Document zQ7qdLV5vDVy1GXmNRNMzm7BR

373 7 ff ORIGINAL COVANCE ARIRE- 0790 Sponsor: 3M St. Paul, Minnesota FINAL REPORT Study Title: 4-Week Range-Finding Dietary Toxicity Study with N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) in Rats Author. ! PeterJ. Thomford, PhD. Study Completion Date: July 5, 2000 Performing Laboratory: `Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595 Laboratory Study Identification: Covance 6329-224 `Sponsor Project Identification: 3M T-6314.2 Page 1 of 373 - 2< 23 = 23 22 = 43 2R Contain NO CB! - 00423 1AnIRIAC Covance 6329-224 _--_ Tew QUALITY ASSURANCE STATEMENT `This report, with the exception of Appendix 7, has been reviewed by the Quality Assurance Unit ofCovance Laboratories Inc., in accordance with the Food and Drug Administration (FDA) Good Laboratory Appendix 7 was generated by and is the Practice Regulations, 21 CFR 58. The responsibilityofPathology Associates data in International. study director aTnhde sftouldlyowdiinrgecitnosrpemcatniaognesmweenrte. conducted and findings reported to the Tnspection Dates From To 0067//0143//9988 0067//0143//9988 09/16/98 09/25/98 10/01/98 10/09/98 10/19/98 10/22/98 06/02/99 06/02/99 05/02/00 05/03/00 Phase PProostloicfoel Review Data Review Data Review Report Review Protocol Amendment Review Report Review Date Reported to Study Director and Study Director Management 0067//0143//9988 09/25/98 10/09/98 10/22/08 06/02/99 05/03/00 Representaldie Quality Assurance Unit 0DaSte J 2000 2 00424 CovanMceT6633291-42224 STUDY IDENTIFICATION 4-Week Range-Finding Dietary Toxicity Study with N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) in Rats Test Material N-Methyl Perfluorooctanesulfonamido Ethanol (MeFOSE, T-6314) Sponsor 3M Toxicology Services Building 220-2E-02, 3M Center St. Paul, Minnesota 55144-1000 Study Monitor Andrew M. Seacat, PhD 3M Toxicology Services 651.575.3161 Alternate Study Monitor Marvin T. Case, DVM, PhD 3M Toxicology Services 651.733.5180 Study Location Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595 Study Director Peter J. Thomford, PhD Covance Laboratories Inc. P.O. Box 7545, Madison, Wisconsin 53707-7545 608.241.7207 Study Timetable Study Initiation Date In-Life Start Date In-Life End Date Study Completion Date June 8, 1998 June 12, 1998 July 13,1998 July 5, 2000 3 0425 CovanMcTe -636219-4224 KEY PERSONNEL 4-Week Range-Finding Dietary Toxicity Study with N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) in Rats Study Director Study Toxicologist Study Coordinator Supervisor, Small Animal Toxicology Supervisor, Dose Formulation Supervisor, Chemistry/Tox Support Supervisor, Laboratory Animal Medicine Clinical Pathologist Supervisor, Clinical Pathology Anatomical Pathologist Supervisor, Anatomical Pathology Peter J. Thomford, PhD `Thomas E. Ryan, BS Nil van Bruce-Konuah Nathan E. Snortum, BA, BT, ALAT Dixie Bushee, BS, LATG Brian Schoenike, BS DonnaJ. Clemons, DVM Diplomate, ACLAM Robert L. Hall, DVM, PhD Diplomate, ACVP (Clinical Pathology) Ronald Markevitch, BS, MT (ASCP) Richard Hamilton Bruner, DVM Diplomate, ACVP Pathology Associates International Deborah Pirkel, ALAT 4 cse4azs PURROSE uss CONTENTS CovanMce66312942224 Page 3 HousingandMAEREIOE ..c...ccccosssssmermmmsssmemmusssmmsssmmssssssersesseesssessssssese1ss2s Group Designations and DIEtary LEVIS .........ovwcrcersrrssssmmsssmsssssrns 13 Clinical ODSETVAHORS ...ccuvvsssssssmsssssssessmssssssseessssssssssssssmsssssssssssssssssssssssssssssenss 16 BOY WEIGccRo IS errcrssssrororsosossssnsesssnensnsnsnssissssssssessssesesessn1n6s CSHerCuAm PPerfAluNorOooIctaOneGSYulf.onricrAcridtLsevesl n(PnFOsS)tDeetceromisnaotisono..s............r.....o.... 1166 NECTOPSY c..coccnrsrsassmmrismessmssssseressssssssssssmessms sssssssssssssssssssssssssessssss1ss1s OFZAR WEBS vecsrsmsimmsmmnsmmsnssmmsmmmsmmessesssnern1s Cell Proliferation Tissue Collection and Immunohistochemical Evaluation.................. 18 Palmitoyl-CoA Oxidase Tissue Collection and ANalySes..............ccu.corwessssseesrissssnens 18. s cseazy CONTENTS (Continued) CovanMceT6&3219-42224. Page Body Weights and Body Weight CHANGES vrs: 2 `Serum Perfluorooctane Sulfonic Acid Level (PFOS)Determination ...................23 CF ell Pre oliferation Tissue Collection and Immunohistochemical EVAIUa--tion--...--...--........24 Ee CONCLUSIONS..ccrrrrmermsmmmmsmmsmmmsmmsssssssssssmssmsnn 25 SIGNATURES. 20 PATHOLOGY REPORT... 28 (COMMENTS ONTHEDATA ccs: 33 COGDeEnSer,alACBoBdReEsVaInAd TAIBONDSI,CAVNHDOUNNSI.T.S.......rrrrssrsssssssmss 3358 CAbobdreesvfioartiColnisniacnadl PUniAtsBfoOr CIlinOicRal YHE.ma.tO.IO.gYrrrevrnsrsssensrs 31 40 `Abbreviations `Abbreviations and and Units Unit for for Clinical Clinical CREMISITY UTIYSIS evens veers 42 4. Codes for ARRIOMCAl PALROIOEY...rvss 45 TAB1LEReSsults of HOMOgeneity ANaIYSes (PPI) ..evrsrrsvsssss 41 2 3 ResOufSltabtilisty ARBIYSES Results of Dose Preparation A(RPAPITY)Sev S (PPI)r ... sSU49 4 5 SSuummmmooaffaCBrloirndyiycyaWleOigBhSt EDaTtVa A(8O) Ne S...v ....e vrrssn sssss nssse: s: 5543 6 7 Summoaf Brodyy Weight CRANE Dat (8) vrs: SummaryofFood CONSUMPHON DA (8)... 38 62 8 9 SSuummmmaarryyooff TCleisnticMaalteHrEiMaAl OCIoOngsuYmDptaitonA.Da.t.a .(M.E./.Kgr/sdvayv)s.esrsmvsresn-es6068 10' Summaryof Clinical CRESIEY DA... 11 SummaryofClinical Urinalysis Data 12 sess:16 6 004z8 CovanMceT6633291-42224 `CONTENTS (Continued) Page TABLES 12 Summaryof Absolute Organ WeightData(2) ..........ccccuecsseeresersssesssssrsserrTe8s 13 SummaryofOrgan-t0-Body Weight PErCENtages.......v.v.vrerrvrerrrrssene8n1 14 SummaryofOrgan-t0-Brain Weight RAtOS............ccceerseerssssssessennsssessssssn8s8s 16 Incidence OfMICrOSCOPIC OBSEIVALONS ......ccc.vvvvevsvserssseseeresessssssssssessnsre8rn9s 17 Incidenceof Severity of Selected Microscopic ObSErVations............c....veweuseree9r7s PrOtOCO! DEVIBONS ...cvccevvrervrsssssssssrssrrmssessssesssssssssssssssssssesesssssssssssssssasssnes9s9s Protocol AMERMIENt NO. 1 ..c...couuummssmmmmsssmmsssesmssssssssssasmesmsensmm1sm7e Individual Body WeightData (2) .....c..oevewseserssesmssosersmersssosms sss 134. Individual Food Consumption Data (8) .........wwsseewesremssersssssssssssssseesessssesesns 139. Individual Test Material Consumption Data (mg/kg/day).............ccceoversrsrsrssers 143 IndividualClinical HEMAOIOGY DaA...vv.vvvvrvrseerrrssrssssrssssssssssnsessessscssssssesss JT Individual Clinical Urinalysis Data...............coceoussseeessisssssssssssssssssssssssssesssssessessss 167 Individual AbsoluteOrgan Weight Data (8) ...........ccccuveerrrusseseesssssssssssssessssssees 180 Individual Organ-to-Body Weight PErCentages...............oouuusescessssssessssssssresssees 192 Individual Organ-to-Brain Weight RALOS ............ccccceeeeercsnssssessenerenssssssrsssmnsoeress 204 Individual AnimalPathology Datd.........euveveererererrrvsrrorsmssesseneneononn 216 Coll ProRRration REPO cccns eccmcnssusmmmmmssmsssssersmsssessssssessessssmsssssomeen 500 , 00429 ConTe se52e24 ABSTRACT `The purpooftshies study was to assess the toxicityof the test material, N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) when administered inthedietto ratsforatleast 4 weeks. Six groups of Crl:CD(SD) IGS BR rats were exposed to N-MeFOSE in the dietforat least 4 weeks. Eachgroup contained six males and six females. The dose levels were . 0 (control group), 1, 10, 30, 100, and 500 ppm. Food was providaedd libitum, except when animals were fasted. Water was provided ad libitum. The animals were observed twice daily (a.m. and p.m.) formortalityand `moribundity. At least once each week, eachanimal was removed from its cage and examined for abnormalities and signs of toxicity. Body weights and food consumption data were collected twice weekly for at leas4t weeks. Blood and urine samples were collected for hematology, clinical chemistry, and urinalysis tests from all surviving animals. after 4 weeksoftreatment. After at least 4 weeksoftreatment, blood was alsocollected fromallsurvivinganimals for serum perfluorooctane `sulfonic acid (PFOS) analyses. On Day 32, theanimals were anesthetized, weighed, exsanguinated, and necropsied. At necropsy, macroscopic observations were recorded, selected organs were weighed, and selected tissues werecollectedand preserved. Samples of liver were collected from all surviving animals for palmitoyl-CoA oxidase activity (by Covance) and proliferation cell nuclear antigen (PCNA) evaluation and liver PFOS analysis (by the Sponsor). The animal that died on test was also necropsied, but organ weights were not recorded. Microscopic examinations were done on tissues from each animal. One animal given 500 ppm N-MeFOSE died on Day 25. Allother animals survived to the scheduled sacrifice. No clinical observations were noted that were considered to represent primary effects of the test material. Lower body weight, body weight gains, and food consumption in animals given 500ppmwere test`material-related. Dietary administration of N-MeFOSE at a dose level of 500 ppm for approximately 4 weeks was associated with several effects on clinical pathology test results including `moderately lower red blood cell count, hemoglobin, and hematocrit; lower absolute eosinophil count; mildly higher urea nitrogen; moderately higher albumin and mildly to 8 00430 CovanMcTe -636291-24242. moderately lower globulin; markedly lower cholesterol; mildly to moderately higher total bilirubin, aspartate aminotransferase, and alanine aminotransferase; and moderately higher hepatic palmitoyl-CoA oxidase. Of uncertain relationship to administration of N-MeFOSE `werelowerurine pHformalesfed500ppm andsmalldifferencesforanimalsfed 100ppm including higher urea nitrogen, albumin, and alanine aminotransferase (males only) and lower cholesterol.Ofthedifferences for animals fed 100 ppm, only the difference for alanine aminotransferase was statistically significant. Mean absolute and relative (tobrainand body) liver weightsforallmales and females given 100 and 500 ppm N-MeFOSE were significantly increased over control values, and these variations were regarded as treatment-related. All additional mean organ weights, `which varied significantly from control values, were considered to be within the range or normal biologic variation, or were manifestationsofslight weight loss associated with physiologic stress. `Treatment-related microscopic findings were restricted to theliverand consisted of minimal to severe centrilobular hepatocellular hypertrophy. Hypertrophic changes were slightly more severe in males; and at the high-dose level, liver cell swelling in several males was associated with acute necrosis. Necrosis was attributed to restricted blood supply (ischemia) from swollen liver cells ratherthandirect hepatocellular damage. Additional microscopic findings were consistent with common, spontaneous alterations in laboratory rats or changes associated with stress, nutritional deprivation, or tissue processing artifact. Based on the resultsof this study, dietary administrationofN-MeFOSE to Crl:CD(SD) 1GS BR rats for at least 4 weeks resulted in adverse effects at a dose levelof500 ppm. `The no-observable-adverse-effect level was determined to be 100 ppm. 5 00431 PURPOSE CovnSceM 6T36291-42224 The purposeofthis study was to assess the toxicityofthe test material, N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) when administered in the diet to rats for at least 4 weeks. REGULATORY COMPLIANCE `The study was conducted in compliance with the FoodandDrug Administration Good Laboratory Practice Regulatioanss set forth in Title 21ofthe US Codeof Federal Regulations, Part 58, issued December 22, 1978 (effective June 20, 1979), and with any `applicable amendments. TEST MATERIAL AND VEHICLE `Test Material "The test material, N-Methyl Perfluorooctanesulfonamido Ethanol (MeFOSE, T-6314), Lot No. F-11364, is anoffwhite powder. It was received at Covance on August 3, 1995. Information on synthesis methods, stability, purity, composition, or other characteristics that define the test material is on filewiththe Sponsor. The test material was stored at room temperature. Vehicle `The vehicle was acetone (Spectrum Quality Products Inc., Gardena, California), Lot No. LH0253 (expiration date: June 2000). It was received at Covance on June 23, 1997. "The vehicle was stored at room temperature, Information on synthesis methods, stability, purity, composition, or other characteristics. that define the acetone is on file with the manufacturer. 10 00432 Covance 6329-224 - OO OO OO wre Reserve (Archive) Samples A reserve sample {approximately 5 g)ofthe test material wastakenand stored at room temperature. These samples will be transferred to the Sponsor after authorization from the Sponsor. Disposition Remaining test material was retained for future use (see Protocol Deviations page for exception). TEST SYSTEM Test Animal Male and female Crl:CD(SD) IGS BR rats were obtainedfromthe Raleigh, North Carolina, facilityofCharles River Laboratories, Inc., on June 2, 1998. The animals were 3110 37 days old at initiationoftreatment. The males weighed from 144 to 194 g, and the females weighed from 114 to 158 g at initiationoftreatment. Identification Each animal was assignead temporary number upon arrival. Before initiation of treatment, a microchip identification device was implanted into each animal. After randomization for placement on test, each animal was assigned a permanent number, and the microchip was coded with the permanent number. All data for ananimalare recorded under these numbers. Acclimation Forty-one males and 41 females were received on June 2, 1998, and acclimated in Animal Room 349 for10days before initiation of treatment. In general, anima in this shipment appeared healthy. During acclimation, the animals were examined for abnormalities indicativeof health problems, and body weights were recorded for all animals at randomization. 1 00433 Covance 6329-224. -_ ure Housing and Maintenance `Animal Room 349wasused for this study. Environmental controls for the animal room weresettomaintain 18 to 26C, arelativehumidityof 30to 70%,and a 12-hour light/12-hour dark cycle. Variations from these conditions are documented in the data and are considered to have had no effect on the outcomeofthe study. Theanimalswere housed individually (except for the first 7 days of acclimation when `animals were group-housed) in stainless steel, screen-bottom cages. Certified rodent diet #5002 meal, (PMI Nutrition International)wasprovided ad libitum, except when animals were fasted. Thediet is routinely analyzed by the manufacturer for nutritional components and environmental contaminants. The results are on file with Covance-Madison. `Water was providaedd libitum. Samples of the waterare analyzed for specified microorganisms and environmental contaminants.Theresults are on file with Covance-Madison. Therewereno known contaminants in the diet or water at levels that would have: interfered with this study. Animals not selectedforthe study (five males and five females) were removedfrom the study room and used for training procedures. JRuasttsifhiisctaotriiocnally have been used in safety evaluation studies and are recommended by appropriate regulatory agencies. PROCEDURES This study was conducted in accordance with the Protocol dated June 8, 1998, and Protocol Amendment No. I. The protocol, protocol amendment, and protocol deviations. are in Appendix 1 2 00434 Covance 6329224 -_ MTeu2 `The animalswere examined by alaboratoryanimal veterinarioann June 10, 1998, and found to be suitable for study consideration. Selectionofanimals forthestudywas based on clinical observations, body weights, and otherdataasappropriate. Animals were assigned to treatment groups using a computerized blocking procedure designed to achieve body weight balance with respect to treatment group. At the time of randomization,theweightvariationoftheanimalsfor eachsexuseddidnotexceed 2 standard deviationsofthe mean weight. Group mean body weights were analyzed using Levene's test for homogeneityofvariance at the 5.0% probabilityleveland found to be homogeneous. Animals were assigned to the study according to the following design: Group Designations and Dietary Levels Number of Animals Dietary Levels Group Male Female (ppm MeFOS)* T (Control) 6 6 0 2 (Low) 6 6 1 3 (Low-Mid) 6 6 10 4(Mid) 6 6 30 5 (Mid-High) 6 6 100 6 (High) 6 6 500 a Dose levels were expressed asppmof MeFOS. b. The control animals received the basal dict only. Dose Preparation Dietary concentrations were based on the test material as supplied. Diets were prepared pretest for homogeneity, and twice for use in the in-life phase. PreparationofDiet for Group 1. The appropriate amountof diet was weighed into a labeled container, and acetone was added at the same concentration as the high-dose: concentration. `The combination of the diet and acetone was then mixed for 15 minutes. PreparationofDiet for Group 6. Each dose level was prepared independently. A specified amountofdiet was weighed into a labeled Hobart mixing bowl. The required `amount of test material was weighed and transferred into a labeled container. Approximately 5mLofacetonewasadded to the container and mixed manually. 13 00435 CovanMcTe -6362391-24224 Incrementsofapproximately 5 mL acetone were added as necessary until the test material haddissolved.Toprepare apremix,thediet wastransferredinto a labeled Hobart `mixingbowl.Thetestmaterialandacetone wereaddedtothemixingbowl,overlaidwith 2 portionofdietfromthe mixing bowl, and thoroughly mixed. Aportionofdietfromthe mixingbowlwastransferrteod a secondmixingbowl,mixedmanuallytorecoverresidual test material,and returnedtothe firstmixing bowl.Thecontentsofthe mixing bowl were thoroughly mixed. PreparationofDiets for Groups 2through 5. Each dose levelwasprepared independently. Aspecified amountofdiet was weighed into a labeled Hobart mixing bowl and a specified amountofdiet for Group6 was weighed for cach diet. A pocket was forminethde feedinthemixingbowlandtheamountofdietforGroup 6wastransferred to the pocket. The contents ofthe mixing bowl were thoroughly mixed for 10 minutes. Samples for dose analyses weretakendirefcrotmlthye mixing bowl. The prepared test diets were stored at room temperature in covered containers until dispensed into feedingjars. Retention Samples `Samples (approximately 100 g) were taken from cach dose preparation sampled for dose analysesand stored at room temperature. These samples were discarded on December 9, 1998 (see Protocol Deviations page for exception). Dose Analyses Analyses for the concentration of test material in the dose preparations were done by Covance using an analytical method, MP-M324-MA, supplied by the Sponsor and validated by Covance. Homogeneity was determinedforall test material dose preparations once pretest. One sample each (approximately 100 g) from the top, middie, and bottom of the dose preparations mixed for homogeneity analyses was collected, divided into three subsamples. for extraction and analyzed for test material content. All samples were stored at room 350436 14 CovanMceT6E3219-42224 temperature until analyzed. In addition, one sample each (approximately 100 g) from the top, middle, and bottomofthe 1-ppmdose preparation mixed for the in-life portionofthe study was collected, divided into three subsamples for extraction and analysis, and analyzed for test material content. To evaluate the stabilityofthe test material in the diet,foursetsofsamples (approximately 100 g each) were taken from the highest test material concentration used for the study. One set was analyzed on the dayofmixing; asecond sampleofthe high-dose preparation was stored at room temperature for at least 19 days, then analyzed. `The third sampleofthe high-dose preparation was stored at room temperature for 32 days, then analyzed. Another sampleofthe high-dose preparation was stored at room temperature for 62 days, then analyzed. The remaining sampleofthe high-dose preparationwas storedin a freezerset to maintain -10 to -30Cfor weeks,then analyzed. In addition, three samples (approximately 100g each) were taken from the low-dose level preparation mixed for the in-life portionofthe study and analyzed. `Homogeneity samples collected from the middle ofthe low-dose preparation were analyzed on the dayofmixing and used as the baseline value. Samples (approximately 100 g)fromalldose preparations were analyzed. The homogeneity sample collectedfromthe middleofthe low-dose level preparation mixed for `Weeks I throug4hwasusedfordoseconfirmation.Allsamples were stoatrreoodm temperature until analyzed. Methodof Administration Dietary admixture was used because the potential routeofexposure in humans is oral. `The dose preparations were administered ad libitum for at leas4t weeks, unless otherwise specified. 00437 15 CovanMceT6.3829I-24242. Clinical Observations Theanimals were observed twicedaily (a.m. and p.m.) for mortality and moribundity. Signsofpoor health or abnormal behavior were recorded as they were observed. At least onceeachweek, eachanimalwasremovedfromitscageandexamined. Anyunusualor `abnormal findings were recorded. Body Weights Individual body weight data wererecordedon the firstdayof treatment and twice weekly thereafter. FInodoivdidCuoanlsfuomopdtcioonnsumption data were recorded twice weekly during treatment. Serum Perfluorooctane Sulfonic Acid Level (PFOS) Determination After at leas4t weeks of treatment, animals were fasted overnight, anesthetized with carbon dioxide, and blood (as much as possible) was collected via cardiac puncture from all surviving animals. All samples were collected without anticoagulant, allowed to clot, at room temperature and centrifuged. Serum was harvestedandstoredin a freezer set to `maintain -60 to -80C unil packed on dryiceand shipped to the Sponsor for analyses. The samples were analyzed for PFOS. Results of analyses will be reported separately by the Sponsor. Clinical After at Pathology least 4 weeks of treatment, blood and urine samples were collected from cach animal. Animals were fasted overnight, and urine was collected chilled (approximately 16 hours before blood sampling); water was provaidldibietudm. The animals were anesthetized with carbon dioxide; blood was collected via cardiac puncture. Potassium EDTA was used as anticoagulant for hematology tests. Animals were bled in random order. The following were evaluated. 00438 16 CovanIcMe T63-291-42224 Hematology red blood cel (erythrocyte) count hemoglobin `white blood cell (leukocyte) count differential blood cell count hematocrit segmented neutrophil count mean corpuscular volume. `mean corpuscular hemoglobin lymphocyte count monocyte count `mean corpuscular hemoglobin concentration. eosinophil count platelet count basophil count Reticulocyte count smears were made and held for possible future examination. glucose urea nitrogen creatinine total protein albumin globulin cholesterol total bilirubin Clinical Chemistry alanine aminotransferase `gamma glutamyltransferase aspartate aminotransferase calcium inorganic phosphorus sodium potassium chloride appearance volume specific gravity pH protein urobilinogen Urinalysis glucose ketones bilirubin blood `microscopic examination of sediment `The remaining urine (up to 10 mL)for each aniwamsstaorled in a freezer set to maintain -10 to -30C. Samples were packed on dry ice and shipped to the Sponsor. Urine samples will be stored by the Sponsor for possible future analysis. Necropsy A necropsy was done on the animal that was found dead. Afterat least 4 weeks of treatment, all surviving animals were fasted overnight, anesthetized with carbon dioxide, bled for clinical pathology tests and serum PFOS samples, weighed, exsanguinated, and necropsied. Animals were necropsied in random order. - 00439 CovanMceT632e9-2224. The necropsy included a macroscopic examinationofthe external featuresofthe carcass; all externalbody orifices; the abdominal, thoracic, and cranial cavities; organs; and tissues. OAtrgtahensWcehiedguhltesd sacrifice, the following organs (when present) were weighed; paired organs were weighed together (see Protocol Deviations for exception): adrenal (2) brain epididymis (2) kidney (2) iver ovary 2) spleen testis (2) thymus. thyroid (2) with parathyroid Organ-to-body weight percentages and organ-to-brain weight ratios were calculated. Cel Proliferation Tissue Collection and Immunohistochemical Evaluation At the scheduled sacrifice, representative samplesoflft lateral lobeofthe liver were collected from each animal and preserved in zinc formalin. After fixation, samples were embedded in paraffin and shipped to Pathology Associates International for proliferation cell nuclear antigen (PCNA) evaluation. Resultsofthe evaluation are in Appendix 7. `APtatlhmeitsocyheld-uCloeAdOsxaicrdiafsicee,TiasssaumeplCeol(leacptpironoxainmdaAtn5ea0llyy0smesg)of the right lateral lobe of liver was collected from cach animal, flash-frozen in liquid nitrogen, andstoredin a freezer set to maintain -60 to -80C until analyzed for palmitoyl-CoA oxidase activity. Liver PFOS A portion of Analyses the liver was collected from each animal at the scheduled sacrifice and stored. ina freezer set to maintain -60 to -80C until packedondry ice and shipped to the Sponsor for PFOS and metabolites analyses. Resultsofthese analyses will be reported separately by the Sponsor. 00410 18 CovanMcTe 6.38291-42224 `Tissue Preservation `The following tissues (when present) fromeachanimal were collected and preserved in 10% neutral-buffered formalin: adrenal (2) aorta brain cecum cervix colon duodenum esophagus epididymis (2) efyeemu(r2)with bone marrow (articular surface of the distal end) Harderian gland heart ileum with Peyer's patch (lymphoid aggregate) jejunum Kidney (2) lesions liver lung with mainstem bronchi Iymph nodes (mesenteric and mandibular) mammary glands (females only) ovary (2) ppiatnucirtearays prostate rectum salivary gland [mandibular (2)] sciatic nerve, seminal vesicles skeletal muscle (thigh) skin spinal cord (cervical, mid-thoracic, and lumbar) spleen sternum with bone marrow stomach testis [(2) preserved in Bouin's fixative] thymus thyroid (2) with parathyroid trachea urinary bladder uterus vagina Zymbal's gland Tissues were shipped to Pathology Associates International for processing. The adrenals, brain, eyes, kidneys, liver, mesenteric lymph node, pancreas, spleen, testes, and ovaries fromeach animal were embedded in paraffin, sectioned, and stained with hematoxylin and eosin (see Protocol Deviations). The tissu slides were examined microscopically by Dr. Richard H. Bruner, DVM, DAVCP of Pathology Associates International Bone marrow smears from the feomfuearch animal at the scheduled sacrifice were prepared, stained with Wright's stain, and retained for possible examination. 00441 CovanIcMeT6-36203-124224 Statistical Analyses Levene's test was done to test for variance homogeneity. In thecaseofheterogeneiotfy variance atp $ 0.05, transformations were used to stabilize the variance. Comparison tests took variance heterogeneity into consideration. One-way analysisofvariance (ANOVA) was used (if applicable) to analyze body weights, body weight changes, food consumption, continuous clinical pathology values, and organ weight data. Ifthe ANOVA was significant, Dunnett' t-test was used forcontrolversus treated group comparisons. Group comparisons (Groups 2 throug6h versus Group 1) were evaluated at the 5.0%, two-tailed probability level. Only data collected on or after the first day of treatment was analyzed statistically. RECORD RETENTION All raw data, documentation, records, protocol,andspecimens generated as aresult of this study will be archived in the storage facilities ofCovance-Madison for a period of 1 year. One year after the submissionofthe final report, the Sponsor will determine the final dispositionofthe materials. All raw data stored on magnetic media, the protocol and protocol amendments, study correspondence, and an original copyofthe final report will be retained by Covance-Madison. PCNA evaluation data, paraffin blocks, and tissue slides will be retained by Pathology Associates International. Liver, urine, andserumsamples sent to the Sponsor and analysis data will be retained by the Sponsor. 00442 2 Covance 6329-224 -_-- Tew RESULTS Dose Analyses tRehsruolutgshof3. the homogeneity, stability, and dose preparation analyses areinTables 1 Mean valuesofthe homogeneity analyses ranged from 102-268%, 95.9-102%, 93.7-97.0%, 94.4-95.8%, and 94.0-101%ofthe theoretical concentrations for the diets `containing the analyse 1, so 10, fdi 30, 100, and etsmixed on 500 June ppm 11, N-MeFOSE, 1998, for the respectively. Because diet containing 1 ppm the r were esults high of (118%, 268%, and 129%), they were reanalyzed. The results of the reanalyses were 116%, 114%, and 102%. These results indicate that the mixing procedure produced a homogeneous distribution of the test material in the dose preparations. Resultsofstability analyses of samples stored for 19, 32, and 62 days at room temperature and 8 weeks under frozen conditions, indicated that the mean concentrations were 90.2%, 83.4%, 70.6% and 97.2%, respectively,ofthe theoretical concentrations of 500 ppm. Results of stability analyses of samples from the 1-ppm theoretical concentration, indicated that the mean concentrations were 132% and 72.6% for the diet `preparations mixed pretest and the in-life portionofthe study, respectively. Therefore, the dose preparations were stable for 62 days at room temperaturestorageand 8 weeks `under frozen conditionsfor mean concentrationof 500 and 1 ppm, respectively. "Themean concentrations ofthedose preparation analyses for all levels ranged from 63.3% to 114%ofthe theoretical concentrations. Thesedata indicate that the levels of N-methyl perfluorooctanesulfonamido ethanol (N-MeFOSE, T-6314) in the dose preparations were acceptable only for dose levels of 10, 30 100, and 500 ppm. Clinical Observations and Survival Clinical observations are summarized in Table 4; individual data are in Appendix 2. Individual animal fate data are also in Appendix 2. 2 00443 CovanMceT6-3G201-42224 One animal given 500 ppm N-MeFOSE died on Day 25. Thisanimalexhibited severe hepatocellular hypertrophy and moderately-severe liver necrosis at microscopic exam. All other animals survived to the scheduled sacrifice. No clinical observations were noted that were considered effectsofthe test material. Body Weightsand Body Weight Changes Body weight and body weight change data are summariinTzabeleds 5and 6; individual data are in Appendix 3. Although not statistically significant, animals given 1, 10, 30, or 100 ppmN-MeFOSE had lower mean body weightsthanthose ofcontrols for mostofthe study. Test material related lower body weight and body weightgains were noted for animals given 500 ppm. For males and females given 500 ppm, statistically lower body weights were apparent beginning on Days 8 and 11, respectively, and continuing throughthe endof study. Mean body weight gains foranimalsgiven 500 ppm were lower than those of control animals throughout the study. Food Food Consumption consumption data are summarized in Table 7; individual dataarein Appendix 4. Statistically test material related decreaseisn food consumption were noted in males given 500 ppm throughout the study and in females given S00 ppm beginningonDay4 and continuing throughout the study. The overall mean food consumption for males fed the 100- or 500-ppm concentration was significantly reduced compared with that of the controls, and the overall mean food consumption for females fed the 500-ppm concentration was significantly reduced compared with thatofthe controls. There were no significant food consumption differences noted in animals given 1, 10 or 30 ppm N-MeFOSE. 30444 2 CovanIcMe 6T3-21924224 `Test Material Consumption `Testmaterialconsumption dataare summarizedinTable8.Individualdataare in Appendix 4. Animalswere fed diets containing 1, 10, 30, 100, or 500 ppm N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314). The mean amountsoftest material consumed by the animals in these groups were 0.087 to 0.140 mg/kg/day; 0.816 to 1.325 mg/kg/day; 2.432 to 4.030 mg/kg/day; 7.768 to 13.192 mg/kg/day; and 35.168 to 62.612 mg/kg/day for males, respectively. Values for females were 0.096 to 0.147 mg/kg/day; 0.848 to 1.399 mg/kg/day; 2.612 to 4.124 mg/kg/day; 8.485 to 13.802; and 38.527 0 62.217, respectively. The overall test `material consumption ranged from 0.105 to 44.590 mg/kg/day for the males and 0.111 t0 45.050 mg/kg/day for the females. Serum Perfluorooctane Sulfonic Acid Level (PFOS) Determination Resultsofserum PFOS level determination will be reported separateblyy the Sponsor. Clinical Pathology Hematology, coagulation, clinical chemistry and urinalysisdataare summarized in `Tables 9 through 11; individual data are in Appendix 5. The Pathology Report containas discussionofthe data. Dietary administration of N-MeFOSE at a dose levelof 500 ppm for approximately 4 weeks was associated with several effects on clinical pathology test results including moderately lower red blood cell count, hemoglobin, and hematocrit; lower absolute: eosinophil count; mildly higher urea nitrogen; moderately higher albumin and mildly to `moderately lower globulin; markedly lower cholesterol; mildly to moderately higher total bilirubin, aspartate aminotransferase, and alanine aminotransferase; and moderately higher hepatic palmitoyl-CoA oxidase. Ofuncertain relationship to administration of N-MeFOSE. were lower urine pH for males fed 500 ppm and small differencesforanimals fed 100 ppm including higher urea nitrogen, albumin, and alanine aminotransferase (males only) and Tower cholesterol. Ofthe differences for animals fed 100 ppm, only the difference for alanine aminotransferase was statistically significant. 23 00445 CovanMceT6.36291-42224 Cell Proliferation Tissue Collection and Immunohistochemical Evaluation Resultsofcell proliferation and immunohistochemical evaluation provided by Pathology Associates Intemational are in Appendix 7. Resultsofthe cell proliferation evaluation will be provided by Pathology Associates International. Liver PFOS Determination Resultsofliver POS level determination will be reported separately by the Sponsor. ATenramtionmailcbaoldPyawtehioglhotgs,y absolute organ weights, organ-to-body weight percentages, and organ-to-brain weight ratios are summarized in Tables 12 through 14; incidences of `macroscopic and microscopic observatioanrse summarized in Tables 15 and 16; the incidence of severity of microscopic observationsis summarized in Table 17. Individual dataare in Appendix 6. The Pathology Report contains a discussionofthe data. Meanabsolute and relative (to brain and body) liver weights forallmalesand females given 100 and 500 ppm N-McFOSE were significantly increased over control values, and twhheiscehvvaariraiteidosnisgwniefriecarntelgyafrdreodmacsonttrreoaltmveanltu-erse,lawteerde. cAolnlsiadddeirteidontaolbmeewainthoirngtahnewreaingghetso,r normal biologic variation, or were manifestationsofslight weight loss associated with physiologic stress. Treatment.related microscopic findingswererestricted to theliverand consisted of `minimal to severe centrilobular hepatocellular hypertrophy. Hypertrophic changes were Slightly more severeinmales;andat the high-dose level, liver cell swelling in several males was associated with acute necrosis. Necrosis was attributed to restricted blood supply (ischemia) from swollen liver cells rather than direct hepatocellular damage. Additional `microscopic findings were consistent with common, spontaneous alterations in laboratory rats or changes associated with stress, nutritional deprivation, or tissue processing artifact. 50446 % - Covance 6325-224 OOOOOO mre: CONCLUSIONS Based on the results of this study, dietary administration of N-MeFOSE, T-6314 to Cr:CDTMSD) IGS BR rats for at least 4 weeks resulted in adverse effects at adose level of 500 ppm. The no-observable-adverse-effect level was determined to be 100 ppm. 204417 25 SIGNATURES CovanMcTe -6632391-24220 EA ppe 4: Ni van Broce-Konuah Study Coordinator `Covance Laboratories Inc. &3, 7 Study Pirector Covance Laboratories Inc. Sy 5, 2000 Date 55 2% 50448 - REFERENCES Covance 6329-224 wTeM2 Dunnett, C. 20:482-491 W., "New (1964). Tables for Multiple Comparisons with a Control," Biometrics, Levene, H., "Robust Tests for EqualityofVariances," ContritboPurotbabiiloitynansd CStaaltiifstoimcisa, ((e1d9s6.0)).I. Olkin et al., Ch. 25, pp. 278-292, Stanford University Press: Stanford, `E`xWpineerri,mBe.ntJa.,l"DDeessiiggnn, aSnedcoAnndalEyds.i,soCfh.Si3n,glppe.-F1a4c9t-o2r6E0x,pMerciGmreanwt-sH,i"lSlta:tiNsteicwalYPorrikn,ciplesin New York (1971a). WSienceorn,dBE.d.J,., C"hA.na1l0y,sipsp.of75C2o-v8a1r2ia,nMcceG,"rSatwa-tHisitlilc:al PNreinwciYploerski,nNEexwpYeorrikm(e1n97Dt1eabs)il.gn, " 00449 PATHOLOGY REPORT CovanMcTe -636239-124242. SUMMARY `The purposeofthis study was to assess the toxicityofthe test material, N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) when administered in the diet toratsforatleast 4 weeks.Thetestmaterial wasadminaitdsosteleeverlseofd1, 10,30, 100, and 500 ppm. Dietary administration of N-MeFOSE at a dose levelof 500 ppm for approximately 4weekswas associated with several effects on clinical pathology test results including `moderately lower red blood cell count, hemoglobin, and hematocrit; lower absolute eosinophil count; mildly higher urea nitrogen; moderately higher albumin and mildly to `moderately lower globulin; markedly lower cholesterol; mildly to moderately higher total bilirubin, aspartate aminotransferase, and alanine aminotransferase; and moderately higher hepatic palmitoyl-CoA oxidase. Of uncertain relationship to administration ofN-McFOSE were lower urine pH for males fed 500 ppmand small differences for animals fed 100 ppm including higher urea nitrogen, albumin, and alanine aminotransferase (males only) and lower cholesterol. Of the differencesforanimals fed 100 pp, only the difference for alanine aminotransferase was statistically significant. Treatment-related microscopic findings were restricted to the liver and consisted of `minimal to severe centrilobular hepatocellular hypertrophy. Hypertrophic changes were Slightly more severe in males; and at the high-dose level, liver cell swelling in several males was associated with acute necrosis. Necrosis was attributed o restricted blood supply (ischemia) from swollen liver cells rather than direct hepatocellular damage. Additional `microscopic findings were consistent with common, spontaneous alterations in laboratory rats or changes associated with stress, nutritional deprivation, or tissue processing artifact. 20450 3 _--_-- CovamnIcMerT6-36e239124224 METHODS Six groupsofCrl:CD*(SD) IGS BR rats (six animals/sex/group) were feddiets containing the test material at a dose level of 0 (control group; fed basal diet only), 1, 10, 30, 100, or 500 ppm. Before the schedule sacrifice and necropsy during Week 5,bloodand urine were collected for hematology, clinical chemistry, and urinalysis tests. At necropsy, macroscopic observations were recorded, organ weights were obtained, and issues were placed in fixative as specified by the protocol. In addition, samples of liver were collected for evaluation of hepatocellular proliferation (by Pathology Associates International), determinationofhepatic palmitoyl-CoA oxidase activity (by Covance), and analysis for PFOS and metabolites (by the Sponsor). The animal that died on test was also necropsied, but organ weights and liver samples for the special analyses were not obtained. Microscopic examinations were done on the following tissues from cach animal: adrenals, brain, eyes, kidneys, liver, mesenteric lymph node, pancreas, spleen, testes, ovaries, and lesions. Statistically significant differences cited in the Results and Discussion section are based on comparisons between thecontroland treated groups. RESULTS AND DISCUSSION Mortality Animal No. C94523 given 500 ppm N-MeFOSE died on Day 25. The remaining animals survived to the scheduled sacrifice. Clinical Pathology Individual values for hematology, clinical chemistry, urinalysis, and hepatic palmitoyl-CoA oxidase are in Appendix 5. Mean values for each group and the resultsof statistical `comparisons are in Tables 9 through 11. 2 00451 Covance 6329-224 - MTeW? Week 5. There were several statistically significaonrt otherwise notable differences for clinical pathology results between controland treated animals; only oneofthe statistically significantdifferencesaffectedanimalsfedlessthan 500ppm.Differencesconsideredto bheemeaftfoeccrtisot;fltohweetreastbsmoaltuetreiaeloswienroephliolwceorunrte;d hbilgohoedrcuerlleaconuinttr,ogheenm;ohgilgohbeirna,labnudmin and lower globulin; lower cholesterol; higher total bilirubin, aspartate aminotransferase, and alanine aminotransferase; and higher hepatic palmitoy-CoA oxidase. With the exception oflower globulin and higher aspartate aminotransferase for the females, these differences. were statistically significant. Of uncertain relationship to administration of N-MeFOSE were lowerurine pHformales fed500ppmand smalldifferencesforanimalsfed 100 ppm includinghigherurea nitrogen, albumin, and alanine aminotransferase (males only) and lower cholesterol. Ofthe differences for animals fed 100 ppm, only the minor difference for alanine aminotransferase was statistically significant. At dose levels below 100 ppm, clinical pathology results were unaffected by treatment. T(dheecreefafseecdt)s,oanntdhegleorbyutlhirnoc(ymtiledplayrtaomemtoedresra(tmeoldyerdaetcerleyasdeedc)rewaesreed)c,oensoissitneonpthiwlitchouanntimals in relatively poor health, filing to gain weight appropriately. Mildly higher urea nitrogen `and moderately higher albumin were most consistent with mild dehydration and indicated the effects on other parameters (.g., the erythrocyte parameters) might have been greater ifthe animals were normovoleic. The mild to moderate effects on alanine aminotransferase, aspartate aminotransferase, and total bilirubin were indicativeof the hepatocellular degeneration. The effect on cholesterol was marked, but the mechanism for change was not apparent. Moderately higher hepatic palmitoyl-CoA oxidase was indicativeofperoxisomal proliferation. Anatomical Pathology Individual anatomical pathology data are in Appendix 6. Individual absolute organ weights, organ-to-body weight percentages, and organ-to-brain weight ratiosarealso in Appendix 6. Mean values for absolute and relative organ weights for cach group are in Tables 12 through 14. Incidence summariesofthe macroscopic and microscopic observations arein Tables 15 and 16; the incidenceofseverity of selected microscopic observations is summarized in Table 17. 2 00452 CovanMceT6.3&29I-42224 Unscheduled Death. Animal No. C94523 given 500ppm N-MeFOSE died on Day 25. Microscopically, this animal exhibited severe hepatocellular hypertrophy and `moderately-severe liver necrosis. `Terminal Sacrifice Organ Weights. Mean absolute and relative (to brain and body) liver weightsforall `males and females given100and 500 ppm N-MeFOSE were significantly increased over control values, and these variations were regarded as treatmen-related. Alladditional `mean organ weights, which varied significantly from control values, were considered to be. `withinthe range or normal biologic variation, or were manifestationsofslight weight loss associated with physiologic stress. Macroscopic Observations. Treatment-related, gross changes were restricted to the liverand stomachofmales given 500 ppm N-MeFOSE. Animal Nos. C94521 `and C94522 displayed enlarged livers, and in Animal No. C94522, hepatic enlargement was associated with discoloration (diffusely brown with light areas). Microscopically, liver changes were attributed to hepatocellular hypertrophyand necrosis. In addition to liver changes, dark or red mucosal areas were presenitn the glandular stomachofAnimal Nos. C94521 and C94526 given 500 ppm N-MeFOSE and in the glandular stomach of one control male (Animal No. 94493). Gastric areas were compatible with carly "stress" erosions or ulcers. Microscopic Observations. Treatment.related microscopic changes were restricted to the liverofboth sexes and consisted of hypertrophy (swelling) of liver cells in centrilobular regions of the hepatic lobules. Occasionally, hypertrophic liver cells were associated with acute hepatic necrosis. Hepatocellular hypertrophy was not observed in controls or in animals given 1 or 10 ppm N-MeFOSE. At higher dose levels, hypertrophic changes were slightly more prevalent and severe in males,andat dose levels of 30, 100, and 500 ppm N-MeFOSE, all males displayed minimal to slight, moderate to moderately-severe, and moderately-severe to severe liver cell hypertrophy, respectively. Liver cell hypertrophy was not observed in females given 30 ppm N-McFOSE; however, at dose levels of 100 and 500 ppm N-MeFOSE, hepatocellular hypertropihny females ranged from slight to moderate and from moderate to moderately-severe, respectively. Hepatocellular hypertrophy in both sexes was compatible with the proliferation of 31 00453 Connce 2928 IMT-63142 cytoplasmic smooth endoplasmic reticulum. Althatloowuerdgoshes hypertrophy was restricted tocentrilobularregions, at the high-dose level, hypertrophic hepatocytes often ext intoe pann lobud larre egiod ns. In additionto hypertrophic changes,moderate liver cell necrosis was observedintwo `malesgiven 500 ppm.Necrosiswasattributedtolocalischemiaassociatedwith livercell swellingandocclusionof regionalbloodsupplies.Minimalhepaticnecrosisinoneofsix `malesgiven10 or 100ppmandin oneof sixfemalesgiven 30ppmwasconsistentwith common hepaticalterationsinlaboratoryrats. Allothermicrofsincdiongpswierce: consistent with common spontaneous alterations in laboratory rats, including changes relatedto stress, nutritional status ortissueprocessingartifact. RoL.b Halle , DVr M,Pt hD Diplomate, ACVP We hardATorarn DRiipclhoamradtHe., BArCunVePr, DVM PathologyAssociates International ets 3, 2000 Ds 00454 32 CovanMcTe-6632391-24224 COMMENTS ON THE DATA Variousmodelsof data inthisstudy. calculators, computers, and computer Because different models roundoffor programs were used to analyze truncate numbers differently, vslailguhetslyinfrsoommethtoasbeleisn (ot.hge.,r mtaebalness,,fsrtoanmdianrddivdiedvuiaaltliyoncsa,lcourlaitneddivdiadtuaa,lovralfureosm) mstaatyisdtiifcfaelr analysis data. differences. Neither the integrity nor the interpretationofthe data was affected by these: `The numberofanimals listed in the headingofthe summary tables forclinicalobservations reflects the numberofanimals assigned to each group at the startofthe study. `cTohnedsituimomnawraystoabbsleerfvoerdclwiintihcaolutobrseegravradtitoontshiendsipcecaitfeitchneatnuurme,besreovefraitnyi,mraelvsersfiobrilwihtiy,ch a `number of incidences/animal, or the lengthoftime the condition persisted. Otanblleys.observations other than normal are indicated on the summary clinical observations `Ecaocmhmeannitm"alAnwiimtahlohbassernvoatsiiognnsifriceacntofridndaeisdng"s"Noirnmdiacla"tetdhoronutghheouitndtihveidsutauldcylihnaicsalthe observations tables. `iTnhdeicsapteecdifwiictdhetaai"lCs"fcorancobmemfeonutnsd ainttthhee einnddiovfideuaalchclignricoaulpobfosrercvaacthiosnesx.tables that are: `stTahretdoayfaosftiundiytiwateieonkof(t.rge.,atambeondtyiswe"iDgahyt 1r,ecWoeredked1o."n DBaoydy1 wiesicgohntsiddaetraedaraeWeenteekred1 abtotdhye weight, a body weight recorded on Day 8 is considered a Week 2 body weight). Body weight change data the following study are calculated from week (c.g, Week 1 the first day of the study week to values are calculated from Day I the first through day of 7) and (aer.e8.i,ndWieceatked1 ivnatlhueestaabrleesinwdiitchattehde adsay"Dbaeiyn8g")t.heWfeirestkldyayfoofotdhceonfsolulmopwtiinognwaenedktest tmhaetefroilallocwionngssutumdpytwiaeorenek c(ca.lgc.u,lWateeedkfr|ovmatlhueesfiarrstedcaalycouflattheedsftruodmy Dwaeyek1 ttohrthoeugfhirs7t).day of s`iTghneivfiaclaunetsffiogrurseusmtmhaarnyisaanpdprionpdriivaitduealfotrestthemadtaetraiadluecotnosluimmpittaitoinonasroefrtehpeordtaetdawciotlhlemctoiroen `and reporting software. 20455 3 CovanMce6631294-2224 COMMENTS ON THE DATA (Continued) Diet test material concentrations providedbythe data collection system (PTS) are calculated to the nearest 0.1 ppm. These values are used for calculationoftest material consumption. For diet preparation purposes, the valuesare rounded to the appropriate accuracy for the balance used. Food consumption values are reported in whole numbers; however, PTS carries food consumption values to one place to the rightof the decimal for test material consumption calculations. The differences in values generated do not influence the interpretationofthe calculation. `The comment "SPILLED" on individual food consumption data tables indicates that food consumption was not recorded due to spillage during the interval. "The comment "NOT TAKEN" on individual food consumption data tables indicates the animal died before the endof the food consumption interval. Differences in the population size (N) on the summary tables for clinical and anatomical pathology are explained on the individual data tables or the codes sheets. The calculation for individual test material consumption is: Test material consumption = FTC BaaDitBCyoWetttofiotS(putiy nBlyWRGED Fi where: Daily Body Weight Gain = 7Lt eBttyWWhoo e f gFo oofodythBytWeeoigh and: Day Factor = (FoodConsumption SarDt ayDay fF Body Weghtof ev 224 Conmtion tel, and: Food ConsumpFtonidoCnomImnpteirovnalB=D. Fond Compton St Dy On pages 4 and 7ofthe protocol, the test material is indicated as MeFOS, T-6314 instead ofMeFOSE, T-6314. 90456 34 CODES, ABBREVIATIONS, AND UNITS General Codes and Abbreviations Codes for Clinical Pathology Abbreviations and UritsforClinical Hematology Abbreviations and Units for Clinical Chemistry Abbreviations and Units for Clinical Urinalysis Codes for Anatomical Pathology CovanMcTe -6362391-24224 Note: The followinglistsof codes, abbreviations, and units are used by Covance. Some, but not necessarily all,ofthis informationmaybe needed for this report. 00457 35 CovanMcTe -6632391-24224 General Codes and Abbreviations WK N Mean; MEAN SD; S.D,; STAND DEV; STANDARD DEV; sd NA P c UNSCHED DISPATCH TBW # co Week. Numberofmeasurements in a group. Arithmetic mean. Standard deviation. Group mean is significantly different from the meoaftnhe control group (Group 1) atps 0.05. No value; not applicable; not present. Present. Comment foundatthe endofeach group for each sex. Unscheduled. Observations transferredfrom the in-lfe `moduleofthe data collection system to the necropsy module for reference during necropsy. Observations are duplicates of the last in-life observations. Terminal body weight. Number. Clinical observation. 30458 36 Ns QS/QNS NR FS sc SH H SL L st 1 NF u DT/DOT DB el TE RE EE SE PC PD Pr PL PA co HB PLASMO NO AGG FR UTD NO COAG Covance 6329-224 MTs Codes for Clinical Pathology GENERAL CODES No sample Quantity not sufficient No repeat (sample Fibrin strands volume not sufficient for repeat analysis) Sample clotted Slightly hemolyzed Hemolyzed Slightly lipemic Lipemic Slightly icteric Teteric Animal not fasted Unscheduled/moribund bleed Animal died on test Died during bleeding Technicianjudgment to repeat test Technical error (instrumeonrt technician error that results in supnialclecde,petnatbrlyeodaftian,vael.igd.duantaa)cceptable instrument output, sample: Rspeeclolrindginergroerr,roirnc(orrerceocrtddeadtei)ncorrect data, .g., wrong number, Entry error (incorrect keyboard entry) Sampling error Platelets clumped Platelets decreased Platelets increased Platelets large Platelets appear adequate Color interferes with test Heinz bodies observed Plasmodium No aggregation Fractious Unable to determine No coagulation 50459 3 CovanMcTe 6-3B291-42224 Codes for Clinical Pathology (Continued) RESULTS NOT INCLUDED IN STATISTICAL ANALYSES Hemolyzed clinical chemistry or coagulation samples. `SParmoptlhersomfbrionmatinmiemsal(sPaT)t gurnesactehredtuhlaend5i0ntseercvoanldss. ABclteievdattiemdepsar(tBiaLlEtThIroMmEb)opglraesattienr times than (PTT)greaterthan 30 minutes. 110 seconds CODES FOR BLOOD CELL MORPHOLOGY Tpohiekifloolclyotwoisinsg (scPaOlIeKw),aspoulsyecdhrtoommaesaisau(rPeOtLhYe)d,eghryepeocohfraonmiasosciyato(sHiYsP(OA)N,IoSrO)ba,sophilic stippling (BASTIP) or the presence of Howell-Jolly bodies (HJBODY), toxic neutrophils (TOXNEUT), or atypical lymphocytes (ATYPLYM): Seale Degree p `Normal for the species. 1 Slight 2 Moderate 3 Marked 4 Not applicable Presence Not present Rare Few Moderate Many APale B Straw C Yellow DDark yellow URINE APPEARANCE Color E Amber F Bown G Red H Green 1 Black P Bluelgreen Q Ble R_ Orange Clarity 7 Clear K Hazy L Cloudy Miscellaneous M Debris 0 Feces 00460 38 Covance 6329-224 -_ MTeuM2 Codes for Clinical Pathology (Continued) URINE CHEMISTRY MULTISTIX STRIP T UrincGuoose _UrineKelone ~ Negative Negative + 100 mg/dL + Smgdl ++ 250mg/dL ++ 15mg/dL ++ 500mg/dL ++ 40mg/dL +H 1,000mg/dL +++ 80mg/dL Hb 22000mgdl ++ 160 mgldl UrineBlood Negative + Small + Moderate +++ Large Urine Urobilinogen ~ 02mg/dL + ImgldL ++ 2mgldL +++ 4mg/dL +H 8mgd (1 mg = approximately 1 Ehrlich unit) Urine Bilirubin ~ Negative + Small + Moderate +++ Large URINE SEDIMENT Cells, Crystals, Casts, and Comments A Amorphousurates Q Sperm B Amorphousphosphates R Fecalcontamination C Uricacid S Pinworm ova found D Triple phosphates T Pinwormlarvae found E Calcium oxalate U Paraovsaifotuned F Calciumcarbonate G Granular casts H_ Hyalinecasts 0 Notpresent I Cellular casts 11-5 per field J Waxycasts 2 6-10perfield K_ Unknowncrystal 3 11-20perfield P_ Mucous threads 4 >20perfield Bacteria 0 Notpresent 1 Few 2 Moderate 3 Many 39 00461 Covance 6329-224 wre Abbreviations and Units for Clinical Hematology Test Red blood cell count Hemoglobin Hematocrit Mean corpuscular volume Mean corpuscular hemoglobin Mean corpuscular hemoglobin concentration `Platelet count Mean platelet volume Reticulocyte count AHbesionlzubteodryetciocuulnotcyte count Erythrocyte sedimentation rate PArcotitvhartoemdbipanrttiiamlethromboplastin time: Thrombin time. Activated coagulation time FiFbibrriinno/fgiebnrinogen degradation products Platelet aggregation Collagen Adenosine diphosphate `Alpha 2-antiplasmin Bleeding time Methemoglobin Plasma hemoglobin Myeloid/erythroid ratio Estimated myeloid/erythroid ratio D`iWfhfietreenbtlioaoldbcleololdcoceulnltcount Nucleated red blood cell count Corrected white blood cell count `Segmented neutrophil count Band neutrophil count Lymphocyte count Monocyte count `Eosinophil count Basophil count Anisocytosis Polychromasia Abbreviation (Units) RBC(E6/ULor X10/4L) HGB (G/DL) HCT (%) MCV (FL) MCH (PG) MCHC (%) PLT (E3/UL or X10%/uL) MPV (FL) RETIC (%) HREETIINCZ((E%3)/UL or X10*/uL) ESR (MWHR) PT (SEC) PTT (SEQ) TT (SEC) ACT (SEC) FBR (MG/DL) FDP (UG/ML) PAGG/COL (%) PAGG/ADP (%) ANTIPLAS (%) BLE TIME (SEC) METHGB (%) PLA HGB (MG/DL) M/E RATIO EST M/E RATIO WBC (E3/UL or X10%4L) NRBC (/100 WBC) COR WBC(E3/ULor X10%4L) N-SEG (E3/UL or X10"/uL) and % N-BAND (E3/UL or X10*/uL) and % LYMPH (E3/UL or X10%4L) and % MONO (E3/UL or X10%4L) and % EOSIN (E3/UL or X10%uL) and % BASO (E3/UL or X10%uL) and % ANISO (1,23) POLY (12.3) 00AGR Fy CovanMcTe-6632391-24224 Abbreviations and Units for Clinical Hematology (Continued) Test Poikilocytosis Hypochromasia Howell-Jolly bodies Basophilic stippling `Toxic neutrophils Atypical lymphocytes Aqueous white blood cell count (right eye) Aqueous white blood cell count (left eye) Abbreviation (Units) POIK (12,3) HYPO (12.3) HBAISBTOIDPY(-(,11,22.,33)4) TOXNEUT (-,1,2,3,4) ATYPLYM (-1,23.4) REYE (WBC/UL) LEYE (WBC/UL) a 304G3 - Abbreviations and Units for Clinical Chemistry Covance 6329-224 uTeW2 Test Glucose Urea nitrogen Urea Creatinine Total protein Albumin Globulin Albumin/globulin ratio Total bilirubin Direct bilirubin Indirect bilirubin Cholesterol Triglyceride Urea nitrogen/creatinine ratio Total lipids Phospholipids High-density lipoprotein cholesterol Low-density lipoprotein cholesterol Uric acid Aspartate aminotransferase: Alanine aminotransferase Alkaline phosphatase Gamma glutamyl transferase: Sorbitol dehydrogenase Lactate dehydrogenase Creatine kinase Amylase Lipase Palmitoyl CoA oxidase. Calcium Ionized calcium Inorganic phosphorus Sodium Potassium Chloride Magnesium Zinc Strontium Tron Abbreviation (Units) UGLNU(M(GM/GD/LD)L) UREA (MG/DL) CREAT (MG/DL) TPRO (G/DL) ALB (G/DL) GLOB (G/DL) A/G RATIO TBILI (MG/DL) D BIL (MG/DL) IBILI (MG/DL) CHOL (MG/DL) TURNI/GCR(MEGA/TD(LR)ATIO) T LIPIDS (MG/DL) P LIPIDS (MG/DL) HDL (MG/DL) LDL (MG/DL) UA (MG/DL) ASTISGOT (IUL) ALT/SGPT (IU/L) ALK PHOS (IU/L) GGT (IU/L) SDH (IU/L) LDH (IUL) CK (U/L) AMYLASE (IU/L) LIPASE (IULL) PCOAO (IU/G) CA (MG/DL) ION CA (MG/DL) 1PHOS (MG/DL) NA (MMOL/L) K (MMOL/L) CL (MMOL/L) MG (MEQ/L or MG/DL) ZN (MGIL or PPM) SR (MG/L or PPM) FE (UG/DL) a 3046s4 CovanIcMeT6-36293-124224 Abbreviations and Units for Clinical Chemistry (Continued) Test Excess iron Total iron binding capacity Unbound iron binding capacity Percent iron saturation Plasma cholinesterase. Red blood cel cholinesterase: Brain cholinesterase Caudate putamen Hippocampus Frontal cortex Cerebellum Bicarbonate. Serum hemoglobin Serum bile acids Fecal bile acids Average fecal weight Fecal bile acids (calculation) Osmolality Electrophoresis Albumin Alpha-1-globulin Alpha-2-globulin Beta globulin Gamma globulin High-density lipoprotein Low-density lipoprotein Very-low-density lipoprotein Insulin Adrenocorticotropic hormone. Cortisol Glucagon Triiodothyronine: Thyroxine Creatine kinase isoenzymes BB MB MM Abbreviation (Units) EX FE (UG/DL) TIBC (UG/DL) UIBC (UG/DL) FE %SAT (%) CHEP (MUML) CHER (MUML) CHEB (MUML) CAUD PUT (UMOLIG) HIPPOCAM (UMOLIG) F CORTEX (UMOLIG) CEREBELL (UMOL/G) BICARB (MMOL/L) SER HGB (MG/DL) SBA (UMOL/L or MG/DL) FBA (UG/ML) FFCBCA W(MGGT/D(aGy)) SMO (MOSM/KG) EALB (G/DL) EA-L(GDL) EA2 (G/DL) E BETA (G/DL) E GAMMA (G/DL) E-HDL (%) E-LDL (%) E-VLDL (%) INSULIN (UUML) ACTH (PG/ML) CORTISOL (UG/ML) GLUCAGON (PG/ML) T3 (NG/DL) T4 (UG/DL) CK-BB (UL) CK-MB (ULL) CK-MM (ULL) 2 00465 CovanNceT320E-2:24 Abbreviations and Units for Clinical Urinalysis Test Abbreviation (Units) Urine volume U VOL (ML) 8hour urinevolume Specific gravity 8HR VOL (ML) SPGR Urine osmolality 'U OSMO (MOSM/KG) Quantitativeurinary/cerebrospinal `QUAN PRO (MG/DL) fluid protein Urine protein excretion PRO EXC (MG) Urine chemistry Multistix strip Urine pH UPH Urine protein U PRO (MG/DL) Urine ghicose UGLU Urine ketones UKET UUrriinnee bbilloiordubin UU BBILLOD OD | Urine urobilinogen Urine reducing substances 'UROBILI URE SUB Microscopic examinationofurine sediment `Red blood cellsperhigh-power field RBC (PER HPF) `White blood cells per high-power field Epithelial cells per high-power field `WBC (PER HPF) EPITH (PER HPF) Bacteria per high-power field BACT (PER HPF) CCaryssttsalpserpelrowl-opwo-wpeorwefrielfdield (CCRAYSSTSTA(LPSER(LPPEFR)LPF1 or PER LPF2) Urine appearance URINE APP1 or URINE APP2 `Comments `COMMENTS Miscellaneous Codes and Abbreviations for Clinical Pathology Fecal occult blood Fecal parasite detection Hemolytic potential `Osmolality Not applicable Not applicable `Not applicable OSMO (MOSM/KG) " 00466 _-- CovaMnScMeT6T36S293-12224 Codes for Anatomical Pathology Code Definition ANIMAL DEATH CODES T Terminal sacrifice D Found dead EX NOT TAKEN MISSING UNSUITABLE AUTOLYTIC EXCLUDE MACROSCOPIC CODES OInrdgiacnatweseitghhatt onrotgatnakweeni;ghextpilsaneaxtciloundegdivfernoimncnaelccruloaptsiyonnsotes Organ missing or lost OOrrggaann atuecthonliyczaeldlyaunndsuciotualbdlenoftorbweewiegihignhged `Weight was taken, but was excluded from all calculations MICROSCOPIC CODES BC-odes Prefacing NeoplParismtaircyF,ibnedniinggnsneoplasm MN- Primary, malignant neoplasm Metastatic neoplasm I X- Locally invasive neoplasm Other neoplasm Code Definition Distribution of Findings Focal Diffuse Multifocal as 00467 CovanM ce 63T 29-224 Codes for Anatomical Pathology (Continued) Grades 1 for Severity or Amount Minimal -the leastamountofchange thatcanbe observed withthe 2 light microscope Slight - less than average amountof change, butreadilydiscernible 3 aMsodaebrnaotrem-althe average amount of change that is expected for a 4 lesion Moderately severe (marked) - amarked amount of change with 5 pSoesvseirbele- laosgsreoaftfaumnoctuinotnoofftchheanagffeewcitetdhcperlosbaobrloerlgoasnsosffunction of the affected cell or organs and frequently involves large areasofthe organ Other Microscopic Codes TL Total P Finding present - Finding not present MN Mean TISSUE ABBREVIATIONS Abbreviation IN GL STOMACH, GL STOMACH, NONGL SALIV GL, MANDIB LN, ANT MES/PANC AUDITORY SEB GL LACRIMAL GLAND, EX HEMATO NEOPLASIA LACRIMAL GL, INT CAVITY, ABDOM SALIV GL,PAROTID LN, TRACHEOBRON CATHETER EXIT CATHETER ENTRANC CATHETER EXIT Definition Lymph node Gland Glandular stomach Nonglandular Mandibular salivary gland Anterior mesenteric/pancreatic lymph node: Auditory sebaceous gland Exorbital lacrimal gland Hematopoietic neoplasia Internal lacrimal gland Abdominal cavity Parotid salivary gland TCartahcehteeorbirzoantcihoinaslitle:ymexpiht nsotedefrom the body Catheterization site: entrance site into the vessel eCxattrhaevtaesrciuzlaatri)onasssieo:citaitsesduewsi(tvhatshceulcaarthoerter near its tp 46 00468 323i82833s 3 sz 3 B 33385888258%82 m 22 | |g secdgi ineig= q8l5d5g3 EE S| 885388888 LE i3 PzZ E|3 328 [3|gs| sa SeEdRa5s3R%d5az5 EsaR% zss 2-2 0p5%25g2 3E2z3 58 || owShSERa=8z.zs9 Eggsans-5f8s|f: 5 5 2% === 2233 IpEs| E55a5aa=EnmasnE88Esanagiagylls 368 enfant 32] 3 FTE 1 is 2 355 iq& : J 30469 CovanMcTe -6362391-24224 `Table 1 (Continued) Results of Homogeneity Analyses (ppm) Mixed 6/11/98 4-Week Range-Finding Dietary Toxicity Study with N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) in Rats T6314 (ppm) Sample Location Replicate 1 Top ro 2 12 3123 Mean 118 (118) Top" 1 123 2s 310 Mean L16(116) Middle 1291 2 Lao 3 37 Mean 2.68 (268) Middle" 1 LIS 2m 316 Men L14(114) Bottom ro12 2 1s 3121 Mean 129129) Bottom" 1 1.01 2 096 3106 Mean 1.02 (102) a Each value in parenthesisi the percent of theoretical. b Reassay. C0470 a8 CovanMcTe 6.38291-42224 Table 2 Results of Stability Analyses (ppm) Mixed 5/19/98 Per4f-lWuoereokocRtaanngces-uFlifnodnianmgidDoieEttahraynoTlox(iNci-tMyeSFtOuSdEy,wiTt-h63N1-4M)etihnyRlats Storage Conditions _ Replicate T-6314 (ppm) 1 500 Initial 1136 si 2 13s 482 3125 522 Mean 1320132) 505(101) Atleast 19 days, room temperature, To 2 Mean - 457 444 451902) Atleast 32 days, room temperature Me2 an .- 420 414 417 83.4) 8 weeks, frozen T2. Mean - 494 477 486(97.2) 62 days, room temperature 1 2. Mean - 304 402 353(706) a Each value in parentheses is the percentof theoretical. 49 00471 CovanM ce 632T 9-228 `Table 2 (Continued) `Resultsof Stability Analyses (ppm) Mixed 6/30/98 4Week Range-Finding Dietary Toxicity Study with N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) in Rats Storage Conditions _ Replicate. T-6314 (ppm) 1 Initial 1 2 Mean 0.777 0.674 0.726 (72.6) a Each value in parenthesis the percent of theoretical. 00472 50 3a234 8 = 28.58... gy 5/8 |. i Eel z 22 Sl zoos 2 88 5 EH = 3 28 28 3 en = "LQ ane EER 32 aaold A8QK[3 Tif 3 gt E95 Hs 8 cdi 2 FE E 28 E8 RE8L3E%T i a :2 i3s 53 801 i352d|1.4 ds3e@rSgSnZzCeZIIRsE3HsE8IisT2E eo.aa.B5R. 5E5E2 moefean foc f2E2g84e] yx .yv 55:3 - [2EH:%E% ee 00473 3g3gg i3 8 a 5g _ i2%s g- i 23 |3 gad |g 5gE 2 E f2 L el I|=EB[5 o@ SiETEE . 25 2s ogg2EE||:2 8 Ff 33S |2 hr 3: EI Z| ow cn0474 Fi [Ela pi Eo g FE FE EH EE : 20475 iPogSd 0 JEL Pei 3f3ggOEE LarE egd E esd eE gf wad oAg oEpt Eoe ' s EEL E88 | lori gd wgd esd vgn esd vgR ens i ai 3% ER CURR OTRRORR RR A BH 3 [J gg pnp RT AT B RT RTe RTE |e] og sd gh est opt od opt DHE EE EEEEE Pog... om omozo8 00476 [PI on P she s BIlRe IE EE EL Code a oa 20477 LE EL Th Ffg EgfB| L|vaRrE cowgveesedveegnh CoEkCoEadRUoiERog % PfLEE iid i BE 82 "38 FR "RR VRS VER UR CHE ELBE EEE i 8. e eo 2 2 = ow 20478 8x :| | i iP 4| Hf a { 8 } : | 3 egn iy ;4| : gd ogi wgd | oy 7 i|i iii Iet "oERyR . aBq Lnck]i zh Ei FL pe Hg gh gt ogd {}agg de3.0 :LE Dies _ Bi Ppl lar atl al 38 BE lanl wg ond end end end wnt wnt 2 i i [os] gf end ead end ext gd en i | eh eg egw eg vgs ean eget ead La xl eh wg os end wad esl EE BEER ERE 20480 Fi I i Dg ar od? FEA la to S 3BEL RE Pay g4 oo a EEL {ell ad ond wgd | lr wa? wg ood HE Ee Pol foe . 00481 Fool or 5 i # | bo oni wzd end obf ead wid wed Bi EEL SE BB lzrl wad wat if 9 = PaHE EE wat iis i | iH egn enn Daeg] ead eg eat end wed wad wen TT tie enn wn 5 1 eed end og wf ood ti eg? egl wnt wnt end og wed ; BE apERERRE (EE EO 2 00482 Pi i sel Poulos ih i esd od an D HBB Pa 3! fogs tL Do ea eet a? CHEE EE % &8 a ~ 00483 Er a gL TEL a atates ie 1 | dog (82 wd ex? ent og=t oh esl ee Pel lat] wf ol og eed of od 1 BT lot eet eg? ead gl oa ETE Ct oof EE CHE BE EEBREE El... moon 2 um 8Fx o" g1 i & gd Eo Pei PjrgagEeeg TE 53 | imakl00e00go ess HE Ba! 920485 oF i PE 3 3 i ! ig} oga epd gn end eg eps ean 3 Bl Bld d :i a Padi BLT a ond ond ed wadoad os? 3 UR 8 | i~ak] eg2 wzs ex era OR Dnt wa eet eat of og? uel od et eit upd end wg end wd eg? DEE GLEE ELE | 5 "We e 3 2 = 8 50486 LFH oo (hoe Ei i s EB PORE esr eat eg PSHEm Eg . TPE P 8E3 i a[RrEw]eeetlepg ig fy BBioE e. y EINE lect of od DRE Le I 3 00487 Em BREEIEE Pof lenEaEnEsnAsE , mmamngan eid Jog il | EE EE OER ce ORD me ORE me eg RE AR Eases Bi Ei L| imgsw3oZ m233 3o3moedms edod mwiad enss ue BEEEREZ 5 Pll i BEREDAD 5R88H 00 EE . EEREEE: : H PTT Tl am omen om ow | yy SESE NEES HE EEEEEEE Dl eee [igs CE as FE fey PEE FLEE Pai ome IBRE Pods EE Poadl 00439 # 8 fra fer Li f CEogsge s8ie 8gfe 8o3e 8se RaF 3 Ee a : iiB5 glo. ade F ofc ee Re ale wdfe eBw Tink Ee Hoa 3 #3 gn 8 : qi uGl ERoEds ig " 0g 1 a3 ae sEhe sobssR sade 2 pRB ow Ca BLE OBR OEE Bi. . = 2 & 8 00490 ir fi . - 2 - = = gL ae Fed gh gl Eo Bopha gd San i Bo i 5 gE 3.28 41 ofc ofc oZe oe ole ow itd ff Ee Ee ade Ee age Lm 8 sid 3 ade 2%e affe afc Zo win B y: eEe. Sfe afc ose Be wRe aE Ne =Sw gl EEE oE. EOE OEE OE fii. . 2 =: 3 3 50491 # 8 gC a ee [i PoEoe FETE EELREE gel I eEa me se se oe FEE js 0 : CL e iGiidf beyP sn S o AF s E 3: i i : #1 wfe ne oa we 4 efe 3 ofe 2 ele ; :LI gE Fe pI BOB OEOE OE fii. . = = 3 3 50492 i i CL '2 a Ce Fo we oY Ei Be de od oS ode 2 2 ag |joEee eve ome JHI.ayo GBgi 2. Be oS ea oh%e o8w ow ] . i i 5 Ei PS i EOEEg3| Re <fe ofe XPg E o oko C nie a3L 28 i | fe ole wle af wBe ole 1 all Ol :: Wo PoE EE es OE sOEs Bi. . 2 50493 # 3 i] gee gge 3de ge mage 3 8 | afe aFe ofe of Fe fe : gi ee ofie sie gfe ge oe 1iplgf gg AE 2 ES 3B EI BE 2Iig i REEL EER De ame we we fe fe EE ame a DEER em ee eRe le on oR i A he ode gle gle gh Fe |HoI Ei do Bog a oF i, BoE.oEOR OER fi. . = = 8 8 00494  : Te oS We ol. ut im a4" 2 2 2 a 2 BHoods a ome a oe fh ag] EEE s Bogs ogt os ge ge gh pe hig gira ] . ii, i gf 3% gfe phe ste te HFOaEE PoeeT oehl oetl oehl Wah eot. Eola song gE 83| rBelf me gE ase gee ge Jpoi gi. BLOB OR OE OH .=283 50495 [ EE ug| de Be fe ade ode EN : FEEL PPE oE oP gov a oen doam la foc SS3i0i8g mg. TTT fo wSe TOTES <he fe cfle o%e 2 il,8 = & EEJ cE Pa ase fd IBk Oi ogade gaove osee no gRe Re g8 g 8| t BBO. OB.OBEOE Bei. . = = 8 30435 : ` Ze ede ode WO. J3 sige ge gh gh gh gh of i foe oe ae ee : i 4 PET Em og gt gh ge 8 ee. HfifAi oml oePe SaRaR . iin 41 FETE igs fei a os aE gh oh i BPoopgfp Fshe OEide gglre sohge sie oamle i poBOBE OR OBE Bei. . 2 = 3 3 20497 # 8 of ar Doh od joi pibh cd odd oo Wow e Ph Bi se 58 =% #3 4% 84 PHi 3omHoB woR e Bnn en. i agi. . = = & & & 50498 F of i P H2I & BBe A fe ofe AGe oe od ia 3E0EG0, sp Se oziae ogfge oafgc gfe o2g iigifi FF EESE F FEE IERIE i al a opoBR OER BEE BR. Lo: oe 3 oz ~~0r99 F:o EoDT B aE e L Pog cE esc OR moa P treR n I grEatSaT le Bid FiEgl E oFmEe eRl EhmmoEm i BET ssw DEET mE ls DPEERRE gAE Epd Egb Agh 50500 Fool 8 Foon an Bg 82 3 G0 FEE EE Ex | i* i i i i i PoE TE eo i 0 bose ssl esl ssi ird I FidelpE23Tg oEBSly <3iE WE SEY BG 1ah)E Le EE BW oh EH LroEmasPSa 8 std EEE r i E 8 hii omi omi i si : i foe EE BFi el30 E woEm oy ef Pog iT) Teel te Top mes Phim om DOE el EWE. om GE SE I BE L PEROT ER E sR snl coosor EE og Te 2Poa bod | Pdae oggif ani EEE ph Ee jie LEB ERE Priirmaal U 0 L#8EdBE 5s ETE Te Tee Te IHE i LE Gob ossl RosmOosEm bors Ba EE Por aE es C[EEaRlES H ow B+ oB p EeEE PE en A md = 60502 dd riEeEp ge Fr es eed Ez | I 1 sel eal | gal A EE 20HE i0ifoell wsBdEl w_dg& eiPRwEd AFO BN PoE Lp BBL fHpiigol Lie BE EL EE =F BE = = if ig) he fodoeal ssl asl asl pe EE EE POEL Lo ii fib 58 38 3Ep 28) HEHE pg DEIE gee! salon oc iE bow=Rl o=Bi J=gi I=i 00503 : Bo am EE EE pede EE. sod PPoEEL Posil qe caE e wl sow c TBEEEB EERhE. FREE Lm E EE Go EL mlel WEBE mos WIEST Pgglq omB meE s 8 B08 a om om PE Ee RE C PORE eL r WEs E. GsEE oWmE bpDaElaEeR gb pGdlb akEed 0 aiEm gafm FL 00504 ! LOGE oE Coed DOL os Biol som yg rie : fp [ve] ERE Pol eglE eal fg ogre sii LrEEE 555 B2i2i!| I FE g eHE l es S2E3! E2E5! EE HY Ea PEL EE Ppalcites gu { SEE 858: gif grEI 30505 Poy sx. LE 3 ELE 8d Poa i Lm; m| r {oEaE Pg Laas 3 2g3iio%e 8& i a 8 peErms o[EiRPIR-sIllERl1fh #3i51e7 3333 ol dee Gobel ssl Po gE 5BE doh 8 08 BE5 Tore al sm HER EER L PEy LE gn E woEs Eoa DPosEtLeEl gcEolognEs oagE i ggrEh: ig oC Poa LE 2 00506 poo. RE AEE. E PI L Bald osi oBi i i rE Ep Ee PEL i BOLEEE8 EB TRE Cod Fd 2! FBiL ow oa ge le EE oe | == oes eg Eel 50 Eome E ogEow PPEaTnEosTET ee og a HEE DERE gnE gE EH ged gE 50507 Epes gLE EE poe i Eo y BE TT f,0 sgiE smi flog ABE EE HE FooBg ss eR bDEgE otEE EAaEoa Ea 50508 poppin i fry JD ape eee ee eee : Ely PP F oE oosoides cree ceo oe oe ve oe SiBgiidh3iiifdhfiEl BBoBgB . i{Cga 1: bk=foh Ei Pi : gg 0 PE OR E eB PRA 3 AE 203 La :8 gDnts fade2is0 L {RgIE Fi20l,| sS5l8i8g iF r ; i. ai a mHie og BSEg4 2JE 50509 Pod fpoonmn gino gp Fibooooioni iiEg jMpE aREenag ig ih BB BE yo Ho EE P CEELREE, hHeidi 50540 g EEDA Poort Te i i frgr TT S0S wn men sommes wn non jE hm Eilon TrTmm ne een menene ve vee Fomg iif THIN T vow en onnnes wn vee shhEFu EEHYE a HEkB .: Ios pif oF EEE sFog28g1 5 Bi ig cI g ii P: od: i | Pos 3 PPoosgt osi bg 00[I 3 i Po : PgR LEoEs 99 PcoiE leEms bo[aEtA Cf gn Tg fg hg "1 ne511 ; PEI III EE A hd aa da Paine PRT hE ai s Bl ogsii gE 8 gd 5 i Eid [(BF IBBB BBg D a iE Bog or Po EiFl eio 111 P:o : Rg LPoogE ogo: P!o PPooga EREsl DBL gg PEE | E4 FI fg : C:o ! BL i pa PETE5. H ReE isE i&i 00512 3 Pirginm TT ee ee ee pg RRR EE P y BE EEC seiee we eo oo so ee oe PEL IIInIE sh HEHEHE E GE [ ra d i Bi i OE ii i dyblg h5 E5 LEi R5Ed : Poli i PPoor bbCEod L; obCbo : Ei i id : E BaE I rEeniEd,: 50513 BoojpannTII boheme CB gGiellniann oomoonolri PETee oe oo oo oe oo BEIT i Biiiia- oe = EEE - - ow NEN jn EER EE PEL NoRoo Poa kBBEE bb Porn bd P bE atE n og b L go 00514 f BE FfB R iin EnnIIIIIoIiIilL Hy iggiPPolgigiEinge i eo i i id HE (H RE 8 BEHRH BoEudRi igd INEEEEE i d 11a. By y FI1IEREREE LFhalhteird Poydpnnoonoos B glii leng mm nnn gf leon TTT ShE ajiuEnRaRgnig PE Eh BERLE |sg iE P! ionrE : FR Po 4 bob Cdl I 00516 Booofemmooonne Eon SITIIIT IH Ee goggle mm TT tihg TpEEREREEYE BAyn Ppoga Poa iEhTbTBTE BE Poh n i oPe Ed NPURE BE E BE AER C BFIEIE RERRD E IEN PH E p ey gi f ER, 20517 : ims finns se Elis SE tpi : Billin= moeCS eo n 3 80 ig i i Sa Bhb ob i prt Rl Co boy Pl Co Lo Cy qh Ppl PRE Bit EAE l  oo jipnmmomm F 2 LpLnt4 opi osneqS esoseneyEA ame users3 gf ine EOE iLaY 3 47s 3 PRT eee an 3 : - % 4 formed eeeseeeg eo eel omg lz igvyoenToeyeeseooeg veeg eee SFB psa great raeanagg tag rane LE CEL 5 3i HEk i ioe i py Po | i COE he PEt d PEE Poog R ogEiel 7 : i : } 1] Po& 00519 APPENDIX 1 Protocol Protocol Deviations. Protocol Amendment No. 1 Conwacre 63e29-224 00520 98 CovanMcTe-6362301-24224 Protocol Deviations Protocol. Test material. Disposition ofTest Material. After authorization from the Sponsor, any remaining test material will be returned to the Sponsor. Actual Procedure. Remaining test material was retained for future use. Protocol, Dosing Procedures. Retention Samples. "Samples (approximately 100 ) wil tbeemtpaekreantufrreo.mUcnalcehssdousseedprfeopraraanatliyosness,amtphleseed sfaomrpdloessewainllalbyesedsisacnadrdsetdoraepdpratoxriomoatmely 1 month after completion of th inlife phase." Actual Procedure. Retention samples werenotdiscarded approximately | month after completionofthe in-life phase. Protocol. Termination. Organ Weights. At the scheduled sacrifice, thyroid (2) with parathyroid was to be weighed. Actual Procedure. One thyroid with parathyroid was not weighed for Animal No. C94539. P(rwohteoncoplr.eseEnxtp)erwiimllenbteaclolDleescitgend.fProomstcmaocrhtaenmimParlocaenddurperse.ser"vTehdeifnolowing tissues 10% phosphate-buffered formalin" Gross lesions were not (0 be processed and examiped microscopically. Actual Procedure. Some tissues, required by the protocol, histopathologic examination. Mising issues are listed with were not available for appropriste comments n the pathology data sheets for individual animals. Summary tables do not includethemas Having been examined. Gross lesions were processed and examined microscopically. These deviations are not expected to have affected th results of th study. C0052 9 Protocol COVANCE.> Sponsor: 3M St. Paul, Minnesota PROTOCOL Study Title: 4-Week Range-Finding Dietary Toxicity Study with N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) in Rats Date: June 8, 1998 Performing Laboratory: Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595 Laboratory Study Identification: Proposal No. 90545C Covance 6329-224 TLhq,2 COO05RR 100 Study 4-Week Range-Finding Dietary Toxicity Study `with N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) inRats Comnce 6329-228 ee Purpose Toassessthetoxicity ofthetest materialwhenadministeredinthedietto rats for at least 4 weeks MmSponsor "Toxicology Services `Building 220-2E-02, 3M Center St. Paul, Minnesota 55144-1000 Study Monitor Andrew M. Seacat, PhD 3M Toxicology Services Telephone No.: 612.575.3161 Facsimile No.: 612.733.1773 Alternate Study Monitor M3aMrTvoixTin.coClaosgey,SDerVvMic,esPhD TFeaclseipmhiolneeNNoo..:: 661122..73733.31.7571380 Study Location Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595 Mailing Address: PO Box 7545 `Madison, Wisconsin 53707-7545 00523 101 Covance 632P9a-g2e243 Study Director Peter J. Thomford, PhD. Covance Laboratories Inc. Telephone No.; 608.241.7207 Facsimile No.: 608.242.2736 Toxicologist. `Thomas E. Ryan, BS Covance Laboratories Inc. Proposed Study Timetable In-Life Start Date: June 12, 1998 IAnu-dLiitfeedEDnrdafDtatRee:poJrutlDyat13e,:19O9c8tober 18. 1998 LRaebgourltaaatttoorrwyyPirClaocmtbpoiclceioRnaedngucuceltaetdioinncsoampsltiafnocrethwiitThitkhee2Fo1oodftnhedDUrSogCAdomoifnFidesdtereuriaolnGood Regulations, Part 58, issued December 22, 1978 effective June 20, 1979). andwithany applicable amendments. "ARAnlelipgmrauolcleaCdautrriee9soiCannnFsdtR,hUiss1p-e4r.SottIoanctotelhmeaeornpetiinnicoonmopfltihaencSepwointshotrhaenAdnismtuadly dWierlefcatroer,tAhctestudydoes not unnecessarily duplicate any previous work. "QeTuhaaelriprtnoytsoAcsoUslu.irsatn(ucQdeyALcYo.nduTchte, parnodlfiifrearlatrieopnocrtewlinlulcbleeaaruadintgeednbyevtahleuCaotivoanncdeatQa,uanlidtyreport ianalybseesu,ddiattead, bayndthreepQorAtUwoifllbPeatahuodliotgeyd bAsystohceiaQtAesUInotfem3aMtio`nEanlv.iroLnimveenrtaanldTescehrnuomlogy and Safety Services. 00524 102 - Test Material Covance 6329-224 Paw INd-eMnettihfiyclatPieornfluorooctanesulfonamido Ethanol (MeFOS, T-6314) TLhoetlNotumnbumebrerswillbe maintainedintherawdata. Purity Responsibility ofthe Sponsor Stability Responsibilityofthe Sponsor Storage Conditions At room temperature: CIhnafroarcmtaetriiosntoincssynthesis methods, composition,orother characteristics thatdefinethe test materiali on file with the Sponsor. Reserve (Archive) Samples Areservesample (approximately 5g)ofcachlot willbe takenand storedat room temperature. These sampleswillbe transferred to the Sponsor after completionofthe ini phase. Dispositionof Test Material After authorizationfromthe Sponsor, any remaining test material will be returned to: A3nMdrToexwicMo.loSegaycaSte,rvPicheDs BStu.ilPdaiunlg,2M2i0m-e2sEo-0t2a. 535M14C4e-n1t0e0r0 Telephone No.: 612.575.3161 Facsimile No.: 612.733.1773 00525 103 Covance 6329-224 he Animals Species Rat Strain Crl:CD'(SD) IGS BR CShaorulrecseRiverLaboratories, Inc, Raleigh, North Carolina. P`rAegfeeraatbIlnyilteisasttihonaonf6Twreeeaktsmoefntage,butnotmorethan 8weeksofage `Weight at InifiationofTreatment 10010300 Numberand Sex 36 males and 36 females IIdmepnltainftiacbalteiomnicrochip identification device: Husbandry Housing ivius (may be group-housed during acclimation). Animals wil be housed in suspended, stainless steel cages. DCoietenhtiefriweidseRospdeecniftieDdi.etT#h5e00di2e,t miearolu(tiPnMelIyNauntaslioynzbeIydtetrhneamtaonnulf)acatduriessfuor,nuuirteiosnal components and eoviroumenta contaminant. Specified nutrient aad conning analyses are on fileatCovance-Madison. 104 90526 Covance 6329-224 - bes Water Adlibitum, Samopf tlhe weatser are routinely analyzed for specified microorganisms 2ndenvironmental contaminants. The results are onfileat Covance-Madison. Contaminants Therearenoknowncontaminantsinthedietorwater at levelsthatmightinterfere. with this study. Environment `Environmentalcontrolsfor theanimalroom willbesetto maintain18 t0 26Ca. relative humidityof30 to 70%, and a 12-hour light/12-hour dark cycle Acclimation Atleast 1 week R`Saenledcotmioinzoaftainoinmals for the study wil be based on body weights, clinical observations, `andotherdataasappropriate. Animalswil computerized blocking procedure designed be to assignedtotreatment groups achieve body weight balance using with a raensipmeacltstoofetarceahtsmeexntusgreoduwpisl.lnAotttehxecteiemdeo+f2 srtaannddoamridzdatieon,vtheiowefaitghhtetmveiarainoatwieoningohsftt,he andthemeanbodyweightforeachgroupofeachsexwillnotbe statisticallydifferent at the 5.0% probability level. Justification `Ratshistoricallyhave been used insafety evaluation studiesand are recommended by appropriate regulatory agencies. 00527 105 Covance 632P9-a2g2e4?. Group Designations and Dietary Levels eT Grow Ma"NluemberofAnFiemmaallse Dietary Levels (ppm MeFOS)* 0 T(ControD" 2 (Low) 6 6 6 6 6 6 1 10 3a ((LMiodw)-Mid) 6 5 (Mid-High) 6 6 6 30 100 500 6= (DHToihgshee)colenvterloslaarneimeaxlpsrewsi6sleldraecseipvpemt.hoefb6aMseaFlOdiSe.tonly. Dosing Procedures `DMieettahroy,d7ofdAadymsihnwiesctkrfoatiaotnleas4t weeks, Treatment will continue through (bedary before necropsy. T`RheeapsootnefnotiraDlorsoiutnegoRfoeuxtpeosureinhumans is oral DeovsedelooPupreeedpaebrpyaatCitoovonanascwei.llDboesmeicxonceanctcroartdiionngstwilltbhesbtausdeydsopnectihfeicMmiCxFinOgSprcooceedrur8e2 Supplied. Al dose preparations will be SIOred at FOOT (CTETRLUE: `SSRaoemrtpeelnaetmsisol(nyasSpeapsrmoapxnlidemssatoerleyda100rgo)owmiltlembpeetraatkuerne.roUmnelaescshudsoesdeorrepaanraalytsieosn,stahmespeled for Sales wible discarded approximately | month aftr conpetionofthe in-life phase. 00528 106 Commer 329224 JS.) DoseAnalyses `ByCovausinngacmeeth,odsuppliedbythe SponsorandvalidatedbyCovance: Homogeneity `Homogeneitywillbedeterminedforaltreateddoselevelpreparationsoncepretest. Onesampleeach(approximately 100 g)fromthetop,middle,andbottomofthedose: preparationsmixedforhomogeneity analyseswillbecollected,dividedintothree subsamplesfor extractionandanalysis,andanalyzedfortestmaterialcontent. All ``seaamcphl(easpwpirloxbiemsatteolryed1a0t0gr)ofom tretmhpoeertamotpu,remuntiilanadanldydbzoedtl.toImneoaf,dthde1i-potpnmiedsoaomsnpel,e preparation mixed for the in-lfe portion ofthe studywillbe collected, divided into threesubsamplesfor extractionandanalysis,andanalyzedfortestmaterialcontent. Homogeneity analysiswillberepeated ifbatch size changesbymorethan 30%. Stability Four setsof samples (approximately 100 geach)willbe taken fromthe low-and shaimgphl-edossceollelveecltceodfncreonmttrahteimoindsodifedoiefttpherpreetpesatdromsaiepxtreedipparoreatnteissotn.swHiolmlobgeeanneailtyyzed on tdhoesdealeyvoeflpmriexpianrgatainodnumsiexdeadsptrheteebsatsewlililnbeveadliusec.arTdhede.rOneesmaasamiopmfltenhspefhirioglmhnl-doogewse-: pTrhepeatrhaitridosnawmiplllebeofstthoreehdiagthr-odoosmetpermeppearraattiuornefwiolrlabtelsetaosrted19adtaryso,otmhteenmapnearlaytzuerde.after atleast 32days,thenanalyzed.The remainingsampleofthehigh-dosepreparation willbestoredin afreezerset tomaintain-10to 30Cfor 8weeks, thenanalyzed. lIenvaedldpirteipoanr,atthiroene msiaxmepldefsor(atphperionxliimfaetpeolryti1o0n0ofgtehaecsht)uwdiyllabnedtaankaelnyzferdoamctchoerdliown-gdotsoe: stahmespclheesdcuolleluescteeddfforrotmhtehseammipdldelseooffptrhee-lteoswt-hdiogshe-ldeovseelpprreeppaarraattiioonn. wHilolmboegeannaeliytzyed on thedayofmixingandusedas thebaseline value. Dose Confirmation `Samples (approximately 100g)fraloldomse preparwilalbteainaolynzesd. The. `mhiomxoegdfenoeritthyesian-mlpilfeecpoorltlieocntoedffrthoemtsthuedymwiidldllbeeoufstehdefloorwd-odsoseecloenvfeilrpmraetpiaorna.tiAolnl: sampleswillbestoredat roomtemperatureuntilanalyzed. 107 00529 Covance 632p9a-g2e24d ObservoafAtniimoalns CFmlaoircnbhiucanandliimOtabyls,werirelvclabotreidooibnnsgsefrivnedidngtswaicetdhaelylay e(aomb.saenrvdedp.m.)Afloarsmtorotnacleiwtyeanedklcyac,h `ibmraorlmwaillflibnedinogbssoerrvaendi(ncdaigceatwiiolnlobfeonpoernmeadl,wainldlbteheraencoirmdaeldw.iAlddbietiroenmaolvfeidn)d:ings wil berecasotheryarde obeservded: Body Weights `Each animalwillbe weighedat leatoncepriortotreatment,on theistday of treaandttwicemweeeklynthetreaf,er. FFooooddCcoonnssuummppttiionovnillberecordefodr eachanimaltwice weeklyduringtreatment. Clinical Pathology AFfrteeqruaetnlceayst 4 weeksoftreatment NumofbAneimarls Al AMn`imetalsitwoiflchClobleowlofielaclsatbtdieeodpngootvaeusrsniiaguhmtEsnbDlTtoAodwfoilhlebmeactoollloegctyedefsrtso.m Uajruignuelwairlvlebienc.olTlheceted chilled overnight (approximately 16 hours). 050520 108 Tests Hematology Covance 6329:224. tel red blood cell (erythrocyte) count hemoglobin he`mmaeatnoccorriptuscular volume: ``mmeeaannccoorrppuussccuullaarrhheemmoogglloobbiinn concentration p`lwahtietleebtlcoooudntcell (leukocyte) count differential blood cell count blood cell morphology reteixcaulmoicnyteed)smear (made,butnot Clinical Chemistry glucose urea nitrogen creatinine total protein albumin globulin cholesterol total bilirubin `algaanminmeaagmhiunaomtyrkatnsrfaenrsafseer:ase aspartate aminotransferase. cinaolrcgiaunmic phosphorus. sodium potassium chloride Urinalysis appearance volume sopHecific gravity protein urobilinogen glucose: ketones bilirubin mbilcoroodscopic examinationofsediment Theremainingurine (up to 10mL)foreachanimalwillstoredin freezerset (0maintain -1010-30C. Sampleswillbepackedondryiceandshippedto: K3iMsEJn.vHiarnosnemne,ntPaHlD.Technology aad Safety Services 935 Bush Avenue Building St. Paul, 2-36-09 Minnesota. 55133-3331 TFeaclseipmhiolneeNNoo..: 661122..777788..66107168 00531 109 Commacei2t9t26 Urnsampleswillbe ire by he Spans fopsilefreanalysis SerumPerfiuSuloforricAocdo(PcFOtS)aAnanlysees AFl rimael aaqfntdeNauatmebeaetr4onfweAsnckismoayflseam pra, 4-C~- we satoflot MethodofCollection ne gon Anuigmaarlsvweiinl.lSbaemfpaslteesdwoivlelrnbighcotl;lbelcoteoddwi(stphporuotxaimnacteolsyg2umlLa).willbecollectedfroma tFg~p" `BaSlmaopmolpdelsesaHmwapinllldebsiewnihglarlvbeestaeldlaooweddt1o0rleoinatfrroeemzetresmpteroamtuarleainadnc6e0 e10-d80.CS.erum Sampleswillbepackedondryiceandshipped to: KiSMsEJa.vHiaonnsmae,aPtlDTechnologyaudSfeyServis 5B3o5ilBiunsghA23v5e.n0e0 STetlPeapuhlonMeiNnom:es6o1n2.5757183.36-0313831 FacamiloNo: 6127786176 Swielrlubmesreapmoprlteesd iselpabreataenlaylbyyztedhfo SpPoFnOsSoarndmecaboltsbytheSponsorResults Termination i NUencstcohpesdiuclsewdiSlalcbroidfoincee.saAnnidmDaelasthtosbescrificdwillbeanesthetizedwith carbon dioxide,weiag ndeh xsane guid nat, ed. {ASocfrhreedianutillceeaadlspStaatc4rhiwofleioecgkeysotfeeteaanmdePnRtOaSlslasmuprlveisv,itnahneinmsanlesswtihlrlizbeedfvsiitehdcoavrebrnoingdhito,xiHdoe,d weighed, exsanguanidnneacrtopdsi,cd io 90532 Covance 6329-224 a... Postmortem Procedures Necropsy The necropsy will include an examination of the external featuresof the carcass; all external body orifices; the abdominal, thoracic, and cranial cavities; organs; and tissues. Organ Weights At the scheduled sacrifice, the following organs (when present)willbe weighed; paired organs will be weighed together: adrenal (2) brain ekpiiddniedyym(2i)s (2) liver ovary (2) spleen testis (2) thymus thyroid (2) with parathyroid Organ-to-body weight percentages and organ-to-brain weight ratios will be calculated. Bone Marrow Smear From the femurof each animal at the scheduled sacrifice only; made but not examined Cell Proliferation Tissue Collection and Inmunohistochemical Evaluation At the scheduled sacrifice, representative samplesofleft lateral lobe of theliver from each animal will be collected and preserved in zinc formalin. After fixation, each sample of liver wilble embedded in paraffin, and the paraffin blocks willbeshipped to: Sandra R. Eldridge, PRD Pathology Associates International 15 Worman's Mill Court, Suite [ Frederick, Telephone Maryland 21701 No.: 301.663.1644, ext. 2201 Facsimile No: 301.663.8994 50523 m Covance 63P2a9g-e22163 pRreoskuilftesrwaitliolnbecepl nrucloearvfotriiigndeclnues(iPdoCniNnAt)heefvianluaaltireopnorwti.ll be done on the samples. `a`tPtalhmistcohyeld-CuolAesOaxciridfaiscee,TiasssfaumoepmCloeela(lacepchptarinooxniimamaantadenlAdynaf5ll0ay0sshmefgsr)oozfenthie riqguhitdlpaitterraolgleorb.eof T{oheeivieverrwssisalleslwiblelcboelsloecrteeddin freeze sttomoan-60to 80Cuntilanalyzed by Covance for palmitoyl-CoA oxidase activity. `fALriteveszeeererPsdeuFtlOetSdosmAaacnriainlfytisaceii,sn -a6p0or1t0i-on80ofCt.he`Slaimvperlefsrwoimlcabcehpaancikmeadlownidlrbyeiscteoarneddsihni&pped samoplies.wiHlalnbseean,nPhaD,l3fyoMrzEPneFvOidrSoannmdenmtael TtecahnbolbooygtylheaiSnpdtoSnaesfeotsry:RSeersvuilctess.wiLlilvbeer reported separately by the Sponsor. Tissue Preservation Tbe folowing isses (whenpresent) from eachanimalwill be preservedin 10% oeutral-buffered formalin: ao`ardtreanal (2) jKeijdunenyum(2) lesions brain cecum lJiuvnegr with mainstem bronchi cervix colon lymph nodes (mesenteric and mandibular) i duodenum esophagus `mammary glands (females only) ovary 2) epididymis (2)) pancreas efyorsemu(ar2rf)awcietohfbtohneedmisatralroenwd()articular pituitary prreocsttuatme `Harderian gland heialretum with Peyer's patch (ymphoid Salivary gland {mandibular (2) sciatic nerve aggregate) seminal vesicles 0053% 12 Core 6329-226 re DE `skeletal muscle (thigh) thymus. skin thyroid (2) with parathyroid `spinal cord (cervical, mid-thoracic, `and lumbar) ssptleerennumwithbone marrow stteostmisac[(h2) preserviendBouin'sfixative] trachea urinary bladder uvtaegriusn.a Zymbal's gland Histopathology The adrenals, brain, eyes, kidneys, liver, mesenteric lymph node, pancreas, spleen. testes,and ovariesfromeachanimal willbeembeddedinparaffin,sectioned,and `stained with hematoxylin and eosin. "Tissue slides will be shipped 0: Richard H. Bruner, D.V.M. DAVCE POahtihoolOopgeryaAtsisooncsiates International 6217 Centre Park Drive `TWeelsetpChhoenseteNro,.:Oh5i1o3.4757096.99600 Facsimile No.: 513.779.9603 Tissueslideswillbe examinedmicroscopicbaylDlry. Brunerand theresultsfromhis. evaluation will be includedinthe final report. Aftercompletion of the examination, slides will be returned to Covance-Madison. Reports Onecopyof thedraftreportwillbe sent tothe Sponsor. Therewpilloinclrudetthe following information: Experimental Design and Methods Rdeossuelatnsalyses `mortality cbloindiycawleoibgshetrsvations 90535 13 Covance 32P9a.ge2214s bfoooddy cwoenisghutmpcthiaonnges tcelsitnimcaatlepraitahlocloongsyurmepstulitosn oorrggaann-wteoi-gbhotdsy weight percentages o`rpaglamni-ttooy-]bCraoiAnwoexiigdhatsreaatcitoisvites mm`eialcclrrpoorssocclioofppeiricactiooobbnsseerarvsvasatteiisoosnnmssents (provided by the Sponsor's designee) LeSvtaetniset'iscatlesEtvwaillulabteidoonne totes peterogensiyofvarianceatp < 0f.o05v,atrriaannscfeorhmoamtoigoennsewiitlyl.bIe unstehdectaossteaobiflize the variance, Comparison tests will take variance heterogeneity into consideration. Owenieg-hwtsa,ybaondalyyswiesiogfhtvahraidnanagctsea,.(IAffoNtoOdhVecAAo)nNsvOuimVlpltAbieoinsu,ssiecgdonin(fiiifpcauapnoptul,sDiuccnalnbieini)tctat'lospatan-iatbleoysltzowegibylobdye vuasleudesf,oarncdoontrrgoalnvweerisugshttreated group Comparisons. IcfotvhaeriAanNcOe V(AANsChOoVwAs)sigwiiNfliCbcaeOnucVseieAfdsortsobigoandniafyilcywazeneit,gbhootvdsaayrtiwWaetieege-hatksd,j1u,wsiiotenhdemn-ewiaaanylsabnowaildlyylsiwbseeiougfshetds ofotrhceonctorvoalrivaetres.usItfrtehaeteAd group COMpaRSOrS. G5r.o0u%p tcwoom-ptaariilesdonpsro(Gbraobuipls l2evtelh.roOunlg6yhdvaetrasucoslGlercotuedpo1n)woirllabfteeretvhaelufairtsetddaatytohfe reatment will be analyzed statistically. attrtahceteonndosfto1yfaeaalriazeftheaivsesbuesesncecoofmitmsheseruaieucsdaittteehdddbrfyianftalthereeSpppooorrntts,osirfi,gnntoehrdeenbqyutheteshteaeusdduirtdeeyvdidsdiiroarnfestcotf. raenpdorstubwmiiltltbeedctoontshieerSpeodnsfoirna.l and Awnilylmboedipfeircfaotrimoendsoart acdhdaitnigoensatloctohset auditeddraft report 10 the Sponsor. requested |yearafer ssuanes 4 00536 Covance 6329-224 -_ hee Two copiesofthe signedfinalreport (one unboundandonebound)willbesent tothe client. RecordRetention All rawdata,documentatriecornds,, protocol, speancdfinialrempore tgenneratseda,sa resultofthis studywil bearchivedinthestoragefacilitiesofCovance-Madisonfor a periodof 1yearfollowingsubmissionofthefinalreporttotheSponsor. Allrawdata Storedonmagneticmedia, the protocolandprotocol amendments, study correspondence, andtheoriginalreportwillberetainedbyCovance. Oneyearaftersubmiosftsheifoinnal report, all ofthe aforementioned materials will be sent to the Sponsor, and a returnfee will becharged.The SponsormayelecttohavethematerialsretainedintheCovancearchives foranadditionalperiodoftime, andCovancewillcharge a storagefee. Ifthe Sponsor choosestohave Covancedisposeofthematerials, adisposalfeewillbecharged. PCNAevaluationdata,paraffinblocks,andtissue slideswillberetainedbyPathology AssociatesIntemational. Liver,urine,andserumsamplesseat tothe Sponsorandanalysisdatawillberetainedby theSponsor. 90537 us PROTOCOL APPROVAL Covance 63P2ag0e2t2?4 Linda) oH `Andrew M. Seacat, PhD Study Monitor 3M Goud] 2/93 Date LY { -- Study Bifector Covance Laboratories Inc. bly 50538 116 Protocol Amendment No. 1 COVANCE> PROTOCOL AMENDMENT NO. 1 Covance 6329-224 4-Weck Range-Finding Diey Tosiiy Study with N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) in Rats TSpomor WM SCPmlMmeen Study Monitor: Testing Fact: Andrew M. Seacat, PAD Covance Laboratories Ic. Madison, Wisconsin Study Director, _ peter J. Tromfor, PhD "This amendment modifies the following portionsofthe protocol: Effective June 8, 1998 1. Pwiatgheth.e dTioe,caluddetthehefovleliocwiknegusseectdiotnod.issolve the testmaterialbeforemixing Vehicle Identification Acsone ThLoetlNoutmnbuembresrswillbe msotained in the rawdara. POunriftlye with te manufacturer SOtnabfilleitwyith te manufacturer SAttorroaogem Ctoenmpdeirtaitounrse 305239 n7 Protocol CAomveanndcmee3n2t9N-o2.26| Page? CIhnafroarcmtaetriiosntiocns.synthesis methods, composition, or other characteristics thatdefinethevehicleison flewiththemanufacturer. Effective June 19, 1998 2. Page,ClinicalPathology, MethodofCollectionToindtihatcaadiftfereent `methodof collectionisrequirteodprovideaddibtlooid.odelnetaethle text in this section and replace with the following: Animals will be fasted overnight and anesthetized with carbon dioxide; blood will becolvliaceardciactpunectudre.Theanticwiolbeapogtasusiulm EaDTnAftor hematology tests. Urine wil be collected chilled overnight (approximately 16 hours). 5. Page 11,SerumPerfluorooctaneSulfonic Acid (PFOS) Analyses,Methodof Cadodlilteicotniaoln.blTooodifnodricPaFteOtShaatnaadliyfsfeesr,ednetlemte tehe ttoefxtchoilnltoehcitsidsoenictiorneqaunidrerdep1l0acperowviitdhe the following: Animalswillbefastedovernightandanesthetizedwithcarbondioxide;blood (as. `muchaspossible)willbecollectedvia cardiacpuncture. Samwiplbelcolelectsed. without anticoagulant. 4. Ppraogcee1d1u,reTserremqiuniartediofno,rSccohlleedcutlioendofSaacdrdiiftiicoen.alTboloionddifcoartePFaOcShaanngaelyisnisn,edcerloeptseythe textin this secantdireoplancewiththe following: Atfhteenraanetsltehaestti4zwedeweiktshofcatrrbeoantmdeinotx,idael,lsbuirevdivfionrgcalniinimcaallspawtilhlobleogfyasttesetds oavnedrnPiFghOtS. samples, weighed, exsanguinated, and necropsied. 50540 18 ProtocoCl oAvmaennced6m3e29Nn-ot2.241 --_-- reve -s m3 Effective July 13, 1998 5. Page3,Quality Assurance.Toindicate thatqualityassurance fortissue. processing will be dboyPantholeogy Associates International, delete the text in this sectionand replace with the following: `Theprotocol, studyconduct,andfinalreportwillbeauditedby the Covance Quality Assurance Unit (QAU). Tissue processing wil be audited by the QAU of Pathology Associates International, OhioOperations. The proliferation coll nuclearantigen evaluation,data, andreport willbeauditedby the QAUof Pathology Associates International, Frederick, Maryland. Liverandserum `analyses,data. andreportwillbeauditedbytheQAUof 3MEnvironmental Technology and Safety Services. 6. Page 12,PostmortemProcedures,Histopathology. To reflect the decision to shiptissuesto Pathology Associates Intemationalfor processing, delete the text in this section and replace with the following: Tissuewillbeshippedforprocessitnog: Ms. Sheree Lovelace: Pathology Associates International Ohio Operations 6217 Centre Pack Drive. West Chester, Ohio 45069 `The adrenals, brain, eyes, kidneys, liver, mesenteric lymph node, pancreas, spleen. testes,andovaries fromeachanimalwillbe embeddedinparaffin,sectioned,and stained with hematoxylin and cosin. Tissue slides will be examined microscopically by Richard H. Bruner, D.V.M. DAVCPofPathology Associates International and the results from his evaluation wbieinlcluldedinthefinalreport. After compofltheeextamiinaotionn,slidesand tissues will be retumed to Covance-Madison. 20541 119 Effective July 20, 1998 Protocol CAomveancdeme6n3t29N-o2.24| ewes 7. Page2, Study MonitorandAlternateStudy Monitor. To indicatethechange intheareacode,delet thetextinthesesectionandreplacewiththefollowing: Study Monitor `Andrew M; Seacat, PD T3eMlephone No.: 651.575.3161 Facsimile No. 651.733.1773 Alternate Stady Monitor Marvin T. Case, DVM, PhD 3M Toxicology Services Telephone No.: 651.733.5180 Facsimile No.: 651.733.1773 8 Page,DispositionofTestMaterial. Toindicatethe changeinthearea. code, delete the text in thesesection and replace with the following: ARer authorizfartomitohne Sponsor, any remaining testmaterial will be returned to: Andrew M. Seacat, PhD. 3M Toxicology Services Building 220-2E-02, 3M Center St. Paul, Minnesota 55144-1000 Telephone No.: 6515753161 Facsimile No.: 651.733.1733 9. Page10,ClinicalPathology,Tests, Urinalysis, Paragraph2. Toindicatethe changeintheareacode,deletethetextinthis paragraphandreplacewiththe following: `Theremaiurinnei(unptgo 10mL)for eachanimalwillstoredin afreezerset(0 `maint-1a0itno 30C. Samples will be packed on dry ice and shipped to: 00512 120 -_---- -m rr Kris J. Hansen, PhD 933M5EBnuvsihroAnvmeenntuael Technology and Safety Services Building 2-38-09 `StT.elPeapuhlo,nMeiNnon.es:ot6a5.1.5757183.36-0313831 Facsimile No.: 651.2.778.6176 ProtocoCl oAmnenncdeme6n3t29N-o2.241 Pes 10. Page 11, SerumPerfluoroSuelfconticaAncied(PFOS)Analyses, Sample Handling,Paragraph1. Toindicatethechangeintheareacode,deletethetext in this paragraphandreplace with the following: Blood sampleswillbe allowed to clot at room temperatureand centrifuged. `Serumsampleswillbeharvestedandstoredin afreezerset tomaintain ~6010 -80C. `Sampleswilbepackedondryiceandshippedto: Kais J. Hansen, PhD 393M5EBnuvsihroAnvmeenmteal Technology and Safety Services Building 2-38-09 STte.lePpauhlo,neMiNnon.e:sot6a5.1.5757183.36-0313831 Facsimile No.: 651.778.6176 Effective December 15, 1998 11. Page13,PostmortemProcedures,CellProliferationTissueCollectionand Imumunohistochemieal Evaluation, Paragraph 3. To include examination of liver sections wil be stained with hematoxylin and eosin aspart ofthe cell proliferation evaluation, delete ths paragraph and replace with the following: Proliferation cell nuclear antigen (PCNA) evaluation will be done on the samples. In addition. liver secwtilibeostnainsed with hematoxylin and cosin and examinedmicroscopically. Resultswillbe pro forivncluisiondintehefdinal report. 121 20543 [-- oo AMENDMENT APPROVAL pLr ao IW Sa] =Study Monitor sane 1001n2197 - Study Dis Covance LaboratariesInc. 2 00514 APPENDIX 2 Individual Animal Fate Data Individual Clinical Observations Tew Covance 6329-224 30515 123 LgI o. {B8 .i of |p, |33R32R3RTREXIRIAIRTIIRCERRLZERLALT P53ERRI| gidsaasadasassaasanaaanaacanansosuds H3IEp m FEm HRa EERE Th RE 2 ER {R288 228828098293388R598288588838 i |% GEEnaaRnaRanaRaRRRAnaaORARARRIRED 58 figl:eceeeomermmmeeeenereeereean : ||p Ene lummusssgasauaeuanssns ganda ia dy [83] ees mannnannn sve serama ane i481 [|FESEB eEeRi EeEEAg SrEeAbR racrnR eooe0rtE ea0e0E 0b 00R 000 3 : ii 00516 P[oEgE iz . 8 pss a iBgr | P InEmNmEmEmRsReRnEnEmLnEnEnLLnceonumRnAnEaEnRnEnEnEeSnNnGeEnSsE ii Bi 3 SaeRniancannnan neta nnereiainey . P20 Flannagan "3 i Ee = ifR i =E 3alsasiasmessasanasaneasssassensany fleens nn TE En ieeauns 2589s 33uyasns 138 a5asentesnnaRnsnIRn UNGnRESRS Bl 20547 He iF o E Iayi .{88s 55 |spi5088 LBEo jH 2i0e i bai4n7aaE%s fii iE 3a FEE0s aan 3 ig E lia oH gfe Ein i 88 00548 Hp : i{gHai PE gr Lig Ele FEE Bd ji : ig: tH IEEEREY] EE OGRE i gieeesss Lefizzzzzg Raia is EEE [din C | EalBee IE IEEEEEE] 50549 Port gLall iLlh OE JeEiL eEhE Eg JE 1 ain l 1I BERrREe tfHEgIeiL,iR|E[THIEEHEEE ied 5 |CRglEerTraEee P18E23E0 E233E 3333 PA eee DPgHiIzEsEsEsIaEeS 2 30550 FPooloo i Ei CE LE LE Ea E RagiE LBol jSEiBgELfTL=a 8 Fogel : ii; ig if 5388% down BED iiss i CIdEofliEiEiRiEs ELEERE Ps jE 3 zi I Ee ERE iPEgRsE 3E33Ea3: H0551 FPooolh i i 1]gs: aeh 20g oq SIH i 5 Fogg SEED gid Bo Eran $F [EEEEE: 3| 2s3le3s3ez4z3s EEE EE jg jgErza PR e= 20552 CE |p LE HH] gf og EE Lf iA|a rEfo F180 5 - Pghip | = SH figEhig| nn gig fits BIC OiRERigG i gizzssss TE CBee 30553 Foc sob og LH LE |B jig0 EE pEa d 1 Sag8i GEE [ig iff SHE eas 5 THEE HBiitg ooiatafaeesiyt Hii L| gglizezgzzzaszeae REEERER | BE aw vman ER I Bier 2 00554 `Covance 6329-224 _-- IMT.63142 APPENDIX 3 Individual Body Weight Data (g) 30555 133 Bo- FF smmaa aR BEE NR DER muse sma sms BER {liid] = i DE mmm osm sen ER 1 Ele sow sus mes ons gi H3 EEE - | 5% gmmnmz g3sssd ssesey ARE SE [Be i [ARIRRN [ARARAR SERRA hE saasse smmEm BMA mR fed BBEl F amass GREED RREMAR REE gq ; S BiE maaan GRR aERRR BERR CLEEToTma sms E En E HR } a : GEERAY g SRRARR y ERRERE 4 ENER E Ef P a5g3 s#PoEm3es angnooeomEs faBI3nEEE aBEmS 00556 Boe Fm osama moms mas EE PF om mmm mam sem CE sm mmm mam mn A100 | Po 88 2RRSSS sesmIz smmens i1a8 ;Fpayos2% 3s93m888 SomMeEns ssmmeas igaieil : Flom mmm mmm sam 8 sei gw LE: 38 Bor on RR 33822 osm RsaRmRa ess mem RR5R28 sss i i p 59 gp BSAERE gp EANEEE g oman [! ]U:E38 g g3338e g: RSaArReEe g 3 28E 3832 3 j i 23 FEL aNasRg 883253 00557 FFooa PF mame mun mau EB D5 mem mmm onEE BE DE me mm mem mE 1 } Bi ssmess mesass osasEmd EER fd JE SE Lal i 2 | & tH| sEoAuEzEaReE aRmEeEnReEsE sEoRmMeRnEsR 23553088 jiilgy l | 8 Di8sh0 9| mse sen mum am 28I 8 | 2% seems sesswy gsmgsR 333 Bid Br gaa sams smn SE 5 sens soneen @snenen foms DEL semen umn | names i i 535558 is3333 i 533338 fg :i 30850 883058 388888 238% 00558 [i - Fam sane EF (Rm nm i Bog A100 EE l| ei un Bi mmm sum z i a" 28 aes PHL : i g i | 5 ; 5% 3Ruce 2faFi ii EHF = mam Biel oa ses | 5 2a I zanngs | = ju joan DgEgDOBBg lBoEgEe 20559 APPENDIX 4 Cove 6329-224 Te Individual Food Consumption Data (g) Individual Test Material Consumption Data (mg/kg/day) 00560 138 Fogg fae! mand mmm mmm osm Sd : i ize Iss3se s9gess 3msams ess S81 sald . : i i BEES IMEI 3AEERR Seen iid. 2 3 i ! ! $8392 geIsee sssopy see igi i i 1E szamse zmmsss amessy ess #0 i =R38E8 SPARST sssRys pees igi pr 255232 529338 Tog 255383 ETR ETReEse AelE: rrgeen i: reggae :i fot 3i wars sgl i 533383 5333338 i 333852 3am ooosel FPoonl Pe 33 gasgms Re ome wade Ela Les BE ss meres sspemr senesd SE : ZP8F0 L3em gn sessgz oceans essraaEenn iHf Ei S= mOe TcToEeR 3OIRRT GGSSSR i i Es 2 | i870 me 333535 rzmme FGESER desoss RESRIN mzeunx wl : 33 g Segesy y RERRRE g SRERER te : => : Psd zazene 3 880as 2eenen iE 5 HEE fH sme C0562 Por 5 23333 goRRIn wir Seas sfEE20 oo Bo 5%) sesesn goesas seesan mass : g tl amale RUSRGR 3RsEEs sess EE DRE 5og8h8018%i canes msess ssumes omne 5 % : 3 a =ssRge sRmgey snsNeR eRe 5: BEiErr) senses samess smsaem mex i g FRsRaR f awares oaeseee foams wl i neresR i sens i nesaen i EE g[ l i gageF s 33335E 3 $Ea2a Fr 30563 HEE dlH]y 3 Seseen si 5HE Foe weeess HHITL E L ee FE woe 1h oR EE i iw 53 399333 gE ee Banas I i #3 3 s8eae pda tam 1E2 3% 83088 og 00554 1 &5 Fa d1 i i IO: oR mm si i Lo mmm ommmommnoam PE :i ommmommm mmm am pi PiHe mm omen omen ow g PE op nm ommmoammm on: i i5 lig o| mmmoommmoomAdmdma mginv lPl rooSmpIooammnoaEmnETomn jel 3 Pi 7 TE Ee ay 2 2 g gg! 335833 i gzsese 235302 i gaze Eb ALEol oooohe smn ams R iEC sd mmm emeanm BEd | f Hoe I Onmn SER BEEm Sg FPElE]asal na ogsememns ogsommmemaos smmomseme 3 TEE Pe eee cam sem ie $2 dRdgRd SdSess slid 18} | iH } 3 gigs dese mmm rg HEE EE EE DieibTomi oom di em i mmm 20566 Pog | 3 Lo | ol wg goat a TEipm momENOEEm nm ePEo ammo: wees ii SERRE mE mm iib!iilqa[.ER WEE gue ny E HgasiE! EFl| ouom nm :: H ioPm fwemi mmm ki| "5 g EFroIn : NN : on JrorjI eg EER i pan nr {asso spo i [| EiE : a B38E358 : f 83 a 838858 ] 00557 APPENDIX 5 Individual Clinical Hematology Data Individual Clinical Chemistry Data Individual Clinical Urinalysis Data Covauncer632e922a4 20558 146 iF J mm mma am H [ 2 o! mma2. I mmm =. mm f; oBB e EEE sews oie mien sie wesews ume sail id : : 5 380 Ge) gp oAdeddd dF cdanes ef; eddnsd of ti3%g 3fgp.i EoeEvacRar Eee I EnvEenEn IaESe f HomEmEonnn fESie = I FEE AMEE 2 damads 20 ddaddn 3 i & i saga ade xmnnn ae asones oe hi grog spose, EERE LL 3am, med nL I5EaEmE , 20569  8 of . | i i gunn se 228388 8 ssmene efe A3R887 A osm oie 23232 3 iPoLEe 2 Seeds: g nsRsSR Rp AASRs 8 i i g J - a 2! Erman ote Bocoee te Banos oa IEF TRE ERE Fim - T3 UEBaal , Bogie eAdmenisr doteg 2 dsameeenm gae gasemean z odFte gd TEmE ENR EERE Rd i & 90570 ii oo Eof i=z ; asses ac sasess ate esasen aie BE Pog egemer ef mammes ate Tem semen aie em Hi cefIloEielE]3 esses ode cssuee o3v cusses ode -) o $8 BE gap even af maens a3 aannen ade Ld iil g B:OE4 RF AanEnnNes TteI MannEnen fe iovaionne i i ) gd oY;me se gamer oR gannes the Fi PE - LTT g wren of sen Pe fame oe frac Bg pre pea dElrs3 232388 3 E3383888308 34. 3 eee 333852 oi. 00571 i A i Bi=.l; [ 5 aoy ssszss soe mmeene le szases soe gemcen ode ; seEER ule ngeng aie Vighils : ! Pike ozmece 4% genises au eee of Li [a F 8 La ves fe awn fe . semen ode 8 i i 2; Brancusi Bonnncn o3e agnen wie gl 41 Fauenm nne sie E nEsnnEen afe egiaena go [SPREE Eh st i sp i | pm BN Pome ir 20572 PF Bfe H 111 3 Bi! : $ : ; sfoieg if i i i i i i Fighgl. : 3 2 THIEL bE PE EE 888388 333338 & 585850 30573 i Bfyli,e 1, , i EFiE efi; 23t FH ee fggels fF . % 3FLaEEi, teensy . teen - [RE HEE THBo , Pasib: 30574 Sem g gm g sm in Bo : i PoE g 3 SET 538828 STRESS F .5 oko 8afass lib goo gefh fassss Melb 3 if gt 83 g HEEL i OE = rPgggese To .zommemsn ue ousssma gE: fat ED : og5 nam eg eg SHE giPT8 O SgLaEmSed suHmEReRd mmnste d (2a:y ope Ssoriaisishr oD2 EzEpEEoEsR oR2 EgEeErEmEsE OiTfS g=E Woo gBEesE pf seed of HeBels = a 00575 comm g anmntf aim,piFn Ekb : is i in TT I : perme OBE z prep--l m2 sE sszss oo pansaosnm p"5 dBRiEE i cpesmmse 5 ogumsser T s smmun gIiE EBi oioi t 025 aBbEuBnEuEaE |gapemeea obie i amona aouuin d!l Jit. FEE Fgmmr poem nv 4 Sf oshEEEr nb EEE 6 EER & iwl 20576 gi i sgfEg | wseRss ae sssses ste sasssssie 3 Be i; oBEr. 2E5EEE El mevean gfe : e%tees e@e regese ole . eecces e3e ;graeeecde gaaesceSe Pi ii,fieo, aetn nde g qeqeeny nfe anenaatende 2 gE gf iF = Ty LE i i i gd foams of iE ) pny ab famed I qureen ede agama ole . EREASEEL ot Fumonos oe fronns oie funni Bogue opamme pee 30577 F | i j 8 :! ggij - Conv; - oem } coo oe . g f | 232328 57 EIER8 87 SEARER an F2y olE Boig gfgi = cess ote ame o.d emo. . :f2 iI aa Bh . % & # 3 concen afe Benenns aie Bananas v3 i] g21 o docmsae oe E menRans <8 nEuneEas ade E gLy, miconan oafle gewronen whee op<aeeonnn ole 2 : : ] Bg fpomms pgEmm i Sampm dilantin CO0578 # 3 ggrgeg FF 8 2 Bi! & ffoipgie if !i i Pathsl. . 2 0 gE gd FEIN NE ` EET i pELEL EEE &I s - 2 (EEBE BE RE 030579 i he Bhi . io. Poti i CHEE ' gPf iijg hEEa,le . TEptEi 1 gs "E380 5 nan ERE 5 I oon EEE 30580 I & g mo wee od a Be nsenan Be 25 of i | emnan Pe meses fe LEE Tn me i3 iBi g|g T erern alep wens af naman ade ssmase ef mee vevers ufo aLEEBa PaErnensaate l5 oargm mf tan 3 a bij ie, l36y3 3ft m f3e e a fibo oe ne - B3 HBE Oy ems he smemn mie mnsss ole Uo ben a fame fans 1 i i Bilin BEE THEE 00581 F 3 i gi TT i ewes oe ge oe of 4 BE seemss oBe gmnann ofc esas oie 28 Pon J I i Ed 2 veeees t seenea wenen Ww ih 55 HY LE oanan Se B ecuane oe Bonney ofe gjli.Hey ge:mm: a 2 P SEEiR gLFi weenve ale HA envmns uef anes wie PRT BOS i : zaman ade . samen wr : RRsaR AY i TH :i :! <gfE gl 7% o3onHeEsEsR oERiTe |0 oagEeEeRsAagg w29e speo5n8y3 a& e 00532 # 8 i! geones JOST ove werosg ede 5 s38ass 7r 83sEEE av gssssss nc pout I 2 : Boo ames et sss re ssn oe } !fio5ai l i smmtdnds g Amngdmsy sSee, t dmsosm a4 ii, i of Pomme ie Bares sn Banos na Pogdpep prea gaa game Ti EEi gdFoccen o ifasneos 0% gFosaes o% i5 e1: Asm3Em a : zscsan ade : namsms ade foi 555333 ge f 333553 se i 288253 ge 5 8 & & C20583 # Ei ; he] 3 ae do mmm mmm mm oi } . , Boo Pog 38 mms ment sms ye mmm BEE ER oi ERE Ey . HTE igh= o sEnmnennn nto 8oannoe ne ste a Boon1 es 2a 2 + #8 i5 $3 D8 arene ome 5 coves oe 8 cocee on Pode i i i fal FRIES EER ED TASER EE Ld i . 5. azemes ade oagsons ae ommamn een gid i 105384 I i mais eRe smessc wie sass 93 gel TTT mma me oe 22 8) GB9g1 m seinm e vRe cmomnamn fe sooamnnsma ofe FM, jig od mm, i om, i mmm cpSEEHaytFamoersnv2 Puavmnnae fe faaennnne <he s ahs Eg 36 F 3 g S53TEEEe L sFg enene ataee ononnn of 3 oennane u3e = i i gai & = i i $TOI gx og maz sh mummy oe smeses oie 3% i. 3 EEEEEEREE 583353 33 i 38R80% ate 508 i $H5i05i0E0RSE.n. FE ENNELL . EEESEEEE., 30585 5i sl 8 Lg FES BE sozmuz ate TT canon ofc 2AsEsa Se <eeeRs mee en oe agausn ofe ayaunn fe jal ; ; dE nenona Ge cwmann ale susan fe .Pi2l3oni at Foon oe Boe i ot Pom i = = 8 TiREtpLF cnanes0o8 f umanan nde 2 reece fe i gx gi ils 2 3 gy Ld NE . go i sagegs as i ggsges gee 3 segeEs gee Bligmme le HHL 00536 # i j EERE sm seo fo mmm mmm mpm Eg - : s. gBo.et smsssssmsssacsc gsaasmsImEieoat gmamsems ge Hp HEED . ! E i EE 5 HERS 3 End HLiE BgT loT melmertli ams a . 3 fEggesl 2 i kl ML adit ; ; 2 ha p TR ge : f3o Femme ge ifame ot i{one Hoge lagi liEEe 30587  . - = 2. doo mmm mmm mmm Ed i , Eo sma ommms ge EE TC Pad Lo}b% i iJ prmemn Te,ompaen 5 HEE * og EEE arin oe Bornes o3e Basins oie TRErRiE ag d E i EEE gi hd Si TEhalLE icvone whe i econ of : oooeee oT ~E ERE] foi ogee - gi 3 geen 5 =. 3 ee Fame 8 i i 00538 i 3i Ero i LE hy i 5 3 B. PEST ERT pan fre 3 iSiiigi Bo mmaE TmEmNm E Ls ERmug: .8 iSHE#E2 2] ;FRoEeEsIEon ;oEfeE dl one Bi osim3aidnd 8d1ae HI : "f 30539  i do LA E : i 3& 5Hel j uao agen s afe oIusRsoRne IaT f oaNoqSnn ole i Pash `8.0 ai ET F2 EEi SEdo T i Som gh iSm ih : Ei . . . i Bilgm famma BELT i 50590 ii [A CE : aFO =a g z : FiPsLhHC. LL : a i gi. 2 2 i dtr i #. i a >} i ssasss | 358802 4 ssmmee lsssan Bo. " - . 00591 # 3 ; Ee .1- 3BElElEyH s lgt ty :pr i 3 Easfae. fousee 3 aman kg 20522 ) $822332 2222332 282222 222228 2 ! seem geet Fn Fa 5 fod i ih ? comes Eoocoone Ey SE STITT core or on oma 13 1H2y iG2 : 8 IE co Fb hal i - g ix ETE 2 cenmee aceee vee ones 1 Si EE Pi ooF bE hg Fi xd EB 58588 go88 8885S s58888 152 i {5 = EEEREZ nyje EXEREY EZZORE ZEEEER fas JE g gE 3 30593 22322 9 229922 2 | seep5 Ty55 (is88R BsE. cocoe basen bg i 2 ERE i : : bot ge meso Pmeoen pgzEEEES - TET dif] emp gE HIE dish gn i HE EQERE ZEEZEQ fis 78 ore 3333 | i 2 of 020594  i Eoid ;: : ` bat : : : 2: B; oil8 men S=. i on f8 om TH Bro mma mmm mmm: i:SH3EiE EELeIeT oe i aneT ell ne STene s ay = i = 8 Eyl 5 a"ggds 2 ; dndids dn i ssgeed REF i ; i i 3B8 fF E53m0% .a. DAoMEEE. DSoEnEuH,G | "i 30595 I i 4i Eo : i8 g} EE i i [ i. #a| FFTIRNR "Be 5PAweNsoIoNn Ioffe R acnE nce oA fie : HE : 1 78s gms oafe nEmEEI EET id BET BEEES aT EE =z ET PERE Dap one Fadi oi fan oe : gh gree gas gree 50 us) %osseze 6 uonen % paagay "2 50598 = i5 2851 23 i Cee TT Cie -- B=yr 1 1 2 geo i 2, 0%, 2 fF Poot 1 t t 1 BEE i 5 3 pe del 10d 8 2 Sia. Bl : : ; 3Bog& : i2 : i 4 Boseeto oozene conten f 33sec. on 5 mans aan ann on 50597 8 :B Lo Baa it: i:d LPiigatt E} L 2 fg Pogo 2 8 Vad sigdn ina na EE g : Flot BO. g 3g8E0| x Egm aEge zRRERm:&ecBe@n RnaReEse ieddl C0598 & 2 kl E| aavmz assam wows avai iz gE : EB i 82.882 So0%0f 2 oxy fooff. Hesse. or HPRali TvE1E : jlgBRi i = ih sii 0 0 : OE Bl wrt Gowns amano nts " i Pl 2 2 i Ei omeenn geen oeees freee i gi i i i LE SBlH]2 ooo 23 cocooe &s cocoa &z cones 30529 $# & 2 5! 2 B= apaam amr Lox EiEEEl cece cocem Laight t 2 CiijtledC3 z HEE 3 iB El I cocoon g ccccoe stH! E3 Fi ens 20600 -_ CovawnMcTer.636e2391-24224 APPENDIX 6 Individual Absolute Organ Weight Data (g) Individual Organ-to-Body Weight Percentages Individual Organ-to-Brain Weight Ratios Individual Animal Pathology Data 20801 179 'Pog| RsmeEsssaEnimasgiensu2m81s33 ' PTE PRE ESE ol : 1 dasa es $5 AF BoE | Cod vod Co p& Bi o| gosf HceEggnRs B23iEagaGnes!Esaiaser PE ge mEm E88 Exe wo 2 PT mmammam CM i smnsmmsmanmm Umm nEEE | i Joi RERERE "F ann, FE E CoE LEAL jidtias feat PEE gl Bo ff Pg 5 xenmnniB femennsl] een0 000602 i" PE Eo eens sabes Big oo SELE LER Eo sd al i i PoE lms mm LD iEnmEmeRn EmiEgEm TPr1o0 B Eo a eogno lassses) mEsiisegse i gm [EAR RRRSR = 2 i 3 [BE RISE jSesiliLdditl fm ee lone saline i i POE EEEE lf BHopbes HEeEE mBReE BmEas EAT j ! LFEii8aRRsIoTAnN 2oEnEgamlEVEeRliaognd ; Ph ORE CoE DH | gEE ee 3DiE88 080 e aRRGSad NEEdE C Heidi 20803 i -i EE he sel i 0 ELEERE gobpp sipO omo[BR 0 ERSEELE mHISmTILGmRIGeAaAanS f {gad : i " [a i a mim 2 Pog oh Bm oma TE GER Rsesdisdesses IE peverteet gE i dae i PP{8EE5R% BSasleLeim Eel ee7 3 dE C20504 # i -i Po o Ji Eo | sPoEe 1 C i l EtNhdI oo 1 Pia gl 3 Pg or ns i P h E gi Lo iEii Lo oCo | oi Po 5 i = dorms n : a iDdE ee : Co LamnHF-H naE msRE Pg | HEi E Bo SHEEagpHSilHHE L : LE nf ffreemeeens] hi ans : ) 20605 i so Po phi 81 Po | PE i;| m bh r Poa 0] 2 B BE Cn voy | Haile | LE $11 ed . 20506 Fos li i EE go rdEoin Bg 3 OE EE IEEE :i PoE Hg sfieErr moislo bd 0 8 i 0 ELE Eg fr Ba OIFIR im giamenn | TE 3 (F3S1eas aaadind i DPgg gEsliamedliEnnE! Eof PRE DE | in mELinHaElR | PET hel Teen 0507 ` room Pow .i ' jessie reese a BBo F,gEi{a3m33n35o03w0 oIEmEEamImEiEm EogEi Il EEE Cod Cod sr omizgssas ae iadognn 2913E : Bio, ERLE mem aE fog oT SidBEi B4p | t4ece oCoieiEsaEsERslLgWm ssmmmnme RgpiWza 2 PEEL TEE POR Lo HE oe ae! sain } i fy TE a= RRA, FE D3 me malin all EERE IRAE PIE gt EenEE 00508 3 1 LTT eee EC ely | HELE EER . kEBB OB F, iviE gge seiE mszsest R scEinEne GRE om. i Bg oi opa.] siN zes'EniA vssR sEn RI3EiamEse Jiggd E#E o i5i5:8 2 58 aEyLfiEERE LniEmeREsEn LfEiEs g5 cE OB wi eh i i [I BUTE HR Re Bo se momen nia ht BH 12{338, S3i33823%, z2izzzd DE Bla cabana oo i { Bi BER REERER 4 |gDE ase ER see + 3 PEEoes E dlr] 20509 Pog osssms Loom B[E ifiroRgosE ymCCEDm EIEEEs RD OE FEPEEOEW L Co FPPOooRda oLmmiLet m eeealemge | BogRRaeieddddiaeCssssd| CPfRAhme U8 gla) ambos on | pPHE misl e d El 22 C0550 [4 2| i Lo Cod gn nb FEE H CEL A p80 &3 i Vi :i :| 2 fl i 3 E 8 Efi bo: i :Podi gq Oa2 BL| E3n. !Co i C:o i i Db mee i ; SERED 2m ismssss BE ss A 1852 D1 fe eelse oe i 8 Bien a jRRRREE 8 I PB eet dat od PEF asmsans funsane fame 20611 #x od Lo Poort g INE gr R iE g biho fa ati P00 Lo z H2 E 1i PoEI vE Co pai BBilogPiEleEsS mmaE n am Ly PI i ; Dal ee lel a PEERaL]E i 208652 F =g i Gb b) di E sCoEdD Teo | I SEER pig Po 1 | x bHiaE {Edi Bo FBilio i PoBdooloE io Co $d B 20 gF 8 eiBz3Ll Egs jiasmsm8saaadl 3a8n i DP1 RfTe m ene Cp EEE Paw DEE ming [-- PPEeSoplel LiIT)E 20613 CS ii PE E EE EERE RE :: i A o Pii E= oruLl L| mgEe oea=as---moeFao baes 13 7 oem ERs s Bic a od Co Co = PPooEp =| ppeaemE EeEeRE 3 1Tjssdses wes [a == PH selomner lemma fmm FE meesnid fmmemnxif wens 20814 EpilgisiT 0don: i Po E plELA E erEeR ojE n FprRpEglE Be=Hp toENB EumEawSeno= nan 2 BiohsE Hum(e1sS sii: | iIP i B i P=W o ii a2ne = T [Rag3EE C, 88 i[fsiigrae]rs *Bl p ofilmnmim mmn we Fe CL RET EEE i HE ma = H rr g eel bformomnned dlexa"n; 30615 FS od Fiz ofs nu RE i F- [as i pL TRE EEEEN Pog mm ig 0 250 0 la ae lsgges' us | din HLnEamE EF 15 i 8 B RielL lid ee inset gn | 2 iifi 1 P{ BEEE.EiL%3:E3 iE3mgE3EERR SofOB 1Tym wianmegae | iE (B1331ed3 136653 nS3 Pl gina mm ;DOiE Hpleiatg eeeer i PE ogsiim Bia 00516 Fool Eo gb LED i2 POEL vd !i .i EoEl i Bos Prim of 0 5 33 880 if 3 sf vod co Blob i aaE loEFs. : 0 i |i i Bi dT mai EE Eg ifZ C0817 F- cro Lod 8 "SEEI go PEL POEL Do Eglo peer I IH PE En : PRs BRoE ieEs mEEeEn Ee : 4 Fa af me an ol DiE #oameen E HRE e HEH DLEgE gBaalidB e i e gEhGin eemner| 0N0548 Foal go LEEL EE nib fer 10 gd EL ai 5 ALEA EHEEETrLEI 0 Enon 3 a2 | g.1 i :i HiiPodi wildeH r tee e gg | | i BH LL P PEEEgLrE] Ed 10649 7- FIA 3 ISRER BOER : gi | feeaessess posse mee ee Po ; PEELE EERE Biot 'eizzssng) 5 isamERE 3 EE Pod of TEs femme PPoOgREl spCFiee lnT[iigEmBEsasEgsmzRLgTpR iISgMgEAEEsReERdC LBgpR aOaEmRsE pSpidg EEEos gn iEeEHe EEGS :HO g EFpReBaEGg Da EoLslb fe nan aes i i UE en Hop pEEEE Emm DE hmmm EERE EG PIa gu uEniEsaaRnnatEss (E3E30RSaEsE BERE: DHE 3n PTT Bhan2 8 Te fone TE 00520 PoE &+4 eBp|}| f(BeiigRmRE3eE)e83s23 eiERneRaAsRntGe)i 3a3n1ia3cEisRalRs dil eee ae lasentool Ee i (BIEEE 22 mEasn. anisms Pog oE Tm Pop He 5 | BSE i niEE : [SE gE mmm JR aims CA SEE OE TR lll on lesan eyisess i i : i PELE REEL 8 Tip kooBE 0 ; i wlio iPOEi [ok aEiEeE ERaEiEdedniTeEs HB i F; o EicEes 2a8e Enemsasens 2am mE PEE ggisasl o lescecal naan PEE LEE LEE 20821 Fog mass i wood HE lg le gf gfe iopE size a ENS go EET g1a3g3Aa CT fOoE So lanes) mg Pog EoEE aE i jiiogA a se A URE23 sEeRgaLaE3 g SE dm | Co gE gE BE GE WEEY `al i . i HE T i Oi B| E: EEE eERnR Loge ee PT TE Po RL i dai VEE gglen Co REE dle ' a0622 PFooes go Fo i vod Lo i i i Lo Lo EFi EL8 gDsi bo Lo = fag i Tid Bg Co HE = SE ogi Fo Lod Lo PEoiRs Eo Co Cod i 3 Poin #BE | i | izssses) 2go iRzassEszlEmn EbeHe DE [| fo eeloe go RaRRRE, A% RERRRE CRS IRE 4 [I . 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PEE Po gd PVLeEleeEs laig eBo gBaR EEE 0 [giBaH P Pl E sh 58 10749 F og1 BigL l i1Ey E as BE 1 Re gol Sem B gi BO d: fE ags 5 iLiEs aHaEn g|i Poking Poa iF2ri1 d BEglE f II aE ERdELlE FFI oF a E miegl POoEaD gBifilietifEeui BE hed BF | "Tigg,BE3E 4 | BS | us. inoomcfed 8 BoEEjRuE s L [PoogisEaieemgbgn D[aE EElH EN CRE li | edie i Bppfi" tt] * | RSs 3 8" 00750 Poof Pho Pond am Rarities | ran i | i ghd iol . 1. oli iE L BB el Bm ETIS PPiHglEe yPRBEogeibil .B3E dome i gBsE | Reldip8iisimimdaisGEmEeRaEtnL gIEkF 3N ohPog HEE E CR o F[Ea L | ta EE atEllneeeee i | iA {i iool I DPE coorss We Fooi dGs fi lL || hE BoOa aE T, og6lpg Ed4REEED Poadifh, gist T progaulrindn TioEE pd qi 3T $ goLp 8 p gz BEe E gan i83 BB0F0 h kaetdie BEoglus FDA eianetgr JEatn l] by [fait i :< 00752 PFooolnyd meLo | ER lnsipmseeee | Lh |i | pH| RheRs liP1E BE . iFORdee c ETalg : i 5 iE PolaE 4B RRA ] 3 z| {BE emoworcwi | ' ii q Lgity 2 ok 7 i : : a iPoogdn iig taEsl 21 * 8mm i lem HY iL 4ER 1 EH ' CE eh Pall a CEE nem | GF EE pam 0 {emi BE EE PF enovss PogToasb i1) |PEE5gE| EgoiE%gE.. i1i a ee ARTE go a| igaElEi Bo S.BBE BE Ee | dia |e og Er ig oan i pp Lat PDom8 HHyodaere Pod Es dEv a 3{ooBOTGaEtEaSrEs P TR ooTHnREaE B Bo im man BTIgE dmiertlh mel EEL | a S3ibhi gE aynf es niiyE |Lge HT B5gigsaita: fit 28! ied iif 3 ; C30754 Por ammo ' PE[EhhEIchin La || ; Pha 7 lead 1 | jgiennt Hi o,i gfhnp3 EBEn SEREEt2) cPo o Bie og Ct FPEREEELERtChao i iP :oHE Lgiy gie:iFer iLiOB iEase f i 3: Bop gmem BBR i0 udme in! 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BEL ba i GRBEE 1 oa ii BR. le WB [i igh! C Pod H3 : C0771 FE, ME i Balkei 1iL hi se g BLgE ohfif 1i BF es | iol b 1PooBag Hh aSfaBdl]tER S; IoEd aaied ihb le le8 5 B BipE moE he,def ahd [doe Fo i )' Cno7IR PEC PFooilonamI Igo iDogiEggic cnivm Eeeeees; 0D | | gE 1oadingL oEgE Bfd LBEl mmmn 0 1 IL B 1EE0 E:LPEa=Es, JioB HE plasma LGR 1 i gBl SEE iEE 1aE 87 ooha gb EEyN : LE aoa gop | E iEgigEsgamssi . WEG i pPalee gLhE C [PeLh E Faet |5]5 {dhe PEE | ZEER| ii g 10773 hs 1 I PE EEE b rr ; B iiEB HOEEFob1 ulBBEyElaeds fH on aE dh 2L al Hog mk df ma q EE Glin Gn E {BES gHE i | E| flitliniet fBaE {Figi C"I i )' COTE BPof ootdiyad mm1, Dohme | ESE Lo i : Hy 1 EE BAER B ogBgilne ie le (1b Bg LEEmE, al oh i! { Cl F iaeeEI Es : q EE mty py : || ggeaedi pBasassetd } giz5. hs LR 5 cers HH Bg , 1, iy Por inm tl 1 hi i PE igh. 2uBe. i pe S| G"Bglafnogtr gi gE iLEi EheaaEd fl EEE. 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EL Eg 2 S5E BL gma | 2 4 len gl | er Hh | Rest! | o2sEET i ah LL ge bo #8 2 C0777 Pe i = LR Ph s 1 Ch {is i rE Wy! giEoruid PaHrelr i | i iB gEiilg | | 4 a ft b1i i3 Big B48 PELE i ii i 8: i at `| Ii Hl apd isi: z2 | fis i | Bil dle fg egEd! pl H3 a8 Hii iLi e i i gif Hd BB 2 l[I g a Faile:t gi : Him i Arik: 2 i | fra ;i i i : al Bind ls LE ele i . {i Bgod gifgmet 1 Fog ) damm GaEmies Ll i | gn 1 oq gol Bn LI ii Pid : RET P3 yEntLgeit LbaEEtE,eEy iPf o gSaemsa EgEti : oh Heh POE ici JiO ei : CPolE ibCaameBE dHEal PrH LA l egl new ane | OoraBf |EBeEet Hikes } di . coorro Pod End 5 i 3g EE0g il Wh 1 da pla a Ea i Hig io g 41PoBnEEREe BEy fSSatihidg5| H HofE das Piog d p5 paitd h ii PogB4f1 rmeaeirl Li i E [gr de ean | dy Ef ;i dHiEaEilcinn BBan [g EnE ds {geESlhi i ti | Eres i | ZAR) ]. J APPENDIX 7 Cell Proliferation Report CovanMcTe -6362391-24224 Note: This appendixofthe report contains information supplied by Pathology Associates International and has been reviewed by theQualityAssurance Unit of Pathology Associates International. 20731 359 Covancre e19i22r8 Cell Proliferation Report 77 4CompanPyaothfoSleoagnycAessAopclieastteosnitsarnaamtaiotnosnsComaraton =eA ee eee cousrouTBmAoTIONREPORT WEEKRANGEFIE NDINGDIAESDTOAAORGNYTENs OTOXAVIARCNEIGTRLY3SLTMUODP1Y2O4SWEI,THT4N51M4E)TIHN YBLA.TS PrepAmEDFOR: BrUDoxEiLcAoLLGo0YE0sS%mrveCieE1cN0e0Ts0ER J PATO HOLOGFY ARSESA ODMCIIEALTRLEMICSDIOCNU2S TH7RE0,,R,NUATTEIO1NAL wav 00 e RR Te G eA GST 300 20782 ee TConres e3292n24 CoPnotnSCollyt Re n (ap=t TAoFBCONLTENETS | CELLFROLIERATIONREPORT IL TABLES Im. SIGNATURE PAGE Vv. arm: IV. QUALITYASSURANCESTATEMENT 10783 361 _--m-- Covance 6329-224 MT CoFivsea SCetllyPNoBtefrsoion t CELLPROLIFERATIONREPORT Page PE4R-FWLEUEOKRROAONCGET-AFNIENSDUILNGFDOINEATMIADROYTEOTXHIACNIOTYL(SNT-UMeDFYOWSIET, HT-N63-1M4)EITNHRYALTS COSV TUDA Y NUN MBERC632E 5-24 PURPOSE d`iTehteptuo rrpatossfeoorfatthleeassttu4dywowcaksst.oassessthetoxicityofthetestmaterialwhen administeredinthe `rTehpieessreenptosrtth,seucbenlsilsptreodlibfeyrPataitohnoflinodgiyngAsssaoncidaintteesrIpnrteetmaatitoinofnoalrC(oPvAaIncteoStthaedsytNuudymbSpeorn6s3o2r0,-2I2M4,. ciPteerd fi"4-nWeoekrRouomgEctohtaFnmionled(iNns-gMsEFDiOiSefEt,moTy-n6T3ao1x4im)cIiintRyadtSso"w.dAyll awisthpofeNtMhceetttahsyskls DsroucigaAtdmeidniwsittrhatPiAoIn'sGpooortdiLoanbeorfstthoirsysPtruadctyicwee(rGeLcPon)dRuecgtueldaitinocnossmspsleiafnocretwhiitnhTtithleeF2o1oodfatnhde U0SdCwoidtheoanfyFaepdpslriaclaRbelgealaamteinodnmse,nPtasr.t 58,issuedDecersber22, 1978 (effective June20, 1979), MATEARNIDMAETLHOSDS Tierme Collfoer CcelPtroliifeoratnion Shiepxetaonciemiainllsaprperrolsicfxerpateiron.poAmpseictniognroofwtphsel1ethirsoeurgahll6obweeorfetshaeclriivfeircferdodmueraicnghwoefe6rkat4sfpoerr sspcexcipfeircagtrioownsp.(Tgirsoeuupssbl1o-c6)kwsawesrfeisxheidpapnedd.ptroocPeAsLsfeodrtsoepcatiroanfifnignbalnodcsktbaiyniCnogv,aFnrcoempeearcphrboltooccokl, c2eslllniduecwleaasrapnrteipgaerne(dPfCoNrAF)I,&&Eemvaarlkueraotifocnealnpdriolmimfoemroahtiiosnt.ochemical detectionofproliferating ImmrenchistfoocrChelelPmroilisfetratrioyn S(eScutpieoxfnisoosftpPairuasf,fFiiss-hceurbSecdideeudtitfiimc,ePsitwtesrbeucrguht,aPtA5)jtxo aennsduprleaacdehdeosniopnosdiutriivnelgypcrhoacregsesdisnlgifdoers SPOCPNAf.orSitmamnudnaocidsitochmemismry)m . Brioeflmyhe,tthii ossdusess weecrteiouosnesdcwetoreshitanicnue tbiastsem udewsfii otrhPacCmNonAa o(ciPoAlnTal paenrtoixbioddaysteo.(PACBNCAE(lDitAeKKOi,tl,oto#t0#1P6K,-P6A1I0N0,o.PAAI17N2o3.) aKnd3r2e6a)gmenettshreoqdufiorerdtfhoertdheteeacvtiidoinno-bfitothien aauntdigMe)n-waantsilboocdaylciozmedpblyetxh.ePcChNroAmaegxeprne3s,s3idoinzimnicneclblseinnziadlilnpeh(aDseAsBo;fStihegmcealClchyemcilce(aGly,CoS,,lGo,t w#a1sSHiEn2c0l1u)d.edTiinstshmeessteacitniionngsrwuenraencdcoonusinsttedeofrwsistutdhtyhateimsaistuonextyhelaitdn.wasAnnoetgiantciuvbeactoendtwrioltshltihdee primary antibody. CnOTSA 362 CovanMceT6-32891-42224 CovFeinnce!SCeealdlPNralbefrir63tR2= e9ip-eo2n2nt4 Cell ProliferationMeassrements Feqourmacioetyltloepf,ostraetixnitironagnb,epperavoiaccleocsmestiiiionengrsm,pdetiosdieefcsetwriteoirnoeinn,ign,sptapctehreur#s8eodsfKoctplefollwirImiabcgeelililfnsig,c(abcti.il5eo,ndc(ue1cn0tt0r)ielpotibtouhjleaulridugome,r IPiangdisof.ic1ta1t)iwohenatn(od2do0t0lehXir)si.tinoTemdohberepyphesourlcoooegrisnicincagigs)satmogef,eahsse.tpa3Ct0eo0lc0lypbteesprtioncoyStpelhsaiwsaiea.os1ft0frhtaehennedcqoruemallnltyacisyfecitleledecait(teadhboeiflgiiehnnlegdrs `pmeirmaaviloenalv. Haistfboomrocureplhslelooltgfyewretaiodfni.therassessedbyevaluatingthe serilHAEsideforcach Statistical Analysis TPhTebeSttwadeeeantc'osnttreoaltt(atdwot-rseisdtemde,ntumgerqouuaplsvuasriianngcMei)cwraossosfetEdxtcoetlevsetrfsoirosnta5t.i0s.ticAalPsvignaifilocafnu0ce.ie0n5 vasjudgedtobestatistically significant. RESULTS CentProliferation ISnidtti`evrTishdieugpanelisrfeisceiaamntatellgymebodeftgwproeoeoulnpicmaoaentetirnnogclheeelnpldapttrrooesfaiytfteeedasgt3ri8oounddpesatocaframmriaenlperedeboseyfnettmehdealilaenbSeaeltcist.nigoinndIe(xTa(LbTl)edsid1annodt. Imnimruoamlapw6emraelreepso,rttheedrfeowratshinsoGProCupN.Asidopresentfor mismalC34523;therfore, fiveoutofsix Histopathology `Sieththieecossamfarmtoeemyntlphienesstoaadmscieiontdsieeissnmd.(soHIbnAldEoic)vkifsdouurashleiasdtnfoiopmraaptlrhfeoiplnaodrgiaintcgiesovnaalonufdatgPirCoonNuApt-ossfoaamciainlmieatdraistlecitsdhereseiwnpterererespersnetttaaeitdniieondn. Appendi1x Th{hiegrhtedsoasieetsmsachlooefwrtpehedesn,Pro2CcnNhdeaAtngwseaoisihiniintgnthhideniolsitevhieofsresttminsansdluyee.roaTtfhsmecalailcveehrcnsodnftfoaemimnoaelndeferomacitasdl-thnhieacgtrwhoodsuoilssdewaialtnthdeortuttwhoe= ETeepemcarmaittiavneteifnffelcmtarsmdateotrayirneespdobnysea.niTnhcriesanseecdrPoCsiNsAwLaLsnot accompanied by &secondary. 10735 363 _-- suvptaRY Covance 329.224 MTs? CFommetSctoyNa5-- e538 Pages Inthe presentstudy,celfproliferationwasmeasured within theliverofmaleandfemalerats fromcomtrol(0ppan),lowdose (1ppm),low-mid dose(10ppm),mid dose (30ppm),mid-high dose (100ppam), and highdose(500ppm)groupsafter 4 weeksonstudy. Nostatistically significant increases incell proliferation,asdetermined by thePCNA labelingindex(LI) were `observedinmale orfemaleratsafter 4weeksofN-methylperfluorooctanesulfoentshamniodlo. n0736 364 Covance 329-226 wrem `FinalCellProliferaRtepioornt CoSv tudya Numbn er6c 329-e 224 Paget IL TABLES Legend SEM =StaEn rrod r ofa therMed an no737 365 cowmezs Icroer mmee eE e de a i TW Goa 1oisew| Tw Gem we | IW Comes oveew | TW Cone |oaom%| TW cosas |_oasew| Wea |oasow| sem | ese | Tw Cow osaew| ea [3-105 (owt)|W |Cesses |oarre| eee e---- | Coa|s ox0 amw4| WT Cosson|oeew| tera He T wee w s cessor| |oosaw| reine TW Cowso |_oosem | e---------- 0.225 --------| ae 7 MTCesie |ozsim| BIE 71 cd Mean |ozien| - 5- 100ppm (uc-+ii 5 Tw Cows |oss| Tw ey Coestr |oasaw | =--C E e F ai n iaae - : ehse TTTwoe |os es| rE et nO838 366 Covance 6329224 LL ] CoSvtayNon. 6c2302e24 CRETE [o ccoossF aass ||o oosmu|| T EEF --T -- F cues oCYon | Pea rr e| E-- e ------ TL f --F ----------cess oak | CL [ [F Fc Te coa uss | | o os asram s w|| ASet ==c&= E Fa r 1 t taa mo[or.ta eesm|x Bee ------ [ |_cessF ar |ois%| T FoF s [os ss oon eam] fF |cosso |oosox| [A 5-700-- omc-- am -- 1| Tosse|x emma 1i [oooessn| rasa EE Wen erm] lso opmon| n F ToassT | 0.183% TF cess [oie] T MFearn -- oa (NG: not determidnuesdid ER Pret | 10739 367 - 0 CovawnMcerT6e3e219-4u2224 Comesly ie Se3t5 IIL SIGNATURE PAGE Submited by: ProjectManager: Sc ednaeR_ ElddG ridge, PRl D. } Project Paihologin: CarolyMnoyedDVM,Diflomate, ACVF Baie S/5-0 Bue TZ5 oo 368 30'790 ee Coavanmce 6e329w-22e4 CovFiennaelsCSeelaldPyroNluimfebreatrio3n2R9Pe.ap2ogr2et4s. IV. QUALITY ASSURANCE STATEMENT 20791 369 ConMeT6a32i9e22s4 imEEeHr----PPea--tttho--olloo--gmyAA--ssssoo--cciia--attees--siInn--teemran--tatiio--onnaalrl --S ----E----en CellProliferation Report 4WeckRange-Flning DietaryTocSady with N-Methyl PerflucroctEtahannoel(sN-uMetFOfSEo,Tn-6a31m4)iind Raota CoSmtymNeebr 652924 QUALITYASSURANCESTATEMENT Thiscellproliferation projecthasbeeninspectedaodaudited bythe PAIQuality me Eedaby t ece Poi okf en reA d.eThe hBoom pi ho AsmrsnesUnit(QAU) #8 requizedbytheGood LaboratoryPractice(GLP)regalations Dest Inmection. fwio itz u 03/31;04/04/00 [Sr-- Mery PhaseInspected ovis Masnagement/ProjoctManager SPB D tudySDae taandn conpsor fSaiwondiunnno 2 Coat Ame tebaR Gc % ks RR RA n07IR 370 Covwancre 6e329-28 CovaFinncaelSCetluldPyrNoluimfebreatrio6n3R2e5p-o2r24t Pag9e APPENDIX I C0793 3m - 0 CovaSnMciTe .6r38291e-4222s4 Fi Dat olPrioRegnen: PeruWcIerneodksciRaecmgaAo iFoineddirngEDxiBtataryioTeexm(ieVcktAypSFPthOaddRnye,wgil1tth-aoL31gv)is: hes AvimalNumber _ Sex CCun n TMM DoseGroup [1.0Opppmm ((CCanoioml)) CCooeunns MM 1-1-00 ppepn ((CCoonntsrooll)) ous couse M 11-00ppppmm (Control) (Canol) Ccoouun MM 2211ppnm ((LLooww)) Cuoamne ceousn cout Ccoousuens. Ccoouus coouussy coeessito cen foeu] oouss ccoousursre ccuose cceoutn oun ccoouusse = cu= ss MM 22-11ppppmm ((LLooww)) MM 2211ppeenn ((LLooww)) MM331005 (Loowwnind) MMo 310370pmLGoowwniid)) MMoo 31100pmm CLoewwmmiidd)) *x 443300ppppm((uuiitt)) M 30ppm(i) M 430 pum(i) xM 44--3300ppupm ((i4)) M Mo 5511 00ppmm0 (MetN0 ig)h) M51ppm0(ib0 igh) MM o 5501 0pmmm0(MMaibth0 hiigghh)) M M 51 506p0ppmo0 m(M(iicg0 hihg)h) M M 66550000pppp ((iigghh)) M M 6500ppm (igh) 6-500ppm igh) M 6500pp (igh) Htsiogie Findings NNooSSiigganifiibcaonttFFiinnddiinnggss NooSiSigginfiificcaannttFFiinnddiinnggss NNooSSiipgiiffiiccaannttFFiinnddiinnggss NNooSSiipgiiffiiceanntt FFiinnddiinnggss NNooSSiiggniifficcaannttFFiinnddiinnggss NNooSSiiggpuiiffiiccaenntt FFiinnddiinnggss NNoo SSiiggnriiffiicacnuttFFianddiionggss NoSigificant Fiodings NNooSSiiggnaiiffiiccaarnttFFiinddiinnggss NNoo SSiggppiiffciceanntt FFiinoddiinnggss NNooSSiigpniiffiiccaannttFFooddiinnggss NoSignificant ndings NNooSSiipgiiffiiccaanstt FFiinnddiinnggss NNooSSiigguiiffiiccaannttFFiinnddiinnggss NoSFiogciafilcNaenctroFsinidsings NNooSSiigpniiffiiccaannttFFiinnddiinnggss NNooSSiiggniiffiiccaannttFFiinnddiinnggss FFooccaalNNeeccrroossiiss. NNooSSiiggaiiffiiccaannttFFiinnddiinnggss 00724 a2 Cove ance6e 329-224 Tt P4e-VIrenedfkivRikbmnaloAnrmivongeHDcsieetEtttaah-crayasTmooFlsze(i\ecri-kayMpFSEainlhFdnOidofSaydElogw,isToaci4ah3gnNL1i-in4vmMe)orclit:ngkdyRlaets _AsmscieNenwber SeFx Ccooemns F F ou F paved cousz cous F F cous couss F F cuoutse F Ccoeoss F Fo couse Fo Ccoossa FFo se Fo cuosusm Fo Coasts Ed F Cousens couse F Couss0 F cous Fo us Fo ccoouussses Fo Fo Cousss Fo Covsa s Fo Cy Coussy F Coussh couse FF coasez F TDOoppwmCr(oCowur) 1-0ppen (Couto) 11--00ppppeunm ((CCoonnttrroal)) 10prea (Couto) 1-20:p1p7epnm(C(oLntorwo)l) 2:pen (Low) 221:1ppppmm ((LLooww)) 21ppm (Low) 2.1 ppm (Low) 3:10pmCowmid) 310ppm Commi) 32100pppmm(Looww-mnid)) 10pmGownid) 3043p0mpp(mo0w50m)d) 430pp (id) 430ppm (Mid) 430py (ic) 44-:3300ppppmm0(M5id)) 5p1pm(0idhi0gh) 5p1pm 0 (Mid-0 high) 55100-ppppmm1((Ma0idhdis0ah)) Si00pm 0g) 516-0500p0mpmpe(n(HMighh)) 500pen(igh) 500ppm High) 66-550000ppppmm ((HHiigghh)) 6500pm(igh) ~~ToJSTiwgasieicgeneaFtiedpos No SigaificantFiodiogs NNooSSiiggnniiffiiccaannttFFiinnddiinnggss NNooSSiigganiiffiiccaancttFFiinnddiinnggss NoSignificantFindings NNooSSiiggnniiffiiccaannttFFiinnddiinnggss NNooSSiiggnuiifiiccaanttFFiindnidngisngs NoSignificantFindings NNooSiSgiaginiffiiccuannttFFiinnddiinnggss NNooSSiiggnaiiffiiccannnttFFinnddiionggss NoSignificant Findings NNooSSiiggnaiiffiiccaannttFFiinnddiinnggss NoSigificantFindings No SignificantFindings NoSignificantFindings NNooSSiiggnniiffiiccaanntt FFiinnddiinnggss NoSignificant Findings NoSignificant Findings NoSigaifican Findings No SignificantFindings NoSigaiicantFindings NNooSSiigpnaiiffiiccaanttFFiinnddiinnggss NoSignificantFindings Vous! Necrosis NoSFigonsiaflicNaenstroFsinideings NoSignificantFindings 10795 373 SOOM WE