Document RJ9eV5XvE67vYMbkeMwVx2Ee8

fR 226 _ 1357 FINAL REPORT `ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS SPONSOR'S STUDY NUMBER: T-6295.25 FINAL REPORT DATE: 16 DECEMBER 2002 000433 TITLE- ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC 'ACID/CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS ARGUS STUDY NUMBER: 418-018 SPONSOR'S STUDY NUMBER: T-6295.25 SUBJECT ABLE OF CONTENTS PAGE L SUMMARY AND CONCLUSION It A Methods. kl B. Results 14 C. Conclusion 110 mo DESCRIPTION OF TEST PROCEDURES ol A Conduct of Study 1 B. `Test Article Information 04 C Control Articles Information 0-4 D. Vehicle Information ns E. Test Article Preparation and Storage Conditions 6 F. `Test System 7 G. Husbandry 0-9 H. Methods oi qm RESULTS m-1 A. Morality m1 B. Clinical Observations m-1 C. Necropsy Observations v00434 m2 ii SUBIECT PAGE D. TWeerimgihntasltBooTdeyrmWieniaglhBtosdayndWeOirgghatnsWeighs and Ratios ofOrgan m2 E. Body Weights and Body Weight Changes m3 : F. Absolute (dss) and Relative (gkg/day) Feed Consumption Values ms G. Maing and Ferility m7 H. CacsareanSectioning and Liter Observations m7 IL Nara Delivery and Lier Observations m7 J. ObCsleinrivcaatliOobnsservations from Birth t Day Postpartumand Necropsy ms K. Blood and Tissue Analyses me L. Histopathology of Hearts and Thyroids FI Generation Pups m2 REFERENCES mas APPENDIX A - REPORT FIGURES Figure 1. Body Weights - Fo Generation Female Rats - Groups 1, 8 trough 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, 6and 7 As APPENDIX B - REPORT TABLES Table 1. Clinical Observations - Summary - Fo Generation Female Rats Bi Table 2. Necropsy Observations - Summary - Fo Generation Female Rats B9 Table 3. WTeerimgihntaltoBToedrymiWneailgBhtosdyanWdeiOgrhgtan-WSeuigmhmtasray-ndFoRaGteinoesr(a%ti)oonf Organ Female Rats B12 Table 4. Body Weights - Premating - Summary Fo Generation Female Rats B-15 Table 5. FBeomdaylWeeRiagthst Changes - Premating - Summary - Fo Generation Bs ii 000435 SUBJECT PAGE Table 6. Maternal Body Weights - Gestation - Summary -FoGeneration Female Rats B21 Table 7. Matemal Body Weight Changes - Gestation - Summary Fo Generation Female Rats B27 Tables. Body Weights - Lactation - Summary - Fo Generation Female Rats B-30 Table 9. Body Weight Changes- Lactation - Summary - Fo Generation Female Rats B33 Table 10. AbsoluteFeed Consumption Values (g/day) - Premating - Summary Fo Generation Female Rats B36 Table 11. RelativeFeed Consumption Values (g/kg/day) - Prematin-g Summary Fo Generation Female Rats B39 Table 12. Matemal Absolute Feed Consumption Values (g/day) -Gestation `Summary - Fo Generation Female Rats B42 Table 13. Matemal Relative Feed Consumption Values (g/kg/day) - Gestation Summary - Fo Generation Female Rats B45 Table 14. Absolute Feed Consumption Values (g/day) - Lactation - Summary Fo Generation Female Rats B48 Table 15. Relative Feed Consumption Values (/kg/day) - Lactation - Summary - Fo Generation Female Rats B51 Table 16. Mating and Fertility - Summary - Fo Generation Female Rats B54 Table 17. Cacsarean-Sectioning Observations - Summary - Fo Generation Female Rats B57 Table 18. Litter Observations (Caesarean-Delivered Fetuses) - Summary - Fo Generation Female Rats B60 Table 19. Natural Delivery Observations - Summar-y Fo Generation Female Rats B63 Table 20. Litter Observations (Naturally Delivered Pups) - Summary FI Generation Litters B66 Table 21. Clinical Observations from Birth to Day Postpartum - Summary FI Generation Pups BIS iv 000436 SUBJECT PAGE Table 22. Necropsy Observations - Summary - F1 Generation Pups B78 `Table 23. Clinical Observations - Individual Data - Fo Generation Female Rats ~~ B-81 Table 24. Necropsy Observations - Individual Data - Fo Generation Female Rats B-102 Table 25. Terminal Body Weights and Organ Weights and Ratios (%)ofOrgan `Weight to Terminal Body Weight - Individual Data - Fo Generation Female Rats B12 Table 26. Body Weights - Premating - Individual Data - Fo Generation Female Rats B-135 Table 27. Matemal Body Weights - Presumed Gestation - Individual Data - Fo Generation Female Rats B-148 `Table 28. Maternal Body Weights- Lactation - Individual Data - Fo Generation Female Rats B-174 Table 29. Feed Consumption Values - Premating - Individual Data - Fo Generation Female Rats B-187 `Table 30. Matemal Feed Consumption Values - Presumed Gestation - Individual Data - Fo Generation Female Rats B200 Table 31. Matemal Feed Consumption Values - Lactation -Individual Dat-a Fo Generation Female Rats B213 `Table 32. Mating and Fertility and Days in Cohabitation - Individual Data - Fo Generation Female Rats B226 `Table 33. Cacsarean-Sectioning Observations - Individual Data- Fo Generation Female Rats B239 Table 34. Litter Observations (Caesarean-Delivered Fetuses) -Individual Dat-a Fo Generation Female Rats B242 Table 35. Fetal Vital Status- Individual Data - Fo Generation Female Rats B245 `Table 36. Natural Delivery,Implantation Sites, and Pup Viability and Sex - Individual Data- Fo Generation Female Rats. B248 Table 37. Pup Body Weights Pooled by Litter from Birth to Day 5 Postpartum - Individual Data - FI Generation Litters B261 V 000437 SUBJECT PAGE Table 38. Pup Vital Status and Sex from Birth to Day Data - FI Generation Pups. Postpartum- Individual B274 Table 39. Clinical Observationsfrom Birth to Day S Postpartum - Individual Data - FI Generation Pups. B-287 Table 40. Necropsy Observations - Individual Data - F1 Generation Pups B292 APPENDIX C- PROTOCOL AND AMENDMENTS C1067 APPENDIX D- DSETVAINADTAIRODNSOFPREROAMTTIHNEG PPRROOTCOECDUORLAESNDOTFHTHEE TESTING FACILITY D1toD-6 APPENDIXE- CERTIFICATE OF ANALYSIS E10E2 APPENDIX F- HOMOGENEITY AND CONCENTRATION ANALYSIS F-loF21 APPENDIXG - TEMPERATURE AND RELATIVE HUMIDITY REPORTS G10GS APPENDIX H- BIOANALYTICAL REPORTS (ANILYTICS) Hl 0H-125 APPENDIXI- BIOANALYTICAL REPORTS (PRIMEDICA WORCESTER, SPONSOR AND SRD) Iltol444 APPENDIX J- HISTOPATHOLOGY REPORT F037 APPENDIXK - HISTORICAL CONTROL DATA K-10K8 APPENDIXL- STATEMENT OF THE STUDY DIRECTOR Ll APPENDIX M- QUALITY ASSURANCE STATEMENT M-1toM2 000438 vi 418-018:PAGE 1-1 TITLE: ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS ARGUSRESEARCHPROTOCOL NUMBER: 418-018 SPONSOR'S STUDY NUMBER: T-6295.25 IL SUMMARY AND CONCLUSION `The purposes of thi study were to determine whether the co-administrationofmevalonic: acid or cholesterol could prevent or antagonize the adverse matemal and fetal effects (reduced matemal body weight gain, increased incidence of stillborn, decreasedbirth weight and decreased pup survival) observed in previous study with PFOS (Argus Research Protocol 418-008, 3M Study Number T-6295.9) and to better define the noobserved-effect-level (NOEL). A. Methods' Female Crl:CD(SD) IGS BR VAF/Plus rats were used for the study. The rats were received in two shipments designated as Replicate 1 and 2, respectively. The rats were randomly assigned to 13 dosage groups (Groups I through 13), 14 ras per group per replicatefor Groups 1, 2,4 through 7, 12 and 13, 14 ratsfor Group 3 replicate 1, 15 rats for Group 3, replicate 2, and 10ratsper group per replicate for Groups through 11. The first eight female ratsperdosage group in Groups 1 to 7, 12 and 13 of Replicate | with a confirmed date of mating were assigned to Caesarean-sectioning on day 21 of gestation (DG 21). The remaining female rats were permitted to naturally deliver ltrs. The test article was perfluorooctane sulfonic acid potassium salt (PFOS) and the control articles `woesrmeosmiesvmaelomnbircaanceidpraoncdescsheoldesdteeiroonli.zeTdhweavteehric(lReOswDeIrHe;00.).5% Tween 80 and reverse. a. Detailed descriptions of all procedures used in the conduct of this study are `provided in the appropriate sections of this report and in APPENDIX C (PROTOCOL AND AMENDMENTS). 000439 `The dosage groups and dosing schedule were as follows: 418-018:PAGE I-2 Nomber| _ penstcaion [[T=[TenVeonnteacoomceomoorr|| R[3DS0I0OMmg0F|| [onTemtpe PaROS rTTi50o0 mgs 2mg/kgPFOS + 500 mg/kg. # Mevalonic Acid Mevalonic Acid ||o5[|ooTacemuipmrmaiPecOmSnT || |SSS5o0o0ammmtpg/ihkegy|| 7 TagksPROS Cholesterol Swmgie Foto] [8 | | omergrros || OSmgkgPros |Notspplcable| | TOT Tmphg?FOS |Notspplcable| 1a2theTrodoLdto1d0sumogienaurtes | 5h +2S03d0mdeomasater 058Tween 80] ropitio | osnremoro | S50o0 mmgikeg romomemos | SSo00mmpie 2 me/kg POS oesenrewernoom|| wveeawpmoonn || -2 mg/kg PFOS. 500mg/kg. Mevalonic Acid -- omNot applicable 08mokgPFOS | Notappliabie | ImpgPROS | Notappliable | 12 mplkg PROS Not applicable The dosages, concentrations and dosage volumes were as follows: LCeonimfpaoinodn : Comcgeimnaion | DwmgiVg)os [[rosoTubemooi[ 0[0 0 ---- 00---- 5 5 [VerosiwoenseAc Tso w mo0 [eros TorTow 5 5 5] ] [[perroorsssTor 1T T To ora eo 5 x 5 5]|| [[eT CrroosNseToT i n e dene Tow owT 5 5] ] Dosages were adjusted for the most recently recorded body weight and given at approximately the same times each day. 000440 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 liter) or day 4 of lactation (DL 4, rats that delivered a liter). FI generation pups were not directly given the test ticle, control article and/or vehicle, but were possibly exposed to the test article or control articles during matemal gestation or via matermal milk during the lactation period. Rats were observed for viability at least twice each day of the study. Observations for clinical signsof effectsofthe test article and deaths were made daily priotor dosage: administration, approximately one hourafterthe second dosage and at the endofthe. working day. These observationswerealso recordoend the dayof sacrifice. Body weights were recorded weekly to cohabitation, daily during presumed gestation, on DL I (rats assigned to natural delivery) and at sacrifice. Feed consumption values were recorded weekly to cohabitation, on DGs 0, 7, 14, 21 and 25(ifnecessary) and DLs 1 and. 5 (rats assitgonnateurdal 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 conditionofthe dam and litte during the postpartum period and viability index. Matemal behavior was recorded on DLs 1 and 5. Litters were examined after delivery to identify the number and sex of pups, sillborns, live births and gross extemal alterations. Each liter was evaluated for viabilitya least twice each dayofthe 5-day postpartum period. FI generation pups in each liter were: counted once daily. Physical signs were recorded each day. Pooled liter weights were recorded on DL 1 (birth, livebor pups), 2, 3,4 and 5. Eight rats from dosage groups 1107, 12 and 13 (Replicate 1) were sacrificed on DG 21. Blood and liver samples were collected from these rats. The rats were Caesarean sectioned and a gross necropsyofthe thoracic, abdominal and pelvic viscera was. performed. The number of corpora lutea in each ovary was recorded. The uterusofeach at was excised and examined for pregnancy, number and distribution of implantation sites, live and dead fetuses and early and late resorptions. Placentae were examined for size, color and shape. Blood samples were collected from the rats assigned to Caesarean-sectioning. Following collection of blood samples, the liovfeeacrh rat was excised and the liver weight was recorded. A portion of each liver sample (right lateral lobe) was flash frozen and 000441 418-018:PAGE 14 mpoaritnitoanionfetdhferolzievne.r wTahsefmiexdediainn glliuvetrerlaolbdeehwyadse.frTozheen.reAmasiencitnigonpofrrtoimonothfetrheemaiivneirngwas frozen. cFoeltluescetsedwefrreompoeoalcehdfbetyusl.ittTerhaenldivleirttefrrboomdeyacwheifgehttuss were recorded. was collected. Blood samples were: One fetal liver from alictther lwietreer wdaivsidreedmoinvteodtahrnedefsiaxmepdliensoglfuetqeruaalldenhuymdbee.r.ThTewroeomafitnhiengsafmetpallelsivweersreinfreoazcehn. `The remaining samples were flash frozen in liquid nitrogen and maintained frozen. tOhnorDaciLc5,tahbedroamtisanaslsaingdnpteelodvincatvuirsaclerdaelwiavserpyewreforremesda.crifBilcoeodda,nmdilakg,rhoesasrtneacnrdopisvyeorfthe bsalmopoldessamwpelrees,cotlhleechteeadrtfranodm lmiavteerronfalearcathsdoanmDwLer5.e cFoollllecotweidn.gTcholelelcitvieronwoefimghitlkwaasn.d r`emcaoirndteadi.nedAfrpoozretni.onTohfeeamcehdilainverlisvaermpllobee(rwiagshtsltaotreerdalfrloozbeen). waTshefhleasahrtfaronzdenasaencdtion fromtheremaining portionof the liver were fixed in glutcraldehyde. The remaining portion of the liver was frozen. OsinngDleLScr,ospsu-psescwtieorneosfactrhiefhiceeaddaantdtehexalmevienloedftfhoregfrroosnstalle-spiaornise.talNescutruorpesaynidncelxuadmeidnaation of the cross-sectioned brain for apparent hydrocephaly. Blood samples were collected from each pup. FpuoprsRecpolmibcianteed1., bFloorodRespalmipcaltees2w,ebrleoopdooslaemdppleerslwitetrere, psoaomlpeldes(tfwroomlitmtaerlsepaerndsafmepmallee wliittthei)naenadcthhdeopsoaogleedgrwoeuip)g.htTrheecorldiveedr. frOonmeelaicvherpfurpomwacsaccholllietctteredp,ooploowlaesd r(beymosveexdpearnd fsiaxmepdleisn golfuteeqruaalldenhuymdbee.r.ThTewroemoafitnhiengsalmipvelressiwneeraechstloirteedr fprooozlenw.erTehdeirviedmeadiniinntog three: stawmopmlaelweaasndflatswhoffreomzeanleanpdupmsaifnrtoamieneadchfrloitzteenr.(pTohoelehdeabrytssewxerpeercloiltlteerc)teadndfrwoemrethfeifxierdst in gluteraldehyde. Thyroids were excised from each pup, pooled (by sexperlitte) and retained MfeimcarloescFoIpigceneexraamtiinoantipounpwfarsommdaadmesooffteheachheaorft tahnedvtehhyircoliedcofnrtormolon(eGrmoaulpe1a)nadnodne: 2 mg/kg/day PFOS groups (Group 13). B. Results N(moevdaelaothnsicwaecriedactotnrtirboult)a,bl3e(110.6thmegt/esktgoPrFcoOnStr+olmaervtiaclleosn.icOanceid)ratanidn ea(cchhoolfesGtreoruolps 2 control) died as the result ofintubation accidents or natural causes. All other rats survived (0 scheduled sacrifice wl04he 418-018:PAGE I'S `The numbers of rats with excess salivation, a perioral substance and chromorhinorrhea during gestation were significantly increased in Group 5 (mevalonic acid control) as compared to Group 1 (vehicle control). These increases were attributed to an aversion to the taste of mevalonic acid; the incidence of these observations was comparable among thethree mevalonic acid groups (Groups 2, 3 and 4). Allotherclinical observations during the precohabitation, gestation and lactation periods were considered unrelated to the test or control articles. All necropsy observations were considered unrelated to the test or control articles. Terminal body weightsofrats Caesarean-sectioned on DG 21 were significantly reduced in Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively). The weightofthe liver was significantly increased in Group 7. As a resultofthe reduced terminal weights in Groups 6 and 7 and the increased liver weight in Group 7, the ratios of the liver weight 10 the terminal body weight were significantly increased in these two groups. All other terminal body weights, liver weights and relative liver weightsofrats Caesareansectioned on DG 21 were unaffected by PFOS or mevalonic acid. Terminal body weights of naturally delivered rats were significantly reduced in Group 13 (2 mg/kg PFOS alone) and in Groups 6and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively). The ratios of the liver weights to the terminal body weights were sreisgpneicftiicvaenltyl)y,irnecfrleeacsteidnginslGirghoturpesdu9,ct1i1onasnidn1t3er(m0i.n8a,l1.2boday w2enimgghd /tskganPdF/oOrSslailgohntei,ncreases in liver weights in these groups. The liver weight was significantly increased in Grou3p (1.6 mg/kg PFOS + mevalonic acid). The ratios of the liver weight to the terminal body `wmeeivgahltonwiecreacsidi,gnriefsipceacnttilvyeilnyc)raenasdeidniGnrGoruopusps6 3anadnd7 4(1(.16.a6nadnd2 2mgm/gk/gkgPFPOFSOS+ + cholesterol, respectively). Body weight gains for the entire precohabitation period were significantly reduced in Group 13 (2 mg/kg PFOS alone) and Groups 6and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively). During this period, gains were significantly reduced in Groups 6an7odn DSs 22 10 29.and 29 to 36; and in Group 13 on DSs 29 to 36. `Additionally, body weight gains for Group 12 (1.6 mg/kg PFOS alone) were significantly AresduacreedsuoltnoDfStshe2s9e tcoha3n6geasn,dbbooddyywweeiigghhttslwoessreocsciugrnirfeidcainntlthyisregdruocuepdoinn GDrSosu3ps6t6o a4n2.d 7 on DSs 29, 36 and 42. Body weight gains for the entire precohabitation period in Group 5 (cholesterol control) were significantly increased. Premaing body weighs and body weight 1.2 mike. gains were unaffected by mevalonic acid and dosages of PFOS as high as Body weight gains for the entire gestation period were significantly reduced only in G(1r.o6uapnsd62amngd/7kg(1P.6FaOnSd+2 mmegv/aklgonPiFcOaScid+,chroelsepesctteirvoell,y)r,esGpreoctuipvsel6y)a.ndGr7ou(1p.s6 3anadnd 4 2 mg/kg PFOS +cholesterol, respectively) and Groups 9, 11, 12 and 13 (0, 12, 1.6 and f2irmstg/wkegekPFofOtShealgoenset,atrieosnpepcetriivoedl.y)Thhaedresiwgenrifeicnaontsliygnriefdiuccanetd dbiofdfeyrewneciegshat mgoainngsfaonrytohfe these dosage groups during the second week of gestation. Group 13 had a significant 000443 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 along with mevalonic acid, the effect on body weight was less PFOS severe was and aadpmpienairsetdeorveedr a shorter period than PFOS administered alone. Body weights were significantly reduced i(n2 Gmrgo/ukpg 3PF(1O.S6 m+gm/ekvgalPoFnOiSc a+cimde)voalnoDniGcsa7citdh)roonugDhG1s0.4Tthheroeufgfhec1t3o,nanbdodiyn Gwerioguhpt4was `more severe and appeared over a longer period when PFOS was administered along with c2homlges/tkegroPl.FOBSo+cdhyolweesitghetrsolw,erreesspiegncitfiivcaenltoylny)rDedGucs0edithnrGourgho21u.6pGaenssdta7ti(o1n.6baonddy weights `8wetrherosuiggnhif1i7caanntdly2i1n.crDeeasspeidteinthtihseecfhfoelcetsotefrcohlolceosntterroollgarloounpe,(bGoroduypw5e)igohntsDiGn thSe, groups administered PFOS with cholesterol (Groups 6 and 7) had significant reductions in gestation body weights. BreodduycewdeiignhGtrgoauipnss9d,ur1i0n,g1t2heanfdirs1t3i(v0e.3d,a1y,s1o.f6 tahnedl2acmtgat/ikogn pPeFriOoSd awleornee,sriegnsipfeicctainvtellyy). `The average body weight on DL was significantly reduced in Group 13. When PFOS `twhaasnaPdFmiOnSisatdemriendisatleornegdwailtohnem.evBaolodnyicweaicgihdt, tghaeinesffweectreonsibgnoidfyicwaentilgyhtrewdausceldesosnseDvLesre1 1`G0r5ouipnsG2r,o3upan3d, b4u(tmaevvearlaogneicboadciydwcoentriolg,ohn1.Dt6 Lasnsd 12amngd/5kgwePrFeOcSom+pmaervaablloenaimcoancigd, rweesipgehcttiwvealsy)m.orWehesenvePreF.OSBowdays waedimgihntisstoenreDdLaslo|nagnwdit5hwcehroleesstigenriofli,ctahnetleyffreecdtuocnedbiondy Gbrooduypwsei6gahntdl7os(s1o.c6caunrrde2d mogn/DkLgsPF1 OtoS5+inchGolreostuerp7o.l, respectively) and a significant Absolute and relative feed consumption values were significantly reduced in Group 13 (125m(gre/lkagtivPeFoOnSly)a,lo2n2e)10fo2r9t,h2e9entt0i3re6 parnedm3a6t1in0g4p2e.riAobdsaonldutweitahnidnrtehliastipveerifeoeddon DSs 8 to cduornisnugmpthteiolanstvawleueeskowfetrheealpsroemsiagtniinfgicpaenrtiloyd.redAubcseodluitneGfreoeudpco1n2s(u1m.p6tmigo/nkvgalPuEesOSwearleone) sriegsnpiefcitciavnetllyy)roenduDcSesd 2in2Gtroo2u9psan3da3n6d t4o (412..6 Raenldat2ivmeg/fekegdPcFonOsSum+ptmievoanlvoanliucesacwied,re s(iGgnriofiuc4pantonllyy)r.eduTcheidsienffGerctouopfsP3FaOnSda4ndonmeDvSaslo8nitoc 1a5c,id1w5a10s 2r2e,fl2ec2te0d 2in9tahned 36to 42 spirgenmiaftiicanngtlpyerrieodduciendboatbhsoglruotuepsa.ndWrheleantivPeFfOeSedwcaosnsaudmmpitniisotnerveadluaelsofnogrwtihtehencthiorlee:sterol, cthoensefufmepcttioonnfveaelduecsonwseurmepstiigonnifviacalnutelsywraesdumcoerdeinseGvreroeu.psAb6saonldut7e(a1n.d6 arenldat2ivmegf/ekegd PFOS +cholesterol, respectively) on DSs 22 t0 29, 29 to 36 and 36 to 42. This effect of PcoFnOsSumapntdiocnhovlaelsuteersoflowratshereenftliercetepdreinmatthiensgigpneirfiiocdanitnlybortehdugcreodupasb.soRleultaetainved freeleadtive feed cioncnrseuamspetdiionntvhaelmueevsaolnonDiScsac8i10d co1n5t,r1o5l 1g0r.o2u2p, 2(2Gr1o0u2p92a).ndAb1stool4ut2ewaenrde rseilgantiifviecafneteldy consumption values were significantly increased on DSs 29 to 36 and absolute feed 000444 418-018:PAGE 1-7 `consumption was significantly increased on DS 36 to 42 inthe cholesterol control group (Group 5). Absolute and relative feed consumption values were significantly reduced during the first week of gestation in Groups 9 through 12 (0.8, 1, 1.2, 1.6 and 2 mg/kg PFOS alone, respectively). Absolute feed consumption continued to be significantly reduced in Group 13 on DGs 7 to 14, and relative feed consumption was significantly increased in Group 12 on DGs 1410 21. Absolute feed consumption values for the entire gestation period (DGs 00 21) were significantly reduced in Groups 12 and 13 (1.6 and 2 mg/kg PFOS alone, respectively). When PFOS was administered along with mevalonic acid, effects on feed consumption values were comparable to the effects of administration of PFOS alone. Absolute feed consumption values were significantly reducedinGroups 3 and 4 (1.6 and 2 mg/kg PFOS + mevalonic acid, respectively) on DGs 0107, 7 to 14 and. 01021. Relative feed consumption values were significantly reduced in Groups 3 and 4 on DGs 0107and 7 0 14. When PFOS was administered along with cholesterol, effects on feed consumption values were also comparable to the effects of administration of PFOS alone. Absolute feed consumption values were significantly reduced in Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively) on DGs 0107,7 to 14, and 00 21. Relative feed consumption values were significantly reduced in Groups 6 and 7 on DG 0 to 7 and significantly increased in Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively) on DGs 14 1021 Absolute feed consumption values during the fist ive daysofthe lactation period were significantly reduced in Groups 12 and 13 (1.6 and 2 mg/kg PFOS alone, respectively). Relative feed consumption values for the same period were reduced in Group9s through 13, reaching statistical significance in Groups 9, 10, 11 and 12 (08, 1, 1.2 and 1.6 mg/kg PFOS alone, respectively) values. When PFOS was administered along with mevalonic acid, effects on feed consumption values were also comparable to the effects of administration of PFOS alone. Absolute and relative feed consumption values were significantly reduced in Groups 3and 4 (1.6 and 2 mg/kg PFOS + mevalonic acid, respectively) on DLs 110 5. When PFOS was administered along with cholesterol. effects on feed consumption values were comparable to the effects of administration of PFOS alone. Absolute and relative feed consumption values were significantly reduced in Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively) on DLs 1 t0 5. `The number of days in cohabitation, the fertility and pregnancy indices and the number of rats with confirmed mating dates during the first and second weekofcohabitation were comparable inthe thirteen dosage groups. Cacsarean-sectioning observations on DG 21 were based on eight pregnant dams in each of Groups 1 through 7, 12 and 13. No Caesarean-sectioning or liter parameters were affected by dosages up to 2 mg/kg PFOS alone or administered with either cholesterol or mevalonic acid. Totals of 1710.20 rats were pregnant and delivered liters in each of the 13 dosage g1r,o1u.p2s,.1.T6haenddu2ramtgio/nkgofPgFeOstSatailoonnew,asresspiegcntiifvieclayn)tl,yGrreoduupcsed3 ian nGrd4ou(p1.s69antdhr2oumggh/k1g3 (0.8, cPhFolOeSst+ermole,varlesopneicctiavceildy,).reTspheectnivuemlbye),raonfddGarmosupwist6h aalnldp7up(s1.d6yainndg o2nmgD/Lksg1PtFoO5Sw+as 000445 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 Groups12and 13 (1.6 and 2 mg/kg PFOS alone, respectively), Groups 3and 4 (1.6 and 2 mg/kg PFOS + mevalonic acid, respectively), and Groups 6and 7 (1.6 and 2 mg/kg PFOS +cholesterol, respectively). `The numbersof pups that died or were presumed cannibalized on DL 1 and DLs 210.5 was significantly increased in Groups 12, 13,4, 6 and 7. The numbers of surviving pups. per litter were significantly reduced on DLs 2,3,4 and in Groups 12, 13,3,4, 6 and 7. A dosage-dependent patternofreduced pup body weight was evident on DLs 1,2,3,4, 5 and/or 110'S in each group administered the testarticle. 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)andGroups 6 and 7 (1.6 and 2 mg/kg PFOS +cholesterol, respectively) had significantly reduced pup body weights on most weighing days. When average pup weight was normalized for liter 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, 12 and 13 (04,08, 1. 12, 1.6 and 2 mg/kg/day PFOS, respectively) were also significantly reduced from Group 2 (mevalonic acid control, Group 5 (cholesterol respectively, over the same days of lactation. control) and Group | (Vehicle Control), `Adverse clinical and necropsy observations associated with reduced pup viability and p2omtegn/tkiaglPrFedOuSctailoonnei,n mreastpeemctailveclayr)e, oGcrcouurprsed3ianndGr4ou(p1s.61a1,n12d2amngd/k1g3 P(1F.O2,S1+.6meavnadlonic acid, respectively), and Groups 6 and 7 (1.6 and 2 mg/kg PFOS numbersoflitters with pups that were cold to touch occurred in + cholesterol). Groups 11, 12, Increased 13, 4,6 and 7. The numberoflitters with pups not nursing was increased in Groups 12, 13, 3,4, 6wenreds7t;iltlhbeorinncorrefaosuenwdadsesaidgniinfcilcuandtedininGcrroeauspes7.inNtehcernoupmsybeorbsseorfvaptuiposnswiitnhpnuopsmithlakt in trehsepsecttoimvaeclyh),inGGrroouuppss39a,n1d0,41(11,.612anadnd2 1m3g/(0k.g8,P1F,O1S.2,+1m.e6vaanldon2imcga/cikdg, PreFsOpeSctailvoenley,), aofndthGisrooubpsesr6vaatnidon7w(a1s.6siagnndif2icmagnt/lkyginPcFrOeaSse+dchionlGesrtoeruo6lp,.rAelspleocttihveerlcyl)i.niTcahleainndcidence necropsy article. observations in the FI generation pups were considered unrelated to the test Clinical chemistry parameters were generally treated with or without cholesterol and 1.6 or unaffected in the DG 2 mg/kg PFOS. Total 21 dams and free that were Ts and Ta in `wdearmessaidgmniifniicsatnetrleydre1.d6ucoerd2. mTgh/ekLgDPLFOwSaswistihgnoirfiwciantthloyutinmcerveaalsoedniicn atchieddoarmcshotlheasttwereorle ardemdiunciesdteinreDdGme2v1aldoanmisc aadcmiidnainsdtePrFedOS1..6 Loi2rvermcgh/oklgesPteFrOolSlaenvedlsinwDerGe 2s1igndiafmicsantly csiogandimfiinciansttleyrerdedmuecveadloinniDcGac2i1d daandms1.c6oaordm2inmigs/tkegrePdOmSev.aloLniviecratcriidgloyrccerhiodleeslteevreolls awnedre i1n.6croeras2edmgi/nkdgamPsFOcSo.admLiinviesrtLerDeLd cahnodleHstDerLolleovrelmsevwaelroeniinccraeciadseadnodr1s.i6gnoirfi2camngt/lkyg PEOS. 000446 418-018:PAGE I-9 Cholesterol and LDL were significantly increased in the fetuses from dams that were treated with 1.6 or2 mg/kg PFOS. Free T, 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/or 2 mg/kg PFOS.Theclinical chemistry paramofecht oleestr erosl, 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 fetusesfromdams coadministered `soimngenveiaflioocrnaicnctoluayctiimdnicnorriesaceshoreldeedisntmeDervoGall2ao1nndifce1t.au6oscedrs 2 mg/kg PFOS. Liver HDL afnrdom1.d6aomfs2amdmginsistPeRrOedS.1.6 levels were or 2 mg/kg P FO S 0S4er,u0m8,ch1o,le1s.t2e,ro1l.6woars2smiggn/ikfigcaPnFtOlSy.decTrheeasgelducionstehewalasctsaitginnigfdicaamntsltyhiantcrweearseedtrienattehde with 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 Ti levels in lactating dams administered 0.4 (free T, only), 0.8, 1, 12, 1.6 or 2`admmgi/nkisgtePrFeOd S1.2w,er1e.6soirgn2ifmigca/nktglyPrFeOduScewderaendsitgontiafliacanndtlfyrereeTdujcleedv.elSseirnluamctcahtoilnegstdearomls was significantly decreased 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 in the Tlayctwaetriengsdiganmisfitchaanttlwyerreedutcreeadteidn wtihtehlamcetvaatilnognidcamascitdhaantdwe2rmegt/rkeagtePdFwOiSt.h mTeovtaalloannidc farceied orcholesteroland 1.6 or 2 mg/kg PFOS. Cholesterol inthe 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 increasedor DsiLgni5fidcaamntslycoiandcmrienaissetdeirnedDLme5vadlaomnsicadacmiidnoirstcehroeldes1t.e6roorl 2anmdg/1k.6goPrF2OmSg/alkognPeFaOnSd.in Clinical chemistry parameters were not significantly different in the DL 5 pups from llaecvtealtsiinng tdhaemFs1tghaetnewrearteiotnrepautpesd wfirtohm0l.a4c,ta0.t8i,ng1d, a1m.2s, 1.6 or2 mg/kg PFOS. administered 0.4, 0.8, Free Ts 1, 1.2, 1.6 or 2Sdmmgi/nkigsPerFdOS0.w4e.r0e8soifgn|ifmicaanthlyPrRedOuScewd.ereFrseiegnTifsilceavnetllsy irnedpuuepesd,fhroowmelvaecrt,atiengsdlamwsere significantly increased, in pups from lactating dams administered 1.6 mg/kg PFOS. Total Ta levels in pups from lactating dams administer0.e4d, 0.8 or | mg/kg PFOS were significantly reduced. TSH was significantly increased at | mg/kg PFOS. Liver triglyceride levels were reduced or significantly reduced in DL5 male and female pups fdraomms dcaoamdsmiandimsitneirsteedrcehdol1e,s1t.e2r,ol1.a6nadnd1.62 omrg2/kmgg/PkFgOSPFaOlSo.ne and in DL 5 male pups from 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 T, 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 000447" 418-018PAGE 1-10 lactating dams that were treated with cholesterol and 1.6 or2 mg/kg PFOS and triglycerides were significantly decreased in the pups from dams that were treated with cholesterol and 2mg/kg PFOS. Total Ts andfree Towere significantly decreased in pups fromlactatingdams that were treated with cholesterol and 1.6 and/o2r mg/kg POS. No microscopic changes were seen in the heart or thyroidofthe male and female pups whose dam was exposed to 2 mg/kg/day PFOS (Group 13). C. Conclusion On the basisof these data, it does not appear that coadminisotfrmeavtalionoinc acid or cholesterol can prevent or antagonize the adverse maternal or fetal effects observed in a previous study with POS (Argus Research protocol 418-008; 3M study number T-6295.9). `The matemal no-observable-effect-level (NOEL) for ths study is 0.4 mg/kg PFOS (the 0.8 mg and higher dosages of PFOS caused an increased liver weitotgerhmintal body `weight ratio,decreasedbody weight gain during gestation and lactation and decreased absolute and relative feed consumption during gestation and lactation on days). `The reproductive NOEL in the dams is also 0.4 mg/kg (the 0.8 mg/kg dosage decreased the duration of gestation). `The NOEL for viability and growth in the offspring is less than 0.4 mg/kg (dosages of 0.4 mg/kg and higher caused decreased pup body weights when normalized for liter size). apil deled "Deo ( )7 GeorgE. Dearlove, Ph.D., DABT Date Associate DirectorofResearch 4 AssociatdeGD.irYeoctrokroefnRehse. aDrAchBT Date. and Study Director 000448 418-018:PAGE I1-1 IL DESCRIPTION OF TEST PROCEDURES A. ConductofStudy Al Sponsor 3M Corporate 55144-1000 Toxicology, 3M Center, Building 220-2E-02, St. Paul, Minnesota A2. Testing Facility Argus Research, 905 Sheehy Drive, Building A, Horsham, Pennsylvania 19044-1297 A3. Study Number 418.018 Ad. Sponsor's Study Number T-629525 AS. Purpose of the Study ``Tmheevapluornpiocsaecsiodfotrhcishoslteusdtyerwoelrcea:n1p)rteovednetteorrmiannteawghoentizheerthoef andovtecros-eamdmaitneirsntarlatainodnfoeftal ewfefiegchtts (arneddduceecdremaasteedrnpaulpbsoudrvyivwaeli)gohbtsgearivne,diinncraeapsreedvipoeurscesnttudsyti(llAbrogrnu,sdReecsreeaarscehd birth ePfrfoetcotcolelv4el18(-N0O0E8L,)3.M study number T-6295.9); and 2) to better define the no observed AS. Study Design `The requirements of the U.S. basis for the study design. Food and Drug Administration(FDA) were usedas the A. Regulatory Compliance b`aTshiesrefqoruitrheemsetnutdsyodfestihegnU..S. Food and Drug Administration (FDA) were used as the The study was conducted in compliance with Good Laboratory Practice (GLP) regulations of the U.S. Food and Drug Administration (FDA)TM,the Japanese Ministry of `HweearletnhoandedvWiaetlifoanrsef(rMomHtWh)e TMGLaPndretgheulEautiroonpsetahnatEacfofneoctmeidctCheomqumaulnitiytoyr(iEntEeCgr)i.ty oTfhtehree sotfutdhyi.sstQuudayliatryeAdssoucruamnecneteUdniatnfdinhdaivnegsbedeernipvreodvfirdoemd ttohethiensSpteucdtiyoDnisrdeucrtionrgatnhdetchoenduct Testing Facility Management. 0Qa449 418-018:PAGE 11-2 AS. Ownershipofthe Study `The Sponsor owns the study. All raw data, analyses, reports and preserved tissues are the property of the Sponsor. A9. Study Monitor Deanna J. Luebker, MS. A0. Alternate Study Monitor John Butenhoff, Ph.D, DABT, CTH Al. Study Director Raymond G. York, Ph.D, DABT A2. Technical Performance TJoohdndFJ.. BKailmleitnto,, BB..SS.. ((RDeirseecatrocrhoAfsLsoacbioartaet)ory Operations) Alaine L. Casey, A.S. (Laboratory Technician) BCrhirainstKo.phKeerlKs.chRu(pNpeecrrto,psB.ySL.a(bFoorramtuolraytTieocnhLnaibcoiraant)ory Technician) A.I3. Report Preparation Raymond G. York, Ph.D., DABT Jo Ann Frazee, MS. (Study Coordinator) PCraimsetlinaaJP.eSthruefseclut,(RB.eSp.or(tDaAtdamiMnaisntargaetomre)nt Team Leader) A.14. Report Review Valerie A. Sharper, M.S. (Directorof Study Management) AS. Date Protocol Signed 21 August 2000 000450 418-018:PAGE 1-3 A16. DatesofTechnical Performance A162. Replicate 1 Rat Arrival Dosage Period Rats Assigned to Caesarcan-Sectioning (42 days before cohabitation and continuing through DG" 20) Rats Assigned to Natural Delivery [42 days before cohabitation and continuing through DG 24 (rats that id not deliver ier) or DL 4 (rats that deliveredaliter) Cohabitation Period Male 1 (7daysmaximum) Male 2(7daysmaximum) Scheduled Sacrifice (DG 21 Caesarean-sectioning) DG 25 Sacrifice No Confirmed Date of Mating Sacrifice. Delivery Period (DL 1) Scheduled Sacrifice (DL 5) 22AUG 00 29 AUG 00-02NOV 00 29 AUG00- 18 NOV 00 09OCT00PM -16 OCT00 AM 16OCT 00PM -23OCT00AM 31 0CT 00-03 NOV 00 05 NOV 00-09 NOV 00 17NOV 00 31 OCT 00- 15 NOV 00 04NOV 00- 19 NOV00 A161. Replicate 2 Rat Arrival Dosage Period Rats Assigned to Natural Delivery [42 days before cohabitation and continuing through DG 24 (rats that did not deliver a litter) or DL4 (rats that delivered a liter)) Cohabitation Period Male 1(7daysmaximum) Ma2l(e6 days maximum) DG 25 Sacrifice Delivery Period (DL 1) Scheduled Sacrifice (DL 5) 05 SEP 00 14 SEP 00-02 DEC 00 2051 ON CT00O 00PPMMV -- 0017NNOOVV0000AAMM 20 NOV 00-23 NOV 00 2160NNOOVV 0000--2093 NDOECV0000 a. DGisan abbreviation for day of (presumed) gestation. b. DLisan abbreviation for day of lactation/postpartum. 000451 418-018:PAGE [14 A. Records Maintained Tvehheicolreigcionamlpornepeonrtt,sraarew rdeattaainaenddirnetsheervaercshaimvpelseosoffAregaucsh Rleosteoaftrchhe. cAonntyrolpraersteirclveedand dtriasfstueisnaarlerreeptoaritn,eadfienrtwhheiacrhchtiivmees otfhetShepoTnessotirnwgilFlacdielcitiydefotrhoinrefiyneaalrdiasfpteorsimtaiioln.ingAtlhe unused prepared formulations were discarded at the Testing Facility. Unused bulk test article was retumedtto he Sponsor. B. Test Article Information B.. 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. BA. 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 test article. BS. Analysis of Activity Information regarding the identity, composition, strength, and purity of the test article is on file with the Sponsor. The purity is 98.9%. A Certificate of Analysis is available in APPENDIX E. C. Control Articles Information CL. Descriptions Mevalonic Acid - white with a yellow cast, semisolid Cholesterol - white powder C2. Lot Numbers Mevalonic Acid - 070K26603 and 080K2618 Cholestero-l 119H0218 000452 418-018:PAGE IIS C3. Dates Received and Storage Conditions `oTnhe1 mAeuvgaulsotni2c00ac0i(dlowta0s7r0eKc2e6i6ve0d3)fraonmdS2i1gSmeapCtheemmbiecra2l0C0o0m(plaotn0y8,0SKt2.6L1o8u)i,s,aMnidssstoourreid, frozen. The cholesterol was received from Sigma Chemical Company, St. Louis, Missouri, on20 July 2000, and storedatroomtemperature. 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. AnalysisofPurity Neither the Sponsor nor the Study Director was awareofany potential contaminants lriekseluystoofhtahvies bsteuedny.prTesheentpuirnittyheocfotnhteromlevaartliocnleisctahcaitdwoisualpdprhoaxviemiantteelryfe9r7e%d.witThhethpeurity o(flotth0e7c0hKo2l6es6t0e3r)olainsd95Se%p.teTmhbeerex2pi0r0a4ti(olnotd0a8te0sK2f6or18t)h.e mTehvealeoxnpiicraatciiodnadraeteAufgorusthte.2004 cholesterol is July 2004. D. Vehicle Information D1. Description 0.5% Tween 80 prepared using Tween 80, ayellow liquid, and reverse osmosis `membrane processed deionized water (RODI H;0). Reverse osmosis membrane processed deionized water (RODI H:0). 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 available from a continuous source at the Testing Facility and is `maintained at room temperature. D4. Special Handling Instructions `Standard safety precautions (useofprotective clothing, gloves, dust-misVHEPA-filiered `mask and safety goggles or safety glasses and a face-shield) were taken when handling the vehicles. . 000453 418-018:PAGE II-6 DS. Analysis of Purity Neither the Sponsornorthe 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 datefor 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 o y TeEell = N oeN l CaHn EEeL ieI neEE EE 000454 418-018:PAGE 1-7 E2. Analytical Results Samples were sent to Exygen Research, State College, Pennsylvania, for analysis. PFOS levels in the Da0y and 10 stability and concentration samples bracketing the range of concentrations and conditions of this study were determined. Analysis of samples on d1e4viFaetbirounarfyor2P0F0O2Stoin15thFeebdrousairnyg s2o0l0u2tisonhsowased9a3n%a=ve7r%agaenpderrcaenngterdefcroovemr8y3%sttoan1d0ar5d%, `when compared to the assigned concentration, which was not considered to be significant. Resultsofthe stability and concentrationanalysesare available in APPENDIX F. F. TestSystem F1. 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 forthe purpose of breedingandare not consideredpartofthe Test System). F5. Rationale for Test System The Crl:CD(SD) IGS BR VAF/PIus rat was selected as the Test System because: 1) this strainofrat has been demonstrated to be sensitivtoe reproductive and developmental toxins and has been widely used throughout industry for reproductive and developmental toxicity evaluations; 2) historical data and experience exist at the Testing Facility"; 3) the test article is pharmacologically active in the species and strain; and 4) this strain has been used in previous reproduction studiesofPFOS. 0004Ss \ 418-018:PAGE 11:8 F6. 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 EJ. Breeder Male Rat Data Number of Rats Approximate DateofBirth Approximate Age at Amival Weight (g) the DayafterArrival Weight (g) at Cohabitation - Replicate 1 Weight (g) at Cohabitation - Replicat2e Shipment 1 ~ Shipment 2 150 150 29FEB00 20 MAR 00 Tidays 72days 245-339 286-344 473-767 537-748 452-773 593-791 F3. Method of Randomization Female rats were received in two shipments, separated by two weeks. The first shipment was designated as Replicate 1 and the second shipment was designated as Replicate 2. Upon arrival, the male and female rats were assigned to individual housingon the basis ofcomputer-generated random units. After acclimation, female rats were selected for study on the basis of physical appearance and body weights recorded during acclimation. `The rats were assigned to 13 dosage groups (Groups | through 13). There were 14 rats 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 fist eight female ratsperdosage group in Groups 1107, 12 and 13 of Replicate 1 with a confirmed date of mating were assigned to Caesarean-sectionionng DG 21. The remaining female rats (including those with no confirmed mating date) were permitted to naturally deliver litters. FS. 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 ear tag. (Gey Band and Tag Co, Inc., No. MSPT 20101) inscribed with the rat's designated a Sec APPENDIX D (DEVIATIONS FROM THE PROTOCOLANDTHE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY), item 1 000458 418-018:PAGE 119 unnuimqbueer,pesrexm,anteesnttarntuimclbeeri.denCtiafgiecattaiogns wanedredomsaargkeedlevweilt.h the study number, permanent rat Pups were not individually identified during lactation, al 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. G22. Study Rooms `hTahlelwstauydaynrdoionmdsepweenrdeenmtaliyntsauipnpeldieudnwdietrhcaonmdiitniiomnsuomfofpotseinticvheaanigrefslopwerehlaotuirveofto a a1n0d0%humfriedsihtayirwethraet mhoandibtoereendpcaosnssetdantthlryoutghhro9u9g.ho9u7t%tHheEsPtAudyfi.lteRrso.oRmotoemmpetreamtpuerreatwuarse targeted at 64F to 79F (18C 10 26C); relative humidity was targeted at 30% to 70%". G3. Housing cRoahtasbiwtearteioinndainvdidpuoasltlypahrotuusmedpeirniosdtsa.inlDeusrsisntgec,ohwaibrieta-tbiootnt,oemaecdhcapgaierso,ferxacesptwadsurhiongused ainsstihgenmedalteoranra'turcaalgdee.liBveergyinwneirneginnodilvaitdeuratlhlaynhDouGse2d0,inFnoegsetnienrgabtoixoens.femEaalcehrdatasm and cdealgievesrizeedlsiatnedr whoaussihnogusceodndiintiaocnsomwemroeninnecsotmipnlgibaonxceduwriitnhgtthheeGpuoisdtepfaorrtutmhepeCrairode. anAldl UseofLaboratory Animals". Gd. Lighting `An automatically-controlled fluorescent light cycle was maintained at 12-hours light: 12-hours dark, with each dark period beginning at 1900 hours EST. GS. Sanitization Cage pan liners were changed approximately three times each week. Cages were changed approximately everyotherweek. Bedding was changed as often as necessary 10 keep the rats clean and dry. a SReEePOARPTPSE)N.DIX G (TEMPERATURE AND RELATIVE HUMIDITY 000457 418-018PAGE 1-10 G6. Feed Rats weregivenad libitum access to Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) in individual feeders. G7. Feed Analysis Analyses were routinely performed by the feed supplier. No contaminants at levels exceeding the maximum concentration for certified feed or deviations from expected nutritional requirements were detected by these analyses. Copies of the results of the feed analyses are available in the raw data. Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to havebeenpresent in the feed that would have interfered with the resultsofthis study. G8. Water Local waterthathad been processed by passage through a reverse osmosis membrane (`aRnOd/.orwiantdeirv)idwuaasl wavaatielrabbloetttloesthaetrattsaactdholtiebhideturcsagfers.omCahnloaruitnoemawtaisc awadtdeerditnog sthye.stem processed water as a bacteriostat. G9. Water Analysis The processed water is analyzed twice annually for possible chemical contamination (Lancaster Laboratories, Lancaster, Pennsylvania) and monthly for possible bacterial contamination (Analytical Laboratories, Inc., Chalfont, Pennsylvania). Copiesofthe resultsofthe water analyses are available in the raw data. Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the water that would have interfered with the resultsofthis study. G.10. Nesting Material Bed-0"cobs bedding (The Andersons Industrial Products Group, Maumee, Ohio) was used as the nesting material. G11. Bedding Analysis Analyses for possible contamination are conducted semi-annually. Copiesofthe results ofthe bedding analyses are available in the raw data. Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the bedding that would have interfered with the results of this study. 000453 H. Methods H.1. Dosage Administration The dosage groups and dosing schedule were as follows". 418-018:PAGE I-11 e ee T To oem | sono | wosreenss| tooo| E|[RTomoEmer| mi,[ovmeee| [es nmme,| a ma em|i|mosneyy |J re | een] parremss||opstooe | voeumross|we] [o0Tomtmramsos[|oorrmm | [ottmtaarross | omens | a See APPENDIX D, items 2 through 4. 000459 418-018:PAGE I-12 r=r= | om | em | oa `The dosages, concentrations and dosage volumes were as follows: TToomee o0r eewm Cr T ome TE aTee e `The rats were assigned to groups as follows: | me [om perme] = [Eoomen|aon rm s=mohTr oinJlroaelgsdun| 1.6mgPFOS + |[1 om om| 109 1093109, [0 I [a [2 [rer 7 | Cholesterol 10967 10993 T 0.4 mghkg PFOS_ [30 Notapplicable [5 Tos PFO [20 "Notapplicable [0TimphgPFOS | 20 |Notapplicable | impkgPFOS | 20 |Notapplicable 10998" 10998 11586-11599 11099511008 | 11600-11609 [11009-11018 [11610-11615 |11019-11028 |11620-11629 | | 11029-11038 11630-11639 [=] 11063.11066. a See APPENDIX D, items 5 through 7. 11061, 11064, 1106s 000460 418-018:PAGE I-13 H2. RatfiorDoosangeaSellecteion Dosages were selected by the Sponsor on the basis of previous studies conducted with the testarticle. H3. Route and Rationale for Route of Administration rTohuet,ortalhe(egxaavcatged)osraougtee cwaansbseealceccuterdatfeolryuasdemibneicsatuesree:d;12))init cios mopnaeroifstohnewiptoshstihbeledireotuatreys of human exposure; and 3) it i the route used in previous reproduction studies on PFOS. Hd. Method and Frequencyof Administration Dosages were adjusted for the most recently recorded body weight and given at approximately thesametiemacehdasy. Dosages were administered according (0 the previous table. The mevalonic acid dosing needle was wiped clean before administration for each rat Female rats were given the test article, control article and/or vehicle daily beginning 42 days before cohabitation (maximuofm 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 DL 4 (rats that delivered2litter). Rats in the processofdelivering were not given test/control article; such rats may not have received any or aloftheir daily dosage(s) on the dayofparturition. FI generation pups were not directly given the test article, control article and/or vehicle, but were possibly exposed to the test article during maternal gestation (in utero exposure) or via matemal milk during the lactation period. HS. Method of Study Performance H.5.a. Fo Generation Rats `Within each dosage group, consecutive order was used to assign rats to cohabitation, one. male rat per female rat. The cohabitation period consistedof a maximum of 14 days. Female rats with spermatozoa observed in a smear of the vaginal contents and/or a copulatory plug observed in sifu were considered to be at DG 0 and assigned to individual housing. Female rats not mated within the first seven days of cohabitation were assigned altemate male rats that had mated and remained in cohabitation fo2r maximum of seven additional days. Rats were observed for viability at leas twice each day of the study. Rats were examined for clinical observations and general appearance at least once during the acclimation period". Observations for clinical signs of effects ofthe test article and deaths were made. a. See APPENDIX D, items 8 and 9. 000461 418-018:PAGE II-14 daily prior to dosage administration, approximately one hour afte the second dosage and atthe end of the working day (approximately onehourafterthe third dosage)". These: observations were also recorded on the day of sacrifice. cBoohdabyitwaetiigohnt,sdwaielryedruercionrgdpedreastulmeaesdt goenscteatdiuonr,inogntDheLac1c(lriamtsataisosnigpneeridotdo, nwaeteukrallydteolivery) and at sacrifice". Feed consumption values were recorded weekly to cohabitation, on DGs 0,7, 14, 21 and 25(ifnecessary) and DLs 1 and 5 (ats assigned to natural rdeelpilveenriy)s"h.meDntuorifnfgeecdohjaabristwataisondowchuemnenttweod,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/or a copulatory plug observed. in situ The rats assigned to natural delivery were observed for adverse clinical sigas during vpiaarbtiulriittyioan,bdiurtrha.tiTohneorfagsestwaetrieona(lsDoGob0steorvtehed dfoaryftehrteilfiitrystipnudpexw(apserocbesnetravgeed)ofamnadtpiunpgs that result in pregnancy), gestation index (percentageofpregnancies that result in birth of live liters), number of offspring per litter (live and dead pups), number of implantation sites, general condition of the dam and liter during the postpartum period and viability index (percentage of pups bom that survived five days). Matemal behavior was recorded on DLs 1 and 5. Deviations from expected maternal behavior were recorded, when and ifobserved, on all other days of the postpartum period. Hb. F1 Generation Pups Litters were examined after delivery to identify the number and sex of pups, stillbors, live births and gross extemal alterations. Day | of lactation (postpartum) was defined as the day of birth and was also the frst day on which all pups in a liter were weighed (pup. body weights were recorded after al pups in a litter were delivered and groomed by the. dam). Each litter was evaluated for viability atleast twice each day of the 5-day postpartum period. Dead pups observed at these times were removed from the nesting box. FI generation pups in each litter were counted once daily. Physical signs (including variations from expected lactation behavior and gross extemal alterations) were recorded each day. Pooledlitterweights were recorded on DLs 1 (bint, liveborn pups), 2, 3,4 and 5. a. See APPENDIX D, items 8 and . b. See APPENDIX D, item 10. See APPENDIX D, item 11. 000462 418018:PAGE I-15 HG. Gross Necropsy" H.6.a. Fo Generation Rats Assigned to Caesarean-Sectioning Eight rats from Groups 1 to 7, 12 and 13 (Replicate 1) were sacrificed by carbon dioxide `raatssphwyexriaetCioaneosnaDrcGa2n1-.seBlcotoiadonandneaddlgivreorsssanmepclreospswyeorfethcoelltehcotreadcifcr,oambdtohemsienaraltsa".ndTpheelvic . viscera was performed. Gross lesions were retained in neutral buffered 10% formalin for pthoessriablwedfatuat.ureUteevrailouaftaipopna.reRnetplryesneonntpartievgenapnhtotroatgsrawpehrse osftagirnoesds wlietshio1ns0a%rae mavmaoilnaibulemin sulfide to confirm the absence of implantation sites and retained in neutral buffered 10% formalin for possible future evaluation. The numberofcorpora lutea in each ovary was recorded. Theuterus of each rat was excised and examined for pregnancy, number and distribution of implantation sites, live and deadfetusesand early and late resorptions. An early resorption was definedasone in which organogenesis was not grossly evident. A late resorption was defined as one in which the occurrenceoforganogenesis was grossly evident. A live fetus was defined as a term fetus that respondedto stimuli. Nonresponding fetuses were considered (0bedead. Dead fetuses and late resorption were differentiated by the degreeofautolysis present; marked to extreme autolysis indicated that the fetus was a late resorption. Placentae were `examined for size, color and shape. Blood samples (at leas4tmLeach) were collected from the rat assigned to Caesarean sectioning via the inferior vena cava and separated into two approximately equal aliquots. "The first aliquot was placed into EDTA-coated tubes and the second aliquot was transferred into serum separator tubes. The samples were spun in a centrifuge and the resulting serum (divided into two aliquots) and plasma (one aliquot) were transferred into labeled polypropylene tubes. All samples were immediately frozen on dry ice and maintained frozen (<-20 C). Following collection of blood samples, the liver of each rat was excised and the liver weight was recorded. A portion of each liver sample (right lateral lobe) was flash frozen in liquid nitrogen and maintained frozen (70C). The median liver lobe was stored frozen (S-20C). A section (approximately 0.3 to 0.5 cm wide) fromtheremaining portion of the liver was fixed in gluteraldehyde for possible electron microscopy. The remaining portion of the liver was stored frozen (5-20C). Fetuses were pooled by litter and liter weights were recorded. a Atable of random units was used to select ane control group rat assigned to Caesarean-sectioning from whichal tissues examined at necropsy were retained, in order to provide control tissues for any possible histopathological evaluations. of gross lesions. b. See APPENDIX D, item 12. See APPENDIX D, item 13 d. See APPENDIX D, item 14 0004R3 418-018:PAGE I-16 Caps and labeled tubes were weighed (combined weight, to the nearest .001 gram) before (empty) and after retention of pooled fetus samples for subsequent use in ipdheanrtmiaficcoaktiinone,tidcataeonaflycsoelsl.ectSiaomn,plsetutduybedsayw,esraemlpalbeelieddenwtiitfhictahteiosntaunddy cnoulmlbeecrti,onliter timepoint. Blood samples were collected from each fetus via decapitation. Blood from aapnpdrtohxeimraetmealiynionnge-fheatlalfbolfotohdewfaetsustersanisnfeerarcehd liintteorswearsumplsaecpeadraitnotro tEuDbTesA.-cTohaetesadmtpulbeess (woenreeaslpiuqunoti)n waecreenttrriafnusgfeerarneddtihnetorelsaubletliendgpsoelryupmro(pdyilveindeedtuibnetso.twAollalsiaqmupoltse)sawnedreplasma immediately frozen on dry ice and maintained frozen (20C). "The liver from each fetus was collected. One fetal liver from eachlitterwas removed and fixed in gluteraldehydeforpossible electron microscopy. The remaining fetal livers in each litter were divided into three samples of equal number (when possible). Twoofthe sniatmrpolgeesn waenrdemsationrteadinfreodzferno(z<e-n2(0<-C7)0.CT)h.eFreetmaalicnairncgasssaemspwleersewdeirsecafrldasehd fwriotzheonutinfluirqtuhiedr evaluation. H.6b. Fo Generation Rats Assigned to Natural Delivery On DL the rats were sacrificed by carbon dioxide asphyxiation and a gross necropsy of the thoracic, abdominal and pelvic viscera was performed. Blood, milk, heart and iver samples were collected from maternal rats on DL 5". Gross lesions wereretainedin neutral buffered 10% formalin for possible future evaluation. Representative `photographs of gross lesions are available in the raw data On DL 5, each dam was removed from the nesting box and individually housed for approximately four hours. The dam was injected intravenously with one unit of oxytocin approximately five minutes before milk samples (atleast 100 kL per sample) were collected. The samples were immediately frozen on dry ice and maintained frozen (20C). Following milk sample collection, blood samples (atleast 4 mL each) were collected from the ras via the inferior vena cava and separated into two approximately equal aliquots. The first aliquot was placed into EDTA-coated twbes and the second aliquot was transferred into serum separator tubes. The samples were spun in a centrifuge and the resulting serum (divided into two aliquots) and plasma (one aliquot) were transferred into labeled polypropylene tubes. All samples were immediately frozen on dry ice and maintained frozen (<-20C). Following collection of milk and blood samples, the heart and liver of each dam were. collected. The liver weight was recorded. A portion of each liver sample (right lateral lobe) was flash frozen in liquid nitrogen and maintained frozen (70C). The median a See APPENDIX D, item 12. ` : 000464 418-018:PAGE I-17 alilvleorwlporbeopwearsfisxtaotrieodn.frTohzeenf(ir<s-t20cuCt)s.tarTthedethoeatrhte wriagshteoxfctihseedvaenntdratlwomicdultisnweesruerfmaacedeatto. twhaesampaexdeansdtaertxitnegntdoedthaentleefrtioorflythaenvdenvternatlramlildyltionethseurpfualcmeoantatrhyeaarpteerxya.ndTheextseencdoendd cut (tahprporuogxhitmhaetelelfyt 0v.e3nt0ric0l.e5tcomthweiadsec)efnrdionmgtahoertrae.maTihneincgutpohretairotnaonfdthaeseicvteironwere fixed in gluteraldehyde. The remaining portion of the liver was stored frozen (<-20C). RBaltosodthaatndditdisnsoute dsaemplleisavlwieetrtreer nwoetrceolslaeccrtiefdi.cedUtoenriDwGer2e5satnadineexd awmiitnhe1d0f%oragmromsosnliesuimons. sulfide to confirm the absence of implantation sitesTM and retained in neutral buffered 10% formalin for possible future evaluation. 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 necropsyof thethoracic, abdominal and pelvic viscera was performed". Rcaatussethoaftddeiaetdhororwmeorreisabcurnidficcoenddibteicoanuosne tohfemdoaryibthuendobcsoenrdviattiioonn wwearse meaxdaem.inTehdfeorrattshe were examined for gross lesions. Representative photographsofgross lesions are. haveaairltaabnled ilnivtehresraamwpldeastaw.erWehreentapionsesdibaslepr(neovtiopurselcylduedsecdrbiybeadutfoolryrsaitss),assseirgunme,dptloasnamtau,ral delivery. Pregnancy status and uterine contents of female rats were recorded. H6.c. F1 Generation Pups Pups that died before examination of the liter 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 5 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 ltt 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 examination of the cross-sectioned brain for apparent hydrocephaly Caps and labeled tubes 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. 000465 418-018:PAGE [I-18 `Sample tubes were labeled with the study number, rat identification, date of collection, study day, sample identification and collection timepoint. Blood samples were collected via cardiac puncture from each pup. For Replicate 1, blood samples were pooled per litter, samples from male and female pups combined. Approximately 1 mL of blood was transferred into serum separator tubes; any remaining blood was transferred into EDTA-coated tubes. The samples were spun in a centrifuge. and the resulting serum was divided into two aliquots of approximately 200mLand `approximately 300 mL of serum, and stored frozen (70C). Any resulting plasma was transferred into one aliquot and stored frozen (<-70C). gForrouRpe)pliAcpaptreo2x,imbalotoedlysa0m.3plaels. woefrbelopoodolweads(wtawonsliitetreresdpeirtosaEmDpTleA-wciothsitnedcaucbhesd,osaTghee rceomanitniingg balvodotdewassitrlanisfesrreedrinwtoanseGriuvmisnepaortaotoorstubaesc. tTshessaadmrpleesdweSroeresnpun in a (-70C). Resulting plasma was transferred into one aliquot and stored frozen (<-70C). `The liver from each pup was collected, pooled (by scx per litter) and the pooled weight recorded". One liver from each litter pool was removed and fixed in gluteraldehyde for possible electron microscopy. The remaining livers in each litter pool were divided into three samples of equal number (when possible). Twoofthe samples were stored frozen (S-20C). The remaining sample was flash frozen in liquid nitrogen and maintained frozen (70C). The hearts were collected from the first two male and two female pups from each litter (pooled by sex per litter) and were fixed in gluteraldehyde. Thyroids `were excised from each pup, pooled (by sex per litter). Thyroids were retained in neutral onto buffered 10% formalin. The remaining carcasses were discarded without further a See > APPENDIXD, item 16. 000466 H.6.d. Sample Shipmentand Analyses 418-018:PAGE 11-19 Contin Tm Ei [SSeemm sshgawt17 [s20c~~ [CovEer r rite|S76oR -- [iver section |Gluteraldehyde TpT oAmboireswoTfohuclos sc.htoseo&] feueTs E15,T13H),GL0oL HpDL1. 11 wiglycerides' |Spoor PLoweabohnemaenaear | -- eS-- |Sponsor | PossibleEM_______| Choir ert Fooledse erum sT ue | 205C -- -- tyes LTSora-- hhoaloe,eeeTo B1igT3h5eS,)ssLi(oeiGsoHpL.1 11 [[LCihveerr Tipveor ets|[GleueraCldehyde |SSppoommsoorr HeERRTRTE) || PPoosslibelbeBoM_h_e_m_e_]| = cholera. igheerides E[SS emiT--ET i s-- a0ATniSs_s--_TpprooTT oslnhoTm l,--r7] SB 15, 3h)T LooaiprHfaS Le.e1T1s sheeted lr [rE e e EPR SpMN Aol. [Livermediniobe |s20 [iver section Gluteraldehyde sponsor |Sponsor [ros | | PossibleBM______| Cholcaerah gheerides TeRT. ,parndyTSsH levesls. ThToeadild pCihteyerwa!s apis for LTDHLR,HEDoLnahBonroyrwer. OTT 000467 418-018:PAGE 11-20 D IE=T = ee PEa a RieEaEa [PupsReplicate 7] wiglycerides" pape a RE a I r = E Wiens and 2 mg/kg PFOS group (Group 13). 1) and 2 mg/kg PFOS group (Group 13). Resultsofthese analyses are available in APPENDICES H and I. H7. Data Collection and Statistical Analyses PrimedicaArgus 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 AutomatedData 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). 000468 418-018:PAGE 1-21 The following schematic represents the statistical analyses of the data: Typeof Test' 1. Parametric : A. Bartlett Test 11. Nonparametric A. Krus(ka7l-5W%altliiess)Test SiagtnTifTMicant Not Significant Significant T Not Significant Nonparametric Analysis of Variance Dunn's Test Significant at " Not Significant B. Fisher's Exact Test (75%ties) Dunnett Test IIL Test for Proportion Data Variance Test for Homogeneity of the Binomial Distribution a. Suistically significant probabilities are reported as eitherp<0.05 or p<0.01. b. Proportion data are not included in this category. . Test for homogeneityof variance. 000463 418-018:PAGE 1:22 Gacrioducpon1tr(ovle)hiacnlde cGornoturopl)5d(acthaolweesrteerofilrsctonsttartoils)tidcaatlal.y cGormopuapreId(vteohGircloeucpon2tr(omle)vadaltoaniwcere. tPhFeOnScoamlopnae)r.edGtrooGurpou2p(sm8e,v9a,lo1n0i,c1a1c,id12coanntdrol1)3 d(a0.t4a,w0e8r,e1c.o0,mp1.a2r,e1dt.6oaGnrdo2u.p0smg3/akgn.4d (c1o.m6paanrded2.t0omGerokugpsPF6OaSnd+7m(e1v.a6laonndic2.a0cimdg)/akngdPGFrOouSp+$c(hcohloelsetsetreorlo,lrcesopnetcrtoilv)eldya)t.a were: Clinical observations and other proportion data were analyzed using the Variance Test for Hweoimgohgtes,nebiotdyyowfetihgehtBicnhoamngieasl,Dfiesetdricbountsiuomn"p.tioCnonvtailuneuso,uslitdtaertaav(e.rga.g,emsatfeorrnpaelrcbeondtymale pHuopmso,gpeonpeibtoydyofweViagrhitasn,cepsu(p""maorntdaltihteyAdnaatlay)swiseroef aVnaarliyaznecdeu's,inwghBeanrtlaeptptr'ospTreisatteoffi., Bartlett' Test was not significant (7>0.00D)). If the Analysis of Variance was significant (inpd<i0v.i0d5u)a,lDgurnonueptst.'sITfethsetA"nawlayssiusseodf tVoariideanntciefywtahsensotattiasptpircoalprsiiagtneif[ii.cca.n,cBearotfletthte's Test w10as75si%gntiifeiscwaentre(pp<r0e.s0e0n1t).),InthceasKersuswkhaelr-eWatlhleiKsrTusekasl-WwaalsliussTceds,twwhaesnslteastsistthicaanlloyr equal sstiagtniisftiiccaalnts(ipg<n0if.i0c5a)n,cDeuonfnt'hseMiendtihvoidduoafl Mgurlotupisp.leICfotmhepraerwiesroengsr"eawtearstuhsaend7t5o%idteenst,ify the Fisher's Exact Test' was used to analyze the data. `Count data obtained at Caesarean-sectioningof the dams were evaluated using the procedures described above for the Kruskal-Wallis Test". 000470_ 418-018:PAGE III-1 HL RESULTS A. Mortality (Summary - Table 1; Individual Data - Table 23) N(moevdaelaotnhiscweacriedactotnrtirboult)a,b3le(t1o.6thmegt/ekstgoPrFcoOnStr+olmaervtiaclleosn.icOanceidr)atanidn e$ac(chhoolfeGstreoruolpsco2ntrol) died as the result described below. of intubation accidents All other rats survived or to natural causes. Observations scheduled sacrifice. in these rats are `daDyam1210(9D2G6 i12n).GroAudvpe2rs(emecvlianliocnailcobasceidrvcaotnitornosl)inwcalsudmeodreixbcuensdsssaaclriivfaitcieodnoanndgessotfattoiron clihqruoimdofdeaccersyoonrrDhGea1a1n,danadrdeedcrpeeraisoreadlmsoutbsotraanccteivointy,DcGhr1o2m.orThhiinsorrratheloas,t weight after DthGe e1s1.ophFaegeudscaonndsutmanptdiioscnolvoarlauteisonweorfethuenrleefmtaarxkialbllaer.y aNreeac;raolplsoythreervetailsseudespaeprpfeoarraetdion in dnoervmeallo.pmTenhteallitatgeercso.nsTihseteddeoafth1w4alsivaettermibburtyeodstothaant ianptpuebaarteidonnaocrcmiadelntf.or their RThaetr1e0w9e3r6einnoGraodvueprs3e(c1l.i6nimcga/lkogbsPerFvOaSti+onmsebveafloorneidceaatchi.d)NweacsrofpousnydrdeevaeadloednaDdSar2k. red clotted material in the thoracic cavity; all other tissues appeared normal. The death was attributed to an intubation accident. Rclaitni1ca1l5o6b2seinrvGartoiounps5in(cchlouldeesdtedreoclrecoansterdolm)otwoars amcotirviibtyu,npdaslaecaripfpieczerdaonnceDaSnd1c6o. ldAdnveesrsset:o tgroouucph.onFeDeSd c16o.nsBuomdptyiwoenivgahltuwesaswerreeduucnerdemoanrkDaSble1.5 cNeocrmoppsyatorreovteehaedlredratthseisnmtahlils dosage ifnlutiedsstianlelsowteherrettiwsissuteesdapapnedacroendstnroircmtaeld.atTthhee jdeeajtuhnuwmasanadtrtihbeujteejdutnounmatcuornatlaicanuesdeas.dark red B. Clinical Observations (Summary - Table 1; Individual Data - Table 23) The numbers of ras with excess salivation, a perioral substance and chromorhinorthea dasurcionmgpgaersetadtitoonGwreorueps1ig(nviefhiiccalnetlcyonitnrcorle)a.seTdhe(ps<e0i.n0c1r)eianseGsrwoeurpe $at(tmreivbuatleodntioc aanciadvecornstiroonl) 10 the taste of mevalonic acid; the incidence of these observations was comparable among the three mevalonic acid groups (Groups 2, 3 and 4). `Awlelroetchoenrscildienriecadluonbrseelravtaetditoonsthdeurteisntgotrhecopnrtercoolhaarbtiitcalteisobne,cgaeusstea:tio1n) athnedilnaccitdaetniocnespewreiroed.s. `nTohtedsoesoabgsee-rdveapteinodnesnitn;claundde/dorl2o)catlhiezeodbsaelorpveactiiao,ndoecnctuarlrperdoibnleomnse t(omifsosuirngr,asbrionkaengroorup. smiwsoallliegnndeidgiitn,csiswoorlsl)e,nchsrnooumto,darcedrypoerrrihveagai,nsalcasbusbsotnanpcaew,slaacnrdimlaitmibosn,,bsecnatbtoani,mmoiustshi,ngtioprof tsacialnmtifsesciensg,,spwtoolsilse,nseoafrt, odrehlyiqduriadtifoence,se,mraaclieas,tiroend,sduebcsrteaansceedimnoctaogre,acltaibvoirtye,d pbarleeatihning, appearance, cold to touch, and ulceration or scab on chest or limb. The significant increase 000471 418-018:PAGE 12 (Gpr<o0u.p011)1in(1t.h2emign/ckigdePncFeOoSfloacloanlei)zeads caolmoppaerceodinatotGherobuapck1d,uwrainsgctohnesigdeesrteadtiuonnrepleartieoddtion the test article because it was not dosage dependent. C. Necropsy Observations (Summary - Table 2; Individual Data - Table 24) A1l)lthneecirnocpisdeynocbesserwvearteionnost wdeosraegceo-ndseipdeenrdeedntu;nraenldat2e)dtthoetohbesteersvtaotriocnonotcrcoulrarretdicilnesonbelcyaounsee: oaftbiontah gkriodunpe.ys,ThaecsaelcoublsuesrvianttihoensbliandcdleurdeadndmitshsihcakpeenendKbildandedyesr, wliaglhstidniloanteioGnorfotuhpe2pelvis (+mcehvoalleosnteircola)cirdacotnhtatrowla)srastaacrnidfipcuepd bteiscsauuesienitthheasdtnoomascuhrvoifvionngepGurposuopn7d(a2ym2go/fklgaPctFatOiSon (DL 2). Necropsy observations in rats that were found dead were described previously. D. TTeerrmmiinnaall BBooddyy WWeeiigghhttss a(nSdumOmragrayn -WTeaibglhets3;aInnddRiavtiidousaolfDaOtraga- nTaWbelieg2h5t)s to DL. CaesareanSectioned Rats Terminal body weights of rats Caesarean-sectioned on DG 21 were significantly reduced a(spcSo0.m0p5aorrepd<t0o.0G1r)ouinpG5rovaulpuses6 (acnhdol7es(t1e.r6olancodnt2romlg)./kTghPeFwOeSig+hcthooflteshteerloilve,rrwesapsectively) Gsirgonuifpisca6ntalnydi7ncarnedastehde(ipn<c0r.e0a5s)edinliGvreoruwpei7g.htAsinaGrreosuulpt7o,ftthheerraetidouscoefd ttheermliinvaerlwweeiigghhttstoin the terminal body weight were significantly increased (p<0.05 or p<0.01) in these two groups,ascompared to the cholesterol control. AselctoitohneerdtoenrmDinGal21bowdeyreweuingahftfse,cltievderbywePigFhOtSs aonrdmerevlaaltoinveicliavceird.weiTghhetsroaftiroaosf iCvaeersawreeiagnh-t t+omteevramlinoanlicboadciyd)weaisgchotmwpaasresidgntioftihceanGtrlyouipnc2revaasleude((pm<e0v.a0l5)oniincGarcoiudpco3nt(r1o.l6),mgbu/tkwgaPsFOS considered unrelated to the test or control articles because the increase was not dosage. dependent. D2. Naturally Delivered Rats Terminal body weightsof naturally delivered rats were significantly reduced (p<0.05 or pin<0G.r0o1u)pisn6Graonudp7 1(31.(62amngd/2kgmgP/FkOgSPaOloSne)+cahsocloesmtpearroel,drteosGpercotuivpel|y)(aveshcicolmepcaornterdolt)o, and Group 5 values (cholesterol control). The ratiosofthe liver weights to the terminal body weights were significantly increased (pS0.05 or p<0.01) in Groups 9, 11 and 13 (0.8.1.2 and 2 mg/kg PFOS alone, respectively), compared to Group1 weights and/or light (vehicle control), increases in liver reflecting weights in slight these reductions in terminal groupsas compared to body the Group 1 values. The liver weight was significantly increased (p<0.01) in Group 3 (1.6 mg/kg PFOS 000472 418.018:PAGE 1-3 +wemiegvhatlto3ontiahcnedtaec4irdm()1i.na6asalcnobdmo2pdaymrgwe/edikggthotPGFrwOeorSuep+s2img(enmvieafvliacoalnnoitncliycaicaincdci,rderaecssoepndterc(otpli)Sv.0el.Ty0)5heaosrrcapto<iOmo.ps0ao1rf)e,tdhietnoiver GGrroouupps2 (mevalonic acid contro, and cholesterol, respectively), as compared in Group6s to Group $ and7 (1.6 and 2 mg/kg (cholesterol control). PFOS + E. TBaobdlyesWe4itghhrtosuagnhd9;BIonddyivWiediugalhtDaCthaan-gTeasbl(eFsig2u6retshr1otuhgrho2u8g)h 3; Summaries - El. Precohabitation `rBeodduycewdei(gph<t0.g0a5inosrfpo<r0t.h0e1)enitnirGerporuepco1h3a(bi2tmatgi/okn gpePrFiOodS (aDlSosne1)ta0s4c2o)mwpearreedsitgoniGfricoaunptly| {2v5echiocmlpeacroendtrtool)G,raonudpG5ro(uchposle6staerno7ldco(n1t.r6ola)n.d D2umrgi/nkggthPiFs OpeSri+odc,hoglaeisatserwoelr,eressipgencitfiivcealnyt)l.y reG`Adrduoducitpeido1(n3aplo0lny.,0Db5Soosdry2p9w<et0io.g03h16t,)giaansincGsormfopouraprGser6doauwnpidt1h27to(hn1e.Dc6oSmrsgr/e2sk2pgton0Pd2Fi9OnagSncadoln2otn9reo)tl0wg3er6ro;euapsnivdganiliunfei.cantly r1e0d4u2c.edAs(pa<0r.e0su5l)toofn tDhSese2c9htaong3e6s,anbdodbyodwyeiwgehitgshtwelroesssoicgnciufrirceadntilnytrheidsugcreodup(poSn0.D0S)si3n6 Groups 6 and 7 on DSs 29, 36 and 42,ascompared with Group 5. Body weight gains for the (cholesterol control) were entire precohabitation significantly increased period (DSs (p<0.05) as 1 t0 42) in compared Group 5 to Group 1 (vehicle control). dProesmaagteisnogfbPoFdOySweaisghhitgshaansd1.b2 modgy/kwgei.ghStigganiinfiscwaentreinucnraefafseecstoerdrbeydumcetviaolnosn(ipc<0a.ci0d5aonrd pT<t0o.0412,) Ginrobuopdy1w2e(i1g.h6tmgg/aikngs PinOGSroaulo8pne()0o.4nmDgS/skg1 PtoFO8,SGraloounpe)3o(n1.D6Smsg/1ktgo P8FaOndS + a`cmiedv)aloonniDcSasci1d)to.o8 n DanSds22921t0o3269waenrde2n9ottoco36n,siadnedreGdraonupef4fe(c2tomfgt/hkegtPFeOorScso+nmtretovlalaorntiiccles because they were not dosage-dependent and did not persist. E2. Gestation B(po<d0y.0w5e)iognhltygianinGsrofourptshe6eanntdir7e (g1e.s6taatniodn2pemrgi/okdg(PDFGOS0 +to2ch1o)lewsetrereols)ignificantly reduced G(1.r6 ouapnsd32amnd g4 (1P.6FaOnSd+2cmhgo/leksgteProFlO,Sre+spmeectviavleolnyi)caancdidG,rroeusppsec9t,iv1e1l,y)1,2Garnodup1s3 6(0a8n,d17.2, b1o.6dyanwde2igmhgt/gkaginPs,FcOoSmpalaorneed, troestpheecitricvoerlyr)eshpaodndsiignngifciocnatnrtollygrreoduupcse,df(orp<t0h.e0f5irostrwpe<0e.k01o)f tthheesgeesdtoastaigoen gperroiuopds(duDriGng t0thoe7)s.ecTohnedrweeweekreofngoesstigantiifoinca(nDtGdsif7fetroen1c4e).s aGmroonugp a1n3yhoafd a 000473 418-018:PAGE III-4 significant increase (<0.05) in body weight gain during the third week ofgestation (DGs 141021). Body weights were significantly reduced (p<0.05orp<0.01) in Group 12 (1.6mg/kgPFOS alone) on DGs 2through 16, and inGroup 13 (2 mg/kg PFOS alone) on DG 0 through 19, compared to Group 1 (vehicle control). When PFOS was administered along with `mevalonic acid, the effect on body weight was less severeandappearedover a shorter period than PFOS administered alone. Body weights were significantly reduced (p<0.05 or PpS0.01) in Group 3 (1.6 mg/kg PFOS + mevalonicacid)on D4Gthros ugh 13, and in Group 4 (2 mg/kg PFOS + mevalonic acid) on DGs7 through 10, compared to Grou2p. (mevalonic acid control). Theeffecton 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 6and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectiveloyn) DGs 0 through 21, comparedtoGroup (cholesterol control). Gestation body weights were significantly increased (70.05) in the cholesterol control group (Group5)on DG 5, 8 through 17 and 21,as compared to the vehicle control group (Group 1). Despite thi effect of cholesterol alone, body weights in the groups administered PFOS with cholesterol (Group6s and 7) had significant reductions in gestation body weights. E3. Lactation Body weight gains during the first five daysofthe lactation period (DLS 1 to 5) were significantly reduced (p<0.05 or p<0.01) 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 (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 (S0.05) on DLs 110 5 in Group 3, but average body weights on DLs 1 and S 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), comparedtoGroup 5 (cholesterol control), and a significant (<0.05) body weight loss occurred on DLs 1 to in Group 7. 000474 418-018:PAGE II-5 F. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values (Summaries - Tables 10 through 15; Individual Data - Tables 29 through 31) Fl Precohabitation Absolute and relative feed consumption values were significantly reduced (<0.05 or p=0.01) in Group 13 (2 mg/kg PFOS alone) for the entire premating period (DS 1 to 42) and within this period on DSs8 to 15 (relative only), 22 t0 29, 29 10 36 and 36 10 42, compared to the vehicle control group. Absolute and relative feed consumption values were also significantly reduced (p<0.05) in Group 12 (1.6 mg/kg PFOS alone)duringthe. last weekofthe premating period (DSs 36 t0 42). `Absolute and relative feed consumption values were unaffected by dosages of PFOS alone as high as 1.2 mg/kg. Absolute feed consumption was significantly increased (p<0.05) in Group 8 (0.4 mg/kg PFOS alone) on DSs 29 to 36; and absolute and relative feed consumption values were significantly increased (p<0.05) in Group 10 (1 mg/kg PFOS alone) on DSs 15 10 22. These increases in feed consumption values were not considered related to treatment because they were not dosage dependent and did not persist. `When PFOS was administered along with mevalonic acid, the effect on feed consumption values was comparabletothat of PFOS alone. Absolute feed consumption values were significantly reduced (p<0.05 orp<0.01) in Groups 3 and4 (1.6 and2 mg/kg PFOS + `mevalonic acid, respectively) on DSs 22 to 29 and 36 to 42, compared to Group 2 (mevalonic acid control). Relative feed consumption values were significantly reduced (pS0.05orp<0.01)inGroups 3and 4onDSs 0 15, 1510 22,222.9a0nd36 to42 (Group 4 only). This effect of PFOS and mevalonic acid was reflected in the significantly reduced (p0.05 or p<0.01) absolute and relative feed consumption values for the entire premating period (DSs 1 10 42) 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 (p0.01) in Groups 6 and 7 (1.6 and 2 mg/kg PFOS +cholesterol, respectively) on DS5 2210.29, 29 10 36 and 36 t0 42, as compared to Group 5 (cholesterol control). This. effect of PFOS and cholesterol was reflected in the significantly reduced (p<0.05 or Pp<0.01) absolute and relative feed consumption values for the entire premating period (DS 110.42) in both groups. Relative feed consumptionvalueson DSs 810 15, 1510.22, 22.10 29 and 1 10.42 were significantly increased (p<0.05 orp<0.01) in the mevalonic acid control group (Group 2), as compared to the vehicle control group (Group 1). Absolute and relative feed `consumption values were significantly increased (<0.01) on DSs 29 to 36 and absolute. feed consumption was significantly increased (<0.05) on DSs 36 to 42 in the cholesterol control group (Group 5) as compared to the vehicle control group (Group 1). 00047s 418-018:PAGE 1-6 F2. Gestation Absolute and relative feed consumption values were significantly reduced (p<0.05 or p=0.01)during the first weekofgestation (DGs 0107) in Groups9 through 12 (038, 1, 12, 1.6 and 2 mg/kg PFOS alone, respectively). Absolute feed consumption continued to be significantly decreased (p<0.05) in Group 13 on DGs 7 to 14, and relative feed consumption was significantly increased (p<0.05) in Group 12 on DGs14to 21, compared to the vehicle control group values. Absolute feed consumption values for the entire gestation period (DG 0 t0 21) were significantly reduced (p<0.05 orp<0.01) in Groups 12 and 13 (1.6 and 2 mg/kg PFOS alone, respectively), compared to the vehicle control group. `When PFOS was administered along with mevalonic acid, effects on feed consumption values were comparable to the effects of administration of PFOS alone. Absolute feed consumption values were significantly reduced (p<0.01) in Groups 3 an4d (1.6 and 2 mg/kg PFOS + mevalonic acid, respectively) on DGs 0107, 710 14 and 0t0 21, compared to Group 2 (mevalonic acid control). Relative feed consumption values were. significantly reduced (p<0.05orp<0.01) in Groups 3 an4d on DGs 0to 7 and 14 10 21. `When PFOS was administered along with cholesterol, effects on feed consumption values `were also comparable to the effectsofadministrationofPFOS alone. Absolute feed consumption values were significantly reduced (p<0.01) in Group6s and 7 (1.6 and 2 mg/kg PFOS +cholesterol, respectively) on DGs 0107, 7 t0 14, and0 to21, compared 10 Group 5 (cholesterol control). Relativefeedconsumption values were significantly reduced (p<0.01) in Group6s and 7 on DG 0 to 7 and significantly increased (p<0.05 or P=0.01) inGroups 6and 7 on DGs 14to21. F3. Lactation Absolute feed consumption values during the first five daysofthe lactation period (DLs 1 105) were significantly reduced (p<0.01) in Groups 12 and 13 (1.6 and 2 mg/kg PFOS alone, respectively). Relative feed consumption values for the same period were reduced in Groups 9 through 13, reaching statistical significance (p<0.05 or p<0.01) in Groups 9, 10, 11 and 12 (08, 1, 1.2 and 1.6 mg/kg POS alone, respectively), compared to Group 1 (vehicle control) values. `When PFOS was administered along with mevalonic acid, effects on feed consumption values were also comparable to the effects of administration of PFOS alone. Absolute and relative feed consumptionvalueswere significantly reduced (p<0.01) in Groups 3 an4d (1.6 and 2 mg/kg PFOS + mevalonic acid, respectively) on DLs 1 to 5, compared to the Grou2p (mevalonic acid control) value. When PFOS was administered along with cholesterol, effects on feed consumption values were comparable to the effects of administration of PFOS alone. Absolute and relative feed consumption values were significantly reduced (p<0.01) in Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively) on DLs 1 to 5, as compared to Group 5 (cholesterol control). 000476 418-018:PAGE IIl-7 G. Mating and Fertility (Summary - Table 16; Individual Data - Table 32) `The numberofdays in cohabitation, the fertility and pregnancy indices (number of pregnancies per number of ats that mated and rats in cohabitation, respectively), and the. number of ats with confirmed mating dates during the firstandsecond week of cohabitation were comparable in the thirteen dosage groups `The number of days in cohabitation was significantly reduced (<0.01) for Group 6 (1.6 mg/kg PFOS +cholesterol), as compared to Group 5 (cholesterol control). This finding was not considered treatment-related because it was not dosage-dependent. H. Caesarean-Sectioning and Litter Observations (Summa-rTiabeless 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 1 through 7, 12 and 13. No Caesarean-sectioning or litter parameters were affected by dosages up to 2 mg/kg PFOS alone or administered with either cholesterol or mevalonic acid. There were no biologically important differences in the liter averages for corpora lutea, implantations, liveanddead fetuses, early and late resorptions, percent dead or resorbed conceptuses, percent live male fetuses or pooled fetal body weights. No dam had a litter in which there: were no live fetuses and all placentae appeared normal. `The average number of resorptions (total and early), the number of dams with any resorptions and the percentage of dead or resorbed conceptuses per liter were significantly reduced (<0.05 orp<0.01) for Group 13 (2 mg/kg PFOS alone), compared to Group 1 (vehicle control) values. These findings were not consideredtreatmentrelated because an increase, rather than a decrease, in the incidenceofresorption is the expected effect of a toxicant. The percentage of dead or resorbed conceptuses per liter was significantly increased (p<0.05) in Group 7 (2 mg/kg PFOS + cholesterol); although this value is above: the range observed historically at this Testing Facility", the value is comparable to the concurrent vehicle control group (Group 1) and reflects the low value in the cholesterol control group. LI Natural Delivery and Litter Observations (Summaries - Tables 19 and 20; Individual Data - Tables 36 through 38) "Totals of 170 20 rats were pregnant and delivered litters in eachofthe 13 dosage groups. "The duration of gestation was significantly reduced (p<0.05 orp<0.01) in Groups 9 through 13 (0.3, 1, 1.2, 1.6 and 2 mg/kg PFOS alone, respectively), Groups 3 and 4 (21m.6g/akngd 2PFmOg/Sk+g cPhFolOeSste+romle,varelsopneicctiavceildy,),reasspcecotmipvealrye)d, atondthGercooumpess6poannddin7g(1c.o6ntarnodl a See APPENDIX K (HISTORICAL CONTROL DATA). 000477 418-018:PAGE Il1- values. The number ofdams with all pups dying on DLs 1 to 5 was increased in Groups 13,3,4,6 and 7; the increase was significant atp<0.01 in Groups 13,4 and7. "The pup viability index (number of live pups on DL 5 per number of iveborn pups on DL 1) was significantly reduced (p<0.05orp<0.01) in Groups 12 and 13 (1.6and 2 mg/kg PFOS alone, respectively), Groups 3 and 4 (1.6 and 2mg/kg PFOS +mevalonic acid, respectively), and Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively). `The numbersofpups that died or were presumed cannibalized on DL 1 and DLs 210 5 was significantly increased (p<0.05 orp<0.01) in Groups 12, 13,4, 6 and 7. The numbers of surviving pups per litter were significantly reduced (p<0.05 orp<0.01) on DLs 2, 3,4 and. Sin 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 1 to 5ineachgroupadminitshetteestrarteicdle. Groups 11, 12and 13 (1.2, 1.6 and 2 mg/kg PFOS alone, respectively), Groups 3 an4d (1.6 and 2 mg/kg PFOS + `mevalonic acid, respectively) and Groups 6 and 7 (1.6 and 2 mg/kg PFOS + cholesterol, respectively) had significantly reduced (<0.01) pup body weights on most weighing days (DLs 1 through 5). When 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, 12 and 13 (04, 08, 1, 1.2, 1.6 and 2 mg/kg/day PFOS alone, respectively) were also significantly reduced (pS0.05 or p=0.01) from Group 2 (mevalonic acid control), Group (cholesterol control) and Group 1 (Vehicle Control), respectively, over the same days of lactation. Al other natural delivery andliterparameters were unaffected by dosages of PFOS as high as 2 mg/kg administered alone or in combination with mevalonic acid or cholesterol `The average number of implantation site, the gestation index and the numbers of livebor and stillborn pups were comparable across all 13 dosage groups. The number of dams with stillborn pups was significantly increased (<0.01) in Group 8 (0.8 mg/kg PFOS alone) and significantly reduced (p<0.05) inGroups 10, 11, 12 and 13 (1, 1.2, 1.6 and 2 mg/kg PFOS alone, respectively). These significant differences were not considered treatment-related because they were not dosage-dependent. The significant reduction (pS0.01) in the. percentage of male pups on DL 3 in Group 4 was relatedto the increased pup mortality in this dosage group and notadirect effect of PFOS with mevalonic acid. J. COlbisneircvaaltOibosnesrv(aStuimomnasrfiresom- BTiarbtlhesto21Daaynd P22o;stInpdairvtiudmuaalnDdaNteac-ropsy `Tables 39 and 40) `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 2mg/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 liters with pups that were cototloudch occurred in Groups 11, 12, 13,4,6and 7. `The number of litters with pups not nursing was increased in Groups 12, 13, 3,4, 6 and 7 the increase was significant at p<0.01 in Group7. 000478 418-018:PAGE IM-9 Necropsy observations in pups that were stillborn or found dead included increases in the `numbersof pupswithnomilk 1.6 and 2 mg/kg PFOS alone, inthe stomach in Groups 9, 10, 11, 12and 13 (038, 1, respectively), Groups 3 an4d (1.6 and2mg/kgPFOS 1.2, + `mevalonic acid, respectively), and Groups 6and 7 (1.6 and 2 mg/kg PFOS + cholesterol). `The incidence of this observation was significantly increased (p<0.01) in Group 6, as compared with Group 5 (cholesterol control). All other clinical and necropsy observations in the F1 generation pups were considered unrelated to the test article because: 1) the incidences were not dosage-dependent; or 2) the observation occurred in only one litter. Clinical observations included decreased `motor activity, gasping, labored breathing, not nesting, exophthalmos, swollen limb, tail problems (missing, portion missing and tip black) and no milk in stomach. The necropsy `observation of protruding tongue was significantly reduced (p<0.01) in Groups 8, 9, 10, 11, 12 and 13, reflecting the single occurrenceofthis observation in the vehicle control group (Group 1). A single pup in the mevalonic acid control group (Group 2) hadno oral `opening, no eyes and displaced ears; as a result, the incidence of this observation was significantly reduced (p<0.01) in Groups 3 and 4. One pup in Group 8 (0.4 mg/kg PFOS alone) hadatan area on the median lobeoftheliverat necropsy on DL5. All other pups appeared normal at necropsy on DL 5. sn K. Blood No significant and Tissue Analyses difference between co (See ntrol APPENDICESH, groups (Groups 1, I, 2 Jand and 5) K) for any of the. KKil.a. busGestation Day 21 Clinical chemistry parameters weregenerally unaffected in the DG 21 dams that were treated with 1.6 or 2 mg/kg PFOS alone. Clinical Chemistry Values (mg/dL) of PFOS alone [ParameterTCholesterol T_Giucose | LDLDw |HDLDir | Triglycerides |MevalonicAcid| lll llrll `The total and free thyroid hormones levels for Ts and Ts in dams administered 1.6 or 2 mg/kg PFOS alone were significantly reduced (p<0.01), compared to the vehicle control 000479 418-018:PAGE III-10 rII E tl l ww leltld ed e h l Bl kl iRedl ioSirdl "Thyroid HormoneValuesofPFOS alone Liver cholesterol levels were significantly decreased (p<0.05or p<0.01) in DG 21 dams administered 1.6 or 2 mg/kg PFOS, respectively, compared to the vehicle control group. Other liver clinical chemistry parameters were generally unaffected in the dams that were CCr EEI eee c[Toitneeo e[TwroionEol li[y--Wooe--pipueeTG20)wwwaee]nt| treated with 1.6or2 mg/kgPFOS alone. increased (p<0.05orp<0.01), albeit not dosage-dependent, in the DG 21 dams that were coadministered mevalonic acid and PFOS. Clinical Chemistry Values (mg/dL) of PFOS plus Mevalonic Acid [Parameter T Cholesterol|"Glucose |LDLDir|HDL-Dir |Toglycendes | Mevalonic Acid| 5 6 rld l ll d a ed dl litMraddl ET | ese Fer [Ts 2 "The total and free thyroid hormones levels for T3 and Ty inDG 21 dams coadministered `mevalonic acid and 1.6 or 2 mg/kg PFOS were significantly reduced (p<0.0Sorp<0.01), . Significantly different from control group; p<0.05. *+ Significantly different from control group; p<0.01. 000480 418-018:PAGEIII-11 Thyroid one Hormone yValucas luesooff PFFEODSSpplluuss Mera Mevalonic Acid on I [iE na | C0SmSHfow oRlo|SPT75R0S GSIEk l T || l OG40T|EEGEEl T RSBoisGSol| I llllRl Liver cholesterol and triglyceride levels were significantly reduced (p<0.01) in dams coadministered mevalonic acid and 1.6 or 2 mg/kg PFOS. Liver LDL and HDL levels were significantly increased in dams coadministered mevalonic acid and 1.6 or 2 mg/kg PFOS. Liver Clinical Chemistry Values (mg/gm) of PFOS plus Mevalonic Acid Cone [Parmeter | | Chfoloaesorl| | wa LDLDir | wae 1 "ae | | HDLDir |Tngiyoendes | I aay SlI5lIl ill Com >[oTM 1=9 [TMaTM | Clinical chemistry parameters were generally unaffected in the DG 21 dams that were treated with cholesterol and PFOS. Clinical Chen Values (mg/dL) of PFOSplus Cholesterol [Parameter |Cholesterol| Glucose | LDLDir | HDLDi| Trgiycendes | [mCoenta[|7P2 %o[mSaSsS|=5S | oa5ere| " Ben| T [Some[rao=y[TaTmT| =TaEE [<TM |TMEaTTM | "The total and free thyroid hormones levels for T; and Ts in DG 21 dams coadministered sep cholesterol and 1.6 or2 mg/kg PFOS were significantly reduced (p<0.01), compared to the * Significantly different from control group; p<0.0S. - Significantly different from control ps0 group; p<0.01. 00041 418-018:PAGE III-12 ome[og ot 2TT or] Thyroid Hormone ValuesofPFOS plus Cholesterol PcGroans |MOS07l 0h55 |r Ta1po l 9|I 064o 2025 | ToMgl 0i7l iiad 1C6omueh6ps | 0020055 | S207 @<9| 00 7| TH 20697 Grp | 00050000 | BEB ZEST | 0MOTE| TP Eos | Glos 2mphg )0.082% Liver triglyceride levels were significantly reduced (p<0.01) in DG 21 dams coadministered cholesterol and 1.6 or 2 mg/kg PFOS. Liver LDL and HDL levels were increased or significantly increased indamscoadministered cholesterol and 1.6 or 2 mg/kg PFOS. Liver cholesterol parameters were generally unaffected in the dams that were treated with 1.6 or 2 mg/kg PFOS plus Cholesterol. Liver Clinical Chemistry Values (mg/gm) of PFOS plus Cholesterol cGioE ups I I a 0a5l l T350a3l 200lS l II 0 al Faal ll = GTrSOl PFOS concentrations were significantly increased (p<0.05) intheseorfDaG 21 dams `administered 1.6 or2 mg/kg PFOS and in dams 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 dams administered 1.6 or 2 mg/kg PFOS. ------------ ** Significantly different from control group; p<0.01. 000452 418.018:PAGE 111-13 PFOS Levels in DG 21 Dam Sera and Liver BP " oom) p Na Se na GrowAd | rEAaTS l ETS Grows | 799%01548 na EeTe I Grow1 rill G4rmoyw. CET [[masmGopge || wa | wa] na |wa] - Gantt EE |%,| NA.2=mNyotshed 2 Sponsor selected the subsets 0 be analyzed, K.Lb. DG 21 Fetuses "siTghneicfliicnainctallycihnecmriesatsreyd p(aprSa0m.e0t5eorrspoSf0c.h0o1l)esitnetrhole aDnGd l2o1wfdeeuasseistyfrloipmopdraomtesinth(atLDwLe)rewere treated with 1.6 or2mg/kg PFOS alone. * Significantly different from control group; p<0.05. 000453 418-018:PAGE Ill-14 Clinical Chemistry Values (mg/dL) of PFOS alone IiE lKdd Bll BilKdl l cidi=l T3285 [61218 W213 a rrrrrrrr Com [Ta [mT2a155[a[Taox ]7aTM[=r|ed "The leveloffree T was significantly reduced (p<0.01) intheDG 21 fetuses from dams that were treated with 1.6 or 2 mg/kg PFOS alone. `Thyroid HormToonaleT,V|aloTufoaPelFTOssS alone Ty Fe Venice @ 0) ld yi 6 8 0 Ill alMd id 2 0 a 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 levels were generally unaffected in the fetusesofdamsthat were treated with 1.6 or 2 `mg/kg PFOS alone. Liver Clinical Chemistry Values (mg/gm) of PFOS alone 0 IrG(rVouepni12 slllWl &lMT00020000l0|lW007 Il 00 52097 @ "The clinical chemistry parameters of cholesterol and low density lipoprotein (LDL) were significantly increased (p<0.01) and triglycerides were significantly decreased (<0.01) in the DG 21 fetuses from dams that were treated with mevalonic acid and 1.6 and/o2r mg/kg PFOS *+ SiSginginfifiiccaannttllyydidiffffeerreenntt ffrroomm ccoonnttrrooll ggrroouupp;; pp=<<00..0051. 000484 418-018:PAGE III-15 [oa|7a [7a] Te ar]Ta [Sa] Clinical Chemistry Values (mg/dL) of PFOS plus Mevalonic Acid [Freer[ Chose ] Ghee T W000 WOLD Jrehens NGpo vio| 6 Sor Tee were [a Se So>s Semis| " | Seas Ser GT [WI | wee Freer - 2mghg 28308 `tThhaet wleevreel torfeaftreede Twsitwhamsevsiaglnoinfiiccanatcliyd raendduc1e.d6 o(rp<20.m0g1/)kignPtFheOSD.G 21 fetusesfromdams CTohS myrmoeidro|HorSa moanre rVoalo|ue|sToifGtPoFOfrRSEETp|lus MeGvoalroni|c Acigdm | TwFoamT| PI r allllll IPclIPPO il dl [Soma[r0oo2%m||P7RGDoLreT [EPtR Ro G| ] |{owSo0 | Liver cholesterol, HDL and triglyceride levels were significantly increased (p<0.05 or p<0.01) inthe DG 21 fetuses of damsthatwere treated with 1.6 or2 mg/kg PFOS plus `Mevalonic Acid. Liver Clinical Chemistry Values (mg/gm) of PFOS plus Mevalonic Acid etic o s o o fe 8 A a| | Comm: sTome [PTM5aTM] og | og "The lincal chemistry parameters of cholesterol, low densi lipoprotein (LDL) and high density lipoprotein (HDL) were significantly increased (p<0.05orp<0.01) in the DG 21 fetuses from dams that were treated with cholesterol and 1.6 or 2 mg/kg PFOS. "Significantly different from controlgroups; p<0.01. 690485 418-018:PAGE III-16 [0 COa0A d or[oaad pirdd [Wwalael|Wwaes: aell) Clinical Chemistry Values (mg/dL) of PFOS plus Cholesterol `The level of free Tswas significantly reduced (p<0.01) in the DG 21 fetusesfromdams that were treated with cholesterol and 1.6 or 2 mg/kg PFOS. e CTETrreLmleo[olTfitotIooTo lebtYbnooooeetleeeffToviwr] Thyroid Hormone ValoufPeFOsS plus Cholesterol Liver cholesterol and triglyceride levelswere increased orsignificantly increased (p<0.01) in theDG21 fetuses from dams coadministered cholesterol and1.6or 2 mg/kg PFOS. Liver LDL and HDL levels were generally unaffected in the fetusesof dams that were treated with 1.6 or 2 mg/kg PFOS plus Cholesterol. Liver Clinical Chemistry Values (mg/gm) of PFOS plus Cholesterol FS Tri tm we i3s) [Parameter T"CholesterolJ LDLDiw_1 WOLDW |Trigheendes | PFOS concentrations were significantly increased (p<0.01) in the pooled seraofDG 21 fetuses administered 1.6 or 2 mg/kg PFOS and in fetuses coadministered Cholesterol or Mevalonic acid and 1.6 or2mg/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. 0Qo486 PFOS Levels in Pooled DG 21 Fetal Sera and Livers IFC C E FoEaE[E T oRea|EirT . owS e] 2mg/kg 6) NA 418-018:PAGE III-17 CCES T T Tw E 0.4 mg ns C 2 a E CT T LEomTT a K2a. Dams `The clinical chemistry parameterof serum cholesterol was significantly decreased (p<0.01) in the lactating dams that were treated with 0.4, 0.8, 1, 1.2, 1.6 or2mg/kg PFOS alone, significantly increased (p<0.01) in lactating dams treatedwith 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 or2 mg/kg PFOS alone, compatroethde vehicle control group. * Significantly different from control group; p<0.05. ** Significantly different from control group; p<0.01. 000487 Clinical Chemistry Values (mg/dL) of PFOS alone Lr hires [om].| Te 418-018:PAGE III-18 Tr [roe| "55 | The total and free Ts levels in lacdtamasadtminiisnterged 0.4 (free Ts only), 038, 1, 1.2, 1.6 or2 mg/kg PFOS were significantly reduced (p<0.05 orp<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 or p<0.01), comparteod the vehicle control group. foe] Thyroid Hor TFJ mone Values of PFOS alone 0= T=> [ B ik A l lP lorl e|Pl r rlWl ield rloiRi ewi)ll [Eomfre mn vo| ee[ote gtreenaetreadllwyituhna1f.f6ecotre2d ming/thkeg DPLFO5S.damAlsl tohtahtewrelrievertrcelaitneidcawlicthhe1m.i6sotrry2pmagr/amkegtePrFsOwSeraelone. * Significantly different from control group; p<0.05. - Significantly different from control group; p<0.01. 000488 418-018:PAGE I-19 CI T Eo=R Ta aTea e al alll [hA 2ee al | m e wl Liver Clinical Chemistry Values (mg/gm)of PFOS alone `The clinical chemistry parameters of serum aT cholesterol was significantly decreased ome|5a|kar |ove LinpeTxeT] PFOS and cholesterol in the milk was significantly increased (p<0.0i5n) the lactating damsthatwere treated with mevalonic acid and 2 mg/kgPFOS. Clinical Chemistry Values (mg/dL)of PFOS plus Mevalonic Acid : "The levels of total and free Ty were significantly reduced (p0.01) in the lactating dams that were treated with mevalonic acid and 1.6 or 2 mg/kg PFOS. Thyroid Hormone Values of PFOS plus Mevalonic Acid [ICPahE rotmtCeOe[eIwedr|| wweoro||oiher |ewneo) Liver triglyceride levels were significantly increased (p<0.01) in the lactating dams that hl, parameters were generally unaffected in the DL dams that were treated with 1.6or 2 Le * Significantly different from control group; p<0.05. 000459 418-018:PAGE 111-20 mg/kg PFOS plus Mevalonic Acid. Liver Clinical Chemistry Values (mg/gm) of PFOS plus Mevalonic Acid Cam[oe|oer oe me) eva i in i |e| geTe ` in. in aWS a ll 2 io io) Levels of cholesterol in the blood and triglycerides were significantly decreased (p<0.01) in lactating dams that were treated with cholesterol and 1.6or 2 mg/kg PFOSandthe `blood level of glucose was significantly increased (p<0.05) in lactatingdams that were treated with cholesterol and 2 mg/kg PFOS. Clinical CheCmihsotreysel|ValuCehosle(stmegro/ldL) of PFOS plus Cholesterol PcGGrioowwps [|Se672922l 1375||l 2WT295257753 | TRI Tail zE M[TWaxel i0l1 |MFrALTll IFGop tOL1lST | l SI8238 | HOSE| 91l 8 | $0i913l ll laTchteatlienvgeldaofmstottahlatanwderfreeetrTeataenddwiTtshwcehroelessitgenrioflicaanndtl1y.r6oedru2cemdg/(kp<g0.P0F5OoSr.p<0.01in) the "Thyroid Hormone ValuesofPFOS plus Cholesterol params| uaii a bo snl. (Chester o Vom I Tmghe 5 5 5 ll v5 lW&lWS 5 rial Liver iglyceride levels were significantly increased (p<0.05) in lactating dams coadministered cholesterol and 2 mg/kg PFOS. All other liver clinical chemistry p2amrgam/ektgerPsFwOeSreplguesneMreavlallyounniacffAeccitde.d in the DL 5 dams that were treated with 1.6 or * Significantly different from control group; p<0.05. ** Significantly different from control group; p<0.01. 000490 418-018:PAGE IlI-21 = [fLiuvermCleinic|al ChGemomesVa| lues (Chlesero i G1Lo%epng? aaona 2 is reTi (Lmg/ogm)boef PFO1S plusWCohoLlDesrter| ol Togwds i ip in an in 20Go01)7 Tosidoo4)E = PFOS Levelsin DL5* Dam Sera and Livers Group | 002m0L0)1 ehicle ), 52b0o 87 (MeGvrsoown?ic| 12722737 [[oSammee[ [TT7 oHOM as 20 [ Swa a]| Grows iE Grow | 10=019357 Grow1 | THRTE 0G4rmows | TESTE| WSIS Grows | 7262697 GTromup 10 Grow 11 | 60% 10357 Grow713 | G0: | THO: BEF| 02& a TT 2008 A=2mNo Anaad ==SSopmonesodramelsewcteerdessuacbriifricteodbdeuaena0lys.urviving pups on various days. * Significantly different from control group; p<0.05. 000491 418-018:PAGE IlI-22 K.2.b. LD 5 F1 Generation Pups "The clinical chemistry parameters measured were not significantly different in the FIgenerationpups from lactating dams thatweretreated with 0.4, 0.8, 1, 1.2, 1.6 or 2 mg/kg PFOS alone, compared to the vehicle control group. Clinical Chemistry Values (mg/dL) of PFOS alone [Parameter |Cholesiersl | Glucose |LDL | WDLDi |Taghycerides |MevaloaicAcid | LI Ihd d Tl dill el lrl|ll r l0all e llul o eB laallll[Bil eildr Tmgh 14) 14) (14) wo The free and total Tq levels in DL5 pups from lactating dams administered 0.4, 0.8, 1, 1.2, 1.6 or2 mg/kg PFOS were significantly reduced (p<0.01), comparedtothe vehicle control group. The thyroid stimulating hormone (TSH) was significantly increased (p<0.05 or P<0.01) at 1 and 1.6 mg/kg PFOS, but not in adosage-dependent fashion. IIJ Thyroid Hormone Values of ANPFOS alone TTAT+ 0[l re moroel l1l PO [hiel llll il p<0.01) in DL 5 female pups from lactating dams administered 0.4, 0.8, 1, 1.2, 1.6or 2 mg/kg PFOS. All other liver clinical chemistry parameters weregenerally 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. 10492 418-018:PAGE 11-23 Female Pups Liver Clinical Chemistry Values (mg/gm) of PFOS alone [CA l EEE TTbrArr [oommcl el eeerar0l|BNlhell [Parameter Cholesterol T---_TDLDir___| HDLDir |Tghoenides | EtTdTe ee ge) Liver triglyceride levels were decreased or significantly decreased (p<0.05 or p<0.01) in DL 5 male pups from lactating dams administered 0.4, 0.8, 1, 1.2, 1.6 or2 mg/kg PFOS. All other liver clinical chemistry parametersweregenerally unaffectedinthe male pups `whose dams were treated with 0.4 to 2 mg/kg PFOS alone. a AU a Male Pups Liver Clinical Chemistry Values (mg/gm) ofPFOS alone CaTod mde werTe) Levelsofcholesterol, low density lipoproteins (LDL) and triglycerides in the blood were significantly increased (p<0.05 or p0.01) in DL 5 pups from lactating dams that were treated with mevalonic acid and 1.6 mg/kg PFOS. * Significantly different from control group; p<0.05. ** Significantly different from control group; p<0.01. 0094393 418-018:PAGE 1124 [PPCal5sinGm6ieeocuaeplrsC|hemiCsitNrosylsarVtoa6llu||esTE G(lamsgoz/odesLl )a||of(P$FO3OLE2S7D5pll|us MHevFDalLonDlic|AciTdoipzcPeendsels||Me5l3o2m7ei0Ac2l| 7l TST | T2657 | 308 00al Wl l TsT +6l7 | 70828l55l pe 3 & LtheavtewlseroefttroteaalteTdswwietrhesmiegvnailfoinciacntalcyiddeacnrdea1s.e6dm(gp/<k0e.0P1F)OiSn.DL5 pups from lactating dams Thyroid Hormone ValuesofPOS plus Mevalonic Acid PO perth pi pt apm. po E Trr r p evar 5 6 @ 5 W KlW a l lk ll 0 i a 'NO VALUES FOR THIS GROUP Lliacvtearticnlgindiacamlschtheamtiswterryepatrraeamteetdewristwhe1r.e6 PgeFnOerSalpllyusunMaefvfaelcotneidcinActihde.DLTherfeemwaelreepnuopsliovefr sMaemvpalleosnifcorAfceimda.le pups of lactating dams that were treated with 2 mg/kg PFOS plus a P r r e ae | [PFoemmalee Prups |LiverGoCleisneicnatl C[hemistryIDVLaOlu:es (mg[/gm) WofOLPFDO:S p|lus MeTvoaglwoeneidcsAci|d Otevaoric) fi) Gn Pe 1 mph 5 & Llaicvtearticnlgindiacamlschtheamtiswterryeptarreaatmeedtewristhwe1r.e6 PgeFnOerSalpllyusunMaefvfaelcotneidcinActihed.DLTh5ermealweerpeupnso olifver samples for male pups of lactating dams that were trated with 2 mg/kg PFOS plus Mevalonic Acid + ++ SSiiggnniiffiiccaannttllyy ddiiffffeerreenntt ffrroomm ccoonnttrrooll ggrroouupp;; pp<S00..0015.. a Group 2 significantly different from Group 1; p<0.01. 000:494 418-018:PAGE III-25 0 rw Wl MalePupsLiverClinicCahelm [Pummeter | Cholesterol | al si li Values (mg/gm) ofPFOSplus MevaloAnciicd LDL:___[_FDLDi I Tnghoerides | [Sot] NO VALUES FOR THIS GROUP Levels of low (LDL) and high (HDL) density lipoproteins were significantly increased (p<0.05orp<0.01)in the pups from lactating dams that were treated with cholesterol and 1.6 or 2 mg/kg PFOS and the blood level of triglycerides was significantly decreased (9<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 TEE N rlal WlllWl al l ilMillll Levels of total Ts and free T, were significantly decreased (p<0.05orp<0.01) in pups from lactating dams that were treated with cholesterol and 1.6 and/o2r mg/kg PFOS. II F J Thyroid Hormone Values of PFOS plus Cholesterol EN ril l lM ill Liver clinical chemistry parameters were generally unaffected in the DL 5 female pups of lactating dams that were treated with 1.6 or2 mg/kg PFOS plus Mevalonic Acid. Female Pups Liver Clinical Chemistry Values (mg/gm) of PFOS plus Cholesterol [_Poumeier |Cholesiesl | LDLDw | HDLDi |Trghcendes | CE [oe eeder |eli * Significantly different from control group; p<0.05. ++ Significantly different from control group; p<0.01. a. Group 5 significantly different from Group1; p<0.01. 000495 418.018:PAGE 1126 Liver triglyceride levels were significantly reduced (p<0.05orp<0.01) in DL 5 male pups ocfhedmaimsstrcyopaadrmaimneitsetresrewdecrheolgeesnteerraolllyanudna1f.f6ecotre2d ming/thkegmPaFlOeSp.upAsllofotlhaectraltiivnegrdcalimnsictahlat were treated with 1.6 or 2 mg/kg PFOS plus Mevalonic Acid. Cm|oa |omg |e|e) Male Pups [PomGroeups L|iverCCiloilniscsaml Che| mistry 372045 Values ToLDu (mg/gm) | T004200100 oWfOPFLODS:plu|s CholTesotegroelow 0005 1832680 Cremer) an) an an 2) 16 [Co2 m |7a | woo&p [ooo m| Wgo | PFOSLevelsinPooledDL 5FetalSeraandLivers iAd & (Vehicle rl I ll EnaT Eee = [omeT sa | wo | Groups 52200 Group's T3775 G2rmoup? 155a0)000 0G4omupdh | S31 =2767 = [mi1 my e[THT=7 16250 gNA]| A2=mNgot Analyzed 0) (a BQ=LSp=onBseolroswelQeucatnediisaubisoentsLimibte analyzed. T* T e Significanta ly different from control group; p<0.05. ** Significantly different from control group; p<0.01. 000496 418-018:PAGE I-27 L. HistopathologyofHearts and ThyrooifdFs1 Generation Pups (Sec APPENDIX J) The type and incidence of the histomorphologic observations in the heart and thyroid of the male and female pups from damsofthe vehicle control and 2 mg/kg/day dosage groups are shown below: SeDoxse Group M1 M7 T NDoa.mNPuop. 10199 1101 59 1091 09 TNHo.YRexOamDined 1 HNEoA.RNTormal 1 NNoo.. eNxoarmmianled 11 No microscopic changes were observed; all sections examined were within normal histologic limits. 000497 418-018:PAGE 128 REFERENCES 1. SItntuedmyatDieosniaglnCaosnfMeodriefnicceatoinoHnaorfm:onUi.sSa.tFioono;dGauniddeDlriuneg Aodnmdientiescttriaotnioofn t(o1x9i9c4i)t.y 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). GoodLaboratory Practice Standardfor Safety Studies on Drugs, MEW Ordinance Number 21, March 26, 1997. 4. European Economic Community (1989). Council decision on 28 July 1989on the acceptance by the European Economic Communityofan OECD decision/recommendation on compliance with principlesof good laboratorypractice. Official Journal of the European Communities: Legislation. 32 (No. L 315; 28 October): 117. 5. TCehsrtiss.tiaEnn,viM.rSo.nmaenndtaVloyPtroetke,ctPi.Eo.n A(g19e8n2c)y.,IWnasVhiivnogRteopnr,odDu.cCt.ivNeaatinodnaMluTteacghenniiccailty Information Service, U.S. Department of Commerce, Springfield, VA 22161. 6. Christian, M.S. (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). Embryo and Fetal Developmental Tosicity (Teratology) Control Data in the Charles River Cri:CDBR Rat. Chasles 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 LaboratoryAnimals. National Academy Press, Washingion, D.C. 9. Salewski,E. (1964). Farbemethode 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 homogeneofitthye: binomial distribution. Statistical Methods, 6th Edition, lowa State University Press, Ames, pp. 240-241. 11. Sokal, RR. and Rohlf, F.J. (1969). Bartlets test of homogeneity of variances. `Biometry, W.H. Freeman and Co, San Francisco, pp. 370-371. 12. Snedecor, G:W. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 258-275. 000438 418-018:PAGE [11-29 13. Dtruenantemte,n,tCs.wWi.th(a1c9o5n5t)r.ol.A mJu.lAtimpelre.cSotmatp.arAisssoonc.pr50o:c1e0d9u6r-e11fo2r1.comparing several 14. Sokal, RR. and Rohlf, F.J. (1969). Kruskal-Wallis Test. Biometry, W.H. Freeman and Co., San Francisco,pp. 388-389. 15. Dunn, OJ. (1964). Multiple comparisons using rank sums. Technometrics 6(3):241252. 16. Siegel, S. (1956). Nonparametric Statisticsfor the Behavioral Sciences, McGraw- Hill, New York, pp. 96-104. 000499 APPENDIX A REPORT FIGURES . uoRg00 *, 418-018:PAAG-E1 DT iE %283 o8*% `23 "wi *x3 2% =82= zi hE 5 i :: = ~21 maeEl 3 H 8 E EA B. & Ea sgt EoZuYd 8$i on8g a5 3 #25: gZ0ofd 23 o Po2 8 & 853 :5 3 RECN = J = AR> t a= E2 N vdaeiss s=z =8 2 2=bvaaewnwt:sa =~=8ga roma ~5 i 2: Seraw: z> be wall - amwcatn -~ Sonsrey I3x "a: 32 ENx eS2 a CE %: g 8&8 35 8() H&om8 & 8 000501 418-018:PAAG-E2 z Ta 8: -- .5 0 4{i ii : 80588 '3 i5E3: zii 3 IiE 2= i 2 3% , Ti 5 x3 H = 8 = i1,022 0> %= E0ywd E =2%S i583 ; LES M>eaa T8h [=r BES ,> et -~83 $8Es goog LLEV b>h g3g >Vo0 zEd gv > -~ iga Cg eo - 28 333 4 - R5 :5 "3.s23 3 "TE : 3% 8 & 8 w8orm8 000&5028 = () 418-018:PAG-E3 iP ------ il | z Te : vied BE ; : -- = 8218}% z81i -- 5 3 _-- a a p Z6 53 2 8s g = fe == g i2, oE u8d In~ ow- =:Zz EZS ooo =2 : 50wE3S "~ % 2Zsh gu Lo 538. EE = 20 bd Lgaugge 8 oz EELo a p==o 28 se = 528 2 st -= o- yn= -= & i y> a= <3,3 g% >i 5_8E =$ i CE : $ 8 % % 8 8 8 8 #8 8 * (9) tHo1am 000503 APPENDIX B REPORT TABLES 000504 418-018:PABG-E1 3 [BS legit iE Eo ;| P 3 mr opi manmii el pr pEeEdEiamiiiliii Eo, conve aaa iE 3 ig=i HEC r i El EeptWm EaaimaLiaLieLian fol it Blgiemmirnoo Ei hE see oo HE Bhl, iiinidigeen 333 35 3PR 3 ifs Bgiiogt PPoloa pa PgScCyonp fainrd opRB gsf. if fspaariadhas Ped il fg5f8igia ! Hk EEE FOP EE ESE 00oses 418-018:PAGE B-2 I bol Lomiminiitacs 3 iszi go Po 3c mE RR 3vss ol . 4 rma Coes zoos psycso ith [I : igs? frill eres o.oo SEES si fits cows waaay 28 8i H0 EEl 2 name mee ooo oo oo -iiBsEeSrS3 Bg itp 3c omew sesso pail a Hiiltpe" FF[E]EE ge t I oe hsape gf JHE] pFS gSiisgEall: HEE HENS BERL HIER HE fidpiiit f PPEEIEE aooses 418-018:PAGE B-3 Poe IHIIWIIILLE Po Eo 8 FH pPo oll i Pod 1 opEpm ARI tEEmemamaaaaaidie ie EPo,rir yam am asa eas5 LPalL rummiiiiin EET a Ed iE3E i`D1ogu HHRoel Bed E gi C i3 805 fgmemmomai omasoaaasaas i1g] (Ef . eio 183 2.8, fRaEED fg PogiEid EE gE oss BEE 5 fia Poleltop pili i Pigiggy oF os3REEE 000507 418-018:PABG-E4 To Pod eiimiiiaiy iL o E iifs Eig i Po eli gsi i i ie EE igg2 Lin As gy BEE EE 8gEx ET8:RinHagiIgHNFo " nn mmo co RANI I S 5 I 5 8 S ~~ S O~ nN ~iiigG8hog88 Bql0o0g0 a ii Ly 3 i dg:0, : I PopEe Pgh 3 , i Eigi anh Eig oBg onEon HE giziEs gCp- dlEileERiEE Rxags.prie8bff iblEEdR 000508 418-018:PAGE B-5 Pols g P E oni i Po dy HI gi 5 1 Pode rE [0E,RiTf oui170 FoRRIIIFNISSIIISNUIiSg i4fd ifs if di fiEil8: 18H8h3 Ei i Bi: i3EEest : SE poodginn iii Iilypseihbe Bi ateriel fel io, lpziEBEE o if (geri i328isd fp ifgjereeis preiilbaglie 0Q0509 418-018:PABG-E6 g PoeE HIE | NN E:o PEE go Po Eig EOE rll $ fg F p, 8 & Rio FOE :: aay : Pigog4 HI i gf ries IidE pg3i2 HH `Beal Biig Fgtoigb ggEe, gi HEE a, --12 2-H aEnE EEEH: i855 HEH Biol fF, 1 aE soopfiflip; : bohn pPP oroaEdl gtitliipe igiiifdif elfaetg.tTEoinE 2 2 Eggi 43 53%. 000510 418-018:PABG-E7 i Por niin i i !H I i 2 i iE Po pens Sinai Sg E81 iizz iFr:og iHlt 5: ChEptem eae gd P"EER ig: iE3 E Hi Iif HHiat wif : Sh ii fF Rog f aid Pjopiomaabndgit pr HEY iin 1 plieadk fF SERENE ooosua 418-018:PAGE B-8 Poi g Poi h FEfeFlE Po sn 3c 33d AR 3N5s5 1: nd; ESOSR 3 ! i: S HE EE gTeBo Pi lg RE5ENE8%iding gE, DEA e naz gez cosa 3PEyas 5ig iBfE i8H8]% hosi3gnheHE izls i 5 . si Py dll EH 3b fia Boy mip, 8 CF0if g iOE HiI,EER] pRB Big 3 f2 is g HIRI {1EE gE si EoBEiigE3E si(Bi32 000512 {oer [PI o is iH go FE i1g iI meei.raad PL Eirini HEE iE i FE fiLnnsiis shel is #3 : i3 Eebiesirc ag BgL, i 1 Bio... gx fit TOR gi 3 32 Po i : l fein, i Hic LE ogigHpidEiz EiiDd 418-018:PAGE B-9 000513 418-018:PAGE B-10 i : g EiE g iIn Po i FE iy Pig qi igi iti PoE il: fo, Ert 0me ee 0 BH HB ih 11g Pin if HL HEE Fi i i : J zzz 2 ro Jafig 0 snob. Fo, ==2= Ipo, FA ERE oz "15 g (fel 1BRsEiE finn PH o imsid 32 i8p8 a3% Ram #5 EF 43 ER BEiifia: 000514 i Pog Pode. i ii i:o t old i 1 iif PE } Paid 8 sl b i deprte 77 hE g pio l iHff3 gi : in EPrRdIiNighI fon1d PIIILE roan EP : yimE iFiRiiER ER E EEEuL 418-018:PAGE B-11 000515 418-018:PAGE B-12 Pio oe Dano Lion FE gid id $ PET a IIE g3 i [I Eo 5 ini I fo if 1 fr FF I o 7 iid ara iid BEE aif a hoa aif =n LE PEE I. : 14 r44d] gg fo f I F [HE BFTH gg g i oti hinn 3 zac 8; EEE gp i-nE. BE "sig iin LllE, Siler iim Tl Dll gh sine, fii P spoda,BEig8,PRiEE $0 giiba iia cE : TUE 000516 418-018:PAGE B-13 Prodi ih Fc PBfE IE PBiLoo Spb 3d Lo za RMLs Bi iiiEs aad 3EA BLE Pr f$5eoofgi gE og EHE Lofc i 1 ig HE 5 EER 5ir7r0dt 3 ered ea] 2g flinsm 7; sash RE i HH EF IEEE EEREG Sia. 000517 418-018:PAGE B-14 i 0 1g FP FAi|g Py 1 iit feed iPFrope I orc $ongid fr10in - iIiiH EEL I HI | iad PEt LE3 CoiHeEl oe TwIaEa guTa Haiz Leo i fgE | HE ! HE 233g: Bh sPippEE oc Ba f E gn E ls B Baio3c gs : oid Py dsrirpEc ; sss8d tFiEeEd 1 gIrsiBaE J ssiigd32 F fii des HE i232 Pr OHIE HEIR Loess 418-018:PAGEB-15 gp TR Saas IE gop Po, 3ge Pod E8o ,00 Eos, AEE Thre siriias romeed se FzRiIe iFiRe aE:E AIIiiLA EEE Piitzis gg ei | Bri, BFiEEHEE iz Fi EEEERE] soriio: Fs ggg RISER a eEeEeEaRnEeIlNd Solr l pig RERERREG Pligg enans ii bgggqeeesnend E # i8%:% ga 000519 418-018:PAGE B-16 Pole H Ea E [EE Pio oi or i{o, Eidel 2g frFi fil gfe sip ign i.: i ozrzznii FEEREEEEEERSE i i: gpLmiEgEnEaAnE BEI EIEEE [I P13 [I zzziizzif roonoiiiog EPdr HE iiiiiiilef Py HEH Eg ifs HEH 3 HH ow non ow 8 [BEIT folimifirzzaafaHg HIER HE 50a - } 000520 418-018:PAGE B-17 Po PoE PogHE.H fo i MT S g y Bil tBi EE fal LE FH gz 2 i stg vin Hi Bi; i BE : g.aaiind iiiiiii 8s a won w ow | i : ARTTLESEN dcoiozoziaoraiao;gf HH [1 il EEE RRR ooo REND Pg i ag3 [I] siiiiiiigEh file fon p2Po O0l%iflEii88sigHgc e ~ a et m n og do 8i(g 5l8d 3hs 38 000%21 418-018:PAGE B-18 go TE ii EEi LiL Po g Po oTiroood FERRARA saneisnedesi sani * hE Po d1313i13 3 PEL, niin P[IPE ELAEErE rE r FETE PRL g rw oa sr a ji, fitiary el EIT #0 35; TaiR irra z idiiig om Tiiriigde al I S d N = lL ipiiifdiiiiidiigis EDoLyigEgRifEEfC aga s sgoiis EiiE f figfipgeaaaazag : wt 000522 418-018:PAGE B-19 PoE, O E 87R gC P i L [NE ! Pia fai g FI unin L iiio iia ag i :; LL Titi FE i ig is oe ogi til gpPTT HERR HE tinasisida niin 1g PE [HHE i .. $ii33idi pn ISSIR EERRE 3 | HEE 2Do giesgigE zg C - .a. n- ..siligggisf Domeliesesieg i Pidlpgst Ey : 008523 418-018:PAGE B-20 I g PioPfdE E FI E Io bgoiydf. Ries Fgg oo= gie.i 2gfEc &ogi iki i iil Bia HEeEo EI FgH i Bio. HERE : LrnL iLai.iidniii.inadl EEEEER ; erLnoo.riariioiaon.oiioiiioogg F TE REEE EEEEEE REHPEo O2Q roasr ii E:s piyeiere 1a AsE n CoE sii i3iiisg gam EERER OE E ;zs SsEg RRE. . EEE in823228 EoB rpHilEiEggEeReasEaEaE ERR Li] dol 000524 418-018:PAGE B-21 po TR i Pd ETT g i Po 3 igniag ogpedriidary senza basnsal iiiiiiiiied fem sm RRe RR s $32322222228 ome ama, EE FE yg BE: PRpitrr ggfi fines Ho E Li Eg E dsif fiir iiiissssiagd Tiicsiiiigsa Soemm msm E Es a rr rllirian EEEEEEEE EEE gz [ITIIEIILEYG EEREEEEEEEIH F AiaiiiiE iinalocs| IJErErRlEri Ei EiRaEdREMEIR i * igi EERE RR RENEE Dppifferrrenssasid fF OQRiER: E ize a00s25 418-018:PAGE B-22 8 5 od rRiEiEiEiIiEiRiEiEiEcRd gEio dmmimaa pPSoiEniEoisRaEimiEoinEniEnLiLiERyE gi$id EB ogigeins fFil goed 2idigiizigali 2aaasaiiiiis sTEiEiRiFiEiRiEiEiEgEo) Ti iRiiii iid ii iiiadiaeiie EE tiiiiiiiig. ou Bo EEEEEEE2 EEE: uo shEig, TERERIIAALLLG iam gBp id87 7 zErsoiiiiniiiiiiiiaiiigiyfois 1 Sac ddddddsidtidk icz ory a TEEE EETEIEIEEEIEIEEIR IHIE EL Tia : ~ isesd 3 & :3%:2 g = a2 = 2232 3 2 18 83: 2HEocRo HEE iBSgBiiFB e2g2.2 Ge oEuEEnZyEpZo:x:ooEpEOyoCp IEE33GEGE - to 000526 418-018:PAGE B-23 Bi E LiEE fhe :Ec : fPieieiieiw aaain lilal RILEAAAAEE EERE R EER RR Pid cea iiiiiid fi fei i FBErEgT, Lif BH, f diiii niaf niaii igg FRERERRRRE4Lm Dn BE srsrrriroson Bic gi PREiiiiiiEg iy feslt soe Pog 1i8e:3s7 PEs Porroeene aul P Ey E isiEiiiiiiasazagaiHian REESE 000527 418-018:PAGE B-24 z Pd :g PELL... Z ry &fogHE , iz iFiEiEiEiE iR aE tiE iE iN y 5 i [A E fiiii33883; 1} Cd Po PfrIiLtE, 1Dhaahieiefnieiniaaea.g 4 Plo Fi fin ngz l |Wl8l! . Beit C BeC Cdie Ca s DIllsurrES.rsh.iiiras.ias.oiepdtTglTeel 3B% ou43 ip ERIEEEE SIE | gf og Pi 5in iiil CRSEEREERTIEIEERIEEEERIsaBnT RIE EERE PEE RRREERER HL e 000528 418-018:PAGE B-25 TG i Hh Eolas i go I1 fd Eric y eBii i i. sll ! Priiiiiiiidd poraoanooad GREREREEEE i i Piiiiiigiid Giiiifiiiii Hi}E [I orci H38I5 0 ii [IiOEEs Sii3iiisiisn forodgsEiEigdsrrraaaaag ii im: 0aoszs 418-018:PAGE B-26 Po g PiEg : LL. Ei i Po HPEoRlEl Pyles gE PiEEeIE BoEgEg got FErUoRgRT i: $8 HELL gE tPiriiiiiiiaiiiiiaii:alg SRLARRR REE Ra EEE EAiEE : PCiriRiriiiitiiiiLA:LLl priniriid #ERRIAXAERA Ci d i rre rrerEaonaPocffl ESRoEoSoEiEoiEiEIRoIdEE Ggnx PB Poisar gisiiiiiifai:m IEEERE ER RRRR Po, iE of (Basi Softy BaoazaaaozaSgEHsD omfiieessazaartaig PEER Ep 000530 PoE iPoo ETT Po ELL. 8 TTT PE Eli: HET Pl, rE 1F.I.R.E sir CoE Luis rand cali nou Seen! Pi LBEpS pitas fel 55: 8 TrT palma: Te FEEL gon oe -~ i fw 2F BdEy8ER pITiI raigi LBioLo LTiiibiii ignsl P2 i smgl , cEF.oiTaTTcoigEhails Ey HepEig opE ie f (88:3 FE 3 Bye: 418-018:PAGE B-27 Q00531 sl Lo Eis! [I P goE E Ptae.a.r.i f g u ETT PSEoERa gi Pod p i Peai lend i Pog gD, ii EBT oi Ed P 5g EBidlen 5 8 i Fi PLoo DnooginEeE EEoCs Pirelo df 1 gi EEEEREBTH sig i HER Cp:r oifilsgpi,iieg30rcTeoRssR HoiBigalsiEd EE fig8iE EE iE ar 418-018:PAGE B-28 uuuS32 io g ELiE d Eo irgias Ei E LoE . R ooo i885 go Pel ;: Pr : PPe iBtl s opigd :E8E :0 382g; "i LiclosidFE $88 fife i ITLLHEse rol Egg gBiilt re BE P1 LE PoE sess enng HPES7opd eAREERd83y3333 Eoiiipipaaad py 418-018:PAGE B-29 A goer Bio I ETT gPoo Pogfs giiviizss PfrEi ars ch dy FE, of FE Fia l gE iEiEd 2o2o.E0dfF P11r1 y rgd c.f BE i 00. SE ogi g8 2 Bgr E ih =a:HEoHf F TiEaRn soon BL iE ER 1 2 FE EEN P3O.E ogi8g9iF c88g.| sizEmii ogifires Pris 8. 418-018:PAGE B-30 000534 i 14 i iz i Poin, ,, 3 g SoooTgR Res om 5 i, Pog {girfiteze gi F 2 EPT :H[I ERRgg Bro di BE g: rE i BE i Pd HERI TAD PRLS ii i8i PP[oi ood Ege ih RR 1 HP&HE Pod Br 820 Si oyTiigE EEL5 3g58i% g3Poo-lEiIisT8iRHi,EE RcsIE oi BEB iR.E BHiE sgss Por iEREEEE ES 418-018:PAGE B-31 000s3s : zl Pod... in 3 id g Pad gi Ii EE [I Eo poiviizeas Pi g 2:08 fii Beh sig ivfidas El Hae 0 Poe ool 3i 5 Cog Pg 110 Ha no Bag ERT Pon Hi sl gine 5 0 === 22 So 418-018:PAGE B-32 fPEodolirgiggsifrrFass 000536 Po0 iJ EE Pgoo iii epizmanx of EPELL, iRE P2E i E gL L. gil LHif A ir ogg iETllHecienss 3 ; 2giln HE 1... iin fHfEIRE 2gTT ofJo. CgailE,B gg ig 5 Ez1i8oniy LER EE EERE 418-018:PAGE B-33 v00s3? Po ; FIEbE , ,.. Po Pg P i8igdie..e Eros Logi Pe Pik 210g 58 imgif mmx HLBEEER EE Li SHe E8H A Plds Ps id ai on oa Lar iE L% Ban ia mi iogle RHHH iPoeiigzs pBerdi 82 : F3l1asak g 8 iE3EE : flssly Ii Tig 3 SmELpiioan PoEsodiigsriEiBrgEE eR a 418-018:PAGE B-34 000s3s Po PEo oodies. Eo gi gE i i fig fifinans 5gE8iaa g Bid 8: aRiEEbEEE Brod HByERR | <i iH ig Ls ig oo: tiiEg EH ir an tay CEBHE : Tip Ppa, Bi iz Pilea DPoiEisE,tig llE i fF EERE ECEL. 418-018:PAGE B-35 000539 418-018:PAGE B-36 go TE Bo g Pom $1] 3 : ; ; Pl. fF FHR i BL fF LL 2 5] ! $PE8L0L Bg 5F% i2 . sfilipi0 s BIg Brof RED CEES saaarar pode iigaaa) a =a2s=z2z2 i Lr go RARE Too Leese = 2782 FEE nmpzrnaan d AEEEEEE i Aisi nwa ahaa! 43% RafUprgaimaaiio I gina FF osannar Hi riiizaizop SP gs ofril isedinbailoclTiaT eneE aesAdBE BgigEml Pafigeriiigiign 000540 418-018:PAGE B-37 Po [[I IidEe, 500 ir g Bi [HE EE : iogl ] sR Ei Ly i naasioaaid 404. TEETER ; fg ara band LEE is rrrrrer Co EF Eg Ec fo iniine i 3g IREERE ERE: dhniiihe nd lg BrBil 8 fe f8 F5H : 8 : GG5485 hin HI a ioEEiss d 4 5 a 58 id g3E3gs 5l.a1s Priya Hie d3 l8SileggFER Pip i, ReoeoeE T ozEiH H igg oy Gili P DOSrEfiE iT rr EegL pilL doaipgE. inias fRORERESFEIEEZ 700 ooosa 418-018:PAGEB-38 io ; Pol Lari PEEaRiEl EEsydd EE ; il gigi PRN g 88 Eo Bi E 88. ivfin Bi : 365 i oi EEE gi ge BEL BELO trabPE iiil osiiis [iI d HE sani fan yr RIAIAIRCECRD Fan PEER 1 PFE 3E3 Pofiane iopidEd inn f3iiiiiogEun PREIEHEaEm EI Ly GHEE fPiiiiimpfgiepapapayayaysy ipiyf 000542 418-018:PAGE B-39 HFE I eiITT0 EEE nsEeoE EzEsRiEEoii B gfompie proRoEREdERaioGd fr s P Pi T, R LiEmEeRsE PE Pr $E wfpl1o i0e0, ne ifiras ISIE zFAEoRidrrEsdoEevoRn FTELR,IL gs Wiis iE FEEiERlI gn BEoiogb LliL llL ie B[ 1 rHo1ETLTisiiriigiiai:oLgiEiH:n BD tiEiEiigg bE PgPoalie iimaigced rtrpiDgoi rornRg ixpEohi c il fF (EBi5E PAegst ] 000523 418-018:PAGE B40 Ps g Popioiddi DopERR Fc ! SFiE diE . pgEE REE fr i PTeEi ;| ECs . Ci RE EERE [iI iEISCEHFRPA SC RI0SMD ERIE Be TToiiiiiig Le gor wE g fu E E o0g- i wTiElsd 8E5E , RimEgitr F BHeERRi 2 l: Gi 2 5880 gli Po [iPIia LE33}2g Lifzsi.e.adi Bfoa R2IE2D CaRDi af og23a8n BEER TRE P ios3y& o4sE3a4e%e ' Hill Sgfssse EEER RR| E HEy I dPLBoigpiEg lEaZaE iiT lgEg C I igsif BE gogo yg imng dsiiiit i..335EREE oy OR fp (BEE iepiaEgg panne EE i-is072t 000544 418-018:PAGE B-41 PoPon PE gin fil PePio HE aigE { Pde Co arniiic ooohiddan PEEREd ! !: EEpEeAaEtN! Sirrdnoiog i A Cd io2 eHElE l: B3aPEfan Ei TEESE gpm & : EH POE Be fBlEe = 3gi1iiiiaigigi|ggfieannn crit Poor, Lee Bas ital 8fo 5fig 3 LS pErEiD RRERi rEa RodoLs pshf1EaEss EiEiEl Pai8g 2ip 3i2d% 5% EEE Piig et goosas pperle Eos EE EE EEE Lean Tt tata FT t REL JIg EaRmi ies rr aFaLn,s isoioin EAA NINE FEC ii ios fi ERR ES l.oig ns wow oe3eE E sFigE fieLcias 8c [Ee 85: : Tiooeadndanel ffD3sE EEE TUT gn o 8 ow oa 0 BEER EBER EEI Ea N EEgE RaTR n gSe2f7 08 LLB: iiii iiniis s=.cp f8 ii E ipiE ies DFEoEPLisHeiTg 8I0ETEFE iPgiil gECy liespif BiEiegagg.g piireEEeIE fF BRIERE ia: 418-018:PAGE B-42 000546 418-018:PAGE B-43 0 Pos 3, isl ii Pia. P2 E HEH 8 fi HE Pit Fob, : g TERR fii PFEeil EsREedERY e ihn Ladd P7 EoaRleElellPoE3 Co RE 4 SRE Loe LLooad Taigaens 3H: OG 3d: e E 850 Bel Bei PCoE nLZ RR PEE fsa gi PyiiB og b 3 Doel, gn TEE o iggit 2 Egos owe 3 EERE eae da ibBB38aar in13 aiEEEEEE ILL 000547 418-018:PAGE B-44 so, [EPEELoEEds 11.0 REfi Pi ! ph 1g her gE g ii PE5: Li gd E dr opie PEiSii&nnniE ; ; arn omy : ig PiEd 3333 EERE L1gg iB2efl BL i i hy hit 23%e giiiiigin PHghIrEeEaREsS 1ain PPrEomsiiEddergy E$a E 000548 418-018:PAGE B-45 3 TTR EFEoEgp i i F100 go EEE R PoEi.E fi pia 43313 g Eis Foo Ei odd #ReE lg Pr taza } ggg Hii d TE ciesiza Eg Freel ooo EEA Poo .E3.8E.80 oigoEsns i 23s HEEL BHigyipT3iF R stEiL l aI aHngn pei EEM DEC sass in = Piiff aE Pifielbeeny pe Ea EEE iBeddet 000549 418-018:PAGE B-46 a0 Bois ER P rF0 igEg ies g i: Pos EEE] Po Flea f S Cees : Dsreeel 31 Pl BTo oL fii Pood, LEER 3 FE i~fi8o8 foi gE El di sis inciaa i PPo og i... 4 cont of goorEM ERER 2OR Pod Pog SoneI]Boa pod Hoo hdg iy b CCiEuEaln i: iL. spn B1 EE ET sinE ggfihE un g= g f ii FEE8T8E; pst PFEEplH g ress p185i.3 n22g22 S[oFoR BTEH, i f Dogcge pEiiEEEE RR foRgbEEEfEA aQoss0 418-018:PAGE B-47 Pid EE gE orFE: 3 iii i1,0 Pho ! PL, PLE Loin laa PF3o3d8.. TET LL : DES OIRRE by Eos [I Mgplocipie L AEIEAS L8 oau Bgietg FEETCEByE, HEE i Rin Br BE Sasi |B gilin 1202 cciGiRiEEiRilAfshg Poy BELL hE sigs gy i.rdiiEE fo ldnpigEaeE wo 009551 : farinaaf Po Borie ip rr gE PPEf omea gEoeo Planes ig i8iiF FE gl! ii i ui Pidd Sis Tiiido od i ii kBE iif Fioag Hgigi, TTT gE gi gre i RHs] a Ga i: oH Psonic PrPadnliepraett HE t iryl 418-018:PAGE B-48 .`Qo0ss2 io gE byfeeer FE Pe Phy fet tii ET2 Eig:i Poiidizens TE i 1 Po Pd Ci Fo v4Eel0743 Cn HE ERT g i5 1tg! Pd h i Ta ogei HEE Posh oPEeRE HE i fils igiPogisd BE 1 son Efe. Bui :dDoi igghimiPsEgE) HES5oEEo.2 HEE REEEY La 418-018:PAGE B-49 .A ooosxs Po i girgin asf a Eogi ES NE ig 880 i Piodg gf io PPo il gy BG [HiRIL 5 tpfaas HE iPsE isd dbEH sg ai 837 Hei | DoErE igi cfgedoiitlg cP lEliie ni 418-018:PAGE B-50 3\ ao0sse, ET EE Po il ppt for Ld PEER Ly Ey Ld | SO FI $n LL EiEREEE ggg Frio Bagless BE 2EF gE ; gBEriTR RRR HE ad Fora -ii i3oH iio SBzi.e.. 1 oSTRgeasisg wi 2 = = = = g 5 2B32%% 2P,lasB0,0 SEgieE.Tfiemins pogriieg mE EEoopioidgiEiliepraetgiieidsLl. 418-018:PAGEB-51 000855 FE : byde. i PionizidigE...soaiii gE * f HPEEz RE HPPI odd Elie Lis giEo i FH fyie sGoEEited azz gs iLgi Poa iiofrg i oi dgilEa #Be1i PHOREE HioL... iin 5;0.8 Fg1p. hheEb i 8OE :flip S<2FEi " ibgeiliilifc foprdiglpeilisgdaeedt TnElEl : 418-018:PAGE B-52 000556 Po Pal i PEidiiaae 3 ii i iP$5li0 i iiid iil 3 fit sd P1E1E, iBt LiiElE 3id E Eiggan: LPo H Hb38re5o E PJioHi el Eig Hi... $i Hig HgIE pi aEdE iPla8,! SHE fs i405 PPErRaE lEiiiEnEeL 418-018:PAGEB-53 4a0557 418-018:PAGE B-54 gi FET 5 os go omnsoi f Ca oan ToT ; P I o olr aer iosea oois oaa eeiz oog s 8 i zal gE FO sfc l8icad cL ifais - 5s 3i Bsmai FP I EC HEE i BEE 0 Tse ss ssid 5g5 iiI RriEaT oofEEfo RETigi 2: - 232 HHERilIEEEfeE a L + 3 H ming 85: i..u EZ E zza iish B10 er gsi i PiCreiggiiEfEglzonfoef bIfgiwslh Poe EmEBRag gn IIEE in siEfRiIiDeioCgE uoeEigfyagdar HF 000558 418-018:PAGE B-55 il Pope Poy bof, iin Lois FPreid Hi88 ingirsgr Bhp ig GE Hy LE BL Be aizas ! rm i iiE 3 = oz noni FoF Tiisyg o.oo: an H35E5 ossilig PLnily ganna ; fipEg or bo ; oils Po5 Higeig2eRr= Edgouo goo gER EEE: oovsss 418-018:PAGEB-56 HE g PPi Oog EllaLi.n foo RET gL Eo Eo i LiLtLLii Es | i : Lipeita si fPaillg EEE Ga SEE ivEiE oda Fs Tihy gt i5s Lo add so Coaeiby og | di iI o aHaiiLei 8 i= pis = FOE ozmiilshy BSLEosd 33Lo or gmE P :DpeidgiiEl EiEl BoF hnafOogE,ifissfmer Pilgeist gFEer2 3dg oe s oegTHOR0 EEED : o0sso Q005! 418-018:PAGE B-57 Fo Po i CF :Po Fei P Pf oi ie,] fai: Pol Fi g 8] | | iio oz obs. ; TIEINTITILCLE | -iTiirt ogior3ze oza ort o_i Tir Lisi EE ; i $i i Es i Hi i: Lib duidaz:tt gi Cid 8888 i jit Php, feng 000 Lgl : Cie si is EE gs L132 2 gi k 5g SE i} E EE rEiSe FRER i R$H3E18 H1L ' 0Qos61 418-018:PAGE B-58 gy P FOoE dThs gis 0 ioPel Pils Eg Bf Fi g B07 get boil ELrgRRED ses Lslos si: 2 aes ; i BT gen oreteosggl i fF dsoss oT ! 111 1 133 : TogaA RTIA NTTE CEE E i! i TIF odor:i FEES $3: 0% o1Tioo:ioos HHEERRH j; - BHAel |i :; ! B BE IE : cLhipd c a.i idp dereo ss #0 LF. g2 3 i { [I i Sdihdp dfergrsti,d tif bcahd PERoEpiifRgErEeaiEpE ri i gi is d 83 133 0oes62' 418-018:PAGE B-59 ! pat d244 3 + 4 AE bi.=pd8 Pg NTE I ie Eghgiblo Figs HgEiliE fEERiE i oo. : TiiiHTiNT LEE: er Tos ! sort ozo: EOE ii aE i [SE gi SCOT $98 i 5.3. 8 85z. zi EP ETie rE 5h ol : iE gE 38 5 f g 3 WIR IRRE EFR iFEfEieigEhsRiEtI iRIEgail 000563 io fF 11 py fy gid fh Eel 1: ERE i ae l nd fi : Eilon sf dee rig Ei E E I NE 2 gc i is BEE 0 4 4 4 aig g3 rin: E3 EgSi3 EgREriP n]Eost CElindefoED 418-018:PAGEB-60 000564 FI ; Poly fF EE gE LL LL g BoosopEno= of5 r8 og Fi gfoog i| 2 Fig i gFFegb> gop iE op [EE iF ai fro ; ir ; Btilorosgg Eicon gE ; [LE | $i sss a 8sf C50! [ PRY 5T7yggid , 3BEEE DLER HG tPridkeisgf 8E 418-018:PAGE B-61 o00ses pl ; g Pi odn. a oo fgc FEE gg! : RE[I ; dhe 11.5 JA { PE i EOE i fof orr ong sfc oEr rol Brociidn E #1L 3d at : i2H ss 4 4} Fe fi a{P,goiin0yr,biasH HEEYN PEt Pome os bo. 418-018:PAGEB-62 000566 418-018:PAGE B-63 PLL Trg aif Pgo omoriREEeD aoe nin Poi irs nha oad ETT iig fies oar ce zEi b oohLo.dogs 3EeFB ilTSizR g is ql RTMiFesogy shoedioeiin il I BHiitiagin nig giifz cBiEr Hig iin this Bi3: i.zz2yo.pzzE.EpoexziEilpfl,l Boi po Ei hia ffog oifleiienp BB D0 iig BEE Erinn giles: Piopiyir itr BAH PoPgy fEBii,RE EEZEF F35Eg ihgf ofopriluiss 000567 418-018:PAGEB-64 poFEIN gE y Toda PEL 22% Eo 3EE Pal . flidigzz Tf I R HEE 3 iE ocing at "Fast ogi o# if iCi: nrrg ons FELT io HEA Ti gRE25BiRe PLEcRoIa_F ...E Libis Blo gE HBiEi LsF:RElEiRza. zf3i3adinn [hLIE zsg oFifg fos iinddl HEE EEE RRR ri P PEi EHp EIi E nirall E HTET oooges 418-018:PAGEB-65 gid ii iE ib sasFE fogs. RE Bog Podeidcoar iia i H Pap BRA A RF 2S 1 Hl BEE EERE io Po eo | Bi i i Pa io i oe i i HH = HE] 33 3d i] Hel iid .% 5: se - 13% Rls Hf$ie:io b HgHiind i H5E 3 PPr2E2SoE2oE48 .44op EREE o.z zS_iii3ig3jhgE3iS8sy% LBiL a fg gfF iPg ogHiEfGiE s Cope pg BID: omen Phen Soop Eel digi Dighiie g = i8%:8 8s aEE EPEiEe Baal ETiZE(C4% fF REE CED FF OPED EEL: 000s6o 418-018:PAGE B-66 FE TS 0 & Pod II Tie ne os TY oma aa gt FEEaLilDo tLhOe.te e= mg PE ina PoovormEnt PfClesimgnEoRmE wee id sR gid SIGS S god, 1H go Ripiog F BglE Ey gE Bef. 0Rh iFnF aa 4 a dg3d dg mak #F7E5 Hig 33 agiLE2% i it Lidziz.iaz osu Fghk Fs Lil prgEi bln Eider sf fpsi gl 000570 418-018:PAGE B-67 Polls Po Eo T ga e wanai piiin mE TTiorLe.e Aides gee raga 7iF iE i gE Eo gd : frie 23322 ocoroni rriyr HEREERE oE gE iaE aat gomEoEf Plo EEE ppdof E FriBE EEE ER BE i-die [HEE H EBLAEi E . Giri iii3i FRE G0 iii: Sli: noon si3ii BRIER sizssiif ziiiiioaf dDiodn i ofghieE rina gm nonaal n s::asi ijedd 1E3E33E. 1IEsEiEiEsaRiEoiaoysetfaid ERLE: Tfoeo iiltd E HERR HEL EEEE REE gE OF igRisEE i ahs 8#4, Eguln R EER EEE R BEL]: 1L111 i (Blase: 0005S 1 418-018:PAGE B-68 ! PRT PEL [IERIE EARN lhl Riana Biri EE EEESEE EE Y7ii7m JHrEzfyEz]z 2PE2E3RiE:D Bi0 fiigig orriiii oo HBiE iB bgE ,EcfEiiiEiiEriREaE ntnidESy Hl crEirr Cd fill iy RR POE ERR LLL EEL.l. Ei. RE ! Es RLElei:s BiilE 000872 418-018:PAGE B-69 ioe | gid LL. 20 I if. ZZ- gd Bio,i Eat om jE ; Pie aaa, ald 3il pip mERST 200NkH gFooig [iI pfgfdyisinihleigrsonoeoense mD EoOHdEEs tig | i i: 1g In 8 [ad BH2E.rRIo,0 FEE (ig E TgBhaiiEnt 2 fog feo iBT prghiblglers fEdiags ior prio 0qos73 : 418-018:PAGE B-70 ie I if slit o y H Ph ofgiziIrr LIFE E iE g PaiE. EgHET= RTEEEER TliLL pGrLiao oo ELE $EHER5ERidYi. STLioonudusn gglaat: EpEd E : ii iggy SEEERRENEEPooEs Poe Ps sTiRzIaLaLi bs diol GigE HI Ei. 23333 Pods siiiiiLily Bloke iad [3 oIpERiBERigEhgEfEoEoERoEe FR 5 hl H Bgl BsEFEReEoEoo RREAR 2 182440:000574 418-018:PAGE B-71 Po ft qLh. phe FREE gieses FERRE PLE ] [REIN LR iil Blip REIT saisas : FEE piiiii iin fiicis ER : fisici ow ifiiigiEo Bil | hn ifio p CTR0EE8IE)E BBEiETliiHaym :; ould 2 dR gi gif i aE ah Fg 3 8 8 335%% PgOoLrE ELSBeE EoLLL nE gsEnLe.EB. iin. EE : PifgpgreEras pear E gn 0Qos7s 418-018:PAGEB-72 :EEL dLE a .E i E5a u3 HE iPErEi ens PooiBlegrgaos se : LHo y ELE RI FI EL sib na BF fear IPf id = da En ERE iE 1[HE EE re Er : Dis Segal bbe Polisi $d 1H ; os E iLgfgniiEgfdeiNofoEg gg1 BEgEEloEen iisiEd 000576 418-018:PAGE B-73 IO E E | ari pr anr el H Pal E4444 38s 0 jE HfEiRl iid g ci i Fo BHEEgRE : gio E BrPoEnC sCiais rrooy 25s sian z Fairiss i : gpa: FFCPERCECI TEE og i} [I Cd+ iii hs dTiiange gHhE HHEeRoE IPEs? i BE i. og3iid H pio, EFERED] dLo. aiigiPHoYE IHEEEEEDEREaLmEN g8sf Si iizg f gs Sigal Bt E iHgEynpMdd Sof igiESE 52 igratit 3jaDE dsign3fggiiEdzigezaeaooaoge S3B5prr2 aeaaeg Piste i iohEc8ei2y8e2 FE 000577 418-018:PAGE B-74 Foil EBPoig.i ! Li Pf PPieo l iii: p2 BiuBpuieeBasr REEERE bDhEiaRlEh siiiia Laas 3 3,3,3.5.4.1 PERE PEiiEiiEd ifeo pHiike ERE broiroindgE REZEIT rrr|: coool FEREEEL LY frei Bi Co Gi EEE: 0 lc.ipirir iiiin PCila finde i og mragiaoggit f gg e off 0 CF3RIEE 1PE EEE Jgyh h d: f Hoigaeifelf ---.ocehgroL LL BngiHfgEeal PlER HmEiH heiirrieilarCR b antg 000578 418-018:PAGE B-75 : pe sE sss AL ELTo i jranig 5 8 $558 [EERE gs 3 iE P8 fFmiigf?rsossss i: igi if fissile 333s f$pi Piles TEER de Ei te gi iezal 3% sess tee $3533 HE Bf Prd leioss sss : s 8 i i os osni ! sss Hdai] s ssi iN lk 5 gif: s 8iged fa: 2h os ossifEl Pramiraatil BEL iBodg,a i poe:i Lile P rpBig.iiE leg5 tE rgy ig i ig s : PiEdEice fl 3 5 $5 52 5 383 EE 3H 5. ooosve 418-018:PAGE B-76 Pi, gi ; Poll. E1 vga,il FESS si; 1 Bi ; Poooi"lirifgeEcAscass Sid Hg i Toe iz HA 8 seai idsiifz gggy gi1bHi FEE iE iy il PDo opoaa,igrpeig rfalgi Pbioo:siifgnfigzs : Tiiiniy FE2 ETREE: ooogso [I 418-018:PAGE B-77 Po I : brs g sHiE o : ? 33 i | ;ideifssssss Pyne fi g 3 i ig if if A dp kiessess 5s osssl iHiiHE E 1ia $ sssifflg Brig figs i BLc {(FgEaEtLaSs hii | EE El ll iiztrxa ozosa iipz iit ae gree is TREnn gCLiotfreeid oo SBEEE oEp rd5iionpEpiigEsisc Pp feiirirgg. SREEggiiiest Son osesig Bedi opin iii Plosmiigasifg Bale piniis 2 iEEEIZ g EE 000581 418-018:PAGE B-78 PoE En em i i i Eh am 3 i on ofoou soit Bo Fs 0 3 sil Eo go sii ss ssiIgH 3 laniz ses Goi omg ozs eel: i Si os ssi lavia amr 37 sg og sof fPpot!rs oe iIte og BH HL Si ae agi Lie = 10 ow 0 UR BC: Bil ss4 5 CRnEi Bgeonp Esiagh, n8 oinhinn B PgE al:ihh hoah HCEyR lHbEane niig lEE iEEToEfRE HE 000582 418-018:PAGE B-79 I gL Pog, i: oilTgiT 8g H[EE gd io 2 g: Rk: Le EEEPE ii i as i 4 2 Lit i gis iifE it i sis $i ; if gfgEigg i| ii lig 5 ik ff indis eed Aon oailds grog igi == EEE s1orgy fide pn HBELt, iHE HfHEH Hl i B5f 0 LL ...E Zia. ZZigil f gF dos : Ht. T]ig riigiaE3eE2sf : 2i w 333% HERE EE RET gPomrloRiaS%Eni0ETB@83Ee I C81%HEoF EH ggRiE iiLfE 00uSES 418-018:PAGEB-80 io gE E E iE IoE grt igFE ry EE gi iE ai; ssiz i o i kif | i swig Byid HH nr i Bef: i, L.. ETiE .. zozEiinfsEl gE SH sgt 7 igen 0% iigif B.sg Bile pilin zis 3B Effie: lPpiigg 0% iR8i% BE HEIL SF 000584 418-018:PAGE B-81 : Po Eo io Eo Poi Eo bgosy g SEE gE BA ; ! ! i : : :: it . ud 12 at HH 1 mmm easannnnntia i35Ek igBii IEErESEERTIIH IILiRE RiiiEH iIiIiENsz IRBIEIRtLiIEE E5y01 EEEH iEmIRE EReRH REk RNE ROcREE Ic ERILIIaEE IIHIk NeArNNneNeANHn EERRREnEHiEEtEeue eggd ili e ite n m Eei m s Rs4paa pesimBg s Gig EERE FEEEEEEEE EEEEEEEEEI TPOoSg Bicismarasasziazoc og BENE 3 fifg i i Ean 2 % RERERER 2 iE 0U08sS Po Po Poi ] Eo ! gop iid i Bogogi i; 8 Bild i FREE i$ rE sBersooii dBiEnE gE, HE Eoghant Brosfeamigh Bgl isd BHEERE EeEeS EHE $1 EEEog PEE gi gPi EER Fiagd 418-018:PAGEB-82 . wApsse 418-018:PAGE B-83 Po ] Po i Pgoi I oii I! : EE P| Pr i E isii 3| zi PBbi UEeLBapEtd d(aehHyadmE poghPigo Logs Bestiaanh, CE iP iEREieznnanEafEiBagciiffessizoariisBiiil : iE Enna i2:B:RIZZEEaL 8.88.8 cass g83388. 2838 8:8 58 iliesloseennmmaanl ieee raznena "isl : : HH i BEEEEEEAREEEEREEIIIEAERERE GEEEEEEE iy py i ERG 00587 HE 418-018:PAGE B-84 io Poii Hig pdm I ioi gBoopE iil fii 3 $10 ARE ggg iii EEE HET sar HEN PREECE I ;: i i| gE is Pi 1 g iE EE iHpiEyoG iiEaaagnE pB aniR in] i i cs 5 3 LEE eh 850 10 0T RTagest RRR GR gg i : gi % BREELEEEE EERE aE Bi, g2%ozligimalnaeEieEn pLsD HogppOHosm gBnaihed ig i igs 000588 418-018:PAGE B-85 EE Pid i Ei io i ! gi ; Poin PE PE gfEyi PL om B sf idB i B58o2o1g51 Lia andsu i 3h5s7 ELg LiTmaanlisiiiiiiiir FEi C onipia ilesin ianusi ainans esaic ! ! ; i$ Por eg gprHa.egmoat M 5 pdSi %ic:m Sife2) SEEEALLIEInEeNEtREE is iiiniinialtis gi 8S3ed Ai] 5 if Pog li 4EdAILG | 3IREEEEE a R 4 I44E 44478 83 EEEEE GESEEEAEE BREED igs { 2 JERR ER EEE HH Q00589 ' 418-018:PAGEB-86 Po Po gi i gi Io Foi PE EE Pri F 1E.,0 will ; i ; i : : :; i HEREFE ii: B2 EE1B! mnt, 1g8%.%8% Len 248 28% 51a, BAIR 8 ef onniitelinotlant Brel IH HEI ET go fu oem mE Pl braamr ERLE wis BEE : 000590 k 418-018:PAGEB-87 gi :PEo o11] : Pi : i Pi ; Ei ; gop ii i Iliwm pty Psogfie(Eli inirE BEE iLsf g i 2 2 ziigs Propet iBF 53E8E1|3Hm E aies si5a : 2i g i d8e T i GLs anIe2E LSg EiElxiSEid L5 E1 iHni taEpmnHainRana hal gin iii i an leit|aa EiEE: RE: s 1] OC smC n Jreegyms ATF FEgERER~E SLCE L H sommppmmpe- El nT] Pda i : BiEiEE2 opr: 222% 2 si9 5% sf 22 2 22 (8) Sh 000591 o 418-018:PAGE B-88 o Po E Po io Poi EIoo PEL EF i: irom on ; : ; { ;! ! ! i] jy SE SERVER HT EEE EERE oEE o.& i18a0l sf 2 if E FERH RE i1 Eg8E3 EF F22iz a3pg s2F% 2 ses 5882s 2 oie sz L HisEsE ifeeP afaaEE iRienReisgen B2EpEay giiisf 2 gy 2% aif exfelazel, iHi neha i ibe|i: i31 1 rni R ni at d eSEd i| gf 50 imvmagigeeanes segTesEeziian,aievazciy 5 Ft! GEEIEENEEIANER BMNEEREMEEEEEIEISEEEAL fain i fiiE g i : + 000892 8 Po EA Eo gJo oii Peo Pili HERR I URE 8:0: ig 8B aBs i (g21 gIF oBaitx 5B83riof ime eeis i , Hirai Bi2oggiSnliEiauekida i: iH Hi iz 528 0 1 inaaniy s pFiliFEEE: poz BEE HI Gd 418-018:PAGE B-89 ooogg3 : 418-018:PAGE B-90 Pid foi | Pl] : Boi : pi | dE bro Pi fLir Pel . Bri gh . BEE op, sCfhiiE IBaZgEeInEeLcEcRcEoEnRnIuSuAniieIsGsEoAnInneoncts ; i1s LL gmpap id sZUhRiRzRaigsafaenli EE] end HE Eh Em HE . isk BEL sis i : i i B 88888 mpm dl 8gaa 8 82223284 88 is S OC% I(ZBIiDIiR2E8IEE3E8Y% 300 B2E2EE3EE3T pgEsEsEsEyR E3R 000894 oAgFy gSiizs I 418-018:PAGE B-91 Po Po :! Py io ! Eo ! i ii ! Poi : PE HEREE : FI 5 EgRiElEl] iITHH Be mC si Eig i Bfffeziaani" 5 fifi tgaatnnnngdif bFfHRI pnliEEEi $70 ifgeanigess ; 0} mE Pligg gis jPo r BES EH Zig : } 000895 418-018:PAGE B-92 PPooi HE : bPo oi i PE Hs EEL so: PFeiir sfgd Er odmow pH sf g ili i; EREgsf ; } iz tailds op ial? g id 25 if [BEFORE SRGSEZIJCRRRRNNANRiE yal Hatnh ein BEF (EiEiaRRERRELyRPrc A iARRRRZaiiadaaril LER RHE HEE EBgg g20: PEE isd pple mouEE dg i g i0f% if EERE43AE E8EE % RE FEEEIEEgiaES: :i 000596 418-018:PAGE B-93 EEE i Poi ! Po i Boi | gi i 3 ii ! P& ro[i i: PE ! 2 EFG i i2z Pom or ag Prim or on wis FD onnnnnnes fp mln] gi f50 EE izih En EslIEIn AIEiie Bed is EigiizEaa 3 EEE 3 & (Bip ERnEERRRIEEE PE 2 iz 2 000597 418-018:PAGE B-94 i Pyii Eoiid Eli El FE ; || i :Y gE BEE EEE Eig Ey pi 58 3 141 1, %pupgp S9g% 9985 2..8%44...80% 8 SERRE i1 pyioni+iEEEBRH RaRRdRRRRRE Ls Ra EnsTs33ti8iilnaatailt g 5 EERE DoUigialyy { Z gigi82 tH EEZ #8 243@agdaa EH sssess risa: op mess oF 3223833 233882zin 1 ZIER 5} 000s98 i po gi : Po Poi : 8 : g Pd i EE ! fl t EE ! $8: irr mit To iiiihiE EEE Ea22r:s EEE nmi 5BBD5r% iEiBdC nePfEfEgeCRE,iEiEfIffEeaSsT:ds 5 Fpl (ETEGRGENEELE iiE:yp f iitia fasn lannangRa lid 8 F iTIEIRRRRERERNIEEL; FEE PEE FE EE is $85300% asptsrisrgsasEaEEiiaa d i : i EERE, gTooEBsEE E5 OEozaBisL if ig 2 418-018:PAGEB-95 000599 418-018:PAGE B-96 Po Eo ] i8 o ;| th : Poon [EE EfEiLi a !: PE 2 ! gE 3 i Tr um om iif Bn stan dane BE. ieilimmmmriecommedr mmaefoancooil l EEE 3 eeeen afiilanadatiam annbeatilif] Hi i:ET|H : shes D487 gp geet EEFF O EE@F EE EiEAH)H ToD ifipiiiEEEr i i HE st BERET sii pir od Tt me iH #4 000600 418-018:PAGE B-97 io PPooii ; : Eo ] Po ! To io ii : i EE : ns HALE BEL gn gg el f is g ol;s. iisf p10 mmm sig i, Ey jBEzEEEEEEsEzon anazis n iad38:2 BE isidizsneniannanannnananfiEi tina ify Bro al BE 2 sasgazaeisias ge sigsesiaBil ; i$ i E sEsERREEE Ly, FRR 35 {RB14ERFEREESFEREERESEESSFEREEEREH IHCE iteH TE 5 900601 418-018:PAGE B-98 Po | HEE i $ ioi :: I gid :; Ei i tPiy HBepgis n HE eHHI Epil $8 H] g 0000 LE iz gif . rs Be EB EEE LE EEER EE ERE EHS EE 8: 2 H[ ByeEa+Hda HHELa E m EEnE nEi EE HHe EE HE i $FFiaslioiiEi saapes: afeEe : : i i8 2883 283 FsEmEeT pjehfef B3388 [HE Pgip BEER OER OER EgHyI 418-018:PAGE B-99 i Po i Eo g Po i Po PEsii gte rF l d Pi ir : : ; i ; :: ;;1 f gid si 8 0 inpzmasmsmagmcsipacgpeisicel Hi iH Bf o eipifERRREECESESieastaniitanannisd 852 F (nEiin3e3a3s9a58c5e5a8n9s3e8n95d3i3b5a3i3b5o58n303U3E3E31GR38EE #0 fer ii pggaarind ::i ] Lome HEL PE 45 000603 418-018:PAGEB-100 i ; Eo i Eo Po | Toi i Ebeo fyi | : Egig iN Eri ogg og Lg LE oz ib Bp InmunnnnadmnEn Mb1g s manR tis| E, EipgiifiguniEREgRERERELEcu. BiNtatriiacaanfagennagtaBiBRiifiEEniti.ligd Beeld ELITIE gi s Fiji i SIR HIEe FEEEG OP BES EEEEEEE ist Dd 1 OF 4 PgoSa iBfIiEnEiEaRsEsEzEerEsEyoIszIssIinAi gopnid sEnEnEnRnIEEEEEReMiIsgi ; gil ig: 000604 poi Eo Ell Iii Pi be i080 418-018:PAGE B-101 ! | i SEE Br fi i iniEnfterrteuinzaiteecriteieyipiafsfaiaigiefsffteieifiecnegleeeende?, 3d Hini a Ei oo foommeummmiy bi HH HER i2aiainaakendiae BEE BRRRRERIE EEN I} fe a $8900 iZ i Ln i810 33 3 ee ax gaa" ial 55 PEI SESIIEIINE 333 3iaf Fl fa. i i (EjERRREIERREEEEE 22 2 EERE 000605 418-018:PAGEB-102 g Pi } Eo |I PLo L H lnR m BQ Gi EEEERENERCRENECERERESERERERE] 4 FIRE IR FOE EEEEEEFEFEREEREEEEEEEFFFFFIF Boel 57 BE He 38 2 ing! SOOO : gt 1 ize TiREinianabate eat fr ds wi 5 fF EE 4 000606 418-018:PAGE B-103 8 iLPoo Po dy 2I i Hg2Hy 0HddEddddHdddEdd HcaeEl o fo HHH ah D orfpb mamma IEIIIEIIALD GE gfinsk fp 8 mama Hilla dE Hiddddddd Bd 1& i0% dseens di 1 HH a 0 pane dannii BiCEce mmm fan, | Bgl Ei i : i fiiiseessss 8 Sheree 2 i Ey "i i, 8s si gibi 3io gf idgiEv% i i HE i HHH : EH Bat i[HsHh] 000607 LE i; Lo E o0 iLo } i1o tLdl I HEE Ri E HF 8si% Ez RiEfsD! veeestIiEnd EEN 1 Ho, aloofd 8 ; IfEiEg: m58asggag%:i%4e3 Pty Be PLE :a ig: 3 OF IgE: 8d 418-018:PAGE B-104 000608 Pod 418-018:PAGE B-105 i 8 FI Po Lr rr ry i [A i5 Bef $b8Eopgiidd 1 | 2 MmHEBMAmEAALE 1 Sidddds Elec sssd G4 digs Bd 64 4 841 Pom maaan Prd EEE RRR] gi BEo Eii1 BiC! e288m88m88aoe8 gzdmBEno4 e232n8e3 3oe4 & : i =8 550 0, :Posfiigkgd PH i382 isk: aiskge 000609 ig Poo ii 2 : | 3 Pd $ i gi Dol as BE os r Esoagli 3 d EER i PrL opmH dide h HHEo Co Bsiir oBel LL. HpiE ow is: LiiF 2g pf oasd a 2 saif } Efi gC `2 fy bE PLE : iH Tih a Hy HiL 418-018:PAGEB-106 000610 418-018:PAGEB-107 EE { Poggi EE 3 POLE OE 2 i3 g EE 8Eg oEg OgEi: E Pie og 2 2 2 2 8 2 2:3 F z PoE le oe 25 2ft 5e 52 52 82 8;: sill ERE Roop Pl Es Bd S43 Bs 44d Bd 54 Bd BSE ; [I g oE ad HE HERR AEEEE EE Pinan mnnnanns | Pr i hhmbmbubbbha,l Pe gBeEEEL lil hee GE id eee ea. aif BY igic oc Bg i381 2 2 Br Bo. mmr oss ome gE 2 sss 2 gg vow ow 222 iE] 3 ii i 3 Bi FEEEER gor HE ! 31: a iigs; `5d 000611 15 418-018:PAGEB-108 Boil ggg fofofofogi ii 2 2 2 2 2 8 2 8; 3 Po FEE EEE i000 pry romeo orl 2gs 0 Pog PRR 4 C4 OPOBR;ROROBGG Cj Ee fd 3 4 1 Po faa { | BB ~B -8 8B B 8 ~5 -8 8 -8i se Haddad Poipmaanataagdtiat o 3 1s fr imnbRibHnnE,| g iF f iHEE: Br Ei B88ogFiat i, ae a FEiEf Bggfiems 22 22 2 2 8 3 8} ge i: l B pm EB ot soza oszgos soizot iospe SE ih BE Fi ging EigHgs io, Bigg ig] [PEPTH i`3E: 000612 418-018:PAGEB-109 Po Hn i i rl i: io i i! hy Bl idddddedddidiidiis OBE :Po Pf ; dddddddgd. 1 PPo E Bmrm iemr BaE i HHHERE for annum ils FEET in ii i! : GG dasnmsseanianies He i 0% HLHf H aanu aian Iiia IiNnNG DGo0 wrens ! 3 H BRERaEERa EE 8gS hi EE : 2 iggi a i in ikigs 00513 fais 418-018:PAGEB-110 sib Poise 2 Pole 2 gif 8 2 D BgoU g Bd gdsddddids IELRoEdIiEN t gi Hi sf gE RIRRLEESEN EERE 2 2 2 ee 2 tPois:s 64 64 Bd GR GR GR EE 1d FI gi F [. 44d 640 1 RF Rf { ! Phi hmmmnmmn hak, siz ida! idx BLE 1 L HoiodelngomnaERaEginisG2 4sa2 ma ii 55 Eo if: 85 i 8 ; R 0pEE roo reszesszzo: of op EEE ogrrc isk iE gi aE s Figg [I 3, gl RE igs LiHdlH: LCC1 GigE Pi od4 2g 2 gi 20 gi E 3Poo i ni s d2 aggii iIit tAid| P 2 i i a 3 h 5 1x poamg iioggs 0g sas lei ia. HTH foEigifrel iElaesi fF fri dimbamh, kg a i BBEToLEED even i $ iziiossi i ge 5EEgE DLEEEmResE gE si wen ow EiiZ: sms if i 5: BspErRG oilbst {883 fyb Eigen Be ifs Pin: EEE 1} He 418-018:PAGE B-111 000615 Pe i 418-018:PAGEB-112 Pigg B Pole FEPoor 22 EE2 g 2 2 gi 5 E e eEe E8 F Pol Pond orr 2 EFS FAFFEIFR FS LIFTER TR TR FR FI EERE EERE EEE fo EEE Ed Z i ig -8 8388888 ~ "gE 88 8 8 +8 +3! = Pr LinEEEBILERERE,] g {1f iHEy: Ee i 2s gE EH B12 d LL ies ea ape a aif pk ng Ho iffd8a2smmses mme o22s a&2ris2 is 8B5g% f8EsE:E sBgEEaEsiSy $fiF EMEEIEBRB OE ieh HHEE HE 3 : i#x 00Q616 ial 418-018:PAGEB-113 =gff oiiEfo:f zFoE3Eo:o%EotEi fj jg% gg EE g Pie oe 222 22 i iitie:r eg 2 2 [EE prrorel g 0 PEE BREORELZ 3 CoRR i Posie sal sl Bslsll Dpioladadliidddaddiidndg B80 gi 8X 8X XX 32 3% g2 2 52 521 if [EE peg Ei 2g ize! s22 2 2 2 fe a i 1: CIEL 0 jg P0 E5oEsHs:Is oIsoE;oInE:Soiasf 8 i] ogi E iE8: figs jE ERLE iBad 000617 418-018:PAGEB-114 Eo iI Eo : fl iaddsdddsdddddidaadi 1 Po Hit i i , Hilla rf amass | go ti 5% 7 is FI i { i seasssssissnnainnan tt i oB1gE.2! aaEi psrpeeeeenrrrnneeiinfE i Pg i HEE i223 if eh i fg izes FE 12gf iil fais ; : 000618 418-018:PAGE B-115 PFEo CE [I 2 Po Poe : Csi Sidddidide. 1 Po lim Lig ; i, Hinman opi SECEERERRRsEeRsiREEE. DFE ams | By i g2 iB: sddsszasmsgazdddsaasis i Ho 0 8i5 p0.E8E HseaEmszazszsasazazaaaoieps: i fy : iE OF IEE! 2d4 000619 2 Eo to i 418-018:PAGE B-116 po HlRRHED I ln AEH iP fl 1 iusdeddedddided bd 44) 1 pr | ommER Ea] srg tr HE HE [| g zB a3amaaasadazaaas 21% % iBtr i8 1c25f! oSrEaErEaEnRiRsRsEEaRgRREEREAENNSl XOL 10 g Eg Pi, 7igs EE HH = BRiasES 5 izes od zi fala 000620 418-018:PAGE B-117 g Eoi f{pd , HEm RIB El iPos igddidddddddddaiisl 1 Bil i; i 4 8 LE i! i sid HiEo i Eig Pog : ; HE ii sees i cveeenernngrennonninE sissies |i i: &B83 i: i a 000621 418-018:PAGE B-118 & [I 2 3 i+ 2 2 2: 2 2 i E i o {Ld : 2 2 21 2t ddd 04 gdddd Gd ddddddddd Eoid - 88 5 gg HUNGER Doi SEE IE ERMC BEOBSELMERE El 2 25 &t [sBE f bd ddd E41 1 8 888 8! BEE RD: frida faa fam am Bn, Eplee ii rid lL eee. i Emme mma #1858 8 sss ii BEER $silp {lig fF ssess or EREEEE iai dg nme seen sf ; sssessiery BBEREEIERG 000622 i siz g bel BER: ik 8a: 58 lal FE JI PoE Po Pg Ea 1 HIRE | I gi iesEni E E ogi dimen od gf El aEE HgER5R I 0 T TIT] [I ig gB8rE8eRIITEE eeseifsEie B38o%iepsi wegeiCfoedd Honan g EEfL iHiEs FH jsf iit inn TEop sEE,RIEa:g Eos (382 PE HE gle 418-018:PAGE B-119 00Q623 418-018:PAGE B-120 PoE FF bd Pr Poli itt 11 EEL I 3 i e 28 e2 e2(A ezg e2 22 ereid sb I RE poopEtHmanaaEig PoEs S 4s fd S43 Bd 83 Bs Bs 4343 3 Bai 1 EPo ogo TSEH EREE SLEE RGELL c GEEhSEiGc EL fridiunminmiunRaRnn fei is? ELH H,dbmosr i! EH g8 4 8 3 mismo B28 2 BR 4 4 mns gddd 2 13 sb 2i HH iH 32 FE BF BREE 232 % BERES GZ ik fiir f2 sFigag i 000624 iE HL 418-018:PAGE B-121 Poli opr og go adsl Pole oe og 2 2 2 FEE ii 1 Pie3oe:oe r ge 2r8 oepiidfF FEES 70 TE TR J TO A 3 COBH RY I mira titgr f E posr Rnui ian ay i biog EE EE ERE EE BE EE OE BED 3 friiihnhrabhaib gREiN iHqE: TA isd gg it ELE Pt Th i zg gE 4 3 23 & 3 gat} 3B5IC osi pgii,fF BOEz EE2 OEO op oisgE: of 2 i igh? iii : fist iE iges fPi5 a ilgs ii(REkdE 000625 418-018:PAGE B-122 Po ; EI Pi iF dE is g3Ei0 Pd if: ig 8 Piro 8 G4s: iE HE Pflr 1 Li Hi: Bso Eps i iiB ii38e5: EEL 33 *i 85 tH B gaELL HLast hE. 1 H a5 8E 2 ir gp [IARARIAZAINRIRCEIITsizasssscisid reeieens iiafn Pog Bp senna fT HEE doc !' "000626 418-018:PAGEB-123 To ii PL. i if 51 il ig FPE Ei iPodi HH {iE EpA% 2 i HE gi ji 2h i Ey Pa if a FiRz if i iEoREid gra ify; HE, rsrmmssrssmsunnnne sesses VE iT i | isidezdizondeasasadacs nd $8 FE 1 liiiieiencaviavacacnas ssosaa gilt 5 1 HB : 7 i ividgdidsisidiisiiniss sipi h DEORE i 3 iE IEEE EE EEE iy 000627 418-018:PAGE B-124 PLo e iirdi gi i H$IFRE 0 Py 1 irSPg rE i Po ii fs fel og | iE: 80 ig FL RF E E p EE o E BF 8% | ii BE lssnissaies sam Hi iE Es HHEEE H i L1i:En8 EHTEiEEnE Cog iE| anh EEE LefhTE ig8 x3 merino gb EE HaElE Fy umn me ssJn8 BEET eveeviiie viaee rerenereee JEAERS FLOP 55g7 i1 BJZE i F% ees penig H i(noiiiEdRdR.IsNiRdRiIsEdZ sT:IdA8R4A 1II:RdI:BSBsRIsR.IsRcZssTocabYBEESf ig! 3 32%: oo 000628 418-018:PAGEB-125 fy FEEh iG tro re pi iti Hy Z i Pod HEH RIE if 5 HH gor i Li PE r h, d PoyFi8g82 gsfh:0 EiBE Bi38e3 ele graigd i itghE gf: Grou EIEmERan sige ielE i2i3s8 5g,i i[aRwIaRnIesARERAEEEIAI: sraH msnE arsRE Es sdszsaddBsa|y oifffiisssssi: sp BE i iS gl reererernian is a, ige2s - bi: gs zz gf iziiddddidieg:n Li gE if tag igth * ig iLifrrnsfneedeniiitagiy siti 000629 is 418-018:PAGE B-126 EI o. i qiE iai te gi fSPeey 0 igfignt 1i1L) 0 P Piroo Hiag Taldt mSrEO 3L:e E spiegE h iRO T[HFiHl SEEf. g Hee pi izriszszzisarszas apines sasssisits Sal 5 lsrssssssasenner zene syassiiREE 8 Ez 0 gd = i igzzanazzddanzads = =z 3332358273 i ieveveveuvessesse erase aecnci EERE P PrEyEDnmmenmnhbaiGa e cro 1 HEHHINHERRI0E8 00030 418-018:PAGE B-127 ; 1] 7| i PLooi gEEE PPiiEy g3 HEi ir 8 Pr 1a i i: EHyH Pb yr ii ih gH a m iHgi e} e 3 iaal Bg hssmsnrenasene iensn ssd dgaHt fy R-- I-- I fy mmm aaa i: 5 Higgs gi EE 1%; mEmmRERER gle 000631 418-018:PAGE B-128 PiP[I L si iEE i i PE PiEE iy Teo Pro aE `ze L if 3ef EZ 4 BE i : i sismzesmmizin Fig yEt i iif isf iHu itha JiCF E5g Hi ieiifsHi [Ee 3108830180 i800% Ea gi m eeenp ernm ine Saaai aanJi OY PPa: hpp cD isnigEsa EadIsiEsiEn diTd Ocne iRgnigRs diiene itil IEE LL ! 000632 418-018:PAGE B-129 Po e PL He FE E N Hiz E3 PtEe HHEH : g:o 1 1]i iHg y ii ie Fy i Ee gL ii iE fPrL i Pgfd gE ii HE TREE iz8e HELE Ch HLeage: iE [i] Hip smmmsmmsesalnf 223 15,0 iersrenesvensaneerncieliy 25 if 2% fgRaiaiiziiisecaiiiiziols gE feeescascscsscsaaciainla f oo0% SirE piigaasmgsdsddgaizediidzdsisgaisdidgiiStdsdEs) 2DEoE HBnlicniceenencnencnncccenanneBl] IEEE Ri HHH = l "EY 000633 418-018:PAGEB-130 : ig E1L i 0Ii iits ig y0: | Ld HHNH PE iH Fg iE dd 3EE i Pd iifs g 80 i iE iz Pd ig EL di LE Zz Pd [A i E Pi iLoEe peli iE [HH bE FE TE i i } isi C: h% fgg it gEE 2 EE ia EE eedd 6 5g gBi 133330 33 7 233% aHaBlirFy tidmm es nme 2ehr PFD 3 ieissass fff gindesess gti bE an pi ! gPy i of iHia BEERn CNRERn EREEe GEENENREEV PRETEEN i2v 000634 418-018:PAGEB-131 co #3 PPEe tinh t$y30 1 i ix 1 1 ih 1iidh i Ea iE GE 2z Pi FPre Ht E5E gsTipotsgg ii:gi aIyEiEeiE ge HH i8 2i ; Jeti iE mmm HHtH ign shensnszsensaissigSil dd fh mame H8i0 BF 0 Tj [ieTeRe rseEsesssssisnsiasiaisisiascaiigfiizlgy o5 ah Ze dndessdinadiadipth PoE olf PRR le 000635 418-018:PAGE B-132 Po ie 1:0 1 11ERNE iFTE [I irPy i : i Pi [E EE Po i Pi fr Bslped iE Fa 7 gg u i Be | ii i i ip BRE itHE iiIHs ii ig i4fss id 2HE] Li S1E LH EHsf ii Ta 3g FF joi io eeceeones secscone fil $3 0g iTis gifsiisss sipsisieipft FLOP bn i BFR [BIRRRRRRAERESEIEEEEGLD 000636 418-018:PAGEB-133 EL go NE Ig ipl if at 0 [EE Ea HH Py di ip EL i CE o g dadpen3iE Ha igghk a il if i Co Be HgtH BL momma sell a Bir ti idgie oe E2 51g oTfE iggE P2i00ds i vuansna.ansasa oiE5EE iE ad seauniainiRuieiend 0 iiHgigTunasgTeUnUnUaUsTnTaUnUnUnAnNnNaRaIsAaAsReAnRnSngeRig 25a5i1, 4fiE aszdizE zzsissE sassizaisniazanns doii: 000637 418-018:PAGEB-134 Iif Eiyh FiF: gie PE HEH RENE iy gfir qCEE pe a iE [EEE 823% B8xg i iigi! i83%3e3 tH: EB gli BE, momma ff Bx Bip ei dsre Hil Fy mms shi 3 Pp fF PEE i ivervivesieoiivesa oie. ia iBEEY teasing NER IE iieieneeienesennsnangi a 2iBE fr! gE JE RRR EE al 1 000638 418-018:PAGE B-135 Pid Eo : Ei i Poi ; Eo ; Po { g iii i si : 38 Boigsit i; EET E$o 5gliasiBlgsrssassasainaindsdiinisiii:! gg| igitr nna RRARIRRRARARRRAAAR E Berf 1 inl lissspsdndsiesidissisasdiiasi ge = iisiiiiael5l3 88% eifizissssissddddidididddiddsdsasis 2. % (oRNNAINARNANANAnAnAnAnAnanAneIg 23 oC IFLIN FE } 3%is 000533 418-018:PAGE B-136 so gi ; fo. | gf ; Pos Eo ii : i gsRi ;; fio ; gFiE g EAH 3 I! gf , (Fi (RRERARREINENRGAIERGRRIIEERY fpf mmMRbaiananGn| o B00 ei Biigsiasaiidninieitainaiandesidt i 8t0s Lloie isssisiisiiinaene0 nrmnmmmssmnossaeaeaneentig 13 Dogs de Dos islasmesssmaamenarsrarazaiaeanaiBrY) Eg rsii (53352 IEEEEEE EER ARRRRAERANER L3E2 35s 00040 418-018:PAGE B-137 io : Poi ; iiioC ; Poe i. Ep i g 8 if ! i Pgiii i 8 sig ;; [EER : $ Bi iE oe isi i: . 8 (TigiARESERE IFREREICATRIRCARARNEEY FET da gf. i |BREEBES, SRRRERERRRRRALARARIRE VED asssstsesnadisddiidiinaiisl i a i 850 nasacaasdgsiddsdisiianissiaLsAi 3i oSxo i (iErIiS3E3REEREIEEERIRIRRARRESERRIIEINERRIIRIEIRMEERRIEIREIRSIENgAEZ gE i2Eia Co 000541 iPoo Eo [ Poi [IE LE pir I Lrn il Pi ioe ni i 418-018:PAGEB-138 : : ; ! : : i ; i 2 ial Liiiidssssddisigdsisiisiiisgil EEE ligisiisdsiidiiigdssidsiiiag Bo HPCE HE EE He ER 5 fy I gosr Er TIEIERRRERRERIRARERRARRANARRERARIL.L tr BeioBreBrcEroIszIagEiiEziEiiEiIISaEdEEasIanOR[iiEOLiEi 000542 418-018:PAGEB-139 Po Pod Boi i gH i if, ir] :| HI 5 i: gin iiiiiiisiid ; gg He : : BEeF5 1 Ll iLommsresssintoniniiniinaiaiing)i He oT LF FI ARERRARARARARRARAARARARASNA Ld zz i35.s 000643 418-018:PAGE B-140 io [IE Eo i; Ei : io ; o Iot s !: Ego,itii ii Pin : gg iid ; o8og iiEe ;: Boil | Bg. inl ipEisdsceRsgiddisspsgisaiias Hi Co isiiisiiiiiiiiiiiidiiideiss 8 i giR |SREISRRRISINRRATRRAILRINILE EH Boy igid {Est [HE EERIE felcsrE sreHssrzBsEassErrEzsEesanaEsaEsaEs nLasHe ; gi i385 000544 418-018:PAGEB-141 EEE ; 1 i Eo : Tf ] Eyl i ssRi : ii Egfiielld :: igifip : 82 4 ial : gB Bfs EinE !] I. {fFSRdRuRAAERiEIf.ZiRiIsIiIiRrIdCRR: iOIfLaAnNdRdIsLiLsAdA:S|HT] HE . . (i% iF f8 2g59,Dc 718:RiEBiIRiNigIscRImsAsaRRidAdRAReEedSdiMAedSddARiNisSdiRAsdRinRRedAnRdEiSidRinNNiaIaiRRiAaaTiiRRiiEelR!i]t tt HBEF FL sinnniiiianb 00 ia El BISRRRRNAAAARAIRRITANIANANANNRN! 8 2 EE isis Pi (33. 000645 418-018:PAGE B-142 i g g ioi i i| Poi : Eo ! $i1,00 i gi Ifi ! gg ii ; FEE i 0g isi i ieigiizadisiRasinniRaniig He ne U BE amEmEsma |g Bgr Cop LFi iiiigdesissiiisddsie [RRARRRRRIIRMEEERARIZ 1 OY S8 0F8 eiiiispapasisisnisisiadaniitS iogSy glenn 8 8% {BIRANNNARARIARARANARR1R2 5 EEG 138s 000546 418-018:PAGE B-143 iii : gi ; 8 Pid [EE i i EFo EI RA ! go, REE | gos fi 3 : Ei : Ea fff i :| Bou i sf ixizidsRddaisiadddddenisg! 0g | (S{FFRNRARARIRRRARERALRSg fq [I 148.4 000647 418-018:PAGE B-144 Po Eo ; ii ; EOC : ILE | ggo, Bi | Fail IRENE : [TSI i 18 L pdgdadauniaiatasudes si f T ixilidegsddddianiadaddadi E:T ial ijdifiiisidndiasiidgs! i a lifgidiisitisiiiesessi BEE a Blsgsigsisiidaiieaigsit 6 Sp Egi omen ogigii 1H HEME gE 2 HEE HHH HEH : 23.s 000548 418-018:PAGEB-145 g ii g Poii i: boi, LEE ! islig ! Egoit : gEEig ig ;: Lge oo B figiisiasiadnsidddsiding HERR iii BBe ETimi Co : ifffddruasdddsnsgag! 28 5 7) [FNARREIRILTLLREAZARE. B28 ial iddsgsdiiiisiifsiisii. if EE 8i2. ia(iTlIiBgIRgAiGdAdRiRdRgRiAsNdIiEsRsEdEiNiEiRnIig.t iob 5s2i fC l H; assqdsil | 8i Py FH Doe g soi iEImEEmREmEEmIIaIIaEInIIaEIaNEbnRIunNME PE #0 . 900ca 418-018:PAGEB-146 io Poocn PL gHEo8RiRfEPR pie oid id C8 l i: : ; eseseesi | Bl ries. BRE ol legsisiidsiidsisisedinniiasl| i i 3 3 [FRATARISIRRRENERAIULARARERAR yi ig g @EIST FiBEEEZEEEERIIEESIEIEISEEESECEIEIEIEIE IEIEIIERANsL Pi i 32a. 000250 413018PAGE B-147 Po Eo | Ei | Ei i Io : LIER : ior Eo, i IEE ified : o i5 ,8 i: ge fii | gg ivi 2 i PitEMS lE aiBE lasE cisE ccsdE sEdEoEE iEgEeEE iEsLiEaE EsiEsEE sEiEdE EaLaSc 5% ixifiisddgidisdiddsiisiisisdis EF Ll ipuussssssiisitiatinienniiig 1ERNeEl erties. 1 27 eifiasiiddddddsdsidisiciadadagin :: 5 E i iiggaBitfy S o. 1 iiziBapiIsEsiEisEeeIviEisERiEaIEisEIReRsEAiReAIsRsEIvSeIi0biIi)i PE {35s 000581, 418-018:PAGEB-148 B20 } TE msmiassiessiaiine [EE itent sande dadd) BOF i -i dfidnzidnndnnacizsfdaadenss) Tr 1 [ IRRRRRRRRRRRERERRRRmRAm FE .: 8 {owiEiiggadddddadadasddddandaddidd: 53 8 0 BE vi iERASSERERGRERRRIARRERRERRARE; i gf F on0-0 i[fngEsffRdRsssisfsAnnaRsaiRiIiifffRdRsRvEsRzRaRsRsRnRaIsL 3g BE i EA sini [iRRRRRRRRAIRRRARARRRGRARRANN ly : BommmnnhmmninB fC iE igh 2 2 ifs leennsccassstascsnnnasceccacnitfd EEFRLUINE EE gz i i203 000652 418-018:PAGE B-149 i ggi PRL i; 3 ET : fF ial FE Bog ii cod EO 8: aliigsisdisseddii2dndsssediinigdinid]i gi | EEiTii oRii g[RgRdZiEdEiCdIdIuRdIgRdReRgRuAdIsAiIgAgNESsIrReEsNvEaIgNiY g 8 0 ii HE i. i [RRRIRRARERARRRAZARRIRZAIRER g Bie ssssadenneneddduneessiiasnl i ol iiieisesiseies ks if 3 Fiji RRERRARIRRARERRARARERERENERN 2px oPogF E iiZ Possssnnsmnmnssiaiannn a1 PEE ese tessassaessennnBaEnS So ! ""oqocsa 418-018:PAGE B-150 Biel idisdssifsidssidsdssddadiiadsl $0 ] 8 8 vi iAadddddsdddddiidadazasaiaiidal ! soi i : fms [E I -maini esd tf 00 Ti RATRREARRRARERRARRRRREREREE; 4 CgHf lEoI o"0 i[RiEsRAiRiSieiiIiINiEiREiRiAEsNiAiREiSeESiRiRAiRi:Pi: BBiop lsmemsgsaaniiinsniigieiisiisaiiiiisiloiesd] Lio inl EE FH 2 nesses HE [fi FRRARARRRRRRARIZLARRERIENAN 20s BEL of FE gngdaiiidiiiiiiinsiantan 1 gt pd EEE HE000554 418-018:PAGE B-151 1] : i gin ;* Pe Pri i : ial geist Hsdigiagddeid iil frase E30 aiEisannnaaesnebunnriniiiaidd 3 i Fi [ARARESRRRRRREARERRERRRAREANY i FE : ig BBeEiD sl g is igiddssissdslidesddsiisiissdsie] Ino) AREER Big ii +id. snsnatnan[IieaneniainistoHff Se Ei igi { 55d [AP sb ssnshine 2: &: EFF g5 gE (B71iE3333333222RRR2ARA2A0222201%0 i EN 0003SSs 418-018:PAGE B-152 ai gEiReds aiddsdadididadddadias] Eo : Eel lsaiiedd seddiidddsriiddaiinial fog oi ; $0 g Ei viidssess iE sRnddsddsddiiiad! 2 80 oiBidsadsdd sessdddsdisisesisngasi Fi jginnUnnnn nonnunnansmanmmanonEn P Fog i Ti iTARRREAR RsAeRnAsCIiRnAiRRiAiCnRiERsEiNsARiEnRsL 4 Cb iii ceiriiiisiiiiiiiist 1 gf F070 Bei oi BERERRI i of NEIRARIIRERBLARNREERR 3 H i : [fi RRRRRRRgRARARARARRRARARARRRER (202 z EG Te] : i Ly i s5 ig5s :PonDERE BEElElRnRiAiSiEiRaMeIsEiEaRsMiAssRiAaGzAiNzSiRsAaEaEiRsAiRiIiSfLiCE Bi i idl 000556 418-018:PAGE B-153 Egoilia0 8 dia gio 0 nifigssddsc g 8 ipinnoTonn Bf iYiiepeees ; TERRE FPEo : i : : ddfsdsdds fissiifesdsi mmmmmmmER EERE sesdsdiieisnsiiedadsii FTRIRARINIRIARIRRIANS Fi i Lymn snag go 1 sf 8 1 si iERZEZEE RRRSZSGRRBNERIENEREZL: gf Foie liaagdd dnddasddiadspsgdsisil i{i10; 23JisRsRgRsAsLaRsLtRaRnAaRdIiAsRiAnRuiRsAuRdRaAnRsNaRnAaRnRs 2 f0xd fig \ iE s Hlf s iLgarreneebHI iassseunintinncioes inn 9BES PB ee mbitesHR Bog BhipiERERsafaRfefefiofacfasfanisiiies. ' 0005s? 418-018:PAGE B-154 iEor ERiissisRdadini~aidddadiiaisdds) Eo ; Esl ifpdsfsiisisdsisiseisisdniis! op rin foi igiddgifddaddisisisddisdaiiisi fo 3 E doiEs ;; E00 nsesiiiiiiiitinsianinis EE oDtl oi-RBilgtisitdiieiiesidsidiesniiciitsietiistiidiencgiiide)i 4 i ; ig BEL 8 : 4 iii B838 o2t %PREcGiigfIilsEdEgsEisEdEdEiP issiiiE dsiisE dEdEiEiEsEnR Esiili8558 ER it So """0o00css 418-018:PAGE B-155 Ha F gL iF g iii [EE & i i i HBoEg REET i :; E ii sigma an un oHcaoeHl gESl o essnsnassssisininninati.! i ti Eres ~ PERIL FE Baio HH HEHE EHH i: iE H 23 E0 tiL plinesadedsdiaididiiidiiiaisdeiiniiiaincaiiEileiEl Ei ht 0 si gamnnianssnnnissiaaadinie 01 [PEEEEELiiiiicansasensncafecenns(eE8n5en5 Ce " 000cs9 418-018:PAGE B-156 EEsTlH idsdddadsiiiaa sddndndnl| i f; : do fr gi (RARRRARRRAIASINAZR ssssiiiiaiiniii IARRARARRY fagissses RIN PPopf| TiBiIiRRdREiRnARdRReEcRRiRIdIcANdN sRiRdRdRgEiRdEdRdRl! 4 i : Lo jest : BE Boi iigsdcddisisisidsisfiicidisidiel $i i 5 EE i g 1 aBD gid sssssnsaantianinsboerinnni1ni e0e 5 og iB EE : i | EHEERSEREINE 000560 418-018:PAGEB-157 Bosioi Cfhei "i io: 8d | Poi i ! i imi, igdaiidfsiisaaddddd ddnddfids) LOR aiissssiddasdiididdd Rees Hoo ; i L Fei isissseisiictizniigiiidS%I,sE HH i Tj RARARRAMARAAAAREAS A gE )) `az 000561 418-018:PAGE B-158 Biel iggeidgsisicdsisisdadsisisisd gop nT PEaiidmesma: BF oi isigddsicsisdesisiiiseaiiisidl gp pgpronnTnImmmmmEEmREAREEEEE I :; ;| [E EE b Cifi iesee iiier iiitiiiin: 8 8 oiissadeiasadisiidadigisnsisgg! Pio gg0i| oeiIc<i/sXiRgEiRiSsRsEeZsEdRaLiIdRaIdNiRsIdRnRiRdAsAtRaAgRiRnRgSlid3g U1. mses ERIE HE 23 Pop pnnnnTNAnSRusnannasnamannenee 8 i soi ig SEE ei isdssssdsdssisiesserseisifsisies 8H2E%RI IERIE PEE iB srunsanisasenetensInneity op igi essiiesessneenenEsE 2 12:5000662 418-018:PAGEB-159 i] Ei | Eo lal : IEEE i ff ial be |: Boe .0 omiiffidiisAssssiidasiififsdsEisaieainiian: EI : iE Co cE 1 oejiripniEgRifdainandagnfadndadtaiiadasisaiangsI] 5 8 1 (REZRERERRRRIIRERERERRIREZARR HR BIEHEREFH EEE HIHT LEEE | 180 el pesdimsddagsdidnizdisisdaandieg B Blo:EE osipipssddasdninipiasaiininiinitiiaegdy Pop E igs La EER |if, {Rivvwansrirrirpinsmrtyiterti]nks 000563 418-018:PAGEB-160 Ei oei iididdsisddsgissidsdfdgdsidsl [IEEE EEE 3 & (HI : RAENNSRERRRRESRARRNARRRANRRR, E E0i 3 g sandiiiiinininiiiindg: gi niRRRRRARARARRRAEAE ; of Cl nama, | Bai . 5 Bei i ik ELL! ii ii i - iedsss i, dodsssigsEaSC As 2 BF nssniaiisiia01 Ph eset1B o 3 | yifiFRRRRARASGNSSRSNEEAStenomeniled :Pos3 EFin iH mmE mnR nRR nnEnaRnaAEnn to *voos6a 418-018:PAGE B-161 io Eloi E Fi Rd te Bia [EERE : i| ; i i i if: DEo.EE eifisserdsssassssiedsdaddiingisl 2B ie i FiFHIRE EH EE EE HE EE : Boel i 12 BEE on andeddisiiiddiddiiipdddadsie] BE it { i* ii] EeREsRRrReRMsRRiBAsRRsRGeRRsAsRAaRAiRAiREaR i1if0sf0 sp Fisil gadci iiiis t] HH FERRI [Fi] 22 iB ieeeccesnnenetecanansnansnneipfd ERE [I id iZaf 000565 418-018:PAGE B-162 E IE : gi i i Eel gasigidsssniiidds 8 Fol liggiddisdcsisiiiiig Eo i ioe Lo. i gE i fF iBlgscaiasaiasicassdsis! sb i PL Hsseiiniiiineiisl . Fi [SiNRNARAARAAARARAmSnen: sg 217 {RRERRERARRERRRRARENR] 5 i Dna 88 5 | HEE giio gHB50RfSE i (ljRiEgRiAiRcAdsSsRdAsNiEgIiNssAgNsAiRcRiI5sRlg - Bisel Hs, ofilgsiasidsddsidniiiealidii3Ei5g8 Ph einen BE LL iE gooce6 418-018:PAGE B-163 E 18L 7 ; fF al ; fTEg i ;; 5 Fa igidii sesdsss assis E Pio smee PD ai sgsinninanineiigdl | Beri if 88 sl Rdffdisindddadaseodf BHiEL=Ltei 5 #g1r0 assa i14 [og5 iBfiiziazsEsgEssissmsaE3sissEasEssIssEiiRid LE 2 goose? 418-018:PAGEB-164 DL Ls sss Pel i ! gi 0 ; Sol iades dessriasiiiade D8 0 viBigssis dgsiissidssingl SEE lasagg ddssganiaiiisdl 2 Li. 2 Eni idRE3E i RRBIINZEERRl 2k E ; [RRA S00 cil igebiaassanirenaioailg i{ dl BgeELLfi eiigfi igadsndiaaa) daiiii2fs idg EEE gt iPos 8BiokaamicnBeebfeifenremanncdnEeeShnS g to: (EPPliipiEREEZEEREEEIEZIRIIRRI3NL%. 000568 418-018:PAGEB-165 [EE ; Bg oBbiaH ihd :i 2 3 FH PE 88 isl igogdf ogd8 siiers EnaRl gobi ; HIE REFEREE HHS EL 0 omizidsndn adsddddddadddl rE : psn ---- ` L i . on SH ; it 2 ; i (RERAAPARIAIRARAAAARNL 2 8220 TY FRR RRR 0 IgERp I0E iHg EE EEoEE EEEEEI E H FE a Pll nant BE ER Co 000569 418-018:PAGEB-166 Po Peli : 830 igsssinisssssisiiii IE ie ; Bio i& Ph at si JiEIRRRERRRANAARINEANERRIEE fill iteieicnsnnncasanaipld PROSITE LG geosio 418-018:PAGEB-167 r 11] [IEEEE Boia) P2i1e)l 4g Foro BOF Biiavlii| ouGdEg odgdEE Foil Er ; ; ` i ogHdaEdsEi 3 EGCl alislgsiiiaaasiisisdag; 2 | TI FARRRERRAIEREFREASER] 8 Eg i i {RRRRARARARARIAIRARES 2 i | mms | BED insessdsdddssndndsdadie] g E00loeid imssisa. nsisiIiniieth HBg EDBoiaf giiitsghslosoasaneniniasianiisa0 1aneHed 33DoTifs. faiaiis.t.eenasaeeennnnnne8s HaEBE g B00 3 veosTL 418-018:PAGE B-168 FE Eo E3 eflf 2 Poi i | RiOg sGeRAdSdRdAsRsRiRsRdNiRnRdAsRdEiRnR | Pai i ; | g E| 20 PIEi Poni Pod "i iE old gi it LL ais ZREGECAEEREAIERNER!| gisdsdsdsicadisagl RURACRRARARARARARLL| desenniieiniinning Eri i i 8 g : : ie RANRRAIRASRARRRLIN! 5 gf F100 id dedusnuaddidainangl iBygi RIE ER EH RH EHH if Epi i=l cs 85 gg ign isis #1 hai fig aE Pop REiinieassessasasrenfenis PE 3:2 000572 418-018:PAGE B-169 po : Ei PE $a fr BOF aii fii 0% el id gf pp SED aiBls fi S i ; : : ; gsisiefiss sasad | ! sgdsgdcedssdssiduil TTT gpssisdsassisisads nN : sf 1 ni if ppissdndsnggsseisdi Beeb HH iHyEos iF isdadsddngdfaddnddli| He agmmiiiamainizing of it i i IR FgRRRRRARARARARAARES AOR Bog ig [I Bononnninnn i fig feenneccccfesnannanl & 3 ip EERaEEERAIIEIERAREOAL. zi i EE gq0673 418-018:PAGE B-170 Bgoeal | ETLe - | RINE EEL gastdidsidiiddandnddadadied: ssssisssdnsiiiaasndadiess; i Ee mamma ERRRRRE Ee SE BELT . ie 8 ti e EHBDi Ed Tni pigiedsiicisiasimsiees nzinsssddsi3ssaigl gf E Edel Fh friitececsncescacnsnananaiattila )) 000674 418-018:PAGEB-171 Po } FI El B Pon i gE "1 PEs 3 fel id ; PEL gogo | sf 1 RD i RREARZINAGARANRIAGARRARANRA: BFE Pf ii IRICEi 1:g BE 5 ml epdsudmisdsnissdzdniaddidagd isl 50 2 | xisifiasesisiidsidiisssidsissdas oil BE nnn Pop E [Fi] 2 fils isecetassccnascanacancesecata ini? 000575 418-018:PAGE B-172 Biel lidgdidciidsddiideidnisnisass fog id i 1 ol lsdgisddddddddsdriststsisisis! Bog ii edd Edda 1a0d gE ie : E00 -iliddndddsddndddaddadadaddaded; Fl iis. | iELFTI ARREARSALERIRRRRERRIRRENAREER [i i ERR is is 1 ssn FFE og :iti REAR RANRANRANAR ARAN NARS 1E0Eh s 2: i i= HBoNg HiEEPLiyiEIREBe EREEs IIIs ITIe TIBEs RIRItEeEGE0EG1E HE [ER] 000576 418-018:PAGE B-173 Po Li EN + PET tH ti. i EHR HEFEEEEELEE E EH gis V1! ogi sesiminiiniiuinaiiinidunsen I E0R0 : =iiizgdssddddsdsidsdissisiiiisel Ei i 2 Bo seins | Bf fv aaiaianaRaa LBErE ni igmdeddsissiddaniisiiiicsiiiziEcsinidsssslis]it gE ia iis Eb i igh 8 sf sms HEME gti t 5: i0E8hiicpiigfsfIafsfafnfefaRfiEaRisiRtiaiiafaiafaiciaisiiiiaiiiiiineisns Eri 3 Co Uoas7? 418-018:PAGEB-174 io g gi i i| Ey | RE io ; HgEy0RiR0E | | [I i : Pi j Pi 1 Ei F : EE : 30 i Bio is Bp nis go, iE IH $i: ips Eo1jpirRiRgRgaEnEoEzsEgRsEssRsAsEsRsaEsEaEnsEiEfLX HE EH 000678 418-018:PAGEB-175 i ERE gi ; gi i E Booi i i PEPo i: i3 E80d i; g ogi ii; ; Ee it : i HERE f : FEE gi : gsi f ! Es [I i BL f i i [I : Bi E LviLgisdia3lddiindiagT dddE itsis ge gdh BL isasshasiiniidnanden0d0 ig iE HH] [EER LL HEHEEERE ELE EY ii 000679 418-018:PAGE B-176 Po Poi Eon pi0 g3sE igi IP E EHE gi Ep : : :; om mr off EE ge 222 28 | gsE ofi idgeio32 sepee eofgt | 2F0i00000 BE mE on oin TR EEE 5 855 55 | ig: gilIlE E E ER EF EE gEyiiiyr Er rEg HBore ieoandaiiiatanaliiis Pogif i BR #2 goocso 418-018:PAGEB-177 gi gi E Eoid io g PE i gi HfELiE gs i1 I piEBEERREuEeeEgeEr : | ijizezizazEs : : i i ; i:: gErEeE pEEoEp OBBi zs zap ni $1 BEEN [IE iEisssesnnss 5 igiefeeseeer oc 0 iEingEamsyEs 58553 i3spEzazer {EaBEEEEEE 35% 0 0 isasmemzas E EIBEEEEEE Bg rgmmaass Brant 222 gegfe! ree PRRie! sew small gap zaziii EEE EEECE! may swsdsi BEE BEESE ses sneer i 1 cop nnIIEERALRIEANNN 8 Fis! 2 gig HPL3, iEiRRAARsRAiARtAZsARiAIiNaRAeGiSt01sg HEME (34 si igs LE iz 000681 418-018:PAGE B-178 Poi ! 111 f il] PfEiL0 i |:! [I ; Pail : 8 gi i iid | HERE ; $ Pii iE :; pil iE ; Batg ii ! Hoi i : fe : : is 21 8 E00eip viiiidsm idspsBesiecaiisi3s sBp LfisBaminassan5sisaFEinsieOigLsF P$og 1if iieH 2 ; | [ iz 000682 418-018:PAGE B-179 : Ei i Po ; go, ; HSoeEE i: dE gi BPoei h l Eobo - s: gEHi oe BEE fos ipEE i igize E 30 ijiee P ELCERiTE imr sf | | (EE grEiomo gf Fm Selim Bc::iss gB Ff igs HERE og EE OE 222 2g ii eee e B aEmEooEr Eg EEE & Eli EEE fg omer rE ozo: 3b 888 3 3 Ei. ggg gg 3% i52t 2 ieii siBBgssBiliai cBaaafanasit fogil PE iigs FfEg] j=iE BEEFBERRREEERNEGREESRRELEREEEENENsEsEzRg Ek gE 13% 000653 418-018:PAGE B-180 3i gi E Eo o ii g PEi il EE iF Rises IERIE : i i` i i fr gE i ommmogmn HA 2 less 228528 28 28! E fi igier e ereceR fee RR! FO EE RE 170 iTimE on 5% 5 | i (EE k sEEEEk.aEEEE 5W3EEE 3k3k.! BE (555 REERE z3E 3% HH] ii ists seEss Ess ssi Eoiiizzz opEEiEE EE BE ES: i i533 3533888 83 85 8= p 0{i0 s{eEffg EsEeEstEEeE "mEeE RERaIiE, 8203 0vi8iifR4RepRRRARRaaARRARi`s3 H2% I; TiTiHYPER JiSBURRRARTERREIIRRRRIERNITRFERRERI|LIE i, if [HH El ; ips 418-018:PAGE B-181 "EEE : Boi ; oid : g RgEyi Ei i!; gf ; i 30d i PPeeFo ;:: fogEERE :i HpE dRRL | EERE : gC: EHgpEeiREE iiis fmm gf Fi iy BH , ET IH $i ips : joo HERREERERTG 000685 418-018:PAGEB-182 ro i i EE 2Eoiid ii gid ; gos | 3 4:0 i g Pgid : Pin 20 : #1 Brg i BLT 513 vilidsdnyiipipisanicissis Bod ssniapnssasae 0 Pr ig 418-018:PAGE B-183 Poi : ii g [EE i; 2PE Pi i tgois : Fg g Ei : Ei Eo [ERE HE E EEEiRsI!E ei g2 50 i i BByE BPo oi Be g if 2: : ios 3sB2p2cd: Eifsa mfmsisniini0iigf gi ih 2 Ei ig? DEoEEmEEEEEEEL 0 418-018:PAGE B-184 i : io : Pgoi !; giiB50i0d i:: P Pii : g feEi ;; fn : RRL gg i ; s bepi : iH, | fe! is Bia i i: gli 52% (7c iH ZESREERIESSEERIAGIZIEAz E 3 iog iBiRGUEERRRE ERRGEAe SARAiRLI :db iE (i3g%s Pfodr; o r 5giREEm EEEERRa EERRGGn ANASMjiE 0 00688 418-018:PAGE B-185 Po Eo BE iii EG BPooi i fi Ei Eri i: i :! i gi gi feline Poe fri Eb gEioinerr foford HERREEEE Ts He rIEi of: 3E iEoi i 8 5 53 r i i Piiog1s% Eoos: gBpi, iorzos EE is H EE EL R . EiE is OF IDigimeemndsindudddidddinlg Pg ot i [ Ss i1 migzssssp sscrees mig 000s 418-018:PAGE B-186 gi fo gi Eo gos [EI EEERE ee PF rem Ss oEmamr 2 oLpoii EE 1 IRE BEEEEE g 2 | iEiss see oEo Bi iigfiiegsE apmepe BEE tlemamr P; EEPEEDEEEE Bin: M1 HERE 0 1 10 & gi i (2% 333 5 ci i iss 533 : ; : i g esa ; mm LD ogEmEe Ems ni BEEEEEEERE BEDE Eo EB! ggess 93. g! sRpRERsRrR sBRsEn eRBl! pzanr oan, E fE EEEEEiL ni mmmig 85855 553 5: EZEZE EZ I! 33833 85g 3: SBfi: viciBRaEREAARRRRREaREasiE: sis 5 i5fi7iB:BREZRECERERRERRINAEE!; z 3! | Bog ipiEEEEINIRIEERRRGRY @00c90 418-018:PAGEB-187 to ; Po | Eo i Eo i PEL jE ; 5 Bind i E3fi80 ;; get i ER isiseriiiigiciisiieniiddl 58% 0% lggscediidciiddeddddddddiasail 4 sf TD {addsddssdsddsdiddisadssisdng Bl } LL 2 i; 0 smn Ih HD fimmmnasiiiaasiasdeadniif of 3HRgN E lig E EE. RER EEEO FEE ELFEEiIg 113 P0:7, ii (HigEIoEiGEsElE ii : c (IERRIEARm EEIRATARa ERIITONNp EIAIhE3gE3 ii [EL 000691 418-018:PAGE B-188 LE | Poi ; f Poyrici ; EEE PIE : LHR : Lisl | og igi i i, 1 heat RBEf NidRE 35 TI% EE ED EEE EEE ER FEE EEE EE F[I O iggpedsddssdeddidicedidaidisg 0 inn, essen, ih ios i Boe inn} EE [4] jRRRAAURRRICROLURRRARARERREERIZ IS BigpoLrfT DldvsidviisisnidsinaiaiiagiiiSiEfEoiaEl I 3 gEEE iEsysk ipg3'y 3 ai nBRE EBLBRERA RRN ERONBRRRERN ELE OIR ERO ERTERNRMNRRIILEOEI,R8G0 000692 418-018:PAGE B-189 i Po Eo ; Po Telly FgfI groiatn ii Epiit : gigi g D5f fgiige!lsdagd3 go 888 fh ifpssdes i, ie! LL = ; i sgdedTsdddidsdddiasi'ddanaiadss! ! gedgdsdigiidncasienddl vr g B82 u 0% imssdnd-3sadndnd-essandignienl; H55E% 3i5i LPpiemaEiis eaieieiagiesid EsiEt iit.| ilmmnnlen: nsinenntsaiiiniiiaeinqgligd] 1o3l 2 ai EHoE, LA i. IHHI fi Ei 000693 418-018:PAGE B-190 EE Lind [ EEi E ;i PToEon iis | Ein iii : i gf f iLiE :; gLoEg giitgi:s ii [DoEgRLiETiTiddsgadadgaddddgdndddndsdddagi 8 fF ldsdissddiddaddneddddndsdaedd HE Le FEESIRE EEE EEEEEEEE PEELS FEEAEH] : EPER:NiE ideddsisd-ta nasdsdddidenidingg 1i sf Fil ig $id i i 2H snnsananestnans aan | tis srs Hh of {i ibiessntenitititisitiiiei-iin] iY i D0 oipiEEEpEIEiESERERIIIRIAEAACiiG Bi 30000694 418-018:PAGE B-191 so : | Pi i gi [EERE PE gPgE iF 5 ei fidt gi, iiaEl : ! | :ii : : I MLL cE LEEEN E EE PUD emmmmmmsagntias E Dit lividsdtddasdansiialenidaiiag C GHI1MIREEE EERE . LEEEEF iHEFEEH HIi E E IE H i tD.iE smaB maL ITT E Tirsr L d r ag 132 re ER HIE 8gp B 2 i lai:ss: daniaaniiandainng ig if 33 0 igi Heal ls= i3=iHzsEnsHzsIcrHssIseNseEanNsIsuNcsGascBaEzoeisk 000595 418-018:PAGE B-192 gi i g foi i: boii i EEeg : FI ENE ft Hi Lei gg ieigl i g Eog iiggiiEe:l i| BOFERMIREL EEL ERLE SEEEEEEEE EE ; gz oot ; ef 1% ligndasddeaidsidcsiniisivicil Bit I FERRE EEEEEEEEEE EEE PEREEEE TI BE [i [EERE TEEPE FEELEEREEE ECEERE ELIF 35 8 aid: R1E2E 333 HHEECH ipisensdndidadansianddindddangiifs $o8p2 Sob imi sisinaasiiisdingssiiiiiag i $5 (LFIFASHSSSSAASCARIARANZLDLIANATIELEET FHI HI leads Do:5 i iizeiiearnsRsReaearaeRPEBiIESBBfEfNiEiIaSEIIIaOiRiEiNiRiEERiifiAisoiOsn 000696 418-018:PAGE B-193 Poi : Po : Pell fog iii | 2PbaiEioilg |: tlOf iti i i,t g 8 igigl i SHI 3 iHg:E :i Tog iiiEidedesadaiagidgddedginddizdad BC ; 88 Bi% idiividssdsnddddadiensisicang f Bg Pos 5 if [asddddddunsnndddanddniient'y i BEEN Bp 8 itiglesdsisqssanaddnariadasadaindifiy 1033)2 sf f Bums Pri 1] Ba gE Fo ELE 000597 418-018:PAGE B-194 i EEoo : i F byge :; Pid | EL ! Pail : 8 gif! ! EO BEMEIEEELLE EEREEERE SEE giinoesiiiisiiedgiel gio ei TR 8: % inl lgdesdddddddidddddngd! E HY vasiter-viiigienls I Br: in13 pannsesnnnedegannnn i $i Bi sfpF2 3BoLTiEd8i:adsndsddnessasdasiniEigge 23E723 g 3 : (RRIIIEIRIIIIIIIIIIENE RUSS Ei : [EL ET 000698 418-018:PAGE B-195 Ti : PEoi i i pi: io 1101] i [FIE i. Eioiitn id, oigif $ 3gfgiiggii * : i; ;: i i iii; gg tat CTT TTT 8 8% igeddidddedsidissddadl gf 0% ldgsigsgiedddsgieiis Gf EE ieee BE BHEE EaIiInPETTTITTITIIIPTaf T I Bf fi EpmnmRmARaRRAEEmERIRIL HM scpeTiRidesssisnsdsiiniiaddlHs I310 HRI iEsgsl iiip:i spspEpmEmmemEnnmnaEnEnnEaHnRniInEdRn 2 EG 35.5 000699 418-018:PAGE B-196 yi ; EoPid i; Eo | Po : iii Pi, : : gil i P Ee i ;: goed i ; i3iE! PEofE REiigs:erssiinidiaiaaa!i 5% 2% isgisiessicifssddsgdsl 4 sBif. ist i? SE iddgsissfsciidddidddsi 8 Fir ois SRnnAERERRSAsEs :3 HEW EEE E LEEES HR EH BEE ns iiuiiiiiiiisssgiiaas Hi : [ie sss 000 332 8FD8 E oid iem isaseasm diennaia rans 8a2l30 g Eid SEE :Fl iEiaissremzrsssssassu(BsBisaszlisll 0s EERIE GR PR #555 000700 418-018:PAGE B-197 gi i Eo ! Po 3 ii : gp ! P Prg in,c :: 3 Bini ; Bois ; g 2E:fT:ig i| $f : gf giiE gi? . rivasl : gSf a tijiiinidddadedadadeadiniaii 58 i) lggidssiddisedidgdgasi f gif.fiinT) iSzHdtndisigzrzrasEsEssecdgdidigsdaeisdgs | 2z BHys Logis BCD desesdenideissidandly i ie bili BSpf8 f iniLignigssdsiasisiaiisidsisiFdR jeigpERARAmRRARERLIIAEERRL iO00 gf 8 tH siiisiiianieiniee i (BIEEARIIRARITINATIRASE 01 3: fogEisigh H {gaMia BDoDnl irpiisEaRzEaEzRaEzEzEzEeEsEsamsEziaiaizisfiifiifiiiidl 0 HE ` 0007701 418-018:PAGE B-198 EG : EEE ! 2 piiill i; gHE50R0HEE ; PSiights :;: PtEigti : gp |GET $182 lgginasiiicississdedsssinisisl gf 0 iN idSdddddvasdsddsidaiisdeneigl f [815 5 lissicideidsisdsicgesdsisiaiidl. i33H5 5 igi, TnRTNNT SUASTASSSSSSESSoiIRie 223 Hf lms gS a BH ] - Pit egDs |HE33 FE]siii ig 8%3 Ssh Er ENS RA AC MNS Sn saannes 33 SBHEiE IEhE f~iEnszEyssErrsEsIsBEnsRssiEsisBassE insRfIiR iEsd 000702 418-018:PAGE B-199 ii. gi i Pi i A gEi ;i Po [FEE : gEfiirei ! i Ps gPiel i g 8 isigh i gp bain ERR a 858 FD ldedsddiddsiesiidsiiiiisiiisdl 4 FEOF iaD [7 TUUTTONTR SAASASSSmESsIEss 2 Bi.i %; (ddoiniddefdddinisieisgeuindnsEfgdSdsdsisddagigsi i8 i foifa mimEEhamingeal BE [HE EI iy 332 0h EE 2 init mm iiidrdddssnssssssossesasEssn see s0r.BoiiEiigidsasssiadagdsasae nding ig 7q0 fii gi DorDo ziEiBzEiEsEsEsERaEsEsEeEcEiRRsEsRiIsnsIiRiaIsasziEiiaiiOibiaieislsz : : 600703 418-018:PAGE B-200 PL : Pe | Paiiod !: EE ! gE 0 ! s Bo : [ERE ; [I t i ji i HERI : Broo i1t Ha ipdditiaadaititinaddditean]g ai BHEaNioJas.min .Iisdd $F UE ssaiasnisiaaanaasaaniBHia FM ieEgg iD PoEo oEigEpo EEBMEEh IBME. LIIm RRMAMARe ENNGB[NiAEG]LS FTE gi 000704 418-018:PAGE B-201 Pl i PPLE ; FioEsioid i; i: Pi : i ii 3 i i : iy g itiEi oi E; i fed : $ PFEip i iia : id 3Hk E3E si 3 z3 gH-o Bi 1B0! miiimidcsdsmdsdidBmiddbddissnaddsudainrseid |g3 iy Cj mssmnlamnnn fi L$5 7rgsadiniinininfen e anaBiBeEEsT 000705 418-018:PAGE B-202 1,p0lo : gio | Pr 8: i i Lg IE31 ]i Erb gs ERI iE :i E fs 1E P [HE EE ;is He HI Bal 5 : go BgBEEEE2Boiai lii[gReEgEsRgErRuE%S0Ed +fRm dRfReTgRidR.rLiAdEsLdEiIsRsR gRiiifs e; df3 Hsh ED0 RTEieisddsaiiifidsesddadisiedssisiidcfsassg 8 Dlsmsnskessssiisinianiin BU s[PoRUeE HE mEmEmEmEoBaEEdEeEtEesEEeE EeeEHEEEE] gE : igdis 000706 418-018:PAGE B-203 1 | IE PEERE ;; EE OG i 3103di i i EPR i ii is i EE ; Pid : Lye ten wi i HE oo Hi BEECH id eidiiddngd sdf i TBHHEEyEES i ipieeieimsdmissssiadiaissseiesissii=cSiLeagcezndsst SFLTEE iagn!snsaisanseninnianadaHaaedE|s fd . igat [Fem 000707 418-018:PAGE B-204 10 : $f g Eogi i i| EE i Bop8: oii i i! IE ] LfEiR EEE gig Bil gl [FER gi 3: 3 PEE HERE EH EHH P iq , i; : io: if: ig i *; iiE}- fiiididistnnnig if Ps = $2 zp | IBIGESREOREITUUERIARRIRNNGINEESIER.S HtE Ci eiHg imneerreindIwee 1uEdlgy zo: BH {seassssancencansta ceateeees Hi 3fg iHBEgiTinTH IBsESE IISEBH IOROISIGIEEGIsEniLfiiE: v0GT08 418-018:PAGE B-205 po, : Pio4: io i PE | PE ffeot : Pig : ogi il i rT i 3: 30: ig 2 BE Ei ededddiddidn ddddddedadisi] of Bil Ejrl so iissa ieiin iiiin iiai:ejsibBES HPoEpMEg fisHf]l 000709 418-018:PAGE B-206 gE3s0i ti i ;! PED ! EPEE i ei i i Pr Bo1z 0o h i; [I ; fiogi i Po ! wd iE i] BSE g Efogi H[EHRE i Do HiI E: mamas ann] BHEy mT ilisiis eddidie ndndiedasmdsnedsdasdtisd JiBons REN HE :#121: iin tten iain HIEiE fopidi oft Dos ELinimaininininaaiaisnaififl BE i 000710 418-018:PAGE B-207 PL | gFirriFoi i i iE : 8EEfi ii :| IEE i Eglo Pi fl 3 FE ig i gb * gr WHi,i 08is 080 F[E1E EE . i, ii 4ff :: iEq g HH Bl0D pemmmaua Bih $50 ssinaenaninsanindSReEdY PE een Bin Eg 3 824 000711 418-018:PAGE B-208 PL EE RI ; EE} ; T2E001 fei i Lo | PEbo TE i RE | Bl i qBeioonoo `d qHI e BD dag amma Bi BEL aT ie aEo man IiHsaGhkt 2 P ERE iiTiisusndnasiiidiaiiHainEtgiteYsyr D DLEOR mEahtdeatubt aniiesnons : i A Hy 000712 418-018:PAGE B-209 PL EEN EE ; SL Fei i ! i io. i ; gi Edi ! LPogEi ;: EcPoon iig REFER is $80 immsstassnasedsizanis lg BiEi aim a iressccs 103 0 Joc msn iE DDoogsEuEeELm pinesm ie stiie im eas eH0sEs g aE2 000713 418-018:PAGE B-210 iB,E ! Pio ; 38 i 2 tB i 0 iCo iPer Poda Pi on ai HIE Hoa :1 iFli r yr en ir sresae siid a 41 BgiE E Dy p E im ieseea sggsn ases SfHEsE 850 idErmaissndnaidadasddiiifyes D HERR o IE bb. ii e i 4Fo(ERipiZEE3EEEEERiifiRiBiiiessaiss:' 000714 418-018:PAGE B-211 Pe g EoEs ;: EEG ; PE : PE ; i HE ; TFiE !: 0 i i ge Big i f FFimia i5 5g% i, izi dBEai. CF Fitg Hig simmsaaennl EfEg RE lip penn ied Eig isk FHI HEE iia i DogooRoebplRRnRaEEtREnRnERaROmNRnRaBBnRRnARnNnREndLEiiS Pet Rt 000715 SE -- -- 418-018:PAGE B-212 Lin ii go, 00 EE gtE Eogi i: FEE E fein Feil bro gid g Egb 9miiIHin 8I8g,:0 i1 i HE RIEEE :: } : ! : : : ; 3ii f iigg 4 HEEL EE LEEEERE EH i ii Semi GE TE siiis addnndie indesie aidinaas n iHIEE Pi 3E0E RigH Eayy Pg 3 F e ERR n ER Le 000716 418-018:PAGE B-213 pl EEE gHoEp RiEiSd i 2g 8B:iti :; 11 : E{efii |: HIER ; OF i gi Eg +b i Eh Lo RBiREE HLE d 8 8: 0 Ha] sig HH Big HE s85p7 oDiinfiigdisiiesedeasiidadataiadifHfRY Drs ismmsmnsnasazzaBin fog igiEEEEEiazianzzEaaEn ese :2 (Es 000717 418-018:PAGE B-214 io : EEE ] Pid ! ge a ; E gEi 8 ;: Lik : fod sc 0 iE 4 i if Pri i SipE oeigiEmm2is LE 32 Por irirprieressessesnanicBs Bop i ipiEREREEAIGRRIEEEREREL gE 12% 000718 418-018:PAGE B-215 PEo o fii i gPrEi il Pet g i ig LOL gsiScrg fii iti 8 0p3o BEBE Err Bx 3 : 58 THEIFE HENEIEE So iwiwi o EE ; : :: : : EE mmeozae ememeyosBr RoEo EE OED om8 o LR adI IRIEE EE HE EEE EE iEs a i ipiBZBERERREARRARRZNZANZI88 gil gf. :: : 000719 418-018:PAGE B-216 IEEE : 3gop8 iiiidd BTgoigEll PirL gPeogiflg 8E8diii Eerener 20% 0 iEinpmnsmer F igisopmpmrar ii !i! ; :i see srsrel; EER BREED gps ogpmss gz [0 ifiggzenenes eae g2288! R8eg 0i"iienggeaepenpmeeenen eee map peeee! omaenn EF 30 if: {sEjEsEaEaEzRzEaEs sas sams EEE GEEEE: BE ham aon E210 nmnaenen nm ARNG fig BEEEEEEE BEE GE 2$803Ei pi-iip5e8a33n3a8n3e8s8 je8s8s3 n33e8s33s!a [L8I Fi, iDJ If EER EEEEL FE EI: EEsstifs EoyoEi 5 og immmmmEESy 000720 418-018:PAGE B-217 Poi PoE : Epil i 2 TF 3% 1 g1 fiF i pik f| i$0 2 OEE Pad psg i : i : i :: HERES ir : | : HfErill sf iis 14 hilo #7ER TE ianegaeannaaniid So: isisgsszessssgszsrissesiif i : i% BEERREEERRRRRRRAAEAS 000721 418-018:PAGE B-218 EE il : [EEEsREEi i:; g Ei i EE i gE eiPloi}gt gi! 3tgio iE igi E PErifeteamger ofg Foz BoEg Fifer oammorof gf goggEo: qiguiifrk E88%O:& :Eegi zB! ieiss 288 2 i fieg3iii"iness oeesemor2 oBy B@i BEiEomm op i[ER REpEiCs OCREOI0% F Soi izz BEER ORF Eig H0E2 ioifviizszs HozHo ozg zoz iClif fi: i i? Df Hesliiederden i 1 EEEREREREEEG : 000722 418-018:PAGE B-219 Po g Eoi E3 pfiiil 3:0 gPaBiill SF EpeE Biio08 il ELE Fp | i: ; i i ;: i ; g Potd : mceimpe Popems opel omer anf in 82 i ifisz oe ssecer 82g31 i"ie5e55rp epemesffesrr BUF iEEB BEESEE B5 E ERT DoiEE Kk kLkikmaESEk iB E 8 E 0 i E iossno5 mbon3mo5gEEoEEss EE TE j33eias B10: ifinegduaetes gee 2p! gfenenoaenii 53F 23: WEEREE EEED: gEGe85nim8ag8i.l Bzs za! Canoasit g Fini IH] PE Li eT Eo i piERREEEREMEERRRLMERRES ER i28 000723 418-018:PAGE B-220 ri f,001 : Bosi: i; EERE Pi gHsEiRRN i! if : 8 hie i 2: i Bhi FE Hgriilld EiEEii ;nL $88 ig diLF gf 2 i iigs 18 dddrssiddussddnsiory BE Py i 3R igiigU ggasasaL sesneanE sanic. 000724 418-018:PAGE B-221 Po Pi Ei ! Esgi3ioi:l l i;| iE ; | Po : Pili} : Pro Fon | gr3 ; Fl Hi oo is B il 2EiEsi fi5i5 izi g#iv1in E EmeE pppaE nagBE Pgiad iE Fos iriamsssmmsaaassssssanil { : : {HRRERERERRRANIIISNANE Fy 000728 418-018:PAGE B-222 To : Po PoE ! sii Piiy i: } ji Pro ; gHEERR ii ai i gio i B10 SE 2 i i008 i Eo ~g i Hii 1 $8 FBE i.isf: inzpameenda |]3 oF niFTTTT TUE 3 (EIEIZIIIIIEIEEEZEZIES =F : iz 000;20 418-018:PAGEB-223 Po ; PE Pio sii : PPlE !: fell ! Ei : Pon : Brg ! RgeEdERE i! [FI I 83: i i Pi ie sff aBiilsini Hedy i iiidgz 58: igi g ' sBfLEide iddicis i Ih og iE Is DPooip sosnsEsmsmnmsmamsmamsEaEnEnEE 2 ET # 000727 418-018:PAGE B-224 EE FI ! E fi o, bi |! : gid i R 8 G :i Ph Fi Eo P8yilne ais P: os : BE ore fs Sa iiiogs ff g si: i oEzEs 3HI : i BE ER oz BEiile HToSg iB zE?EE8 if aies & g & EBE ii2 Hp1E20oHel1g3EinEgEiEs fg f f i Fiiisz, 8 Lf pms Pp iB ifF=pi iip:ii3zRsRzRzmRnInIeRsEeReRaRaaIaIaEsRsEsRsEi3sl.d 000728 418-018:PAGE B-225 FE Ei iigil g fii gogo PEFi f gi Er'iRRE 8SF2ii! sEpBeBpEsR 3 : igiEg gEr i | i i i i| i :EI pBEEpEeBrE 2EgRb gBiI gEag sme g 27 1 i%ige 232 2230 ("ier eee Ppp iioigs smn s3%%9 sg; 8 eeeee RRR RB spans omg ou g0 f zfF |i || ((EEE33E8E3E Hi [55 3% i E00 iss sss SFoEsE |i I| E[xEe BaEmE gf = | Tiss 833 EBEEEEEEEE SRERE s3sEs BaEwEmaZn 33383 3E5Es. 3E!: 8h: 553 5. BwAeDg BiiBg sats 8 (Sof1: iejigaiEnE eEEsE i#1isieiB g ii mEEEmEE gifenEeEitfs IM] : 2 : (B{RRRSEERRIIIIIEEEEEE: hg Co ) 000.29 418-018:PAGE B-226 po : g Poi i: Egil | i1giB fi 8fdEE : to 5g ; HIER HE iy wide i i : i greene HEE [ gBgi Ei iixd HHEEeEo NH iiE TREE 1] gi i UBO5RE m BIRERERERIRm ERRRRERRREm RIRRERRR|L 000,30 418-018:PAGE B-227 Po fyii go iL ERE g Bogid tio ifFiE fi ; a |! i i sig i EsBoi E OgE:irrrrressssssssssssanaaaannn is f heel jit FFE 2 Pry : 000;31 418-018:PAGE B-228 Po FI g TE i fal tig i i ; Eee ;i : sepenssagaessnessaans] Pein PPorpie d !: iri i sbi | TE Borghi i ggg is iy co girrrrsssjesssmmmsssssenanaseen Heid ; is hBeE i: i5 feo i: rip i 000732 418-018:PAGE B-229 i : FLL Po ; Er ii i i IF E iiiccnnsssnnsengancannnns) i goed lie ! gigi i i { gg glosssuossuuossiuosisoossuuont Pogi oHEH i: wii 1 i NE resssrrresssssrooesssssneens if oi LE # FE BE iisg fre ai I giv L fs gg TT AranaaA r nanny Eg i" OF iE piERESsEESENSSRIIRRRRITEREAL "000733 418-018:PAGE B-230 i : Ei PsEd gs Eoin i 118 i i Benen [IFRR EE :: Pilg : gPaTElE: ; ii cE i HEH 8 IH] SERRE z id i gi') glrsssreses ns snanna ann aanaaa if i gE gBihoi : i: {Po 5 gLioad f i Tria 8 cl ' 000734 418-018:PAGE B-231 ny I Il] EEG gi i i gPobli :; 3g ei i i ogi FEI i { LE s bib eaves Hw) ER : gz3 5Liilgii i if H EBoS il Blsarrsszaszsszsszessasseseesiif HPEE LE 2; HEH iE 5 g @ 1EE a g Eid opis TLE Bo.2 iif:f it i ig ci13g3s3o3p3i3n2s3i3s3ERERnRI2RcEERsNsSnSsIEIsEaRmEilfL 00073 418-018:PAGE B-232 211) ri 2 ot i i Eig | if : gi i sige : Pid w23idigi ei ;i : [i Hd de i HE 1] go ial : if H 1p18l0 -HiMsEsRszMsRsRsGeeNrGsNzaIzEsEsRzaRsEsRsaEiRsAsEssEaAiAf : : 000736 418-018:PAGE B-233 Eo : g PEi i : E Lo 1 1Hg Fig i 2 10 Ef i I iE i Bry 4 sift IH iE i gEi: REPo :4 sHpEEEie s nti 80% gf iiEs sg oSg iisli i iis Erdman $s ` 000737 418-018:PAGE B-234 bo | Sigaiid fo |:: Pi ilk Se gil] : ! Boi i gE i EE gsr ifitg e IiH 1 EE ernnenen He | 8B5rg 0 El i: s H[EELEEEenerenmmnnnnenaeni`s gf IH Fog tiLr PE i8 i i8 PF b[8 iEimEEmEmEImEEnInIInZEmInIInEnEInIZtL : : 000738 418-018:PAGE B-235 Po i, PPgg :! Bio i ;fF3gi!fBleeagenanccanansnsnani; iF : iii : Pgogi ;| iis ] [ EE E| | | givovevovouuusussououe] fait ! gig i 2 Fig : Bip, 1 i 1 izmrrrrrssrreensennn il g HiE e ifa BEE iH BeEill i$ sf PE i2 go2 hdd 8 Fof3 iinll e5 lEeRsErRaRsRrEaEsEnRrEeEnEsEaEnSiRsEnSsCY Co 000759 418-018:PAGE B-236 Poi byB 5 P go l ;; 16 Pe2l g F Fi E igi 2, E Siig gz fig iE kw E$oiii gEilnefrmmnnmn i gE gE ge Po HERR 2 3: TE: HE EER CEL ! ii i 1; nnn }if i `i5E 8 la i] ig :E 1 RIESE Srmnmmmmenn iz vee:40 418-018:PAGE B-237 Po Pri i FgogE ;: i : Eee geil jE : tro : E0R0% ; ! Hsf EbiLRlnRie iisd giE 2$ i-i; Big ddd i 28g 2 it i: i : 5 BFE: iE 3g Lit if gs 7i gg: =nTronmnnTasonnannannnIagIat i: z 3 PPoir p :2 g 1 mlscaNmsreNC OTERSES Ra RN NDS 000741 418-018:PAGE B-238 EE [EE : Bi i Egil gril ;: g Pi sig i i gE oE8 ERgk i: Pe i Bolg i: f 7 ig t i iBrgEE ;i i $ [i irserrrrsssrroeesssrcenerssif :5 PE ie: iis pie i 28 02 0 ig: te sp EE i $Pogiisl Ii z i iIIIEEIRNIAIIIIICEIENNNINEZL. ' 000742 418-018:PAGE B-239 : HE iii rasan Jes) Pigg) iremmeeen | rmemmeen rere {FHoigtg elameesssser || pleemnssneees]! reeesneeeses)i TEBoEgi rgd eese IPERE El lvececoes PogEifRi AEs E 3 [IE [Blonemonen |Clleemssenelifusseneaa]: }| iaccacsseihfiiccacsses!i 1 i ! i igi : [finneconooifinononcos! yg BEE iH ie gE TTT cl TTT Bfitihy i 1 "ig gid HE fevganeanki ronawenn] Jravrweroif :i 1 HEHE HE EEE 000743 418-018:PAGE B-240 i il i {szamzass| {razazaal azassan POT ammsnsel lesszenssl bzeeesaee] ID1E 0 gl llaeneersesearneer]] olnpsemsrsansned] firsgseeesnneensss)] : i Hi II 8 ipkitie i. i $Ei3 OEEFliagR ii 3U %Ei lecopsovmeosona}Po li eesseccelPo jeecovese)i fogFiziE : E2ii:flenoancnniiB Blonnononniiasinoonooont! EiLy BEme3one3Tees Hifi i: i gi i Li Ll 1 Jrsnesaes; jannanne| jrevazzaziy fy Hi i H 000744 418-018:PAGE B-241 fla gE RD lasenses) lnsszenen i eenessesd i ; I gly feenmanal fesnaeenl fmeasead EOE reaerene) freeones] lgeeeaed T3 lELEa lLamesesess]sl lLeeaesreeagmeaesnl] lbpmrsesaaeeaeznd) fIg rogHigsy oniere] lnenoE ene] feL anavgeed gf pin gine Pi Pi = iFEElgi SFi fn eeeccd cecl eleceeseecn]nt dfeenesceocoes]} Eling i Ll : 2 EiingiEpiihfieceicneeseno]y cpeomonnnneoeri feoeme nsse ent BoaI HTH 8ee ifs ee: Bor iligd Eg8REF o Ri iin feceee] Leeeonnnsif Piid Piid fa gr big fzmazent ennzennad imszzeny BE IEE ieeverenni fesnezenzl izeegeseaid oa { :i F pifRimHsmEesHeEs psFmIsRsInIaEsIiIlRiRaRsEsRnEsReEsRiIdG oo 000745 418-018:PAGE B-242 Poi Ei gai i gE gi iii fii ! LI ii i i ! i i i Li Ll i Li : ; i Ll : i foi i LEE ig iB ! gil i=igizanennar ii znzznnan if innnnnnna! HE BER ig ia i a6P3ERanEib LGaRceEmeEnnNn | lOssEmeRrnEseRl lRegEesNzsEsEel HE HE il Li : HEL ii Li : BHEED RSHHIEANomracenali l lasesaess] lsi ssaesaad BL HEE i ig i 2 : Co 000746 418-018:PAGE B-243 bepi i iH : ERIE I Li ; : Eig sm fs EEEsUiEeiiEEeernnn iifdenrenene g if oooneeend; EE i 3 ! PLT Ber i GEE mnED AumnoanEm Br Hi | ! E3S8E iSiHgiEsi e| esemmnaliirsoresss] fsi easass)i BEE gi iq EE . : - Ph PY 000747 418-018:PAGE B-244 io { Ll [gEEE Li PPdd C[i i ;| Egglloo 1i i3 |: gli PE 1Pi i!i i: RAN | pr ffFoe ntnn]flfrennennn]Fleennenand: foElEdelgizmsennasi&fiozanazzziiniaznazaze! sed) iii Li Ll ] lg BoE EB [8581i2fii yor ii! i : iizfsigczieegssinsi| (iRss2s2sXt3iRc%sii 2ifaeNmAsEsReRrEs. Bwge? d z b i gE Gi by oo Pd Hi i i oo 000748 418-018:PAGE B-245 zEoi*i E It E HPo EAR LPiLi id he iHLi E IiisgH ER Le wd E PL on TePamh selioee eee <i1 Pio LID gp nol ne TT Pp IT Se LE Elid eee iE} mete] BE nif] <eccesss iE ceecesiyi seseesaif 5% 8 i-if cxcsccan iE] Bo eeecce | 8 5 Ll cccsTeen | HoT Heo i 200 lull weeccccc | | Hell | HE ini i weeceeed <ccscuzait cRecsendd | cExceTI ace][i | cccccrcc<ecc<eis || << :; Semcecaciy aeRaennnly cI cccuiT uc)ig <ewccemnweacnsi]] 2 BZ Bal] ccxessanBl | occcccmacl | occccncaain HE i i i: 000749 418-018:PAGEB-246 , By Pboenoo nnn i ial cccmececl |oemeae ae ac <i? : fif2i1 <somescndi| aneenne 1 Ea ec wee iTfE & i (2d ccememac] | occccccnsifl we xe iy PLE g 1TH eee igi ceeseneld UT ce eee of i? i Iii Se aecnend]l] ve wioeels 8. 7 2 iniisf] ccel~ eccn~iifE:l c~leccceciHfHl co coceciidE 88 ELT eeeiB] cecnaniei] Ze TEIN B15 i cecccosa] | ceceiece] | ocosaceials id [rip eereeend | esecccund | ceeneendi EE crccecne cesmnnasd eneccecif BE Ll cewenns] | owecnenen] | aenacaesld Propane Dans } } 000750 418-018:PAGE B-247 coed : Sd Pi Pi i Pon Po ii Hi i P Po ono o een a cdLoedo toee ad Bop iil cme ce xi} se mee] | oan reed] PJlisig ceeee weve elnl ] woe woulid| wonneeneiyf PELL aa ecennncid 3 : i2i8l <a eel <cccscci | ocxasceeit t i8 i =iial ee iHHH eenigi wccses~esi1 l a EL aad cceTecnnin} cenecaseip B22 Ll] con Bead] | erensece] | coleeedell BiE. cee cient | oeedeelelH l | e ceeeii ecii HH le eee "nwenseel | sesessesil FERNY iad Fieger Sos iEiBiesizsasnaifieszorrsanifieazasssosif i 3i EEE FEEEEHEEE pEAIREEERS : 000:51 pl g Eid H Poiagk ; ALE ER RRE L EE : gai gg i ; $i Eg : en: 418-018:PAGE B-248 E00 ce inzenneenened g fi ! i Ee El IEE al engrveagrunnceraval : Hi gh ssmssmsazmenzene 8. 0 iis. wecoces! E i : i EE EE : H id TLiiBgEEeTGERo ARARe ARRn ARAa RAIRn ARIo LiIag P2 EEapigsrazssazsraiiazaani1ic goorsz 418-018:PAGE B-249 Bsoigi i P EioriEgmEnia:ass saammmmanaes EER Eel gg ii i OF nail Ep, Tm iIeil hie ge i: maemrmeas | i red lt: 5 : it Tinrangeneeeee anasnn] g id! SEE ED : : Tleezegereesues evnencl oo sp E00 LH i Z 5 iiiH. : i [fgg manateeannaantanasan vg Sox EEE een isd ; Cr 000753 418-018:PAGE B-250 iL g fi ! PoE8 2 Ee3le.s Lmeenmne smsannzesmmazzeinaanunsin Pe by goin DRlpnIInT III HFieddo mmm W i Di oog, fee sees semeneenennis Hr impel coon cemeeenne F Fi385x3 3 i ii fii.EEEeiPia8g82e 5-a3d2n azEssRazdseaaoes zmanzaitig: Feo 8,8 ii gd 2 1 HE ' iE twd gor EE reessszzzessaneeeBsF Hi 0005 418-018:PAGE B-251 gi Eid : feild : gi i ! Loos 8 oii i i foro Ei i: Eh PRPRRNREPSPNPRiS pti iif H LIE i I 0 edgeinnnzeszazs roessazasi GEE a it ; CE Ranh HELE #7ER Lh | i iis I=FOE ig1iiieE8sEEE8 amanmemansbax ssanaasaiiicsis D 1Fifi p BEpiERERp EEIRIiiiRm amaEERi.C UE 00055 . 418-018:PAGE B-252 gid Bog ii i i P EI i ifgEs zi; mmms sdnaz one osweasn aszeuanasdi EEiEE ! geiiil f! y g2 tleencneez ov ogo weran} DRL fib lig Ld oo FHT HR id NON i I edgeinenenner rire wrens! il Pl Etpelenannas gas cosas 2 C sfin! hTls oiskd Fa {iE lannsnanabadanafanana FREE ie gp0ise 418-018:PAGE B-253 g Eid : fEoor gHdph isesesensessneznsznaaananinnaann Pei Fg : P PoE.lee beg INIT ggEh iis i naan]i EEE ieee eneiegael E5pE8 TE ELC re gennne nen canna ; SEE lime HE tn eesssanssanesazes i BE igee JRRARSSHSARSARARAnTEL OE 8i5D 5 Eo S b i spe sHz azHmsEs asi i 3 OE IgigReTIRRse FRAAARERNRIE i Pi if sop menpsmammmmmnt 418-018:PAGE B-254 1] EE : phFor imbi es 1 {BER {5ARA% FRunREszNs0Ee' PPeoEn Pai BEEiL Lyi re Thomann 8 os i HE i : : are ia P EPErEr gii n n.ifk ld ok BELHEEig aTTirvieemreern cweeenvgeeraerreigeeeaenndd fCgE El ,i Bi [figs ieee nonzoesssoenes i g $0g 00 iEgrhgeisenns HERRE naab3i:f2a:deenh5el3l sBidpf 3 : , 1i3eigBgEaE seenalannnnaanananas tToTg Por EE ereessrrszere1rs HIRE] SER REEBEEIIZEZIIZIZIRENI oc 000758 418-018:PAGE B-255 SEE Ei : fF EE ennnennnnnanas P pe i :: fg ; Ty gE i epee jae ved Ep gen. toIIIIEIII BpoipdT e IL To Er E |BEEi g gliiismrenansenenesid gE IF so if Ee HEH Wl 3:z u iigeiE:B8E87EANANANARARRNANRRANANIitigs op iB CERIREEREEREEEEEREEENEINEC 0007S9 418-018:PAGE B-256 TE i i : Bee mane LEI PET fei fg Dg oa i ; sanmannet] ] pda miemeen ooo enegeeennd did omen EE TE lee we as Tigi i mmezeennn]; f FgrE, i Dooghr ener se TT mnznnenesa]: 8 0 Es EidEEDoE i iE. I snig HfElEo, ITH 5% (HghE 2Poy Piiitgigne eenbu nkabanannninittnyy HEE HL i Cb owpmmmmmmamn 11] g Bid gai ii Po all pAb Pg) Fig : 418-018:PAGE B-257 : : Pig faith meee Lx i 0 gfe ees remasmazzasnaanal iE 8, 1 i Hon i PEogNitiGEERe linsbanannananaananiasn3 g = 8: 3 ie OF IED THERARSSASASSSsSffEfEIIIiLc 000761 418-018:PAGE B-258 EL geil : pHE hiRRTIR |: i i Hin EEEEEEENE EEEE EEE EE i Pop lnm EgOiE gsET | cevang:aen moennnen]; gil EZ Erie meenennen meonnand SEE EL Tail iim ceegennei [iHEi gies sssssne ersneans][i iffgEo BReEsaEif smampmafEaefRar csmnassmlmzsal f s2E 0 3 5 is Tsing id i iat ig 1} 1 58E- | abeunnnanantannnnana 3 H8Es MELparipzsaasinzasiaiasiasiini 3 if EEjiEEEEsiegsmssisisansi.. ) ' 000762 418-018:PAGE B-259 El 2 gid i i 8 BE ; PE PYae2 pli i i: Poem EOE iE LL een nienan a ii shoe nm Fei TTT i giE 1E0ol,edgei ne aezexsszasanas niisk PLE eerie1] S88 82 0| ii3f8eE=! ; nSE3Ss3fe83 meaznFiZaz3 zi1%E ih LE HH gil ig 5g [ERR Iu i 1 i3iEEEibenEannannnnnnnnna(lSnS 418-018:PAGE B-260 ii fBooEr iEafElieammesmnzaanmnenaannanaansn ugfi PE : Peon : tel BoE Theme $1 iriilLO A3 FHaiit e ix Z i igEE=izemsszzzsszexansas =) Gee Bg Br Heed gHf y Likyf Fran ih Cog} BEEBHEEHEEC oooves 418-018:PAGE B-261 I gE EE gos FELL Vii ELER EEI it is i i giddassamanneniaiil? ti iE i gE iE i Bowl By gr ELL sir i [i ieaaneeasanianiazasi f 1 ig opinnNmmmga iz i 2 pisEeRREsdaeRengly HER |#1I EE 2 pmsi2 fd 8 418-018:PAGE B-262 PE Le il i EI | 2 ito rit I PyE 8 : iammademennan? mmmil Bmp SEi ii fPiig] By isasagasaadadc seiteni] :8 onl ann Br i: HEE :2 ig i : ; 5 BEE Haagig BEL Hi2i80i #1 ie IH HEEHREREG Pri i 418-018:PAGEB-263 ph 4 F1i0 d ik Pgogi ! Poor HE IT EE Sfo FE HE so Pia Jr izgiE doan iig oma ii i geammiaa zPorEi BE bE 3 B11 gid 2 sdge gn ddAg" dri, 58 x i i 22 . if sHeoii GE E i1 d &t : Piogieds ass gnsgriaiiendig i SilriPoodis i i3i S& EEiDb nlFgEeEBIeEHBRrErNgGnaRnalt iil i : i HEHE 000767 418-018:PAGE B-264 bo EHgE E3 E i EFEFLL Ls TLEid PiPlgows PLiigb id PgRiEd a I ii. 1a 5i -PoEn in 5 it Pai Pie pu SEE EEE Bag ii gle a vgR 22 ig Boi 38 3 0 Hy |i] dy HERE 0 mmmoro1 ip i $EEEE 0: : i pemmmsame gisd<gegeg A gAAz + ig : 2is BiEiEf 85 if FfErEaT 3 5 `3! piGREERIedEIdiiiEiesigld iigE osennesaecesoannznEenY { BE 5 igs 000768 418-018:PAGE B-265 Boi Efi te iP5i 0 EEL mSisa mssminivsooaam i : i said| ! }i | 1 fEEigFE Pil B odpi dBrl ii s po =PHIRI namrEaE a asEm ran Hoian ifi i a roan sy nait i: ii: hien emisi i :EiHf EE 1 P-i- Foy mas33smsasmsusaiasagias iid ] ane i co 00076! 418-018:PAGE B-266 Pil FPrEi SEEF i ET Fpl RE f Poi e sie y iisf eiiss git 33 RE ue 5it Eh gcEz 0 iB: og eB HIME HY iizg gggg 22 3i8 BJ2f5 00 WgiEeiEifiEensdEiiaLdTM LHEis gE shell Po fi i BL IRANI E i:I i: iigz SEL 2. fed ereereeiaeienie iRsassRarsssasnisinanig i cr i` : : 000770 418-018:PAGE B-267 ERE gPialil !frEii ty Ei og FE Ti Ls i2f Ppoor rki Po oe Fe BIZ 4 g Bik og FEC Ror SgEipR02ies22 o2s gg2 iifg fgooep iEig gims oEgdg 811iE seo oiei EE, EEE BE ig ERE gizes 8 ge g Aa" gar i gE sido boFrnBe ftieg BB 8E5 Ee 00 .pi: ETE Ee2l E ife2 dRE e2sat LfifEBei: ge E Lid ggErid 5 [FIR Bl FERRER Prd } EOF EE [4 000771 418-018:PAGE B-268 Lr PE 5ERFi : iitE Pri it i LEE if Pp immmnnnugnnt 2B CimmEsatiniinaitiie . i i 2anasvany aReRsm Rif HpEiRHdE 8E BBgr ip p TC pm EER A z gE i] EEE meiE hi op HEEREESNEL BHii i+ #000 pnmmmmnnm Pri 0 = idinggingaasassaiacasasiaied i i giabg emma 000772 418-018:PAGE B-269 PE fr 8 PE E 5: fei |! } i pm y Hig iy i wun fi iI fi. gop ii 1 3 EE 3 EER H : i gl] Fiesaes fg f Frases gf if f Brio 315d i1f HL EnREEE, Ped i OF TER ig 000773 418-018: PAGED-1 DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURESOFTHE TESTING FACILITY 1. Rats were ordered to weigh 175 gto 200 gat receipt,rather than 175 g t0 225 gat receipt. This deviation did not adverselyaffectthe outcome or interpretationofthe study because the rats were asufficient weight o go on study. C2 `The following dosage administrations were performed from two minutes early to - EiEEioEHE EsR msaataE)..h|E1==A o[Epi>TEmeE:E. 60minutes late. BER ike 1 Ea 3 FeaI rl 1.6mghkg | 16SEP0O DS 19 an 2 10930 aie] | 1 G CA l e Le 000774 418-018:PAGE B-270 g3 i F1P0i0 PE Pei E11: ibfe Rf DBpi i BgiEZEiZi Tgo eaig i B? y{ELpia gE [ERE i iHf }it : || gSienngsiasmsssassseaasds sRaRiilp [I i apmmRgEniait a ig HH] 0 Bigs FuzsaasERssnaadiig a af8 1 |i i: i iiHf Bf giRemmasiidiineigaci] fPiiend i|" Pop oEEp 4 418-018:PAGE B-271 gE if E EEg is is ' gi ie P21000 i gis gman ame PE i IEE i g t 5 j% sesddgiad fPiia By gL g8 imm: e giirLiod i3 Fazazsas p FREEd ERig iz i gk : i gi g2: i0 . #100 PEE iis gif sssRszeRs sadnavaRig if ig munpnEnn i EERE FEEL score 418-018:PAGE B-272 ERE ; ii RE gg Poi gir P ELid Th HEBRiI gi: 1:4 | :0 pd Pi mmm oon ik 3 u GRig:es avatEFd EiEf CER REMEE i Haag 5 [HE Biel gk : ig 1f is zi fe eisiidsEscasis dig eo Po Ser Ti 8 DE idEFog i EEL i piniEEILINEEE Ci if : pop EEp EERE 0007777 418-018:PAGE B-273 ; Bi) 1 PL fii FEL bLi y pom sig : fd I i| tadE ie oEL Lari EE Tog fzeig:o1 m88 ofrfn ig B23 Pi git sez ger og 4 7 ig Peolois or osmoad gEfEZ E i iigE 8EE 8 EozEgEEoOgEiEg ii Pid BELT ge & ' iH ted i i gp RRR, woe TI 418-018:PAGE B-274 Egil ; Ean EER i g Pislon: gBE fEiixgiBi iiy ouol HHE E| i io bt ms 8 1d fg 0 dom mr ff J miami: i Bf sip Bgl Bfgl] g pL e Li BL 50 TD a ei EIEIO EH mmm ee m mm im n gE gp iono nninm InHIR DOE Emma RIRRERIIIIIIIIIIIIIL i: :# iLT L I IIIIEIIIEIIIEIIIiiiiii ERIE Ege 0779 418-018:PAGE B-275 pico PEoEr PHE hi P : FLINiEred 2 5 ini Bi IA FPrraLtb nEnL P8 heFrafilmlepl nIgk fBhool n dmpie n B55 i, rime 1}i i;i its 0 fI adi L roi onk ad anni 88 Ei] fiiiiicaceses eceseai 3B BBoep5 7h 88 FIL BE pT 58 iol 22 FE .l imCrpEEneIpeLb slIii INilL jIiiiiiiiiiil CIRIISIIIIi Blrnssersmnmses 8lccc<Ba<<<<csn LB Zm IZIily i OES iE iii gg smmmssiady <<<<<< BOF B$5L500 f srIm friiim iiieiifim iiiiang so fmmmpmmmnnli s Fon lmnmErnssssssniniicignd op BEEING 000780 418-018:PAGE B-276 Por PBordisa :: Paid : jing P PiE g s: io otisd Y sR o, b Soimann, i2g : fp EE EERE ig ~ i iv sheeogee eee fy pion SEEGER ofp ini DIETER NENG BBiF oBg ieili ifeeow gzeeegsr gmpeenpmEeTeefgEnenneell i;8 i Peli Sina of Hgiocicboop en aantnnnintt4 gE i 0% ness en EE F 0 0 izE= gTe= zeTegressss~iils Plo Sma sf zit SESIIEERTISIINeNit al g hddplnnsn PTE : 000781 418-018:PAGE B277 Pode i : Bioigiit , {HEeAk PP ofrlixiyili ELOoP Pp mE : i Ti iszesese ee ep i xeidLa mmHemiEgiF HE eeeseei x - ii iceeceeeees seeeeesee! i: 32 : ii iezoeepeses 288E89RR) it of |i jemesmesess sessesene of E 3 {i ie EeEEesse eeeseegee; Fr G11&f 5 | i HEH i2 i 4 35% IT 3 i" HEHEHE HLA 4 ieEEeR=eEer eEesesges! iz fisEeseeszes ersesesss! i: Bigssseesses sEgeieee gi pinning dioEesTicier seessesasiind Hisccossaresssescessesiie : : i aaa tiaatiaei eld 2 } f SronTTmnTEnmennen i Uo0TER 418-018:PAGE B-278 IPS P PE B :: 2g 8420 ii pis : Pingu g Piimg grrr gid E EF faE i gi sR esesosO o oss L< giE pn HEIEL og Epo Enid i SRE Bee Fli Pool theo Hg. Lai :$Cin Po dmmmmooparonn i moomoo i To gle om B mmm sme cond i goon ge sn omIn gE OE Rliiiiie, Bees ceceeiE pms ii SiIIIIIIIICEIIEIIiiYY mmm gl i 5 EiniEpp BH3BEEIEGRERSIEISENINENiEes gg, 418-018:PAGE B-279 sisi ! EEN Eis i a Bool i i id ; RENE josie ; ERNE ii Eat Fim if Pree 2 EE Pd EPoIpova HREgOOrieE iEnHt fl. 0 Mens ad at oT oEEvED pEegeEvRescEl Gy 25 3 iT $8 fF | | Bf ii 3 gf 70 BEE Ep BSEEE Tel 82% 10 EEvER gRvegeswgpang! i | E-~geepEe~geacpgeep! i | EesTeepEv~peFEEEe~f! i ingErensemesresceiitpliiigedsesisil) fy TF eerie if phmmmeeetiianineiilil f BgllEemmEsIeaeamtnInIcecnniaTneiIaicBnagEynhE Bimazzzoupgrzgrgrge~ngilid 85 Ti FieEsresrerrerereesczigi] 0 i BipETrreepeszgregmzgriig 2 fi EREIanERIIaNiRetiig gl { EE Coord 418-018:PAGE B-280 3igFoingi i` PED EG Piiees kb i EEC g iii - gE ii figzz = gv se 8 EFEF iin0l oo ii iieoreEeen-n snaazmRnzoemneEnRn jzEees seemzevie 43 0 i jeEEeT EReREREEe i: t eB EG gi E eB} i oa8d: U2E8 go ERi de f ge! i $8 E i i ieEe= zseeseee ese! i Ll Ee $0 BEB 1.0 ig| i 58 0 H] 2 ii mmimnnanl kB igeeer zeegseste ERR! iz iiiaex nemiamacn asani BC igEzac sessssece gel i fimEms seenesevs evel Hi Siesser ssesesise reese dik 555 070 $57 i: a 22 fleses= seseserye sEeriioc ieeerfesseeense eres i350 EiFessie=socsgnsnemrasn=mscetnssna7nnsl28liy arannnenesienania ph i p Bp EREERRRMEEAREIIN 0007TES 418-018:PAGE B-281 Po Prd ! Pogin : 80s tf yi] : FOE is it % ig Elsi aor dg iiigrrmnnge said ggfigi ZHicem ccccmcccm ace + orcacnag} i 8 ini Cimmsomoser ons EF Bip lil ERNIE 52 Eni Bgl 38 2 |] 888 iT gg 8 iv iveemsiessieenoiesasl of es ee lcccxncccccccccccccc<] 88 mms Jocererseressecssrect] X rizlzzzzsczezszgrsaszs: 5 poms B B$p1.0 gB EmL mmI mmN aaN Eai gC TEER DOE rmmmmnmniiniioiooignd To ili LTTE : i Ep RERRRERERI 000786 418-018:PAGE B-282 iE ; I ied : SoBe gE RL i his ig Imi P PlEiLngEmgr Piiigimmg m Eames fi. amin ii | 0 EEdE form id reas a EER a Sop isl BR 2 lo! $F IL Bgl mii mmm spn E lccccx cc < <<csccnscci i dll nin i ponnn Slug FEL it git gMizIIaLFe uaiuiiamii if je pinEIIEER 8 a 2 8: srzzzfzzfrfrrszeszes ite S38 Ce finn PE Emm Pc smmmmrmmriiiim PEE iH 000787 418-018:PAGE B-283 Pre 3EB E igi BEin ": i; : ; Fils ror pig gsi forgriouorig gE TIS RL Elsi gangs og mgm i : ff Poon Poypoiml i: Tlrrnor snnssnnning mrrommmmigeg i izmrosoammsmmssrsenn BE me mmm i Bop man mmmmeen i H0yg Ti ileh eIgonnEIaIiIInLiD |fp BF i+] 2ifst sfsdapsmssnasninl i gp p Finig Biss sIssIsIssIssIssNniDngEinDieEdy 0p mmm fF gir s Ft png ey dorodrbe ss mmseme mnnsn iioiig ognie isDlAdE : i HE nERRERELRE AR 000758 418-018:PAGE B-284 I, ; P2o1i"n1 IR ; {PiEnE iE: ii pFeiPsniiapiEgEloL pFdoTE LoiLgEld| gyi morn Ph. dni Ed PBood. DCeELeEnD i onaE n gd eff 01 ITE fh S Biota oanog By. ETE ene h TERRI Conn bb i E i BRmIErane gst e EEtE ig 1 Le agin gonhy 1 sop ppp in m g ay $ gin SEL i EE : HE geome 418-018:PAGE B-285 Po Pind : a Big i i Fit i gf ir i PEiEmRE Pog: Pisem tn pPprlonpaEiemEe fihg pPfoliin S HPEiIiTmHmEOpaEE LLgE Bpri EHIETTEEENNNGNGGTGD OH EiEoRIEnEoRmE s i g TL sementiaiiast =i BE i STR gE EREeIIIgiing =i gL Pama i $207 JRE jin Poo BEHOLD, EGIL Pop PRLEEBBBIEINEIIGE 000790 418-018:PAGE B-286 PoE giPE a :i pi : Bog if i gE is EE, ig EE g Eto ae Print Pyotr seid i fi oii BCRFe ioih Fol BEEUHOERED 5 sf FE |i jE REET EEREEREE GE ies oemseee gee Boel dy 0igee5epciREeSaSnEsE GSeEmReRsEs al: (EETERER""BE EE288 EI Sf Brg i. Ems mIEILE 5 i | izETeEeve~29 90EPSE 2 if it gi gi IE_S8e"aaiesassis gi gs 3f5 gFin Bignitmimieimieteiganssnessensneasesn 1iniii: ie: fosretsaaasacie gris EH i jm 4 2 0! FigsTseec=zEeesessssfsilig 2 fi fpEtrrassiaesiianaata iff i Di i(iBiEEREiBEEEEREEIEIIIIIIEIIRIEIIIGISIIIENEIEeHsS 0007"91 418-018:PAGE B-287 i $50 f E bio d Dose Piatt Epon EE Fifi i wih [:5 a) l deli bes sed:: ilREaTled fiieedeide psB3fsdssl BERED TRERREEOELy f1gif Cora 1 Ld BE if g0i 0 i "IEE is F EPnHiEE $f igs: ' EF * iH] i 2 ji i8 iii#i ~ Pas 000792 418-018:PAGE B-288 i iERLd gy ; 1g8 fei, 23 dao g gPoE 1:oo1i3i8g 8l.i1d iomiei[E8hR1Ilgui Eo TEESE refe enele ffi tiite Hisdyat oy Ph olprres masts; HIFTigiI22E 22g g FEE Bidirer. gig iE ELF gi: 82ggologsoagosgid anon iig dani iig 3 gE if = iy . EPos id gi 8 o8fs Pik EOF Edd i gi igs i4145000793 418-018:PAGE B-289 PoE i Pd i BLE 5 P Py idd i ii! 1 GE - sS PoF il pieEimo.megeedCea pg ibiBbnEBN Eo cHleee Billie H: e [ip igithnasyliti np df iE pp peEp EEE RE sf ifE4 OEE PE Lil IR I T HE IIR SER I r om RE tiI d y EEG ei ogh Li 1a g Baoio BE BED HER IH ta i ' 3 pz os:opziioz: EE EEE E iif3 53 o8o ii; PER HR Hi 8F c, aIbPi Pioshitih 5x iEHiHif i 8 PE 2 000794 418-018:PAGE B-290 Peo che i Po gi Eo sBoe5l : i2 d P oEE fi PePopG,ppaHtoebueanLE s dn | P Piror igvimerdmneb iend des ge 5 BBE BEL HEPBiC d; $i TPEEER I SER gp TT TAT FE . toa i iit meld it sB g: i Bfizr isz sss a:o ogs ii;H gf eER EERE REE 232 Biih Pig! pdSroEggre LIE HH 25hnPH - E3H to 2TH3 is 000795 i g Fele oifgF og EEE PS oo8 dihiErRei fPifiiaittgsiidessl P fg e ie mk a Ph i in 1 mil 1a i HHoil i4 g lipgk, gPEgEgL Hog 3 prt PEE i nL 418-018:PAGE B-291 000796 418-018:PAGE B-292 EEL 8Eoi i : peE: : bdiiui 8 ig Rifpig og Eff a Beasin D Pog HoH orn oie Pip EGER REET EEE HEE i Poiiiiiidcad icy [I 5 Bi a fd Hi 30 le i 418-018:PAGE B-293 iolg 5 ht] EE eo boyd PB ddd sddddd CiB4 44 ad dddds 8 3% PD og dil MILS NE EU Dorb rom rn amin ridley 333333 3 33idE 0 5 gBil 2 BUELGORRORERRRI Zam R iiaf oERRE COHN HIgh i Prd io: ok : HH 000798 je 418-018:PAGE B-294 Dd PoE [I ePoo WEEERELORHEEB OdBEhLE PEo oPRih n i HEIyRbaa RnpdYlmiapalin fo : Ee i sz & | Bi EM Hy : Ei I i Po (8% ii 1 Fibs : 000799 418-018:PAGE B-295 FTE FI Pi PoE Poi Po kam i 0 2E gazzd 8 H:Pa LBE Po apy dln D bo L aigihandog GOdNd daalpaian ve: El ik B88 i,B + 4 New amn wma ana IFT [EE BE Fo- .oo 3 iied dy Hi Egle PEERS i 00800 ` 418-018:PAGE B-296 LPP oo oE hdmo i EEeJ 1 EEgaly ebb ed ofnhlh i iki inf frdedte 2 Hay : Lb BiG BELLE ff PETE ii iL EE, 1 ii2 % ig & Pim HH Fo eosor - 418-018:PAGE B-297 pMoard i z Po i8 g g g8 4 8 wan HE gif : 38 iE I EE aA al Ea BEo i gHh nanddaa ddni e anpey p in gf ist gh 3 BE, 5 Bx 2 tel [HME y 2 iii POE 000802 i Lue CL Le Spipnpapaid tata EiDaag udgdbpdee oddn sdediegea 1 gdi Pilg 000803 418-018:PAGE B-299 bE Dol EE BR EB ee d bi RH ET PoiaiE fi t g 808 i g 50 iPy wih i He BoCl, Phd i ii 000504 ie 418-018:PAGE B-300 fP i ooog gpt addH y oaE HN o Co H EMEEniAh : a mlygy DpL 0 ifh nHanat aih n fp gn p SqEo ge Pil EEE iHi i i 000805 i 418-018:PAGEB-301 DPo E ajdaiE bgEtadrooold d froioCoEgCgEtldEg2gf tBfaaglEiacSEhEgaE gHn $o1g. dg dg igs ghddE Baet pits ddailosf $F Peo . i12 qi. 4 8g2 83Cig808x i ;Bi iiit 000806 i 418-018:PAGE B-302 Poa it Cd it 4p dif oa ime Etin Doo g addddgdn he Hpaaiyn fi eis Sid Pre BoE h ft i 000507 418-018:PAGE B-303 Po gmap Eo820 a. ! Po $0 hha Hh i og1izHzgizdg ozi gBEl E ggsE BBRoEsEsiE15}3 paisa HEF RRL dala dp igs dg gg pf app Pil iH gi HEFL { 2 iE 3 i a 000 UB id 418-018:PAGE B-304 Eon ond po BBD BR RNG ro i af PERRET Hin Pgoi. nBedlE ed a HE afendte dEnE gHdE a42t0, sigh AE Hi: Bobo ! i02 {iiz i i i iH i 000809 Hfi 418-018:PAGE B-305 JEEo REnLE PmRpNi Ld Egaton nic in bop HER Poo Eagle a i Po SREB Ty oggg hath iE4 Ld Nid iE {PE gm Ec! iE B HEi ELs 23 3 8RE5E 2 iH xy IEEtt R8 .E;E B { ih i : 000810 je 418-018:PAGEB-306 EF iE bb Po z 2 i% ob abr Bd i AS mah foi iPifa 3[E8H i!8 i8 i23 iid: PPoo.E EEHHBEEHRIIILE ELERG E aHE ignn Big BEE. BEE BEET OEM LE Pritam tia pti Fii1l i tH HR iB A iff BE. ith gi it iii: $57 ig P Phgiif snidz [HEI a.i538 RIt iifhak iss s 000811 418-018:PAGEB-307 HL EE ;po ig ; I FF Eo age iad 5i B8 oi i P[ ooE namg g a h 1.1 Bafa HEEREE: She Baking ( FlAy 5 ia Ligi: i a 8 UF 7 - iiE 5 Fmmmmnn om - i"iaE ort fd gE B 000812 = 418-018:PAGE B-308 PCi oob1 1 DlFobEETdoEh coh on bE La ig A fad EoD HEM BEdik [i 41 4] iEiBf wpa 418-018:PAGEB-309 eo PELE bu SEo o His Eii !d La8 ddgf if I fo glih i1p1sgaE l p dh PP DoLiHdga E idERIdEHgiEHEitaey1 Baas B22: 1 1h i5: gf 8% 8 1 iif J i * ooos1a a 418-018:PAGE B-310 po[I Pia83 o pq] i%3 SERIRR ERE EHE Pog 3 i pt Lg P{odidnd ui dpenstt L0EgH iE Pop ddaddonaiiniingh FE 3 Hie 3 0, iw NE fife 0001S iH 418-018:PAGE B-311 : 11 gi Eo fg i REP EPPELI | Pod 3 5 Po BEE EE PToooon HoHah dihak bpo o.pplim dyuds dediaits Cod fd g gf i% CahREEClRd: Hdo h daefay Ged0E das hl dn He o o gef :g Egi so z F 2= igyi ld HE : PE z=i 4 gsE iig ji . jit 00016 i 418-018:PAGE B-312 Eo fd EB 0 Pfo oo EgeR BfREaE EfcEHia HIE 3: PSEo oudpielgnilaifmmEEbaEnganatagnigbmnlil o iil ly in gi Li if Hi Bil fib a i 000537 i! 418-018:PAGE B-313 poop hda bd PoE 3 : gs d3 H 1i 2 58 : Poi i gE { it i Ep ud dally PoE agai ay aft iyy : D 2 aPLdB dhe deB3H0 das dagdis dFEi He Ho s RIS HE BopoEkc- Ee PEE iH i: 000818 418-018:PAGE B-314 ii . Eo gh ih gi Pi fo liete 1d Po diate Eo tdaldas defy 6 0addg aal a00n0sd a4% afhel Hir Hi Print pris id dE " 1y5 H] i1 000519 i 418-018:PAGE B-315 3Po LH Poly HEdg R4 E Eo lpia bE ubyd ; eit Poop gi PE alin EERE RE RE Eh gEod.aHEddE 1dAa dhna aARE dHlE BgsE il ig LHyi ii HH i : iA: 000.20 i Lo fo did fo iE gay Loo Han piEo oLghHaEnE i] iibiteuig Pi ELE. mi5g BEoiiog - iH Li 1 Hy ; iif Ran i iii i 418-018:PAGEB-316 000:21 APPENDIX C PROTOCOL AND AMENDMENTS 000822 418-018:PAGE C-1 4 PRIMED CA ~ I -_ AmSsisRSeheceanhDLovea, Bbaldsing.ncA TeeTphbooVnnoe r52a115.5)P14A931417890184073 PROTOCOL 418-018 SPONSOR'S STUDY NUMBER: T-6295.25 -- STUDY TITLE: AOcnied/GCehnoleersatteiroonl RCehparloldeuncgteioanndStNuOdEy LofIPnvFeOstSig-atMieovnailnonRiacts PURPOSE: cToh-eadpmuirnipsotsreastioofnthoifsmsetvuadlyonariec taociddetoerrcmhionleeswthereotlhecranor not p(Srrteelvdbeuoncmte,dodrmeaacntrteeamagasolendibzobeidrtythhewweaeiidggvhhettrgsaaeinndm,aditeneccmrraeelaassaeendddppefuertpcaelsnuetrfvfievcatls) o21b6s.e0r0v8e,d 3inMasptruedvyinouusmbsteurdyT-(6A2r9g5u.s9)ReasnedatrocbhePtrteortodceofline the no observed effect level (NOEL). TESTING FACILITY: A9r0g5uSshReeesneyarDcrihveL.abBourialtdoirnigesA, Inc. HTeolresphhaomn,e:Pen(n2s1y5l)v4a4n3ia.871190044-1297 Telefax: (215) 443-8587 STUDY DIRECTOR: RArsaasyyommcoionantddeyGDo.irrkYe@ocptrokrr,imoPfehd.RDie.cs,aeDacrAocBmhT SPONSOR: 33St.MM PCCaeounrltp,eorrM,aitnBenueiTsdooixtniagco2l52o50g1.y4246--100200 STUDY MONITOR: ALTERNATE STUDY MONITOR: Deanna J. Luebker, M.S. 3M Corporate Toxicology 3TeMleMpehdoincea:l De(p65a1r)tm7e3n7t-1374 Telefax: (651) 733-1773 J33oMMhnCMoeBrdupitoceranlahtoDefefTp,oaxPrhit.cmDoe.l,notgDyABT, CIH Telephone: (651) 737-1962 Telefax: (651) 733-1773 000523 418-018 PAGE C2 Protocol 6P18a.g0e128 REGULATORY CITATIONS: ISnttuedmyatDieosniaglnCaosnfMeordiefnicceatoinonHoafr:moUn.iSs.atFiooond; aGnuiddeDlriungeAodnmidneitsetcrtaitoinonof(t1o8x9i4c)it.y to reproduction for medicinal products. Federal Register, September 22, 1994, Vol. 59, No. 183. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. JfoarpSaanfeestey MSitnuidsitersy oofnHDeraulgtsh,aMnHd WWelOfradriena(n1c99e7N).umGboeord21L.abMoarracthor2y6P,ra1c9t9i7c.e Standard EaucrceoppteaannceEcboynothmeicEuCroompmeuanniEtcyo(n1o9m8i9)c.CoComumnucniiltdyecoifsainonOoEnC2D8 Jduecliys1i9on8/9roecnotmh-e tmheendEautrioopneaonn Ccoommmpulniiatniceesw:itLhepgirsilnactiipolne.s o3f2go(Nood. lLab3o1r5a:to2r8y pOrcatcotbiecre).: Of1f-i1c7i.al Joumal of REGULATORY COMPLIANCE: "This study will be conducted in compliance with the Good Laboratory Practice (GLP) regulations cited above. ADlilrecchtaonrgaensdotrhereSvpisoinosnosro,fdtahtisedpraontodcomlaisnhtalalinbeeddwoicthumtehnetperdot.ocsoilg.ned by the Study Tahned tTheestrienpgorFta.cialnitdy'wsilQluianlsipteycAtscsriutricaanlcpehaUnsiets(oQfAtUh)oswiellpoarudtiitontshoefptrhoetosctolu,dythceonrdauwcdtaetda atthe Testing Facilty in accordance with the Standard Operating Procedures of Argus Research Laboratories, Inc. QShAoUulfdoratnhyatpofractiilointyowfiltlhceosntduudcytbceritciocanldpuchtaesde biynsapescutbicoonnstarancdtoarudo:r bryestpheectSipvoenrseosru,lttshe apnhdasreepionrstpsecftoirotnhartepsotrutdsyapnodrtiroenpoarctcaourddiitnsgwitloltbhee sSuObPmiSttoefdthbayt tahiaittfya.cilStyuc10htchrietiSctaludy Director. The dates of the inspections and report submissions will be incorporated nto. 2 QAU Statement generated by that facilly and provided to the Testing Facilty for inclusion in the final report `tThheerfeipnoarltreapcocrutrawtilellyinrcelfuldeectas tchoemprlaiwandacteasotbattaeimneendtdsuirginnegdtbhey tpheerfSotrumdaynDciereocfttohrethsattudy aSnhodutlhdatsialglniafpipclaintcadbelveiaGtLioPnsrefgruolmatGioLnPs wreegruelaftoilolnosweodcciunr,theeaccohndwiulcltbeofdtehsecrsitubdeyd. in detail, together with how the deviation might affect the qualiy or integrity of the study. 000524 418-018:PAGE C-3 Protocol 41P8a.g0e138 `STUDY SCHEDULE: See ATTACHMENT 1 to the protocol. TEST ARTICLE AND VEHICLE: Identification: Test Article: Name: Perfluorooctane Suffonic Acid Potassium Salt (PFO), LPohyvsBiactaclhDeNsucmrbipetri:on: ~~ 2Li1g7ht-colored powder. Specific Gravity: 08 Purity: 98.9% Expiration Date: NA Information on the identity, composition, strength and purity of the test article is on file with the Sponsor. Control Articles: Name: Mevalonic Acid. Physical Description:~~ White with dark yellow cast, semisolid LSoptecNifuimcbGerra:vity: 0N7A0K2603 Purity: Approximately 97% Expiration Date: August 2004 NPhaymsei:cal Description: Lot Number: PSuprecyi:fic Gravity: Expiration Date: CWhhoilteseteproowld.er 119HO218 9N5A% July 2004 Information on the identity, composition. strength and purity of the control articles will be maintained in the raw data. Vehicles: 0.5% Tween 80 in reverse osmosis membrane processed deionized water (RODI Hy0). Supplier and lot identificationof Tween 80 to be documented in the raw data. Reverse Osmosis Membrane Processed Deionized Water (RODI H;0). 000525 418-018:PAGE C4 Protocol 41P8a.g0e18 N10eibteheprretsheenStpionntshoervneohrictlheesStthautdywoDuilredcitnotrerisfearweawriethofthaenryespuolttesntoifalthciosnsttaumdyi.nants likely. Therefore, no analysesother than those mentioned in this protocol will be conducted. `Safety Precautions: Gclooavteasr,edutostb-emwisoymHEdPuAr-infgefroermdulmaatsikon, parpeppraorpartiiaotne aenyde dproostaegcteioandmainnidstarautniiofno.rmT/lhaeb Material Safety Data Sheet (MSDS) is attached to the protocol (ATTACHMENT 2). Storage: CBounltkrToelsAtrtAirctlieclCeo: mponents: VPerheipcalreedCoVmephoincleent(s0:.5% Tween 80): PrepFaorremdulTaetsitonAsr:ticle RRoooomm tteemmppeerraattuurree.. RRoooomm tteemmppeerraattuurree.. Frozen (20C). AJlullitaesntGaurltbiicnlseksih,iMpamnenatgsertootfhFeorTmeusltaitnigoFnasc,ilaittytshheopurledviboeusaldydcrietsedseadddtroetshse attention and of telephone number. Scahritpomnesnsthsosuhlodubled lianbcelluedde iapnpfroorpmraitaitoenlyc.onTcherenriencgipsiteonrtasgehocuolnddibteionnostiafinedd sinhiapdpvinagnce of shipment FORMULATION Frequency of Preparation: Formulations of PFOS (suspensions) will be prepared weekly at the Testing Faciity. The vehicle (0.5% Tween 80) will be prepared weekly. dMeeivoanliozneidcwaactiedr.will be prepared twice daily in reverse osmosis membrane processed Cholesterol will be prepared as a suspension once daily in 0.5% Tween 80. Ddeotcauimleendtparteipoanraotfifoonrpmurloacteidounrperseapraeraattitoancwhielldbteo tmhaiisnptraoitnoecodlin(tAhTeTrAaCwHdMatEaN.T 3) and 000826 418-018:PAGE C-5 Adjustment for Purity: Protocol 41P8a.g0e1s8 `The test and calculations. control articles will be considered 100% pure for the purpose of dosage Testing Facility Reserve Samples: `tThheecSopuornsseoorf wtihlilsrsetsuedyr.veTahseamTepsltein(1g Fga)coiflteyawcihlllrotesoefrtvheeabuslakmptelset (a1rtigcloeru5smeLd)duorfing s`etaucdhy.lotSoafmtphleescownitlroblearstticolreedanudndveerhitchlee pcroemvpioounselnytcsituedsecdondduirtiionngst.he course of this ANALYSES: tShaempcoluersseadodfittihoenasltutdoy.those described below may be taken if deemed necessary during Bulk Test Article Sampling: INnofoarnmaaltyisoensoonf tthhee sbtualbkiltteystofartthieclbeuwlikltbesetcaortnidculectisedondufrilienwgitthhethceouSrpsoensoofrh.isTshteudy. Certificate report. of Analysis is on file with the Sponsor and a copy willbe included in the final Analyses of Prepared Formulations: Stabiity: Sctoanbcielnttyradtaitoanfsoar npdrecpoanrdeidtitoensst article of this formulations study are on bracketing the range file with the Sponsor of and will not be wdeeetkerlmyiantetdhdeuTreisntgitnhgeFcaocnidtyu.ct of this study. Test article suspensions will be prepared Homogeneity Analyses: Homogeneity course of this of the study. test article A syringe in prepared will be used suspensions to withdraw will be verified samples (5 mL during each) the from the tEoapc,hmisdadmlpelaen(d5 bmoLt)towimllobfethdeivhiidgehdesitntcootnwcoenatlriaqtuiootns oanndthpelaficrestddianytoo fglparsespacroanttiaoinn.ers, aolniequooft 2(3mmLL)anwdillobnee rofet3aimnLe.d aOt ntheeaTleisqtuiotng(2FamcLil)itwyilalsbae bsahcipkpuepdsfaomrpalnea.lysBiasc;ktuhpe other samples will be Testing Facilty usptoornedthuenrdeeqrutehset porfetvhieouSsploynsciotre.d conditions and discarded at the 000827 418-018PAGE C-6 Protocl 418.018 Pages ConcentrationAnalyses: oCfotnhciesntsrtuadtyi.onAofsytrhienpgreewpilalrbede tuessetdarttoicwlietshudsrpaewnssiaomnpslewisll(5bemLvereiafciehd)dfurroimngeathcehcourse gceosntcaetnitornatainodn oponsctenadtuarli.ngEeaacchhsaofmpthleef(o5llmoLwinegacphe)riwoildlsboef tdhievisdteuddyi:ntoprtewmoaatliinqgu,ots and pslhaicpepdedinftoorgalnaalsyssciosn;ttahieneortsh,eroanleiqoufo2t m(3LmaLn)dwiolnlebeofre3tmaiLn.edOantethaeliTqeusotti(n2gmFLac)ilwiitly absea baancdkduipscsaarmdpelde.at BthaeckTuesptsinagmpFlaceisliwtiyllubpeonsttohreerdeuqnudesetr tofhethpereSvpioonussolry.cited conditions Shipping Instructions: Samples to be analyzed will be shipped (frozen on dry ice) to: 3DaMvCeoErphorreastmeaTnoxicology 3M Center Building 236-0C-48 St. Paul, Minnesota 55144 TTeelleefpahx:one: ((665511)) 773333--51077703 Both the recipient and the Study Monitor willbe notified in advance of sample shipment. DISPOSITION: Prepared formulations wil be discarded at the Testing Facilty. All remaining bulk test article will be retumed to the Study Monitor at the previously cited address. TEST SYSTEM Species/Strain and Reason for Selection `The Gri:CD(SD) IGS BR VAF/PIus rat was selected as the Test System because: d1)evtehilsopstmreanitnaolf troaxtihnassanbdeehnadsebmeoennstwriadteeldy tuosebde tshernsoiutgihvoeuttoirnedpursotdruycftoirvreeaprnodductive and developmental toxicity evaluations: 2) historical data and experience exist at the Tstersatiin:nganFadc4i)litthyis";st3r)aitnhehatsesbteaertniculeseisdpihnapmraecvoiloougsirceaplrloyduaccttiivoen sintutdhieesspoefciPeFsOSa.nd 000828 418-018:PAGE C7 Protocol 41P8a.g0e1?8 Number: Initial population acclimated: 3`e6a0chvidregsinigfneamtaeldearsatRse(ptiwiocastheispm1 eanntds2o).f 180 female rats Population selected for study: 3an3d2 2fe0mianleearcahtso(f2G8rionuepasc8h 1o0f G11r)o.ups 1107, 12.and 13, aEisgshitgnmeadtetodCfaeemsaalreearnat-sseicnteiaocnhinogfoGnroduapys211 1o0f7p, r1e2suamnedd1g3es(tRaetpiloinc;attehe1)rweimlalibneing female rats will be permitted to deliver ters. Body Weight and Ac tFheemyawliell rbaetsewxilplecbteeodrdtoerbeedattolweeasitgh56frdoamys17o5f age10.2A2c5tugaleabcohdyatwreeicgehitpts,wailtlwbheich time rreacnogredsewditlhbeedianycalfutdeerdriencetihpetfainnda wrielplorbte documented in the raw data. The weight Sex: Fbeemuasleedroantlsywialsl bberegeidveernstahnedteasrtearntoitclec.onsMiadleereradtspaorfttohfetsheamTeesstoSuyrscteeamn.d strain will Source: Charles River Laboratories, Inc. TLahbeorraattosrwiielsl,beIncs.h,iopptehdeiTnefsetirnegdFaccairlttoyn.s by ai freight and/or truck from Charles River Identification: Fo Generation CRoa.tsInca.r,e pNeor.maMnSePntTly20i1d0en1t)i.fieMdaulseinrgatMsoanreelgivseelnfu-pniieqruceingpeeramratnaegnst(iGdeeyntiBfaincadtiaonnd Tag nFuemmbaelresrautpsoanreasassisgingmneednttetomptohreaTreystniunmgbFearcsilay'rsecberiepetdaerndmaglievernatunpoipquuleatpieorn.manent iadnedntbifoidcaytiwoenignhutmsberercsorwdheedndausrisniggnaecdcltiomatthieons.tudy on the basis of physical appearance 1 Generation: Pinutpesrwmisllonfotthbeeitienrd.ividually identified uring lactation; all parameters will be evaluated 000529 413-018:PAGE C-3 Protocol 418.018 Pages ANIMALHUSBANDRY: Al cage sizes and housing conditions are in compliance with the Guide for the Care and Use of Laboratory Animals". Housing: Fo Generation Rats/F1 Generation Liters: Fo generation rats will be individually housed in stainless steel wire-bottomed cages `except during the cohabitation and postpartum periods. During cohabitation, each pair opfrerastusmweildl gbeesthaotuisone,dFion tgheenemraalteiornatf'esmcaalgee.ratBsegaisnsniignngednotolnaatetrurtahlandedliavyer2y0wiolfl be individually housed in nesting boxes. Each dam and delivered liter will be housed in a `common nesting box during the postpartum period. Nesting Material: Bedding delivery. material (bed-o'cobs) will be supplied to female rats assigned to natural BAneadldyisnegswiflolrpboesscihbalnegecdonatasmoifntaetnioans nareececsosnadruyctteodkeseempit-haennaunailmlaylsanddrydaoncdumcelenatne,d in the raw data. Room Air, Temperature and Humidity: `fTrheeshanaiirmtahlatrohoams biseienndeppaesnsdeednttlhyrosuugphpl9i9ed.9w7it%hHatEPleAastfiltteenrs.chRaongoemstpeemrpehroautruorfe 1wi0ll0b%e wmialilnatlasionbeed maton6i4toFre(d18conCs)ttaont7l9yaFnd(2m6aiCn)taainndemdoantit3o0r%edtoco7n0st%a.ntly. Room humidity Light An automatically controlled 12-hour light:12-hour maintained. Each dark period will begin at 1900 hdoaurrksfElSuTor.escent light cycle will be Diet: Rats will be given Certified Rodent ad libitum from individual feeders. Diet #5002 (PMI Nutrition Intemational) available 000.30 418-018:PAGE C9 Protocol 41P8a.g0e1s8 Water: Waantaeurtowimlaltbiec awvaatielraibnlgeaacdcelisbsitsuymsftreomm. iAnldlivwiadtuealr bwoitltbleesfartotmacaheldoctaol tshoeurccaegeasndorpfarsosmed tphroocuegshseadrweavteresreaossamobsacitsermieosmtbatr;apnreocbeesfosreed uwsaet.erChisloerxipneectwieldl btoecaodndteaidntnoothmeore than 1.2 bacterial pcponmtacmhilonraitnieonatatnhde time twice oafnannuaallylsyisf.or Water is possible analyzed chemical monthly for possible contamination. Contaminants: 1N0eibteheprretsheenStpionntshoerdnroinrktihneg Swtautdery oDfirtehcetonresistianwgamraeteorfiaalnyatpolteevnetlisatlhcaotnwtoaumlidnainnttesrfleirkeely waittehxtthreemreelsyulltsowofletvheilssstinudtyh.eTcheretiSfipeodndsioetr. isThaiwsarloew-olfeaveploctoennttiaamlicnoanttiaonmiwnilalnntotpresent irnotuetrifneerleywpietrhftohremerdebsuylttshoef ftehiesdsstuupdpyl.ieTrhoerretfhoorsee, mneontaniaolnyesdesinotthhiserprtohtaoncotlhowislel be conducted. RANDOMIZATION AND COHABITATION: Eo Generation: eInacohr)desretpoarfaactieidtabtyetswcohewdeuelkisng., female rats will be The first shipment rwielclebiveeddeisnitgwnaotsehdiapsmeRnetpsli(c1a8t0e rats. 1 aanssditghneedsetocoinnddivsihdiupalmehnotuswiilnlgboendtehseigbnaastiesdoafscoRmeppulitceart-ege2.nerUaptoendarrrainvadlo,mrautnsitwsi.l bAfeter `aacncdlibmoatdiyonw,eifgehmtaslerercaotrsdweildldbuerisnegleaccctleidmaftoirosnt.udTyhoenrtahtes bwialslibseofaspshiysginceadltaopdpoesaargaence groups based on computer-generated (weight-ordered) randomization procedures. cWoihtahbiintaetaicohn,doonseagmealgeroruapt,pceornfseecmuatlivreat.ordTehrewiclolhbaebiutasteidontopearsisoidgnwirlaltcsotnosist of a vmaagxiniamlucmonotfen1t4sdaaynsd./oFaremcaolpuelraattosrywiptlhusgpoebrsmeartvoezdoainosbistuewrivleldbeincaonssmiedaerreodfttohebe at dmaayte0dofwipthrienstuhmeefdirsgtes7tdataiyosnoafncdohaasbsiitgantieodntwoililndbieviadsuaslighnoeudsianlgt.emFaetemamlaeleratrsatnsotthat have mated and wil remain in cohabitation for a maximum of seven additional days. Tahceonfifristrmseidghdtafteemoaflemartaitsngpewirlldboesaagsesiggrnoeudpt(ogCraoeupssar1e1a0n-7s.ec1t2iaonnidng13o,nRedpalyic2a1teof1) with mparteisnugmedadteg)eswtialtlibone. peTrhmiettreedmationniantgurfaelmlayldeelriavtesr (including liters. those with no confirmed 000831 418-018:PAGE C-10 Protocol 4P1a8g.e01180 F1 Generation Pups: wDhaiych1 aolfl lpaucptastiionna(lpiottsetrpaarretuimn)diivsiddueaflilynewdeaisgthheed (dpauypobfobdiythweaingdhtiss also the first day will be recorded on after all pups in a liter are delivered and groomed by the dam). ADMINISTRATION: Route and Reason for Choice: Tdiheetaorryalro(ugtae,vatghee)erxoaucttedwoassagseelceactnebdefoarccuusreatbeelcyauadsmei:ni1s)teirnecdo;m2p)aritiissoonnweiotfh tthhee possible routes of human exposure; and 3) tis the route used in previous reproduction studies on PFOS. Method and Frequency: Dapopsraogxeismawtielllybethaedsjuasmteedtfiomrestheeamcohsdtayr.eceDnotlsyagreecsorwidleldbeboaddymiwneiisgthetreadndacgciovredninatg to the tmaebvlaelionnitcheaDciodsdaogseinLgevneelse,dlCeonwiclelnbterawtiipoends aclnedanVoblefuomreesasdemcitniiosntroaftitohne fporroteoaccohl.anTihmeal. Fo Generation Female Rats: (Femmaaxliemuramtsofwi1ll4bdeaygsi)veanntdhceotnetsitnauritnigcltehdraoiulgyhbedgaiynn2i0ngof4p2raesyusmebdefgoersetactoihoanbi(traattison ansatsuirganleddeltiovCeareystahraetadno-sneocttidoenliinvg)ea,r dliatyer2)4orofdapyre4spuomsetdpagretstuamti(orants(rtahtastadsesliivgenreda tliotter). nRoattrsecineitvheeapnryocoersasllofofdtehleiivrerdianiglywidlolsnaogteb(se)goivnetnhteesdta/ycoonftrpoalrtaurrtiitcileo;n.such animals may 1 Generation tFo1tgheenteersattiarotnicpleupdsurwiinllgnmoattbeemadliregcetsltyagtiivoenn(itnheutteersot eaxrtpioclseu,rbeu)towrilvliabemapotsesmiabllymeixlkposed 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. 000832 418-018:PAGE C-11 Dosage Levels, Concentrations and Volumes: [oe ren[| oeTomeein|serine [+Towcecows[2| woomo|omens | woo | a [= ET= oaFnmE=mme=e||aNN =+E[= |||= = mmaEanme||i coa eE leml| |NP=EC=e n |+Towsorros[0| w [ oimparos [wo | C|oeTToommmomrrerossT|7o0T Tw T| Co Tames| TT comprareess ||w] e | amps|u| [TomesTo[Tempra |] LoTempero [a0Tw| eoosgwos| we | TTT fom [otTomTORR | wee] lComvomoemsee[ [0 01 T %TTT eonomaovmvmeman || [imocos[ow | we||eusomcomemven | [omens[0Tw[2 |eonsmovmmemven | ere ToTo[0Teomowconmmmn| CoosToe Toe To |eumowrommmmmn| eeeTT oT Teuonsommmmn| [woe 0ToTT eemousonsemn| ES [[eooos [ TveoToowo| |[0e|weceeomiornmom]un| 000833 418-018:PAGE C-12 ANALYSES AND MEASUREMENTS - Fo GENERATION: Protocol P1a8g.e01182 Viability: All Periods: Atleast twice daily. Clinical Observations and/or General Appearance: Acclimation Period: Atleast once. Dosage Period: Phroiuorratftoedr otshaegeseacdominndisdtorsataigoen,anapdpartoxtihmeaetenldyoofntehe working day (approximately one hour after the third dosage). Day of Sacrifice: Once. Matemal Behavior: Dbeahyasvi1o2rnwdill5bpeosrtepcaorrtduemd.daAlnyy. observed abnormal CalpipnriocpalrioabtseerbvyatthieonSstumdayyDbierecrteocroradnedd/omroSrteudfyreMqouneinttolry.than cited above, if deemed Body Weights: Acclimation Period Atleast once. Dosage Period: WgeesetkaltiyotnoacnodhaobintaDtaioyn.1 pDoasitlpyadrutruimng(fpatrseassusmiegdned to natural delivery). Sacrifice: Terminal weight Feed Consumption Values (recorded and tabulated): Dosage Period: W(ifeenekcleysstoarcyo)haobfitpartieosnu.meOdngedsatyasti0o,n7.an1d4,o2n1daanyds 215 and 5 postpartum (rats assigned to natural delivery). Fneeceedsscaornysutmoprteipolnenviaslhutehsemfaeeyd.beDruercinogrdceodhamboitraetiforne.quwehntelny wthoanractisteOdcacbuopvyethifeitsiasme cage with one values will not fbeeedrejcaro,rdreedpolrenitasbhumleanttedo.f the feed jars will be documented. Individual 000534 418-018:PAGE C-13 Protocol 1Pa8g.e01183 Mating Performance: oMbasteirnvgawtiilolnbeofesvpaelrumaatetdozdoaialyindaursinmgeathreofcothhaebivtaagtiinoanlpceornitoedntasndancdo/nofriarmceodpublyatory plug observed in sit. Fertility Parameters: Fertilty Index (percentage of matings that result in pregnancies). Gestation Index (percentage of pregnancies that result in birth of ive liters). Number of offspring per liter (ive and dead pups). Number of implantation sites. General condition of dam and litter during the postpartum period. Viability Indices (percentage of pups bom that survive 5 days). Caesarean-Sectioning Observations: Esiegchttiornaetds fornomdadyos21agoef gprroeuspusme1dtoge7,sta1t2ioann.d T1h3e(Rfeeptluisceastweil1l)bweillrbeemoCvaeedsafrreoamnt-he uterus and pooled by lerfor body weights. The rats will be examined for number and distribution of: Corpora Lutea. I[mPpllaacnetnattaieonthSaitteasp.pear abnormal (size. color or shape) will be noted in the raw data]. Live and Dead (A live fetus is Fetuses. defined as one that responds to stimuli; a dead fetus is defined as daetaedrmfefteutsuessthdaetmodnosetsrantoitnrgemspaornkdedtotosteimxutlrieamnedautthaotlyissisnoatremacroknesdildyeraeudtotloyzbeed; late resorpiions.) E(aArclyonacnedptLuasteisRdeesfoirnpetdioanss.a late resorption if it is grossly evident that organogenesis has ocurred if this is not the case, the conceptus is defined as an early resorption.) 000835 418-018PAGE C-14 Protocol 4P1a8g.e01184 Fetal Observations: `Body Weights: Fetuses will be pooled by liter and liter body weights willbe recorded. (Only body weights of live fetuses will be recorded.) lood and Tissue Samples (See ATTACHMENT 4 for tissue collection and processing): Caps and labeled tubes will be weighed (combined weight, to the nearest .001 gram) before (empty) and ater retention of pooled fetus samples for subsequent use in cpohpairemsacoofktihneesteicweaingahltyssewsi.ll Tbeheisneclwuediegdhwtisthwiltlhebepadcokciunmgelnisttepdrioinr ttoheshriapwmednatt.a, Saanmdple tubes will be labeled with the study number. lter identification, ate of collection, study day, sample identification and collection timepoint. Blood samples will be collected from each fetus via decapitation. Blood from tapupbreosxainmadttehley roenmea-ihanlifngoffetthael bfeltouosdewsililnbeeacthralnistfeerrwrieldl binetoplsaecreudminsteopaErDaTtAo-rctoubaetse.d The `alsiaqmupoltess)w/iplllabsemasp(ounneianlaiqcueont)trwiifllugbeeatnrdantshfeerrreesdulitnitnoglsaeberluemd (pdoilvyipderdopiynlteontewtoubes. All samples will be immediately frozen on dry ice and maintained frozen (<-20C) until shipment for analysis. The liver from each fetus will be collected. One fetal iver from each fitter will be. rmiecmroovsecodpya.ndTfhixeedreimnagilnuitnegrafledtaelhyldiveerfsorinpoesascihblleitfeurtwuirlel abnealdyisviisdebdyientloectthrroene samples of equal number (when possible). Two of the samples will be frozen and stored (s-20C) until shipment for analysis. The remaining sample will be flash frozen in liquid nitrogen and maintained frozen (=-70C) until shipment for possible analysis. Carcasses will be discarded without further evaluation. Sample Analysis and Shipping Instructions Abpeprsohpirpipaetdefsraomzepnleosnwdilrlybiecemvaiianotvaeirnneidghftromzaein.until shipment for analysis. Samples wil One of each pair of serum samples. frozen liver samples, and liver samples fixed in gluteraldehyde will be sent to Dave Ehresman. at the previously cited address. The tsoamDpalveetEuhbreeasnmdanliver weights and a packing lst will be included with the samples sent 000836 418-018:PAGE C-15 Protocol 6P1a8g.e01185 The and trreimgalyicneirnigdess.erTuhmeasnedsalimvperlseasmwpilllebsewislhl ibpepeadnatlo:yzed for LDL, HDL, total cholesterol Or. Saroj A. Das Ani Lyics, Inc. 2Ga0i0thGeerrsabrudrgS,trMeaert,ylSaunidte 22008077 TTeelleefpahxo:ne: ((330011)) 992717--00146383 Plasma mevalonic acid levels will be measured. These samples wil be shipped to: JPirmimJeedrisceayWorcester Laboratories 5Wo7rcUensitoenr,StMreaestsachusetts 01608 TTeelleofpahxo:ne: (508) 890-0151 (508) 753-1834 Both the recipients and the Study Monitor wil 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 0 of presumed gestation to the time the frst pup is observed). Litter Size (defined as all pups delivered). Pup Viability at Birth. METHOD OF SACRIFICE - Fo GENERATION Rdeactaspiwtialtlibone.sacWrhifeincedpobsysicbalre,bornatsd.iopxuipdse aasnpdhyfxieattuisoens.wilFlebteusseascrwiiflilcbedeasnacdritfiiscseudesvia collected at approximately the same time each day. 000837 418-018:PAGE C-16 CROPSY - Fo GENERATION Protocol 4P1a8g.e01186 Gross lesions will be retained in neutral buffered 10% formalin for possible future evaluation (a table of random units will be used to select one control group rat assigned 1o0rdCearetsoarperaonvi-dseecctoinotrnoflrtoimsswuheiscfhoralalniysspuoesssibelxeamhiisnteodpaatthonleocgriocaplsyevwaillluabteiornestaoifnegdr,osins lesions). Unless specifically cited below, all other tissues will be discarded. Blood and processing): Tissue Sample Collection (See ATTACHMENT 4 for tissue collection and Cbeafposrean(edmpltabye)laenddtuabfetesrwrileltebnetiwoeniogfhseadm(pcloemsbfionresduwbesiegqhu,entot utshee nienaprheasrtma.c00o1kignreatmi)c awneailgyhstess.willTbheesiencwleuidgehdtswiwtihlltbhee pdaocckuimnegnltsetpdriionrthtoe srhaiwpdmaetnat,. aSnadmcpolpeietsubofesthweilslebe. lsaabmeplleed widietnhtitfhiecasttiuondyannudmcboelrle,ctainoinmtailmiedpeonitnitfication, date of collection, study day, Female Rats Assigned to Caesarean-Sectioning: Oeinghdtaryat2s1doefsipgrneastuemdefdorgCeasetastairoena.nb-lsoeocdtiaonndinlidveorssaagmeplgerosuwpisll 1b1e0c7o,ll1e2ctaenddfr1o3.m tTheh.e time of sample collections will be recorded in the raw data. Bclaovoadasnadmspelpeasra(attedleianstto4twmoLaepapcrho)xiwmialltebleyceoqlulaecltaeldiqfurootsm.thTehreatfsirvstiaaltihqeuoitnfweirlilorbevena pselpaacreadtionrtotuEbeDsT.A-Tchoeatseadmptulbeesswailnldbethsepsuencionnad caelnitqruioftuwgielabnedttrhaensrfeesrurleldinigntsoesreurmum (pdoilvyipdreodpyinlteonetwtoubaelsi.quAoltls)s/apmlpalsmeas (woilnebealiiqmumoetd)iwaitlellbye tfrraonzsefneorrneddriyntiocelaabnedlemdaintained frozen (<-20C) until shipment for analysis. wFeoilglohwtiwnigllcbolelercetcioorndeodf.blAoopdosrtaimopnleofs,eatcheh lliivveerrosfaemapclhe r(aitghwitlllabteerealxcliosbee)d wainlldbtehefllaisvher frozen in analysis. liquid The mneidtrioagnenliavenrdlmoabeinwtialilnbeedffrroozzeenna(n<d-7s0toCre)dun(t<i-l2s0hiCp)muenntti for possible shipment for alinvaelrywsiilsl.beA fsiexcetdiionn g(lauptperroaxlidmeahtyedleyf0o.r3ptooss0i.b5lecmfutwuirdee)anfarloymsitshbeyreelmeacitnrionngmpiocrrtoisocnoopfy.the The remaining analysis. portion of the liver will be frozen and stored (<-20C) until shipment for Female Rats Assigned to Natural Delivery: Blood, milk, postpartum. heart and liver samples will Time of sample collections be collected from (blood and milk) matemal rats on day will be recorded in the 5 raw data. 000838 418-018:PAGE C-17 Protocol 4P1a8g.e01187 Ohonudsaeyd 5foproasptppraorxtiumma,teelaycfhodurahmouwrilsl.beThreemdoavmedwilflrobme tihnejencetsedtiinngtrbaovxenaonudsliyndwiivtihduoanlley usnaimtpolfe)oxayrteoccionllaepcptredo.xiTmahteelsyafmipvleemsinwiultlebsebiemfmoerdeimaitleklysafmrpolzeens (at on least 100 pL dry ice and per maintained frozen (s-20C) until shipment for analysis. Fforlolmotwhiengramtislkvisaatmhpelienfceorliloercvtieonn,abclaovoadasnadmpsleepsar(aatteldeaisntto4tmwoL aepapcrho)xiwimlaltbeelycoelqlueaclted waillilquboetst.raTnshfeerfriesdt ailnitoqusoetrwuilml bseeppalraacteodr tiuntboesE.DTTAh-ecosaatmepdletsubweilsl baendspthuensiencaocnedntarliifquuogte atrnadnstfheerrreedsuilnttionglasbeerluedmp(odliyvpidreodpyilnetonetwtoubaelsi.quAoltlss)a/pmlpalsemsa w(iollnebealiimqumoetd)iwaitllelbyefrozen on dry ice and maintained frozen (s-20C) until shipment for analysis. Following collected. collection The liver of milk weight wainlldbbeloroedcosrdaemdp.leAs, ptohretihoenaroft eaancdhlilvievrerofsaemapclhed(arimghwtilllatbeeral lobe) wil be flash frozen in liquid nitrogen and maintained frozen (-70C) until (s5h-i2p0meCn)t ufnotrilposshsiipbmleenatnafolrysainsa.lyTsihse. mTehdeiahnealritvewrillobbee will be frozen and stored excised and two cuts will be msuardfeacteoaatltlhoew approepxearnfdixaetxiotne.ndTahneterfiirosrtlcyutanwidllvsetnatrrtaltloytthoetrhieghptuolfmtohnearveynatrrtaelrym.idlTihnee asencdoenxdtceuntdwitlhlrobueghmathdeelesfttarvteinntgritcolethteo ltehfet oafsctheendvienntgraalortmai.diiTnheesucurtfahceearatt tahnedaapex sfiexcetdioinn (galpuptreorxailmdaetheyldye 0fo.r3ptoos0s.i5blcemfuwtiudree)afnraloymsitshebyreemlaeicntirnong mpiorctrioosncoofpythaenldilvoerrwliilglhtbe microscopy. The remaining portion of the fiver will be frozen and stored (s-20C) until `shipment for analysis. `Sample Analysis and Shipping Instructions: Appropriate samples will be maintained frozen until shipment for analysis. Samples will be shipped frozen on dry ice via overnight mail One of each pair of serum samples. frozen matemal liver samples (right lateral and mEnehdrieasnmalno,beast),thaendprelivvieoruasnlydchietaerdtasdadrmepslse.s fTihxeedsianmgplluetetruabledeahnyddeliwvielrl wbeeigshetnst taondDaave packing list will be included with the samples sent to Dave Enresman. 000839 418-018:PAGE C-18 Protocol 6P1a8g.e01188 The remaining serum and liver samples will be analyzed for LDL, HDL, total cholesterol and triglycerides. Milk samples will be analyzed for total cholesterol. These samples will be shipped to: Dr. Saroj R. Das A2n0i0LGyetircasr,dInSct.reet, Suite 200 Gaithersburg, Maryland 20877 Telephone: (301) 921-0168 Telefax: (301) 977-0433 Plasma mevalonic acid levels wil be measured. These samples will be shipped to: JPirmimJeedrisceayWorcester Laboratories 5Wo7rUcnesitoenr,StMreaestsachusetts 01608 Telephone: (508) 880-0151 Telefax: (508) 753-1834 Both the recipients and the Study Monitor wil be notified in advance of sample shipment. Scheduled Sacrifice - Female Rats Assigned to Caesarean-Sectioning: On day 21 of presumed gestation. female rats wil be sacrificed, Caesarean-sectioned, and a gross necropsy of the thoracic. abdominal and pelvic viscera will be performed. dBelsocordibaedn.d tUitsesruie osfaamppplaersen(tbllyoondonsperreugmn/apnltasramtasawinldl blievesrt)awiinlledbewictohll1e0ct%edamasmoprneivuiomusly s1u0lf%idfeotromacloinnffiorrmptohsesiabblseefnucteuroefeivmaplluaantitoant.ion sites and retained in neutral buffered Scheduled Sacrifice - Female Rats Assigned to Natural Delivery: Othnordacaiyc,5 aobfdloamcitantailona,nfdempaellveicravtisswcielrlabweilslabcreifpiecrefdoramnedd.a gBrloososdnaencdrotpissysuoefstahmeples (blood serumiplasma, heart and liver) will be Collected as previously described. Rats that do not deliver a litter will be sacrificed on day 25 of presumed gestation and ebxeasmtianineeddfwoirtghr1os0s%leasmiomnso.niBulmoosdulafniddettioscsuoenfsiarmmptlheesawbisllennocteboef ciomlplleacntetda.tioUntesriitweilsl and retained in neutral buffered 10% formalin for possible future evaluation 000.40 418-018:PAGE C-19 Protocol 4P1a8g.e01189 Dams with No Surviving Pups: Dams with no surviving pups willbe sacrificed atter the last pup is found dead, missing or presumed cannibalized. Blood and tissue samples (blood serumiplasma, heart and `Tavebrd)omwiilnlableacnodllpeecltveidc avisspcrereaviwoiullslbyedpeesrcrfiobremde.d.APgorsotspsarnteucmrodpastyaofforthtehetshoerdacaimc,s will be excluded from summary tables. Rats Found Dead or Moribund: Rats that die or are sacrificed because of moribund condition or abortion will be emxaadmei.neTdheforratthsewicllaubseeeoxfadmeiantehdofrormogrriobssunldescioonnsd.itiWonheonn tphoessdiabyleth(enootbpsreercvlatuidoend ibsy autolysis), blood serum/plasma, heart and liver samples will be retained as previously dofesfcermiableed rfaotrsrwaitlsl absesriegcnoerddetdo.naAtubroarlteddelifveetruys.esParnedg/noarndceylisvtearteuds apunpdsuwtielrlibneeceoxnatmeintnsed to the extent possible. Uteri of apparently nonpregnant rats will be stained with 10% b`uafmfmeornediu1m0s%ulffoirdmeatloincofnorfipromsstihbeleabfsuteunrceeevoafliuamtpiloann.tation sites and retained in neutral TESTS, ANALYSES AND MEASUREMENTS - F1 GENERATION: Viability: Postpartum Period: LTihteerpsuwpisll ibneeaobcshelrivteerdwfiolr bdeeacdoupnutpesd aotnlceeasdtaitlwyi.ce day. Clinical Observations andlor General Appearance: Postpartum Period: Clinical observations and sex will be recorded once daily. Clinical observations may be recorded more frequently than cited above,if deemed appropriate by the Study Director and/or the Study Monitor. Body Weights Postpartum Period: Days 1 (birth), 2, 3, 4 and 5 postpartum. Pooled litter weights will be recorded. METHOD OF SACRIFICE - F1 GENERATION PUPS: As previously cited for Fo generation rats. When possible, pups wil be saciificed and tissues collected at approximately the same time each day. The time of sample collection will be recorded. 000841 418-018:PAGE C-20 Protocol 4P1a8g.e02108 E1 Generation Pups Found Dead on Day 1 Postpartum: Pstuaptsustahattbidriteh.beTfhoreeleuxnagmsiwnilaltiboenroefmtohveelditaerndfoir mpmueprvsieabdiliintywwaitlelr.be Peuvaplsuwaittehd lfuorngvsitatlhat s`ainndk twoillhabveeiddeinetdifsiheodrtalsysatfitlelrbobrinr;thp.upPsupwisthwiltuhnggsrotshsatlefsloiaotnswiwlillbebeidpernteisfeiredveadsilniBvoeubionm',s Solution for possible future evaluation. Should postmortem autolysis preclude these evaluations, it will be noted in the necropsy data. F1 Generation Pups Found Dead or Moribund on Days 2 to Postpartum: Pups found lesions and fdoeratdheorcasaucsreifoifcetdhedumeortiobmuonrdicbounndditcioonndiotriodneawtihll. bPeuepxsamwiitnhegdrfoosrsglreossisons fevoaulnudatoinond;agyrsos2s10le4sipoonsstopfarptuupmswfiollunbde opnredsaeyrv5edpoisntBpoauritnu'ms wsiolllubtieonprfeorseprovsesdibilnenfeuutturrael buffered be noted 1in0t%hefonremaclrionp.syShdaotual.d postmortem autolysis preclude these evaluationsitwill Scheduled Sacrifice - F1 Generation Pups (See ATTACHMENT 4 for tissue collection and processing): Olensidoansy w5ilplobsetpparretsuemr,vepdupisn nweilultrbael sbaucfrfiefriecded1a0n%d feoxramamliinn.edNfeorcrgorposssy lwielslioinnsc.luGderoass esixnagmliencartoisosn-soefctthieoncroofstsh-esehcetaidonaetdtbhreailnevfeolroafptphaerefrnotnthayld-rpaorcieepthaallsyu.ture and bCeafposrea(nedmpltabye)leadndtuabfetesrwrileltebnetiwoeniogfhseadm(pcloemsbfionresduwbesiegqhute,n1t0 tuhsee nienaprheasrtma.c0o01kignreatmi)c analyses. These weights will be documented in the raw data, and copies of these wleaibeglhetdswwiitlhbteheinsctluuddyenduwmibtehrt,heanpiamcaklinigdelnsttifpirciaotriotno, sahtipemeonftc.ollSeactmiponl,esttuubdeysdwaiyl,l be. sample identification and collection fimepoint Blood samples wil be collected via cardiac puncture from each pup, pooled (by sex per aliltitqeru)otanpdersseepxarwaitlledbeinptloafcoeudr i(nttwooEpDeTrAs-ecxo)aatpepdrotxuibmeastealnydetqhuealseaclioqnudotasl.iqTuhotepfeirrstsex will be transferred into serum separator tubes. The samples will be spun in a centrifuge and the resulting serum transferred into labeled (divided into two aliquots)/plasma polypropylene tubes. All samples w(iollnebealiimqumoetd)iwaitllelbyefrozen on dry ice and maintained frozen (<-20C) until shipment for analysis. 000842 418-018:PAGE C21 Protocol P4a18g.e02118 The liver from each pup will be collected, pooled (by sex per litter) and the pooled weight recorded. One liver from each litter pool will be removed and fixed in gluteraldenyde for possible future analysis by electron microscopy. The remaining livers in each liter pool will be divided into three samples of equal number (when possible). Two of the samples will be frozen and stored (s-20C) until shipment for analysis. The remaining sample will be flash frozen in liquid nitrogen and maintained frozen (<-70C) until shipment for possible analysis. The hearts will be collected from the first two male and two female pups from each liter (pooled by sex per litter) and will be fixed in gluteraldehyde for possible future analysis by electron microscopy and/or light microscopy. The remaining carcasses will be discarded without further evaluation Samples will be shipped for analysis as previously described for dams and fetuses. 000843 418-018:PAGE C-22 Protocol 4P1a8g.e02128 PROPOSED STATISTICAL METHODS": Aapvperropargieastea.ndAdpdeirtcieonnatlagpersocweildubreescaalncdu/loatreadn.alLyitsteesr vmaalyuebsewiplelrbfeorumseedd, wifhaeprperopriate. Type of Test! I. Parametric I. Nonparametric" A. Bartlett Test" A. Kruskal-Wallis Test (575% ties) Significant at p<0.001 Not Significant Significant at p<0.05 Not Significant Nonparametric Nn of Variance Dunn's Test Significant at ps0.05 | Not Significant B. Fisher's Exact Test (>75% ties) Dunnett Test Il. Test for Proportion Data VofartihaenBcienTomeisatlfoDrisHtorimbougteionneity a. Statistically significant probabilfies are reported as either p=0.05 or p<0.01 b. Proportion data are not included in this category. c. Test for homogeneity of variance. 000844 418-018:PAGE C-23 Protocol 4P1a8g.e0z138 DATA ACQUISITION, VERIFICATION AND STORAGE tDhaetaPrgiemneedriactaedArdguursinAgutthoemcaotuerdseDaotfathCioslsletcutdiyowniallnbdeMraencaorgdeemdeenitthSeyrsbtyehmaannddotrhuesing tVaibvualraituemd,Tseumpmemraartiuzreedaanndd/RoerlasttaitviestHicuamlildyiatnyalMyoznietdoursiinnggStyhsetePmr.imAedlidcaatAarwgilulsbe AReultaotmiaveteHdumDiadtiatyCoMlolneicttoiroinnagnSdysMtaenma,gMeimceronstofStyEsxtceeml,[tphaertVoifvMairciruomsoTfetmpOeffriacteu9r7e and (version SR-2)] andlor The SAS System (version 6.12). Rpeercsoorndnselwilwlitbheinr2e1videawyesdbayftetrhegeSnteruadtyioDni.recAtloroaringdi/noarl arpepcroorpdrsiwaitlelmbeansatogreemdeinn tthe aalrlcrhiavwedsaotfatwhiellTbeestsiunpgplFiaecidlttoy.thAellSoproignisnoalrduaptoanwirlelqbueestb.ouPnrdesaenrdveidndteixsesdu.eAs wicllopbye of Srtepoorretd, aatfttehrewTheiscthintgimFeactihlietySpatonnsoocrhwairllgebefocroontnaecyteeadrtoafdteertemramiilinnegtohfetdhiespdorsaifttifoinnaolf these materials. RECORDS TO BE MAINTAINED: PTreosttoaconldaCnodntArmolenArdtmicelne,tsV.ehicle and/or Reagent Receipt, Preparation and Use. Animal Acquisition. Randomization Schedules. Mating History. Treatment (i prescribed by Staff Veterinarian) General Comments. Clinical Observations andor General Appearance. Pharmacokinetic Sample Collection, Processing and Shipment. BFoedeyd WCeoingshutmsp.tion Values. Caesarean-Sectioning Observations. LNiatttuerraOlbsDeerlviavteiroynOsb.servations. Gross Necropsy Observations. OPrhgotaongWreaipghhsts(i.f required). Study Maintenance (room and environmental records). PFeaecdk,inWgaatnedr/oarndShBiepdmdeinntg LAinstasl.yses 00045 418-018:PAGE C-24 Protocol 4P1a8g.e0128 KEY PERSONNEL: Executive Director of Director of Research: Research: Mildred S. Alan M. Hoberman, Christian, Ph.D., Ph.D., DABT Fellow, ATS ADsirseocctioarteofDiOrpeecrtaotrioofnsReasnedaCrocmhplainadncSet:udyBaDribreacrtaorJ:. Raymond Patterson, G. York, B.A. Ph.D., DABT Director of Directorof LSatbuodryatMoarnyaOgpeemreanttio:nsV:alJeroihenAF.. Bamett, Sharper, B.S. M.S. M`aCnoamgmeitrteofe:AnDimeanlaOCp.erLaetbioo,nVs.aMn.Dd.Chairperson, Institutional Animal Care and Use Consultant, Veterinary Pathology: W. Ray Brown, D.V.M., Ph.., ACVP FINAL REPORT: AbecfoimnpalriezheednfsoillvoewidnrgacofnisnualltraetpioorntwwiiltlhbteheprSepopnasroerd.onThcoemprelpeotritonwilolfitnhcelusdteudtyheand will following: `Summary and Conclusion. EEvxapleuraitmieonntaolf TDeesstigRnesaunltds.Method. ADpatpae,ndPircoetso:colFiagnudreAss,sSocuimamtaedryAmaennddImnedinvtidsuaalnTdabDelveisatSiuomnmsa, rSitzuidnygDtihreecAtobro'vs e GLP Compliance Statement, Reports of Supporting Data (f appropriate) and QAU Statement. The Sponsor will receive one copy of the draft report and two copies of the final report. INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMENT: TInhsetitpurtoiocneadluArneismdaelsCcrairbeedanidn tUhsisepCroomtomciotltehea.veAblleepnrorceevdiuerweesddbeysctrhiebeTdesitnitnhgisFapcriolttoyc'osl that involve study animals will be conducted in a manner to avoid of minimize discomfort, distress or pain to the animals. nTehceesSspiotnysfoorr'scosnidguncattiunrge tbheisloswtuddoycaunmdentthse ftahcetftahcatttthhaits iinsfnoortmaatniounncnoencceesrsnairnigythe dpurpolciecdatuirveesswteurdey mavaayilbabeleobftoarimneeedtfirnogmtthheesStpatoendsopru.rpNosoeasltoefrtnhaetisvteud(yi.n vitro) 000846 418-018:PAGE C25 Protocol 4P1a6g-e021s8 REFERENCES: 4. CThersitsst.ianE,nvMi.rS.onmaenndtaVloyPtreokt,ecPt.iEo.n (A1g9e8n2c).y,IWnaVsihviongRteopnr,oDd.Cu.cNtaiativnodenaMluTteacghenniiccailty Information Service, U.S. Department of Commerce, Springfield, VA 22161. 2. Cnharlitsrteixaon,neM(.PSr.o(c1e9e8d4i)n.gsReofprNoadlutcrteixvoenetoSxiycmitpyoasnidumt,erNateowloYgoyrekvaAlcuaatdieomnsyooff Sciences, November 7, 1983), J. Ciin. Psychiat. 45(9):7-10. 3. LCaonngtr,oPl.DL.at(a19i8n8)t.he EChmabrrlyeos aRinvdeFrCertia:l DCevDeElopRmaetn.taClhaTrolxeicsiRtyiv(eTrerLaatboolroagtyo)ries, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.) 4 LInasbtoitruatteoorfyLAanbiomraaltso.ryNaAtniiomnaall RAecsaoduermcyesPr(e1s9s9,6)W.asGhuiindgetofnor,tDh.eCC.are and Use of 5. Salewsk, E. (1964). Implantationsstellen aFmarUbteemreutshdoedreRaztutem. maArkcrho.skPoatphiosl.chEexnp.NaPchhawremiaksovlo.n 247:367. 6 tShneedbeicnoorm,iaGl Wdi.strainbudtiCoon.chrStaant,isWti.cGa.l M(e1t9h6o7d)s.,V6atrhiaEdnicteiotne,stlfoowrahSotmaotgeeUnneiivterysoifty Press, Ames, pp. 240-241 7. BSoikoamie,trRyR,.W.aHn.dFRroehe,maFnJ.an(d19C6o9.),. SBaanrlFertatnscitsecsot,ofpph.o3m7o0g-e3n7e1i.ty of variances. 8. SMneetdheocdosr,,6Gth.WE.ditainodn,CloocwharaSnt,atWe.GUn.iv(e1r9s6i7t)y.PrAensasl,ysAimseosf,Vpapr.ia2n5c8e-.27S5t.atistical 9. tDruenantetmte,ntCsWw.ith(1a9c5o5n)t.rolA. mJu.liApmleer.coSmtapta.rAisssoonc.pr5o0c:e1d0u9r6e-1f1or21c.omparing several 10. WSo.kHa,l,FRr.eAe.maanndaRnodhlC,o.F.JS.an(19F6r9a)n.cisKcrou,skpapl.-W3a8l8l-i3s89Te.st. Biometry. 11. Dunn. OJ. (1964). Multiple comparisons using rank sums. Technometrics 6(3):241-252 12. Siegel. S. (1956). Nonparametric Statisticsforthe Behavioral Sciences, McGraw-Hill New York, pp. 96-104 000847 PROTOCOL APPROVAL: FOR THE TESTING FACILITY I Gdor Deariove, Ph.D., DABT Associate Director of Research LAD dG. P ASstsuddtyiaDitreeDctiorrector f Df \DABT arch PmCle DCeCrneaamCC.taLomeinbto,enssVi.hMi.tDo.nal Anima Care and 418-018:PAGE C-26 SWe.s HALT Date _2lAvGCe Date atl Geren Date FOR THE SPONSOR Missed]... Deanna J. Luebker, M.S. `Study Monitor bed Bililff] Teme So John Butenhoff, omar Ph.D., DABT, CIH _&laa/aaa.. Date so put zoc0 Date 0005.48 418-018:PAGE C-27 ATTACHMENT 1 STUDY SCHEDULE 0oo0&4 ATTACHMENT 1 418-018:PAGE C-28 ProtocPoalg4e181.001128 SCHEDULE REPLICATE 1 22AUG 00 RAantism)a.l Receipt - Acclimation Begins (Female 29 AUG 00- 12 NOV 00 29 AUG 00 - 20 NOV 00 CDaoessaagreeaPne-rSieocdt-ioFneimnagl(e42RadtasyAssbseifgonreed to cohabitation and continuing through day 20 of presumed gestation). Dosage Perio-d Female Rats Assigned to tNhartuoruaglh Ddealyiv2e4ryo(f4p2rdeasyusmebedfgoersetcaothiaobni(traattison that do not deliver a litter) or day4 postpartum (rats that deliver a iter) 0169O0CCTT0000PPMM--12630OCCTT 0000 AAMM 10 0CT 00 230CT 00 310CT 00 13 NOV 00 Cohabitation Period (Maximum of 14 days). Male 1 (07 days) Male 2 (07 days) First Possible Day 0 of Presumed Gestation. Last Possible Day 0 of Presumed Gestation. CFiaresstaProesasni-bsleecDtaioyni2n1g.of Presumed Gestation Last Possible Day 21 of Presumed Gestation Caesarean-sectioning. 310CT 00 17 NOV 00 04 NOV 00 17 NOV 00 gFierssttatPioosns)i.ble Delivery (Day 21 of presumed Last Possible Delivery (Day 25 of presumed gestation). First Possible Day 25 of Presumed Gestation Female Sacrifice Last Possible Day 25 of Presumed Gestation Female Sacrifice. a. The study initiation date is the day the Study Director signs the protocol. b. Replicate 2 wil be initiated two weeks after the start of Replicate 1 (see Page 2 of ATTACHMENT 1). QQO850 ATTACHMENT 1 418-018:PAGE C29 ProtocPolag6e182.001128 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 DNaotsuaragleDPeelriivoedry- [F4e2mdaalyesRbaetfsorAessciohganbeidtattoion tthhartoudgohndoatyde2l4ivoefrparleisteurm)eodr dgaesyt4atipoonst(praatrstum (rats that deliver a liter). Cohabitation Period (Maximum of 14 days). 20510NCOTV 0000 PPMM---0081 NOV NOV 00 00 AM AM Male 1 (07 days) Male 2 (07 days) 26 OCT 00 08 NOV 00 First Last Possible Possible Day Day 0 0 of of Presumed Presumed Gestation. Gestation. 16 NOV 00 03 DEC 00 gFierssttatPioosns)i.ble Delivery (Day 21 of presumed Last Possible Delivery (Day 25 of presumed gestation). 20 NOV 00 03 DEC 00 FFiersmtaPloessSaicbrlieficDea.y 25 of Presumed Gestation FLaesmtalPoessSaicbrlieficDea.y 25 of Presumed Gestation 20 NOV 00 07 DEC 00 First Possible Day 5 Sacrifice (Dams and FL1astgePnoesrsaitbiloenDpaupys)5. Sacrifice. 01MAR 01 Draft Final Report 000:51 418-018:PAGE C-30 ATTACHMENT 2 MATERIAL SAFETY DATA SHEET 000852 418-018:PAGE C-31 DATA SHEET satm. caPnautle,r Minnesota 515-184040--1308040-3677 or (612) 737-6501 (24 hours) Copyright, ALL rights 1r9e9s8e,rveMdi.nnesCootpayiMnignianngd/oanrddoMwannluofaadcitunrginogf Company. this inforaation for the is allowed provided purpose that: of properly utilizing 3H products 1) tphreiorinafgorremeamteinotn is is copied in full With no obtained from 3, and changes unless 2) neither the distributed wciotpyh tnhore tihnetenotriiogninaolf iesarnriensgolda porrofoitthertwhiesreeon. DTIRVAIDSEIONNA:ME: 3M CHEMICALS FC-95 FLUORAD Brand Fluorochemical Surfactant ID98N-U0M2B0E7R-/0U1.0P3.-C7. 00-51135-09054-1 98-0207-0104-5 92Z8F-.00201012--01808448--15 00-=511.35-09362-=7 98-0211-3916-1 ISSUSPUEERDS:EDEJSa:nuaNroyve2m9b,er190S9,8 1997 DOCUMENT: 10-3796-9 0000--5511113355-.0092035151--82 1. INGREDIENT PPOOTTAASSSSIIUUMM PPEERRFFLLUUOORROOAALLKKYYLL SSUULLFFOONNAATTEE............ PPOOTTAASSSSIIUUMM PPEERRFFLLUUOORROOAALLKKYYLL SSUULLFFOONNAATTEE............ POTASSIUM PERFLUOROALKYL SULFONATE...... C.A.S. NO. 2795-39-3 82 329847201--499-93 -633 6~03827720--2555-1-5 21 PERCENT --886 -o76 Sa 2. PHYSICAL DATA VBAOPIOLRINPGREPSOSIUNRTE::..........................c.c.c.. VEAVPAOPRODRAETNISOINTYR:A.T.E.:............................ SSPOELCUIBFIILCITYGRAINVIWTYA:T.E..R.:..................... PERCENT VOLATILE: .........ouens BME .evveeemiinnneeiaaeaaiiein VMIESLCTOISNIGTYP:OINT:......o.o.o.i.vi.i.u.i.i.n.n.n.n.e.n.s NIA NNIIAA Ns/lAight ca. 0.6 Haters) 0(%Bulk) T= 8 NI(D0.1% Aqueous) NID APPEARANCE AND ODOR: Lignt colored, free flowing powder. 000853 Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 8Sim:aaryFO-209,5 F1L9U9G8RAD Brand Fluorochenical Surfactant 418-018:PAGE C-32 mace 2 3. FIRE AND EXPLOSION HAZARD DATA FA FLLAASPHE MPBOLIENTLL:IiWkITiS ocLVcEE.LLe:Lo1o.I1eLeL.o WNNoIImAAe Fore ionTEMPERATURE: 11... NIA EXTINGUISHoINGnMEDtIoAx:ic, Dry cheical, Foan SPEABB CIALEEFFIRBEre aFtIaGaHTtIiNvGePnRFceOieCosEtsaDnurUihrRnusEg,'S,d:ewshiainnsctdl.udainbenrgea1thehgesil,ngaf,aacpespaerlmafats-ukc,so,ntaabnidunnekde,r cost ay Sovering for spoked ress of the head. UNUSUALEFIREE ANDoEeXPsLOtSIiONoHnAZAsReDcSt:ion for products of comsustion. : 4. REACTIVITY DATA smasnLTY: scable INoCOtNPAaTpIplBiIcLaIsTlYe.- WATERIALS/CONDITIONS To AVOID: JAZARDOUS FOLYNERIZATION: Hazardous polymerization will not occur. \AZSARaDOmUSeDESCeOxMiPeOSIVaTapIoOrNcsa,PrReOGnDaUsCeDTsiSo:xoirdeP,artOixciudleasteosf.Sulfur, Hydrogen 5. ENVIRONMENTAL INFORMATION or spOr neeOspoeseauteionstofraovsaiothdeurstisnegc.tioGnAsU.TIOVNacuAusv,icbuusen wcelteansewerepcionugld Sepraue aetal conatner seal the container. RECOMMENDEoneD eDtIheSePtOSctAooLu:utaterreusauylst or tne Lowest ECSo or LoCiBrnO ssqeSueoarnt.ciecntrcDa0otnincooentn.trusaetiinoicnnisneprrgaortdeeuactteisrn oatrnhan Ttr Eerriaae mlti!ve.GoaE bptearpteio coen porrodo wuacsttse e mpirlolducitnacliundper+esfHiFa.nceisliOtaoyfspa3pseacrlsoimtuinstdiottoe 0085; 4 Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately ee ee ee mee -- S4a0nSu:aryFG2-35,5 1F9L9U8ORAD Brand Fluorochenical Surfactant "5 ENVIROWENTAL INFORMATION (continued) 418.018PAGE C-33 PAGE 3 accept chemical Waste. ENOSOVIeRrNrOMimEeaNrnTiaAySLterinDniu ATogAFn/:iLLnse;hpoL4tnCgiS-sDH,r.mFaacEtrChSoe0c,ahdirDiuamsp)hn=no6in3a(PaMigas/ge1np,anaR=laei5sn0bop8wr9o/1Ts;reolusCtsO()Ds==a3.l80m0ea4g/l, S/o: Booz = wil. REGVUoLlAaTtOiRlYe Voc Less OHIrN2gF0aOnR&MiAcETxIeCOmoNpm:tpouSnodlsv:entNs/:A. N/A. SSincre reegulaa tions vUa5r.y, EcPoAnsHualztardaopupslicWaabsltee rNeugmublearti=onsNonoer a(uNtohtorUi.St.ies EPA Mazardous.) TTShCiAs, prEoIdNuECcSt,coCOmSpLl,iesAICwSi,thMItThEe acnhdemiKcoraela.registration requirements of EPPCRRAWAHzAZaAnRDD:CLNoA.SS:PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: Yes 5. SUGGESTED FIRST AID : eveEihciOotTeTasAc.eTi:Gyetfliumsmhedieyaetse wmietdhicallargaetteanmtoiuonnt.s of water for at least 15 SKIaoNmmcCieOnNsiTtAmeCelTt:yydflculsohthisnkgi.n WIifthirlrairtgaetioanmoupnetrssisotfs,watcearl.l aRempohvyesician. Wash Contaminated clothing before reuse. INHHAsLATLIoOnNs:symptoms occur, aigns symptoms continue, rceamlolvea ppheyrssiocniafno. fresh air. It IFOrSiHnALkLOtWwEoD:glasses of water. Call a physician. 7. PRECAUTIONARY INFORMATION " : EYEavoPiRdOTEeCyTeIOcNo:ntact. Wear vented goggles 000555 Aoorevaations: NID. Not Determined N/A - Not Applicable CA - Approximately 5Z0n8u:aryFC-299,5 F1L9U9O8RAD Brand Fluorochemical Surfactant 3 PRECAUTIONARY INFORWATION (continued) 418018PAGE C-34 Pace 4 KIOA eN NaPROoTdsEnkCiT:nIOcoNor:nst"iabructty.fl rWguelbbaoervre.sappnraUodseperifaanrteoenogtrlhoemvoerfseolloWfohwenitnhgehanafdsoltlielnrogiwailnt(ghsi)s necessary to provent skin contact: are head BT BSeoy'OeaetanPeylaeptneoeoevtiepatrochslteiyirtvoaino.nfyilttiehPmderseontfaeeoscltclihwvlieonrggiadermmaet(neSrtaisraaln(seo:xt)h.er than gloves) should {ECCeOeMWIEENDEDaVwbEapeNrlrTooeIwp,LrAarTseItPcOeroNom:vleioncddaeeldseuxsfhxfaipucosisteunrtveenvlteiinmltiatiteli.aotni.oInf Utesoxehamuaisnitntaaviwenenltli:lation Set adequate, use appropriste respiratory protection: 1Ea ACSEPIORATrObRroYerasPtRhiOibiTnanEgsCeTdoOIfSOoHNdnA:usartie.rgbuolrSanetelieocnctso:nocneenhtarolfaft-imtoahnsek fofoGlucsltoownitanangmdinKmaIinOsttSsH raaenpsdppirroiavnteodr, Tulalfnacke ssuupppplliieedd aaiirr rreessppiirraattoorr,.full face Gust and mist respirator, PReEDVnEEoNTrIOaNsacOs,FugAdnCrlCayInDkEwNioTftAhLSsaoIkaNepGESwaTnhIdeOnNK:autseirn.g ThKiasshPrhoadnudcst.afHtaesrhheaxnpdolsiendg and Before eating. HECCoOuMpH.ENcDoEnDtaSiTnOeRrAGdEr:y. Keep container closed When not in use. . FIRNEontAlNaDssEaXbPlLeO.SION AVOIDANCE: OTHNNCEeehReesnuPo.oRkkEmiChanAatgUzi.TaoIrnOdSNoaAvooRsfkYintdgheIecNFoWOhmtRipoMlobAesaTicIteUOiosNoi:nnagndpt/rhooirdsucstpasrookedmuecnatntdiocanlneeaddreisTnuolstetncetiniofnora4atoifon Shas sos. VMIS WAZARD RATINGS: WPEEARLSTOHN:AL2PROFTLEACWTMIAOBNI:LITXY:(S0ee RpErAeCcTaIuVtIiToYn:s, 0section 7.) ExposuRE LIMITS INGREDIENT VALE WIT TYE AUTH SKI SPOoTTAiGsSTInM PPEERRFFLLUUDGMORAOLAKLYLL SSUULLFFOOWMTTEE.... 00.11 MMGo/mMaL TTuWaA m 3 YY PSOOTTAASSSSIIUiMM PPEERRFFLLUUOORROOAALLKKYYLL SSUULLFFOONNAATTEE...... ~~ 00..11 ~~ MMGG//MM33 TTWHAA 3OMM YY 000.58 Aoorevistions: MD | Net Determined WIA - Not Applicable GA - Approximately Sa0n8u:aryFC2-39,5 F1L9U9O8RAD Brand Fluorochemical Surfactant EXPOSURE LIMITS (continued) 418-018:PAGE C35 Paes NGREDIENT VALUE UNIT TYPE AUTH SKIN OTASSIIM PERFLUGROALKVL SULFOMATE... 0.1 WG/M3 THA aM Y eneS1.KaIpiNotnNegOnTtAimTauIlcOoNuc:sontmLreiissbbtruaetndisosnuabntsdotaetnyhcee,esoveieinrtadhlielrcatebxeypdoaswiuirrtbehornb*eyY' torhu,endecmrourteaSKnIepNoaurstriecfrueolruatretloy, direct Contact with the substance. Venicles can alter skin absorption. 1OSUHR:CE OFanEXPROeScUoRsEmenLdIeNdITEDxApToAs:ure Guidelines 5. WEALTH HAZARD DATA IYWpEa1iC3nO6,NTEAayCneTd:Itrerairtiantgi.on: signs/sysptoss can include redness, swelling, i SKM"IiNilgdnCOsN/STskAyiCanTp:tIornrsitactainoninc(laufdteerrperdonelsosn,gedsweolrlirnegp,eataendd ciotncthaicntg).: ; Weaxytenbededabstoirseb.ed through the skin and persist in the body for an ;| IWWAaAyLATbIeONh:arstul if inhaled. MTaiyne.be absorbed by innalation and persist in the body for an extended Single overexposure, above recommended guidelines, say cause: SIorrreinteastsionof (tuhpepernosreespaindratTohrryo)a:t, sicgonusg/hsiynagptaonndsscnaeneziinngc.lude IFISnigAeLsLtOiWoEnD:is not a Likely route of exposure To this product. Ithlilsnesmsatemraiyalr.esult from a single swallowing of a moderate quantity of May be naraful if swallowed. "wTWAiGtEaNgIeCnIiTcYi:ty assays indicate the product is not autagenic. 000557 Abbreviations: NID Net Determined WIA - Not Applicable CA . Approximately ManDvSa:ryFG2-99,5 F1L9U58ORAD Brand Fluorochesical Surfactant 418-018:PAGE C-36 Pace 6 "a HEALTH WAZARD DATA (continued) REPTRoOtDUtCeTrIiVtEog/eDnEiVcELOiPnHEthNeTALraTtOXaItNSo:ral doses below maternally toxic Towels. OTHCeEaiRtifHEopArrLnoTidHuactHprAoZ1pAaoRsDnsottIiNoFKnnOoRuM6nA5.TITOoN:contain any substances regulated under A Product Toxicity Summary Sheet is available. SECTion oaGE DATES vero SECTION CAANGED SINCE November 05, 1997 ISSUE Sobrevistions: NID | Wot Detersined WA - Not Applicable Gh - Approximstely ToTehHePLcIoiErnDrf,eacrtsIaNtaCsiLoUnDofINiGnt,hethBiUdasTteMN.aOtTiesrsLiuIeaNdlI.TESDafoenTt0,yMAADKiNEtYSaNIOSMhPeWLeAItRERDA(NRMTSAIDRESRS)A,NTiYsEXPObRFeElSieSvEeDdORto AnPEEeRRtCFhHOeARrNMTAANtBGnIEeLIOSTnHYUpSOrRAoGdEuFcItOTFNEiSTaSRA1DF%EO.RfAorUsPeAarRTpIaiCsrUtLirAceRuslpaPorUnRsFipObuSlrEeposOfReorCanOddeRtSseEuriiOtnFaibnlge for mCUaaanqeuraestltyencettwniottdhheinofuscehueseanudasresrpaspppLlikicncaoatwtilioeondng.eof aGn3idv3eMcnonptrtrohaaelu,cvta,riitesto1ymseoefosfsefnnatciticoahrls tarhteahtat hSaarciveeeurtarovapluurapotseeShaendShsupirtoasdluectfoTro duesteerrsminaeetuhnoedthoefrusite 1osr Faiptplfiocrati3on 3DIMuneperrroorovritsdh,eesroemiminosftsoeiromnapstoisoeonirbiianllitleeylreatcTithoratnosnieclaencftotrrhoisnsiacssnafSorsrasensrstvfiieocrne,satyo1ihtmasavekecsursetnsooumletresd. Fepresentations as To its completeness or accuracy. In addition, IInnffoorrmsaattiioonn oibntatihneedMSfDrSomaavaildaabtlaebasdeiremacytlynotfrobem a3sH. current as the 000858 erR ooucP T #:AMCA850T3 SFKEETM,-CVAaMlTEi,Gd 6C/D2H0L0NO0 L=TDE7A8SKASTRTaEI4GE1R8Sss-IO0Ien1lG8o:aa6P9Aw0GiEsSChs-37 . On 07/25/2000 15:03 FasS otas ar ore a 57 1il0oi8.i0.h1nesiupcirasul,cePMhOosnter6:e3e1t0331,4 U1S71 3765 LTaexr:ge8n0c0y32P5honSe0:52314 771 5765 AeA ack SEGRICOaNTAL1.OG<+<: leer = = = = = co=soC0H3EMICAL IDENTIFICATION- = = = = === = rewCrans:#1 . . - COMPOSCThToILOENs/TIENRFOOLRMATION ON INGREDIENTS - = = = = = s1-sss MEFe: Woc:amme2c0o0-3532 stOE D onefse R-5-E53)NL.-oC3wH-O0+LLE&S:(T63E--NCB-HE3OT-ALB)EE=STTAE(-NSO-CIL3*)-3C*E+H7OSACL--HEC0OSHLLTOEELSRE=TYS-LCTSHE-ONAELL-NEC3-SO-3TWB-EOE3RLTEIATN-AO-LD+OYL+TCHHOO$LL:6E-STE3R-INE meC ErSACRYE OROKYCHn+OL(E-S)TC-HSO~TLEETNSETERhPOaRLzOaVnIoTsANoImNwmDzrIcaTION - << o-oo - SECDOTRKToASeaNtnOToAFAVACAIOLNAATBAECLTE,LLIMLME.DIAFTIERLSYT-FALIUDSHMEEAYSEUSREWSI-TH=CO-PI=OU=S<A=MOUN=TS Of WATEERR EFORoFATCoNLTEAACS:T, 13IMMMIENDUITAETSELY WASH SKIN WITH SOAP AND COPIOUS ABIHEOOTUaaNinTSietDOhF,.WARTEiENrRO.VBERETAoTHIFNRGESHISAIDA.IFFIICFULNTO,T A Touts, WASH OUT MOUTH WITH WATER SGPRIREVOAEVTIHODIXENYDGGEPNGE.IRVSEONARITSIFCIOCNISCAILOUS. SpcraCSshnhiclh ACOPNCOHTNYATSMAMIIICNNIAATATENEDDCLCOLTOHTHIINTGHIRBEEFOFRIEGHTRIENUSGE.MEASURES = - = = = = = = EXWThAIaTNBEGoRUsISSHPSRITANOYGK.IDMEE,DIAORY CHEMICAL POWDER OR APPROPRIATE FOAM. SPESCRIEAVLENETFLIReCEOCFNoITwAGiCHATIIINNWEGIDTHPBRORSCEKEAIDNTUHRIAENNSGD AEPYEPSA.RATUS AND PROTECTIVE CLOTHING 70 soUcNrUTiSNoUEnTASL8.TFOIoXREICnANFDeUMEESXPYLUIONSDNIEORNCSCFIIHAOADEZNACTROADNSLDITRIEOLNESA.SE MERSURSS- - <= = = = CGSiHAzEEMEDIPCRAOOLFT,ECSTAPIFLVEAETCYECLGIOONTGHGAILNEBGSA,.G GALNODVEHSOLADNDFOMRASWKASTE DISPOSAL. SeeTIAUoVEn0NII>ITLAReTAEISeIANRnGEADUAoSNoTD WDAS0H "SPILHLANDSLIITENGAAFNTDERSMTAOTREARGIEA-L-PI-CK=UP- I=S=CO=MP=LE-TE=. . cecnRteiren 10TO CHEMICAL SsEAzTTeETITiYonGO8B.GGoLEsS.on conzous persons mrorsction- - - - = 000859 CNIOOMSPHA/CMISSHLAE-RCPHEERMOIVCEADL-RREESSIPSITRAATNOTR.GLOVES. a an comminted 18 he SuccoTnasgeof our Customers. Emplazens end opA SANSA AE hare 22 Geen ah SPD wn = 2a - Re NR Cas Sey 418-018:PAGEC-38 mEeeiTM n an PO CORY vcr, i anaerseroerott 0 SECTION 14. = = = = = = = = = - TRANSPORT INFORMATION - - - - = = = = = OEL=MAK 600.60 eee sa ammo em mm wine ProdocT 8: C8503 en mn om 2a 418-018:PAGE C39 AME: CHOLEDSRTREIRBOhaILtmSLnEME1CiIOTUaOSSSL o OCT dSan007S7/H/2E23E5/,/2200V00a00li1d1586:/023:0000-3"Fax 8e00n-w22c5-o50p8m2 e+ (e31m4)iTmT.a5757 -- - - ATRACR CCACNCRERRREeVIeEW::GROOwPis3 58;: TThHeF 4103921i; Nwooss 1B0i:; THTTHSHEUEDL1S37L0,0I161,T1E9E8370220 NHEOEEkSsLSe1E9tn7h4o5SSxEEC4Ci2TPrDIRoOOnNGGoRmA88eM((sBb;))198nCU8iHN,sEPMUNIBECLGAIALSTHIEIVDNEV:ERNETSROHLRETY-AC/LSOARFAELTDYEACSSESMHABOYIRRE:129% periEE1IoE0RA%TeEo16o.Cn=TEETSTuTroSCnUsOsAwTRiisoEsnzNsoiInsaLLBT(EToLS35ICm.AETeVUSESs)DEDDm0AorIoAwBnEaBArCASSOiERo,RAnECGTUIDSEU".T 5s00os5w, ,fMoOrLMsGIunNsCDCoLnIsNGES TEFOERLURERKAOOSHACLLANROoTEnnaS8RAooDw.NDEILTZDuIeOLUIAAABLBOLVTEEERMOPRSRODAUANCNDTY.CDONNSOEOAETGTEINOENVRSEERSSUOELFTISSNAOGLEE.TOAFOIRWAOCE OF AT TonH ? 1935 STIoGHAW-aAKELDRDIVCLHIMCITOED PAPER COPIES FOR INTERNAL GSE ONLY a 000861 hare ecunmmnine14 rthe LSuocenPSranhgiereo3urrCusta omer, adFmpSlaeyleres and 418-018:PAGE C-40 Eis ors Material SafeOtuytOuDsUeasPatromavaes:S71h2/51e20e000t00 verse 10 Section 1 - Product and Company Information -- Parnoddu--ct--amber ScCoiem.ptsaoneya,rZmps,Couey S=hin rane SOaLcoMemErVCArLamOeNnC ACID LACTONE S2So5lm0Saoravvmcroe.rree3e0. US SoiTs wsn Emergency Phone: "razr 2050 estms Section 2- Composiioninormation on Ingredient -- DLMEVALONIC ACID LACTONE 76260 No. : FSammomeme conraos Section Hemwras leeenificston c-- oForrcarm-- aeomas-- oTnotoLxcy-- ,Rpree fe-- r Se econ-- 1 ----rma Section 4 -FiratAid Measuerets oFmovaElxopueosurweah4ruwinwater sve a3sare acis Cats aTihtailo.nrEaxmpoonsur0eesha17 Bes ve aca respeston raion GHISEgve gen. DIenrcmaasl1Excpoouucrsmn washskine wi soupay ncops auofvrate. EceaEsxep1oauriea. neste sheye wi posamour of wfe ratar k16 sen -Sec--tio--n 5. Fm ire Figm htinegm Myeaseures [-- as me Aoignain temp: I Flenmesiny: NA EtCnWgiauniraisnanyg.MeCdairason sane. cham pw,oraes oan. 0008262 418-018:PAGE C-41 FirsPtriogthetcitnigve Equipment Wearse containedbreathingapparatusandprotectiveclothingtoprever Cortactwihskinandeyes. `Section 6 - Accidental Release Measures WPeraocrerdeuspriersat)oro,f cPheermsiocraml!sParleecaugtgieo3ns.) rubber boc, and heavyrubberGoves. AbMsoerdotfnhosraCnoldeodafnvisenrgmUipc.ue andpaceincosedcontainersfor dsposa.Verdiate rea an complete. washspl 81 afer mena kup Section 7 - Handling and Storage HanUdsienrgExposure Aoi inhaaton,AVOidCOweihaeyecs stkin,andCot. Avo StorSauges.ble Keep 1gnycosec. EIORGRGOf epeALeSexposure. `Section 8- Exposure Controls / PPE `ESnafgeitnyesarihng oCaonncwtreoyelesbarn.Mechancalexvaust ures. PersRoenssp!irPtrootreyctive Equipment 'NHaInOdS.HMSHA-approved resprator. `ECroempatible chemecabresistant gives. `Chemeai sey gagges. WGeansehraclonHtyagmiiennaeteMseCssuorems.before reuse. Wash norougn __`--Se--cti_9o-n--Phy-- sical/Chemical Properties. #Aopesrance Color Fay vege afer handing FSoolrdmtedmassor ragments Molecular Weight 130.15AMY Property on MBEPEPPRaRannggee VFraepeozrinPgraPsoanitre VSeatpuorrstDeednsViatpyor Cone. SGBu/lDkeDneanariyty `Odor Threshold Value Na 2145c. 150C NNAA NNAA NNAA NA ATt emperoartPruesaruree. smmg `PSaiggema2Chemeal-Wass? `Sigmt a-Aldra ich Cai rporetion OOOO 000863 -_ 418-018:PAGE C-42 VR VT oed oo res n=NNARA rFrooeinCnoueicrt NNNAAa ee aerymamis. NmaAate Po" Ce ovncaer rtt sN-NAA TeT Scecttoionni1o0-SSwubbiilytyePeannddRe Reesscciivivyy e etereeer ree rp-- Sreoon oa. Cfrmeipreored Sr wry wre J [a r-- ivSeornede Section 1 Toxealogieal information [Sa fRries Ecrriactmoarstewe ME itasPorty tesaanapUeoT, sarsrenBsesT. SS Som sndymptmet Expocs a rps sto eop v Ses PAR, ECS mr ET Section 3. Disposal Considerations a J romethoo of Onesof Som=Praeprneinemctuhwansupmwretrsmobo Section14 Transport formation oorrope Shing am: ore snamsacremeat- iter Smi earGarren 6005564 -- 418-018:PAGE C43 Non-HazfaorrTrdanospuorst Thesubsarce Coruieres be RonnazaGous for anspor. urParoper ShippingName: Nore NHom azaforArl Tdranapsort. Non-hazaaardraorspuorst. `Section 15 - Regulatory Information U`nkeSd3S1iA3tLeissRtReedg:uANisotoryInformation Sec1t6i-Oothenr Information TWnomaibrnorr.e sohrnaatnonhsbdeseaveideoFbreacyorAer:bautrGoEeSsU okpYoumPrAn0Ch9naglOfnTocmecaar twriahlb(neeuAsbeodvoenplryOa0u.:.gSuecerSegvre35reof rviroac eodrppaaps cekrncgospisfoorar receldusebonyo.nsrcoaniolrsv1sri. Copyright 1999SarmaArh Co. LiarsGarsd make Sigma Creme wags? Page SigmmaAuedesCarptorsion 000565 --_ 418-018:PAGE C-44 ATTACHMENT 3 TEST ARTICLE, CONTROL ARTICLE AND VEHICLE PREPARATION PROCEDURE 000866 418-018:PAGE C-45 ATTACHMENT 3 Version: 418P.r0o1to8c(o1lA64U1G8.00108 Page 1015 TEST ARTICLE, CONTROL ARTICLE AND VEHICLE PREPARATION PROCEDURE Test Article: PFOS Control Articles: ~~ Cholesterol Vehicle: M0e.v5a%loTnwieceancid80 in R.O. Deionized Water for PFOS and CRh.oOl.esdteeiroonlized water for Mevalonic Acid A. Purpose: TofhedopsuargpeosfeoromfultahitsiopnrsocofedPuFrOeSi,s tmoepvraolvoindiecaacmied,thcohdolfeosrtetrhoelparnedpatrhaetion 0.5% Tween 80 vehicle for oral administration to rats on Primedica. Argus Research Laboratories, Inc. Study 418-018. 8. General Information: 1. All formulation containers will be labeled and color coded. Each label will snpuemcbiefry,thceonpcreonttorcaotlionnu,mbdeors,agteestleavretli,clpereipdaenrtaitfiiocantidoant,e,Aregxupisrabtaitocnhdate and storage conditions. 2a. _Su_spenDsaiiolnys of PFOSX_wil bWeeepkrelpyared: _For__daysofuse 2b. Formulations of the control articles will be prepared: X_ Once Daily (cholesterol) _X_ Twice daily (Mevalonic acid) 2c. _Th_e 0.p5a%iTyween 8X0_VehicWleeekwillybe prep_arFedo:r__daysofuse 3. Suspensions will be prepared at a final dosage volume of mL/kg. 4. SXa_fety:Gloves, lab coat. goggles or safety glasses and faceshield X_C DHuasltf--MFiascte RReessppiirraattoorr FullFace Respirator/Positive Pressure Hood Tyvek SuivApron 5. Dosage formulations of the test article and control articles adjusted for Free baYsees and % Purity. X__ No (Calculations based on 100%) __ FreeBase __ Pury 000867 418-018:PAGE C46 ATTACHMENT 3 Version: 418P-r0o1to8c(o1l6418AUG0010)8 Page 2015 TEST ARTICLE, CONTROL ARTICLE AND VEHICLE PREPARATION PROCEDURE 6. Sampling requirements: Cited in protocol. 7. Storage: Cited in protocol. NOTE: hTihgehtdeostsaargteictloe tshuespleonwsdioosnasgwei.ll bOencperetphaerefidnaalsvoalsuemrieasl dairleutaicohnifervoemd,thsteir bars are to be added to the containers; mixing shouldoccur during preparation, aliquotting, sampling and/or dosage administration. C. Preparation of the 0.5% Tween 80 Vehicle: 1. Add 2985 mL of R.O. deionized water to an appropriately labeled container. Heat the water to 50C = 5C, then add 15 mL of Tweens 80 and mix until uniform. D. Test Article Suspension Preparation: NOTE: Prior to preparation of the 0.40 mg/mL suspension, precalibrate an appropriately sized container to the desired volume with R.O. deionized water. 1. Tteosptraertpiaclree(tSheee0T.4E0SmTgA/RmTLICsuLsEpePnRsiEoPnA,RwAeiTgIhOtNheCrAeLqCuiUrLeAdTaImOoNuSnt) oifnto an appropriately sized, labeled, pre-calibrated container. QS ad to the r=e5quCirfeodraampopruonxtimwaitthel0y.350%mTiwneuteenso8r0unatnidthheeTaAt/hSedmiisxstoulvreest.o 80C 2. bOanthc,eatdhde taesmtaagrnteictliechsatsirdbiasrsotlovetdh,e croenmtoaivneert,heplsaucsepeonnsaiomnafgrnoemtitchestiwrater Spluarteetahnedremiisxauvntiislibtlheevsorutsepxe.ntshiiosnwiellquaiclhiireavteesthteo dreosoimretdemempuelrsaitounr.e). B(eB.e sduorseagtheatgrtohuepss,usapleiqnusoitotinngi,s dmioxseadgeprainord/toorasnadmpdluirnign.g preparation of other 3. To prepare the 0.32 mg/mL suspension, remove the required amount of 0C.A4L0CmUgL/AmTLIOsNusSp)enasnidonad(dSeitetTo EaSnTapApRroTpIrCiaLtEelPy RsiEzPeAd RgAraTdIuOatNed cylinder. AQRSTaIdCLtoEtPheREfiPnaAlRrAeqTuIiOreNd CvoAlLuCmUeLAwiTtIhO0N.S5)%.TwSetoepnper8t0he(SgereadTuEatSeTd cylinder and invert several times to ensure proper mixing. Transfer the suspension to an appropriately sized, labeled container. Add a magnetic 000868 418-018:PAGE C-47 ATTACHMENT 3 Version: $18:0P1r8(o1t6ocol 416AU.G 00108) Page 3015 TEST ARTICLE, CONTROL ARTICLE AND VEHICLE PREPARATION PROCEDURE `sainrdbdaurritongthperecpoanrtaatiinoenr,ofploatcheerondoasamgaegngertoiucpss,tiralpilqautoettainngd,mdioxspraigoer tanod/or sampling 4. 0T.o32prmegpa/rmeLtshues0p.e2n4simogn/m(SLeseuTsEpeSnTsiAoRnTIrCeLmEovPeRtEhePAreRqAuiTrIeOdNamount of QCASLaCdULtoAtThIeOfNinSa)l raenqduiaredddvitotlouamne waiptphro0p.ri5a%teTlwyeseizned 8gr0a(dSueaeteTdEcSylTinder. cAyRlTinIdCerLEanPdRiEnPveArtRsAeTvIerOaNl tCiAmLeCsUtLoAeTnIsOuNreS)p.ropSetrompipxeirngt.heTgrraandsfueartetdhe ssiurspbeanrstiootnhetocaonntaaipnperro,prpilaatceelyosnizaedm,aglnaebetliecdsctointpalianteera.ndAdmdixaprmiaogrnteotic and during sampling. preparation of other dosage groups, aliquotting, dosage and/or 5. T0.o24prmegpa/rmeLthseus0p.e2n0simogn/m(SLeseuTspEeSnTsiAonR.TIrCeLmoEvPeRtEhePAreRqAuTirIeOdNamount of QCASLaCdULoAtThIeOfNinSa)l raenqduiaredddvitotloumane waiptphro0p.ri5a%teTlwyeseizned 8gr0a(dSueaeteTdEcSylTinder. cAyRlTinIdCerLEanPdRiEnPveArtRsAeTvIerOaNl tCiAmLeCsUtLoAeTnIsOuNreS)p.ropSetrompipxeinrgt.heTgrraandsfueartetdhe sstuispbeanrstiootnhetocaonntaaipnperro,prpilaatceelyosnizaedm,aglnabeetliecdsctoirntpalianteer.andAdmdixapmraiogrnteotic and during sampling preparation of other dosage groups, aliquotting, dosage and/or 6. 0T.o2p0rempga/rmeLtsheus0p.e1n6simogn/m(SLeseuTspEeSnTsiAonR.TIrCeLmoEvPeRtEhePAreRqAuiTrIedONamount of QCASLaCdULtoAtThIeOfNinSa)l raenqduiaredddvitotlouamne waiptphro0p.ri5a%teTlwyeseizned g8r0a(dSueaeteTdEcSylTinder. cAyRlTinIdCeLrEanPdRiEnPveArtRsAeTvIerOaNl tCiAmLeCsUtLoAeTnIsOuNreS)p.ropSetrompipxeirngt.heTgrarnasdfueartetdhe sstuirspbeanrstiootnhteocaonntaaipnperro,prpilaatceelyosnizaedm.aglnabeetliecdsctiorntpalianteera.ndAdmdixapmriaogrnteotic and during sampling preparation of other dosage groups, aliquolting, dosage and/or 7. 0T.o16prmegpa/rmeLtsheus0p.e0n8simogn/m(SLeseuTspEeSnTsiAonR.TIrCeLmoEvPeRtEhePAreRqAuiTrIedONamount of QCASLaCdULtoAtThIeOfNinSa)l raenqduiaredddvitotlouamne waiptphro0p.ri5a%teTlwyeseizned g8r0a(dSueaeteTdEcSylTinder. ARTICLE PREPARATION CALCULATIONS). Stopper the graduated000869 418-018:PAGE C48 ATTACHMENT 3 Version: 418.P0r1ot6o(c1o6lA4U18G.0001)8 Page 4015 TEST ARTICLE, CONTROL ARTICLE AND VEHICLE PREPARATION PROCEDURE cylinder and invert several times to ensure proper mixing. Transfer the suspension to an appropriately sized, labeled container. Add a magnetic stir bar to the container, place on a magnetic stir plate and mixprior to and during aliquotting, dosage and/or sampiing. 8. Toprepars the 0 mgimL suspension, add the required amountofthe appropriate vehicle (R.. deionized water or 0.5% Tween 80) to an aPpRprEoPpAriRaAteTlIyOsNizeCdA,LlCaUbLelAeTdIcOoNnSt)ai.neArd(dSeaemTaEgnSeTfiAcRstTiIrCbLaEr to the container, place on a magnetic stir plate and mixpriorto and during aliquotting, dosage and/or sampling. E. Preparation of Mevalonic Acid Solution: 1. Wlaebieglehdtchoenrteaqiunierred(aSemeouTnEtSoTf AmeRvTaIlCoLnEic/VaEciHdICinLtoEaPnRaEpPprAoRprAiTaIteOlNy CALCULATIONS). 2. Astdirdbaarptprooxthiemactoenltyai8ne0r%, poflaRc.eO.ondeaiomnaigzneedtiwcatsetritpolattheeacnodntaagiinteart.e Aundtidl athe control article has dissolved completely. 3. TthreanfsifnaelrdseosliurtieodnvtoolaunmeapwpirtohpRr.iOa.teldyeisoinziezdegdrwaadtuearte(dSceyeliTnEdeSrTand QS. to ARTICLE/VEHICLE PREPARATION CALCULATIONS). 4. RCoevteurmtthheegsroalduutiaotnedtoctyhlienodreirgiwniatlh caongtlaaisnsers.toAppdedraanmdagmniextibcy sitnivrebrasriotno. the container, place on a magnetic sir 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). 000870 418-018:PAGE C-49 Arachis Socwisersonrs Version: 418:01A8U(G0106) TEST ARTICLE, CONTROL ARTICLE AND VEHICLE PREPARATION PROCEDURE 2. Add a small amount of 0.5% Tween 80 to the container and wet the cholesterol by using a glass rod. QS ad with the 0.5% Tween 80 to the. final required volume (see TEST ARTICLE/VEHICLE PREPARATION CALCULATIONS). 3. Add a magnetic stir bar to the vessel, place on a magnetic stir plate and `mix until uniform prior to and during dosage administration. Written by: Approveaby, Date: 2100 ante: (ToeKZ wi Clarification: No __(Yes(See attached clarification form.) 000871 418-018:PAGE C-50 ATTACHMENT 4 TISSUE COLLECTION AND PROCESSING 000872 -- roost 418-018:PAGEC-51 ETTissue Collectio T_T n and Processing Iso TW aCC i ll [Tver | Gluiersigehve RT[NM [Baiiven Tew TW eros | PosubieEM___| Toros | z__ 2 [D" BlaooEdiGesasoSnmBiadnasm --mm [seam Teo 80 Toros P z- r b=o [mediniobe Teo To eros | a mT [DaySacawonbams ___-------- 7 [ik Thoowsem TT -- Teso `Blood [ipl Teo [8sem Te 20 Tawbwes | Toulcholeserol| TPWL I 7TMTPeFvOaSl.oncaad | cone | | meganion: Ts%0 IE 1 PFOS EET [A Fe T[weeTrej e me m [DBloowoSdPospurmPeomopluedpssex--fiu_er__--|1--o--psma [eso [ese Tego TPWL Tm [ : m= aoae Tiver | Posledisexttiner [ative Too-- = TAM |Mevlomesd | "Toros | TPros | 000873 418-018:PAGE C-52 r~PRDPRIMEDMEDICA ArW s ReseaL ch h LaboI rse toie, oc. CE ------ EC `ONE GENERATION REPRODUCTION STUDY CoE ALONIC OF PFOS - MEVALONIC ACID/ SPONSORS STUDY NUMBER, 729335 Amendment 1-13 Sep200 1. fThearsate contin ore Meloni Storage (page 4ofthe protocol): Acid shuld bs ren er tan oom -- Tse vase gus Syn PO Toe comet sates Dave Even shelling: DDecCEveEsraniyos Elal nsEeasrlo 000874 Any revisions made to this finalized amendment must be made by subsequent `amendment. Reason for Change: `This change corrects the protocol. 418-018:PAGEC-53 Pro"cAomlen1d8mee.en0et182| ope badacsigen fiomal Jou % Dodson ee LL `Associate DireofcRetseaorcrh Altos Director of R =L3:55P 00 Study Director htc Mlle 50 MiswaafrebtlsYoo CahnadiaUrpsCe.ersCLoeonbm.om,IinVsr.teMien.uDi.onal Animal Care Date DSteuadynMnJoa.niLtuoerbRer, M.S. Date Spl Jenks ofr J`AolhlnmBautteenShtoufdfy,MPohn.Di.t,orDABT. CTH Date Aamneynrdemveinsito.ns made to this finalized amendment must be made by subsequent 000875 r, J MEDICA 418-018:PAGE C-54 Ars Research Laberaicrie. Inc. 905TeSlheepehhoHynoeDr:rsi2hv1aem3,,)BuP4iA4l3d1i89n70g14A04 "Teefax: (219)43.8587 PROTOCOL 418-018 ONECGHEONLEERSATTEIROONL RCEHPARLOLDEUNCGTEIOANNDSTNUODEYLOIFNVPEFSOTSI-GMAETIVOANLOINNIRCATASCID! SPONSOR'S STUDY NUMBER: T-6295.25 Amendment 2 - 22 November 2000 1. AllemateStudyMonitor (page 1 of the protocol): "The telephone number for John Butenhoff. Ph.D.. DAB, CIH is (651) 733-1962, rather than (651) 737-1962. Reason for Change: "This change corrects the protocol. 2. Sample Analvsis and Shipping Instructions (page 14 of the protocol): "The following paragraphs will replace the paragraph which sates that serum and liver samples will be analyzed for LDL. HDL. total cholesterol and triglycerides: "The remaining liver samples will be analyzed for LDL. HDL. total cholesterol and triglycerides. Serum samples collected from all dams and pups will be analyzed for total ctrhioglleyscteerriodle.s.gluTchoesef.irtsottpalriaornidtyfrweiellTsb,eTaanaalnydsiTsSfHorlteovtealls,chLoDleLs.teHroDlLanadndglucose. The Second prioritywillbe analysis for total and free Ts. T, and TSH levels. The third prioriy will be analysis for LDL. HDL and triglycerides. 000876 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: Dr. Saroj R. Das Ani Lyics, Inc. 200Gerard Street, Suite 2000 TGealitehpehrosnbeu:rg, M(a3r0y1l)a9n2d1-200186787 Telefax: (301) 977-0433 ProtAomcoeln4d1m8e.0n128 Page? ReafosrChoangne: t`TihsissuechsaanmpgleewsaasndmatdoepraitortihteizreeqtuheesutsoefotfhseaSmppolnessofrorinaonradlyesretso.include additional 3. Scheduled Sacrifice - FI Generation Pups (page 20 ofthe protocol): p(eErffleictteirv,esDaamtpel:es3fNroovmemmableera2n0d0f0e]maFloerpRueppsliccoamtebi1n,ebdl,ooradtshearmptlhaenspwoiollebde ppeorolseexd. ASpapmrpolxeismwaitlellbye1amliLquootfebdlaosodfowlillolwsb.ertartahnesrfetrhraendaisntdoesscerriubmedseipnapraatroargrtaupbhes3; any srepmuaniinninagcbenltoroidfuwgielanbde tthreanrsefseurlrteidnginsteorEuDmTAwi-lclobaetedidvtiudbeeds.intTohtewsoaamlpilqeuostsw.illThbee: afilrisqtuaolti(quaoptpr(oaxpipmraotxeilmyat3e0l0yL200ofuLs)erwuiml)l bwielulsbeedufsoerdPfFoOrSanaanlaylsyissiso.f tTohtael scehocloensdterol, aglcuccoorsdei,ngtottoaltahendprfiroereitTieTs d,esacnrdibTeSdHinlteveemls1a.nadboLvDe.L,AHnDyLreasnuldtirnigglpylcaesrmiacewillevleblse. ctrhaenmsifsetrrrieedsifnitrsoto(naeccaolriqduiontg.1Retshuelptriinogristeiersudmeswiclrlibbeedpirnioirtietmiz2e,daabsofvoel)loawnsd: tchleinnical fPrFoOzeSn s(asm-p7l0es.C) Aulnltislasmhpilpemsenwtillfobeaniamlmyesdisiately frozenondry ice and maintained ReaforsChoangne: `This change samples for awnaalsysmeas.de at the request of the Sponsor in orderto prioritize the use of 4. Scheduled Sacrifice - FI Generation Pups (page 20 of the protocol): ((tEfwfoecltititveersDapteer:sam17plNeowvietmhbinerea2c0h00d]osaFgoer gRreopulpi)c.ateSa2m,pblleosodwislalmbpeleasliwqiuloltbeedpaosoled bfeoltlroawnss,ferrartehderitnhtoanEaDsTAde-sccoraitbeedd iwnbpeasr.agTrhaephr3e.maAipnpirnogxbilmoaotdelwyil0l.b3emtLroanfsfebrlroeoddiwnitlol sseerruumm wsielplarbaetodrivtiubdeesd. inTthoetwsoamaplliequsotwsi.ll Rbeesuslptuinnginpalacsemntarwiiflulgebeantdratnhseferrerseudltiinntgo one aliquot. The serum wil be prioritized as follows: clinical chemistries first (according 000877 Any revisions to this finalized amendment must be made by subsequent amendment. 418-018:PAGE C-56 Praomseend41m8e.n0t1s8 Poses 10 the priorities 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. `Reason for Change: "sTahmispclheasnfgoreawnaalsymsaesd.ea therequestofthe Sponsor inordertoprioritizetheuseof 5. Scheduled Sacrifice - FI Generation Pups (page21of the protocol): [Effective Date: 3 November 2000) Thyroids will be excised from each pup, pooled p(obsysisbelxepferulietteerv).alTuhaytirooni.ds will be retained in neutral buffered 10% formalin for ReafosrChoangne: `Thischange was madeatthe requestofthe Sponsor. Hop nese paid LIQ 22-00 `Assocgioabte.DDieraercltoovreo,fPRheDse.arDcAhBT Date ARsityebilaotned DG.irectYoofrko/fPn]B.lseaDABT Date Study Director hewnthd23s Mana] ttl wlerte0 CahnadhirUapCse.ersCLoeonbm,om,IinVstt.eiMte.utDi.onal Animal Care Date DSetuadnynaMoJn.iLtuoerbker, M.S. Date Pl 2 Billonbocts 1/3 roc JAolhtnemBautteenShtoufdfy, MPohn.iD.t.orDABT.CIH Date 000878 Any revisions to this finalized amendment must be made by subsequent amendment. PRIMEDICA 418-018:PAGE C-57 sp T toee ns nets rw PROTOCOL 418-018 -- SPONSm ORS STUe DYN1UaMBm EyR:2T0-125525 CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS A 1. ControlArticles (page 3ofthe protocol): -- Tinto Rea forsCho angne: pega 2. ControlArticles (page 3ofthe protocol): For rots mevalonic acid, lot number 080K2618, expiration date September 2004, was used `RefoarCshaongne: JNa Additional mevalonic acid was required for the preparationofthe mevalonic acid 3. SampleAnalysisandShippingInstructi(poangse 14ofthe protocol): Si EPlasma mevalonic acid RI Sa levels will be measured for the following 5 dosage , groups: er PFOS (Group 11), 1.6 mg/kg PFOS (Group 12) and 2 mg/kg PFOS (Group 13), rather than all dosage groups. Mevalonic acid levels may be measured in the lower PFOS dosage groups after evaluationofthe resultsofthe above analyses. Remaining samples will be retained at Primedica Worcester Laboratories or the Testing Facility 000879 a rsens ete vo Rana aed ey ebASE 418-018:PAGE C-58 ReafosrChoangne: Ponoiln1e8r.ta01y8 "Tis changs was made a th request ofthe Sponsor. 4. SampleAnalvsisandShippingInsrutions(page 1ofAmendment2othe protocl): Total and free Ts, Te and TSH levels willbemeasuredforthe following dosage (grGoruopsu:p 1V2e)haicnld2e Cmognt/rkogl P(FGrOoSup(G1r),ou1p.21m3)g,r/aktghePrFtOhSan(Garloduopsa11g)e, g1r.o6umpsg,/kTgotPaFlOaSn.d free Ti, Ta and TSH levels may be measured in the lower PFOS dosage groups after evaluationofthe resultsofthe above analyses. ReaforsChoangne: `This change was made at the requestofthe Sponsor. Dotlrn Midna Dearlove, Ph.D. DABT Date dG. Yorfk, d. DABT Date te Director of Research te Director of Rsearch and `Study Director hntldendd Sia C. Lebo, V.MD. 17sDaeMaDeasnas. Luace, AMSt. l sDtuoe / and Use Commits Chairperson, Institutional Animal Care `Study Monitor Po) Ezy "a or John Butenhoff. Ph.D., DABT, CIH Date Altemate Study Monitor 000880 aamyenrdemveisnito,ns made to ths inalized amendment must be made by subsequent rPRIMEDICA gis RmhSrre 418-018:PAGE C-59 Telephone: (215) 443-8710 rrotocoL aizars `ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/ CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS `SPONSOR'S STUDY NUMBER: T-6295.25 `Amendmen4t - 18 April 2001 I. ELGenerPauptsi(poagne 10oftheprotocol): [Effective Date: 21 August 2000] Day 1oflactation (postpartum) is defined as the dayofbirth and is also the first day on which allofthe pupsin alitterare weighed. `The pups will not be individually weighed; pooled litter weights will be recorded. TRhiechafaonrsCghwoansgnem:de be consist ih Tos, Aly nd Mesemers- F1 Generation, Body Weights. 2. Scheduled Sacrifice - FI Generation Pups (page 20, 21, page | of ATTACHMENT 4 and item 5 of Amendment 2 to the protocol): Histopathology will be performed on the heart and thyroidofone male and one: female F1 generation pup from eachoffour litters from the Vehicle Control group (Group 1) and 2 mg/kg PFOS group (Group 13). Ifanydifference is found, histopathology will be performed on the heart and thyroidofone male and one female FI generation pup from eachoffour litters, 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. New Britain, Pennsylvania 18901 Telephone: (215) 345-7070 Telefax: (215) 345-4326 000881 Any revisions made to this finalized amendment must be made by subsequent amendment. 418-018:PAGE C-60 Rea forsCho angne: `This change was made at the requestofthe Sponsor. Prnet ia=sr:n MeO Moi en, AoE D|Dieraercltoorveo,fPRLeDse.aDrABT Date At1R2aodymcSiaouheddGDD.iicYoeerrknf,e.K0adJeroan Date frmndon same 2d Ue Commits eresaH. Wood DVM. Date Chairperson, Institutional Animal Care uneadoltdic amb! DeanJn.Lat r, M.S. Date `Study Monitor lon. Geilantufy Apal TF, 7 eras Sy John Butenhoff, Motor Ph.D., DABT, CIH Date 000852 Benkyiresvisiions made fo thi Gnalized amendment ust be nade by subssquent 418-018:PAGE C-61 905 Sheehy Drive, Bidg. A Toirgerems}(01150454438710 Tefax (215) 43-8587 ~~ ARGUS RESEARCH Charles River Laboratories Discovery and Development Services PROTOCOL 418-018 ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/ `CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION INRATS SPONSOR'S STUDY NUMBER: T-6295.25 - 0 Amendment 5 - 4 February 2002 1. Shipping Instructions (page 6ofthe protocol): (Effective Date: 29 January 2002] Homogeneity and concentration samples shipped to Dave Ehresman at reshipped (frozen on dry ice) 3M to: Corporate `Toxicology for analysis will be 3058 Research Dive Emily R. Decker (Principal Investigator) Exygen Research State College, Pennsylvania 16801 Telephone: Telefax: (814) 272-1039 (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 inspections and audit the respective Research will conduct criticalphase results and reports according to the Standard aOupdeirtatreipnogrPtsrowcielldubreessoufbmtihtattedfacbiylittyh.atfSacuiclhitcyrtitoictahlepShtausdeyinDsipreeccttoiro,n RreapyormtosnadndG. York. The dateofthe inspections and report submissions will be incorporated into a report QAU statement generated for protocol 418-018. by Exygen Research for inclusion in the final 000883 Any revisions to this finalized amendment must be made by subsequent amendment. Reason for Change: `This change was made at the requestofthe Sponsor. 418-018:PAGE C-62 Peiat 1n T00s12 rge . Dearlove, PhD, DABT Associate DirectorofResearch . Date" YW i VA 7 R & ond G.p, or)Ph.D, DABT Date Associate Ditectopdf Research and Study Director Meera sstontd epi Theresa H. Woodard, D.V.M. Date Chairperson, Institutional Animal Care and Use Committee asec]dietsoso Deanna J. Lueber, M.S. Study Monitor Date PUT Rdtm John Butenhoff, Ph.D., DABT, CIH Date Alternate Study Monitor 000884 Any revisions to this finalized amendment must be made by subsequent amendment. 418-018:PAGE C-63 905ShctyDove, Big A TLTeeeifpharocnes(:2t12)51)514)04483.3188576710 A R G U S =-- RESEARCH Charles River Laboratories Disancd DeovelvopmeentSrerviyces: - 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 r-- e -------- ee --Ame-- ndment-- 6 - 9Oct-- ober20-- 02 ------ 1. Shipping Instructions (page 6ofthe protocol and Amendment 5, item 1): [Effective Date: 14February 2002] The samples shippedto Exygen Research willbeanalyzed using the LC/MS/MS conditions found in the attached pages. Reason for Change: `This change was made attherequest ofExygen Research to clarify the analytical `methodology to be used for the analysis of the samples. 2. Shipping Instructions (page 6of the protocol and Amendment 5, item 1): em(iEflfye.cdtievcekDeart@ee:xy1g6eSne.pctoemm.ber 2002) The e-mail address for Emily R. Decker is 000885 Any revisions tothisfinalized amendment must be made by subsequent amendment. Reason for Change: 418-018:PAGE C-64 Popcrae1v8a.a0s18 `This change was made because the -mail address was changed. il # 4 E. Dearlove, Ph.D. DABT jssociateDirectorof Research ya J Te Attell SPAN p90c702. Date Raymflg G. York, fh.D., DABT Date octate Director0{ Resfarch and Study Director ReneC Lp 0S Mio meliphcttlls Dena C. Lebo, V.M.D. `Member, Institutional Animal Care and Use Committee Date DeannJa. Lucbket, M.S. Study Monitor olufom, Date FriB t:etty 10)1for. J`AolhtnerBnautteenShtoufdfy, MPohn.iD.t,orDABT,CIH Date 000886 Any revisions to this finalized amendment must be made by subsequent amendment. E n RESEARCH over ios. 418-018:PAGE C-65 LC/MS/MS System and Operating Conditions (Turbolonspray) Mass Spec: PE SCIEX API 3000 Biomolecular Mass Analyzer Interface: SHaCrIvEaXrdTiunrfbuoslioonn pSpurmapy Liquid Introduction Interface Computer: Dell UltraScan P1110 Software: PWEiScnidexoAwNnaTslyst 11 HPLC: HewlenHPPacQkuaartdP(uHPm)pSeries 1100 HHPP AVuatcousuammpDleegrasser HP Column Oven CHoPlLuCmnCoTleummpn.Ge3n5esiCs Cs (Tones Chromatography), 2.1 mm x 50 mm, 4 MInojbeicltieonPhVaosle.:(A1)0:s2LmM Ammonium Acetate in ASTM type | water MFolboiwleRaPthea:se (B0).:3 mMUetmhiann.ol Ti0me 0A 4B 00 00 100 10 m7s oe6 4 4 iItnsmtaruymebnet mm x 30 npeecfeosrsmaarnycet.o adCjuosltumthnesHwPitLhCdigfrfaedrieenntt diinmeonrsdieornsto (oep.tgi,mi2z1e mm) and columns from different manufacturers (Keystone oBebttaasiinled.Ci etc) can be used, provided equivalent chromatography is Tons monitored: APnFaOlvSe Mode Transition Monitored ReAtpperonTxiitmmaeit(eominn) ncguive | 499599 440 000887 REE Boer, usa i enci om RESEARCH ProPcreovReenseRarecshs.. On the a day-to-day basis, the batch of mobile phase, erce.tention times may vary slightly depending on Example Tune File Parameters Tihnestfroullmoewntiotnginvsatlruuemsenatr.e provided as Also, these vaanlueexsammpalyeb.ecAhctaunagledvalfureosm may time vary from to time in order to optimize for greatest sensitivity. `OTnhicse ttuhnee ifnisletriusmtehnetn ius steudneddu,rtihneg orpotutiimniezeadnaplaysriasm.etTerhseatrucnisnagvepdroacseadu"rteunmeafyileb".e repeated as necessary to ensure optimal sensitivity. `Tune File Parameters ICSo-nltorsporlasy 42S0et00 DPF-PD-eFcolcusutseirnignPgotPeontteinatlial 25310.00 EP-Entrance Potential CE-Collision Energy 100 10 CXP-CollisDiFo-DneCfellelctEoxrit Potential 30500 CEM:-Channel Electron Multiplier 28000 Gas Flows Nebulizer Gas. Set 12 Curtain Gas Collision Gas 13 4 TIS Temperanure 350C Calibration Procedures a sItnjaencdtartdhe(psraempearvedoliunmMee(ObHe)tweinetno 1th0e1L0C2/0MSu/LM)So.f each calibration b. sUtsaendlainredarc,urI/vxesweairgehtgeednesrtaatneddardfocrurevaecsh fsoertqubayntilfiinceaatrionr.egrLeisnseioanr fuaslilnigngthoeutaspipdreopri3a0te%,sobfatsweadreonsysittsemc.alcuAlnatyedcacloinbcreanttiroantisotna,ndmaradys obfeceaxlcilbruadteidonfrstoamndthaerdcsaltihbartamtiaoyn cbuerveex.clHuodwedevmeurs,ttnhoetteoxtacleendum2b0e%r of the total number of standards injected. . The comelation coefficient (1) for calibration curves generated must be 20.9925 (220.985). If calibration rest I outside these 000858 Na E vgnD cam E en hs asosracecar `loipmeirtast,itonh,enanadpptrhoeprrielaetveasnttespestosfhosualmdplbeestmakuesnt tboe ardejaunsatlyiznesdt.rument Sample Analysis Inject the same volume used for the calibration standards (between 10 to 20 ul) ofeach sample, fortification, control, etc. into the LC/MS/MS. Each sample must be analyzed in duplicate. a Standards comesponding to at least six concentrations must be included in an analytical set. PE ts nyof re b. Inject an entire set of standards (six) at the beginning of the run and injections must be bracketed by standard injections. prs c. The concentration of each sample, determined from the standard curve fortification, based on the control, peak area etc. of is the analyte in all standards injected during a set. The standard responses must bracket responses of the residue found in the sample set. I necessary, dilute the samples and re-analyze to give a response within 000859 Xe= Kno E TEI APPENDIX D DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING "PROCEDURES OF THE TESTING FACILITY 000&90 418-018:PAGE H-72 poE I-- 1E5E RSi EEBBeHeSrWaatoy E EEET EcRotTee,BTOS TEE SiE REE ooo FEE SPECIES: Bl RAT sos ue BHDATE REPORTED: 02/13/2001 Bronr Sows ACCESSION: B 0035745 TT *TET J-- J m172 wuo/RpL 4n8 y- 9,6 EEhe mazovomoNE ii [Ei E n3o-8l, To iy 50 - 100 owsoe aosrto wveernoa. w2os?0-120a rizT3, FREE amo0.00 iy PG/ML 208 = 28 Laboratory DiregotoFg: oPrIgP! . Den, TD. [Ep-- HY,Ty, ooese1 418-018: PAGE D-2 DoGsraogwe | tdenificaion TPoFmOgSh+g || 2218SSEEPPOO00 Cholesterol | 0o7c0CrTO0|| 02I1N0OCVT0O0O| 7 |ZmgkgPFOS| 1072NSEoPVOeOo| +Cholesterol | 2181S0EcPT000| 120CT0| NDuomsabgeer Dayorsiudy | AEdamrinyiosrtLerueed DDSS1S5 22 DpSs2u4 22 DG2D0G.8DL2 22 DG2D1s.DL2 2 DSaS41.5DG0 DS45.0G0 210cTo0| Gs.11 ooi1NNoovvooo|o bGoa6t 172NNOVO00V00 |DS50D.LD7G1s4.5, T115I72-.1S1113E58855 1s09n84 1057120,91803973 115Tk0,98151585 11150869--119019549985 1099100,99140992, 101-099190819859, 1099171,59110998 11591-11599 1isgs Tbheesecdatevhuieattsiiomenes ddeivdinaottedadwvaesrssemlayllaaffnedctththeedeovuitactoimoenoocrciunrtreerdporentatnioonomfotrheethsatnudfyour days of the approximately 60 0 80 day dosage period for any rat. 3. Aretcloeradsetdofnoeretvheenftoolfldoowisnaggeratasd.ministration and/or postdosage observation was not DGorsoaugpe [II VehicleConrol |"28SEPO0_| [21MevalonicAcidConral_|_28SEPO0 | S15 DS15 |Tisoe-11512 | 11513-11524| Tbehceasuesdeesvuifaftiicoinesntdiddatnaotweardevearvsaeillyabalfefetcotetvhaeluoauttectohmies poarrianmteetreprr.etation of the study 4. Dosage administration was not performed for the following ras. [Co] sense | tims|owe |2 [ie| Dosage Dosage Not Day or [7]Zmg/kgPFOS +Cholesterol | Cholesterol | 8SEP00| DS15 | 11596| C00 1 imgigPFOS | pros |010CTO0| DSI8| i623 | bTehceasuesedeivtiwataisonassidnigdlneootcacduvrerresnecleyfaofrfeccatcthheraot.utcome o interpretation of the study 5. MOenva1lOocntiocbeAcri2d0,0w0,erDeSad1m8i,ntihsetefroeldlotwhienignrcaotrsreicntGvrooluupme3,o1f.t6esmtga/rktigclPe.FOS + 000892 418-018: PAGE D-3 [oe| | | ) nL) [mse Te as [CossThTa [oseTe 15 Cosa TT 5 Tbehceasuesdeeovnialtyifoonsurdriadtsnowteraedvaefrfseecltyedafafnecdttthheeaodudittcioomnaelovroilnutemreprweatastisomnaolflt(h0e.1sttoudy 03mL). 6. POnFO1S0+OcMteovbaelro2n0i0c0A,cDidS,4w3eorreDadGmi0n,israttesre1d09t4he30t.h3r2oumggh/1m0L95c6onicnenGtrroautipo4n,o2fmPgF/OkSg, raatdmhienritshtaenrtehdeth0e.40.00m8 gmg//mmaLLt c5onmcLe/nktgr.atiAopnporfoPxiFmOaStelaty250mmLikngu.teTshleasteerdetvhieartaitosnsw.ere cdoirdrneoctt daodvseargseelwyasafafedcmtintihsetoeurtecdotmoealorofitntheerprraettsa.tion ofthe study because the total 7. Ogrno2u0pN(oGvroeumpbe7)rr2e0c0e0i,veDdL13.9,mraLtof115te8s9taritnitchleer2amtghe/rktghPanFO1S.5 +mLC.holTehsitserdoelvidaotsiaonge doifdexntortaavdovlerusmeelyreacfcfiecvtedthweaosustmcaolmleoanrdinttheirspwraetsatasiionnoglfetheevesnttudybecause the amount 8. Ctlhienfiocallloowbisnegrvraattsi.ons, body weights and dosage administration were not recorded for [ED1oTs2age] T6mgsPeROnS Treks PROS | oNOuVED|ompbrssesass | GDG1915 o7x0v eo G62112 GG192 GGo9 DD6G1120 TROVE DDoG1120 GDG1111 GDG1101 G10 rT1a03n9 e| 1111008212 1t1e0s8?3 1166ss 1nie6ssto n1es2s HTeessst l1eesssT Hnees Liso b`Tehceasuesdeesvuifaftiicoinesntdiddatnaowteardevearvsaeillyabalfefetcottevhaelouuattecothmeeseorpairnatmeertperrest.ationofthe study 000893 418-018: PAGE D4 9. Data for the following rats were not collected due to a computer filing error. ee I TT |T |VehicleConwol |"20SEP00| DS7 |TIs0i-1512| C5rm ww [5 ICholestrolControl |200CT00| DG10.7 |10965.10966| `These deviations did not adversely affect the outcome or interpretation of the study because sufficient data were available for evaluation of this parameter. 10. C CETEesmEoer peoeS lte]o=re Lo The feed left and/or feed fed values were not recorded for the following rats. `These deviations did not adversely affect because sufficient data were available to the outcome evaluate this or interpretation parameter. of the study 11. Maternal behavior was not recorded for the following rats. CE ee [or gre [1[Vehicle Comrol___|"04NOVO0|__DLI sh iE [2 MievalonicAcidConuol |04NOVO0| DL1 LC 1.6 mg/kg PFOS + Mevalonic| 03 NOV00 DLT Loge] || 11090239.11s0924| 10977 These deviations did not adversely affect the outcome or interpretationofthe study because sufficient data were available to evaluate this parameter. 000894 418-018: PAGED-5 12. The terminal blood collection data (time collected, volume collected, performed by and date) was not recorded.forthe following rats. ([ [wErTe m r wwven |TowEe neswT[o]e [6 TTmy/kgPFOS+Cholesterol| 03NOVO0| DG21 | 10980 | [81 o4mgrgPFOS |"20NOVOO| DLS | medi | C0 TmghgPFOS |22NOVOO| DLS | ues | SR`These deviations did not adversely affect the outcome or interpretationofthe study 13. On31 PFOS October 2000, + Mevalonic A DG cid 21, the dosage maternal liver weight group (Group 3) was for 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 14. [BE] The pooled litter ee weights were not | or recorded for the [og [oe| pupsofthe following dams. [CFT odmgigPFOS |mNOVOO| DLS | tise | Sp, `These deviations did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. 15. On 19 November 2000, DL 3, the necropsy observations for rat 11554 in the `This deviation did not adversely affect the outcome or interpretation of the study `because sufficient data were available to evaluate this parameter. 000895 418-018: PAGE D-6 16. Thewei oftg heph oolt ed liversamples wasnotrecorfodrethdemale pupsofthe following dams. Ca[see [EBooas| toon |owe | wots |sumer| [1| VehicleConwol |25NOVOD| DLs | Tse | Veron acd "These deviations did not adversely affect the outcome or interpretationofthe study because sufficient data were available to evaluate this parameter. All deviations are documented in the raw data. (coped Jr = Ray G.York,Ph.D., DABT Associate Director of Re: h and Study Director led 202 Date 000896 APPENDIX E CERTIFICATE OF ANALYSIS 000897 418-018:PAGE E-1 Certificate Of Analysis FC-95, Lot217 Mar 9,c 20h 00 This samplewas analyzed hme ssmpl RichM.aParyfedr LC/MS, H-NMR, UF-NMR, andelemental analysestechniques.The results ta ig a eeley The I S ="7 E YS Malsionaly, intheigs amedistributionofthesigewet ddestermined:using"9'pP.-NMR technaindqfouunedtso [co iym | mie {ormalchain,where xismainly7) EERE [ co T Fo 3%CF-CF3m )E e-p o50;fp K op |T me er 0 ts d| [CFs)C-Co E2)e m 305K gm | i8 c| CFC. CCE)(CED, 50, K ismainly 4,an x#d 0) 000898 418-018:PAGE E-2 3e SIGMA. S sa T05rs mmSem prion on DPrR-OMDEUvCATLNOoN:ICMiAcCeI?D CTEACRTTONIEFICATE OF ANALYSIS so: 674-26-0 LFoOnRNMoA: W0E7I0GKH2T6:03130.1 FORMA: Caiy 00; store 1 A FREEZER mer SracricaTion wzswirs NevEAnaN IGTEHrEn Eoak vation Coroms STILT FuREnE 0TE.RVIEEERRYSSLEIRESHHEILGAEYYo Zann FAATNT YRLLOR Tommy SoNSTSTET wi STRUCTURE rr BY IR ORTodt " 5 E-- TTITReE A-- TION~Tr TTAe-- ron.%-- . 9377%--eesti------8-- 3.; 2% oc AccEPTANGE oATE Swit 2000 Rvp Feibee ESHEtRAnRL,LBATEtS !ar8L7/S tT2ut6/10e s0MTSSaIcLtaTem111T1t elTnoIiLnOeSCAETUDND118 i 0eTr siooniABcHIsS ok be ATL A IE Se, a 000899 ar commited 8 Sun of os Conamars Fosters ond APPENDIX F HOMOGENEITY AND CONCENTRATION ANALYSIS REPORT 000900 418-018:PAFG-E1 STUDY TITLE One Generation Reproduction Study of PFOS ~ Mevalonic Acid/Cholesterol Challenge 4nd NOEL Investigation in Rats DRAETQAUIREMENTS Analytical Method Requirements STUDYDIRECTOR Reymond G. York, PhD, DABT ANALYTICAL PORTION COMPLETED ON October 30, 2002 PERFORMING LABORATORY Exygen Research . 3058 Research Drive StPahtoeneC:olle1g4e.,2P72A-110638901 STUDY SPONSOR 3StM. PCaourlp,orMaNte T5o5x1i4c4o-l1o0g0y PROJECT Study Protocol Number: 418-018 Exygen Study Number: 023-069 "Total Pages: 21 000201 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. ErdyR. Dicker Principal Investigator Exygen Research Ray d G. York, Argus Research st .. DABT DM eaJo.nLucnebkaer aJS. tbiy `3SMpoCnsoorrpoRreaptreesTeonxtiatciovleogy Exygen Research Ioffe Date Sueno Date Dlatre ?fave 000302 Page20f 21 Sty oc 1385 418-018:PAFG-E3 QUALITY ASSURANCE STATEMENT ges. "on Coon Resection Sy o 105Merlo:AlCl] Exygen Research's Quality Assurance Unit reviewed Exygen Study Number 023-069, entitled, "One Generation Reproduction Study of PFOS -- Mevalonic Acid/Cholesterol conduct according to Exygen Research's Standard Operating Procedures, the Study Protocol, and all applicable Good Laboratory Practice Standards. All findings were reported to the Study Director and to management. rower Phase bei. Date emsnm Inspected sucht Dunn Exygen StudyDirectorand wmms Management saen Sponsor Management Comte aw wm am oFmoe own os mm Er Angels Quality L Pre rgan Assurance Auditor elon for Date 000903 418-018:PAGE F-4 Exygen Study No. 023.069 CERTIFICATION OFAUTHENTICITY "This repor, for the raw data for Exygen Study the study. Number 023-069, is a true and complete representation of . Submitted by: Exygen Research 3058 Research Drive State College, PA 16801 (814) 272-1039 Principal Investigator, Exygen: iNE Scientist Exygen Research Exygen Research Facility Management: A RichardA, Grazfini,PRD. President Exygen Research Study Director, Argus Research: Aste pr A] RAragyumsiRledsGe.arYcohrk, P{t .pasT `Sponsor Representative, 3M: Date @-our-oe Due 1y-0ov 02. Date Deanna J. wy MS. 3M Corporate Toxicology Enygen Research Date 000904 Pagedof21 418-018:PAGE F-5 Exygen Study No. 023.069 STUDY IDENTIFICATION One Generation Reproducti`oanndStNuOdEy LofIPnvFeOstSig~atMieovnailnoRnaitcsAcid/Cholesterol Challenge STUDY PROTOCOL NUMBER: 418-018 EXYGEN STUDY NUMBER: 023.069 `TYPE OF STUDY: Analytical SAMPLE MATRIX: Dosing Solutions `TEST SUBSTANCE: Perfluorooctanesulfonate (PFOS) SPONSOR: 3MCorporate Toxicology St. Paul, MN 5514-100 STUDY DIRECTOR: Raymond G. York, Ph.D., DABT Argus Research 905 Sheehy Drive, Building A Horsham, PA 19044-1297 SPONSORREPRESENTATIVE: `TESTING FACILITY: ANALYTICAL PHASE TIMETABLE: DeannJa.Lucbker, M.S. 3M Corporate Toxicology 3M Center, Building 220-26-02 St. Paul, MN 55144-1000 Exygen Research 3058 Research Drive State College, PA 16801 Study Initiation Date: 0821/00 Analytical Start Date: Analytical Termination Date: 0214102 02/15/02 Analytical Report Completion Date: xx/xx/xx Exygen Research 000905 Page Sof21 418-018:PAGE F-6 Exygen Study No: 023.069 PROJECT PERSONNEL RTehseeaSrtchu.dy TDhierefcotlolrowfionrgtphiesrspornonjeelctfrwoamsExRyagyemnonRedseGa.rcYhowrke,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 000906 Page 60f21 418-018:PAGE F-7 [Exygen Study No.: 023-069 `TOAFCBONTLENETS `GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT Page ......occcoevvreienrenn 2. 6.0 DESCRIPTION OF ANALYTICAL METHOD ....cccccoonmmmrmmemnrnrsssisosssessnenss 10. 66.3.2 PCrHeIpaOrMatBiOonGoPfhSYtandardsc nd FOrific caion SONTIo Ons er 1110 66.45 TDesOcriSptSionSoEfTISnHsVtrAuYment ncdrc Opersing Conditions... 1111 7.06.E6XQuPaEntRiItaMtEiNonTaAnLd EDxaEmSplIeGCNAI.G.UR.ON IIeo I 12 9.0 CONCLUSIONS... eee 14 10.0 RETENTION OF DATA AND SAMPLES........ rss sssssssaserssssssassesss J Exygen Research 000907 Page 7of 21 418-018PAGEF-8 Exygen Study No.: 023-069 LIST OF TABLES Table Page SummaryofPFOS in DOSIng SOIUtion SApIES........c.ccccrerrece 17 Figure 1. Figur2e. Figure 3. LIST OF FI Page Typical Calibration Curve for PROS .....cvevvncnssnscsnscnse 19 Chromatogram Representing a 0.5 ng/mL Calibration Standard for PFOS... 20 Chromatogram SEE: 0214028) c Representinc g Dosing Son lution Sampla e (Exygen ID: 0200283, tne 31 LIST OF APPENDIC) Page Appendix A Study Protocol 418-018 (Exygen Study No. 023.069) and Amendments.. 22 Exygen Research 000908 Page Sof21 418-018:PAGE F-9 ExygenStudyNo.: 023.069 1.0 SUMMARY Exygen Research analyzed dosing solution samples for the determination perfluorooctanesulfonate (PFOS) according to protocol 418-018 (Appendix A). of Recoveries for 10 the assigned PFOS in the dosing concentration. solutions ranged from 83% to 105% when compared 2.0 OBJECTIVE `The objective of dosing solution this study samples was to using determine levels the analytical of perfluorooctanesulfonate conditions described in (PFOS), Protocol Amendme#n6t. INTRODUCTION `sTohliustiroenposratmdpelteaisulssitnhgetrheseulatnsaloyfttichaelacnoanldyistiisfonosrtdhesecrdiebteedrmiinnPartoitooncoolf PAFmeOnSdimnetnhte #d6o.sing `nTuhmebsetrud4y18w-a01s8.initTiahteedaonanlyAtiucgaulststa2r1t,d2at0e00w,awshFeenbrtuhaeryst1u4d,y 2d0ir0e2c,toarndsitghneedanparloyttoiccoall termination date was February 15, 2002. 4.0 TESTSYSTEM Twenty-seven dosing solution Research on January 31, 2002 samples were received and logged in by Exygen frozen on personnel dry ice at Exygen and placed in frozen storage aSsasmopcliaeteldogw-iitnhatnhdischstauidny.ofSctuosrtaogdeyriencfoordrsmatwiiloln bceankebpet fatouEnxdyginenthReesreaawrcdhataanpdacaktarguee copy of the storage records s available upon request. 5.0 REFERENCE MATERIAL TEnhveiraonnamleytnitcaall TsetcahnndaorldogPyFaOnSd SwafaestyrSeecreviivceeds.at Exygen on May 17, 2000 from 3M 000909 Exygen Research Page 90f21 418-018:PAGE F-10 Exygen Study No: 023.069 TmahteeriaavlaiPlaFbOleS iwnafsorsmtaotreidonfrfoozren.the reference material is listed below. The reference Compound ExygenControlNo. PFOS SP248 ICRNo, SD009 Purity(%)Expiration Date NA 01/01/10 `The molecular structureofthe reference material is given below. PFOS Chemical Name = Molecular weight = Perfluorooctanesulfonate 499 (CyF11SOy) CoF17[8I --O 4 Note: The neutral molecule and standard form from which PFOS (anion) is derived, is potassium perfluorooctanesulfonate [CgF1;SO3K], molecularweight 538. 6.0 DESCRIPTION OF ANALYTICAL METHOD 6.1 Extraction Procedure Each sample was diluted in methanolpriorto analysis by LC/MS/MS electrospray. 6.2 Preparation ofStandards and Fortification Solutions sStthteaannsddtaaarrndddassroodlluu(tticiooonrnrsewcaotsfedpPfrFoerOpaSpruerwdieyarteaanpdcrooenprcaersneatldtraoctoninotJneannotfu)a1rin0y0m1ep0t,gh/2am0n0Ll2..byFAdrinossmionltdvhiiivnsigsdou1la0ultmisogtno,ocfk3 1.0 pg/mL fortification standard solution was prepared by taking 0.1 mL of the stock and bringing the volume up to 10mLwith methanol. 10 mLwith methanol. A 0.1 pg/mL fortification standard was prepared by taking 1.0 mL of the 1.0 ng/mL fnogrt/imfiLcasttiaonndasrtdanwdaasrdpraenpdarberdibnygitnagkitnhge 0v.1olmuLmeofutpheto0.110pgm/LmLwsittahndmaertdhaannodl.brinAgin0g.0t1o 000910 Exygen Research Page 100f 21 418-018 PAGE F-11 `Exygen Study No: 023.069 A set of standards containing PFOS was prepared by dilution of the 0.1 g/mL various calibration solutions inthe following manner: Tnitial Cone. (ug/mL)' or or 01 0.005 0.002 0.001 0.001 Volume (mL) 05 02 ol 10 10 10 os Dilutedto (mL) 10 10 10 10 10 10 10 Final Co0n.e0.05(ig/ml) 00..000012 00.00000025 0.0001 0.00005 `The stock standard solution and all fortification and calibration standard solutions were. i stored in a refrigerator (4 % 2C) when not in use. Documentation of standard preparationcanbe found intherawdataassociated with this report. 63 Chromatography Quantification of PFOS was accomplished by LC/MS/MS electrospray. The retention timeof PFOS was ~4.4 min. 6.4 Instrument Sensitivity i The smallest standard amount injected during the chromatographic run had a concentration of 0.0001 g/mL of PFOS. 65 Description of Instrument and Operating Conditions Instrument: Micromass Quattro Ullima Computer: Software: Dell UltraSean P1110 WCiOnMdPowAsQNPTr,ofveesrssiioonnal4Workstation AP200 HPLC: Hewlett Packard (HP) Series 1100 HP Quat Pump HP Vacuum Degasser HP Autosampler HP Column Oven 000911 Exygen Research Page 110f21 418-018:PAGE F-12 Exygen Study No.: 023-069 HPLC Column:Genesis C; (Jones Chromatography), 2.1 mm x 50 mm, 4p Column Temp.: 35 C Injection Vol.: 10 pL Mobile Phase (A): 2 mM Ammonium Acetate inASTMtype I water Mobile Phase (B): Methanol Flow Rate: 0.3 mL/min. Ti0me %A %4B 0 0 100 70 0 100 75 60 40 no 6 40 Tons monitored: Approximate APnaRlOySte neMgoadtieve Transi4ti9o9nM5o9n9itored RetentionTai4me(min) TPunaerFialemeters CIoSn-Ttorsoplrasy 42S0et00 DP-Declustering Potential 51.0 FP-Focusing Potential 2300 EP-Entrance Potential 100 CECollision Energy CXP-Collision Cell Exit Potential 10 5 DF-Deflector 3000 CEM-Channel Electron Multiplier 28000 Gas Flows sat Nebulizer Gas 12 Curtain Gas Collision Gas, 13 4 TIS Temperature 350C 6.6 Quantitation and Example Calculation ``TThweenpteyakmiacrrcoaliwtaerssmoefassuarmepdleanodr tchaelisbtraantdioanrdsctuanrdvaerwdawsergeenienrjaetcetded(uisnitnogt1hexLiCt/wMeiSg/hMteSd.. cloinnecaerntrreagtrieosnsiwona)sbdyettehremMiniecdrofmraosmsthseofetqwuaarteiounssinbgelsoiwx.concentrations of standards. The Exygen Research 000912 Page 12021 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(ulaitneiaorn re2grceaslsciuolnatpeadratmheetearms)ougnetneroafteadnablyytethefoMuincdroimn apsgs/smoLf.tw(atrhee equations for serum are shown). `Equation 1: Equatio2n: | Analyte found (ng/mL) =(Peakasrloepae-intercept) Analyte found (ug/mL) = (anal. found (ng/mL) x DF) x Lug. Where: 1000 ng DF = Dilution Factor Equation 3 calculated the percent recovery. `Equatio3n: Recovery (%) = (asnaamlp.lefocuonndc.(u(ugg//mmLl)x) 100 An example of a calculation using an actual sample follows: Dosing solution sample Exygen ID 0200283 (Set 0214024), where: peak area intercept slope dilution factor sample con. = 180 = a13ss = um = 200000 = 400pgmL From equation 1: Analyte found (ng/ml) = [1380-43545 720773 = 18SngmL Exygen Research GO0Y13 Page 130f21 418-018:PAGE F-14 Exygen Study No. 023.069 From equation 2: Analyte found (ugmL) = (18S ng/mxL 200,000) x Lug 1000 ng = 30pgmL From equation 3: % Recovery = 347000upggi/mmLL. x 100 = 93% Not: This example calculation was done using rounded numbers, and therefore may be | slightly different from the values shown in the RAW DATA. 7.0 EXPERIMENTAL DESIGN "The set of samples consisted of an instrument blank, a set of calibrations a the beginning and throughout the run and the 27 samples 8.0 RESULTS Individual recoveries for PFOS in the dosing solution samples are detailed in Table L `The average percent recovery + standard deviation for PFOS in the dosing solutions was 93% 7%. A typical calibration curve and representative chromatograms of standard and sample are given in Figures 1-3. 9.0 CONCLUSIONS `The concentration and homogeneity of the dosing solutions were demonstrated by the results of this report 10.0 RETENTION OF DATA AND SAMPLES `When the final report is complete, all original paper data generated by Exygen Research will be shipped to the sponsor. This does not include facility-specific aw data such as instrument logs. Exact copies of all raw data, as well as a signed copy of the final Exygen Research 000914 Page 140f21 418-018:PAGE F-15 Exygen Study No: 023.069 Raneasleyatriccahlarrecphoirvtesanfdoraltlheorpiegirniaoldfoafcitliitmye-ssppeecciifficierdaiwn d2a1taC,FwiRllPabret r5e8t.ainReedtaiinntehdesEaxmypgleens of reference substances are archived by the sponsor. Exygen Research 000915 Page 15021 418-018:PAGE F-16 Exygen Study No.: 023-069 Exygen Research 000916 Page 16.0f21 418-018:PAF-G1E7 Exygen Study No: 023.069 Tablel. Summary of PFOS in Dosing Solution Samples ET xyeen T Sponsor T Pek Foywed hFoened SConae. mReee DF Awa (ogiml) (pmb) uml) (% 200285 Tof6T OAmpl) BAUGH 200000 1380 185 311 40 95 000284 3of6MO4mYmD2BAUGO 20000 152 205 410 40 103 0200022885 So1fo6Bf(2004mmpmpll))I8BSAEPVOGOD 20200000 1N5D51 2N0D9 4N18 D.40 -105 0087 1012008myml) IBSEPO S000 95 132 661 8 8 O0002385 110o2r021060nmypnl)) 1IB8SSEEPPO0D 0S0O0OO0 2T1i5s6 029932 1166 21600 99% 000029%1 11ooff22002342mmyyaall)) I1S8SSEEPPOO0 0200000000 1806779 L14414228 22600 9%50 000% 1of2040mpSnElP) 20000 1385 18% 72 40 9 000000229938 31ooffM6OTO44mmpPmMlD)2Z7ISSEEPOPDO 2000000000 1149253 21091) 343 4400 91%01 0095 00% Sloof6fB2(0OmApRmpTOLIZNIOSVEOPG)D 202000 19313 1N7G6 mN2Q 4-0 8- 0C200002997 110fo22(00.1068 mmgy/EmLD)OOILNNOOV.V000 ~~ 50S0O0N00 21004026 217383 0@0003%0 11oof/220022600myymmD)O0LINNOOVVOO00 22000000000 743 863 052 114 00001 102032mymDOINOV.D 200000 1056 ldo C0000030023 110fo2200.m4p0mmlyyEIDSONIONVOOVYO0 02000%132 1N7o9 002003030058 11ooff22(000186nmyynml)) I1SSNNOOVV.OD0 SS00000 21008012 2183 00306 10f2(020mpnl) ISNOV.D 200000 S02 105 CC00030075 10101122002342mmppmll)) IISSNNOOVVOOOO 220000000000 26 115 109 15 200309 1012(040mg/nl) ISNOV.D 200000 L461 199 6165 81060 88 198 20 9 22831 23200 895 N38 o.S08616415 18600 888 21 20 105 27 200 91 339096 4200 19060 ND =NotDetected NQ = Not Quantifiable (A peak was detected at the corresponding analyte retention time but was less than the lowest concentration of the calibration standards (0.1 ng/mL) Exygen Research 000917 Page 170121 418-018:PAGE F-18 Exygen Study No. 023-069 Exygen Research 000918 Page 180f21 418-018:PAGE F-19 `Exygen Study No.: 023-069 Figure 1. Typical Calibration Curve for PFOS `CCaaoimmrpamotiuonnnodsa1frBeamea:rTEnEVTaO7tSS:x0.193105245 CuRarsrpoynos"yCpoesaE.xOanmi.9ExAco,Wong: 1c Avsans: None x 00 os To 1s 20 28 30 as ry as Tom Exygen Research 000919 Page 19.0f21 418-018:PAGE F-20 Exygen Study No: 023.069 Figure 2. Chromatogram Representing a 0.5 ng/mL Calibration Standard for PFOS coma, a5mpm snirs anton on3 - T[ orehn s ssa | Exygen Research. 000920 Page 20of21 418-018:PAGE F-21 Exygen Study No. 023.069 Figure3. Chromatogram Representing Dosing Solution Sample (Exygen ID: 0200283, Set: 0214024) pr-- ann 321 " ToPran ey ueaoesv Exygen Research 000921 Page 21of21 APPENDIX G `TEMEPRATURE AND RELATIVE HUMIDITY REPORTS 000922 ARGUS 418-018:PAGE G-1 Temperature and Relative Humidity Report Location: Room 17 Protocol Number: 418018 RangeofDates: 22-Aug-2000 14:44to 12-Nov-2000 08:59 STpaercgieetsR:arnagle: TToottaall NNumubemroobffHDoeauyrsrs:: Total NumobfeDatra Points: TeESTE 1893620 1956 Relan tive oHumidity 1986320 1956 Mean ( SD): MMoadxaimnu:m: Minimum: NE NumuberomofE fPPbooiinntetssHE iinrgh (0)0: %): 06 (13) | 566 (248) 773190 577008 638 07 190:54 ((800.)9) | 19155 (890.919)) Report Generated: 30-Nov-2000 at 14:02 COMMENTS: REVIEWED BZ Y: l ate: 3 2570) 000923 ARGUS 418-018:PAGE G2 TemperLaotcuartleoDne:vRiaotoiomn1s7Report Protocol Number: 418018 Rangeof Dates: 22-Aug-2000 14:44to 12-Nov-2000 08:59 TSpeemcpieersa:turarte Target Range: 07-DSaetp2e00~0~ T06i:m0e0 07.Sep2000 07:00 Te6m3p8.0 sasl 84F to 79F Date Time Temp. H=Vaowoutof rraanngege -|High L= valugou ofrat nge " Low Report Generated: 30-Nov-2000 at 14:10 +//Thessdeviations didnotadverselyafecttheoutcomeorinterpretationofthestudy. The following deviations) impacted on the outcomeofthe study as described: StudyDirector: X Ze 7 x = Date: 30- Mht2-d) 000924 ARGUS 418-018:PAGE G-3 Relative Humidity Deviations Report Location: Room 17 Protocol Number: 418018 Range of Dates: 22-Aug-2000 14:44to 12-Nov-2000 08:59 Humidity Target Range: `Species: rat Om Date we Time RHoe.m 30% to 70% Date Time RH. = ValuotsofrRanEge RHigahtio__HLa=VmaalGuyutoef rangeReport Generated: 30Nov-2000 at 1418 / ves etretesty htnon msnos "Thefollowing deviation(s) impoantc het outecod meofthestudyas described: StuyDirector : i 7 I Da20t MeRD:? 000925 ARGUS 418-018:PAGE G-4 "Temperature and Relative Humidity Report Location: Room 18 Protocol Number: 418-018 RangeofDates: 05-Sep-2000 14:00 to 03-Dec-2000 13:59 THarget aRange: TTTootoaml NNNuome moobobfff DRBoe aeaeytirers:F:orne: CEE Tempers p4g He Relative Humidity aorns HMH-- seaen (n SD): `pNNurumomobffabPPoeoeitntrtrss tHinigRahn&g do] (4): 162208282 (05) | 2281082 (241) 2ooa0ms 0o | 21m 0600.03)0 ReportGenerated:27 Mar2001 at 16:18 coumenTs: REVIEWED BY: V7 4 br one 3280 000926 418-018:PAGE G-5 ARGUS Relative Humidity Deviations Report 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 osDOantzeo0 TiO1m0e RTHo.zH 30% to 70% Date Time RH. =ValusoutofrRanEgEeR-eHliighv_eLHa=VratlyuCoe3utof ran-Lgoew Report Genarates 13-00c:2001 a1 16:57 resvansdd etaytc sume aes "The following deviation(s) impacted on the outcome of the study as described: ZL 7 StudyDrecir: A mond /d 2 one: _(3-DT-0) 000927 APPENDIX H BIOANALYTICAL REPORTS (ANILYTICS) 000928 418-018:PAHG-E1 CLYTICS cers sre si 00snovo 2m Chins: AA3TR5rG8gUohLSsuRSaIeEeENyEmACNORaCREPOLARRACTRAETDORIES30,1-9W2e1-.0168DBpaoEtsFEaeaxSSn:oleRlpp3oLt0uad1Le-v8T7eE7t-Es0433o1t2e/t0e8r/t2o0v0t0 (215) 443-8710 Ffoesceasssion Sip)ec. | Gp?SexAgdee CGHGOLLE"ST GLNGU/CbOLS~E LWDOL/-DDLIR HDMLG-/DDLIR TRMIG/GDL rage 1+ ng 96 319 o 104 000929 418-018:PAGE H-2 CLYTICS cou svm.si 00 soos vo om ents 2250 nIEsNpCAORCRHPOLRASAOTREMTDURIE3S0,1-9T2N1C-0.168DatFsaxS:o3l0l1-e9c7t7a-n04:33 cis BIEREL nee Zoe JeEssy DRIVE onDate epere Received: sep 12/08/2000 (215) 443-8710 RocemsionSpec. | Gp SexAge GHoLEST ghcos [pion room pme No. II --. P MG/DL MG/DL___ MG/DL MG/DL MG/DL croup 12 000930 418-018:PAGE H-3 Client: BARGURS ARSIESNYECAORTRCHPOILRABACOTREASTDOR_IES3200,10-G9Ii2Nr1aC-r.0d1S6r8eBDtia,tteeSFuaixSCt:eoLl32I00l01Ns,-cE6G7taR7et-Yhd0e:4r3s3b1ur2g/,0M8D/220008077 BBOEREanBy d1s0ue- Date Reported: 01/f2186f/.2001 Cutent No. 1028 Study: 418018 DANS GD21 Species: RAT FneoccessionS7pBec. ppBoooaoSglgiiiteeeez ie1i0ed3e3st0 Bpppoeoaoiaogmcisesestiiiettnde wetapn Group 3 GppSSeexxAMgee CCHOBLEES'T GLWUG/CoOLSE IDMLo-/oDiI=R HWDoL/-oDLIR_TWRaI/GbL 3333 EfF of 3i 5728 1i1i0af2 3iii% 4$ w FAn i ]#8 8 4 3 3i 333 :iof 338 ataH38 it FB I 8E 3 f5e Wea me 31 3Ryp 8DpBooooojoooineggssii03:ee4s 4444 kEiof pggpoooaoameneiisaisii1ge0est% i4i4 fooofff ytooagn Group 4 13i d 384 E ia8 1320 88nowo03mm 8a8$io11m8 iii2$ $ 2 i80 .% 8 83 s#e1 i0Be s2 e miay Mdaass Reference Range i@- Hnec 8e- 8o- aHo Page 3+ 000931 418-018:PAHG-E4 LYTICS coms sive. sn20 cscs, wo zor Chtons: BNARGCOIMIRESNECAORLCRHPOI.RAOARTAETDORIZS3,01-9m2e1-.0168D2oa2t5ee0FaxSoS:ov3lLp0i1es-Sc9e7ti7Ra-ed0:433m12e00y/2e00r0 (215) 443-8710 xSiseesion s%pec. GpSexAge CSHOORLTESTGGLHUCGOSE IWDLR-TDIR EWDeLr-eDRIR TMREISG. Mean cron5 83.6 100.4 8.5 28 348.8 J Mean 75.3 98.5. 5.9 a1 191.9 000932 418-018:PAGE H-5 CAYTICS so ciue sro sam 0 como vo mom SOEFsNhna.eaeINdc CORPORAo TLELD 301-921-0168I8a2r5eG2aFaxsSi :oEp30rE1e-n9Mt77aS-s04331e2n/0s0e/2m00e0 (215) 443-8710 FAecscession S2pB ec. GOppSSeexxAAggee CHCHOOLLEESTST GSLEUyoCeoO.SE LMDOL/-oDbIR HDMLO/-obDTMIR TERBI/GSL Mean axou7p 77.9 106.4 12 46.6 200.9 000933 418-018:PAGE H-6 CIYTICS coco sin taco wo wm + ARGUS RIESNECAORRCHPOLRABAOTREATDORIES30,1-8I2N1C-.0168DateFaCx:el30l1p-c97t7a-d0:433 Stent 3B0(2O21R5S)EuR4i43t2BDy87R2I01V0E0u- DDaattee RReecpeoirvteedd:: 1021//0186//22000001 Crtent No. 1028 Study: 418018 DAMS G21 Species: RAT jRoecceessssiioonn S3p8ec. | FBBp0o00dR03l300e1Eun4ds5e 11i009n30e01 BBBooooogetliieae e1de0sl8t POSIBLE sewapn Group 1 GOppSSeexxAgAgee 11ifFEF 1111:OoFF Tp4i,,TTOOTTAALLTR3,ETTOTALERREMET3 1ae e:48xs3 g 89me8.Ess1 0fS8.7il7s8 S8B:3E588 agukiEs 8:38 Ink 8S8mEB &mM sgae 7R3AerRs aSnR ThSHw nB31.6f282 nIRaPHt ait Lueiis FNREEBELT4 8800.BB339 08 8B3 8B 2a3R8 pBBoeo0mll00eda2zes0a::1 1neH1eel0i4iee0 iiB12 E:EEF 3BBB0oo0eoo0ll303ea3s0e8e0ses HHHHeoOels H1112 :FEEFF weepan Group 12 3880:::.88808880 384es:.88%s22 ous o8e 3.9 ninn; 8p8 8:1a38s88 a88e:::88888888RaE4:Em 8 8SS%ER hhknBBEi 88&888E 33 2Di3s8s iTai, 313a8 o4s%s Reference Range ge 3. soo o- 7 100 rage 6 + smo 13- ila 2.5 000934 418-018:PAHG-E7 CLYTICS crus som st 0 stor. wo Client: ASREGULS ERIEESNECAORCRHPOLRABAOTREMTDORIES30,1-8I2N1C-.0168BDaagtseFaSCx:ol30lR1g-c67tI7e-d0:43312/00/2000 BEML HORSHAM, PA 19044- Date Reported: 01/16/2001 Client No. 1028 Study: 410018 DANS GD21 Species: RAT Afceceession3SpBec. | [pBRooSiIoomiEn0s i1H1e0es5Its BBBBOoooBBieeIE HlHHeeEeseE Heopan Group 13 BBBBooo8oos0sii3oeg0iii1ssn3at i01is0s0i8lss1 BBpoogoao igagieiale as iii:isse seeapn Group 2 GpPSSeexxAAgdee H1i3 bEE 1i1i33 EFfb f131bbEF f1f1bFb TB4e,yTbeO-TALTR3y,TD0LTALFFReEEmT3 TwSHep eSce8lel8 WHwhaEBar edseeBnar n1IayaYl ae88:8888 a dBEB Bema ni mahm 38 GeoanTm Lunatn FNReErEyTA ga 3aohl 8R88:%R88 em g$FS5s58ON3mR0eEE8r 08a3 se 1BB7E a0 0088:3a84 8 Ssgaast 3afdakEs E 8 8 gE RB1Rm oE 8b8:EE5 TAn h[apmBIw hnEE aoaen Reterence Range 33. HmIe 9s Page 7+ smhe E1S3- 000935 418-018:PAGE H-8 GLYTICS cs sos, sare sm INCORPORATED 301-921-0168 Fax: 301-977-0433 Client: AS0R8GUSSubREmSyEADRaCiHveLABORATORIES, INC. DDaattee RCoelcleeicvteedd:: 12/08/2000 HORSHAM, PA 19044- Date Reported: 01/16/2001 (215) 443-8710 Client No. 1028 Study: 418018 DAMS GD21 Species: RAT fAcccessionSp8ec. | GCppSSeexxAAggee T4F,TBOTALTR3,yToOTALFRRFERE"T3 BpB0o00a033gd0ii1ee8rs1111000998333030 333 kEF g09:i00o00 2448381:.383388 030:.23088 BBB o000o0333001i06es:s 111000899333138 333 % 0g0:l00a06 ge392e101s36 oooiilis BB 000033001s7 1100933370 33 FF goloooo 247113873 @0::3331 M5e8an 000073 Tehwaeoras 3l1a3s Group 3 1W8Hha FFREREMT4 z1.C i06 T 0o:l0d3T 2ifsdfs 9oiiisd2 1I:ST3 60.l0o%E Leats 0oe8s BBB 00000033300011167}90 11100099944475 444 EF EF BBB oo3o0033l00e1177:s5 111000989848)85 i4& E BB 3o0033g0iss 1100338883 ii F M5ea8n Group 4 g0g.io0oo0 64g5gl.:48e88 900:.83575 I g8i:g0s0 E 3388::8788 90:01h3 S8:o0o0 1388::883 80:380 o 4ssls5'08 11874 421.:58858 000l:.060384 o1l7a+8I 00:176 3li5f 0u.0g8 2il.o3se78.0l7e333 Reference Range 37 - 1s000- 8o0Page 8 + a57T-0 1a8s - 000936 418-018:PAGE H-9 GIYTICS INCORPORATED soc sto sn 0 300 mem 301-921-0168 Fax: 301.977-0433 Clientt: A26R5GUSSmmRzEaSyEARDCRHIVLEABORATORIES, INC. DDaattee CRoelcleeicvteedd:: 12/08/2000 oREmAN. Ba 10044- Date Reported: 01/16/2001 (215) 443-8710 Client No. 1028 Study: 418018 DAMS GD21 Species: RAT Aececession S8pec.| BBB 000000333000111777978 111000333588805 BBB 00o00033300o11i88e)0; 111000333666132 BB 00003300118843 1100956645 M5ea7n Group 5 GpPSSeexxAAggee 355 E E 333 EE 35 EFF TF4RTEOTTALTB1,BTEOTAL FRRPEEm13 9o1:3d05a07 2e871a:18m39 0o.8y3 208:::38371 8sgae8ils3d3 oooselsse 00::0389 e8713800 _ o0tse 5Bs 7i6.533.8 e38 TRSeHha 3E.7l2 2i .64 1.68 2Ti.d5s4t4 FRREETERT4 8o:3R0 800:.33168 001:3211 2l8i1 BBB 00o00o33j00o11188s7es 111000999777285 &&& BBB 00000033300011188058 111000393787808 &&& E EF BB 00003300115921 1100398821 66 FE M5ea5n7 Group 6 000:.001000 ee32s8:.:313775 900l3az8se 2.72 000::.522471 0001::000000 4ge31i:::8333: 09o:3f20r7 010.29%88 o08.l31a7 80::0000 4423::3388 G030% iIdEa ooolti Twoio" sLaSan 3A3B3 1T4e5t2 1e3e8e Reference Range 73- s28o0- 80rage 5 + a57T 1a.s9 000937 418-018:PAGE H-10 GLYTICS espe ss 0 comme wo wor Client: ASRRGEUBS REIESNECAORbRCrHaPvOeLRABAOTREATDORIES30,1-8I2N1C-.0168BDaatteeFaxSC:RoE3l0Ii1Ts-Ec97Et7Ye-"d04:3312/08/2000 OTREB)AN.hhaTBhanad10044- Date Reported: 01/s1i6d/2001 Client No. 1028 Study: 418018 DAMS GD21 Species: RAT jAactceessssiioonnSgppaec c.| GGppSseexxAghee p2p5 ooogoaoe3ielniassi:eid110ne83e8e8l85 777 iOEEF 7 pBFB e0oH0l3sg0T1ii3e8 11iH 8t08e88s8 E 777 k weeapn Group 7 TL4U,ITGOITALTB3I,OTTOATAL FBRUERETT3 TISHo| aaaoo880r i dm51dE27 af8 ooiRl 2nbbfHaaf 3a88:888%88 BmidaEyAl 8B 88Hd BB La. 33 S087 ae 3W0P3 FIREELT4 aS0 o.Rl10 880 8::B8818 iank Reference Rannoge 33- 1s8o0. 98 - ssh7- i139- Approved ---------------1l___ pate ---ilfel pe Page 10 of 10 000935 418-018PAGE H-11 CGLYTICS orgsson sos 0 0m CHenatnt: AARRGUSSuRREIERSNLECAORDCRiHPvOeLARBAOTRAETDORIES3,01.I9N2C1.0168DBaatteeFaRCxeoc3le0ll1s-vc9e7td7ai-d'0:43912/12/2000 F(O3R1E5R)AN,427P8A71019044 Date Reported: 04/si1d7e/d2001 Client No. 1028 Study: 418018 DAMS IDS Species: RAT AAecscessionS7pBec. 53p8oo0oo3d300e8si4is37 11100038500988 BBBo8oo0As t11oeaa6lri N5e8an Group 1 GpPSGeexxAAggee 111kEF 1IIFEE CGHUOOBLESETST GLSEUVSCROTESE 8a8 5 18852 1ie 88% 3138% 73s Is%s LMDeLy-oDRIR HMDEL/-oDRIR TWReI/Gbn 337: 2iH 2 s24as5 18 i7 b1i7d7 n1d2 a1g9a3 naidse BBBo888o000j333o000s883s909e308 1111111000631333903 11118080 E BBBo88l0033e00s2%9:8 1m1i1eg0z2se7 B 8330s ozs iIIo8 E 18 F M5ea8n Group 10 aE7nz%d 115a58E97 s23i 4i537 2238888 E3x8 8i1s5l 18 i583 bi1388 abI0fi} Swees 817%5.8 23.7 s4a2t8 319837 Reference Range 5s0- 4- 80Page 1+ $9-3fox 000939 418-018:PAGE H-12 cot E BCEAA e EYTRAIaACSnmogoremsasogBn5t2ssswHSEa2Emo0IGcesHEoasEmme1en0v/owa0o0er gaa re meen, rare (215) 443-8710 AcNocsession SBpeec. | GpPSSeexxAAggee CCHHOORLESETST GGLhUvoCeoO"SE LMDRLyo-pTMDIR HDHRLLG-PDIRIR TRRIIGC~~ Boososss 1g if 8 1% i 32 cro 12 ng 96 319 0 0 104 000940 418-018:PAGE H-13 CIINYCOTRPIORACTESD cSorroeroomsn 0Fa2xso0rocrraoems o vo wor Client: AARSGEUSRREESPEARRCHELABORATORIES, INC. DBaattes SColRlecEted: 12/22/2000 ESRERANC Ba 10044 Date Reported: 04/17/2001 Client vo(.2151)020443-8710 Study: 410018 DANS 1S Species": RAT HSeosesaion S7pB as 5BBBgooaogsieiooceeedness TeHMisoeestss Boss fMsaeesan Group 13 8BBBoooomoogesgosoesesrstz ii11a08e0n%1 BOSE IE yteognr Group 2 GpPSeexx Ahgaee GCOHLORIESST T GSLEUUSGETet IRpSLEbTIN WMDALRDTIN TRNSEL. 1HH13 fEEE Bf 5 8 # B i a 8 o] E T7 1 T g8 a 88 8 a38 G0n w eaf.3 w#17T I0Bn 1113 GBEB B 8 8 a n h Bom ag oxB x uam 1 fF wf 8 14 a3 7Ba HBeEs RS3a H8:a3 iBnYe BBBBoooooonstneenysesI0dN0o:Gse 3333 fEOfFFf syeogan Group 3 a88Fo E11E88iT8 T2on73hes 3:1 Po8ns oma08% TFEa 0 igs Reference range 8wo me Page 3+ 98 -98 -3:301 000941 418-018:PAGE H-14 LYINCTORIPORCATESD p30ieserocto8.s Fars0o,rs:oot7utor wo sr Client: AE RGUS n RESEAa RCH LABORATORIES, IC. BDiattee SCoRlLlAeIcNtEeSdY: 12/12/2000 B(O31R5E)AS443B-y872010044- Date Reported: 04/7217/2001 Cltent No. 1028 Study: 418018 DAMS IDS Species: RAT hAececessionS8pec.| GOppSSeexxAMgee H pBppoo0ooo0g3eE 0en6li1st1eid10sos9tn4ee3 B4444E IoFf poems 4k ydeegan Grow 4 p5pBoooaoomsoggsseesae0i aii10no9t5ee7es:25ffoEf ppoooigneeed ites ffoff seseagn Group 5 8Bgoojs0ssss 10077 Eof ference Range Ret ne CCHHOOLREETST GNLEUUCSOESE a $ 6 9 o a m184 &i G25 iWmPs $ s 5 i I m BiB 74 i 3 7 HBeWs s $0 ou o- qa- 96 319 Page 4+ IMLUDLR-DIR HMDLE-RDIR TMReIiGo. 2$3: 4 E 2F 8 I1 E .943 2S @ & 1tar m3 s iies :3 8a7gmam38e $ i8o3n % 135 eBsp uieys 0$ nRoo us e- 0-3 0 0 104 000942 418-018:PAGE H-15 CGAYTICS socruesvo sin 0, anor wo me rts a INCORPORATED 301-921-0168 Torr: Fax: 301-977-0433 BRE SoSSammy DRIVE rBaete mfoecmaeteveedsss" sare 12/12/2000 crt ne met (215) 443-8710 gays casos ov 108 species mr Noo.ccassion S8pec. B5000033005e6s8e 110093893: GpSexAg`9e CEHJOBLL"E_ST GWLCU/CbOLS.E LDMeL/-oDLIR HMDOL/-oDLIR_TWReI/GbL 6& FE 8517 115%2 133s 8 e $8 000943 418-018:PAGE H-16 GLYTICS crus sim si 0 comer vo me Client: A3RBGUSSuReIESNyECAORbCrRHtPvOELARBAOTRAETDORIES30,1-9I2N1C-.0168DBaEtEeSFaxCS:oRl3E0l1Ne-cE97tE7e-Yd0:43312/12/2000 O(2R1B5A)N.443B7a871010044- Date Reported: 04/27117/2001 Client No. 1028 Study: 418018 DAMS IDS Species: RAT AsSeecessioniSpBec. BFB5Ro%oio0e3er07s6 m1i1ed0ee0:e8A BOS il fseean Group 8 pBB5oooososijtotasaesld1 ii1l1it0e0tl9 pBBBoooOoologSelmaEmsse ddiHliBElt 2seahn Group Gp SexAggee 853 :IE 8 CCHHOORLESE"ST GELTUECRSO"SE IWDRLJ-oDEIR [a5 I 1i%g 3?3 8i 2 aa0 I3mes n1at DMoLj-oDnIR_ImReI/bSL r$E#r#R0 25750 EI 3 Aames 8883 EE 8E H so I a. ldasie $s&$ 8B F2E Iious 5535 ERokE #$ i 0 s aiak8 $ii ##330 00838 S2i iBsa383a 7dl 8135h Reference Range 9 w- 7a- 0- g- 3 96 319 o 104 Page 6 + 000944 418-018:PAGE H-17 CAXTICS cro son toes we Client: ApRGUSeRIEt SNECAORe CRHPOLRABAOTREATDORIES30,1-8I2N1C-.0168BDaaEtSeFaxRC:oEl3A0lI1e-Tc6E7t7Ee-Td0:43312/22/2000 BTOERERaaBa n10044- Date ReBpP orted: 04/f1ir7s/2001 Client No. 1028 Study: 413018 DAMS IDS Species: RAT fAascesslonSp8ec. | pp5Bao0so0o3tl0ao4ss7lIi10eee08 Bpososesssitii eoapn Group 1 GpPSSeexxAAggee 111 kIof 11ikEoF TF4d,,TROOTTAALLTT33yTSeOrTALFBREoEjT3 E5T5e8sontwwoeesois. i ea11an4 4 dar hWEB 8EFB TW 537 r eile oapgs TRaejim. FRNeEjEbuTA n 1n.i28 uk 80.:888 nek0863 Lneows 8o0f7 pBE0o8g0so3os30oee%sse8es:0 81l111i0%18e9 1I18o0 EEF 18k pBEBgoooo%diegieecs:eei d1Hleee0ess i0110o0 B Bos eR BH wsepan Group 10 09.:8382 9 0 7odp3pa.s6ip6 e088.u8kH6 p24g3, 00iB.Ey3E1 S88S4:a%35 ef28e%g%d S8d8uh43g Ba RaEEE Bk8 8EBB Sap 82:8 88 ni aTa8e BTeaEm 8as Lwmn an Reference Range 9 3. so. 7 100 rage 7+ 0-57-19 0 34a 2s 000945 418-018:PAGE H-18 GIYTICS co arspn sme 1 sams mr Client: pBmSGUuSSBREIERSNEECAORBCRRHPIOELRABAOTREATDORIES30,1-5I2N1C-.0168DBaattseFaSCxEoA3l0Il1Vg-Ec97Et7Ye."d00:5312/12/2000 H[SREGRANCRBaP10044 Date Reported:g 04/17/2001 Client No. 1028 Study: 413018 DAMS IDS Species: RAT RfeeecessionSp8ec.| GpoSexAg90e T4B,eTBOeTALTR3E,TDOETALFERoEfEkw13 1N8Hop pBBooo0og3aog0see5es0sds8e 11i11i80be3%y2 1Hi1 EEE IE 0TaaE38E7 hTemlEEHe 0a 4 S.6E1 1b.i4+g5 LE B2B o00%0003308e6%l06:2: 3 8330888 HdMisses 110 iii E IE ee83:s8328 msMRliss 852 dial SRoEEF NE mRBH oe BoE IEE HF 8:38 Sb 88 8% seBaHn T4is8s eEa.aEss 537Bs LLiNsBe Group 11 FWRoEyEbrTA 08 To.3+i8 o8853y oOnD aie PBBoo0Rs0o3s0sEe60es7 iO1M1t0eE4s1 BB1H2o FEE Keepan Group 12 S08I:4L43A88 a26d7I:.t0aR 91 R08o.4F4NEn14 V.l4Fs+9SN 808.B2321 3T8e TBaawm daeB Lhaup aa4nB B 0030608 11053 13 F Reference Range J 0.24 ass 0.26 0.97 0s 3- seo o- s7- 19- 7 100 o 3a 2.5 rage 8 + 000 HC 418-018:PAGE H-19 CLYTICS ove se se 5 gamer wo om INCORPORATED 301-521-0168 Fax: 301-977-0433 Client:3A0RGSUuSmRzEASYEARDCRHIVELABORATORIES, INC. DDaattee RCeocleligvcetde:d: 12/12/2000 HORSHAM, PA 19044- Date Reported: 04/17/2001 (215) 443-8710 Client No. 1028 Study: 418018 DAMS LDS Species: RAT eoecessionSipec.| GprSexAg9e TSA&,DTEO-TALTN3G,JD1LO.TALFRPEO/EML73 TNSGH/ML BpB0o0003s300e8623s361n1110e086y51 B1133 EEE B 0030637 11064 13 E 8 00.:2335 8h761:.E7988 0.76 0.4 3.48 0.82 0:38 eel2s ols0 179 B 0030628 11065 13 F 0:8 85:88 0d 214 M5ea7n dT2e77d7 TDeabl.3eir3 34994 11.087s Group 13 FNRGE/EDLT4 0.25 00o.li1Zl7s6 T1i5s8s3 BBB o00o003j30002s83s8323 111000089232331 222 EEFFE BB 00003300332356 1100893237 32 EF e5a8n7 Group 2 422..:233251 s8913l.:20y86 00o.78i83 i22:3383 18f3e:.261 o11l3s8 21.068038 8188.1558543 .1a22828 oa1.ll0ea4 011..%0221 2oa1s5e2s 901s5t3 1le.s9s82.82944s BBB 000000333000533532786 111000988342829 333 EEFE B 003060 10941 3 F eS%aBn0 Group 3 000:.:001081 6s780e.::53%70 0o0.l86a5 g12.1u17d28 0oo.3yl0 0:33 66.35 _ol78 _olss olin 128833 Tee5h.753 L4e%es 11.2H28 2B7e Reference Range 73- 1s000- 0Page 9 + a57T= a189- 000947 418-018:PAGE H-20 CLINYCOTRPIORACTESD _ ganio-seoiotsese sFaaxe s0or-ca77ooums svowor Client: ASRGUSERESSEARCEH LABORATORIES, INC. BDaakt2e SCoRlLlIeNcEtSeYd: 12/12/2000 BTIEEEHCRByM1s0us- Date Reported: 04/21771/2001 Cutent No. 1028 Study: 418018 DANS IDS Species: RAT AAeccessionESSpec.| GpPSSeexxAMgoee 5BpBooooaioeo0eweimieianj2n0ie3:4ns3 441ffEooFff ppoooegemistiten: iiff Htoogan Group 4 BB5Booooooosgoosaseees0 ii1i0dn9eee5ss7 3f22 fEF pBooogeedi ieten:fffF seegan Group 5 5Boooos0zsees 10977 fFE Reference Range ne T4Tu,,TTOOTTAMLLTR3U,/BTeOTNTAL FRRETE 3 S og8ai3n a fESryBe SeoBsmR Sa2 shgm 8 BA 2G38 eaamno sw 28 p E.8S0 aeoWs saeen nB1n0hss0 BBEO8ouRbR R&ER Suoee sWiIgRs enalr 08.080 sB o i 036 3. soo e- 7 100 0 Page 10+ TNSeHhm Ioe1Emyg aw Luiese 0be3.3EB2 88HR aoLH 0u.g2 so 34 FNRaErEnTd o8o0ghls &H am 0ai2.nng7 aopR a33% ouBa yo- 2.5 000948 418018,PAGE H21 CYINCTORIPORCATESD csoorcororsoessyn sFtaex 2301s47a70m4 s wo sr Client: ABRGRUSEREESEARSCHRLABORATORIES, INC. BDaattSe SCoSlIlcEtSe!d: 12/12/2000 BTEEERaeBy d1s0us- Date Reported: 04/31771/2001 Cuent No. 1028 Study: 416018 DANS IDS Species: RAT ReescessionS9pec. BB5poooonoagsememileassa ii1i0tn38ne3 NTeeegn Group BbBpooooomogeiooeeseiessos tii1e0n0s:e9:5 HEHE seran Group 7 f 8HBpoooEosmooEsp7gijiH03eN98 Bolas: Reference Range GpPSSeexxAAggee TFAAT,OOTTAALLTR3/,BTLO-TAL FERG7EMELC_13 1Nsejwn___ IFoofF 8le g:of8 a 7sI3i.E6s8 on8aln nonegys TamE TaeEas mono Lnmw FNRGE/EbLTA o88 83zH8 an 1777 %Iookb 0s8F.C:d0I80 I SgsueEse Sa fn 80 S3Sd3 sk E HE 13B2 MR R 0s hE &F TBaEOTehas sSee Lnaais ae 8E ff ffof geB neolsoOasaWnlege 0fBM7gIR9 na Dk &E 008.84R7 ef Ha nk a 8 33- 8 seo 89- hst1- 31d9- Page 11+ 0003849 418-018:PAGE H-22 CCLYTICS csi ses ns vo mom cuient:ent: AJRaGgUSsERIEPSNNECAEORCRLHPEOLARBAOTRAETDORIES30,1-9I2N1C-.0168DBaattteFaCSx:ol30lE1e-c9tH77e-d0:4331a/sasaco0 B18E)E4atBeynad1s0ue- Date Reported: 04/d1a7ti/2001 Client No. 1028 Study: 418018 DAMS IDS Species: RAT fiRossassionS8pec. opPSSeexxAAgdee A4,RBOETTAA- 1K3DI0ETAL RFRoEmEs03 INgoEpe FNRoEsEbrTA BFgooRoo3al0El7e6iE1le1iR0s0t8 88fokfF Bost HR 8 TLLaE8EnE samoegesEBse 0a d8.E80 1bbb3EEb5 08o8.8slB8 e385 SH hw 8 seoapn Taeo 7Ba.yeie oessm Lomaen aas Group 8 5BpBoooasoojwgloaeseem:: 1niH1te0d0yn0 9323kE pBBpooooosgniietgee MidiitdtEee 2222 of fF Mseeagn Group 9 80g9.8030io#8srn88e dSEousBRs 2.23 ELda 088 8.:332 8H Sa:3h88 Ooa a Nd 8 s8fk%l nfapyuRi an 8 83 Tee eLsas sAm Luawy aiEm ReSfherence Rang"e 33 . 2s8o0. o - 2sh7- Eidse ApprovedSag=ewem1m3eoetedt1m2mmeenn Date ~4Ai2A0 000950 418-018:PAGE H-23 CAYTICS css 020 sons uo zr Client: A5R08GUSSHERIEEHSNYECAORDCRRHIPVOLERABAOTREATDORIES30,1-9I2N1C-.0168DDaatteeFaxCR:oelc30le1ei-cv67te7ed-d:0:43312/14/2000 BORERAN. Ba 10044- (215) 443-8710 Date Reported: 01/16/2001 " Client No. 1028 Study: 418018 LDS MILK Species: RAT N[oc3essionS2pBec.| GpSexAge gMHGo/LDELST 5BB080000333111000333789 111000939001818 111 EEEF B 0031040 10913 1 E 22i78o io B 6031041 1081 1 1 EMepan 816%.8 Group 1 TTT BB8 000000333T11000s87019 111111000123910 111000 EE 172o BBB 000000333111000888382 111111000232435 111000 EFF 385o BBB 000000333111000888756 11i11l00o22287e 111008 EF F a21137 M$7e5a7n 1156.133 Group 10 Reference Range s48e Page 1+ 000951 418-018:PAGE H-24 CLINYCOTKPIORACTESD 301-c02r1u-s016s8 esFasx:3001,.9c77a-0n433e. vo zor Client: ABSRU0GTSULSSDHIENREGERSYAEADRRCIHVLEABORATORIES, INC. DDaattee CReocleligvcetde:d: 12/14/2000 HORERAM, PA_ 19044 Date Reported: 01/16/2001 (215) 443-8710 Client No. 1028 Study: 418018 LDS MILK Species: RAT NRoo:cesslon SSppece.c: BBB o00o00j33ii1oc0ss8ss0 111111000332129 BBB 000000333111000880333 111111000333435 BBB 000000333111000989356 i1111100033378 1 M8e7a0n Group 11 GCpPSSexeAhxgoee GHJoELTEST 1I1I11 EEE 1898 1I111I EEE i13s0 11I11I FEE id39S 880l81 TT -- BB 60003311009878 1110044s1 1132 E 340 $Me5a7n 217 Group 12 B 0031099 11059 13 F MEeaan Group 13 T[3TT Reference Range 856 Page 2 + 000952 418-018:PAGE H-25 CAYTICS oars sen sams wr Client: AeRoGsUSRREIESNPECAORRRCHPEOLRABAOTREATDORIES30,1-8I2N1C-0.168BDaatteeFaCSx:oRlL30lA1sI-cN97tE7eS-dY0:43312/24/2000 B13O1R8E)RE$C43B7a8mdsous Date Reported: 01/ov16/2001 Crient No. 1028 Study: 416018 IDS MIX Species: RAT e Jgoession spec. r Gp Sex Ade ioLpST rr BBpBBoo0ooom03mse1ne0det4in2iiie1ee0d9dy2:s1 i2fff offoFf 53:30 TTT MTeeagn 5faa Group 2 BHpoooEunoEiez toaIE33 Ef of 3s8 sdeeagn a32 Group 3 pBp8 oooooyonignggsoe1ii0ttr9ee5se7 Boe ie f332fo%%ffob 23:$3 FH] BoE ff ywoupn 3 nis Group 5 Reference Range wi= Page 3+ 000953 418-018:PAGE H-26 GLYTICS cia sm.si 00 arasurovo wor INCORPORATED ertens ange Be ere ne. "aac Sarita ag 30% Bussey DRIVE 301-921-0168 Fax:301-977-0433 Date Received: 12/14/2000 HORS N42 8710 16/: Client No. 1028 Study: 418018 LD5 MILK Species: RAT Jgoession gp P roe CHORE on rw crou6p jo a cron7 . ro . 000954 418.018PAGE H-27 CAYTICS nosso sm 2snesvo sr client:ent: ASROGEUSSHERRIERSNYECAORDCrRHiPvOeLARBAOTRAETDOR_IES30,1.6I2N1C-.0168BDaattseFaxRC:oOlA30lA1eI.cS97tE7eE:dY0:43312/24/2000 BBO1R8ER)AN4;hamBeAn1d19044- Date Reeppoorrtteedd:: 01/011/616/2001 Ce lient No. 1028 Stue dy: 418018 IDS MILK Spee cies: RAT Jesession ggec pSex Age GHOLEST 30031070 13008 8 F 17 Te KEeEan 018:.28 Group & 8BB000O033110O07713 11121000019 353 EEEF B 00307 iol: 3 EF 139i 2 BBBo0o%o0333iii000%77ses 1ooGiiisE 333 EEFFE B 8830 Hols 3% 83bh) 1 Mea8n 2E3D.1 Group Reference Range 3108 - APpPrpOVreovedage 5 N of L5 peattse -----+eiZi/ 000955 418-018:PAGE H-28 CLYTICS sem. 0 0 csr io om chiens: ARLRGUSLESIESLNENCAyORCIREPOIRABACTRENTDORIED30,1-921-0168DpBaa3ts2seFaxsBS:eEel30lAp1t-e9Tt7r7aEa-d0:433s17u0/0e/s2z0o0r0 (215) 443-8710 FhgogecssieonssionS5ppec.| GpSexAge CSHOOLTESTGGLLUUCTOSE IWDLS-RDIR HWDL-eDIR TMRIeG aroup 1 000956 418.018 PAGE H29 GLYTICS 1 cone som 00 stor wo or Client: ABRGLUSEREIESPNECAORCRHPOIRABARTMETDORTES3,01-9I2N1C-.0168BDaeteFeaxSg:oR3l0Rl1A-sS9c7Et7Re-Yd04:3312/08/2000 BRoERERMaaBthnado0u- Date RePpoorrted: 01/121661/:2001 Client No. 1028 Study: 418018 PUPS GD21 species: RAT F ee r 8 Gr ILES i GLuGesE IRVGRTR ERR IA S pBFBoggooorisseoetnreeee:ssrHHHeeesSms 11133 Bootosed Hess 13 W #8I 20I 8 Ei0B 8 0% B a BBoH Hui 0% 0B 8 gggooeslaedeetss HHHooeeeess 11i33 & 888% 0#$ %8 Bx0B 303B wetapnn prea rFeEeEalicor=aIli CvaO Group 13 B80gs0%oo033l300e0aas2%z]2ee 2111000088031i11s]52 2222 8 so30das 1081s 2 Bo 8#00m837 #008 fB 0toBm Hais 2 0H 0i4#B 8Bogeosaeentnse 1dio0to8s s}22 BB2 20878 n 3 fFBEd]i yseagn B2a 8aa Bpta BBep i3e Group 2 Reterence Range 8wo me Page 2+ 98 -98 -2:1s 000957 418-018:PAGE H-30 GLYTICS 200 Girard Stet, Sue 200, Gaiters, MO 20877 Clrienetn:t: A1R0G0U5SSRIEESNEECALORRCEHPYOLRABAOTREATDORIE3S0,1-8I2N1C-.0168DBaaetzeFaSxC:ol3R0l1e-Sc97t7Te-d0:43312/00/2000 BBUHEBOEamBy d1s0ue- Date Reported: 01/f316//2001 Cuient No. 1028 Study: 418018 PUPS GD21 Species: RAT RKeassenlon g8ee opsen han GGOlOLREST p5 oenmaenn1i0e3033 7a& GGLUeCOSEe 858 RViRn BWeRTn GRIES: r22m 3ii7 533 FHpBERooREeosieg pease 333 Boas ing 3 1E8Ha88] F582E%] 8ii 2i3#8 3333 888 2# weeapn G833 e8e 8ma 3lr p=)s Group 3 BB5Booooogsiodazaear aai1e0esg3i4sess 4 44 Boone 18 o832s 8 a83a8 8si2s ii1B 3 i# 5i33 3 BBBoooognsaeiniig?ns 44 2i@ i8a$ i88 ii3 335 weegan S2T3 hBsoeses 1Bp #Bg Group 4 Reference Range iw- me Page 3+ 89-08 -35 000958 418-018:PAGE H-31 Cutanrents A28n0a0Css,AAnISNSeYCEONnTRPIOARRGACRTAESTDORIESo 30,1-9I2N1C-0.168s B2a5t5sFs8aexSS:e2Sn3R00i1Its -ec9S7raE7a-Rmd0:4a3312/0w0o/2z00m0 BBEhEeLy one pee Papers 03/16/2001 ctiant vo. 2020 (215) 443-8710 sendy: faso1s us Gon specter: BT gcession E gp eep SSeex hAege GCHLOLEEST GGLUUSOSES L LJon L i MG/DL __IMeG/,DL B0030249 10958 8 54 62 30 13 34 erou6p 000959 418-018:PAGE H-32 GLYTICS csp 2020 gaps sr Clients ABRSEGueES IRpIEESNESCAORRCHoPOoIRAuBA-OTREATDORCE3S01,-9T21N-C0.168BBnaaatttFeeeaxSSR:oe3Olp0lo1L-gr9etE7te7adS-0d:4:331021//0286//22000001 ctent voH.oe1)0M2a8datenad seuays ateots pos 021 Species: AT/16/2 jm eer gees oPSSeexhe QUEST Ge WEeRT Rgelsi RAL mRieb B3 o0mdosom0ooei3iiro0oane2ree6eslss5s ii1tels0oomet9nse8eeser5s Boene les 77 J g6w #48 00w5220Bn0% 8 4#g #7888 E1uxno6mr 9B i 2830338B 2 pulls g 8 8 un 3% aroup 7 rrMean 6a4, BI70.3 OFT45.6 OHH 14.4 30. Reetfeorpeennccee TangRange 8w- H3se nage 5+ 28 -28 -1:Fe 000960 418-018:PAGE H-33 CLYTICS cress sn 50 sc vo sr Client: ABRGEUSLREIESENECAIORCERHPYOLRABAOTREATDORIES30,1-8I2N1C-.0168DBaEtSeFaSxC:oRl3H0l1Is.cS97tE7e-Ed0:43312/00/2000 EN Date Reported: 01/16/2001 Client No(.2151)028443-8720 Study: 410018 PUPS G21 Species: RAT aSeecsession S1Bpee Gp? sexhe BAE,DToETAL R13o,TR0T FRRCETE INgoEp ENReEyo BBBBB oooo0uo0gse3t0deae2s1nlde7 diii10nso9eso0::s1 els}}}11 08E.:0808800..00 0.00 rT BBgoeuueetdessd ii10eo50l3}}i 88G:8588 10.800 0.08 sean 3 Ti a Group 1 S5.D. .845 0s boBpomooseolsnni HimHetoetlte:se Bootede diate 1111B23 I 0ag8.o088s0 8808.:E80808 oo se Ee 80:.8080 BBpoooosdoeenn iH e tty B BI 5eH:eR8 8a888 0.00 tweeann 5 3 ; 3 Group 12 Reterence Range 33 Bseos o8 Page 6+ Smho onopa- 000961 418-018PAGE H-34 CLINYCOTRPIORACTESD 301c.9o2u1s016s8 i sFax e201.9s77o.04s33o. vo or Client: 2A5R8GUBSunRgEaSyEARDCRHIVLEABORATORIES, INC. DBaattee CReoclellavcetde:d': 12/08/2000 ROREHAN, PA 15044- Date Reported: 01/16/2001 (215) 443-8710 Client No. 1028 Study: 418018 PUPS GD21 Species: RAT hoecessionSSppeee:c. 5 B 8og8oo33s0eo%zzaea3s1 ot11o0ss8e3 BB8 888830333000%33e30d l111io0cs6es2s 3B 8888330%6e27 o1ie0es3 H5e5an Group 13 GCppsSeexxAghaee T4B,GIORTALTN3,mTOTALFRREpEmTS IWgAha 111333 13 58:0:.090880 1.16 8:88 1m 116 111333 13 008S:::l888o008 8252::::8803888 83 feacs 5TE FNRoEEuT4 a8:a38 088.::088088 89 BBBB 8o80o30z02z33s57 8030s 111000000111758 10018 322 2 880:.:800088 588:.6:483 0:08 0.07 BBBB 08o808o33330000352%33d:05i 111100000308338%08 2222 5:88 28.:9308 5Ke8an 8? iFTs 8or7 Group 2 Reference Rannoge 33- Bsoo"- 89Page 7+ a7-T0 a1d3- 000962 418-018:PAGE H-35 CYTICS crs est 0 cnr. zor Client: A0R8GUSS RRIEESNECAORDRCeHPrOLRABAOTREATDORIES30,1-9I2N1C-.0168BDaaEtSeFaxRC:EoA3l0Il1Ve-Ec97Et7Le-"d04:3312/08/2000 BeORREASnBd a 10044- Date Reppoorted: 01/111661/2001 Client No. 1028 Study: 418018 PUPS GD21 Species: RAT ARececessionS8pec. | GhpdSex Ag9e0 TB4e,BTOeTAL 7R3OD1E0TAL FFRoEjEwL13 TNSoHp BBB o8800o8o3i30ge2a03dy53z 1i1i808s398e333d80 3 8333s 1653 33333 BBa0B3K0R8 1I8N3 33 HBeaHn Group 3 0832.80%880 028B.808E80 oe 8:88 88::8888 82::3988 87 nTogsse 08 FRWEoEbLTA ~ 3:i 88 38 BB3 o80003a3020d431 Bg838ai: 1i20g03s0it4es5 100i &4d 380:.880880 02.0%0 5 0.00 8:88 08.:0808 B 88808833300a80i4s8s 1110088588880 44 pet its 4 83a%%8 1u8maS 8:88 Se 80.:0808 Moeoan Group 4 30 3 2.928 08 o 3 T Reference Range 33- Bsooo 08 rage 8 + h5t7-1393 - 000963 418-018:PAGE H-36 GLYTICS so cous so 00 canon vo om Client: RAERLGUES REIENSECMOARCHPOLRABAOTREATDORIE3S0,1-9I2N1C-.0168BDaattFseaxCS:oR3l0El1I-e9cE7tE7e-Yd04:3312/08/2000 B(o8R1s8R)RN4:43B-8a72010044 bate Reported: 01/112e6//2001 Client Wo. 1028 Study: 418018 PUPS GD21 Species: RAT L3RocessionSBpeec. oOppSSeexxAAggeeTTHiR,ETOETAL TR3,STOETAL FRRfEE"T3 1W8hHaFR REE AT4E BBB50goo0oeo3l3lte0esa3ses0ess 1ii10d8os3se3esd8s 2323 8088::08880888 o.a0 2.96 0.00 0.05 BBBFoogRoosllesesEaees:Ei11ktRse0ess 8:33 88888:::888888 81B8:83B88 o.oo 80.:088 Koeapn 38 Tmiee T8o 583%7 Group 5 8BB5 o308s000333o0883mi35:887 21i100807%es2 5BBBoooooaool3lto0eessaeernls 111i88d80se7a:?8 Meeapn croup 08.8080 03.0B0 oe 0.00 0883.:::08880888 0.00 oso 0.04 08.:0808 8:88 8:88 0.00 8:88 08 BL78e6 s 08 8"04 o8 T Reference Range 3P Boo 8 E Sh nd age 3 + 000964 418-018:PAGE H-37 IeDD(0 J ---- Client: 3AR8GUSSuRbIESNECAORDRCiHPvOLRABAOTREATDORIES30,1-8I2N1C-.0168DBaatteeFaxSC:oRl3E0l1Ng-cE97tE7a-Yd0:43312/08/2000 B1O5R8E)AShiaBT8anad10044- Date Reported: 01/Hi1s6t/2001 Client No. 1028 Study: 418018 PUPS GD21 Species: RAT fo bi Op sex hee BUa BEd T RyBaE dRwa Mw REO Bg g8G3o3330o023a8ec8se Booze 111100883338888s758 7777 088::088088 1.06 000 0.00 0.00 B2Rsg0e803H 33000s3ae7%sR 0 111880383H883E880 777 03.080 ooo 0.00 0.00 Mweaen o8 i +653 08 0 8 Group 7 Reterence Range 33- sBoo. 98 - EHs7O- 1.9- ovat emma deeene Date --eiflile Ape Page 10 of 10 SK 000965 418-018:PAGE H-38 CIINYCOTRPIORACTESD _ s30o19c21i016s8 e sFamx: 3001/6s77a-04m33me 20m citesnt:2A0R8GUSSuERzEASYEARDCRHIVELABORATORIES, INC. DDaattee RCeoclellevcetdetd': 12/12/2000 HORSHAM, PA 19044- Date Reported: 01/16/2001 (215) 443-8710 Client No. 1028 Study: 418018 PUPS LDS Species: RAT jAgcccesessisoinonSgppec. | GpoSexAg\9e CJHGOILBELS|T GLHGU/CbOLS~E_IMDGL/-ODLIR HDMLG-/DDLIR TMRGI/GDL gB 800000333000686333371 111000888001881 111 B 003063 10913 1 4150728 31285882 32325 2$2560 203 213 0% 37 2 28 iE B 0030638 10933 1 et 25 fF] is 332 e58an 1i08t.2 2d4o7l 356.6 7272 32085%.4 Group 1 BBB 000000333000666777345 111111000321039 111000 BBB 00000033300066677778 11111100033338 111000 BBB 00000033300086e78s8:0 1i11i10o03f38e7 111000 Me8an Group 10 1118387 j22e1076 22226 333235 22721398 iiio53 i32s28i22 23388 33be8l 22f8a3g 131778 17187078 Fk3Hd7 i338 31783080 121 a 1F7Os 247)1 334.7 189835.2 Reference Range 5488- 3ius- 8o- 98 - 132c5 Page 1+ 000966 418-018:PAGE H-39 Ie:04DOF J ---- chtents BNUEEEERIENRLCANOCRHoPOnPRAeBAOTREKTDORIE3S0,1-9T2H1C-0.168Bspaa3tt2eaFaxSCR:eoEpl3o0lR1rs-tc9Re7td7aE:-d0:433001//2106//22000001 cutant vo. 2028 (215) 443-8710 stays aso rs 105 species: RAT R Jozenisonesspion St gppec. Tp5 SSexAhge CGHOELT TEST GLRUCsOSE LrT DLe-DIR HfDrLeDnIR TRfIsG axon 11 yen aroun 12 5.D. Be We FT OF 3 0 3 --. 000967 418-018:PAGE H-40 ctionros s3oBCn AEIECNYCEOLTFRPOIORRATCTEESDD Bo30Oc1-c92aE1s-0i16o8nFB.eFtsatxsSe:3S00R1-I9c7S7-0s433t12/v1o3/2200m Ban re ara (215) 443-8710 feSosstsssionTE3eBec. Gp SexAggee CCHHOOLLEESTST GGLeUyCScO~SE LMDG/LD-LD.IR EMDG/LDDLTR IMRGI/DSL J -- Mean 167 288, 52 34 312 Mgeoapn 311%8.7 2356%8.2 189%) 254,7 3766:.33 000968 418-018:PAGE H-41 CLYTICS cngsan 0ams vo wor Client: NER B22 EERIE 1a/na/ao00 ARGUS RIESNECAORRCHPOLRABAOTREATDORIES30,1-8I2N1C-.0168DateFaxC:ol30l1g-c97t7e-d0:433 BB EIBHE E BL y isons Date Reported: 01/11861/2001 Client No. 1028 Study: 418018 PUPS D5 Species: RAT fRgocsesessiaolnonGgep s arPsseexxAMoae sGCOHOLLEESST T GGLEUUGSEoTSE IrBoLDbIA EMED/obR ImMiEn BB5 oooaxsseesee1ii0sE3e7788 m H RE om E m o3$s%$ Ea 4E a Bt yreegn BGoyo8myouoH. B5Y Beasl Group 6 B5 ooogs0eesn3 1i0s0es 7 yowupn Group 7 B5BBgoooeo0iaxjge0e6essssss giM2n0sa0at:8e 2228 BBBBogogoeooiigxageeeessesssts HdMgiaaetdsse 2222 Bones HR 2 Reference Range m woa m 23 a8 02 nBL OB 88 s 3% h0% m B we O0 Wa8s 373i8 3# 8 B s 8 % ose n H Ho o o8 33i8 B g 5 #0 B a %ae $m i rH iw- Hpe- 8e- 89-3HS Page 4+ 000969 418-018:PAGE H-42 CAYTICS oosp e 1 gsm wr Client: A3R8G8USSuRmIESNyECAORRCRiHPvOeLRABAOTREATDORIES30,1-9I2N1C-.0168DBaatteeFaxCR:eozl3a0ll1g-vc9e7td7a:-d'0:43312/12/2000 BTRIEERCMaaTBeanad1s0us- DateSop Reported: 01/x1)6/2001 Client No. 1028 Study: 416018 PUPS IDS Species: RAT FoJosesasioen ssion Sgpoeecr. 5 oos0ses 13008 sreeagn Group 8 8BB2googooooisiig0geeeesessssse 1dH11io100eh%9 5BBBoooooooxxieeeersstts tiHHitidteee GpGpSSeexxAagoee CgHiOoLgpEeSnT GCLhUycCoOseSE L[DrLop-eDIR ErDL-iDIR TGRiIGg 8 Ha Twaes oawn. 5 Tae w wma e3p i#m3a 8982 3 mwEB LeEomos 25i3 FI8 LB i m8 3 88 353 FH B A o M 333 7B Eo Eik Mean Group 9 S.D. 119.1 11.2 221.3 66.1 31.5 5.4 37.1 12.8 175.1 oa Reference Range ng w- - 9- 96 319 Page 5+ 0-3 0 125 000970 418-018:PAGE H-43 CLYTICS com res. sm20, ctr wo sos rte AEBREETERRoIENCEsORPNOaRATEED ,301-9m21e-.0168BpeaaettstsFaSSmx:eEap30Rol1rI-ie9E7st7aS-s0a433ssan/yasaasraaonneon (215) 443-8710 SFeosm!ssaion s2n'es. B0030631 10906 Gp SexAggee TT44/,BIET0AETAL TR3,OIE0TAL FFRoEjMELT|o TNaGE/ML 1 0.45 39.28 FNRGE/DELTA crow3n Mean 017 37.71 2.36 Tote 000971 418-018:PAGE H-44 GLYTICS nar sro se samo wo sm Client: 8A0R8GUSSubRsIEaSNyECAORoCRRHrPvOELRABAOTREATDOR_IES30,19I2N1C0.168DDaatteFeaxRC:eoc3le0l1ie9vc7et7de0:d4:3312/12/2000 HORSHAM, PA 19044- Date Reported: 01/16/2001 (215) 443-8710 Client No. 1028 Study: 418018 PUPS LDS Species: RAT f Rooeo saion) Spec. pBB0o00o03g300esed8ss2s h1131e0023n52 BBB Q0G0o03330o0eesese7s 11111100033335 BBB 000000333000e6ss5ss0 11i17i00o33l78e M5ea8n7 Group 11 GpPSSeexxAAgdee i1111 iIIIII 11II11 TB4,LTTOTAL TR3/,BT0LTAL FPRGE/EMLT3 8o8:.:800800 1W033h3.2i78 880.80%80 800:.:908800 39.69 0.00 08::0800 3333114%3 old 06 5329.1538888 .l0e0i8s TNseRjun _FNRGE/bELTA 9.089::18618 956.::903930 "0o1028 B 0030691 11049 12 0.00 42.35 0.02 MSeaYn $s 382.35 8"oz Group 12 B 0030692 11059 13 0.00 40.17 0.15 0.01 M5e8an o$ 0o .17 8as 8S01 Group 13 Reference Ranngge 73- s26o0- o0rage 7 + F5P7R. 1.8 - 000972 418-018:PAGE H-45 CLYTICS or sue 0 us nm o wor Client: AFRGUES T IoRNgECSEOBARRRCiHPvOELRABAOTREATDORIES30,1-9I2N1C-.0168DBaattFeeaxCS:oO3lI0l1Se-c9N7tA7e-Yd0:43312/22/2000 H3O1R5ER)AN5C437B8a71010044- Date Rep9o2rted: 01/16/2001 Ciient No. 1028 Study: 418018 PUPS IDS Species: RAT hReescessionS8pec. | GpPSSeexxAAgdee TaB,eTyObTRATLTR3o,TEOTAL FRReEEpT3 1W8eHpw 5BBBgo0oeo0olx33o0a0e6ded3sds8 1i1i05sn933ad81 2222 a88S:s85Es7 A9Bf2Si.R3Ug3 8oE8mR om oa Boe iy 2 youpne sal & 4Te%e mWah wr danh Group 2 | B8B ooo%eodjM00Eesdsdsy 11i009k0339 333 088.::880880 323888.:6219 o.e8 setoagn 38 703.8633 8eT Grow 3 8BBB 8oo0o8ooj3s30008eeeeslsdssse 21110800958563:7s 5 22 B3 goexeeds 1I85e68 32 soepan Grow 5 0888.:::2338080 3sWa2oah3s oSHo aa 88:33 GiideB T3a3 gBeaasws 3ET IGE FRNEejEbrTA a88O-:o8E38 8:38 a8s 08.:081 T1e8n8 8088::.830H886 8:8 T8E%E Reference Range 3 Bo E8 E She nEdT Page 8 + 000973 418-018:PAGE H-46 CLYTICS aus synsi 3: stows vo sr Client:3A5R5GUSSwRaIESNyECAORDRCrHiPvOeLRABAOTREATDORIES30,19I2N1C0.168DBaatteeFaxRC:oelc30le1ei.cv97te7ed.d:0:43312/12/2000 HORSHAM, PA 19044- Date Reported: 01/16/2001 (215) 443-8720 Client No. 1028 Study: 418018 PUPS LDS Species: RAT jiSosisslon s8pec. BBB 000000333000668538220 111000339787537 MSeTan Group 6 Gp2 SexAwJee TB4&,/IBOETA-LTN3G,/ID0LTAL FPGR/EMELT=5 TNsG/ML___ 6& 080.:.000000 33a80d:.53d88 0.00 6.00 8 PLECT7IN 23 o8 FNRGE/EDLTM 05.:0800 08 BB 00003300863523 1100959857 77 M5e8an Group 7 BBB 000000333000668353758 11107190090090 &@ BBB 000000333000686383309 111111000000334 88& BBB 00O00o33j00o86s66e3:: 11111100000075s &8& Reference Range 0.00 9 800::.000000 020:::080080 608:::808000 33 - 25.90 28575 383073.:563273 7g35i33ss A439%L.:93R82 s28o0- 0o.l0o0s 9G.o0o0 $0- 0.01 986.::080311 985.::93028d a 57-138s - Page 9 + 000974 418-018:PAGE H-47 cient: aBgEusLAAIESRNEECAPNORRGIEPROIRABAOTREARDORIE3S0,1-9I2N1-G0.168BBDaaatttFeseaxSSR:oe3lpR0lo1-grE9et7te7Yad-d:04:331021//3126//22000001 Client HoT.351)028443-8720 study: 410018 POPS 105 Species: MATtak SJocessemioen sien gmp esonGe SSeex RaaoeeRTAR,OTOTALTRi,ITOTAL FBRREETTS IWghe FRRERELTM croup 8 | Bones Hale 3 gBoaodggiee nuoo 33 Mean croup 9 9 gos Ba om gis [ $88 WH ow gseg 0 15.825 Told 7 100 0 3a 2.5 approvedSugcecenTrSehnem0ennnene Date w-illidll. 000975 INCORPORATED 301-921-0168 800-237-2815 QA AUDIT REPORT hTSoedeTrfePpooorrtartleoiprsoytretPdraabncedtliocwaelslwaasansdrseowvciiiteahwteeEddPAfroaGrwodoicddnoagmLtspaalbiowwareenarrcteeeorwryrieetvPphiroearwtctehtedeidceFfsDot.Aro mTaenagaermeent.and consistency and the fin TToihere ncmi ietihiondcsTeefulwseiectdths wthtehereeFdDaAtthaea.ndmeTEtPhhAeordGesofoodrd,eLsacbtrohirebsaeetdorsytaundPdireasctthwieceerser.epdoormte FQrAaAnukdliitnorB,. Newaan sponsor: AR6vs RESEARCH 1ABS stoox: 4/401 REPORT TYPE: HEM, 73T,, TSH FT3, FTHy hive AUDIT DATE: 1-32-01 REPORT TO MANAGEMENT: 1232-0) AUDIT #: or 063 SATE3 S[UfBMsITTEDHTeO CLIENT Te 34 Rrigwind Yeux -- vNasAYcEMENT 17%27/ . 000976 418-018:PAGE H-49 CALYTICS crus som 200cana. vo om Client: HAJREGSEUSRSREIESNSSECAORCCRHoPHOLuARBAOTRNEIDORIES30,1-9T2N1C-.0168BbDiaattteeFeaxRSC:oeRlp30loS1gr-ct9Ete77edE-d:0:4330042//3071//22000030 Client NoH.OR102e8iaTen1d Study: 410016 105 MILK Speciesh: iRAT Py No. I P ge MG/DL BPBppBo0oooo0m3mmsa5m5ssso2m9 i1dvHu1eie5ae0t:s1 11111}Ffoobff 1} 1ii163H52 8 TTT ppsBoooommmmeeessssyi HHHHaaassls poames uEle 1111 bB 1} gFiH3e)9 BY gpsoeanagmso nuHzEs 111 ooff 333 yeegan 1585% Group 1 bppBooooogoutsissgeeeeoisnse H1eHesee2ets0 1111088 E goosen Hen 18 Jfiii)r % BBoommEsenenHieles 118 F 1i] Reterence Range s- 9 96 Page 1+ 000977 418-018:PAGE H-50 CLINYCOTRPIORACTESD a301.s021.e0168. sFamx 2.01:s977a-0m433 vo am Client: ABH8RO5OR8GTSULHSSDAuIMREN,EmGSREyAPAARDCRHI1V9LE0A4B4O-RATORIES, INC. DBaattee RCeoclellsvcetdeid': 2/01/2001 Date Reported: 04/17/2001 (215) 443-8710 Client No. 1028 Study: 418018 DS MILK Species: RAT ERRERT fer 5 P Sex he SEL - 5BooGosiseellss 111828 11b0 ai1t TT e5a5n 81054.2 Group 10 BB8 OooGsvIeeErrSs0 pots H1H1Ee3Ed0 He I1I1 kkI IIE B 00osesz lie IIE 88%76 7 BpB o8880s3sseeed3sdi pe l1i1is6gl3ee7 ee 1ii1 Er nov 12$8752% KEeaAn 88:22 Group 11 5BBooosoidssseezes7 m1m1ee4ll0: 11122 kEF 23& Reterence Rang"e 85 - Page 2+ Q00978 418-018:PAGE H-51 GLEYSRTI IORACTESD 2S00GiNrarSdSto,SuFiate s20o.vaGrahrroshnusrg, NO 20877 Client: ASREGUES RREESEARSCRH ALABORATORIES, INC. BDaatse GCoRlRlIsScEtSedY: 02/01/2001 BTOERE)RAhNaaBmeanad10044- Date Reporteatd: 04/asf1zr7/u/0020 Client No. 1028 Study: 416018 IDS MILK Species: RAT ee EBeee p5 ooardzeeso 1l1iset aPSsexeAege gCHeOREe 1I2 EEB 09i%% Tn ppBBooooossEeeeElst gHlMleeSell pogiels He iiIIEEf: Bk H&82]3 oes nes iF seeagn 8 B75i3 Grow 12 5ppoooooismseedsass Bagel 1ilH6ieE5gsE8: 11B33 EEF Bk 08HH2yi soeayn 3E3A55 Group 13 bpooossssezsmses f2 F a Reference Rannsge ia - age 3+ 0Q0979 418-018:PAGE H-52 CLYTICS a ersmt saanrnvo om tenes pBEosELsILaENCmOeYRoPOauRsAoTmEaDToss3,01-9e2e1-.0168fvBaegeiFstaxSSR:Ae30pR1EoS-r9H7tE7Ls-E0433oa41n72s01 cute size (215) 443-8710 sya s caso1e 1s NE species az ene gee he Gg B 0035545 11517 2 FE 118 reterace-- sarse a- 000980 418-018:PAGE H-53 CLYTICS css e 50 amsp vo wor INCORPORATED 3019210168 Fax: 301.877-0433 Client: AB3R0OG5TULSBSTuRNEEGESRAEYARDCRHIVELABORATORIES, INC. HORSHAM, PA 19044- DDaattee CReoclelicvteedd:: 02/01/2001 Date Reported: 04/17/2001 (218) 443-8710 CI lient No. 1028 StuE dy: 418018 LDS MIT LK T SpeR cies: RAT jgcession gpee- % 9 mer 5B000033%s3seees 1111334872 44 EF 2665 Mea5n 1i8t8 e Group 4 B3B 0o000o33s23s33e67s0 11111153358e852 B 0033370 11363 253 EEEF 5 FE 11053936 137 BBB 0000003333338887773; 111111333662s78 333 0032374 1136s 3 11103040s 5 8BBo00000338338277s52 111113336%5 323%& 182878 M5ea8n 51070.%7 Group 5 B 0035578 11574 6 F 72 Reference Ran9ge 848% - Page 5 + 000951 41-018:PAGE H-54 CALYTICS INCORPORATED cSorsrrroneusomsstFaew 0soragrraodsm osm Client: A25R0G8USRRRESREARBCRHIELABORATORIES, INC. DBaEtEeS RCRolIlIeScEtSeYd: 02/01/2000 E(SB1R8E)RA4C4sB78a720100u4- Date RepPoarTtEeSde:EJRG0e4/17/2001 Client No. 1028 Study: 418018 LDS MILK Species: RAT Rr geain fee e. m sox dan gee en ron B5pDoaooloimesaertEs 1HnH1EeI57SeE5 fkEFIFE 7#138 BppFooRzooEaElemsH:eMiaeisEae(?I E fF i13s2 183 soeapn 78%s Group Bppooeousmgeeye uiMEisEa 777 EoRFFE #0 Mweapn F5:e3 Group 7 p8BoooosesEemo 1mn1es60?:0 58 oEEFF 12774] Reference Ranige 8a - rage 6+ 000982 : 418-018:PAGE H-55 CAYTIOS porns su sr uo ar Client: ASRSGUSBuRIEeSNnECAORrRCiHPvOeLRABAOTREATDORIES30,1-8T2N1C-.0168DBaEtFSeaxSC:o3R0lA1l-Ie9cT7t7Ee-E0d4:3302/01/2000 B(E2R15E)RRE4S42B7y6720sous Date Reppoorterd ted: 04/17/2001 Client No. 1028 Study: 410018 LDS WILK Species: RAT SFoEeessio--nSpas. BppBaooosnmeEssme1ls1e5lse0ss BFBR oeEm HAey Heopan opPSseexxahgee gSmEeTmHEer 8353 EfFF i3paH8 3 3k iii #fr4e] | Group 8 BpBpaoogomndsEEessseetRor meHHeelelnl 3332 kEF poEshi Hels 3 1i983% 3 [ppBaReasEesseEser A Hddeeellrse 333 kf i28388 weeagn T380%8 Group 3 Reterence Range 45 ApprovedBag--s=nmTs-t3le7linmemen Date LZ 000983 418-018:PAGE H-56 GLYTICS o som.sis 0 amass 0 om + Axcus, mIeNsCoOnRsPOpRABAGTREATDORIE3S0,1-9T21e-.0168atFaaxS:o3l0i1-g9c7t7a-a04:33 Cypens BRE oui $05 SuEsHY DRIVE Doauttea RReepcoerivteedd:: 0022//0223//22000010 cts wo. 1028 (215) 443-8710 seutys 410016Duis 105 speciesBA:T a SieBeeeG GoE e gre B pee B fae e Bmme. I. 000984 418-018:PAGEH-57 : GLYTICS 210 Grr srs St 220, Garr NO 2677 Chteonnts a1B70g00B8EPBIEBRSNTCAORECRHPOI.ARRAOTRNEIDGRIES30,1-9T2G1-.0168B2oa2it6eeF2axSSr:ol3Ae0i1gS-ae9t7L7.e-d0s433cSze/vo2a0nm ret (215) 443-8710 geudys 4itois ows 105 Speciems BAF Sfgoenseion mler SEpeeesT er SexAgS e GHG OLEST GLgUCeOSE IWDrLo-bpIN MRDLy-eDIR IEMIhG rou 11 000985 418-018:PAGE H-58 CALYTICS con see st10sirwo ,sr INCORPORATED 301-921-0168 Fax: 301-977-0433 ne nize, sae pe Som ci Bu3,STEAY DRIVE Date Received: 02/02/2001 crs nt rat ys H(O2R1S5H)AM4,43-PA8_71019044- casovo1sD0a8te species: Reported: mr02/13/2001 jroececsesisosnion Sgmgeecc. BB0o0o35e8d2:3 1H1e65s4s GGppsSeexxhAagee CCHHOOLLESETSGTIGCLOUSCOESE LIDDLI-RDIR EpDLT-DIR TJRIGG 1I3 EF Ead 21088 31 E3i5 12 1% 5 aro 3 000986 418-018:PAGE H-59 CAYTICS ces rm st, sites 0 om Clieenntt:: AMRSGOUES RREISENECMPORCRRHPEOLARBAOTRAETDORIES30,1-9I2N1C-.0168DBaet8e2FaxCS:ol30lH1e-c9tI77e-d0:43302/02/2002 BHEORLSBHhE Byd1o0us- Date Reported: 02/7133/2001 Client No. 1028 Study: 410018 DANS 105 Species: RAT NJogcceesssisoinon Sgppeec. | BpppBooo0om0ss3s5er7mm8sae7r1aHin1aii5:s0aas1 BpBpooooammmsosimsiiietiiasless BgBBpoeooodddamEsemmeeieinrln ysoesgn Group 1 bBgBooooooyoseaseeosesr 1hHHi6eee0dl pgBooEaoEeEmeeSle HiHlEee Reterence Range GpPSSeexxAAggee 1T111 E}fF 1111 G}ooff i111o ooofff iF 1HHHPfBE iHHfff TT33,TTOOTTAALLTB4d,TTOOTTAALL TRSeH m $5a om5a.se6r4 1BR 3n.33i0 EE 1Eob6Rng8 ggE mEfuRB pBERBH 3bobdnyE gmGe8iEe eRexeRBR Ra nEgeE aa oi fa GRE3T iE an E Les FFRarEmEsT3 eg08 a.4nnE3 eoSeyBiB 8eSosn8yRa ae 2wsBe9.nR832 8N0o3a%e7n EznuEaskRn &osguRins e @i9 es%sn BnnRooeSnik s8oo 33-1ST-S9 FRReEpEu1.4 0ao18.68dn%2 on ue8oa%Rd oo8f%n gm uoo8smBp ooemkn 312a- Page 4+ wuud987 418-018:PAGE H-60 CLYTICS occas sve. st 0. st, wo er ene: Crients Ah B9R0E5GUSESHe REREIEHSNYECAORDCRRHIoPVOLEnARBeAOTRAETDORIE30S1,-9T21N-C0.168DaoaastteesFaxRnS:eeocpl30eai1irg-vtc6e7at7dde-:as0:4330a2t//0120//22000010 (215) 443-8710 FFoE-- iesionEmes. BB00o35s80s81H16E3E8 -- GppSseexxAdgaee 1T33,TOOTTRALT5i4 TTOOTTAALLTTSHee FBRoEEuT3 FRRrEEbT4 uHFF 3A 1.70 0i .10 0n.6l0 08.0%9 0o.1s8 oe 100 7 3a 2.5 oCeas8 418-018:PAGE H-61 CLYTICS crue som sn 0 gata. vo sr Citent: ARGUS RIESNECAORCRHPOLRADAOTREMTDORIE3S0,1-9I2N1C-0.168BateFaxC:ol30l1p-c97t7a-d0:433 on [0 A 20%, Ed]DRIVE DDaattee RReecpeoirvteedd:: 0022//0123//22000011 Client vo(.2152)028443-8710 study: 410010 MKS Ts Species: RAT Jm pm oemoEnnE 3gg E HBbFEoTef:e h e Ra TE wgLaa TGLoesRaaas BihhLnpee a,ies EoBeageLimaE FWEo8ohLHpl BBgBBoooaobasihndtgfieeeaaadiss hhneieeeetenes BBHB ffIof Boog hee Bf deiEwheEge gies geekpdaamdpmd 9 pnynoarmHngm rg eeoeonaadmen oh Segopyainh on BBBooooooomdesadenlegneegstr Bodie 1BBBfffI Bf Hfmgaaair pemedaRas gogeuemnem eoeseamdmr ooBodnhl orrl Twhm TEEmE awes aamm aamn Group 13 raterence Sunnage 1w80o 31- Sghe7e 98 . 3133- approvedGawogenseSrF".r eereere nate HEL 3/3060 9009589 418-018:PAGE H-62 CAYTICS scons sie ste 0sao,wo zm chiens apBngesEs pIvLNACROGRHPOMRASAOTRENIDURIES30,1-8N2C1-.0168BtbiatstFseaxSSm:SaeRMp3RS0EeME1r-Ee9E7aE7a-S:0c:43a3/2o/a13r/a2o0o0s1 (215) 443-8710 SNeo.sser e bi e se he SGJBL MG/nDeL __B Mo/e bL|BMG/aDL _BMGr/DL ro 3+ 000990 418-018:PAGE H-63 CLYTICS scm som. 020csv wo om crient:+ a3Bn0Ec8R,REETBEAIbDaNsCAaOnCcRHhaPoYOJuARiBAC-TRAETDORIZS30,1-8I2N1C-.0168aBbaagsteeeFaSSxR:oeSlp3A0loE1tr-Eet9R7te7Ead-"ds0s4330023//0123//22000010 cJo aetenntivno(.21ge51es)024843-871o0p ssevxuhdaye: g41o01g6oANCe Sgug1eo0e8t WSGEpeIcies: BBEATREBE, croup 2 re spocossmuess simee BpPaooidmdipneiaein 33 11 213 oif BpgE Poloinunmdmeiemt iilammeyee 11 2ooff if g, We LL mt ow oo g#Boom 8 mm#sm : 133fog8o8ong oBm 8C8f goe8eo 0B @#8f 1 :F 3 m88B #5 u0o%n J go Ms 8 sage 2+ BT la 000991 418-018:PAGE H-64 CGLYTICS com see st 10 spars wo em Clieenntst: MAREGUSS ERIESPNECNOIRCRHPLOLRABAOTREATDORIE3S0,1-9T2N1-C0.168DBaatteeFaxSC:oR3lL0l1Ss-cE97tR7a-Yd0:43302/02/200 C1tent BTUoLrIEeINhC a3t,haio0uivo. 2028 Study: 410016 DANS Date 15 Reported: Species: 02/s1i3d/2001 BAT jTBoceamsooiomn mgnee Egigetc teeG4TpssEeeIxhhaeee GGEIELo8SET SGGiUIiEeIDSesEsIDVPpTTE EBo oTnb BMIiGonm BBpBBoogoovoooiisousssemeeeeseceette HEuivtEEise 441i4 | @g B B3 oi nEi $ :i io8 orB #4 W0o%u ppBBBooaoooogdoasgemseseeenrrrHnosnits:s 4fff1 fff gg8giinai [I] iit iP0o8B E28og u3a semoian 1: op? wyzaTgos id HI 5m $85 8% 3d iE 8 -- bBpgooooossagsseegerrnsss mufnasieeee poosser ine 3f23 f%EfF ff pooiseso nized 2 iPg gOi i,38 2giie :3i Toon$o8e iH] rg#3 a BBoOcaEs ii 2i: Foteserce Serge niook $ i88 58 aou we me 2- me ig nt 96 319 0 80 104 pose 3+ 000992 418-018:PAGE H-65 CLYTICS scum sve.st 0,sitawor,er Chtans agus EIEaNTCAOAGRHPOTARBAOTRAETDORIE30S1,-92I1v-e0.168DatsFaxE:a3l0i1-p9e7t7a-t04s33 Hast BIEL" one $05, BHEESY DRIVE DSaotoem RSeecpeeirvteedd:s corm 02/02/2001 vans se meet (215) 443-8710 study: 41018TNE 05 Spectess RAE fSgsoceensssiioonnSgppeec. GpPSSeexxAhagee GCCHOHLOELSESTGLGULICCOOSE IMDIILS-HDIR HRDLU-EDIR TfRIeG croup 5 0090993 418.018:PAGE H-66 CL{NYCOTRPIORACTESD csoorouzrsovessve sFaexS0O1.9c77-o063r wo sr cutenc:+ ASRRGSUUSSRREERSEYARBCRHrvELABORATORIES, INC. DBaattee SCoRlRlIeScItAedY: 02/02/2001 BBERRC Bh 10004 Date Reported: 02/13/2001 (215) 443-8710 Client No. 1028 Study: 418018 DAMS IDS Species: RAT fgTcemnestnoEnR3ep=sT oOnpSeexx hAageeGGiIoOLLEESSTT GGLUECSOTSE IRDoipRiR MMoSbL.I EWRbS |! 3pBBpoo0ooo0ool3sEdE5sss2ee0teEi1ti1iHEH1s3Eel8EEr8 1777 :FoEEr 7 38$ a8 i i1i9sn4 & is 1133i i 7@$&58 a88383 oa 3 5 00 ppBBooogos0sdi3Eds8se0eteeiid1d1ii2eas8ss0 7777 Boinen nEst 7k [I #i A0 i a is ii:$ 883Hoo.9322 ia8 pBpBooodosmdsinstiaiHiAeesEEse 7777 :ofokFk gS#i0 ise in : 8$i2 a8in seeapn 5#3 T3ises 483 m#a3 aBdH Group 7 BpDpoooogsyasssen1iis tdh11ei6e0ee0 8&&88 kIEF LE 5 EF w48w & i11a8 a a8 si5 $ p32H% & a32s8s af 2 8 88 BppooeoanMIRalI hHeEs 88 oofF g a aiB 33 8" 888 Reference Range w& - Hnea- 80- 82- f3oi rage 5+ 000994 418-018:PAGE H-67 GLYTICS soomar smzngimme wo mer Lient: ARGUS REISNECAORCRHPOLARBAOTRAETDORIES3,01-8I2N1C-.0168DateFaCx:ol30l1g-c9t77e-d0:433 Sie usBuESAl DRIVE Date Received: 02/02/2001 Client TEE ld HORSHAM, PA 19044- No. 1028 Study: 418018 DAMS Date Reported: LDS Species: 02/13/2001 RAT S-- mii) oiEee 5Booo3osanas 1n1e60l7 TepP SSeexxAAggee GCHHOORLESETST GSLEUjCSROTSE WLDLL-DIREDWLoDLIR ZWReI/Zbu 8 EEFF EBTREY 332 75 385 BoSdsa ae epaen A ssss 11%0 4f7l e#s8 8873 Group 8 BppBooooooydsdmesssdesseslienue 353 IoOkE 8 podeege nels 3 of # a 81 i d1m sin .i i si&$ s aa338 3 a iy ppppoooodsmme ehaHigsEEhs 88s5 fxoF 83s wo aiis% iii : $ i58 i38&2 Keeagn 3 3 HHe%a 1nmd imsie 1B0Ya Group 3 Reference Range ig o-oo. 9- 96 319 Approved PPT Page ee of 6 2- 3- 80 104 ate ~SLLL Bat 34 000995 418-018:PAGE H-68 LYTICS sooussrm ssn mm store mom crtenntts: ABNRIEGLOUBSHSRCEIESNREBCAPyORRCRHE1P0ROL0ARaBeAO-TRAETDORIES30,1-9I2N1C-.0168DBDaeateteseFaCSxR:oeRlp3H0lo1Asr-ctT97teI7ed-Ed:0:4330o2a/1/1o33a1//22000m1 Fe eR Client Fo. 2028 Study: 416018 PUPS IDs Species: RAT fecemeion gp Pi ha gGOe 50533728 115017388 1 Te GGeR 33m i WnSB Wele t Bieh 33 3 8a a H 323B 2o0g08oo33ir22r77eE a33ds03 H1HMB3EG8BNSa 8//AB5N0D31111 m Bm Hoe B M33d8 Hi 3383i #5B B 0 n faa FL] 3 983373) HAH sereagn 1 m Tieee Ia mBte 8Bg i8hy Group 1 83 0go0ga3ss2se7T73ass8 1HH3Ea0/Rg63Ie3 11i3 n 3 woo m 22i8 3 3B B3 a aaw 38 038032m73l81e8R5ene 111 steogan Fw c o HPeo OR ia 3 eose FL pRee BoYg Group 11 B5 ggoa3ss7ap0 H11ses0esslar 12 w moW m 3 63!1m Roterence Range iw- 7 He -9 8 -8 8 1135 Page 1+ 00096 418-018:PAGE H-69 GLYTICS soco 300 0smsoswom Cate+ naBnaguEs SIELmNEeCeRTOASRRCeHLPOAYnSROeARTAEIDORIE3S01,-82T1i-C0.168fJbaatrtFseasxSe:op3n0el1r-te9c7ae7da-st0s433oa/23/2001 crt naan (215) 443-8710 says aasoss om 15s Pspecter: afas/e0f oSemgoo ee er sexAge GgOaLgIeST Ggiieioest Iniepe REfLrDitER mBiek oxoup 13 os f- Hm 0 BT 0009Y7? 418-018:PAGE H-70 CLYTICS cous sm 50 0 nso. vo om cutene:wnt: SAJR3OGUETSE,SEERAEIESNLECCAORCRHHoPOTARuBAOTRNETDORIE30S1,-92T1N-C0.168DbBaaattseeeFaRxSc:oeSlp30loS1sr-Ect97teE7ed-Ed:0:4330022//1032//2200000m cient noH.OR1E0T2M8 ahnad study: 4asois UES 105 Species: mT/ SJoeao aien mmgpe or7SSeexxAhagee R i omaT n asn/eT ants 1 EgIw g EoInEMo g L ISue g Oe nIROgTTAL Re GgeILpyhyoFsFURo0gReEpSeeT FFEE8oeER.hn4T on BB ossooeeiimtttirnaaedd dHnsitaaeeeine 111 or wFSrisROt Eoggo iodneg egmw goan SGsie ETaly LhEon 3 556 croup 1 pr Eoin Hal B eroup 11 gE ge PE En sw I 000998 418-018:PAGE H-71 GLYTICS snormsp 0 cst vo wor Client: ASRRGEUShREIESNECAORSCReHaPtOLARBAOTRAETDORIES30,1-9I2N1C-.0168DBaattFesaxRC:o3El0l1Ns-9cE7t7eE-d04:3302/02/2001 : BBO1R8R)AC443B-8a7201s044- Date Reported: 02/11331/2001 Client Ho. 1028 Study: 418018 PUPS IDS Species: RAT | FRegsoaesesaiioonn Sgpgeeec.. Gopp SesexxAMgaee Ip3,gTaOTAL|TBaTROTAL7R38h.a FBREETD) FRREEETA | BB8 00808333253777444822 111g18s6e84/58e//60501 111222 Megaen 3iR3g.e6s9 0G2 .0R0 h1L.e6G2 0fS.0ke0 0gS.0eE1 i J0o5.3788 T0h9eo%s 1W4E3 L6oo%s .Soe0d8 Group 12 83 o8o3a3s2y7a4s2 y11e8s8s8 655 1133 Hwogan 18.0:4 80.8088 ase 08.:8080 80:.8029 3F30i8 .0 5S8 T8o1 Group 13 Reterence Range Bsoo- 33- me 88 . 1i3- approvedSago a' 4l of e 4 n pate ~nt. vuu99s 418-018:PAGE H-73 ANI CIYTICS cocoms sce sm 0 stem 2m Client: ANREGURSERPIESNIECAORCRHPOLRABAOTREATDORIE3S0,1-9I2N1C-0.168BDaattseFaxSC:ol30Rl1s-c97Mt7e-d0:433oaj02/200 f1318o) 443-8720" Date Reported: 02/711331/2001 client Ho. 1028 study: 410018 PUPS 05 Species: RAT fReogseesnsiioonn gppee oCnpSseexx hAgaee GCHOHLESGT SGChRHiUCcOoSEs DKRJoDL..N pMojon. IMoNrbEi BFg03y 782 1r 1e20/ee as 18 3 eons ety), 10 1W% TR323 EH BH OBE 3 w 8 mi Fo o& Group 10 rr Per oBN ORS pd uh sgtiisatraese nnaiisiemtse 22 m mo om m 5 op #8 0B Bom Group 2 8 Wm 3 Page 1+ BL 001000 418-018:PAGE H-74 GLYTICS ons sen sms arms vo mom Client: JRGUS RIESNECAORCRHPOLARBAOTRAETDORIES30,1-9T2N1C-.0168DateFaxC:ol30l1s-c97t7e-d0:433 3B0R%EIRSAuNEM sABlDn aRI1V0E044 DDaattee RReecpeoritveedd:: 0022///103332///22000011 Client No. 1028 Study: 418018 PUPS LDS Species: RAT rAeccceession Sp3Bec. | GpPSSeexxAAggee CCHHOOLLEESTST GCLSUCEOTSE IMLDeL-TMDIR EMDRLJ-oRDTIR TRREIIGS B5 80803385778598 111185449077352380 33 HFoYCRTTY 2mn E 3Im ] Neegan W Tiss e ep 5R0e 7W5 BS ms, Group 3 33? 888g88303333222s777782259888 11H111s125e385i888v17/E735e896d889 &5 3B 8888332277833 HHaRgSdlse) &3 seegan Group 5 [H w EEO B o og 3i524 i $ #0 i 8am H# o 8#8 ia Buan 0T0is wmen 3347 8337 23886%s 8B2 0o08033333e2527777e668s845 HH1111E5E37I84I2/550R705 && 3 8833780 138/38 sereagn Group 6 m wF# oE a8 m1 Hi BPiaOW an. E@iioa # 0i $0 a1m $8 #38 BB g R ZBiYse Reference Range n 9 qa. 96 319 Page 2+ 0-2-3 0 80 125 002001 418-018PAGE H-75 CLYTICS oss se 0 coms vo wor INCORPORATED 301-6210168 Fax: 301.677.0433 ClieonTt: aAuRGUSRREESyEARbCaHivLEABORATORIES, INC. DDaattee RCoelcleeicvteedd:: 02/02/2001 oRERE: Ba 10044- Date Reported: 02/13/2001 (215) 443-8710 Client No. 1028 Study: 418018 PUPS IDS Species: RAT JAoceceeaslsoinonSGpeee.c.| GpopSeexxAngeeegCHoOLpEST GGLoUCcOeSEpLDnL-pDIR mp HDL-DIR TRgIeG B5BooEaissR7s6s di11i5eE8s7 77 BB0oo 8f2H5 8=&@ # i 8E5T8) eBasn T2i EBnh m8g wHme 1835%3 Group 7 B83 8088008833335222777777772848 1111131S8888080//30E875N8001828 888 B 8833778 1E0s/E0 8 speasn Group 8 1Fw0L86AooB+3i807 33#3H 23 ii aaek 038 i i 38 PT5o0s BEnhs B3eg Bpgta #a8 m 8B38 088396303333882777773037288 11HHg61eh17ih/6eeSn 9332 B 8833780 Hales 2 seeagn Group 9 100 1# a3se 38 23330 PPR FH i i we ES 3 EHO] Tos HBeRs W3ma apee uimns Reference Range 2aw. m- 0 08 -08-3:bi Apperporoved <-ecaeSeeenmecas pasete wdirldidlos 001002 ANI& {ISOIPAGENTS INCORPORATED 301-921-0168 800-237-2815 QAAUDITREPORT shGohoeedEreeEpor rit ar li)stBe`dPrabaecltoicwaelswlaasansdrseowvciiiteathwtheeeEddPAffrioaGnrwodoicddnoagmLtspaalbiowwareenarrcteeeorwryrieetvPphiroearwcttethedeidceFfsDot.Aro Taneagemaent.-eR meistency and tTa hhee metehoddsmse(iuiwsaiestdths wtthehereeFdDatAthaea.ndmeTEthPheAordeGsfooorddee,LsacbtrohirebsaeetdorstyaundPdireasctthwieceerser.epdoornte FQrhaAnukdliitnor5, Newnan sponsor: ARGUS RESE GACH 1465 stooy: 4/501% REPORT TYPE: my 73, TH, EH FRETS, FRETS AUDIT DATE: 2-15-01 REPORT TO MANAGEMENT: 15-91 AUDIT #: 0)-0%% ; i3l/iiSfteo0w1erreies 2 ~T--o 7eCLeIEeNT nul Lajmine auc AosENT ITF T0) Os 0206; ANI& 418.018:PAGE H-77 CORFGRATED dotsaroiee s0ozar2s QA AUDIT REPORT sTGohhoedererLepapoborrottrialttiosetreyEdeFbtreAilccotiweUsIvlaasensdrceowviiitaehtweeEddPAffsoiaGrnwodoicddnoagmLtspaalbiovwareenarrcteseorwTyrieevtPpihroeawrctstthseei,dceTsO0.}00 RTahenaEgnemaent.re tency and the mathods used were the methods descrived staunddiesthyeerts edconte hTBheee e meeeh ets'tthheeFdDaAtaa.nd TEhPeAreGfooorde,Labtohresaetory Practices. FQrhasAkuidiintoBr: Newman seonsor: ARGVS RESEARCH 1465 stony: 4/8018 REPORT TYPE: cok AUDIT DATE: a-15-0/ REPORT TO MANAGEMENT: 15-0! AUDIT #: 01-121 s/fifor VF DATE (SUBMITTED TO CLIENT 28 Ruqind York Se Event 215 70/ 001004 CFLYTICS socom see,st 00 srrwo s,m clients 3r350E8 BIRNRLCAORRCEPOLROAROTREADIORI3D0S1,-92H1-C0.168 pBuattseFax:SSeS3l0iH1-nS6c7tE7a-Y0d4:33 0200/00 H(O2R1S5H)AM4,43P-8A71019044- Date Reported: 10/10/2001 rreeecession gpeece.| OOppSseexxAAgsee LLDnLip-TDRIR HIDNL-CDEIR CSHOvLeEST TmReIGn 001005 418.018,PAGE H79 cYTICS 200 Girard Soe, Suita 200, Gatersburg, MD 20877 ant: ARGUS RIENSCEAORRCPHOLRAABOTREADTORIE3S0,1-9I21N-C0.168 DateFaxC:o3l0l1-e9c7t7-e0d4:33 Suis 30BH%UO,ERLSSBUHECMEaHBYTDyeRnId1VsE0us- DDaattee RReecpeoirvteedd:: 0120//10170//22000011 Client No. 1028 Study: 416018 FO C/S GD21 Species: RAT fcesemionenionEgepes SpppoeoomnnapsttaMiieEee ppo Booommoommniuiiteteee yeepsn Group 13 bpppooooommmmmmeeermr e1ii0tol:ie5l pppLR oooEmoommiCeeesls ii10gt8is8 steogan Group 2 er7 sew BBBfEf agioee IJDL-rDiR Di IDIER eo enr om 3 SE cEhoElTsst mBie 13n8ae 6818hH BBBBoEEf: BF ggegexlae NSeSiiEEfd BbiLREBE asgiinEEs G5 SRR E88 TSiHr TdELh uBEeS eGW g 2f3i %ffoFf ff e0ge.:e05389083mE ge 8 3kRI0nBE1 a1uR.E8aE8 3 8h ffff g8 84e7 8NS3EE 3BIdEN a mIW TA ee E Tai nuPem 3uia Reference Range 08o- 89- o8 - g8 - Page 2+ 061006 418-018:PAGE H-80 | & CLYTICS cou som. 0 0cra wo ors cleietnts ISrSgSsEBEIANRCECDAORaRCnHPOeIRAAROTRENDIORIE3S0,1- TiC.921-0168 BatFea Bate Solisctad: x: 301-977-0433 Recafvedt' 02/07/20 01 H(O2R1S5H)AM4,43P-A871019044- Date Reported: 10/10/2001 ASeesmmaion Sfmeeee oopp sseexxAhgaee ILDOLNDIIR EDDRLURDYIR CSHOILEEST TWwiige B 0037120 10948 4 crou4p em a8 in uy 001007 418-018:PAGE H-81 CLYTICS INCORPORATED 1 crs re 3019210168 st Fax: 0 cm 3019770433 wo zm Client:SA0R8GUSSamREmSyEARDCrHivLeABORATORIES, INC. DDaattee RCoelcleeicvteedd:: 02/07/2001 HORSHAM, PA 19044 Date Reported: 10/10/2001 (215) 443-8710 Client No. 1028 Study: 418018 FO C/S GD21 Species: RAT hAec.cession s3 peco.p Sex Age LDMLG-/GDHI|R MHDGL/-oDMI|R CMHGO/LEGS_T_TMRGI/GGH BBB 000000333777111888897 111000993586880 353 EF E B 0037150 1038) 3 EF 00o:.o16d36 920:.:86378 333.30a%7 11e0g.ll3a70 081 oie za ln BBB 000000333777111399321 11100033363z2 353 EEEF B 0037182 10ses 5 F 000::300800 o9&i5 238 333220 3&1 sBllae3 10'17 0:61 oles 313 Tela \ M5e8an e2n8) 5218s 23.80981 92.553883 Group 5 BBB 000000333777111999567 11100099977725 & EEE BBB 000000333777121990890 111000889778880 && EEE BB 00003377330012 1100938812 & EF e5a8n Group 6 000:.:57371 02o.:i68e37 233.9sd0 87s.ll5d317 $00:0:8783 0ole%zs 33ye3%e ls7le1a8s 00::3330 0_o6lesl 33350 _ a7.l3a5 T1a2o2s8 LReie 23,97023 73 .726 Reference Range 89- 06 - 9 - 05 page 4 + 061008 418-018:PAGE H-82 BCEALXTTICS so ors s3o255200S0HI3RE3mamz/07/020m0 Client: ARGUS RIENSECAORRCHPOLRAABOTREADTORIE3S0,1-9I2N1-C0.168 DateFaxC:o3l0l1-e9c7t7e-0d4:33 ETORREERAN.ahBa d10044- Date Reported: 10/10/2001 Client Wo. 1028 Study: 418018 FO C/5 GD21 Spacies: RAT hRsoeoessionEipee. 5pBB0oo0oo3ao7mzs3E0see3t 1e1d0e8e3s88ee5 BBB8a%o3t7h3s0essi10ti08e8 BOERNE Mfeain Group 7 Gp sexhe [WOIBRI 7777 %EEF oeSRss8 7777 kk|oF ee5 :ai3 BTee ROTLR GrSoEwTs 0n 8a.4883 n 73 n7d5 eSE8Eyg8 anh2dnEs 8Te8es nHeEe gWmea 6snI.3EnR8 115i8s%S 7LaEm Reference Range 80- 08 - 08 - 8o- Aproperoved ed Daatcee --2l2/2afer 001009 418-018:PAGE H-83 CAINYCOTRPIORACTESD 30c12o1n0s168 sFatx:3c01-6m77-0o433n,vo mar Client: 2A0N8USSumRmEaSEARDCRHIVELABORATORIES, INC. DDaattee RCoelclegicvteadd:: 02/07/2001 HORSHAH, PA 19044- Date Reported: 10/30/2001 (215) 443-8710 Client No. 1028 Study: 418018 FO LDS REPL Species: RAT fReoecession S8pec. | 5BBB 00000000333l6e6e77775g3s708s 11100o93s001882 10812 BB o00o3l6e7r6e2r 1100991132 M5ea8n0 Group 1 G=pSexAg9e 111 E 111 F IMDGLJ-aDnIR 080:000066 880:::080680 0Jy3 HMDeLj-wDIR cWHOGLNssT 080:133781 333.i:3038e oo0:d@3se3 333:8m678 136587 3Tiss TWReIjGen 2188.:84338 i1a8i:s3d8 3iL0e0es BBBo00o00j33eeessaiilsis ii1ll0eo1za9sl 111800 E E BBB 00o00o33j6c8aa1ll7se 1lille0gszzses 1I10o8 E E BBB 0000003336c8aa3zi9os i11l18o02z27s0 11I008 EFE N5e8an Group 10 800::.080880 o001%i8 lI2.af8d5 739.%5A: 800:::080880 0oo:i3dd7 5zf1a0as0 aa7lolds 080:::080850 o98::i33s81 E258:383 37dtishs TBoCoErC"R TasBs Tt2308 9.80) Reference Rannoge 98 - 08 - 0$ - 06 Page 1+ 001010 418-018:PAGE H-84 GLYTICS noussoe. m1,cota woze INCORPORATED FIC ssi 388Suma onrve 301-921-0168 Fax:301-977-0433 Date Received: 02/07/2001 rte nHeOREM)ETIM4aT8710 ys 38010 70 108 3303o.psep;ecies: aT430/: JceosniconessionSgeeee.s. BB0o0o3z68e2s1 1i1o02e9 GpGp SesexxAMgoee I[DpL-iDnIR M[DnLp-nDIR CGhoILLETsT TTRIGG u iF E 08.135 8 0.41 23.:7133 e.3:a321 oro 2 C1011 418-018:PAGE H-85 CALYTICS soconsonsu 0 sortvoe.rm Client: ANBRSGEUUBSRHREEIESNTE3CAIORRCRHP1AoOL0RAuBAsO-TREAIDORIZ3S0,1-8I2N1C-.0168BDDaaIttEFeeaxSRC:oeR3lpA0l1oM-er9ct7te7ed-0d:4:33010//0370//22000001 C1tont No(.2151)020443-8720 study: 410018 FO 105 REPL Species: RAT S S fBeoeciieans gggsesc Om nBpe Ef Se exton S RaroenaRes e MR efoogHgEn GhojLspaen5hH|me MGeB1i/3o.R,e3w8 BBBooodsneeneeisss BBBEEf sfeian gSeh esie timE HmaEe a sreoalo ierralironr mrrr Group 13 BpBBBoooooodnnnnegeeereassss ititieooonstnmnss 33311 %F| GeggoaRon8s eeop SBrmR l IE3Ih3RE 3 8Bag%R ean To The se 1038 Grow 2 .D. 1069 Ll L547 10:38 ppBBoeooosmeenerrsenssonttosomtne 3333 %fF goesannee eSpomRmf 3RIn3Hn8 204u3%M3 oveagne Te oTma Gaarp Guais vps Rewtetreanczeence aRange o: - 8g- :9- sg- Page 3+ vot012 418-018:PAGE H-86 CLYTICS socrs ros2s0 gone. oor Catents ARGUS, RIESNECAORRCHPOLRABAOTREATDORIE3S0,1-9D2N1-C0.168DateFaxS:o3l0l1s-c97t7e-d04:33 30B(H8%1ES8H)UEE4RS4EA3ST-,87D1R0IVoEouclsent vo. 1028 study: 418018 20 pDaattee RReecpeoirvteedd:: 105 REPL Species: 1002//d20a07d//22000011 TAT essseaaion s2pB ec. B0036772 10943 TopPpSseexxAAggee ILDOVLCRTER R ENDGLjpaHi|R cMHGojGtHE_sT mMG/a oM re 0.00 0.26 2.95 18.57 Beales io: on croup + gn RE BE ine Wr EE Tin Ba gomens is ff ggoenEiaEl lIlEeR ffff croup 5 Fa gp ee ng an gplE BBhn pTEE gTEH BEE. WP um ye 4 001013 418-018:PAGE H-87 LYTICS oon sm. 30031 amor wo ar Client: ASRBGEUSRRIEENSECAOBRRCRHPEOLRABAOTREATDORIE3S0,1-9I2N1C-0.168BDaattseFaxRC:oL3lI0l1Ns-c9E7tS7e-Td04:3302/07/2001 SRREA:haBaan10044 Date Rep>orted: 10//3300//2001 Client No. 1028 Study: 418018 Po LDS REPL Species: RAT fAoccession S5pec. | 5BB[0Roo0TS3Enl8eg7R8Hal8E1ne0s9l7e7 sgeean Grow opP SexSex AMgooe f8 FFIE LWDBLj-oDnIR IMDLo-jDoIRwcNHoOjLonE_STTRWIojGa oSSeo3geo5 e0S8f.Ei 7nEI.8dRn1 9nS.a3nl4 ad E Ts As has 3W3e08 hizle B5Bo0oo0l3ee6r7sr9i0 Boer 2ie10se00ee9%:e8 7777 EFEfFE BeBe IE 7 oF H3ean Group 7 0288.:8088880 d03 d.3sk7 3diE.u4EEs5 81dg0e.%E8s8 8:88 838 3: iS 78 aBes SuIeides 8pBooongoeseerrrsetes Boke 1iHH0dk9eY9:e0 8888 EoEoFFF BENE HE 8 F Reterence Range e9 8 880::.880808 3 80d.a32 n333.sh034 af85.a33e7 888 83 nk o- o- 0- 0- o 0 0 0 Page 5+ oc1o14 418-018:PAGE H-88 (D 3%: 4 )(OSJP-- cutenes ant: EE Bitz SRI ca/ors200 ARGOS BIRSNICAORRCEPOLRABAOTREATDORIE3S01,-92T1H-e0.168BateFaxC:o3l0l1s-c97t7a-d04s33 BEEBE, use bate Repocteds 10/30/2001 client NoH.ORS1T028Rad Study: 418018 0 10S REPL Species: RAT90H fe Egee S g eommi mara idm aenst ef2 foft EEaE gagegSeee ge gsBpeE eae MaE ad1baem BLoflf poooifesdsaHalge tof rree HWtEHOHH,OE38 aEE Pp E inamm same 8 p$ 5g ooooimpdum teciemsoeres 1elHH1ea0ee0tts 332f2 }fEooff ooieens Hef eggggaefEer n2EaE ao R31BIamEE o8IIm0dEE Bh Ew BE os EPemmsoinisgesen 2 oF f BRgi paermil mOBEE taolml EIER oomk Ee i oT son's treaties ae o- 9- g- grppro0vegraorer0reen0ee 0tate L3208 vewvis 418-018:PAGE H-89 GLYTICS 200 Gar Set. Suto 20. Gathrsurg, MD 20877 Client: ARGUS RIENSECAORRCHPOLRABAOTREATDORIE3S0,1-9T21N-C0.168 DateFaxC:o3l0l1s-9c7t7e-0d4:33 ng BE T EERR y E BL DyRIuVsoEue- DDaattee RReepcoeirvteedd:: 0120//7010701//22000011 Client vo. 1028 Study: 418018 FO LDS REP2 Species: RAT JFoeoseisonession Sgpeee.c. pBgooagggattgseeessseotssri vHnHasEass:e BB3Boooomuoweetescestts:ei HHHHaaaatseles BBBpooooadmlseeesceetinsio ilHaidaale?? Bpoeddeen Hit weegan Group 1 pBBpooooelsnemezd enHdezegn ggBoaoogtdeeness HeaanR Reterence Range GpGpseexxAdgoewILDoLg-iDnIR 1111 E eegaerle 1111Bbb eagge88ee 1111 bfF ageeee8g 11 kof ggoes 83 HfDLp-DIR cHCoOLLETsTTRTIeG oa&eyend 0h bb1bas8nl bat a5u84fg3 Ed ef neei hbbIEEEN i8niE3iE ge8eee%d bbbhEEnn I8gaRdl 8 bE 8S 0rrr w ue rnyie BR1B0REbEE IE 0sg see0 i oSoaiit se oH inbEesERgs 5E8a.3R3E0 IH 68 BRFE gae8 eeed E BR oR n o$ - 89- 9- g- Page 1+ oc1o16 418-018:PAGE H-90 CLYTICS crass sn 0 sama. vo Client: ARGUS RIENSECAORRCHPOLRAABOTREADTORIE3S0,1-8I2N1-C0.168 BateFax:Co3l0l1-e9c7t7e-0d4:33 Hen 9BB0I5REISEHCEEEHYByDRIsVoEus DDaattee RReecpeoirvteedd:: 0120//0170//22000011 Client No(.2151)028443-8710 Study: 416018 FO LDS REP2 Species: RAT SNoosersion bSipee. onP SexSeAxMv9e MOOLjDoME|R HMGO/oLMT_ GMoGm/Ge_r_mMSo/,GH Sppooemmeegnss aniiiaee BBBEEE ggG:ir8eg0 os&sidf 3In3Rg0 5L9N.E3E3 seTeagn 38 TA ET hoe mWoEn Group 10 ppppooooommmseeeerrsrnzisiiuieieee3eld 01HH4offEoFf pone io: 0gee.:00e08 on 9ogadaet L1LLI3BR 8 8Il.0ge8 oie 2% LR Ld BpppooomneeednnasstesHeielyetss iiHHof:f: ggee:ee05ee0 o8oSu4hEs1 IIBIEtHE IoI8idh% ereagn 38 ATEe LNEaPn G1a8s Group 11 opoooyeermy nnseo 1B2 FE 08.:080 0S3B3 1n.f9 4e.%g Reference Range o8 - o8 - 8o- g8 - Page 2+ 001017 418-018:PAGE H-91 CLYTICS cous som 200 starv.o om Client: ARGUS RIENSECAORRCHPOLRAABOTREADTORIE3S0,1-8I2N1-C0.168 DateFaxC:o3l0l1-e9c7t7e-0d4:33 02/07/2001 ent: 0E$T O02R5S3RSANE HNECeEHYABL aDRI1V0E044- DDaattee RReecpeoirvteedd:: 10/10/2001 Client Wo. 1028 Study: 418018 Fo LDS REP? Species: RAT J No: T p5 ooo3nereas kir ) y ry H11e64l3 I13 EEF e 9 HGjoHe | MG/GH__r _ MG/GM___ Ge80:o00s80 ooi.as0 1EL.8iB3 MG/G 8hi:eE1e - pBppooooodnteeedrtret hHHdeeeelllsdes iiiBE:EF poems He: iE 8ee9:%8088 8g&BFl S 00 83 RR nnRniypEm BaBiWnm RE oi RpBBoosooesseetets? HHHHeEees IIiI:fFE SSe:0e088 aB8iE2 omLEnEE TaaEd8 soeean T9o9o% TBieEs gEaen 312ha Group 12 BpDooo0opm36see74tss8 h1ei3ti6ees5sr8: B111333Ek:I dies: BF eF80.:R%00I838 SC 0h3Rr vm2m.R2dH6I 18.8 asad e:08 oid hE Bm pB3Doo0odd0eeerr7Eiistid HHdieesssse B1B3EE: Boeal deer IE 888:::080888 2:08 %oSdfi SE RBESEk 18 i3 les sees 8:85 Sif RE BE Boe nF Reference Range 08o- 98 - o8 - g8 - rage 3+ ce1018 418-018:PAGE H-92 AYTICS 200 Gira StetSuite200,GathersM,D 20877 ction:Sent: 10BPR ARGUS RIENSECAORRCHPOLRAABOTREADTORIE3S0,1-8I21N-C0.168 BDEaEtSeFaxSC:Eo3A0l1Ml-Ie9Sc7Et7-Re0Yd4:33 ca/om/2000 2 1318) "a4aN m872dP Date Reported: 10/3100,/2001 Client No. 1028 Study: 416018 Fo LDS REP? Species: RAT Axcecession s8pec. Sppoeemmegersmueiesess wteogan Group 13 BBppooooddoneescssiiieaoo nsii tnitess ppo[oegddR eeesiseE itaia Eles pBBBoooodosedeeoenerissiniiEztaeEss pone rweegan Group 2 "opSex Age IBDLI-DIR REDLT-DIRCSHOELTEST TBRIkG 1BBEEE ceF oe TooI ln R 3B.E00 5 1w6.l44 STips aTiEs aurve e nike 211ffEoff 1 of 0aaa.08880 80ooaeFHz 1LR n7Eis af ga 8.B3 a8 8% Ih uk i of 22ff: aaeg88s8 g:8 eoi oBii Sw hLnLiEBpL LR 8eual3iRk gs f2fffI aSe:5888 S8So R8 I b n& Bo gIkE 83 TSnn iugpn sam Reference Range o8 - o8 - o8 - o8 Page 4 + 001019 418-018:PAGE H-93 CLYTICS cous som 00m0tas.wo sor atone:ent: RB0gSuESasHpEEaIEsHNSaYCaOnDRcRyPIoVOEpnRaAneoTmEsDcoRIT3S0,1-8T21h-e0.168 aDsaatttseeFax:gRReoe3clp0elo1-igrt9vet7ete7eded-0:d:4:33 1020//0170//22000013 chiens Hon 2026 (215) 443-8710 Study: 418018 Fo 105 REP species: TAF Ei Recession Spee. G5SexAge a IDLDIR Ba EDL-DIR a choiper mmIG 001020 418-018:PAGE H-94 CLYTICS scons som. 00 star. wo or INCORPORATED 3018210168 Fax: 301.977:0433 Client: 8A0R8GUSSumRzEwSyEARrCiHveLABORATORIES, INC. DBaattes CRoOlLlIeTcEtSedY: 02/07/20m HORSHAM, PA 19044- Date Reported: 10/10/2001 (218) 443-8710 Client No. 1028 Study: 418018 FO LDS REP2 Species: RAT NAoc.cession g5pee. 58B 0o0000333%66eeedssss0 11111123583334 BBB 0006003336cc8ee3ss3s: 111111588353576 e5a%n Group 4 op SexAse i44 EEx 444 FEE HIDLjDIR 088.::008308 808:::00000 "008058 MWGDjLoDmTR MGGE/oGEHe_r_mMGi/GMe 0oo.ii1si8 | 2Il.e0Fs8 1i100ll.42e72 3000:282 iz_1lilsag2 11z1a3.ll8so3z1 T10o5s%" 2t.i0e8d 8152.9718 BBB 0o00o03j3geceeessssse 111111533586851 533 FEEEF BBB 0000003336e6ee3sz07s 11111s3366;s4 335 EEE 8BB Q00o00i33cccceceea:s0 11111135366678s 555 EEE BB O00033cGeeeess 1111837702 553 FFE M5ea8n7 Group 5 086.::080060 000.::110178 1Ii.le7as4: 86s..i322820 880:::080800 900::033806 IiIlleeass l15:a28s00 088:::808600 008:::90127 IIlllgess8 esellieams 86::0000 06::3877 i1s3e8 s_siisse 0$ Toozs Tf1i.se'az 6l.a7z9e8 Reference Range $9- 80- 89- 80Page 6 + 0C10x1 418-018:PAGE H-95 CAYTICS com rv. sn201, csr, wo sr Cotent: ARGUS BIRNSCEAORRCPHOLRAARGTREADTORIE30S1,-92T1C-0.168 DateFaxC:ollected: 301-977-0433 oni LBoEHERE SL a ous- Dpaattee Rseacpeoirvteed:s 1002//1007//22000001 (215) 443-8710 hJozeoneicon ession gspec. "Gp SSheexAge aIDLn-DIR a HDL-DIR gCHoOnLeES? TmRtIG TTT 061022 418-018:PAGE H-96 GLYTICS socsun 1m namo io am Client: AL RGUS E RIENSECAOP RRCPHOLRAABOTREADTORIE3S0,1-8T21N-C0.168 DBaatteeFax:SCoS3lH0l1O-eE9c7Et7Re-0Yd4:33 02/07/2000 BHOIRRE Rah8 d1o0u- Date Reported: 10/11300/2001 Client No. 1028 Study: 418016 FO IDS REP Species: RAT - fSgcesionie gee Be vee A RRR a EET EHEB T e We ppSBoooemsemassssie Bomsess HnvtTiaaiiesmnens 77177 k2f ggogeerees ge eoegdiHne ga ImiEbeEnh EE8.Ra3 pe gree gids BE SE p(ouResio nian 7% stega?n gee 38 gE fi Ta E u hae TE Bo ever 7 B8Booogoooagesgeseeeenansys e1dH1eseeeeerre Bogieese Her f8fffffE ff gggg oeioeg e gegaams ggieg egna EB1n2gBe0 3m 4sep7iRA1e ol ze ge pB53ooggotoaeeaeseeeresdlses MHHdeeeeeesssl secs f8ff fb ff ggggieeig eegeBHmh gBIreeeRn g9 naidg steogan Taer Tamr iuayn TLaem Group 8 Reterence Range 9 o- 9- s- g- 0 0 0 0 rose 9 01023 418-018:PAGE H-97 CLYTICS sc sv ss 0 canon vo mo Client: AAgBR0RGE5UGSE,URgSRRuEEReISEsNSEE3CAAORRRCCPHoHOo.LuRAeAB-OTREADTORIE30S1,-92T1N-C0.168 DBaEtFSea Date xCS:o3O0lM1lI-p9Sc7Et7R-a0Ed4:33 Reported: 02/07/2000 10/10/2001 Client vo(.2152)024843-8710 Study: 418018 FO 105 REPZ Species: RAT S ESre eeg aE a Rr a a o BTE BSE2ET.6 BWieee BBooornsee insai:s 33 f1 pBoomeenme nnaer 3 I gseese eonm rnegm ogig ggoo eonh xImn g9EH araup 9 Reerence Range } 0-9-9 9- . roved es ir d pave i2iofifeulli: App: Page 9 of 9 e 0C1024 418-018:PAGE H-95 CALYTICS coussve se 0commonv.o mom Clients us RIASNHCAORCREP, OLRAAROTRENDIORIE3S0,1-9T21i-e0.168 AEBSESRHEEEMY DRIoVnE e PatFeaxS:o3l0l1-s9c7t7a-0d4:33 Boaatsee RReepcoeritveedd:' 1002//1007//22000081 aston. toBe15w)ets44378710 study: 418018 0 105 REFZ Species:: BAF JAescsecn ession spec. G5Sex Age Ba IDL-DIR a HDL-DIR CeHOaLEST TBRIeG -- 001025 418-018:PAGE H-96 CALYTICS crus. so 20 amass. vo mar Chtent: BARGUSERIENSEECAORRCPHPOLRAABOTREADTORIE3S0,1-9I21N-C0.16 HEBER 8 oou- 8 DBaatsFeeaxSc:oO30lL1lL-s9Gc7E7tR-a0Yd4s33 bate Reporveds 010z//1007//22000m1 catont vo(.2151)028443-8710 study: 418016 FO 108 REP species: AT m a E PSomhme iE aoRshea Ga T a gran EGOReE mfae 1 E1 e gw ea l hpnER oxo 7 H HLET PomaE AE fof Mean ngeee fBiH rnee osau sg FH I ie "002 118 1.017 7.828 nage 8 + 001026 418-018:PAGE H-97 CYTICS anorsne san 0comprwior INCORPORATED 301.621.0168 Fax: 301:977:0433 lient: SA0R8GUSSaRmESyEARDCiHveLABORATORIES, INC. BDaattee RCaozlallevcetde:d': 02/07/2001 H(O3R1S5)HAM4,43-P8A71015044 Date Reported: 10/10/2001 Client No. 1028 Study: 418018 FO LDS REP Species: RAT ANcoc:essionSp8ec.| GOppSexSexAhgoee 5BB o0Oo00333se777000:38 1111i66111213 533kEF BBB 00000333686777000788 111ii6ee11i6as 533 EEEF BBB 800600336e37r0i78o 1im1ie6e1ls7s 335kEFE Mea5n Group LRDyL-nDIR EWDeLjDokIR cHSGojLowE_ST TwRoI/Gow 080:00g08 o00.:y31 2L3 .0F6 1a1Ef.l9i:8 000:::000600 oo9l3n nIiigeie iggilEef 600:::000000 oooyim n3Iidif $7o1i73s o$ 1 ol TTahte T3ee8r Reference Rang%e $o- $9- 80- 69- . ApprovedPagee o5 sof pate --L2/2/oL 6C1027 418-018:PAGE H-98 GIYTICS rcsso se 0camsv0mom Client:2A$B5R0EG52UNSSEuHEREEIEESRNEYBCAyORDCRRHI1PVsOLE0RA4BAO-TRENTDORIZ3S0,1-9I2N1C-0.168 BDDaaatttFeeeaxRRC:eeo3ap0llo1l-Vrc9et7tde7esd-d0':4:33 0120//0370//22000011 Client No(.2181)024843-8710 Study: 416018 FI /S G21 Species: RAT jocematonason bfpeece. s Gepn BSeexxahgase T[BRiIDNTN EPRRYLEGQomUeEr mEbaR. 5BBBoooooooglddieeeessseseeseste 11ndoa0e0s3re1 1 11 Booesel dosed} Segg:oe0er808go88:nh0et7 Bh31u2g3g8 135n.8g0%8 gee gf 1M a BBBoooomaoecssseeerr ftatoesse}11 a8g::8088 888::%88 3i3h8Bm L4 LEn sdeeagn 83 S oi W Sass i8gn Grow 1 BBB ooooooooanun7eeeo1snns 1mnHioi0set0esy 1B112f22 Boonen nig 12 0ggg.::e000e080 g:08 oo0o.ii0t82t g:8 R331.R3HmR8 aE 5oa B.nE0y 53 BBBooooonnnoeeis hnHiostsey 13i22 ggg:e0ie8 8giif8g i 3EE3 L2EsgS sweegan 38 S Tn ui Tham snaue Group 12 Reference Range 08o- 98 - 98 - 8oPage 1+ 001028 418-018:PAGE H-99 QALYTICS cous yo su 100garveo .ar Client: ABBRIGEUESENRBIENSEEBCAyORBRCHPsesOLoRAuBsAO-TREATDORIE3S0,1-8I2N1C-0.168PBDaattteeeFaxSCR:oOe3lLp0lTo1sGr-c9tE7teR7edT-d:"04:330120/1/3030701//22000001 TORE) 443-8720 client No. 1028 Study: 416018 FL C/S GD21 Species: RAT $ Sm DoN5o.opaioel Eea 1uLiegs -A 3 MG/GegSM_:ee_0_re8 Ba MG/ooeGfMeft ae HG/331GH3gG Be MG/B5GME8 Poopp5pgoogouaozeeeesnsde naghstteee 11i1B33 FR A]i gggg::eee0eee8 8g8og:8:r88 31113dBM e3 fayda gi 85 hha Vi Bone esTeeaRgn 38 Tan aupm Snein Group 13 B325oggoooaoyzseesessaseeeelsss 1111008108152 Booster 1088 322 2 0Fggg.::Re000Ie088 0.00 88g:::0880 1 Ci22.88Oe87 473 i1ie3p hE ns BB5ooo0oieess3iiit i188s8ks0 322 wean ggg:e0eee g8 9:d8 3ReE _ af8e 38 T8o%e huegn n3h sep | Grow 2 || Reterence Range 08o- 8o- 8o- 8g- | Page 2+ | 001029 418-018:PAGE H-100 CLYTICS cossin si 0camov.o wor Client: BANGEUSSERIENTSECAORSRCHPEOpRABAOTREMTDORIE3S0,1-8T2N1C-0.168BDaattFeaaxSC:o3Sl0Hl1-sS9c7Et7e-Y0d4:3302/07/2001 BH3E58R) Radab8nal10ue- Date Reported: 10/3360H/2001 citent No. 1028 pSotudy: 410018 FL C/8 GDISSRpeEcies:RRATE Jocemalon gees gs3oigmeaeneesrsiiies nd1o3ys0e Gp ex 333 av ri [ER GOL Me eeooeen o 5S.e0s1 n b5.E98 8E3.e338 B5p8ogggoaammsieeeessssirtisesiidtteeoesnnsnys ponent 3333 3 gggg:ei8eeg0 g:8 po8gee88rt Be 4 gpIalRg $3 3IeIdd%nes etagn 5 T0o8 isgrn T1emm Group 3 pB8ooooooosmajeseenoessnsdzsii1toogomseatness bogacsss lon 444 4 eg0F.:E08I0088208.a08 g:58 ob 3 5g0a 3g48sB8 Tee an BBoogmmoeeesssaesls dedooinsse ggg:ei0eg8 gpgeeee f4 Eme a183E08 wseega?n 3$ pgeEra w st r1e3 Group 4 Reference Range o- 3o- 39- 89Page 3+ 0C1030 418-018:PAGEH-101 CLYTICS crusstm.mn, com,wo zm Client: A35R60GsUSRESCIEESNAECARORCRCEHP,OELRABAGTREMTDORIZ3S01,-92T1N-C0.168DBaattFeeaxSC:So3Ll09l1-Sp9Ec7Et7Ye-"0d4:3302/07/2000 BoiEeL)L4E42B78y7101s0as Date Reported: 10/20//2001 client No. 1028 Study: 418018 FL C/8 CD21 Species: RAT aSeomsaeTenBGeoo ovosenx exhheaee ILBiRDITR BBOiLa RghGonermWboan. 35F 3 gogaanjieesnasR s0o d11e0s0ae 3322 Bouessy dose ggGgi:ee0oes8 g:08 o8eeaa8klt oi 3RI22f3R3 dy 5LR83R2E3 L&R gig oe ne a BgBoooom3oeesssssees ii1ot0ee3es8d 33f ggreie 8 oe 3B 4n%L Nteagn 38 TBHo aus hHaEm Grow 3BB ooggvomuaueegeensossses ld1t0eeo9med1: 3 goznt done eg0g:.:e800e008 o0ge.h0ta3 f44443gms8 LI79.:RR3098 3H HR 3Boggsaosireanl:r 1dee8sn8e 8 e[ge53e SC 2h8 H ER 58 388 weegan 38 Tgro Taiss 7Lanm Group Reference Range 9 0- 9- 9- o- o 0 0 Page 4+ 001031 418-018:PAGEH-102 CGLYTICS 1coussion. 0 0samwoo 2,m oxants MB35EG8RSUNaERBIEESNRECAORDCrREisPvOLeoARBuAOTRAETDORIE3S0,1-9T2N1-C0.168BDDaaatttFeeeaxgRS:aoei3lp0alo11sr-v9cte7tea7ed-'d:0'4:331002//3007//22000011 cient No(.5581)02844a872d study: 418018 F1 C/S GD21 species: RAT301 RBm FogoeroosinaonensE gomremEe e or7] SeUNTEMGcaaTa Mejoeedalr eWelngeemke|mweagBsceE BBBBBoooooooodinaziimeeeeitdrscs ljnejoesoosseesesese 77727 Benn eEggGRIEea ge goe8geeg8ee rnnyyRemgw eogIund8w te er 5t TaE gaee aTmm sap 7 seretfoerreenncie Tonnge 30. 3g- 3 - Sgs - Hpge 2, Page 5 of 5 vn oa uL1032 418-018:PAGEH-103 + ro CAYTIACSEncnseon ston0i.asas:trwo 27 Suen INCORPORATED SREBy SRE 301-921-0168 Fax:301-977-0433 Bate211552Y" 02/07/2001 (215) 443-8710 FieAccession spec. "Gp Sex Age a ILDL-DIR Ea HDL-DIR Ee CHOLEST TRIG TTT wom2 J. ge 0 0 418-018:PAGE H-104 GLYTICS 200Girard Soot,Suite200 Gaersbrg, MD 20877 fants ARGOS, RESEARCH LABORATORIES, TNC. fate Soliscted: INCORPORATED 301-821-0168 Fax: 301-977-0433 02/07/2001 e33est BREE, one 205 SHESRY DRIVE DDaattee RReecpeoirveeedd:s 10/10/2001 ctent vo(.2151)028443-8710 Study: 41086 71 105 REPL Species: TAT faseaion Eggeee. aGpsex Ao a [oupin a WRI EQOaH m[BeiG : orous 10 vor Fpohaamtye BmEy page i py OTR He ona g BE enBE 4iho BnEw aE EH IE 5 SE an fae - 80 88 rage 2+ 001034 418-018:PAGE H-105 GYTICS 200 Girard Srot. Suite 200, Gaithersburg, MD 20877 Client: ARGUS RIENSECAORRCHPOLRAABOTREADTORIE3S0,1-9I2N1-C0.168 DateFaxC:o3l0l1-e9c7t7e-0d4:33 i eat B2T0EE8 ESBHEEaSRtTBeyDdRI1VsE0ae- DDaattee RReepcoeritveedd:: 0120/3/010707//22000011 | client vo. 1028 Study: 418018 F1 LDS REPL Species: RAT Rocesaion Gps. .oNBgBop.ooogom aiseli1aHeee popeBBpoooammsmaea MenlR BONA HIE ,; yBeean Group 11 5BBBooooooiaoezesosssto 1aHH1t0ae2e9 BppBooooooovoeessdststeMa HonBM Boohee Ho ytoupn Group 11 op SexAge GibiR GEIR homer uc, TTT 5 hHiEEf23 i: MG/Se0G:oM88n0 a8 MG/oGod SSd% MG/Lnd3G.Mkd7t3 MGgpa/5G.EeE3M8 iHoHoo:Eff Hf agaee88le foo8iafd%te nnhBhfiE OSegfsdh 5:8 8% 3 Wl 38 T8e8 aumn iBndn iH1HH1 kk Hk 0aae.808088o8 08.l1 a8 gf 3nLn.ifB4l8 aSgR70Ep1 hi aH HohioXdEk Sea68s888 8 i 888B1 if4BhRp% aa0ahshl 83 T8oGe Tahea Isols Reference Range o8 - o8 - o8 - 8oPage 3+ 001035 418-018:PAGEH-106 CAYTICS scson0uttt m.voswor rents Ciien Anas aIpNoCpaOaRcPhOpRAAsGTREADTORTE30S1,-92T1V-G0.168 BEHEL o 38% SURERYDRIVE Bate Seligetad: Fax:301-977-0433 eteDate RReecpeeirveeadd:: 1020//0370//22000011 crtent vo. 1078 (218) 443-8710 stacy: axs01s 1 195 REP Species: BAT a eaella ra Ba Sa Be oxoup 12 ! --_ Mean 0 .07 3.97 8.82 J . g- gt 8 3 001036 418-018:PAGE H-107 CAYTICS osssom sm20,comoio2. INCORPORATED 301-921-0168 Fax:301-977-0433 SLA LL vision ont B90O5LSLHOEEECHYBaDRI10V0E4s. (215) 443-8710 Date Received: Date Reported: 02/07/2001 10/10/2001 " cre wD IE ers atin 73 108 Em specions BT JmomaienBgeoelreer sBeexoereD ggp Dinhie glgeuna gWmiae vow2 oro 2 cron 2 erent ae 0 0 0 C1037 418-018:PAGE H-108 CILYTICS mse se 0cana0 .um Clients N33i00g8,usRSEIENSSECAPORRCEPHCOTRAABOTREADTORIZ30S1,-92T1i-e0.168 BaagtFeeaxSS:o3H0l1l-Ag9c7Rt7-aE0d4:33 0a/0r/20m catant RoBH.EORA1ER02E8eEaJtenr 1004ssturdy: 4r 18018 $a 1 10D5atReEPLRepSopretceide:sE:tbB1/A0T/2100H/2e001ne Lp ge be | h PBoommdeinnE m 33 kok hepr rn e E sh eE nSa Go$SEl8aEo gR4eIhE i Mean aroup 3 8pBBBoooooonmmumrnnnioegmgs ie1ii0ess0l3eee7 3fff5}ff%f polwraeayn 2 of croup 5 0 047 4.17 17.933 ogggpe2hfE oSEoonabsEe 3dn$iee3EEdm 1lism6e.Htn6e6 3STROShWEEE hOsEaERm EfhaEnn BPpiasohuinimdsisfieyee::gfoxf tere Tori uuSEEREaeHt ni3gm8 Bommimy P $0 8r8 .8 pve 5+ 001038 418-018:PAGEH-109 GLYTICS cossom. 500csr,wo mm Client: RARGEUSLRIEINSECAORRCHPOLRAABOTREADRORI3Z0S1,-9 TNC.21-0168 DBaattFeeaxSS:3oU0l1l-I9c7Tt7e-E0d4:33 oo/0r/z0m fo pate peporvets ao cient ro(.2151)028443-8710 study: 418018 71 IDS REPL Spectes: RAT35/50/2000 Eagoesneison meRSpTee PIHU MEGGT a MGT ERUaGeST iG TTT `youn 73 uBeq AF ik ESHE croup 5 ppBooomnmnnniiiennesffffE $vui8ee GgOeEm ih1.Ee63 oBBeha pooyd 7? TBEOWiEE EEEa eroup BH BoslE omiR 0n0m ox pGepeR npsemw] i1LE8E a LuEp evoue 2an 3 =H TFFHE San Reterenceerence maRarge os- - 93 - :g- gs - roe 7 UG1069 418-018:PAGE H-110 CALYTICS 0 umssro.som23,comer 0 em INCORPORATED 301-921-0168 Fax:301-977-0433 rns TpEm A rn, me. Butte SSoOrMeEt cayanszons : TE herd /30f. 1 HORSHAM, PA_ 19044- Date Reported: 10/10/2001 Client No. 1028 Study: 418018 F1 LDS REP1 Species: RAT fen gpa seas Go an one a Aossslon Bees. op SexAge LBL-pTR EDLDIR cHOLEST TRIG ores 7 orn8 reterene mange 338 001040 418-018:PAGEH-111 catens CALYTICS ose apEH3gsvaLapein pronase. INCORPORATED 301-921-0168 st smpoes vo wum egBeeisFtaxpSS:3e0Ep1S-rL9i7E7Ia-0sS433 aSon/0nr2e00 tere on (215) 443-8710 ses axons 7 120 ms scien: foammi E gpeeeSe ees i DOLE E rdT G GOReIiee, rou S-- eo 3-3 001041 418.018:PAGE H112 CLYTICS occu so st 1 an. wer crtent:+ ABRRGSUSSRIENYCRESOEDAKRRCPIHVOLERAABOTREADTORIES3,biaIzNvCo.nse BDaattFeeaxSCSoR0lH1l.Ie9cE7t7Ee.Yd0:40 02/07/2002 BTORoERAaNC MaBna d1s0ee- Date Reported: 10/a1d0/2001 Client No. 1028 Study: 418018 F1 IDS REPL Species: RAT SfossemsTen Bee=s. 5Bpp0oo0ea3o7aue0s8ude1 21nn1b0gt0n0 Bppooeseahts dlHittby [Riz eoapn Group GCpp sSeexxAMgoeeISL ioI w 33 B Gao8o EMDeLjoBwI|R 0a.083 CHHCojieg'sT 4f.3a4 WwIo/GGx 1H3E.7B3 5o83 F 3 g8ea::008888880o8::h888 888 8% LgLioEeBe iaaMi7ewd ne an 0:8 8% aE HE 38 T0os5s Thiegi 1a 3,116 Refeerreennccee RanRagnge g0- 3o- 2g- 9g- sPrpoverd ogGecoresi of 10ree once wl 12for 001042 418-018:PAGE H-113 GLYTICS conssem. 00 aswo om + ARGUS RIENSECAORRCPHOLRAABOTREADTORIZ3S0,1-9I21N-C0.168 DateFaxC:o3l0l1e-9c7t7e-0d4:33 cient H205LoSREaCagal38D1RdI1V0E0ue- DDaattee RReepcoeritveedd:: 1002//1008//30122000011 Client vo. 1028 Study: 418018 F1 105 REP2 Species: WAT AspRpeeoscaeetsasaiarosn Snn5npeeasce. pBpBoooososmraeasdlas tidneeaeed pppBoooessmgenaasasinia naeel sppooeummtuHHaaa wseeagn Grou 1 bB3pogooounaosrtaseeisnsneeaesrn pBpooommprianHaesed Referenecnece RaRange GCT1ppsESeeoxfxAAgsee 1% L[DRLagE -oiDnrsIR HWDbLjoe-oiDeE nnIR CHMOo3ILoEkE8ST TWRe1IIjE8Go.EE4w3 1o11 }fIof 1k egeeege ogSilfz w3IsE mBBRgR 0.00 009 3.86 3.2 ooo1 fffof e ggseeeeoeinSarhH gE 8 oBIniRnr BHBwELEn BE un 1p BTS iRe aT8ig% 380 aNEm MB hgeEs 1111XXkoR 1% 0Geg.0e0e00 so8eaed80ee 33 II4HE6 2mn1aie. ge oe dE a 11kM 9gi8g e8r% mNEE I BSE og - s9- g9- :o- Page 1+ 001043 418-018:PAGEH-114 GLYTICS 200GirarSie, Sut 200. GathersburMgD, 20877 Client:SARRGULS ERIEENSECAORRCHPOLRABAOTREMTDORIE3S0,1-8T2N1-C0.168 DBaatteeFaxCS:eo3Ll0A1l2-e80c7Et7E-eE0d"4:33 02/08/2001 BBEERELEatBey d100u- Date Reportsd: 10/f1i0n//2e001 Client No. 1028 Study: 418018 71 IDS REP? Species: RAT JoosoeesoseiioonnSgppeca. ooppsSeexhAogee ILDLo-pDIeR fe FDI-DIR CGhoutozsTTjRIeG 5ppppooooopimmmm n Hnipsaaean1111oKdkk Go o.o7 asi 35.3 ae00.88000 og 0.0k6 n n2.g83 1BB1.YR38 ppoempdeid 11 % eSs6e8 e8bh nnfL dIaEl NTeeagn T8o0e oamy aE ger i 1708 ! Group 1 BBBpooooosoo7seso0edr nn1H1iii62ggg0 1i1i08bffEEEFF BpBBooooooveeeoilnslnHdieeeg 1B118 EEEF pond bas BF yeoapn Group 10 a0aF.000I0 oFoelzcRI 3in.d3H4 AB87RE3 eeeg::8e08es88 oGeoifilB 1R3EIA3t Radaingts 85 oh aE 36 83 aTo9i Tuhiam anladm Refeerernceence RaRannge a0- g9- 8o- qg- Page 2 + 061044 418-018:PAGE H-115 CLYTICS soc svo se 2.camwoo .sr Client: DARGEUSREISENECAORSRCHPEOLRAABOTREADTORIE3S0,1-8T2N1-C0.168 BBaatteeFaxCS:o3Ll0l1A-s9cS7t7e-H0d4:33 0/08/2000 : a Toi)nehame710 Client Yo. 1028 Date Reported: 10//2100//2001 Study: 410016 71 LDS REP? Species: RAT Lo omeE eeese Se hege IDhEipERWWaDGSEoamer mjEe, BpBBBooo0oc0no3oa7ess4g0rt:1 Boos n1eHH1ede6de2tdz0 Hels BRi1B0YfBMOE 10 0sggg.ro0eage0e gee 0eege.rs0node6g om 31naB.e0BERd2 1He1He.iEn7ng2 Ba ad Ea gre ger 3h M8 BBpooocoudzseser HHHeeellsee RB18EHK Gga8t sedu n3a a3kd Mveagn T0er dToms Suayw a1n0dg Group 10 pp8po oeooyauassisee poo nHmHsaaeem ned OH1HofEfI HE g 0gg0oe0oe ol 0ae1zms cee ge sas 43 gde we 116R8.2h%6 na a BBBBoooedoossanMHseeetls iHiHffFf ggieege gggeea 3BmRaE 1a 38 wHeeapn 3 TaRn iuew hPaan Group 11 Reefteerernecnece RanRagnge 9o- 9o- g9- o9 - Page 3+ 001045 n 418-018:PAGE H-116 CFLYTICS cs ste0cr ams. wo ar Client: ARGUS RIENSECAORRCHPOLRABAOTREATDORIE3S0,1 INC. -921-0168 DatFeaxC:o3l01l-e6c7t7-e0d4:33 ent: B$T0ER5.HEL)SRHAEhCEiHaYBmeyrDaRdI1V0E0ae- DDaattee. RReepcoeritveedd::: 1020//0180//422000011 Cutent No. 2028 Study: 416018 F1 IDS REP2 Species: RAT Ames en geeeee p ppoooopo aioee 1nnh1eaesld ppppeoooneoontl nhgHiEgdeR pomn ne Neeegn Group 11 pppboooeoosostzpevsszses nnH1ieeislltglie Dpppooooooomn Ha HHealEtl Bon HE weeagn Group 12 eCrp sex hseahe i3iiBNE iiHikkEo HOR Dvoape m Riop n GWormenerEWee, aGgs:o0f0r0 oSE eHnH IB 1138B. RBB19.RwE13 eegeeeeese88ooo8Rhy e880 of BBE aEE R 8 e8x3 as Be 38 GA3 hBaSe D8na i1i13fE:fE 1: a0eg.008e0 gee eSSonmER 98 3E nR.i8B3p3 an an3.ni8 3A abd iiI1 EF: egee%e08Eo8Rn 1LNEAE aRlgeE TSeer ETatn pWYn aTaae Reefetrenrcence RaRnange a0o- o9 - 9o- 3g- Page 4+ 601046 418-018:PAGEH-117 GIYTICS socom sve sasrs0 mer Client: ARGUS RIENSECAORRCPHOLRAABOTREADTORIE3S0,1-9T21N-C0.168 DatFeaxC:o3l01l-e9c7t7-e0d4:33 en 3B018R81E8S)UREA4M4A3B-LD8a7R1I01V00Eee- DDaattee RReecpeoirvteedd:: 0120//ta01l80l//22000011 Client No. 1028 Study: 418018 F1 LDS REP2 Species: RAT Nios.ession S8pec. opPSSeexxMAege IDWBLr-aDMIR MMDoLj-aDTR cMooLjesmst TRNoI/Gox pppBBoo0oo0oo37aeoo41sd9 ln1nb1ieie6e4ldet0 1ii1B2 kEMN Booed Hee ik 0eFg8F.3:E0888I030080oSS .80lf9 E3aBBR.1HfTbE6BR H8uGe.b5dR1E41 ~ BpBooossoausla HHneesestt BiikXo eeee8e88eo8dk bk3hi maasEil HToeagn 8To%i eEsee gWPm R1Em Group 12 ppBoooossoiee l1niiieesete B1B3 EFE 8e0.00880 8o%omn EE3.E30LIh7E.k89 weBaEn 83 d I u Sen 310,0407 Group 13 BBoogssp7aazss n16e3t4 B13EM o8o:o8 8oBm 3 338 7O.B2R] Reference Ran: 0- o- 9- g- ae 0 0 0 Page 5+ 001047 418-018:PAGEH-118 Client: ARGGUS LR{ENSYEENOATRCFHIGTRAABCOTREMSDSGRIESia,oacoTrIoCi.sseoDeatsFeancCos2l0ol,reccrtraeodum:ms wo srr client 3BT0oH%1,R8B)NUEG4EdHaYAtDaRnaIdgVoEne vo. 1028 study: 410018 P1 bDaattee RReepcoeritveedd:: IDS REP? Species: 1002//3610/3080//0220001 BAT m Hggesnton gpoe. Pe exRM eeEGeT e mWefe an Wgeeen"e mMe eer,on B 0037430 1yr1o6ru5n6 13 M w 0S.i0r0ag0T.a1n1 SR 3u.7n6 W T5a.3n4 ~ croup 13 opEBBooooooevindmididaidsilse sudmnimisesegy 1312fo%f22x Joshi ig ff oosgsoeeeeoses gegooaupnmee 333un8smge9 1 nLuwyamn see gag dm apg BBBBBooouonoosidisinsseaginnnhnigsmzgnme ff22foofff22 goods nse 2 f gGgsoecerse ge egggawlrs gd m2nm8Emm3 GmndEnaaEg see em EBoodoiitse gse 2fof2 uvory hE E GnR OTH HRE m gan LdeEan axowp 2 Refearence Range 0s - w3 - g: - 3g- rage 6+ 001048 41801EPAGE H-119 4 GLYTICS 200GirStree, Sut 200,Gathers, MD20877 i|| Cliceenntt:: AHRSGUESBRIEENRSECRAORBRCPHROLRAABOTREADTORIE3S0,1-9I2N1-C0.168 DBaatEeSFaxC:Oo3R0lA1l2-e09c67t73e-S0d"4:3302/08/2001 1 B(SCLHORRCTERBy ety100a4- Date Reported: 10/3010/2001 {Client No. 1028 Study: 418018 F1 LDS REP? Species: RAT |i 3gooessiselsoinonsgppeecc.. |Coe Bpoom mnmgmiHusaee ||PBopE Bo0o0g3ms 7im34si2 ponte nai1E1as5ag1et8 | BpBooomnsaimtaiiann ' Dopp B 0037350 11526 iB 0037351 11527 Meogan Grow 2 5pBRoooooooamrssasseee iH1n1ii5a2aa8 ppBooomommdeesls iHMaB3l wseeapn Group 3 CGpPSSeXxMAge f3i BuX 232f3 okK 3ifo 22M 2M MICDLJ-oDKIRwECDjLe-xDI|R GMhoooLnEsT Seg:o0o088ee8B321383B 08e8.:8e08e808 S0i e.1Rh0 ERB2.9EEi8 8a0.:o00r18 o0S.0nd3 b4H5yfs S88 0.00 0.04 SR 0.07 0.12 38 2.93 3.16 TBooer EesR 3Nh6e TcR/IGx 21u3.hs01 a8 m6.8E38 J7kO.3nB9 LB 9.96 5.25 d10,s80 3333 oEOff 3 eR0g8.Ce00rO80 0e.0n3 i 23 h4.2E7 11 838 Bs 8% SR ER am 33 F 0.00 0.08 2.6 8.74 T8o%y a8ss 3h,7I85 i137 Reofteerreennccee RangRange 90- ao- 90- 3g- Page 7+ 001049 418-018:PAGE H-120 GLYTICS 200GianSirol.Sut200,GathersM,O 20877 : i Client: AERGUES RIEENSECAORRCPHOLRAABOTREMDTORIE3S0,1-9I2N1-C0.168 BUTIENE Bh so0ue- BDaatteaFaxSC:o3L0lI1l-Cg6cE7t7Se-"0d4:33 Date Reported: 0a/0s/20m 10//1100//220000% | HR haterad Client No. 2028 Study: 416018 F1 IDS REF2 Species: RAT Sgeoiosnession Sgpeeec. Sonia nnsa OoppoSeerxAbgae J IDL-DIR fWaivpaiAc Aho TEMfGr e. Est 33 BOE SFoTrI eTeCs 2.08 132 WE DLo oopBpoopeagemmmmmssmste poms hHHHaaaagkl 3333 pomp Has 3X g[ggeee3see oi ot8eneHH ER R3 4 3BR Ry a aSlR : Neepen pSrreaalirarraslie yueir SE | row 3 5BBgoooooocuin7aaeecssess 11HH1a53as5t8 Booaes HE 3333 EfE 3 0egCC.0iEH08oJA00 0og.di4JE44A 3.0%82I 3HaH1ii3Rdg21 pppBoooeouooamirlt Hilaiagsgge 3233 of ok gegg:ee8eee8 g:08 9oEg:da0ies8 88 3 RnkEhy iannpeeagd ppeaen s Ha:3 fF ytepn g:8 Tay of a Ta Es eNep esi h1Ea Group 5 Reference Range 8o- 98 - 8o- 8g- Page 8+ 061050 418-018:PAGE H-121 CLYTICS imssive sm 2.camavroomo.m tents ARGUS BIENSECAORRCYPOSRAAORTMEIDORIE3S0,1-9D21G-.0168 BateFa gollgcred: x:301-677-0433 crtens $veB 01.38181S)0E3E 8E44R3]-D07R2i0nvEasetudy: 410080 Dbaattee RReecpeoirvteedd: P1105 REF? Species: 0120//70110801//22000011 RAT SJooeseslonmaionBgeeees eGpp SSeaxxhaAege IQDRLDIR EWDLaDnIRCoSlemner TRRoIlGo B 0037360 11558 5M 0.00 0.11 4.31 23.45 ~ J rege 5+ 001051 418-018:PAGEH-122 GLYTICS sccm sv sm.smswo mer Client: ARGUS RIENSECAORRCPHOLRAABOTREADTORIE3S0,1-8I21N-C0.168 DatFeaxC:o3l0l1-e9c7t7e-0d4:33 B1us8O1E5B)RuSL4s4a3lB-D8aR72I01V0E04e- DDaattee RReepcoeritveedd:: 0120///011800///22200000011 Cuent Fo. 1028 Study: 416018 F1 IDS REP? Species: RAT Sosennion ames. YSppo.ooonammlpom B nnlnaiiae nasetl ppBpoooodnmmeep nnMIiaaEgsdE . wBeaEn Grow pppooooszmsEssss 11n1i5zs3e2 yoreupn Group 7 BpBooeonmrAmsNepiuMiEse Nteoapn Group 7 op oP sexAge ay Ipipin MG/GK MDLpIR MG/GK GhomEst mI MG/G MG/GH 6 E ag8e:8e8 ooSHHR 1RRu8EEh eORE8EE ok 0.00 0.08 3.07 9.7 38 pArrralniirririLeEr 777 OEoFF 00.:080 oomn 4aaE 1B3.a32 38 3 TEE 7E7E5s 777oXk 0.00 01 _3.25 8.48 38 8Ti a3 s B8 ae Refferreencnece RanRagnge 0go- oa - 99- o9 - Page 10+ 001052 418-018:PAGE H-123 CELYTICS soc sov. sto 3.caro wo zm hte: ABnPasLAIERNSOCPAORIRCPHYOTRAABGTREADTORI3Z0S1,-82T1N-C0.168 tr 2Db2aa5ttF2eeaxSSR:oe3H0lpA1lo-Sgr9etE7te7Ra-d0d:4:33 100//0180//22000011 crtent vo. 1620 (215) 443-8710 seatys 410018 71 105 5EP2 Species: TAT s foenion me gee. oape sexoe t E UR RE aRt G GCa a Wi B 0037488 11600 8F 0.00 0.08 3.64 11.24 - J I Retarence Rang 3-8-8 3 061053 418-018:PAGEH-124 CYTICS ocr soe 020 comer vo mor Client: ABRBEGUSsuRIkENSaECAORDRCiHPvOeLRAABOTREADTORIE3S0,1-9I2N1-C0.168 BDaattFeeaxSC:3oR0l1lI-e9Ec77tE-eY0d4:33 02/08/2000 BROoRERRANa. tBia d10044- Date Reported: 10/731001/2001 Client No. 1028 Study: 418018 F1 LDS REP? Species: RAT FNoo.sesslon sppece.c. 5BBooogaa3d7rada9e8 poo n1n2eE6ll1sl1 nels CpoppoooopyzdaeeeiniLedeilleeysl Baste Hels ; Hoopan Group 9 opBoos%o7iaimeeae pose neneeullrys nel BpBooooscysaaes ponmee hnneeelilsss gle pen is Neopan Group 9 opmSEexAMgee IDWLi-nDIR EHDeLy-oDRIR cRMoojLegsTTWRoIjGon 333 EEFE 3k o2&:a88 ee 0Sh1imsf hE i33.a820 5 1BB53.Ey882 8338 kEEF e e288o n Se8RX3 3333% 3s mgiass el 3F 8:8 8: 37 Bn 83 8 Te 3N7Ia 1Raem 3333MM 3x 088.:00880 0a8.2X0 ee o f 8 n333.i35s7 1aiI6n1SEd4 Ih iE: 5333 MM 2a8 0:888 o40emnhB 3nd38imE B#i5bg3Se 78 T3ie%r TB32E08 B15E.3S38 Reteerernceence RaRnangg:e 2o- 8o- 8g- 8g- y Approved ohfoe Date --e2fel PP? Page 12 of 12 e 061054 418-018:PAGE H-125 CAYTICS soc sum sismoes omer INCORPORATED 301-821-0168 800-237-2815 QAAUDITREPORT hTCoeeo rEbeopTroratA listeIrdaabcnetdliocawelslvaasansadrsneodwvciiiteathwtheeeEddPAffrioaGnrwodoicddnoagmLtspaalbiowwareenarrcteeeorwryrieetvPpihroearwtctethediedceFfsDto.Aor aTRmageamanteR msistency hTa hee mmeethdodses efuMtsietdsh twtheehreeFdDatAthaea.ndmeETthPheAordeGsfooorddee,LsacbtrohierbsaeetdorsytsuadPdireasctthiweceersre.epdoornte _GFrasykile Be. Neewman QA Auditor sponsor: _ Acs 485 REpoRTTYPE coon 0, iE ADIT DATE poa00 stop: _4I40if RETPOMO ANAR GEMT ENT 0-33-91 AUDI#T 01-901 Lobe 5, te 0 e DR s_R. oy LpTECToR p= RAGE Aol 061055 APPENDIX I BIOANALYTICAL (PRIMEDICA WORCESTER, REPORTS SPONSOR AND SRD 001056 418-018PAGE IL FINAL REPORT VSAPLEICDTARTOIMOENTORFICA MGEASTHCOHDROFMOARTTOHGERAAPNAHLIYCS-IMSAOSFS MEVALONIC ACID IN EDTA RAT PLASMA FOR PRIMEDICA ARGUS STUDY 418-018 Primedica-WorcesterProjectNumber: PABX-BVA PRIMEDICA ARGUS 905 Sheehy Drive, Building A Horsham, PA 19044 001057 418-018:PAGE 12 2PRIMEDICA 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-Worcester Project Number: 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 tue Date November, 2001 VL DB, Nfl 1/20 Mark A. Netsc/h Date Project Scientist DepartmentofAnalytical Chemistry Primedica- Worcester 001058 418.018PAGE 13 JPRIMEDICA FPirniamledRiecpao-rWtorcesterProject number: PABX-BVA ForPrimedicaArgus Study Number: 41P8a-g0e182 COMPLIANCE STATEMENT This project was conducted in compliance with the Good Laboratory Practice Regulations, 21CFR, Part 58, Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Numbweirth21p,rincMiaplrecsh o2f6g,o1od99la7boarnatdorCyouprnacctiilce.deOcfifsiicioanl/ recommendation on compliance Journalof European Communities: Legislation 32 (No.L 315; 28 October): 1-17. There Were no deviations from the aforementioned standards, which affected the quality or integrityoftheproject or theinterpretationofthe results inthisreport. ML a, Feb `Mark A. Netsch / Date Project Scientist toto 001059 418-018:PAGE 1-4 GPRIMEDICA FPirniamleRdeicpao-rWotrcesterProject number:PABX-BVA ForPrimedia ArgusStudy Number: 41P8a-0g1e8 `QUALITY ASSURANCE STATEMENT The folloawrietnhge inspection datesand report dates of QAU audit/inspectifonosr Validation Of A Gas Chromatographic-Mass Spectrometric Method For The Analysis Of Mevalonic Ac Ini EDd TA RatPlasmaForPrime Ard gusiStcuday 418-018, Project. `Number PABX-BVA. Critical Phases Date Inspected Date Report Submitted to Project Scientist Management 1.LaboratoryProcedures. 10/19/2000 10/20/2000 10/23/2000 1. Raw Data 11/07/2000 04/06/2001 04/06/2001 2. Draft Final Report 03/26/2001 03/26/2001 04/04/2001 `TFhoer TFhinealAnRaelpyosritsOfofr VMaelviadlaotinoinc oAfcAidGIansECDhTroAmaRtaotgrPalpahsimca-FMoasrsPrSipmecetdriocmaetArrigcusMeStthuoddy 418-018, report number PABX-BVA-01-62, 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 with principles of good laboratory practice. Official Journalof European Communities: Legislation 32 (No. L 315; 28 October): 1-17, on 11/7/01. The results as presented accurately reflect the raw data. Nie, 2 `Quality Assurance Auditor Date 601060 418-018PAGES GPRIMEDICA Primedica-Worcester Project number: PABX-BVA Pages FinalReport ForPrimedicaArgusStudy Number:418-018 `TABLE OF CONTENTS PageNo. ANALYTICAL REFERENCE STANDARD CHARACTERIZATION/STABILI.T..Y.8 VlidBHOD DESIG reer rrerrersmmmnsmmesssmmmsssssssssesens 1 RESULTS AND DISCUSSION...c.ccorermrssrssssssmsssssssssssssssssssssssssssssssssmssnss 14 VAlGBUOR RESUMS.cecrreerrscrrrsermsmsssssssssssssssssssssssmsssssmsessmessessassessssssesssssssesss 14 `Water/Plasma EXITaction COMPAIISON .........cvmmersessssssmssssssssssssssssssssssssssssss 14 PLOCISION errerrerserrersrrseressenemsssmsm ss --------------------------. 1 FS i ----, -- SUBIILY crerrrerermrmrermmsmmssssssmss---- UT CONCLUSIONS cnr 18 geod wo 418-018:PAGE 1-6 GPRIMEDICA FPirniamleRdeicpao-rWtorcester Project umber: PABX-BVA ForPrimedicaArgusStudy Number:41P8a-g0e1s8 LIST OF TABLES, FIGURES AND APPENDICES TEXT TABLE 1 PageNo. FIGURE 1 Day 1 Validation CalibrationCurve .........cewewsseesessed TABLE 1 Summary of Interpolated Mevalonic AcidLactone QC StandardConcentrations TABLE 2 `Summaryof Back-Calculated Mevalonic Acid Lactone Calibration Standard CONCENTALONS ecco ereresrssssserssmmmmssssssssssssssssss TABLE 3 Mevalonic Acid Lactone Extraction Data& Recovery Calculations ..............25 TABLE 4 `Internal Standard Extraction Data & Recovery Calculations... 26. TABLE S `SummaryofLeast-Squares Linear RegressionConstants and Analysis Dates.....27 TABLE 6 `Summaryof QC Standard 72-Hour Room Temperature Stability in Matrix.......28 TABLE 7 Summary ofQC Standard Freeze/Thaw (3 Cycles) Stability inJIT -- TABLE 8 Summaryof Interpolated Mevalonic Acid Lactone Dilution QC Concentrations for Dilution VAldBtON. ...oersersssssssssrsssssssssssssssssssssssssssssssssssssssssssssssss 30 001062 418-018:PAGE 1-7 GPRIMEDICA `PFriinmaledRiecpao-rWtorcesterProject number: PABX-BVA For PrimedicaArgus Study Number: 41P8a-g0e186 LIST OF TABLES, FIGURES AND APPENDICES -`CONCLUDED PageNo. TABLE 9 6-Day Room Temperature Final Extract Stability Back-Calculated Calibration SHANAATd CONCEMIBHONS .vvereercreerrrsrrsrmrmsssmsssssserssssssssssmssmsmmssnsssssss|3 `TABLE 10 6-Day Room Temperature Final Extract Stability Quality Control Standard COMCENITALONS -.crerrrrrsssessessaessrtassssssasssssmesssstsss 32. TABLE 11 `Summary ofControl Blank EDTA Rat Plasma Concentrations... wm----33 TABLE 12 + `Summary of Unique Lots of EDTA Plasma CONCENMTRLONS..everrevrverssssssssess:34 TABLE 13 `SummaryofInternal Standard Peak Areas.sssressmesessess----------------------- TABLE 14 `SummaryofPlasma QC Standard Concentrations with Inter- and Intra-Day SUMMATY SLASHES .vvrvvvrreeevesrrsssssssssmssssssiss ssssss sss sonoerrsrenns IT APPENDIX A APPENDIX B Representative Chromatograms from Validation Day 1 .sneS2 001063 418-018:PAGE 1-8 Primedica- WorcesterProject number: JPRIMEDICA PABX-BVA ForPrimedica ArgusStudy Number: 41P8a-g0e1?8 Final Report CONTRIBUTING PERSONNEL PROJCGt SEHERSE rrr RESEATEh ASSOGIRIE sors Mark A. Netsch, B.A. Heid Gagnon,BS. Director, ARalytical CHETSIT esse: JES A. JETSEYP, hD. 001064 418-018PAGELY PRIMEDICA Primedica-WorcesesProject umber:PABX-BVA Pages Final Report ForPrimedica Argus Study Number:418-018 ANALYTICAL REFERENCE STANDARD CHARACTERIZATION/STABILITY AnalyticalReferenceStandard: `Common Name: Physical Description: Lot Number: Storage Conditions: `Expiration Date: Date Received: `Amount Received: Supplier: DL-Mevalonic Acid Lactone MMeevvaalloonnioclAcectiodnLeaocrtoMnVe oLr `White crystals 47300/1 50498 5`S4e3pteCm,bdeersi1c3c,a2te0,0s2t(orAessuingdneerdnbityrogen Primedica) September 13, 2000 5 grams `Aldrich Chemical Co. Intemal Standard: `Common Name: `Physical Description: Lot Number: `Storage Conditions: `Expiration Date: Date Received: Amount Received: Supplier: 'DL-Mevalonolacetone-4,4,5,5-de MVL-de Clear liquid U-295 2245C September 11,2002 (Assigned by Primedica) September 11, 2000 0.1 gram `Cambridge Isotope Laboratories CinhtearnarlastcantdearrdaiinstdzhSaetratebsiiploiontsyn:ibiTlhietyochfatrahceteSruipzpaltiieorn, oafs tihsethaenamleyttihcoaldosftasnydnatrhdesainsd, fabrication or derivation and stability determination. 001065 418-018:PAGE I-10 GPRIMEDICA `FPirniamlodRiecpao:rWtorcesterProject number: PABX-BVA For Pimedica Argus Sudy Number: 41P8a-g0e18d ARCHIVAL STORAGE ArchivalStorage: TheoriginalFinalReportand raw datawill bemaintained for a minimum period of five years following submission of the final report inthe Primedica-Worcester Archives in Worcester, `be contacted for disposition instructions. MA. After five years the Sponsor will Archival material will be indexed by Primedica-Worcester Report #PABX-BVA-01-62. 001066 418-018:PAGE I-11 GPRIMEDICA FPirniamledRiecpao-WrotrcesterProject number: PABX-BVA. ForPrimedicaArgus Study Number: 41P8a-g0e1810 ABSTRACT: A procedure has been developed and validated for the determinationofmevalonic acid in EDTA rat plasma. The procedure involves the conversion ofmevalonic acid (MVA) to mevalonic acid lactone (MVL) and the analysis of a liquid/liquid extract by gas chromatography coupled with mass spectrometry (GC/MS) using positive chemical ionization (PCI). A mathematical factor to convert sample concentrations of MVL to MVA is included in the Laboratory Method in Appendix A. Calibration and quality control standards are prepared in water since mevalonic acid is a naturally occurring compound in plasma and concentrations vary with diet. The intemal standard, MVL-ds, was used for quantification. The results for the validation indicate that the method is sufficiently linear, specific, reproducible and accurate to support the analysis of mevalonic acid in EDTA rat plasma samples. 001067 418.018:PAGE 112 PRIMEDICA PFriinmaeldRiecpso-rWtorcester Project number: PABX-BVA For Primedica Argus Study Number: Pagel 418.018 INTRODUCTION: Tdehteerombijneicntgivleeveolfs tohfismevsatuldoyniwcaascidto(MdVevAe)loipn EaDndTAvraalitdpaltaesmaan. analytical method for EXPERIMENTAL DESIGN: Overview: The assay described in this report employed the conversionof mevalonic acid (MVA) to mevalonic acid lactone (MVL) and the analysis of liquid/liquid EDTA rat plasma samples by GC/MS using positive chemical ionization. The internal standard, MVL-ds, was used for quantitation. The validated assay covered the concentration range of 10.0 ng/mL to 250 ng/mL ofMVL in EDTA rat plasma using 100 pL sample volumes. Materials and Methods: Refer to Appendix A for a detailed description of materials and methods employed during the course of this were prepared in water at validation the lower study. limit of In addition, quality quantiation (LLOQ control (QC) standards 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 and dilution pprroepcaerdeudretousmeidfmoircthfienawl aetxetrraQctC csotnacnednatrrdast.iOonneassseutomfisnoglu1t0i0o%n 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: Tcohmeprasissaeydowfabsraccokmeptriinsgedseovfenf-ipvoeianntalwyattiecralmarturnis.x cTalhirbereatoiofntcheurfvievse waintalhystiixcarleprluincsatweseroef water matrix quality control (QC) samples at four concentrations, six replicatesof EDTA rat plasma matrix QC samples at three concentrations and six replicates of rat matrix control samples (EDTA rat plasma with intemal standard). Multiple water matrix blanks and water matrix control samples (matrix with intemal standard) were analyzed in each 001068 418-018PAGE 113 OPRIMEDICA Primedics-WorcesterProject umber: PABX-BVA Page12 Final Report ForPrimedicaArgusStudy Number: 418-018 run. An analysis of the method recovery was included in the third analytical run, which consisted ofan extracted calibrationcurveand a solvent calibration curve. Theanalysis of freeze/thaw (F/T) stability and room temperature (RT) stability, both in water and matrix, wasincludedinthefourthanalytical run. The fifth analyrtuin wcaasa l re-injectionofthe extracts from the first run to evaluate the final extract `stability when storedat room temperature. assay performance parameters Text Table 1 lists eachvalidation that were evaluatedforthestudy. analytical runand the TEXTTABLE1 Validation Course I Day1 Precision, accuracye,iTvoarleyn,cyod waiepasn EE | [| TM [Precision, accuracy, Eneaermiityv,aplenecye. `and water/plasma EE `Precision, accuracy, linearity, recovery, dilution accuracy, precision. andwater/plasmaequivalency rr EE Parameters Evaluated: Mevalonic acid is a naturally occurring compound in plasma. The concentration levels found in blank plasma were anticipated to be above the validated lower limit of quantitation significantly (LLOQ) of 10 ng/mL. This skew the results of plasma level QC's of at background the lower concentration concentration would levels. `Therefore, calibration and QC standards were prepared in water matrix to evaluate precision, accuracy and linearityofthe method. Thesecond set of QC's was prepared at three concentration levels in EDTA extract and quanitate MVL equally rat plasma from water to or evaluate plasma the ability matrices. of the method to The plasma QC's were also usedtoevaluate matrix stability. 001089 418-018:PAGE I-14 GPRIMEDICA PFriinmaeldRiecpao-rWtorcesterProjectnumb: PABX-BVAForPrimedica Argus Study Number: 41P3a-g0e1183 `Water/plasma extraction equivalency was evaluated by the analysisofsix replicates of eachQCstandardconcentrationlevels inbothwaterand plasma. Meanpeakareacounts ofthe isotopically labeled mevalonic acid lactone internal standard were calculated. The differencebetweenthe water andplasmameanpeakareaswereexpressedaspercent difference. The acceptable limits were +10% difference. The isotopically labeled internal standardwasused 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 concentratitoon interfere wi thet resuh lts. 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 comparedto the high QC concentrationand didnotmake asignificant 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 replicatesofthe QC standards prepared in water over the courseofthree validation batches. Accuracy results are reported as % bias. Method precision for QC standards is expressed as % variance. Inter-day method precision and `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% RSDand % bias, respectively. Recovery of the assay was evaluated by comparing the absolute peak areas in extracted csotnacnednatrrdastitoonsthaossseumoibntgai1n0ed0%frreocmovseorlyv.ent standards prepared to mimic final extract Linearity of the method was evaluated by visual inspectionofthe calibration curve and examinationofthe correlation coefficient (r) for each standard curve. Freeze-Thaw (F/T) stability in both water and plasma matrices were evaluated by analyzing six replicates of quality control samples prepared at two levels, which were `subjected to three F/T cycles,priorto their extraction and analysis. 061070 418-018PAGE 115 PRIMEDICA FPirniamleRdiecpso-rWtorcesterProject number: PABX-BVA ForPrimedicaArgusStudyNumber: 41P5a-g0e1814 Room temperature stability in both water and plasma matrices were demonstrated by analyzingsix replicatesof QC standards prepared at two levels which were left standing at room temperature for seventy-twohourspriortotheirextractiaondn analysis. Six-day room temperature stability of final extracts was evaluated by re-analyzing the day-one validation extracts consistingofduplicate calibration curves, six replicatesofQC `standards inbothwaat ndpe lasr ma matrices. Aunsisqauyespplecaisfmiaciltoytswfirtohmreusnptercetatteodernatds.ogenous compounds was evaluated by assaying six RESULTS AND DISCUSSION: Validation Results: `Water/Plasma Extraction Equivalency: wTahteeraboirliptlyaosfmtahmeatmriectehsowdastoeveaxlturaatcetda.nd quantitate mevalonic acid equivalently from The equivalence was evaluated by the analysis of six replicates of eachofthree QC `standard levels in water and plasma during the first three validation runs. Mean peak area counts of the internal standard (isotopically labeled mevalonic acid lactone) foundforthe plasma matrix QC's during each run were compared totheresults for water matrix QC'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 summaryofresults. `The comparison was also evaluated by the analysis of six replicatesof high-QC standards in water and plasma during the first three validation runs. At this concentration level (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 summaryofresults. 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, 001071 418-018:PAGE 1-16 GPRIMEDICA Primedica-WorcesterProject number: PABX-BVA Page 15 FinalReport ForPriAm rgue sSd tudi yNuc mbea r: 418-018 the calibration curve and quality control sample prepared in water can be used to quantitate mevalonic acid lactone concentration levels in plasma. Accuracy: Inter-day and intra-day accuracy were acceptable for the assay ofMevalonic acid lactone in water over the concentration rangeof10.0 ng/mL to 250 ng/mL. Intra-dayaccuracy was evaluatedbytheanalyosfisisx repolfieacchoafftouerQsC standard levels in water during the first three validation runs. Mean concentrations found during each run were compared to theoretical nominal concentrations and the difference relative to theoretical nominal concentrations was expressed as % bias. Percent bias values for the lower limit of quantitation (LLOQ-QC, 10 ng/mL), low-QC (25 ng/mL), `middle-QC (70 ng/mL),andhigh-QC (200 ng/mL) standards rangedfrom--4.8%to 0.1% over the three analytical runs. Refer to Table 1 for a complete summary ofresults. Inter-day accuracy was evaluated by the analysis of six replicates of each of four QC standard levels inwaterduring thefirstthree validation runs. Meanconcentrationsacross these runs were compared to theoretical nominal concentrations and the difference was expressed as % bias. Percent bias values ranged from --3.6% to 1.4% across concentrations. Refer to Table 1 for a complete summaryofresults. 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%. SeeTable 2 for a complete summary ofresults. 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 replicate QC standards ranged from 1.3% to 4.5% across concentrations. Refer to Table 1 for acomplete summaryofresults. Inter-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 inter-assay variance estimate of the interpolated concentrations for the replicate QC standards ranged from 0.4% t0 1.2% across concentrations.Referto Table 1 foar complete summaryofresults. 001072 418-018 PAGE 117 GPRIMEDICA Primedica-WorcesterProject umber:PABX-BVA Page 16 Final Report ForPriAm rguesStdudi yNuc mbear: 418-018 The inter-day precision statistics for the back-calculated calibration standards ranged from 1.6% to 3.0% relative standard deviation (RSD) across concentrations and analytical runs. See Table 2 for a complete summaryofresults. Dilution QC: The dilution QC results were acceptable. Six replicatesofthe dilution QC with a predilution concentration of 200 ng/mL, were diluted with water by a factor of5 prior to extraction and analysis. The mean concentration found was compared to the theoretical nominal concentration (40 ng/mL) and the difference relative to the theoretical nominal concentration was expressed as %bias. The result was ~1.8% bias with an RSDof3.0%. See Table8 for a complete summaryofresults. Recovery: Recovery values were calculated by comparisonof mean duplicate spiked and extracted cparleipbarraetdiontostmaindmaircd pfeinaakl aerxetarsacitn wcaotnecretnotrtahteiopnesakasasruemaisnogbt1ai0n0e%d froercosvoelruyt.ion Rsetacnodvaerrdys ranged from 32.9%to 39.6% for mevalonic acid lactone and from33.6%to 42.0%forthe oinftreersnualltss.tandard across concentrations. Referto Tables 3 and 4 foar complete summary Linearity: The assay was linear for mevalonic acid lactone within the calibration range of 10.0 ng/mL to 250 ng/mL. Figure 1 shows the 1/X" weighted least-squares linear regression plot with the actual `spiked calibration standard data points for one of the validation runs. Linearity was also indicated by the correlation coefficients (r) obtained, which were greater than or equal to r0e.g9r9e8ssfioorn ecaoncshtaonftst.he first three validation runs. Refer to Table 5 for a summary of Specificity: Mevalonic acid is a naturally occurring compound in plasma. The background ccoonntcreonltrbaltaionnk lEevDelTiAn trhaet ppllaassmmaaQmCa'tsriwxasduervianlguattheed bfyirstthetharneaelyvsailsoidfastiioxn rerpulnisc.ateTshoef inter-assay mean concentration found was 16.6 ng/mL. Refer to Table 11 for complete results for the control blanksofplasma. 0010:3 418-018:PAGE I-18 GPRIMEDICA PFriinmaeldRiecpao-rWtorcesterProjectnumber:PABX-BVA ForPrimedicaArgusSty Number:P4a18g0e1187 `The variationofbackground concentration levels in EDTA rat plasma was evaluated by the analysisofsix unique lots ofplasma during validation Day 2. Theresult was a mean concentration of 15.8 ng/mL. See Tables 12 for complete resultsofthe six unique lotsofplasma. Stability: The acceptable criteria for stability evaluations were a mean bias of <+15% from the theoreticalvaluesexceptforthe lowestcalibration,Low-QCandLLOQQCstandards, ` wherme te heaccvriidtela raicatl owneerto eh<e4tnh2e0o%i r.etic cDaulevatlouetshuesperdefsoerntceheofPlbaascmkagQroCusntdancdonacrednstwraetriengthoef mean concentrationsobtaindurti hen samge analytical run from the analysisofsix control Plasma QC standards. Room temperature matrix stability was evaluated by analyzing six replicatesofquality control samples prepared at two levels, in both which were exposed to room temperature for water and EDTA 72-hours prior to rat plasma matrices, 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 acomplete summaryofthe results. pFrreepeazree/dthaatwtmwaotrlievxelsst,abiinlibtoytwhawsateevralaunadteEd DbTyAanraaltypzliansgmsaixmarterpilciecastetshatofwQerCe standards subjected to four freeze/thaw Refer to Table 7 for cycles. The values for % bias were a complete summaryofthe results. within the acceptance criteria. 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 period of six days when stored at room temperature. See Tables 9 and 10 for the final extract stability results. Studiesof long-term storage stabilityofmevalonic acid in matrix at -20C are ongoing. 001074 418-018:PAGE 1-19 GPRIMEDICA PFirnail Rmeepodrtica-WPororjeccetnsumtberr: PABX-BVA ForPrimedica Argus Study Number: 41P8a-g0e1818 CONCLUSIONS: Overall, specific, the results for the reproducible and validation indicated accurate to support tEhDatTtAheramtetphloadsmwaassasmupflfeiciaennatllyysleisnefaro,r `mevalonic acid content. 001075 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-20 Page 19 FIGURE 001076 Primed WorcesterProject umber:PABY.BVA FiouR1E Day 1 Validation Calibration Curve an 418-018:PAGE 1-21 2 . Pa FHi 42 -al .. MeveoricAc nat Plasma Validation Day 1 _ -- VSGpiree:aocosomivsamrssoe | wCmomat w intmPans mm 0010.7 Primedica- Worcester Project number: PABX-BVA 418-018 PAGEL) Page21 TABLES 001078 Primedica-Worcester Project number: PABX-BVA 418-018PAGE 123 Page22 TABLE 1 SUMMARY OF INTERPOLATED MEVALONIC ACID LACTONE QC STANDARD `CONCENTRATIONS WITH INTER- AND INTRA-DAY SUMMARY STATISTICS Devt RReeppl2 RReepp3s RReepps6 Mean % Bias TheoreticalNominalConcentrations (ng/mL) 100 250 00 20 899613 22560 707.1 20020 995318 25209 313 119966 995725 27490 748 119959 9562 262 76 1598 "8% 22% 19% 10% Day2 Theoretical NominalConcentrations(ng/mL) 100 250 00 mw Repl 087 24 202 Rep2 Rep3 929 103 238 21 a1 84 119955 RReepps 99.0170 223388 20 119934 Rep 102 2s 3 195 Men n 9664 2064 663 196 % Bias 26% 24% 24% 20% 001079 Primedica-WorcesterProjectnumber: PABX-BVA 418-018:PAGE 124 Page 23 TABLE1 (Concluded) S`UCMONMCAERNYTROAFTIIONNTSERWPIOTLHAITNETDEMR-EVAANLDOINNITCRAL-ADCATYONSEUMAMCIADRQYCSSTATTAINSDTIACRSD Day3 The0oreticalNo0minal Conce1nt0rations (aogimn) RReeppl2 s0e1 2m29 m16 mamg Rep3 oa 254 06 20 Rep4. 9.96 246 700 198 Reps 9.84 248 700 199 Rep6 NA ns 69.0 188 Meaan o5m mss m61 wm Bias 2m ae 0% ase IInocmraassasyyvvaaccccsiimnaee 4152%% 2057%% 112%% 014a% Ioterday Mesa "Bias 19674 1mss e1o 119s7 a6 2% lew as NA= Not Available. Thissamplewasaccidestalyspilledduringpreparation 001080 Primedica:WorcesterProject umber: PABX-BVA 413-01:PAGE 125 Page24 TABLE 2 `SUMMARY OF BACK-CASLTCUALNADTAERDDMCEOVNACLEONNTIRCATAICOINDSLACTONE CALIBRATION Theoretical Nominal Concentrations (ng/mL) 100 200 00 500 200 150 20 Dwi 91s 200 30007 5016 wm1s 1ase a2ss Dw2 s0s31315 mN6e S04297w1s 1ums 22m Dws 90s3 917 NNss sa78 wwsr w us a2s SdMDaen. 01200% 015992 036058 41939 26414a84 a2mm WRaSD 30s% 286% 22s% 2sm 30s% 21s% le6w wBas 00% OS Lm om 06% Ae Law 0010051 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 126 Page25 TABLE 3 MEVALONIC ACID LACTONE EXTRACTION DATA & RECOVERY CALCULATIONS Extracted Suadards Soluson Standards % MomReponeAress RepomeAras Resovery ssualz a8n5s 11908616 0926%% ssuas3 110859765 2997653 317%% ssuuss a63144 1627789 32692%% sa? 3 25380 n% MSied.aDnev. 0306342%7 %RSD 74% 001002 Primedica-WorcesterProjectnumber: PABX-BVA 418-018PAGE 127 Page 26 TABLE 4 INTERNAL STANDARD EXTRACTION DATA & RECOVERY CALCULATIONS Extracted Sundards Sobuion Sundards % MeanResponseArea ResponseAres Resovery ssaatz a6a 1154091599 "3903s% sa3 S365 15158 asa ssuuss $060547 141723893 s20a% ssau?s ssaunss 115522286 3u6s%m Mean 7% S%idR. SDeDv. 08072%1 001053 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-28 Page27 TABLES . SUMMARY OF LEAST-SQUARES LINEAR REGRESSION CONSTANTS AND ANALYSIS DATES Slope Day1 0.006514 Day2 0.0063508 Day3 00062253 Days 0.0062800 Days 00065156 Intercept 00113750 00082756 0.0067910 0.0060925 0.012850 ComelationCoefficient(1) ~~AnalysisDate: 0.99975 1017100 0.99939 101800 0.99884 10/19/00 0.99891 1020100 0.99981 1023/00 vU1054 Primedica-Worcester Project number: PABX-BVA 418-018PAGE 129 Page 28 TABLE 6 SUMMARY OF QC STSTAANBDIALRITDY72I-NHMOAUTRRIRXOOM TEMPERATURE RReeppl2 RReepps3 RReeppss SMueDnev. "RSa D Bias WATER QC's `Theoreti2ca5l0NominalConcentrati2on0s (ng/mL) 22318 11991 223s8 11533 223s0 119544 02332 11927 196% 106 % 5% 40% EDTA RAT PLASMA QC's Theoreatica2l Nominal Conccoaioonzs (ng/mL) RReeppl2 343521 210909 RReepp3s 33342 0 119s5 Reps 36 194 Reps ns 158 SMude. aDenv. 056397 a19x6 "RSa D 20% 225 % 4 Bias 9% 21% += Mean concentrationof ix. conrol Plasma QC's analyzed in the same azalytical batch G01065 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 130 Page 20 TABLE? SUMMARY OF QC STANDARD FREEZE/THAW (3 CYCLES) STABILITY IN MATRIX Repl Rep Rep3 RReeppss Reps Mean Su. Dev a "RBiSaDs WATER C's 20 `Theoretical Nominal 20 Concentrations (ng/mL) 23 194 16 194 6523 119944 2503 11926 ns 194 042 126 6 5 5200%% 3006%% [EDTA RAT PLASMA QC's ReRepp2 Rep3 Reps Rep 5 Rep6 Mean SuaDev "RSD "4 Bias 2 `Theoretical Nominal Concentrati1on2s20(ng/mL) 3n4s4 210904 29 197 36 193 323 1% 324 184 332 193 03504 5559 20% 20% 29% os% * = Mean concentrationofsix controlPlasmaQC's analyzed in the same analytical batch. 001086 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 131 Page 30 TABLES SUMMARY OFCOINNCTEENRTPROALATTIEODNSMEFVOARLDOINLIUCTIAOCNIVDALLAICDTAOTINOENDILUTION QC `Theoretical Nomiaal2C0o0nc0entration (ng/n) Repl "04 Rep2 295 Rep3 w7 ReRepps4 83891 Rep6 9 MSue.aDnev 319136 %RnSD 6 30% % Bias 18% p*r=iDiotloruteixotnraQctCio'numnddilatleydsciosn)ceatraion was200 g/mL.(15dilutionperformed 001037 `Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE 1-32 Page31 TABLES 6-DAY ROOM TEMPERATURE FINAL EXTRACT STABILITY BACK-CALCULATED CALIBRATION STANDARD CONCENTRATIONS `Theoretical Nominal Concentrations (sg/mL) 100 200 00 00 200 150 20 087 198 302 502 89 150 254 102 197 20s 494 9056 16 253 Men 100 198 304 a3 903 148 254 a 2 2 2 2 2 2 2 Bias 04% 3% 12% 04% 0% 3% Le% GC1038 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 133 Page 32 TABLE 10 6-DAY ROOM TEMPERATSUTRAENDFAINRADLCEOXNTCREANCTTRASTTIABOINLSITYQUALITY CONTROL Repl Rep2 Rep3 RReepps4 Rept Mean SdDev. o RSD Bias WATER QC'S `Theoretical Nominal Concentrations (sg/aL) 10 250 m0 ww 989 43 8s 198 017 251 7 198 105 255 7 197 917057 2274 63 17 200 198 101 23 9 199 100 27 65 198 0550 O42 0826 103 6 6 6 6 ssh 20% 12% os% 00% 2% 21% -l0% EDTA RATPLASMAQC'S Theoretical Nominal Concentrations (ag/mL) nl ne Loar RReepp!2 335404 ns 756 195 189 Rep3 238 762 192 Rep4 22 74 191 Reps 316 07 186 Rep6 57 79 185 Mean 33 n 1% Su. Dev. n 131 i 226 6 378 [3 URSD. % Biss 39% 06% 31% 03% 20% 21% = = Mean conccntaion binedonthefirstdyofvalidation 0010.9 Primedica:WorcesterProject number: PABX-BVA 418.018PAGE 134 Pages TABLE 11 SUMMARY OF CONTROL BLANK EDTA RAT PLASMA CONCENTRATIONS Rep Rep2 RRReeeppps3 Rep6 SMtedaDenv. "aasp IneAssaoy Men "Sisd. DDev. DlConcentraDtinonzs (ng/mL)Dad 164 165 0 162 159 168 111676346 111667134 11m67183 158 162 170 o16s5 o1s6s4 a1s0o s5m sam usw 11686 03500%6 061090 `Primedica-Worcester Project number: PABX-BVA 418.018:PAGE 1.35 Page 34 TABLE 12 SUMMARY OF UNIQUE LOTS OF EDTA RAT PLASMA CONCENTRATIONS LLoottzt LLoottas LLoottse SMuetaDenv. RaSD Concentrations(ug/ml) 11602 116681 11706 214518 1553% vl0s1 . Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 136 Pages TABLE 13 SUMMARY OF INTERNAL STANDARD PEAK AREAS `Water QC's Davi Day2 Day3 LowQC Repl Rep2 30905 par0 sswn1 ReRepp3 S"91608 sossi 6 sss RReeppss S1827 sex201 aE0r Miso RReepzl aa wss0r2 2wo 0 ReRepps3 parem Ss5m7 ssae7l9 RReepps5 5E0e24. 5o88n1 5s9i6z0 HghQC Repl Rep2 021 sas asoens 5s19e7 RReepp3s r3ks68 039590 Ss1o9m RReeppss si5s3t1 S2007 7o8s4 Menara 821 sn sm OLL0u2 Primedica-Worceste Project number: PABX-BVA 418-018PAGE 1:37 Page 36 "TABLE 13 (Concluded) SUMMARY OF INTERNAL STANDARD PEAK AREAS Plasma QC Darl Daz Deva Lowoe RReeppl2 aa0 a5s3u6s3 6a1s0t0 Rep3 3850 6736 6067 ReReppsd 53038540. 5315804 55910599 Reps S13 5093 Eg Mido ReReppl2 3s0s808 s1"5071 0s4a0y RReeppss owusn 60sm63 Pae Reps s132 S601 En Rep6 4988 6044. 5746 HighQC Repl ast as sous Rep2 5208 5474 5811 RReepp3s 56070920 6a08s8 So6n1a5 Reps sen 73 9 Rep6 3508 5471 5467 MenAwms 4847 5397 so7 `ComparisonofPlasmaOCvsWater QCMeanAreas Difference 05% ow aan 001093 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1:38 Page 37 TABLE 14 SUMMARY OF PLASMIANTQRCA-SDTAAYNDSAURMDMACORNYCSETNATTRIASTTIICOSNS WITH INTER- AND Davi RReeppl2 RReeppt3 RReepps6 Meaan Bias %Differe(nTcaebvlea1W)ater QC Dav2 RReeppl2 ReRepp3s RReepps6 Meann % Differe%nceBivassWater QC (Table 1) `T2heo0retical Nomina0l0Concentrations 2(a0p/mL) 33445 7"73 119918 33204 7733 119929 2522 73 119803 a61 n5e 1694 24% so 2.0% 20% TheoreticalNominal Concentrations (sg/mL) 20 0 20 1332 75694 119948 3304 793 210926 334581 34 119949 3460 96 1697 360% 95% a055%% 001034 Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE 1-39 Page 38 `TABLE 14 (Concluded) SUMMARY OF PLASMIANTQRCAS-DTAAYNDSAURMDMACORNYCSETNATTRIASTTIICOSNS WITH INTER- AND Dav Repl Rep2 RReepp3t Reps Rep6. Mean a % Differe%nceBivassWater QC (Table 1) `Theoretical Nominal Concentrations (ag/mL) 250 no ow 349 755 198 345 768 197 351 7.1 199 342 79 195 334877 7"610 210952 49 763 198 [ 6 6 39.6% 90% 1o0s%% Intra-assay variance estimate 23% Inter-assayvarianceestimate 24% 18% 20% 17% 05% Inter-Assay Mean a %Bias 340 757 196 18 13 18 36.0% 81% 20% 001095 Primedica-Worcester Project umber: PABX-BVA 418018PAGE 140 Page3s APPENDIX A LABORATORY METHOD 001096 Primedica-Worceser Project number: PABX-BVA 418-018:PAGE I-41 Page 0 PRIMEDICA CORPORATION Worse Masachuers Ares voLnuAlbnFhoandPaFvor By GEMSD. LNumber_bvaLEn RedesNumber 00 [EE ------ Yee 1 er 12 repwastns )VedyrD) eLee _uletoo semen: __{3Main SA numepr rs NN Bogencorr owe 0pt]8he be: life 001097 Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE 142 Pagedl [FRa Sh Ne 1 Pup Tchoencepnor of fims LeanbysMinho l(LMs) 10pdlssrbyGpOrMoScDe.sbo comcly dime 1 Tshpe erorspovided nisL re ale Forhe ganifictonofmaleic 5 1. TPhieennneuE(nDMTVtAD):p, TDyooriEvnDTaaA.dnTactcilornaemnolvaaagbneetc+con1dv(0enMeAo)e0oi35sv0 nofogp.tommfe.reoonvf eciadod SmpeinEDTAsingth convodro 8 chin ection ow 3 DefationAvbrevisions cMics: GrVoicsC)hSrSaoamnmmeoigaDndsehyrr JWovne NMMeeerrrmocninoaAacccokneconsor DI MeloniAc Lacs o3cvia: DCuIolMyiemCinoonnoCthoesosneA4354, + Minera 4 mien DDoNLMMnecrrilecod ncini,SaigCscaCmbhrieidmgioesHCanop, seLib4oors.onnc5,7ri5c.g9-8ea% o4cd,eo MaEicvikyiiennesear7i.dB,iker,BaHkPeLs,C NaPdLeCorrascve ecnae Forompeeadla)pTeaerke,kraebg,enEMdeSecn,oHPlLCresvn SDtoedoootmretl.vva1e1AMBliadkl.errHePaMLpCIp LOwdaeorreo,i raoicinatin Wen, Nore AFL 0. hs ghpro a wLLuUB Primodics-WPororjceteusmibeers; PABX-BVA 418-018:PAGE 1-43 Pagdez fFersmniep,kHaiintobmisdniGnaEPopedas,rmadee sive 2 CPForkneemEaT Ea ereniteitnt0e 5srrvitnrs 1 il [TEoa---- ye r C Vfo r ana Toa e ne Viennr earsks eti tsnn E iGE cetncE a6Dr8RihiSeoeA sa0m2ii5102 fm ikeaie Lttoeteimaev:pe ieator piso [or ee tn IFO -- ---- tpra baoc at erSlotdnfgr Dea pisaarfieelbeen lhtmaeriaccineenp hdeb ve omnLgoe ofhpani3nrecHsaosslEyoTnArloetsemEives h oeccotm n ee o Shaeba saetto Casoamameonca mtesceoo pets etoososmEDoTrAt Tinrteos wo oe teo nmt a,eie eeen creeewoey yeaba ene iTToh me Fels 001099 Primedica-WorcesterProjectnumber: PABX-BVA 418-018:PA1-G4E4 Page43 51 PropunionofRegents: Nos: thervolumes then thosepied maybpreparedwin hesane proporions 5.11 Mabylene Chiorde2-(P30:r10o, pv)aSleilie,n `SCtoomrbeinero9om0lmmLpeorfsmaertehy.lTenheecchxopirvieownidthai1f00omLi.osf 2oplronpanoolcowdeick.aher rparaion. 52 PreofIater)StaandtardSeobincns C1o0n0c%enrrieonlcalscuntosieodnbsaerrbeas.eTdhesfoulmloiwnigngtholdedsapndeepdreeferrcenhcieemonr+ials er Csuopngceesaediopnprsosrecha.cAcppparbolpersinedmwodiilflibceatdioocnosme0enecdihn hee auryyorncobmoioakl. Allsander Ltvortiioconnssmawyricelhliabnegmoerbeheec1sp5-i20pnrepiudalrouaeteniso.nnuolteesohbevrewiel.bTerhwtee. xOnpgoiingroSaeatboiireohense 52.1 ineral SunSdtoack(rSAd) MapYprLovi,meily u1i0d0mgr.ooWmeitghemhepvsal eaddMiVpLurdc,hasTedirn viaahsencMomVtaLnGien,g1r08 5m0omuvnoofuMmVaLr,niikc.heWomeehireempgtsykv.hBirli.nSotbovioalcuimeewwietghhMs 0Qovwaherhe 0mia. The minal MVL-4, 1 concnrtion of ut sonis2000wml. 522 memeSundar SpikingSohn DIientseor2v0o0luimle.woithfMIrI-sQowniare ssnodcmkin.ISTAh) mnoom1i0a0lMmYLvLol,ume Fas. concof eis snoluteioniis40op/nn 53 PrcpwatonofCalbaion StandardStockSohtons Tmodoiifkoaloiwoinnsg s1aenadchrhreeparrpteieodn sRcomhienma)e sioncsegnigaetsioindsawptpraoaccchp.iAbpiperaoapdriweiellbe iGsoh cacuhiemvieendwtnhheirnerdecparnionteiboeoka.nFaotrcar]acmlpbr,atiif ohnesorcykes,thnovmoinoamlecoofne0eiSaoicokn SSacntdirondssupiikdinignsslbosteouncconn!cdelnionscaanebeamcohdiiefvieedd.sSaondaatrdthre noeminfalectalreenaeeisonere Sa55n0dme s10 obleo1s00w%iplurbeem.Sotraendda1r5dw2e0ighwsn ied reo comeiedforpory. All ote aibervis.OngomgSabi disaeesblshing th expirationdis ofhoeslutions. S30 MYL Primary Stock (8) 001100 Prins WorricsbeerPABXBVA _. 418-018:PAGE 145 -- wi SeE eA T Lrs 52 " E r secai m E ome e m rm r , ra, 1FTE oeomeaeoR ms eytStbi15e.eeeBR SP BEeeg etme AE ei aL me a A E ry r tg en Co CullbriionStandardSpikingSeiwiienPreparation] I gan | P|-- | Fe [SST SecondaryStockB[ve8 10[0 | wow___| [C552 Seconda SlackB| 997 1750 ase geo | [CSS SecondaryStockB[505 150 [280 30 | [CSSA SecondaryStockB| waz | so | ase soo] [CSS PraryStockA1237 T7000 | ase woe | [CSSe1Pema Siocka 1 5% Too TasoTwo | rS E e--o--E -------- T --S ------ce CCSS7|PrmanySockA 601 | hoor 30 | m0] o1101 Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE 146 Pages Eore sDav72 Ree PraFetplea,rlevciobadylwmulaieilnnd,.swaiTtnhhde0an.r0l2do5sn0cmohnLec.ednftyoraoef nsopaeycviebyCcaod lmabnoin2S.ki50intmngLbSooofoM.InS(OCSS) F Suniurs emm me Se ag in oCromeeroeiatsion | nym arama| [E oowo Teem rToles loo--| [[m[me Csommaaa0Toosmoommoe |eoeer oes wswemw n wmm] 0o]] [CssTam om ove mm Tio] 35 Irparonfuiloyn Cool (0) Sock Solos mehGdeifoaoltlciwoinnugInahmrneedpacaeheristhreaarenrcihgoodocnk.crSmahaaeronrceegmrcgasioenss2pioens .eApraed dpwiaelbe ih1e0lc0%oopurrie.enSatda5n2eod0fwheseiunelesosneovveedsrbe rc,omeORtFOaREpArASyOR.YSAhirsadarcsoosohn 350 Priary OC Sock (AR) Nnu oecMeiVfu orLnicisenhymaonsadcaotpucendserro2fgs0so$or4uoomfcMhssoVvtiouatcodf dBat. wSeighred WvViotLlhcuomouensRpaccrkc.eniDrmroiaftnchgyosto1vs00olmlyvuofrmMe1V0hL0c0slrdaalcteersod irxi.3h10e0nm.na 552 secondary OC Sock (0) "rirnsengStoe1l0ru5v.0o05ml2l0wo0uifphmhcLehe.PyrismcaernyOeC1S0dtaic.k (TAhA)eimiaor2r5.M0mOLLvceonrcnTko.f 001102 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-47 Paged6 FreiTeaToi ere Io 56 PreeofmutsiiyCooonl SpkingSolis(0CSS) mTGooicfaooltloownir sngsharenm adcurhtdyha renaortren bgioodk.Aahlmlenulminceromngvcaoeensrdttswrpitleacchss.eArpprsopnen2we0i.lClsbeles Prooeapdanrie.GvCSr.tonoonnins2a5.b0imlevadleencreecfaksb1inhohwes pniheonbldeubesloowf,heAlm Sboionnlrcubonugah1bveomiwni getypcrsotp.rFiie]tyYounresiofotdeesoudthyrcss! ersaioniopty dcrmenedin my cho. VC ect SoSosneepi SSaoin ) pVresre Fro Vebems| [Oo [COCSS0W|Secondo;QCSoar88316 c |-- 30 350[7m]| 57 PrparionofQuayCool(OC) Sandor fn Water CSopmibnisneS0i0omnL.(ofOMiClSwa)saheow.s ion vhe ybl.ebvist:h1.0 mL.ofxh iy Control |= Ee Siok ation [P Chisoc[oss Ton C nyTwTmo]| Croc _|ocssinon | om Too ww] 57.1 OEncme )reaored,saiguevitaelOwCilhmaOnncaErts oucgppess1d5s0pr9ossrweenlya1.220mkC. vei etofmm y. 0U1103 `Primedica-WorcesterProjectnumber:PABX-BVA 418-018:PAGE 148 Page? r -- T . 5 SeaI C tonto l meetSt 111 mTerm---- AS pstmanto ertit me ismi fr toen vpzomaeeas--em--en--t----s $e. rSsmreySi tot 1 --ar------------------------ T Te S er rm E om mE a mCT s-- . 10 TI A S ee r o L , n e fnrea n 1 uSrmeeparpiitrag a et 41>Cn ontes mins 061104 Primedica-Worcester Project number: PABX-BVA 413-018:P1A4G9E Page dg 3814. Tpomeor hbeborenod eb(erspc) ye iopew 15mlconicalbosom. S15 Repenttheprevio threspe. 5.816Es1p0o5srtehorganiclyetodynesin Turkowap 440-25 aaproximtely S17 Andtds50'.41 ofhechy)cee 0 och abe0dvores for mii f 5 $218 T elena Topvn siteoHomret e4vroiolwee ishpeborni ovspeiora.dEe.xNcote:eI bceoxnsseswpiosrotre10sdyr)ycsewrheilelwoardsingfornEgl.y hy oybe 59 Amica Condons (GOMSD maysipeforamfoellodws: 590 Oven Coven: JiAWc,eDs210,30m. 025mm1D,025om fim ifillTTneem:per. 31050Cminus OvenRamp: (Crnme, Fewl3T)ew. FiTmiom)e S50000 T0w 335%% RonTime: approni14mmaianys 592 we RIniceioSnoVhonl,ume: H1epsLanes MToeem:pers. 2Sp0iveCss PPauppeePToowe. 07S50m0miUmeinc GtueliBow: H33eimmUminve Fowkams, ConanFowMode 01105 Primedica-WorcesterProject number: PABX-BVA 418.018:PA1G5E0 Page 49 593 Mas SoaveDesir SSoome:ode: fhemni emi FScivonimCvoonmpsieoitn: 2oS 0 ea looMoi srmgn (19) SovaOar SToietvsivoo smanoeoseako2f1 NNwasaouTetmt, oToere 534 tonsMoris [EpCompor--nd |----Nem--oto Duell Ration aWmEe oE= Tt m5mee wreleivsest,raanbiemoso W RTcopte m rcootma.aA.C1HR r tainmoimngaroa ha phayesoedsw umlpaa.TET 530 EAantsit!yRanSmeieessacdnoCtmowimnppeoosf(ewraockwinogwsirn:chlyienerrmvesr1e pur)d TaOynonSniecrea)of te oc ty mr3 m endthier.eDon ra eto hreoinonsgeOivesr.iTobeoe shAnnywiponesiics! nhd epswhGcChpslono npc 1 Comins $101 b repoenesi onrswaioilt opln a smsde MiPi cCas loy. g cSedofsoSdvtial.iMpame for 001106 `Primedica-Worcester Project number: PABX-BVA 418-018:PA1-G5E1 Page 50 5112Coompruotecaothnievree1n1Xus-iweoringt(hipesrdnaod.saotrfsqoVufaLrteeisncvaliaear)spnisnsgisvoannliradeltiEnxehcselprekcive rm (or qs uale. S103 Uoismmienpagthei0poennhkmerpngrymirooeffMhrLeeparinmaiwloayncea(otriiponaicsfostnfhsrtnl,leadmeraematinneedahnred)rinptes riengswtaele Tcepends oquent. Coomrdoenst $114 T10et0r0qpalruoo,tfgMhmYe Ainips)wofhndepidornpnosgfsMbyYbLoyemimuotpellroeyrsnpwbleyiag3suhmtsoadfycMbonVevLcenoi1vo3en0vr.ae14dle0 SoSlnBalloowfMuVmLcianmpplalsmha.wingheconversionof pl copcmtaien som X a 00pmols X lm x 192peel -- ores ww S12 AccepaneCri S121 Caron Sundar S124 TCooenlceonwrearifornitaocfhquabneiatwioinn(L0LOQ%)saofndhrebeocrk-clsoumlotse)d $1202 ALN15o%b0eorthnnrno'mbeckcarleseoledscomorantcs.ertbiewnilah 51203 oAimwionnwiehmeuncmwoofin7mg5%1i4ocfnahlreicntabo.rsi(oaNnnoSeuani.daTrlhiis,usimlambexeeitrmohauenbodufc4k aniedinebbtosrkp) wh aalyiog0of 14 arto 51204 Aatlmasicnns(aUn1i0a0)msasetmLoLeOQhaeobdack hceaueplperlcoincofnraion 061107 Primedica-WorcesterProjectnumber:PABX-BVA 418-018:PAGE I-52 Page s1 5122 QualiyCnQCt )Sun! t $1221 TLo3e0l9owofetoemvoelmOC'sccaeeleta)dccoonmconsritritoonn.rstbe ila 51222 AolclamhonOaCsrcelsuetesdccomoeensncioen nmrsabeiwiothnin 1%of $4223 Amini of6%ofa}OCsmutmeetthecut S126 ACovnacsamtiomnieenOcC ec.achcameron ve vs mecthecaeucd 5123 BasandCokntreols controlbakshouldhae espa (pk rart) hn equ 033% ihe west ectedLLOQ albestionsandr hTeelcoowenstsbeekpsedGLnLwOoQkec)aslhobunlidnavaendaerpoose (pekaen i) 3300of S13 DnaReporiog 5.10.1 SeamspletceonQceuneauionnsteLsesatai(BmoOeLnf)wetcabriosandswillbe lagged 3 513.2 oSovaecvrrsoouppdlildeevowcliuthmoeMrielnhmt-ahQiswnte.herIrilgirh-rcoinncniads.incgidsnrren-pssdlaeleywizl,lrpaobvieded tarshwilerepo #Above he Queniaion Lim (AQL. 6 RevisionHistory nial sbraorymetod. oc1108 Primedica-WProojrecotnsumsbcerr: PABXBVA 418-018:PA1-G5E3 Page 2 APPENDIX B REPRESENTATIVE CHROMATOGRAMS FROM VALIDATION DAY 1 601109 Primedics-WorcesterProject number: PABX-BVA 418-018:PAGE 154 Page 3 PeAreaaRepkort fm tren o SanghNam: ek unAne 070001852 re SCaASsI,AATAPABOOVAALDEX amr Comets Comma foi m ower Pedmse 3 wa ws 5 eon Tie eran 23 noes 0c1110 PrWoies nrjtc sberPABX.BVA -- 418-018:PAGE 1-55 ouEbtRe H9EIs L: cr ometTasioe onnspavsoe55 bortiee:be EpeEin DpsRenbeona or 7 smear l|F =4 e| oA | . A i PP enn L r y Se nr T tt | os xa Eh EERE | Tou: I WOGOON | rermimeSermo NL mn 001111 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-56 Page 55 Pas AaRept PY -- SO --p-- -- ron-- -- A. rir I m=m SE 151i-m2e gn 001112 Primetica-WorcesterProject umber:PABX-BVA 418-018:PAGE 1-57 Pages BDMaacarEeFile DI\ARSDDARTAeVErAeS\uPnaAsBcKi.BcYaAtViLo-n06t2e-p1o\r0t62300(20.70SERo_eeuevrivaeiiwaoelrd:)2ian [X-al 46 xacRegAraTion Paceent:iasa eine.oaxs pv % 878 Tacesrator) p=r= --------E\ --," |[Bl Do \i |{| J Lm i e E - R Ja\ E e E he ;i [uni I | VoormaronSun es mr ms E' ET ! i{ \\ || e are h a te 5e a aaei conten PIA AN Wed Occ 10 12:00:22 2000 mez 001113 PinesWorcs Projectube PABX-BVA 418-018:PAGE 1-58 Pages? Pekaap moi m Eopren eJ SEC I ansmamosarn. sesnm d ott comptes SE mam gp 001114 `Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE 1-59 Page58 Guassicacion tepore (GF Reviewed) Y=SmStaatraetiPeie B VSDDATIY \PAB\PARE-BYRVS-063-10621003.S0p_fuectkaviinat:]s3ox antTAThed"Br B\RCKEFHCPDARKOBVA\H (RTE Integrator) A | P= i | | pui f1H I| f1e== EEEREEE. GRe J tm Te e]| EE -- | nesp: 567 |i E mm E oJ\ E imEmEe] A @tT=om3TEENUTTI me| oN | Ci is a a ve Wn am em Tm Te TE Th 7% 1B 78 mim th 001115 `Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE 1-60 Page 59 PeakArea Report Semmes Sumpter050 att tm AChaps 21, mare 001116 `Primedica-Worcester Project number: PABX-BVA 418.018PA6GE1 Page 60 boo JN uascicacion Repors (07 Reviewed) @ RDB EaatTaonE File N DB:5\'S M0SeDDSA0TgeAe\ePAraBa\rPsAeRX-BVAVL-062-1\0621004.ODEpe_EraVtioarl:: sax 4C6hanIeacWegarhacaiobn RBaPsCuHmEsM:\1c\eKetEnTcI.OpOS\FARX_BYA.M (RTE Integrator) fo coma n 1 | ad | iI Ji |ii [| Lo fo ETihmoe. TrTee 7hB Taee g Te Tr R TR bTe rRomEe| a esp: 501 --1 i| i| | LEST Wk eeik 4m um 7m 1% TB 18 ie TE Tw 7h ve iE |noes: a3 \ ] /\ | is is iwen veal TE Te iE i 1h TR Te TR ie ie Gn0BeD TAEOVAM Wed Oct 10 12:41:01 2000 pez 061117 Primedics-Worcester Project number: PABX-BVA 418-018:PAGE 1-62 Page 61 Peak Area Report Steen sue oomni sn summoSAnsBram 21 resr et tnimssr mma comple mil fm tm oeamne re nttm ct tem esee Stsm [ET -- oo 01118 Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE 1-63 Page2 Quncitation Report 0 Revievee) @ SBHsaoxtEraEePile + b:\RWSDE_EATnAVeRAB\PARK-BV1A0V6E2-100653.-SZp_eoraVitaolr:, fan 2L5 aEessEat?ion DFuraRms: reatoeB.pnpane va (ere sacegeaton) om ----w--------h ---------------- | il |= fit || i | |= ; J\ | be EER RE EEEEN w[Paeiaset B13h1s 02007 A eeeBOREL: RRR .. $499. RT|| o Fr A | ak am ik Im Te 76 ve TE 7H 7 1k a. - Amount 0.00 te i. [nd A "Reap: 3749 > i i |i| A Lin ok se ako "Sm om ako om 1 3% TE 1% 76 7% om Tm 1m2 ocaio05.D PREXSAN Wed Occ 36 33141120 2000 rage 2 0c1119 . Primedica-Worcester Project number; PABX-BVA 418-018PAIG-6E4 Page 63 PaakArea Report [ senr na e sw ounmEor 1520 metS Ti PoA CD BATAPADPABCOOUEAN mateves Gem3podt Cwomepiles Dawiol wmm Pe=g Behe 061120 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-65 Page 64. i= i | aseteasion sepors 142 savin) esrie| iy Rapa aioe vin Y=A froma} Va e D -- A Ba one aa sv. (07 1acegeacons Te T ee -- iit SS Te Te Fo ii RE a= Lo | SE a i i= ot |} ee ee ii | JA a JiI --| ThTE 1s i SERBRiEeTThhTTeei 0) EE TEs eeee CE00ED PARIAN Wed Oct 18 12041:39 2000 J 061121 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-66 Page 65 Peak AreaReport [SeSamranva ees r omdCtirn 3148 nr O Wta,SaaAhrL heboAExavi 57 eke Gmm3elr cmwmpeium DmWinol min SeEamn Dine oo1122 Primedica-Worcester Project number: PABX-BVA. 418-018:PAGE 1-67 Page 66 uaseicacion Report (07 Reviewed) oiDEBaecaRaPrle; DB :\NSDDR NTR\E PAS\PABE-BYA1N06A2-1006672.-SSopreecers:vtieanls::1t37a8n oan is WER": 5 RPh E \NETHODi S\PAK_BVA. (RTE Integrat--or) ----y |{= | [om fp = Mmm | |i Jit | AREER A ! iirasp: 4062 J : i ie A iE aw ee em am ov ok 6k 7m Tho 1k 1 1s 1 te Th i1 | | im ie) ocrioon.o BAKE wed oct 18 13:41:59 2000 pas2e 001123 Primedica:WorcesterProject number: PABX-BVA 418-018:PAGE 168 Page 67 Peak AreaReport ser oT oto sro esa mtoEmRahS a sBR eon nsaoin maJr--t+ emm3ods meWaet pn DWeowRotman Smee 001124 PrimedicsWorcester Prject number: PABKBVA 418-018:PAGE 1-69 _-- gussicacion gore (0 Savio) oiTRBaoEg2120 1 I BLEEDA m R N RonE ATIONSToaesdTiirihB1ey fof ERA SE -- ]i i. bfoe p SETTER JMratiBne ore i | I | ih i LN TEE ) ---------- | I [lme m C2aE 3 | 5 isis an wk oh 8GBTE 1% 7h Tn 78 7k 78 7h 8 1m | i | Emse an am eh ok ae Te f | J\ | we is 1p 1s tm vm ww vm) 001125 Primedica-Worcester Project number: PABX-BVA 418-018:PA1-G7E0 Page 69 Peak AreaReport. Semen: crm ad [RCxDnLaanE om.e:DrA SomATAPABPABLEVALO1G mvreVm enemmc 7 me2 t omag Ain IWo B Saeasmi Spice 6C1126 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-71 : Page 70 = i Ouuncseation Report (07 Revioveds @ uHBDaIrtoaSrFike | Dh:RDn CiATAe\BAsSa\PnARK-BVAVL-062-1\0621009.S0p_EerEvViioar:]f3ar 15 TacEegrEacAion D params: resto.m cms asxva. (e78 acegrator) fr -------------------------------- |= it | | \ ! feps= EE EE EE' TSAEe on |lm gr E A E in \ | i [MemEAe nn TLEM BTe a em e| Or 1 fA 1| II --] | i| {087% we im a in Wk wm tm ve 1m Tk ze is vw ik teie 0621005.0 sREX AN Wed Oct 38 12:42:37 2000 rage 2 061127 Primedica-Worcester Project umber: PABX-BVA 418-018PAGE 172 Page! PeakAreaReport NeneSTeRoEpNa:B0E ae Oe o Si Rort07 JRCCE Ll BRSnioorn mone r3a wa ll WoW: hilo ecmmsn naz 20 rons Go1128 418-018:PAGE I-73 Primedica-WorcesterProjectnumber:PABX-BVA. Page72 oBmerniieie+vIvHmmEemETeEommecenSoioe nsere p 3Tstv.i3 LegE ies DpeEn,ATEE neo ce scr 7 I | I'd | | } i I] it | T 5. TE rw im Th Te 13 7S Pa [nasp: pes ee JI1 LEee)| Thik ee em ek onme Tm1 0s 1k ie im ve1h ve ie) | Rasp: 4071 | | JA || rp TETEE TET nines man te cs 2 se om _ C0119 rimetics arcs Pict umber PABX.BVA 418-018:PAGE 1-74 ngen PeakAreaRepon RrEe ESsE mtrm nr EEIRE acess nT m7 --caEHme------E--TE---- mmr iz rt 001130 imeiWorcs Pictamber PABKBVA 418-018:PAIG-7E5 Page oSgtine1s:iHAmvmIaaTmIlecrtotv in rath irieepEseogiewen I ET DT eons.svn a saps = = /I |. i= E EEEE W TT |Resp: 2034 | Ia J\ n | \ | JN i eT A i Te Te a se sk 7h 7 ; | er TR Tm. Te. Tm, | i be A | (GEE ve in we en es am te 76 TE 7% 7a TE TM TR th 3% 001131 Primedica-Worcester Project number: PABX-BVA 418.018PAGE 176 Pages PeakArea Report P sar:d cv oom Sntirm 12 rm Bc ESAruprmwsas avian, wore5 mea3ns Gomweetum TEeEfol MoBaARE Sele [ES ---- or 001132 rin Worse risume PABKBVA res 418-018:PA1.G7E7 oBgI EoziIe;HNEEvm RaTmYocnr asor s sore 3frr.oa0if,e e A IT B ,EI e rreen 2|rv=l AiA | | E 3 EEE J E| Ii I\ | ------------L-- ------------ ol EER i oS 48 4 aiIEThTRTh 1%kk 7% iktk |oN I ER ee eh we ene 48 Th Tl 3% 1% ve Th TR Thkik 001133 Primedica-Worcester Project number: PABX-BVA 418.018PAGE 178 Page 77 PeakArea Report spot socuicoen ompn ryan 0 r [E -- aBrnpiovpasseas, erraomtae? Gop3elr Gwaaius IWSoRmm Baouam febieie httnmtttreett pont. Pos wt na 200 res 61134 Primedica-WorcesterProject umber: PABX-BVA 418.018:PA1G7E9 Page 78 m= 1 jl Guastitaion Report (07 Reviewed) ouDSMaetEtaoNnFile 1+EDB:\ESu D_EDATRA\ePReSI\rPeARK-BVA\E-062-310673013.0S_TpTeVriaal:cta3a3r 15 TacegeacionT Pazmamia:arEib.roos\PARKvA (RTE Tacegracor) ---- Tm i | it | | ol i | j= . J\ | = F[eeaenee,s45s 35403 4% 6r ah 1 0% n aR E 3 R TE Te TE TE TR Te re | | i ms rem m morc | onei on: " 5s | A orer| | PRE 1| _ --_-- A- i oGaions.D TAREEAM Wed oes 20 12143556 2000 nage 2 001135 Primedica-WorcesterProject number: PABX-BVA 418-018:PA18G0E Page79 PeakArea Report Sm 1 Are omepe rs rm En AEHeA,SATAPADPADVALIEL, aVer4 omp3edr Gmwpeiem DeW lis oSo imi gm 001136 pisteWorse jcnumb PABX-BYVA 418-018:PAI-G8E1 geo erie BV BNAcB uiacioe n torr s 10SEISsovviaett3 ouEwE o eezE riE n mS car xT o oeE m 7 met rss ------ ------ e A | Ha= Ait i| i > T E BT )I T=: b CE EE m i e ) n Eas --- | ; Ji iI TE iE se he ean ek wk 7m 761% 7k 76 7B 1m1% iwiT cores mesa ws oot a0 sees 00 not 001137 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-82 Page 81 Poak Area Report [Sue mp ar me 1l:1800y Pa6ns oe eur:l200 028 ermenJ met ABEA R t Soper commpiuss Imfe) emi Bag re Tnsor87000 2.48 I. 01138 Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE 1-83 Pages2 J -- @ ofE IurcaanPile E D:\iWSD_gDATAhr\PaABi\PARE-BUAA-0G3-1A0GH0IS.D.S_TpeornViinti]: t15a J TE? SRE-- Bhons\onsxswan (x72 saceseacor) Fo = % |- fi ! i wd i i i= Lor $5IE 8TB _48 oR i\ WT Tl TR e ve ve me | 1 oni II (7.13%) Si | cnn hi a Te 0d a ve em | o = EHR jii |; ; Jiy | e EmmE ERe REEe a GGii6isD PARAM Wed Occ 18 12:44:34 2008 nae 2 001159 Primedica-WPororjcecetsnutmeberr: PABX-BVA 418-018:PAGE I-84 Page 83 Peak Area Report Sempre ot ra tein: chs narebeoePsonSAABhA.BSRATAPASPADCOEVLATN, stVem comets conmpmuc: Dei Bm team Bambee Qo1140 Primedica-WPoajroctenusmbiecr: PABXBVA 418-018:PAGE 1-85 Paget auantseation sep 107 seviewedt @ SHBuecsaForerile [BD:D EHAO ET SPY AD\PABKBYR-063-2\GGEIGRE.D.S_eoaiiitodt:]}2t6an 4E 5 nesrT avion PDarseT: BTSEOIT.hDoosenaxsv. are ceracor) bee - i p= i i egwp ET 8368 Ee T TNT T e Te 1 Tai% eg1_,m Tk TTmm Tm i S woop e 10s mone i fAl @iOweEEeteltnenHsseseoera6g%eew 6% ek ; em im 7hSaTiHntTR Te8:0T0B im a1m. te 7 | |i iil ii A | ET | cries EEN wedoe 38 sareesss 2000 wz 001141 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-86 Page 85 Peak Area Report o [SScump-laen:vCeorm] oesa cant: 0172001004. even ATESLE urns UAL, amen egeds cmmpue Imi RB mMmT tei 001142 Primedica-WorcesterProject number: PABX-BVA 418.018PAGE 187 Pages Guaacitation Report (07 Reviewed) EaBecgaNanpile D3I5\'HScSeeD-_r3DuNeoTA0\aPA1Bse\:F0PaABK-BVAVE-062-1\0621017.O0Ep_erraVtioxr:: n3n ou 4s tavA egracion pahcarnCs:AmTAEINETT.HPODS\ASK VAM (KTS Integrator) eww Dom it | j= i i ! In i foe TRSvevee t e ie hi im Tein 7h Te TR Te ih 18 r Hm m | || Iin |i P=Hers 0.1W 69) ieT RoiE aed te ae ik ir k i resp: 860 a |e E Veie sTEEwe Tei5 TH 1s 1h hh 7h 7k EOI. PABKBAM Wed Oct 10 32:45:13 2000 rage 2 001143 Primedica-WPororjcecetnsutmbeerr;PABX-BVA 418-018:PAGE 1-88 Page 7 Pek Area Report NotSaumn iamA :22 He Ai ct 1701920 meCnEpPad aomeCAAEABATAPADPABSVALIELN, etuvame fompeds Goggues Iminl mo tame emme Preee zn 245 aes 001144 Primedica-WPorrojcecetnsutmbeerr:PABX-BVA 418-018:PAGE 1-89 Page 88 Guincication Report (GT Reviewed) @ Dr=hatoieaneFile:|D:B\eiSeDRDAoeTnAn\PaAiBv\ePorABX-BVA\A-062-1\0621038.SDTa_ErVaisaa: t18n 45 sovEageEacRion PDacaHsa: LwrENME.o3D \FAB _BA 4 (RTE Tacegracor) - INn || il ! fboeeY-onE :r 35Te TR ET e eTRTR EEiAe -- Aeee Tm EE Te 6 T--_R-- Te te i fie | . i o E iSaTe ve Th etEmEeEE paTtT h e1hTRe Te e him r a tek ie h nap: Bs .A 1|| RR he Th Th ta 1h ik ik Te TR TE TR Genioien maxmM Wed Oct 18 12:45: 2000 nage 2 uc114s `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-90 Page 89 Peak Area Report NeseSaemieanme:5 FAuCO0 IinEe p0 si a 7201843 tte eethea AaEeSESAATAPASPABKSSUAENT meV me Gmmets Gmmeiues Imi mepm lo egg e1146 Primedica-Worcste Project number: PABX-BVA 418-018:PAGE 1-91 Pages0 3 J Quinsseacion Repors (G7 Reviewed) ouDfEatraNpFile + DTeiy\OWSRD_DATA\aEtAgeSr\ePABK.BVAVL-062-2\G621035.SDmoe_eerVsiiat:h h129an 16 oteEgeEaciTon EarRaPneE:iawtTsEWDIET.hPans\PAEK Sv H (R73 Tacegracor) -------------- ------ pe TS TE Powreamr: ySo. a8 Eg TS ae TE --Eeat: THeoge--t-- e 7=] | ii iI=E Sa ----p -- p mm ra mf Owiisp! mr -------- m| ew i me Jil in en ee an im em om aw Tw Tw 1m TR Te im 7E ii rp er =u . l , ty J| 7% TE im | osm MBAR Med oct 18 12:45:52 2000 foes oe1147 Primedica-Worcester Project number: PABX-BVA 418-018:PA1.G9E2 Page 91 PoAreaaRepkort o NeSamt ame:B2105EOWAi ou ptcany11003083 armeCneERtInBSUPSAraph eA SAO mammi eSe Gear compe Img beam Seige ru aTne 080250 500 [ 001148 418-018:PAGE 1-93 `Primedica-Worcester Project number;PABX-BVA Page? pM Rees Fe ite e DAVIDDO ATA\PiOe\qPuBaEn.tiFzIaRtViLon-OT6a2p-e1rt\06O20.DSoRpp_epe:vcViiieiawsle:rdI2a0 [1=v5ooIsoatsaasgreaanciiconn BTaarM aas: KE TEEETU .E T panevLan (R72 socegracer) a |- i I | . eT TT TR IA1 TET TT RR TE TR i; er ra 1 i if i! EE ERR 43 E eR a i Qie Tere gen ! ----RR----------} i i eA : [557% os am we on ak em 1m 1% tre 1 tem re Ge scitoto0 maxon ved out 30 12a 2000 So 001149 Primed Worst Proj be: PABX-BVA 418-018:PAGE 1-94 -- Pea raRept en sTsRE mSpEmn EET ames. wen 41150 inci Worcs Project umber: PABXBVA 418-018:PAGE 1-95 Paes sEE aocgse:ieH+ BpoumEFahai mpa[nTa T crES-- ee unck 2h3e @ i1S0EsImapcScion cDanR: Tpve suman sn ee sepacon rg= rs} ! |= or wi ii | 5 | EE EE Amount: T 6.00eT E7 = . Oal RE EE i ie ERR ELAE 55" eai\| i i CE de soa Wn tm am me vw re 7m 16. vi e Tk h im wm L6G1i51 Prmedica WorceseProject number:PABX-BVA 418-018:PAGE 1-96 Pages PeAreaaRegkort [J Stame rns oCserr ms EAN SE mma onn meh 3 a wmono= c11s2 Primedica:WorcesterProject number: PABX-BVA 418-018:PAGE I-97 Page 6 Quantication sapere (07 Reviewed) @ HDrucyakePieHD:\ASD rEDrAL TPAB\IBARK-BUA\L-062-1\0621022.0__SmpeeernViior: 2ii2n 2f8ootcegeasion recR use: sme p T -- wr emmy - il i EETe TE xafcepn: mooLh ne 1! i A i i Ji | ESE a ep:T3300 i xee i Ea a rar -: A f!i 1i `A aaa osziczz0 ma wed oct 10 12 2000 nage 2 001153 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1.98 Page 97 Peak Area Report Sangin 2c rs ompre z 160 matDeutFonharha5ABmDA.VBAATAPAPAA10R6E aar rmenea:37 meats cometum IS am Beam gpa 01i54 Primedica-Worcester Project number: PABXBVA 418-018:PAGE1-99 Page98 Quatication Repore (GT Reviewed) sBSaattaonE "FileS|+ D33:E \\0GeDr_-DA0T0A0.\RmAS2i\1Pe0A}BE-BVAVL-062-1\0621023.0S_feraVaitaol;:]2i3on [ Fra 45 IncEegeRatiTon pBearaRmCs:AaRiaE(EDNEDEFPAOX_0BV8AH (RTE Tncestacor) -- --- ww, fi |i - iti i Do ge I T ep ia Se i | Te RA Yseopn: B1i3o (7.134) mAe Res 1| i | @iTrzetent>:I6m 130s0e s=k im sh am el Tm "1i%ne1m: 1 \ 1%So1ee -- g-- Fh]i i Ji | ERETwwe ieTe Te Te ve 7 eae GGrionn.o ASEAN Wed ose 18 33:47:10 2000 sage 2 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-100 Page99 PeakArea Report neSFEl [CEn -- wonosTEmIEEaIRS marr. soSn ATTIE 001156 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-101 Page 100 Quncitasion Report (QF Reviewed @uDRFa=ocarR File A1 D5 : N SDh OKCTA\PS AaB\nPeABE-BYAVL-062-1\0621020.S0E _oevniiaE lt:or3a4!n 5aTacEegEeaRcion paraRmei:sRTLEvDTi.7008\eA _BVA. (RTE Tasegrator) p = ari",> - it i | [rrr EETToLTieE nge ETE e TR Pnhaaamromtrome m . ee 7 lee eh HF A E: C= ih ex ee en am emuiTa e TetTh ik vsEEim im 7h TRm I1h E | i i I} | in i 4 Toe wa akT oe ea5 e Te reve te Th TR TR GGE020.0 PARKOVAN Wed oct 10 12:47230 2000 rage 2 001157 int TAA i mnie-- -- mR tig Ey me ar edMm omSa:TAa SEKIAnerseAVsKALE ae 001158 Primedica-WorceserPojct number: PABX-BVA 418-018:PAGE 1-103 Page 102 uancicacion tepore (07 Reviewed) PY aBMecraaUrFilSe 1 SB3EEDCRATPABA \nSReEK-BYN\S-063-\GREIGES.D.S_mepenaiailn: a35n 1anSatEagEeRaEs"ion B parame: e TEDha onemat x ava. ars Sates =r te tyy) ol: itfi |! - Ii : pe I Ee, Tee i we Te IT( nTdT i A-- fi --i | A fi =fe +S--i--E ----R VR dkiTE. EThd is 5T a t e Th 18 ||1 ee men EiA | EET ew i Te Te Te ei certo PABWAN ved oct 18 12:47:09 2000 rage: 001159 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-104 Page 103 PoakAreaReport o [INSwiiae:3Hip14a0i0ame mmhS essItO 280 ESBoARBAeGEAL, baa Gem3ets coFmhmpam Inwioa mmm Be8ma Sei 001160 rimsWorserjc umber:PABXBVA 418-018:PAGE 1-105 Pape on asics | in oenss oqBhEnie TZuEm mEesDmo TTe in op TE SRT mano te Sse tereree wenn 1 - lih i i wi ii PT ii CTE nN iE TH i ek tm ih we SE TE ZT EeE70 CrIe T a LLr G --_ TT --_ A _ TE x se sk im eh ek am 7m i ! JAN - 3% TB7mre 1 im % Tm1% 1m| ii || in In te wh il ih em im7 Fe im 7H 16 th Te TRITk 00111 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-106 Page 105 PoakArea Roport o NomiSasRmi eame HB0AWSa DamhCiene20mn208 coom3uir cowmispele IWmiommo SR&T else Go1162 Primedica-Worceste Project number: PABX-BVA 418-018:PAGE 1-107 Page 106 uncicacion Report (GF Reviewed) @uoDMancarT PileOD1: BhRSeDRDNeTA\aPAa eBNPARK-SVA\L-062-10621077.3B_FpreerVnitarl:: 27 45 xacTagEeaRcAio"n BprP acae:instArEe.TD H\POABED_BVAS (RTE Tncegeacor) ---- --_-- oe E rarer B rip SpTEreeTR \ ReTsopn:: 2103519 (7.130) i ee A Ce EerTred | !1 iRK {| mn JAN. | ro TE| 062017. PARKOVAN ved oct 18 13:48:28 2000 nse 2 001163 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-108 Page 107 Peak Area Report NomSauRmpe:3A :0 Lowva oeAS cs:le700 230 atBentPa SABhBSAATAPABIVPAANERLCT, are emi n0" foms3edt cowmapu Iwmiom BeaAmE taippe ce1164 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-109 Page 108 By i Guascicacion Repore (GT Reviewed) DRsaeocaolneFile D3:\AESD_itDoAnwTeA\wPeAaBrn\PsARK-BVANI-062-2\0623026.STDpheecsViioanl!: 28 @ =#a 5 tasegearion aparS ams: TERP T. N -- p | ---- -------- wEw--# -- --------------| Do I i Lope a vi a a eon vE edR e 7S5TEah ve TR TR neon: 1 i fmm Or a WeFr e aJw Ae aa resp: 310 . = eet! | A ! in A Te wEonEasseaieTeseeTeed1ah e7h ge 75 thsT aemE nrsime eTeE) 0028.0 PASKSAN Wed Oct 36 12:49:48 2000 sage 2 001165 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-110 Page 109 PeakArea Report Y Noma[corre soc P--S--ST-- meACrutn ]zo 258 naummdm aahEaoma ecoAAcBzin isSomAoATACABOVPAALGE. mafVuelr i ra5 Gom3gude Gwoemepitass Impl ofmw Paeml Snes cu1166 Primedica-Worcester Project number: PABX-BVA 418-018PAGE L111 Page 110 Ouancication Report (07 Reviewed) ouDREaetahonPile :D:3\N0SeDe_zDfoAoToAn0\PaAzt\esPrAhRK-BVAVA-062-1\0621029.ODTpo_enreaVtioarl:: 2H0a 1a5nIentMeagtrhaitsion PDaIra\mHs:PCHREINEIL\.NETAODS\BPVAAB.KM (RTE Integrator) F---- = ---- i --! | i i Cane! Ii |i peo i Tee ih ee B Resp: 3o 5> ro : i oe I oFrii tiae ss E 0260e |reap 4789 ER TE ONTEE . a ae ih] a | F Te Vb we oR h TE (EEL re Tn - Te1%1mTh Tn im Th 0621029.0 PAEXBVAM Med Oct 26 12:43:07 2000 tage 2 vo1167 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-112 Pagel Peak Area Report o NoSmem:350 00S OmpCvt:i00710 mena ndamesEAUECrammeanra, mn fone mmm ofa bm tess Smee oc1168 Primedica-Worcester Project number: PABXBVA 418-018:PAGE I-113 Page 112 Quscisation Repore (GT Reviewed) @ ioBuocaEntile1| DN e1\AiEE Dn_DAeETA\aSPAsB\PABE.BVA1V10L6-21006302.-Sfp_earsVtioarl: m30s 15 tncEegrRaciTon cEaRne:AamyUTEETH.OEOE\PABBVEA. (RTE Incegraor) pte ~~ feimeny -- xm) i 1 C | wlg E erwd tE ir ee E r El a|i ifeon!: 385% TI Ai |i | i IA TE S P"oet E rr E STR oe: S002 RTERooEd:E a08Te Te Th Em . !i| ! \ i (ivam ameiks shIET. eE78 Te Te TE TR 7m 76 | Genon0.0 PBCIAN Wed oes 0 32:49:26 2000 rage 2 061169 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-114 Page 113 Peak Area Report NemoSamFo eamsa:A3:0O0NEna oe ienn te1023037 SRT SURBaers oonn mare Goap2ele mmwpsem Teo iel mSa ME hah resto eee 2012.48 fuses 001170 ST. - 418-018:PAGE I-115 o A Fi it Be Cuan Method: Di\RPCHEN\I\NETHODS\PABK_BVA.M (RTE Integrator) RRme __ = / ; ao; |mL pny ii i A }Amount 5.00 ie I i t i TE _TR ewe im Ti e s TE IE TE vm im oh iA | 001171 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-116 Page 115 Peak ArvaReport Nomasamt am:A30oLAowPaans pi can oro357 R SR BnpR usestsommionan mem Goo3mets cowmmnpiam DeWowmo taam bela rn naTon 101805012.40 et 001172 Primedica-WPororjecctensumtbeerr: PABX-BVA 418-018:PAGEI-117 Page 116 ustication Report (07 Reviewad) @ Domnat=anEFile :hDN:\SeMSED_DReAoTnnA\PSAhBe\PyABX-BVA\1-062-1\0621032.S0E oecsWcaorlS .: h3a2n f 16 Taci egrasion S sagas: srEnT.AE -- Er nesy hi! iIt i| a I | pe A RR RT TE E xeap, 361 E E|sSe i i i oisnmesmwme ke k R re ee G d lBeG 7%TA7Ehs1siisk s7% iikehinivT ek aeE fat as a ee Resp: 3950 e # i ns i\ | en us am vm ve Te eis is Te TR im gm 0621032. PAXSAM Wed ocs 18 12150105 2000 nage 2 001173 Primedica-Worcester Project number; PABX-BVA 418-018:PAI-G1E8 Page 117 Poak Area Report NomsSamo ameP31OCoArtTP0mS oepS canmz0016 RL BL arson, mS com2pet Cmmwpioues mimleomBeeam bose ot saTe 80800 250 ret 001174 418-018:PAGE I-119 Primedica-Worcester Project number: PABX-BVA Page 118 Quinsication Repore (07 Reviewed) @ DTiBazecEeoaNrFile +1 DSa:E\SDt_DRAeuTnRe\PrATBaia\vPeiAeBK-BVA\-062-10622032.0_BT pervsiialae :t t3o3n 1a5 sacEagRraEti"on raxierne: RTEWDkIETERGDS ABBAW (RTE Istegeacor) fo TT v-- - TT] |mer r ee re e ewed Tenem: a0n ayn |Co] H | [a hd is r Te ew en sm im Tm 7% = EY 35 To im im Tm | ooi rp: seEasT a0) ree PRA| E e ere BR ee ii | | i ! i i f ES r me eteeem 5 Te Tie e eR] Te GGIIOILD PBEM wed ct 18 12:50:20 3000 rage 2 001175 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-120 Page 119 Peak AreaReport sem am ce Contes san CE SS A kee mn omgm3ose Cowmwpe Dwlaowgm be=im Smpe co11ve Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-121 Page 120 Quancitation Report (GT Reviewed) BSDaecEtaoAnFile |DA3:4\NWGCShEDDoAHnToAnh\PaAcBco\ePsrAeRX-BVAVL-062-2\0621034.S0TpaeerVaicarl:! a34 @ 1a5 TSacRegIrEaRcAi"o?n DPIaziaRmGsi:eaRnTyEWLEIHT.ODS\PABC_BVAM (RTE Integrator) poe - -- --y =wy | el ii ii ih EEEETEEET TEE TE -- M{naoap:o4r8-- 20 ona , re"---- --{ i Ne ee] Ew wh TTT ue ie gh vi ih ik i @ nap: sdosessen m ji ------i } ii | rr Pr irmeraAYTS rarer 06210300 PABKEVAN Wed Oct 16 12:50:4 2000 rage 2 01177 Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE 1-122 Page 121 Peak Area Report NoboSum eanme:3AS0R 0Av5i5e8 hnS:mz0055 re ST EU hese A, ror 5 Gompuat cmmmiies Ign lm SANT SNRS ---- vans 001178 418-018:PAGE 1-123 `Primedica-WProorjecctensumtbeerr: PABX-BVA. Page 122 Quncstacion Repore (07 Reviewed) PY DacaonFeile:R| D3E:3\EeWeSeDC_RDEoAnTnA\PAToB0\rPsAsRK-BUA\A-062-10621035.DS_EperaVEitaolr:,Sh3a5n 1n5 esatHeEgErRaocei"oTn B parame:I erAEER mTHDODSC \PABK_H BVA.M (KTS Integracor) | = + dE A A +m)1i Ei ool /it| i i L=o Ii || Iees 015 Ch 5 TE Ve TB h eR TE7TETET= h15Te 7 T=e mel {rea sp 713s 1 ! lR em AmE e mA e A E it R EEE |i i f i & wea ap: 4n 797eem TT w-- asWe amim ew ei 3 Te ih vw ve ti76 TR TE te | Ge0ED PAOVAN Wed Occ 18 32:53:03 2000 rage 2 001179 Primedica-Worcester Project number: PABX-BVA. 418-018:PAGE 1-124 Page 123 PeakArea Report tC Lo oomptran 15 aom ios epatae ammeFScArn Ae SiL6$,00D.8ATAPABSo ABLOVAIOE men mecnttano57 Compete mpi IS gm BeAmE Semen 1180 Primedica-Worcester Project number: PABX.BVA 418-018:PAGEI-125 Page 124 [TR -- DrEacaanEPileR{Dh:iE \ASDBDATAa\BABI\PABK-UANA-062- \GKEL036.DSfo_eiriVtaaoarl!:tM2]6a [ Fes 1I 5 tacaT geation agusi:nTsECIa.oos\paz va (KT Taceseator) NR = A | -- hiit } |= I\ pp TR RBTTTh PTE TE Cn i i i! formes cme IiN iS hn TGgeTATei QCr LED e ) ae | |lomo JA | ; a] marSriSr GGri0360 PABA Wed oes 26 12:53:22 2000 nose 2 001181 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-126 Page 125 Posk Area Report Semen oa oonpot34 naC em dama :SAAF Bn S,ACATRPARPP ABLOVA OL, meranr me2ds conwmpoiam Imoimin mowam omghe 00112 Primedica-Worcester rojoct number: PABX-BVA 418-018:PAGE 1-127 Page 126 uansstasion Repore (GF Reviewed) @ DacaonFile Hx" 1 DEhESEDRDAiTA\Pa AB\TBeARK-BVAVL-062-1\0E21037.DS_mpeeeraVitaolr:! w37m G#5ianTtocWeEgEehaetai'o?n DpazBssaP: gLrWaEnFI.CDS\PAS BVAN (RTE Ttegiacor) FF=eg" "te t 1| - i [i I AEER T EER ERIAEEE EE E P [an gar i e000 I hn -] i i T nir an: S012 o Ts E we w i Tk k TE ik ih re amoR TE ; i i i Ii i 5 ow ve iiume wisTe7 53k16 a8 Tw Tn aie GGmon.D PAE evAM Wed ost 18 32is1s4z 2000 rage 2 001153 Primedica-Worcester Project number: PABX-BVA 418-018PAGE 1-128 Page 127 PoakArea Report oanSSRamRa: cSEeN t oon oanyts4 meSSLP AasARPAADPABCOVOALN te mimi Se Gomp3oss Somgapium Inoga)mmo hiomme Sef sme ne ere 1281 rt 001154 Primedics-Worcester Project number: PABX-BVA 418-018:PAGE 1-129 Page 128 Quanticacion Report (07 Reviewed) @ iBacoahntFile+DT:E \aWoScDE _DoAoTnA\PmABd\muPnARK.BVAN1-062-1\0621038.C0Ep_ecaVE cioarl::SH38an 4a5 nTacHegEraRtEio"n pB arams: sTEe IKNETT.H2ODS\Pm ABS_SVAM (R78 Integrator) fo ee en R 1 =- iiit ||| EEE w [|onees 81331 0.0m RIS | | [-- iSTE -- eveEeS Th 7h im ve 78 Th Th im Te || == | } Ji | Ea ah is vn am am ve 7% 7h 1m. Te 1 Te TH 1h te Gea1030.0 PASKBVAM wes occ 10 12:52:01 2000 rage 2 001155 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 130 Page 129 Poak Area Report Sanam: C0me onto nan13 ammC eto er3PSAeB,ABATAPABPABCOYAN SLY rsetVe 30 Gmsoss Gomgeima Imam jm mpi Simp 001186 Primedics:WorcesterProject number: PABX-BVA 418-018:PAGE 1-131 Page 130 Quuasisation Report (GT Revieved) DTT atoerPile R : D{:\NSD BDNiTAd\E ePAnB\PeAeRX-BVAVE-062-1\0621039.0SEpeEcVsiiaolr:: t3o8n @ : 4a5 rtacEegEraRtEio"n BpIaramcsh:ownrWEDRT.DiHPoAoBBSA\H (RTE Integrator) Tr, 2 i\ | I i\ J !eerEeOrTe E iriei re 7Tle TR e eRe Te TRe Te | | {e rongr21r 56 o aI 11 |\ i @S e font 1e 35 (71262e) is iE |naap: 4477 hve veRETEE SeTe k veTe y i | EETe Te Th Te Ta ao acaien mera Wed oct 18 12:52:20 2000 rage 2 001187 Primedica Worcester Project number: PABX-BVA 418-018:PAGE 1-132 Page 131 PoakArea Report o NooaomRiaem:4A3GS0SLoAwPanne . [eo ye } matReedHr ABCESUAea ABavALOE warrenami mses Gmmplee Dim mo emame Saige 001188 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-133 Page 132 astieacion Report. (07 Revie Bg Muca EFe ideE+ 1uRmDmDaAmTAa\PAnD\PARK BYRVL-GGE-\GRRIOND.DSperVieEiAsrLs:: i$0an Y= 1s sovegracson mara:iETEONTA 3 p RE f= i i -- oe IEr EEt i Ji RR Tg MemmELL. ESLE A | --| | A | Te Te TE gE @L": aiTna:s Se ------_ Jmcunti 0.00. TR H-- e! _. dN in asi ik ew en ew ee ve rh rm iw ie Tk Te 1%Iw 7m sition.o pOOMN ed oct 20 12:52:40 2000 --_ 001109 Primedica-Worcester Project number: PABX-BVA 418-018PAGE 1-134 Page 133 Pesk Area Report Somers Ee at] ar oseimm ttF hamre eAcBen Eo0,n0sBAATAPADEABLOVEA2N1 saurvlm momeeenr1: ma3cs GoEmNme ITmiemmo Saeam mioSEe 001190 pinesWorcs Pfc umberPABKBVA 418-018:PAGE 1-135 page13 pmmuen.ee: 33S:EmemTnnNcusPtPomSR sRTrReOGTIRON7LDRrveiaCiess:E8 @ uE toFsgrE aeion eEReAnTrE Eon in 8 Ttsgmcr = i - aIt |1 || Reap: 588 SE A - peEe [ree 9c | |lem een a Ah | = Ere evo meESS torCae Saas 4 i i { moe meeI= ee]i 001191 PrimedicsWorse Project numb: PABX-BVA 418-018:PAGE I-136 Page 135 PereaRpkt RS IY seg--EE EASE enacoin, mae 001192 : Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-137 Page 136 Quancication Repore (GF Reviewed) DRSaecEaoSnPile LDdEEi\NoGSeDa_DuoAoTw0A\PwAaBt3\eP3rARKBVAVA-062-1\0623042.DO_opmeeraVtioarl:: t4e2yr = 4e5 mJatRegErRaatiAoTn Paramese:k KTEEDITT.E HPAOXBYSALM (RTE Iategacor] mg Dd eee} hn || p= I I i i hweeeT EE TvveT ihShBTSlTE 7 7 7 ve 1h i ik 1 serps 707 i \ | ee IN | || T Gaeeeee eh ewe a Tae TtE Th i. Vehidh ie 7R 7BTE |neFsopnt: a53s31 re . | | i | [Erarrears re 0621002.0 PAB BAM Wed Oct 10 12:53:18 2000 page 2 001193 Primedica-Worcester Project umber: PABX-BVA 418-018:PA1-G13E8 Page 137 PeAreaaRepkort nesSeRmpRre: SEuoNN a E+ oT A ep LL mer meds Gomme DEA Saimin 001194 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 139 Page 138 Quuatitation Report (GT Revieved) @iDRaecEqaonFile}I +DT: W0EeE DeOgAToAnE \PAB3\1P0ABK-EVAVL-062-1\0621043.Sfp_eicaVticoarl::ad&]ay JA | #a6 nsncBegEraRcEioTn pB acane: r gT1EWIENEHDOi 0S\PARn XBVA.M (RTE Integrator) Jr er |j = iAi |ii e ET e {reps 2297 i ] i i {ifi |i i I Tah v6 eis ih JA15% 76L1o5% hm R-- B | o romp: 3r 024 re BEY. i+ i i i iETE h Tve wn a ik inEoh T eb Te E Taa Aih in 3E h 7 Te imT veTE i 0621000.0 MBEAN Ved oct 10 12:53:38 2000 page 2 061195 Primedica-Worcester Project number: PABX-BVA 418.018:PAGE 1-140 Page 139 Peak Area Report samptane105 ome son zor mntuonmaaamecHScEouOS, ona avaasn merenmthnce7 mete Gmspum Dail) mn DesmE Siig 061196 Primedica-WorcesterProject umber: PABX-BVA 418-018:PAGEI-141 Page 140 = ] DBfartEayNePile E: DO:y\KN=SD_e wDAeToAnVaBy cAeBQr\uPaAnStKi-tSaVtAi\oAn-0R6e2p-o1r\t06210(KQ.TBDeRoee_ervciVneitwaoelrd:!i)a4e4y : @ ix 1E 5 saceo geacion pEagaEns: gdThWE.Pah\ ASoX SVo (KTS Tacegracos) rer a Sm Pp -A Ii gp i wn 5 \ 1 i i| || Qel eeJ m Wm o e m\ e TT --------1 i ie | | i A | TE tw se sw sm em em ew Tm 710_1E EaI | ccrion.> PABKEAN wed oct 0 12:53:57 2000 noe a 001197 Primedica-Worcester Project number; PABX-BVA 418-018:PAGE 1-142 Page 141 Peak Area Report [eI m umpa:i30r 610e 0wan Oe Suarnns i200 410 ttJSreem PAeRyRA APURISI i= me2ts camwpntum leWiom Baam Spe et soTe 1200 1250 raat 061198 Primedica-Worcester Projet number: PABX-BVA 418-018:PAGE I-143 Page 142 fsE ercaiepE e + DO BDp DAATAPiAaS\urBsAtRiStBaYAtViEo-n0C3f-ep2o\rOeGHOUSG.1D_DmReemveiVreitwa,slsd:)145 ou1E rtatE sgationDpAaRns: i8naneeastman (x7 tegracer) rm [I] wba meer IiI || -- i\I i| |[fsAyre A RH jl | aieTET\ eEiaERTo 7 Teisn imr1]m) | wary | } Ci ee ni io LDR %TT _ e i im i% m Oe EER RaW: -- ree SA Ii | i i i Line%_ so tem en em em 1 10 18 1% 16 10 m1 me 1) ccniow AE BAW Wed Out 28 3assea? 2000 es 06119 Primedica-Worcester Project number: PABX-BVA 418-018:PIA-1G4E Page 143 Peak Area Report NormSaunmiteamma:2O10A04rns oeAontyre 28 tana uSoenbFe PFaoAmBBRAeCSEsAATAPASSABLOEVLA mi b rot57 Genels Gumpum Imi mm beim face 01200 Primdica WorcPreojescttumeberr: PABX-BVA 418-018:PAGE 1-145 Page 144 oQss araaierile. ND:u\EInSDEEpATeHn\PRS\J BARKBVAVR -062-1\OGHIO-- NE.BToDpp_oe:r-- Vtitkl:lf4io6 J Eo Dee -- E\pT aus ova. (kT cegiacon) ir=nitia T [.] it i J wFoen pra--oTa=rE oaa n, Ree= If i A a LEsis To eh sm em is TIE Th Th vkih TE TE i ) i "Yon:135 (7.160) eeeLs - ! I | PPP SSo ItAA e ai |i 061201 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-146 Page 145 PeakArea Report ssosrcMOP oompm ra 0 JOR ra n am 0F10S7S0ATAPABOAGXOVALSE1L maramaa n57 Sem3mes Gmmwewtus Tewiol mgm Be2gmi Sighs [E-------- noes 001202 Primodica-Warcesier Projectnumber: PABX-BVA 418-018:PAGE 1-147 Page146 Cuascicacion Repore (07 Reviewed sacs Pile DAD ATAVPAD\PARKBUAVL-OGE-3\GKEIOT.D vial: 47 @ uE e LaE ma Eee 4R 5 Ioved peacion pS arase: ETEONT2R BE roe emmy fodel Ii ii Co i T = 1| EEE RRGEm EP1S yAERE EEE | A | fore orm on am A oo | LE 5% 2B TE TE Te iB 6 vn Te fE R 2 en EereT a sk te T en osak aa 1m ! |} A ] 1% 7EH mTEeTre ETk E 1m 1T% te rE 001203 Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE I-148 Page 147 PeakArea Report Y NoteSsRaenaPsOLoOwPNann [ ina emamann edoSAAh BDS.ASATAPATP: A OAT2 rei com2mer Gwomime ssn DeoelmBo twameEc beihe 01204 PriWomrcsdPiretcumbaer:PABX-BVA 418-018:PAGE 1-149 Pages pg Berypeile +pLyEE DmDmI, TAasBtALuL 0t62\eOETIONR.1D0.5L_aSeeiwatreLht::sg8 eEF J | EEE -- I yon sw (ks Smsagacon) mgen] rm \ i i | I I | f[L E e| EE EEr E E g p pJA ae EEi B[rormrtine = RBe BY e eee ) | iA i| b r ee red { Reop: 3330 1 ] I be IN Lome eke am si sh ak Te tmve rmvmve 1%im | imverir m ] Wt BES tan 2 tation rp 001205 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-150 Page 149 PoakAreaReport NSoamim Name CortPm oeArcsi 00520 TT 0TAPASOPVAAL B mem5 fempels Cmipiies Dein mo tmmi Dapmie 001206 `Primedica-Worcester Project number: PABX-BVA. 418-018:PAGEI-151 Page 150 uactication report (GT Reviewed) SBF aecrerieFilE e DVN DATA\PARNPARK BYAVE-0G2-GGEIONS.DSfpercvtiinats: t3ax @ E n15ksnceA graciion D acase: xI R2ceveE nas va. (75 ocegeacont [ma| i | I | {F om |Ii i ibe CiprnaE SrEroE r SSy ETRt R| n E TG E EER E|> ; I | w S Er ee d Ne e | En --_------ }i |i | Seammews wee crits TEAM wes oo 18 TES 190 nage 2 001207 `Primedica-Worcester Project number: PABX-BVA 418-018PAGE 1-152 Page 151 PoskArea Report Sam cco oom rs7 er a at . esSEDBACATAPDAUABNL PA atv e5 mel Gnmpiues Dei! Bommel Pt Tn:0100 1255 nae 001208 Primodica WorcesterProject number: PABXBVA 418-018:PAGE I-153 Page 152 aRMconaee:pile B BEDiDHTY A\PAeDe\ParAuReKs-cBsVcAaVcAi-o0n63p-o\r06e23050.(8@_FS_fpRreeacvsiiieiwnet:d!) 5t9ax on 16 1=otEegzaoionEcee aisoe:oswT\EpDIAEEaV x_svaT.sW (873 Tatege--a_c--on) | | Il ; ) LgFe prasTSR n Eh A Te ik --} ren: Toke fmm O EN rIl i STI Cr th ih k JA ieTeTeIh TR ie i --1 | { 1a Ee s ocrtose.s mAEBAN wes oct 38 32:55:58 2000 ez 061209 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE L154 Page 153 Poak Area Report NoSmumpaanr:A1S0CHOve mASorz0851 [OR eTy ESnapsan, mere mes cuspium Ima om basmi SNES e1z10 primedics WorcesterProject number: PABX-BVA 418-018:PAGE 1-155 Pages cuancitarion Report viewed) oTpfAarcaeanPile D\NED DATA eFiABE UAV-0GE-\OGHIOSL.DsTm_e:eViarl:JBi3h3 1s sotEegzaAcion R Fucus: ATT ED sE ans un. kT Tncegracons ger t P= fi I | Vo lh i ET EEE ER fa----,... bn oe Lh | eTeohn: iin Bhsk wk ew ih 6% em i " E 1m 7% 7B ve ve ik vm 1% Tm 1m |\ fl i Frese 001211 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-156 Page 155 Peak AreaReport o NoSbums Nam:Px0ABLOAWvs oontS e nsz ermSor oamaaTtaimroen PDozA1E0t B52AS0ATAPABPABEVAIO meenaa Vremom37 Gomm3ess cwmmapum IWmgomlm Saee ige 001212 `Primedica-Worcester Project number: PABX-BVA 418.018:PA1G5E7 Page 156 Gunsicacion Report (GT Reviewed) tE DaotratePS ile 1DA B:RDDcRATAe\PAsBe\PeABL-BUA\1-062-1\0622052.0_S_fpaeacsVcioarl.: m5a2x @ uC TREAToa DeRE NRRoDs\a PBAVSA K (RTS Sacegeacor)A m= i | Pm Dod |{ i| |oe m E e R teRR Tee Te R Te TRe TR TE T d T MFI eL E ----i vas ER 3 5.00 fi | i ii\ i| ph vk te Te is ik he O naen: 4187 y ; ER 1 |- _ oJi i| ocai0s2o PARCEVAN Wed oct 18 12:56:32 2000 rage 2 001213 `Primedica-Worcester Project number: PABX-BVA. 418-018:PAGE 1-158 Page 157 PeakArea Report on`Sarmote Harm: EER 83 GC LLO Water ti DateAcauies: 107182000646 rSE TI TSA E cepcsinen oen Smm3ott Su=mp INJ ES mm Swami Sean 001214 Primedica-WorcesterProject number: PABX-BVA 418-018:PA1G5E9 Page 158 Quanicacion Report (07 Reviewed) D3fat3ea%tFialel1 De t:y\e HSD_tDir AG cTA\wPay AtBe\rFARK-BVAVA-062-2\0621053.O0Bp_aerraVtioarl::e3KrAY [ I=a 15 tncegracionon pLearamsC:iaTsEDET.HODS\PABK SVAN (RTE Tategiacor) he -- nei I eei i i P= i | | psi ie in ie Th i te n ie weep aa hP e om A 23 Tein i i\ TSTTek i iin rae 1 i | TE EE ER Om5es3g: o o46 e . i i | Te ie wewe ve ie ie veTe is va e 1saie ik viTkaaave ak Oea0sy.D PABKSVAN Med Oct 26 2:56:51 2000 rage 2 001215 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-160 Page 159 Posk AreaReport o Semen tree om smn: ren rm D ada are:SPn ASBAATe apABOAR EAIHL, meet Gemm2ets cwnimesttm Immpol mwn emEiami Bum er rae 001216 418-018:PAGEI-161 `Primedica-Worcester Project number: PABX-BVA Page 160 gEsocagtruiee :b 2SumpmP aE meFsA R RTE E-- LDmaeValG56e @ =roksrsIgeEs:ionDuc,TSTEfoessa to sepsis = - = | |- i it | 9 = EEA EEERa REEEE {necp:"ads AI | e fp EA R | fon: 135 (7.159) |Resp: 3508 A - ! mn i ee Lan ew ew ok ew em ew aw 3m 3% im si Te ih am vm 061217 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-162 Page 161 Peak Area Report o NonSeamRo asm:P2A 0S0PEane Do dSur:R10200725 naEm atP HsaADUPnAASAPH OVAL enm Gmmelr Gosglum Dain badge Paige 001218 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-163 Page 162 Qunttasion Report (07 Reviewed) oFE BaurcaetPilR e L D:\EHR SDDRATA\EnABaAoPdAYBK-BVANA-062- 1\GGRL088.SDf_preacsViioatl!: t5a5n 1E 5 aveE sracionEpactass:ewrERmTops\esax_avan (x72 tateseacon) fe mm ---- |: iIlh |i {sl IIa) |i [ Breiap! TJukEa T--" --R E e Th :T B IX Te 1m 1m 7m. a0! |1i iii i| : A QLrieasEs:is4a 3T 08 TIATRTeTm i |i ak e%sm im ew en se ek 7m Th 1B 1% S=EEME Te 10 ve im =I | |: = ocaioss.o TASK SVAN ved oct 18 5257130 2000 nase 2 001219 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-164 Page 163 0 res sie -- Sapo 1 av-- 061220 Primedica-WorcesterProject numb: PABX-BVA 418-018:PAGE I-165 Page 164 uascicacion Report (OF Reviewed) @ af E ca a piE del DE :aSODrArTA\PAmB\PARK-BVANA-062-1\0621056.0__Cmoasvteiearl!:et56on 1E 5 tacE egracionDpacRa:TETEOENEc.oE s\ SVAN (KTS Tncegracor) = Te 1 || =ol; iiit | -ui /I i| |. Kw 5 i % e: Te Je 3% Rom BT . } | ~ eR @e%nit u3s0en N | TLEEETeR7TeTe e e poou.rs Ta] , | i oe i | inik se aka eh ak 4m 7m 7% 1B 10 Te Th TE 1m im im oGriose.o PAECIVAM ved oct 18 32:57:45 2000 ge 2 00121 Primedica-WPororjeccetnsumtberr: PABX-BVA 418-018PAGE 1-166 Page 165 PeakArea Report NomSaemple: scons eeha owaez :804 tment Tetehaon PBAAGEBB0T8 RPAROVAANBE2C:1, tenia5 omm3edt Gwmompwium Tomlommeam Seige 001222 418-018:PAGE 1-186 FINAL REPORT `GAS CHROMATOGRAPHIC-MASS SPECTROMETRIC ANALYSIS OF MEVALONIC ACID IN EDTA RAT PLASMA FOR ARGUS STUDY 418-018 Primedica Project Number: PABX-BBA PRIMEDICA ARGUS 905 Sheehy Drive, Building A Horsham, PA 19044 001223 418-018:PAGE I-187 oPRIMED!ICA FINAL REPORT `GAS CHROMATOGRAPHIC-MASS SPECTROMETRIC ANALYSIS OF MEVALONIC ACID IN EDTA RAT PLASMA FOR ARGUS STUDY 418-018 Primedica Project Number: PABX-BBA `Submitted 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 1of 187 Issue Date: November 7, 2001 A @ DUBE 1/7 Project Siem lark A. Netsch / Date `Bioanalytical Chemistry Department Primedica-Worcester 001224 SPRIMEDICA Primedica-Worcester Project Number: PABX-BBA Final Report 418-018:PAGE 1-188 Page2 PriAmrgues Sd tudi y41c 8-0a18 COMPLIANCE STATEMENT "This project was conducted in compliance withtheGood 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 with principles of good laboratory practice. Official Journal of European Communities: Legislation 32 (No. L 315; 28 October): 1-17. There were no deviations from the aforementioned standards, which affected the quality or integrity of the project or the interpretation ofthe results in this report. Drsaguts 1170 MPraorjkectA.ScNieetnstcisht, B./ADa.te 001225 PRIMFDICA Primedica-Worcester Project Number: PABX-BBA Final Report 418-018:PAGE 1-189 Primedica Argus Study 41P8a-g0e183 QUALITY ASSURANCE STATEMENT The following are the inspection dates and report datesofQAU audit/inspections 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 4L1a8b-o0r1e8t,orryepPorratctniucmebReerguPlAatBiXo-nBs,BA2-10C1F-R1,4P5a,rtw5a8s, rGeovoidewLeadbfoorratcoormyplPiraancctiecweiStthatnhdearGdofoodr Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997 and Council decision/ recommendation on compliance with principles of good laboratory practice. Official JournalofEuropean Communities: Legislation 32 (No. L 315; 28 October): 1-17, on 11/07/01. The results as presented accurately reflect the raw data. NNN Quality Assurance Auditor wed Date. 001226 PRIMFDICA Primedica- Worcester Project Number: PABX-BBA Final Report 418-018:PAGE 1-190 Pages PriAmrguesStdudyi41c3-0a18 TABLE OF CONTENTS PageNo. QUALITY ASSURANCE STATEMENT ....cooovsmmmsmnnssmmssssssssssmisssmsssmssssmsssssssssssnss 3 LIST OF TABLES AND APPENDICES ..ccccrcnenrnnnssessnsssnininionrsS CONTRIBUTING PERSONNEL vcs ANALYTICAL STANDARD CHARACTERIZATION/STABILITY ...cccoooovmrrrnrrrrsnns T SAMPLE RECEP .rrrrenerrsenrrrsnonenensosmseseserereres Calibration Standard Accuracy and PTECISiON ..............couwmmssmmmsmsssmsssessssssress 9 QSutauldiytySACMoPntIrEolCSOaNmpClEeMAcTcAurOacRySanr d PreCiSIOn .r ..........r .cummrrmmrsmme 10 10 CONCLUSIONS.....cnsurmummummsmmsmmmmmsimummmmmmmmsirssissnminnsoe JW 001227 PRIMFDICA FPirniamleRdeicpao-rWtorcester Project Number: PABX-BBA 418-018:PAGE 1191 Primedica Argus Study 41P8-a0g1e8s LIST OF TABLES AND APPENDICES TABLE 1 `Summaryof Back-Calculated Mevalonic Acid Lactone Calibration PageNo. TABLE 2 `SummaryofInterpolated Mevalonic Acid Lactone QC Standard TABLE 3 SummaryofMevalonic Acid Lactone Least-Squares Linear Regression CORSLANS AA ADBIYSIS DAES... 1 TABLE 4 SummaryofMevalonic Acid Lactone Concentrations in EDTA Rat IBS SEUY SAMPLES erste 1S APPENDIX A Representative Chromatographic Data - Batch No. PABX-BBA-1-047-1.........23 001228 PRIMFDICA Primedica-Worcester Project Number: PABX-BBA Final Report 418-018:PAGE 1-192 Pages Primedica Argus Study 413-018 CONTRIBUTING PERSONNEL PIOJECE SCHENMSt rss ssssnononon: MATEA. Netsch, BA. Director, ARBIYHCal CHEMISTY....cvrrvesrvevvseneveneneneer Ji Jersey, PRD. ARytical CREME... Yaa Villalobos, AC.E. REPORt COOGAN sss: Brenda L. Brooks 00129 GPRIMEDICA PrFiinmaeldRiecpao-rWtorcester Project Number: PABX-BBA 418-018:PAGE I-193 PriAmrguesStdudiy 4c1P8a-ga0e187 ANALYTICAL STANDARD CHARACTERIZATION/STABILITY AnalyticalStandard: `Common Name: Physical Description: Lot Number: Storage Conditions: Expiration Date: Date Received: Amount Received: Supplier: InternalStandard: `Common Name: Physical Description: Lot Number: Storage Conditions: Expiration Date: Date Received: Amount Received: Supplier: DL-Mevalonic acid lactone Mevalonic acid lactone or Mevalonolacetone or MVL `White erystals 47300/1 50498 543 C, desiccate, store under nitrogen `September 13, 2002 (Assigned by Primedica) September 13, 2000 5 grams Aldrich Chemical Co. DL-Mevalonolacetone-4,4,5,5-d, MVL-d, Clear liquid U-295 225C PSreipmteedmibcear) 11, 2002 (Assigned by September 11, 2000 0.1 gram Cambridge Isotope Laboratories CharacterainzdaSttabiiloitny: The characterizationofthe analytical standard and internal standard is the responsibility ofthe Supplier, as is the methodofsynthesis, fabrication or derivation and stability determination. 001230 PRIMEDICA| Primedica-Worcester Project Number: PABX-BBA Final Report 418-018:PAGE I-194 Page 8 PriAmrguesSdtudiy 41c3-0a18 ARCHIVAL STORAGE ArchivalStorage: 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 Primedica-Worcester Archives in Worcester, MA. After five years, the Sponsor will be contacted for disposition iRnesptorurctt#ionPsA.BXAr-cBhBiAva-l01ma-t1e4ri5a.ls will be indexed by Primedica-Worcester 001231 SPRIMFDICA FPirniamledRiecpao-rWtorcester Project Number: PABX-BBA 418-018:PAGE 1-195 PrimedicaArgus Study418P-a0g1e89 SUMMARY: `Sample Receipt: `Samplesin this project were received in good condition from PrimedicaArgus Laboratories in four shipments between the datesofDecember 5, 2000 and February 13, 2001. The 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 analysisof a liquid/liquid extract by gas chromatography coupled with mass spectrometry (GC/MS) using positive chemical ionization (PCI). Calibration and quality control standards were prepared in water because `mevalonic acid is a naturally occurring compound in plasma and concentrations vary with diet. The internal standard, MVL-d,, was used for quantification. The method was validated for the extractionof mevalonic acid lactone from 100 uL EDTA rat plasma samples over a concentration range of 10.0 ng/mL to 250 ng/mL. vTahleidactoimopnlceatne bdeesfcroiupntdioinn tohfe trheepoartsscaiyteadnadbosvuem.maSraimepsleofaniatlsyspeesrffoorrmtahnisceprdoujercitngwetrhee initiated on January 2, 2001 and completed on February 15, 2001. See Table 3 for the analysis datesofeach batch. A copyofrepresentative raw chromatographic data from the first batchof sample 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 each 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). Summariesof back-calculated calibration standard concentrations are provided in cToanbcleent1.ratMieonasnaancdcuarnaaclyy,tiecxaplrersusnse.d aIsn%baiddaist,iorna,ngperedcibseitowne,eans 9m7e.a9s%uraendd b1y02%.7R%ealcartoisvse rSutnasn,dard Deviation (%RSD), ranged from 2.2% to 4.9% across concentrations and analytical . 01232 PRIMFDICA Primedica-Worcester Project Number: PABX-BBA FinalReport 418-018:PAGE 1196 Page 10 PriAmrguesStdudiy41c8.0a18 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: Samples where no peak was detected or the interpolated concentration was less than 10.0 ng/mL before adjustments for dilution factors, the assay lower limitofquantification, were labeled as "BQL" (below quantitation limit). Some samples reported as BQL were analyzed with adilution but due to limited sample volume could ot be reanalyzed. The detection limit for these samples is the lower limitofquantification (10.0 ng/mL) multiplied by the dilution factor. One samples where the interpolated concentration was greater than 250 ng/mL before adjustment for the dilution factor, the assay upper limit of quantification, was labeled as "AQL" (above quantitation limit). This sample could not be reanalyzed due to limited sample volume. `The result for this sample was estimated to be greater than 12,500 ng/mL (250 ng/mL multiplied by the dilution factor of 50). Interpolated concentrations for all remaining samples are expressed in ng/mL. Refer to Table 4 for concentrationsof 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. 001233 Primedica:Worcester Project Number: PABX-BBA 418-018:PAGE I-197 Pagel TABLES 001234 `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 Theoretical Nominal Concentrations (ng/mL) 100 20 00 00 20 10 20 PABX-BBA10471 NR 199 296 486 S49 12 249 101 200 NR 489 916 150 245 PABX-BBAI0S41 104 198 303 484 884 150 246 982 193 301 50 91S 155 251 PABX-BBA-1-0561 103 198 309 450 878 150 248 968 200 302 S12 894 150 254 PABX-BBA-LOSS.1 985 213 307 481 84 12 249 968 206 309 481 80 12 248 PABX-BBA-1-062-1 973 202 305 486 82 153 242 NR 205 310 S00 912 151 24 PABX-BBA-1-06S1 104 196 305 467 856 149 255 101 186 309 426 938 16 255 PABX-BBA-1-06T1 937 194 302 468 870 148 235 994 29 314 S120 12 us PABX-BBA-1-06%-1 9.14 190 296 522 908 155 239 107 206 324 496 96 147 240 PABX-BBA-I-072:1 100 197 304 485 921 144 239 NR NR NR SL3 920 19 246 PABX-BBA-L07S-1 NR NR 341 461 910 M5 249 997 19.0 310 455 386 16 251 Mean Std. Dev. n %RSD Nominal 995 200 308 490 901 12 247 0396 0972 10s 202 237 S08 554 16 18 18 20 2 20 20 40% 49% 34% 41% 26% 33% 22% 95% 100.1% 102.7% 979% 1002% 1013% 98.6% NR = Calibration standard excluded from regression, data not reported 061235 . Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-199 Page 13 TABLE2 SUMMARY OF INTERPOLATECDONMCEEVNATLROANTIICOANCSID LACTONE QC STANDARD Buch `Theoretical Nominal Concentrations (ng/L) 20 0 0 PABX-BBA-1-047-1 s21e 67132 119894 PABX-BBA-1.054-1 2uss 60504 118837 PABX-BBA-1-056-1 22ss 66592 118842 PABX-BBA-1.058.1 2732 6612 1189 PABX-BBA-1-062-1 2210 2655 11858 PABX-BBA-1.065-1 2285 66401 118942 PABX-BBA-1.067-1 2246 68648 1I8t3 PABX-BBA-1.069-1 223s2 6ea4 11858 PABXBBA-1072-1 22112 18 21902 PABX-BBA-1-075-1 22353 6a1s6 11896 SudM.eaDenv. 22193 63052 514867 %RnSD 8i9s% as25% 2290% Nominal 956% 950% 93.6% G+r=ubFbasi"leTdestto.meVeatluteheeaxcccleupdteadncferocrmitseurimamaanrdydseatiesrtmiicnsed to bea saistical outlier using 001236 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-200 Page 14 TABLE SUMMARY OF MEVALONIC ACID LACTONE LEAST-SQUARES LINEAR REGRESSION (CONSTANTS AND ANALYSIS DATES BauchID PABX-BBA-1-047-1 PABX-BBA-1-054-1 PABX-BBA-10S6-1 PABX-BBA-1-0S8-1 PABX-BBA-1-062-1 PABX-BBA-1-065-1 PABX-BBA-I-067-1 PABX-BBA-1069-1 PABX-BBA-1072:1 PABX-BBA-1-075-1 Slope 00067118 00062552 00061528 00060042 0.006104] 0.006457 0.0064673 0.0063214 00064268 00069212 Intercept Correlation Coefficient(rn) AnalysisDate: 0.014046 0.99956 ooo -0.007087 099953 on 0.007974 099965 py 0.006094 0.99909 2301 -0.006886 0.99954 012601 0.008650 0.99802 020101 0.002970 0.99698 020701 000018303 099789 0207/01 00090496 099919 ozo 0.01975 0.99652 oso 001237 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-201 Page 15 TABLE 4 SUMMARY OF MEVALONIC ACID LACTONE CONCENTRATIONS IN EDTA RAT PLASMA STUDY SAMPLES Animal# Group#Generstion. ~~Concentration(ng/ml) BachID 10902.GROUPI-FO 10903-GROUPL-FO 10904-GROUP1-FO 10905-GROUPI-FO 10906-GROUP1-FO 10907-GROUPI-FO 10908-GROUPI-FO 10909-GROUPI-FO 10910-GROUPI-FO 10911-GROUPI-FO 10912-GROUPI-FO 10913-GROUPI-FO 10914-GROUPI-FO 173 PABX-BBA-1-054-1 87 PABX-BBA-1-084-1 263 PABX-BBA-1-054-1 260 PABX-BBA-1-054-1 360 PABX-BBA-1-054-1 205 PABX-BBA-1-054-1 365 PABX-BBA-1-054-1 321 PABX-BBA-1-054-1 207 PABX-BBA-1-054-1 351 PABX-BBA-1-054-1 198 PABX-BBA-1-054-1 342 PABX-BBA-1-054-1 53 PABX-BBA-1-054-1 10901-GROUPI-FI 10902-GROUPI-FI 10903-GROUPI-F1 10904-GROUPI-F1 10905-GROUP1-F1 10906.GROUPI-F1 10907-GROUPI-FI 10908-GROUPI-FI 10909-GROUPI-FI 10910-GROUPI-FI 10911-GROUPL-FI 10913-GROUPI-FI 09 PABX-BBA-1-054-1 68 PABX-BBA-1-054-1 BQL(DF =10,<I00 ng/ml) ~ PABX-BBA-1-054-1 408 PABX-BBA-1-054-1 "3 PABX-BBA-1-084-1 BQL (DF = 10,<100 ng/ml) ~ PABX-BBA-1-054-1 146 PABX-BBA-1-054-1 327 PABX-BBA-1-054-1 252 PABX-BBA-1-054-1 428 PABX-BBA-1-054-1 161 PABX-BBA-1-054-1 316 PABX-BBA-1-054-1 10915.GROUP2-FO 10916.GROUP2-FO 10917-GROUP2-FO 10918-GROUP2-FO 10919-GROUP2-FO 10920-GROUP2-FO 10921-GROUP2-FO 10922-GROUP2-FO 10923-GROUP2-FO 10924-GROUP2-FO 10925-GROUP2-FO 10927-GROUP2-FO 10928-GROUP2-FO 2300 PABX-BBA-1-058-1 1550 PABX-BBA-1-058-1 130 PABX-BBA-1-058-1 1500 PABX-BBA-1-08-1 1850 PABX-BBA-1-038-1 1140 PABX-BBA-1-058-1 9.7 PABX-BBA-1-034-1 522 PABX-BBA-1-058-1 159 PABX-BBA-1-054-1 42 PABX-BBA-1-058-1 1780 PABX-BBA-1-058-1 218 PABX-BBA-1-034-1 2060 PABX-BBA-1-058-1 BQL = Below quaniitation limit. AQL = Above quanitation limit DF = Dillion Factor 001238 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-202 Page 16 TABLE 4 SUMMARY OF MEVALONIC ACID LACTONE CONCENTRATIONS IN EDTA RAT PLASMA STUDY SAMPLES Animal#-Group#-Generation ~~Coneentration(og/L) 10915.GROUP2-F1 10916-GROUP2-F1 10917-GROUP2-FI 10918-GROUP2-FI 10919-GROUP2-FI 10920-GROUP2-F1 10921-GROUP2-F1 10922-GROUP2-FI 10924-GROUP2-FI 10925-GROUP2-FI 10927-GROUP2-FI 10928-GROUP2-F1 29300 AQL (estimated 23,200) 15100 17000 24000 12900 6 168 326 17400 821 1m00 BachD PABX-BBA-1.08-1 PABX-BBA-1-038-1 PABX-BBA-1-062-1 PABX-BBA-1-062-1 PABX-BBA-1-058-1 PABX-BBA-1-062-1 PABX-BBA-1-038-1 PABX-BBA-1-054-1 PABX-BBA-1-038-1 PABX-BBA-1-038-1 PABX-BBA-1-038-1 PABX-BBA-1-062-1 10929-GROUP3-FO 10930-GROUP3-FO 10931-GROUP3-FO 10932-GROUP3-FO 10933-GROUP3-FO 10934-GROUP3-FO 10935-GROUP3-FO 10937-GROUP3-FO 10938-GROUP3-FO 10940-GROUP3-FO 10941-GROUP3-FO 10942-GROUP3-FO. 158 PABX-BBA-1-047-1 1670 PABX-BBA-1-038-1 1440 PABX-BBA-1-058-1 1220 PABX-BBA-1-058-1 1440 PABX-BBA-1-05-1 866. PABX-BBA-1-058-1 1530 PABX-BBA-1-088-1 1410 PABX-BBA-1-058-1 451 PABX-BBA-1-08-1 1380 PABX-BBA-1-062-1 416 PABX-BBA-1-058-1 32 PABX-BBA-1-058-1 10929-GROUP3-FI 10930-GROUP3-FI 10931-GROUP3-FI 10932-GROUP3-F1 10933-GROUP3-F1 10934-GROUP3-F1 10935-GROUP3-FI 10937-GROUP3-FI 10940-GROUP3-F1 10942-GROUP3-F1 156 25500 28500 9770 19300 9430 13900 13400 12700 321 PABX-BBA-1-047-1 PABX-BBA-1-058-1 PABX-BBA-1-058-1 PABX-BBA-1-08-1 PABX-BBA-1-088-1 PABX-BBA-1-038-1 PABX-BBA-1-058-1 PABX-BBA-1-058-1 PABX-BBA-1-038-1 PABX-BBA-1-058-1 BQL = Below quantiution limit. AQL = Above quantitation limit D* F= =EsDtiilmuattieodn vFaalcuteo,rDF = > 12,500 ng/mL. 0012359 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1203 Page 17 TABLE4 SUMMARY OF MEVALROANTIPCLAACSIMDALSATCUTDOYNESACMOPNLCEESNTRATIONS IN EDTA Animal#Group#Generstion Concentration(g/ml) BachiD 1019094434.-GGRROOUUPP44--FFOO i13n PPAABBXX--BBBBAA--11--004477--11 1100994456G.RGOROUUPP44--FFOO 2156900 PPAABBXX-BBBBAA-.1-1005568-.11 1100994478.-GGRROOUUPP44--FFOO 1166010 PPAABBXX-.BBBBAA--11-.00487--11 1100994590..GGRROOUUPP44.-FFOO 1776300 PPAABBXXB.BBAB-A1-.10.5088--11 1100995512-.GGRROOUUPP4A--FFOO 195.610 PPAABBXX-BBBAB.A1.1005487-.11 1100995543..GGRROOUUPP44--FFOO 10955-GROUP4-FO 11010600 PAPBAXB.XBBBBAA--11.-005588--11 . 203 PABXBBA 1047.1 10956-GROUP4-FO 24000 PABXBBA-1-058-1 1100994456-GGRROOUUPP44--FFLI 1015094479.-GGRROOUUPP44--FF11 1100995501.-GGRROOUUPP44--FFLI 1100995534-.GGRROOUUPP44--FFII 225530000 PPAABBXX-.BBBBAA--11--003586--11 2018630000 PPAABBXXBBBBAA--11-.00588--11 2109300000 PPAABBXXB-BBAB-A1--10-5088--11 1918100000 PPAABBXX-BBBBAA--11.-005588--11 1111003216--GGRROOUUPPIL11--FF0O 1111003323..GGRROOUUPPII11--FFOo 1111003345-.GGRROOUUPPIH1I--FFOO 1111003367-.GGRROOUUPP1I11--FF0O 11038-GROUPI1-FO 967a PPAABBXX..BBBBA-A11.004477.-11 220s PPAABBXX.BBBBAA.-11.-004477--11 3773 PPAABBXX-BBBBAA--11.-00487--11 83800 PPAABBXX.BBBBAA.-11.-004477.-11 "26 PABXBBA-1-047-1 1111002391--GGRROOUUPPIII--FFII 1111003363..GGRROOUUPPHIIL-FFII 11037-GROUPI1-FI 1144 PPAABBXX--BBBBAA--11.-004477--11 2i0n2s PPAABBXX.BBBBAA-.11--004477--11 157 PABX-BBA-1-047-1 BAOQLL == BAebloovweqquuaanniiiiaattiioonnlliimmiitt DF = Dilution Factor 01240 Primedica-WorseProject Number: PABX-BBA 418-018:PAGE 1-204 Page 18 TABLES SUMMAROYF MEVALROANTIPCLAACSIMDALSATCUTDOYNESACMPOLNESCENTRATIINEODNTSA Animal# -Group Generation H1010.GGRROOUUPPIIZ2FFOO 214553 Conceaation (ng/mL) il00o44w52.-GaGRRROoOUvUPPPIII2ZZFEEoDD isS2is3s 1Hi0Gk47Ee.GGGRRROOOVUUPPFIII22FFFYOO BQL(OF=21185<iOngiml) 1L110o055s01-.-GGGRRRoOOUUUPPPIIIZ22EFFDOO 211205 i0sz GROVFIZFD os n10o044w54aGRCRRoOOUUUPPPIIIZZZEEFIYI S2rist i1000454706..GGGRRROOOVVUPPPIIIZZ2F1EI! 1i57l0 11605515-GGRROOUUPPIIZZFFYI 5i5f6 n1Io0Gs5Ss4G.-GoRRROOoUUUPPPIII3SRFSOY BQLMF=2EhS3<l0sgml) 11io00s5578.GG0RRROOOVVUPPPIIISSSFFROOD 30248s 11111000665015.-GGGRRROOOVVUFPPIIISZSFFFoDo %115720 1111000666425.GGGRRROOOVUUPFPIIIS>SFFFoDD 2n5i50 111006656.GGRROOUUPPIISSFFoO 5m53 1L1100085S364.GGGRRROOOVUUPPPIIIZSSF7F1I1 ano>1 'BA1Q0LL38=.BAGeblRoovOweVqPqIuaLmnF1iiaatiioomiinntt ao OF = Dion Far BechID FPPAAABRBBXBBBBBAAAL0L105055666111 FPAFAABBBXBBDEBEAALA1LL0055S66].1 FFAPABABXB.DKBBBBBAA1AI0O5SS6G.]11 FFFAAABBBXBBBEBRAA-ALLS0055S6611 FAPFBAABBXKX.E.BBBBABA-A1L10O05S56S6111 FFFAAABBBXBBBBRBAAALL1S00S556]61 FFAABBRBBAA1100556611 PPAAPBBAXBBKBBBABB-AAL1100O56S626111 FPFAABBXABBbBBaaABAL1o00.s55e6611 FAF FABBXBBDA DBBAAA1100B 0555666.111 FFFAAABBBXXB.DBBBBAAALLL00O35S66S111 FFAABB BBBBAAL00556611 FFPAAABBBXBBBBBBAAALL000555661611 FAB DBA10561 oc1241 Primedica-WorcesterProject Number: PABX-BBA 418-018:PAGE 1-205 Page 19 TABLE 4 SUMMARY OF MEVALROANTIPCLAACSIMDALSATCUTDOYNESACMOPNLCEESNTRATIONS IN EDTA Animal#-Group#-Generation 111008S90.GGRORUOPUIP3I-FF11 1111006632G.RGROOUUPPLI3SFFI1 11066.GROUP13F1 1111550021..GGRROOUUPPIIFFOO 1111550034.GGRROOUUPPI1FFOO 1111550065..GGRROOUUPPIL-FFOO 1111550087..GGRROOUUPPII-FFOO 1111550150..GRGORUOPULPFFOO 1111551121..GGRROOUUPPIIFFOO 11115S1I43..GGRROOUUPP1I FFOO 111351156GGRROOUUP22.FFO0 1I1SI1S71.3G.RGORUOPU2P-2FFO0 1111551290..GGRROOUUPP22-.FF00 1111552231..GGRROOUUPF22-FFO0 1111552245..GGRROOUUPPZZ..FFOO 1111552276..GGRROOUUPP22.FF0O 11528.GROUP2.FO 11115S2350..GGRROOUUPPS3-FFOO 1111553332..GGRROOUUPP33FFOO BAOQLL == BAbloovweqquuaamnicaattioonnimmict. DF= Dilution Factor Concentration(ng/ml) BQL(DFf=r2,0nginl) m1514 sis 0m12 BQL(OF=22,65<0nginl) 21687 215s5 119809 702 21684 1n6m1 21630 1a335 115s0 21476 830566 m a1ss hrre) BatcIhD PAPBAXB-XBBBBAALL1005566-.11 PPAABBXX-BBBBAAL11005566..11 PABX-BBAL1056.1 PPAABBXX--BBBBAA-L11006655--11 PPAABBXXBBBBAA1L.006655..11 PPAABBXXBBBBAA-L11.006655--11 PPAABBXX.BBBBAA-11006655..11 PPAABBXXBBBBAA--11006655.-11 PPAABBXXBBBBAA11006655.-11 PPAABBXXBBBBAALL11006655--11 PPAABBXXBBBBAA--11006655--11 PPAABBXXBBBBAA-11006655..11 PPAABBXX..BBBBAA--11007625.11 PAPABBXX.BBBAB-A1006655..11 PPAABBXXB.BBAB-AL-006655-.11 PPAABBXX-BBBBAAL11006752..11 PABX-BBAL1 065.1 PPAABBXXBBBBAA(LL006772--11 PPAABBXXBBBDAA1-L007722:11 001242 `Primedica-Worcester Project Number: PABX-BBA' 418-018:PAGE 1-206 Page20 TABLE4 SUMMARY OF MEVALONIC ACID LACTONE CONCENTRATIONS IN EDTA RAT PLASMA STUDY SAMPLES Anima)#Group#-Geperstion Concentration (ng/mL) BachID 11534-GROUP3-FO 1111553356--GGRROOUUPP33--FFOO 11537.GROUP3-FO 1111553389--GGRROOUUPP33--FFOO 11540-GROUP3-FO 111314524-1-GGRROOUUPP33--FFOO 11543-GROUP3-FO 128 PABX-BBA-1-067-1 8210 PABX-BBA-1-072-1 375 PABX-BBA-1-072:1 141 PABX-BBA-1-067-1 2a5n30 PPAABBXX--BBBBAA--11--007722--11 3168m0 PPAABBXX--BBBBAA--11--006772--11 1 PABX-BBA-1-072-1 347 PABX-BBA-1-072:1 11544-GROUP4-FO 11545-GROUP4-FO 11546-GROUP4-FO 11547-GROUP4-FO 11549.GROUP4-FO 1111555501-.GGRROOUUPP44--FFOO 11552-GROUP4-FO 11553.GROUP4-FO 1111555545--GGRROOUUPP4--FFOO 1111555567..GGRROOUUPP44--FFOO Ld 1550 97120 164 821 404 483 457 308000 + 38 8 0 sa PABX-BBA-1-072:1 PABX-BBA-1-072:1 PABX-BBA-1-075-1 PABX-BBA-1.067-1 PABX-BBA-1-067-1 PABX-BBA-1-072-1 PABX-BBA-1-072-1 PABX-BBA-1.072-1 PABX-BBA-1.075-1 PABX-BBA-1-072-1 PABX-BBA-1-072-1 PABX-BBA-1.072-1 PABX-BBA-1-072:1 11630-GROUP11-FO 11632.GROUP11-F0 11633-GROUPLI-FO 11634-GROUP11-F0 1111663365--GGRROOUUPP1L11--FFO0 11637-GROUP11-FO 11638-GROUP11-FO 11639-GROUP11-FO 81 254 PABX-BBA-1-067-1 PABX-BBA-1.067-1 258 PABX-BBA-1-067-1 296 PABX-BBA-1-067-1 8038 PABX-BBA-1-067-1 "03 PABX-BBA-1-067-1 387 PABX-BBA-1-067-1 358 383 PABX-BBA-1-067-1 PABX-BBA-1-067-1 'BQL = Below quantitation limit. AQL = Above quaniation limit D*F==VDailluuetiwoansFaccotnofrirmed 001243 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-207 Page21 TABLE4 SUMMARY OF MEVALONIC ACID LACTONE CONCENTRATIONS IN EDTA RAT PLASMA STUDY SAMPLES Asimal#Group Generation~~Concentration (ng/mL) BachID 11640-GROUP12-FO 11641-GROUP12-FO 11642.GROUP12-FO 11643-GROUP12-FO 11644-GROUPI2-FO 11645-GROUP12-FO 11646.GROUP12-F0 11647.GROUP12-FO 11648.GROUP12-FO 11649-GROUP12-FO 11650-GROUP12-FO 11651-GROUP12-FO 11653-GROUP12-FO a3 PABX-BBA-1-067-1 342 PABX-BBA-1-067-1 476 PABX-BBA-1-067-1 146 PABX-BBA-1-067-1 258 PABX-BBA-1-067-1 175 PABX-BBA-1-067-1 265 PABX-BBA-1-067-1 355 PABX-BBA-1-067-1 102 PABX-BBA-1-067-1 197 PABX-BBA-1-067-1 23 PABX-BBA-1-072-1 246 PABX-BBA-1-067-1 381 PABX-BBA-1-067-1 11654-GROUP13-FO 11655-GROUP13-FO 11656.-GROUP13-FO 11657-GROUP13-FO 11658.GROUPI3-FO 11659-GROUP13-FO 11660-GROUPI3-FO 11661-GROUPI3-FO 11662-GROUPI3-FO 11663-GROUPI3-FO 11664-GROUPI3-FO 11665-GROUPI3-F0 11667-GROUPI3-FO 324 305 395 ns 18 BQL(DF=1,<I0ngil) 381 312 168 420 280 BQL(DF= 1,<I0ng/nl) BQL(DF= 1,<I0ngiul) PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 11501/11506-GROUPI-F1 11504-GROUPI-FI 11502/11507-GROUPI-FI 11505-GROUPI-FI 154 BQL (DF =4, <40ngiml) 192 BQL(DF=3,<30ng/ml) PABX-BBA-1-069-1 PABX-BBA-1-065-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 11508/11503-GROUPI-FI 11509/11510-GROUPIFI 11512/11511-GROUPI-FL 11513/11514-GROUPI-FI 264 PABX-BBA-1-069-1 258 PABX-BBA-1-069-1 33 PABX-BBA-1-069-1 205 PABX-BBA-1-069-1 11515/11524-GROUP2-FI 11517711520-GROUP2-FI 380 393 BQL = Below quantitation limit. AQL = Above quantitation limit DF = Dilution Factor PABX-BBA-1-072-1 PABX-BBA-1-072-1 0c1244 `Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-208 Page 22 TABLE 4 SUMMARY OF MEVALONIC ACID LACTONE CONCENTRATIONS IN EDTA RAT PLASMA STUDY SAMPLES Animal#Group#-Generation ~~ Concentration(ng/mL) BachID 11519/11518-GROUP2-F1 11521/11516-GROUP2-FI 11523/11527-GROUP2-FI 11525/11528-GROUP2-FI 11526-GROUP2-FI 25 PABX-BBA-1-072-1 29 PABX-BBA-1-069-1 214 PABX-BBA-1-069-1 152 PABX-BBA-1-069-1 90 PABX-BBA-1-069-1 11536/11537-GROUP3-F1 242 PABX-BBA-1-069-1 11538/11534-GROUP3-FI 395 PABX-BBA-1-072-1 11540/11530-GROUP3-F1 193 PABX-BBA-1-069-1 11542-GROUP3-FI 23 PABX-BBA-1-069-1 11543/11529-GROUP3-F1 340 PABX-BBA-1-072-1 11547.GROUPA-F1 11552.GROUP4-F1 11630/11633-GROUP11-FI 11632/11636-GROUP11-F1 11635/11637-GROUP1I-FI ~~ 11638-GROUP11-FI 11639/11634-GROUP11-F1 513 339 27 240 BQL(DF=2,<20ngil) BQL(DF=2,<20ng/ml) 214 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 11640/11641-GROUPI2-F1 11643/11647-GROUPI2FI 11646/11644-GROUP12-F1 11648/11651-GROUP12-F1 11650-GROUPI2-FI 11653/11642-GROUPI2FI ~~ 23 BQL(DF=4,<40ng/ml) 147 219 24 BQL(DF=2,<20ng/ml) PABX-BBA-1-069-1 PABX-BBA-1-072-1 PABX-BBA-1-069-1 PABX-BBA-1-069-1 PABX-BBA-1-072-1 PABX-BBA-1-069-1 11654/11662-GROUPI3FI ~~ BQL(DF=2,<20ng/ml) 11656/11655-GROUP13-FI ~~ BQL(DF=2,<20ng/ml) PABX-BBA-1-069-1 PABX-BBA-1-069-1 'BQL = Below quantiation limit. AQL = Above quantitation limit `DF = Dilution Factor 001245 Primedia:Worceses Project Number: PABXBBA 418-018:PAGE 1-209 Pages APPENDIX A REPRESENTATIVE CHROMATOGRAPHIC DATA - BATCH NO. PABX-1-047-1 0c1246 Primedia:Worcesir Proj Number PABX-BBA rages 418-018:PAGE 1-210 [---- 0 ImeE ns oeA s Cndg (. om3er okm:)e S:E2ER- me San 01247 meteWorst ProgetNamba PAB 5A zs 418-018:PAGE 1-211 f[ r rPmern ft Q @- E Eo PE ------ fatto ------ ! i ; ! I : 001248 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-212 Page26 Peak Area Report teres: oedo1n3011t548 arma eaaFdaeaan,AASXOSOANTAPASPABCOOOATI hatVb " ili lh Bs ll ol Te 1osksptrd inon rtntee. Pet Te 1801 1004 [ 001249 ees Hors open PBA rr 418-018:PAGE 1-213 OT ERATE ens or emt I hr Ta i oN 001250 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1212 Page 26 PoakArea Report Serres Odo om2i011:50 rm ReaTtiarre HSBEAATAPABSPBAASB0K1 aPo omer Gomes DME gp tau tase [ET -- I 001251 Primedica-WorcstrProjectNumber: PABX-BBA me eR 418-018:PAGE 1-213 Page? i EE TERR Thinie ve ThRe TETE TEREET T Tow re eee a Jeon i J | re none mma Tn _ 001252 `Primedica-Worcester Project Number: PABX-BBA. 418-018:PAGE 1214 Pages Peak Area Report . seems: oehn: 1 30 eranC bo ePnot :MSCEHA DATAPABPABLEBAT 1, mat Hi5" fompeds omgpium Imai Baum Saihe 001253 Primedia:Worcester Project Number: PABX-BBA BfiAn R5 Tcms sone svar , @ ET Ba Dacormane sa. (7% tasegeasor) 418.018PAGE 1215 Page Spr ---- sone mang es a rs 001254 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1216 Page 30 Peak Area Report same xems onmi 1201102 RLSumeeresonnion mmm opel Gmpiues Imgl beam Pete eT 11001 1048 ges 001255 Prinedica WorcesterProject Number: PABXBBA 418-018:PAGE 1-217 Faget fBeBjYm ames vTe,ar i ee EA ERe TR EEA W or ena i i E A E EEE EEE = _ N EEEEET eeeTee gern warn rents Senin wt 001256 Primedia Wore Project Number: PABX-BBA 418-018:PAGE [218 Page [---- J ot rr wm ELSomsronn, weeRE ws-------- _ 001257 Primedic WorseProjct Number: PAB BBA 418-018:PAGE 1-219 Pag3es EBBucEgide D7YEmDamAm TP BALA 04 SOE R.5R2i0aa0t:,3 @ET EA TOER C08\PN ARE_BRAN (RTE Tategracor) i i Em Meese TEEEEEEETE ThEEeEee A ; EEE EE Te 3 Tie 7% 001258 Primedica-WorcesterProjectNumber: PABX-BBA 418-018:PAGE 1220 Pages PakArea Report @ IEEE gm Sor Su Barroso mane EA Gomes comes RED wm hesme tame 001259 Primedica-Warceses Project Number: PABXBBA 418.018PAGE 1221 Pages B ceriaR : veE n mmm oermaoie QT BT onapan 2 steer eee en i ta TE ieaTheTeTETeTERTE ! E EEE LEEEEERTe EEEE e Ae EE J oh CRT Tk is ak ww 7h 7h TETh Te ve 7h ThTe Te 00120 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-222 Page 36 Peak AreaReport NonSaanRoennaeme::b1 xa5Ta00 1067 oed [=e201: 1127 er T ataABt EhAATe APABPARLABALGAT mame Gep3ost fwmam IwmiomBotome tome oc1zel Primeica-Worcese Projet Number: PABX.BBA 418-018:PAGE 1-223 Pages? on a Sica rie mDuna s manA807 oun T5 vtiet,,3 an REE E EonS s aan (x7 scarcer - | i ee N E \ E | Spe EE CRT a NN | ae he E sh Rl3 eR ie R % TeE Te eke e 3e h im e TR ons eam san atte on -- 001262 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1224 Page 38 Peak AreaReport spire Or da281 1747 enuemothhPaemnArDAiBUAtTSeAA.PABPABKBBA01, nanetri m arcv7 fm2ol coampe Imngowwm esomme faite hr coe ie rtgnreee. 001263 PrimetcaWorstPrjctNumb: PABXBBA rage 418-018:PAGE 1-225 J FBra iPaR----------5 WE. QE EETETwne s an sre iN fn TTTe cee e eee r oE = ERa a Nnp i T ANR NARR ERE ins pan nm nas --_ 001264 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-226 Page d0 PeakArea Report Serenxcomor oosemi 10 aTPRama:A07005S0.ATAPASBAPLAK hraerVumr O batne 7 fmm3ets mwmiea DoE pe) w twuim tes hra rn en re gon epee a. 001265 ET Sass ile B,DBATBOR NOAOUTI. OOR Viah: 3 E o: D rr gt=tt se a 418-018:PAGE 1-227 ] tr Momt eons T A E Te Te TE er ees $8 TT AN 001266 Prmedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-228 Pages PeAreaaRepkort @ RsEamNmeIxN10. [ Ed-- r a Semae DhSTAPABSP0A1B1C. meme omp3eds Te cmmapiue Immao) w beam taimane etentreotrr etre ue1267 Primedica-Worcester Project Number PABX-BBA SSErpae:iEte Ro0p0mEms ene n a on oa EnsSBtttiil 30 WE 2A 418.018:PAGE 1.220 Page 63 i hen ve wh sk enihewth 7h im 7k 7%Th T7k h TR TR E wn E 1 | io>EE EEG EEE em a ; EasNe N ea 001268 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-230 Page dd. PeakArea Report NounSaRmepnlee::F0A8C0S0000360 On h--n 1251 1048 tanakaaire DDAASAKATOAAPAPABLEOBTA hte Hoi fmi5pct: Soamptue Iwnfow4 Beawmne ite 001269 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-231 Page ds L S E ite pr 1s I 5 aean sw an ow ak76Tl th7h ve Th TETRTERT Ny FUSE= RSL == \ | EEE he ee Te em 061270 Primedia:Worcester Project Number:PABX.BBA 418-018:PAGE 1-232 Pages PeakArea Report sen aromnio [-- ED Tie: DSAATAPABPASKSBALO1 hatVb 3 Eo) %1>3 001271, Primedica-Worcester rect Number PABXCBBA 418-018:PAGE 1-233 Pager B saa FlI e DEED BMR RB ABAA-aer TIREDRbata 36 QT HRT onansan 3 ssesracer a -- rr E matt Ll igh DT RR RRR] [ | JN conn mean eon sen rs 00122 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1234 Page 48 Peak Area Report @ TsemE eameE cN A10 ounpEoon:121 120 rm F ee GAALBS SOAe TAPADPABKABAIO1) haere Gmpeir Gompem Imgel omic time 001273 `Primedica-Worcester Project Number: PABX-BBA E QL 100 R Sp SE E--------] T. 2 TT Eman sp re svprers 418-018:PAGE 1-235 Page 49 mmm neem i EEE ETE A NE EN EEE rr EE TE TE TEEI IE Nn eeTEE rareSR A Te Te ee Te ee 001274 Primedica-WorcesteProject Number: PABX-BBA 418-018:PAGE 1236 Page 50 PeakArea Report Soman cross [---- areeTtieEPEICAATAPHBOABCOOA1I1 eeni me3 s GEomSpium Immgoaaomme yume J meet 001275 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1237 Paget B sata Tila e 0n DSATAePA ARALR\oE uTRR.E=via.l: 30 TT STDrees, 3. ovement gms ) mle on ree oi TR Eh 16 th tetn 1h Wh 7BTeTh 7h 78 TR Te th EE ner: 205) EE | EE @ET Eee TR iei ieni ih TRThhe Te Te veTRTR cones mers Tsim sen es 001276 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1.238 Page 52 Peak Area Report NotbSonaknhoebarne.:F10C9S94B390U0P8570 OneAoco m201e3505 matuoanatpFreeaPsme:s.DAaBl6Ri2H3nC0 ATAPASDOAPAX erraonmVaitaame 57 Aen me2lt Cowmopwlam Ifme)owBm Mmam fase oe bo ee en etrr pt apr emp. 001277 Primedica WorseProjet Number: PABXBBA gEii; LogEp ERp --------_STea [eenrg NA 418-018:PAGE [-239 Pages pe Tre No TEE | rr ee TE IE a TETIE IE Ne IR TTTTrer ree Be Tm -------- --tRTtesakk tk An SE ew ve nth 1h 1k 7h Te ih mk ve 001278 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-240 Page sa Peak Area Report NosSeamRo eam.:F1A0B12B8GrROUP061FO. on h2a e 012525 toAEDATAPABOABCA0RA1I mann5 me3 u Gmmiplem ImE pl ma meimi teimbe [Er ---- re. 001279 rimdinWore PretNumberPABYBBA 418-018:PAGE 1-241 ages HER dares TE er QTE SamT os Pass nx RTE tovesator) Lema All wh AB se ik teGh am em tm vevote 76 7k76 7H TTR R rm er ee Nf I Thamee ak am an am ak ve 7h ih 7h 7% Th Th ih om me 001280 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-242 Page s6 Peak Area Report [t ISai mo hv ae 1e 0337.3s 5009950 oeAocr1n3012:045 unsTeonis eem DASAKDEATAAPABPABCBIATS01. nemo fomf2pedt Gmwmgsiues Iwmaomwm mwem fauses Tt oe tr oter repr te. 001251 Primedica-Warcesies Project Number:PABX-BBA 418-018:PAGE 1-243 Pages? sBEaaErie 5a u11m0SaEpmne B47NeRTIO.SMReebi: er Q 3T DHEcevnes, sn re vapene er e JE rrr rr Fg ENE NE : r o N i a r y Se Ee Ee R ETReNn e SO I. 001282 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-244 Page 8 Peak Area Report NosseamRp amm:FOGNOP56 oe Aouee.: 12012130. cotLuoteFeapbameDPeArSSEOn:SE8AATAEAOBANEAA, erm aSrre ao157 meeats Cowmipsium Immpol or tn ere et gti SmamE Dim' e et norn 001283 PrimedicsWoPrrojestNumeber: PABX-BBA 418-018:PAGE [-245 Pages9 r RL a LS U neIE2an.1 br "| : PP rrr TR EE RE toa N eT ||| CE ho 001204 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-246 Page 60 Peak Area Report InAtNaem: r182i0.e6051 oeASsiom 12012120. LSSermon mR Gonm2ndr Coi mmpiue Dwefeol wRm Tm SRROe 001255 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1247 Page 61 untacacion wepore 101 evieves) REDaeEtoaRnFile : Da:1%\KabSnD OS aAT\PnAAH B\PABK-BRA\I-04T-1\047ION).D_S_FpeeraViiearl.: 33 QE ER ons ean soa (872 socegracor) FRR <2 ry iERTERE Epa BERR ee a HE Egre agpt 2 3 | EE Timma raeam a th veTeTeTET Th TeThTeTE 001286 Primedica-Warcese Project Number: PABX-BBA 418-018:PAGE 1-248 Pages Peak AreaReport Seams cc oot cnon o NotwbookRefwwnce: PABX.08A-1-047 `Oparaor: meoe psrmss S sonsras amson moebreAeTErS I = EE 001287 ; Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1249 Page 3 B Baca ileE BEE D BATAPPKBBAV-07- NOUNS=v=ia: .30 FQrESEATBR eco panes E(g07 Iacegeuser) en - i A ll. A PPk || Ny Ee mrTgp aehe ae) TEvE e ih iki 7h 7 7h 7s 7h Tete Th ieTe 001288 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-250 Page 64 Peak Area Report Samm nz E21 onetei: nz SA Braemaorn meme Gme2pas Cwomoplm IE nn e mo M) eum Salis 0012:9 PrimediaWorcester Project Numbers PABX.BBA ernmentwin BR REE =. QL SR Eom. es crc 418-018:PAGE 1-251 Pages oe ELELE EE TTI_ee0 E EER R EEES E EEE 001290 Primedics-Worcester Project Number: PABX-BBA 418-018:PAGE 1252 Page 66 Peak Area Report NotnaonkRnemtre::PxA0B0EuAD107 Oehfeen] 201223 am uT n aPdhe aamm::FuAn ArIB1DB20DA.Aa TAPABPABXORAIG01) arnteVat ric 57 fmpaoit Cwoimnpe DeE gnl MI PmaN ebioste 0012351 `Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-253 Page 67 rHee5msnny RE QcimTa E DTT f cena,h8e cpr i ER EE RE EE Fhpa -- am LL a | Te R N e o TeTe] a 001292 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-254 Page 68 PeakArea Report NowsocSkaRmoran: 1A0B3R3SG0O1UP0S7 1 oeh=e3s2e0 anE ahmt :m ASaGla EeS0CA0Ti APABPABXr BIST, mame fomm2els wmmipstum IE mg e MeumE tayo Te ihn en et etmin er 1 rn. 001293 Primedica-Worcester Project Number: PABX-BBA BRE i QE SRE. x se 418-018:PAGE 1-255 Page 69 Spe ---- leah WR Ge e% sw an ak wm tm Twih ve ve Th Te Th TE TR TN F y ------ I TET aea a ah ak em ve veTE Th Te Th Th TE Th) 001294 Primedica-Worcester Project Number: PABX-BBA. 418-018:PAGE 1-256 Page 70 Peak Area Report Samet recurs owetome 01232 nue"ia aoPFeiNNaaPumen AiUB7SED7BD00A0TAPABPABXSO7A1Y. arerimekcoteoNmanm7i? ments cee Ing wm Pada mime 001295 Primedica-WorcesterProject Number: PABX-BBA REDaeRcanDile 0s.1IW%EDtAS TAl \SS AB\ABK BRAVL-OU7-\GKTION 0STpEeicadi: 37 HT SER osm sn ee seater a 418-018:PAGE 1-257 Page 71 Le 4 8 4% G6 6 oe 80 Ge ek 0m ie vm iw 18Teomohve tm tego rETraeSaasarea om>em ------------------------| | I TET ee ee ih ha a ve veTe ve3 Th 7h TETe Cons mers The gan 10 152.8 2000 ruge 2 0C1296 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-258 Page 72 Peak Area Report NoSoustea:: 1P32B55A00o7f31 on sa c 12012322 em oapFTeldle amanosrAGBAr tLCSeNBTmAAPASPABCOB47A.1N) ntrrtVtHnam:57 Bion Goads Cwoimspl DaEfI a Magmic fais wl12s57 ne oi an os 418-018:PAGE 1-259 Ei RET eo =F @RSTfstST -- SO a | --_-- > pea A | TRTRww kh we sh amakTk5% vk 7h ve 7h vm 7h TE rm 001298 `Primedica- Worcester Project Number: PABX-BBA 418-018:PAGE 1-260 Page 74 PeakAreaReport Sane ame: TORO 1 oomAccu:1201 32 rem E CA CATE APABPABCSOAN 011, herman3 Compost commptess Dopo be badae Pate 0012.9 Primedica-WorcesterProject Number: PABX-BBA 418-018:PAGE 1-261 Page 75 SSmrpaEere : 5m .o08u0 i B amesn a AoeeeSTuivHaita ,30 @ET ERTL NETKCOSa \PALE_ BAN (RTE tncestator) hai em oR EE BE EEEi I -- edarrT AN Jf a rT 001300 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-262 Page 76 Peak Area Report sarees crouse: ueAcne 301601 tnaoeatmhnodeeNHaPaaomeeW1A E08,2CA0ATAPABPABCSOB0A1N, amroavnaemae: 76 onpeds Gmmpiun Imjinl Bm Magmic baie Te 1i tr otrtgrpertkm. 001301 PrimediaWorcester Projet Number PABXBBA SJoEL|SrUaESp----gLoliig;t QT ARTOEincos\PAS BAA. (RTE Tategeacor) 418-018:PAGE 1-263 Page? i TR ER TE a fon 1 IGe Pt RE RR| FA ARA tOS shS swAh AE W V Ve tn YR ve ve i IR 7R_TR i AN Chaeseee Re 001302 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-264 Page 78 PeakArea Report [SStamleeamte t525eSrPOUP530 ou Aosmn 1301021 LSSA saan cr. meer1 fom2melr Te comaptes Imwpol Eln Deomm Mme he sotmr iet et re 001303 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-265 Page 79 serie vn cenasn oromen pts Eb EET OTT HT on sn ep) Emme om ee Rm 1 +m FE Srp ap r ER RR RR @ g E E=B = r e T] e ; I TE TE Ee th TTTe7a 7h hhete 001304 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-266 Page 80 Peak Area Report NonSeumRevamee:A3KsGSRAOUPS1 ovSern 01201 een pTaitoa ABSEEG1ATAPABBPBAA0S1K1. eva Gomes Compe Ini fein aioe oteotno te pred1 001305 Prmedica-Worceste ProjectNumber:PABX-BBA 418-018:PAGE 1-267 Pages: uc ie 5,00 BoA aEAor oO Stat 43 BF ELEN TT ET ronan son 0s serge i meee i IE IR E eieIN TeTRTSTkTAAT Nh er ; A JN Tin aw iesk eknk se ve 6 7ih k i i Te tl ve1hok Th 001306 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-268 Page 82 Peak Ared Report [Se an ta:t083vRiOUnPdSS omcomre 1301190 aom ueEnnotve aaamna.s:O0M1n SO0D0I3A0ATAPABPAB AYU. Wrearae vamec Compete Comepgams Depa fy Emmi tmpmpe [OE ------------ 001307 Primedics-WorcesterProject Number: PABX.BBA RJaiJ SPmycnm= -- aSouol-- TT EET amar, gon st em 418-018:PAGE 1-269 Pes :fe T SEERAo RTE ERE ET EEE EEE moe | aN Em TT aE ae ak vm ak am amom 7s Tk imievk Thih Th Te 001308 `Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-270 Page 84 Peak Area Report NonsaumR p rane: ABs 1SGHAOUP0S7E0 oeAocroes 1301 120 CaTi he:SMD.SATAPABPABLEBAN O71 materrrr ee2ls Cwoimpu Ia spwln Smita 00139 PrimediaWorseProject Number:PABX-BBA 418-018:PAGE 1-271 Pages iEeLjAu c RmsoSB_rtt [Re aa i RE Mey iE a te oh ikhh Th Tb 76 7k 7h ihik 7h T hO i th iN eTe e 5Ya TeEv ee 001310 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE [272 Page 86 Peak Area Report Sem ome mares owede 1201 140 TL AEBABAR, wa comes Gmmpine: Impl Boheme Seppe ro eb hn te rr pin etti [rp---- nor 1 001311 Primed Worcs Project Number: PABXBBA ge? 418-018:PAGE 1-273 I BBFE {IaREEpE --pBA--t LTTE E tiettnis eorssoSrA Eyre ---- f+l TE hEem Tm aeJw vm ox ve ve i om iw ie im 3} 001312 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-274 Page 88 Peak Area Report emsSamRp aeme:O6862S5R0U5R36 1 oeAScqr 1301155 evn eatiHPaee:SPSAOBAATAPADPASKSOBA7N1 mereimo 6 Gompeds smmpiuem Df IB MARE ie 001313 Prmedica-Worcester rject Number: PABX-BBA goEricpe:rR ite 1Iov0eES mmoTARA E eT ETON.TBSREYoi: 6 QE Gms sn srms A 418.018:PAGE 1-275 Page i. E ea eE eTl TRTE Tee a TeTR TR TE M"Lei ram Sat 7 oh Rlle i A I H TT E E ve ee aTr a TeTe TRThTeTreai] 001314 imeiMoros PrjctNumber PABXBBA Feo 418-018:PAGE 1-276 [-- 0 ISEpinEs TEU. ooorps EI amaemnann. wSn RE rt compe BI mate oye 001315 FS rn 418-018:PAGE 1-277 on rene Tr er QT EEmo spre . i: a ELE T E | RE EwGe th 4m 4% ek sm3%7h Tm 1%Ie1% vw 1h 1k Tm TT NEN TT T 001316 Primedica-WorcesterProject Number:PABX-BBA 418-018:PAGE 1-278 Pages? PeAreaaRepkort seve stasis JO. JO eS meiscamarann wanes fempest egg pow Ina Mm Delma tegmee wr ---------------------------- 001317 rind ores rf Nbr FAX5B or ms =i 1045 -cRo0Pe-r0 Ta er @RT EE RPNES MEFODS\ PABK_BBA.N (RTE Tncegtasor) J 418-018:PAGE 1-279 Pr en A T RTEeh E ieih wnR gkLTLheT_hR 7_h_ve_1h_v_kAv_mR1_E8_Rth_R| EN i TAR aE ek ak ak ahve aw 7h Th 7m 1x ve vk ve imok ve | 001318 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1280 Page 94 Peak Area Report NebuocRinar.a:FoEeSG0HO1UP4L7FO OuAocra 301258 menepePee:SPASCHDAATAPABPABLIBAI S41, harem ammeat cmmplem Tmgnl lB OSMRE SUE 001319 Primedica-Worcester Project Number: PABX-BBA 418.018:PAGE 1-281 Pages EffarcerEeile 1 VoDvDTA\mPaARIABKBRAL-GO0-1OUENRD__pfreaVriia 48 QL DRT Konasn ae see) I Emig mmrermemm mr em eee8 Th S GhSE 6in 8ak 1pJ in ih ve ibvm 7h ve th Wa ew se i | eA o S R iAnv i e Th Th ih 1h e ih ih ih hh NN 00130 Primed Wore jectNumberPAB.BBA a 418-018:PAGE 1-282 Pree kpor 0 SsrRrE sa ssio nra ETE masonsn ER 001321 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-283 Page 97 ie omSpNene ta [Rind =] J] E wi T1 gEee Nn 001322 Primedica-WorcesterProject Number: PABX-BBA 418-018:PAGE 1284 Page 98 Peak Area Report NonsaumRpenaem::P1A0S4H3GR1OU0P4L7ES oo Aocire 1301337 SETEATON15, nen comamer Tn cmpiionme Iwnnomgo te=am Sige ee et re pnrdnr. 001323 `Primedica-Worcester Project Number: PABX-BBA Bse iIe 5 EsRxnnEaE 8 (QrLpsin eEe gR re T ex seer 418-018:PAGE 1-285 Page 99 a ai mm Ee ------ 001324 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-286 Page 100 Peak Area Report NetboSoakRneeammoe P0ASE088S10T1 oeAoonre 1301357 er ep aPt AACuneAmABCoaAI 1 arvmenVo cea mente Dupe tml Syphe or en eke strt pt npr mn. 001325 418-018:PAGE 1-287 `Primedica-Worcester Project Number: PABX-BBA Page 101 Ssiee 5LESEDRJ AeSa ta 5 QL ERE pn ev a re renmeme mms JTIE TE i fe \ ; TEETE Te Te Te TeTe TE eh P rr R or EE Nh _||| Eh A ah ee 001326 `Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-288 Page 102 PeakArea Report NoseSsameo amee: A03S5K1SS7A0UNPLTEG [= ------ erbata hBAt EBRGBA paresani on mameSs meas comple Doe kg mem eum [-------------- 001327 primedic Worcs Project Number: PABXBBA mses wre sens Emam =. ( TEEnnio rs pr mr 418-018:PAGE 1-289 Page 103 resem ree TEETE TE Te ih ie a 7s Th TE76 7ie 1h ve 1A eS k i Ne y ER -- TEE EeeeE h TeTaTh he Te eh th TE 001328 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-290 Page 104 Poak Area Report NoboSamFootnaee: P0A5S3COGPOU5T1LES ou h =1t 301438 emma oeunerTdeoaaam:.SaFMEA0SAATAPABSBAA BE O71 ausmmeenmatireo5537 m2s Comwewtic uwghow Regi Sigg 0C1329 PrimesWorcesisProject Number: PABX.BBA 418-018:PAGE 1-291 Page 105 feE rranic ea o0u3sn S syR TOUTE SptuSttl: 3 QE SRTEnna s or nrc)mmmmm FUN or rrrrrhn aa E ETe | NN r E dri T E Tr TE TTgp Ee eTer e-- EThTTA o RT N Te Te eve Ta e A e 001330 `Primedica-WorcesterProject Number:PABX-BBA 418-018:PAGE 1-202 Paes Peak Area Report semen otros [---- RS Eu Bsaesscapanrs,mom Gomcomie Gmmpilem Imp momen SUES [I ------ 001331 Primedica-Worcester Project Number: PABX-BBA 418.018PAGE 1293 Page 107 SHsaaErcaEtrileL O1iDlRDaIEAPrARDAKCRRAS-00-PGATIRC.D_STpEeiViit:l 50 QT SIeEe as--o a geen gr" i I h Ee Te he TR RE Mp pram AN E eESv ra --e ---- r EEFT 8% -- --e--e --e -- e ee]]| -T rrr T MT E T T TR i 001332 Primedica-WorcesterProject Number: PABX-BBA 418-018:PAGE 1294 Page 108 Peak Area Report seman: crt ote 31825 ee C BentSAUSIEAN ppssonexasaronn warmer Gomes cmmpene Inge) mo oemyme Syme 001333 Primedica-WProojretcNeumsbeerr: PABX-BBA pe rie 5s BAER Ena ome ia: 5 T= (LH ETE ms om ror 418-018:PAGE 1-295 gis 4 Tapper wo 1 I ea ee : EEE eh \ | Te ve Tee a EeE e) anes meaan Teaeneants0 re 001334 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-296 Page 110 Peak AreaReport PNSal mplet: 000r4UPteLryE oeASruon: 1301526 eee tTeHaa t SDAABARTSAAPABPABXOOAIA matVe fmemnds Gomme Impl bo msEmE me 001335 PrimedWorcProjeect sNumtbe: PABX-BBA 418-018:PAGE 1-297 Page 11 Bses N00EESasoo Q haE i ETE mons tn E4E. sper 3 TTT TTT ET ETE a oes EE | 001336 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-298 Page 112 PeakArea Report NomsSoaokmRoehnaon A10S5K7SAOUP4L7E oeASocie1301555. EAT SEATS er cmn2dt | Gmwspoie Imogwmmm me hren nenee et rn er ne rp 001337 es. e re ESA Ea ERE @HT Neu HO0S\ PAR BIA 2 (RTE Integrator] roe 418-018:PAGE 1-299 em TRTRE te Wh iE Sk 7h ve 7h 7B ve 7k TR UR tkim EE ee o et o e J e N e 001338 Primedica-WorcesirProject Number:PABXBBA 418-018:PAGE 1-300 Page 114 PeakAreaReport [---- o NotebookRatsrsnce: PABX-88A-1.047 owes ree Opwewor: ESESsmonissmnnn. rE Goes Gmepimes ee A mpm wm Bap Spe Cp epnt 001339 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-301 Page 115 Ree an TE wr Our ESRE o" ne. 1 ee serSR eeeAAUR Ae 4% 4 AT ARAW le 130 a 7X 1% 18. 7% ve immm D E EE eE e RE C e --_-- e N n sas aaaa 001340 primateWorcs ProjectNamber: PABX BA Page16 418-018:PAGE1-302 [pe sper eganes o NetbookReam: PARKBOA1-47 Cpe. reSETR, apacsomann wn 7 fo FT rive ---- 001341 mt oso Pr Nbr FARKBA i a T serenT e = 2X ion fia QIBisDwocsPass Bea. (RTE epsacer) ng 418-018:PAGE 1-303 oh FIP:riaP saryars T NE ME REFINE MET -- a hen oper Ee oN NN ] 001342 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-304 Page 118 Peak Area Report NemSoamFootnam:e P0AS6CSGEOAU0RS8E oreh= ens: 1301654. smm2ets cwomipsiues Dwngom wmo sgTimme Symp etenee rtprtntri. 001343 medics WorraessNuembrerPABXBBA 418-018:PAGE 1-305 neo cri 50 sgcnis n ws n 7 ttt AE iammen TET prides QTE? Da moosn ena swan x78 Invegrater) i" HEEE Wr hee HE ; |! - -- a a-- N -- he 001344 Primedica-WorcesterProject Number: PABX-BBA 418-018:PAGE 1-306 Page 120 Peak AreaReport Samm crm [om STLaBA DTAPASACOA 11 Parr meas Gmmpies Inga mo spam sme 001345 pimetinWorcester Proje Number: PABXBBA sHueeie NvsEgmSEmTaSABsyurtonsp TIsATfe=eWs 1 EEE BI ros pE a san (TE dntegacor) 418-018:PAGE 1-307 Peis = I Fa EEE i A = TTeTTe Te Ta Th TeTe EEE Te Th ee 001346 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-308 Page 122 EI EmsEmmren a ---- o NotebookReterwnce: PABX-BBA-1.047 Operon: LT 001347 `Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-309 Page 123 QL EEenemE as er serrcor = FONar rt NI PII TN El ppp | EE EE MEME EY | i ---- Pe Re -------- o _ N]| rE 001348 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE I-310 Page 124 PoskAres Report @ SsaT n ta:IsRR oons fdae730 ar S Seb HA EnD T papaE s0 none ree 3 Eo moa oon To 011585 ret 001349 Primedica-Worcester Project Number: PABX-BBA. 418-018:PAGE 1-311 Page 125 F fH oe EBumS am RT2Ho, it or LTE SE oarssa. 47 nope El Ege EEE ER TE TE 3 O len tkie h wRgnTbTE e ihTh vA ik e 76 Th kh i i TR E e ee The ee 001350 Primedica-WorcesterProject Number: PABX-BBA 418-018:PAGE 1312 Page 126 PeakArea Report MonsSoanmpRlenam:e:P08A6B3SSBRAO1U0P1LD omh3Seq0o1822 etSbebTo IHo NATBSBB,A upeasaronn veer coms compe DED by mmm tie [R---------- rien e 1 1558 oe 001351 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-313 Page 127 ie EE 00 pTLA bien TE Q oT T Ria ivoomspeass = Ssea.xa(RaTEgSateszacr or) m my YE I Ee HAA ouE Eh th hh ETEp Th Te The Th Th Th RiE AN TEva weve vee aTaohehTa eh we 01352 Primedica-Worcester Project Number: PABX-BBA 418-018PAGE 1-314 Page 178 Peak Area Report NoteanmRoneamee: 1P0A4S8SGARONU4P1ED ueA rrc1e832 tortJbeibor:oABC5ARRS ei com2ets cowmapste: Inwgeom beim tage oe ekei et lpnrd et rp 001353 PrimesWorcesterProject Number: PABX.BBA 418-018:PAGE 1-315 Page 129 fcEreyrtm e135a ApmR nyBRELTEiSttael 4er PR a mmm ome 1 EEE AEE h Ee RT WErN gp eer eee)! ee A ee E fin e See) _r _E ___T N E 001354 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-316 Page 130 Peak Area Report [SSeamtvart: nezanroa1o onhSema 301022 em heda e ame:SSAr AABTBAPAPABLEBA1L.am vrtS me3ts Comopn u Tm[ pulERm] eme Ee 001355 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-317 Page 131 E ErgeEoomE mmAes S5Era O-- S DE mn, a ee peT r m I F< ee E A e T_ e ae_ e 001356 Primedica Worcester Project Number: PABX-BBA 418-018:PAGE 1-318 Page 132 Peak Area Report Y NomsoSoakmRo oamse 1A5C85S3A50OUPT50 [= ------ nanBantam: ABBCarne AB 101. was omn Gme3nge wGmimpsiies Immoowwsm em=i tne oemn oe enn strt gt pe eed 001357 `Primedica-Worcester Project Number: PABX-BBA 418-018 PAGE 1319 Page 133 Sas ie ve SpA Ietl 46 FE Ter (ERIEou ux or cmrcn ee py mmm mm EI EE Te TR TRE ESE RE RE A ET re sn Ee cence, NN ET ER Ee ee em | I E EE h EE mm | 001358 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1320 Page 134 PoakArea Report [IRmlcalnees85GvReOrUPED [=e ] r i SATA en -- Gome2sur cwoimpsies Ie mgw tmmel biggie 001359 Primed Worcester Project Number: PABX-BBA 418-018:PAGE I-321 Page 135 fWBeri | SRTEREB ED B2 EEfs Q 2 T ERmE s ne 0 seen | el i eeRT raga eerBe a : EERE in ww eeak se em em aw Tm rw rm vm ve vk jw tn ve tm | 001360 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-32" Page 136 Peak Area Report NotSremRaenare:PSpAsRsGOSUPL56SS ornAEcurda 1001951 atC aod aeF PAGBsBATP ACABEABK: BALSA,hase imo6 feng3pedt Cnwmpegte DeE fel H oMmimE Salm 001361 Primdica-WorcesterProject Numbers PABX-BBA 418-018:PAGE1-323 Page 137 oBaongEeiTe Lvl0mEApEDEs IISYRiuYla 08 QFeTE EE eoa ns sua cer sero mere rie.$10 6 6X 8% Slo $8 670 6a 2 30 76 16 TN 3 140 180 2 IN 1M 18 : I Nh FoTET PRE resem seems} C e _------ N ee 001362 Primedica-Worcester Project Number: PABX-BBA Peak Area Report 0 I SereR me vE cr 418-018:PAGE 1-324 Page 138 onfom2m0 i10 emm3ete coEnEmponm Demool afn team bE fr---- re 001363 Primedica-Worcester Projct Numbes: PABX-BBA i 5 sRmte wee g wt wen EE B E O E Ea EenEr x x scmrom 418-018:PAGE 1-325 Page139 m ee im r on e rrred Ta rarTaal TE EE e E e ee Te Te TR) 001364 Primedica:WorcesterProject Number: PABXBBA Peak AvenReport PR sepium sao 418-018:PAGE 1-326 Fage 140 [ =a-- 3 oe rE 3 001365 to PBA Eada TE QL EfT os pu spar ta 418-018:PAGE 1-327 re ET Ta TEE TE Thie 1h TETkTe 1a Te in RE i Ee @ my ENee i TE TTN PET T | TEE ak thE Nn aeThTe ve 3s aTe te hE78 | 001366 rms WorseNabe: PABBA 418-018:PAGE 1-328 re 162 Pakhren eon PRE RST miEos er EEE O 030 N pnppAmssOAT maa coms mp SE 3 om og ree reepa mer et 001367 rime WorProjsetNtoh PARKBB gEreo RmEp gEEC o QTE HeSAi NE 00a 8\PALn E BRAN (RTE. Integrator) set 418-018:PAGE 1-329 ST Le TERETE Th Tete teTe 7h T7 h Th Th TeRL o e ee m e RE ] E | -- EEE easneE s E E E 001368 Primedica WorcesterProjectNumber: PABX-BBA 418-018:PA1G33E0 Page 144 PeakArea Report serene oncrcini10 ot3o110 RLSeBrAPASAa 11. met fem3mes mEpai IgwnolEn oBaEAmE fms 001369 pmsWorcePrsojecttNuembrer:PABX BBA ie sg QTE Ea moos pane sax (RTE Tacegrator) | - 418-018:PAGE 1-331 --_ : FEI ar -3 ar TE TI ENE EEIETTT ia SE \ i| i Cem PSXEBAR The Jan Li 5:08:30 01 Tage. 001370 Primedica-Worcester Project Number: PABX-BBA 418-018PAGE 1-332 Page 146 Peak Area Report Sametam: tsar 50 ue Aegina 1301130 ean eedoenresSASAKEBBAATAPABPABKEBA O1 hen vb} Semp2mar Gwmmspem Dmw jlelRB meoammtc mae 001371 Primedica-PrWojoecrtNcuembseer PABX-BBA EsRTinA o sa m sn Bis QL DREears, 8 spent 418-018:PAGE 1-333 Page 17 ror wm E rE e a 472072.0 PARK BRA. ' The dan 280 0mis 2 rage 2 001372 Primedica-Worcester Project Number: PABX-BBA 413-018:PAGE 1334 Page 148 Poak Area Report Samm: ser eA 2011150 menT ono: SASSIASATAPABPABKEGB1A,S banm on3 Som5est cwmmipstiun Dmelomwm EMEeR MER ATon er ot atrn rtnt . tO rc1811508 uae 001373 Primedica-Worcester Project Number: PABX-BBA anscacion prs at svievas fsEiaEerile oahvetDBIIAaPEPAR GESSfpeecVakls. QR imG oosanas san (E sosapracon) 418-018:PAGE 1-335 Page 149 bre F a CNEE ME ME MEME MM I-- o Tar SeeimLee | J\ | cones megs a ane 001374 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-336 Page 150 Peak Area Report NomsSamep nhaen: 10B2L5O5O0A010011150 onAoc r1301 1210 fomgpect hr ewepitas Ime) Bein Beimhe er rnot re pn rr en. 001375 Prmedica:WorcesesProject Number:PABX-BBA 418-018:PAGE 1-337 Page 1st cs rite 3:0 TABRA I -08 OT UI Sia 20 damn TE er Q BmE DT corms rsan wa r sneprcon mmm rrswoaga momo --- :i femmes aN T ETEGE kae R 1% sk3kS TR 7%EhS ve vE e tk iR h ik S th No ] | --T--R----E--e---- v--kieTe veThe aTavs aA! 001376 Primed Worst Prjct Number PABX.BA 418-018:PAGE 1-338 rae Pereahpkrt oo -EmmEE ss arss, eSn ER 001377 riesven rfcoe: PABBA mrs rte rN TE LST SE ennasn x sepsis ers 418-018:PAGE 1-339 Seg meee Eee * SAT BE EE| Beery EEe N e- 001378 prime WorcProsjectNumber: PABX.2A 418-018:PAGE 1-340 rage 15s Pree kor 0 IspEp EE gEiSon wi e I... 7 = WEE 001379 prWmorces dProjeiNumnber PABXBBA 418-018:PAGE 1-341 Page 155 awHpoe {RISnEEILDE AR 1S0TEl QL IT rans a spon fee gl AR VR te TR NEAR Gk Ge 7% Te vmTw Je ve ue in 0 ue Hrep TA eEy EE !| NN RT fTTeeee ih ee o TTT Mme BO AN | e ha e Re E RTe) 001380 `Primedica-WorcesterProjectNumber: PABX-BBA 418-018:PAGE 1-342 Page 156 PeakArea Report [I Sumpwianae:i1tnCeAOtLP)IISO unAScnme: 13011340 atoBu raeaaome PoAAeBBBAATAPABASOAS mear n te omet7ST Com2pas eo Gmpoesnm Tmmilno) mgm mesamic Spies onei et rt in ed re 001381 | Primedica-Worcester Project Number: PABX-BBA waresescion wore tus ives sa rie sive opamp mane tas 7 HER TE LEESIE Sey nrivoos\ pax saa. x (K72 Toeprator) 418-018:PAGE 1-343 Page 157 a PARRA TREEEE ERR E ERAEE EEE 001382 `Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-344 Page 158 Peak Area Report MombSoonkoebrNaanri:n P1A16B25SGR8A0MUPOU1T11 ou AOpanicar.1i3011:330 am sHuaaaPldie aHemarem::D4PA7n UB1KD0.7.88O0AATAPASSBPAA4E1X1 hanraikmanmaabraernS7nT compost pcpiues a ws ISIE wm rem mete om ua Te rn i oe eos ed gnvo ted1 nn. 001383 Primedica Worcs Pret Number PABX-BBA 418-018:PAGE 1-345 Page 159 SJBatARSSELRA IEtriSuiEtE] i ET EsE no gan sos oh =e re | hoa fr Rg E E E R a RhR hhhE 001384 Primedin-Worcesie Pret Number: PABX.BBA 418-018:PAGE 1-346 Page 160 PearsRpt 0 SsEeRnmcEe msEgs ra mTERIER apacssmann, nS Ct mee Sw meme te 001385 Primedics-Worcs Project Number: PABX-BBA A PAuTsEmRmonfiy A RES Br. QL ES emma, wr spre 418-018:PAGE 1-347 Page 161 -- I ET eh Te TR TE TTR TR RR a, m E e A emR ee N CAREan sk aeeh wm ik vm 7% ih in Te im te on vevm) 001386 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-348 Page 162 Peak Area Report o MoSmasmaenan:1B0O3O30N01051711 [Se o e tnobebTeihamn:SAOSESO00ATAPABPABLABA O1 etvvikPmoet80 foamels cemmpgues Dafa Mm tmuma tame 001387 ' Primedica-WorcesterProjectNumber: PABX-BBA ustication agers ux revives oHra iEle R0EASRISE AIAGS\IO.ETViy n 80 HRT Koma. ce snrcon 418-018:PAGE 1-349 Page 163 . Te e TET TE u ih ie ik i T Toe E eE e T ETR E S uhne Aiha g Te 7h t7heVe ThTeenvh e kea @ 1 oN I! TERE kak eh iw we7h 7a7h ve 7h i ve Th vee 001388 PrimeicsWorcesterProjectNumb: PABXBBA 418-018:PAGE 1-350 Faet6t PereaRnpkrt sega secre wTerEaASacssmoon. enTeRrSs 00139 Primedica-WorcestesPojct Number: PABXBBA sin Pres 1g shiny 7 oo Bo QT I wv jn se sgn Eewl 418-018:PAGE I-351 Page 165 [rrr a re eS0 orar Ee TeeU RR EEITRe TReeROeR ) Ewe a ReeAREEee Rea 001890 Primedica:Worcester Project number: PABX-BVA 418-018:PAGE 1-167 Page 166 Guanettacion Report (@7 Reviewed) @ af EuceEaRPile p D:i WDDAr TA\BnABiIPeARK.BYAVS-062-10624087.0Si_pevcaiialt:tsf5ta2] SATE?DIREEons pamova (R78 Taceseacor) pettt ee [= f i = I | P= i i = Th I | B[riiar TE BS iw se --i --eo--e--m am e A B RE Th 2 IE Te Th Te Ih tk J P mT Fermoy e . ede TN Em Tye gha e } xeon. on : h0. || ! JA | ERE i TT re ceracsno mamma Wea occ ab 13:38:08 2000 nase 2 001391 `Primedica-WProorjeccetnsumtbeerr: PABX-BVA 418-018:PAGE 1-168 Page 167 PeakAreaReport Nobo`Saemoranm:P2AB rOkVWAo1t062 omSAcrtnuaa a082300123 ar GeHiaFde FiienhaPamamn c::cADsMB0t S8DB8DV0AATAPABPABKEVANO1E, nnueVuim e mmia ar:5507 Gomands 2 Commitems is Dee) km Beam Pmtsmss om : PoC nd Tn: 101020001258 woes 001392 Primedica:Worcesies rojct number:PABX.BVA 418-018:PAGE I-169 Page168 Guustitation Repore (07 Reviewed) @ suSFeoncrrtatieFile +hD:\eWSDDaAT PABa\PARKBVAVA-O621\0G21058.DB_Tperciiissdt:! i58an f 15 tacee grasion L pacuss: wrapC SOE S---- p a n i eras \ P[om oi it A i| i ofMAVoLm"-ysJ NTN A I A fo TR et end QE a Ee a AA ee NN { fear 13576-0001 Ji HE I ! A il | A TER EWR ee vk TE Te Te TS Te Te Te i Giricse0 PBIAN Wed occ 18 13:38:ae 3000 noes 001393 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-170 Page 169 [-- sm tg ER EEmrsrnSERS tomTes co=mpte ER g=oaa tye 001394 Primedica- Worcester Project number: PABX-BVA 418-018:PAGE 1-171 Page 170 Gunticaion Report (@F Revived) DBEartaaEtFile +IDB:\EARSD_EEATA\BwASat\ARK.BVAVA-063-1\OGZAOS0.D.S_moeresViiaolet:] es5a3x @u: 1a5 tntEegeRaciSon parAarmie:maKTEIeNbE.cDos\PARKBVA (RTE Tacegracor) rr a i 1 | | i pe E EEE EEE W+ fia ne otYou . A i : meanw'"AenTee Al| ou ea nae: Be 1 {Reps 2 | e t eeI | (a a me ee ee mR 0621059.0 PABLIVAN Wed occ 10 32:58:47 2000 rage 2 001395 `Primedica-Worcester Project number: PABX-BVA. 418-018:PAGE 1172 Page 171 Peak Area Report NoSammbp ramee3A55S70A1 T06 Oepri cmzn eo08 nareDsaTHepmoatpmaoeePSoAAcARSStSYAATAPARSABCOOV2AL5 mmnVeemma0ST me3as cwomismslum ImWg)om eaets Deimee 001396 Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE 1-173 Page 172 | | (uascitacion Report (GT Reviewed) @ isTBaotrE=atiNePile + DB:\WiSDe_DAnTaA\cePeRrBn\IARK-BVAVL-062-\GG210K0.DST _ouraVtioae rl!s s0an 48 xacL ugracion ri orsas: FTn EWIENEE0S\t PARE_BVA. (R73 Incegrator) ------ { nl | ! [LBne] \{ |: Po Ju i fTiene 45 EH Tw oh ah GE iE a 4k Te. 6 TH 1h Te 1k TE TR Te tm Tain 1 LE brore me corms m eTrmeine R m7h 2m 7sm1k 753%ik th 1 ika is ! naoaant a0ss crs eee A y1i iee J i\ A || aiih a nih TB Te TE Te 6 7k TE TR TE GGra060.0 PABKBVAN Wed oc 18 12:89:08 2000 nage 2 001397 `Primedica-Worcester Project number: PABX-BVA 418-018:PAGEI-174 Page 173 reeumrem -- -- EERrEEsE ns wSe a RE 001398 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-175 Page 174 - I Ouaseicacion Repors (GT Reviewed) af EcaRPa ill DE: MCSDDRATAPhAeBeNPreAtRyK-BYAV1-062-1\0G21061.0_S_ZpacosViioarrl:: nf1an [ Fra 15 imcreseraacion pS agane:ORTEUR TEISOSE \FABCL BVA. (372 Sncegeacor) fr jMI eones nET orE TSER R A m TE } TRR TT TIRT Ta 1| i A : it ] P fnfoaoa anm: iSdE oneT3601 EER ee EE E-TE R e L ssT me T ee--!i |! |I i hn | erem essa EEE ocaono mmxman wes oct 16 12:59:36 2000 [ 0013<9 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-176 Page 175 Peak AreaReport Sang me 32STO ountot ren n Re e Hm emASSSCBBAarnes avALIE, mV or R femm2eds cowmpste IwRMowln taang Sai 001400 `Primedica-WorcesterProject number: PABX-BVA 418-018:PAGE I-177 Page 176 cuiscitacion Report (QT Reviewed) @uEDoSatnal"File+N DS:a\AeR GeDiOaAoTn\naPAcBe\rsPiAaRnX-BVA\E-062-2\0623062.0STpEeVciasl:ita6a2r 1a5n1eatRegEeEaStEion tB acama: TLe ENEEOS\Pi ASXBVA 0 (RTE ntegiacor) |- I | of /i ] | | T|aoreefssopn6:3013363035.63%38070E 4 Eew E FNE Te Tw Te Tm Ee ie. W-- iE Eyf mE et | =] = = . ! io me JA - | ho ee ek es en Im Tw Th 1% 1 rv ie oen062.0 BmxBAN Wed ocx 28 12:59:47 2000 ge 2 001401 -- I" 418-018:PAGE 1-178 PO mm -- -- a nervea Se a -- ABATPOVAABPABCOV0A5La7 net 5 001402 Primedics-Worcescs Project number: PABX-BVA 418-018:PAGE 1-179 Page 178 Guatitation Repore (G7 Reviewed FY DEacaRrePa ie DEi :DEr DATPAr B\BARX-BUAVL-062-1A0621063.0_Sgpeeeiiesrl:: fa3n f15 lmtesracion Furams: wEBNT. pg er -- {= i | = ii 1| pReyeTS EERE > ET Er TEs TE R EEeT |i ii | I i ESI a i ih woEeTh d/\i iATe Ea TeWAe T)|| sean: sees 1 i! ifi | bera e E ome oh Re |i Geri0es.0 eRe IAM Wed oct 18 13:00:06 2000 roe 2 001403 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-180 Page 179 PeakArvaReport o Seon ToSwe oom pontro 030 ar CEeem PLPe :SPADn E.BSAATAPADPABCOVANISZ Warum Vem bs m2t Gwuasm Seton TTaeo am S=m Slime 001404 Primedica-Worceser Project umber; PABX-BVA 418-018:PAGE 1-181 Page 180 uicacion Report (@F Reviewsd) fF suoca PhiR e +ay0:E \= SD_DATAr \BASNPABK BVMA-062-1\0621064.0SEp_eervViinr:! 5a4 Qu: 1E 5 tnceT seacion pD aramea : xTESDoIEnS s aa ova. (x7 Tocessaton) fr _ = A | I gv] 3 I | ho Nn TPrheoss4A 11051000.030 8 i ER tw3 -- TuI1V- 7E% Te im 161hIm iE | fs i | i| i ER RR oi Tr ;! | ; 1 ifn |! Ii . i Li ie i ie aRmam we 7% 7m 7k Te 16 Te im am GGRION.D PABKIVAM Wed oct 10 33:00:36 2000 [ 001405 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-182 Page 181 PeAreaaRepkort NmsaRmoArama:15T08 tm ems:mct 00 PL SLs SATAPARPASS VANES, mame6 Gomg3eds Coingnas soni Io mim Ba5im Shieh 001406 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-183 Page 162 Gumsication Report (F Reviewed) ouDfI aocaraPE ile ED:a\WED Dr AE TA\PAaBi \ErABE.BYR\A-0G2-1\GG21065.DSZpeenivtisall]: 6f5ax 15 ateEsrRacEion E sacams: wrLm EME.F2IoDS\Pi ABE_BVA.M (RTE Tategracor) ---- TE + {Po ows ifA || Lo i | p=E TE EEE T EEE R i \ E RE| f[iainee: er Ra|ping: 600 i| i1iA\l _| . raap: sr N 85 i N li | _. JAN J eR mee Te 134 te 7a Te eh RTE cirioesD PBAVAN Med oct 38 13:00:45 2000 nse 2 001407 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE I-184 Page 183 Peak Area Report Sams 32STO Onto rz 1038 naCmEMeeTo3S ,SC ATAPABPADCOUALOE te iemet r66 Sem2mes compeinles Dmw iiel oBw aim tame Pr a ee 18001200 moet 001408 Primedica-Worcester Project number: PABX-BVA 418-018:PAGE 1-185 Page 184 Quancisacion Repore (07 Reviewed) Fi0lnlen DfE acaoridae n m0r\yD_BAgTA\aPiABr\PtABK-BVR\A-062-1\0G21066.DS_p_oerreaVtieat:]1f8a26n [ kE 15=inteT gracion sSacaesel: xIrREoE3se rex ava (ee zoceseacor) fr | myf ioe I i . A i | feoa [T se arnE n = T T . RRo| nJ FeSTE \ TSTR ER TETR ThE R T T8TE -- T i| i fi | J | erEp!:i656s a a Ge WJ 1 i i 1 dN i In on se sk ie an sm am Tm 7% 7B 1% Te7HTE1% 7m 1m OG2I066.0 PASKBAN Wea Occ 18 13:03:04 2000 nage 3 001469 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-352 Page 166 Peak Area Report MotaSamRienra:c1P0A1SGOIOL0PI311 umA-- cqua1301 008 eCm EeoTsie a an:SPDAr AATBAAPARPABLEEGAUT, harman Compost eT Cmptte Inge) gm temic belie imeee rr rn rd nt nd. 001410 PrimedicaWorcesterProjectNumbes: PABX-BBA furceie oeme R mncuscitAacis oon rprsTRO6LSfvoiYntie:s8 TI ERIE, te sracnt 418-018:PAGE 1-353 Page167 1h = rg eeAB oe a.NNTE a ee Ta Thev ve Ee ae worse maaan i an oe 001411 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1354 Page 168 Peak Area Report MenSoamRoeann:2PA0BCBA107 reh= ue 19911509 et Bataomm SASoGEASTOAAPABPAXAOB0I1, mareVo11 Comaets comwsipsuum Immmomjg twumml meee 001412 `Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-355 Page 169 E H2 ii E nLSRTpEaEmAr ss er5t0L [= Method : Di\KPCHEN\1\METHODS\PABX_BBA.N (RTE lategrator) i a EEE a r ir e ee EEE R EREEE R RRR 001413 medicaWorcester Prot Nuhr: PABXBBA 418-018:PAGE 1-356 Page 170 PeakAraReport 0 IEEE. hd meESI S arT cane, enERR pt sone EE gy ene sg 001414 Primedica-WorcesterProject Number: PABX-BBA. afaieide op B myi IMAA COS IDIarTevtehy 36 ETI ERTS rons so e revraers 418-018:PAGE 1-357 Page 171 Fo AseTT Tara a TeThee | TR fo, : Wiper aA i C ar r ea 04NGEN PARE ERAN ha Jan 18 14:49:48 2000 - Page 001415 Primedica-WorcesterProject Number:PABX-BBA 418-018:PAGE 1-358 Page 172 PeakArea Report saree scomor medine 201 1540 rumenO atABT F0ADATAPAEP PARK BAL meena1 fmmaei cwoimepen InNe e Bo tw mink Baie 001416 rimedca Worcs ProjectNumber:PABX 3B SSBig Er EEER yeteSEeeltli QTE STevI o sn 8 regener 418-018:PAGE 1-359 Page 173 fois wm ae akak AT Gh ak re Th Th rh Te 7 Te Th TRTH Et p-- Eee em ee TTR an ve wk i| N ih ak ww vk iu 7hvs 7s hk aimm7 e h) 001417 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-360 Page 174 Peak Area Report seo oom 2 160 nnerSomiat he:SABPR.SEAATAPABPAAIROK av ev r"0 omnes comgpmum Imi in emi olin J TS -- 001418 Primedica-Worcester Project Number: PABX-BBA Eacrsei EVDEE REE asesaeS son topeesTL0SrTwervieinte,s 8 QTE IE omar sn srs 418-018:PAGE 1-361 Page 175 Ooor ar ao ria h Svar try tt oR Fh mrE ea Thiea e TE eh heR Ee E ReeeT RE 001419 PrimedVorPsrojecstNumrber PAB BBA 418-018:PAGE I-362 rage 16 [y---- ees og an EE mass snSE TM Em FIT 001420 PrimediaWorcesterPojct Number: PABX.BBA e sitea50eSm+ curAatoe tr 0vet-ank h9g I TmEee rmsn tripennr 418-018:PAGE 1-363 Page177 = mien ER eedanaR Ge sRhn 0 Ge TeTH Tk 1BTeTe im IR TR Deo hn TT ESS ae eh A = bo IE i Lek ae el alo ak em am aw vi sw ik iw ve 3% im rh im Th 001421 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-364 Page 1/8 Peak Area Report MotaSumRpenraene:2P1A5B7B0A 067 ounA orc100e 1 1600 er LEAT SE TAALS101 mame r meats cmwmapstam Dwanomwm taan unt 001422 I. rn 418-018:PAGE 1-365 @HaT fei -- 1h spa rR memy oN JTEET Ee ih eT h Th hiE eTh Th Th i Th TTT 001423 Primedica-Worcester Project Number: PABX-BBA 418-018:PAGE 1-366 Page 180 PeakArea Report sommes oweAcne01 1700 eCr eo toaa P PBAt CSSEBCAATREABBSALAOB71K, menVimo1 mme5lr wcmnmgium Inwgo e Emme Bim 001424 nS FASTA Fgeratoe:ga cin wesSmEa EE Roosman tr sepa 418-018:PAGE 1-367 -- A eee a Tr | os ETE re EL re emt I TTTTR 001425 Primedica-Woicester Project Number: PABX-BBA 418-018:PAGE 1368 Page 182 Peak Area Report NosesaRmpmle.:2P1A57B0B5.A1067 DueA=o]: 201725 rmaCEepiep:o GABSSSBCBAATAPABEABCO0O1N, aiver5 coment comptes Ini) wm team Semsm 001426 `Primedica-WorcesterProject Number: PABX-BBA OuncicacionReport (07Reviewed) Sars ile | ove SAA T oeNEE ED Vial: 33 ERT TE (QBee EwRomenBsRrReer rrros pTa.ee (RTE sSnege racor)x 418-018:PAGE 1-369 Page 183 -- ee aoSR4 akan A uk se1ThTh3%Tl3hveTn7H Te rr mrMe88 creeper o Em s We aiEke hak iE 38eh 7h5h 76TETR 7h th TE E TE ehEar Ae eh 001427 Primedica-Worcester Project Number: PABX-BBA 418-018PAGE 1370 Page184 PeakAreaReport smmeteziee J ope: 1 170 mme3ls mwaege ImEgelEBohm sume Tr trer greed [r------ es 001428 priWorcms PaoetNemeber:PABXBBA E SseLAg PH oviE s treR s sppiin?s OT HR ma ene ee ren 418-018:PAGE 1-371 Page 85 tne _ RR Th th TR Th oe ve Th TR TE TE Te TR TE TE Te ey I E rE e Nh e 001429 Primedica-WPororjeccteNsumtberr: PABX-BBA 418-018:PAGE 1372 Page 186 Peak AreaReport NoaSurRo s2P5A7HS0a7 1047 oe ha i: 1201 48 maneemThPoemACSESDABATAPABPASKBSO4A1I, memes omm3etr wGeomspie Iwoihol mWo teomm Mamie 001430 Primedica:Worcester reject Number: PABX-BBA 418-018 PAGE 1373 Page 187 oSmrpcetrie RBHiuS Ym Em A [ER r07eC GR ST-- uEckSivts:h 30 - E A E DTT mrs, sons sve a r ETe 1 gp tek heth Eee ee EE 001431 418-018:PAGE 1:374 3M Medical Deparment Study: T-6295.25 aM Medal Deparment Study: T-6295.25 Analytical Report: FACT-TOX-169 LRN-E01-0180 Anaiycal Feport: FLAACNTET0O1X0118609 Study Title DeitnerthmeinMaetviaolnoonficthAeciPdr/eCsheolnecsetearnodl CCohnaclelnatnrgaetiaonndoNfOPeErLfiIuncvreosotcitgaatnieosnulSftoundaytein(RPaFtOsS) Analytical Laboratory Report Title Determination of the PresFelnucoeroacnhedmCiocnaclenintrRaattiSoneroaf SPaemrpflleuso.rooctanesufonate (PFOS) Data Requirement Not Applicable Author 3M Environmental Laboratory Study Completion Date July 06, 2001 Performing Laboratories Sera Anaiyses Sera Extactions: 3MEmirormentalLaboratory PaceAnayicalServices, Inc.--Tier2 SuitingS2t:9P6a:u08l,M8N35B5u1s0h5Avene 170M0eEmemapSoilries,!SMEN5S5u4i1t4e.100 ProjectIdentification 3M Med`iAcraglusDIenp-aLirltemSetnutdyS:tu4d1y8:-T0-168295.25 3MAnLaalybtoircaatlorRyepRoerqt:ueFsAtCNTo.TOX0-11-061980 Total Number of Pages 68 30 EnvronmanialLaboratory 3M Environmental Laboratory 001432 Paget Page 3M Medical Department Study: T-6295.25 `3M Medical Department Study: T-6295.25 418-018:PAGE 1-375 Analytical Report: FACT-TOX-169 LRN-E0I-0180 Analytical Report: FLARCNT-ET0O1X--0116890 `This page has been reserved for specific country requirements. 3M Environmental Laboratory. SM Environmental Laboratory 001433 Page2 Page? 3M Medical Department Sudy: T-629525 aM Medical Department Stay: T-6295.25 GLP Compliance Statement 418.018PAGE 1376 Analytical Report: FACT-TOX-169 LRN-EOL0IS0 Avalyical Report: FRAiCET0TrO.X0-118609 Analytical LaboorSfaatmPoperlryefslR.ueoproorotcTtiatlne:esufDoentaetremi(nPaFtOiSon) oFfiutohreoPcrheemsiecnacleiannRdatCoSnecreantration Study Identification Numbers: T-6295.25, FACT TOX-169, LAN-E01.0180 "AdTmiisnsitsutrdaytwioans(cFoDnAd)ucGtoeoddinLacboomrpaltioarnycPerwaictthicUeni(tGeLdP)StRaetgeuslFatoioodnsan21d CDrFuRg Part 58, withthe exceptions i the buleted is below. Exceptions to GLP compliance: + fTohretrheewaenraleyttiwcoalspthuadsyed.irTehcteorisn-fforetshtisudsytupdhya;soenwafsorctohnsidanrfedpthoaseenadnadttohnee generation and shipment of specimens. The analytical study phase was tceocnhsniidcearlepdetrofostramratnactethoef areaccehippthoafstehewsaessepneicailmyenssefpoarraana,lynsoise.feScitnc5e the + `Aeuxtpoemcatetdedfrdoamtathcisoleexcceipotniosny.stems have not been vaidated as required d`aactceo.rding to 21 CFR 58.130(c). Thehardcopyprintout is considered the raw + dTehtersmtaibnietdt.y of th reference standard and intemal standard were not DeannaJ. a f, M.S., Study Director WarWving. Case, DV7MG. PRO. Sponsor Represeniaive Cate { TBaotres 200 Kisfteinb. HL ansen,. Ph.D. P-- rincialAnalical Investigator uDnatee C2) Wikr am K. Re agen.2 Ph.D. Laboratory Manager aM Environmental Laboratary 3M Environmental Laboratory CTaaiso s7or 001434 Page Page 3 SM Ml Deparment Sd: T25525 SST 418-018:PAGE 1-377 Anais Repo: Fa ACTTORA9 J--m-- s `GLP Study--Quality Assurance Statement AnsysLarTTsroenoerRespsorctaTiels: onD me (Pe ESfPht evPorecsa enhceeanmi odsCioSnocarnn taton Sty denfcatonNumbor:T425525FACT TOX-165, LANEDLO180 TtGAae tRmos EapTchnoTn 8tTne ngiiersa roSnayn ange [r|o ee mepe ris] [ow|evor w[ aww [em | eo we [amew |somone | om[um [om| |omi|momo|s cwz [ so ewn| [mors |own[soon |seem | Sesmsee r z gr*!e sanm------ IM Environmental Laboratory 001435 [- Page 4 418-018:PAGE 1-378 3M Medical Department Study: T-6295.25 3M Medical Department Study: T-6295.25 Analytical Report: FACT-TOX-169 LRN-E01-0180 Analytical Report: FLARCNT-T0O1X--0116890 Table of Contents GLP COMPIANCE SIBBMENt cvvrrrsrnsstetnsmssssmens3 GLP Study--QualityASSUTBNCE SHAIBMEN eens SHUdY POrBSNAOCONMNDUEIIOIS..vvntnsssinnsnes LiLa SS -------- TOS SYSIBM vrs SPECIMEN COIIECHON BN ANBIYSIS ...c..coerrrennmirsns `SPECIMEN RECEBPN! MBINENANCE snesd `Chemical Characterization of the Reference SUDSIBNG ..............wmerens 10 Method Summaries. ----------------------_| F PIOPATRIONY MOOE G... rrr --nn--n----11| LL ------------------------------ Data Quality ObECtves and Data INQ ......ursvsssmersssmnesn: 13 Data SUMMary, ANALYSES, BN RESUS...covercoersssssines snes: 18 `Summary of Quality CONE! ANBIYSES RESURS......cresmenrrss1s4 SHEBMEN Of DAA QUAINY rrr 14 SUMMAIY Of SAMPIO RESUS... 18 StatMetihodssatndiCaIcCUIaBIOlNS uence15 SHAEMENt Of CONCIUSION. rir ES ---------- 1 AppendiAx: CONEO!MaIaFNdTIesCtATeCISE.......coovntines snes 16 ADPENGX B:PTOIOCO! BNA DEVIBHONS..corresrrnsrsen sens 1 Appendix C: Extraction and Analytical Methods . --) ETS-8-4, Extraction of Fiuorochemical Compounds from Serum for Analysis Using HPLC-Electiospray/Mass SPECtO(1M6 PEAGNE,S).........vemesmessss: 31 ETS-8-5,Analysisof Potassium Perfiuorooctanesulfonate or Other Fluorochemicals in Serum Extracts Using HPLC-Electrospray/Mass Spectrometry, (11 pages) ............. 46 J------ J---- J-- Jc -- J ---- 3MEnvironmentalLaboratory 3M Emronmental Laboratory 001436 Pages Pages 418-018:PAGE 1-379 3M Medical Department Study: T-6295.25 `3MMedicalDepartmentStudy: T-6295.25 -_-- List of Tables Analytical Report: FACT-TOX-169 LRN-E01-0180 Analytical Report: FLAACNT-ET0O1X--0116890 `Table 1. Female Rat FO Population Demographics for Study (Argus 418-018)...........8 Table 2. Characterization 169. of the Analytical Reference Substance in Study FACT TOX10 Table 3. Target Ions Monitored in 3M LaDOTRIORY ARISES... 12 Table 4. Determinations of the LOG in the Analyses of PFOS EXIACS ........... 14 `Table 5.FCAhaCrTacTteOrXizAa1tiBon9oc f the Contre ol Matrices s Used fos r Sera Anae lyses in Ss tudy 16 `Table 6. Charactorization of the Test Article in Study FACTTOX-169........ccceumrees 16 `Table 7. TOX 169 Data Summaroyf PFOS Concentration--Rat Serum (ug/mL).......... 57 3M Environmental Laboratory SM Environmental Laboratory 001437 tages Page 6 3M Medical Deparment Study: T-6295.25 9M Medical Deparment Study: T-6295.25 Study Personnel and Contributors SDteuadnynaDiJr.ecLtuoerbier, M.S. B3uMiCionrgpo2r2a0te26T.o0xi2cology (Medical Department) St.Paul, MN, 55144 Analytical Chemistry Laboratories. S3oraEnAvniaryonsmeesntal Laboratory OM Lab) KInivessteignJa.tHoransen,Ph.D. PratAnaycal 418-018:PAGE 1-380 Analytical Report: FACT-TOX-169 LRN-EOI-0180 Analytica Report: F(ARCTEDTOIX0.18609 S3pMoCnosroprorate Toricology B3uMilMdeidnigc2a2l 0D.ep2a0r2tment MSta.nPianulT,.MCNa,so5,51D.4V4.M., Ph.D., Sponsor Roprasontatve SPaecreEAxntarayciticoansServices, ne. Te Facil 3M Lab Contributing Personnel LiRshaoAn.daGDliocmke"n MHaarrollednaO.M.JoHhenysinogn" BKooblWJ.. (WKyunsnhiewein) Swartout" cantapss cnones Location of Archives LAlalboorriagtionrayl.rTahwedatteai, parrtoitcolceoal,ndanadnaalnyatliyctailcraelfreerpeonrctehsatvaendbaerednraerscehrivveedsaamtptlhees,3MasEwnevilraosnmtehnetal sLapbeocriamteonrys.pReretsaeirnviengstaomtphleesanoafltyhceaclopnhtaoslearoficnesansdiuvdeyhaircloeacrochmipvoendeantttshae eSMstEonrveidraotnmtahental testing facity (Argus). aM Environmental Laboratory SM Emronmental Laboratory 001438 Tage? Page? 418-018:PAGE 1-381 `3M Medical Department Study: T-6295.25 SM odeatDepartmen Say T428525 Analytical Report: FLARCoT--ET0O1X.-0116890 Arce AECT TsO:o160 Introduction and Purpose Th purpos ofthe stu is 0 determin th presence and concanaton of pEeerafmlumoiraotocitoanneosfutlhionPatrees(ePnFcOeS)anidn rCaotnsecreansraamopnleosf tFaakoenroinoaccacnoercdauntcoenwaitths (08) rns the 3M protocol, SSMaeeorvrnaelaaaotnlaitacsteAaecisadf/oowCarhlooaloesimtrearmoolaBCohFoalSmplsebanOygedoraaPnaldgaaewNvaOal:EgsLe oTaIfhnnvmedesematinsagatsmtiioaofnShSaotenrudSdSgyhsianpoRiwantawsgs."saFodeamoaoslaermFwpsOlienBse VPaEsGSmGaasesd, aawmailalnayt2o0b0e7r cute tog PFOS ns onsemed fet ove (NOL To sy TF TeosrtsSyosttem ngs atwars Sop Biotr Tae 50. POEM A.SS-- tCreouoSsr eo.Ciaommd9m52o1anr8swwpeoreorstvo sooepmabtaaaitonoP,EnhOdedcssoom,innF0go5Da%olTuwegitndao32(0te1snrreoBsee,oedier SSomeer htaomt Sesvearea aGoo)upo.ddoo+p4o5satosaar d(aiGooartaGnoveerrsaAogveo move `The test system species and strain selected was the Cr:CO*(SD) IGS BR VAF/Plus rat received ftiraoicmoOCrhasyaroflF2eOsgaRoitarverroraLt(aMobaanoerratT.tsaobrliwfoeesrw,eeIrenecr.nitpeaArcmaniGehntLlSyati2daegngtai.f.i1edSuGstainn1dgaaotMvnonaetfts seweelfrw-epeieeercsnivnagdbeoalraensd Table 1. Female Rat FO Population Sotpetai DemografporhSitucdsy (Argus 418-018) I I ee -- [mO ee T S cnaigT emosrmemroncerss | [ [Coomse mm[ |u8&| G |oa mmrmrmoo esws.eoms e||m [omer |enmrrossoome|n [a Tw m |e osmomgrs ros | [omw omo en 1o 2T 1 osmmomrgprsos || [ oommeeG rn T T | = e w| 1& e iozemmeomtmT agren rerosos || 001439 PaB M Emmnms enaitaboo rages Pages 3M Medical Deparment Study: T-6295.25 3M Mocical Deparment Stuy: T6295.25 418-018:PAGE 1-382 Analytical Report: FACT-TOX-169 LRN-EO1-0180 Analycal Report: FLAACNT-T0O1X--0116890 Specimen Collection and Analysis pInoohleedanraaltyttiecralsswteurdey sreenptor0tedthheeareM, 2E3nv5isrearnamesnpteacliLmaebnosractoolrleycatenddfaonamlyfzeemdalfeorFPOFaOtSs.aTnhdeF1 pnruemsbeenrteodfbseelroaws.pecimens collected for analyses in the analytical phase of this study are Specimens Collected from Study Groups 1 through 13: `SSeerraa SSppeacciimmeennss----5544 ssppeecciimmeennss ((FF1O pFoeomlaeldesl,eGr,D2G1D,21C,aeCsaacrseaarneasenctvieocnt)ion) ``SSeerraa SSppeecciimmeennss----4798 ssppeecciimmeennss ((FF1O pfeomoalleeds,tedra,yd5ayof5laocftaltaicotna,tinoant,unraatludreallivdeeriyv)ery) BElnovoidrosnpmeecntiamlenLsabwoorraetocreyntfrriofzuegneda.nSdeornumcrwyaisce.then harvested and shipped to the 3M `mSeetrhayis-afmaprtloeustyw!ereteheerxt(rMaIcBtEe)d.bSegaimnpnliengexotnra0c5tsFweebrreuaarnya2l0yz0e1duussiinnggahnigiho-nppraeisrsiunrgerleiaqguiednt and crhersopmoantsoegmroanpihtyo-reilnegcmtordoes.prPayF/OaSndleemvemlasswsersapeqcutarnotmietattreyd(bHyPeLxCt-eEmaSlMScaMlSib)raitniotnhevemrulstuisplaen extracted curve. Analytical deta are included in this report. Specimen Receipt and Maintenance TLahbes.3MAllEsnpviercoinmmeennstawlerLeabroercaetiovreydrfercoezievnedinrgatosoedrcuomndsiptieocnimoennisycoilcleecatnedd awterAergiumsmeRdeisaetaerlcyh ptraacnkssf.erArfeedrtoexsttroarcatgioenaatt2T0ierC2,t1h0esC.peScpiemceinmseannsdwtehreeetxrtarnasctpsorwteedretoroPtaucmeeTdicoeldfroonzecneopnacikces. ``Ccoonmtmreorlcmiaatlriscoeusrcuessedanidn sareeraparneasleynsteesd pinerAfpoprmeenddduAri(nsgeTeOTXa-b1le695)w.eSraempoblteasinaendalfyrzoemd at the 3IaMboErnavtiorryonamte-n2t0alCL1a0borCa.tory wil bo maintained for period of 10 yoars and wil bo stored ai the 3M EnvicnmentalLaboratory SM Exsironmental Laboratory 001440 "ages Pages 3M Me ------- dical Department Study: T-6295.25 418-018:PAGE 1-383 siGa R Analytical Report: FACT-TOX-169 Chemical Characterization of the Reference Standard R ointmoR irnnoeSrroRtees sorlos (KPFOS) es Sop See TT rewwwswmwon | E=i[ = ===e it ene ea ze l [[SCmoemcmomoinm| s| Fe omr mee[w Ese| [=[er[own | [Prveesbocrion| Wtocytatopova | whaspowder | SwEps--_ ow 1 w=7 Ww] 3M Environmental Laboratory 001441 cage 10 418-018:PAGE 1-384 IM Medical Department Study: T-6295.25 `3M Medical Department Study: T-6295.25 Analytical Report: FACT-TOX-169 LRN-E0I-0180 Analytical Report: FLARCNT-ET0O1X--0116890 Method Summaries Following is a brief description of the methods used during this analytical study by Environmental Laboratory. Detailed descriptions of the methods used this study tahree 3loMcated in Appendix C. 3M Environmental Laboratory PREPARATORY METHOD. + ETS-8-4.2, "Extraction of Fluorochemical Compounds from Serum for Analysis using HPLCElectrospray/Mass Spectrometry" Analytical serum samples were extracted using an ion-pairing extraction procedure. An ionpairing reagent was added to a laboratory sample and the analyte-ion pair was partitioned iEnatcohMIeBxEtr.acTtheed MlaIbBoEraetxotrryasctamwpalsetwhaens rreecmoonvsetidtuatnedd pinut1.o0ntmoLoafnimterotgheannoelvaapnodraftiotreruentdil dry. through a 3 mL plastic syringe attached to a 0.2 um nylon filer into glass autovials. AmaLynca MeTHoD + ETS-8-5.2, "Analysis of Potassium Perfluorooctane-sulfonate orotherFiuorochemicals in `Serum Extracts Using HPLC-Electrospray/Mass Spectrometry" `The analyses were performed by monitoring one product ion selected from a single primary ion characteristic of aparticular fluorochemical using HPLC-ESMSMS. For example, molecularion 499, selected as the primary ion for PFOS (CaF1zSOx) analysis, was. fragmented to produce ion 99 (FSOx). The characteristic ion 99 wes monitored for quantitative analysis. `3MEnvironmentalLaboratory SM Environmental Laboratory 001442 Page 11 Page 11 418-018:PAGE 1-385 deci Dparmen Sy: T25525 SAAT asi Repos FjACTETONA [RwE s itm eoomer Tooling eesti fingadung th anaphaseofsy. Liquid Chromatograph: Hewlet-Packard Series 1100 Liquid Chromatograph system CL PT DS i CeorE otF8$ nrnEeh o, ky=Ewo422eaes Analytical column: `Keystone BetasiiTM Cy, 2x50 mm (5 ym) F CMasstSpet ecTtromeiter:eMtcroSmaosvs APUMass Spectrometer Quattro I" Triple Quadrupole system [[SroemRasn2kreeintttemaRoenctan o11r0o 4 ST ros os ws Tweros | 70 | 500 001443 Em ro: 3M Medical Department Study: T-6295.25 <M Medial Department Study: 6295.25 418-018:PAGE 1-386 Analytical Report: FLARCNTE-OTOLX--0116890 Anaytca Report: AeGoTt.TOoXi-1e6o9 Deviations Deviations from the original protocol and methods are included in the Appondix B. Data Quality Objectives and Data Integrity he folowing data quality objectives (DOs) wara indicated in the protocol for tis study: + Lweiingshatriknyg:.The coefficient of determination 1) equal to or greater than 0.990 using x. + CLailmiibtrsatoifonQcuuarnvt,adteifoinne(dLOaGs)t:heThloeweLsOtGstiasnedqarudattlhoatthie blootwhesttwaoctcismpeisabtlheesmattraixnbdlaanntrkhdaend 1s calculated within 230% of the expected concentration. + A`Sclcaenpdatracbsl,eprPorveicdiesdiotnh:eyQuaarleitqyuaconnittraotlesdawmpilnestahreesreelqeucitreeddctaolmbraasttio2n5r%anpgree.cision + CshoonuflidrmbaetwoirtyeMne.thods: Ifa confirmatory method s used, an amendment o ths protocol + DToetmoonntsotnrmateio(naopfprSopxeicmiaftieciltyy7:3PFmOinSutiedse)n.tbfyictahieonchweirlabctoesruibssttcapnrtiimaatreydiboync(h4r9o8m)aatnodgrtahpehic characteristic product on (99). Data Summary, Analyses, and Results LDaabtoarqautaolriytyproobtjoeccotlivfeosrfPo ACthTeTaOnaXl-yt1i6c9al(psheaesAeppofentdiisxs)tudwyeoruetmineetdwiinhthteheSeMxcEenpvtiiroonnsmennottaeld in his report. am EnvironmentalLaboratory 3M Enronmenal Laborator 001444 Page 13 Page 13 418-018:PAGE 1-387 3M Medical Department Study: T-6295.25 `3M MedicalDeparmentStudy: T6295.25 Analytical Report: FACT-TOX-169 LRN-E01-0180 Anaiycal Report: FLAACNTEOTTO-X0-118609 `SummaryofQuality Control Analyses Results Linearity: The coticent of dotermination (1) of the standard curve was 20.990. Caalniablyrsaitsi(o1nxSwteaingdhatredds):ofQuaannteixttartaicotnedofratthseotraargmeattarniaxlcyutrevsewrausn bparsieodtrooneancehagrroruepgroefssion `lsinaemaprlefst.oHvierghthoercluorwvpeoirnatnsgeonmtohsetcauprpvreopmriaaytehatovethbeedeantad.eaLcoiwivcautravdetpoopirnotvsiwdietah pbeetatkerareas tlheasts mthaaynhtawvoetbimeeesntshiatgnoifftihceanetxtafrfaeccitoendbblyanbkascwkegrroeudnedalcoivvealtseodf t1>hediasnqaulaytlei.y Oaccdaastiaonraalnlgye, a`Qsuianngilaetmiiodn-orfanegaechcuarnvaelyptoeinwtatshabtawsaesd aonn otbhveiroeusspoountlsieerofmoanyehsapveecibfiecepnrdoedauccttivlaotnedu.sing tMheethmoudlsti)p.le response-monitoring mode of the instrument (see Appendix C, Analytical LicmaiibtrsatoifonQcuuarntviet(adteifoinne(dLaOs)t:heThleowLesOtQvailsideqsutaalndtaortdhewiltohwinest3a0c%caopftatbhleethsetoarnedtaicradlivnatlhuee), and is at east two times the analyte peak area detocted in the matrix blanks. (See below) `Table4,DeterminationsoftheLOGintheAnalyses of PFOSExtracts + Blanks: Al blanks were below the lower imit of quantitation for the compounds of inerest. Prwehciicshiwoenr:ePrreepcriosdiuocnibwlaesodevtitehrimni2ne2d5%byoavnearlytshiesvoafliedxntreaactredracnaglei.bration check standards, InasstirnuglmeesnetruPrmecexitsriaocnt.: PInesatkruamreenatawlapsrerceipsrioodnuwciabsledetotewritmhiinne2d%b.y roplicate (n=7) injections of + sItnatnedranradlsS,taTnHdParFdOsS: wTahse niontteumsaeldstfaorndqauradni(laTtHiPoFn,OSb)utwwaassaudsdeeddttoomallosnamopolrresgraonsds. ihnastttruimedntnoftaivluarrey. mTohreestuhoagna2t5e0r%efsrpoomnsteheofmeeaacnhwaintahliyntiecaalchuannawlaytsicvaelrirfuine.dSfaomdpelteersmwiinteh dofevrieasnulttsn. to standard response were confimed by reanalysis and are marked in the table Statement of Data Quality Irteifsenroetncpeosmsaitberliealt.o vTehrietyontlryuemreeacosvuerryemofeenontfdoagcecunroaucsyaanvaaliyatblferaotmtthiissstuiemse,wietxhtoruatctreaddiolabeled csaelriabrcaattiaonacruerqvueasnatnidaimvuelit-oe2v2el5%coonrtignrueiantegrc.afbraton verifications (CCV), indicate that the 3M Environmental Laboratory $M Emuronmental Laboratory 001445 Pago 1s Page 14 418-018:PAGE 1-388 3M Medical Departmen: Study: T-6295.25 `3M Medical Departmen Study: T-6295.25. Analytical Report: FACT-TOX-169 LRN-E01-0180 Anaiyical Report: FLAACNT-ET0O1X--0116890 Summaryof Sample Results PFOS results have been comected for purity of the analytical reference material. + Samples from Control Animals: Low levels of PFOS were often detected in the sera of the. `control animals. These levels were significantly lower than those found in the low dose test animals. + Samples from Dosed Animas: In general, PFOS levels found in the sera of the test `animals increased with dose level. Detailed sampledatatables are presented in Appendices DandE. Statistical Methods and Calculations Statistical Append methods were F for example limited to the calculation of means and standard calculations used to generate the serum samgle ddaetvaiaitnioFnAs.CTSTeeOX- 169. Statement of Conclusion Under the conditions of the present studies, the fluorochemical PFOS was observed in the sera i of all FO generation rats dosed with the test article and in all F1 generation rats from FO dosed rats. aM Environmental Laboratory 3 Environmental Laboratory 001446 Page 15 Page IS 418-018:PAGE 1-389 304 Matis Deparmens Say: T-6295.25 54Mod DeparmentSy. 629525 Avalyieal Reporc FLACRTN-TEODX-11601950 AnayiclRAfCerTpiToOtXni16:d9 e------ErP err----T -- T Appendix A: Control Matrices and TestArticle Table 5, CharacterizationoftheControlMatricesUsed orSeaAnalysesInStudy FACT TOX-169 [Cr eormeoran 1| hwetwseuem ||EoTmwsT esun ||ERawie soown |[_|frwatesoernnme|| [oFwomseuotwasn| | Potosom || meowwsn|| Ftorosen || ioseeu _|| Table6.CharacterizationoftheTestAtle nStudyFACTTOX-169 [Te | pa osi etm ocaronts ioss__| TT -- CE-- [oemertomonee[aw ______| rm 1 so sw Emaonmanatabortay 3M Environmental Laboratory 001447 Papas Page 16 3M Medical Department Study: T-6295.25 3M Medical Department Study: T-6295.25 Appendix B: Protocol and Deviations 418-018:PAGE 1-390 Analytical Report: FACT-TOX-169 LRN-E01-0180 Analytical Report: FLAACN-TETOO1X--0116890 `am Environmental Laboratory 3M Environmental Laboratory 001448 Page 17 Poge 17 3M Medical DeparMmEeemnmitroSstnnunday:nTT-i62m95o.2r5 S00if8cc0asuman 418-018PAGE 1-391 Aaslytical Report: FACT-TOX%-169 a_i 3M Determinationofthe Presence and ConceenrtarsateioniotfePerfluorooctanesslfonate (PFOS) in the "MevalonicAcidCholesterol Challenge and NOEL Investigaion Study in Rats PHASE PROTOCOL 3M EnviroPnemrenftoarlmTiencghnLoalboogryat&orSaifeesty Services 3M Env9i3r5oBnmuesnhtaAlveLanbuoeratory St Paul, MN 55106 1P7a0c0e EAnlamlySttirceaeltSSeEr,viScueist,eI1n0c.0 Minneapolis, MN 55414 LabFoAraCtTo-rTyPOrXoNjuemcbteIrdeTnOtXif-i1c6a9tion 3M"ATrgouxsicIno-liofgeySSttuuddyyNNuummbbeerr4T1682-9051.825 3M Environmental Laboratory $V Environmental Laborators 0601449 Page 1019 Page 18 3M Medical Departmen Study: T-6295.25 418-018:PAGE 1-392 Analytical Report: FLARCNT--ET0O1X--0116890 ProtocolFACT-TOX-169 Determi`nMaetviaolnoonfictAhceiPdr/eCsheonlceestarnodlSCtCohunacdleylnetInrdgaeetnaitonindfoifNcaOPteEirLofnluIonrvoeoscttiagnateisounlfSotnuadtye (inPRFaOtSs) i the Sponsor 33MM CMoerdpiocraalteDeTpoaxritcmoelnotgy BSutilPdauiln,g M22N0-525E1-4042 `Sponsor Representative 3MaMrvCionrpTo.rCataeseToDxiVcMol.ogyPhD. 3BuMilMdeidnigc2a2l0D-e2p6a0r2ment STte.lPeapuhlo,neM:N(655511)47433-5180 Study Director Phase Locations. Principal Analytical Investigator (PAY Analytical Testing Laboratories D3eMaCnornpJao.rLauteebTkoexricMoSl.ogy B3uMilMdeidnigc2a2l0D-e2p6a-r0t2ment STte.lPeapuhlo,neM:N(65551)147437-1374 Kistn J. Hansen, Ph.D. 3M Environmental Laboratory B9u3i5ldBiunsgh2A-v3e8-n0u9e SU Paul, MNS5106 Proposed Phase Timetable AnalysesAnTaelrymsiensatSitoanrtDDaattee P1a7c0e0AEnlalmytSitrceaeltSSeEr,viScueist,eIn1c0.0 Minneapolis, MN $5414 JFaenburaurayry202,6,20200101 aM Envicnmenta Laboratory $31 Enaronmental Laboratory 001450 Page 2019 Page 19 3M Medical Deparment Study: T-6295.25 418-018:PAGE 1-393 Analytical EE Report: FACT-ET0O1X0-1169 1. sruoy DMeetvearlmoinniactiAocnido/ftChhoelePsrteesreonlcCehaanldleCnogneceanntdraNtOioEnLofIPnevresftliugoartoioocntaSnteusduylfinonRaattes(PFOS) in the 2. Pureose "FTOheganaelytincalefpehmaarsleoe afattsheitsxsptouisdeydoisednednsFiIgngeednteroaetviaolnuraattepleuvpeslpsootefntPiFaOlSliyenxspeorsaesdpetociPmFeOnSs ionf AInrcg.uTsieTrnI-iffeaSctiluitdyy.4A1l8l.s0e1r8a.sAalmlplseesrawsialmlpbleeaswnaillylzbeedeaxtttrhaect3eMd aEnPvaicreonAmnealnyttailcLaalboSreartvoircye.s Data quality objectives for this study ae indicated in section 12. 3. REGULATORYComPLIANCE "GThoiossdtuLdabyowrialtlobryecPornacdtuiccteeRdeignualcactoirodnasncfeor tNhoenU-cnliitneidcaSltaLtaebsoFraotoodrayndStDurdiuegs,AdFminiaslisRturlaeti2o1n CFR Part 58. 4. QuauTyAssurance "dTahtae,3aMndEnfivniarlornemepnotraotl LdeatbeorrmaitnoerycQoumaplliitayncAesswuirtahncGeooUndiLtawbiolrlaatuodriytPtrhaecstitcuedyRecgounldautcito,nsr,aw this protocol, and 3M Environmental Laboratory Standard Operating Procedures. 5. REFERENCE STANDARD FOR FACT-TOX-169 Potassium Perfluorooctanesulfonate (KPFOS), CiFirSOSK, CAS 2795-393 6. TesrSysTem Tehaicrhicgernoudpo,soengerboluoposdosfafmepmlaelewarastscowlelreecgtievdefnrtohmetsiexsfeamacleeFbOyoonradlay(g2a1voagfeg)esrtouattei.onWi(attkin CsiaxesFaIrpeoaonlseedctliotnrisng)o,n rdaoym2s1ixofgfeemsatlaetiFoOn o(natdCaayes$oarfeaanctsetcitoinon(iangf)e,r annatdurfarlomdesliixveFr1y),pofoolemd . ltihteeIrsMfrEonmvdiaryonm5eonftallacLtaatbioornat(oartye.rnSaeteurfaollldoelwiivnegryt)a.bTlehfeoreaadrees3cr1i2psteiroansopfelclimseanmsplsesent0 received. 3M Environmental Laboratory SM Environmental Laboratory 001451 Page 3019 Page 20 418-018:PAGE 1394 3M Medical Deparment Study: T-6295.25 Analytical Report: FLARCNT--ET0O1X--0116890 Protocol FACT-TOX-169 EE [m |oie,| tn Numberof Specimens per Dosage group and Dosage Levels dave Consarvan emt + FFPiofcwTooimmmpempprggrrrrrooosssT T s e ee ----s |_ T s _ s ||| [[FoirlfaatmmoemenmrrrrorsssT T T e6&1 1T o s 6 I 1--1 6 &os 1|| 7. SSePrEaCsIpMeEcNimReencsewliPllTbe received from Argus Research Laboratories, Inc. a the end ofthe inJainfde pwhearseeroenceJiavneudafrryo2z0en01on(edsrtiymaictee.d)S.peSceirmaensspewceirmeenisdewnetirfeiesdhwiiptphedsabmypolveernmuimgbhetrcsou(raiber rCpeeegqciusietsmeternendusmwsbietenhrtstthooert3hneMu3mEbMnevrEisnrvaoisnrsmoiengnmnteeadnltbaLylabALorargbauotrsoarRtyeosraeynadwretcrrhaenLrasebfcoeerrieetvdoerdtiacnasd,rteIrcnazcc)ekteufdpoorancsctroeocrreadigipent.g,Atlo {fhoer Sdaammapglee,Trreacceikpitn,gsStoyrsatgee,miSdteanntidfaircdatOiopne,racthianignPorfoccuesdtuordey. pDreottaoicloslosf,sapnedcdiamteanwiilnlspbeection presented in the phase report. 8. PREPARATORYMETHODS [`ECToSm-p8o.u4,nd"sExftrroamctSieonroufmPofotraasnsailuymsiPseursfilnugorHoPoLcCt-anEelseucltfroonsapteraoyf/oMtahsesr FSlpueocrtorcohmeemtmriyc"als Arneaalgyetnitc=alasdadmepdletos aarleaeboxrtartaocrtyedsuasmipnlgeaanndont-hpeaiersiantg eexftornacptaiiorniprpoacretdiuiroen.eAd ninitoonM-UpSaEii.nTghe IMaBboErateoxrtyrascatmipslteheisnrreecmonosvteidtuatenddipnut1.o0nmtoL8onfitmreotgheanneovlapaonrdatfiolrtueartedilthdrroy.ugEhaach3 ecxat'acptleads.tic: syringeattachedto 80.2um pylonfilter ntoglass autovials i 001452 am Environmental Laboratory : 53 Ensivonmental Laboratory Pago als Page! 418-018:PAGE 1-395 3M Medical Department Study: T-6295.25 - Analytical Report: FACT-TOX-169 ProtocolFACT-TOLXR-N1-69E01-0180 9. AwauynmcaL Memioos [ETS-8.5, "AnalysisofPotassium Perluorooctanesulfonate or ther Fluorochemicls in Serum Extracts using HPLC-Electrospray/Mass Spectrometry" AniaonlycshairsaictsepreisrtfiocromefadpbarytmiocnuliatrofrliunogroocnheeoamricmaolreupsirnogduHcPtLiCon-sEseSlMeScMteSd.fFroormeaxsaimnpglleep,rimary `fmuorltehceurltaoriproond4u9c9e,sieolne9c9te(dFaSsOt)h.epTrihmeacrhyairoacntferoirstPicFOioSn 9(C9yFis1rmSoOnyi-t)oarneadlyfsoirsq,uasnftriatagtmievneted `analysis. Minor modificationstothepreparatoryandanalyticalmethodsmaybeimplementedatthe discretionofthe PAL 10. DATA QUALITY OBUECTIVES 10.1 Linearity t"Thhaenco0e.f9f9i0ciuesnitnogfLdx eweitghteingr. (*m) oiftnheastatndaird cournve must be equalto orgreater 10.2 TLhiemiLtsOoQfwiQlulabneteiqtuaatlitoonth(eLOlGo)westacceptablestandardinth calibrationcurve, dweiftihniend+as3t0he%olfotwheestesxtpaencdtaerddtchoantceinstbroattihon2.timesthemat blankand iscalculated 103 A`cQucaelipttyacbolnetoPlrseacmipslieosnare required to meet + 25% precision, provided they are quantitated within the selectedcalibration range 10.4 UFsaecofoConfnirmfamteotrihyodMirastuhsmoedd,saanamtendomeart oyhis prowtillobecwroitiln. 10.5 'DPeFmOoSnisdterntaitfiicoatnioonfSwiplelcbiefiscuibtstya,nteitact.ed by chromatographic retention time (approximately 7.3 minutes), by the characteristic primary ion (499) and the characteristic product ion (99). Minor modifications to the Data Quality Objectives may be implemented atthe discretionofthe PAL " 3M Environ3m0eEnntvailrLoanbmoernattaolrLyaboratory 001453 Pagosors Page 22 3M Medical Department Study: T-6295.25 418-018:PAGE 1-396 Analytical Report: FACT-TOX-169 LRN-E01-0180 ProtocolFACT-TOX-169 11. SPaUcBe-ACnOaNlyTtRiAcaClTSEeDrvAiNceAsL,YISnIc.S(Tier I Facility) will be performing the extractionofserum spLeacboirmaetnorsyfofroranaanallyysseiss..APlalceextArnaacltyteidcsaalmSpelrevsiwciesl,lbluecs.hwiiplplefdotlolotwhaell3aMpEpnlivciarbolnem3eMntal EAnnvailryotincmaelnItna.lLSatbaonrdaatrodrOySpetraantdianrgdPOrpoecreadtuirnegs.ProceduresandthefollowingPace PSS-Admin-01 PPSSSS-.ODPCS.-00S1 PPSSSS--OOPPSS-0023 PPSSSS.-OOPPSS.-0054 PPSSSS--OOPPSS-.0067 PPSSSS..OOPPSS-.I038 PPSSSS--OOPPSS--1156 PPSSSS..OOPPSS--3312 EPSTSS.9O4PS0-37 PSS-MTR-01 PPSSSS-MMITRR.0026 PPSSSSIMMCT-R0.108 PPSSSS..ADRMC0-032 QLuaabliNtoyteSbyosotkesm, Logbooks, and Phone Logs Use and MaintenanceofUla-Turax T25 Homogenizer HRaazwarDdaotuas Waste Disposal UUsseeoafnCdoMmapirnetsensaendcGeoasfeNs-iEnvtahep LAaubaolryattcoarly Evaporator CUlseeanainndgMNaoinn-tdeinsapnocseabolfeNVAoNlOumpeutrriecIPTiWpaettieersPurification System ULasbeoraantdoMryaiCnatlecnulaantcieoonfsLabRefrigerators, Freezers, and Ovens GUlsaesaswnadrMeaCilnetaennianngceofthe Fisher ScientificIsotempFreezer UOpseeraatnidonM,aiMnatienntaenncaencoefSahoadkCearlsibrationofLaboratory OOppeerraattiioonn,aMnadinMtaeinnatnecnea,ncaenodfCaSlhiabkreartsiaonnodfVpoHrtMeexteMrisxearnsd(p3HMESlOecPt)rodes CCaalliibbrraattiioonnooff CCeerrttiiffiieeddTWheeimghotmeSteters/Thermocouples VVeerriiffiiccaattiioonnooffCCaalliibbrraattiioonn oafntdhUesEepopfeAnndaolryftiPceatltBoarlances DPuircshapsiongsoofifLAtarbicohroisvnteorMyatSeurpipallises Statistical EvaluationofData 12. STATISTICALANALYSIS . StEaxtiasmtpilceaslomfetthheodcsavliculllabtieolnismiutscedd iontthheecaanlacluylsaetsiowniollfbmeeisnacsluadneddsitnatnhdearpdhadseeviraetpioornts.. 13. RAerpepoorrttoftheanalyteresultswillbepreparedby 3MEnvizonmentalLaboratory.The report will include,but mot be limited o, the following, when apolicable: 1133.:12 NDaatmees uapnodnawdhdircehstohfetphheasfaeciwliatsy pineirtfioartemdinagndthceompphalseet.ed. 13.3 A statementofcompliance by the PAI addressing any exceptions to Good Laboratory Practice Standards. 001454 3M EnvironmentalLaboratory SM Environmental Laboratory Pog ols Fage23 418-018:PAGE 1-397 3M Medical Department Study: T-6295.25 Analytical Report: FLARCNT--ET0O1X--0116890 ProtocolFACT-TOX-169 13.4 Oabmjeencdtmiveenstasntdoptreocoerdiugrienaslaphsatsaetepdroitnotchoel.approved phase protocol, including any 13.5 Identity, purity, stability and thesolubilityofthe reference standardunderthe 13.6 cAonddeistciroinpstoifonoadfmtinhiesmtreatthioodn.s used to condtheutesctst). 1133..87 AAdedessccrriippttiioonnooffatnhycsipreccuimmsetnasn.cesthatmay haveaffectedthequalityortheintegrity 13.9 oTfhtehneadmateao.fthe PAT and the namesofother scientists, professionals, and supervisory 13.10 Aperdseosncnriepltiinovnoolfvtehdeitnrtahnesfpohramsaet.ions, calculations,ooperations performedonthe actoan,clussiuomnmsadrryawannfdraonamltyhseisaonfaltyhseeasn.alyticalchemistrydata,and astatementofthe 1133..1112STthateisstiigcnaeldmaentdhdoadtsuesderdeptooretvsaolfuaatcethhoefdtahaei,nidfivaippdluiaclasbclieen.tistsorother professionals 13.13Tihnevloolcvaetdiionntwhheeprhaesrea,iwfdaaptpaliacanbdlteh.e phasereportaretobestored. 13.14 iAnsspteactteimoennstapnrdeapuadrietdsbwyetrheemQauadleitaynAdstshuerdaantceesUonfiatnlyisftiinndgtingesdraetpeosrttheadttostthudeyStudy DirectorandManagement. 13.15acIcfeitpitsende,cetshseacrhyatnogmesavkielclobmeemctaidoenisonrtahdedfiotrimonosfa1naafmienanldrmeepnorttsaufterdibt yhatshbeeeSntudy aDmierencdtoerd.,Tthheeraemaesonndsmfeonrttwhielalmcelenadrlmyenidte,aatinfdywtihlepbaersoigfnteh biyntahlereSptourdttyDhaitreicstboeri.ng. 14. LOCATIONOFRaWDATA, RECORDS,AND FINAL REPORT Ofraciigliintaatledaautdaitosrocfotphieesstthuedryeodfu,rwinigllibteparvoagileasbsleaaatd3beMfoErneviacrcoenpmteanntcaeloLfatbhoerapthoarsyetroeport. `bWehleonwtwhiellphbaesreetraeipnoerdtiisnchoempalrectheidv,esaol fo3riMginEanlvpiarpoenrmdeanttsa,liLnacblourdaitnogryt.hoAsleltceormrseslpisotnedding tprraoicneidnugrreesc,ocrdqsu,ipcamleiabtraptrioocnerdeucroersd,s,anidnsmtertumheondtsmwaiilnltbeenarnectaeilnoegdsi,nstthaendaarrcdhiovpeesroaftitnhg.e 3M Environmental Laboratory. 14.1 Tahcecforodlilnogwitong3rMawEndvaitraoannmdenrteaclorLdasbvoirlaltboreyreSttaainndeadridnOtpheersattuidnyg Pforlodceerdiunrtesh. archives 14.1.1 Approved protocol and amendments 1144..11..23 SShtiupdpyicnogmreescpoordnsdence 14.14 14.1.5 RApapwrdosvtead final report (original signed copy) 14.2 14.1.6 Electronic copies ofdata The following supporting records will be retained separately from the study folder in the archives according to 3M Eavizonmental Laboratory Standard Operating Procedures: 001455 +EnvironmentalLaboratory 3M Emiranmental Laboratory Page7oto Page 14 418-018:PAGE 1-398 3M Medical Department Study: T-6295.25 Analytical Report: FACT-TOX-169 Protocol FACT.TOLXR1N6-5EO1-0180 1144..22.21 TCarliinbirantgironeceocrodsrds 1144.22.34 ISntsatnrduamrednOtpmearianttiengaaPnrcoeceldougrses, Equipment Procedures, and Methods 15. DATA/ SAMPLERETENTION A`lmlaistearisnpedecbiym:ensremainingatertheazalytcalphaseiscompletedwillbesent 0and D3aMveCoErbpvoerastmeanToxicology 3StMPCaeunl,teMrNBl5d5g124346-0C-148 TFealxe(p6h5o1n)e7(367514)775343-5070 16. PROTOCOLAMENDMENTSANDDEVIATIONS PSltaundnyeDidrcehcatnogreasntdtthheeSpprootnoscoolrwsiRlelpbreesiennttahteifvoe.rmAofwmritteenanmweinlddlubmeemcaotnsessiidgenoreeddtbaystpshaert oinfdithceaptreodtionctohleapnhdawsierlepboerta.taAcnhyeodtthoetrhcehfainngalesprwoitlolcoble.iAnltlhcehfaonrgmeosftowtrihtetpernodteovcioaltwioinls,be: signedbythe StudyDirectorandfiledwiththe awdata. 17. ATTACHMENTS 17.1 AMattetraiaclhSamfeetnAyt:Data Sheets (MSDS) for Reference Standard "M EnvironmentalLaboratory SM Enviromental Laboratory 001456 Pace srs Page 73 3M Medical Deparment Study: T-6295.25 18. SianaTuRES MarviWn T:iCasse, sD.VH..TPGhoDr. Spomsor Represeaaive 418-018:PAGE 1-399 Analytical Report: FACT-TOX-169 Procol FACT-TOKRRYED1 0180 3 ape eSetar. Deanna Jw . ml `Study Director Date TKrl isteneJ. Hans-- en, PRD. Principal Amalyieal bvesig0aD1/ai2e4/o01 r M Envionmental Laboratory $31 Emarommental Laboratory 001457 Pago9ers Page 26 418.018:PAGE 1400 3M Medical Departmen Sudy: T-6295.25 Analytical Report: FACT-TOX-169 LRN-EOL-0180 Record of Deviation T identification 'seidFyACpTra-gTeOsXi-N1o6,9,~ Li# ~ 0m1-01s80,Argus418-018 Tee `Deviation Type sor `0Method [J EquipmentProcedure TT (Checkone) XProtocol [J Other: : `DosimenNumber Daofewemme FACT-TOX-169 z Ti Descrip0t2i/o0n1/:01 "Theprotocolsafes that 17speciiicnsWl be veveived of G6EBvROmRGIALaboEry. Ac2t3u5aslpePcirnosecnesdwuerreelrpecreoicveedsis:i_ EnvironmCeanbotriaorly. TW Actons Taken: Co (sasuamecndmhent issued, SOPrevision, etc.) ee --TT RecordedBy ~~ TTT "hae - On A one os/avln IV. ImpactonStu /Prd ojeyct NoWverse pactontoeouicome Of hs stay. errvarert rpm+. on fir Sree "4 05/24 [0 Autchoroizemd iByn(Stu7dy Direectolr /yBroject Lead) SpodeTRaepcuanteDheo. oMobovlCase. Moin : TG I EonvmirEon5me0n3tL0ooratry np SM Environment! Laboratory DSaateat) 3115 500 by SyDicerDePvieatiLondHo8. 001458 TT) Page 27 418-018:PAGE 1401 3MMedical Deparment Stuy: T-6295.25 Record of Deviation T Taentication Analytical Report: FLARCNTE-DTLO.X0-118609 "Study/Project No. FACT-TOX-169, Lims # EO1-0180, Deviation Type' OSoP (Checkone) OProtocol 418-018 _ _. VEquipment Procedure 0 Other: ETSs42 DocumentNumber ~~ I DescrDiap2et(ios1n):o5-fo2c02o1u/1m0e1nce | TRyeSqueicreodnPr1o0c-1e2duaren/dpro1c0e1s-s37 regarsFrwater DnsGd 7 ats Ds or Ge dy [2)SesionI1..4 Preparesnd spike one standardcurve for cach study. 32))SSeemcctetiisooennqu11a11l..11..o22tDhonosoastmpexlatemrvapocltleluvemoseslsti.hmaensa0r.e5meLsof amantr1i.x0. il, vac andar witmiax AScohxvPartoecstluarcnlkpraoncedsss:x lodIk wereS88 0 oh igs Fisof Gls 3) Fouexacted cirves wer prepared - hice with iil nd ral volesof03 mi and "onewith initial and final volumes ofL.OmL. S3i)mFMpoalrneyovssatmposlesalwemru0e sep3xhmterelaitcLfteooeerdfiwvirsitahlwe,aanvsoinliiautvimaaelagibvnlofelo.hurmmHaeottliweoesnvs,etrh,anC0a.v3esmLH.eRresfTeorrtPortehpeaarettaochields.| nialo finalvolumeunder0. mL. Co _(ouchas amenTitl.imAecnttiootnusedTaSkOePn:rein. st) This Geviation was wien. -- Reds ow Kelly Swann KUM TVDiomnpaactAonnSh7iPrdojeyct { c221/01 22), 1&2)AddifionQaClisiimproveamndewillntnot adverselyaffecthss tudy. | 4l3e))shTBheicsaauc0so.eu5rntsmheeLomfweiatlholobdneifswanolsttcaahakigrenactbgtheeecredaiauzsaeded.tfhoer rvotlhuomedsa<0.n5tmLb,eseacmphle=as with initial rted For volumes cxvac<ibomnLs. Robustnes ofthecurveswilntbeadversely affete. | EN ------ --&rh02/22/01| |ATuibEoFraximzoeSdn4By0(,SbmoiudryeeDirrweictloer /Projeci Lead) pio sty DeDD as iTai Ga . me s 001459 5M Evironsmheandyt DLaubeorcaktoryFre Ocsens bude fhainwar glllutrtin Ho 0 1 Poge 22 418-018:PAGE 1-402 3M Medical Deparment Study: T-629525 Record of Deviation Analytical Report;FALRCNT--ET0O1X--0116590 1. Identification 771 __ SudyProjectN_ o.-- | DeviationType (Checkone) Sop r T OE Freie OProtocol Other: fs L 5A O ~20/ I. Description: Required Procedurclproces: | (| GaPstmatiisne deFoduc1e2ost 2Turlitlzasts sobPrterrud t t Linfaean | als a mn edocs arr] ActualProcedurgprocess: [Zpo lcone Tcmsei 0 bjt Zc Ga i a oiDomkainotdsl| _ (suchas amTil. eActniisosndusedTm,SakOeePnr:envisiton, ec) - ap r ap ieLSLarpteosanetes tmap r eecrmDa sahesoson iilllplling olyyyly,TA at cfiovT il For Recorded By Prk Kleoe I = Vi ay TPrejact TR advo apple pn ofleaa | Date A-N 20/ RuinedBy (SudDirTecPtorrgealead) Dw T= ijEviromenaethe bToresoCrfor Sway Ts De Dros TA 2 btytes p(rsTiAcpssemoriims.0 | 001460 $M Envronmental Laborators Page29 418.018PAGE 1403 3M Medical Department Study: T-6295.25 3M Mtcal Department Study: 629525 Analytical Report: FLARCNT--ETOO1X.-0116890 Analytica Report: F(ARCvTET0O1X0-118609 `Appendix C: Extraction and Analytical Methods This appencix includesth folowing methods: EETlSe.c8t-o4s.p2,raEyxMtraascstiSopneocftlrsoomreotcyh,e(m1i5capalgCeos)mpounds from Serum for Analysis Using HPLG- `[ESTeSr-u8m-5E.x2t,rAancatlsyUssiisnogfHPPoLtCa-sEslieucmtProesprrafy/lMaussoSrpeoctorocmettoyar,On(t1h1eepsraFglueusot)rofchoemnicaaltsien 3M Environmental Laborarory Co141 Pege 30 3M Medical Deparment Study: T-6295.25 : 418-018:PAGE 1-404 Analytical Report: FACT-TOX-169 LRN-EO1-0180 3M ENVIRONMENTAL LABORATORY ' MerHoD EXTRACTION OF FLUOROCHEMICAL COMPOUNDS FROM SERUMFORANALYSIS USING HPLC-ELECTROSPRAY/MASS SPECTROMETRY Method Number: ETS-$4.2 `Adoption Date: 03/01/99 Effective Date: 3/2| ! Approved By: pl ff Laratory Manager. Ube tH Group Leader oofbafey Date asoi/er Date L0Scoreaaveuica00m00o 00y 00 1.1 Scope: This method is forthe extractionoffluorochemical compounds from serum. 12 Applicable compounds: Fluorochemical surfactants or other flaorinated compounds. sk g13 w Matrie ces: Rn abbit, ai, bovine, monkey, and human serum or other fluids as designated in EgeQ20 suwwarvorMemop 8S72.1 Tsheilsfopneartfeo(rPmRaOnSc)eboarsoetdhemreftlhuoodrodcehsecmriicbaelsstuhrefapcrtoacnetdsufrreofmorseerxutmra,cotirnogtpheerrluuiordo,ocutsainneg-an 8O:le thioen spaamrpilnegarnedagetnhteaannadlymtee-tihoynLpseirr-biurpayrltiettihoenre(dMnBtEo),MBAEn.TonhepaMnIBgEreexatgreancttsisade 10 G10 Q removed and put onto a nitrogen evaporator nti dry. Each extract is reconstituted in @3, 1.ofm0ethmanoLl, thenfilteredthrao0.2uhmgnylhon filterusing a3-mLplastic 001462 2ard695 ExvacionofPEusTrsoc8he4mi2cals fom Serum Page 10115 3M Environmental Laboratory Page 31 3Md Medical Department Study: T-6295.25 418-018:PAGE 1-405 Analytical Report: FACT-TOX-169 LRN-EO1-0180 sdyermionngsetrianttoedg:laPssFOaSut,ovPiFlOs.SA(,AppFlFiOcaStAiAono,fEGtFhiOsSmEe-tOhHod, PtoFsOeSvEenA,flMuo5r6oc,heamnidcaalssuwrarsogate Standard [see3.0Definitions). 22 Thesesample cntse sre follwing method ETS3:5 oer sppropr 30 DeFTIONS 31 PFOS: perfluorooctanesulfonate (anionofpotasium sak) CiFisS05TM 32 PFOSA: perfluorooctane sulfonylamide CuF:sSONHy 33 PFOSAA: perfuorooctane sufonylamido (ethyacetaeCFsSON(CHiCH,)CHCO 34 EWFOSE-OH: 2(N-ethylperfuorooctane sulfonamido)-etbyl alcohol (CuFSO:N(CH:CHyCH;CH:OH 35 PFOSEA: perfluorooctane sulfonyl ethylamide CiFnSOMN(CH:CHyH 36 M56: CoFnSON(H)(CH:COOH) 37 Sumogate standardTHPFOS: 1H-1H-2H-2H perfuorooctane sulfonic acid 40 WamnmesawpCavmons 41 Health and safety warnings 41.1 Uhasnedluinnigvearnsailmparetcisasuutei,onwsh,iceshpemcaiyalcloynltaabionraptaotrhyogceonast.s, goggles, nd gloves when 50 INTERFERENCES rr-------------------- 51 There are no interferences known at this time. sOEouewesr 6.1 The following equipment is used while performing this method. Equivalent equipment is acceptable. 61.1 Vortex mixer, VWR, Vortex Geric 2 61.2 Centrifuge, Mistral 1000or [EC 6.1.3 Shaker, Bberbach or VWR 6.1.4 Nitrogen evaporator, Organomation 615 Balance (01008) 70SUAND MATERIALS meer 71 Glows 7.2 Eppendorofr disposable pipetes, plasticor glass (or equivalent) 73 Polypropylene bottles, capable of holding 250 mL and 1 L (Nalgene or equivalent) Exracionof FuEcrToShe8n4s2cals rom Serum ez 30 Emironmental Laboratory 001463 Pages: 3M| Medical Departmen Study: T-6295.25 418-018:PAGE 1406 Analytical Repori: FACT-TOX-169 LRN-E01-0180 74 Volumetric flasks, glass, type A 75 40mLglassvials(-CHEMorequivalent) , 76 Ceniuge tubes, polypropylene, 1S mL. P27 Labels 78 Bottk-top Dispenser ~3.01t0 10.0 ml or a 5-10 mL graduated pipette, glass 79 Syringes,capableofmeasuring 5 uLto SOUL 710 Graduated pipettes 711 Syringes, disposable plastic, 3 mL. (B&D or equivalent) 7.12 Syringe fers, nylon, 0.2 um, 25 mm 713 Timer 714 Crimp cap glassautovialsand caps 715 Crimpers Note: Prwiaotetr.ouRsiinnsgesgylraissnwgaerseaamnidnbiomtusm,ofri9ntsiem3estwiimetshwmietthhmaentohla,n3oilnasnedsf3rtoimmes3sweiptahratevies 8R 0 eacewrsapSTapmos 81 Reagent grade water, Mill-QTM, Nanopure Il or equivalent 82 Sodium hydroxide (NaOJ.HTB)ak,er or equivalent 83 Tetrabutylammorium hydrogen sulfate(TBA), Kodak or equivalent 84 Sodium carbonate (Na;COy), LT. Baker or equivalent 85 Sodium bicarbonate (NaHCO), JT. Baker or equivalent 86 Methyl.T-Butyl Ether, Omaisolv, glass dislled or HPLC grade 87 Methanol, Omnisolv, glass distilled or HPLC grade: 88 Scrum or blood, frozen fromsupplier 89 Fluorochemical standards 89.1 KPFOS (PFOS) (3M Specialty Chemical Division), molecular weight = 538 892 PFOSA (3M Specialty Chemical Division), molecular weight = 499 893 PEOSANoH (PFOSAA) GM SpeyChemica Division), moc weigh = 89.4 E(FOSE-OH (3M Specialy Chemical Divison), molecular weigh = 570 89.5 PFOSEA (3M Specialty Chemical Division), molecular weight = 527 8.9.6 MSS6 (3M Specialy Chemical Division), molecular weight = 557 89.7 CSuurFriosgSaOtseHs,ta[nTdHaPrdF:OS4I-)H,, mpeorlfeicuuolraorocwteaingchtsu=lf4o2ni6c acid (1-H,1-H, 2-H, 2-H 89:8 Other Aorochemaisacpparolprsia,te 001464 SM Environmental Laboratory Ex~cacionofFEorToSch8em4i2cals fom Sem Page 31" Page 33 3M: Medical Department Study: T-6295.25 418-018:PAGE 1-407 Analytical Report: FLARCNT--ET0O1X--0116890 810 Reagent preparation NOTE: Wphreepnarparteipoanriangddsiffaecrceonrtdvionglluym.es than listed in reagent, standard, or surrogate. : 8.10.1 1100N0 msoLdbieuamkheyrdcroonxtiadieni(nNgaO5H0)0m: LWeiwagthera,pmpiroxxiunmateallyl 2o0l0dsgaNraeOdHis.soPlovuedr.inSttooar.e ina 1 L polypropylene (or equivalent) bottle. 8.10.2 w11aN0tNsero,NdiaSuOtmoHhrysdoinrluoatxi1io2nd5emnt(loNap3OoH1l)0y:0prmDoLip.lyuvitoeelnu1m(0oetNeicNcquafilOvaaHkle1an:n)1d0b.broiMtneg.atsourveo1l0ummeLuosifng 810.3 0oS.fo5TpMtBrtAorxaiinbtmuoayail41ea4Llmtyomvoo3lru4immeuLtmroihcfyc1dor0notNgaeinNniasnOuglHf5.i0te0((mTLABAtw)had:eteWrdae.siAgd1hj.u0asmptpLorooxfpiHmNatO1e0lHsyi1snl6go9wlgy, 25%he pH changes abruptly.) Dit to vole with water Stor ina 1 L. `8p.o1l0y.p3ro1pyTnleeBenAede(rdoerquuseiiqrnueigsvaa|lNecnhNte)cabkOotpHtrleis.ooltuotiaocnh us to ensure p = 10. Adjust as 8.10.4 0.25 M sodium carbonatesodium bicarbonate buffer (Na,COYNGHCOy: Weigh arStpropvrreooxnmiamata1teeLl(yNp2Go6Hl.Cy5pOrg,o)opfyilsnetonodei(u1omr1ecqavuroiblvouanmlaeettnerti()cNb&fo;uaClseO.ya)ndanbdin21g.t0ogovoflusmoediwuimth vate. 811 Standards preparation 8.11.1 Prepare PFOS standards for he standard curve. 8.11.2 TProerpoacreheomthiecralusortocaherniacdealaacscterapntddaarbdslse, 1(sfoapepxraompprilaet,e.nsMuwloirckoimnpgosrteanntdard solution containing approximately 1.00 pg/mLof PFOS, PFOSA, PFOSAA, 8.11.3 WP{heFeiOagSchEtuAsap,lpwrMeo5ixg5ihm6ta.taeFnlodyrE1s{0Ft0OamSngEdo-sOfHwP)iF.tOhSK"itoo ot1h0er0msaLl.t,vmoluumetlribctyflaiacsokprarneldctriyeocnord cwteiogrh.toFofPrRcOxaSmp=l4c99h.eCmaollceuclautlearthWeeicgohmtcotfioKnFFfOaSct=obry538u,sianndthtehefmololloewcilngsr equation: molecular, PFOS (49) `molecawir, KPFOS (538) ~ 07 (ComesteHnewsr) 8.11.4 Bring to volume with methanol for tock standard of approximately 1000 g/L 8.11.5 Daiplpurtoexitmheatsetloyck50soplutLio.n with methanol for a working standard 1 solution of 1000imL xS mL) =s0seinl 8.11.6 Daipplrtoex.woSrOkipnggisLta.ndard 1 with methanol for a working sandar2d souion of 001465 $M Enviromental Laboratory Exrscion of PEarocsheeamircal fom Sera Pagesoris Page 3d 3M Medical Department Study: T-6295.25 418-018:PAGE 1-408 Analytical Report: FACT-TOX-169 LRN-EOL-0180 (ustmnees) ---- ont : 8.11.7 Daiplpurtoex.wo0r.k50inpggs/tmaLn.dard 1 with methanol for working standard3 solution of (i(Sougminiinxtiont) 03004 812 SurrogateTHPFOS stock standard preparation 8.12.1 (WCeuiFgyhySaOp,pHr(oTxiHmPaFteOlSy)50i-n6to0m25g0omfLsurvrooglatue smtaefnltdaasrrkdia1nc-dH,r1-He, 2t-hcHe,ac2ot-uHa,lrweidght 8.122 B1r2i0n0gptogvmo.lume with methanolfo asurogate tockof approximately 10008.123 Psrteopacrtkeo a1su0rmrLo.gatveolwuomrektirnicgfsltaasnkdaanrdd.bTrriangnstfoevrolauppmreowxiimtahtmeleyt1 hmaLonffoorsulamrogate working standard of 100 pg/mL. Record th actual volume transfered. soseepHeoNe 91 All samples are received frozen and must be kept frozen unt the extraction is performed. 92 Allow samples to thaw a room temperature or in lukewarm water prior to extraction. 00 QuALITY ConTROL 101 Solvent Blanks, Method Blanks and Matrix Blanks 10.1.1 Solvent Blanks: An aliquot of 1.0 mL methanol is useda a solvent bank. 10.1.2 aMnedthuosde aBslamnekst:hoFdolblaonwkisn.g this procedure, extract two 1.0 mL aliquots of water 10.1.3 McotnutiroxlBmlaatnrkisx:fMraotmrixsbtluadnykscosncteeoplreapnarield frercoemivoendewoifthhascaechsosuarmepelse: s1e)t; 2s)taudy csoumrmoegractiealmlatyroibxt,aailnseodosbatmapilneedocfotmhmeerscaimaellsyp,ecbiuets oafsathdeifsfteruednytasnpiemcailess; tohran3)thae mstuodynaknoirmearlyat(cs.eg.r isftruadbyb)it. 5Thseemda{t0rgietxnoeruasteedsetapnedanrddonscuwrvheastamnadtrCiCxiVssusfeodr afor the curve. 10.13.1 cSutruvdey,cpornetpraorlemtawtroi(x2c) umartrviex--blItahfneksstuusdiyngcotnhterosltumdaytrcioxntirsoslemdatfroirx.the 10.1.3.2 Cproempmaerrecdiaulslinygocbtoamimneerdci(aslalmyeosbpteaciineesd)mmaatirriixicnutrhvees--aImfethsepeccuirevsesisthe SSvtauidlybalneimmaalt,ripx.repare two matrix blanks sing tis same commercially 001466 $01 Environmental Laboratory ExacionofFuEerroscsneam2cas fom See Pagest 1s Page i 3M Medical Deparument Study: T-6295.25 418-018:PAGE 1-409 Analytical Report: FACT-TOX-169 LRN-EOL-0180 10.133 Scounrtrionguaitnegmcaatlriibxractiuornvvee--rIiffiacastiuornrosgaamtpelemsa:trix is sed for the curve and t a). preparetwo(2) matrixblanksusingthesurrogatematrix. b) Al`msaotr,ixprseppiakree/maamtaitxrisxpbikleandukpwliictahteeaacthosnee loefvmela)truisixnsgpiakceosm(mesrectiaillay available matrixofthe samespecies asthestudyanmals. 102 Matrix spikes 10.2.1 Study Control Matrix Curve No matrix spikes are prepared. 10.2.2 Commercially obtained matrix curve (same species) No matrix spikes are prepared. 10.2.3 Surrogate matrix curve: MsattudryiaxnsipimkaelsaanrdenaescuerrsosgaartyeifmamtraixxiissnsoetdafvoaritlhbelceuirnvteheasnadCmeCsVpescaimepslaessth(ce.5., rtaobbmietassuerraabmlaeylebveelusosefdetn0dgoegneenroautes satnaanlydtaerdinctuhrevemsofnokr eaymsoenrak)e. yPsreerpaasrteuadyn,d due athnealeyxzteramcattiroinxfsopritkaergaentdamnaailyrtiexs.spike duplicate samples to verify the accuracy of 10.24Pcroenpcaenrtereataicohn)MuSsianngdaMsSamDplaet cthwoose(2n)bkyvtehlesa(nuasluyasltl,y taypliocwallaynsdemraidf-rroamngaceontrol group anima received with each sample set 10.241I`fmatthreirxespiikneost ussufifnigciceonmtmseerrcaiaavlaliylaabvlaeilfarbolme mtahtercioxnftrroolmgtrhoeups,amperepsapreec:ies as the study animal i 10.25 pPreerp2a0resoanmpelmeast,wriixthspaikmeiannidmmuamtorfix2smpaitkreidxusppliikceastepaetrelaevcehllpeevrelblattceh.dIifn a10b.a2i.c4h Tinocwl,uodershmioghreratnhgaen2le0veslsa,mples, ditional spikesmaybe orepared at the same, 10.26 Iaft maopprreoxtihamnat2e5ly%o2f-t5hteimseasmtphleesexapreec<ieLdOLQO,Qt.wo matrix spikes should be prepared 10.27 1adfdtihteiomnaajlormiattyroifxtshpeikseasmsphloeusldaebeaproerpaarbeodvetothaepphrioghxirmaantgeesoafmtphleeccuornvcee,mrations. 103 Continuing calibration verifications (CVs) 10.3.1 vPerreipfaircaeticoonntdiunruiinnggacnaalliybsriast.iPornevpearrifeicaantdioannaslaymzpeleCsCfoVr ifnosrtreuvmrenytasssaaybriun, regardless of the matrix type used to prepare the standard curve, 10.3.2 pPrreeppaarree tcahchinciotnalticnuurivneg(cialci.bcraittihorn vtehreisfitcuadtyiocnonrtoroml tmhaetrsiax,mecommamterrixciuaslzdmattorix of same species, or surrogate matrix). 001467 A Environmental Laboratory ExvacionofFuEcrTaSe8h4ei2cas fom Seum Pageo1rs Page 5 3M Medical Departmen Study: T-6295.25 418-018:PAGE 1-410 Analytical Report: FACT-TOX-169 LRN-E0I-0180 10.3.3 cTahleiberaxtpieocntceudrcvoen:cteynptircatailo,nstohefltohwe tCoCmVisd-wriallngaelolfwtihtehicnutrhvee.rangeofthe initial ` 10.34 Pcornecpeanrter,aattioanm,ipneirmgurmo,uptwoof c1o0nstaimnpuliensg.caFlobrraetxiaomnplveer,iifficaatsioanmsp,leesaechta=t a34d,ifefiegrhetnt (c8o)nccehnetcraktsioarne.prepared: four (4) at alow range and four (4) at a mid-range 10.3.5 Amdidditoirohnisg!hc-ornatnigneuicnongcceanltirbartaitoino.n verifications may be included at the same, low, 110 CAUBRATIONANDSTANDARDIZATION 111 Prepare matrix calibration standards 11.11 aTvraainlsafbelres|ermaLisofuaspdp,ropprreipaatreestewroummattori&x1b5lamnkLs,cuesnitnrgitfuhgee tvuboe. lIfoucfommsmeeecracially `available for most study animals. 111.11 aDveapieanbdlei,nag uspurornogsattuedymagtorailxs moraiyf baneaulysteed-ffroeregceonmermaetricoinaolfstehra cisalniobtration sattansdtaurddi.eFsoifrqeuanxtitaatimornaobfpbielsxterreeamme,alyybleowusleevdelas oaf tshuerraongaaltyetmeaitsrriexqfuiorred. 11.1221vfomlousmtessaemqpulaelvtooltuhmeessaampeleJevsosltuhmaens1..0DmoLn,otexetxrtarcatcst ltesas tnhandw0ia.t5h0rmmadtLrosifxmatrix. Record each sample volume on the extraction sheet. 11.1.3 Wsehrialbeeptrweepearnianlgiqauottost.al of thirteen aliquots in 15-mL centrifuge tubes, mi or shake 11.1.4 TTywpoica1l-lymLusaelitqhueotsst,aonrdaortdhceronacpepnrtorpartiiaotnesvaonldumspei,ksienrgvaem2osucnutrsvietmeatdriinxTbalbalneks.| ai tthweoemnadtroiftxhbilsanskesc,tiaonndttowpoikmeetohnoedsbtlaanndkasr.d curve, foratotalofine standards, 11.15 rRaenfgeerstaonvdatlhideatLiionneraerpCoartliErTaSt-i8on-4R.a0n&geE(TLSC-R5).f0o-rVca-l1i,brawthiiocnhcluirsvtesst.he working 11.16 SsteaendSaercdts.ion 13.0 to calculate actual concentrationsofPFOS in calibration 112 Tsuorreoagcahtestwaonrdkaridn,gbsltaannkd,acrodnttoinaucihnigevceheackc,onasntdasnatmcponlceeandtrdatainonaphparotprfiaastewiatmhoiunnttheof ccaolnisbtraanttiocnocnucernvterraatnigoenoifn2a.ll5sanmgp/lmeLs-a1t0a0p0prnogx/immLat.eUlsyua5l0l0y,nsga/mmoLleosraotehesrpickoendcefnotrraation as determined by the analyst. 113 E10xtersatcatblsipsihkeeadcmhantriiaxlsctaunrdvaerodsnftohlelmowaisnsgs1p2e.c6t:r1o2m.e1t6eorf.this method. Use these standards 41 Emsroumental Laboratory Exvacion of PuEcrTosch3e4r2mias fom Serum 001468 Page70f1s Page. 3M Medical Department Sudy: T-6295.25 418-018:PAGE 1411 Analytical Repor: FLARCNT--ET0OLX--0116590 : Approximate spiUksiinngg a1m`0oTmuanbLlteos1ffomrasttrainxdards and spikes `Woarpkpirnogx.stcaonndca)rd `Apnparoyx.fiinnamlcaonrci. of 1 T Bm | [so | 10 0 m oosom mm | = m12.1ooObtgainfrozensamples and allow to thaw aroom temperatourrien ukewarm water. 122 Laanableylstai1l5msL,poSleyepraotpayclheendewcorekishfegeet (tuAbae cwihtehtnheAstourdysmniulmibeewro,rskasmhepelte)IDfo,rdae and Zocumening the remaining steps. 123 V1o5rmteLxpmoliypfroorp1y5lesnescconedns tcheen twbae.ne 1.0mLor othe appropite volume 0 the 124 Retum unused samples o freczer afte xtacion amounts have been removed. 12.5 wRoerckoarbdetshte.intial volume on the extraction worksheet (Atschment Aorsimilar 12.6 Ssptiankdeaarld 3ssamdpelsecsr,ibbeldanikns1a1.n2d. standards, that ae ready for extraction with surrogate 12.7 pSabrpseicpkraeircbeaemdcahitnrcia1xl1b.s1rp,aiskoierosnTiastnbaeincdea1srsidanrmtyahtsaindxsecwiiotnhm,ihfenorgstphcpaerlciobaprbratrsiaeotnmosontuacnndutavreodsfs.sttaannddasr.d asAlo 12.8 Vsaomrptleexsmfiox t1h5essetcaonnddasc.d curve samples, mtx spke samples, ad continuing calibration 129 Check o sure the 0.5 M TBA regent sat pH 10. Ino, aust accordingly. 12.10 TSioeaerabcohnastaempblue,fa.dd 1 mL 0.5 M TBA and 2 mL of 0.25M sodium carbonate/sodium 12.11 Ubsuirnygeaenrb.ottle top dispenser or 5~10 ml. graduated glass pipette, add 5 mL methylteri- 12.12 Capeachsample andputon the shakerat setting of 300rpmfir20minutes. 001469 MEnironmental Laboratory ExcsionofPearsraoanz e fm Seu Bugesarts Page 38 3M Medical Department Study: T-6295.25 418-018PAGE 1412 Analytical Repor: FLARCNT--ETOOLX0-I1S609 1213 Centifuge for 20 to 25 minutes at astingof3500 rpm or until ayers are well sspaated. 1214. Label afresh 15mLcentrifugetbwith the same information a in 12.5. 12.15 Remove 4.0 mL of the organic (top) layer (0 this clean 15mLcentrifuge tube. * 1216 Phuotuse.ach sampleon the analytical nitrogen evaporator until dry, approximately 1 to 2 1217 Add1.0mLofmethatnoeoaclh cemtubieusfingaugrgadoeted pipete. 1218 Vortex mix for 30 seconds,o longerifneeded. 1219 Luambbeelra,1a.n5immaLl lnausmsbearutaovnidagle(nodrelr,ows-avmoplluemteimaeuptooivnita,l mwahterinx,neicneaslsasroylv)enwti,thextthreascttiuodny Gate, and analy) performing he extraction. 1220 ASueapc1h2.a128t5momth,is0s.y2riungme.nFyliolnemriensthotihkeltaboelae3dmauLtovsiyarli.ngeandtransferthesamplefrom 1221 Cap and stor extractats room temperatures oratspproximai4elCy until analysis. 1222 Cthoempstluedtyebtihnedeerxtraction worksheet (Attachment A of similar worksbeet) and include in 13.0 DATA ANALYASNDIS CALCULATIONS 131 Calculations 13.1.1 CCaallbealtaitoenacsttuaanldacrodnsceunstirnagtitohnesfoofloPwFiOnSg,eoqruatthioenr:applicable fluorochemical in _ Lo id_ +isfd_ xscmoontceem nmdat+onb mfastt m(a4o r8e/7eL)lf a) 1pip concenmiiTSon(48 mfof PPFOOS in mais 1M 14401 eThe m methoo d detev ction lP imit (m MDL)m is anale yte ano d matrm ix specs ific. a Refetn ro MDe L repos rt ftohre sdpiesccirfeitcioMnDofLthaendPAiLm,iMoDfLquamnatyitantoitonbe(LdeOfQi)nevdaflouresso(msceesAttudtiaecs.hments B and O). At 182 Tthheeqfuoallliotywoifngthqeuaelixttyraccotnitornolansdamapnlaleyssias.e extracted with cach batchofsamples (0 evaluate 14.2.1 Method blanks and matrix blanks. 14.22IdfupsluimcoagtaetseammpaltersixoisvuesriefdyfeoxrtrcaucrtvieonancdfiQciCe,ncmya.trix spike and mati spike 14.2.3 Cinointtailncuailnigbrcaatliiobnrcautriovne.check samples o determine the continued accuracy of the 143 Refer to section 14 ofETS-3-5.o2rmeihod performance criteria 0C1g70 $3 Enrommental Laboratory Excicionof Faeerhsertl om Sram Pueselis Page 39 3M Medical Department Study: T-6295.25 418-018:PAGE 1-413 Analytical Report: FACT-TOX 169 LRN-E0I-0180 150 NAND Wi 15.1 Dispose of sample waste, flammable solvent waste and used glass pipette waste using ` `propermethodsandbyplacingeachintheirdesignated wastecontainer. l6ORecopps 161 Complete the extraction worksheet attached to this method (or a similar worksheet), and include in the study binder. 17.0 ATTACHMENTS 17.1 Attachment Attachment AA,) Extraction worksheet (a similar worksheet may be substituted for 17.2 AttachmenBt, MDL/LOQ valuesand summary 17.3 Attachment C, lon Pair Standard Curves worksheet (a similar worksheet may be substituted for Attachment C) 18.0 REFERENCES 18.1 The validation report associated with this method is ETS-8-4.0 & 5.0-V-1. 182 FACT-M-3.1, "AnalysisofSerum or Other Fluid Extracts for Flaorochemicals using 'HPLC-Electrospray Mass Spectrometry" 183 ETS-8-5.2, "AnalysisofPotassium Perfluorooctanesulfonate or Other Fluorochemicals in `Serum Extracts Using HPLC-Electrospray/Mass Spectrometry" 1A 90 recrepDocoments 19.1 ETS-8-5.2, "Analysisof Potassium Perfluorooctanesulfonate or Other Fluorochemicals in Serum Extracts Using HPLC-Electrospray/Mass Spectrometry" 20.0 REVISIONS Revision Revision Numb1 er Seon 12.1 Changed includ`esRaemaplseosniFcroare Rtervoiomsitoenmpera. oDwatse `Secon 12.13Addedtheshake peed. 2 S`Seeccitioonn 1121.,172F1eiamviolnaeme`ipo1ca0smsiLun:' pfortomadpjeusftleudcfrooronciteaslsivoonlusmiees les haa 10 ml. 89.1 AUK PROS 89.3 AS Hi PFOSAA 1021024, 142.2 Add informaion abou winsuo mai, lary contol mtx and spiking the curve, change spikes 0ev2e0 sramplyes 1100.:1ACdladriotywpourrptoseoafbcouotntcnosnsionlgacaliiblratsieonr cwheicknstnd ot uocommercally avaiable In genera, make hss specific or equipmentsupplies. Sebi wate for Mlli<QNalgeneor equivalentbole maybe ied. 001471 3M Environmental Laboratory Extractionof luoErToSc-he8m4i2cals from Serum, Page 100115. Page 40 418-018:PAGE 1-414 E-- E[eThE i e|ExTaE meR||EEagmR? || traction Worksheet ETS-8-4.2 er TT=LR-E01.0150 | S-- iTSI SS WE SA -- H----r------------------ ---- ws |-- 1 r1 ---- 11 ---- rrr rrr 1 rr rT rr 1 -- rT 11 rrr freeeeerere-_y-------r1 rT rrr 1 fe ------------------------------------ I wl t--]et----------r---- ee----AA.TES,WN"SrSi (SNW--N---- rr TT ---- rrrrT 1 rrrT rrTTT A AA.SV SS Wh,S S ------ rrr rT Yd] ee cesmen-- -------------- rrrTT rrrr rT 1 --r----r------ 1 1 1 -- rT -- TT r _---- T rT TT [P_ os_ eim_ iof_ osM_ BAO_ MIO_ B=______sae___ 1__ [ismoeemotomwei neasmbLoal rieber____________TeA_____1____| fou By bee Ere `methanol o oes 1 re001472 : SePnE a een (ng/mL)| (ng/mL)|Approximate concentrations tobeused for preparing [PPOs [PFOSA | i7a | 555 |151 |479 [ [sosgmn icig oomm gmliiooegml|1 [PFOSAA |346 | 205 [sogmiioongml| EeB E Sa EEr oos d A e n m ie [PR|O5.S 11E 182A 5 ng/ml 1000 ng/mL re 001473 SR : wt CET 418-018:PAGE 1-416 LRN-E01-0180 caromen]sST=E| | T T [[irForme[|moomwn[ouwmn||wwwm||swmons|| [[rieors[|omrom [[vooomm|[oom ||vm|| P--N--Bvdoroel r Ro T [[iFmam[[oommere[[nmoen||wrws ||swrr|| comoWroiiTdr| Raei | Ta T [Fim ome won|wn[wwe| sttty2 EEE nn 001474 _-- 418-018:PAGE 1417 : TRN-E01-0180 . P E C=| r=r Tm [fiioome pwmoss[[woewenn||owww ||uisawn |] [To mon[m won|o wim | -- Bir S=S = [[rFearmee[[ommn|omonn|ownm[|wns|| [[ roar wTm|o Lovmoon|[m womn[|o wwiorn]| on S =|=-- TE | -- [Erie om [seo |ww [| [pare[mes[wen|wan |suo | Tm 001475 3M Medical Department Study: T-6295.25 A18018PAGE 1418 Assytical Report: FACT-TOX-169 LRN-E01-0180 Analyst) TonPair StanESdXtauArdMdyPCLnuEmuberr:-vFleuisds + APnrespydast:es: BFilnaklsaoldvaenednTnNt:: {fsmsc Study AnimalMatrix: wa TaMretgneotdiarmeviissiosn:: FCmixsdapprox. 0500ppm: FFSCCummiirxsrstidosaaigpdppaarppoptrxores0S.Oo01O0px0rp.:p ne opp fei nsonce AYGcootounaeconcSPenrotoraostionFsoTSfwOseStmaAneAdTMarEdsWSiaOnmtShmeEEFCOmSiSotEmieAnmethSwaniaosleo|| AAIm FADm [00TosapoolTose_wpmlTasouml tsar [oso oso [os [asm Tosa Tasoa r[|otoeninT eso [oom | lomils | Los| isoef WT%asi sonn[r psroae[gsmr aaks1 oorn oomm ios [Fsoosoor--Bfwsiaoir7TX tisSiA ozk | F sorATA haosali [Nlsooorr om[[oooso 1l0os0 [im CFarilEocnTukleatedBrcoTiSoeooemrne cPeFRnOTeSotrworifsaBtFFatenaOidimSanorEsdnsiFsnFFtoOrgThSaeewEmsAeeramPagMeirt1Tr6omixn: SRaeSbarbaoitmpra AsAurp [26s Sg----mi | 263 [Tos spolsti | 248 | 262 253 Lo da | adby WS | Surrey.| | Final conc [ors m--hoW bf oktRI Eooq id| apmi | En 2a e t a 8T% w0NNAAghIfoRedH AFTaSse ,|| sw | = [enTRros-- YS F| e TE : T5rae 2 ee | D r c Uee a a 2 a1 TTT a1 - 001476 ArachnCelonPi Sundid CaEvveassionofPETSr.442ofbomSeram $M Ewironmental Laboratory Pageset1s Page ss 3M MedicalDepartmentStudy: T-6295.25 : 418-018 PAGE 1419 Analytical Report: FACT-TOX-169 LRN-E01-0180 3M ENVIRONMENTAL LABORATORY ` Meson ANALYSIS OF POTASSIUM PERFLUOROOCTANESULFONATE OR OTHER FLUOROCHEMICALISN SERUM EXTRACTS USING HPLC-ELECTROSPRAY/MASS SPECTROMETRY Method Number: ETS-8-5.2 Adoption Date: 03/01/99 Author: Lisa Clemen, Kis Hansen Revision Date: 2] 01 Approved By: Yoh A a Laboratory Manager 0s fi foy Due Lt te Group Leader hacs a Ce Technical Reviewer oz/ei/e) Date 22 ot: ol Dae RD Ezp n 3 1oscomawapuoamos 11 uSscionpgeH:PTLhCiscmleectthroodspdreasycirmiabesss tshpeecantarloymseitsyo.f serum extracts for lurochermical surfactants "S12 Applicable Compounds: Fluorocherical surfactants or ther fluorinated compounds, or Q other ionizable compounds. B10 13 Miatdriacens: Ravi, rt, bovine,monkey. and human serum,o other fdsadesignated nt 001477 2= worsens $31 Environmental Laboratory: AntiofSEertusmsExstrazct Usog ESPMS Page 11 Page 45 3M* Medical Deparment Study: T-6295.25 418-018:PAGE 1-420 Analytical Report: FACT-TOX-169 LRN-E0I-0180 20SvaryoPMEm + 21 pAltehorugfh souprpormteadmebntyhacodva.elCi-adraetbfiounlafaotsrtemenotsidtoncsomhmoonblueypluasideddtmoam tricee s, Qtht iCsaissahtheroeisgd reat Veaxrtiraabcitlietdyfirnsoemrsae.Trhuimsomreotthhoerddfleusicdrs,ibuessitnhgeHaPnLaCly-sliescotfroflsuporraoycihmeamsiscaslpseucrtfraocmteatnrtys, of CShiamrialcatresryissttiecmoafsaappapnrotpcriualtae,floTrhoechaenmailcyasls,issupcehrfaosrtmheedpbeyrfmloonriotoocrtianngesauslifnognlaetieo(nPFOS) atonifounr,tmhezrv=eri4f9y9.thAediddietnitointaylolfy,sacaompmlpeosumnadybbyedaetneacltyiznegdudasuignhgteartainondseomfmtahsespsapreecnttroiomne.ter oDpgmmoss 31 quAadtrmuopsoplheesryisctPermessaslulroew fIoornivzaartiioouns m(AePtDh)o:dsThoef iMoincirzaotmiaosnsbyQuuattiltirzoinIgavanrdioUulstsiomuarctersip,le p`rAotbmeoss,phaenrdiciPnrteesrfsaucrees.chTehmeiscealinIcolnuidzeabtuitoan (eAnPoC)t,mTihteerdmo0s:prEalye,cterio.spTrhayeiIoonniizzaattiioonn(pErSoDc.ess in these techniques occurs at atmospheric pressure (c., not under a vacuum). 32 presEsluerec,trwohseprreabyylioonniszaintisono(ESl,arEueStIrt:anasifmeerotrhedondoofthiongiazsatpihoansepevrifotirnmyaecdhtaartgmeodsdprhoeprliects "These charged droplets are produced by the application ofa strong electrical fell. 33 (MSM/aMsSs):SpTehcetrAoPmeItQruya,ttMraosIslaSnpdecUtlrtoimmeattreirpl(eMSqu)a,dTruapnodleemsyMsatesmssSapreecetqruoimpepetderwith qrautaidor(umpozl)eamnadsssusbesleeqcuteivnetldyetdeectteocrtse.d.ToAnssianrgcleseMleSctimvaelyy dbiesecmripmlionyaeteddfboryimoansdsettoeccthiaorngoer a series (MS/MS) for more specific fragmentation information. 34 quadCrounpvoelnetsiyosntaelmsv.(pZos-tsp1r9a9y8)prutoibliezein2t"eZr-fascper:ay"Thceonlfaotresmtatmioodne.lTshoefsMpircaryomeamsisttterdipflerom a pdirroebcetliysaotrtthheogcoonnaelatpoetrhteurceo,naefearpeprausrsei.ngItnhrtoheugchonavteonrttiwoonuasl cpoantfhowramyatiniotnheitcoiuanitmeerd S`imcaciinrtoeden.ancTehaoruegthhethseamceo.nfHigouwreavtieorn,sZ-dsipfrfraeynct,omtphoenmeentthsodasndofcoonpveernattiioonn,alclceoamnpiongn,enatnsd are ncootmpcaotmipbalteibwliethwsitohmeonoethaenrotZh-esrp,rbauytsoylstyemwsi,thetSci.milar systems (c., Z-spray components are 35 QuaMtraossILryinlxeSqoufatdwraurpeo:leSsyysstteemmss.ofCtuwrarreentdleysiMgansesdLfyonrxthheasspWeciinfdicowopser9a5tiaonndofWtihnedsoewsNT 4i.n0stvrearmseionnts.(MiAcllrovmearssisoQnsuaatrrsoimIiTlaorr.UFloirmamotrriepldeetqaulaldsrsuepeotlheeMmaasnsuLaylnsxpeocrifMicas(0sLtyhenx NT User's Guide). 4W 0 agvmesawpCavmons 41 Health and Safety Warnings: 4.11 Uesre ncauptailovnoowkyiatgsh tohfe avoplptargoexcaibmleast5fe0olr0ty0heVporlosbe. When engaged, the probe 001478 Ward 695 $31 Emironmental Laboratory Ansys ofSEerTumSE8xi5r2ac Using ESMS Page2of11 Page 47 3M Medical Department Study: T-6295.25 418-018:PAGE 1-421 Analytical Report: FACT-TOX-169 LRN-E0I-0180 412 Wanhdecnlohtahnindgi.ng samples or solvents wear appropriate protective gloves, eyewear. 42 Cautions: 421 DIoftnhoebtaocpkeprraetesssoulrveeerxcpeuemdps4s0a0bboavre,ctahpeacHiPtyLoCfw4i0l0ibnaitriat(eSa8u0t0pomsa)tbiacschkuptrdeosswunr.e. 422 Donotrunsolventpumpstodryness. sObvemeReNcEs 51 sTtoormaigneiomriazeninytpearrfteroefinncsetsrwuhmeenntaatniaolnytzhinagtscaommpelseis,nTceofnltoanctswhiotulhdtnhoestbaempusleeodfroexrtrsaacmtp.le s6o1 EEoquuiepwmeenwtrlistedbelowmaybemodifiedinorder tooptimize thesystem.Documentany. modiinftheiawdcataaastmetihododevinatiosns. 6.1.1 MwiitchroamnaeslsecQturaotstprraoyIiToonrizUalttioinmasoiuprcle quadrupole Mass Spectrometer equipped 6.1.2 cHoPm1p1a0r0tmoerntA,gialnendtaluotowspaumlpsleersolvent pumping system, solvent degasser, column 10Steps MatERMLS 71 Supplies 7.11 High purity grade nitrogen gas regulated to approximately 100 psi (House aif or nitrogen system) 72 iHnPtLheCaawnidaata. colin, cis ob dtbm y heanalystad ocurred 7.13 Capped autovials nd capped 15mlcentrifuge tubes 80 Reagents ADSTANDARDS 81 Reagents 8.11 Methanol, HPLC grade or equivalent 8.12 eMqiulivla-leQnTMt,wa3t0edr,faalylwbaetperrouvsieddedinbtyhiasMmieltlh-oQdTsOhoCulPdlbues Msyisltie-mQoTMr owtahteerrvoerndor 8.13 Ammonium acetate, reagent grade or equivalent 82 Standards 8.21 pTyrpeipcaarleldydtuwroinmgetthheoedxtbrlaacntksi,ontpwroocmeadturriex. blSaeneksE,TaSn-d8-c4i.g2h.ter, matrix standards re SM Ens onmenti Laboratory AnyiofSeEmTsE8xa5c2t Using ESM. 001479 Page zortt Pog 48 3M Medical Departmen Sdy: T-6295.25 S18.018PAGE 1422 Ansytical Repors: FLARCTN-ET0O1X0-118609 99.01 SaFrrmeepsshrtoemrHeadarinnpcsatuapnnpdeeadrdustaovriplrsepoarrceadpwpeidt1c3acmhLacnnytsif,ugEexiturbaecseudnsliaanndaalrydssisn. d samples % 92 pIfparnoanliysmiastweillyl 4be Cd,eloafyead,reoxotrmatcetmepdesrtaatnudraer,dsunanldasnaamlypsliessacnanbbeepreerffroirgmereadt.ed at N 10.1 SO olventO Blanksu , MetmhM mod BlN anks aaY d MatrC ix BaO nks NIBOL 10.11 nSoclevendsurlianngkts,hmCeotuhrosdobflahnekssaunddm10tGxeHaenknsafecpormeipnaraetdiaonnaGneaalryzeedddauriansgt. 10.02 `Asnaamlpylzeepraepe.ast one solvent lnkprio t0 each calibration carve. 10.13 Mpeasttisblanks should be alyzed with each sample Ist tht includes undted 102 Matrix Spikes 10.2.1 IrSfeecrpuairrvseeusdapnnedbmaeathosoradklQeeCyamrseeaparr.epm(aetr.e.rdmisonnpaksseuyrrneodgra)ateatmnaxdtrusilxiz(kee.gGd.upc0lcuvaiererisynvrreaebbsit 10:22 Tecxurtrraavncetissopniaenefdsfimceietrnhceoy.d QC ae prepared i th same mati as samples, no adiioal 10:3 Continuing Calibration Verifications (CVs) 10:3. Choenciamliinbrgtciaolnfcrartvieo,n verificatiornes analyzed 0 very th conimed accuracy of 10:32 Ainaalryz,e tiwotcalifraaiorn stofarndasrdpso(rsoaacnaacenh soof2apvseos)gfeaenveercytoieon0 (en ne wih at 62 tw albraon andar. 110 CALTARNDSATANTDARIDIZOATINON T1.1 iAnaelyzelotrhieextbryacfieedarmriegriecsaolnf.rawieoingshaednd1e.dTroerfortcoeadcthosuegthof5x1i0r,ci ts. TMhaescsarLvYeT or other sutable softwar. 112 1Te3ahndyczuervtehdeoscasnnodtsmceuervee.quirents, peor routine aninuace, era samples, ox 113 FFoor npurpomseys boefancceucraecysw1h0eansqeuatnesahienleowveelndofoanhaleytgeha esnid omf sthocfatlherciaorvnecurve rCiapthpenrroottsghi1am0na0oi0ftlthpyepe)f1u.0lslparTtainnsogdfeowrfsitlmohubem,cs3ttaapndmpaayrctdeboucur1ra0bvc0eey.pnApeExftuaimhpetdlreg:e(nwerhlaehtnneeztcFtagelrmrbepartsniaginieogonontfwocetquhiureagvnhcetuiirtnavgteeo.(f5 (1 450 SV Envromnal Laboratory Ani oSErsrssz Using ESS [-- Page 49 3M Medical Deparment Study: T-6295.25 418-018:PAGE 1-423 Analytical Report: FACT-TOX-169 LRN-EO-0180 anhidghachoingchecnatrravtei.onIfstthaisndaisrddso.neI, ino amlsooraectcheaptnaobnleeptoonbrtesahkotulhdblienucasrerdanigneconmtomoanlobwetcwuerveen tphpebcaunrvdest.heFhoirghexcaumrpvlee,matyheilnoclwucdeurtvhee mpoaiyntsi:nc2l5u0d.e t5h0e0.fo7l5l0o.wi1n0g00po,in1t2s5:01,pp5b,.25, 100, 250 12.0 PROCEDURES 121 Acquisition Set up 12.1.1 OdensitghneatMoarsestLery,nlmasati2n dpaigeg,oisfttteussptayesaarm-pmloe-dlasyt,naanmde.a Sexatveretthhaetlswitlalsinicnrsetarseu.ment throughthealphabetwitheachadditionalist forthat day. `Example Sample List: [YYMMDDa or DO10712a IYeaiynsetarurmoefnttensatm(e01()D for "Davey" `DMDM==dmaoyontfhtoefstte(s1t2)(07) t`ha=efiersxttsamcplae insto (ordnun))ofth day (the next sample lst will nd with `b," 12.12 Adasys,iganndafial3eingaimte usesqiunegnttihaelifnlsetrnuummebnetrdtehsitgsntaatrotrsewtietrh, |thanldasit2ncdirgietbsaoysfoyenesearf-omrocach flename. `Example File Name:IYYMMDD## or DO10712001 TYsi=nysetraarmeonfttnesatm(e01()D for "Davey") `DDM=Mdmaoyniofhotefstt(e1st2)(07) ##=3-digit sequential file number starting with | through 999 (001) bAoltstol,eansupmabretro,fatnheinsjaemctpiloen ivto,luamsesiagnndasmaemtphloedde(sMcSr)iptfiorona.cquiring, an inet fi, 2 12.13 sTeoleccrteSatIeRa(Smientghloedf,ocnliRcekcoorndiMnegt)hoordMEdRitMor(bMuutltiopnlienRtehaecMtiSonStMaotnuistoPrainneg)a.nd.Set TsoctnitzhaetiaocnquMiosidieonasstaarptparonpdrisattoepantimmeas.sSsav0e4a9c9quiosriotitohnermeatpphroodp.riIafteMmSaIsMseSs. Also cionlsltercutmeedn.tsSeareeMeimcprloomyaesds,MaadsdistLioynanl pGrUodIuDctEjTonOfDraAgTmeAntAatCiQoUnIiSnfIoTrmIaOtiNonfomray be additional information and MRM 12.1 Teyxptircaacltleyd tmhaetrainxalsyttaincadlarbdast.ch run sequence begins with solvent blanks and a set of 12.15 SSoalmvpelnet ebxltarnakcstsshaoreuladnableyazneadlwyiztehd tpewroioCdCicValslyintjoecmtoendietvoerrpyososniebl1e0atneanlystaempclaers.ryover and are not considered sample extracts but may be includeassuch 001481 SM Emironmenal Laboratory AnsysofSerEuTmsE8xs2: Using ESS Page sar Page 50 3M Medical Department Study: T-6295.25 418-018:PAGE 1-424 Analytical Report: FACT-TOX. 169 LRN-EO1.0180 12.2 Using the HPLC 1221 Set up sample tray according to the sample ls prepared in Section 12.1.1. 5 12.2.2 Sapeptr-ouppritahteeHfPorLoCpttiomtahlerfeoslpolnoswei.ngRceocnodirtdiaocntsuoarl actoncdointdiiotnisonisn tthhee ainnasltyrsutmecnotnsiders logbook: 12.2.2.1 Sample size = 10 L injection 12.2.2.2 Inject/sample = | 12.2.2.3Cycletime =10.0 minutes 12.2.2.4 Flow rate = 300 ulin 12.2.2.5 Mobile Phase (program) 2.0 mM Ammonium acetate (in HO) [ogomin.Tow TT "90% | [Loomin. TTM70%1 003% | [S50min "705%| su | [750min | os --T--s&| [800m | o% 17 o0% | 12.3 Instrument Set-up. 12.3.1 Refer to ETS-9-24 for more details. 12.3.2 Check the solvent level inreservoirsand reflif necessary. 12.3.3 Check the tip. thTehsetatipnlseshsousltedeblecafplialtlwariythatntohjeaegngdedoftedhgeesp.ro1bfet.heUtsipeisafnoeuynepditeobcee.to check upnrsoabteissfhaoctuolrdy,bedicshaescskeemdblweetehkelyp.robe and replace the stainless steel capillary. The. 12.3.4 SOebtsHerPvLeCdrpouplmeptstcoo"mOinn"g.oSuettoftthehefltopwofot1he0-p5r0ob0e.L/min orasappropriate. 12.3.5 Taruomunodntthheeinpitorfogtehne.prAobfei.neRmeiasdtjusshtoutlhdebtepeoxftpehlelepdrwoibtehi0fn0onimtirsotgeins olbesaekirnvge.d. 12.3.6 Tchhaenginestinruomrednetru1s0eosptthiemsiezepatrheamreestpeoanrstsz:the following settings. These settings may 12:3.6.1 Drying gas 250-400 iers/hour 12.3.6.2 ESI nebulizing gas 10-15 litershour 12.3.6.3 HPLC constant flow mode, flow rate 10 - 500 uL/min 12.3.6.4 HPrPesLsCuries<o4p0er0abtainsg(cTohrirsecptalyr.a)meter isnotset, it i a guide toensurethe 12.3.7 Carefully guide the probe into the opening. Insert probe until it will not go any further. Connect the voltage cables to the probe. 001482 3M Emonmental Laboratory Analysis of SerEuTmSEx8tr5a2ct Using ESIMS. Pagesof i Page 51 3M Medical Deparment Study: T-6295.25 418-018:PAGE 1-425 Analytical Report: FACT-TOX-169 LRN-E01-0180 12:38suPrmimntatrhyeptaugneepaanged,stMorSe fiinle,thHePsLtuCdypabrianmdeetrewrist,hsaamcpolpeylitsatpaendditnhteoMtihcerionssotfrtumWenotrd log. 4 12:39Cvleircsikoonns,stsacrtabpuptrtoopnriinattehMeaMsassLsyLnyxnxUmSaEiRn'pSagGeUI(DhEi)s.maEynsvuarreyasmtaotnagnMdaesnsdLysanmxple `number incalllusamdpleestsobeanalyzed. 1D30amaAmauysisapCALculamos 13.1 Calculations: 13.1.1 Calculate matrix spike percent recoveries using the following equation: Recovery =OObbsereveddRReesl -MeetrrielBlnaknkRReesses 13.02 Calculate percent difference using the following equation: % Diference Expected Cone Caaleutaoende. 100 1(3g./0m.4L):Calculate actual concentration of PFOS, or other fluorochemical, in matrix (Con(eI.noiftPVRoOlSuCmaelofeMfarormreS(d.nC>urv+e_nmgi/mfk)Sur_roDgirleussaondneFresc]ior) 1010p075 FinalVolume nL) 4.0 METHOD PERFORMANCE. 14.1 M`meatschioxdspDeectifeicct.ioPnleLaismeitsc(eMEDTLS)-8a-n4d.2L,imAittotafcQhumaennttitBa,tifoonr(aLsOtQi)ngaorefcmuertrheondt,vaanlaildyattee,dand MDL and LOQ values 142 Solvent Blanks, Method Blanks, and Matrix Blanks 14.2.1 aScotlivveentstbalnadnakrsd, imnetthheocdalbilbarnaktsi,onancudrmvaet.rixblanks values must be below the lowest 143 Calibration Curves 143.1 Tbehtetecr.oefficient of determination value for the calibration curve must be 0.990 of 3M Emironmental Laboratory AnsysofSerEuTmSE8x:tr5a2ct Using ESS Page 70610 001483 Pages? 3M Medical Department Study: T-6295.25 418-018:PAGE 1426 Analytical Report: FACT-TOX-169 LRN-EO1-0180 14.3.2tAhleleaxccteivpeticoanliobfratthieonLcOurQvpeopionitn,twshmiucshtmbaeywdietvhiiant2eu5%poftoth3e0%t.heoretical value with 4 14.3.3mCuaslitbbraetdieoancsttiavnadtaerddtsowdiitshqupaelaikfyaraedaastalesrsantgheanthtawtomatiymbeseatfhfeeccutrevdebymabtaricxkgbrloanuknd. levelsofthe analyte. 14.3.4 Ltootwheordahria.gh curve pointsmaybe deactivated to optimize & linear range appropriate. 14.3.5 `Nmoatybiencdleuadcitnigvlatoewdiorfthhigehydpeoviinatstedmroorpepetdhaton2op5t%imfirzoemtthehelitnheeaorrreatnigcea,lvcaulruvee wpohiennts the curve is evaluated over a linear range appropriate to the data. 14.3.6haOsneappoeiankt abreelaolwetshethLaOnQtwmoatyimreesmtaihnemaacttirviexeblvaennikf;hitodweevviearte,stmhoerLeOtQhawnill3b0e% or defined atthe lowest point with acceptable deviation. 14.3.7 AthvealLiOdQca.librationcurve must contain atleast active points above and including. 144 Matrix Spikes 14.4.1 T`choenceanvterraatigoen.maRtercixovsepriikeespoeurtcseindteorefctohviesrireasnsgheosuhlodublde bwietdhiisncus3se0d%inofthteheresppiok.ed. 145 Continuing Calibration Verifications (CCVs) 14.5.1 Cpoenrcteinntuirnegcocvaelirbyrawtiitohninsam2p5le%sofwitthheinstphiekeldinceoanrcreanntgraetoiofnt.hIefraunCmCuVsitssohuotswiade of this recovery, subsequent data should ni be accepted. Acceptable data must be bracketed by the curve and passing CVs. 14.6 pIfecrrfiotrermieadliosntedthien styhisstemmetahnoddspaemrpfloersmraenacnealsyezcetdioonriostn'htermeatc,timoanisnatendaentceermmianyedbbey the analyst, Document al actions in the appropriate logbook. 44.7 1fodoattnaoatrede otno btaeblreespoarntdeddiwshcuesnsepderifnotrhmeatnecex corfittehreiarehpaovret.not been met, the data must be 15.0 POLLUTION PREVENTION AND WASTE MANAGEMENT. 15.1 pSiapmeptlteeweaxstrtaeicstdwiassptoesaenddifnlbarmomkaebnleglsaoslsvecnotntsaidniersspolsoecdatiendhiinghthBeTlUabocroanttoariyn.ers, and glass l6ORecoros 16.1 Tinhfeorfmirasttipoangienoclfuedaecdheidtahtear pianctkheethgeeandeerra,tiendthfefaooostteurrdyormuhsatndhawrvietttehneofnotllhoewipnagge: study or project number, instrument, sample matrix and time point, date, and analys. 162 Acodmaptoaupnadckseutmimnaclruyderseptohretffoolrloewaicnhg:tardgaetta arneavliyetew,squumanmtairfyy cfaolrimb,raMtiaosnsrLeypnorxtqfuoarnteiafcyh (3) target analyte (curve), method report, Word document lstng set-up parameters, tune 84 $M Environmental Laboratory AnaloyfSseEriTusmSE8x5ac2t Using ESMS Pages oil Page 53 3M Medical Department Study: T-6295.25 418-018:PAGE 1-427 Analytical Report: FACT-TOX-169 LRN-E01-0180 ``qmueatnhtoitdyrseapomrptl,eMraesposrLty(ncxhrscoamnantionggrmame)thod report, HPLC method report, sample ft, and 4 16.3 Fpaorracmaectherasn,alMysaisss,Layfntsrprsicnatninnigntghmeetthuonde mreeptohrto,darnedposrat,mpWloerldst,doccoupmyeanntdlitsatpieng,insteott-huep Instrument runlog, The original is maintained in the data packet. 164 Oqunanetaicfyh psaamgpeolfertehpeorqtua(ncthirfoymcaotomgproaumn)d,trheepfoorl,loqwuiangntinfcoarlmbartaitoinonmuresptorbtei(ncculrvued)e,daenidther minetthheodh,eacdaelri,brtahteiofnoo(ttehre,moerthhaonddawnrdictaelnibornattihoen apraegeu:suasltluydyasosrigporocjdetchtensumabmern,amien)st,rament, analyst, and date. 16:5aTrheeeanlaleystcmutstridnaoctleunadneiddoicnnitcaiaalclthhplefaigyres.t Ipfagneiitnalsaapnadcdkaettaeasrleonngoa:setlheeicritntrioalniannccdalduladlteedy, they must dae and iil each page. 16:6 S`AutmtmaacrhimzeentdaAtafuosrianngesxuiatmapblleesoofftawsaurmem(acr.gy.sEpxrceeald)shfeoerti.nclusion in the final report. Sec. 167 bBaacckkuuppeleelcetcrtornoincicddaattaaintoinasptprruompernitatleogmebdooiku.m. Record th file name and location of 1717..01 TAAtBtLacEhSm,eDntIAAG:RDAaMtSa,sFuLmOmWaCrHyAsRprTeSad,shAeNetD.VALIDATIONDATA 180 REFERENCES 18.1 FcAoCmTp-oMu-n4d.s1f,ro"EmxStrearcutmiofnoorfAnPaoltyassissiUusmiPnegrfHlPuLoCr-oEolcetacniersouslpfronaayt/eMaorssOtShpeerctFruoomreotcrhyermical 18.2 EToTnSi-z9a-t2i4o.n0/,Ma"sOspeSrpaetcitornomaentderMaQiunatternaonIcIetoifptlheeqMuiadcrruopmoalsesSyAsttmeomspsh"eric Pressure 18.3 The validation report associated with this method is ETS-84.0 & 5.0-V-1. 19.0 AFFECTED DOCUMENTS 19.1 E`TCSo-m8p-o4.u2n,ds"EfxrtormacSteiornuomfPfoortAansasliyusimsPUescifnlugoHrPoLoCct-aEnleesiurlofsopnraatyo/rMiOatshserSFpleucotrroocmheetmriyc"al M Emiremental Laboratory AnoyfSeiru1m5E8x5tr2act Using ESIMS 001485 Pages ol Page sd 3M Medical Department Study: T-6295.25 418-018:PAGE 1-428 Analytical Report: FLARCNT--ET0O1X0-118609 200 Revisions ReNvuimsbieonr ReasonForRevision 1 SSeeccttiioonn 61.11..12AvClearraifgiecoatfiotnwoofcH urvesP .nosty1 ssttaenm1 dcaormdp0 voanleune0 st,sa.r used for SSplecoctittioionnng 11li72n.e1.ar2Cr4egCrhelsasfiroraniomafnsindtocasfdcadhgsteomdlievntoehentnetB1rt/adxopw.Ae.ighting of the curve. ReDvaistieon 04/02/99 2 110012CAdldeidooswrhceinobnasnkfoswwehern.rosmri swd. 111013SRpeecitysraenygsceltifornCCcV.vbesthe pls. 111213 CAlltlyowwhnatidsohfcuurvv.doe otreir. 112211.1CCiatrtyy aymppleeusnt.10. 121433CChhaannggesstoempilaelpss.Arinpsencdspiortsypaownes.ofcalison cue. 114433..33WWhheennttoodderaactcivoatecclleeaannssaannddsr eiionnoeShnaakssrpenon: 1144::4DMeordiis ovlaottiioonnsnnddiweooffCCV.pk 116405.AEd rreiproofeCCnoVr.ext nddoumeniion, Ausamen Samar Spates"AntiofSo arsEeass UsingESAS M Environmental Laboratory 001486 po pag: 53 A sss418-018:PAGE 1-429 LRN-E01-0180 b sEa SE =Ewhay:Dan BErEe e Laboratory Study # 5 addl EI A RIerseemreen `Slape: Taken from linearregressionequation. AuachmenAt: Summary Sus Spreadsheet leon "ETs.852 001487 Pe. 1lof1 418-018:PAGE 1-430 rennin rei a Appendix D: Data Summary Tables p u==iT be |a=aTwz=aTo= |oa] = oF | eE =i| a Esl = o=s [r= pH=efs | =[wr |w== w] = EEE i= HE= Ee eEa EntSEEE 0 re 001488 3M Medical Deparment Study: T-6295.25 4 Medial DepaStruym: e62n95.t25 `Appendix E: Data Spreadsheets 418.018PAGE 1431 Analytical Report; FACT-TOX. 169 LRN-E01-0180 Anayica Report: FLAACNT.ET0O1X.-0116890 $M Environmental Laboratory 001489 Page 58 3M Medical Deparment mans nme Ee DE. 418-018:PAGE1-432 ssi mero EEE EEE [TlElElE sf fl, |. 001490 BS Fase 9 418-018:PAGE 1-433 eenEET lin = fe = =e Swe | TET Cm = HE = PE lm ilEElE dE |. a 3M EmvuronmentalLaboratory 001491 i ge 60 418-018 PAGE L434 3M Medical Deparment Sudy: T-629525 Analytical Repor: FACT-TOX-169 J. gre SE enere ... LRNEOLOIS0 Be SEE [SlE E E T. E = EE eTi= E EfT. | TIEEELEEE i - 5 SEI smevemmesen 001492 1 Enironmental Laboratory : Pages! $0 TE EEei E-- ee. EET 418-018:PAGE 1-435 oben TOC =F = EEE Cope Jom @[% | 5 Iolemml = | | wm | = LEEE81:8 LIE Emre te Tee Lee 1. 1: E 001493 418-018:PAGE 1-436 3M Medical Department Study: T-6295.25 0 Mecca Department Sud: -6295.25 Analytical Report: FACT-TOX-169 LRN-EO1-0180 Anayical Report: FLAACNT-ET0O1X..0116890 Appendix F: Example Calculations FormulaUsedforSeraAnalyseisnStudy FACT TOX-169 AR (ng/mxLDF) xEV (rm) EVD) x 010004mgg =Reported Concentration (ug/L) CalculationUsedforGroup3,FO, GD21,Animal ID 10830F $3.0ngmLx400% O1s0mmLL x 0_0100mugg = 707 pg/ml. ADRF--DAinlaultyitoincaflacetsourt from MassLyn summary FEVV----VFionlaalmexetroafctsveoaleuxmtera(c1i.e0dmlunless otherwise noted) SM Environmental Laborators 001494 Page 63 418-018:PAGE 1-437 3M Medical Deparment Study: T-6295.25 4 Mecial Deparment Stuy: 6295.25 Analytical Report: FACT-TOX 169 LRN-EOL0IS0 Avalyica Report: FRANG-TET0O1X0116890 `Appendix G: Interim Certificate of Analysis $31 Environme ol Laboratory 001495 Page 64 418-018:PAGE1-438 3MMedical Department Study: T-6295.25 . Analytical Report: FACT-TOX-169 LRN-EO1-0180 - CenS treoAnaF lyte icae l_Laa born SaatloeD Croileegm se.PATe IEnc. Phone: (814) 231-8032 Fax: (814) 231-1or2(85143) 231-1580 INTERIM CERTIFICATE OFANALYSIS Revision 1(9/7/00) 4 CentreAnalytical Laboratories COAReference#: 023-018A * 3MPRreodfuecrte:ncP#e:FOSSD,-L0o1t8 217 Purity: 869% a |rome| Vials N(ECRPIVS) 21. CMaalgcnieusmiom 3. Sodium 45.. PNIoiotcnakseslium' 7_ Manganese [Teal mpeyGM [mms Te (@LCMS) re R(elGaetnesd)Compounds -- POAA Positive 21. 00.000081wwheei 5. L439wie 455.. <600..008040591wwwiiwimr%h 7.0001 wim [| Twn | ) 033wwe | io Trorga1 niCchAlmoorirdee (0) 25.. FBlruoomniddee 3 Nie | 7. Stoolmee f| om31 TmEA | EomEaN | emercarAbmonys || 230 Hiygdreognen | 55. sFluuorrine cosazsoita 3M Environmental Laboratory 21 TThheeoorreettiiccaallVVaalluuee ==01%78% 3+. ThTeohreteicoalVrVaalleuueec=05a.%9l5% 5. TheoreVatlvie=c6a0l% amy 21 0"sowsmm% 35 0<000p9awdwmm% 7&. 0800776wmkm 2L 0Si1mmmms 34. 0010 wa%m 21 01224e84wwehant%h 31 E17s6 hwewaitnh 5. sal was rete 001.496 Page ss 418-018:PAGE 1-439 3M Medical Deparment Study: T-6295.25 Analytical Report: FACT-TOX-169 LRN-EOI-0180 Centre Analytical Laboratories, Inc. 3P0r4o8neR:e(s8e1a4r)c2h3D1i8v0e02 Fax (814) 251-S1a2t5s3Cro(8l14)lP2Ae31-6g1850e810 INTERIM CERTIFICATE OFANALYSIS Centre Analytical Laboratories COA Reference f: 023-018A DateofLast Analysis: 0831100 Expiration Date: 08/31/01 `Storage Conditions: Frozen <-10C Re-assessment Date: 08/31/01 F"lPuuorirtiyde=, 033%) 01.0509%% +- (NsMumRofimmpeutraitlieism,pu1r9it3i%e+so,r1g.a4n5%ic+aLcCi/dMimSpuriimtpiuersi,ti0es3,88%.+41P%O+AInAo,rganic TotPaulriitym= p10fur0o%rma1lil3ttes.t=ys0=8961.39%.%09% "Potassium is expected in this salt form and is therefore not considered an impuity. pobusreirtvyebdyfoDrShCisissagmepnleer.ally not applicable to materials of lowpurity. No endotherm was "Sulfur in the sample appearsto be converted to SO, and hence detected using the dientoergramniincatainoinoninmtehteheoldemceonntdaitliaonnasl.ysTish,eeannidoinnrgescuolntfiadgerneceestwoelthliswiitnhtetrhpreestualtfiounr. Based on the results, the SO isnot considered an impurity. SHTEFABA TrHiefpluulolruooacreotbiucyarciicdacid NPFFPPAA NPoeonftalfwuoorrooppernotpaannooiiccaacciidd "Theoretical value calculations based on the empirical formula, CiFinSOyK" (MW=538) "Thie wrk was conducted undet EPA Good Laboratory Practice Standards (40 CFR 160). . COA023-018A 01 Environmental Laboratory 001497 Page2ct Page ds 418-018:PAGE 1-440 3M Mi)edical Deparment Study: T-6295.25 Analytical Report: FLARCNT--ETOOXL-01I6S90 Centre Analytical Laboratories. Inc. 3048 Research Ove Sato Calege,PA 16801 Phone: (814) 231-8032 Fax: (814) 231-1253 or(814) 231-1580 INTERIM CERTIFICATE OFANALYSIS Centre Analytical Laboratories COA Reference i: 023-0184 LC/MS Purity Profile: [CC -- CC Tma pumy -- [ wetmme% oeow -- r am m ] oa -- im Taw mA Note: TheC4and C6valueswerecalculatedusingthe C4andC6standardcalibration curves,respectively. TheCSvaluewascalculatedusing theaverageresponsefactors farvoemrtagheeCre4saponndseC6fascttoarnsdfarrdocmutrhveesC.6LainkdewCiBses,tatnhdeaCr7dvcaurlvuees.wascalculatedusingthe Prepared BC y: rSBt A BaLe222) ReviewedBy:Sci(24. Ce Iytical Laboratories the LfaboonrFaltaohreyrtMyanager, Genre Analytica LaboratoriesDate 001498 coxonaisa 3M Environmental Laboratory Page3ofs eage 67 3M Metical Depasmens Sady: T-6295.25 Sac eparmns Sty 7285.25 Appendix H: Report Signature Page 418-018:PAGE 1-441 Amlyical Reporc FLARCNTE-DTIOX0115609 Araiyica Report FTACoTrTOo:r1o69 Deahnlnao. mLoaapkner/d31S. StnuddyDirsector pBlate es DeGaece,rDVeM. PhDSpoorFopresoratve bate L he fo Kristen J. Hansen, Ph.D., PrincipalAnalytical Investigator Lune , 2001 Date Witp am K. Raaga en, Ph. Laborato Manager ocBabe ey 3M Environmental Laboratory 001499 Fage 68 418-018:PAGE 1-442 PFOS Concentrations in Rat Livers. `Southem Research Institute: Study A344.1.4 001500 418-018:PAGE 1-443 Methods `1:W5e (fibrystwperiegphatr)ewdictohntDrIolwaitsesru.eThhoimsowgaesnuasteedbtyohpormeopgaerneitzhiencgalraitbrlaitvieornfsrtoamndcaorndtsr.olWates sapliiqkueodteisnokftnohwenblaamnokunttissosufetheosmtoagrnteicaltee(.PAFObSl)anaknd+ iinntt.esmtadl. satnadndaarbdla(nPkF-OiCnt). isnttdowere prepared with each calibration curve. `aTnhyeosfamtphelsees swaemrpeleaslswoehroemowigtehniuznsepdi(k1e:d5)blbaynwkeciognhttrowlitlihveDrIhwoamtoegre. naDitleutpiroenpsarmeaddaebotove. Then an equal amountofinternal stanard (PFOC) was add to each sample. Then to both the samples and carbonate/bicarbonate buffer, satnadnd5a0r0dsuwLeofadidonedpa1irmiLngorfeDagIenwtat(e0r.,5 1 mL M. of 0.25/0.25 M tseolturtaibountwyalsammmioxneidumbrhiyedfrlyoxaindde)thaedwjuestaedddteodp2H.51m0.L5owfietthhsyoldaicuetmathey.drTohxiisdem.ixTthuere was csehnatkreinfufgoerd1athr25o0n0arplpamtffoorrm5mmiixne.r.ThAefteetrhyalnahcoeutrattehelasyaemrpilserseamroevteadkeanndofefvaanpdo.rated to dryness under dry nitrogen. The residue is reconstitued and filtered through a syringe filter into autosampler vial for analysis We then perform HPLC MS/MS using a MRM experiment on the samplesandstandards 001501 S`uSoeuythAer4Re1se4arch Insitute PEOS in Rat Livers FileName_ Sample Name CMoenea.su(raegdi) 6600228822000045 FFOO 1100990086ccoonnttrrooll 51.85523 6600228822000076 FFOO 1110590113ccoonnttrooll 0.327468838 66228822000089 FFOO 1111550054coconnttrrooll 1150826 66228822001110 FF11 1100800069ccoonnttrrooll "81206087 66228822001123 FF11 111051011ccoonnttooll "8a.9z04 66228822001145 FF11 1111550023ccoonnttrrooll "1100257 66228822001178 FF11 11010000..44mm90ook90oa 315775 66228822002119 F11 1116100000..440mmogi1kkaa 1T3e9a7s 66228822002524 FF11 1116012006..440mmgoil1kkgg 231253 68228822002245 FF11110149111..666mm4ggik0kgg 5112475 660228822002258 FF11 1116141181.66mm4ookk2aa 6051399 6228822003209 FF1111111166..664m4mogh48kag 6052017 66228822003323 FF11 1111605549 22mmoahhog. e03232 66228822003345 FF11 1111665565 22mmoglhhgg 6660542s 6600228822003387 FFOO 111160000400..44mmgglikkgg 3518022 66228822006410 FFOO T11166001300..44mmoilkgg 855 66228822004443 FFOO 1116143161664mmool0kkga 1932412 66228822004457 FFOO 1111664452 11.66mmooikkag 98109245 66228822004580 FFOO 1111864588 126momhoklgkg 98143829 6228822005512 FFOO 1111668547 22mmgghhgg 11018978 6600228822005535 FFOO 1111858022m5moka9gk 11038508 61282056 FO 1126m5ok4g 1162 "Pup and Damsampleswere mixed together during preparaton 5QL =below quantitation imi< 12.5 ng/mL. OR gig CCoanlec.ula(ntgelgd) ssaall ssaall 21.020615 asLa ssaal ssaall 260377435 13011.7852 7918.002279 111961..870502" 71486.8%95 234052,.308908 315063.213629 218919.,486605 254882081 4158550393 112123..220390 1871.302851 1a5s90s15 113539..803314 1111.0417418 "s1.501 418-018:PAGE 1-444 001502 APPENDIX J HISTOPATHOLOGY REPORT 001503 418-018:PAGE J-1 RESEARCH PATHOLOGY SERVICES, INC. 438 EPahsotneB:ut2i1r6A-v3e4n5ue-,70N7e0wFaBxr.iai2n1,5-P3A451-84930216 `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. , DAB.T. Associate Director of Research Argus Research Laboratories, Inc 905 Sheehy Drive, Building A Horsham, PA' 19044 SUBMITTED BY: _ WR Bron De)? 2002 WW. Ray Brown DVM. PhD Veterinary Pathologist December 13, 2002 001504 418-018:PAGE J-2 (ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/CHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS PROTOCOL418-018 SPONSOR'S STUDY NUMBER: T-6295.25 HISTOPATHOLOGY REPORT TAOFB CONL TENE TS Page REPORT Method cocoons RESUMS coors ssssssm--------------. sss eens sss:3 QualityAssurance Unit Statement ............... rss 8 001505 418-018:PAG3E ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/CHCLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS 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 Cr: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. [on| en[mTvom | ote|oSrez2mr2g| |[e [2Tom on [wen [oe] |[m [2[e me [oem [Ta |mmm o | wr [Di[m 2[emor m| ome | om, = EE = = [ram || mem | ww = [aTm o[oe my [omar [|] [oe[om|or|rowm s | oregon C[ovme||mmo5a| | rrrwwooTss| oreoperr |u| [ovTom|or Tows| ores [C0o [ omr o T|a2r e |Tew s s|| soorrees [we| To 5 me OTF PEpe 5Sars ero 8 SR 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 Research PathologyServices, Inc. ;- a 001506 418-018:PAGE J-4 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 gestation (rats assigned to natural delivery that do not deliver a liter) or Day 4 postpartum (rats that deliver a liter). Rats in the process of delivering were not given the testicontrol article. Male rats were used only as breeders and were not considered part of the test system. F1 generation pups were not directly given the test article, but were possibly exposed to the test article during matemal gestation (in utero exposure) or via matemal milk during the lactation period. Dosages of the FO generation rats were adjusted for the most recently recorded body weight and given at approximately the same times each day. On Day 5 postpartum, pups were sacrificed and the heart and thyroid were collected and preserved in 10% neutral buffered formalin. The in-life portionof the study, necropsies, and recording of the gross observations at necropsy were performed by the staff of Argus Research Laboratories, Inc. Representative sectionsof the heart and thyroidof one male and one female F1 generation pup from the vehicle control group (Group 1) and 2 mg/kg PFOS group (Group 13) were routinely processed, embedded in paraffin, sectioned, and stained with hematoxylin and eosin for microscopic examination. Upon completion of the. project, all raw data (remaining wet tissue, paraffin blocks, microscopic slides and histology records) will be returned to Argus Research Laboratories, Inc. for archiving. Re arch Pinoy Sonica. Ic. -- oo 001507 418.018:PAGE J-5 ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACIDICHOLESTEROL CHALLENGE AND NOEL INVESTIGATION IN RATS PROTOCOL 418-018 SPONSOR'S STUDY NUMBER: T-6295.25 HISTOPATHOLOGY REPORT RESULTS: `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 PFOS dosage groups are shown below. sDeoxse Group: 1MoM DNuammbNeurmobfePru:ps Examined: 109109 1101 59 F7 oFi] 109108 110159 TNoH.YREOxIamDi:ned No. Normal 11 11 11 11 HNoE.ARETx:amined No. Normal 11 11 11 11 No microscopic changes were observed in the heart or thyroid of the male and female pups exposed to 2 mg/kg of PFOS. The sections examined were c- within normal histologic limits. 7 Research Pathology Services, Inc. -- -3 001508 418-018:PAGEJ-6 PFO`SON-EMGEEVNAELROANTIICOANCIRDE/PCRHOODLUECSTTIEORNOLSTCUHDAYLLOEFNGE AND NOEPLROITNVOECSOTLIG4A1T8I-0O1N8IN RATS `SPONSOR'S STUDY NUMBER: T-6295.25 HISTOPATHOLOGY REPORT SUMMARY: one MfiecmraolsecopFi1c egexnaemriantaitoinonpwuapsfmroamdedaofmstheofheeaarcthanodf tthhyeroviedhfircloem oconnetrmoallgeraonudp (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/kgof PFOS. Research Pathology Sevcee, ne. -- - - " 001509 418-018:PAGE J-7 `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 QUALITY ASSURANCE UNIT STATEMENT rC5eo3poutrrht spGeoupfsRaAtlrelyasateAsoapsnresccrohtarsnPioacfehaotslhUeonugktdyoisfSseRuaeerssepereaoa,crbecosIhsvinen.agNi,ananmldviwoceegrryoeesncSoueppaiectcTeosadl.Tidiae1ds.praeepccaricoatnodiogman,pnw1h0aicihhsnte1owpsSaitanphroooldcoeaagidrGcroeeOovpsdaelrauLaoatitaiimnsoignttPnaarens.dd Pracics reuslpeeldnoharnosc. SuotndDnes s Mhioccs UtSeFitFdorngdpsaosonob)o Progt,Sipa2o r.cn16e5m%nc onsv5G6i3 Sond00gdst,Go arPritnRgods Fol.21CaF rs, CGooeptmeonyEcnoCnOoECCmDosmmesuLno1ia8ctpa)yim,anCria2t0ee6ndo5 ncoorpo 28.rw 1e 5189csecdaorsyohocEtxvo,OnBcroonrl aapresNiorcfMoash 2 8Wt (8).GodLotrorc SrStySis nOgMG oLnesonQfuroalemittyeteAdsspurrueasnhscee,ncUSonnatgdsnoudcoafbOarpsereSadtyiinn.gsprTeocoicouSnsiuweensreydpeplreotmoedCpaAs ensheocwGinooobnedlsoLw+.abnoTorheeirresdwPerreoaetnoirdreovvsi.a Port smite 10 he Sy Decoorn Decaoe13r. 2002 DDaptescoifn Suvetass |DataemssRespeomreted ioaStueiRrabpreecsts 4QGui0mp9aa0no1i MaPsTteeormmiSaecihsoednule GGwaoaoov ii12i1i3a0a:2 GaGGnooawo Ew`mSoeeosnananya GGGaanoao; Tijananananmaee IGGTAiRSDo0T HosontaavoneprEatntieydaioyn [ GGoaw 7 aJnaanesse GGCoE0maT!t FReOspnaanmbrPesrceeospiannrgea GGowssen iTToaanees oB0BDiI,a1n0701| FDrsohrespetrt 0908T0o,ae10z1701 1a3n1s30:2 RH areh aW. RrarH,Zo65kbo,sB85S anor Soe Quaity Assurance Unt RessochpamoogyServes.oe. = 001510 APPENDIX K HISTORICAL CONTROL DATA 001511 SUMMARY OF REPRODUCTIVE INDICES Cr:CD(SD)IGS BR RATS DAY 21 C-SECTION 418-018: PAGE K-1 PERIOD JUNE 1998 - SEPTEMBER 1999. NUMBER OF STUDIES 13 NUMBER OF RATS: TESTED 252 PREGNANT 23 FOUND DEAD 1 ABORTED 0 DELIVERED 0 NUMBER OF RATS PREGNANT AT CAESAREAN-SECTIONING 234 NUMBER OF RATS WITH SINGLE CONCEPTUS LITTER: LVE 0 RESORBED 0 ABORTED 0 % PREGNANT AVERAGE # CORPORA LUTEA AVERAGE # IMPLANTATIONS AVERAGE LITTER SIZE AVERAGE # LIVE FETUSES AVERAGE # DEAD FETUSES AVERAGE # RESORPTIONS, AVERAGE # EARLY RESORPTIONS. AVERAGE# L ATE RESORPTIONS MEANOr% ES 176 149 145 00 05 0s 00 RANGE/STUDY MEANOr% (87.5100) (164-191) (140-163) (136159) - (:1-1.4) (1-1.4) 0.) 001512 418-018:PAGE K-2 SUMMACRrY:CODF(SRDE)IPGRSOBDRUCRTAITVSE INDICES 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 (G) AVERAGE FOR FEMALES (G) AVERAGE % DEAD OR RESORBED CONCEPTUSESILITTER RANGE/STUDY MEANOr% ~~ MEANor% 303 (125714) 00 - 1000 - 494 430-57.) 528 (5105.48) 5.40 (6.15563) 512 (4.82:529) 33 (08:88) 001513 SUMMARY OF MATERNAL NECROPSY OBSERVATIONS Cr:CD(SD)IGS BR RATS - DAY 21 C-SECTION 418-018:PAGEK-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 UVER Left lateral lobe, tan area. UTERUS Moderate hydrometra. INGUINAL AREA `Subcutaneous, tan mass. onrightside RANGE/ STUDY N % N% 1040 01 (040) 1040 01 (042) 1040 01 (045) 001514 SUMMARY OF FETAL GROSS EXTERNAL ALTERATIONS Cr:CD(SD)IBGRS RATS - DAY 21 C-SECTION 418-018:PAKG-E4 PERIOD JUNE 1998 - SEPTEMBER 1999. # STUDIES INCLUDED 13 # LITTERS EXAMINED 234 # LIVE FETUSES EXAMINED 3083 ALTERATION EYES) Eyebuigesdepressed JAWS Micrognathia HINDPAW. Extradigitpresent TAL `Threadiike RANGE /STUDY N % N% L 1 043 01 (042) F 1003 01 (003) L108 01 (042 F100 01 (003) L104 01 (045) F 1003 01 (003) L104 01 (043) F 1003 01 (003) L: LITTER INCIDENCE F: FETAL INCIDENCE 001515 418-018:PAGE K-5 `SUMMARY COCFDF(ESTDA)LISGOSFBTRTIRSASTSU.E ALTERATIONS DAY 21 C-SECTION PE# RSTIUODDIES INCLUDEDJUNE 198 - SEPTEMBER 19889 ## FLIETTTUESRESSEEXXAAMMIINNEEDD 1214850 ALTERATION N% RANOGN E/%STUDY BRAIN Dilation of lateralventricles L 2 1.11 02 (083) F206 020012) HEART Septal detect FLo1o0s08 001100004028) VESSELS Umbilicalartery,descends intnoloemfitnoalteuanratreyry,baadbsdeenrt Avonaacphaesasaensddeosrospahlatgoutshe Lefftciarotlghiedrrhiigshetstctaortoohteid Right carotid rises to the: cflgahvtioanltherightsw- ~~ Pumonaryartery. small Somiunarvalve,smal Ductottuheslaerfttesruiboscilsaavtiaanched Great vessels, iansposed FL 33 01.2667 FL o22 01.1161 FL 11 000586 FL11005.08 FL 11 000586 FL 11 000586 FLo 11 000585 FL1100508 FLo 2 2 1.11 016 0022((0001.21)) 00220(001823)) 00411 ((000462)) 00-110(-00482)) 0011000420)8 00-11(00028) 0011(0004028) 00.-11(00.-0462)) 0-1 (043) 01007) uns Aabspenatnidcacrdacaiobles, FLo 11 000886 004110(000482)) KIDNEY(SP)eis, sightdiation Pens, marked lation FL1100508 00110000475) FL 11 005068 00-110(000475)) FL LFIETTTAELRIINNCCIIDDEENNCCEE 001516 418-018:PAGEK-6. SUMMARY OF FETAL SKELETAL ALTERATIONS Cr:CD(SD)IGS BR RATS - DAY 21 C-SECTION PERIOD JUNE 199-8 SEPTEMBER 1999 # STUDIES INCLUDED 8 #LITTERS EXAMINED 180 # FETUSES EXAMINED 1332 ALTERATION SKULL Eye socket: small Mandibles: short No% L105 F 1.008 L105 F 1.008 RAN/ SGTUEDY Nw 01 (042) 01 (006) 01 (042) 01 (006) VERTEBRAE `Thoracic: Centrum,bifid Contum.fusedto arch + 4present L 4 222 F 4030 L 1 056 F 1.008 L 105 F 1008 01 (048) 01 (006) 01 (04.8) 01 (006) 01 (048) 01 (008) Lumbar: Fused 8present +Centrum, fused to arches L211 F 2 015 L 105 F 1.008 L 1.05 F 1.008 01 (048) 01 (006) 01 (048) 01 (008) 01 (048) 01 (006) RIBS `CervicalRib(s)present L 12 667 F 14 105 One or more,wavy L 633 F 8 060 One or mare, incompletely ossified (hypoplastic), ornot ~~ L 2 111 ossitied F302 Fused L 105 F 1008 4present L 10% F 1.008 05 (0-208) 06 (0-35) 02 (095) 03 (018) 02 (08.1) 03 (018 0011 ((000462)) 01 (048) 01 (006) Li LITTER INCIDENCE F: FETAL INCIDENCE 001517 418-018:PAKG-E7 `SCUHMCMDA(RYSOD)FIFBGERTSARLASTKSE-LDEATYAL21ALCT-ESREACTTIIOONNS ALTERATION MANDuUpBlRicIaUteMd No% RAON N/SGT%UEDY LF o11000s8 0011 ((000485) STE`ORneNEoBfRmAoEre incompletely Aossysmimeetdroifcnotossified Duplicated LFo4e0232 LF 2210115 FL1100058 0022 01o2) 0011 ((004058) 0011 ((000485) XIPHDuOpIlDicated LFo1t 000ss 01 (045) 01 (008 HIENxDtLrIaMBdigi present Lot os 01 (045) 1 emur,bent FL1100088 0011 ((004088) : F 1008 01 (008 LF:: LFIETTTAELRIINNCCIIDDEENNCCEE 001518 SUMMARYSKOEFLEFTEATLALAVOSESRIAFGIECASTION SITES CrDi:ACYD(2S1D)CI-GSSEBCTRIRONATS 418 018:PAGE K-8 #PESRTIUODDI:ES INCLJUUDNEED1998 - SEPTEMBER 19959 ##LFIETTTUESRESSEEXXAAMMIINNEEDD 1313810 SKELETALAVERAGES MEAFNETUSLITTREARNGEISTUDY HVCYEEORRITVDEIBCRAALE 098 700 "THORACIC 13.07 CLASUAUCMDRBAAALLR 35.0902 7a RSITBESR(NpaUirMs) MANUBRIUM 13.05 100 SXTIEPRHONIADL CENTERS 310%0 FOREPAWS (Calculated as CMAERTPaAvACeLrAaSRgPe ApLerSlimb) 400000 PHoAarLsA.NGES 560208 HINDaPvAeWraSge(Cpaelrcumlbat)ed as TARSALS 02 oPiHMGAErTL'AAsTNAGRESSALS 54.0800 521 (0.96-1.00) - (13.03-13.14) z(5855.97) (a1769 (13.02-13.12) (29z8400) (39>-9400) (owas) (000m (4.73-4.87) (s81:650) cu1s19 APPENDIXL STATEMENT OF THE STUDY DIRECTOR 001520 ,PRIMEDICA 418-018:PAGE L-1 saog n Baases PROTOCOL 418-018: - ONE GENERATION REPRODUCTION STUDY OF PFOS - MEVALONIC ACID/CHOLESTEROL `CHALLENGEAND NOEL INVESTIGATION IN RATS SPONSOR'S STUDY NUMBER: T-6295.25 Tis nl report cel ects oe rw dace duis peormnce STATEMENT OF THE STUDY DIRECTOR of the study. No deviations from the U.S. Food andDrug Administration (FDA) Good Laboratory Practice Regulations; Final Rule, the Japanese MinistryofHealth and `Welfare (MHW) Good Laboratory Practice Standardfor Safety Studies on Drugs" and `the Organisation for Economic Co-operation and Development (OECD). The Revised OECD PrinciplesofGood Laboratory Practices" occurred that affected the quality or integrity of the study, with the exceptions in the bulleted list bellow: There were two study directors for this study; oneforthe in-life phaseandoneforthe analytical phase. The in-life study phase was considered to endatthe generation and `shipmentof specimens. The analytical study phase was considered to start at the + Automated aa cllcton ystemsav notbesnvaldeas eid sccding 0 receipt ofthese specimens for analysis. Since the technical performance ofeach phase was entirely separate, no effect is expected from this exception. 21 CFR 58.130(c). The hard copy printout is considered the raw data. The rtabilityofthe reference standard and internal standard were not determined. Son vo pa oe Associate Director of Research nS recor Argus Research Laboratories, Inc. a U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. 1 `apanese Ministry of Health and Welfare (1997). Good Laboratory Practice . - Organisation for Economic Cooperation and Development (1998). The Revised OECD Principles ~ Good I aboratory Practices [C(97)186/Final). VU1S5<1 APPENDIX M QUALITY ASSURANCE STATEMENT vu1sR2 rPRIMEDICA 418-018:PAGE M-1 Argus BReseeaCrmchoLnabor5aSetoraiaes gnInc 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 StandardforSafety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. `European Economic Community (1989). Council decision on 28 July 1989 on the acceptance by `he European Economic Community of an OECD decision/recommendation on compliance with principlesof good laboratory practice. Official Journalofthe European Communities: Tegislation. 32 (No. L 315; 28 October): 1-17. `The undersigned indicate that the report is an accurate representationofthe raw data. Data `provided by the Sponsor or a subcontractor were not audited by the Primedica Argus Quality Assurance Unit. `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: near npscion Dass _ pD TsF y DaFs Som TestArticle Preparation Blood Collection Caesarean-Sectioning Tissue Collection Natural Delivery/Litter `Oam/Litter Sacrifice Milk Collection 04 OCT00 310CT00 310CT00 310CT 00 02 NOV 00 06 NOV 00 06 NOV 00 11 OCT00 310CT00 23 NOV00 03 NOV 00 03 NOV 00 08 NOV 00 08 NOV 00 110CT00 310CT00 03 NOV 00 03 NOV 00 03 NOV 00 08 NOV 00 08 NOV 00 U01523 418-018:PAGE M2 Observations Inspection Phase --_mspection Date(s) Date(s) Findings Date(s) Findings Submitted to Study Submitted to Director Management In-Life Raw Data Formulations Raw Data Report Tables Report Text Soin Bapn i8JANOI, 19JANOL, 22JANOI to "6 JAN 01 and "9 JAN 01 to 31JANO1 01 FEBO01, 05 FEB01, 07 FEB 01 to EERO 09FEB01 and 19 FEB01 25 FEB Ol to 28FEB 01 Se5FFEEBB o0l1 ntod 23 MAR Ol to "I MAR 01 17MARO01, 30 MAR01 and 02APR01 to 03 APR 01 to 20 aAvPRRo0O1L, 13 APR 01 and 16 APR 01and 17 APR 01 18 APR01 04 MAY 01 and 0177M3A00Y101 i00CT01 30OCTO01 JAN O02 04FEB 02 27 MAR 02 10 DEC02 LBS sso 135.12 Mafthew J. Vaneman, B.S. Due Manager, Regulatory Compliance. 01 FEB 01 01 FEB01 19 FEB01 19 FEB01 01 MAR 01 29 MAR 01 01 MAR 01 29 MAR01 03 APR 01 03 APR01 16 APR 01 16APR 01 17 APR 01 17 APR 01 18APR 01 07 MAY01 ren 100CT 01 310CT 01 31JAN 02 04FEB 02 27 MAR 02 10 DEC02 18 APR01 07 MAY 01 173uL01 100CT01 310CT01 31JAN02 04 FEB 02 27 MAR 02 J0DFC 02 001524 SenEngen regen CyathiaM. Kelsch Date FQuranlviitpyAesAsuudriatnocreAssociate and