039865: 53 000g0 22:10000 0.00 5:02 SMe8a7n 80 5T0is To l"0o3i7s Group 5 BBB 000000333000332335987 111000999777542 B55 000000333000337668310 111000999877086 BB 00003300238633 1100938822 & esa8n7 Group 6 o0.o0o0 30:.2000 0.00 0.00 000:.:003000 0.00 0.04 0.00 001:0988 80.:680 0.00 90::0980 0 i27%8 s 0 "04 8o Reterence Range 37 - s1000- 80Page 5 + a5T7-1293 - 000533 418-018:PAGE H-37 Client: BARguseRIEnSNECAOReCRHPOJRABAOTRENDORIE3S01,-82s1e-0,168= DateFaxS:er30i1s-c97r7e-n0:433-- BERNE Nou Soe pares er client vo. 1020 (215) 443-8710 seuays 410010 PUPS cont species: maT R Joeaion gi T PSex Age E puTOTAL BROE T EET IS Rh F ooofoooa oonnneneesiiiiigggosaeisnl ]7 SEB8Ea6 oe ome 0.00 0.00 E m onongegs imgs J oErBo owe outs stoi 7 Mreeparn 0 oe +653 08 03 Reference Range 33 mBe ti= hr- a1- rove oes demon. pate --eilltle: ha Page 10 of 10 + 000534 418-018:PAGE H-38 INCORPORATED BNEELL en (215) 443-8710 301-921-0168B28FaxS: 30R1-9E77-04331102000 Date Reported: 01/16 16/21 FEjccession spac. B 0030631 10906 SET Ghee Mee pon ge "GpSexAge CHOLEST GLUCOSE LDL-DIR HDL-DIR TRIG ~~ 1 57 292 25 26 203 erou3p 000535 418-018:PAGE H-39 ANI chtonts (07/07)(0 JF -- Aansgiemeraanenr1Mop VpBats SoEStE am INCORPORATED 301-821-0168 Fax: 301-977-0433 2000 i oats segerend, oupreranes rtare e (215) 443-8710 els AVANIR WRG Te sPepreseeBt 1 jfS ooecseesl sniongy3g pec. HGp exAge CGHOOLWfTEySToGgLUmCsOSE LpDLr-DoIwRRHDgLI-nDE IR TmRmIGnS.h Poa na #om 8 8m croup 13 croup 12 vre n croup 13 wr seterence mange pPr OF TOF BOOP OFT w0o mnme aoe ooo ain rage 3+ 000536 418-018:PAGE H-40 CYINCTORIPORCATESD s301o.62c1-0i188o sFaox:n30e1.6G7a7i.n0e4r3s3iurg, MD 20877 Client: BA9RO05GZULSOSHIENREGEHSYEAADRCRHIVLEABORATORIES, INC. BDaattee RCoelcleeicvteedd:: 12/12/2000 H(O1RS8HAM4,4a PT8Anad19044- Date Reported: 01/16/2001 Client No. 1028 Study: 418018 PUPS LD5 Species: RAT RAec:cession S8pec.| 8B5080000333000888333837 11100089832331 BB 00003300863305 1100992373 Me8an Group 2 Gp Sex Age GMHGOJLBELS|T GNLGU/CbOLS.E_LMDOL/-oDLIR 332 i12i28s8 12a37373 3i218 33 i1i0s7 13333 3is 313290 L 198.2C)32 GMDGL/-LDI.R TMRGI/GBL 3332 132013s18 223 13733 383:85 518as%4 BBB 80000033300066844431 111000389332283 333 M5e5a0n Group 3 1i24s08i2 322560:73 82a5 33a026 3323332 31870 2888% B52H. 3 i31l2e BBB 000000333000e86i44e53 11100039385677 335 BBB 0000003330806e44i75s 1110003335e65ss 322 MBeaHn Group 5 1132205 123387287 32223 23380 17281835 2176:4 33268825 2301 3388 83281%3 5187 #z85z0 51h 825h,7 237868.33 Reference Range 38 6 37as- 8g- 89- 1325= Page 3 + 000537 418.018PAGE Hoa1 Client: SAREGUSS RRIEESNECAORDCRHPROLARBAOTRAETDORIES3,01.I9N21C:.0166DBaatteeFaRCxeoal2e0lf5g.e0e7td7et0d':0m12"/12/2000 BORERANC Ba 1s044- (215) 443-8710 Date Reported: 01/16/2001 Client o. 1028 Study: 418018 PUPS 10s Species: RAT AcRce:essionS7pBec.| Gp Sex Age B5B70800603330068835330 11180803377807 % Moeagn Group CMRGO/LDELST GMLGU/CDOLS_E T eomtI a4348 B 15758 imo LMAGL/-DpLIR 3$582 wHn. BRMLG/oDpLIA EHRe/ISEL iSsT ia5 BP T B Tes BB 000033086e5s3i 120808935 77 Hooean Group 7 1m 01 m200 23 a8 239 e wm BHe T8a F1%C 3 55B 5 oo06oo0033330o08ee63as52ds5 11111109889388983298 828 3 855 8 8000000033330088ee88ee28rd83 H111a81s%88::: 28 5 8638283 1188s Reference Range 1ww1ro4 82829 B F# CO a 8in FSr IR @i- qa 2133 28 B35 A% Ra3e%s EEH3i2 # Ei Br 3 ia 8 B 5 #0 Hl 0 8 -98 -3.hi age 4+ 000538 418-018:PAGE H-42 ANI Client: Ar RGUSg RIESNECAORi CRHPOLRABAOTREATDOR_IES30,1.9T2N1C-.0168BDa3=t2eFaxRG.oLl30iE7s.c8E7t7aE.s0s08812>/12/2000 HEORE1RA5NS 5Ba01s044- Date Repioorktieedd:H . 01/Br1i6s/s2001 Client vo. 1028 Study: 418018 PUPS IDS Species: RAT Ahcecsession spec. Gpsex AgoeeCSHEOBELTETST GLEUJCSOSE LDRLV-RDIR HHDLR-VDIR TREIRIGS.. B 0030664 1Hs1ee0ag0n8 8 Group 8 BW1W2s2 #wnh227 ETYo37 pEee35 whr1a4s2 2BBB oo8ooli330eeesesses H11H380oa0%9 3389 BBB8 oo8s8g83eee0erests HHoHooltRaEe 3338 wepann Group 3 wB B m o i8a FH5i30 #o80s 8IooEn 2EiEI I.i EH333 3 F8A0 138I hWti I#0s Es HHEa 8 ea Reterence Range 8= mHe- o8 Page 5 + o -oo3. 0060539 418.018PAGE H43 Client: AS3R5GUSS RRIEESNECAORBCRRHPEOELARBAOTRAETDORIES3,01.I6N21C:.0166BDaatteeFaRCeoclse0livev:c0e7td7e?0d':0m12"/12/2000 H(O2R1S5E)RN4.43-B8a7101s044- Date Reported: 01/16/2001 Client No. 1028 Study: 418016 PUPS 10S Species: RAT ffeoecession s9pec." B55B0008000333300006883333133 11110888328002%88 Beage ih Meoparn Group 1 GpSex Age 111 i1 TS4B,TEOTAL TR1E,TT0TALFBRETES73 IRSoHhe Fg044I3s Easla oes FSEiC 285 ow 07s aHs TBe3e8 AToRs FRREEDEETi 8808::.:88088868 T8o8e 5BBBoo88go0lj33e0eeeernr7s:Ea a g1H1t0e1s9 1111B880 8bbb 888330833330006ee777a3688 H111118e88222ad82 1111S3g8 BIER 118 18 Megarn Group 10 8880::.08808880 I2siBB: 8o8o8 zas J08.:B0811 8888:::3388888 40s30:81.3e0810 oo ooo 8380.:::08881 8:88 nT EIS8 3355 8To1ne Reference Rangoe 33 - 8sBo"- 8oage + S57h 313s- 000548 418-018:PAGE H-44 ANTE INCORPORATED 301-921-0168 Fax: 301-977-0433 fosession Spec. Gp sex Age T4,TOTAL T3,TOTAL FREE 73 TeR FREE Td -- Reference 9 7 100 0 3.41 2.5 000541 418-018:PAGE H45 CLYTICS cies sss sin vo sor Client: A0BSR2UGS3USEBER"IEESNECAORBCRRHPIOELRABAOTREATDORIES30,1-9I2N1C-.0166BDaaEtSeFaCRxoAl30lI1e-c6Tt77eT-d0:69312/22/2000 BB SRERAI NS BL a 10044- Date Reported: 01/16/2001 Client No. 1028 Study: 418018 PUPS LDS Species: RAT NAoc.cession S1pec. 5BBB0o880o033a330g006ee83x388ss 1111800823332358:1 B 883088 1833 J eg | Group 2 5BE08R0a33I0%6eE4i1s 1108022392 Hoeann Group 3 Gp Sex Age 1U4G/TDLO__TAL 1N3G/TD0LTAL FPRGE/EMLT3 NsGH/ML _FNRGE/EDLT4 2222 08S888E500 J5F32S3.R8Dd3 oa8sn3m oss oe 080::00488 8 2 83 #8: 8:82 T#E8s wWahz 8wr T[EECR 5 33 0a8::.800880 8s2e82.::e98s oes 08.:0818 78 700.8632 8Ta "85855 8BB 0o00oo3gg0ee6ii4sc4 1110889258s7 533 B B 803033006i4s5 1100937608 8 5 Megaen Group 5 08S.382820 A9d30.8r588 o8a uae 08O.:08Y68 a gid 8:88 0.22 64.00 - 3 3 TBTeaacs z3p 13 8 T1o8s5s% Reference Range 33 s8eB 98 - hst7o 13dsrage 8 + 060542 418-018:PAGE H-46 ANIL INCORPORATED A 3016210168 Far. 201.670 pens" ig Accession Spec. | GpSexAge SR RR EE T4,TOTAL 13, ToTALFREE 73 En ish FREE TAT" B 0030650 10977 6 0.00 40.98 0.00 TT 000543 418-018:PAGE H-47 Client: pLBguLsLREIESNECAORCRHPOLARBAOTRAETDORIES3,01.s62e1-,0168BBpaaattteeeFaxRSo.ep3Ro0rr1Lt9e7t0Snsmeaso1i1/'%1262000 Client to. 1028 (215) 443-8710 Study: 416018 PUPS 195 Psppecies: maTfd ffoceoslcon ession spac. B 0030664 11008 GpSex Age THa,ATOTALTR3,ATN0TAL FBRREET73 TiSHe 8 0.00 44.97 0.00 FRREhETi "To.03 oroup 8 FIESnR g HE Fame} ggeese afrig en iE g0.e00 croup 3 rence 9; 7 100 0 3.41 2.5 Approveq =emesrSA. pave willi ot. 000544 ANTE 418-018:PAGE H-48 INCORPORATED 301-921-0168 800-237-2815 OA AUDIT REPORT TGThhoeeod rfLeiapnboaorlrtartleoiprsoytretPdraabncedtliocawelslwaasansdsroewcviiitaehtweeEddPArfoaGrwoocddoamLtpaalbiowarenarcteeorswyeivtPihreawctethdeiceFfsDo.rA maacncaugreamceynt.and consistency and the findings were reported to aTinhcecucromametptelhlioyadnscreefuwlsieetcdhts twhteehreeFDdaAtthaae.ndmeETtPhhAeordeGsfooorded,eLsacbtrohirebaseetdorsytaundPdireasctthiweceerser.epdoornte QLn aAukditd orB. a Newnn an sponsor: AR6uS RESEARCH 1A6S sTuDY: #/60/F REPORT TYPE: HE, T3,T, TSH FT3, FTH, citer. AUDIT DATE: 1-33-0) REPORT TO MANAGEMENT: 1-32-0) AUDIT #: 01-03 DATE SCRfMeIrTTEDSTr0 CLIENT 7 dd igwind Yai Ase ToT weENEN77T 75) 000545 418-018:PAGE Ho49 GIINYCOTRPOIRACTESD 301.s021-01n66 sFoasn20067c5menus vo so Client: AORSGUSBREERSEARECRHELABORATORIES, INC. BDaattee RCeoZlelfeVcetdetd': 02/01/2000 HCORISRANC: Ba 10044- Daatete eReppoRreptoertde:d: - 04/41279/4220062 Client No. 1028 Study: 418018 LDS MILK Species: RAT ANoc.cession3SBp;ec.| BBBBoooooo0nli3ssssssaadaziids 12i111e25880:81 BBBboo8ooio8dse3seidds HHiHaiaaesls:: BbbBoooooGooies3sesssldiitsss saadeislea BBooaosesdi?z HHesld Moeran Group 1 Gpol Sex Ag9e 1111 %fEFF 111 fF 1i1 f 11I1 ffffFFF GRNQELBELST |TTTTTTTTTTTTImmmmmomsee------eoe T8iees TTT 1B$3e32 1i38369% Wi3$e3 1338 #15%2 BB|5 o8o0o03si3is5ee6el0?ey9 H111e&6l20l0 ied 11i0 fEfFF Rf 117388 18 BBBoooos3ogceehidit HHHieegdh i1B8 FFfF 19788 Reference Range 810 - Page 14 000546 418-018:PAGE H-50 INCORPORATED IEE pos (215) 443-8710 301-6200188 bas 201000persoura Deve Reported: 04/17/0000 BD 04/27/2002 Ajiecs icon essionSipgec. | Gp7SSeexAgRne gol GHOLEST |TTTTTTTTTTTTTTmmms--mm-o- B 0035616 11628 110 F 84 EE croup 10 ] 060547 418-018:PAGE H-51 Client: ABRSGUSSEREIESNECAORBCRRHPEOLARBAOTRAETDORIES3,01.5I2N1C..0168BDaatteeFaxRC.eo2l3al0f1ev6ce7td7es0dTM:0820/"01/2001 H6O1RS8RAN4.7B8a0010044 Date Reppoorrtteedd:: 04/17/th2001 Client No. 1028 Study: 418018 LDS MILK species: RAT NAocscession S1Bpec.| GpPSSeexxAhgoee bBpBoooo3dg3edeie3sed0 ddH11iee6gl8tls3e 11B1333 EfF BBbbo0ooo0o3laessdeesdd:zs HHHdeeeellsdi iB1iFff eKepan Group 12 GCCHHOORLEEST|TTTTTTTTTTTTTTTTTmmmmmmm------ To2i9s$8 = E&8iH B738733 BBpBoooosysssseeeessn ili11ii6eg5t:8 BBB13 ffE 8889 Neogan 23555 Group 13 BBooossesumes 32pfF 8 Retereernecnece RanRagnge @0 - Page 3+ 060548 418-018:PAGE H-52 CIINYCOTRPIORACTESD 3s0o1.o52e1.s0168 sFasxn. 5001-9n77-08s33 wo om Client: B AARBSGUSSRREESYo EARDCRHIVELABORMTORIES, INC. DBatEe CSolUlecIted2: oxjeuszons OREBNABa1 - ate Reported:ea 04/17/2001 Client Yo. 1028 Study: 418018 1DS MILK Species: RAT fAoccessionSBpeece. | GpPSSeexxAghoee p5po0og3ai3aa8dz4is3z posed 1idd1iii5a1laa7s ls;77; EF kf BpB8oog3g3smaeeetaistd B 83sear iii1sa2dn2 dial 333 ok 3 B5pog3o3sseesaa:: ddiiissndste 32fo Keegan Group 2 5p3o9oe8oaia3sa2szs]ee 3838 1i111i5232d89 iii 333kEfF 3k pppoogooe3a3aRaze2eyed d11i21a233gd 333kk ppooo3amze iinigi 33 of Hgeaen Group 3 CCHHoOLREEST I33s9 1188%71 81i%e #iH8 ipreh} 27i 10288% 1i18381 331:.39 TT Reference Range 8s%0 rage 4+ 000549 418-018:PAGE H-53 CIYTICS INCORPORATED Bs ce (215) 443-8710 cree ce sen cans vo wn 301-921-0168 Fax: 301-977-0433 9 bate Reportads 04/27/200s = P S4/27/2000 F J B= 9 BOJOLJ e -- B 0035565 11547 4F 269 TTT reterere rede n- he 96 000550 418-018:PAGE H-54 Client: ASRSGURS ERIEYSNECAOBRCRRHIPEOLRABAOTREATDORIES3,01.I6N21C-.0168BDaatteeFawRC.oela30lf0e-V0ce7t0demtde:ss02/01/2001 BHOREA,HAN; PPaa 11s044- DateReppoorrtedd:: 0044//1177//22001 Client No. 1028 Study: 418018 LDS MILK species: RAT ANocscession siBpec. Bb5000ooo0333ss5see5Rd7ds5 1la11i25Ez78e5 BB5BoogGooool3issssseseEe:sds iH2diiAsg2egSr: Hoeparn Group GpPSSeexxAAggee GRCHQOLBEEST TTTTTTTTTTTTTITImmmmsemme--eeee ff5 fffF 11F523e88 TTT ff fffF 1B46H28 183 #T7or5s BB5ooooo%yi3ssesseeadrs 1i11a3ser3z 777 }fF #42 seoaprn 8i:s3 Group 7 BB50o00s0338ss3es29s30 11H18e60E?0 58fffEF 122743 Referennece RangRange 180 - Page 6 + 000551 | 418-018:PAGE H-55 Client: AB9RO0SGTULSBEIHNREGIEERSNYEACAORDCRRHIPVOELARBAOTRAETDORIES30,1-9I2N1C-.0168BDaatteeFaxRC:eocl30el1ie-vc9et77de-?d0:43302a/01/2001 FORSEAN, PA 19044- Date Reported: = 04/17/2001 Client No(.2151)028443-8710 Study: 418018 LDS MILK species: RAT ARecscessionSp8ec.| GpPSSeexxAgAdee CGHEOILBELST| BB00o00o33335s%5s39a%3d 1111115880663:5 85 FE f 1188588 b55 00000033133335%58s7 11111188080s78 5661330 11888 855bkfF 8F 3i18%e8 ies Me3a0n 5 3% TTTTTTTTTTTmeeee- ! Group 8 BBBoo0oo0333ss3ee6oo0or: 1H11e66l11:31 533 kFEFE 1953728 BBB00000303333%6000d8 1Hmeegldi B 0033c0 ies 8353 kEF n833i% 5B 0Co0333ece0ss liiiesltse 53 F 110888 ! Moeean Group 9 810%8.3 Reference Range 5- aed Appr Page nd 77f 7 P2279 000552 418-018:PAGE H-56 ANI& IYTICS .. Giana Seat, Suto 200, Gaitarsburg, MD 20877 Clients gBE YuETstoyLh ReEIITNECAEORERYEoPOAeRRCARTAETDORIES3,01-9T2G1-.0168DHF agttesFaxRB:eeE sp3o0e1r-et9e7r7d-::04330-- 3/13/2001 client vo. 1028 (215) 443-8710 study: 419016 OMS 1D species: RAF ANoso anaB2B eeP se C PE abEnT T uNTE || Re oC GE SEIBEST Se SEUSEE Ew TIm y. i MEISE B ERUSRTR R ERIS, aTeTBR8 um IIP F Pooooo aaa annn namy 1111}f}!I BEML I: R88g B A H ii Bl i;iif 3#88B 3 f3a0B og GF FfFH PEEmiMEEsAmtE iEEeEEl ll| ff If 88gg gH iiiiff ii$ iit o4#B28E fOdB om aro 1 vreran wEEonsheoe IBEED E Eha jPBSpiiomnImnumunmmTnmEe WnHHHEEtiE BiMME HE HE qS82gP A 0i8o3m s ii{i{1 m22Z2z o0imm 0B i4 FButaEseEnss sHorEes HE woa ne ee aeBaE J 96 319 o 80 104 seg 24 000553 418.018:PAGE H-57 Client: L ARGUS REIp SNECAROCRHPOLARBAOTRAETDORIES,301.I5N2C1:.0168BDaEtEeFaSCxoEls0lR1e:c9It77eE.d0:839eajenjanee H2O1R5ER4A4N78B7a1010044 Date RepPorted: - 02/31a3!/2001 Client No. 1028 Study: 418018 DAMS LDS Species: RAT Joceeion gee adex nae gions gic gren gron ge AccessionSpec. | Gp SexAge CHOLEST GLUCOSE LDL-DIR HDL-DIR TRIG p50o0d3a3s3s0s8 n11e63s8 Hil FF Meepan Group 11 853 i173 $5 8& 355 6#5.17 017%5.6 4 6$0.i4 812%0.2 BBBBo88ooia8gsE3aainio iHi11gei64ils0 iiB12fEfE BBBBo8o%o8Gs33senERriNes lddiiiitstetidlse BBiEEf 1k FBBBoo8RS%3Es3ERe2in8ESs3 iliiitgeshsd ii1F3kfF BORE NE # eeapn Group 12 83&a 81e728e9 13:2 58#6 1&a583 #3i 112830 :33 2#3 8f2t2 5ii8 333%85) i33 &21] a#i 838? ii338n$8 3i 8@5 8a888 #30 n1N5 33da S0o:8Eee Reference Rangie 29- I7sa- 8o0rage 2 + iz- H3t- 000552 418-018:PAGE H-58 ANI& GLINYCOTRPOIRACTESD s301-o521.o0168s Feax 230001.-8G7a7t-he0r6s5b8ur, MD 20877 Client: JgUs RESEARCH LABORMORIES, TNC. Date Collscted: D worst Bo a oes aeReppoorreteesds: . o02y/r1m3e/e2e0e0s1 Ciient No. 1028 Study: 415018 DAMS IDS Species: RAT ANec:cession sHpec. pBpPBo0ooo0g3mi5ia8ms2e3nHH1fn1ee6ae5lt4 pBBBooooomomamtn iHHHeeEE pBp Booodo enEn tNeeEel Mteeagnn Grow 13 GpSex Ag9e HH1BB3OfIEEF BBBBEIIE BBBBEEfE SCCHJObLELST GHLGU/oCiOo-SE 48424 23ii0B8 $ q d l i ii A &# EA 13 Sn I T ie LNDOLjo-b-D_IR 5i4 :33i 3:23 4i3s HDMoLj-oDLIR_ TWRei/CbL 3228$ 39 8143i2]]5 IHi& i33 8H g 3 i Es ]a3e 3me 2w:e2 Reference Range i@- 2 He -9 8 -2 8 to3dPage 3+ 000555 418-018:PAGE H-59 Client: AINXCOYRPTORIATCESD 320010.G9i2r1a.r0d16S8ree, SFuaxt. a20001.:0G7a7h.e0r0smo8urg ASRSGUSSEREESREARBCRHIELABORATORIES, INC. Date Collected: MO 20877 H0O1R8S)HAMM.a Bhaad10044- Bate Recafeds 02/02/2001 Date Reppoorrtteedd::-- 02/021/133//;2001 Client No. 1028 Study: 418018 DAMS 10S Species: RAT fijeoseession s9pac. Gp Sex Age BBp5 oooood0iid3sise7eeasidr 1l1i12s58e08:1 128 111 IfEF 1I B8pBooo0oao0iii3sds7iii8eod8drt i1i111ai828gls8: 111 1 If BBBBoooooooaioigsssiieeeedsd ai111t28?e8 wal 111 fIF 1f 5Booooiissaecse 1i3i1a 11 FIf eeaan Group 1 G3/,DTLOTAL TG3O,/7B0DTAL NTeEpm w7 sileeay nee 381.3830 1 a L1.E8 Si Jsgsteueerenr LL13dE8 nds a hhfE NE ssmgoeelaeers ga1idees 1:38 faniiglr 3g ssoae 8a:8E2 833 B$3i1a,s ilaam Lngass FPROEELE'TSFRARPEETEI obNadE) gE a ooee: oss ge8El Sif seopnne ose 3g8EB Et oounee: ge 8o3f 3 a oane 378s BBBBooogoouostsstseseesodc::rs 1Hi1e6g3d0 1iedi HH1 ffx if B88 ogoooo33iz3sasc00sse 111111e3ggF iiil II Reference Range 4j26e.88s2 wdeaadn 889:.3%387 oeeesd fn2iisa gig geoansr gil Roly agoaukzse aglEr "dess ooones whRE fSia ggEi s0o- 33- S$7h0 80- i1s- Page 4 + 060555 418-018:PAGE H-60 GAXTICS oss se 0 comes vo on Client: ApRrGUS REISNECAROi CRHPOLARBAOTRAETDORIES3,01-6I2N1C-.0168BDaatteeFaxRC:oAl30Il1eN-c9Et77eY-d0:43302/02/2000 BC ORERI ANS BM a 1004s Date Reppoorrtteedd:: 02/02/13/2001 Ciient No. 1028 Study: 410018 DAMS 05 Species: RAT hReescession Spec. GpPSSeexxAAgdee TR3TB0ITALTTHETTOTALTREg EBRRERRES EFRRREEETE HBoEssEes H iis EIE H7I0 8 Tone nosee a00ns uoini yeBeagn Group 11 2$3338 aTemss Rieps oaea anah BBpbooooomduomsdeeiEidsoiipi1ies1eres 1B1B2 PBfE BBpBoooogsogiisseth ieeHteet:n nBHBffff FpBoodoEaommElnsbnHeeets HBIf Hf Bene HE Hteeagnr Group 12 dB3 3.4E3F18% 8 L0.R00 nIE11gnR3 gSs0.eEn03 ooaounnms #Bgf88aa0 Be 8 8 eeRa SR bIbbkRgm BB oseosmmamo sp oooonmmn gu aE3 BadFr 8eg83xn3 Bgonkrwp sseskime oooedemnd E an H Tho iwgen aa8e a aa Reference Range Bsoo- 33-7$.hT8o- 113sPage 5+ 060557 418-018:PAGE H-61 Client: 3SAB8R50G8aRUSRnEERsEISpANEaCAnORcCRHsHP.OoLARnBAOTRAETDORIE3S01,-92I1N-C0.168DBDaaattteseFaxSCR:eoSplH3ol0I1reS-tc9Eet7R7de-Y:d0:4-330022//0123//22000001 Client Wo(.2151)028443-8710 study: 416018 DMS 105 Specten: RAT NFoosenion 6p ene ena RNG/DRL__ A RUaG/RDOLR TR NG/ML _EPRG/EML= ENGR/DEL F ppBgoooooosmesedR sed: hLeueessE etst E nu4ntf:f gw|Sineeaeoowsf rrrI peg eeeealk eeoeanmn mre gx rn eg Ex IBBBBoooonEeedglliEilnnEegee iHB1}Efk nt a gmgaiee mf eooeennpr em yo1ariphm pm geogohmdny eegeuRnne en BBBooeeilense BiHk:i fggeaEd goemoe eaeemn oogoneh oooHnn porg croup 13 Hwimn HowE TWEat Tm m Ean Suturanie Bangs ng s- 3- sr- e- na- 100 7 3a o 2.5 ApprovedSage eSeeSr / 6 pare A7L 060558 418-018:PAGE H-62 CLINYCOTRPOIRACTESD 301-r521-e0168s sFaaxn 0201.9u77.m0608n wo sm Client:2HAB0ORE%RGEU8RSSA0NER.ERSEBaARBCRH1sE0L4A4B-ORATORIES, INC. TEE M42 nad BDaattee RCeoclellevcetdesd': 02/02/2001 Date Reported: 02/13/2001 Client No. 1028 Study: 418018 Das Lbs Species: RAT JAcrcessions8pec. 5Bsb0oo0o3ga5ma3s3en4 1neH1ei5sig3t?0 B5BBo80o8o6333a22a2:3d%8d3 H1tiiiEggedAsdl bB8oea3saesdidy la ied Ne0an Group 10 Gp Sex Age B11i80 FfF 111898 II IiBfF MCHOOJLOEST RGELjUSCLOoSE LMDesLo-b.D.IR HMDeLy-peDTMIR TRaIrGe.n W B afiy i niz 23i 3 T$8T20T i a3333 &28 i3is 8 ia i3i { &ai 3 aB8 8 #E0I 33 @ aiit 2 8 iw ma n33 E8m 5u80d3 BpBBooooo%ieeseaRsszdsdiuiaasrl:s 332 ooFf 3f BBBB8ooo%nensReisehd HHiiaaaEd? 3fffffffF BFFRRoEEnEEetT:HEERiadI ff Reterence Range 88s 8 11i%% ix 2:i i 885s00saiis P8F 8E H.i3B% $:i ig 88 aa2883 888in 33: &8io i3n s88- 7a 8o- 820-3d.o Page 1+ 000559 418-018:PAGE H-63 AYTICS 200 Girard Set, Suite 20, Gaithrsourg, MO 20877 Client: A25R60G8,USRERREISENEACARORCRRHEPEOLARBAOTRMETDORIZ3S0,1-9I2N1C-0.168BBaaEtSeFaxSC:oOl30Ll1s-Vc9E7t7eR-d0:433025/02/2001 BT EEBEE BL y ious bate Reppoorrtteedd:: 02/13//2001 Crtent wo. 1028 Study: 415018 DANS IDS Species: RAT RAecscessionS#pec. | pBoeonnens 112] seegan Group 2 pBppoooooasgmselesssms a niuisgasl BpBBoooosopseeaednaHananeat pFpRooeEsddEE sea nHueaaalI ppoodnee iHya steeagnn Group 3 GpSexAge f2 fE 3333kEOfE 3333kof 3 kf 3333 koff Ff CKHGOJBLEETST GLNGUJCOOLS-E 8 TTTi 3Be 0Ge%a n [ ag Io ]mis &#g 80 isa1in8k 8%8 d 6 i038 H2o i GF1 EE ims LMDGL/-DDLI=R HDMLG/-DDLIR TMRoI/GBL 31 %53 afl. aIEE IBmsa 2is2 8F aIA] .iim i3i: &3# 0 82i40 i:: 2@ii a8288 3 8gm2 3s m25s amis ence Range Refer . @- u- 96 319 Page 2+ 0-3 o 80 104 000560 418-018:PAGE H-64 POLI INCORPORATED (215) 443-8710 RE 301-921-0168 Fax: 301-977-0433 o NAocscessionSBp'ec. | GpP SexAge CHMGO/LDELST GLMGU/CDLO.SE LDMGL/-DDLIR HMDOLDE.DIR TMAeTySL B 0035863 11544 iE 59 163 2 a1 211 B 0032877 113288 fF 3 138 3 72% 3% 000561 418-018:PAGE H-65 ANINCTORIPORCATESD .30.1-.42.1-.016St8eet. SFuatxe 2a0007,:9G7a7.i0t08e8rs, MD 20677 Client: A0R5GUSSEREESREARBCRHELABORATORIES, INC. DBaattee RCeozlellecetde!d': 02/02/2001 H1O5R)ERAiaTBaind1s0as - Daattee ReRpe>oprortteedd:: 027/31337/220000 Client No. 1028 Study: 418018 DAMS IDS Species: RAT Ac2cession s8pec. GpSex Age GMHGOJLBELST GLMUEC/SOLS-E IHDO/Lo-b.D-_IR Bbb o00g00a33s5ss8ae8ss4e 111118517639 %:3 FFEf speaen Group 5 a108388 1B38t9 :3s a #3 0m B E6 HMDe/Lo-bD.IR 72E0e 5188 TMReIjGSL 113383 3 35s BbBBooo8oso33sss3aee8esy8s 1ud3si71e:2d Hed 6efEI bbBBoooooogoiiieseeedass:s:t iHii3aaa7eld2 fffIF bbBE0ooR0a3aiEsasRHsetHsd HiHaea::dTO fF bEoRosIasEt iHaId ff Moeaen Group $ sB E s 83 v 31s s: 2352 2 H58& [ 8s $Ai i ]13 23 3 22& is af3tR3] 39 aiio dd1aa% 1% 33 28&$ i18i3 8 g Ba in n $i 288 88 Hsie OTiHnNa 4a3a R8es saria Reference Range 88. 7M a- 80Page 4+ 820-32oi 000562 418-018:PAGE H-66 ANI CLYTICS so cssivn si 5 cama vo mo Client: fJgB oRsUpiS S ReEISNEACRP OCRH,POLARBAOTRNEFDGRIES30,1-9T2N1C-.0168DFaavtRseFaxRC:eopl30oi1rs-tc9e7t7de-:a0:4330-- 2/13/2001 Cuient wo. 1028 (215) 443-8710 Study: 410010 DS 05 species: RAT fReineegee Re er GRRET gGGTeiWT a BET Imen fFFF Seoedmedde a nll 111TEoooozfff gA 8g oo m# RT 7T 1E 1 m EF oz f n B& pE FfFoaooudnsdseh teahanenEEo771 ofoooffp ggB$ poo1o #E# :1 i1 88## 83 8u00n#H BBFFoollaaalgiiinnneg 11o7 ofooofft ggg m o 408 f i11 8E 88 B=#5 Group 7 gyoear WS Ehees E TE EHS Hmda FBBIgoeeomdmmdmnisiiunnnugseseene 2833 oooIfrr wgg $2 o0 m M# om 111 75 Bo85s g m08i#g gBamEmaReLr tfor: Reterence Rane wo# gq0m Hs 3 SeT e 3 aBTe#8 aas & rage 5+ 080563 418-018:PAGE H-67 Client: A3RGUSS EREIESNECARBOCRRHIPEOLARBAOTRAETDORIES3,01-5I2N1C-.0168DBaatteeFaRCxeoclsel0f1ev:ce9t7d7e0d':0 02/02/2001 HB ORSRAE NC BM a 1s044- Date Reported: 02/13/2001 Client No. 1028 Study: 418018 DAMS LDS Species: RAT EL AccessionSpec.| GpPSSeex xAghaee COHLOLEEST GLCUiCeOSE LiDLn-npIN HpDiLo-BnIR TiRIeE BBBodouo:ersseged initeielssls ff3 FfE 8 C_ Em RiT :25 52785 8&Er sBeEaXn Group 8 5 ss 8lo%s 417 8a5s 8e3a BbBBoo8oooaidsiseeseddsesss dHieeienhn 9ffx BBB5 ogoioe3siseeeeldld?e eeHHeetHrleed f222 Ff 5 o0se3s de 8 Noeagn Group 3 # # so 1 18 8i1m ii$s 58iss aw838e8 s5 [iA iatg 3ii3 3$ i&8 ii38y8 @ e#a0 oHWn : 3npa @ h3e2e a i ion eterence Range Raters Je 8. m- o- 96 319 0 Nomrovegroved ooSpye 20-3. 80 104 pare L s7laL tes 000564 418-018:PAGE H-68 INCORPORATED 30121-0188 Fax. 301.977.0433 Client: A9R05GUSSHEREEHSYEARDCRHIVELABORATORIES, INC. DDaattee RCeoclelievcetde:d: 02/02/2001 BORERANS Ba 10044- (215) 443-8710 bate Reppoorrtteedd:: 02/13/2001 Client No. 1028 Study: 418018 PUPS LDS Species: RAT ANec.cessionS3pec.| GbSexAg9e BBB 000000333538777233809 111111335000421//550067 111 BBB 000000333338777333371 11111183210029877/885110103 111 B 0033733 113137314 1 M5ea7n Group 1 CBHGOJLBELS|T GMLGU/CDOLS~E IMDGL/D-LD.IR HMDGL/-DLD.IR TRMeI/GbL 1i101l70 333122278 333%2 22248s 322913835 1i113s16 23i1i44s5 a43 22235 32117311 is iss is 3 33 5113506 F2e6i2t.1 738H.4 8313.7 821075.7 BBB 000000333358777333758 11111i66e3335027//86e33373s 111111 BB 00003383773385 11i1e633s9'/634 1111 M5ea5n7 Group 11 121ii1s84 231604711 i238s7 3E28d8 222104872 i1i2ss 2i0s17 33%2 330 3Z1e3e b11d8 E1L9I5S.A4 36.8 383.8 f2r2e9t.s2 BB 00003335774410 111168440e7/8644s1 1122 Reference Range 1i3s2 2s1d7 586 -7431s)- 239 0- 236 020- 7 263 1235- Page 1+ 000565 418-018:PAGE H-69 CLYTICS cv se cst vo INCORPORATED 301621:0168 Fax: 301-677.0433 = Client: BA90RU8GTULSDSIHNERGEEHSAYEARDCRHIVELABORATORIES, INC. DDaattee CReoclelievcetde:d: 02/02/2001 HORSHAM, PA 15044- (215) 443-8710 Date Reported:. 02/13/2001 Client No. 1028 Study: 418018 PUPS LDS Species: RAT HAococession s3pec. GpSexAge CMHGO/LDELS_T_GMLGU/CDLO.SE BBBT008008333558777444233 111111665584038/7664521 i1122 11315525 222253738 SM7e8a7n 11800.44 1251075.4 Group 12 DMGL/-DDLI=R HMDGL/_DDLIR TRMIG/GDL 25E3H0] 33i61s ii29es33s 3136.2 p35t2 E2a3t5).8 BB 80003355774465 111i6e5346/655 1133 MEeEaNn Group 13 110722 222127 3801 332 22535 #13l7)s 3213305 3556.15 435%.5 12445h Reference Range s4e8 - 371s4- 0Page 2 + 820-3 125 000568 418-018:PAGE H-70 CLYTICS nes sum ue wo INCORPORATED 301-521-0168 Fax: 30167-0433 Client: BASUR0PG5LUBSSIHNERGEEHSYAEARDCRIHVELABORATORIES, INC. DDaattee RCeoclelievcetedd:: 02/02/2001 HORSHAM, PA 19044- (215) 443-8710 Date Reported: - 02/13/2001 Client No. 1028 Study: 418018 PUPS LDS Species: RAT ANoc:cessionsdpec." GpSexAge BBB 000000333885777332098 T1111132500042177350078 111 BBB 000000333888777333331 1111118221002897/7858101130 111 B 003373: 118137314 1 SM7e8a7n Group 1 N3G/DTL_O__TAL iis3s8li.e87s23 ii8ll:e3e:8 38:98 433%.756 1UG4/DTL_O__TALTNGi/ML __ 0o01l-8e67s0 110.318778 0001:1585477 1i90ll%6o 0:32 olsl 61187 1e.ts058 FPRG/EMEL.13 FRNG/EDLTEA 000l:.o00080 o00ll01113z1 o00llloo00 0oolllo1i81t 0:00 0.07 l"o1z03 BBB 00000033388577733375 1i11l16e63338a07j/8e63d37s3 111111 BB 00003358773353 111163389/634 1i1 e5a8n7 Group 11 333235:1.884558 090:.000880 111..300579 g20:.i00g00 980:.000311 2377::2338 00:8682 00:.7788 8:6:9900 09::0021 7357.0292 002124 1i0s1 3o 1To810x5 BB 00003385774410 11118644e0//e6d4s1 1123 Reference Rain$ge 3385:.5185 3500 - 9.6:9003 73- 11951 80.8062 4 $57.0 5 89- 60i.o0r1 21:.39 - Page 3 + 000567 418-018:PAGE H-71 Client: ARGUS REISNECAORCRHPOLARBAOTRAETDORIES3,01-9I2N1C-.0168DateFaCx:ol30l1e-c9t77e-d0:433 9B0R5 SSHHEEEHLY DRIVE Date Received: 02/02/2001 Client NoHH.OORRS1HS0A2M8T, hPAa_ d1904S4tu-dy: 418018 PUPS Date 105 Reported: . 02/13/2001 Species: RAT RAecscessionS9pBec. | GpPpsSeexxAAggee 1R33,BOTTOALTALTB4BTONTALTRSHw FRREeEi13 FRREEjEbL14 5BB 0o808n3353m7784s33 1HH1ai6yt4e3/7e45w1 111322 Se Bf o8L e8s EbiaElEE o&es o8RaE8l] wTeeagn PSo3s 80To8es ihs is lost oioo Group 12 8B o8o333s3z7a4s2 m11e8s8t/ess 1B3 1B7s88 0.00 as 08.:0808 08:.8080 seeagn 5F0Es 3 E 3 g8 T8orh Group 13 rence Range Rate nae so. 3. sme o- 19- 100 7 3.41 0 2.5 AroveySageV4 - of -- 1 -- pate Lada. 066568 418-018:PAGE H-72 oxroaEmretHiHpEyiRmtEHSct:s,0oHFwen.sags BSGT J eacstmino 1e Bm8nL (3013) S9121-01r168 aor (FAnX) BSpr19eEE7e1E7-S0fH4hE33eEBcmEomer:: $52) ga 4 By Saints og SE SET ancus cums sora frBeRsaEE, mermorms iiron evEenrtotn slo3-e8io,n er varme vom `TSH, RAT QNS NG/ML 0.57 = 3.41 fe T3, FREE olen 0.00 verme PG/ML ro -as Laboratory Sieg Director: so)Saroj R. Das, Ph.D. SO SY,op 060569 418-018:PAGE H-73 CLYTICS ogres se css wo zr + MGS, SIENACROCRHPOLARBAOTRMEEDORIES3,01-9W2e1-.0168RateFaxS:ol30t1e-e9e77a-t0s433 Chie BEES au 905 SHEEHY DRIVE DDaattee RReepcoeritveedd:: 0023//0125//22000011 (215) 443-8710 ARecscessioniSBpec. | GpSex Age CMHGO/LDELS=T GLMGU/CDOLS=E LMDGL/-DDLI\R_ HMDOL/-oDbIR TmReIsGon B 0035749 115197518 2 110 238 30 44 173 B 0035754 11536/537 3 149 217 53 Seco 32 247 000570 418-018:PAGE H-74 CIINYCOTRPOIRACTESD 3s0o12c1-i018s8ion sFaex. r30o1.9G7a7t.n0r4s33our, MO 20877 Client: A5BR0UG3PULSDSIHNREGEEHSYAEARDCRHIVLEABORATORIES, INC. DDaattee RCeoclelievcetde:d: 02/02/2001 HORSHAM, BA 19044- Date Reported: 02/13/2001 (215) 443-8710 Client No. 1028 Study: 418018 PUPS LDS Species: RAT NAoucceSs3pesc.i|oGnp Sex Age BB 00003335773576 1111354430/735230 33 Mgeoapn Group 3 MGGH/ODLLES=T GMGL/UDCLOS=E MIGD/LD-LD.IR EMDGL/ODLIR TRMIG/GDL 114358 228348 1302 3228 23374 1155.5 28B62.3 5B0e 332.3 289%5 BBB 008000333533777588850 11111133538591877/885766089 555 BBB 000000333333777666231 111311733166%33777836647 553 M5ea80n Group 5 11102122 322285583 2i374 323s3 22858339 iiiiisas 33323%37 42i"1 2i33t3d 3317718 T5.3iss 23885%.3 384h.7 :32.7 73866%.73 BBB 00000033353377768845 11111188853'77"64'7/357785 6 BB 00003333776657 1111838834/7538709 66 M5e5an Group 6 1i73s1 233280773 4i37 p4h370 81r98d3 ii 2i4s3 i32 3382 334233 71284.2 2B43h 3B5W2 338% 22135%.8 Reference Range 588- 317s4- 8oPage 2 + 2 8 0-3 125 000571 418-018:PAGE H-75 Client: INCORPORATED 301-921-0168 Fax: 301-977-0433 EBesEiteer ARGUS RESEARCH LABORATORIES, INC. (215) 443-8710 Date a Collected: an ANcoc.ession s1pec. Gpsex Age CMHG/ODLL_E__ST GMLGU/CDOLSE LDMGL/-DDLIR HMDGL/-DDLIR TMRGI/GDL ge 96 319 o 80 12s Approved ------==EZ ooo. pate --dfiil0 060572 ANTE, 418.018:PAGE H-76 CAINVCOTRPIORACTESD oaoocron2rsotessen s80s02n372c815 aswormss QA AUDIT REPORT tGhohoeedR zLeapboorratT PlisitenadcbdteilcowaelslvaasansdrseowvciiiteathwtheeeEddPAffroiaGrnwodoicddnoagmLtspaalbiowwareenarrcteeeorwryrieetvPphiroearwtctehtedeidceFfsDot.Aro mT anage emaenlt.eRe mtistency and tTa heeemee thodrsmeeuwsitetdsh twtheehreeFdDaAtthaea.ndmeTEthPheAordeGsfooorddee,LsacbtrohirebsaeetdorsytaundPdireasctthiweceerser.epdoornte Flraankluint5t. aNewenan QA Auditor seonson: JRGVS RESEDA 4485 sre 415016 REPORT TYPE: he, 75,14, TSH ners, ETS AUDIT DATE: a-15-01 REPORT TO MANAGEMENT: go15-0) AUDIT #: 0-078 Sid3/sSleoW.tI,TIED T7OsCLIENT nuk Lainie Vacs Mmaom ToeT 060573 ANE, H8018PAGE HTT INCORPORATED 301-921-0168 800-237-2815 on aupsT REPORT STGohoeed rLreapborosreaitloirseytePdrCabcretlieotwss]wa`sianssdrncedcwviiitaethtwheeeEddPAffroiaGrnwodoicddnoagmLtspaalbiowwareenarrcteeeorwryrieetvPphiroearwtctehtedeidceFfsOot:Rro Trheemagenaelnt. orency hTBheee emedthoedseuse ed hw"eehreeodAatthaes.admeTEthPheAordeGsfooorddee,bsacbtrohierbsaeetdorsytaundPdireasctthwieceerser.epdoornte TonaoMkuidiintorBY Newman sponsor: ARGYS RESEARCH 1465 sToDY: 4/015 \mvoRs Typ: CHIL AUDIT DATE: a-15-0/ REPORT TO MANAGHNENT: 2-15-0) AUDIT #: 01-121 Stfei, e fo TvESAyTO CLIENT, 28 Daiqand Voix SSeET TET) 060574 418-018:PAGE H-78 CIINYCOTRPOIRACTESD 301.s52i1.a01s68yo sFaxu3e01-9s77a.0v60a0s vo wor Client: SAORSGUS RREESEARBCRHEELABORATORIES, INC. DDAaEtSe RColAleTctEed: 02/07/2001 HORSRRNC Pa 10044- Date Reported:. 10/10/20 Client No(.2151)028443-8710 Study: 418018 FO C/S GD21 P Species: 3072008 RAT jAoccession s9pec. pbp50ooo0aa33ai7ia1ssz3le5 1t11808e338e808:21 BBb58080E00333777iI11e33t80N111888G333888788 Meopan Group 1 GpSexAge LHOLE-RBIR HWDRL-IDAIR CRHEOELETST TBRITGC i11 fEF 1 8 o0.a83 es fa 0.e5e5 83 132.88B3 aE n11.gE97 ug 111 8ga:ae5ss5 o8ai5Ee i3as3R aWepiifls iF 88 8 nN RB 5F3Es a3 Suoeom 7Liessgs BBBBo8Oor7Nna ulHisEtee Hite 1BB2 EEE BE BBBpooEao033AdE2iiNase 11H1e18l8ge8 ie iiBfffff BF eeapn Group 12 1ae.a90s3 of8ss3e 1 2n.3e8 a56.y%99 o98::e638 &8f ao8s38s Ss i f3e%r 1E fBIRRa 3 sas 88 ni 5 7dh TEeh hBaEs hLEi Reference Rang9e 08 - 80- 3o- 8oPage 1+ 000575 CLYTICS ie sve. sn 20, sims wo wor Ciient: aRgus AIRNSECAORRCEPOLRAABOTREADTORI3E0S1,-92m1e-0.168 Date Sollscted: Fax: 301-977-0433 fSioianamBe=c en sexhAegee LLDRVLo-mDTIR EMDoLj-opMIR CHMoGL/EMST TMRGI/GoM rage 2+ 000575 418-018:PAGE H-80 i 5) Chient: A3BAR Re5Ge8EvUasSR,mRRItEN ENSgbCEpyOAARRCRPsoOcoLRAuABeO-TRENTDORIE3S0,1-8T21N-C0.168 DEaRteFax:b So3l0l1-s9c7t7e-0dy 4:33 -- sate Reported. 10/10/2001 client Yo. 1028 study: 410010 70 0/8 Go2a Species: RAT S fase ee s e Oe a a rBna PS jalh mumir eer 1T1 Eoif gE gEE eoemw Gaee wget rrimEa orTeEa FpPn Pelaliinmuntin iieieeren 3o313 foooffff ggg$$EEE88 sgsossewgee IrprrEmmmm gooigrnEeme Group 3 ywogun BgroeTrm aEEn aamn ypFfpoeoiogmaaimasmbmmieiomnsdees f4fffffffE Phu ike 1 of eg8$gna%3r s3gggmn8Ee 1r1zImiBkE Lo8ggfngme gn eg ri fy gpaenngile f4obf yerggn gjgg gsgR rimm fgan T OEES iWgEs TTamn Group 4 Retezence Range get - 58 rage 3 + 58- 8g- 000577 418-013:PAGE H-81 GLINYCOTRPIORACTESD s301-o921-o0168s sFaex. 320001,-9G7a7i-n0a4r3s3our, MO 20877 Client: A5B0RU8GIULSDSIHNERGEEHSYEAARDCRHIVELABORATORIES, INC. DDaattee CReoclelievcetde:d: 02/07/2001 H(O2R13S)HAM4,43-PA871019044- Date Reported: 10/10/2001 Client No. 1028 Study: 418018 FO C/S GD21 Species: RAT ANoc.cession S1pec. | GpSex Age LOMGL/G-MD_|IR HMDGL/-GDMIR CMHGoJLGEMST TMRGI/Gow B8B 000000333777111388789 111000999556890 555 EEEFFF oolllo1el2s 000.:1883873 33373%017 11T00e..l73a70l BBB 000000333777111989203 11100099866321 35HE EF F 9001l13s0818 0001:l346:72 3221::275200 [88.41733 BB 000033771133:3 f10o9s6e3s 53 0F o0l1e0l0 00113885 52::1421 150:1273 | M$e7an 2i2783 511256 2`.395981 57.938683 Group 5 BB8 000000333777111999758 111000899777524 HssEe EFF BBB 000000333777112990850 111000989877068 HeE EF BB 00003377320012 1100888812 ee FF MSe8a7n Group 6 000ll.847731 o09.:l68d97 2.33:.918088 6781:.345271 1golllesa7s [o0l5l62a5 52283%s 877..783788 00:18530 o_olleesl 229%6 s7l.a328 i"282086 T1e825s8 2Z.a1s2f3 7[.371286 Reterence Range 9- 9- 9 - o- Page 4 + 0060578 418-018:PAGE H-82 CYTICS ocne sen san cop vo om Client: ABSRUGSUSEERIRENSYECAORDRCRHIPVOELRAABOTREATDORIE3S0,1-9I2N1-C0.168 BDaatteeFaxRC:Oo3Sl0al1Ie-9Vc7Et7ae-S0d4:33 02/07/2001 2H(O20R1E82R).AN8:814"0Pa78010044- bate Reported: 10/10/2001 Client No. 1028 Study: 418018 FO C/S GD21 Species: RAT Afcceession s9pec B5B088080333777333080325 1110003988%95 Dpp 8o83%s373e30ess 1t108e88e88ss0 EpoRsIeEs Hi0eIe: HEeaHn Group 7 "GpSexAgeLDwLe-raDnIR HDWeLy-aDHIR CMHEOjLGHETST TRMeIjGem 777 EF 08o.:a34t58 080::.8858 332.3378%5 697.:53%88 777 7 aER8gI 88 8 8A8 8:3 n3aH 3% 17S%sE ash 8:8 88 BE 7de T8o8s T3h8e9ss 78.538 eRetfeerence Rangae 0g - 08 - o9 - 0 - Approved dlr PP! Page 5 of pate ---2/0/0: 4: 4 000573 418-018:PAGE H-83 LYTICS cre cr se 0crn io sor INCORPORATED 301-921-0168 Fax: 301-977-0433 9; FILE BEES SSIMEE 02/07/20 Client: ARGUS RESEARCH LABORATORIES, INC. Date Collected: (215) 443-8710 Pp / Arcecession SBpSec.| GpPSSeexxAMgee [LDRLa-nDIR HHDULR-TDIR CoHEOSLETST TmRiIea, ~~" nae 0 o o 0 voge 3+ 000580 418-018:PAGE H-84 CAINXCOTRPIORACTESD 3c015s2101s68 e sFax:t30016c770o80m8 0 or Client: AfHRiGaUSa tREaSEARCH LABORATORIES, INC. BDaattee RCoAlLlIeVcEtEeYd: 02/07/2001 HORSE Ba 1s044- bate Reported: 10/30/2001 client No(.2151)028443-8720 Study: 416018 Po LDS REPL Species: RAT ARcecsession S8pec. 5ppooooinseaetzi hHieienn BBpDoeeseainesEeRRsedss nnehieeRdde ppeeees HHsde Hoopaen Grou 11 pBppoeeeoaaeessnzo mH1n1ee0e4ls1 segaen Group 12 5 0036833 11059 Reference Range GpsexAge oiHl kEE nHIHookk:: oHoofk HIDBL-RDIR HDMLR-RD"IR CSHEOELERST TWREITGS 08e13a5 ae0.fR1 n2B.H7R3 8B8E.H4B7 eaa8:a6888 88a833::0 Ld3 npEa a MWEiRBg ae8883 3 n3i% i7dd a TT H Tar TN5Eae ainda BB1B2oFE:E 8d80:.a880e880 &8S0.3f32 E 1 13.B9 E EH13.Re08 B Toi 83 Tama Suse 1i4s 13 F 0.29 ous 2.26 suse o3 - 98 - 08 - o8 - Page 2 + 000581 418-018:PAGE H-85 CAYTICS score 00 cao wo wor INCORPORATED 301.921-0168 Fax: 301'677-0433 Client: A50R5GUSSHREEEHSYEARDCRHIVELABORATORIES, INC. DDaattee CReoclelievcetde:d: 02/07/2001 BH(OU2R1I8SL)HDAIMN4,G43A-P8A72019044- Date Reported: 10/30/2001 Client No. 1028 Study: 418018 FO LD5 REPL Species: RAT ANcoc.essionSbpi)ec. | GpPSSeexxAAggee BBB 000000333666888333465 111111000655137 3nnFFE BB 06003368883378 1110066d5 3IFEF M5ea5n0 Group 13 ILLIDELRT-NDIR HWDeLy-aDMIR CHNOeLjcEHST TWRoIjGom 00000000000 000.1232336 63a.:l5i32 211235.ll3288e0 001:1030 00:4475 3_3ll3789 111slldse1 1"605835 T2e%" T1ig%er iiTse.sgTes BBB 000000333666777666354 111000999332321 2:3 ExEF BB 06003368778687 1100993247 F:I or M5ea8n0 Group 2 0o0i.0l10s1 000.:238771 3&4.135319 19l0.a71d64 06:0000 00:3333 z38i1s 1io1ln7ds 8"o8s,s 1113a T8347386 110).i2a684 BBB 000000333666777687850 111000990324891 333 EFEFE B 0038771 10842 3 0F e5a8n7 Group 3 000.:320030 000.:354831 323.1l37e481 1880.:l05s992 0:36 0.4 3l67 8.5% "3o1s6s T10a8ss 3G.i2s7'5 s1uads Reference Ranugde 9- $0- 0 - $oPage 3 + 060582 418-018:PAGE H-86 CAYTICS ares 1, carn wo Client: ASREGSUSEERIERSNECAORBCRHPROLRABAOTREATDORIES30,19I2N1C0.168BDaatteeFaRxC:eocl30el1ie.vc9et7de7".d0:0002"/07/2001 HE ORSEAa N: Bt a 10044- Date RepPorted: g10i/3a0/200 Client No. 1028 Study: 418018 Fo 105 REPL Species: RAT ARscscessionS9pB;ec. | BBE5 oRooGuEs3oee7E r7r3iis1r e00ee4s3 bBoooolleenrse 1es8s Moepaen Group 4 GpSexMAagee dE ii I i fF LRDLJ-RDIR HMDLR-RDIR CgHoOLnEeST TmReIG, e0oa:-ao00se60 ig0f.idE2ns6 ii2m.EEE05 BEemEagmRr 0o:i0e0 8 0:8 3zBa 81::30 fT=a JTEhJiE i6aAn Emha TTT bBBo000s000333s676e7878s070 t1s1oo0ess9ee5lss7 25fffEFF 2 fF BB 000033ee77aa3: 110o5s7es6 52 FE Mgeean Group 5 gga9:i.0ge90s0 oo80.3di380 i 233.:%088 n9n9.:de580 ga9ee 6o:d3a 333BF 8 pal 0To0T cTdae iSoPn 2Th3ie3sy BB0O0je7Eas 11009781 F Reference Range e 0.008808.28 f41is m11.s02 $9- 8o- 8o- 8o- Page 4 + 000583 418-018:PAGE H-7 AYINCTORPIORCATESD .30.1..521.:01S6t8ool, SFuatxo302010.,57Ga7i.th0e4rs8b8urg, MD 20877 Client: OH ARRRSEGEUiASSN:RRiESEEBAaRBCRH1I0E0L4A4B-ORATORIES, INC. DBaattee RCoElLlIecVtEe'd: 02/07/2001 Date Reported: 10/30/2001 client No(.2151)028443-8710 Study: 418018 FO LDS REPI Species: RAT NA e.ccebSip)esc.s|iGo pSn ex Age BbBo00%e00s33ee6re77e83ss5 I1e100l83E97l37 &f& kEfEbFF Meegan Group 6 BBB88o03803e6er7r89es0e e1i1%00e9ee9%s5 7777 EfEFF Boe 7 fF Bsaean Group 7 B5BBoo000s003e33er66r7e7s9l3e5 n1910s809e390:80 8828 EF EfFF Bases HE 8 OF Referenrcence RaRnanggee LHDGL/-GDHI|R HMDGL-/DMIR CNHGO/LGHES&T TRMGIjagm ge80:od08ss09 6ggo:ia3itr3 311a:aBB8n 3BaeiHEnsi 0T82 3Th8a S3es L11i7gs 0g08::.:00080008 8808.33338%7 3R33i.I3s4EE6 10 1p0.df83 5:06 83f 3B 8% 83 erys TBIE: isa Sg80E:.Te80I80 88B03.3ch2BE31 330)4 W3saf63a.1t 6:66 0:33 38 8d 0 - 20- 2o- 9g- rage 5 + 0605821 418-018:PAGE H-88 PEERLE OD wou i iE GIYTICS ocr sues cars wo sm Client: NYigLusERITESNEICAORnCRHPYOLRABAOTREKIDORIZ30S1,-92I1N-G0.168BaatteeFaxSs:er30Rt1r-e97Ee7n-s0s43302/07/2000 client HORERAN, BA 15044. ro(.2151)028443-8710 Study: 438018 Fo Date Reported: 105 REPL species": 10/30/2001 TAT BTnS FesnarnTeuR 1e m Bn f Y e 12? & he T NG/gaGeM| MG/fE aGdHENOEjSnS GaeM|RMjnHeMi Imannniy 1i:: yrern g gee EdE IAE OiIeEs SWEOET,RC TaiEs iTaan croup 8 I ppooaaposncn nsematoass i mt10la0:s fff33 filoxf gggg0eagge ofgpnadEmm nIbrpmEEma aaRssneHma wB 0o036812 1r1oe0ap1nr8 3 F 0T.00EE0H.E27 TE2Ea:8e6 TT7.mm82 SO, ng g- g- se gNepro0vegSusoernA To A L 0 p0ace BL5 L 000585 418-018:PAGE H-89 CLYTICS oss son cscmors wo om Client: pugvs gestaRcy tAoRAIORISS, he. INCORPORATED 301-921-0168 Bate Lenses: Fax: 301-977-0433 HORSEAN. Ba 19044 (215) 443-8710 Date Reported: . 10 po /10/2001 ANcocsessionS1pBec. | Gp SexAgoCe LHDLo-nDIR WMDLR-RDIR CSRROOELESETST FRERIIaS, TTT B 0036600 11501 1F 0.00 0.09 1.43 5.45 TT 000586 415.018:PAGE H-90 CLYTICS guse e20 gs sm v0 oom Client: p ARGUSeRIENt SECAORRCeHPOLRAABOTREATDORIES3,01.5I2N1C:0.168 BDaaEtSeFaxSCRo3El0Al1Ie-Sc9E7t7Ee0"d6:38 02=/07/2001 H( ORSRAC NC BE a 1s044- Date Reported: 10/10/2001 Client No. 1028 Study: 418018 FO LDS REP? Species: RAT jfeoeoessiong8pec. pp5 ooe03nee7eis Hn11e6es7 pMeean Group 10 Gp sexAge LHDRLya-RDTTR MLROTTR R cRHEoSrTsst mEiEcjG II10 FEE 808::088088 f08.f18 13h.g3l0 5au9l.s3g3 33 a33 huise Hniman pp5 oao0m0nn3e6eag72snn2 nen11a6sa3l0 ii1i1 kkEEB pBBpooaennnaeeessss HHnHaaaalels iiiiokEk: pean HGS Ho: speaKn Group 11 p5 0o03n67g31 n116e40 B12 FE Reterence Ranngle 8a80::.8880880 a oa0.im4 eaa8:88888 k& aaBdH J 8a 83 BT3h0e 80.8080 S0B3 80- 89- rage 2 + h hh1.Em79 I fasounse Ihkhlhtn EnaadEnad nd 8 LNRs B8oa n1.f9 2a%. 8o- 89- 000587 418-018:PAGE H-91 CAYTICS oss sre. se 20 cana wo zor Sens: tWy L SINCPOPRPEORATEDRIE3,01.6h21e.e0168 2TH5ISFaxS:B3M01i-T877Pt-0433 ose BA Bp AJoecmeiconession spec. Gp SexAge IoDLu-lDIR al HDL-DIR CHOLEST TRIG avons 32 posers nies BR 8:88 iz 1d 1% 000588 418-018:PAGE H-92 CAINYCOTRPIORACTESD o 301-92c1-016r8 sFiaxe: 3501-9c77a-04m33s, wo wr Client: BA50RU5GTULSBSIHNERGEEHSYAEARDCRHIVELABORATORIES, INC. DDaattee RCeoclelievcetde:d: 02/07/2001 HORSHAM, PA 19044- Date Reported: 10/10/2001 (215) 443-8710 Client No. 1028 Study: 418018 FO LDS REP2 Species: RAT NAo:cceSHps ec.s|iGop Snex Age BBB 000006333666777583358 1I11i16c66e64s7 B33 FF0F M5ea87n Group 13 MDGL-/DGIR HMDGL-/DGI=R MHGo/iEGs=T mMmG/oGM 9o0l-lo0os0o 00o.:l12i13 222.810521 12f61a.147z%7 "R0E)15 "1i0s3ss 23.5376 1887.4008 BBB 00o00033l6c6ee11l4se 111i11s85i11e75 32FH oF fF BBB 000000333666e66i11s97 111111838131s0s 323 EEEFFF BBB 000000333686666737120 111111533233310 FF2E dEF BBB o00000333e6ee6e22ss5s 1111113332227s6 32FE FE B 0036626 11328 2 oF M5ea8n7 Group 2 900.ll000000 000.1l100287 113 :.7736 65e.:30n88 00011l000000 0o0lll01l82 i11l71s7 88e::s03s68 990:::000000 0o0:11y02 II2l1ds3s73 s&8i:i2388 og0llloogooo l9oolldos8s 1iil8ea3s 788::a3558 0lo0 oles ile 5.48 o I"0o87s 1G,7r11 Ts1.0asst2 Reference Range o0 - 0- 0- s0Page 4 + 000589 418-018:PAGE H-93 CIINLCYORTPOIRACTESD s3c01o.6n2e1:s0168 Fsaxt: 23001.9c7o7.m06m3o3n vo em Client: ASRGEUSSREESEASRCHELABORATORIZS, INC. BDaitte RCoRlLlAeTcEtEeYd: 02/07/2001 HHoREERAMN: Pna d10044- Date Reported: 10/10/2001 Client No. 1028 Study: 418018 Fo LDS REP2 Species: RAT Achecsession g8gec. SBBBoaooosinsgeeeeedsrs ma a iisns BpBBooooggsgieltlaeees aHHaaaee:d BBBBoooogggdlelllaeees imiiaaianll BBoogslee diiaels yotogan Group 3 BBp8 ooooasoetjtceeeeesdnds nda1itilsnetsee BBBooggotteeeeeiitz Haiaall Reference Range Gpsex Age LWDLT-RDIR HMDLR-RDIR CSHOELTEST TWRIeG 3313kkEOE 8o88:::o888o888 oiaafHRe ni1L7gnE8 asuiinfEa 3333%%ORff gee8:::88888888ea8&nER nLnLEgEm nRuuiEdds 3333 kOOOfff ggRg::8Rg8e8 eSeE&CRRBA nnmgEmI 8eHd ad 33 kfF 88::880 89% mhRE haE 8Too8r i Thai Lheess sloyans i444fkEEBF 08ea.0e880 08a%.08n8 sBa 1sY% 1N1me.BlB82 fiikff e 88%8 8SSe1 ie 2 aBiEe amnnduil o8 - 8o- 8o- 8o- Page 5 + 000590 418.018:PAGE H-94 CLINYCOTKPGIRACTESD s301o.02c1-01s68uvn sFaaxe: s301.5a77.06v55 vo wor Client: BARSGUSSRREESPEARRCYHELABORATORIES, INC. BDaItEe RCoRlAlAeIcVtEeSdY: 02/07/2001 F(ORCERrANo,tPta y10044 Date Rep502orted:sedj1i0a/L1i0n//2001 Client No. 1028 Study: 418018 FO LDS REP2 Species: RAT hAececession ggpec. ppB5oeoo%doseideeeeedeiigss 21a158a52 aed Bpoossdees iaisses Moeaen Group 4 GpsexAhgeeLWDELi-apRITMR HHEDULE-RDIR i44 fEFFE if gee 0.ee03 S 8S0:i19es8 fiff 8&:8888 &aa BT9o8s 8Ti%s ECRTHO TTRIeL Gw EST 313.%%05 Ld IB10.EE33 1 nnyy HHEg hualr 3 isase BFB8RoEoo%Eo%aa3ceeeE ssssts disH 1as2es8 25 EB ff ppBDooodooddgedgeeeseesst iaeitezet:e: 2233 kf [EBR odRdesEel vHeeIt 2 MBeEaRn Group 5 S80.o80o60 oh01im1 in17En4 eaeasRs e 88g8:o88o88S8o23fi8a hhndiRetd 8nI8dgR 8e e:66088688 S 8 n nnfa gadEdd 8:8 8:8 bg % 87 803s Tuegz afi3s Reterence Range 80-03 -0.8 8oPage 6+ 060591 418-018:PAGE H-95 CLYTICS ocr suense 200 esr vo a chert: RJREELINEECORRTPOPRAOTERD E3,01-9Toe.21-0168 BGRaEtEeFax:Bg3E0t1M-9aI77-S:0433 cajorszom TL A gun Reporiads Sorserzens (215) 443-8710 AcJicaession spec. op SexAge LDBLo-DIR HoDLo-DIR CoHOaLEST ToRInG croup 060592 418-018:PAGE H-96 CAYTICS ogre svo. se 0 as wo or Ghionss SEE SPIES PACCRETE, re. INCORPORATED 301-821-0168 SLE EAE Fax: 301-977-0433 A HORSHAM, PA_ 19044- Date Reported: 10/10/2001 . AFEcc--ession spec. Gp Sex Age LBDLa-DIR a HDL-DIR CHnOLeEST TmRIeG B 0036686 11593 7F 0.00 0.14 1.72 8.00 - crou7p 000593 418-018:PAGE H-97 ANTE. CLYTICS cine sr sae 0 sana vo wor Client: BAgJRoEGenUsES,oSSmSIEeNeSE8pCAOaRRCnHPogOuLRAsABOTREATDORIE3S0,1- 9T2H1-e0.1 68 BDaattseFaxS.SoS3l0Hl1:sS6c7Et7e-Y0d4:33 Date Reported: | 1602//1007//22000018 Client No(.2151)028443-8710 Study: 418018 70 105 REP? Species: AT gRieosneealong3ee Re H PF engy eR er n e pf he aaTp g$oE0a RmTp eeemnn Goeme nLremEs Emae faunHems FPfPPeoaommemmagneeneannnnueaaarerl Pomona oo2ggoffffof 3 of gggggeeeeE exgggmanmm rinirxnyge oogTaeRnaEd es eH En SE Group 5 yrogun 3 THC uyLam TTamm Reference Range 9 -3g -9$c 8g- NSSs N 000593 418-018:PAGE H-98 CAINYCOTRPIORACTESD 301-c921o-0r16s8 o 0Fa1x 3001.9c77-0s433r wo wor Client: A5B0RU8GIULSDSIHNERGEEHSYAEARDCRHIVELABORATORIES, INC. DDaattee CReoclelievcetde:d: 02/07/2001 H(O2R1S5H)AM4,43-P8A71019044 Date Reported: 10/30/2001 Client No. 1028 Study: 418018 FL C/S GD21 Species: RAT Neo:cession Sbip)ec. | Gp>SexAge IMDOL/-GDHIR EMDGL-/DMI|R CMHOGLMEST TRMGI/GGM | 5BB 000000333666939338980 111006339000513 111 B 0036967 100d 1 800::000088 T0oo:l8oo82 33l:.a72s88 523.ii0as34d 0:08 olan 38 3I3% BBB 00000033366639388e32s 11i00o33s00os7s 111 B 0038365 10530 1 000::000000 o001a3r52333iHs 4a3ili3sg8e8 0:00 0:00 3:88 _4lis Mea5n A Tooro 3a.e3d98 4f.e9d33 Group 1 BBB 00000033377700011T45e 1ii1ii0ss6ss0 111222 BBB 000000333777000111789 11i11i00g44s780 111322 BB 00003377007201 i11i0s3:2 1122 N5ea87n Group 12 000.0000 0gg.le0et2z 333.2aa8 38g5i.gS0s6 008::00000 @0g::l00e33 333:g338 S7si1lg8s8e 06:.0000 08:0038 331:3336 gSliise 0 TJ0I21T0 T3.as 5.8463 Reference Ran3g!e 98 - o- $Is 80Page 1+ 060595 418-018:PAGE H-99 CGIYTICS oo creo 020 as vo wor INCORPORATED 301-521-0168 Fax: 301-977-0433 Client: BA5RU0G5IULSDSHIRENEEGHSYEAARDCRHIVELABORATORIES, INC. DDaattee RCeoclelievcetde:d: 02/07/2001 O(R21S8H)AM,443P-8A71019044- Date Reported: 10/30/2001 Client No. 1028 Study: 418018 F1 C/S GD21 Species: RAT - ANcec:ession s|pec. BBB 000000333777000222343 111111000555643 BBB 000000333777000322785 111i110005e6820 BB 00003377002258 1111006663 ' M7e8a0n Group 13 "Gp Sex Age IMDGL/-DMIR HMDGL/-GDMI=R CHMGOJGLM_E__ST TMRGI/GGM 1333 000l0l000000 o000.ii00033i 333.3l1e081 533.3l8s12h bbee3]} 000:::000000 000::i00g862 3337ia313 es8ll3sa7:i i3 00.10000 900i:0032 _322ll7870 _ a42l7s 0 TIo7sE" EET3TzHi s25i9e1n BBB 000000333666399666768 111000999111785 222 BBB 000000333866893776019 111000999112980 222 BB 00003366997732 1100892285 32 M5ea57n , Group 2 i 000::.000000 o00l.lo00r03 323l.ia9ss70 4s4i:.g97s69 000:::800000 003:l:0o06z3 4a3:dl0oi14 4g4ll9aoz 00::0000 00::0000 _33lie87s _ 551l2s4o o8 1C6o0o8s Ts3iiet3s 51.4d3 | ReftoerrenceRangoe 6[Ed 00 - 08 - S0 - i Page 2 + 000596 418-018:PAGE H-100 CAYTICS crn sre ss 0 canons uo zr INCORPORATED 201-6210168 Fax:301:6770458 Client:3A0R2GUSSuEREEHSYEARDCRHIVELABORATORIES, INC. DDaattee RCeoclelievcetde:d: 02/07/2001 H(O2R1S5)HAM4,437PA872019044- Date Roepforted: 10/a3d0/2001 Client No. 1028 Study: 418018 F1 C/S GD21 Species: RAT ARecscessionSbpi)ec. | GpPpSSeexxAAgdee IRDaL-kD"IR HKDeLy-aDnIR CHNeOiLeEwST TRwIWeGjem BBB 000000333666999777684 111000999333210 333 0001l.000000 000l.lo00735 a5al.le0ss9s 9sg.ll0sa8el BBB 000000333668998777879 111000998333138 333 000i::030000 00000lo233 is&llgl3d1 s77iladee1 BB 00003368938801 11009s3a70 33 06::9000 o60o2n a3l8d1 6_6.l2360 M5ea8n7 S0 Tloosiss TNa;Es38 7i.l95e3 Group 3 BBB 00000033366639388852 111000338444s57 444 BBB 00000033366693388875 o1100s998do2s 444 BB 0000336633388 1I0s9s8a3 44 MSe7a8n7 Group 4 008.::099000 g0gl.lo0e353 535.l07700 111039.015s83 9001::039000 o9glolo%o12 l3d:io9ag8s 87e.l%3i9 08::0900 goalzs 3is0s 1e41l3z2s 9s `Tooizse 5T.82148 92.:53788 Reference Range S0- 9- 9- 0s Page 3 + 000597 418.013:PAGE H-101 GLINYCOTRPOIRACTESD 3a01-r521-c0168s Fsaxo. 23001-9c77.s040t8 wo am Client: ABBHmOSgRuEsRi BRKCEESREBaALBCRH1sEL0A4B4O-RATORIES, INC. pBaaEtSe RCOoLlAlIeTcEtEeYd: 02/07/2001 Date Reported: 10/30/2001 Client No(.2151)028443-8710 Study: 418018 F1 C/S GD21 Species: RAT AchecsessionEsHpec. 5BB088088333566033900003 111000935588888 3B3 88888333ee23ss8e:2s 1a08g35e8xr? 3B8o33he%se 013sa Heoagn Group 5 8BB 8og8083a39ce8es8os8se 1w108i9277t28 F F 5B 8888R R 33730080E E 30 11E T 00837828 3 O80 18%: Hoegan Grow & Gp Sex Age 522 338 33 LHDeLj-oDHIR HMeDyLa-RDTMIR 088.::088088 o88:i888 a8a:8888 88a%% e 8:888888% 78 TBaH SCETH H OTWREL IjGGMEST 331.B7B2 52L.33R3 iu8hy LLuGyR 3iBE I49k8 ius.h sHaRms 68 088::.880880 088.08%3 44fal8s 57L.s9R9 aa88:688888 8888:48%8 hLH33EBR0 ni8aBx8i 8 8:88 8:8 dL Sid 83 S Toa u iaes TLaBe Reference Ranngge 03 - 08 - o8 - 8oPage 4 + 000598 418-018:PAGE H-102 GLYTICS cons se se 0 mo 0 Clients INCORPORATED E p35u8gBsoE aSkEeTyTAREeaFeACET are b Gat iCapen SEA 905 SHEERY DRIVE 301-921-0168 Fax:301-977-0433 Date Received: 02/07/2001 ations To oy (215) 443-8710 svutys 4seuss 72 07% woos, speotens WAT ANcecsession SBpec.| GpP Sex Argaee LRDLJ-ADIR HEDRLIG-RTDRIR GgHROonLEEstST TmRiIgG, ~~ B 0037006 10985 7 0.00 0.05 5.00 8.88 - E soho mse 2 gE Ee ik na croup 7 Reference mange ge oo ae ae o- 0 0 0 0 soprovad weer e'ezerer pave LofLe fonoa op Page 5 of 5 iz 000599 418-018:PAGE H-103 GLYTICS soos 30 common vo wor INCORPORATED 301-921-0168 Fax: 301-977-0433 Client: BA5RU0GI5ULSDSIHNERGEERSYEAARDCRHIVELABORATORIES, INC. DDaattee RCeoclelievcetde:d: 02/07/2001 HORSHAM, PA 19044- Date Reported: 10/10/2001 (215) 443-8710 Client No. 1028 Study: 418018 F1 LDS REP Species: RAT fiAccession s1pec. TTGp Sex Age BBB 000000333777000999423 111000399001s61 111 EFEE BB 00003377008965 1100991143 11 FEF M5ea87n Group 1 IMLGDL/-GD|IR HMDGL/-GDMIR 000000000 0o9.ll0eo8ss 0010000 _09ll1ods 0s "10033,2 C MG/GH M__OTMRGIL /GGM EST 443.ll4ia0sz 221911.1083367 _s3ll1s18 2a61r2g7 ip5t50 l15i.ease2 BBB 000000333777000333201 11100099901061 111 MMM BB 00003377003343 TT0o8s1i3a 11 MM M5ea8n7 Group 1 000.::000000 000.100s86 33d.i89g34o 2ii1B3.l98a88s 06:0800 o0l:a1? i3s8p7 3g0le8s 0 1"o0g23 oezg 1a7l.s8a84 BBB 000000333777111333458 1i111000213193 111000 EEE B 0037137 1i0zs 10 F Reference Range 000.::000000 0:00 S0- 000.il00038s ol07 I s a43l.30lg8e las 9 11338.ll3d20e6 23l83 80- Page 1+ 000600 418-018:PAGE H-104 CYINCTORIPORCATSED s30o1-c921-s0168v sFaox. n30.1.9c77a.04v33a. vo wor Client: BAS0RU5GZULSDSIHNERGEEHSAYEADRCRHIVLEABORATORIES, INC. Dbaattee RCeoclelievcetde:d: 02/07/2001 HORSEAM, PA 19044- Date Reported: 10/10/2001 (215) 443-8710 Client No. 1028 Study: 418018 F1 LDS REPL Species: RAT NAoc:cessionS2p'ec.| GbSexAge IDMGL/G-M_D__IR HMDGL/-GMD_IR CHMOGLJGEMST TMRGI/GoM BB57000000333777111333089 11i11o0022e75 111000 EF F eg9go0oo 0oo0la8yr 41s.11s88288 11S36:.i89d73 BB 00003377178441 111003308 1100 0e0g0o 8l:o3a6 23::3383 1168::3380 MSe8a7n o RToE7I az i1s31e Group 10 BBB 000000333777000777432 1i111000231139 111080 BBB 000000333777000777765 111111000333853 111000 MM BBB 000000333777000677198 111111006332870 111600 MMM MSe7a8n7 Group 10 g9g.lo0eo0e oo9l.gi0yn8 ad4.id22 1132E:.I39S77 ooollgiiggooo ooolll3osar 34al13l38e 1T1a33l:1a33:7 6oo:gg6oo0 8ooll:il7k 333:1138858 598::790s18 0s T3os2e" TLaEaYm 2iisa Reference Range 0- 0s - 6o- S0Page 2 + 000601 418-018:PAGE H-105 Clients NigUE RIENSECAORRCHPOARBACTAETODRIES30,1 TNC. -921-0168 GateFaxEollseiad: : 301-977-0433 (215) 443-8710 | gE y Bocesalon Spec. GpsexAge IEDLaDIR HGDLa-DIR CDHOoLeEST TIRIhG rage 3+ 066002 418-018:PAGE H-106 INCORPORATED 301-921-0168 Fax: 301-977-0433 Noceaaton peep se hae gph ram gions gue ! oro 2 Mean oro oo 9 0 .07 3.97 8.82 o 0 0 0 000603 418-018:PAGE H-107 CAYTICS INCORPORATED EEE ose 905 SHEEHY DRIVE (215) 443-8710 ogre sv sre 0 ass wo sr 301-921-0168 Fax: 301-877-0433 Date oni Received: 02/07/2001 AJecaicenession 3Spec. GpSex Age ra LDL-DIR fo HDL-DIR CigooinEest FiReG 9 0 0 0 0 000603 418-018:PAGE H-108 SPSRT LEOIY INCORPORATED eu iadBE 301-921-0168 ES SEIT Fax: 301-977-0433 ca/oraom EERE ese Sess ramet Wood (215) 443-8710 P Ajecaiocn ession spec. Gp SexAge Er LOL-BIR fe HDL-DIR CgHOoLnEeST TiRIeG 060605 418-018:PAGE H-109 CYTICS cine svn sae vo om INCORPORATED 301921-0168 Fax 301.977-0433 Client: 5BA0RU3GPULSOSIHNREGEEHSYAEARDCRIHVELABORATORIES, INC. DDaattee RCeoclelievcetde:d: 02/07/2001 HORSHAM, PA 19044- Date Reported:. 10/10/2001 (215) 443-8710 Client No. 1028 Study: 418018 F1 LDS REP Species: RAT RNooo. ession S3pec.| Gp sexATge MLGDL/-MbIRMEGD/LTMR cMhGo/lGes TaMGi/oGH B 0037048 10970 5 0.00 0.08 3.52 27.48 M5ea5n7 0 1"068333 3z.e8'85 21.467 Group 5 BBB 000000333777111111321 111000999877373 66& FFEEF M5e5a7n Group 6 09g1.l00e00e _09gl0lo.e0zs7 4a3:l.3l68d6 111762.1.9140s3 0 T10632787 T3ao8s 1h5.E393 BBB 000000333777000834039 111000889787937 6&& M M e5a8n7 Group 6 009:.000080 oo9.z0s7 333:.988820 i1iT7ia.fl3ea7 9s "BoR:g 31.7793 31725,1939 Reference Rannege 0 - 0o - 0- 0o rage 7 + 000605 418-018:PAGE H-110 CAINVCOTRPIORACTESD secon sro son 0. sara vo or 301821-0168 Fax 301.977-0433 Client: BA5RU0SGTULSBSIHNERGEEHSAYEADRRCIHVELABORATORIES, INC. DDaattee RCeoclelievcetde:d: 02/07/2001 HORSHAM, PA 19044- Date Reported: 10/10/2001 (215) 443-8710 Client No. 1028 Study: 418018 F1 LDS REP1 Species: RAT AcNocwession gipec. BB 00003377111145 1100999975 MSe8a7n Group 7 Gp sex Age IHDOL/-GDMI|R HDMOLJ-GDMIR CMHoOjLoEMST TMRGI/GM 77 FFE 00:-0000 00.:10%5 _FaEiTez a7l.e3s7 60 RTodss Tt3lheis 3ai1m612 BB 00003377003532 1100899975 77MM MSeaYn Group 7 00.000 00..0084 i4.d5s5 135:.3332 0 "1o0e2s a"05822 511i3e5z3 BBB 00000033377711111176 111101090090190 888s EEEF BBB 000000333777111313093 111111000000s23 888 EEEFF BB B 800000333777111333:32 111i11o00a00785 88 FEF 8 EF B 0037125 iloos 8 F M$e7a57n Group 8 090:.880880 0l0l.o00z87 333i.8e4se5 z1325..0730e80 9g9:l:0e08e8 g08l1:o00?96 ii3:dg4e0 11S18la33s 99l:0000 o0:l0e7 4i.1o7 15gl.7388 00lloo00 olloess 3il0e72 15i.l7037 0o 0To2s1s 33.5992 512.%933 Reference Range 60 - 80 - s0- 0rage 8 + 000607 418-018:PAGE H-111 CAYTICS oes ses st 0, smo wo ze Client: ARGUSSRRIENESECAORRRCHPEOLRAABOTREADTORIE3S0,1-9I21N-C0.168 BDaatteeFaxSC:oL3l0Al1Se-9cE7t7Ee-Y0d4:33 02/07/2000 BaOsREAaS nBad10044 Date Reppoorrtteedd::. 101/0/10 10/2001 Client No. 1028 Study: 416018 FI LDS REPL Species: RAT hNeeoceSfpaeeion sen ne BBH 5oooaooieiseaese n MM10ee3se8 8H f8 k BBBBooooydoyeoecsmee eHHHoeorese: 888fk pBoodsieess HHekl f3 d Mteogan Group BpURgR IRgRn GghoLEo sT mm Ieme,,er es5T:ge888no8ekr Ii13.EyB90 Im1a.iy5n4 aaas888e uee8ai%g IB4 neEd BmuBEiaa S gig 88 gE Benh BsEe 3 T8on ihain 1Paa:l p8BBoooeoga7muaizeme e1Ha1ee0l0yss 33 3 ofEEFF pBpBoeoooammBvpemeMieee 33f3 }ffF eeapn Group 0gea.::080088888 0g8.p08 iI4f1gEd5 u110n0.b7g30 &ee8::0:88858808 e8o8in%%e kdbfnEEi 1 21 Mi8e 3 TBeR auew mPialn Reterence Range 80o- 8o- 8a- 8oPage 9 + 0806038 418-018:PAGEH-112 CAINYCOTRPOIRACTESD s30o1-0c8010s8 m saxn30.1.9s79.a045m5 s wo zur Client: 2BAA5ROE%GRUE8SRAURRSEERSEBaABRCRH1IsEL0AsB-ORATORIES, INC. BDaattee SColRleRct!ed: 02/07/2001 Date Reported: 10/10/2001 HOE Mahd Client No. 1028 Study: 418018 FI IDS REPL Species: RAT Fheoesslerg8en. or Sex nae BBB2 oo0oo0o3on7se0s6ts8 11008 oHell! 3333 Hi PBBBoooEoooRsssNeee N HdHeelll3 e 238okdX seoagn Group 9 pHRiTpe mIRiIp gSoORmESeTr gTeRI,G oSgg::o808o800 o88geig8sg ahd3aegi m1H3iB3n 8egg:::888058888888%d8 114dB8% gHaMBHnEL 38 T8o3s Tu ioisBR 131s Reference Range 08 8o- 8o- 8o- seproved one Prove Rage 16 of 10 pace 0lr0for 000609 418-018:PAGE H-113 GLYTICS ogre so zo [-- Client: Syuecuns sBIENmSECAORRCHPOLRAABOTREATDORIN3S0,1-9I21C-.0168 EH NI EDaRteFax:co3v01i-e9r77i-e04.33 Date Reported: 10/10/2001 (218) 443-8710 fjoceeasicon ession 3spec. """GpSexAge LRDLi-aDIR HDfL-rDIR GHgooLsEST TRmIiGe. B 0037431 11501 1F 0.00 0.10 3.51 18.40 ~ rage 14 006E19 AIBOISPAGE F114 CAYTICS ogra sron se 200 cms wo sr Client: pugTy RIENRCPORCREPOPRRARTCERDIES30,1-92T1e-0.16|8 GatFea ELEEEES x: 301-977-0433 ROR rd a Accessionspec. GpsexAge rl ul iE LDL-DIR HDL-DIR GioLest gmiG ! Group 1 croup 10 000611 418-018:PAGE H-115 CAYTICS oss sre 20 com wo zr Chant: AyRrGsUS, RSIEeNSgECpAORaRCnHPcOnLRAABOTREMDTORI3S0S1,-82T1C-0.168 B5a3tF8eaxSH:o3l01Ii-s9e7Et7-e0d4:33 c*orneum (215) 443-8710 Pe 10/20/2001 AJacecsicon ession sSpec. Gp sexAge TDL-oDIR HDTL-rDIR I CHoimst TaRInG B 0037401 11620 10 M 0.00 0.06 3.02 11.72 ' 000612 418-018:PAGEH-116 CLINYCOTRPOIRACTESD 301-c521i-0r16c8 a sFaix 3001-9r77-04n08 wo sm Client: ASREGUBSERESEARBCRH ELABORATORIES, INC. BDaattee RCOo3lSlEe5cEtEe"d: 02/08/2001 H(O2R3E5R)AN4S 42B8a72010044- Date RepPorted:. 103/1000/2001 Client No. 1028 Study: 410018 F1 LDS REP2 Species: RAT Achecsessions8pec. BBBSoeoeoyaeaeitig ndiiiiisgem3dee BBBBoOooeLanlEl HHHHaeEese Be HES Noeaen Group 11 Gp Sex Age iiLukH iiii Mk HidM HIeDyLa-RDTIR MHDRL-RDIR C REH T O THREIL 7GG EST aae e:o00e08 88 SS0.yi71: E3ailBs3 8 R100h71 By 88&8::8800888 8 8813 83 a 3 nm ni gugtki 8:8 8d 3 i 87 BTEe aN7ee NInyes BBBBoaoeodysaarsssdaess ddn11iei6els4dil0 iiB12 fEE BB5B888o83e3z77d2e3se0 ddddieiigsekltdes 11Bf if pe He BF Mgeogarn Group 12 e e a0.8000 66 8i o8 8m 88gg:0o000b68 8800::3888 din2.h5pg3 a8Msulhis 333p38 GaMdi3dd 3 eB T$o0o ETImT IWtE Ipnane Reference Range ng 0- o- 9- o- 0 0 0 0 Page 4+ 000613 418-018:PAGE H-117 CAYTICS cms suns st 0, sm. wo ms INCORPORATED 3016210168 Fax: 301.977.0433 Client: BA90RU8GIULSDSIHNERGEEHSYEAARDCRHIVELABORATORIES, INC. DDaattee RCeoclelievcetde:d: 02/08/2001 H(O2R1S3)HAM4,43P8A72019044- Date Reported: 10/10/2001 Client No. 1028 Study: 418018 F1 LDs REP2 Species: RAT fiJao:cession BBB 00000033377744132903 BBB 000000333777444323323 BBB 000000333777444333758 Group 12 S3 pec|. 11111ie66s4i01z ll1i1ig6gi4ess 1i11il8ge8sa5ol5 M5e5a7n GpSexAge 111233 NM 111332mMNM 111323 MMM LHDOL/GBHIR HMDOL/GBHIR ghMoGJeGHsT_mMmoi/eoM 0080::000000 0988.::030535 323.:31358 .8lT.ie5Ed4dd 808:::000000 80&:8133 233853%7 1090::3387 800:::80088 8O0:b30s5 i33:ap7l L1'3idiidggdd 0To7s T0o8se Thasasm: F1l1a1s2 BBB 000000333777583333858 1111116665334:8 111333kEF MSe8a7n Group 13 008.::008000 0S8i.ls1o 333.2380 01733.8330 oS 16 35.865173 130%,407 BB 00003377442288 1111665345 1133 MM Reference Range 08:.8020 0S1s 33.8 7a.d27 0S - 06 - 06 - I$ Page 5 + 060614 418-018:PAGE H-118 SINCLmYgTdICbS iso snsre.n sun corm vo mam INCORPORATED 301-921-0168 Fax: 301-977-0433 (215) 443-8710 NAocscessionSbipec. | Gp Sex APgoee LD[RLJ-GRDTMIR HHDRLU-RTMDTMIR GSHHOOLLESETST TIiRIgS, TTT croup 15 retarence mange SONI 060815 418-018:PAGEH-119 CAYTICS so groom sn sans wo 2m Starr QE AT EI Tr INCORPORATED 301-921-0168 TEE EL Fax:301-977-0433 a Bh soon pate Reported: 10/10/2001 (215) 443-8710 jJocecsaicon essiong3gec. B 0037339 11515 Gp Sex Age 3M IDL-DIR lll HDL-DIR CHOLEST TERITG 0.00 0.12 3.28 13.01 TT genie 2 of ge su a ga Gi 0 0 0 050c13 418-018:PAGE H-120 clients aNnEgTts, SpIENaEtCaOnTRcrPIOLRAABOTTETDORIZ3S01,-9Te.21-0168 2B2u8tF2eaxS:ge30l1Ri-s9c7Te7-a0d4:33 casonszom (215) 443-8710 Ajececsaiconession Sg ec. Gpsex Age LrDaL-lDIR HDL-DaIRkCHa OLESTk TRIG ge 0 0 0 0 000617 418-018:PAGE H-121 GLYTICS orem se 0 ims wo mos Chants gF upiy EINh TCOTRPOARRAITOERDITE3,01-8h21-e0168 BBe3Ft5axSt:a30pR1e-97T7o-0r433 oa/0n/e0m A ak. Jecesaionspec. GpSexAge Rr LDL-DIR fh HDL-DIR GR CHOLEST TmRIe~~ B 0037360 11558 5M 0.00 0.11 4.31 23.45 oT 060618 418-018:PAGE H-122 CIYTICS oo ous so se cams vo om INCORPORATED 301921-0168 Fax: 301-977-0433 Client: AB9R0UG5TULSBSIHNERGEEHSYEAARDCRHIVELABORATORIES, INC. DDaattee RCeoclelievcetde:d: 02/08/2001 H(O2R1S5)HAM4,43-P8A71019044- Date Reported:. 10/10/2001 Client No. 1028 Study: 418018 F1 LDS REP2 Species: RAT AcNcoe.ssion S1pec." BB8000000333777333777152 111111533777485 BBB 000000333777333777385 111111232878280 BB 00003377337787 1113388d5 MSe7a8n7 Group 6 Gp SexAge LMDGL-/DMIR 6&& MMHM 00.0080 &&& MMM o0lloooo 86 M 0.00 o HMDGL/DMIR oo0.lu1ir2 oliz 0.08 012s2 CMHGo/iGgMst_ImMGi/gGM l33.8o71r8 1sT4l.le7Es6s 27: 7.62 3.17 9.75 5Geest 3ele%m: BBB 00000033377744488875 111111583999275 777 FEEFF M5ea8n7 Group 7 o9l.o0o0 0o.l1i1c 431l2d 119s.i3721 0 11606s7 4 7 21178.85315 BBB 000000333777333887109 111111353898327 77 M 7M M5e7a8n7 Group 7 0.00 0.11 3.25 8.48 69 pr6ey 33725 1T)s.as Reference Rang9e 0- o0- S0- 0Page 10 + 000613 418-018:PAGE H-123 GLINYCOTRPOIRACTESD 3c01-52m1-018s8 si Fax. 030,19c7-0a43v3 a vo wor Client: ABSR0UG5ZULSDSIHNERGEEHSYEAARDCRHIVELABORATORIES, INC. DDaattee RCeoclelievcetde:d: 02/08/2001 HORSHAM, PA 19044- Date Reported: 10/10/2001 (215) 443-8710 Client No. 1028 Study: 418018 F1 LDS REP2 Species: RAT ANoc:cession 1Spec. BBB 000000333777444988098 111111666000210 BBB 000000333777444989321 111111688000s43 BBB 000000333777i44s93s5 i1il1le6eo0os7e B 0037437 ilecs MSe7a87n Group 8 Op Sex Age LDMLG-/DGIR 8[8I EF F 09g.:i00g00s 888 EF F o99ll:o00100 888 FEEFF 0991::000000 8F 8:00 "1o8o63 MHGDL/DGIR 000..110338 000::111333 000l10o18s 0:31 T0102987 MG G/Gh H o IMmGIL /GM Est 33388s1 1a117i..20e40 43311i822192 24a5:l:2d98o0 i42llli8os2 12733.215207 3187 13:8 IT5E7E72 812550962s . BBB 800000333777333888332 1111I1666000210 8[8I M M BBB 000000333777333888765 111111666000843 88gMMuM BB8000000333777333889590 111111666000876 888 MMM B 0637391 11808 & M M5ea87n Group 8 909:.08000 000:.l31o019 33.s85 3:38 a15i.s020 fad gg0lllig0de0e o0ol:ii0i38f 3331033018 189s.l30ek72 00o:ll00d00e 0001:l90g88s 2331l37783s 123a0.l70s89 0:00 6:08 3112 1813 So "6o3o11 31.333745 51736.0329 Reference Ranogde 9 - S0- 0 - 0- Page 11 + 000620 418-018:PAGE H-124 ANI AYTICS oes sue Gatarsug, M0 20877 Client: ABRRGEUUSSERIEESNEECAORRRCHPEOLRABAOTREATDORIE3S0,1-9T2N1-C0.168 BDaEtSeFaxRo:RrL3t0A1eL-So9Et7R7eY-d0"4:33 02/08/2000 Client BORERAN. Ba 1s044- No(.2151)028443-8710 Study: 410018 F1 Date Reported: 105 REP2 Species:: 10/10/2001 RAT fHgscennionggec. GpPSSeexxAhveee GBRRIDTER BEDRLpTIN GHROOLLSETSE EmGL, T BBFgpB e0doa0R3am7Es4ms9E8 Hnee1E1ee6rn1rn1 338 F 23 pof Bade ere pf 0GGGSg .88088800 s0i Saee.1lplR6 I qI3gn.onk9m0 m1rBm5ow.eEE8g2 ~ ge ol ym ows BFReEmERHe 3 f Hdoeapn e$:888 o%lee ipne n#9w 83 B TE WPign m2an Group pBB BBoaeoosam adimnssminnnneeenalnn 33p9o 3 ou xxox BBBFeaeoammnuessHnnEaeeE: 3333X Group 9 tseean &G$$0.8880888 8oB s0lBi0p IpnI3hel7 aEa1owam8gn 8GSg:88o888 eS&emHiR Iq3ImBnn EgmwneEm 38 TWeEr iuapm The Reference Range 8g- 8g- 8s- Approved ==---PP! Page 12 of 22. 12 8a- pare --fs2/0L eels 000621 418-018:PAGE H-125 INCORPORATED 301-821-0168 800-237-2815 QAAUDIT REPORT GThoeodrLeapobrotratloirsytePdrabcetliocweswaasndrewviitehweEdAfoGroocdomLpalbioarnacteorwyitPhractthieceFsD.A Tahcecurfaicnyal arnedporctonsainsdteanlcly asasnodciattheed frianwdidnagtsa wweerree rreevpioerwteedd fotor management. Tiahncecucromametptelhlioyadnscreefuwlsieectdths twhteehreeFDdaAtthaea.ndmeETthPheAordeGsfooorded,eLsacbtrohierbsaeetdorsytaundPdireasctthiweceerser.epdoonret oFhraAnukdliitnorB. Newasn seonsor: __Afcus 485 REPORT TYPE cu 10 0, TIE AUDIT DATE 3-9] sTooY: _AI50jf REPORT TO MANAGEMENT 10-33-9/. AUDIT # BA Lofalor. TD DR_R. Yock DATE SUBMITTED TO Via MANAGEMENT (o/24/0/ 000622 APPENDIIX BIOANALYTICAL REPORTS (PRIMEDICA WORCESTER, SPONSOR AND SRI) 060623 418-018:PAGE I-1 FINAL REPORT VALIDATION OF A GAS CHROMATOGRAPHIC-MASS MEVSAPLEOCNTIRCOMAECTIDRIICN EMDETTAHROADTFPOLRATSHMEA AFNOARLYPSRIISMEODFICA ARGUS STUDY 418-018 Primedica-Worcester Project Number: PABX-BVA 905PSRheIeMhEyDDIriCvAe,ABRuiGlUdiSng A Horsham, PA 19044 000624 pe PRIMEDICA 418-018:PAGE 1-2 FINAL REPORT VALIDATION OF A GAS CHROMATOGRAPHIC-MASS SPECTROMETRIC METHOD FOR THE ANALYSIS OF MEVALONIC ACID IN EDTA RAT PLASMA FOR PRIMEDICA ARGUS STUDY 418-018 Primedica-WPororjeccetNsutmbeerr: PABX-BVA Submitted to: PRIMEDICA ARGUS 905 Sheehy Drive, Building A `Horsham, PA 19044 Submitted by: Primedica-Worcester 57 Union Street `Worcester, MA 01608 Primedica-Worcester Report # PABX-BVA-01-62 Page ] of184 Issue Date: November 7, 2001 Wid 2.9050 oto Mark A. Netsch / Date Project Scientist Departmentof Analytical Chemistry Primedica- Worcester 060625 418-018:PAGE 1-3 SPRIMEDICA Primedica-Worcester Project number: PABX-BVA Page2 DFionaallReepeornt FoFrorPrPrmiemdediiccaaAArrgguussSSttuuddyy NNuummbbeerr::441183-001158 `COMPLIANCE STATEMENT This project was conducted in compliance with the Good Laboratory Practice Regulations, 21CFR, Part 58, Good Laboratory Practice Drugs, MHW Ordinance Number 21, March 26, Standard for Safety 1997 and Counc Studies on recommendation on compliance with principles of good laboratory il decision practice. Official Journal of European were no deviations Communities: Legislation from the aforementioned 32 (No. L standards, 3w1h5i;ch28aOfcfteoctbeedr):the1-1q7u.aliTthyeroer integrity ofthe project or the interpretationofthe results in this report, fd o. PutbX 1yss, MPraorjekctAScNieetntsicsht /Date 000626 418-018:PAGE 1-4 SPRIVEDICA FiFPinrniaamlledRRieecppao-roWtno_ rcester Project number: PABX-BVAFoFrorPrPirimmeeddiiccasAArrgguussSSttuuddyyNNuummbbeerr: 4411P88a.-g00e11388 QUALITY ASSURANCE STATEMENT Number PABX-BVA, `The following are the inspection dates and report dates of QAU audit/inspections for Validation Of A Gas Chromatographic-Mass Spectrometric Method For The Analysis Of Mevalonic Acid In EDTA Rat Plasma For Primedica. Argus Study 418-018, Project Critical Phases 1. Laboratory Procedures 1. Raw Data 2. Draft Final Report Date Inspected 10/19/2000 11/07/2000 03/26/2001 Date Report Submitted to Project Scientist Management 10/20/2000 10/23/2000 04/06/2001 04/06/2001 03/26/2001 04/04/2001 The Final Report for Validationof A Gas Chromatographic-Mass Spectrometric Method 4F1o8r-T01h8e,ArneaployrstinsuOmfbeMrevPaAlBoXn-iBcVAAc-i0d1-In62E,DwTaAs Rat Plasma For Primedica Argus reviewed for compliance with the Study Good Laboratory Practice Regulations, 21CFR, Part 58, Good Laboratory Practice Standard for dSeacfiestiyonS/turdeicesomomnenDdrautgiso,n MonHWcomOprldiiannacnecewiNtuhmpbreinrci2p1l,esMoafrcghoo2d6,la1b9o9r7atoarnyd pCroacutnicciel. oOfnfi1c1i/a7l/0J1.ournTahleorfesEuulrtsopaesapnreCsoemnmtuenditaicceusr:atLeelgyirselfalteicotnt3he2 r(aNow.daLta3.15; 28 October): 1-17, Q \. u - al. Quality Assurance Auditor aly Date 600627 418-018:PAGE I-5 PRIMEDICA Primedica-Worcester Project number: PABX-BVA Pages Final Report For Primedica Argus Study Number: 418-018 TABLE OF CONTENTS Page No COMPLIANCE STATEMENT ...cocovvrrcescssnsssssssssssessesssssessssssssssssesnese, --1 QUALITY ASSURANCE STATEMENT ..cvvvvvererrromomessseessses -- LIST OF TABLES ANDAPPENDICES....ccocccveseerrrmosossssssesossees CONTRIBUTING PERSONNEL .....cc.cccrssvsersessssssmmessssssssns ee ---- S-- ANALYTICAL REFERENCE STANDARD CHARACTERIZATION/STABILI.T..Y.. EXPERIMENTAL DESIGN .cccoevoromomsrsmssssersnsessssessmsmsmmssssssssseeo, w--) } MEETS ANA MEOGS voor eeeereessensesnssssss sees sees sesso, 1 Validation DESCHPHON .....cccovvvvvvsvrrersrrssessosnssssssssssnssssessssssseseeseenenn 11 Parameters EVAIAEd .........coccvvvvvvmerreecrsssessessssssssssssessossssosneeneesneen, 12 RESULTS AND DISCUSSION ...ooccoccrvsreseessssssssesesses seeseesessssssssesseeen, 14 Water/Plasma EXITaction COMPAFISON .......evweerseeesessssmrmemessssssesesosn 14 eT RDEICROIVOENRQY.C..c.oersvsersrsersrre eressss sssses smssse sessrr sersse esssmsmmeeeeee we 1166 000628 418-018:PAGE 1-6 PrFiimnealdiRceap-oWrotrceste Project umber: SPRIMEDICA PABXBVA For PrimedicaArgus StudyNumber:41P8a.g0e13s : LIST OF TABLES, FIGURES AND APPENDICES TEXT TABLE | Validation COUTSE ......oveveceeecvssrssreceeroe essere PageNo, ensssssinssssssssssssssananasans | 2 FIGURE 1 Day 1 Validation Calibration Curve........................... I ---- TABLE 1 Summary `with Inter aofnIdntIenrtproal-aDtaeydSMUeMvMaAloTnYicStAUcSiHdCSL.a.c.t.o.n.e.`cQ.CcvSvtsanmdrarrsd Concentrations essen 22 TABLE 2 Summaryof Back-Calculated Mevalonic Acid Lactone Calibration Standard CONCERIBONS w.v.coeoesssseerserses soreness ermine24 TABLE 3 Mevalonic Acid Lactone Extraction Data & Recovery Calculations...................25 TABLE 4 Intemal Standard Extraction Data & Recovery Calculations ......................26 TABLE Summary of Least-Squares Linear Regression Constants and Analysis Dates.....27 TABLE 6 Summary of QC Standard 72-Hour Room Temperature Stability in Matrix........28 TABLE 7 Summaryof QC Standard Freeze/Thaw 3 Cycles) Stability in Matrix..............29 TABLE 8 Summary of Interpolated Mevalonic Acid Lactone Dilution QC Concentrations for Dilution Validation................ooeooeoe.. ES --|| 000629 418-018:PAGE I-7 PRIMEDICA PrFiinmaledRiepao:rWtorcester Project number: PABX-BVA For Primedica Argus Study Number: 41P8a.g0e18s LIST OF TABLES, FIGURES AND APPENDICES - CONCLUDED Page No. TABLE 9 6-Day Room Temperature Final Extract Stability Back-Calculated Calibration `Standard CONCENLTAONS ......ovvvrvvrrsvreeersrrcerssnssssssrsenssssssmsssssseseeees 31 TABLE 10 6-Day Room Temperature Final Extract Stability Quality Control Standard Concentrations .............. aeerereerssse SS ------ 7 TABLE 11 Summary of Control Blank EDTA Rat Plasma Concentrations....... essere 33 TABLE 12 Summary of Unique Lots of EDTA Plasma Concentrations .......................34 TABLE 13 Summary of Intemal Standard Peak AFeas.............ooervrrrromsmssmssennn3S TABLE 14 Summary of Plasma QC Standard Concentrations with Inter- and Intra-Day RS APPENDIX A LabOratOry MethOd.......cccsvseremsmmerssssssssssssssssrsssssssssssssesssessmsessemssssmsensen 39 APPENDIX B Representative Chromatograms from Validation Day 1 ..........couemmerrmmuerrnnns52 000630 418-018:PAGE 1-8 OPRIMEDICA Primedica-Worcester Project number: PABX-BVA Page? F--i_na--l Report ToFrorPnPimmeeddiiccaaAArrgugs usSSttuuddyyNNuummbbeerr::441188--001188 CONTRIBUTING PERSONNEL PIOJEC SCIENISH sts: MarkA. Netsch, B.A. Research ASSOCIate ........c.cooceserseserrrserrrne nssssnsessnn.. Heidi Gagnon,B.S. Director, Analytical CHEMISTY... James A. Jersey, Ph.D. REPORt COOTIAO ...coorcvrsvrssnssrssssvssesesosesosone BrendLa. Brooks 000631 418-018:PAGE 1-9 OPRIMEDICA FPirniamledRiecpao-rWtorcester Projet number: PABX-BVA For Primedica Argus Study Number: Pages 418.018 ANALYTICAL REFERENCE STANDARD CHARACTERIZATION/STABILITY AnCaolmytmiocnalNRaemfee:renceStandard: Physical Description: Lot Number: Storage Conditions: Expiration Date: Date Received: Amount Received: Supplier: InternalStandard: Common Name: LPhoytsiNcuamlbeDers:cription: ESxtpoirraagteioCnonDdaittei:ons: Date Received: SAumpopluinert:Received: DMeLv-aMleovnailconAiccidAcLiadctLoancetoorne Mevalonolacetone or MVL White crystals 4730071 50498 5Se2p3teCm,bedersi1c3c,a2te0,02st(orAessuingdneerdnbityrogen Primedica) September 5 grams 13,2000 Aldrich Chemical Co. MDLV-LM-evda,lonolacetone-4,4,5,5-ds Clear liquid U-295 225C September Primedica) 11,2002 (Assigned by September 0.1 gram 11,2000 Cambridge Isotope Laboratories iChnatreamcatlersitzaantdiaornd aisndthSetrabeislpiotnys:ibTilhietycohfatrhaceteSruipzpaltiieorn,ofats hisethaenamleyttihcoaldosftasnydnatrhdesainsd, fabrication or derivation and stability determination. 060632 418-018:PAGE I-10 PRIMEDICA FPirFiianmaleldRRieecppao-orWttorceserProject number; PABX-BVAFoFroPrrriimmeeddiiccaaAArrgguussSSttuuddyyNNuummbbeerr::4411P88a--g00e118s8 ARCHIVAL STORAGE Archival Storage: The original Final Report and raw data will be maintained for a minimum period of five years following submission of the final report in the bPerimceodnitaccat-eWdorcfoerstdeirspAorscihtiiovnes in Worcester, instructions. MA. After five years Archival material will the be Sponsor indexed will by Primedica-Worcester Report #PABX-BVA-01-62. 000633 418-018:PAGE I-11 OPRIMEDICA FPnrFaiimnlaelRdRieecppaoo-rWnto_ rcester Project number: PABX-BVAFFoorrPrPirmimeeddiiccaAArrgusSSttuuddyNumber::4411P85a.0ge1810 ABSTRACT: EADpTroAcerdaut rpelahsamsab.eeTnhdeevperloocpeedudraendinvvaollivdeastetdhefocrontvheerdseitoenrmoifnamteivoanloonfimcevaacildon(iMcVaAci)d in to mevalonic acid chromatography lactone (MVL) and coupled with mass the analysis spectrometry of a liquid/liquid extract by gas (GC/MS) using positive. chemical ionization (PCI). A mathematical factor to convert sample concentrations of MVL to MVA is included in control standards are the Laboratory Method in Appendix A. prepared in water since mevalonic acid Calibration and quality is a naturally occuring compound in plasma and concentrations vary with diet. The intemal standard, MVL-d,, `was used for quantification. The results reproducible for the validation indicate and accurate to support the that the analysis method is sufficiently linear, specific, of mevalonic acid in EDTA rat plasma samples. 000634 418-018:PAGE I-12 GPRIMEDICA FiFPinnralilRmeeeppodrotnica-WPororjecctensumtbeerr: PABX-BVAFoFroPrrPirmiemeddiicaaAArrgusSSttudyNNuummbbeerr::4411P88a.-g00e118181 INTRODUCTION: The objective of this study was to develop and validate an analytical method for determining levels of mevalonic acid (MVA) in EDTA rat plasma. EXPERIMENTAL DESIGN: Overview: The assay described in this report employed the conversion of mevalonic acid (MVA) to mevalon samples ic by acid lactone (MVL) and the a GC/MS using positive chemical nalysis of ionization. liquid/liquid The intemal EDTA rat plasma standard, MVL-d,, was used for quantitation. The validated assay covered the concentration range of 10.0 ng/mL to 250 ng/mL of MVL in EDTA rat plasma using 100 uL. sample volumes. Materials and Methods: Refer to Appendix A for a detailed description of materials and methods employed during the course of this validation study. In addition, quality control (QC) standards `were prepared in water at the lower limit of quantiation (LLOQ QC, 10.0 mg/mL) using the same stock solutions used for the water QC standards. A set of QC standards (Low, Mid and High) was prepared in rat plasma using the same stock standards anddilution procedure used for prepared to mimic the water QC standards. One setof solution final extract concentration assuming 100% calibration standards was recovery using the same stock standards used for the calibration standards. General Comments: Representative raw chromatographic data from validation day 1 are provided in `Appendix B. Validation Design: Validation Description: The assay was comprised of five analytical runs. comprisedofbracketing seven-point water matrix Three of the five calibration curves analytical runs were with six replicates of rwaatteprlamsamtraixmaqturailxitQy Cconstaromlpl(eQsC)atstahmrpeleescoantcefnoturractoinocnesntarnadtiosnisx, rseipxlirceaptleiscaotfesroaft EmaDtTriAx aconndtrwoaltesrammpaltersix(EcoDnTtrAolrastapmlpalsemsa(wmiatthriixntweirtnahlisnttaenmdaarld)s.tanMdualrtdi)plweerweataenralmyazterdixinbleaanckhs 060635 418-018:PAGE I-13 SPRIMEDICA FPirniamledRiecpao-rWtorcesterProject number: PABX-BVA For Primedica Argus Study Number: 41P8a.g0e1812 run. An analysis of the method recovery was included in the third analytical run, which consistedofan extracted calibration curve and a solvent calibration curve. Theanalysis of freeze/thaw (F/T) stability and room temperature (RT) stability, both in water and matrix, was included in the fourth analytical run. The fifth analytical run was a re-injection of the extracts from the first run to evaluate the final extract stability when stored at room tem assay performance perature. parameter s Text Table 1 lists that were evaluated each validati for the study. o n analytical run and the TEXT TABLE | Validation Course I Day T Precision, accuracye,quTinvcaalreinyc,yand waterplasms I Day? Precision, accuracy, linearly. spec2indiwacieripayse,s cquivaiency Days Precision,praeccicsuiroanc,y,anTdnewaartteyr,pcloavsemraye,quAivTaIlOenN 365 | -- Tr ---- -- rr ------ Parameters Evaluated: Mevalonic acid is a naturally occurring compound in plasma. The concentration levels found in blank plasma quantitation (LLOQ) of were anticipated to be 10 ng/mL. This level above the validated lower limit of of background concentration would significantly skew the results of plasma QC's at the lower concentration levels. Therefore, calibration precision, accuracy and and QC linearity standards were of the method. prepared in water matrix The second setof QC's was to evaluate prepared at three concentration levels in EDTA extract and quanitate MVL equally rat plasma from water to or evaluate plasma the abilityofthe method to matrices. The plasma QC's were also used to evaluate matrix stability. 0006356 418-018:PAGE I-14 PRIMEDICA PFirniamledRiecpao-rWtorcester Project number: PABX-BVA For Primedica Argus Study Number: 41P8a-g0e1813 `Water/plasma extraction equivalency was evaluated by the analysis of six replicates of each QC standard concentration levels in both water and plasma. Mean peak area counts of the isotopically labeled mevalonic acid lactone internal standard were calculated. The difference between the water and plasma mean peak arcas were expressed as percent difference. The acceptable limits were 10% difference. The isotopically labeled internal standard was used to evaluate extraction equivalency because it is chemically identical to mevalonic acid lactone and is not present in blank plasma. Therefore, the internal standard mimics the extraction behavior of mevalonic acid lactone but has no naturally occurring background concentration to interfere with the results. `Water/plasma extraction equivalency was also evaluated by the six replicates of High QC standards in both water and plasma. The endogenous concentration of mevalonic acid was low compared to the high QC concentration and did not make a significant contribution to the concentration results. Mean concentrationsof mevalonic acid lactone were calculated and expressed as percent bias compared to the nominal concentration. `The present bias values from the high QC in plasma were compared with the water QC and expressed as percent difference. The acceptable limits were+10%difference. Inter- and intra-day accuracy and precision of the method were evaluated at four concentrations by analyzing six replicates of the QC standards prepared in water over the pcroeucrisseioofntfhorreQeCvasltiadnadtairodnsbiastcehxepsr.essAecdcuasr%acyvarresiualntcse.areInrteepro-rdtaeydmaesth%odbiparse.cisMioenthaondd accuracy were also evaluated for calibration standards. Dilution accuracy and precision was measured by analyzing six replicate dilutions of a QC standard diluted 1:5 water. Intra-day precision and accuracy was evaluated and reported as % RSD and % bias, respectively. Recovery standards of to the assay was evaluated by comparing the absolute those obtained from solvent standards prepared peak areas in extracted to mimic final extract `concentrations assuming 100% recovery. Linearity of the method was evaluated by visual inspection of the calibration curve and examinationofthe correlation coefficient (r) for each standard curve. Freeze-Thaw analyzing six (F/T) stability in both water and plasma matrices replicates ofquality control samples prepared at two were evaluatedby levels, which were subjected to three F/T cycles, prior to their extraction and analysis. 000637 418-018:PAGE I-15 GPRIMEDICA PFirniamledRiecpao-rWtorcester Project number: PABX-BVA For Primedica Argus Study Number: 41P8a.g0e1814 aRnoaolymzitnegmspiexrarteuprliecastteasbiolfityQCin sbtoatndharwdasteprreapnadredplaatstmwaomlaetvreilcseswhwiecrhewdeermeonlesfttrsattaenddbinyg at room temperature for seventy-two hours prior to their extraction and analysis. Six-day room temperature stability of final extracts was evaluated by re-analyzing the day-one validation extracts consistingof duplicate calibration curves, six replicates of QC `standards in both water and plasma matrices. Assay specificity with respect to endogenous compounds was evaluated by assaying six unique plasma lots from untreated rats. Validation Results: RESULTS AND DISCUSSION: Water/Plasma Extraction Equivalency: The ability of the method to extract and quantitate mevalonic acid equivalently from water or plasma matrices was evaluated. The equivalence standard levels in was evaluated by the analysis of six water and plasma during thefirstthree replicates validation of each of runs. Mean three peak QC area counts ofthe internal standard (isotopically labeled mevalonic acid lactone) found for the plasma matrix QC's during each run were compared to the results for water matrixQC's. The difference was expressed as % difference. Percent difference values for the first three validation runs were 0.5%, 0.5% and 4.4%, respectively. Refer to Table 13 for a complete summary of results. Tinhewactoemrpaarnidsopnlawsamsa adlusroienvgaltuhaetefidrsbtytthhreeeanvaallyisdiastioofnsiruxnsr.epliActatetshoisfchoingcehn-tQrCatsitoanndlaervdels (200 ng/mL) the endogenous level of mevalonic acid was not a significant interference. Mean concentrations of found for the plasma matrix High-QC's during each run was compared to the results for water matrix High-QC's. The results were expressed as %difference. Percent difference values for the first three validation runs were ~2.0%, 0.5% and 0.5%, respectively. Refer to Table 14 for a `complete summary of results. The percent difference results were all within the acceptable limits of 10%. The extraction of mevalonic acid lactone from water and plasma are equivalent. Therefore, 060638 418-018:PAGEI-16 SPRIMEDICA FPirniamledRiecpao-rWtorcester Project number: PABX-BVA For Primedica Argus Study Number: 41P8a-g0e1815 qtuhaentciatlaitberamteivoanlocnuircveacainddlaqcutaolnietyconccoennttrroaltisoanmlpelveelsprienppalraesdma.in water can be used to Accuracy: Inter-day and intra-day accuracy were acceptable for the assay of Mevalonic acid lactone in water over the concentration range of 10.0 ng/mL to 250 ng/mL. Intra-day accuracy was evaluated by the analysis of six replicates of each of four QC standard levels in water during the first three validation runs. Mean concentrations found during each run were relative to theoretical compared nominal to theoretical nominal concentrations and concentrations was expressed as % bias. thdeifference Percent bias values for the lower limit of quantitation (LLOQ-QC, 10 ng/mL), low-QC (25 ng/mL), middle-QC (70 ng/mL), and high-QC (200 ng/mL) standards ranged from 4.8% to 0.1% over the three analytical runs. Refer to Table 1 foar complete summaryofresults. Inter-day accuracy was evaluated by the analysis of six replicates of cach of four QC standard levels in water during the first three validation runs. Mean concentrations across these runs expressed wasere%cobmiapsa.redPetroctehnetorebtiiacsal vnaolmuiesnalracnognecdentfrraotmion-s3.an6d% the to difference`was ~1.4% across concentrations. Refer to Table 1 for a complete summary of results. The inter-day accuracy statistics for the back-calculated calibration standard concentrations are also represented by % bias. The % bias values for the calibration standards ranged from 1.6% to 1.7%. See Table 2 for a complete summ ofaresrultys. Precision: Inter-day and intra-day precision was acceptable for the assay of mevalonic acid lactone in water over the concentration range of 10.0 ng/mL to 250 ng/mL. Intra-day precision was evaluated by the analysis of six replicates of each of four QC standard levels in water during the first three validation runs. The intra-assay variance estimate of the interpolated concentrations for the 1.3%to 4.5% across concentrations. Refer to Table replicate QC standards ranged from 1 for a complete summaryof results. Inter-day precision was evaluated by the analysis of six replicates of eachoffour QC standard levels in water during the first three validation runs. The inter-assay variance estimate of the interpolated concentrations for the replicate QC standards ranged from 0.4% 10 1.2% across concentrations. Refer to Table 1 for a complete summaryofresults. 646639 418-018:PAGE 1-17 PRIMEDICA FPirniamledRiecpao-rWtorcester Project number: PABX-BVA For Primedica Argus Study Number: 41P8a-g0e1816 fTrhoemin1te.r6-%daytopr3ec.i0s%ionrelstaattiivseticsstafnodrartdhe dbeavcika-tciaolncu(laRtSeDd)caalcirborsastiocnonscteanntdraartdisonrsanagnedd analytical runs. See Table 2 for 2 complete summary of results. Dilution QC: The dilution QC results were dilution concentration of 200 acceptable. Six replicates ng/mL, were diluted with of the dilution QC with a prewater by a factor of 5 prior to extraction and analysis. nominal concentration The mean (40 ng/mL) caonndcetnhteradtiifofnerefnocuendrewlaatsivecotmoptahreetdhetaoretthiecatlhenoormetiincaall ScoenecTenatbrlaetiofnowraasceoxmpprleestseedsuamsm%arbyioasf. The result results. was ~1.8% bias with an RSD of 3.0%. Recovery: cRaelciobrvaetriyonvsatlaunedsawrderpeeackalacruelaasteidnbwyatceormtpoartihesopneoafkmaeraeans odbutpaliinceadtefsorpiskoeldutainond setxatnrdaacrtdesd prepared to ranged from mimic 32.9% t0fi3na9l.6e%xtrfaocrtmecvoanlcoenntircataicoidnslaacstsonuemianngd 100% recovery. Recovery from 33.6% t0 42.0% for the internal standard ofresults. across concentrations. Refer to Tables 3 and 4 for a complete summary Linearity: `The assay was linear ng/mL to 250 ng/mL. for mevalonic acid lactone within the calibration range of 10.0 Figure spiked c1alsibhroawtsionthseta1nd/aXrd wdeaitgahtpeoidntlseafsotr-soqnuearoefs tlhienevaarlirdeagtrieosnsriuonns. ploLtinweiartihtythweasactalusaol 0in.d9i9c8atfeodrbeyacthheocfortrheelaftiirostn ctoherfefeicviaelnitdsat(ir)onobrtuanis.ned,RewfheirchtoweTraeblgere5ateforrthaansuormmeaqurayl otof regression constants. Specificity: Mcoenvceelnotnriatcionacliedvelisin a nawrally the plasma QoCc'csurwraisngevcaloumaptoedunbdy in the plasma. analysis The of six background replicates of cionntterro-lassbalyamnkeaEnDcTonAcenrattraptiloansmfaoumnadtrwiaxs during the first three 16.6 ng/mL. Refer to validation runs. The Table 11 for complete results for the control blanksofplasma. 000649 418-018:PAGE I-18 PRIMEDICA PrFiimnaeldRiecpao-rWtorcester Project number: PABX-BVA For Primedica Argus Study Number: 41P8a-g0e1817 `The variationof background concentration levels in EDTA rat plasma was evaluated by the analysis of six unique lotsof plasma during validation Day 2. The result was a mean concentration of 15.8 ng/mL. See Tables 12 for complete results of the six unique lotsofplasma. Stability: The acceptable criteria for stability evaluations were a mean bias of <15% from the theoretical values except for the lowest calibration, Low-QC and LLOQ QC standards, where the criteria were <320%. Due to the presence of background concentrating of mevalonic acid lactone the theoretical values used for the Plasma QC standards were the mean concentrations obtain during the same analytical run from the analysis of six control Plasma QC standards. Room temperature matrix stability was evaluated by analyzing six replicates of quality control samples prepared at two levels, in both water and EDTA rat plasma matrices, which were exposed to room temperature for 72-hours prior to their extraction and analysis. The values for % bias were within the acceptance criteria for both concentrations for the 72-hour room temperature stability assessment. Refer to Table 6 for a complete summary of the results. Freeze/thaw matrix stability was evaluated by analyzing six replicatesof QC standards prepared at two levels, in both water and EDTA rat plasma matrices that were subjected to four freeze/thaw cycles. The values for % bias were within the acceptance criteria. Refer to Table 7 for a complete summary of the results. Six-day room temperature stability of final extracts was evaluated by re-analyzing the duplicate calibration curves and the six replicates of QC standards, in both water and EDTA rat plasma matrices, from the first day of the validation. The solvent in the extracts evaporated from the vials during the storage period. More solvent was added to each vial to reconstitute the extracts. Results from the re-analyses demonstrated that the extracts were stable for a minimum periodofsix days when stored at room temperature. See Tables 9 and 10 for the final extract stability results. Studiesof long-term storage stability of mevalonic acid in matrix at -20C are ongoing. 000841 418-018:PAGE I-19 GPRIMEDICA Primedice-Worcester Project number: PABX-BVA Page 18 Final Report For Primedica Argus Study Number: 418-018 _ CONCLUSIONS: Overall, the results for the validation indicated that the method was sufficiently linear, specific, reproducible and accurate to support EDTA rat plasma sample analyses for `mevalonic acid content. 060642 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-20 Page 19 FIGURE 000643 Primedica-Worcester Project number: PABX-BVA FIGURE | Day 1 Validation Calibration Curve 418-018:PA1G-2E1 ros 20 ol2 Premier et 16 2. oa- Foe as i 04 02 erMevealoVnailcidAactiidoninDe Raayt1Plasma ee _: _-- | _"~~ || Slope: 0.0065514 _ Y-int: 0.011375 : fw~~ fCosrrt: 0.99975 || 0 00 0 = 0 0| Concentration in ng. Rat Plasma 000824 Primedica-Worcester Project number: PABX-BVA 418.018PAGE 122 Page2! TABLES 000645 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-23 Page 22 TABLE | SUMMARY OF INTERPOLATED MEVALONIC ACID LACTONE QC STANDARD CONCENTRATIONS WITH INTER- AND INTRA-DAY SUMMARY STATISTICS Day1 100Theoretical2No0minal Concent0rations (ng/mL)20 Repl 9.63 26 701 202 Rep2 891 250 687 20 Rep3 951 250 678 196 Repa. 938 29 683 196 Reps 975 20 614 195 Rep6. 992 239 08 199 Mean 952 22 7 198 o %Bias 6 48% 6 22% 196 % 106 % Theoretical Nominal Concentrations (ng/mL) Dey2 100 20 0 20 Repl 987 24 69 202 Rep2 929 248 68.1 195 Rep3 103 20.1 684 195 Repd 907 28 682 193 Reps 9.10 28 680 194 Rep6 102 2s 63 195 Mean 964 24 683 19 n 6 6 6 6 % Bias 26% 24% 24% 20% 060645 Primedica-Worcester Project number: PABX-BVA. 418-018:PAGE 1-24 Page 23 TABLE I (Concluded) SUMMARY OF INTERPOLATED MEVALONIC LACTONE ACID QC STANDARD CONCENTRATIONS WITH INTER- AND INTRA-DAY SUMMARY STATISTICS `Theoretical Nominal Concentrations (ng/mL) Day3 0 m0 me 2 Repl 94 ms 706 198 Rep2 01 252 701 i97 Rep3 949 254 06 200 Repd 9% 26 700 198 Reps 984 28 700 199 Rep6 NA BS 0 188 Mean 97 26 700 197 n 5 6 6 6 %Bias 22% 6% 01% -Ls% Invaassay varisnce estimate 4.5% 25% 13% 18% Interassay variance estimate 12% 07% 12% 04% Inter-day Mean o %Bias 964 244 690 197 17 Ek) 18 18 B6% 24% La% Ls% NA = Not Available. This sample was accidentally spilled during preparation 000647 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-25 Page 24 TABLE2 SUMMARY OF BACK-CALCULATED MEVALONIC ACID LACTONE CALIBRATION STANDARD CONCENTRATIONS, `Theoretical Nominal Concentrations (ng/mL) loo 200 300 00 0 150 20 Dayl 9% 10.1 200 00 307 300 06 497 895 ss) 151 144 254 254 Day2 984 103 195 93 96 36 504 2 908 e17 152 136 250 250 Day3 103 9s 97 209 30s 306 s17 8 en 848 17 146 261 251 Mean 100 SWDev. 0296 199 0562 30s 0681 99 134 894 266 148 314 253 418 o URSD 5 30% s 28% 6 22% 6 27% 6 30% 6 21% 6 Le% %Bias 00% 05% 17% 02% 06% 16% 13% 000648 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-26 Page 25 TABLE 3 'MEVALONIC ACID LACTONE EXTRACTION DATA & RECOVERY CALCULATIONS Exuscied Sundards Solution Standards MenResponseAreas ResponseAreas ssuu2 a7n85s 10196861 sSuuss 1015879.65 a29763 sus S144 8678 sSuus? p84e3) 215237890 SMd.eaDenv. %RSD " Resowery 93926%% 335871%% 362% 3n2a0n% 0306342%7 7% . 000649 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-27 Page 26 TABLE 4 INTERNAL STANDARD EXTRACTION DATA & RECOVERY CALCULATIONS Extracted Standards Solution Standards MeanResponseArea ResponseArea ssaul2 65184726 1154091599 sSuu3s S030645 1150125883 sus S657 14739 ssuue? ssaumss 1155222866 SMtde. aDnev. %RSD % Recovery "30093%% 3250.4%% Ban 33465%% 0301372%7 87% 660850 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-28 Page 27 TABLE S SUMMARY OF LEAST-SQUARES LINEAR REGRESSION CONSTANTS AND ANALYSIS DATES Slope Dayl 00065514 Day2 00063508 Day3 0006223 Days 00062800 Days 0006516 Intersept ~~ComelaionCoefficient(1) 00113750 059975 0.0082756 099939 00067910 09988e 0.0060925 099891 00112850 0.99981 Analysis Date 1017/00 1018/00 1019/00 102000 1023/00 660651 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1:29 Page 25 TABLE 6 SUMMARY OF QC STANDARD 72-HOUR ROOM TEMPERATURE STABILITY IN MATRIX WATER QC's Theoretical Nominal Concentrations (ng/mL) 250 20 RReeppl2 2218 119519 Rep3 Repd 2289 119933 RReeppst, 2290 119944 Mean 23 192 Std. oDev. 04632 1697 RSD 19% 10% "Bias 68% "0% EDTA RAT PLASMA QC's Theoretic4a2l Nominal Concenlrat1io9n2s (ag/mL) RReepp? 33412 210909 Rep3 340 197 RReepps 33326 119045 Rep ns 188 SMude. aDenv. 036397 a19x6 %RSnD. 206 % 226 % "Bias 09% 21% += Mean concentrationofsix control Plasma QC's analyzedi the same analytical batch. 660652 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1:30 Page 20 TABLE? SUMMARY OF QC STANDARD FREEZE/THAW (3 CYCLES) STABILITY IN MATRIX WATER QC's Theoretical Nominal Concentrations (ng/mL) 250 200 Repl 23 194 Rep2 26 194 Rep3 22 194 Rep4. 28 194 Reps 20 196 Reps. 23 192 Mean 2s 194 Su. Dev 04n2 126 n 6 6 URSD. 20% 06% % Bias 6.0% 30% EDTA RAT PLASMA QC's Theoretical Nominal Concentrations (g/mL) 320 192 Repl 3s 194 Rep2 344 200 Rep3 29 197 Reps 36 193 Reps 23 190 Rep6 24 184 Mean 32 193 Std. Dev 0.304 559 n 6 6 %RSD. 24% 29% % Bias 29% 05% * = Mean concentrationofsx control Plasma QC's analyzed in the same analytical batch. 000653 Primedics-Worcester Project number; PABX-BVA 418-018:PAGE I-31 Page 30 TABLE 8 SUMMARY OFCOINNCTEENRTPROALTATIEODNSMEFVORALDOINLIUTCIAOCNIVDALLAICDTAOTNIOENDILUTION QC Theoretical NominalPCoonycenraton (ng/mL) RReeppl2 02943 RReepps3 "a017 RReeppss 33899 MSte.aDnev 319136 RnSD 305% "Biss Sm * = Dion QC's undiluted concentration was 200 ng/mL (15 iuion performed prior to extraction and analysis) 060654 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-32 Page 31 TABLE 9 6-DAY ROOM TEMPERATURE FINAL EXTRACT STABILITY BACK-CALCULATED CALIBRATION STANDARD CONCENTRATIONS Theoretical Nominal Concentrations (ng/mL) 100 20 00 500 200 150 20 087 198 302 502 899 150 254 102 197 305 en 9056 146 253 Mean 100 198 304 03 903 148 254 n 2 2 2 2 2 2 2 %Bias 04% 13% 12% 04% 03% 3% law 000653 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 133 Page 32 TABLE 10 6-DAY ROOM TEMPERASTUTRAENDFAIRNADLCEOXNTCREANCTTRASTTIABOINLSITY QUALITY CONTROL Repl Rep2 Rep3 Rep RReepps Mean SaDev. o RSD %Bias WATER QC'S Theoretical Nomisal Concentrations (ag/mL) 100 20 m0 20 989 23 ass 198 517 251 a7 198 10s 255 61 197 95 204 63 200 110017 207 23 67 9 198 199 100 247 sas 198 050 042 0m 103 6 5 6 6 ss% 20% 1% osu 0% az 21% ow EDTA RAT PLASMA QC'S Theoretical Nominal Concentrations (ng/mL) mL Bs 108 Rep 350 73s 195 Rep2 344 756 189 Rep3 28 %2 192 Rep 22 ns 11 Reps Rep 316 37 097 118856 Mean 33 n 150 Sud. Dev. 131 226 378 n %RSD 6 29% 16% 206 % % Bias 06% 03% 21% = Mean concenration bined on th ist dayof validation 000658 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-34 Page 33 TABLE 11 SUMMARY OF CONTROL BLANK EDTA RAT PLASMA CONCENTRATIONS Repl Rep2 RReeppd3 Reps Rep6 Mean Sd. Dev. o RSD. Iner-AssayMean Sid. Dev. RSD Concentrations (ng/mL) Davi Day2 Davd 164 165 170 162 159 168 117646 117643 168 173 163 161 171 158 162 170 165 164 170 0536 0529 0190 6 32% [I 32% Li6 % 166 18 0.506 30% 000657 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-35 Page 34 TABLE 12 SUMMARY OF UNIQUE LOTS OF EDTA RAT PLASMA CONCENTRATIONS Concenations(ng/ml) LToot?t 116o2 LLoottsa 116613 LLootts 117760 SuM.eDaenv. 214518 %4RaSD 1553% 060658 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-36 Page 3s TABLE 13 SUMMARY OF INTERNAL STANDARD PEAK AREAS Water QC's Davi Dav2 Day Low-QC Repl 4096 4303 5191 Rep2 4380 4861 EX Rep3 $310 ssi 6016 Repd. 4968 6253 5585. Reps. 4124 5620 6203 Rep6. 6187 6437 3846 Mid-QC. Repl 4323 4827 4928 Rep2 4390 5502 5230 Rep3 as22 5757 681 Repd. 4777 sm 5479 Reps. 5024 S881 5960 Rep6. 6314 6632 5452 High-QC Repl 4021 4124 5197 Rep2 5545 5015 $314 Rep3. 4246 5029 6189 Repd. 3568 3950 5978 Reps. 5531 5027 7684. Rep6. 5458 6200 6335 Mean Area 4821 5372 677 080653 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-37 Page 36 TABLE 13 (Concluded) SUMMARY OF INTERNAL STANDARD PEAK AREAS Plasma QC's Davi Davz Dav3 Lowe Repl 400 as03 6100 ReRepp23 a38250 5631663 s5i0s6t7 RReepps 3S305804 S168504 3S910599 Reps si 5493 sss MidQC RReeppl2 39as8s8o "519517 s50a4z0 RReepps3 swors 5026 a616 RReepps ssionzs Ss064014 6s0n4a9 HighQC Repl 6540 uss sons RReepp23 ss200082 poess sSa6n15 Rep 190 a 6084 RReepp6s se357018 sa3nt 5S436179 Menara 4847 5397 sor `ComparisonofPlasmaQCvsWaterQCMean Ares: Difference 0.5% osw san 000669 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-38 Page 37 TABLE 14 SUMMARY OF PLASMA QC STANDARD CONCENTRATIONS WITH INTER- AND INTRA-DAY SUMMARY STATISTICS Davi Repl Rep2 Rep3 Reps. Reps. Rep6. Mean n % Bias % Differ(eTnacbelves1W)ater QC Dayz Repl Rep2 Rep3 Repd RepS Rep6. Mean n % Bis % Differ(eTnacbelves1W)ater QC Theoretical Nominal Concentrations (ng/mL) 250 0 20 34s 757 198 na 73 191 24 753 192 330 ns 199 22 7 193 a2 n3 190 31 no 194 5 6 6 2.4% se% 20% 20% `Theoretical Nominal Concentrations (ng/mL) 20 0 2200 343 764 32 759 119948 30 %9 202 a4 753 194 348 33 194 351 784 199 340 769 197 6 6 360% 99% 156 % 05% 660661 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-39 Page 38 `TABLE 14 (Concluded) SUMMARY OF PLASMA QC STANDARD CONCENTRATIONS WITH INTER- AND INTRA-DAY SUMMARY STATISTICS Dav3 Repl Rep2 Rep3 Reps Reps Rep6 Mean n %Bias %Differe(nTcaeblves1W)ater QC `Theoretical Nominal Concentrations (ng/mL) 20 0 w 349 755 198 34s 768 197 38.1 71 199 42 79 195 347 357 77670 210925 349 6 763 6 198 6 30.6% 9.0% 10% 05% Intra-assay variance estimate 23% 18% 17% Inter-assay variance estimate 24% 20% 08% Inter-Assay Mean n % Bias 340 757 196 18 36.0% 8118% 2108% 000662 Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE 1-40 Page 39 APPENDIX A LABORATORY METHOD 060663 Primedica-Worceses Project number: PABX-BVA FRINEDICA CORPORATION Warne Masachses Labarmory hiugFor 418-018:PAGE I-41 Page 40 amr nun py J ------ Pe 3 er 1 ream JYVA DY) RL Ie7 se _ulsfo0 wosewste_ Lona ly uel otic SReg Qirgtror of ISanalytical Chemis coms / 660661 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-42 Page dl EARS NEVATONC ACID TR RAT PLASMA BY GEE. WTevabimoneNromMeA0:L8 S [FierverBae Reve T000 1 Purpose CheopnurcpoesemofrohfamseivLoabsonormtseoracy Meth3odl(LMs) isspdieessbey GpOrMoScDed.ur1esacurneydime the 2 Sope TphleapsrocEeDduTrAe. pDruorviindgadthie ehxisecLtMonarmeesvapiloinscestfod (iMheYAq)aniicioanivoenneof1memvaellonoincscisdt 131 iacicneni(nMe1V3L4)p.laTnhse vEDoTbAr.edThceaeisrlnoarabneecon10v.e0rridmove10a2nt5s0 oofmp.atoiflm.eovflmoemvsaisodme Sid in pene EDTA using he conven decried 1 ne akamao schon Beko: 3 DefiniionsAbbrevisions oscD: MGoassChSaeolmesnoegrDasehtyer isMv MnetveanlaomSeunAdcaer Mv MMeevvaalloonnosaAccoindt) actosor DL Mevlons Acid Lacane or ocaMy:L; QDIuL aMeyvsCionnovlesclone4.4.5.5:4, Gravissons! Conse 4 Marist a1 Chemis sDLieesnsen ct cian, StemsChemical Co.spproximatly 97%grade,or DI MevaloassCamcbriidgeobonneeLa-sor4sto.ne,,in5c. 9.9%5ra4de,.or TMeitnhysienteaeh,oJrT deB,a1ker aHkPsL,CHgPrLaCdoegrraeqdueiovralseuntivalen 2Forrumpiecnsocli(1a1.prBoiknerkcroebsoeln,tEgM Sreoernacceq,duHmPaeLlCn ere or sivas CShoiodmaforsmf,tJ.TABahker., HsPaLgCenprcaee.oroer sqquuvilvent eDemr,moNtowtahis,tMAilgpaor.e1Mc.IoLswatiegrh,Poofrsqmoar lcequnvaens 060665 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-43 Page 42 TE ANALYSIS MEVALONIC ACTS TN RAT PLASMA BY GOED" EFarfe eolB1e2 Revers T3000 J Hersnes, 1 Baker HPLCp adeop rcounae-- nt Pooled rt blak pias EDTA 42 Commins PDiisnpaonsean1d5umpLs.conisl bom polypropylene es the Epnpepndornrpeopleyrthsenndeirsates pipeotrequalen: FGiosleyspcranyrernaspivsiuklmowmimphploe-rivngileswtiedh 3137borosmivm alnt oc fsar nt 43 Laupmen VLbRInMdausltto-eTsoPbieeVt Deiesernnoerrqouricviear:ns iSeycmkmaanTuG5h.o6nKsRp LcVnmEvoagpeoroartgouriploele `JAWNDGFCR-cHo2mAm,amDay2i1c0s.b3l0me. 0o.r2s3pueml1e5n,025 um Fim hikes or equivalens HHeeiet PPracckkuanrdd 67169603 gmueccrhroomratcoqgurnaipahnot squialent Hweiwe PPaacckkaarrdd SC9h7e3mSmtaasioene(sGi1v7e01aRtA,eRreosrocnqLl0e1n0)o exsivalnt Mucosot Excel 97 vernon SR-3 or caveat sNee:y pBearifogmeanntc,eesSpenmsa,nosirceodnmumsbclaenbesons provided ht cquvsent Procedure T1haislmmetshoEdDhTasAbebeynGvOalMidSatDedvfiongthe10s0 utssofpevvaornesscTihe4vamtevealdoncicocnidcecornner)anine. 1h21e00r0esnailtm1.p10m.2o50lmeofmm.evoaflmoenivclsondcrit splcahsomns 4EDTAliadaecrEiDbTeAd.tTeheccaocumiearonssof cSert.onnSokepnensN.oseMe1vaslheolni6t1h4.o3 tervaelndcuqruailintgy ccoonmtoplousnedndeprsloersa4h0p0repmed GCornicgeinortmoentshwoildlvvaarlyswithwdei.r sCopnceencitiioens17fnougnadm.sTlhiesdbscohfabroaunrdksoncepnliarsamvaonEDevTeAl inunlvreincte witthehveotqeumasin,Crcaitpcoinllcyurwvees alowqeusaclailciotnovvalm,ieT.hsTmheetvhaoldidhaatison + doraeprsemis EdDTeA malo 3d can CIC esl oh was Ass qu 0606638 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-44 Page 43 AATYRIS MEVALONIC ACID TW RAT PLASHA RY GEAR er] 1 PepinofKenpens Noe: Other vasth thos spcifid maybeprepare vein the sme proportions. S11 Methylene Chiorde2-(P90r10o,vp)aSonltli,on CStoomrbeinero9o0m0 mpl.eorfmmaeh.ylevTehecehxiporraitdieowniethe1f0o0 miLofl2-oprnopanoenanwdemcikx,ar prepara. 2 PreopfnaemrSatantdardiSoohwinons C1o0n0ce%nturraetiaonneclscntoatieodnostarrasbs.edTohn mfolulowminghstrhedspdrerpadratrieofnersennceemser5. le CSountceennevdasipornosarchccAeppparnoplreia3tnedmwiollcbiecdaoicuom1ne0needaihtehgmecdonhooma.! Al andre lilictitsonms elylschxbanmgsoeonrhtehedscfxlp-a2i0pi1rnCeudpnolacerss.saniesdserreid.chTrhiese.xGpann diSebifhoeeYse S21 mal Standard Stock (1A) sMnYpLroniimaeyi1d00sme.ooWmettgehmhpeevsitn 200dd Mi YpuLrc,hasTeadnnevrihsecMosYiLmi.ng08 SsmOuLtvoufluMmeLne,lsht.h Weviaglhehuermcyk. vrili.ngSubvsotluhmee wwiehgMhii1s0lbiwaaterhe Snir The nominal MVL-d, 5 concanration ofto sloon is 2000 wal. 522 mcm Swndard Spiking Sotion Drainesetro2ve0k.am0e woifthtMenUOsmwadter nsdocmkix(.ISTAh) nmokm1s00 mVl.Lv.olt fas. Concenirntonof ialton i 400 EL S53 brutofCalan Stndurd Stock Soutens Tmhcaloowninsg1sorneadcrhdtreepaerrstpiaonmchaee o3asggceseidmpaprtueoasocch.npAspipr1onsdmawicll be d5ocumesnctheedvend weheen rccpateibnoiohke.sasFyotriccxlomcpaleb,ahioen seociks,dthmovmas]lsooufniecni2i06okn SSonnrs swpeikdintgn sswobosnegctonGcenousnioncsanwrbeesmcohdiefdi.edS50uantdthrniomeinsalmcaaelnesailorne SsounmnedsubteonOsDwiplurbee.soSrtenddard2w0eiCghwseieseorve nco hsoemsrredOfnogropianrgkN.abAlill Studies re esalhin te xpiaton doesofhes sluions S31 MVL Primary Sock (A) 060667 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-45 Page ad RACY WEATORIE RET RAT FIRS BY GOSS fem en Nn Totae olta MfsVroDmeeil snsdHraonse tA sgofest ennfgooofrMheV OioBiv.dL os0d. Swiohees WhSeViLmghcomutehsasp.rrniogfv tt1o00ol mgnof Ma V10L08awndid mr.st.nsTh1e0r0mi 32 STercoanidar3y7S5ilckof(0)th Prmry Sch (A) 0325.0 nl. somes fos iinoto nSo 5A0mre Tot eralMVEcree of 533 rpmof Cron SundaSpin (C5)Soins Tchdae fnooolconwuisngmseaen2ndcehdtpsrFepnEvrei8boonosa kheAlnl eouncshdeodoswpreiwceaischpeeSAepeprdrwpodrs5nwcil SEC moinaoesdofraitc.oOmnpri Asbiay ssd ecoos he 524 rAloiurtaoCnSsnwsaeaoorlwsbtkinio29n5vnse0srrmesvwoiolnnucmoeigTwies.1 sFhkotwnv vsfnrteeaeofleboo imine 1 hi EPO 8 roar Scum 4 ody nO CSer Spii So SoinsPrepSareor in| SysSoen SchiSnavion Tinmyon.| Comeemnattion C Secondary SwokB| 16 I 1EC[35w0 ow | C C55 SSecnT oaoytSSooaak8 BA w5 1 0 1 53% ms 00i [wmwo | CE 50 | 535 Omrnceeupmrempa1rem2,12s06yt1C1umStloeCkoebb)ilofpSakswtienviSlowliloh so(gsefsisd 3s220 56 Pepsinof CalinSundar (STD)in Wot 060668 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-46 Page ds. HE ARLYN WEVAT ONC ACTS TN RAT FLARE BY CORTRR THR VAL Eee Dre Never TT IwPrlaepl.aereisncdbaiylviimdriuntaiolnn.gs.iwaiTnhhdea0ri.ds0s2]a8n0ctomhnceLednoatfratootfiosneespvewceiinebsyCaclohimwebraidinoinng1S2.k8bi0 imnLsSolofolwoM,iolnliG-QSS) [Vonlnue )me | VolumnetA)dT ded | Sohwy s |FCo omngcmrer tsrnae | Pis wnamC)] on. Se ImsT E o n OO o1 mN5 eGsSsT 1 soomw Twweo]] C S ESEI TeToO om [[5 eossssa[|soo s w11}osow15o0 ] Csr12s 1 oom |eerTammTw] 55 reparsion of Qusbty Comal (0C) Stock Suions om"TOchiuefmfceoalnlltioewodinnsignshteraenadpcarrhodj(ep1ceprpaircttboieookn.sscmShasenm]earicgd roeelenrednccmsarppetrvsssccehw,peiAspsipiersooapmnredidawt1le0lbbee TW1ih0l0lc% apusrpoe.irS1adonSed-sa2o0nftwCheoeingshesssohvnovoeendswaerne.msOnegoifnrguAyd.yAlSl Sdandsorncsanrmhsabi 550 PriOCmStaockr(ANy) NoAuttnequahiacltklMyef1Lesmcnicnheiyaimoancdohpeaeicfn.fdeAcstaoasgf8ehmaseohrmbio0ngSomfthoVorLcni otc,odfhnedos.fswSeirghende MvWVeoEi.lghcuomomueceaTpmapisrakooxniDmoraiftnteghliys1vs0ollamutmgienofwMiVh10cL0h03ynnsdteacnateadi imn.o3T1h0e0mplo.ne 552 Secondary OC Suck (AD) hBrriiasnSngoe10lvo$ol0nu0memi2wl0.0ohfmhLel.hPlracicmOCanSdtromcynk.(TAhAe) m i3i2o .M0oYiLs .sosnecms ecmraiunc] onsoh.f 000663 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-47 Page 46 svn Ea ` 36 mhPreeepafrcoatlilcoonwaoifnbQsouaaanldihatrydCopnrteWrpolaEsSipSoiknisoncgthSeoemleutCioonsun(sCEesSnSo) sepecse, Aepaprwbe c esceunt.mOSui nsgsvsn rahv.y AsanrtsSB onswl6 rear 1C . 2o0fsles rteaprreoCSSoiuotnvo25l,0imLi. ealtmeert.asksFohvoannshof uabelbspoawy,, sAh elivngaenamncpn Sotia a on aFyopty PAR 58 [CC 2 OCSundardSSpioRkwiEtnognS|oinSaPbrieapanrat|iBonESawin | | San Soiin n owmire|| eComnei || vei"mVtnume|| aopnm [OCSSMED |Secondo Sige 0|EsoOe 3m0 3C5l 000 (OCSSTMGH|Primary OC StockAA| 508 | To [350 | moan] 57 Prparoonof Qual Cone 0) andr n Wake SCormabineS1o00imnL.(oCfEMS)Isvhate. miaeie.piwiot.h 1.0 ml. of schOuiCon eCoarta || Sowian |SCaocnkteSnoiaeton|SpeienksSaVvolounme| Vortaarn. | OCoCnceSnatnrdateirosn sunaarain| my my | omy | lagi [CTTowloCT7OCCSSSSLMODW| T25o5T8 1"Tveoo [[wwwo 3 [ |=m2e 500) || S01 Ohncearearned.aalaorihe OwiCthsmangdsesipopdsprrhomn1 L30m.C ml eiofnwey 660679 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-48 Page 47 TRE ANALYSIS MEVALONIC ACID I RAT FLASNA BY CCAS TRevieianrNumbMeOrA0T:0 Tponie evotB1a3e Never 300 5 Sample Exincion S81 TConrtraolml1n00kofdcuabchasia,ndQruadli(tey sConotfr1o4l)S,maetnhnodek(plseitneplvece . CPoonlcpernurpayiionncvcelh)t.e2s0d sucy sample 0 nial 15ml once Boom S82 A300 4ofMI water 0cach method bank S53 AmAcS dS0b0aLnof he ermal Simard Siking Slut esc whe xcepforthe 584 Vonen th ube for minima ofS seconds. SAS cAoAnDd100 mLof formic seid cach ube nd voresfo min of 5180 Ahlelocwutmvberron o3fMoVn AthefboeMnVchL.or spol 0 mimesls mefo 587 AAS0.500 mLofMII weir cach tbe ant voi for minaof S48 eAGcGo0n.5.0N0omtle.:ofpheirtodfioprmmiesemxcahybuebaneddvo4restfoh rmeinnkiemusof 559 (Caappnrioiumgtaeey b25e0s0ap6p)r.oxDiismtaitnectlyIyemrihnoewasd afpprroxiimaactheloyp15i0e0rbpme Clogs sein anysamplewhich oes ot hve dt leyer S10 TPoolapmrterpyhieenpcsnquueboessa)nadyEer ido mtehwcihndonldouny15rmLcometbono S511 oSfsodesuhetslutee1spliaeytery w10iSh stodeiuUmnesefos(NoBtyeer.SpAprmoessmssuirgly500.105 sgrmaamsy bead 020d the drum, ule beasuh act weigh 4 no ER) S802 hAed8sq1s0comusLoyemretahnydlvenoerecshoforrde2m-pirnopianlofs$ sueciondso. aNcohteubepicpuentning pense ray be vd03d his regen. S813 pCopnrteinfiumgathleyb2e5s00s)p.peimately mites t spray 3500 060671 Primed ores Fj suse: PABBA ages 418-018:PAGE 1-49 are T Poto i a ------------ s3a4r3e8 Tammacesersonare----Co---- t EEm E i om -- e-- ovm------------ A ju ------ =a "TH wm shSbaprni T cm=feeoee.sleh 0iB= Ee De mt SE. 600672 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-50 Page 49 THE ANALYSIS WESALORIC ACTS TW RAT PLASHIA BY GORD 93 Mass Seacmve Desir SSoouurrcee Mode CF1loGwasConrol Sening: AScoquvioDeneM:ode M3SQSouuerce MSD Transtar Line: 594 tons Mortons: CPhoesmieisca lomaan (C1) 2[0rome S60umaivneeslonrMayobreacgsi(SIM0)besang 5 piorseewibout easing the fepe of 2o8o0c 250C 943 Group1:Sin imeapproxi6m00a Compound Nemisallon DTwiemlel ReTwmwioon Nwaeme JiE T--o"o m7i3n) DoweMllVmc,s may be mod1i1sfoiptiemidze1p0e0rformance iH mayRarypatphe rcoriluomnnousmhneo(eRneTid)fuorrminngomnwmcelnaearnace..AcTthse KKTT is CFonSfmdtimuesaiynhgebesatdoipecl.ly beled nema Sundar 510 Antica RunSequenceandComposiven FaiakEchewa3inwtaerwsraostwchiolmoobelDcaloramknpkris(mwepadltoefr(bwnilcsh ccwlinheswacmtheear caaalsnibahranetdionnoirnccalmruvdmeesds)(.)7 psDouaipnlsid)crac aCortOoCnscaunrvdeasr st acof te thes conceneniwoilnlbs mcrpered between the Prlsaanra lDiyon3OiC"owni.lTbheesinonlosfhpilansmastscam]pbiwtacdhepsainwshiOchCplwialnlabespl f----------y S11 Colin S01 CShcrcoempaatloegrmaemgsrawiiloln ossnogmaHiPcCahleymSgiravaotneodrscnidevnists)ll.y iMnsapesct)ed or craton wil be performed when ecesary 000673 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-51 Page 50 RToHvio NumbeVr:A00L iPagce e11Dor1e2 Resear 17080 5112 FColmopuetethee10X'tweegmhaiesd 1ss.snqoufadroeesocaarrrtr)oeencseinodnarredlsatingetes peesspescrise mCpirendeihoesnscteorncs0enl(meL.ofMVL in water eng vhscd Excl 513 USsnipnlgetsh3p0dkherseapriopfhegerasilonea(urteotn conhaene,mdaesaendenhres)in the CionnggenviarlaodnenTcLl sorfeaMdVtLecissw(aortecrqourvapelna)s.msfCoaomlectaonrddresaond fsamc sppropnte S114 {pr1e0oq0u0lespltoelodf,gMthmVecAuninitgnswsofanldn eroripnon fagMsbYyLbyvemimmuwlclcirnorgpwbelyig3shutnmoifaMcyoVnbveLecros(ni1o3vn0e.nv1ea4dlue m17a8)mBgeloomwfMiVtanLaimpplorens.wing heconvenon fs ample oncenten sow xX 00pm Tm i X ime = i52pmo Barer ne S12 AccepanceCrers S120 Calibion Sundari SUL01 cTooneceonwaeisonb. imaofsqubeenasthoinn(L4LO2Q0)% saonfdarod'srbacck<alneoumliieadl 51202 A2N1thoe5frtsh%aenndosm"inabl heorce)ksocnocnecmeimtvosnis.on at be within SULLE CAmoulidcononfc7n5i%rmoifomntherceunoal.tmo(Nnote:sias innswitlaml beertrohudenbdaescdk towennewrhemravyinbegr1e4ccteadiwrheon astnalndyaaridsn.gTohuas, o3fm1a4 xaibrmsotoof4n Sanders ir boc) 51206 wAlioesoines(aUn1d0a0d) m1ushteLmeLeOtQheabncdka-tchaevcupistdlciotnocefision 060674 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-52 Page 51 TE AALVSIS FEV ALONIC ACID TW RAT PLASNBIYA GAD. TReviNsionRNumbeSr:A00T V rags 1D 1012 Neer TT 5122 QuiltyCano! QC) Susndarts $1221 Th2e07owofenteleoveml OCsvceelceccooncnecnaeironn mst be wits 51222 AhlelronheormOsC!'siacural]acconocenntcraetironn mst be within 15o5f $1233 A minim of 86%ofall OC" musk mt hecacultd 51224 Avis ne QCotcach concern vel mst mee the calcite 5123 Blank and Comets AOFchoentloolwWeasnckesheodldLaLvOeG ostpbornssoen(pseaaknrdess rt) es than quel 0 33% "0Thelcowoensttebcltaneksd(1in1.w0at0earbsbhroaulidonavsneiorredspon (pes re i) 33% S13 Dns Keporiog 5.13.1 SRamepwlecheonQcueamnsttiiaotnisoneLisstia(50tLhe).west cbs sends will be ages 35 5112.3 SppavmopplresotenlcyendriwieodnswiprsesMeirlhal whaee.ieg-hcrraiset,ioanndtreasdnrldyeiedl,lpbreovided hgtnsanurgetswplebveorleumpeorseinA.bov1ehheereuaatciionmBstamp(lAesOvLsisbl, he 6 Revision Ilistory nil borsery method 000675 Primedica-Worceser Projet number: PABX BVA 418-018:PAGE I-53 Page 2 APPENDIX B REPRESENTATIVE CHROMATOGRAMS FROM VALIDATION DAY 1 050675 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-54 Page s3 from subtree Peak Area Report Samm: tn oompm: on 352 rere ETESEESenora avn mim fmepelr Commpiue lsfn m tease feimes rtmsmTon ron000 1238 oat 009677 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-55 Page sa Quantitation Report (07 Reviewed) BiDSeaatEraeSrFile +DD3K:3\'NhoScDaeDbAtaTgAee\PrABTa\aPtAenBK-BVA\L-02- 106210030SEpeEraVciearl,: t1an 1a5nSeotVagEraRsAio]n DpTecRaRnCs:HEcAteiEnTtH.OpDS AEX_BVA.M (RTE Incegeatos) hise egi y -- 1 4 Fo mini i? ei" barr, mee i To RERELI HR TE TEv6 Tth m ik Te we EE A nT Wot Found. ey mrneg,olpi e Tn n tr4 \" nso ef i|m] @isfooenet wT se awE sw eA nTE 0 iE 3a 1lmn t ibyt eset iSemen RA a ier rie 7o%e TFeoali tm IR y veim" i A . | re TERRRe 06210010 PASE svAM wed oct 18 12:40:03 2000 rage 2 000678 Primedica-Worcester Project number: PABXBVA 418-018:PAGE I-56 Page 55 Peak AreaRepert Te opt sme ea rare 600EYS Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-57 Page s6 Quiscitation Report (07 Reviewed) oiSRDaethaohnile:i D3x:5\W0sScDe_O2wN0T0eA0\rBAaBs\PiARK.BYAL-062-1\0621002.0_TSpooeraVciearl!: w2an G%5ianrtnctesheaeaio"n 5Fa\reKnRsC:AEeATt\HEaTpRODS\PARX_BVA.M (RTE Incegator) = egy " , i i - I i W[wseiTropn:e: 2T a50 m6T 3 skT4% ve 1h ik em re TRE nTh ik TH oTlelTm-- ve 1T -- h TE e h | ! | | oo Gs E ae ai [ =refsoor pn: 128r 0 riS en ew 16 TEi1 h 1%6 Te TH r~ ----Amou,nT t: 0.00 veinom ih ~--1 i A | i i th ex s6 sn ee nem sm vm 10 1p iw Te im mth 1k im | 06210020 PABSVAN Wed Oct 18 12:40:22 2000 rage 2 060689 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-58 Page 57 Peak Area Report Notes Fteaamre:n0e3swat e OeAS cnem1017200 143) POFr ultaamnee 0U1S0O02C0ATAPADOVEALAGDELL msstuVmommau:s? Gmm3ess Gmmpeetum Bonn mWfOEmesams ta 06081 Primedica-Worcester Project number: PABX-BVA 418-018PAGE 1-59 Page ss Quancicacion tapers (07 Reviewed) @ iScuocFra eile: |H D:H\WE SDR ONTI A\PAB\BARX-BVAVL-062-1\GE21063.0S_mpaenvieiearnl]: d3 a a J RRs" him \Wehshoe osuas. (x78 Toceseacor) ry es, ld fi i i it | Fkrroeysnsl,0103a0y%ppi4ra%--tm--ok--tm--in--a--m o--kT--mRe1=i%nstee--1 Tw00 Te Te Thies| |} ifi | ! | oi[EoEtt ie im Pe egeeT-- TTE I ii\ |i| Ti--Te E B se m E eeIh Te Te Tei cc2i002.0 mOA VAN Wed oct 38 12040103 2000 aon 3 060682 PrimedicsWorcs Project number: PABX.BVA 418-018:PAGE 1-60 Page 59 f---- wn Ha EI omogn JO sCtoTm I sian. moRm rEenEa 060683 Primedia:WorcesterProject number: PABX-BVA 418-018:PAGE I-61 Pages Guascstacion spore (2x Reviewed) @ HBruacaFrePile iDH:mEDaDIAmTR\RBAS\BABK.WAVA-062-1\OGZIGGASmonectviinatl! d4 a S1atrrcRegErRaAtiToTn B tase: soR ins.Rons S na van (x78 sncegtacons Fs ee mm, bl i i bpowoeoi:$e5T orTrT a = oT STa TTR T )TTR R Ta R . | 4 | pe|Ht a soasteosw oem Srn sk Gk TE ge Tn Tm iw iik TE 16 a 7l% iThniemt It I | $2 on sean ew ehsm sx To Te 7m 1k 16 3m im im vm de oerioous mon vas occ 10 aaanios 2000 [ 060681 Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE 1-62 Page61 Peak Area Roport Simp one outer ro naDmuntadaaanmme:ADosUB2S0S08C00A8TAPASPABLOVALE nentavV man am me fometr cmp loli) gn SsAmi mimo Prt ee 101420 1201 pase 060685 A ree 418-018:PAGE 1-63 o BfSIoTrie: HnoEm RomDecneussrcanion seers a8sevi2rtihBfyy --L to enTon Sa:R ratenon sen rTe seg =Tees tho TR GR 0% FEee eT dS ieGR m Te TeTe Te ve Te TR TR TR TE f\ |I er TERE : iE 1% i | Resp: Tak ee tm iE Te ER IE Th ie =| | Lim $3swshsw on ew oo 1m 1 TE TE Te 7 76 Th 1m1s 0068s Primed Worcs Projet number: PABX-BVA 418-018:PAGE 1-64 Page 63 Pask AresReport mmm, SEI eonEA mR anEE Snesovmsownorin mrnrtr fo3ge teEmop)ue GHEDOeEeSs use 000687 PrimediaWorcester Prefect nomber: PABX-BVA 418-018:PAGE I-65 Pages Guastacion repre ar reviews [Yemso EER Te 1STtRaEsEeTr Fg cam:rRSceoemion etvronynvae res senegeraconseen, - Hr ]n '| - i ! Ee EE eee TErr---- ii i| y3i5% teew 6% ow 67i am T Tw im 1% 3%S001m Tw mmm ee AN ] A on oe ie ak i on am ak Teve 3k ie 1 Te Te Th Pwiin ] | Ih tie Th 000688 Primedica Worcs Projet number: PABX-BVA 418-018:PAGE 1-66 Page 65 PeakArea Report EEE. SL. JO oxi oR ns S nr mer congue SE seme oss econo --- 080683 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1.67 Page 66 Quatication Repor (OT Reviewsd) @ RfDietaamlonFile 1R : 3D:\MSD3'O0E AcTeA\3P0A00B\PsAaRtKes.BVA\L-062-1\0623007.0OTpoewcaVcioarl:: te7orw Q#uanItncMeagtrhaocdion 3P!arHaPmsC:HEreIeTt\ntW.EpTHODS\PVAAB.X (RTE Ineseator) [a nes, -- - i Io +EEiEhIsEmTk EEaTVEe E te Te e Tee TTe T R er e EA i{reTsopn: T4034TT T ;| --e [i bToinkTwTeTun us ib is ik va tAamiinkeiu is rh re in im sh | Resp: 4082 i| iyi | CoB em ee am sm ov om weTh Th tk th 7d hs YR ik Er 0521007.0 PABXBUAM Wed oct 18 12:41:55 2000 Page 2 650690 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-68 Page 67 Peak Area Report o rere oom rtwn an nssumantE MinotNan SAEBAue rnenpesxvia amr + mens Gomptus SBeEateDn go tess Sass PressTee sen 2.62 age 1 650691 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-69 Page 6s uancication Report (07 Reviewed) oirRDaetgahionile D3:5\\N0SScDeR-D3N0T0A0\PAaBe\vPoAnBX-BUA\L-062-1\0621008.0Sfp_eriavciaeltr:. ]t&an G#5ian1tntWegEeEaociaoTn DpFarHams:RcrCatSoTHHnOOSI\eRBNX_BYV:A M (RTE Incegeacoe) ; ew . a re r oTpt TSe W--S--reTe R EoTleTsie ihITEPTE EeT oTRre] || [ii ffn i 4 | @LHDO A 0 oe C i WLuWET g a a - E _ Roh TR : 06210080 PABK SVAN Wad Oct 36 13:42:18 2000 rage 2 000692 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-70 Page 69 Poak Area Report SStumaiatm: tConreoeS OnepS caa m017255070 ramen TLCUES Bkoniovans s 51) amet Compost comune Roti Impl lm tela dee 650693 Primedica-Wrojrcctneumsbeerr: PABX-BVA 418-018:PAGE I-71 Lo meen Quaneication Repors (07 Revieveds [TN RDa=coarFilR e | DB : G SOm OATA\a EASEABK.BYA\L-062-3\0621009.0_SEpessvEiidatl!:Sf3 a C#8arracHegEtaRtion SpARasass: xeatar.pons eransun. (ere taceseacons i p. iill | w[ i xso = a EEeEwE em Tw iEFTa% ree 1% tm wm tm ve i IA} Sia NA AAnd Nm rm, i A, i E rhesap:n4e3e 5ss in dkan an ee 76 TARe|oTBnTR 3B s ve R 78 TR ETwil ETERS aR ae sn SE am rm Te TR 7% 1k 1s 18 ik Siw ie G6E1000.0 PAB OAM Wed Oct 18 12:42:37 2080 nage 2 660691 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1.72 Page 71 Peak Area Report Nr otSteemname P110noo00n5 OneSnsm : arcs 47 unretame: 5210100 samt ama? Renin foment Ge Iie) emma ets PowemaT tore 2 [. 660893 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-73 Page 72 PSRYeagtloarttR ie eE{DB:RDEORTAAPABI\EORNuBaKn-tOiVcAaVcLi-on06R2e-1g\e0rGEIGH(0a.r0SmpR_eeervtivieitwnhek!:d)M10r 1Sl8anitncRagRzRat"ion SpEHagEans: vweonsoPS AB s\a. (RSE sacestaer) pprTe TR Tni Te RT | I [resp 3356 | ! E--_--L ee Wfira pen ] i r [SErS iF ar wr aJ} . fit es eea -- emBri | i RE I i] A aon 2 + Primedica- Worcester Project number: PABX-BVA 418-018:PAGE 1.74 Page 73 Peak Area Report mSae me am:m 11 We OM onrco:tss 167 ahdPSD SATAPABBOUALEKL sant Vo mm3 s cnmlpoim IWoowsm heoms Baim Ousmane orR 1303 rant 000657 Primedica-Worceser Project number: PABX-BVA 418-018:PAGE I-75 Page 74 @ HBBaectaFteFile +| Qucization Regore (0 Reviewed) E BB:\WaSo_omE ATA\RAB\SABX.BVA\A-0EZ-1\0G21011.DS_moreecsviiaatl]s a13w a55 ntosEegneaecionBpaRramCWs: TaHTEoDIoT.s\PASSVAKN (RTE Integrators N a eryA mn -i Hi E.sl Hifi | [8 i M|eoURmLeiesp:e p20Ey36rT 18 ie eee TAp mo\eue nt:eTtErEe0er .70t0 TE Te . ee ree 3||/ me @ia I EF Fi \ nToan: 01355 (7.168) _J r Aog we we e rSr A eee ams } E Y|C EP T E m e EeT rniirea | Tl _ OCOD PAB BAN Wed Get 18 12043016 2000 nage 2 oe0s98 Primecics-Worceser Project number: PABX-BVA 418-018:PAGE 1-76 Pagers PeAraaRepkort mmm Se ER EU nmeavons menNERA 00063 Prmedica-Worcester reject number: PABXBVA 418-018:PAGE I-77 Pages @ 1 DiaaFpuiees:DSR:pDmEDAALTGAansRtsaSsion06f2op\oOreEELEEBESr Relvviiiene dw:s 33 pm--w E--RT--SAR w --_oo-- oex.s.-- x7 Socesrac-- ers [ \ | 0) i i n =Epe STr ET TETELo E HETTTRTEiE ECREYrVE ToE E evEi= h lLuox nkoi4 4 hE ts mn em an a em Te St 7 TR eee Ih Te ee Te kh een. Th 18 Th TBH ! A | mime dN SEv6E 1h ee ohLek ihTe ThTe Te TR Te in seik | 000700 Primeica-Worcese Project number: PABXBVA 418-018:PAI-G7E8 Page? PeAreaaRepkort meme ee warAr TI ts I... atm ws 000704 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-79 Page 7s cuties sere soviet @ HEHE Burtt By I oes EsaTm RE enon aaee seeps Um + ou] H Bmrm Ny ww -- sw em is Gm ew htEy jo tw 1m 7% Te Amount: 0.00 7% EET 1m im 11m % | -- ix sx se &% 60 6 x ie iw th 1% ve iM im tm 1k 3 i em Eets rinses] 6% 6X _$% $1 ew 670 6m 6m 10 7 1% 7% Te_7%ym 7m tw tw 000702 Primaica- Worcs Project amber: PABXBVA 418-018:PAGE 1-80 Page F---- neSRE RSEEE: I a. nnEE TScemamas en. enSEE scree ot 000703 FrimeicsWorcs Projectamber PABX-BVA 418-018:PAI-G8E1 rn Cunetacton pore Revived PEofur-nipCiee:I BNSD PmEaAEmTINSAAS 063 OILSoorertviattl:: ie 1 osaIpeEaion D peu:oFETs E en va. (78 Tnceacen) Bhai -------- | { i . ee TE = EET SRT T BeE | A | Pett ar ren mr 1 3 i Lon ex sk Gi ew eh sw 6% 7% 01miw Te Te vm rm im yw! ih | Tims% sk en sm no ssaw 7h ie om 1% 76 7% ve 1wim 1k 000704 primateWorcs Project amber: PABX.BVA 418-018:PAGE 1-82 Paget [-- A ee T= ive 000708 Primedica-WPorrojcecetnsutmbeerr: PABX-BVA 418-018:PAGE 1-83 Page 82 msnisaston gore 98 sentevet @ iErEe fret in Teer: i pS ep R SE omersvn tm ssvugensent 7 : | | fi | rom i fFreee48tEsRsr53r8m5 4% es on 66 te TTm [aNEhNeTRS TPE TELE] | a = ETTre Amount: 0.00 ! i; iA e Er Rm E Tm E EER e iTRERS 000706 Primedica-Worcester Project number: PABX-BVA 418-018:PA1-G8E4 Page 83 Peak Area Report EE nCne omepms 0 reOSEnanea S31U0E1C0ATA AAG YALL messveame:v7 000907 Primedica-Worcester Project number: PABX-BVA 418.018:PAGE 1.85 Page 34 Qunsication Ropers (0 Reviewed) @ SRi aatarePile |+HDB:E\UWSDSR_DARTA\BAAS\PREX-BVALL-062-\0S21616.0.B_forearkviiaSlh: b26h 1S5 tEocesRration BparamRs: TEenE.o s exsaw ere 1acessacon J nowarpr:-- o311I1s RE i TI TEReTsee" eTe ae ls Te ee . | OC E R a Tr wi Bio Ti re mew Te i | Eh TaTe ae Te GEai0ieD PAKAVAN Wed Oct 16 iasansse 2000 nage 2 000708 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-86 Page 85 Peak Area Report NoSmubmiramee 1PCASEoBrune5a68 OeAScauoens: 10172050 100% tmentaenooHanmm t ASE VSATAPARPABLOVA EL, em vlmoma ar7 Gomnde commpiwm lhe gm omedm oem 000709 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-87 Page 86 Ouassitation Repors (07 Reviewed) IRDaeaEonFitle 2D:3\0CWcSeD-_eRD0N0T0A\sPaAsBie\oPnABK-GVA\L-062-1\0621017.0OE_pEervaiasl.: u17a @i a#5nstasWegSziahcasaoTn bvaEc\anNsR:CHwETA\EEITNH0TODS\PABK_BVA.M (RTE Integsator) na vg a ow i |frar sp:n57i7r nTe vn e sencehih FE wk Tniee1% T7R% i TR TRATE TR E ThE 1h | i | . ee oT reas: Is3a8i (7.165) TE ve TTE e 7h Jk rhin th da .E i Re ER N i | a TE TE Te re Th TeTT 0621007.0 Pam SVAN Wed oct 18 12:45:33 2000 rage 2 000710 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1:88 Pages? Peak Area Report NeSse ame:cSEams onSesm 1920 eB osu EcsUionsraps iar2 mar mrttan 1 a3 wier lmowwm mpomme eae 000711 Primedica-PWroojerctcnuemsbeer:PABX-BVA 418-018:PAGE 1-89 Page 8 Guancisacion Report (a7 Reviewed @ arBcaarFerile DD:BD DEAITEARVPRB\EABX.BVA\L-062-Sp1\GiZIOaNS.D rkoViinatel!:t]1o0n L1 sIocaRpeacAion B agama: EnR eMerhoosnE mevan (x78 taceseaton) hcr - em iii i - : i . fp ranaTrsEnEE= R E Ia EEE e ETE || fon: 3i5-300 | i | ji [iin ik--e--w --ew--em on am em ve Ti o 2h 1% ieBaTee te im im im Reap: 5545 hr i || andee ekee in ah iETE Te 1m 1 re th 7m3% 1 TH ocrioies meen wedoct 18 134s 3600 age2 000712 Primed Worcester Project umber: PABX-BVA 418-018:PAGE 1-90 fa Peak AreaRept SS wp on TEsaan. aS tom7ers e=mpr= es5a%s spp wns: -t 000713 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-91 Page 90 Quascication Report (OT Reviewsd) otDr fatapFaile : D:\e NSD_ONTA\GAeB\yPABK.BVA\L-062-1\GE21018.SDfpercaVaiiearml::ew1]a3n #G5ianttocNaagcehaocdion 5f:a\xaRmPsC:HEmNIenMEeT.HODS\BABK_BVA.M (RTE Tacegracor) F------ wm i -] i hee 439 6m 6% Mreesp:mr2oi025s. . Se G3 sm 8 6% 6% T 1% IB -------- Amount: 7% Te1m [FXEm 18 1m_7m 7% 1= i i ieein te an J iy NT -- im en ow sm im en iaih Te rls 7578 . i i red a om em 3m re 1m 7% 7 Je 38 im n iw o| | | er Te 1 16 7h TE 1 | 0621019.0 BABIN Wed Oct 18 12:45:52 2000 rage 2 000714 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1.92 Pagel Peak Area Report NotSaasmpRleeKeatm:e:2PA2G0SSULAOW1W5a6t1er umACcoaumraeta: a10k17720002063 rma uSeAhEeMame:S0M21E0S20C0ATAPABEUNABL am narua mentNnaomna 57 compe Gonmocus Dem momar mma 000715 418-018:PAGE 1-93 Primedica-Worcester Project number: PABX-BVA Page 92 Gti taper AF Soviet oisr RareaePia e 1DED O0r NEai Ai\EABSVA\06P3-1AA0D621K020..0TSeo_eesc:tviiaslh:2e20 rT o srsE sgeacion D param:TETSos\esan svn 808 sosesracers et emt mmm) 0 A | - i : IE a R ERR RE LE L E TAREE : A } OC lEae | [oe ea aw vn Sh a ee RS A | ody | em ako ee rm zie in vwhvGein vk rw 000716 PrimedicaWorcs Projet number: PABX.BVA 418-018:PAGE 1-94 Pages PeskArea Repart mr wg psn SLL SU somes ons men EE come comping maar saseee 000717 Primedica-Worcester Project number: PABX-BVA 418-018PAGE 1.95 Page 94 Quaatication Report (07 Reviewed) @ RDavtaohntFile I D3:5\\T IoSeDe_-DBE NuTooA\PR AaB0\uaPrABX-BVA\L-062-1\0621021.0GEpeEraVcioarl.: m21u 4a5n1eoceeghtaocion DpeHrRuRseC:HENKIEMLET.HODS PABK_SUAH (RTE Tncegacor) Rg reams ef it [rw rareRe Resp: M3a6r1o . | @|naLaams: s53s75 oso `Amo)unt Sop (WIE| fl Fr RT TT TN TNT 060210 PAXEVAN Wed Oct 18 32:46:31 2000 Page 2 000718 primatesWorests Project umber: PAB BVA 418-018:PAGE 1-96 Pages PeakArea Report o SumpteName: EE 21 OC HIGHPlasma AE DateAcauired: 10/17/22000402 EEE urasnsn en 1 i =n 000719 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-97 Page 96 Quantitation Report (QT Reviewsd) @ if Dacata Pie:yPD:\ENSD_EONTAL\BAi BENPABX-BYA\L-062-\0621022.0SEpeeeraVtioarl:: 2m2n 1T5 RsacIegrEacion S pacums: RTETR CIr.ops N eaax_ava.w (878 Zaceseacor) Ty - ) ik i w[f warro EvSrr -- rRm --eRTa ENEr T eTe E nen: 601 A i i Lai i eee | wfeoenn.: 300 138 17.162) Te 7g 8Te TR EE A --!i fi i Snve eee ew ee mn Th Te Te re Te Te 76TR7%El Gen0z0 MBEAN Wed Oct 18 13:06:51 2000 rage 2 00720 Primedica-WorcesterProjet number: PABX-BVA 418-018:PAGE 1-98 Pages? PeakAreaReport @ ERNEENE fa EE EEsamen sR 000721 Primedica-WorsesterProject number:PABX-BVA 418-018:PAGE 1-99 Pages Guantisation epors (QF Reviewed) PY sSeaecra wee ile +| DS:\hSDE _uDATnA\e EAaS\PeABK-BVAVL-062-110672620.0Smo_eeentvitaolt:] 2f3a 45 incEegRraAssTon SsRucess: sTEOEEmEoosmexov (x78 Tncesracor) a, ww, = om = iit } Lo ePy T e TE EE eTsehe Te ee Te TE i Te WHnLouon, iHho 0.0 -- Amount. - "5 -- A } i | oin shS ope: wii tase a sm br e sk E 4m ed e 7% T, e T. R 1% 76T Tk i E im imE vm5i he ih i| Lem an eissm sw om ew 6% Tm Tw 7m 7% Te TR Te 7m 8 Im cero maxavn ed oct 30 12:47:10 2000 nage 3 000722 Primedica-WorcesterProject number:PABX-BVA 418-018:PAGE 1-100 Page 99 Poak Area Report o ronsSSamRplAeName: 2E1GECLOWPrana Em DateAcquired: 10172000 2121 orate SUESonosamanoimisnin maNS 000723 418-018:PAGE 1-101 Primedica-Worcester Project number: PABX-BVA Page 100 J -------- saca File 0:0 HTH Agena Eimo nie UAVS-062-1\GRRIGRA.D_ vis: mses 30 E1 Itmsration pS ane: R naET.SS oveneT nsvn. x02 snsepsacon ri, me =. ; i =e ees 6e104%G--B)58 4% 464%Sm 4B FE5 7e0 700 VETe187kJ& Tm -- Tm 1m i bea i em a i eSi "ew am en em aa k 7 130 EEpTei r 2 a Tm TR Tm | h | i Tea aTaraiE TS ve te 1h TETeTa 000724 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-102 Page 101 Peak Area Report omenOriFi aap hammtoAAEs aSRtSBCsAATAPABAB BYA1021 sireLn aVmamais 35 Semg3pear coEmepu ImTbeel wim tadma faiee 000725 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-103 Page 102 uancicacion Repose (07 Reviewed) oiRDH eatcaortPL ile L {+ D2:5\\WCSGeDm-_trD0Ae0Tl0A\PpAaaBns\neRasARX-BVA\1-062-1\0621025.SDFpeesVaitaela:r mi25v 1C5oasnatReAgEeReaac"sTon vDIarAasReC: HEwTLED\NMTE.TH3ODS\PARKBVALM (RIE Integrator) ---- cma, eee IE ve ve le Tk TT Te ia ie r norm:a 535 s ei e By ji | PalTe ve skSE 4m em ew 1m1o%i7:A 7% 18 im tm tm te im Romp: 44) # ]! fi i EE 5 ee ve sk sn sm ee te vl 7m 7% 1a 1%Tw 1 rk im 0G21025.0 PARKMAN Wed Oct 18 32:47:49 2000 page 3 000726 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-104 Page 103 Peak Area Report Smo acc nm om ear e in 20 ntnmntO MtnsFheme: SSASBEEBuCnATAPADASKSAIL transom fomp3eds cawmepus loninowwm Bagem Smee 000727 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-105 Page 104 Quantitation Report (07 Reviewed) @ iE Sa=taorFN ile|{DO 3 -ee\-aa0NonnSwDaaatre_SornAROKBNVAVTL-A062\-1P\06A23B026\.0TGpaocaviiarl,: 26 [#5EtEacegeacion r pecans: ATED.e SR Rg TT eww i PL a a _ a RT-- a a r -- w sea w: S91 ) i ft PrSotes e rarE Ee igT . Ramp: 434s { I ee iiit ii LBTE Ta aea ee ie He TE Ta ETETe 0621026.0 PABOVAM Wed Oct 18 12:48:08 2000 nage 2 000728 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-106 Page 105 PeAr aRepkort @ wm SE r ERe TAT Smarr, mun 000723 `Primedica-Worcester Project number: PABX-BVA. 418-018:PAGE 1-107 Page 106 [RN -------- @ iHBDaoEcarNeFile |+DB:NDEDNTA\aBAiBr\PABK-BUAVA-063-1\0GELO7.D_SmoaeervViiaolt:: if27Sa 6 sacEeseEacion EvacasRs: ERrEEi8hoos\ena ava. xe snteseasor) PE ----. es ] J | Ie tS SE GE T6 wk te en in "im Erin iE Tee Fe TR te To | ReTsopn:: 2130155 (7.138) i. " }| IA | i Th ew Riga agk ve RE xiot p: ithe oe | =i) / r | A | EE 062101. mBOAM Wed oct 18 12:48:28 2080 sage 2 000730 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-108 Page 107 Peak Area Report sop aceane one nz meFeleea SsCEeSATAPABSPAAIS6K2 tan Gomes compe SNE gn casa pp 088731 Primedics-Worcester Project number: PABX-BVA 418-018:PAGE 1-109 Page 105 Guassiacion Report (07 Reviewed) tDSSaacEaaNrFile 1 0N1\NEESD_eDLAoTAv\aPAaTBs\SPABK-BUAN.-062+5\0623026.0Sh_epeerckviianlt:! 28 6RaarceRgEeRaEcAiDon sazRamRa: sSeWEoROOS\PARKBVA (RTE Tncegeator) BE | fi | 1 fMpreesape:Se re5E30 Eoe aErr E----Ee HR E- E A IEty Ie ARE=I Sr ETeE To phernE eriere| A i A O= o riyEve R--E --TR eTeesSa . TTT e RRhiE| nie aeen Te = mdrae a TeTeTei TTe ie Te| GG0280.0 PASKSANM Wed Oct 19 12:48:48 2000 rages 000732 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-110 Page 109 PeakArea Report Noms mpi eanme:3:S0A0V0LS OsuSn:AOTS ren TRE UESrneonsc mara Somapods Sameimyendaze fain TeWpoe mBm BmAewME Sue 000733 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-111 Page 110 Quantitation Repore (G7 Reviewed) LRDaocaNneFile eDY:\0HESD0_DHAi0TkeA\wPasAaitBse\rBABE-BVA\L-062-1\0621025.0SEpaaraVciaarl:: b29an i esaTnocSesRrSac"ion IparCameH: TEMLET?HODSPABY_SVA.M (RTE Integrator) Free ve -- a I [ET rnEaortm:r 35ir 3 E MTa J E 7 Jl T=|| oi io 5i1k 3she0i2h60Te nap: 4700 aH v.e we TmT`lA7 nouat 7m e ve5.06a te im tkisi> . 1 iit || i ih { Ie ve we neee we ee Thr 7h 76 7e 4 tk In y 18 78 | 0623029.0 PABXBVAM Wed Oct 18 12:49:07 2000 vage 2 000734 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-112 Page 111 Peak Area Report NotaSuRmieamne P23PAaOr0m8a umsSeqr 12200231 rn EE BTAPASOALAYOALL, meri fompear mma loa mo fem age 000735 rimeicaWorcesterProj amber:PABXBVA 418-018:PAGEI-113 rage 12 sremton spre sr on EEA Sore EJ ET E--A _osE em yova x Sscgenecarne - ? - ji | E eeerrors. Poreemeeoremereeege 1. epee i I sk oo EET I Resp: 5002 . i ! i Li sh wn e om seem ow sw Im 1% TE_7% Te 8 TR TR 7m I% || 000736 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-14 Page 113 Paak Area Report NotSaumR iame:A3Se S3U0A 008ns eoee07200233 ompedt Gmmpitas Ise) wo teARi hime 000737 418-018:PAGEI-115 Primedica-Worcester Project number: PABX-BVA Page 114 oRDFaacna eFile| E Dp EDESATm A\PAPGPuAaRnKs.seaAcViLon06p2o1rGeREIGR(S0SFepaveicDahettw:sh33y f 1wesncogracieon paI ns. wanes -- et |e [bI o ER EE Pwanis yarram | i -- RE _53 =i | aoixsA E e: ose oe% sm em em ew Te \Tw TE 7% Amount : 376 TR 0780. im om im im |y Cee e ET Re] oerion mHN wed oot 30 10sied 2000 [ 000738 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-116 Page IS Poak Area Report itn cotoes Onnpeen r3357 SSA EURBnmssmucaunora meee Gonads Conmpitans Tle) i heim ge 000739 Primedica-Worcester Project umber: PABX-BVA A18.018:PAGE 1-117 Pagells Quaatitatios Report (G7 Reviewed) PY RDaecaaonFile:1 5RD:\E3HSE0D_C0DAE0TA\BA22B:\5P7ARK-BUAVI-062-1\0621032.S0EpecaKEtaelr:!Sa32 wee 4asnztovSeEgEeRaAc]ion PDIacaRsse: ix]TEWRETH.DOOS\PAS BVA.M (RTE Integrator) Fo stg en wy fi wd IAit |! I=e Ep ER = r EEETEEHLeE SlT EE y E EE TEE TET Reespr: r30o3 r ) i P|a ESi i iwaREenT e e TrnETd a e Eaieoupntk st threie r1h iemarod xefmon:t 1330s50 nen i ii ara Ji | TT ar GRID PABKBAM Wed Oct 18 12:50:05 2000 rage 2 000740 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-18 Page 117 Poak Area Report o Srna coer ometum:cron Gompoat Smmpttes Inge) @ team feiehe 000741 Prmedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-119 Page 11s Quneisacion Raper GF Reviewed) @ DfHurcaFanPile +h 0t:\yWSE Or_DAaTA\PABNPABK.BUAVL-OG2-10623033.8_Seoeuecnvieaslt: t33a 16 ncsEgeaecion PD arams: ATWENh.rEhn oos assova (x7E tacesacor) ---- ne _-- 1 WJA E i eEraEn ray or - i I o| pE ii. i T = i E 2 hoE TEse TaretE eT a. fp | | i ;| EE Ee ea EE GRID PABEBAN Wed Oct 10 12:50:26 2000 rage 2 000742 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-120 Page 119 Peak Area Report seman scene ones ocn sn OuEt r T aammeeE0A1BE0A0SnenmOVeALA0a61 namca evruamammeen354t7 Gom3es Cowmimpeiues Damliao) mwm me=m sige rma Tne 0102080 250 age + 000743 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-121 Page 120 Quancication Repors (GT Reviewed) PY DSeaetoantFile +| D3:8\WoSeDe_-OaN0T0A\PA0B0\:B3A6BR.BVAVL-062-1\0621038.DGTpheerraVciolr:: H34t E 45 zacO esracion FPazaems: sFTEIWNETF.REODS\PABI BVA. M (RTE Incegracos) = | i oa Meerro TE-- Te e-- T i aT veLC eEa ik i trh fse Resp: 1630 me LS cn O a Roos p: 3560ven e)nt 000 AJi |i ET ieiem TR e Te Te 7a ie YE Te vk wm de || Cert03.0 PABKBVAM Wed Oct 16 12:50:48 2000 page 2 000744 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-122 Page 121 Peak Area Report JOsEami me e 20Ma OWa ueAfrcotti1ty185S umnovanFadihanm:aAEBnEDBcVA nPABPAGKEVANS rmariamuanm:s 135 Compost mms IS Sem Rp roa wen 10082001250 ws 000745 primedica:WorcesterProjectnumb: PABX-BVA 418-018:PAGE 1-123 Page 122 cuantication Repors (07 Reviewed) @ afirnacmgetritFeile +| 5BT:\HERSO_EDRATA\PA"SH\0P.iASBK-BVAVL-062- \OGZLO5.0SfpecaiVtioatrl! ]i33on 15 xacesrationon pacama. wSTEWONET.FHoDS\PA --= ee SYA. (RTE IncegiacorT ) T) i Pow ii | Ee T er Be vee e e rs ie resp: 3133 a . bos rT Ee _ rweaopn:a TI77 (Te IE | a f _| wl -- : EeeaeTT Te ta ThTe | cero. PASKAAN Wed Oct 18 22:52:03 2000 rage 2 000748 Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE 1-124 Page 123 Peak ars Ress an m ESL E nenr EER rr mse a al IE TRC ---- vs 000747 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-125 Page 124 uaneication Repore (Gr Reviewsds @ iatanit ke | I32NS0ESSahnhpianosteo TheroRnienn:g 3c G45anttastegheoasc"ion BPaRcuPnWe:EmHTEOIE0.8D \PABBVKA (RTE Tntegeacr) fT a T ey |i ve: ia) | meEE ee r EE e TR ET Te E TE TET | huwaeep: 1 -- | oe_AMGURE: "0.00 i ii | iA | O (n3e7ono: SS360 is tm hhne a iTe eRE : A loo Jt } J\ . | Liean Wo en we en ak im te 7h vm 3% 1% 1% ve 7k ik th) 062106.0 PASIAN Wed oct 38 12:51:22 2000 sage 2 000748 Primedia:Worcester Project number: PABXBVA 418-018:PAGE 1-126 Page 125 [-- pe mr mS e SRS ErE esus. mE an R com7er co=mpe IT RE E gma E esse Isms at ns 000749 Primedica-Worceser Project number: PABX-BVA 418-018:PAGE I-127 Page 126 Quincitation Repors (07 Reviewed) @iRDSaeyitgfalpolneFil*e 1: DAT:a\G'WGSEeDrD-AaLoToaAgn\PmAaBka\ePirAsRK.BUAVL-062-1\0621037.0STpaeecaVciaarl:. a37v G46uanZ?ncNeegcehaetsion| DsFaaHPnC:HENm\rEEIKNETT.HODS\FABK_BVA.M (RTE Integrator) mm TTT ee IE EveEh ETEe IE TTey Te ETe a TRe wRreaem: 365 ) = a i 8.00 % --}I iI) o|neToa n:iosnonai tToE = enE ee ikTmTeTihm Tg h is ike TeIe TBR TIErn REnyi i I i| 05 en se sisw eh ew. sk Tm 7% TR1% 3% a im Tm Te te 062031.D BABKSVAN Wed Oct 18 12:51:42 2000 Page 2 000750 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-128 Page 127 Peak Area Report NotSeumFioae: 4A200L 140 5ins OeAS co:E640013. nmrS am a ABSA CATAARPABLBYA O21 mtn fmol Gmpdtes Isle) mo twime Seas 000751 Primedics-Worcester Project umber: PABX-BVA 418-018:PAGE 1-129 Page 12 Quincitacion Report (QT Reviewed) @ ioDattanFile | NDB :\KESDN _OEATA\PABI\PARK.BYAVL-062-3\0621036.0Saparrvesiaeln): 28 a45ntencWegirahtaio"n 5ParAanRaC:HITEEIMVEIF.HPODS\PARKBALM (RTE Integrator) ` lA np ? nd Ii i1 | fe nMiosnp B133: 000) i | TR TT TT . es | a EEE Ee aa Mooa i Se 08 e= e EEE . i i J J I 0v % e se ai am sw am vk TR 7h 1% 7k Te ve ih ia vie 0621030.0 TASKBAM Wed Oct 18 12:52:03 2000 rage 2 000752 Primedics-Worcester Project number: PABX-BVA. 418-018:PAGE 1-130 Page 129 Peak Area Report Nom SumRpeame A 0MS OPas DehAeys:eesn000133 ne SEL SCAASABOA BALL, marae Gomme Compiles Ann latin moses Stas PresaTne eat 52 [oo 000753 Primedics-Worcester Project mumber: PABX-BVA 418-018:PAGE 1-131 Page 130 SaDaEotaTrPile :D:B\NEESDERDE KTRA\Ba AB\NBQEuAiRnXc-iBcUaAcViLo-n06R2e-p1o1r0t62103(50.70GoReevcviaiecawo:erd) 39 @ ize ETS G45uaInncNegtrahcion bpFar\aKsF:CHEaHEznET.YOOS\PABKBVA M (R72 Tacegeacoe) [|=a) iAh foL | stie15 TR TE ikTr R i TRSeToEnJ! T1E2 5TER TE TR RTE ;! iLemp. 318s f| } | a i L xE inA :e i ihE ae e a e }SY || f r emmr e JN | 0621039.0 PAKSAM Wed oct 18 12:52:20 2000 [A 000754 Primedica-Worceste Project number: PABX-BVA 418-018:PAGE 1-132 Page 131 Pask Area Report RSeR man. E1oRnEe . oevEne: riz . TE smn, wanSRE pr [ETS -- het 000755 Primedica-WorsestesProject number: PABX-BVA 418-018:PAGE 1-133 Page 132 Guancicacion Report (07 Reviewed) tM RSaotaneEFieR DLhEVDAeTaRany\GBVAA -B062\-1\P062A30KR0.DK.S_rpeerivtist:] f4a0n S#5 aSotlegrIasion S raceme: smomE.iR heoos ass va. re Tncepracors I ---- --_-- i A | - al e 0 T{3ATR | H| Raesp:r1m156on Sa . : r-- | @aieisti:T la sSsoskeeeor=e e ani a--ie--smsm arsa15 6ve.00ge 78 Tn bEiT e i fhA | a ax ek ak `ew eh ei ew i 3 vm dw re ik 16 1h 3% 7% orion TSN Wed oct 18 32052140 2000 [ 00975-6 PrimedicsWorse Pret number: PABXBVA 418-018:PAGE 1-134 Page 133 srg PeAreaRepkort ong ge on EEapE na ma ST om7er m=pi GEElD we sasmr sane emp -_ 000757 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-135 Page 134 Guantication Report (QF Reviewed) FFFSaEcrarile 3:\KSD_OATR\FAeBNiPABK-BVA\-083-1\06EIONRDSZpoercviiialn:t f41h R 5 SonT egracion D agama: wE nsos\mE ex_sva. (x78 Tavegraor) = i ! po TR RS TT ee 7 TeEe inr MeLs: see r-- yor 0.00 ' -- o5 siifeno!n! h Srnorr -ni hhe w EETe ieEe s ea :! | fi iC fomE em ee m ie ea eIe nTeee Ta ; ee seme me EAN Wes oct 19 12:52 2000 rage 2 000758 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-136 Page 135 Str Peak Area Report amt zn2 omTeaNa a DAn PSACTASPABLBANOE mar Gmmaest Gmwmpatiun laegwsEm tw=nm twa Prse uem 10182050 1253 on 000753 : Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-137 Page 136 Quancitacion Repore (07 Reviewed) @ KSDaetgahonFile iE 1 1: 3D0:\GN'SGDe_2DA0AG0TH0A\Pv+AaBsa\erPsiABK.BVA\I-062-1\0621042.S0FpeoraVtiroarl,:mt4]2ay Q46uanttncMeastehaocdion 0p:arHamPsC: ER\TEETDH.OEOS\PASK_BVA.M Ray (RTE Tncegracos) 3 wf ii | wM rre Eo UR ss OU iho am ik TSemoTeuR ne1 oyR TR ETe E aie Resp: 7007 | | i AfA | oiB Tosn: 13i5k(T 77wo7eh6ETveveeth ee oBnA JA re TE TE _ Th is ik ie ih irEeTrEe] - serps 81 . | i JfAy || Ee EE ee ow ee eee Ee e 021042.0 PABKSVAM Wed Oct 10 12:53:38 2000 page 2 000760 PrimatesWorcester Project umber: PABK-BVA 418-018:PAGE 1-138 Page 17 Poa re Rapa esse on EEin eS omett compe SE pn age yee mre rs 000761 Primedica-WorcesterProject number: PABX-BVA. 418-018:PAGE 1-139 Page 138 oFDRSeagttaoIntFile |+ 0I3:3C0SEEDE-O2MN0T0a\0PaABNrPPQAYuBnKc-iBcYaAtLi-o0n62R-e1po\r0t82104(30.70SoReerveaivtieeaewlren:'d)a3 #F6anttoceVgeeiantsi"o?n 5FacaRneo: HwSrEmOeHTo.0p8\oABK_svA.N (RTE Tacegrator) Sve } = i ) IA B A R EE EE w w Tewmifopn8!s3031361 36%363407 8% &; I 1170% 1 | 14 1078 1% Tm TR)y! : ffhh| JA oL! nei iat" SokEme eek em en aHhk--sk--tn--1a %_} TheTRg1% e7% i 7] he om \| | ! bmi ooo SA SE iksk sk sk an ak ak TE To im 3%" 3a 1k rhe Th TH os CEN0LD PASSAN Wes oct 36 12:53:38 2000 sage 3 000762 PrimediaWorcester Project number: PABX-BVA 418-018:PAGE 1-140 Page 139 f-- @ mmo omree ere A... 000763 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-141 Page 140 Quantitation Report (QT Reviewed) =DRSaietkcaoofneFile 1 1:3\NSD 3D`Ao0TcvA-\LaPoowRaoBw\aFrAaeSiKs-BA\E-062-1\O631044.0SEpeecVaicaolr: 4t4w 5anIencnegirnaoci"o?n 5parRamPs:ATE\INNEF.HODS\PARX_BVA.M (RTE Tategeacor) fe= ve 1 rmi > i - I oeptE mtaT tstemneeEEe RT R eTee | TEh TTR wep: P675rom e| en see | i ifflh Es atom ihn em Sp et Th i nis is re a ia ih ETh eikn @reLap 4s1sa aa m | w1 | fi | . IA\ | | Ba5newik wmeewn aTi Te ve iaih ie inieie 0604.0 BABKEVAM wed Oct 18 12:53:57 2000 Page 2 000764 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-142 Page 141 PeakArea Report NomSateRneanme ASK 1B100ewan Oe cErs:irez10 nm e Re e e CAsRBChaps AB ALL araRT omate mesons 3 ron SEED wm wom mame a oss 000765 PrimedicsWorcester Project umber: PABXBVA 418-018:PAGE1-143 huge 142 tsi tre ro 200 2% ornr E + G RA E T rte T AA,brn13857 38 SpI II BE cmses,srnin sen sisgmaeens |C-- iii ! iitl |= A B=oe Tees 670 u136w23 ro0u% EE ; ee 505% 48 Tw 110 1% 1% 76 78% TH. i i |! | Tw =) 1 i ee GN Len e oo 4% ee en_em sw 1m Ti 1m iw 1% 1% Tw im 7m im 000766 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-144 Page 143 Peak Area Report Snes ccorn ometei zm20 enuOmsTHaeildehaAaeGmS:: CA 1A0B0TA0APKPAOYAEX 061, nram menar e: 5? melt ER Gmmpium lef mo ease ress -- otDamaonw 000 284. rage 000767 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-145 Page 144 Quncicacion Report (07 Reviewed) [ DRsaeitsateonFile : Foal 3D:i\oNESeEDR_oaDAsT0A\PmAaaBi\iPmnABE-MUAVI-062-1\0623086.0SaperraVcioarl:: h1a #G5ianItntNeegtrhaocdion OPFaxaNmPsC:HEANTYE\NDET.IODS\PARK VAM (RTE Tutegrator) for TT mm ory ol i i ee en ie sn sk en ew F{-noens:p: 123311s-TTTeee glEii ssma TEaneiomnax me V erp:osem ns ) |} } en Tm in im 7% 78 TE in Te --Amoust; 0.00hiincomsitis /ihhvSeet 7miBn:eTR TEGT08R A ih ee Tee , ;| fii i| in iS ve Tv ih em db th 7 ThTR Te TEE ih iE a) 6106.0 PABEAM ed oer 36 32:54:36 2000 Page 2 000763 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-146 Page 145 Peak Area Report Nom Bo oma namCsEnaFNFna,SPUAABTAASADEIVAANSOLK martheenn fmmett | Gomes Ime) Baim Saimie etwasTm. 2001254 nase 1 000769 Primedics-Worcester Project number: PABX-BVA 418-018:PAGE 1-147 Page 146 foRDaetgS ao"Pile: DB:N \eKScDtDAoTnA\PABa\tQPeuAsaBnXt-iBtVaAtViLo-n06R2e-p3o\s0e62104(70.7O0pReervavitieoawrse::d)4a7 oi ET G45uatnatNeegcehaocdion DPiaHraPs:CHEETMR1E\.ETHPAOBDBSV\A. (RTE Incegeacor] wl A rey it } PO S-Resep.r25m02 onfe fo| is.TAFNen 28m 8 -------- | i ft | ofEE rseeee eEih kwhshf e r i ikE Th TE eeBSsER TEER TE E avee E erT e eaa I W fon 13s ape) Resp: ~ 1 | Ji CEEdeeiEe Eah ei h ik ih E ie Te E RTE E ve BEeTa is 0607.0 BBKBAN wed oct 18 12:50:55 2000 rage 2 000778 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-148 Page 147 Peak Area Report NotmoSoaoRmethaee: $ PAB1 LoAwP0 3a5rs OeAScatm1e0087500360 una,e BEAIe P G) SDCATAPABSPVAANBL S621, mmesarmeni ae: 7 ommels Cmgpiecs Daplal mm Pum faim FrwecTw 0001255 rages 000771 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-149 Page 148 Guntitacion Report (0 Reviewed) PfDY atoa Frilea+Dy:\SeDrDiATeA\SABNiPARK.BUAVL-062-1\0621040.5S_feoerceiviinatl!: f46x f15atiacegracion S vacase:RTEIN.SV-- oa Te me -| Ait | HT=reaeeErE2mSoEneeeGR GR TPE TRe TT Te TE TE % h F | oto nide a e --_a-- O : e I } \ i bCe ET wh IN iTe eeiI oszions.o mEKBAN Wed oct 18 12:58:34 2000 nage 2 000772 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-150 Page 149 Poak Area Report NotmnSaankmRoatinaem:: 5A2 orGPSSmR OeACem: a1n070578 en DuaAFeTMaEme:2U10E4S0S 0. AOAR EKBUA N 521 mamuernatme ST oe3 s cowmspu STSEew maage agen FoaeTw 10700001255 re 1 000773 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-151 Page 150 Quncicacion tepore (07 Reviewed) pBE aatrar.ie:FilE e +B D: G SS o SATsAa\eiPsAeRRKAS\ BVA\1-082-1\0E210NS.SDfpeiraVocisantll:af4]3a @ = us rneP oseac: ion Parana: xrT Ehposena svn (ae sacegracer) ws pewl eAk: s \ 1! - II || meen pF eea peeT Vr E epeNeN e RE ere eer | m [! xYienaer ma = |h| Se --_-- ) |1 i err varios - i ed mire A _er i i we emeaand Sem, Te J Tee Th ve wean a | ! ii iA || ee d| N IE ww ewe ke we a Rm ee || ofaions. mABBVAN Wed Oct 18 12:38:34 2000 nage 2 000772 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-152 Page 151 Poak Area Report NoSammp ane:8A06SSHEute onASsqarrs 1420003.47 nananania vam: AaBssBSAaraPAPBAAIL IEL1Y mans GemgHots Gowmpoilan Imm phalodmwan pm Saipee tO Tn:1012501285 aes 000775 Primedica-Worcester Project number: PABXBVA 418-018:PAGEI-153 Page 152 pfMacoarnride 9:\WED_DATA\PABa\uEaAsBcKi-tBaVcAiVoEn-0R6e2g-o1r\e06R105(0QS.Fo5ReeiviVoieatwle:]d)f5a9 IS hen er fee on ys soceegrnation sagass: TROTos sass van (x72 Tscegeacon) ! I | ih i | E pe. T TTia EE TE | mirrormes ron.1 ee rrr emme+ [B= } 1 {Yo13u1 r (7.138) EE -- it femme ime @ew ik ik am en em em tm gTiota m 1% 1eRY7% Tm Te H g ihe { oe fJIiN\ || oeraoso0 msmIAM Wea oct a8 32:58:53 2000 rage 3 000776 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-154 Page 153 Peak Area Report on r Smn aparm:4A20B0CViAm Ot r mun:y18200087 [e D aEt SN pnpesatATOR: he Smpugs cowisse Innteol wwm teaam mph PotOt aTn 020128 vane 1 000777 Prima:Worcester Project number: PABX.BVA 418-018:PAGE I-155 Page 154 Daca File | uansication feport Gr Revive Di\MSDDATA\BAS\PABR.BVAVL-OGLLINGKELOSLD vin 5 @ ERE EEE goreeer: J J ERT S --E ooosassova R78 tncegracors =' f/i | el Ia i TE EE osprrprmar----------m mde PE f] reemen IJ|owa |i fon: 135 (7.162) Te------me cece tb i | fl ! . en JA _-- Een te ik ee thm om Im Tl 1m 1% JwJk rm 3% rm rw 000778 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-156 Page 155 Poak Area Report [I sampeame:530rLhowwa unsSeaaatmis 17000825 enimoRtedPihNaeammS,eoAz1B055.2AA0TAPABPABEOVALSEL) maruamrkmVeonmi:t 5ST Gnm2est wCmmepium fr Imweow Beaem tape 000779 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1157 Page 156 uanticacion Repose (GT Reviavad) S RDaetgaioE nPile*E|: TDa:R \0MeSeD-_aLDooAawTnAw\aPcAeeBra\PeABE-BVA\L-062-10621052.0GHpeeravsiaarl:: w5a2n @ ud G45iaTnocWeastzhaocdionTO: HpParCeHnE:IIw\EEEITNHT.ODS\PABX_BVA.M (RTS Incegracor) fo Te -- = i | P= ii [I i | BO L{e E e EmeTTEa TTERR Tee TmIuNA TP e eTsrTrEWgITS eRersp:i1n09 0.00 -. rey| i EEE arma @lmaer en ee AEE ee nee norp: 6187 iA |i foo oo SN Lin en TOE WE Teen dee dh 1 re 1 ik rs vk ie te ie 0621052.0 PABKBVAM Wed Oct 18 12:56:32 2000 page 2 000780 Primedics-Worcester Project number: PABX-BVA 418-018:PAGE 1-158 Page 157 Peak Area Roport on Sg an 155Ue ounprs raze ouSreS am oUzrE053S0raossensxaaron moamran ame 57 Somat mmptn DN wm mesma emme 000781 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-159 Page 158 Quisticacion Report (QT Reviewed) oiDRSaocaineFile ED2C:8\\MGEeSeD_0DK02T00A0\PwAaBtr\eaPreARK-SVA\1-062-1\0621052.SDBpeeraVcioarl:: w53ay 1a5nstncTegEzRacEio"n B params: e RTEETi ?HODS\Pt ARKBVAM (RTE Tacegeacos) Pe R rey i=" i1 ! - I i [IM-- erereyTarr-- toow ea Tr-- ET -- a -- TN NT-- R TG ---------- seep: 462 i i i ' i E EaR ve WeR WRTERTTjLiS Ei amaa [| rej sp: 0e 48 e. m it | ! i Eeewewe wh ae em7mie ihre te te ve in ie is oa0s3.0 EAB SVAN Med Oct 18 12:56:51 2000 fae 2 000782 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-160 Page 159 Peak Area Report NotSoamaptNaanmees:5 ASRSct0 P8n DeAamuin:te200 705 namaReaaidaPasn AFAABRSEATAPAPPABICVA"HL ar Som3at Comwmiptstume Renn Impol m teHmE a beshe 000733 `Primedica- Worcester Project number: PABX-BVA 418-018:PAGE I-161 Page 160 Quantitation Repore (07 Reviewed) paca rie piv DATA TB 062 1oGziO8A2 via: st ouSnE EE HG masa Epssais; Sis 16 TacEegrRacion B params:iRIWEin Dn.co d \pAsxs BVA. (RTE Tacegeator) == i | i | i EEE EEN EE JAiAA TEE EEE | ML enapr: atate Amount: hn 0.00 = ere fi 1 oiPsre5aonss:itik 3aa"0e8ker.h1s00 wm en ek iw 3% 7%litH 7% 7av heeTEr TR Ty RB! i i ! A | Len awe am em em es ew vik 1 rk il 1h ve th 1E TR: oeniose0 oASKSAM Wed Oct 18 12:57:20 2000 rege 2 000784 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-162 Page 161 PeakAraRepor @ mI ta RSremeron mEe RE 00078s Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-163 Page 162 Quantitation Repore (QT Reviewed) @ DSiaetataonPile1 0O:3\MSD8DoAEcTeAa\EoP0A0B\BA7B:K3-5BVA\L-062-1\0621055.DSTp_heeecaVciarl:: we5a5rn a #G5anItntwegertahtoiaoTn BpFazRamCs:H1R\TMEEDTNHTO.DDS\PARK_BVA.M. (RTE Tntegracos) ie [= i | | fi i i pep e Er n 6 pohtVRer T aTRTe T R 7h TE e a ern]|: lRoesnp: 2I45r2 ae ---- 2 ---- -- i TEsTe iE we ORE eap: ,4380 rn Oh se am aw TF Ge is ihein 6oh iemie | ---- m. l Se TTT| fi i /\ | am ew es Te TV Ts 1%Te 1 vk 7% TB 7h | 0623055.0 PABKBVAM Wed Oct 18 12:57:30 2000 page 2 000786 PrimedicsWorcs Project number: PABX.BVA 418-018:PAGE1-164 Page 163 Posten Rags J Sra feEriay rec nE BTtNRTsE cans manE -- R comats compres GED wm empme sagne [-- _ 000787 Primedica-WorcesterProject umber: PABX-BVA 418-018:PAGE I-165 Page 164 Ouanccacion Repore (07 Reviewed) @ iB fDa:crapEPailneE :AD:yR\KErD_DeATA\rBaABe\BARX-BUAVE-062-1\0G21056.S0rpeeresvtiaarl]: B25a6x f45 o1ateseacion ParamRs: AETES INE.E P -- Big en, a = - I/fii | iew t TE EEE orETE E xing, 1336 ii i | onR Fi eant: $13s6 asm r Ani|me: a"1.c06 e eaw=d i Ih | ew Re Te TT Te CGRIOND PABKBVAN Wed oct 18 12:57:49 2000 ge 2 000738 Primedica-WorcesterProject umber: PABX-BVA 418-018:PAGE 1-166 Page 165 PeakArea Report [se ammee : cor rmrans emT n) mer etSoaPon BAASATAPABBVAIA0B6C1 sme fge3ts Comami Doo pe n mm Pa aani Sieh 000739 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-167 Page 166 Quantitation Report (QF Reviewed) @ DF HacanFa ile : Di :\WSDn _DATA\d PAiB\yBARK.BUA\-062-100621057.0SepsaarsaVcioarl:: w57r o15atnocEeonseasaio"n 5BaeRsPsC:HERNTEIENTT.HPODS\PABK_BVA.M (RTS Integrator) pr EE I HI = ih | i i - ih i w NorReeecsse e : p 2. TroeS hmoRA 5TESeTsismeTh7V5e Ta Te TR TB 78A= || || I!A\ ES ne oTresr s: 437 EedeEe. oh-- ieheihe \ } |a ii e me wo aw tm7 ve ave is vee Te R o21057.0 mmavAN Wed Oct 8 12:50:08 2000 rage 2 000790 PrineWorsProjtum:ber PABXBVA 418-018:PAGE I-168 Page 167 Peak Ams Report 0 mmm. hl neEEETsSci, mnser fnmeds Gmmpiue Inge m fwaw temas unto i ws 000791 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE1-169 Page 168 Quantitation Report (QT Reviews) PfDY ateatFR ialelE Dt:\yMrSaDDiATA\iPABt\PARK-BVA\L-062-10621056.DGfpeecaVtitoarl.:am5]8y T#5a1nncNegReGac"ionCsYatAanP:CRHTEIRNL.\S NEPFALGEBDVSA.\ (RTE Tacegracor) parang J ne senno k | Poa ern SNA Wrwefson0 s 135fhT0 eE7w000R0 08 Shik -- a I ReTE 5e6yTe ve ve 7a y A PT ~ Ama i Nan m OF Gry io s eRm TR ae Ri T ve TR TE TE ! iA aAN Teh eT -- |t i E TR= E ie aeek TE TR mm TR TR Te e Te eike ik 1 ] 0621056.0 PAB BVAM Wed oct 18 12:58:28 2000 rage 2 000732 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-170 Page 169 Poak Area Report nuC RamF Haae ,ASABr SB,AkTAPADPABCOUALOE1, aument5o ms2ds Cmmpelnlm leTeenmo teeamm bplane 000793 Primedica-WProojrecctneumsbtere: PABX-BVA 418-018:PAGE I-171 ---- Quascisacion Rapore (G7 Reviewed @:iaBEcrEamisFile o rile: Do: WuDi DATR\nByAB\BARK.BVA1V00L6-2100G892..STp_errtvoindt: i32y Jo satEagReaAsi?on S Paras:i weEDT.n 8cosps ase. (KT Tacepeacee Jl || i I! !i | i JDem I1 i Hr iEee2ww OEE Ew EEEeE Er EERE EET TE Yh TRTRTeTeTTrThrEiTnds [im A IA i l * AN nrSM TNmAenS/T LN ae e A, | i aon: hes EET Ban T Ee ha a ] i 1 | i i oJ | Lal as ae am ak eR sk sm vm Tw Tm 1% 16 7k 7h 7% 7h TE | o61039.0 mB AN ed out 18 12:58:47 2000 ase2 000794 Primedica- Worcester Project number: PABX-BVA 418-018:PAGE 1-172 Page 171 Poak Area Report rosmamep HsrSoB orSesmroma: menFESaAoESADA, CATAPABSYSA AB GEL, at ihm om 3 we nom an 000795 Primedica-WorcesterProject number:PABX-BVA 418-018:PAGE 1-173 Page 172 Quantitation Repore (OT Reviewed) @ DRisaecalgiFiolne}: DTL :o\WOSeE De-D3M0T0A0e\PeArP9\:P0A2GK.BVA\:-062-10621060.DOEp_eeraVitaolr:. W60t FaOne itheaT 5\PCHBNA\NETHODS\PABK_BVA.M (RTS Integracor) = ] - Po MRespe: 16m7 e i} | i I| i|: Ii aee i . re fore de QLadEoeEovEr-- e we | resp: 305 ehTehTidM heTe e Te TE ae th ike re 1 ; I i A | 5 en ie ekwe WE iw tk 76 Te 7B 7B Te 10 76 TR 7TR 0621060. PABKBVAM Wed Oct 10 12:59:06 2000 page 2 000796 Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE 1174 Page 173 Peak Area Report Y NormSampFlreearme::2A2G57O0V2Aw1e0e2 oan ASiasr: 1a1n82000022 namesOueidFieaaPmma5:::0SO1AUGU0ES9BD1nD0ATAPABPARXSYAIGE21 amenmuknaeame 7 Gom3els EGmempnium Imi oEmm emdaawy seamoe PowaCTre 1078200 129 vase 1 000797 Primedia:Worceser Project number: PABX-BVA 418-018:PAGE 1-175 Page 174 Ouasticacion Repor (OT Reviewed) PY GMaetraoRnFileE} DT:e\GNeSrD-_2D0A0T0A\PAB9\iPaAtBI-BVA\L-062-1\0621061.S0TpacaVT cioarl::St61ow 4a5 sEncesEeRacSiaoTn DPahcaseC:haRsIE(oWoDES.\BABK_BYA.M (RTE Zncegator) poi aE -- ;= Ii! || frroega (TEE TENET TR |SReasapr: B78T1 TIT RTEesTeTR TE Te TE Te TR TRIE 11 i | ] @PEezoes tironeR i ik hieik 1% 785.0T0-- e TeThTm ie Tres: bese Faeesaa sae Gen0sD ERmRVAM ved Oct 18 12:89:26 2000 rage 2 000798 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-176 Page 175 Peak Area Report erme gm:e 2P1ASSTO. 3 252 ue C intyE0841 nu nnnrdom F aHomme: AE21EB2LB0S.A nsPASKSALE roneVmmoaltNaoammeenn587 onmss moans 3 we SED ow espe oan ge PordCTem 0201250 ont 000799 Primedica-WorcesterProject number:PABX-BVA 418-018:PAGE 1-177 Page 176 Quuntitacion Repors (GT Reviewed) @ DBuarcEaaSFinlet+ DB:\aSOs_DeATn\ePArB\sPAhRK-BVAVL-062-3\0621062.0GEo_eEcVaiclr:! a62 1a5 sacTegEeaRtiTon D sacame: REa EDEHDoos\Pn ARKBVA M (RTE Tncegator) ---- rem iow ii | ww sak om on te |resTopn:: 1133105 (7.1351 I | ; | 4B ew Sh sk 4m TRmosTinee:TH T% 5T0e0 Tw Tk 1% 18 1]=| 1 i iierm TmT eeanTome e Ve iae TAE ie n 1 14 jh in m iA vm e A| new(sGa:: 133!71 Ie . ee i iee i J _ ET va aeie aTe Te TR a re 1h 1k i te) oct0ca.s mmx VAM Wed Oct 19 12:55:47 2000 rage 2 000500 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-178 Page 177 Poak Area Report NoboamRoamne:A2 5TS0U-Aes52 un AS:m10142500161 evn BT UEShes oA marrn3 cam3per Gwoeo Iwmaommo Pam Sie Prtoewa Tr e2001258 get 000801 Primedica:Worcester Project number: PABX-BVA 418.018 PAGE 1-179 Page 178 Ouancstacion Repore (GF Reviewed) @ ESRatoaknPil :D3:ESDDTATA\LPAhB\aBAeBK-BVAVE-062-1\GG2106.0_SEoeraViioalr:! a2n 1C5oantentHeagtrhactaion"Br saUruRsPaC:HE\gNEeFHOnO8S\FABK_BVA.W (X7E tncegrator) fo, EE -- - fi i f[siS xosemmep,oR33e 17 e eTr T TToTce Tp e ITRee eTe Ti i i! iA !i GEE mmCneE m wme Vd o f mmm] Rea s ots ns Lji SS et | ft i - -Ji -- | _ ih es Re ve ve a Te Te te Te | GEI0E0 PAK SANM Wad Oc 10 13:00:06 2000 rage 2 000802 PrimeticsWorse Proj umbe: PABX-VA 418-018:PAGE1-180 Page 179 Pos AmRpt mmm = Jc oIs m=g SyTsT rwy eggme ope 000803 Primedica-WorceserProject number:PABX-BVA 418-018:PAGE1-181 Page 180 Quantitation Report (OT Reviewed) DSM acaar71E a | DB:\P eHSDn_DAaTAa\cPeAhrBo\BeABX-BVANA-062-1\0621064.SDSapraereaVicaolr:: i6a4y @x : v5 incResSeaAtion ph arame: RIi EEDTH.ODS Pa BKSVAN (RTE nceszator) are | Te i --| roeaoTETPTE ETTETTEREE TTRT/r TTERTTT e VnITh E a | Mffoynasg 131 0.009 eRe Afn ! i\ WT | P LEe E ttRn- TeTSet thte ee? f | i! Ii i: iT nTiTTireTp i iee ewrkik te Te TR THe 78 TR 8Th ik 8 021064. PABKBAM Wed Oct 16 13:00:26 2000 nage 3 000804 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-182 Page 181 Poak Area Report Sarena 00 onto as 0 amoDtF uiioiapm,ae: 0AS52EB10DB05C0R.ATAPASEAGKOOV1AN1 mkr tVer-- io Spas Smmpites Imo 9 tesme sae 000885 Primedica:Worcester Project umber: PABX-BVA 418-018:PAGE1-183 Page 182 Guastisation Report (QF Reviewed) aSE coarepilP e {D3:\R HSD_DRATnAe\PrAoBr\eFsARE-BVA\L-062-110621065.0S_Foprenevirasl:itt6o5] @= 45 sacEegrRacionLPaAcerrs:miRTyEWDHNOET0.8?\PASX_BVA.M (KTS Tncegeacor) Fo = pe A " i Po-d [Ii |i ET Ta RR RE TeSTT TR neon: L Ber L . r----i i I | ee Li Fr Tin ea LT --_ iE Ee ih tk ie 3 i o| inafai onn: T0I8 (7.160) BRS ' eet : I | iEaR mee 7a iE 1A Teve ve ve te eel OGn0Gs.D PABKEAM Wed Oct 18 13:00:45 2000 rage 2 000806 Primeica-WPorertcnuemebeer: PABXBVA 418-018:PAGE 1-184 Page 155 PeakAre Report sn sen meInp :ms. sS on RE mons imps SE wr mm ep sonra rs 000807 PrimedicsWorse Prec umber: PABXBVA 418-018:PAGE 1-185 Page 184 50 ENT asesesScOionRRepoEre. ARa nevdieowtehss OHfie Mls ont Imi r= fy NI y ITEnearer 78 srsguscens fe SE ey ii ii I i |= i i - TETTET TE eTrrnors i i em Q|E olx E oes TL IT Te TEVVV Te TSE ige : | coma -- i IN Io Im Te Te To Tm.1m rm 1 i !! 1 a IA in i 1m en ee sk im aw sm am Te Iw IB Im 18 1% 18 1% 3m Tm 000308 418-018:PAGE L186 FINAL REPORT GAOSFCMHERVOAMLAOTNOIGCRAAPCHIDICIN-MEADSTSA SRPAETCPTLRAOSMMEATRFIOCRAANRAGLUYSSIS STUDY 418-018 Primedica Project Number: PABX-BBA PRIMEDICA ARGUS 905 Sheehy Drive, Building A Horsham, PA 19044 000809 pe 7PRIMEDICA 418-018:PAGE 1-187 FINAL REPORT `GAS CHROMATOGRAPHIC-MASS SPECTROMETRIC ANALYSIS OF MEVALONIC ACID IN EDTA RAT PLASMA FOR ARGUS STUDY 418-018 Primedica Project Number: PABX-BBA Submited to: PRIMEDICA ARGUS 905 Sheehy Drive, Building A `Horsham, PA 19044 Submitted by: Primedica-Worcester 57 Union Street `Worcester, MA 01608 Primedica Report # PABX-BBA-01-145 Page 1 of 187 Issue Date: November 7, 2001 71 2 DBL 17 lark A. Netsch / Date Project Scientist Bioanalytical Chemistry Department Primedica-Worcester 00810 GPRIMEDICA fFPironiaamlleRRdeeipoaoreWtnorcester Project Number: P0AB0XB0B0A 00 418-018:PAGE 1-188 PinrcoiaAmmrgsuessSudtyudaiy4s1co5-- .n0as13 COMPLIANCE STATEMENT `This project was conducted in compliance with the Good Laboratory Practice Regulations, 2ICFR, Part 58, Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997 and Council decision/ recommendation on compliance with principles of good laboratory practice. Official Journal ofEuropean `Communities: Legislation 32 (No. L 315; 28 October): 1-17. Therewereno deviations from the aforementioned standards, which affected the quality or integrity of the project or the interpretationofthe results in this report. IDAEIAL yo Mark A. Netsch, B.A. /Date Project Scientist 0003811 SPRIMFDICA F_Pirnia--mledRiecpao-rWtorcester Project Number: PABX-BBA 418-018:PAGE 1-189 rPmriemeddcicAapArugSusuSdtuyddy s41o3P-an0gs1e83 QUALITY ASSURANCE STATEMENT The following are the inspection dates and report dates of QAU auditinspections for GAS CHROMATOGRAPHIC-MASS SPECTROMETRIC ANALYSIS OF MEVALONIC ACID IN EDTA PLASMA FOR ARGUS STUDY 418-018, Project Number PABX-BBA. Critical Phases 1.Laboratory Procedure 2. Raw Data 3. Draft Final Report Date Inspected 01/23/2000 03/29/2001 04/19/2001 Date Report Submitted to Study Director ~~ Management 04/27/2001 01/29/2001 04/27/2001 04/03/2001 04/27/2001 04/26/2001 The Final Report GAS CHROMATOGRAPHIC-MASS SPECTROMETRIC ANALYSIS OF MEVALONIC ACID IN EDTA PLASMA FOR ARGUS STUDY 418-018, report number PABX-BBA-01-145, was reviewed for `compliance with the Good Laboratory Practice Regulations, 21CFR, Part 58, Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997 and Council decision/ recommendation on compliance Official Journalof European Communities: with principles of Legislation 32 (No. good laboratory practice. L 315; 28 October): 1-17, on 11/07/01. The results as presented accurately reflect the raw data. A : Quality Assurance Auditor 2] Date 000812 GPRIMFDICA Primedica-Worcester Project Number: PABX-BBA Final Report 418-018:PAGE 1-190 Page PriAm rgue sStdudi y 41c 8-0a18 TABLE OF CONTENTS Page No. COMPLIANCE STATEMENT .....cc.cococcnnssasssssnnnsssssessssssssssssssssssssssssss ionsssasssssssssess 2 QUALITY ASSURANCE STATEMENT ..ccoonnmmmmssnrsmsssssssssssssssssssssssssssssss sss 3 LIST OF TABLES AND APPENDICES .........coooonmmmsmssssmsrsssssssssssssssssssssssssssssssssssseses CONTRIBUTING PERSONNEL essere sane 8 ANALYTICAL STANDARD CHARACTERIZATION/STABILITY ...coovvvrvnrnnrirnsisians T ARCHIVAL STORAGE ......... - R-------- Calibration Standard Accuracy and Precision ...........ocueurreessssreeessssssesssessssss Quality Control Sample Accuracy and PreCiSION .......c.vewrrssres 10 Study Sample CONCENMAONS .......vuvvererssessieeerresssssninssssessnsnssssssesssssssssssssesss 10 000813 SPRIMFDICA PF_irni--amledRiecpao-rWtorcester Project Number: PABX-BBA 418-018:PAGE I-191 PrPriimmeeddiicaa AArrgguuss SStuuddyyd418Ps-a0g1el85 LIST OF TABLES AND APPENDICES Page No. TABLE 1 Summaryof Back-Calculated Mevalonic Acid LactoneCalibration Standard CONCENtrAtionS ..........cc.covvmvrrrrrs esses. wnrmsssssssssnsnsensssan|n2s TABLE 2 CSOuRmCmEaTrTyRHoOfNISntv erpolated Mevas lonic Acid Lat ctone QC Stanedarnd s 13 TABLE 3 Summaryof Mevalonic Acid Lactone Least-Squares Linear Regression Constants and Analysis DALeS...........covuvreerersooesorsssr. cemsesrmessssssssssssnsnsens 14 TABLE 4 Summary of Mevalonic Acid Lactone Concentrations in EDTA Rat Plasma Study SampIES........ooovecerrrermes eres wnssmssssssssssssssssssssssssssnsss 1S. APPENDIX A Representative Chromatographic Data - Batch No. PABX-BBA-1-047-1...........23 000814 GPRIMEDICA Primedica-Worcester Project Number: PABX-BBA Final Report 418-018:PAGE 1-192 Page 6 Primedica Argus Study 418-018 CONTRIBUTING PERSONNEL Project SCIentist ..........c.curveses terest ersseeaassrens rwwuueee: Mark A. Netsch, B.A. Director, Analytical Chemistry .........cccccveessssssssssiee vrsesssnsnssersJnine. Jersey, Ph.D. Analytical CHEMISL......c.corrvoveurrerrrssenernsnesses REPOTt COOTAINALON errors tossseseereee. YaniTa Villalobos, A.C.E. rvesrsesssneecnns: Brenda L. Brooks 000815 SPRIMEDICA Primedica-Worcester Project Number: PABX-BBA Final Report 418-018:PAGE 1-193 Page? Primedica ArgusStudy 418-018 ANALYTICAL STANDARD CHARACTERIZATION/STABILITY AnCaolmymtiocnalNSatamnedard: Physical Description: Lot Number: Storage Conditions: Expiration Date: Date Received: Amount Received: Supplier: internal Standard: Common Name: Physical Description: Lot Number: Storage Conditions: Expiration Date: Date Received: Amount Received: Supplier: DMeLv-aMleovnailconaciicdalcaicdtolnaectoorne Mevalonolacetone or MVL White crystals 4730011 50498 53C, desiceate, store under nitrogen September 13, 2002 (Assigned by Primedica) September 13, 2000 5 grams Aldrich Chemical Co. DL-Mevalonolacetone4,4,5,5-, MVL-d, Clear liquid U-295 215C September 11,2002 (Assigned by Primedica) September 11,2000 0.1 gram Cambridge Isotope Laboratories CharacteraindzSatatbiiliotyn: The characterizationofthe analytical standard and intemal standard i the responsibilityofthe Supplier, as is the methodof synthesis, fabrication or derivation and stability determination. 000816 418-018:PAGE 1-194 SPRIMFDICA Primedica-Worcester _Fin--al Report Project Number: PABX-BBA PPrriimmeeddiiccaaAAmrguussSSutuddyy4411P38a-00g11e88s ARCHIVAL STORAGE AmracihnitvaainleSdtofroargae:minTihmeumorpiegriinoald oFfinfailveRyeepaorsrtfoalnldowirnagwsudabtmaiswsiiloln boef tAhfetefirnalfirveeporyteairns,thethPerimSepdoincsao-rWorwiclelstebre Archives in contacted Worcester, MA. for disposition Rinesptorrutct#ionPsA.BXAr-cBhBiAv-al01m-at1e4r5ia.ls will be indexed by Primedica-Worcester 000817 GPRIMEDICA Primedica-Worcester Project Number: PABX-BBA Final Report 418-018:PAGE I-195 Page 9 Primedica Argus Study418-018 SUMMARY: Sample Receipt: `inSafmopulressihnipthmiesnptrsojbeecttwweeernetrheecediavteeds ionfgDoeocdecmobndeirti5o,n2f0r0o0m aPndrFei bruAmarrgyeu1s3Ld ,a2b0oi0r1a.tcorTiahese samples were stored at <-20C until the timeofanalysis. Method Summary: Samples in this project were analyzed according to the method described in Primedica Validation Report # PABX-BVA-01-62. The method involves the conversionof mevalonic acid (MVA)to mevalonic acid lactone (MVL) and the analysis oaf liquid/liquid extract by gas chromatography coupled with mass spectrometry (GC/MS) using positive chemical mioenviazlaotnioinc (aPcCiId).isCaalniabtruartailloynaoncdcurqruianligtcyocmonptoruolndstianndpalradssmwaearnedpcroenpcaernetdraintiwoantservabreycawuisteh diet. The internal standard, MVL-d,, was used for quantification. "The method was validated for the extraction of mevalonic acid lactone from 100 uL EDTA rat plasma samples over a concentration range of 10.0 ng/mL to 250 ng/mL. The complete description of the assay and summaries of its performance during the validation can be found in the report cited above. Sample analyses for this project were initiated on January 2, 2001 and completed on February 15, 2001. See Table 3 for the analysis datesofeach batch. A copy ofrepresentative raw chromatographic data from the first batchofsample analyses is provided in Appendix A. Calibration Standard Accuracy and Precision: Duplicate and bracketing seven-point calibration curves were prepared and analyzed with each batch of samples in an analytical run. For cach analytical run, a 1/X'-weighted least-squares linear regression was performed on the combined calibrant data set. Calculated correlation coefficients (r) for the regressions performed were 20.996 (see Table 3). Summariesofback-calculated calibration standard concentrations are provided in Table 1. Mean accuracy, expressed as %bias, ranged between 97.9% and 102.7% across concentrations and analytical runs. In addition, precision, as measured by % Relative runs Standard Deviation (%RSD), ranged from 2.2% to 4.9% across concentrations and analytical 000318 SPRIMFDICA Primedica-Worcester Final Report Project Number: PABX-BBA 418-018:PAGE 1-196 Primedica Argus Study 4P1a8g.e01180 Quality Control Sample Accuracy and Precision: Summariesofinterpolated Quality Control sample concentrations are provided in Table 2. Accuracy, as measured by %bias, ranged between 93.6% and 95.6%. Precision, as measured by %RSD, ranged from 2.9% to 8.9% across all concentrations. Study Sample Concentrations: Snagm/pmlLesbewfohreereadnjousptemaekntwsafsorddeitleucttieodn ofractthoersi,nttheerpaoslsaatyedlocwoencrelnitmriattoifonquwaantsifliecsasttiohna,n w1e0r.e0 wliabtehleadadislu"tBioQnLb"ut(bdeuleowtoqulainmtiitteadtisoanmlpilmeit)v.olSuommeecsoaumlpdlneostrebpeorrteeadnaalsyzBeQd.L Twehreedaentaelcytzioend limit for dilution these factor. samples is the lower limit of quantification (10.0 ng/mL) multiplied by the One samples where the interpolated concentration was greater than 250 ng/mL before adjustment for "AQL" (above the dilution quantitation factor, limit). the assay upper limit This sample could of not quantification, be reanalyzed was due labeled as to limited sample volume. The result for this sample was (250 ng/mL multiplied by the dilution factorof estimated 50). to be greater than 12,500 ng/mL Interpolated concentrations for all remaining samples are expressed in ng/mL. Referto Table 4 for concentrations of mevalonic acid lactone in rat plasma study samples. CONCLUSIONS: All analytical results were within acceptable limits with the exceptionofone value reported as an AQL estimate due to insufficient sample available for reanalysis. 000815 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-197 Page 11 TABLES 000820 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-198 Page 12 TABLE | SUMMARY OF BACK-CALCULATED MEVALONIC ACID LACTONE CALIBRATION STANDARD CONCENTRATIONS BachID PABXBBA--04T1 PABX-BBA-I-0S41 PABXBBA-.0S1 PABXBBA-IL0SS1 PABXBBA-LOGI PABX-BBA-L0SS1 PABX-BBA-LOST1 PABX-BBA-106S1 PABX-BBA-LOTZ1 PABX-BBA-L0TS-I Theoretical Nominal Concentrations (ng/mL) loo 20 300 00 200 10 20 1N0R1 210909 2N9R6 448896 9S469 12 10 249 245 918024 119938 330013 4s8l40 S88L4s 1i5s0s 22s4)6 916083 210908 330029 4s9iz0 89748 115500 225448 996885 221036 330079 448811 887904 12 12 249 248 9N7R3 220052 330150 40806 89122 183 1s 24 24 10014 118966 330059 446176 983586 1e49252855 937 194 302 468 870 148 25 994 29 314 1 20 12 245 914 190 296 522 08 155 29 07 206 324 #6 896 9 240 100 197 304 485 921 le 29 NRONR NR SIZ 920 1 246 NR NR 341 461 910 145 269 997 191 310 455 886 163 251 Mean Su. Dev. n %RSD %Nominal 995 200 308 490 S01 12 247 039% 0972 105 202 237 508 554 16 13 18 20 20 20 2 40% 4S% 34% 41% 26% 3% 22% 90.5% 100.1% 1027% 975% 100.2% 1013% 98.6% NR = Calibration standard excluded from regression, data not reported 000821 `Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-199 Page 13 TABLE 2 SUMMARY OF INTERPOLATED MEVALONIC ACID LACTONE QC STANDARD CONCENTRATIONS Bach ID PABX-BBA-1-047-1 `Theoretical Nominal Concentrations (ng/aL) 20 0 20 S2610 76132 199 184 PABX-BBA-1-053-1 25s 25 654 00 18 187 PABX-BBA-1-056-1 2s 29 652 659 184 152 PABX-BBA-1.058-1 22 233 68.1 682 189 191 PABX-BBA-1-062-1 20 21 642 655 187 188 PABX-BBA-1.065-1 219 265 6a410 184 192 PABX-BBA-1067-1 24 668 86 68.4 183 182 PABX-BBA-1-065-1 2s 22 664 61 187 188 PABX-BBA-1-072-1 211 22 681 210920 PABX-BBA-1-075-1 293 29 616 as 184 I SMue. aDenv. 22193 665 302 187 546 a RSD 19 89% 20 45% 20 29% "Nominal 95.6% 95.0% 93.6% G*r=uFbabi'leTdestto.meVeatluteheeaxcccleupdteadncferocmritseurimamaanrdydseattiesrtmiicnsed to be a satstical outlier using 000822 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-200 Page 14 TABLES SUMMARY OF MEVALON`ICCONASCTIADNTLSAACTNODNAENLAELAYSSTI-SSDQAUTAERSES LINEAR REGRESSION PABX-BBA-L047-1 00067118 0.014046 099956 ove201 PABX-BBA-I054-1 00062552 0.007087 099953 ono PABX-BBA-1056-1 00061528 0.007974 099965 ounsior PABXBBA-L0SS1 00060042 -0.006094 099909 oso PABX-BBA-1062-1 0.0061041 0.006886 099954 o12601 PABX-BBA-I-065-1 00064579 0.008650 099802 020101 PABX-BBA-1-067-1 00064673 0.002970 099698 00701 PABX-BBA-1L-069-1 00063214 000018303 099789 020701 PABXBBA-LOT21 00064268 0.090496 099915 301 PABX-BBA-L07S-1 0.006212 -0.01975 099652 nso 000823 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-201 Pages TABLE 4 SUMMARY OF MEVALONIC ACID LACTONE CONCENTRATIONS IN EDTA RAT PLASMA STUDY SAMPLES 101900930.2G-RGORUOPULP-LFFOO 127573 1100990045..GGRROOUUPPLLFFOO 22663 0 1100990067..GGRROOUUPPLIFFOO 326050 1100990058..GGRROOUUPPIL-FFOO 32615 1100991110..GGRROOUUPPLLFFOO 325017 1100991123..GGRROOUUPPIL-FFOO 139452 10913.GROUPI-FO 233 1100990012.-GGRROOUUPPLLFFI1 110099003+--GGRROOUUPPIL-FFII 10905.GROUPLFI 1100990067-.GGRROOUUPPIL-FF1I 1100990058..GGRROOUUPPLLFF11 1100991101..GGRROOUUPPLLFF1I 10913.GROUPF1 n36s8 BQL (DF = 010,8<I00 ng/ml) 443 BQL (DF =11406,<100 ng/ml) 22572 a1261 316 101901961.5G.RGORUOP2UPFF2OO 2315050 1100991157..GGRROOUUPP22-.FFOO 11510300 1100992109..GGRROOUUPP22..FFOO 11184500 1100992212..GGRROOUUPP22..FFOO 5297 1100992234..GGRROOUUPP22..FFOO pr1e5t9 1100992275..GGRROOUUPP22..FFOO 1728180 10928.GROUP2.FO 2060 BQL = Below quaniiaion limit ADFQL= =DiAlubtoivoen Fqaucatnotirtation limit PPAABBXX.BBBBAA-11..005544.-11 PPAABBXX..BBBBAA-.11..005544..11 PPAABBXX.BBBBAA--11..005544--11 PPAABBXX..BBBBAA--11..005544..11 PPAABBXX.BBBBAA--11..005544..11 PAPABBXXBBBBAA..11..005544..11 PABXBBA-1.054.1 PPAABBXX-.BBBBAA--11..005544-.11 PPAABBXX-CBBBBAA-.11-.005544.-11 PABXBBA1.054-1 PPAABBXX--BBBBAA--11-.00554+-11 PPAABBXX-BBBBAA--11..005S44--11 PPAABBXX..BBBBAA--11..005544--11 PABXBBA-1.054-1 PPAABBXX-.BBBBAA-.11..00S588..11 PPAABBXX.BBBBAA..11..005558.-11 PPAABBXX-BBBBAA--11..005558-.11 PPAABBXXBBBBAA--11..005548..11 PPAABBXX-BBBBAA.-11..005548..11 PPAABBXX.BBBBAA1-1..005548..11 PABX-BBA-1.058.1 000824 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1202 Page 16 TABLE 4 SUMMARY OF MEVALROANTIPCLAACSIMDALSATCUTDOYNESACMOPNLCEESNTRATIONS IN EDTA Animal#Group#-Generstion ~~Concentration(sg/mL) BachID 1100991156--GGRROOUUPP22--FFLI 1100991178.-GGRROOUUPP22--FFII 1100991290..GGRROOUUPP22--FFII 1100992212..GGRROOUUPP22.-FFII 1100992254-.GGRROOUUPP22.FFII 1100992278-.GGRROOUUPP22-FFII AQL (e2st9i3ma0t0ed 23200) 1157100000 2142090000 7168 31274600 18721100 PPAABBXX--BBBBAA--11..00588-.11 PPAABBXX--BBBBAA--11--006622--11 PPAABBXX.BBBBAA.-11..005682..11 PPAABBXX--BBBBAA--11.-005584.-11 PPAABBXX--BBBBAA--11--005388-.11 PPAABBXX--BBBBAA--11--005682--11 1100992390--GGRROOUUPP33--FFOO 1165780 PPAABBXX--BBBBAA--11--004578--11 1100993321.-GGRROOUUPP33--FFOO 11424200 PPAABBXX--BBBBAA--11.-005588.-11 1100993334.-GGRROOUUPF33--FFOO 1836460 PPAABBXX--BBBBAA--11--005588--11 1100993375--GGRROOUUPP33--FFOO 11451300 PPAABBXX--BBBBAA--11.-005588.-11 . 1100993480--GGRROOUUPP33-.FFO0 a13s8)0 PPAABBXX--BBBBAA--11-.005682--11 1100994412--GGRROOUUPP33--FFOO 42176 PPAABBXX-BBBBAA-11..005588-.11 1100993209-.GGRROOUUPP33--FFII 1100993321.-GGRROOUUPP33--FFII 1100993334--GGRROOUUPP33--FFII 1100993357--GGRROOUUPP33--FFII 1100994420..GGRROOUUPP33--FFII 25515060 9278157000 914933000 1133940000 1E27x00 PPAABBXX--BBBBAA--11--004578--11 PPAABBXX--BBBBAA--11..003588..11 PPAABBXX--BBBBAA--11-.005588..11 PPAABBXX--BBBBAA--11--005588..11 PPAABBXX--BBBBAA--11..005588--11 ABOQLL == ABebloovweqquuaannttiitaatiioonnlliimmiitt. D* F= =EsDtiilmuattieodnvFaalcuteo,rDF = > 12,500 ng/mL 000825 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-203 Page 17 TABLE4 SUMMARY OF MEVALROANTIPCLAACSIMDALSATCUTDOYNESACMOPNLCEESNTRATIONS IN EDTA Animal #-Group#-Generaion 1100994434--GGRROOUUPP4A-FFOD 1100994465-.GGRROOUUPPSA..FFOO 1100994475..GGRROOUUPP44--FFOO 101904995.0G-RGORUOPU4P-AFFOD 1100995512-.GGRROOUUPP44.-FFD 1100995543--GGRROOUUPP4A..FFOO 1100995556..GGRROOUUPP44--FFO0 Concentration(ng/mL) 11m3 21456900 1166100 1776300 1559610 11010600 22000300 BuchID PAPABBXX-BBBBAA-1L-004477-.11 PPAABBXX-BBBBAA-.11.-00558..11 PPAABBXXBBBBAA.-11..004575..11 PPAABBXX-.BBBBAA-11-.005556.-11 PPAABBXXBBBBAA..11..00457..11 PPAABBXXBBBBAA--11--005555-.11 PPAABBXX-BBBBAA--L1--004575..11 1010994456..GGRROOUUPPAA-.FF1I 1100994475--GGRROOUUPPAA-FFII 1100995501.-GGRROOUUPP44..FFII 1010995534--GGRROOUUPPAA-.FFIL 252300000 PPAABBXX--BBBBAA--11-.005588-.11 2015630000 PPAABBXX--BBBBAA--11..00555..11 2109300000 PPAABBXXC-BBBBAA-11-.005558.-11 1918100000 PPAABBXX-BBBBAA-11.00S555..11 1111002391--GGRROOUUPP1I-LFF0O 1111003323--GGRROOUUPPII11--FFOO 1111003354--GGRROOUUPPI111-.FF00 1111003376--GGRROOUUPPII11.FF00 11038.GROUPI1.FO 56917s PPAABBXX--BBBBAA--11--004477-.11 72s0 PPAABBXXBBBBAA..11..004477..11 3E7d3 PPAABBXX-BBBBAA-11--00487--11 3100 PPAABBXXBBBBAA-11-004477..11 pr PABX-BBA-1047.1 1111002391.-GGRROOUUPPII1LLFF1I 1111003336-.GGRROOUUPPLLLLFFIL 11037.GROUPI1LFI 117s4 PPAABBXX-BBBBAA.-11.-004477.-11 2302 PPAABBXX-BBBBAA-110-04477..11 157 PABXBBA1-047-1 BAOQLL == BAebloovweqquuaanntiitiattiioonnlliimmiitt DF = Diluion Factor 000826 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-204 Page 18 TABLE 4 SUMMARY OF MEVALROANTIPCLAACSIMDALSATCUTDOYNESACMOPNLCEESNTRATIONS IN EDTA Animal Group#-Generation Concentration(g/ml) BashID 1111004410..GGRROOUUPPII22.FFO0 1111004442-.GGRROOUUPP1I22..FF0O 1111004465..GGRROOUUPPII22..FFOO 1111004478..GGRORUOPUIP2FI.2DF 1111004590..GGRROOUUPPII22-.FF)O 1111005521.-GGRROOUUPPII22.FF00 214355 2su3s 118555 BQL(DF=12,5<l0ngml) 116409 22125 PPAABBXX.BBBBAA--11--005566--11 PPAABBXX.BBBBAA-11..005566-.11 PPAABBXX.BBBBAA-11.-005566.-11 PPAABBXXBBBBAA11-.005566..11 PPAABBXX-BBBBAA--11-005366--11 PPAABBXX--BBBBAA--L100S566--11 1111004440..GGRROOUUPPII22.FFII 1111004456-.GGRROOUUPPII22FFII 1111004570.-GGRROOUUPPII22.-FFII 1111005521.-GGRROOUUPP1I22.FFII 2Ens PPAABBXX-BBBBAA--1L-00S566.-11 311906 PPAABBXX-BBBBAA--11.-005566.-11 8337 PPAABBXX-BBBBAA--11.-005566--11 351506 PPAABBXXBBBBAA--11.00S566.-11 1111005534.-GGRROOUUPPII33-.FFOO 111100555.6G-RGOURPOIU3PFF1Oo3 1111003S87..GGRROOUUPPII33.-FF0O 1111005650.-GGRROOUUPPII33..FFo0 1111006612..GGRROOUUPPII3SF-FOO 1111006643--GGRROOUUPPLI33 FFOo 1111006665--GGRROOUUPPII33 FFOO 2S5203 BQLOF=12,53<10ngml) 20934 316570 215528 21890 61639 PPAABBXX-BBBBAA--11.-006526.-11 PPAABBXX.-BBBBAA--11--005566-.11 PPAABBXXBBBBAA--11005566.-11 PPAABBXXBBBBAA.-LL00SS66-.11 PPAABBXX--BBBBAA-L1L-005566--11 PPAABBXX.BBBBAA.L1L.00566.-11 PPAABBXXBBBBAA11..005566..11 1111005543--GGRROOUUPPLL33F-FII 312990 1111005356..GGRROOUUPPLI33-FFII a630 BQL = Below quantitation limit. ADFQL= =DiAlubtoivoen Fqaucatnotirtation limit PAPABBXXBBBBAA-11-.005566.-11 PPAABBXXBBBBAA11-005566..11 000827 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-205 Page 19 TABLE4 SUMMARY OF MEVALROANTIPCLAACSIMDALSATCUTDOYNESACMOPNLCEESNTRATIONS IN EDTA Animal#-Group#Generation~~Concentration(ng/mL) Bah ID 1111006509--GGRROOUUPPII33.-FFI1 1111006632--GGRROOUUPPI133..FFII 11066-GROUPI3-FI BQL(DF=21,85<20nyml) m1 s1t9o PAPBABXX--BBBBAA--11.-003566--11 PPAABBXX--BBBBAA--11..003366--11 PABX-BBA-1.056-1 11501-GROUPI-FO 1111550032.-GGRROOUUPP11--FFOO 1111550054--GGRROOUUPPII--FFOO 1111550067--GGRROOUUPPI1-FFOO 1111550089--GGRROOUUPP1L-FF0Q 1111551110--GGRROOUUPP1L-FFOO 1111551123..GGRROOUUPPIL-FFOO 1151.GROUP1-FO 1 302 BQL(DF=22,6<520ng/ml) 107 21788 255 190 189 280 272 208 24 PPAABBXX--BBBBAA--11.-006655.-11 PPAABBXX--BBBBAA--1I.-006655--11 PPAABBXX--BBBBAA--11--006655--11 PPAABBXX--BBBBAA--11--006655--11 PPAABBXX--BBBBAA--11.-006655..11 PPAABBXX--BBBBAA--11..006655-.11 PPAABBXX--BBBBAA--11.-006655--11 1111551165.-GGRROOUUPP22--FF0O 1111551187-.GGRROOUUPP22--FF00 1111552109--GGRROOUUPP22--FFOO 1111552231.-GGRROOUUPP22-FFOO 1111552254..GGRROOUUPP22--FFOO 1111552276.-GGRROOUUPP22--FFoO 11528-GROUP2-FO in 161 PPAABBXX--BBBBAA--11.-006655--11 928 160 PPAABBXX--BBBBAA--11..006655--11 135 a PPAABBXX--BBBBAA--11.007625-.11 135 190 PPAABBXX--BBBBAA--11..006655--11 21 146 PPAABBXX--BBBBAA--11..006655--11 856 356 PPAABBXX--BBBBAA--11--007625--11 m PABX-BBA-1-065-1 11529-GROUP3-FO 1111553320--GGRROOUUPP33--FFOO 11533-GROUP3-FO 126 29 PABX-BBA-1-067-1 PABX-BBA-1-072.1 8121150 PPAABBXX--BBBBAA--11--007722-.11 ABQQLL == ABebloovweqquuaannttiitaattiioonn lliimmiitt. DF = Dilution Factor 000828 Primedia:Worcester Project Number: PABX-BBA 418-018:PAGE 1-206 Page20 TABLE 4 SUMMARY OF MEVALONIC ACID LACTONE CONCENTRATIONS IN EDTA RAT PLASMA STUDY SAMPLES Animal #Group#Generstion 1111553345-.GGRROOUUPP-FFOO 1111553376..GGRROOUUPPSS-.FFOO 1111553389..GGRROOUUPPS3--FFOO 1111554401.-GGRROOUUPP3S--FFO 1111554423..GGRROOUUPPS3--FFOO Concentration(ng/mL) 12130 3714s1 2a5n30 3167830 3417 BachiD PPAABBXX-BBBBAA-110.07627.-11 PPAABBXX--BBBBAA11..007627..11 PPAABBXXBBBBAA11007722..11 PPAABBXX--BBBBAA-11..007627-.11 PPAABBXX-BBBBAA11007722..11 1111554445..GGRROOUUPP4A--FFOD 1111554467-.GGRROOUUPP4A--FFOO 1111554590.-GGRROOUUPPA4--FFOO 1111555512-.GGRROOUUPP4A--FFOD 1111555534.-GGRROOUUPPAA--FFOD 1111555556.-GGRROOUUPP44--FFOO 11557.GROUP4-FO o15m50 m1608 2o1n pssy7 308308090 ++ s2i0s sa PPAABBXX--BBBBAA-11007722.:11 PPAABBXX--BBBBAA11007657..11 PPAABBXX-.BBBBAA-11.006772..11 PPAABBXX..BBBBAA11007722..11 PPAABBXX-BBBBAA11.007752.:11 PPAABBXX.-BBBBAA-11.007722..11 PABX-BBA-1072.1 1111663302-.GGRROOUPU1P11-.F00 1111663343--GGRROOUUPPII1L-FFOO 1111663365..GGRROOUUPPII11.-FFOO 11637.GROUPL1.FO 1111663398..GGRROOUUPPII11..FFOO p25e4 PPAABBXX--BBBBAA-11..006677.-11 22568 PPAABBXX-BBBBAA-11-.006677--11 08038 PPAABBXX--BBBBAA-.11.-006677--11 383578 PPAABBXXBBBBAA--11..006677--11 383 PABX-BBA-1.067-1 'BAOQLL == BAebloovweqquuaannttiittatiioonnlliimmiitt D++F==VDailluuetiwoansFaccotnofrirmed 000829 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-207 Page 21 TABLE4 SUMMARY OF MEVALONIC ACID LACTONE CONCENTRATIONS IN EDTA RAT PLASMA STUDY SAMPLES Animal#Group#-Generation~~Concentration (ng/mL) Bach ID 1111664410.-GGRROOUUPP1122.-FF0O 1111664432..GGRROOUUPPII22--FFOO 1111664445..GGRROOUUPPII22--FF00 1111664467..GGRROOUUPPII22--FFOO 1111664489..GGRROOUUPPII22--FFOO 1111665501.-GGRROOUUPP1I22--FFO0 11653-GROUPI2-FO a3432 PPAABBXX--BBBBAA--11.-006677--11 a1456 PPAABBXX--BBBBAA--11--006677--11 2i5n8s PPAABBXX--BBBBAA--11-.006677--11 236555 PPAABBXX--BBBBAA--11--006677--11 119027 PPAABBXX--BBBBAA--11--006677--11 22436 PPAABBXX--BBBBAA--11--007627.-11 381 PABX-BBA-1-067-1 1116635+5-.GGRROOUUPP1I33--FFOO0 1111665567--GGRROOUUPPI133--FFOO 1111665589--GGRROOUUPPII33--FFOO 1111666601--GGRROOUUPP1I33--FF00 1111666623.-GGRROOUUPPII33--FF0O 11116666+5--GGRROOUUPPII33--FFOO 11667-GROUP13-F0 33204s 310s5 BOQL(DF=11,s<10ngml) 338112 21608 BOL(DF =218,0<10ng/ml) BQL(DF=1,<10ngiml) PPAABBXX--BBBBAA--11--006699--11 PPAABBXX--BBBBAA--11--006699--11 PPAABBXX-BBBBA-A11-006659--11 PPAABBXX--BBBBAA--11--006699--11 PPAABBXX--BBBBAA--11--006699--11 PPAABBXX-BBBBAA--11.-006699--11 PABXBBA-1.065-1 11510115/0141-50G6R-OGURPOIUFPILFI 11502/11507-GROUP1FI 11505.GROUPLFI BQL(DF-41,5<440ngml) 192 BQL(DF=3,<0ngiml) PPAABBXX-.BBBBAA--11..006699--11 PABX-BBA-1.069-1 PABX-BBA-1-069-1 1111550089//1111550130--GGRROOUUPPLI-FFII 11S12/11511.GROUPLFI 1ISI3/11514-GROUPI-FI 2248 PPAABBXX--BBBBAA--11.-006699--11 223035 PPAABBXX--BBBBAA--11.-006699--11 1111551157//1111552240--GGRROOUUPP22-.FFI1 380 EY BAQQLL== BAebloovweqquuaanntiittaattiioonnlliimmiitt DF = Dilution Factor PABX-BBA-1.072.1 PABX-BBA-1072-1 000830 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-208 Page 22 TABLE 4 SUMMARY OF MEVALROANTIPCLAACSIMDALSATCUTDOYNESACMOPNLCEESNTRATIONS IN EDTA Animal# Group #-Genersion ~~Concenuration(g/mL) BahID 11115512911/11511531-6G.RGORUOPU2PFF2II 1111552235111512572.5G.ROGURPO2UFFPII 11526.GROUP2.FI n2s9 PPAABBXX.BBBBAA--11..006792--11 211542 PPAABBXXBBBBAA--11.-006609--11 90 PABX-BBA-1.069-1 1111553368/1111553347.-GGRROOUUPPSS.-FFII 1151410514125.3G0R-OGURPO3U.BFSI.F1 1154311529-GROUP3-FI 230925 PPAABBX-XB-BBA-B1A-006792-11 210933 PPAABBXX--BBBBAA--11..006699.-11 30 PABX-BBA1072:1 1111554572..GGRROOUUPPAA-.FF1I 1111663302//1111663336..GGRROOUUPP1111-.FF11 IS/1N1163683.7G.RGORUPOLVPILFIFL 11639/11634-GROUPILFI 531339 221470 BBQQLL((DDFF==22,,<<2200nnggiimmll)) 204 PPAABBXX-.BBBBAA--11-.006699--11 PPAABBXX--BBBBAA-11..006699--11 PPAABBXXB-BBAB-A11..006699--11 PABXBBA-1.069.1 111I66404/116164471.-GGRROOUPUIP2IFF2II 1111664468//1111666514..GGRROOUUPPII22FFiI 1161S1615106.4G2R-OGURPO1U2PFIIZFI BQL(DF=42,3<40ngiml) 21s7 BQL(DF=22,4<20ng/ml) PAPBAXB-XB-BBAB-A1--007629:-11 PPAABBXX--BBBBAA--11-.006699--11 PPAABBXX-BBBBAA-11007629:-11 116S4/11662.GROUPISFI 116S6/11655.GROUPISFI BOL(DF=2,<20ngml) PABX-BBA-1.069-1 BQL(DF=2,<20ngiml) PABXBBA.1.069.1 BAQQLL== BAebloovweqquuaannttiittaattiioonnlliimmii.t DF = Dilution Factor 000831 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-209 Page 23 APPENDIX A REPRESENTATIVE CHROMATOGRAPHIC DATA - BATCH NO. PABX-1-047-1 000832 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1210 Page 24 Peak Area Report Not ameincrm,:P1re047 omeAScoo: 1201 1528 Gomer ammpeus DE wm tmsne mesmo 000833 Primedica-Worcester Project Number: PABX-BBA ge 00 EA nn Bm a, HEI vaso rs rn 418-018:PAGE 1-211 Page 25 3: LeASNTMTuriTnT eTTTpb Sa E ar rrA A th Ee ET n TE TTT EETT | cones man To a 2 dein 00 J. 000834 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1212 Page26 Peak Area Report NorStaonmpRootnaemee: A5B700811047 ownAocari 12011548 mentPnod a.m:ASGSDK, SDATAPABPABLEBAI O1 arv m mEa Gmmgedt commie Del tem SRE Po O1 tTec 1 14 age 098335 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-213 Page 27 @unT nicMi ETH\OPARDK BSAA. (RTE Incogracor] A a AA ; | i E ee ee TeeRRh Ema 000836 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-214 Page 28 Peak Area Report MobSamFpaianmne::1AXSK5B08147 ounAopecr i201e1608 emerOnBnapPlaadaamomtoe:.cuPBnAEAo.SsBC0.AATAPABPABLSOOA4N7: aemmoeatraan mr:7 Gmepess smmptace Dngel fp msm Sule 000837 `Primedica-WorcesterProject Number: PABX-BBA 418-018:PAGE 1-215 Page29 cE peteriE t R 00 N mnEE7 S TiO 5f,Jiai : 3 Q O E ETEmam so re cr mm ro 1 TEE ee1 TeTTTTTe TR RR ee I TT rrE reW eTerJ TeTe Th Te TA CN rrTVE RE ATT Iep ETTIT TM E Te T EE rT rr | 000838 primedica Worcester Pojoct Number: PABX.BBA 418-018:PAGE 1-216 Page 30 peak AreaReport @ E ---- E -- oe-- fr % ro 51=3 A-- rs 839 Primed WorcesterPrec Number: PABXBBA 418-018:PAGE 1-217 Paget gEapae +500 sme Betlt HT 0 oe EE NY|CO J-u | A\\ TE Te eTeeTe eeeR 5 on : ee} a mee ES rareena em ae ew 000349 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-218 Page 32 Peak Area Report NebSoamRioaeme,:P1A4S5C7B04A 1007 ueApco:d 1501 1847 ermuaealFTiaamraeSAcHaBAnESoSnShsATAPABPAXSBAI0411) rneee uemelnNtor Nmaamre 57 Gampedr Ta Gms Imfel oseme bg knee otrt pa rt pnd rote To 118011446 [ 000841 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-219 Page 33 gEeareeaite | 3u1ae pATmAnAenAy ARR IR 3STelteiSr @T HRAKEFHODS\PAKBAN (RTE Integrator] | 4 EEa E ATEJN ER eR TTR Soe po.o as E oa E Re Teh ea mr - N Tr Ee E e T re E TeTTeaEr ThT 000842 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-220 Page 34 PeakArea Report [E SanL am: x5705 oupnec20e1 1:77 merBe:i FERSABarnesagaoAa 073, mero TT 000843 Primedica-Worcester Project Number: PABX-BBA Hear - QTE EHRmany he coger 418-018:PAGE 1-221 Page 35 Tee 810 SR SE G8 4%SR OR SHSw 1 Th 1 ve Te 7h 1 Tm Te vm E a TT EN meRrr ee e j r ih rArpA A ee Nn | TR eT TR ee 000844 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-222 Page 36 Peak Area Report one enPACS 107 ha ~~ il tmeouni nPtooPeidHaomaenm:.:t3P7Ah1G0E,S70S8.A4TAPATOABLSGA O71, earanurhat amomn?S7 Com3%at Gowwmmeissdmms DRoewTsoEano) mbEn mPamcmmamnd PeMdEmRiuo Petwe Teew 11801 1448 hoe 1 000845 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-223 Page 37 HT et ARESOBE Pr --a ; | =:I TEETo t TTN T Tr TTTTrew rr I L wah sw 7 ak sw 7h 71 7m ve ve vw vw vw ve vw A cre moan man see sm _ 000846 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-224 Page 38 Peak Area Report mm oneAcar 1201 1747 rar vedvaSmABSBASarnoAsaaoA0s1K. marys Gaomest Gompus ote) sme tle PreTr 11801 047 fae 1 000847 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-225 Page 39 @nT eesWaTH0S\ PARX_BBA.M (RTE Integrator) bu] wl \ i 2= aay EE -- TE -- eee ve VE Te Te TeTh = 78 7h 7k 1h ie 000848 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-226 Page 40 Peak AreaReport seroma xo on er 1201 007 BT ASTAPASPABSU0AI meme om3er c[ig e Imm gel o If eemi eRe oun ee 1 147 aes 000849 Primedica-Worcester Project Number: PABX-BBA SSHuecaetRerFide BE 1%SDR BBATHEPYPS BALOUT I\GNTIGER ESTpEriVtieels 9 Pe 418-018:PAGE 1-227 Page 1 tr e reo TEIr S he TM TMMipMEe eMEgEeThESeMT Ee A E rr Erie hiresrh aEr T rhase re a Ea E TR eEk 000850 Primedica-WorcesterProject Number: PABX-BBA 418-018:PAGE 1-228 Pag4e2 Peak Area Report nSn amp:AXaCLaOW01 fe Su -- riersD om e ASCSeHCTAPARPBARABTK marmo1t ret osentaptr erat eted FreTi ui 018 [N 00085] primedicaWorrjscNumeber: PABXBBA pEeRapEg Butt TE Iena oe cerca 418-018:PAGE 1-229 Pages TEETA ERES EEE o= o - ee em 1 \ 1: o M T en R T N e h Ea T a TR r eeh T h.iEieA ETveT Th _vI ee TE eTe E 1h taE Te | wwe, gin Sati spon rn wes 000852 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-230 Page 44 Peak Area Report MorSbaneinaeme:: P04A0BGBRA04R370 oweAScaeue: 1201 1046 neectC eadea:SPASSEG8BAarnes Apsara 2 Gom3mnd: Cowmismee: Imweo) wBn ommYimmE nie 000853 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-231 Pages oE EaRriee De AaTmAeDpenBO ATES fi vtig: 3 Q en T HT wn sae ser bwll IIn TT = A TE TEA Te Ee SE ee ewe re are e rr Ec ra on Be eee APE ME ] conersio mans oan 10 se 20 2 000854 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-232 Page 46 Peak Area Report Nournlranmace:1P0A8S3H1SGRAOU6P7ED oneAScaeir: 12011996 arentuBeuPdaam:o :0F7Ae1B02568C0AATAPABPAEXSALT. enatraVmoamNaomesn2557 Smeg: osmpues Defi) a mig Se wp 000855 rimedica-Worestes Projet Number: PABX-BBA ej se QE EEEnno ee scr) 418-018:PAGE 1-233 Page 47 i" L EEE TREN E ETE EE EEE i mS oT Th ie we ek we en am ek YR 70 vr 1% je 7% 7 in 3 3m i 000856 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-234 Page 48 Peak Area Report NotbSaaFmairaomce.F10B63%2SGRaO1U6PE1E veAScearr 12011926 emr enh tASEsRR. = eet Soame Comweomistas Domnowdn mgomm tgs [EU ------------------ 000857 Primeica-Worceser Project Number: PABXCBBA 418-018:PAGE 1-235 Page 9 nsBeeita e rEmsLA a TE8SFFtul 7 O 5 E BRfonE saen p mer . JI rt arroar TREE ENC MPR ea NT _ mERE ------ S eeeN er er EEee E EeeTae e Ea se EEA e Eh EE 000858 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-236 Page 50 Peak Area Report oneSunpeeaameP10O53O50NR0UOP4STEO A-- e 12011945 oun Teaem, 0U41E02D80ATAPATPABLAO1AL ha eenam 4ST Gompuge Gomspine Ter me i et Impml mgmi EmyERe rn sper N0859 `Primedica-WorcesterProject Number:PABX-BBA 418-018:PAGE 1-237 Pagse1 ogE rnegaiieTieE BorpueR BmRmaTan ST RATERSTIa.rttissk 3 er QE Ess re sme J| | 1m | TRteI r twN ak thsh twrm 1sTETe1 R ve te m Im a _h CEE N ew Eee ee SN e Eee iE eeTR TeRe TeSiETeMEwTm ieaT ve a|il 000860 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-238 Page s2 Peak Area Report Sarma recs owe a 208 atereemit haareSPAiBSS8A4TAPABPABLBA 01 mate Gmpuaest Sweimsple Iwmeow fuame muse [TR Fuge 000861 Primedica-Worcester Project Number: PABX-BBA sfeen UovrRsmEn QTE EH enon, BSrutt ae scarcer 418-018:PAGE 1-239 Page 53 = S T E E EE Tere eee I T ET R ee RR Re Te Te Ta A TR J. rs 000362 Primedica-WorcesterProject Number: PABX-BBA PeAreaaRepkort 0 m RE T 418-018:PAGE 1-240 Page 54 mses oa7 t cozmpan Ea E ] ame see wd moma ri os 000863 Primedica-WorcesterProject Number: PABX-BBA 418-018:PAGE 1-241 Page ss BB BaedrieE 5T 1DE Sm NE SCOTETRE TetLvietoth, 10 QAI SES ErtT cosoE nsT own. T(x7 tocegeacm er es pr pEdefaww NN RT E mh h a E S i N e 3 wea ocseres mesma om 10 sao 20m pes 000364 Primedica-WorcestrProject uber: PABX-BBA 418-018:PAGE 1-242 Fuse s6 [-- Hag sym cision o Notebook Reference:PABX.88A-1-047 Overser reexEImEEESEE assessor enErEeS? Comers cemptnes SED sam ease 000865 `Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE1-243 Pag5e7 EE aR EE ar QE BtRoos eax san (RTE tategracec) = 3 = EEE I |\ I ; RE RE EE EE I | Nh]| | eredLT R T r TRT T TI R R E eee FE so 000868 rimedics-Worcese Project Number: PABXBBA rages 418-018:PAGE 1-244 PeakAreaReport mmm oe rr EE eamacamsorn wn mr semen EE esr sous 000867 Primedica-Worcester Project Number: PABX-BBA Be REE a [ pA T--E--E 418-018:PAGE 1-245 Page 59 E rrrE EE ER a reNhe) CRT ee Ee 000868 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-246 Page 60 Peak Area Report NeSamnosaeme 1S 20300o19351 omee= te 12012120 a SDSuh ABSA 241 verve memes Gompiue Dia Bm tugme mimi Tor hi entrgrrr rtprt. 000869 Primetica-Worcester Project Number: PABX.BBA Bptre IouEsEeTns A Slt as EI ET enviar on 2 tops 418-018:PAGE 1-247 Paget iN rr ea i er Te ve 1m vw ve ik vk 3 || CRT Te EE eT ornaments som s# o 000870 imeiWere Prost Number: PABX-BBA 418-018:PAGE 1-248 rgez . Peenamepkert mtn corr pie o Notwbook Reference: PABX.88A.1-047 Oparmior. J BET svsmsonsn aRn EE com7es se=me EHDEne ne 000871 Primed:WorcesterProjct Number: PABX-BBA 418-018:PAGE 1-249 Pages B f2r8ie:iR e 5oE 1v1e0 sT TmnAaiaP oe eRE TEIDSuitatt t30s. LSEUSEE i TEEekesh forseioshcrtaca SE - I | EEE EEE er me Magy grea ERR ak uk ie th se an ah ak re1%7k ER 7h TeTh Th Th Th Th |j TTT M ie Tee 000872 Primed Wares Pict Number: PABX-BBA 418-018:PAGE 1-250 ren RJRE SEwPeenkAren Reept ren star ras o NotebookReference: PABX-BBA-1-047 Operator: pe7 n cowmwpe SHED EsEee spe 000873 Primedica-Worcestes Project Number: PABX-BBA F B cs hiea 1a 51 E m gER TTI -- MBrvoie 2 QT RE ras, srt tr spect - 7 418-018:PAGE 1-251 Page 6s nadSN rr RE a i ry T_T rk va 7a ge a i TTRERAE re ie T eRe eae Teee Te 000874 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-252 Page 66 Peak Area Report Netabmeieanamse:A1 0SK0BO0N 07 oeApcdq20u12a23 armennToid HPaaen: ASASSSKATAPABPBBAABK O71 mareve3 Gmgess Comsgene Doi wm Pwume fess 000875 `Primedica-Worcester Project Number: PABX-BBA 418-018 PAGE 1-253 Page 67 sSMuacreaEtPikeA:oR\HnSDEERATAPY AR\PABCARAL-B07-\BUTLERLD[REevisal 1 Q ElLoS meRS mooo ssaT exsaa. T (RTS tatepeacor) SE r EE eEtERe E ES Er RE EE Ee EE Ea S EEE Ye hE h TSeoTEeT nevR eTheR e | || TE ve we ak ah ak aw re 7 Tm 7% 7%eve imiwte) oorioine maxsmn Tse 0 ands sem [ 000876 Primedica:Worcester Project Number: PABX-BBA 418-018:PAGE 1254 Page 68 Peak Area Report NSaamp oae:3PR3OGSB51 oot i 0c 2200 nenoBuTobhauemsFoSASBiSSeSAATAPASSABCOONIU11 eea nVPra ompesr | cemmpues Inge woeUmT oe rnTr 01 1457 rons 000877 Primedica-Worcester Project Number: PABX-BBA ferries Ee amE Bi TE TIms an spss 418-018:PAGE 1-255 Page 69 rea 8 reese en 6% se 6% ewGn em em 7 vie 1m ik su vk Te im te TR iI 83 86 8% ee & 670 680 6% 70 200 1m 1% 1. evs | i e ereata r Nn ee eree eRe T 000878 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1256 Page 70 Peak Area Report NonaSampelie namee.:F6A8D3S4O7N00o9T51 oeA-- cne 12012352 ommnat Smee Iomflf tmme meme rheetoo etot hnet rdot ind. [------ as 000873 PrmedicsWorcs Project Number: PABX-BBA S2n0 SpEfuYt HATEense re cr 418-018:PAGE 1-257 Fagen! ee A ES o TE ot or v e Te se em or Www vm 7% 1 3 Th Tw am im 3k 3 AN] 000830 Primedica-Worcester Project Number: PABX-BBA a18.018PAGE L258 Page 72 revkares ma NotasoskParnes: PABSOA o8T Se 2 EEE acon, TERE comont comp BED same nen 0008381 Primedica-WorcesterProject Number: PABX-BBA 418-018:PAGE 1-259 Page73 or EET Th OE nmen x om comer | I EEE EE ERE REET rsspo m oo-o E i e rEEEEE EEE TeNehReT eeT | 000382 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-260 Page 74 Posennanarme 0 --SsrEeme mrammms En . JO IIar wn TA mt7 r snpHmp EEHLE sage ume veto tr I 000383 Primedics-WorcesterProject Number: PABX-BBA SHaeFite + E5ivEs SRerEenaero TeTat, 3 E hs T BReonTaeamcarer Ee { 418-018:PAGE 1-261 Pages me EEER EE| FE TR RR r a PE E WE E e ee] e l ee A 000884 rimedicsWorse Projst Number: PABX.BBA ets 418-018:PAGE 1-262 [---- @ IseE en arE oma os=s] enS Eh SAESST arrtmrann, me 000885 teenfossHeeberPARI sen 418-018:PAGE [-263 Qn 20000] RP ETHOS\PE ABK 8A. (RTE. Taceseacor) .rr E eee t E a m EE L Nn M i ae 5 7) Tio 13 7% ve 1% im im 1m 73 i i A wpe A --_---- | th ek se ew ew en sm ew 7m 70 TH 3% ve 7% ve vk vk 3m | 000836 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-264 Page 78 PeakArea Report NeSeamseopanre 1A05G500L90320 ou AScroes 1501621 rma omnaaTodtaPam ASBSEDBACATAPADPAEXSOA 071 atvlm bom o1 fomess ommpitms Imal n hmama fale 000887 medica Worcs Proj Number: PABX.BBA gr op mn fit @ ET BRE Eos \eABE_BRAN (RTE Tntearacor) 7 f\ EER EE rp 418-018:PAGE 1-265 rage o Ie S neee ee eT eee eee ! _r ___ r __ ee J-- es 000838 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-266 Page 80 Peak Area Report Sarge: mar ovten 01041 nimantHeFdoaa,,PMASBCBAATAPABPABCE0BA7T1 erraemint Gom2es mwsosn Iow fhl oSw ame Pace To i ke ceotrr pre et Proso Te 1m 1801 1450 age 000889 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-267 Page 81 TEErTEIREER 4 EE I SEE RE contE sh wt semeners 4 I order Cow -- oo k Eh kein o Te ee Nh heahe ---------- | 400890 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-268 Page 82 -- . crm sian A wonHemmer. wel mst comps SE sesme cmiae 000891 Primedica-WorcesterProject Number: PABX-BBA 418-018:PAGE 1-269 Pages anscaton spore we sevsewer Sa Tie ER i iBaTA BAO \GTODfrou vi. 8 [P Wetae tie A.e Ime I eR An 4% se 4 sw en amse 7kTetk 7h TetkeThTa Te F Er P 1 Ne e P5 e6ik ih ateiwhk ikie7A Tk 7h TETR a EEE EE ararer 000892 rimWorcePssecttNuembrer PABX.BBA --_-- 418-018:PAGE 1-270 revert 0 -IspEinSesENoDsE [wIm rnEEIEENES enAT compere compen SED sas te rae ere ep eee ey Toe us Tess mE sen tr . 000393 Primedica:WorcesterProject Number: PABX-BBA 418-018:PAGE 1-271 Page 85 sacs Tl91e12 CA PE.DPOUR ON.D Vial 40 Ebina TE QTR? Cia ntivoos:passe. (47 snceseacon) uo ]el woe TROTeTBAe ART | /\ SRY Te TR TR Mr Te ee TR Te Te i Ete te en eh th 7h veh TB 6 14 ERER A EE a Eei a ie 7 7a ve7h ih) 000894 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-272 Page 86 PeakArea Report Santime: san 1 oveAca 1301 140 nae ThdeMarm:m ASBsA ABarapa aaa 01, mee me n mp2d: Comwmoies Ina ge! meme ges Tr ia i a rn per rn 000895 `Primedica-WProorjeccteNsutmbeerr:PABX-BBA Sgraeg;rileoop2u0saDpDmNmAaTyA BRO TTIO.D4v,ia 45 L we E DT ops o"x ar=seater) 418-018:PAGE 1-273 Page 87 I BI arrrT RRC EE \ i r FT rr aaS eeegea eaaeaTTR| rr A 000896 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-274 Page 88 Peak Area Report san tan: crs one cau 1501158 oE u ieaa:S71s60Srssmasssons vr and t Gmgpaess ome Cmwspouam Imwe)owln Seg Smee re rn ret in rd1tr 000897 primedice-WorcsierProjet Number: PABX-BBA 418-018:PAGE 1-275 Pages gt RE i h @LE RE ono pa om ees ee eT e EETe TEER Coy eee neBB J IEECu A Eeae ee E ee ieS Te ie TN h eeT hve Th Ee ie h ie th ie 78 | 000898 Primedica-Woress Pret Number: PAB 35 Paseo 418-018:PAGE 1-276 . re PkresRaper ---- ere E ---- EE E mcE r, on woUr rr e T = e HE mm seme en rs 000899 Pm Worst Pcs Number PA3B mSE eEEmm BHeI Oe nen men - f 1 oee /1h EE Rages 418-018:PAGE 1277 Ore EE aa EEE || I Te J 3] SS pn a an SE BN vs 000300 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-278 Page 92 Peak Area Report Sram fsnoers OneAen: 131 230 amesEvmpPaeameEcAtrS1E04SC70ATAPAOSPOMA0B1E1 tnN Fr E fom2ent Gawsomsan Aun ECER E me PrtTr 11801 1500 ges 000801 Primdica-WorcetrProject Number: PABX.BBA 418-018:PAGE 1-279 Page aBtkI5Es R saonB.i . O = E TEeons.u or sec 00] arpa TS Edr TRE J TeTe aEeTMh eR oh | EEE ew hE AER EEE Ea] 0009502 Primatca-Worcser rjc Number: PABY-BBA Puts 418-018:PAGE 1-280 PAeresRakper * sre on ren nenEEEE oearamnonn, wo op3 e coEmape B1 ED 3 sme epg A 000903 Primedica-Worcstr Project Number: PABX-BBA Pages 418-018:PAGE 1-281 Be ARES TE L=IES ERR osm, =secpecon I Tee 07 GH 6% 66 6%Gm oh en em 1m7 1m ITew 1h Te Th ve ve TEa EE Ea ---- | I Ee ie ah weanmei ve th ve ve 7hTR 1h 78 ES TE ah ve ik ik uh ae ehksTR 3k ve 7k kth vm im) 0009504 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-282 Page 96 Pes Ares opart 0 Imm gre renr EERy me mem SED emus sae rosstrasnin so rs 000905 Primedica-Worcester Project Number: PABX-BBA 418-018 PAGE 1-283 Pages? Sate rie: DnsD SATAPEIAK.AAS-007-10UTIOD vial: 49 Neen Ta en QE EE orem,aun ee veo Fe T J i EE rR NEC gry e e uRe he th it gh ETT Te T-- h L Te he ea TT RE G ev ie re ES iekehh ieRh vTeh iThk vee TeeTe iTke Th Te TE orion marsmn Tan 10 1senia6 200s nea 000906 PrimediaWorcs Project Number: PABX.BBA Pagess 418-018:PAGE 1-284 Penk ren Report 0 S--E--E--N-- s--is --_--_-- rons re cmp EE same se 000907 Primedica-Worceser Project Number: PABX-BBA. BJneie LmEas gaEhL TE ET ra, te some 418-018:PAGE 1-285 Page 99 FE EEAEET EN EE REE a-- r eer I EEE RRs E EES EE EE 000908 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1286 Page 100 PeakArea Report sane ccnonies oneam: 01387 erSePi P,o FA53CDEATAPABBP8AAY0B1K1 ma Vi m 5 3 se Tam wm oes Tn vi 500 rage 000309 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-287 Page 101 B Dice FilE e DeRoBATADPAD ASK.BBRVL-003-\aeTIOS0Tevial, 33 Q R Tr ERTEo on | ul vin 72 tnceprcent fy -- = men I \ Tamper e---- CH a 6A % $0I 8% em eheR Sw vk Tn Th 1% 16 78 Th 1h TR x ord @F EE i Br TTT eh kh Te vehee -- EE Nh MM = PET eTTa unions maxsN Thun an 15.0056 zen noes 000310 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-288 Page 102 PeakArea Report Sern: orGroumto ot it0s 137 rerbtTe SAsh8raasoasasax mere omer cpus DRED mo mum msm 000911 Primedica-Warcese Project Number: PABX-BBA 418-018:PAGE 1-289 Spits Susaie + SmysEEPS TTiy r 3 QL DT oononspa. he seraen nee NS AX GN h 8% se en 4k Ge tm Te th tw 167% 7e 18 TRTR egy eM SO iee TEhE Re TR eeeT Te ee 000912 Primedica-Worcester Project Number: PABX-BBA. 418-018:PAGE 1-200 Page 104 Peak Area Report NetboSoakmpRlaemaemn:e1A0S85KSGR0OU0B7A50 OrAocrve 1301434. emer EC GATAPABPABC SOA 071 emvie t Woor n 5 fmtgaets Toe Gmwmipstim Inwf)s Smtr ease or Ptrr in enper ntrn. FtOau sTie 1a 1592 roses 000913 Pimetie-WorcserProst Number: PAB BEA 418-018:PAGE 1-291 Page 108 Fri NC TE er TT ial Eocene (x sacepasons < | a de r J\ e| en To 710 1m 1% 7 in 4 SN 000914 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1292 Pagelos Peak Area Report NonSeamFeienrce 1P0A64SGBLOUoPbeSD Om Srns 130 50 oT w iee amesSaiErcsDs ATAAPARO 01 rVaR vna e7 me2ts Tore Guwmpsiue mimleo) mwm ohahseur seuss toe ct at ron per rtor. PreauTnre nar 1502 rage 000915 Primedica-Worceste Project Number: PABXBBA 418-018:PAGE 1-293 Page 107 TSBahorie 1IASREEEEP ----------4Si2L0r LEE IE osemoe o seare s e = A\ = , ns r %Gr 6sxr ew on ok ok vm r Tie Tm Tm ve 7E % we TR7 TA. E rrTEe Ta TE r i ia m T A 3 1 eT Teeeee 000916 PrimedicWorcs rect Number: PABX-BBA 418-018:PAGE 1-294 Page 108 [p---- SA mgm eenI SI saps eRn RS co3ms coomp4uee SE E wne em case 000917 Primedics-Worcester Project Number: PABX-BBA 418-018:PAGE 1205 Page 100 frie ERE ous sm LE cameos wa BE 3 er WT DI stg i spent ceaOR OR Gh evia ae ah heTeTET Tape -- ETT a 5 AE ib VEt IE i ghT ekTb a eeih h TTe Eve TaeTh veere e aRwake we ek ER GK 4s 5BTh ih va 1%7 vw ih Th TR ouriess.o mexamn the san 18i00i1s duet nea 000918 PrimediaWorcester Project Number: PABXBEA 418-018:PAGE 1-296 Pope 10 rans croFn ---- o NotwbookReferance: PABX.B8A-1 047 retin Operator: EE Srmemeemonn. wel rer re etrey pt ettee 000919 Primdica-Worcester Project Number: PABX-BEA 418-018:PAGE 1-297 Paget Et RT et Me AFeIT EAraE ns p so sigm e =EEEEER EEE EEE SE Resp: Ja0sas' A Rr ELReA EEE ERE EEE TFEE ewTmTweeTA e E Th TeE ee e Stes onan thn ws 000920 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-298 Page 112 PeakArea Report Sree: rca onAci 1301535. eten AECATRPABSPIAALBL vV ar a Goe2 l: To cwmsl re Ismtao) wboratales wma co eootmr prnt pe. ProsomTsee nar 1503 hago 000921 . Primedica-Worseste Project Number: PABX-BBA 418-018:PAGE 1-299 Page 113 urs Tile 0,9 EsT taiA n prT sORIvu8seTiakn:e 7 mean Re Pp -- a] f rE EE d4ao00, one ETETERETE I\ A Ft FE re Snl ReR] R Te T o ie ie eTN Teee Ta va TR Te 000922 -- Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1300 Page 114 Peak Area Report NosSeameeasme AGRS OU0P1E ounAEcoeunea-1301 610 ouA reama ScSrairaepencaen0r veremRntanm 7 Compuge cmmmiuc Def) Begin eile 000923 Prmdica Worcester Project Number: PABX-BBA i -- ve -- F Heoriaemi 5i,s4 l QE ET mn. re arr 418-018:PAGE 1-301 rps 3 \ Sn EE RET a H pE Se ir oar T RER SP RR he| m EEE eT e T eee TR 000924 Primedica-Warcesies Project Number: PABX-BBA Page le 418-018:PAGE 1-302 peak Area Report PY sm ein ov 1a63 nnSbeInTSEES operator wanERR pe3rs co=me EEDI omg spp 000925 Primedica-Worcester Project Number: PABX-BBA [OT---- amsuteReile E DuVmDlBEAnTAa ARAL 00-GUIDSTpEucvniian 3 QE BroT ns onanson w (x72 cegracon 418-018:PAGE 1-303 Page 117 -| In RE TRS RENE Seo ____ TdEtEAeetTSeiR AiRe Ten tTee ThT5eh te @o: hIhn tTeh tn i I E TMT T Irr TTY oemioiso mexsN The san i8 eeenian d06s oes 000926 Primedica-WorcesterProjectNumber: PABX-BBA 418-018:PAGE 1-304 Page 118 PeakArea Report outaSampRloe nae:n A103B50SGRAOU0P7E veAScaanre: 1301654 RT SLEnessa11 wn Goma Games Imflal temic Pgs 000927 primedics-Worcstes Project Number: PABX-BBA EO LE amnion vs 4 Soin 500 LEE HT forma au x xs reper) 418-018:PAGE 1-305 Page 119 Tne pg A $e I r EEG Rer ETeTTeEeEe Tr EheTheE PE C EeeN h Th We ve TeTh ve1aTh Thhh wh 000928 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-306 Page 120 PeakArea Report sim cro out ine 1301713 TS ramen sauna mama a------ Goommons Gmmpiues Dia ge maw Seven 000929 rc ores: rj Naber:PAB BBA re re. Ee Ea Et OE ITE pe srs) J) I --_-- 418-018:PAGE 1-307 | re eI r fN [a -a Te ge SN ee 000930 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE1-308 Page 122 PeakArea Report @ e Santee am: sss c ome1a3n0s1739 renObaeet BASoA pnapaanaaron aren Gom3mngr C[omEmegiums Imnfoin nieti Suge ste hn te otegee otrn JES nage 000931 Primedica-Worcester Project Number: PABX-BBA rg gm cumitacin sors sevens as Q iT ER Eh caveE son. re. cerns 418-018:PAGE 1-309 Page 123 ro en R EE Ve sh we thSESk 7h 1h Th 7h 7%Te Th Rw TE ews ee EEE TeTe Tehg ve veeeTe one ee . i TEE ee ieee ee e VeTeTeTRe Te Te 000932 imtiaciossaos Boj oan FASTER --_-- 418-018:PAGE1-310 peokea Base .-- oman nn EJ nns w--o --_ sop mogee S nme men J - 000933 PimsticuWorcs Poe Number: PABXBBA asin sa ee IRE i ET ERED, sn te crs ges 418-Q18:PAGE 1-311 - \ Sr -- EE ref ET Je 7 Te RETR we Wh ana ve TeTh ae Teie TeTe 000934 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-312 Page 126 nS Peak Area Report crOuRs0 ou Aca: 1301012 fompaeds cmwmpsgnes D[mEfEal tami tiene 000935 Primedica-Worcester Project Number: PABX-BBA 418-018 PAGE 1313 Page 127 BSEiatRstEeFle1 5a 1110 SaATmAPeADnPABA. 1\GUTIOHDSEpEecbkiinsth: 63 er T OTT E ET east, an ts segs gy - | | EM i NE i a LE BrTEese ik wkiAhT 0Wfiie MThahghp Taai Tteae then Tk RT TE E E iERhek Te Te ih 7h Te Te Te TE crices mansan san 10 10m 2062 roe 2 000936 Primedic Worst Project Number PABX-BBA 418-018:PAGE 1-314 Pages PeakArea part . SE SO TT -- 000937 Primedica-Worcester Project Number: PABX-BBA gBrFe IoEe RsTmn grtl TE DT monssha svt 418-018:PAGE I-315 Page 129 ENERRESE EEE TE a ve we in Se AR TR Te Th 7% 7% Te Te Th Te Te sian mang ost sn 22 000938 PrimeWorse ret Number:PABBA ree 130 418-018:PAGE 1-316 PeakAres repr . PR. -- ---------- SOx UO coerce 000939 Primed Worcsies Project Number: PABBA 418-018:PAGE1-317 Page 131 EE IRE :T o- E mETE vt,su hutti ftrisgeoersom eei ere br a RE aETeE EE ERE ENE e aE aa || E oh E haaE 000940 Primedics-Worcester Project Number: PABX-BBA 418-018:PAGE 1-318 Page 132 PeakArea Report onSr star one ean:130191 menoBienTaherFnoaeGPusLtEsCAATACABPABCOBO4AN1 mareeVcoiu:t: pe3ts Conmses IwniowBo tmomp tapes [Sa ---- fae + 000941 PrimeicWere Prt uber. PABX554 418-018:PAGE 1-319 -- fe ops soa $n TE Tron,sm ee sven ee wl I te ETe Ea a a E aee m EI E raTr EE A eieTghehTeae ee CEE AN en 0 WR Th ih ve ih 7h a ih ET cones msn om a st se rs 000942 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-320 Page 134 PeakArea Report NesooSoRieenme 1P05a8SSsOAU4L7ED unAScurra: 1301531 oiea,OASONTAPABPBBAABE 01 mane i7 Gmmest Cmpgues lon dn MAM Pash 000943 Primedica-Worcester Project Number: PABX-BBA i S15 Fle 0E . ATAAB0 NER ARNRCTS Tots Ll 67 Q Se E nd TEfonsta re secgrnos ET | 418-018:PAGE 1-321 Page 135 . Treen FE r J T r r ee ea] TEReenweeJe\ EeTe | 000944 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-322 Page 136 Peak Area Report NotsbSouoFmemamne:s sAmBNsSS0rC0U0PA7SD veApceat: 1501551 mentouVFt ePiienNeaemeActOiBSraoEEes6:8A4TSASPABCOOAL GUT, an ivim m maramsrS0T Gon5ads cmmoepgum Inmfo) wmo twdAmME tuimie 000945 Primedica-Worcese Proje: Number; PABX.BBA 418-018:PAGE 1-323 Page 137 Er SE Eo QE fw" Shes a wTe egrocms mmm om rer RR ry Me a vei wehhoe a a oT a Tawh | ER RR ERANhER REE 000946 PrimedicnWorcester Project Numbers PABX5A 418-018:PAGE 1-324 Fae 38 [p-- sm swilaperis SE ssonarn on SRT T x HEE SO, rs 000947 rimsWorcs Po Number: PABX.BBA 418-018:PAGE 1-325 _-- TE {BLIee y t Rati OLE BRE ca en rs I - i er SE Gm nsw sh th eh 4k sT m ve urh tk ve Th TE1HTHTR a e ELEt Ee ae e RE sw am em amam ew3 vi 7 1% 3% 1h vm 1h 7h 3m | 000348 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-326 Page 140 Peak Area Report NotSaamRaleunnee: P110A91615G007018510 unAEcaient: 1301 1531 sme haTdieabmas ABtCSEAATAPADBAPLAMX mavms a foni3pede Cfomemie Imwiomwm maamme Peon 000949 Primedia:Worcester Project Number: PABX-BBA 418-018:PAGE 1-327 Page 141 rons spore gh i + Spgs EET 43 so2ins rat TE EL = A / ' os et EEE ERE ETE EET Err ga Ae Bee SE I 3 wees aan Tn 0 sense 20m J. 000950 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-328 Page 142 Peak Area Report NotbSaantaeeanmee::2AxBE0801D047 onAScioe 13011050 nmntHeaTde am:SAsBEBerneAseAscasa warmer Gomett compsnms IMM mm meswy tutu 00951 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-329 Page 143 cSucaaFile| B;\HSD DATAPADIPABC-BIAVL-GUT-\GATION 8utiatahh: 233 Qi ERAT TR ns has sah. (47 tncessacoc) Lo aTRE aAe rr Er R98 ERR r Eo E ea eeahe ikieE r 7h e7h e7h vee e e 7h e 7h iheih ih i Ee @ nT 1 I TTR eh a se ve an akee 7h 7m ve veTh ve in vmom orice PEKIN Th dan 30 Leenies 200 nai 2 000952 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-330 Page 144 Peak Area Report 0 mE one ims 301 130 eaFiPe.SA SATASABPABLOBAGIU amanvbr1 Inatrumant Method Nama: PABX 884 meen Gomse mma SER m maim sme ro ee ot me gt eet rn. on Tw81 1858 oes 000953 Primedica:Worcester Project Number: PABX-BBA Gonsataon wepore wr xevieeas ie 3 RACOA 8BLLD ti, 1 ERR edn fi LT TE as, he seasons 418-018:PAGE 1-331 Page 145 J )I ConS TE R Tee TT Te Te Te Te TE & r = rr il NN] TE a a we hai aTeTh ve aTeTETe cmos mes Than 10 enise 20m [I 000954 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-332 Page 146 Peak Area Report NoSuumsbNaame1P6A3BBGAR)OUSP4170 OneAScarr 1201 1130 nnrupenotwCesuotsiFleMaPammeLa aASmBaCrDBCAATAPABPABXSOAL041, meemmeernatno7 ees: compu EAD mums sass Prete aTr 1001 1508 oage s 000955 Primedica-Worcester Project Number: PABX-BBA. JBahrie1 2maEmE ------------SuiTitts 7 ILEI arm pos esos 418-018:PAGE 1-333 Page 147 i. l EE EL EE ET TEE a NN er eee ree oi S a -------- ---- ------------------| | TTT he Td warns van wn th sans nt ree 000956 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-334 Page 148 Peak Area Report NotSooaomReahrame: A10E0S4SGoRnOUoPl50 ueA= cme 201 1150 fompess | Coumptiem Dmfel Bain tees toma Tn i 500 age 1 000957 Primedica-Worceser Project Number: PABBA 418-018:PAGE 1-335 Page hs alathee fret - f QT ShR onepa ssa rm sceseacor RRR-- a - | I \ ee EE RE EE ACEEEE ae a fre Ah ai in ak (hh HoEin ve 1% vm 1m ve Te 828% 60 0 aK ST aM G0Tm v6 tm rx ve 7% ve 1% 7h 7m 000958 medicaWorcester Prot Nbr: PABX-BBA ST 0 IarEenaEsrEe 418-018:PAGE 1336 Page150 w= arps sIs cvoompe BB ED E2 uEme sme FE 000959 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-338 Page 152 erek Rr 0 IeErEeEs I sm nnC EEISES,arneE n A smI : comomHen BE1 D 3 mame tums never sn os 00091 PrimedicWorse Projct Number: PABBA age 5 Ssm ri pa a n siornes 7 [rt Br QE ETEom sn 1 cn 418-018:PAGE 1-339 Page 153 T EE A ES Eh E EEE EE FElwip @E Ho TJ } 83 eM ee 6% ef 6% em a0 ve7x1 re vie Tm_In Im Im | 000962 Primedica-WorcesterProject Number: PABX-BBA 418-018:PAGE 1-340 Page 150 Peak Area Report NowSoacnT tea:F1167SG0a0o159 onec= me 1301 1550 omm2ets Comwpslies Imwok same ee [ET rage 3 000963 rimsWorse rj Norber PAB BBA 100 2 penneA --i ERI aaa fa QL Rnea ov rn 418-018:PAGE 1-341 Pae155 i ETA EEE RE RE EEE EE -- rr Tl] rT series rsp ao sm rier os 000964 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-342 Page 156 Peak Area Report NeesSounmRennee: 1A6B3S8A6T8ob010 DonAScra130r113:10 omer compe SHE oman 1+ Tut I ctr cn anditen 4ot ome [Er -- [SN 000965 Primed WorcesterProject Nember: PABBA 418-018:PAGE 1-343 roger? snes es ees Be REE HE. ]LET ERAT oss sn a sence | EEE AREER EE Fg pgm re TE ee Ee ee ea E EE RE E eT core ean on mse rs 000966 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-344 Page 158 Peak Area Report obSampleianmese 1PAcSEGR0O1U0P47 51 oehpegiene 1201 1330 BATA EESnes 001, mame Gommmost Semmes SSE mp msm ype FroaoTnime: 181 1510 rages 000967 Primedica-Worcester Project Number: PABX.BBA EgoursEisrite o0er BnavA y sBAsT LOw C AE TwI mh p= weYoiag. hr TE QE ERS aes. err 418-018:PAGE 1-345 Page 159 TT o Tee Tah e ve TRThTR TeTER Te re S e e EEeen e fS TTee pe 5m e Th m e h r ee r 000968 Primedica-WorcesterProject Number:PABX-BBA 418-018:PAGE 1-346 Page 160 Peak Area Report suRnAs ame 1caSruoRaI11 oveSnnn: 301 130 nanoBuT osbeentum SoLmeESnOsA T apnpesexanata mraamna1 commer Somme INE wm mean sus ree o te e troert1 nd J---- noe 000969 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-347 Page 161 Be IRE he Q Wo ErEeT sT onso . re cena sor | \ EE TERR sired a0 @ ET ee rel] ee soBER ere iS emt met me soeestream erte takee slo Ww eh aeexi rie 1m iw ve 1% te vm veTm) 000970 Primedica-Worcester Project Number: PABX-BBA Peak Area Report [SSamptames r16i30l151 418-018:PAGE 1-348 Page 162 owes 150114 Gmmets | Comspitues Isa) mo fmim a auc Tne hc ee te pin petnerr. tsme 11 1830 noes 000971 : Primed Worcs Proj Number. PABY.BBA 418-018:PAGE 1-337 - eo smn sig an EER datas Tr J Ii De QE ER cosE e san. x7 tosegeacor) | w= r TTdEE Mme eee p r rirE e N a e r :e Eeeh Ne n | nes mess oso 4 sn os 000369 Primedica-Worceser rojot Number: PABX-BBA [REP ------ Sat Tie :\KED AERPARRA\L P1\AUTIRON.D visi: 40 LS dain" fia QT EEEssasw a smepracer 418-018:PAGE 1-349 Page 163 | ~J / con Te TEE ER Te ROEh TRE Ee ET a JANAN A -- \AA JEE i Ti ee TeTe Tehh @ \ ' I R Ea e | e| 000972 `Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-350 Page 164 sk ra por 0 REE gm oRImSasnansa. sanSsERr RE cons jo 000973 PrimedicaWorcs Projet Number: PABXBBA A FA. 418-018:PAGE 1-351 Page 165 Ee i T - \ wo " EEEEETREEIEEEEE a oi FIRE seems ee tm SB a 8 tm amr \\ i! E E EE RR RE RE 000374 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-352 Page 166 Peak Area Report Sse rum OneAcai: 1301 1045 nanmantT Hed a SAABSSCDAe APAEPARKSSAL0471 marta fonats fempotsues InEfIo) moteume tame To 1 dsrt nope ntrt. Pr Tem 140 11 aes 090975 Primedica-Worcester Project Number: PABX-BBA uanticacion faport (GT feviewed) FEGaoRcreEaFide a .\nED Sr ATA\Bi AR\BABI.BRAVS 047-1 TIORDSTpEersSaiasdt: 82 ey 418-018:PAGE 1-353 Page 167 J || L Leni bna Th ata we an ew AJ m 18N Te 15 7% ve Th VATE TE Th a A E m ~ T r ~ EE= e N BEATe e Th vk veEveehnh erme e AN RT a we en we 7 Th TR 7% ehveve vee Cros mex Tn 1 asian so rose 3 000976 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-354 Page 168 Peak Area Report NebSoamRooarr: 2AS0C vBi 47 [Syor empedt | Gemppem Impl BR team time 000977 Primedica:Worcester Project Number: PABX-BBA 418-018:PAGE 1-355 rege 169 a sie os sem eng vil: 3 RETR be Fe . I me EE RR A TR TR JN The Th hia ora A TeTe Hp ARAM sesk we AR Se Te aK smIk 0 In 1% 16 1% ve 7m a TREE EkiE Rh Te Th Te ve Te va Th Te onerso maran Then ae senior 200 [ 000978 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-356 Page 170 PeakArea Report @ EM. gm man iTntehaa,e BSPAAABT50AAPAESABLOSSA4L1, mv"1 cme comme DAD wm resme omsmas [ET -- rae s 000979 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-357 Page 17] I Le ty Cd Vr | TP Eee RnEn nnJ dRLS R nS E ES A TTTS it iee AA 000980 `Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1358 Page 172 Peak Area Report rman xno otAc1301i 1548 ImanuMe aeaPPldla MHPaaamyme::: A0M4S7S1KO01,B7Oo0nATAPABPBAOARX04.7.1 ta naVmtmHaoe momnen:s 7 fmssedt 2 omplue en Thr 3con ia InMD wm mss tami Tem ws rd rn pr tn Fret unan Tew 11801 1448 Page 3 000931 PrimediaWorcester Proj Naber: PABXBBA 418-018:PAGE 1-359 Page 173 Hoh Ode TE ay 5 a 7 @TRT fat ELAto omen + EER EA RE RE A -- E i r a mera al I | seni tar van tts or 000982 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-360 Page 174 Peak Area Report o NotSaaRmiemA2eS5K7Se00+01s047 umA= car: 1301 168 Ti a.OADOATAPABSPAAL0R6K1 rnc ver Smear Commmmes InN se tees umes | 000983 Primedica-Worceses Project Number: PABX-BEA 418-018:PAGE 1-361 Page17s aries p [or s soso -- 3a Mn LL EIT BIE near on em cnc ]- I|h - i EE E AE REET ag rang ros C A EE Eh a TEE No i i ah a TeeTR A Te Te 000984 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-362 Page 176 Peak Area Report Semmes: oneAcar 1301 1020 . LSESATAPADAOAL 01 man ompess competes Dol) bo teams resist Frano Teen 18 450 [= 000985 Primedia:Worcester Project Number: PABX.BBA E BSiEiE e11 Sm R EE Sm E [R--T -- TITYhTeeak 3 [es ---- - \ 418-018:PAGE 1-363 Page 177 gee MONG a0 @d IHTTEe eete e TEe Ee ieTTee| CTR TR ak ah kk Ti e e 7h ve Th Te Th 000986 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-364 Page 178 PeakArea Report NotaSsuRmeneern:aA2xG57B03t047 OnecSaree: 1391 1.45 aec ndaemest ABPaC CBAAABA AL mame 2 won wom a 000987 SA. i vr gre um my Lt rues 418-018:PAGE 1-365 [ry DRNEETHoS\PABX_BBA.X (RTE Tntegracor) Pd I | N\ J gar A i oy rf ERIE Ee RE JeE T Te TR TeE e eh eT ee ENRE nR 000988 Primedica-Worcester Project Number: PABX-BBA PR ST Peskcaves Report 418-018:PAGE 1-366 Page 130 masgnma io mest compu SED tame me eRSee arr e ora Hee rms --_ 000989 Primedica:WorcesterProject Number: PABX-BBA comssepon gs wr ween aS n pte E BD APTSAVBA7RONTIGH Gck3ttth 233 OTE EE sn ws en 418-018:PAGE 1367 Page 181 I SN cr rr TE ST . PA TER RTEghTe ee Th en RR ET EE Eee me meme I TE TeieihheTeThTRTh ee Tw he 000990 PrimediaWorcesterProje Number: PABX.BBA 418-018:PAGE 1-368 Page 12 Penk aven Fepurt 0 IE----E----E-- . -- ce rene SEESES ommcssann E en IR Smt compe EEL sas mas 000991 Primedica-Worcester Project Number: PABX-BBA. 418-018:PAGE 1.369 Page 183 BSHaacraatFEie R1%GE D GTAP GPuaAnKcsSeaAciLonORepTore IS(07STRpEuecvkViiivnnekt:d]e22r EE EE cra.an a recon ey sii N I wf SR rr EM Wah 0 or psrmmnen @Rva rhieRib 5TE 7 ihih ia 7a h m ie ! i Te ie veih WE ih 7Nh ATRN A a 6 vehhee 000992 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-370 Page 184 Peak Area Report NotbSoukmFieawree::2Pxt5706 1087 ueACcea130r1 1:748 nmnTde oaP:e PAAOSSAET58A4PABSABCEBAT O41, mar Vi ompats | Comgpuues Ioje) Bn baum bate FotToe 1801 1452 ase 000993 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-371 Page 185 Rpg I Bt 2 | T ee ET TETR eh T Te TE TR TE TRETT e E JN T @p -nWawIio etTsktenmd n am wi eike erm3H%epTem iRw 7%T1khTeeihT ve te e)] / | i 000994 pimelcaWorst Prject Number: PABXBBA 418-018:PAGE 1-372 page186 Pesaran Revert romeE CTR pra vn AEE orto oT--------------_ga--n-- 000995 418-018:PAGE 1-373 Primedica-WorcesterProject Number: PABX-BBA Page 187 pgeupsiiee ooaa S ERYaA con I spore S 72Berr8e pi ETI F e E Hm oe e7r er . |J f || E7 E ERAT RR Ae We rrrm BAe ney FH Ea EE EE|U E ee eR T EBLh I CEE a ee\ Tee a Te 000996 418-018:PAGE 1-374 3M Medical Deparment Study: T-6295.25 2 Medical Deparment Study: T-6285.25 Anlyical Report: FALRCNT--ET0O1X--0116890 Anaiyical port: FLAACNTETOO1X0-118690 Study Title DeftnertmheinMaetviaolnoonficthAeciPdr/eCsheonlcesetearnodlCCohnaclelnetnrgaetiaonndoNf OPeErLfiIunovreosotcitgaatnieosnulSftoundaytein(PRaFtOsS) Determination of the PreAsneanlcyetiacnadlCLoanbcoernattaotiroynRoefpPoerrtiuToirtoloectanesulfonate (PFOS) Fluorochemical in Rat Sera Samples Data Requirement Not Appicable Author 3M Environmental Laboratory Study Completion Date July 06, 2001 Performing Laboratories Sera Anaiysos aM Environmental Laboraiory Sera Extactions Pace Anaiyica Services, Inc --Tio2. BuldngS2t..3P5a.u0l9,M8N355B5u1s0h6Avene 170M0iEemapoSilries! MSEN. 5Su5i4t1e4100 Project Identification 3M Med"iAcraglusDIenp-aLritemSetnutdyS:tu4d1y8:-T0-168295.25 aMAnLaalybtoircaatlorRyepRoertq:ueFsAtCNTo.TOEX0-11-601960 Total Number ofPages 8 3m Environmental Laboratory $3 Environmental Laboratory 000997 Page 1 Page | 3M Medical Department Study: T-6295.25 3M Medical Deparment Study: T-6295.25 418-018:PAGE 1-375 Analytical Report: FALRCNT--ET0O1X--0116590 Analytical Report: FLAACNT-ET0O1X--0116890 This page has been reserved for specific country requirements. `au Environmental Laboratory SM Emaronmental Laboratory Page2 Page? 000998 418-018:PAGE 1-376 3M Medical Deparment Study: T-6295.25 Analytical Report: FACT-TOX-169 LRN-E01-0180 aM Modical Department Study: T295.25 Analytical Report: FLAACNT-ET0O1X:-0116890 GLP Compliance Statement Analytical Labor`oaftPoertyilRueoproorotctTaintee:su_ifDoentaetremi(nPaFtOiSon) oFflutohreoPcrheemsiecnacleiannRdatCoSnecreantration Samples Study Identification Numbers: T-6295.25, FACT TOX-168, LRN-E01-0180 TAhdimsinsitsutdryatwiaons(cFoDnAd)ucGtoeoddinLacboomrpaltioarnycPerwaictthicUeni(tGeLdP)StRaetgeuslFatoioodnsan21d CDrFuRg Part 58, with the exceptions in the bulleted lst below. Exceptions to GLP compliance: + Tfgoherenetrhreeawtaienoranleyattniwcdoalsshptiuhpdaymseedn.itrTeochftosripsenfcoeirmteshntissud.sytTuphdheya;asoneanlweyatfisocracltohnsestiuiddny-afrpeehdpa(hs0aesewenadasnatdtohnee Cteocnhsniidcearlepdetrofsotramratnactethoef ereaccehippthoafstehewsaessepneticriemlyenssepfaorraatnea,lynsoise.ffSeicntcies the + e`Axaucptceoocmrtdaeitndegdftrodoa2mt1athCicsFoleRlxec5cet8pi.ot1n3i0os(nyc.)s.teTmhsehhaavredncootpbyeperninvtaoluitdiastecdonassidreerqueidrtehde raw dTahtea.stabilty ofthe reference standard and intemal standard were not determined. Le od MS. Sway Decor Mee Varin T. Case, 16 DVM. Ph.D., Sponsor Representative Cate {Buns 220 Cate KesftoindJ.eFanseLn,bPh..D. PrincipalAnalytical Investigator uTratee C200) Witr am K. Ra eagan. Phe .D., Laboratory Manager cadres Talo 3m Environmental Laboratory 3M(6:Environmental Labboorraatory paged 000999 Pagege 3 418-018:PAGE 1-377 cinDeparmeSonyt T629525 LANE ArFatg PpgeiTkOieDn GLP Study--Quality Assurance Statement AnaiicalLaboratory ReportTie: DeteofrhmPrissannceaandtConiconotatnon riescstoushtas bSaonmainrsspeactteodbakyo.te IMiE.nrToormoenttiasLabwoarvastorreypunaeldlyAsssutranyce InospecteionPaes |E vem [r ee | weincor [em | wo ow [amo [amor |ewooe oawo o [|o omm|| wwe saw [awe | sawn [_swo|somtameno[| seen | seem TFAm lz pHiel Ena ie 1 Lat [-- --_---- " 418-018:PAGE 1-378 3M MedicalDepartment Study: T-6295.25 3M Medical Department Study: T-6295.25 Table of Contents Analytical Report: FACT-TOX-169 LRN-E01-0180 Analytical Report: FLAACNT-T0O1X.-0116890 GLP COMPIANCE SIAEMENL ce. rrnssnmssssssssnsnsd GLP SHdy--QUalYASSUTANCE SIBIEMEN! cc. SHUY PEISONNE! 8G COMBOS... 7 L STOPSEGHSTYIESNIBL CMOBc CHON ANGo ANBIYSISr .vrnrevr onroerre seentoms sosoeoss CIenor ere 88 SPECIMEN RECEP ANG MAIMENANCE vrs `Chemical Characterization of the Reference SUBSIANC ................ccerere 10 ME3MOEOSUNTIIOTNAIMNNENSa.lLaBv OTBIONY s reves s I 1 A PRODAIBIONY MONOG..cr.rssenrorormessoonenroroenemmomsonnemsooroo 11 BOANBIGYOICaecEGrUrDTrIEcNrI.s.e..m..e.e.esorerrsmsomnemsemomsomrmnemrsmnmem--rn--e--rs--o--so--em--n--on--s--soos 12 Data QUaIY OBIECHVES BNA DA INMGGHY verre 13 Dat`a SSUMuMAom,fQuAmaNlBiIatYySCEroSn,tAryoNl ARNEaSIUYSS.e.S. POSITS ....vovror vine coimr sero. 1143 SSUEMBHOTMRETNYROOFfSDAMEEIQGURASUYI.S.......evrrvenewrororwrowrreweormeomreroroeemsmosoeoro 1154 Statistical Methods and CalGUBIONS essere 18 SHaOEFCMONUES.N.. srs 18 APPENGix A: CONIO! MatarndiTesctAeMIsCI... 16 APPENGix B: PIOIOCOI aNd DEVIZUONS vv ammmmmmmiinity `AppendiCx: Extraction and Analytical Methods w-------------- HEPTLSC--8E4l,ecEtxitorascptriaoyn/oMfasFsiuSoProEcChHemOiMcGaYl,Co(m15poPuAnGdEsSf.r.o.m Serum for Analysis Using 3 ETSSe-r8u-m5E,xtArnaacltyssiUssionfgPHoPtLaCs-sEiluemcPieirofslpuroaryoo/cMtaasnsesSuplefocntartoemoertOr(tyh1,e1rpFalgueosr)oche..m.i..c.a..l..s..i.n 46 ADPNIX D: DAD SUMMARY TADIGS. ccs 5 ADDENGIK APDONGIK E: F: EDXABEMPSIEPCIARIGUUSBNNOONRS Lv S..s .c.s .crrrsssrnsnsn ns 58 63 APPENGiX G: IEF COrtiicats of ANGIE... 64 APPEHN:GREiPOx SIGNAIUTE PAGE... 68 3M Environmental Laboratory 3M Environmental Laboratory Pages 001001 Pages 418-018:PAGE 1-379 3M Medical Department Study: T-6295.25 3M Medical Departmen Study: T-6295.25 --_-- List of Tables Analytical Report: FACT-TOX-169 LRN-E01-0180 Analytical Report: FLARCN-TET0O1X--0116890 Table 1. Female Rat FO Population Demographics for Study (Argus 418.-018)...........8 Table 2. Characterization of the Analytical Reference Substance in Study FACT TOX. Table 3. Target Ions Monitored in 3M Laboratory ANBIYSES................e..or 12 Table 4. Determinations of the LOQ in the Analyses of PFOS EXIGCIS v.16 Table 5. FCAhaCrTacTteriOzatXion-of1the8Con9tro.l Ma.trincestUsred sfor nSersa Atnalsyseos insStnudy 16 Table 6. Characterizationof the Test Aci in Study FACT TOX-16 .....ov..ccr 16 Table 7. TOX 169 Data Summary of PFOS Concentration--Rat Serum (Q/mL).......... 57 3M Environmental Laboratory SM Environmental Laboratory Pages 001002 Page 6 3M Medical Department Study: T-6295.25 3M Medical Department Suey: T:6265.25 Study Personnel and Contributors Study Director 3DMeaConrnpJao.raLtueebTkoexri,coMl.oSg.y (Medical Department) BStu.ilPdaiunlg, 2M2N0,-525.10424 Analytical Chemistry Laboratories 3SoMraEnnvairyosnemesntal Lasaratory (GM Lab) KIrnivsetsetnigJa.toHransen, Ph.D.. PrincipalAnlyical 418-018:PAGE 1-380 Analytical Report: FACT-TOX-169 LRN-EOI-0180 Anaytca Report: F(AACnTET0O1X0-118609 Sponsor 33MM MCeodripcoarlatDeeTpoaxritcmoelnotgy SBtu.ilPdaiunlg,2M2N0,-525610424 MRaerpvrionseTn.iaCtaisvee, D.V.M., Ph.D., Sponsor PsearcaeEAxntaryacitciaolnsServ.ces, Ic. Ter2 Facil 3M Lab Contributing Personnel LRihsoanAd.aCDliocmk"en MHKaaerrlollledJn. eO(.MK.JuoeHhhewnyeisinognn*) Swartout" 800 W. Wynne Cohspntt s sev aries Location of Archives LAlalboorragtionrayl.rTahwedatteas,t aprrtoitcolceaal,ndanadnaalnyatliyctailcralafroerpaonrctehsatvaendbaerednraerscehrivveesdaamtplthees,3aMsEwnevliraosnmtehnetal sLapbeorcaitmoreyn. pRaertsaeirnviengsfaomtphleesanoaflytihceaclonpthraoslearoifchleisanstduvdeyhiacrleeacrochmipvoendeantttshear3eMstEonrveidraotnmtehnetal testing faciiy (Argus). WM Envronmenta Laboratory 3M Enironmental Laboratory Page? 001003 Page? 3M Medical Deparment Study: T-6295.25 Mcical Deparment Sy 7629525 418-018:PAGE 1-381 Ansytcal Repor:. FLARCTN-ET0O1X0-118609 Anaya opor AoCrToTOrxe1s69 Introduction and Purpose TpTeharettapuumorrnpoaootsceoianonfoetfshuthosentaPutdrsyesi(seFnoOceSd)taanrdmCriaonnasctrahsntSpaartmeepsnleonoscfekPaaenrnduocironsAcocecnctaornaretneicouneomoifattheh(e+0S8M)priotoscol, MeGeevnrearlacotoinlolcencAtaGeidshocwrelrnsetagoivlreln aPCtFhpaOalScoinbiygeeodraamlnadgnaaNvlOasEg.eL TaInnnvdeesmmtaiosganetmiaoofln iSaenSyfhenrwaraness.sieadmrraerrseaum0nsiis0 VmPaaRtsOerStnaadltoseaedsd,3aalJwalnsuleaiarasy12o00f0bh1ee, rcoadcomiingnGtihealPoFnOSof6movoiolseonnvee4d0s4ec1tclhovoe r(NeOEaL)mTettu wThGreieostsutapaSSsnyo.sngtr4ooe,umoapnsudofs6 f1enm3aalewweerrattas aGwdemoirnsuHtseaerdreadTwPteFheoOnSte5sd0to,ssmyessetvenma.0l.G5or%o0uTpw.e1,eoGnrrtaobuap(o2rstatnadcGoerm.ouiher lSGeoistneatioDornno(CGgaacgmsanr4as2taonanyseewciDhhornmeGtvrooaculopoh)naedbauayactd2o4no,6 cahPnordleecsstouemmremodlienFsgetwmaaatc,aheetdswoomsr3ee0dgaennmeowsknewaasty! Gamay hat do nt Gober a er) o da4n ptparum ras ar dlnr a ay `The test system species and strain selectedwas the Cr:.CDSD) IGS BR VAF/Plus rat received 1fv2rgaof.mtoCemhiyadroflF8eOt3shqepRoiatnvrerrroafLt(aoisbeoosarra,Ttaaoobbruliwteeeswr1,eoIrnrac.a,otpeeIrdmnadnwieidnuhtal6lyy1i(dfeaangtgai.efsi1.edaugnsadinnaagraaplaMoronanmerelttsesrweslefw-repriweerecomivniagleeosasriaendd Tabl1e. Famal RatFOPopulationDemographics forStudy (Argus 418018) SPaetpydi [i[ene essom comoGe rn| ? [t20m| |mtcmon aomeras sere:]| [ameas mes Ts a0 vensmrorrgorrsose:mmmemaeenssscm|s [me ETsT To| anomsemrosessome | [ [m omeee r TT oTsmgcrirmmogsrercosmmn || [o[ merm [|o oe T T cmaow mropnmor]| [o[ menm T 1% o| e T eonmgmw oorrrooss | SM EmronmanialLaboratory S31 Ewironmental Laborato Pages Pages 001004 418-018:PAGE 1.382 3M Medical Departmen Study: T-6295.25 3M Modical Department Study: T-6205.25 Analytical Report: FACT-TOX-169 LRN-E01-0180 Analytical Report: FLAACNT-T0O1X--0118608 `Specimen Collection and Analysis npinuoomtlhbeeedarnraoatlfytstieecrraaslsswpteeurcdeyimsreaennpstortctooeltdlhheeecrt3eedM,f2Eon3rv5ainrsaoelnrymaseesnspteaiclnitLmhaeebnoasrnaacltoyoltrliyeccaatlnedpdhfaarngoaemlyoffzeemtdhailsfeosrFtPuOFdrOyaSta,sreaTnhdeF1 presented below. S``SSeeprreaacSSippmeoenccsiimmCoeelnnlsse----cts5e44dssfppreeoccmiiSmmeetnnussdy((FFG1OrpoFoeuomplaselde1sIt,theGrrD,o2uGg1Dh,21C13,a:eCsaasrseaarneasencstioocnt)on) `SSeerraa SSppeecciimmeennss----798 ssppeecciimmeennss ((FF1O pfeomoalleeds,litdear,yd5ayof5laocftaltaicotna,tinoant,unraatlurdeallidveelriyv)ery) EBnlvoiordosnpmeenctiamlenLsabwoerrastocreyntfrriofzuegneda.ndSoenrudmrywiacse.then harvested and shipped to the a cmSehetrrhoaymlsa-attmoepgrtrlbaeupsthywyle-aretelheeecrxttr(rMoaIscBptEre)da.yb/Seaagnimdnpenlmienmgeaxostnrsa0cs5tpseFcweiebrrroeumaeartnyray2ly0(z0He1PdLuusCsi-inEnggSaMhniSgMihoS-n)ppraeiinsrstiuhnregemrqeuualgipedlnet and erxetsrpaocntseed cmuornviet.orAinnaglymtiocdael.dePtFaiOlsSalreeveilnscwluedreedqiunatnitsiartepeodrtb.y extemal calibration versus an -- Specimen _ Receipt an-- d Mainten- ance --m tLTrahabenss.3feMArllrEesndpvteiocroisntmmoeernnasgteawleartLaa-b2ro0ercaCstio1vr0eydrCfer.coezSiepvneedicnirgmatoeosnedsrcwuoemnrdesiptierocaninmsopenonrcstreycdoilctleoecaPtnaedcdewateTirAoerrg2iumfsmreoRdzeiesanetaoerlncyhice packs. After extraction at Tier2, the specimens and the extracts were retumed cold on ice packs. 3`CocMnotmErmnoevlricmriaoatnlrmsieconeutsracluesLseaadbnoidrnaastreoerrayprawienlsalelbnyotseemdsaiipnnetrAafpiopnreemndeddfioxrdauArip(nesgreieToOdTXao-bfl11a6095)y.weeaSrraesmpaoblntedasiwinalenldablefyrzsoetmodraetdtahtethe Taboratory at 20C 10C. 3M Environmental Laboratory 3M Environmental Laboratory Pages 001005 Pages 3M Medial Deparment Say: T-6295.25 con Sopa Sy PASTS 418-018:PAGE 1-383 Aualycs Repos: FACT-TOX.169 Avant Rar: 2e07sTCo1s68 LRN-E01-0180 Chemical Characterization of the Reference Standard PertuotPoootcatsasnieusmutonats GAS Num(bKPeFrOS2)795:395 pGehraumcircGoahoaccihaacrnaaectatelFroiirozmanutaliato:nuGisneFfdoormSat0hiKson"soactserperfeerseonmceedsiunbasbaunacerMpofoloetrcausblsaeirlumoW:eigh: 537.9 Table 2, CharacteorfithzeaAntaiyioanl Reference Substance in Study FACT TOX-169 C1 a T | ROI E a era EI reaall Samm [[SEeommmes| Fmssoimoc || E=T E [omcl me| iimcvs] Tarrsions n TB E s&m 1 T wm S41 EnsrSoWmeErnrtolnmLaobnoartataoproyratory Page 10 Page 10 001006 418-018:PAGE 1-384 3M Medical Department Study: T-6295.25 3M Medical Department Study: T-6295.25 -_ Method Summaries Analytical Report: FACT-TOX-169 LRN-E01-0180 Analytical Report: FLARCNT-ET0O1X--0116890 AEFpnopvllieornwodininmxgenCi t.aalbLriaebfordaetsocrryi.ptiDoentaoifletdhedemsectrhipotdisonsseofdtdhuerminegththoidssanuasleytdicianltshitsusdtyubdyy tahree 3loMcated in 3M Environmental Laboratory PREPARATORY METHOD + EElTeSc-t8r4o.s2p,ra"yE/xMtarsasctSiponecotfroFmieutorryo"chemical Compounds from SerumforAnalysis using HPLC- pAaniarliyntgicraelasgeerntumwassamapdldeesdw0erea leaxbtorraacttoerdyussaimngplaenainodn-ptahierianngaleyxtter-aicotniopnaiprrowcaesdupraer.iiAinonieodntEnhtarocohMuIgeShxEta.ra3cTtmheeid MpllaIabBsotEriacetxostryryraicsntagmewpaalstettawhcaehsnedrreetcomaoanvs0ei.id2tuautnemddnipynult1oo.nn0tfmoiLtasoifnnitmtoergtalgheaansnsoelavuaatponovdriaaftlisot.reruendi dry. AnaLymCaL METHOD + `ESTeSr-u8m5.Ex2t,ra"cAtnsalUyssiinsgofHPPLoCt-aEslseicutmroPseprrfaiyu/orMoaoscstaSnpee-csturfoomneattrey"or other Fluorochemicals in miToohnleecchauanlraaalcrytseireonissw4ti9ec9r,oefsapeelrpefacrotteridmceualdsarbtyfhlemuoopnrrioitcmoharerimynigicoaonlnfueosripPnrgoFdOHuScPtL(CiCo-ynFEsSSeOMlyeS-cH)tSed.anfFarlooyrmsieasx,asmiwnpagsll.ee,primary qfuraangtmiteanttievde taonaplrysoidsu.ce ion 99 (FSO). The characteristic ion 99 wes monitored for `aM EnvironmentalLaboratory 3 Environmental Laboratory Page 11 001007 Page 11 418-018:PAGE 1-385 5 ioSvDnTmneSoug: TaaE2a5Sst si ed dtP svAnmaR itRetoBeipznrsst,EfACrTTOeN1t0 Liquid Chromatograph: HewettPackard Series 1100 Liquid Chromatagraph system Analytical column: Keystone BetasilTM C,, 2x50 mm (5 ym) ey owBee58 LMaosss pSpoecntrsomeetrer;Miircromass APUMass Spectrometer Quattro I" Triple Quadrupole system a Ls A, Tat. Tagine ontorstinH epersteryArts [e|m omarionm iin|_y provoics n | nitty -- 3M Medical Department Study: T-6295.25 3M Medical Department Stuy: T:6295.25 418-018:PAGE 1-386 Analytical Report: FACT-TOX-169 LRN-E01-0180 Analytical Report: FLAACNTEToOTX0-118603 Deviations Deviations from the original protocal and methods are included in the Appendix B. Data Quality Objectives and Data Integrity The following data qualiy objectives (DQOs) were indicated in the prolocal for this study: + Linearity: weighting. The coaffcient of determination () equal to or greater than 0.990 using 1/x + LcailmiibtrsatoifonQcuuarnvtei,tadteifoinne(dLaOsG)t:heThloewaLsOtQstiasnedqauradltthtathies blootwhesttwaoctcismpeisabtlhee smtaatrnidxarbdlannkthaend is calculated within 30% ofthe expected concentration. + sAtcacnedpatradbs,leprPorveicdiesdiotnh:eyQuaareltqyuacnotniitraoltesdavmipllhienstahreesreelqeucitreeddctaolimberasttio2n57r%anpgre.ecision + CshoonuflidrmbaetworriyteMne.thods: If a confirmatory method i used, an amendment to this protocol + Dreetmeonntisotnrtaitmieon(aopfprSopxeicmiafticeiltyy7:.P3FmOinSutdeesn),ifbiycatthieonchwairlacbteersiusbtsictapnrtiimaatreydiboync(h4r9o8)maatnodgrtahpehic characteristic production (99). Data Summary, Analyses, and Results LDaabtoarqautaolriytyproobtjoeccotlivfeosrfFoAr CtTeTaOnaXl-yt1i6c9al(psheaesAeppofentdhiisxsBt)udwyeoruetmienetdwiinththteheIeMxcEenpvtiiroonnsmennottaeld in nis report. 3M EnvionmentaLaboratory $M Environmental Laboratory Page 13 Page 13 001009 M4 Metical DeprmesSoy: 729525 418-018:PAGE 1-387 Amica Repo: EACTT0%.165 ssSst Sty ans IS CTkt aon Su= mmmaeraytyofTQeucaoyControolfAcnaolymmoRnes4tosfestar iv was20550 Srvagoahao ape Sead narge bv ns telBe ae Fo eS LOS pei pee on er ra a ee Sam leay vebndecid Limits of Qusiaton (L0G):Th LOD eo ms aquaths ostcept sancr ar i 0% of 0 Bric ne Tal.DeterminationscsLo in he rayon ros Estas [rI esTown + Prciion: Paci was deem anesof acd ers co com. tonal Sandaarmdaesn:ThEe aarsesalnrdesso(nwPasFdSetewmeinosadt ta mses an any ns Eon 26 ard]inve rf Gtming Steams uaity ClrReansnmeervseesssaTdoo esepapeuart!seralsSaPvaltfeao nssetvs,iottargd 34 Environmental Laboratory Page 14. 001010 418-018:PAGE 1-388 3M Medical Department Study: T-6295.25 3M Metical Department Study: T-6295.25. Analytical Report: FACT-TOX-169 LRN-E01-0180 Analytical Report: FLAACNT-ET0O1X--0116890 SummaryofSample Results PFOS results have been comacted for purity of the analytical reference materia, Sacomnptrloleasnifmralosm.CTohntersoellAenveilmsalwse:reLoswiglneivfieclasntolfy lPoFwOerStwheanrethooftseenfdoeutnedctinedthien tlhoew sdeorsaeotfetsthe animals. Sa`amnpimleessinfcrroemasDeodsweitdhAdnoismeallsev:elI.n Dgeetnaeirlaeld, sPaFmOplSeldevaetlastfaoluensd ainrethperesseernatoefdtihneAtpespte.ndices DandE. Statistical Methods and Calculations AStpaptiesntdiciaxl Fmeftohroedxsamwpelreeclailmciutledattioontsheuscaeldcu1l0agtieonneroaftmeetahnessearnudmstsaanmdgalredddaetvaiaitnioFnAs,CTSeTeOX169. Statement of Conclusion oUfndalelrFtOhgeecnoenrdaittiioonnsraotfstdhoesperdesweintht tshteudtieesst,atrhteiclfeluaonrdochineranlilcFa1l gPeFnOerSatwiaosn orabtssefrrvoemd FinOtdhoesseedra. ats. au Environmental Laboratory 3 Emironmental Laboratory Page 15. 001011 Page 15 3M Medical Deparment Study: T-6295 25 Mod Deparment Sy. 7020825 418-018:PAGE 1-389 Analytical Report: LFARCNT-T0O1X0.118609 Arata por: AeCTsToox e e e rseer m ors Appendix A: Control Matrices and Test Article Table 5.Characterization of the rir MatricesUsedfo Sar Analyses nStuy FACT T0165 [nE r 1r owes |e mmror |rmoy w rweinr Fr o ze n 20C | F owas rosmn 20C [ro + |meoweo| moon || Guan Frorzoenve2r05|1 Fraagresno2n0C TE Po Table6. CharacterizationoftheTes Al nStudy FACT TOX-160 [[rooemmo || Sie cmous o3r0riLaoebnoreaotosrreysbpm | [S[ erg[ e Gonto tors | pmeFowmo iozev6me| isaa7 n Purity 86.9% Wn Emiormentaitatoatry 3M Environmental Laboratory Pag1e6 001012 Page 16 3M Medical Department Study: T-6295.25 3M Medical Department Study: T-6205.25 _-- Appendix B: Protocol and Deviations 418-018:PAGE 1-390 Analytical Report: FACT-TOX-169 LRN-E01-0180 Analytical Report: FLAACNT-ET0O1X-.0116890 0 3M Environmental Laboratory SM Environmental Laboratory Page 17 001013 Page 17 3M Medical Deparn3mMdeSnEentrvviiSrctoeunsdmye:ntalT-T6ec2h9n5ol.o2g5y PSOu BPaouxl 1M3N3S151333331 ez Tig 642 418-018:PAGE 1391 AnalytPircoatlocRoelpoFrAtC:T-FTAARCNTR--EATOOIX--0116890 3M aso ie DetermiMneavtailoonnoifcthAceidP/rCehsoelnecsetearnodlCCohnaclelnetnrgateiaonnodfNPOeErfLluIonrvoeoscttiagnaztsiuonlfSotnuadtye (PFOS) in Rats in the PHASE PROTOCOL Performing Laboratories 3M Environmental Technology & Safety Services 3M Environmental Laboratory 935 Bush Avenue St. Paul, MN 55106 Pace Analytical Services, Inc. 1700Elm Street SE, Suite 100 Minneapolis, MN 55414 Laboratory Project Identification FACT-TOX Number TOX-169 3M Toxicology Study Number T6295.25 `Argus In-lfe Study Number 418-018 3M Environmental Laboratory 0 Environmental Laboratory Page 10f9 Page 18 001014 3M Medical Department Sud: T-6295.25 418-018:PAGE 1.392 AnalPyrottioccaollRFeApCorTt-:TOFXL-AR1CN6T9--ET0O1X--0116890 Determination ofthe Presence andSCtouncdeyntlrdaetnitoinfoifcaPteirolnuorooctanesulfonate (PFOS) in the Mevalonic Acid/Choleserol Challengeand NOEL Investigation Study in Rats Sponsor 33MM MCoerdpiocraalteDeTpoaxritcmoelnotgy BStu.iPladuiln,g M22N0-525E1.4042 Sponsor Representative. M3aMrvCionrpTo.raCtaeseToDx.iVc.oMl,o,gyPhD. B3uMilMdeidngic2a2l0D-e2p-a0r2ment TSte.lePapuhlo,neM:N(65551)147433-5180 Study Director Phase Locations P(rPiAn)cipal Analytical Investigator D3eManCnorapJo.rLatueebTkoexricMoSl.ogy 3BuMilMdeidnigc2a2l0-D2e6p-a0r2tment TSetl.Peapuhlo,neM:N(65551)147437-1374 Kristen J. Hansen, PhD. Analytical Testing Laboratories B3uMilEdnivnigr2o-n3mEe-n0t9al Laboratory 9St35PaBuuls,hMANvSe5n1u0e6 . Proposed Phase Timetable Analyses Start Date Analyses Termination Date P1a7c0e0 AEnlalmytSitrceaelt SSeEr,viScueist,e I1nc0.0 Minneapolis, MN 55614 January 20,2001 February 28, 2001 3M Environmental Lasoratory 3M Emironmental Laboratory Fago zara 001015 Page 19 3M Medical Deparment Study: T-6295.25 418-018:PAGE 1-393 AnalytpircoatolcoRiepoFratc:T-FTAOCRT-SETO0O!1X0-1169 1. Sruoy MDeetvearlmoinniactiAocnido/ftChhoelePsrteesreonlcCehaanldleCnogneceanntdraNtOioEnoLfInPveersltuiogratoioocntaSnteusduylfionnRaaties(PFOS) in the 2. Purpose F`TOhegeannearlyattiicoanlfpehmaasleoefratthsiesxsptousdeydiasnddesFi1gngeednetroaetviaolnuraattepluepvselpsootfenPtiFaOlSly ienxpseorsaedspteocPimFeOnSs oinf IAnrcg.uTsie[rn-IliffeacSitliutdyy. A4l1l3-s0e1r8a.saAmllpsleersaswialmlpbleesanwaillylzbeedeaxtttrhaect3eMd aEtnvPiarcoenAmpeanltyatlicLaalboSreartviocreys.. Data quality objectives for this study are indicated in section 12. 3. REGULATORYCOMPLIANCE G`TohiosdstLuadbyorwailtlorbye PcroancdtuicceteRdeignulaactcioorndsanfcoer Nthoen-UcrliitneicdaSltaLtaebsorFaotoodryanSdtuDdrieusg,AFdimnianlisRturlaeti2o1n CER Part 58. 4. QuauTy Assurance d`Tahtea,3aMndEnfivniarlornempeonrttatlo LdaebtoerramitnoerycQoumaplliitayncAesswuirtahnGceooUdtLawbiolrlaatuodriyttPhraectsitcuedyRecgounldautcito,nsa,w. this protocol, and 3M Enviroumental Laboratory Standard Operating Procedures. 5. REFERENCE STANDARD FOR FACT-TOX-169 Potassium Perfluorooctanesulfonate (KPFOS), CiF SOK, CAS 2795-39-3 6. TesTSvsrem `eTahcihrtgereonudpo,soengerobuloposodfsafmepmlaelewraastscwolelreectgeidvfenrotmhesitxefseamratliceleFbOyoonradlay(g2a1voafgeg)esrtoauttei.onWi(tathin s`iCxaeFsIarpeoaonlseedctliiottneirnsgo),n fdraoym2s1ixoffegmeastlaetiFoOn o(natdCaayesSoarfealnacsteacttiioonn(iangf)e,r annatdurfarlomdesliixveFr1y),pofoolemd - tlihtete3rsMfrEonmvidroany5meonftlaalctLaatbioornat(oartye.rSneateurfaolldleolwiivnergyt)a.blTehefroreaadreesc3r1i2ptsieornaosfpaelclismaemnpssleenstto received 3MEnvironmentalLaboratory 3M Environmental Laboratory Pagers Page 20 001016 418-018:PAGE 1-304 3M Medical Department Study: T-6295.25 Analytical Report: FACT-TOX-169 Protocol FACT-TOLXR.N1-6E901-0180 Number of Specimens per Dosage group and Dosage Levels D"anod Loveer | (e mia | Cam esareanSacion m Raine |y Lurie e+ L [llaai savssiosens iecsss] T1 T [%[ 1 % e % ]| [los* Gseteers =To 1% rPllloets+mmsCgornieeerrrrreoosssTs =5T T 5T T T T T T 5 ] [FeFrllegmmmeeennneeerrrrrreoosssT T s6T 1 6 % 6 1 5 6 61 1 5 5 5 ] Col Zemenorros 6161%1%] 7. SpecMEN RecePT lSiefreapshpaesceiomnenJsawniulalrbye2r0e0c1e(ievsetdifmratoemd)A.rgSuesraRsepseecairmcehnLsawboerraetosrhiiepsp,eIdncb.yaovtehreneingdhtofcotuhreieirn arneqduewsetrneurmebceerivsedorfnrouzmebneorns adsrsyiigcnee.dSbpeycAirmgeunssRweesreearicdehntLiafbioerdatwoirtihess,amInpcl.e) nuupmobnerresce(ipstb, srepgeicsitmereendswsietnht tthoeth3eM3EMnvEinrvoinrmoennmteanltaLlabLoarbaotroartyorayndwetrraensrfeecrerievdedtoaanfdrtereazcekrefdoarcsctoorradgien.gAtlol the Sample Tracking System Standard Operatiag Procedure, Detailofspecimen inspection pforresdeanmtaegdei,n rtehceeipphta,ssetorreapgoer,t identification, chainofcustody protocols, and data will be 8. PREPARATORY METHODS CEToSm-p8o-u4n,d"sExftrroamctSieonroufmPofotraasnsailuysmisPeursfilnugorHoPoLcCt-aEnelseucltfroonsaptreaoyr/oMtabsesr SFpleucotrroocmheetmriyc"als rAneaalgyetnitciaslasdadmepdletos aarleabeoxrtartaocrtyedsausmipnlge aanndiotnh-epaainrailnygteexitornacptaiiornipsrpoacretdiutrieo.neAd nintjoonM-pBaEir.inTghe lMabBorEateoxrtyrascatmipsltehienrreecomnosvteitduateaddipnut1.o0nmtoLaofnimtertohgeannoelvaapnodraftiolrteuraetditlhdrryo.ugEhaach3 ecxnt'rapcltaesdtic syringe attached t0 a 0.2 jum nylon filter into glass autovials. 3M Environmental Laboratory 3M Environmental Laboratory - Page 4ofs 001017 Page 2! 418-018:PAGE 1-395 3M Medical Department Study: T-6295.25 Analytical Report: FACT-TOX-169 ProtocolFACT-TOLX-R1N6-501.0180 S. AnaLyTicaL MeTHoos SETeSr-u8m-5Ex,t"raAcntaslyussiisnogfHPPLotCa-sEslieucmroPesrpfrlauyo/roMoacstsanSepseucltfroonamteetroyr"other Fluorochemicals in moAonnlaelccyhusalirasacrsteiropinesrt4if9co9r,omsfeaedlpebacyrttemidcoaunslitatrhoerliupnorgrioomcnahereymoificomnaolfrouersipPnrFgoOdHuSPct(LCCiyo-FnyEs7SsSMe0lSse-Mc)tSea.dnaflFryosorimse,axiasimnpfgallgeer,aperinmtaerdy afnuarltyhseirs.to produce ion 99 (FSO;-). The characteristic ion 99 is monitored for quantitative dMiisncorertimoondoiffitchaetiPoAnsLto the preparatory and analytical methods may be implemented at the 10. DATA QUALITYOBsECTIVES 10.1 TLhienecaoreiftfiycientof determination ()ofthe standard curve must be equal to or greater than 0.990 using L/x weighting. 10.2 `LTihmeiLtsOQofwQiulabnetietqauatliotno t(hLeOlGow)est acceptable standard in the calibration curve, dewfitihniendas3t0h%e olftowheestsextpaencdtaerddtchoanctienstbroattihon2.timesthematricblankandiscalculated 10.3 AQcucaleipttyacbonlteroPlrseacmipslieosnare required to mest + 25% precision, provided they are quantitated within the selected calibration range. 10.4 UIsfaecoofnfCiormnaftiorrmyamteotrhyodMeistuhsoedd,san amendment to ths protocol will be written 10.5 DPeFmOoSnisdterntaitfiicoatnioonfSwpielcibfeiscuibtstya,nteitact.ed by chromatograpkic retention time. (chaaprparcotxeriimsattieclpyr7o.d3ucmtiniuotnes()99,).by the characteristic primary ion (499) and the MdiisncorertimoondoiffitchaetiPoAnLs to the Data Quality"Objectives may be implemented at the 3M Environ3mMenEtnavlirLoanbmoernattaolrLyaboratory Pago sor 001018 Page 22 418-018:PAGE 1396 3M Medical Deparment Study: T-6295.25 Analytical Report: FACT-TOX-169 Protocol FACT-TOLXR-N1-8E901-0180 11. PSaUcBe-ACnOalNyTtRicAaClTSEeDrvAicNeAsL,YISncI.S(Tier Il Facility) will be performing the extractionofserum Lsapbeocriamteonrsyffoorraannaallyysseiss.. APlalceexAtnraalcytteidcsaalmSpelrevsicweisl,lIbnce.swhiiplpefdoltloowthaell3aMppElnicvaibrloenm3eMntal EAnnavliyrtoincmaelnItnacl. SLtaabnodraartdorOypSetraantdianrgdPrOopceerdautriensg.Procedures and the following Pace PPSSSS-:ADdCm-i0n5-01 QLuaabliNtoyteSbyosotkesm, Logbooks, and Phone Logs PPSSSS--OOPPSS--0012 RUsaewaDnadaMaintenanceofUitre-Turrax T25 Homogenizer PPSSSS--O0PPSS--0043 UHaszeaarnddouMsaiWnatsetneanDciseopofsaNl-Evap Analytical Evaporator PPSSSS--OOPPSS--0065 UUsseeoanfdCoMmapirnetsesnaendcGeaosfeNsAiNn OthpeuLraeboIrfaWtoartyer Purification System PPSSSS--O0PPSS--0087 LCalbeoarnaitnogrNyoCna-ldciuslpaotsiaobnlse Volumetric Pipettes PPSSSS--OOPPSS--1153 GUlsaesaswnadrMeaiClnetaennianngceofLab Refrigerators, Freezers, and Ovens PPSSSS--OOPPSS--3116 UUssee aanndd MMaaiinntteennaanncceeoofftShheakFeirssher Scientific Isotemp Freezer EPSTSS--O9P4S0-32 Operation, Maintenance and CalibrationofLaboratory Operation and MaintenanceofShakers and Vortex Mixers (3M SOP) PPSSSS--OMPTSR--3071 COapleirbartaitoino,noMfaiCnetretniafinecde,WeaingdhCtalSiebtration ofpH Meters and pH Electrodes PPSSSS--MMTTRR--0062 VCearliifbircaattiioononoffCCearltiibfriaetdiTohnoefmtohmeetEeprpse/nTdhoerrfmPoicpoeuttpolres PPSSSS--MMCT-R0-108 PVeurricfhiacsaitnigoonoffLaCabloirbartaotriyonSaupnpdlUiesseofAnalytical Balances PPSSSS-DARMC0-302 SDtatiistsicalpEovoaflAusractihioinvtoefMiDataetoraianls 12. STATISTICAL ANALYSIS . EStxaatimsptliceaslomfetthheodcsalwcuillatbieonlsimuisteedditno tthhee acnaalcluylsaetsiwoinollfbmeeianncsluadnedd sitnatnhdeaprdhadseeviraetpioornts.. 13. ARereppoorrtTofthe analyte results will bepreparedby 3M Environmental Laboratory. The report will include, but not be Limited to, the following, when applicable: 1133..12 NDaamteesaunpdonadwdhriecshsotfhethphafsaeciwliatsy pineirtfioartemdinagntdhceopmhpalseet.ed. 13.3 PArascttaitceemeStnatnodfacrdosm.pliance by the PAI addressing any exceptions to Good Laboratory 3M Environmental Laboratory SM Emironmental Laboratory Page Gots Page 23 001019 418-018:PAGE 1-307 3M Medical Department Study: T-6295.25 Analytical Report: FACT-TOX-169 ProtocolFACT-TOXL-R1N6-9E01-0180 13.4 aObmjeencdtmiveenstsanod ptrhoecoerdiugrineaslapshsatsaetepdroitnotchoel.approved phase protocol, including any 13.5 cIodenndtiittiyo,npsuorfitayd,misunaibsitlritaytiaonnd.the solubility ofthe reference standard under the 1133..67 AAddeessccrriippttiioonnoofftthhee smpeetchiomdesnuss.ed to condutcht tests). 13.8 oAfdtehsecrdiaptat.ionofanycircumstancesthatmayhave affected the quality or the integrity 13.9 pTehresonnanmeeloifntvohlevePdALinatnhde pthheasnea.mesofother scientists, professionals, and supervisory 13.90 dAatdae,sacrsiuptmimoanorfythanedtarnaanlsyfsoirsmaotftiohnes,ancaallyctuilcaatliocnhse,moirstorpyerdaattiao,nsanpderafsotramteedmeonntotfhtehe 13.11 cSountcilsutsciaolnmsedtrhaowdns fursoedm the analyses. to evaluate the datz,if applicable. 13.12 iTnhveolsviegdneidnatnhedpdhaatseed,rifeappoprltiscoafbleea.chofthe individual scientists or otherprofessionals 1133..1143TAhsetaltoceamteinotn wprheepraererdabwydatthaeaQnuadltihteypAhsassuerraenpcoerUtnairtetloistbiensgttohrededa.testhat study DinisrpeeccttoiroansndanMdanaadgietmsewnetr.e made and the datesofany findings reported to the Study 13.15 aIfcicteipstend,etcheecshtasnogameasrkwyeillcbeomrraeidnocrtethaedidfiootrinomonssfatonafaimneanldrmeentpaifstoseureirdthbtaysthbeeSetnudy aDimreencdtoerd,,Tthhee raemaesnodnasmfeoarttwhielalmcelenadrmleyaitde,ntainfdy wtihlelpbaertosifgtnheed: biynatlhereSptourtdythDaitreicstboeri.ng. 14. LocATIONOFRaw DATA, RECORDS, AND FINAL REPORT Ofraciigliintaatledaautdaitosrocftophieesstthuedryeodfu,riwniglitbseparvoagirleasbsleanatd3beMfoEraevaicrcoenpmtzannicaelofLatbhoerapthoarsyetroeport. bWehleonwtwhiellpbheasreetraeipnoerdtiins cthoempalrectheidv,eslolfo3riMgiEnanlvipraopnemrednattaa,l iLnacblourdaitonrgyt.hoAslelictoermrseslpiosntdeding. trparionceidnugrreesc,oredqsu,ipcamleinbtraptrioocnerdeucroersd,s,anidnsmterutmheondtsmwaiillntbeenarnetcaeinleodgsi,nstthaendaarrcdhiovpeesroatfitnhg.e 3M Environmental Laboratory. 14.1 Tahcecofrodlilnogwtiong3rMawEdaavitraoannmderaetcaolrLdasbwoirlaltboreyreSttaainndeadridnOtpheerasttiundgy Pfrooldceerdiunretsh.earchives 1144..11..12 AStpupdryovceodmepsrpootoncdoelnacned amendments 1144..11..43 RShaiwppdiangarecords. 1144..11..65 AEplpecrtorvoenidcficnoapliersoepfordtat(aoriginal signed copy) 14.2 Tthheeafroclhilvoewsinagccsourppdoirntgitnog3reMcoEradvsiwrionlmbeenrteatlaiLnaebdorsaetpoarryatSetlaynfdraormd tOhpeersattuidnygfolder in Procedures: 3M Environmental Laboratory 3M Environmental Laboratory Page Tors 001020 Page 24 3M Medical Department Study: T-6295.25 418-018:PAGE 1.398 Analytical Report: FACT-TOX-169 Protocol FACT-TOXL-R1N6-9E01-0180 14.21 14.2.2 CTarlaiibnriantgiornecroercdosrds 1744..22..34 SItnasntdraurmdenOtpmearianttinegaaPnrcoeceldougrses, Equipment Procedures, and Methods 15. DATA/SaMPLERETENTION mAlalinsteariansepdebcyi:mens remaining afer the analytical phase is completed will be seat to aad D3aMveCoErhproreastmeanToxicology 3StM. PCaeuln,teMrNBl5d5g14243.6.0C-148 TFealxe(p6h5o1n)e7(3675-14)775343-5070 16. PROTOCOL AMENDMENTSANDDEVIATIONS ofPSlttauhndenyepDdriorctehocactnooglreaasntndodtwthhieelplSrbpoeotnaostcotoral'cshweiRdleltporbeetsheieantftaihnteailvfepo.rroAmtomofceownlr.dimAteLtlnentchsaamwneiglneldsbmteeoncttohnsessiipgrdoentreoedcdbolayswptiahlretbe isnidginceadtebdyitnhethSetpuhdaysDeirreepcotrotr. aAnndyfoltehderwicthhanthgeesrawwildabtea.in the formofwritten deviations, 17.ATTACHMENTS 17.1 MAattetraiaclhSamfeetnyAt:Data Sheets (MSDS) for Reference Standard 2M Envir3onMmenEtnavlirLoanbmoerntaatloLrayboratory Page gars 001021 Page 25 3M Medical Deparment Study: T-629625 18. SIGNATURES FarsiY7:eCaseoBanV.[GPhoDtSpanos eprsenaine 418-018:PAGE 1-399 Analyte Report. FACT-TOX.169 PretFACTTCKERYEO10180 2/ Bi MDeaannaa sLaacrill]esl.SoutgyDlielcotr soDale A-- KristeJn. Hansen, Ph.D., Principal Analytical Investigator 1/21/01 Date HMEmionmanatortoy 53 ue EmirounenalJ LaLbaobroratory Pasnoers 001. 022 pa-ges 418-018:PAGE 1-400 3MMedicalDepartment Study: T-6295.25 Analytical Report: FLARCNT--ET0OIX--0116890 Record of Deviation T Tdentiication Study /BrgjesiNo, ~~ FACT-TOX-16, Lims#EOL-0I80, TT Tm Agusdls-0ls Deviation Type sor OMethod [JEquipment Procedure ~~ (Checkone) XProtocol [J Other: : DoFcAuCmTe-nTtONXu-m1b6e9r . Da02/e01/o01feceumsid TT Ti Description: RequiredProcedurefprocess: I Theprotocolstates thal 317specimenswil be receivedatthe Environmnial Laboratory. A2c3t5usaplePcriomceelnusrwseirpreosreessc:eivied he Enviroriental LTaaboratory. i Actions Taken: h oe ouch osamendmentisE sued,SOPrevision.ete) RecorBdyed TTT mpg - On A ae TV. ImpoanSctudty Project os/avln Noadvimpeactorntsheouetcomeof Gissndy. - ee EE ------ Ee far 2 res AuthorizeBdy (Study Digector /ProjectLead) - Wiconwio Z, ini uly Dah Decne, ak SDaateto 3M EnFvoimronm7e5n.t0al8Labortory (pad StyDecooreovijateondNo.5_ET_| $M Emironmental Laboratory 001023 Page 27 418-018:PAGE 1-401 3M Medical Department Study: T-6295.25 Analytical Repor: FACT-TOX-169 LRN-EOL0I80 Record of Deviation T Tdentiication SigFgACFT-oTOX-N16o5, Li#E0mL-01s80, Argus 418.018 Deviation Type OSOP [MethodOfEquipment Procedure | (Check one) OProtocol 0 Other: DoEcTiSm8en42Number Dae@2/o15f/e01s-c2u2m1/e0n0es | I." Description: R1)eSqeucitrieodn1Pr0o.c1e.d2urneldp1ro0c.e1ss.:2Preparebo wales blanks and tw mal bls fo cach study. 12) Section 11.1.4 Prepndasrpiekeonestacunrvedforaeachrstddy. | 5) Section 11.1.2Donotexact Tes than 0SLofmari. -- 4) Section 11.1.2 Ifmost sample volumes are less than 1.0 mL, extract standards with matrix A |Actual Procedure/process: 1)Si wate blanks and six methodBlankswere added due To ie arge numbofSeamrples. `2o)nFewoiurlexm tracteadna dcufravelsvwol elruempersepoOafreR-d tLhree.with initial and final volumes of0.5 mL and 3) Many samples were extracted with an inal Volume Tess an 0. ml. Refer to the afached S)aFmoprlemovsoltusme/aweimgh<t0p.s5helmetLfoeofrsinseirtaiaw,lavsoalvuamielaibnlfeo.rmHatoiwoenv.er, Grves w|enotrpreeparedwith an niolr final volumeunder 0.5 mL. oo I (such as amenTid.meAncttiisosnused,TaSkOePn:revision, etc) _ "This deviaifonwas wriien Recorded By | Date: Kelly Swanowt Kel) Duonadtm {o2n01 A2/p WV. Impact on Study Project 1&2) Additional OC isi improvementandwill otadversely fect Has ud.| l3e)sBstehcaanus0e.t5hmeLmveitlhobdiesfnloatggcehdariancttheerdiaztead.forvolumes <0.5 mL, samples with initial volumes 4)Thiscourse ofaction wastakenbecause tmhe etashmo!obeendcharacterized for extractions<0.5mL.Robustnessofthecurves will ot be adverselyaffected. _ CO ------ 3b_02(22/0, T`HExAvriamelnBayhl(SoahhoarrdayiDoiirezcteor d/ProjecLtead)~~~ DeviatiD on Re. ue FmE580 gles (ip StyDic oy Le 5ETTP) study Ouch Fos Osos lube (nwo dlollutrtinHo7 00 | 3M Environmental Laboratory 001024 Pee? 3MMedicalDepartmentStudy: T-6295.25 418-018:PAGE 1-402 Analytical Report: FALCRTN--TEODX1--106190 Record of Deviation 7. Identification 774 I see =| `Deviation Typ "Bor pe Ogun reds (Check one) 0Protocol `Other: mee P55 Dme@ofoememes BC, Ti. Description: RequiredProcedurelprocess: _ i SN | Pain Fo 3 7 alhizs uid OF F eintacs (Gaede tedie Cols AFi Te eth rps ante raise pers | A] A The ate A L Ce eB reer pl.FSppuenky F2a220]| S52: uf _somiih, 2 Z Are abn Lotsfeta | pf Jeesstl _ (sasu amencTdI.mehAncttiiossnused,TaSkOePn:revision. etc.) ttf otr eLALidbrrieesra,npT l BSeeDsicoelil2OAnNlyAIaEltlEotial LE- ap a | Recorded By 7 . oF Seat Lr TV. Tripachor Sludy Project Roadrioaapts otis "Date A-2D/ -- soredBy (Sy /DirPecrgeileadl bse | TT H Ernvirore mentpal LrabVoroesoTnfag Tlo"yAldr72s Tras airr DerviaetionpHb,ee l3. TOL 3M Environmental Laboratory 001025 Page"29 418-018:PAGE 1-403 3M Medical Department Study: T-6295.25 aM Medical Department Stuy: T-6295.25 Analytical Repor:: FLARCNT--ETOOIX--0116890 Analytical Report: F(ARCNT-TOX0.11601980 `Appendix C: Extraction and Analytical Methods his appendix includes the folowing methods: EElTeSc-t8r-o4s.p2r,aEyxitMraascstiSopneocftFroomreotcyh,em(1i5caplagCeos)mpounds from Serum for Analysis Using HPLCSETeSr-u8m-5E.x2t,raAcntaslyUssiisnogfHPPoLtCa-sEslieumctPoesrpfruaoryoMoacstsanSepsetcftornoamteetyo,r O(t11hepraFguecs)rochericals in 3M Environmental Laboratory 001026 Page 30 3M Medical Department Study: T-6295.25 : 418-018:PAGE 1-404 Analytical Report: FACT-TOX-169 LRN-E01-0180 3M ENVIRONMENTAL LABORATORY : MeTHOD `EXTRACTIONUSOIFNFGLHUPOLRCO-CEHLEEMCITCRAOLSPCROAMYP/OMUANSDSS SFPREOCMTSREORMUEMTRFYOR ANALYSIS Method Number: ETS-8-4.2 Adoption Date: 03/01/99 Effective Date: 2/2191 Approved By: pp pf Taoratory Manager Lt Ho Group Leader o2/f/ey Date oxpeises Dae - 10 Score AND APPLICATION 11 Scope: This method is for the extractionoffuorochemical compounds fom serum. 12 Applicable compounds: Fluorochemical surfactants or othr fliorinated compounds. 13 Matrices: Rabbit, at, bovine, monkey, and human serum of other fluidsa designated in 5FOwR m the validation report. LU a O2S 0 uuMaRvoFMEmOD 21 Ole Tisouinlsfpoupnraetirenfg(orPrmFeaOangSce)neto-rbasnoedtdhmemeretlthuhyoobrdoecrdh-eusmtiycrlalhsteuhrrefar(cotMcaBneEtds)u.ftrsoAfmonrseocrxnuumsp,cotiingogtphrereralgfuelonuitrdsoi,souaesduidneeg:da(n0 0 G0 Q @& trhe1em0osmavLmepdolfaenmadentpdhuattnhooelm,anohaleayntneie-tirroonegepdnaietvhiarspopouargrahttioatri0ou.n2endulimndtyno.yMlIoBnBaEcf.heerTxthuresaicMntgBisaEr3e-ceomxntLsrtapiclttausittsiecd in 52Word695 ETS842 Page 0115 $3 Environmental Laboratory Exacion ofFlacaehemicals fram Serum Page 31 001027 3M Medical Deparment Study: T-6295.25 418-018:PAGE 1-405 Analytical Report: FLARCNT--ETOOIX--0116890 rsyraingte ientosglaPssEOauSt,ovPiaElsG,S(,AppPlFiOcaStAioAn,oEftXhFiOsSmEe.tOhHod, tPoFsOvSeEnA.flMv5r5oc6h,eraincdaalssuwmaosgate \ 22 TShaensdeazsdam(psleee e3x.t0rDaectfsinaizteiaonnasl)y.zed following method ETS-3-5.2 or other appropriate method. 30 DerTions 31 PFOS: perfluorooctanesulfonate (anionofpotassium salt) CeFir$Oy 32 PFOSA: perfluorooctane sulfonylamide CoFinSO:NH: 33 34 EPFFOOSSAEA-:OHp:erf2l(uNo-reotohcytlapneersfuulofroonoycltaamniedosu(feotnhyalmaicdeot)a-tceiChyyFailcsoShoCluN(CH;CHy)CHO;; 35 CP4FFO7SSEOA::Np(eCrHfu:oCrHo;oc)tCaHn:eCsHul,fOoHnyl thylamide CiFnSO:N(CHiCH)H 3.6 37 M556: Sumoga tCesFsitainSdOarNd(THH)P(FCHO:SC:O1OHH-)1H- 2H-2H perfluorooctane s u lf o ni c acid 4401 WARHNeIalNtGhSaAndNsDaCfeAtUyTIwaOrNnSings 41.1 Use universal precautions, e sp eci al y l abo ra to ry coats, goggles, a nd g l o v e s when handlinganimal tissue, which may contain pathogens. 50 InTerrERENCES 51 There ae no interferences knownat tis time. 660.1EoTauchrceeepfmtoaelbllNoerw.ing equipment i used while performingthis method. Equivalent equipment is 61.1 Variex mixer, VWR, Vortex Genie 2 612 Cenifuge, Misra 1000 or [EC 6.13 Shaker, Eberbach or VWR 6.1.4 Nirogen evaporator, Organomation 615 Balance (01005) 0 71 GS lows uaoMamems 72 73 Eppendoorrf disposable pipetes, plastic or glass (or equivalent) Polypropylene bottle, capabl of holding 250 mL and | L (Nalgene or equivalend $1 Emironmenal Laborators ExeaionofFcekrehseamacls rom Serum Page2015 Page 32 001028 3M Medical Deparment Study: T-6295.25 418-018:PAGE 1-406 Analytical Report: FLARCNT--ET0OIX--0116890 74 Volumetric flasks, glass, type A 75 40 mL glass vials (1-CHEM or equivalent) . 7.6 Centrifuge tubes, polypropylene, 15 mL f 27 Labels 78 Bottl-top Dispenser ~ 3.010 10.0 mL or a 5-10 mL graduated pipette, glass 79 Syringes, capable of measuring 5 L 10 50 kL 710 Graduated pipettes 71 Syringes, disposable plasic, 3 ml. (B&D or equivalent) 7.2 Syringe filers, nylon, 0.2 ym, 25 mm 7.13 Timer 7.14 Crimp cap glass autovials and caps 7.15 Crimpers Note: Pwraitoerrt.o uRsiinnsgegslyarsisnwgaesreaamnidnbiomttulmeso, rf9insteim3estiwmietshwmietthhamneotlh,a3nolinusneds 3frtoimme3s sweiptahrate vials. 80 REAGENTSANDSTANDARDS sr 81 Reagent grade water, Mil-QP, NanopureIL or equivalent 82 Sodium hydroxide (NaOH), J.T Baker or equivalent 83 Tetrabutylammonium hydrogen sulfate(TBA), Kodak or equivalent 84 Sodium carbonate (Ne;COy). J.T. Baker or equivalent 85 Sodium bicarbonate (NaHCO), IT. Baker or equivalent 86 Methyh-T-Butyl Ether, Omnisolv, lass distled orHPLC grade 87 Methanol, Omnisolv, glass disiledorHPLC grade 88 Scrumor blood, frozen from supplier 89 Fluorochemical standards 89.1 KPFOS (POS) (3M Specialty Chemical Division), molecular weight = 538 89.2 PFOSA (3M Specialty Chemical Divison), molecular weight = 499 $93 PROSAAYH (PFOSAA) GM Spay Chemical Division). molecular weight = 8.9.4 EFOSE-OH (3M Specialty Chemical Division), molecular weight = 570 89.5 PFOSEA (3M Specialty Chemical Divison), molecular weight = 527 8.9.6 MSS6 (3M Specialty Chemical Division), molecular weight = S57 89.7 SCuurFrio;gSaOtyeHs,ta[nTdHaPrdF:OS4]-)H,, pmeorlfelcuuolaorocwteaingehtsu=lf4o2ni8c acid (1-H,1-H, 2-H, 2-H 8.9.8 Other fluorochemicals, as sppropriate 331 Environmental Laboratory ExtractionofREuTcxSae8h4em2ials rom Serum Page30f1s 001029 Page 33 Me tiepumeSn: T19535 - Amica Repo: FACTTO%16 418-018:PAGE 1-407 LRN-E01-0180 "0 Reagnti pErpasen ion lfhcioves th bcd ne, snd, orga * 8.0.1 1100N3 sodium nsoOnE i. E hydroxide (NaOF): Weigh `approximately 200 g ae dav. NaOH. Pour Serinto a 8.10.2 1103 s 1LN saodime um hoydronxm ide((NOaOa THI):oBtDiln uAtle 10avONa(NTaABnOAH)sa1rW:10.ooTrhMtepsaasouorvene10sm0sLtoo1eef605 te BopEe 40e3mi 1t aBctLsopeEroA ihhokrotsOiSma=er0. aAds ptr 8.10.4 pp eaC ean to oe. e wi 0S.p2p5roMvimsaotdeiluym2c6a.r5bgonoaftse/osdoiduimucm|abribcoanrabtoena(tNe&b;uCfOfye)r (aNnda,2C1O.0YgNaoHfCsOoyd)iu:m,Weigh 11 SSiamdamTB mereperep7oa0rsi5of fsnaand oo eo snsakee poTpsR,SMOwoOokFCOoRrAd, A113 egeh alvEFoEoarFsE1R0iRmEngOPshP,OCSrto + 00akBvaoreLosTrdoenad fc SIT ws ns 1E1E.8 `moleculwair. KPFOS (538) ms te iDenesosnoiinheol.ifn mefrc Jason) sittigossparodsianly Of08 nL (mgginamnsees)) im rin Eeroas m sen ass 8.11.6 Dilute working standard | with methanolfor aworking standar2d solution of approx. 5.0 pg/mL. 001030 418-018:PAGE 1-408 (apes) 'SOug ImLx10mL) oui S(oae zoe) oosonnins 8.12 i D amit ereO ne t bnrop sotk pm RrANcI 0 Surrogate THPFOS stock standard preparation 5 PE ress ogeusvor filgmtT. iotscps ry y ot --A -- I , 108 oe vecox intoe ne em A _ Neo EHtaoEen lstoasisa rs meri SS n R enhpS E t pSLirsteorhCkEefse, Rmasu Sm-- n -- e -- p ESmrutei sigr sJpoeinre tey yea taapmoes, 3M Environmental Laboratory mtnEmsms --_-- 001031 Page 35 3M Medical Deparment Study: T-6295.25 418-018:PAGE 1-409 Analytical Report: FACT-TOX-169 LRN-E01-0180 10.1:3.3 Scounrtrionguaitnegmcaatlriibrxactiuorn vveer--iflifacatsiuornrosgaamtpelemsa:trix is used for the curve and : &) prepare two (2) matrix blanks using the surrogate matrix. b) Amlastoi,xprseppiakree/maatmratxrsipxibkeladnukplwiictahteeaacthonseet loefvemla)tursiixnsgpaikceosm(maersctiailslay available matrixofthe samespeciesas the study animals. 102 Matrix spikes 10.2.1 Study Control Matrix Curve No matrix spikes are prepared. 10.2.2 Commercially obtained matrix curve (same specics) No matrix spikes are prepared. 10.2.3 Surrogate matrix curve: Mstautdryixansipmiaklesaanrdeanescuersrsoagratyiefmmaattrriixxisiunsoetd afvoaritlhaebecuirnvteheansdamCeCsVpescaiemsplaesst(hee.8.. rtoabmbeitassuerraabmlaeylebveeulsoefde(n0dgoegneenroautes satnaanldytaerdincutrhevemsofnokreaymSoenrak)e.yPsreerpaasrteudayn,ddue tahnealeyxzteramcattiroinxfsopritkaeargnetdmaanlalryitxes.spike duplicate samples o verify the accuracy of 10.2.4 Pcornecpeanrteractaicohn)MuSsianngdasMaSmDplaet cthwoose(n2b)yltevheelsa(nualsyusatl,ltyypailcoawllayndsemraifd-rroanmgae.control group animal received with each sample set 10.2.4. `Imfatrhreirxesipsikneostussuiffnigciceonmtmseerrcaiaavlaliylaabvlaelfabrloemmtahtercioxntfrroolmgtrhoeusp,amperespapreec.ies 35 the study animal. 10.25 Pperrep2a0resaomnpelemsa,trwiixthspimkeinaindmumamtroif2x smpaitkreidxupslpiickaetsepaetrclaecvehllpeevrelbalticshte.d i1nf1a0b.a2t4ch iTnocwl,udoershmigohreratnhgaenl2ev0elss,amples, additional spikes may be srepared at the same, 10.26Iaftmaoprpreoxtihmaant2el5y%o2f-StthiemseasmtphleesexapreecSteLdOLQO,Qt.wo matrix spikes should be prepared 10.2.7 1afdtdhiteiomnaaljmaotrroiifxttshpyeikseasmsphloeusldabreapereorpaabroevdetothaepphriogxhirmaarteeosfatmhpleeccuornvcee,ntrations. 103 Continuing calibration verifications (CCVs) 10.3.1 Pverreipfairceatcioonntdiunruiinnggacnaalliybsriast.iPonrevpearrieficaantdioannsaalmyzpeleCsCfVorsifnesrtreuvmeernytasstsaabiylrituyn, regardless of the matrix type usetdo prepare the standard curve. 10.3.2 pPrreeppaarree tehaechinctoinalticnuurivneg(cca.,liberiatthieornthveerisfitcuadtyiocnonftrrooml tmhaetrsiax,mecommamterirxciuasledmattorix of same species, or surrogate marr) SM Emronmental Laborators ExracionofFlaErToSeh8e4m2icas fom Serum Pageants 001032 Page 36 3M Medical Deparment Study: T-6295.25 418-018:PAGE 1-410 Analytical Report: FACT-TOX-169 LRN-E01-0180 10.3.3 Tcahleiberxatpieocntecudrcvoen:cteynptircaaltliyo,nstoheftlhoew tCoCmiVd-wriallngaellofwitthheincutrhvee.range of the initial < 10.34 Pcroenpcaernet,raattioan,mipneirmgurmo,uptwoof c1o0nstaimnpuliensg.caFloibrractxiaomnpvleer,iifficaatsioanmsp,leeascehta=t 34d,iefifegrhetnt (c8o)nccehnetcrkastiaorne prepared; four (4) at a low range and four (4) at a mid-range 10.3.5 Amdiddiotrohniaglhcroantnigneucionngcceanltirbartaitoino.n verifications may be included a the same, low, 111101 CAPLrIeBpRarAeTImaOtNrAiNxDcSalTiAbNraDtAiRonDIsZtaAnTdIaOrNds ILL Tarvaainlsafbelre |semraLisofusaepdp,ropprreipaatreestewroummattoriax1b5lmainksc,enutsrinigfutghee tvuoble.umIefocfomsmeerracially available for most study animals. 1.1.1.1 Daevapielnbdlie,ng uspurornogsattuedymagiorailxs morayifbaenauysteed-ffroeregceonmarmaetricoinaolfstehrea cisalniobtration sattansdtaurddi.esFiofrqueaxnatmiptlaet,iornaobfbiexsterreamemly blaoewusyleevdelassoasfutrheroagnaaltyetemaitrriexqufiorred 11.1.2 1Vomlousmtessaeqmupalletvootlhuemessaamrpelleevsoslutmheasn.1.D0omLr,otexetxrtarcatctstleasnsdatrhdasn w0i.t5h0mmaLtroifx matrix. Record each sample volume on the extraction sheet. 11.1.3 Wsehrialebeptrweepearnianlgiqauottost.alof thirteen aliquots in 15-mL cenirifuge tubes, mix or shake 11.1.4 TTywpioca1l-lymLusaelitqhueotsst,aonrdaortdhecronacpepnrtorpartiiaotnesvaonldumsepi,ksinegrvaemao5ucnutrsveitmeadtriiaxTbaabrlkes.| at tthweoenmdatorfitxhbilsasnekcst,iaonndttowsopimkeetohnoedsbtlaanndkasr.d curve, for a total of nine standards, 11.15RreafnegerstaonvdaltihdeatLiionneraerpCoarltibErTaSt-i8on-4R.a0ng&eE(TLSC-R8)-5f.o0r-cVa-l1i,brawthiiocnhculirsvtsesthe working 11.16 SsteaendSaercdtsi.on 13.0 to calculate actual concenisaions ofPFOS in calibration 11.2 Tsuorreoagcahtestwaonrdkaridn,gbsltaannkd,acrodnttoinaucihnigevceheackc,onasntdanstacmopnlceenatdrdatainonaphpartopfralilascwiatmhoinunttheof cCaolnisbtraanttiocnocnucrenvterraatinogneoifn2a.ll5sanmgp/lmeLs~a1t0a0p0prnogx/immLa.teUlsyua5l0l0y,nsga/mmpLleosr aortehesrpickoendcfeonrtraation as determined by the analyst. 113 Etoxtersatcatblsipsihkeeadcmhaitnriitxalstcaunrdvaerdosnftohlelmoawisnsgs1p2e.c6t-r1om2e.t1e6ro.fthismethod. Use these standards $MM16EnvironmentalAl LabLoaraboratory Extraction of FEaTccSac8h4em2icas fom Seu Page 7of15 001033 Pag56e 37 3M Medical Deparment Std: 1-6295.25 418-018:PAGE 1-411 Analytical Repors: FLARCNTE-OT1O-X0.118609 Approximatespiking aTambl1efoorstuandanrdstand spikes * Waoprkpirnog. scodnsaUsing 1.0 | A mLofmatrix ne imnmeanteos r [0Stmm--T--% h--50T0oa5onpemem [50pm[5s omspm [[0So0oppemm[15 0 ooass0opmmm [5C0-- C 0s0m0mmwm 1 [2 105Timoros0mnm ]| 120 Proceoume 12.1 122 LOabbaenlf1romzeLn spaomlpylpersopaynldenselocewnt0riftuhgaewuaberowoitmhetmhpesrtuadtyuuemobreirn,kseawmpalremIDw,adratee and Sanoaclyusmteinniitniaglsh. eSreeemaaittnaicnhgesdiwposrksheet (Attachment A or similar worksheet) for 12:3 V1SoTrtexpomlipxrfeopry1i5esnesccoondmse,fhgeentbanes 1.0 moLot.her apprise volume f the 12.4 12:5 RoReecrtourkmdsuthn.eusineidtaslamvpolleusmteoonrtheeeaxttrzearcteixeotnrawcortrikonshmeeotun(tAtsahcahvmeenbteeAn oresmiomveida.r 12.6 SSpiikne dall 3samdpelsees,rvbeldan1ks1a2n.d standards, that are ready for extraction with surrogate 12.7 SpaprsieckpraeircbeaemdchianciTlbLeS,atooprnTisfaitbnaleneckdea1srdienmhasatrnsdsewcicotonhnntihfenoagptpereaoplcriuirratatotenimovonucinutrsovfssttainndatrsd.asAlso 125 SVopriteexsmoinx t1h5eesstaonnddasrd curve samples, mais spk samples, ad continuing calfason 129 12.10 TSChoeenacbckohtnsotaeemnpsalutere,eart.dhed0.1m5 LMT0.B5AMrTeaBgAenatnisda2tmpLH.o1f0.0I2f5oMts, aodjumst accacsobrdoinntgelys.odivm 12.11 bUsaineg arn,bottle top dispenser or 5-10 mL graduated glass pipette, add 5 mL methyltert- 12.12 Cap eschsampleand put on the shakerat setting of 00 pmfor20 minutes, SME wal Laborator Exocf PuEarrashscaoznies boom Sneu Peters 001034 Page38 3M Medical Department Study: T-6295.25 413-018:PAGE 1412 Analytical Report: FACT-TOX-169 LRN-EOI-0180 12.13 Centrifuge for 20 to 25 minutes at a settingof 3500 rpm or until layers are well separated. 12.14. Label afresh 15mL centrifuge tube with the same information asin 12.5. 12.15 Remove 4.0mLof the organic (top) layer o this clean 15 mL centrifuge tube. * 1216 Phouutrsc,ach sample on the analytical nitrogen evaporator until ry, approximately 1 to 2 12:17 Add 1.0mLof methanol tocach centrifuge tube using a graduated pipette. 12.18 Vortex mix for 30 seconds, or longerifneeded. 12.19. Lnaubmeblear,1a.n5immaLl gnluamsbsearutaovnidalge(nodrerl,ows-avmoplluemteiamuetpooviina,l mwahterinx,neicneaslsaSroyl)vewnitt,hextthreascttuiodny date, and analyst() performing the extraction. 12.20 ASttetpac1h2.21285tommth.s0s.y2ripngme.nyFliolntemreisnthoftihlteerlatb0.eale3dmaLutosvyirailnge and transfer the sample from 12.21 Cap and store extracts a room temperature or at approximatel4y C until analysis. 12.22 Cthoempstluedtyebtihnedeerx.traction worksheet (Attachment A or similar worksheet) and include in 3.0 DATA ANALYSIS AND CALCULATIONS 13.1 Calculations 13.1.1 CcaallicburlaattieonacsttuaanldacrodnsceunstirnagtitohnesfoofllPoFwOinSg,eoqruaottihoenr:applicable fluorochemical, in --_LmaFko+fmLosfuxscomnoctaentivda+ionnfil(myaraiemvLl)ure(mL) |Fin!al concentrasHonistmiser $105 imma 1M 144.01 eThet methow d deto ectiono limitP (VDLe )isanR alyteF and mo atrixR specifM ic. ReA fer toNMDLcrepoE rt ftohre sdpiesccirfeitcioMnDofLtahendPAlLim,itMofDqLuamntaiytantoitonbe(LdeOfQi)nedvaflouresso(smeecsAttudtiaesc.hments B and ). At 142 Tthheeqfuoalliltoywoifngthquealeixttyraccotnitornolansdamapnlaleyssiasr.e extracted with each batch of samples to evaluate. 14.2.1 Method blanks and matrix blanks. 14.22Idfupsluircraotgeatseammpaltersixi(0suvesreifdyfeoxrtrcaucrtvieonanefdfiQcCie,ncmya.trix spike and matrix spike 14.2.3 Cinointtailncuailnibgrcaatliiobnractuirovne.check samples to determine the continued accuracy of the: 143 Refer to section 14 ofETS-8-5.2 for method performance criteria. 3M Environmental Laboratory. Estacion of FEluTroSc8he4mi2cals fom Serum Page9of1s 001035 Page 39 3M Medical Department Study: T-6295.25 418-018:PAGE 1413 Analytical Report: FACT-TOX-169 LRN-E01-0180 15.0 POLLUTION PREVENTION AND WASTE MANAGEMENT ` 15.1 Dpriosppeorsemoefthsoadmsplaendwabsytp,lafclianmgumeaabclhe isnoltvheeinrtdweassitgenaatnedd uwsaesdteglcaosnstapiipneetrte waste using 160 Recorps 16.1 iCnocmlpuldeeite tthhee setxturdaycbtiinondewrorksheet atached to this method (oar similar worksheet), and 170 ATTACHMENTS 17.1 `AAutatcahchmmeenntt AA,) Extraction worksheet (a similar worksheet may be substituted for 17.2 Autachment B, MDL/LOQ values and summary 17:3 sAuubasctihtmuetend:fCor, AltontaPcahimreSnttanCd)ard Curves worksheet (a similar worksheet may be 18.0 REFERENCES --_-- 18.1 The validation report associated with this methodisETS-8-4.0 & 5.0-V-1. 18.2 HFPALCCT--EMl-e3c.t1r,os"pArnaaylyMsaissosfSSpeecrturmomoertOrtyh"er Fluid Extracts for Fizorochemicals using 183 `ESTeSr-u8m-5E.x2t,ra"cAtnsalUyssiinsgoHfPPLoCt-aEslseicutmroPseprfrlauyo/rMoaoscstaSnpeesucltfroonmaetteryor" Other Fluorochermicals in 190 ArEcEDDocSMENTS 0 19.1 SETeSr-u8m-5E.x2t,rac"tAsnaUlsyisnigsoHfPLPCo-tEalsesciturmoPseprrfalyu/oMroaoscstaSnpeescutlrfoomreatteryo"r Other Fluorochemicals in 200 Revisions _ ---- Revision Number ReasonFor Revision Revision Date 1 SSecetcioonn11222.113 AChdanegdehde sianckle sspaem.plesrs stroom temper, owo2ss 2 SSeecoonn L2I.,172iEallivonlumepios1.0smL.nftroampaefdusfmosroneilaivoonlsess es tan 0ml 2299.3 AAddad HK0iPPFROOSSAA s1p02i1k0i:n2hge4,c1u4rv2e:,2cAhaGnSgienspfiokersm0aetibvo2nt0ewsirlneyssmog mati, carycnvol msi od 11.013 CAdldteydwpoardpienrgobfoct coonsctlaiassge,cuheicks nd ok ingcomme aly availble In ger, civln: make bole emsasbypeeciificfo cxupmentsuplic. Subsitewater or MiQl Nalgeneo $M Emironmental Laboratory Exacion ofFuEcrTasch8e4m2icas from Serum Page 100115 001036 Fe 418-018:PAGE 1-414 3M Medical DeparmentSuds: T-6295.25 Aralticl Repo: FACT-TO-169 Forrn SSeonrto|ExtaraFcctMitoTnsWo|rkshemFetoeETsS-|8-|4.2aRoE Conv=e LRN-E01-0180 --S-ei Box#___|e WkDay______ Hg/ml -- ug/ml. ug/ml |e i r r rrr merry fr--T ------ T --T -- TT ---- eri e---- ee -- TT r Tr rr t em mrrmmeree ereeemeeelo eer rrr eefeeeeee} rT rT TT rT TTT rr Tr rr emt eee TT ----T-- EE freee]etm SPS rT ese prem fore) Sy --_ FrTTT| rr rrr11 1 tr tt tr -- ---- _-- -- )--|r TT rr Tt Tr tf Tr TT E EE Eer E L kl EE Pipett3emlof 0.25 Na;COV0.25M NaHCO, buffer. EE T me ------n -- e TSe --] -- [DiensciooeneSmlofmetbvbebuneher J ET ton | I] EE ---------- DEE E hmime g E Vm owmLea Te mLLam ma e T SMEnsirorumerntlpLaBboerasto Verto mss -- 001037 Paget 3M Medical Department Study: T-6295.25 418-018:PAGE 1415 Analytical Report: FACT-TOX-169 LRN-E01-0180 MDL/LOQ values for rabbit serum Compound|(nMgD/mLL|)| (nLgO/mQL)|| ALipnperaorxiCmalaitberactoinocnenRtarnatgieon(sLtCoRb)e used for preparing : theStandard Calibration Curve S ng/mL1000 ng/mL S ng/mL1000n; [PF|3O46S |A 20A 5 |S S ng/mL-1000 ng/mL ng/mL1000 ng/mL [MsS6 | 603 | 192 | ng/ml-1000 ng/mL. ['MDPLILFOQOvaluSe5s i7E n a1t.A|bov_in1e,8_to2n|key. |aSnndhguimmla-n1s0e0r0umn.ga/nmdLmonkey plasmawere ot Satsially cdeutrevremsinteodd.etTeromvinceuerqvueisvailnecnacceh. oRfetshpeosnesmeastriinctehsewrae,rbeoxvtirnaec,temdorainedya,naalnydzhedumwaitnhwtehreeaebqbuiitvasleernutm(0 the rabbit responses, therefore, thee MDL and LOG will be the same values as determined in rabbit serum. Please see LOQ Summary and MDL study in ETS-84.0 & 5.0-V-1 for further information. Appendix B: MDLILOQ Values andESxuumsmcairoynofFucErToSc-he8m4i2cals from Serum 3M Environmental Laboratory Page 120115 001038 Page 42 3M Medical Department Study: T-6295.25 418-018:PAGE 1416 Analytical Report: FACT-TOX-169 LRN-E01-0150 [rites |mm|wen |ww|ann] Compound: PFOPSrpuedrange|LCRfrom RabbicSerum| ofsandards | curve | % RReacnogveery . og) | (opm) [o rxe |o m|r n nom|e m e |s ow| Compound:PFOPSreAparedrange|LCR from RabbicSerum| ofsandards | curve | %RRecoopreery|| RRaSngDe ) incor[wore| noe|on|or| [[roxme[|oomrm [[wwosm||voion|wssmo]| Compound: PFOPSrAepAared range| RabbicSeum| of sandards | LCcRurfvreom | % RReacgoveery|| RFaSngDe Cogn) ng/ml) [[Aincee|amo|| yreern||wr]| SMEmironmAepnpteanldi"xLBa:bMoDrLatIoLrOyQ ValuessnEdxSvraucmiroyno_fFsETrSo.8e4h2emriamcaSleus Page 1301s 001039 Page"43 418-018:PAGE 1417 vS om]S | ES i (ng/mL) (ng/mL) | [ic m riooodrn | r=loodr wen |e| soeom]m z| zrTEo Eg ices [mvs [re me | os sos----_ EE EgEe es 3M Medical Department Study: T-6295.25 418-018:PAGE 1-418 Analytical Report: FLARCNT--ETDOLX0-115609 APnraleypsdtast)es: Analye(s): EXAMPLE Ton Pair StanFdiSantrauddlysCnouurmlbveevars:ned-nTFNtl:uids Blank fuidideatier: {Font rms ver MSettuhdoydAineivmiasiloMna:te: `TFaCrmgietxasntadlayptep(rso)x:. 0.500 pr: FFSCCummiirxxsrsttddoatadpgpapprparopoxrtx.o.xe05...00010pp0ppmp::or: {Reged the stands nd 4 prope the os extacusd GOs. AScFtouOanSleconcSFenFwtOreSanAtionsToSFfwOseStnaAenAdardESsWoiOnmtSheEeFCPSmRieOxSoiEnnAmethSanuMoselse.n|| AAmNi FiAWl [sopsloT 05w0pmT aug5ml Tawpsm Tbsa Tos pThooelon tnorls [[0S50000 Tossoor7T|s05;32T|s0osoir |ossaartT|s05o01 | o00s20 1.025 [500W--% | 532 |soi_| sa so| ooo | 101s [C00 Bor serag gprgyow Bu| ooo 1.025 [[0so0o A @ sZ or Xs SofAWSSE KBIoHolyIKNSodT| ooooois0 r1.o0r1s0 [CsooeoT7osronT T ss3a2T T soT i TH sar10[o0o015 t1o.0s20s] CFamaPlirccousmlcatedPFcrFoOoSbnAeceFPnRplOtiSAromMfasttFBaiponOodirSaonrEiwdssiiPFnrFatOalhSeoEtssAeirayFmEalvtsarlicx:iReSatbiuhbimeitwo AAiTed Cees [oreTos | joa |om | 993 | loz| [TasgiT7263 248 | 2524 258 | Surrops [[ToonssTaHs koNZp sMauisFTo FooSkitRmr ITHoy0QLo BS l|Finnaglcmoinc" aa W 29/8 FF8BIRoy Qos,| soo [msTee Tom on [Roe 1 766 | CoreTooTowToo 1 993 | torn | rr ea Validatedranges - approximateconcentrations = | > 2 ni [SemTT pFOS PFOSA_ PFOSAA___EIFOSE-OR _ PFOSEA MSS6. [Bowne|Estimatesonly. Usevalfourreabbsi [RatEstimatesonly. Usevalfourraebbsit {MoHon&maPknlaesmya|Esumatesonly.Usevalfour reabbsit. 3 EnvirohnmemntaleLCa:bLooratPoireySanta CurEvreasctionofuEcrksaasczhefommiSrcalm so1022 Page 150015Page 45 3M Medical Department Study: T-6295.25 - 418-018:PAGE 1-419 Analytical Report: FACT-TOX-169 LRN-E01-0180 3E 3MM EN NVIV RONMI ENTAR L LAO BORN ATORM YY E~ N~ T~ AL : METHOD ANALYSISOFPOTASSIUM PERFLUOROOCTANESULFONATE OR OTHER FLUOROCHEMICALS IN SERUM EXTRACTS USING HPLC-ELECTROSPRAY/MASS SPECTROMETRY Method Number: ETS-8-5.2 `Adoption Date: 03/01/99 Author: Lisa Clemen, Kris Hansen Approved By: WES Le Laboratory Manager Li fe Group Leader Revision Date: 52] / [01 of ly Due oz/eife) Date T[echSnicWal RevLieSwera (oe OLDao te lf 52s=h1h01a m% 8 10 scomamarucaTion 11 iScnogpe:HPTLhiCscmeectrhoosdprdaeyscirmiabsess tshpe eanoalmyseirs .of serum extracts for uorocherical surfactants g . 1.2 Applicable other ioniza Co ble mpounds: Fluorochermical compounds. surfactants o r o th e r f lv orn at ed c ompounds, or {0 & 1.3 vMaaltirdiacteiosn:reRpaobrbti, rat, bovine, monkey. and human ser, or othr fidsadesignated in the 3 = Word695 Ansysof SerEuTmS-E8r-5i.c2 Using ESIMS Page lof 11 3M Environmental Laboratory Page 46 001042 3M Medical Deparment Study: T-6295.25 : 418-018:PAGE 1-420 Analytical Repor: FACT-TOX-169 LRN-E01-0180 20 SouvaRyor Merrion 21 peArlftohromugahncseupbpaosretdedmbeythaodva.liCdaatrieonlftorenmodsotncsohmomuolndlbye psaeddtmoatmriaceis,dsOCoss8there is great : CStvhiaramrariiaalccbattirleeisrdtiyyssrttiionecmmsoearfs5aa.earpTpuaphrmritosoipcrmruieolattatrhheeo,urdoTTrdhioeesedch,areinmubaesisilanltygh,HessPapunLacelChryseafilsotocrhferfmlopbuseyooprmrorocoamhsyekemsotisnaciassglepsse+uusarilfnoaogcnntessaensotysn,(PROS) {r0iounr,bae=ve49y9.thAdedintitonyalloy,fscamopmlpeosumnadyybedaeencaklnyg dwaiunghgtercoanndofmtaecepsepnsecies 20 Denno 31 quaAdtrmuopsoplheesryisctePmrsesaslulorwe fIoornivzaartiioouns M(AePtDh)o:dTshoef nMiizcartoimoanssbyQuwaitrnogIfvanadnUsltsimuarweisle iApnrtotmbhaeesss,pe hatenercdhiinnPitrqeeursefssaucoerese.ccuhTrehsmeaisceaAliTnlOcilSzuPdaeHtbiEuoRtn aI(rEeASPnuo)Rt,.lTi(1hm6. eitremdomtsooto:rnaElye.rctcre3o.svparTachyueIooo,nniizaattiioonn(pErSoIe)s,ss 32 hpreessEselurecech,tarwrohgseepdrreadbryyoIpilooenntisszairteisoopnlru(otEidoSun,ceaEdrSbDry:ahnaesmoepmtpehlidocdattoiftohineonogifza4atpriohonnepgevrlfseortcmryecdeclahtairapt.emsoscpheorisc 33 aQ(utMaSodM/i(aMunspSozs)l):SepamTenahcdstessruAosbmPseeIeetqQrcuuyeia,nvttMtldryaeotsdeIsecTtlSoearptnseed.cdUt.lIroiAommnesaitanteegrrlispe(leeMlMeqSScu)tma,ivdaTerlyuaypbndoedileseecmmsrpymMlsitoaneysamesseddSafprobeeyceoPtqnrueoidsmpeepoettdeecrwhciattrhoger a Series (MS/MS) formore specific Fagrentaton nformaron. 34 pquraodbCreouinpvooelrnetthsioyogsnotanelamlsvs(.poZtsshtp1cr9oa9ny8e)pswrpoeirblteeari.nat"eZIr-nfsatpchre:ayc"oTmhcveoenanfteoorsnm:dat]miocodonen.lfsoTrhomfeaMtsiipcornraoymeamsatsiemtedidp.lferom a mcdaciicrnoettecneaa,tnctTehhearocuognthehetahspeaermcteou.rneiH,goufwreeavteaprn,EiSZsnsegprrtahyrnocuogmhtpho&n(seonhrtusoouadsndpofcaootpnhvewearnytoiinontn.sh]cccoooummnpmtae,sreannsd are. CnootmpcatoimblpeawtihwSitohmeanoethaenrotZhesrp,rabaytynsliysw,ihieS)Fr ystems (1. Z.spay componenatse 35 4Q0uvaeMtrarsoisosInTsLi.ypnAxllSqovufeatrdswriauorpneos:laeSrsyysssittmeeimmlsr.s.ofCFtuowrrarremenotdrleeysMidgaensaesldLsfysonrekththeheessmWpiaenicdsio]owpsspeer5ca5itfiiaocnnd1oWftithnheedsoewsNT instrument (Micromass Quatro I or lima ile quadrupole MastLym of Masiyn NT User's Guide). 40 WARNINGS AND CauTIONS 41 Health and Safety Warnings: e-- r -------- 4.11 eUmspelocayusti3onvowkiatghethoef avoplptraogxeicmaabclleyfSo0r0t0heVoplrosb.e. When engaged, he probe word695 3MEnvironmentaell Laboratory ArsyisofEScrusm Esxo Using ESAS Pae2orn 001043 Page# 47 3M Medical Department Study: T-6295.25 : 418-018:PAGE 1421 Analytical Report: FACT-TOX-169 LRN-E01-0180 4.1.2 Wanhdecnlohtahnindgl,ing samples or solvents wear appropriate protective gloves, eyewear, 42 Cautions: . 42.1 D1othneotbaocpkerparteesssuorleveenxtcepeudmsp4s0a0bboavre,ctahpeaHciPtyLoCf4wi0ll0bnaiirat(e58a0u0topmsai)tibcacskhuptrdeoswsunr.e. 42:2 Do not run solvent pumps to dryness. 5.0 INTERFERENCES e eee e e 51 TStoormaigneiomrizaenyinptaerrtfeorfenicnesstrwuhmeenntaantailoynztihnagtscaommpleess,inTceofnltoanctshwoiutkhlhneotsbaemupsleedofroerxtsraamctp.le 60 6.1 EQuMENT Equipment listed belowmaybe modifiedinorder to optimize the system. Document any modifications in the raw data as method deviations. 6.1.1 MwiitchroamnaeslsecQturoastprroayIiToonrizUalttioinmasoturricpel.e quadrupole Mass Spectrometer equipped 6.1.2 cHoPm1p1a0rt0moerntA,gialnendtaluotwospaumlpsleersolvent pumping system, solvent degasser, column 7.0 SUPPANLDIMAETESRIALS c---- 7.1 Supplies 7.0.1 High purity grade nitrogen gas regulated to approximately 100 psi (House ai or nitrogen system) 7.1.2 iHnPtLheCraanwaldyattiac.al column, specifics to be determined by the analyst and documented 7.13 Capped autovials and capped 15mLcentrifuge tubes 80 REAGENTSANDSTAMDARDS 81 Reagents 8.11 Methanol, HPLC grade or equivalent 8.1.2 eMqiulivia-lQenTMt,waatnedr,maalyl wbaeteprrouvsieddedinbythiasMmieltlh-oQdTsOhoCulPdlubsesMylstle-mQoTMr owtahteerrvoerndor 8.13 Ammonium acetate, reagent grade or equivalent 82 Standards 8.2.1 Tpyrpeipcaarleldydtuwroinmgetthheoedxtbrlaacntkiso,ntpwroocmeadturriex.blSaencksE,TaSn-d8-e4i.g2h.teen marx standards are 3M Environmental Laboratory Ansys of SerEuTmSEx8t5ra2ck Using ESMS Page sof 001044 Page 48 3M Medical Department Study: T-6295.25 418-018:PAGE 1-422 Analytical Report: FACT-TOX-169 LRN-EO1-0180 9.0 SAMPLE HANDLING. 9.1 Farreesshtomraetdriixn csaptpead nauatdroveaiparlrespodarrsceadpwpietdh1e5acmhLancaelnystirsi,fugEexttruabcetseudntsitlaanndaalrydssisa.nd samples 92 aIfpparnaolxyismiastweillylb4e Cde,loafyeadt,reoxotrmactteemdpesrtaatnudraer,dsunatinldasnaamlypsliessccaannbbeepreerffroirgemreadt.ed at 10.0 QuaLITY ConTROL 10.1 Solvent Blanks, Method Blanks and Matrix Blanks 10.1.1 S`oonlcveendturbilnagnktsh,e cmoeutrhsoedofbtlahneksstaunddymtaotrdiextebrlmainnkesifarceonptraempienraedtiaonndoacncaulryrzeedddautrlienagst sample prep. 10.1.2 Analyze at least one solvent blank prior to cach calibration curve. 10.1.3 eMxattrraictxsb.lanks should be analyzed with each sample list that includes undiluted 102 Matrix Spikes 10.2.1 sIefrcau,rsveasmpalneds mareethmoodnkQeCy saerreap),rempaatrreidx isnpiaksesurarnodgamtaetrmiaxtrsipik(ce.gd.upcluircvaetsesinarreabbit pexrterapcatrioeindnefbfliacinekncsya.mple matrix (.g., monkey sera) and analyzed to verify 10.2.2 1`fmcautrrivxesspiakneds mareethreoqduQirCeadre prepared in the same matrixassamples, no additional 10.3 Continuing Calibration Verifications (CCVs) 103.1 Cthoentcianliubirnagticoanlicburravtei,on verifications are analyzed to verify the continued accuracy of 10.3.2 ASanmapllyezse,twwiothcaalmibirnatiimoanmstoafndtawrodspe(ronbeatactheaancdhoaflw2aylsevfeilsn)isahfitnegraenveirnyjeoctnieonto ten sequence with at least two calibration standards. 1.0 CALIBRATION AND STANDARDIZATION 11.1 wAinlallbyezepltohteteedxtbryacltiendemaarergrxescsailoinb,rawteioinghstteadnd1a/rxd,snportiofrortcoeedatchhrsoeutgohfzeexrtor,acutssi.nTghMeacsusrLvynex or other suitable software. 112 Irfetahnealcyuzrevtehedosetsanndoatrdmeceurtver.equirements, perform routine maintenance, reextract samples, or 11.3 Fraonrgep,uirpomsaeys boef aneccceusrsaacryyw1h0eunsequeaintthietratthienglloewveelsndofofantahleytheigaht tehnedloifmitthsoefctalhiebrcautrivoen:curve saaptphreorxitmhaantetlhye f10llprpabnogfeaonfaltyhtee,stiatnmdaarydbceurbveen.efiEcxiaalmptloeg:enwerhaetne stctaelmipblriatnigotnocquuravnetitate cpopnbsitsoti1n0go0f0tpphbe).staTnhdiasrwdsilfrroemdu5ceppinbatcocu1r0a0cypaptbtrriabtuhteerdtthoanlitnheearfurlelgraensgsieoonfwtehieghctuirnvgeo(f5 3M Environmental Laboratory Analysisof SerEumTESx:8a5c2tUsingESS Pagedof il 001045 Page 49 3M Medical Deparment Study: T-6295.25 418-018:PAGE 1423 Analytical Report: FACT-TOX-169 LRN-E01-0180 tahhieghnacuchroivdnegcshe.nctFurorarvteie.oxnIafmstpthlainesd,aisrtdhdseo.nleoI,twinscoualrmsvooeraemcactyehpaitnnacobllnueedetpootibhnertefasokhloltuohlewdilnbigenepauorisnertdasn:igne1,cio5n,mo2m5o,nl1o0bw0e,ctuw2re5vee0.n ppb and the high curve may include the points: 250, 500, 750, 1000, 1250 ppb. B0 o12p.1eoAcc0 queiosivtieo0 nsSset up000000000 12.1.1 dOensitghneatMoarslsetLteyr,nlmaati2n dpiaggiets. osfetuept ayseaarm-pmloe-dlasyt.naamnde.a lSacvtee tthheatlwsilalsinicnrsetarsuement through the alphabet with each additonal list for tha day. Example Sample List: [YYMMDDa or DOI0127 YIeYianysetraurmeonfttnesatm0e1()D for "Davey") DMDM==dmaoyntofhtoefstte(s1t2)(07) ta=hfeirnsetxtsa'mc"plaendlissto(ornu.)n) of the day (the next samp list will end with *b, 12.12 dAasys,igannadfial3e-ndiagmiet suesqiunegnttihaelifnisletrnuummebnterdetshiagtnsattaorrtslwetitterh, 1thaenldasitnc2redaisgietssboyfoyneearf-omrocach filename. Example File Name: [YYMMDD## or D010712001 YIsi=nsyteraurrmeonftensatm(e01()D for Davey") DMDM==dmaoynotfhteosftt(e1st2)(07) ###=3-digit sequential ile number stating with 1 through 999 (001) bAoltstol,eansumpabretro,ftanheinsjaecmtpiloen vlsotl,uamsesiagnndasmaemtphloedde(sMcSr)iptfioorna:cquiring, an inlet fie, a 12.1.3 TseoleccrteSatIeRa(mSeitnghloedI,ocnliRcekcoorndiMnegt)hoordMEdRiMto(rMbuultttiopnleinRtehaecMtiSonSMtoantiutsoPrainnge).andSet sIeotnitzhaetaicoanqMuiosdiieoanssatparptroapnrdiasttoepatnidmemsa.sSsavtoe4a9cq9uiosritoitohnermeatphproodp.riIafteMSma/sMseSs. Also cionlsltercutemde.ntsSeaereMeimcprloomyaesds, MadadsistLoynanlxpGrUoIduDcEtTioOn fDraAgTmeAntAtCiQonUIiSnfIoTrmIaOtiNonfomray be additional information and MRM, 12.1.4 eTxytpriaccatleldy mthaetrainxalsyttaincdaalrbdast.ch run sequence begins with solvent blanks and a set of 12.15 SSoalmvpelnet ebxltarnakcstssharoeuladnableyazneadlwyiztehd tpewroioCdiCcaVllyintjoemctoenditevoerr2yososnieblteoatneanlystaempclaersr.yover and are not considered sample extracts but may be included as such. 3M Environmental Laboratory Analysis ofSeEruTmSE8x5ac2t Using ESMS Pagesor il Page 50 001046 3M Medical Department Study: T-6295.25 418-018:PAGE 1424 Analytical Report: FACT-TOX-169 LRN-E01-0180 12.2 Using the HPLC 12.2.1 Set up sample ray according to the sample ls prepared in Section 12.1.1 . 12.2.2 Sapeptr-oupprithaeteHfPorLoCpttiomtahlerfeoslploonwsien.gRceocnodritdioanctsuoarl actoncdointdiiotnisonisn tthhee ainnsatlryusmtecnto.nsiders logbook: 12221 Sample size = 10 uL injection 12222 Injectsample = | 12.2.2.3 Cycle time = 10.0 minutes 12.2.2.4 Flowrate = 300 yLimin 12.2.2.5 Mobile Phase (program) [fT a acetate (in H;0) [00min | to%1005| [10min TTMi0% 00 | [750min.| 05% 5% | [B00min TT" 10%| 00% | 12.3 Instrument Set-up. 12.3.1 Refer to ETS-9-24 for more detaits. 12.3.2 Check the solvent lev in reservoirs and refill fnecessary. 12.3.3 tChheetcipk.thTehsteaitnplesshsousltedelbecalpaillwriythatntohjeaegngdeodfedtghees.proIbfet.heUtsipeiasnfoeyuenpdietocebeto check upnrsoabteissfhacotuolrdyb,edcihseascskeemdblweetehkelyp.robe and replace the stainless steel capillary. The 12.3.4 SOebtseHrPvLeCdrpopulmetps(c0o"mOinrg. oSuteoftthehefltowp oofth10e-p5ro0b0e.uLimin orasappropriate. 12.3.5 Taruomunodnthteheitporofgtehen.proAbefi.neRemaisdtjusshtotuhled btepeoxftpehleledprwoibtehifnononimtirsotgeisnolbesaekrivnegd. 12.3.6 Tchhaenignestinruomrednetrutsoeosptthiemsiezepathreamreestpoenarstsc:the following settings. These settings may 12.3.6.1 Drying ges 250-400 liersrour 123.62 ESI nebulizing gas 10-15 liecshour 12.3.6.3 HPLC constant flow mode, flow rate 10 -- 500 uLimin 12.3.6 PHrPeLssCuries <op4e0r0atbianrg(cTohrirsecptalyr.a)meter is not et t i a guide to ensure the 12.3.7 Cfaarrtehferu.llyCognuniedcetthteheprvooblteaginetcoatbhleesopteontihneg.prIonbsee.rt probe util it will not go any. 3M Environmental Laboratory AnaisofSerEumTSEx8t5ra2ct Using ESMS Page bof 1t 001047 Page 51 3M Medical Deparment Study: T-6295.25 418-018:PAGE 1-425 Analytical Report: FLARCNT.-ETOOIX--0116590 12.38 JsPorugimntmatrheytpuangeepaangde,SMorSefilnethHePsLtuCdypabrianmdeertewrist,hsaacmoplpeyitsapaendditnhe(Mhiecrpoosorfat rWoyrd 1289 Cvnelurimscbikoenorsn.isnscaelorudbaepuspraoolpnrsianamttpehleMesaMs1a0ssLbsyeLryaxnnaxUlySmzEaedRi.n'SpaGgUeI(DEi)s.maEynsvuarrey saamotnsgndMansgsLsyonmsple 13.0 DATA ANALYSIS AND CALCULATIONS 131 Calculations: 13.1.1 Caleulte matix spike percent recoveries using the following equation: Recaro OCbsBervedRReessh~MMaeriesBlannkk Rest Rey 1312 Calculate percent difference using the following equation: Difernce EEeepoCoe nnee~Ccurlee eesdCd Coomnee,, 13.4.4 Caulate actual concentration of PFOS, or other luorochemical, in matrix. (pg/mL): (GoCI nitniotfolPVROSoCeolef.Muarormmi5e.en)CareniomtS)opx aDiStsuinodnaFra]cor) *| T0i0s05 140 Merson PerFoRvANCE 14.1 MmaettrhioxdspDeceitfeicc.tioPnleLaismeitsc(eDETLS)-8a-n4d.2L,imAittoafchQumaenntittaBt,ifonoa(LiOsQi)ngaroefcmoetmheondt,vsanhailbyaec,dand MDL and LOQ values. 14.2 S1o4l:v2e1ntaScBotllivavenenktsst,balnMadenaktrsdh,oimndettBhhleoacdnaklbsilb,arnaaktsni,doanMncadutrmvraeit.xriBxlablnaknsks values mast be below the lowest 143 Calibration Curves 14.3.1 Tbehteerc,oefficientofdetermination vale forthecairaton curve must be 0.990 or 3M Environmental Laborator?y Analysis of SerEuTmsE4x52e Using ESS Page7atny 001048 Page"52 418-018:PAGE 1-426 3M Medical Department Study: T-6295.25 Analytical Report: FLARCNT--ET0OLX--0116890 1432 tAhle eacxtcievpeticaolniborfattihoenLcOurQvepopionitn,tswhmiucshtmbaeywidtehviinat2e5u%potfot1h0%t.heoretical value with i 14.3.3 Cmaulisbbraetdieoancsttiavnadtaerddstowidtihsqpuaelaikfyar8edasateasrantghaenthtawtomtaiymebsetahfefcecutrevdebmyatbraicxkbglraonuknd levels of the anaiyte. 14.3.4 oLtohweordahai.gh curve points may be deactivated to optimize. linea range appropriate 14:35 mNoaty ibneclduedaicntgivlaotwedorifhtihgehypdoeivnitssdermopopredtthaono2p5ti%mifzreomthtehelitnehaerorreatnigcea,l cvuarluvee wpohiennts the curve is evaluated ova enerar range appropriate to the data 14.3.6 aOnseappoienatkbseelcaowletshsetLhaOnQtwmoaytirmeesmatihne amcatitviebvleannkf;thodweevviesre,stmhoerLeOtQhawni2l3b0e% or defined at the lowest point with acceptable deviation. 1437 tAhvealLiOdQcalibration curve must contain at least 5ative points above and including 14.4 Matrix Spikes 14.4.1 Tcohneceanvterartaigoen.maRtercioxvsepriikeespoeurtcseindteorefcotvheirsireasnsgheoushlodubledbweidtishciu+nss3e0d%inoftrhethpeosrpitk,ed. 145 Continuing Calibration Verifications (CCVs) 14.51 pCeorncteinntuirnegcocvaelirbyrawtiitohninpl2e5%sofwitthheinstphiekendacorncreanntgreatoifont.heIfraunCmCuVstisshouotwsiade of his recovery, subsequent data should not be accepted. Acceptable data must be `bracketed by the curve and passing CCVs. 14.6 pIfcerriftoerrmieadsotnedthienstyisstmemetahnoddspaemrpfleosrmraenacnealsyezcetdioonriosthtermeatc,timoanisnatendaentceermmainyebdeby the 14.7 1andalaytsata.reDo1c0ubmeernetpaolrltaecdtiwonhseinpetrhfeoarpmparnocpericartietelroiagbhoaovke.not been met, the data musk be footnoted on tables and discussed in the text of the report. 15.0 POLLUTION PREVENTION AND WASTE MANAGEMENT 15.1 pSiapmeptlceweaxstrtaectidwiassptoesaenddinflbarmomkaebnleglsaoslsvcenotntsaidniesrspolsoecdatiendhiinghthBeTaUborcaonttoariyn.ers, and glass 160 Recomns 16.1 Tineforfimrasttipoangienocflucdaecdhediatahepnractkheethgeeandeerra,tiendtfhoerfosottuerdyormuhsatndhwarviettehne ofonltlhoewipnagge: study Of projec number, instrument, sample matrix and ime point, date, and analyst. 16.2 tcAaordmgaepttoaaupnnaadclkysteuetm(imcnuacrlrvuyed)er,semptoehrtethfofoodlrlroeewapiconrhgt:t,aWrdgaoetrtadarnedavloiycteuew,msequnumtaminasirtyiyncgfaoslreimtr,-auMpiaopsnasrrLaemypenotxerrqfsuo,arnnctiaefcyh 3M Environmental Laboratory: AnalyofSeErrumseEsxzc Using ESS Page sort 001049 Page"we 53 3M Medical Department Study: T-6295.25 : 418-018:PAGE 1-427 Analytical Report: FACT-TOX-169 LRN-E01-0180 qmueatnhtiotdyrseapomrptl,eMraesposrLty(ncxhrsocmaantnoignrgamm)e,thod report, HPLC method report, sample lst, and p1a6r3amFinoesrttcreuamcrehsnta,nraluMynaslsiossg,.LayTfnthexersopcrriaignnitnniiannlggitmshemeattihnnotedairmneeeptodrhtion,dtarhneedpdosraatt,mapWplaoecrkldesl,doccoupmyeanntdl(isatpiengt. soett-huep 16.4 `Oinqnutahcneaicfhyheaspdaaemgrp,eltoehfertefhpoeoorqtteura(,nctohirfoyhmacanotdomgpwrroaiumtn)ed,ntrohenpoftroth,llpqouawaginent:gifisyntfcuoadlryimbaortraitpoirnoonjmeurcestptonrbutemb(icenurcr,lvueid)n,esdtaerniadtmheenrt, amneatlhysotd,,acnadlidbartaet.ion (the method and calibration ae usually assigned the same name), 16.5atTrhheeeyelamenucatslrtyosndtiacmtaeullasynddianitcnelituaidanelddeaoincnihtieapalactghhe.pafgier.st 1pfangeiainl.apnadckdeatteasarleonngo:aseltehceirroniinciatlallyainndloddaetde, 16.6 S`AutmtmaacrhimzeentdaAtafuosrainngesxuaimtapblleesooffatwsauremm(ae.r.y,sEpxrecaed)shefeort,inclusion ia th final report. See 16.7 Bbaacckkuuppeelleeccttrroonnicdadtataaintoinasptprruompernitatleogmebdoioka.m. Record the fil name and location of 17.0. TABLES, DIAGRAMS, FLOWCHARTS, ANDVALIDATION DATA 17.1 Auachment A: Data summary spreadsheet. 18.0 RererENcEs 18.1 FcoAmCpTo-uMn4d.s1f,ro"mExSterrauctrinofnoorfAnPaoltyassissiUusmiPnegrfHlPuLoCr-oEolcteacntersouslpfronaayt/eMaosrsOtShpeerctFrloumoertorcyhemical 18.2 EToTnSi-z9a-i2o4n./0M,a"sOspeSrpaetcitornomaentderMaQiunattetnraon1cetorifptlehequMaidcrruopmoalsesSyAsttmeomssp"heric Pressure 18.3 The validation report associated with this methodis ETS-8-4.0 & 5.0-V-1, 19.1 ECToS-m8p-o4u.n2,ds"ErxotrmacSteiornumoffPorotAansasliysuimsPUesrifinvgorHoPoLcCt-anEelseucltironoastperoary/OatshserSpFelcuotrroocmheetmriyc"al 3M Environmental Laboratory AnsysofSerEumrsEaxisizs Using ESMS Pugs9or1l 001050 Page 54 3M Medical Deparment Study: T-6295.25 : 418-018:PAGE 1-428 Analytical Report: FACT-TOX-169 LRN-E01-0180 200 Revisions Revision NumbPEer. SSeeccttiioonn 61.11..12AvClearraigfiecaotfiotRnweooafcsHuorPnv1Fes1o,0r0nRoestvysiststaeinmodncaordmpvoanleunetss,.are used for SPleoctttiionngli1n2e.a2r.2r.e4grCelasrsiifoincaatniodnaodfdseodlvtehnet 1rxamwpe.ighting of the curve. Section 17.1 Changed from attachment B to A. 2 1010:.21 CAddledainwsrthreucnitbilofansnkfisor rweehreudnn.surTopae mati is usc. 1101:.31 SRpeegcuiifryesreoqnuliyraecmaelnitbsraotxioCnCcVur.ve before the samples, 11,213CAllalriofwytwohtatrtoudnotcfheaccuurtrvveede.oesnotmeet requirements. 1122..1113CCllaarriiftyy 122 Changes osyapmicpallerlusnt. ID. tomobilephase gradient and specifyflow rai. 11443..33 CWhhanegnetaocdeepteablealicmaicltis.beAtationissptecavinfdiacrsadosrbtaascecedep0tabncaeonfkcarelsiptornasieo.n curve. 1144.:34.M5odWihfeinesetovadleuaacttiiovnateancdliubseaotfomnatstrainxdapridksesw.ithin te ioc range. 11445..51DeEsvcarliubaetsieovnaloufaCtiCoVns.and useof CCV. 16.0 Add requirements for records and dogumention. Revision 04D10u2e199 AuschmenAt:SummarySpreadsheet"AnalysisofSEerTumseExtsra2ct Using ESMS 3M16Environmentalil LaLbaobroratory Page 100611 001051 Page 555 3M Medical Deparment Study: T-6295.25 : Laboratory Study # + sTewsatyMaterial: MMeatthsoadFRienvailsiSoonlv:ent: `IAnmsatlryuimeeanltESqoufiepwamreenrtVeSryssitoenm Number FRielSeqnuamvee:d Value: Sloipnee:reept: DDaattee ooff EAxnisriavcstiiso/nA/nAanlaylsyts:t: 418-018:PAGE 1429 Analytical Report: FACT-TOX-169 LRN-E01-0180 SGSrtaoamumpnl:/eD#To:askeTe:ankfTeranokfmernIonmfcrtoahmeestsuhvdesysiufoodlndecfroa.ludaeri.on. CInointciealntVroaltuimoen ((umgLm:LyT;akTeankrenomrotmhtehse yMasolsdLery.n imegrton summa. Dilution Facttoro: gTa:kenCarlcoumlahteedsbtyuddyivoilddienrg. the ntl volume fom he concsnuation AuschmeAn: Summary Spreadsheet"Analysisof SerEumTESxt8rsac2t sing ESS. 5M Environmental Laboratory Page tof 11 001052 Page 56 418-018:PAGE 1-430 pe|e TURs E Appendix D: Data SummaryTables [pT p r =] [e ros= smoememmre| onEiWT Bone|reen0ee:||ni=mze| a EooeF | Ew |W = EE=>e| `crapschclstord cz =oon mew|mw wssi rss = wp==eid z Ta = m =a tiBeen | wr wr | 2=ow z i e E Ee e e e 3M Environmental Laboratory 001053 Page 57 3M Medical Department Study: T-6295.25 4 Medical Department Sucy: T6295.25 -`Appendix E: Data Spreadsheets 418-018:PAGE 1-431 Analytical Report: FALRCNT--ET0OIX--0116590 Analytical Raport: FLARCNT-ET0O1X.-0116890 3 Ensironmental Laboratory 001054 Page 38 asem ne 418-018:PAGE 1-432 n SE n TT yh bin EE === E | E E i i ene an 1] SM Environmental Laboratory 001055 Page $9 MedicalDepartmen Sy: Ts an ecm EI mas 418-018:PAGE 1-433 cfr: rACT100X ee LRN-EO EEE EE = HEHE: : HESE= NEE a lm 3M Environmental Laboraton: 00108536 Page 60 418-018:PAGE 1-434 3M Medical Deparmens Say: T29525 Analytical Repori; FACT-TOX-169 rm pr msm EEEoo. LRNEOLOISO I Seu EEL EE EEE res | dw | aa elo Ww om | EET ae o i un | I in =a E08 E mmfSEdEeRs Eoy | | a CEE TT TL 3M Environmental Laboratory 001057 Page 61 5M Medical Department Study: T-6295.25 para perrooncoym rEEE Be Ele = cs fo mam EE mEEmma 418-018:PAGE 1435 perAnatlyicailr Repmor:eFLARCNT.-ETOO1X--0116809 a| HEE EE ur EColmtmines[LomLE 0[ E8T==Teme-- a =e EE iE Blam ad EEEET TL] |TEE we HE] EO] TEEE fT] E Zz (z= = rep|tZ 8] 2 | E: BIEEEEE DE = au EEE ee owns xn 3M Environmental Laboratory 001058 Pages? 418-018:PAGE 1436 3M Medical Department Study: T-6295.25 3M Medical Deparment Study: T-6295.25 _-- Appendix F: Example Calculations Analytical Report: FACT-TOX-169 LRN-E01-0180 `Analytical Faport: FLAACN-TT0O1X.-0116890 Formula Used for Sera Analyses in Study FACTTOX-169 AR (ng/mL) x DF x EFVV((mmLL)) x 10g 1000ng = Reported Concentration (ug/ml) Calculation Used for Group 3, FO, GD21, Animal ID 10330F 53.0ngimLx400x 1OmL x 10ug 03mL T000ng =70.7 pgmL DAFR----DAinlaultyitoincaflacrtesourlt from Mass_Lynx summary EFVV----FVionlaulmeextorfacstervaoleuxmtrea(c1t.e0dmi unless otherwise noted) 3M Environmental Laboratory 001059 Page 63 418-018:PAGE 1-437 3M Medical Departmen Study: T-6295.25 Analytical Report: FACT-TOX-169 LRN-EOL-0180 9M Medical Department Stuy: T-6295.25 Analytical Report: F(ARCNT-ET0O1X.-0116890 AAopmpeennddiixxGGr:TIenterrimCCeertrirfiocate of Analysis 3M Environmental Laborarors 001060 Page 64 418-018:PAGE 1-438 3M Medical : Department Study: T-6295.25 | Analytical Rep|or: FLARCTN-ETOOLX0-I1S6O9 Centr"30e48 RAesneaarlchyDtiviocal LaboraSttaotrCoilleegse.,PA i16n8c01, Phone: (814)231-8032 Fax: (814) 231o- r(8114)2 2315-15380 INTERIM CERReTvIisFioInC10A/7T/E00)OFANALYSIS : Centre Analytical Laboratories COA Reference #: 023-0184 ` 3M RPreofdeurcte:ncP#e:FOSSD,-L0o1t8 217 Purity: 365% | amr nwt IE hosvin TT wew | TeaticaNsiRon Positive `Met21. alsMCaagl(IcnCieP/usMmSi)um 3. Sodium 21. 00.0001w0immtm% 31439 wim |&4. PNLiooctnkaeslsium' 7. Manganese 465.. 0<.60.008040591wwwwilmtw%sh 7._<0001 wise eOmBIs) putty [oTAwTeA n . (G"enTs%)oparlty 1 Related Compounds |ToneDeteeid PRPueOsrdAaylAbySDoSNCeRSIGA)|CT NeonaeDlesa || Trorg21a.niFCchAulnooirroidnies (IC) 21 <0as0oswwnms || 83 NBreome 5. Nime +3 <<00000490wwtiime% 5. <0006 wim |.6. Pshaosfpheate || 76.. <08.07067wwtiimwhr% 21 OrganicPTAEcriAads * (IC) 5 mma 21 l<0lmwmssn 5 010wthnn [|E_le&m1e. nawClaeArrnbaaolny 1 ToeorVealtuei=c17a.8l% 4. 028wis % L 1248 ese | 43. sNiuterorgen 5. Fluorine ! 45. 5. ThTTeoohreeetiocoalrrVVVeaaaelllsuuuieee=i-=e56c090a%a%5l% +5 E17wmiinn 5. sadn comin 3M Environmental Laboratory Page tat3 001061 Page 65 418-018:PAGE 1-439 3M Medical Deparment Study: T-6295.25 ` Analytical Report: FLARCNT--ETOOIX--0116890 : CenStor@eReAsneaaclhyOtMiecal LaboraStaiosrCaileegse,PAITnEcR. Phone: (814) 231-8032 Fax: (814) 231o-r (8114)22315-12340 CenItNreTAEnaRlyItiMcalCLEabRorTaItoFriIesCCAOTAEROefFeAreNnAcfeiL:Y02S3I-0S154 Datcof Last Analysis: 0831/00 Expiration Date: 0831/01 Storage Conditions: Frozen 10C Re-assessment Date: 0831/01 F"lPuuorriitdye=, 10.0509%% -N(sMuRm oifmmpeutriatlieism,p1ur.i9t3ie%s,or1g.a4n5i%c+aLciCd/iMmSpuriimtpiuersi,ti0es3,88%.+4P1%O+AIAno,rganic 0.33%) `ToPtuarliitmypu=ri1t0y0f%roma1l3l.t0e9s%ts==8163..90%9% "Potassium is expected in this salt form andi therefore not considered an impurity. . o*PbusseirtvyebdyfoDrStChisissagmepnelrea.lly not applicable to materialsoflow purity. No endotherm was inorganic anion method conditions. The snion result agrees wel with te suler "Sulfur in the sample appears to be converted to SO, and hence detected: using the. doentethremirneasutlitosn, itnhethSeOe,liesmennottaclonansaildyesries,d alennidmipnugrictoyn.fidence to this interpretation. Based STNHFFBAPAA PFPA N"HToeropifftllauufoorlrooaorcpeoetbniuctyaanrcoicdiacciadcid Pentafluoropropancic acid "Theoretical value calculations based on the empirical formula, CiF1,SO;K"(MW=538) `This work was conducted under EPA Good Laboratory Practice Standards (40 CFR 160). conomansa $M Environmental Laboratory Fagen Page 66 001062 418-018:PAGE 1-440 3M Me. dical Department Stuy: T-6295.25 Amalyical Report: FLARCNT--ETOOIX--0116890 Cent3r0Ph4eoneR:Ae(sn8e1aa4r)cl2h3y1D-tr8e0i3c2 alFaLxa(8b14o) 2ra3Stato1eorCr-oi(l3ae11g4es.)2.2P9AT1561I38n308c01. CeaItNreTAEnaRlyItiMcalCLEabRoTraItoFriIeCs CAOTAEROefFerAeNnAc#e:LY02S3I.0S184 LC/MS Purity Profile: FF TmnyTwn) T ae T im s e oora ie C7r sa] Note: The C4 and C6 values were calculated using the C# and C6 standard calibration afcuvrreovrmeasgt,heerreCesspepcoatnniscveelCfySa.csttoTrahsnedfaCrroSdmcvutarhlveueeCs.6waaLsnidkceaCwlic8ussleta,atntedhdeaurCsdi7cnugvratvlheuesea,wvaesracgaelrceuslptoendseusfiancgtotrhse ( PedBy D4iS Br el zor Bupeutes Reviewed By:fSochiennFtlisath,erCetAy lytical Laboratories Dtuoets Laboratory Manager, Centre Analytical Laboratories commas 3M Environmental Laboratory Page3ars 001063 Page 67 3M Metical Deparment Study: T-6295.25 5M Medcal Department Sucy: 6205.25 Appendix H: Report Signature Page 418-018:PAGE 1-441 Analytical Report: FLARCNT'-ETOO01X--0116590 Anaiyical Ropar: F(AACwT.TgoOrX.0116890 Deanna J. Luebker,J1.S., Study Director Lely Date WaTrhnaT.sCwasee.sBV7MG. Ph5. Sponsor Fopresenaive (nCaste 220 RisinJA . HansM en, PeD. PrincipalAnabfical rvestgalor "antee C2001 Wil2 lam K. Reagen. P--h. Laboratory Manager oc by Gate 3M Environmental Laborators 001062 Page 68 418-018:PAGE 1-442 PFOS Concentrations in Rat Livers Souther Research Institute Study A344.1.4 001065 418-018:PAGE 1443 Methods `1:W5e (fbirystwperiegphatr)ewdictohntDrIolwattiesrs.ueThhoimsowgaesnautseedbytohpormeopgaerneitzhiencgalriabtrlaitvieornfsrtoanmdacrodnst.rolWraets spiked in known amountsoftest article (PFOS) and aliquotesof the blank tissue homogneate. A blank + internal int. std. standard (PFOC) and a blank - int. into std were prepared with each calibration curve. a`Tnhyeosfatmhpelseesswaemrpeleaslswoehroemwoigtehniunzsepdi(k1e:d5)blbaynkweciognhtrtowlitlihveDrIhowamtoegre.nDaitleutpiroenpsarmeaddaebotvoe. `Then an equal amount of internal stanard (PFOC) was add to each sample. `Then to both the samples and carbonate/bicarbonate buffer, standards we and 500 iLof added 1 mLofDI water, ion pairing reagent (0.5 | mL M of 0.25/0.25 M stoelturtaibonutwyalsammmioxneidumbrhiyedflryoxaindde)thaedwjuestaedddteodp2H.51m0.L5 owfitehthsyoldaicuetmathey.drTohxiisdem.ixTthuree was csehnatkreinfufgoerd1ahtr2o5n00aprlpamtffoorrmS mmiixne.r.ThAefteetrhyaln ahcoeutrattehelasyaemrpilsersemaroevteadkeannodfefvaanpdorated to dryness under dry nitrogen. The residue ilter into autosampler vial for analysis. is reconstitued and filtered through a syringe We then perform HPLC MS/MS using a MRM experiment on the samples and standards. 001066 StSuoduythAe3re4R.e1s.e4arch Insite PFOSinRatLivers Filo Nama__ Sample Name CoMnaea.su(nrgeidm) 66822861/22000058 7700 1100990096coconnttrrooll 6622881122000078 F00 1110590113ccoonntrtooll 66122881122000098 FFOO 1111550045ccoonnttrrooll 66228822001110 FF11 1100990096ccoonnttrrooll 66228822001132 FF11 1110590111 ccoonnttrrooll 66228822001154 FF11 1111550032ccoonnrtrooll 66822881/22001187 1F11110000..9440mm9ooi0k9kgg 66022881122002119 FF11111106001000..44mmgghg 662288122005242 FF11111166002100..44 mmgkhsg 660228822002265 FF11 11111160..6644mmaai09kgg 660228822002286 FF11111166441211..66mmgaikgg 68228822003209 1F1111614416.1664mmggi8kkgg 66228022003323 FF11111106559 22mmgahhkkgg 6822881122003364 111111665555 22mmaahkgg 51558523 "03..2748663 1150.2896 -91.0.2087 "8.94024 1"012075 a1m53775 11369874 212185 51421475 60513s0 6509.217 66630232 66805426 660022881122003378 FFOO 1111600004 00..44mmggkkgg 3s818022 66102288122004410 FFOO1111660031 00..44mmaaiikkoo 1916555 66002288122004443 FFOO1111664430 1166mmooiikkgg 123012 66112288122004475 FFOO 1111664452 1166mmaaiikkoo 918092.58 660022881122004580 FFOO1116146569126mmaoigkg 91834825 660228822005512 FFOO 1111665674 22mmgghikkgg 11108978 66228822005553 FFOO 111165820m25gmia9khgkg 135 1080 62612056 701162m5oi4kg 162 "Pup and Dam samples were mixed together during preparation BOL =below quantiaton imi,<12.5 ng/mL OR nglg CCoanlec.ula(ntgelgd) BsaLL BBLa 21020615 ssaalu ssaaul asaLu 2960..977435 140313,17582 9184.02297 111961.,870502" 414787.689985 230429.038908 315463.213629 219891,848650 254882001 4458.55030 11123222639 18173.908281 111589508115 115393.903314 151171 116110.154081 418-018:PAGE 1-444 001067 APPENDIX J HISTOPATHOLOGY REPORT 001068 418-018:PAGE J-1 RESEARCH PATHOLOGY SERVICES, INC. 438 EParsotnBuetle2r1A5v.en3u4e8,.N7e6wF7aB0riai2n1,5.P9A45.134650216 ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS PROTOCOL 418-018 SPONSOR'S STUDY NUMBER: T-6295.25 HISTOPATHOLOGY REPORT SUBMITTED TO: Raymond G. York, Ph.D. , D.AB.T. Associate Director of Research Argus Research Laboratories, Inc. 905 Sheehy Drive, Building A Horsham, PA 19044 SUBMITTED BY: Woe Brn Dee 13,2002 W Ray Brown, D.V.M., Ph.D. Veterinary Pathologist December 13, 2002 001069 418-018:PAGE J-2 ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS PROTOCOL 418-018 SPONSOR'S STUDY NUMBER: T-6295.25 HISTOPATHOLOGY REPORT TAOFBCONLTENETS REPORT Method WEUERPII SE Results ... arrears sts rare ser Summary... - i. Quality Assurance Unit Statement eee -- Page ssonsvosseomppinpenspine snes er r er iB 001070 418-018:PAGE J-3 ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS -- eowecowow PROTOCOL 418-018 SPONSOR'S STUDY NUMBER: T-6295.25 HISTOPATHOLOGY REPORT METHOD: Microscopic examination was made of the heart and thyroid of two male and two female F1 generation Crl:CD%(SD) IGS BR VAF/Plus pups of a one-generation reproduction study. The dosage group identification and treatment of the. groups of rats are listed below. C r C"C E E I lT[ om e a m=e|NN=+CCT )[[ |BaFaa[CC=mo| nm|[||r m IIIc e aaoPeeeee| || || NE y m vCm=] ] ] y m]] [ooLomo |2| wm |oowors| w | FoToros[0| wi |ors|_| le ee [on[ares [0| we | pores || [C0o[lveomraesn| 2||w wTo mersr | | e wue ]| TFnRa Sher SET AR 5ws: The FO generation female rats were given the test article daily beginning 42 days before cohabitation (maximum 14 days) and continuing through Day 20 of presumed gestation (rats assigned to Caesarean-sectioning), Day 24 of presumed 001071 418-018:PAGE J4 PFOOSN-EMGEEVNAELROANTIICOANCIRDE/PCRHOODLUECSTTIEORNOLSCTHUDAYLLOEFNGE AND NOEL INVESTIGATION IN RATS SPONSOR'PSRSOTTUODCYONLU4M1B8E-R01:8 T-6295.25 _-- HISTOPATHOLOGY REPORT gestation (rats assigned partum (rats that deliver to a natural liter). delivery Rats in tthheatpdroocneostsdoeflidveelrivaerliitntger)woerreDanyot4 postgiven the test/control article. Male ered part of the test system. rats were used only as F1 generation pups breeders were not and were not directly given consid. the test uartteircloe,exbpuotsuwreer)eorpovsisaibmlayteerxnpaolsmeidlktdoutrhiengtteshte article during maternal gestation lactation period. Dosages of the (in FO generation rats were at approximately the adjusted for the most same times each day. recently recorded body weight and given collecteOdnaDndaypr5espeorsvtepdaritnum1,0%punpesutwraelrebusfafcerriefdicfeodrmaalnidn.theThheearitn-lainfedptohrytriooindowfetrhee study, necropsies, formed by the staff oafnAdrgruecsorRdeisnegarofchthLeabgorroastosrioebss,erIvnca.tions at necropsy were per- F1 geneRreaptrieosnenptautpivferosmectthieonsveohfictlhee choenatrrtolangdrotuhypro(iGdroofupon1e)maanlde and one female 2 mg/kg PFOS sgtraoiunped(wGirtohuphe1m3a)toxwyelrien raonudtienoeslyinprfoorcemsiscerdo,sceopmibceedxdaemidnaitniopanr.affin, sectioned, and blocks,Umpiocnrosccoomppilcetsiloindesofatnhde project, histology all raw data records) will (remaining be returned wet tissue, paraffin to Argus Research Laboratories, Inc. for archiving. -_ Research Pathology Services, Inc. 2 001072 418-018:PAGE J-5 ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS PROTOCOL 418-018 SPONSOR'S STUDY NUMBER: T-6295.25 HISTOPATHOLOGY REPORT RESULTS: The type thyroid of the and incidence of male and female the histomorphologic observations in the heart and pups from dams of the vehicle control and 2 mg/kg PFOS dosage groups are shown below. SeDoxse Group NDuammbeNruomfbePrups Examined: TNoH.YREOxIamDi.ned No. Normal HNoE.ARETxa:mined No. Normal M7 oMBw 109109 111058 11 11 11 11 F F7 103109 110159 11 11 11 11 No female microscopic changes were observed pups exposed to 2 mg/kg of PFOS. in the heart or thyroid of the The sections examined were male and all within normal histologic limits. Research Pathology Services Inc. a 001073 418-018:PAGE J-6 PFOOSN-EMGEEVNAELROANITCIOANCIRDEIPCRHOODLUECSTTIEORNOLSTCUHDAYLLOEFNGE AND NOEL INVESTIGATION IN RATS SPONSOR'PSRSOTTUODCYONLU4M1B8E-R0:18 T-6295.25 --_-- HISTOPATHOLOGY REPORT SUMMARY: Microscopic examination was made of the heart and thyroid from one male and one female F1 generation pup from dams of each of the vehicle control group (Group 1) and 2 mg/kg PFOS group (Group 13). No microscopic changes were seen in the heart or thyroid of the male and fe- male pups exposed to 2 mg/kg of PFOS, R-es_earch Pathaiogy Services, nc 2 001074 418-018:PAGE 1-7 PFOOSN-EMGEEVNAELRONAITCIOANCIRDEIPCRHOODLUECSTTIEORNOLSCTHUDAYLLOEFNGE AND NOEPLROITNVOECSOTLIG4A1T8-I0O1N8IN RATS SPONSOR'S STUDY NUMBER: T-6295.25 _-- HISTOPATHOLOGY REPORT QUALITY ASSURANCE UNIT STATEMENT bceyepdohurreesrueaopflaARlrleaytsaieAsoaspnrsecucfhrtorasPntoachfteehtoUshltenouigtdyiyosSfsieuRsreveeisdpcreeoaascrb,ecosIhvsncei.Pnagha.tanhvdomeliwocbegreryoesenScaoeuprpiavecitrcaosedrismdieneIndacp.cracec1pocarordcraadotniimcnopengh,awfnohiichhseteiohwpeSiatthpaornltodoceagericGdcuoreOoepvsdearlsLautaauiibnoognarFaaritneod. Pracice regains specified in the protoca `eStaynDdoetsciisonofcoclatyaoneopfoUsSicFtooodnnorddOnignAdipnrsorctso.n)a9s94)l.iRortsl, SCoeftretnecerco2H.1a96m6ovnostSohrv: G1ud: CEouUmtSmpuFenoaiondt2yE0co8ofOnaonnmOgicEACCiDosdmiuenn.(ii1Gt96oiy9d.CLoouantcbdoeocPicrrcinanpacolonaatRr28acmoauwtyrimn1sys9:a9iinnseloasRgcl,oao2p1aooCcFtRnbPayorct 5Eancu.pOFEcrmasmna:l feEuropeanCommuni: Legation. 32 No L 31.18 reton 117 soannce aMeimse2bo1fMHeeethrh2.1W68e7.t (1957).GodLarry Pract Sancrsfo SatSueson ngs HW. attoinosnsQfurnaoolmtteytdhAedsusrpiurnorgtaontchcoeelcUSontniatdnsudctaturdodyfbtOahpeseresatdtudiiynn.gspPeTcrhtoeicoesndusumrwmeeasrreayrnpedeproofrrotraompfepdGraoAsmiisnahseopweGcnotioboednlsoLw4a.bnorTuahtdeorereydwPe1rraehcetneoenadrepveeima..: port subrted tthe Study Directonr December 13, 2002 IOoastpeesctoifon Study Phase OatMeasnaRegpeomretnetd to 10DSatteudRyepDoirrtecetdor po44r00B001T MTaPsitrmeerinSnctghoednule ooowuuaa00soott1 1112221111333000022 oosoissoioevtoott MESitmcabrieondtiionmngyg 0008533730010010111 111222/111333000222 oOn7t1zIo0nT HGiasltaopEanmioriyony 72501 Data Verficaion oomns3u1o0t1 orsion 112211330022 121302 027300011 080301 PrReeDpasoturabtmPPirrsoescpieasorsnaitAnigount oosmaisoiai0tnt 11221330022 121m 08080112,711300127101 FDirnaa rreeppoorrtt ovoa102t.131002701 112211330022 R-es_earch Pathology Services, Inc. Kareh o W. Hy aripnrs,ABSke BS Quay Assurance Unit pes Date 5 001075 APPENDIX K HISTORICAL CONTROL DATA 001076 SUMMACRrYCOO(FSDR)EIPGRSOBDRUCRTAITVS.E INDICES DAY 21 C-SECTION 418-018:PAGE K-1 PERIOD JUNE 199-8 SEPTEMBER 1989 NUMBER OF STUDIES 18 TNEUSMTBEEDR OF RATS: 252 PREGNANT FOUND DEAD 2351 ADEBLOIRVTEERDED [3 NUMBER OF RATS PREGNANT AT CAESAREAN-SECTIONING 23 NCUOMNBCEERPOTFUSRALTITSTEWRI:TH SINGLE uve RESORBED 0 0 ABORTED 0 % PREGNANT AVE#RCAORGPOREA LUTEA AVERAGE # IMPLANTATIONS AVERAGE LITTER SIZE AVERAGE # LIVE FETUSES AVERAGE # DEAD FETUSES AVERAGE # RESORPTIONS AVERAGE # EARLY RESORPTIONS AVERAGE # LATE RESORPTIONS MEANOT% 93. 176 148 145 00 0s 05 00 RANGE/STUDY MEAN or% (67.5100) (16.4-10.1) (140-16.3) (1615.9) - 1-1.4) 1-1.4) 0.1) 001077 418-018:PAGE K-2 SUMMARY OF REPRODUCTIVE INDICES CrtCO(SD)IGS BR RATS. DAY 21 C-SECTION AVERAGE % DAMS WITH ANY RESORPTIONS AVERAGE % DAMS WITH ALL CONCEPTUSES RESORBED AVERAGE % DAMS WITH ONE OR MORE LIVE FETUSES AVERAGE SEX RATIO, (% MALESILITTER) AVERAGE FETAL BODY WEIGHT (6) AVERAGE FOR MALES (6) AVERAGE FOR FEMALES (G) AVERAGE % DEAD OR RESORBED CONCEPTUSESILITTER MEANOr% 393 00 100.0 94 528 5.40 512 33 RANGE/STUDY MEANor% (12571.4) - - (430-57.0) (5105.48) (515563) (4925.29) (08:88) 001078 SUMMARY OF MATERNAL NECROPSY OBSERVATIONS CrCD(SD)IGS BR RATS - DAY 21 C-SECTION 418-018:PAGE K-3 PERIOD JUNE 1998 - SEPTEMBER 1999 # STUDIES 13 # RATS TESTED 252 # RATS PREGNANT 235 # RATS DIED 1 # RATS ABORTED 0 # RATS DELIVERED 0 # RATS WITH 100% RESORPTION 0 OBSERVATIONS LVER Left lateral lobe, tan area UTERUS Moderate hydrometra. INGUINAL AREA Subcutaneous, tan mass on ight side RANGE/ STUDY No% ON % 1 040 01 (040) 1040 01 (042) 1040 01 (048) 001079 SUMMCrAtRCYO(OSFD)FIEGTSABLRGRRAOTSSS-EDXATYER21NACL-SAELCTTEIROANTIONS 418-018:PAGE K-4 PERIOD JUNE 1998 - SEPTEMBER 1989 ## LSITTUTDEIRESSEIXNACMLIUNDEEDD 13 23 # LIVE FETUSES EXAMINED 3383 ALTERATION Eves) Eyebugesdepressed JAWS Micrognathia HINDPAWExtra digit present TAL Threadike No% RANNGE w/STUDY L F 1 043 1.003 01 (042) 01 (003) LF110080 0011 ((004023) FL110.0803 0011 ((000435)) FL110.0808 01 (043) 01 (003 L: F: FLIETTTAELR IINNCCIIDDEENNCCEE 001080 418-018 PAGE K-5 SUMMARY OF FETAL SOFT TISSUE ALTERATIONS Crt:CD(SD)IGS BR RATS. DAY 21 C-SECTION PERIOD JUNE 1998 - SEPTEMBER 1889 # STUDIES INCLUDED 8 # LITTERS EXAMINED 180 # FETUSES EXAMINED. 1245 BRAIN ALTERATION Diloflaatetralvientoricnles FLo RANGE/STUDY N% ON % 22 01.1161 0022((001823)) HEART `Septaldefect LFo 11 005068 0011((000482)) VESSELS Umbilicalartery, descends Intonloemfitnoaftuerairntaerryyb,laabdsdeenrt Atonarpasasaenscddeoshrospaehlatgoautshe Leficarotidrisestothe Rifghticargtohteihdrirgithstescotaoroftthied ngntoftherightsubclavian Pumonaryartery, small Somiunar valve,small Ducts aneriosis attached totheleftsubclavan Great vessels, transposed L 3 167 FL 23 01.2161 F 2 016 FL 11 005068 L056 F 1 0.08 L 1 056 FL 11 000586 F 1 008 FL 11 005068 L 1 056 L 1 008 2 1.11 F 2 016 02(09.1) 0022((00-8132)) 00-210(00-1422)) 0-1 (0-06) 0-1 (0-42) 0-1 (006) 0-1(0-42) 00-41((000-462)) 041(006) 0-1(0-42) 00-411((00-0462)) 0-1(0:08) 00-11 0(00-743)) Lunes aAbsepnatnidcac rdiaac lolbes, L F 1 056 0-1(0-42) 1 008 041(006) KIDNEY(S) Pelvis, sightdiation Lo Pelvis, markeddilation ~~ F L F 1 056 01(045) 11 000586 00-11((00-0475)) 1 008 041(007) Li LITTER INCIDENCE F: FETAL INCIDENCE 001081 418-018:PAGE K-6 SCUriMCMDA(RSDY)IOGFSFBERTARLASTKS-ELDEATYA2L1ALCT-ESERCATTIIOONNS PERIOD # STUDIES INCLUDED JUNE 1998 - SEPTEMBER 1859 8 ## FLIETTTUESRESSEEXXAAMMIINNEEDD 180 1332 SKULL ALTERATION Eye socket: small Mandibles: short No% LF 1100058 L F 10% 1008 VERTEBRAE Thoracic: Centrum,bifid Centrum, fusedto aren + 4present FL44 202 L 1 056 FL1100058 F 1008 Lumbar: Fused 8present aCerncthreusm, fused to LF 2210115 FL 110050%8 L105 F 1008 RIBS CervicalRib(s)present FL 1142 616075 Oneormore, wavy. FL 68 303630 o`sOsniefoiredmo(rhey,poipnlcasotmipcl)e,teolrynot ~~ L 2 1.11 Foussseifdied FL310028 4present F 1008 L105 F 1008 RAN/ SGTUDEY Nw 0011 ((000482)) 01 (042) 01 (008) 0011 ((000488)) 0-1 01 (0-48) (008) 01 (048 01 (006) 01 01 (048) (008) 0011 ((00:4088)) 01 (048) 01 (008 05 06 (0208) (035) 0032 ((001985 02 (09.1) 0013 ((004128) 01 (008) 01 (048) 01 (008) L: F: FLIETTTAELR IINNCCIIDDEENNCCEE 001082 418-018:PAKG-E7 SCUrMiCMDA(RSDY)OIGFSFBERTARLATSKSE-LDEATYAL21ALCT-SEERCATTIIOONNS MANUBRIUMALTERATION Duplicated STOEnRNeEoBrRmAoEre incompletely Aossysimfmieetdroircnotossified Duplicated XIDPuHpOlIiDcated HINDLIMB Extra digitpresent Femur, bent No% RAON N/ SGTowUEDY FL110.0308 01 (045) 01 (008) L 422 FL241013 F 2015 FL1100058 02 (081) 0012 ((004152)) 01 (008) 0011 ((000485) FL1100058 01 (045) 01 (008 LF 1100088 LF 110.0508 0011 ((000485)) 0011 ((000488)) FL:: FLIETTTAELRIINNCCIIDDEENNCCEE 001083 SUMMARYSKOEFLEFTEATLALAVOSESRIAFGIECASTION SITES CrCD(SD)IGS BR RATS. DAY 21 C-SECTION 418-018:PAGE K- PERIOD: # STUDIES JUNE INCLUDED 1998 - SEPTEMBER 189 8 # # FLIETTTUESRESSEEXXAAMMIINNEEDD 180 1331 SKELETAL AVERAGES HYOID VERTEBRAE CERVICAL THORACIC LUMBAR SACRAL RCIABUS D(pAaiLrs) STERNUM MANUBRIUM STERNAL CENTERS FOXIRPEHPOAIWDS (Calculated as. average per mb) CARPALS METACARPALS DIGITS HIPNHDAPLAAWNSGE(SCalculated as. TARaSvAeLraSge per mb) METATARSALS DIGITS PHALANGES FETUSILITTER MEAN RANGE/STUDY 089 (0961.00) 7.00 1807 (13.03-13.14) 35.9020 (58-5597) 748 1805 (7.01763) (1302312) 100 - 31.9090 (39-84.00) 0.00 - 400 500 (39-94.00) 828 (804-852) 02 (0007) 480 (473487) 500 621 (58-1654) 01081 APPENDIX L STATEMENT OF THE STUDY DIRECTOR 001085 418-018PAGE L-1 r~,PRIFRIMEDICA i Argu5s05RSehseecahrychDLraibvoer,aBtuoirlidesi,ngIcA. Tel"eTpehleofnaex:: ((221195)) 444433-.88751807 -P--ROTOCOL 418-018: ONE GENERATION REPRODUCTION STUDY OF PCFHOASL-LMEENVGAELAONNDICNOAECLIDI/NCVHEOSLTEISGTAETRIOONL IN RATS SPONSOR'S STUDY NUMBER: T-6295.25 STATEMENT OF THE STUDY DIRECTOR of the st"uTdhyi.s fiNnaol dreevpioarttiaocncsurfartoemlythreefUl.eSct.sFtohoedraawnddaDtrauogbtAadimniendisdturraitnigonth(eFpDeAr)foGromoandce Laboratory Practice Regulations; Final Rule', the Japanese Ministry of Health and tOWheEelCfOarDrgeaPnr(iisMnacHtiiWpol)nesfGooorfoEGdcooLonadboomLraiabctooCrroa-ytooPprreyarcaPttriiacocentSiactneadsndDoaecrcvduefrlororepdSmaetfhneatttya(fSOftEeuCcdtiDee)ds.tohnTehDqeruauRlgeisvt"iysaoenrdd integrityofthe study, with the exceptions in the bulleted list bellow: + Tanhaelryetiwcaelrephtasweo. stTuhdey diin-rleicfteorsstufdoyr tphhiasssetuwdays: coonnesifdorertehde tion-elinfde apthathsee gaennderoanteiofnoranthde shipment receipt of otfhesspeecsipmeecnism.enTshfeoranaanlalyytsiicsa.l sStiundcyepthhaesetewchansiccaolnspiedrefroerdmatoncsetarotf at the: each phase was entirely separate, no effect is expected from this exception. Au2t1oCmFaRte58d.1d3a0t(acc)o.llTehcteiohnarsdysctoepmysphraivnetonutotisbceoennsviadleirdeadtetdheasrarweqduaitrae.d according to The stability of the reference standard and intemal standard were not determined. ARsasjoeclioantdeDGi.reYcotrokr,of(RDesbrcAhBT Date and Study Director `Argus Research Laboratories, Inc. a U.S. Food and Drug Administration. Good Laboratory Practice Regulations; b. Final Rule. 21 CFR Part 58. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice c. `OSrtgaanndiasradtfioorn SfaofreEtcyoSntuodmiiecs CoonoDpreurgast.ionOradnidnaDnecveelNoo.pm2e1n,tM(a1r9c98h).26,Th1e99R7e,vJiaspeadn. OECD PrinciplesofGood Laboratory Practices [C(97)186/Final). 001086 APPENDIX M QUALITY ASSURANCE STATEMENT 001087 PRIMEDICA 418-018:PAGE M-1 Bb Bn QUALITY ASSURANCE STATEMENT Argus Protocol: 418-018 Study Director: Raymond G. York, Ph.D., DABT Sponsor's Study Number: T-6295.25 The protocol, critical phases, raw data and final report were inspected by the Quality Assurance Unit (QAU), to assure conformance with: U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standardfor Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. `European Economic Community (1989). Council decision on 28 July 1989 on the acceptance by the European Economic Communityof an OECD decision/recommendation on compliance with principlesof good laboratory practice. Official Journal of the European Communities: Legislation. 32 (No. L 315; 28 October): 1-17. "The undersigned indicate that the report is an accurate representation of the raw data. Data The draft protocol for this study was audited for adherence to the appropriate regulations(s), as stated above, on 27 JUN 00, 31 JUL00, 15 AUG 00 and 21 AUG 00. The QAU inspection and report audit dates are listed below: Inspection Phase Inspection Date(s) Date(s) Findings `Submitted to Study Director Date(s) Findings Submitted to Management `Test Article Preparation Blood Collection Caesarean-Sectioning Tissue Collection Natural Delivery/Litter Damy/Litter Sacrifice Milk Collection 04 OCT00 31 OCT00 31 0CT00 310CT 00 02 NOV 00 06 NOV00 06 NOV 00 11 OCT00 31 0CT00 03 NOV 00 03 NOV 00 03 NOV 00 08 NOV 00 08 NOV 00 11 OCT00 31 0CT00 03 NOV 00 03 NOV 00 03 NOV 00 08 NOV 00 08 NOV 00 001088 418-018:PAGE M2 Observations Inspection Phase Inspection Date(s) Dates) Findings ~~ Date(s) Findings. `Submitted to Study Submitted to Director Management In-LifeRaw Data. 18 JAN 01, 19JANOL, 01FEB 01 01 FEB 01 22JANOl to 26 JAN 01 and 29 JAN Ol to 31JANOI 01 FEB01, 19 FEB 01 19 FEB 01 05 FEB 01, 07 FEB 01 to 09 FEB 01 and 12FEB Ol to Formulations Raw Data Report Tables, 19 FEB 01 25 FEB 01 to 2285FFEEBB 0011 to 26 FEB 01 and 01 MAR 01 29 MAR 01 01 MAR 01 29 MAR 01 23 MAR 01 to Report Text 29 MAR 01 17 MAR 01, 03 APRO1 03 APROL 30 MAR 01 and 02APR 01 to - 03 APR 01 to 10APR 01, 16APR 01 16APR 01 12 APROL, 13 APR 01 and 16APR01 and 17 APR 01 17APR 01 17 APR 01 18APR01 04 MAY 01 and 18APR 01 07 MAY01 18 APR01 07 MAY 01 Revised Report 07 MAY 01 17JULO1 10 0CT01 300CT01 31JAN 02 04 FEB 02 27 MAR 02 10 DEC 02 17 JUL01 10 0CT01 310CTO01 31JAN 02 04FEB 02 27 MAR 02 10 DEC 02 17JUL 01 100CT 01 310CTO01 31JAN 02 04 FEB 02 27 MAR 02 10 DEC 02 JimsUnni. Matthew J. Vaneman, B.S. Date Manager, Regulatory Compliance ofan yen NEE Cynthia M. Kelsch QPruianlciitpyalAsAsuudriatnocre Associate and Date 001089