Document mpx3BNBnJGk58VXekBbOJmgvZ

SeOpf CCOOXVAANNECEE". ORIGINAL HRI26-077/ SpoMnsor: St. Paul, Minnesota FINAL REPORT Study Title: 13-Week Dietary Toxicity Study with N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) in Rats Autor. Peter J. Thomford, PhD Study Completion Date: June 30, 2000 Performing Laboratory: Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595 Laboratory Study Identification: = ZTT 5A Taf w 4 Covance 6329-225 Sponsor Study Identification: Study No. 3M T-6314.1 Page 1 of 560 Conger "10 G--B--I C1076 1AUIIA0 CovanMceT663219-42125 QUALITY ASSURANCE STATEMENT `This report, with the exception ofAppendix 7, has been reviewed by the Quality Assurance UnitofCovance Laboratories Inc., in accordance with the Food and Drug. Administration (FDA) Good Laboratory Practice Regulations, 21 CFR 58. The data in Appendix 7 is generated by and is the responsibilityof the Sponsor. The following, imnasnpaegcteimoennstwere conducted and findings reported to the studydirectorand study director Tnspection Date Reported to Dates. Study Director and From To Phase Study Director Management 08/31/98 08/31/98 Protocol Review 08/31/98 - 08/31/98 08/31/98 Material Dispensation 08/31/98 04/12/99 04/29/99 Report Review 04/29/99 04/02/99 04/07/99 Data Review 05/04/99 06/02/99 06/02/99 Protocol Amendment Review 06/02/99 04/19/00 04/20/00 Report Review 04/20/00 0044//2288//0000 0044//2288//0000 PPrroottooccooll AAmmeennddmmeenntt RReevviieeww 0044//2288//0000 l( uileolsen Representative Quality Assurance Unit 2 Zo, Aove Date 00797 _-- CovanwIcMMeTr-636e239u1-4a2.215 STUDY IDENTIFICATION 13-Week Dietary Toxicity Ethanol S(tNu-dyMewFitOhSNE-,MTe-t6h3y1l4P)eirnflRuaotrsooctanesulfonamido Test Material ENt-hMaentohly(lMPeeFrOflSuEo,roTo-c6t3a1ne4s)ulfonamido Sponsor Mm Toxicology Services Building 220-2E-02, 3M Center St. Paul, Minnesota 55144-1000 Study Monitor Andrew M. Seacat, PhD 635M1.T5o7x5i.c3o1l6o1gy Services Alternate Study Monitor 3MaMrvTionxiTc.oClaosgey,SDerVvMic,esPhD 651.733.5180 Study Location C33o0v1anKciensLambaonraBtoourlieevsaIrndc. Madison, Wisconsin 53704-2505 Study Director Peter J. Thomford, PhD Covance P.0. Box L7a5b4or5atories Inc. Madison, Wisconsin 608.241.7207 53707-7545 Study Timetable Study Initiation Date In-Life Start Date In-Life End Date Study Completion Date August 27, 1998 DSeecpteemmbbeerr21,, 11999988 June 30,2000 10798 3 KEY PERSONNEL Covance 6329-225 Mme 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 Anatomical Pathologist Supervisor, Anatomical Pathology Peter J. Thomford, PhD. `Thomas E. Ryan, BS Nii Van Bruce-Konuah NathaEn. Snortum, BA, BT, ALAT Dixie Bushee, BS, LATG Brian Schoenike, BS Donna J. Clemons, DVM Diplomate, ACLAM Robert L. Hall, DVM, PhD Diplomate, ACVP (Clinical Pathology) Ronald Markevitch, BS, MT (ASCP) Sandra R. Eldridge, PhD Pathology Associates International Johnnie J. Eighmy, DVM, MS Diplomate, ACVP Diplomate, ABT Deborah Pirkel, ALAT C0799 a Covance 6329225 _-- wre CONTENTS Page Housing and MAIMENANCE......vovvvsrsrsssrsssessssssssssssssessnssssssssssssmsssssssesmsessnes 12 Group Designations and DOSE LEVELS.........v.c.rveverrrisrssssrnsnresssssssssassssessersseess 13 Method Of AAMUISLIAON......vc.cveverssssssssssnsssssssssssssssssssssessesssssssssssssssssnnns 15 BOAY WEIBLS oor senesesnsesesessssssesssnnsroessssssen 16. OPRHKAIMOIORY vvvvrsvsvvsvsssssssossorssinsnsessnsesessssssessesssssennosons 17 Clinical PABOIOBY ..vvrvvororrervresssesesesssesesessnssseseeesensesessonsn 17 Serum Perfluorooctane Sulfonic Acid Level (PFOS) Determination. ......................... 18 OE WEIENIS..vrorrrt re osesnesensoeereoeo1e9 Cell Proliferation Tissue Collection and Immunohistochemical Evaluation................. 19 Palmitoyl-CoA Oxidase Tissue Collection and ARAIYSES.............rvveerrcerrrrrrrrrsrne 19 HTIHSStSOUPEATPLNEOSIEIOVBAYLIO.N..v.v..vcrovccrvevnvrvsssensssrsosnssesssessssesnssesosssssee sssssesss sssssssss sssssssse ssssssssr ssesssese ssee2s2s00s 10800 5 CONTENTS (Continued) CovanMceT633219-42125 Page AA ---- BOY WEIGHS... A--------.23 TB et MaterialCOg NSUMPHONrrr -- : 24 CSeelrluPmroPleirfferlautoiroonoTcitsasnueeSCuollfloencitciAocniadndLeIvmemlu(noPhFiOsSt)ocDheefrenrimcmailnaEtviaolnuation. ...........2.255 Liver PFOSDEtCRMDALON.tenI se: ----25 CONCLUSIONS... 26 SIGNATURES... ttmmmssmsssssssssssmsssses21 REFERENCES...ccvvsnsmsmmmmmmsssssssmmssnssssss2s8 OPHTHALMOLOGY REPORT... 29 PATHOLOGY REPORT... 30 (COMMENTS ON THE DATA ccs: 31 COGDeEnSer,alACBoBdReEsVaInAdTAIOBNDS,IAENDVUINITHS.O.. NS....rvvvrvrcsse43s09 ACobdebsrfeOrvCilianaitcnadilUoPninAtstfhorCOliIniOcaRl HYE.MB.O.IOcZ.Y.c..v.rvs.svsevsvismriimrrsesse4s14 ``AAbbbbrreevviiaattiioonnss aanndd UUnniittss ffoorr CClliinniiccaall CURRESAIITYY S.I.S.....v.e.r.rerssssnmssnss:4468 Codes fOr ANBOTIC PAHOIORY crc 49 TAB1LEReSsults of Homogeneity ARaIYSes (PPM) ..errnrrssssesSh 2 3 Results Results OfStability ARGIYSES (PP) OfDose Preparation ARalySes ...rvssvssessss (PPI) rr: 32 33 4 5 SSuummmmaarryyooffCOlpinhihcaallfOiBcSOCBISVEAILOVNASU.O.N.S......v.r...iernrsssssenrrsmr:c53s68 6 7 SSuummmarmyooaffBBrooddyyy WWeeiigghhttDCahtaang(eg)Data () rss:39 weer: 61 8 Summaryof FOOd CONSUMPHON DAA (8)... 63 6 10801 _-- CovawncMeTr66332e91242n15 CONTENTS (Continued) Page TABLES 9 Summary of Test Material Consumption Data (mg/kg/day) ....................eoo6.5.. 10 Summ ofa Clirnicyal Hematology Data - Week S...........covvrvrrreeerssessscererner6so7n 11 Summary ofClinical Hematology Data- Week 14............ccevermrreemrmmemmeen 11 12 Summaryof Clinical Chemistry Data - Week 5...........cccccmmmmmrsmmrrsserrsirersoneTnSs 13 14 Summ ofaClr iniy cal ChemistryData SummofaClirnicyal Urinalysis Data - - Week Week 14...........cooovrrorerreeersersorreoees8n1s 14... 87 15 SummaryofOrgan Weight Data - Week 5 SaCifice...............oooon 89 16 Summary ofOrgan Weight Data - Week 14SACTHfice.............oooooororororn O1 17 Incidence of Macroscopic OBSCIVALONS ............c.cccocuevsssssssrsssersseesrssssscnes 109 18 Incidence ofMIcroSCOpic OBSEIVALONS .......v.ooveesersusscrsesseesessrsssserenns 112 19 Incidence of Severity of Selected Microscopic OBSEIVAtions..............ow 121 PrOOCOI DEVIBLORS.....ovccvvverrrsssssssssssssmssssmsssssssssssssssssessssssssssssssssssnessses 125 PLOIOCOL....ocessscessssersrerrrrermssmsssssssss masses sssssssssssesssesssssssssmsnsssessoss 121 Protocol Amendment NO. 1 ..vcvvvveveessressersssssssssssssssesessssssssssssssmsessssessssoess 144 Protocol Amendment NO. 2 .....vvveveesvesseersssssssssssnsssesesssssssssssssssseessssosrsseess 146 Protocol AMENAMENt NO. 3 ..oc.voveverveeecserssssnnesssnssssssssssssssssssssssessssssssseeees 149 Individual Animal Fate Data.......oo.eoooeeveeeerssssnessenssnesssssssssssssesssessssssssness 152 Individual Clinical OBSEIVALONS ...........occcvcevrereerrssrssssessssssssessssesssessssoneseess 157 Individual Body Weight Data (8) ........c..covmerrerercerrssssinssssnsesssssssssssssnsmersses 190 Individual Food CONSUMPON DAA (8) .vvvvvvvervsnvnvsmrrersessos on 202 Individual Test Material Consumption Data (Ig/Kg/day)..........co..vrirmmr2i1ns3 Individual Clinical Hematology Data.........ce.vvemevsrsereresrsesosen ener. 224 Individual Clinical UHNalysis Data........co.evveeeeceeercsenssseseesssssssssssmsesssesssseeses 216 Individual Anatomic PAthOIOBY DAIA.....c..cceveveeeeeerssesesscmsssssssssessssesssnessioons 289 CellPrOBERrEPaOt..i.voevenveervsvsssoreninnsesesssssssssssssssmesosssses SAT 10802 7 CovanMceT683219-42125 ABSTRACT The purposeofthis studywasto assess the toxicofitthye test material, N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) when administered inthediet toratsforatleast 13 weeks. Four groups of Cr:CDY(SD) IGS BR rats were exposed to N-MeFOSE inthediet for at least 13 weeks. Each group contained 20 males and 20 females. The dietary `concentrations were 0 (control group), 3, 30, and 100 ppm. Food was provided ad libitum, except when animals were fasted. Water was provided ad libitum. The animals were observed twice daily (a.m. and p.m.) formortality and `moribundity. At least once weekly, each animal was removed from its cage and examined for abnormalities and signsoftoxicity. Body weight data were collected on the first day of treatment and weekly thereafter. Food consumption data were collected weekly. Ophthalmic examinations were done before initiation of treatment and during Week 14. Blood samples were collected for hematology and clinical chemistry tests during Weeks 5 and 14, Urine samples for urinalysis tests were collected during Week 14. During `Weeks 5 and 14, blood was collected from five animals/sex/group for serum perfluorooctane sulfonic acid (PFOS) analyses. At the Week $ sacrifice, samplesofthe liver were collected from five animals/sex/group for palmitoyl-CoA oxidase activity and liver PROS analysis. Animals sacrificed at Week 5 were not necropsied. During Week 14, the remaining animals were anesthetized, weighed, cxsanguinated, and necropsied. At necropsy, macroscopic observations were recorded, selected organs were weighed, and selected tissues were collected and preserved. Samplesofiver were collected from all surviving animals for palmitoyl-CoA oxidase activity and liver PFOS analysis. Samples of the liver were collected from five animals/sex/group for proliferation cell nuclear antigen (PCNA) evaluation and microscopic examination. Microscopic examinations were done on tissues from cach animal in the control and high-dose groups (terminal sacrifice only) and from the low-dose animal that was sacrificed at an unscheduled interval. Microscopic examinations werealso done on theliverand stomach from each terminal sacrifice animal in the mid-dose group, and on the liver from each terminal sacrifice animal in the low-dose group. 10303 8 Covance 6329-225 -_-- wTeu One female given 3ppm N-MeFOSE was sacrificed on Day 59 due to severe laceration of the tail. There were no macroscopic or microscopic changes to indicate that its moribund condition was test material-related.Allother animals survived to the scheduled sacrifice. No clinical observations were noted that were considered to represent primary effects of the test material. Statistically significantly lower mean body weights were noted beginning. at Week 4and continuing through the end of study for animals given 100 ppm. Statistically significantlylowermean body weights were noted beginning at Week 7 and continuing through the endofstudy for males given 30 ppm. Body weight changes were statistically significantly lowerin a sporadic mannerforanimals given 30 or 100 ppm. Overall body weight changes (Weeks 1-14) were statistically significantly lower for all `groups given N-MeFOSE. Although statistically significant only at Week 13, food consumption was in general lowerformales given 100 ppm. For females given 100 ppm, statistically lower food consumption was apparent at Weeks 3, 4, 6,7, 11, and 12. Dietary administrationof N-MeFOSE was associated with lower hematocrit for males and females fed 100 ppm; higher urea nitrogen for males and females fed 100 pp; higher albumin for males fed 100 ppm; lower globulin for males fed 30 or 100 ppm; lower cholestearnodl triglycerides for males fed 30 or 100ppmand females fed 100 ppm; higher alanine aminotransferase for males fed 100 ppm; and higher hepatic palmitoyl CoA oxidase for males and females fed 100 ppm. The effects were relatively mild with the exception of those on cholesterol and triglycerides for the high-dose males; those effects were considered to be ofmoderate severity. Allofthe test material-related clinical pathology findings were more prominent at Weck 14 than at Week 5. Statistically significant and test material-related changes in terminal body weights and liver weights were seen in males and/or females in the two highest dose groups. Statistically significant decreases were scenin the terminal body weightsofmales fed 30 ppmand in `both males and females fed 100 ppm of N-MeFOSE. Statistically significant increases `were seen in the mean liver-to-body weight percentage and mean live-to-brain weight ratio in males fed 30 ppm, in mean absolute liver weight and mean liver-to-body weight percentage in females fed 30 ppm, andinall liver weight parameters in males and females fed 100 ppm. C130304 9 Covance 6320-225 sre Test material-related macroscopic findings were noted at a low incidence in theliverand `glandular stomachofmales and femalesinthe 100ppm dose group only. Liver findings included organs that were large and diffusely dark. Inthe glandular stomach, darkfocior. areas were sometimesseen in the gastric mucosa. Test material-related microscopic findings were seen in the liverofanimals fed 30 and 100 ppm of N-MeFOSE and in the glandular stomachofmales and femalesinthe 100ppmgroup only. No test material-related changes were seen in animals fed 3 ppm of N-MeFOSE. In the liver, one or more test material-related findings affected all animals fed 100 ppm and included slight-to-moderate centrilobular or diffuse hepatocellular hypertrophy, minimal-to-slight coagulative necrosis, minimal hepatocellular pigment, and `minimal-to-slight centrilobular to midzonal or diffuse. hepatocellular vacuolation. In animals fed 30 ppm, centrilobularhepatocellular hypertrophy was also seen, although the incidence and severity was decreased at this dose. In addition, a low incidenceofminimal hepatocellular vacuolation occurred in 30 ppm dose group males, and the liver oaf single female fed 30ppmhad minimal coagulative necrosis. A possible test material-related change in the glandular stomach of animals fed 100ppm was a relatively low incidence of `mucosal erosions. The erosions were ofminimal to slight severity and involved a very smal portionofthe mucosal surface inallcases. `Based on anatomic pathology, clinical pathology, and body weighteffectsat 30 and 100 ppm the no-observable-adverse-effect level was determined to be less than 30 ppm when N-MeFOSE is administered at concentrationsof0, 3, 30 and 100 ppm to Crl:CD*(SD) IGS BR rats for at least 13 weeks through dietary administration. Based on the body weight effects at 3, 30, and 100 ppm, the. no-observable-cffect level was determined to be less than 3 ppm when N-MeFOSE is administered at concentrations of 0, 3, 30 and 100 ppmto Crl:CD (SD) IGS BR rats for at least 13 weeks through dietary administration. Tn the absenceofcorrelative changes in anatomic pathology and clinical pathology the body weights effects at 3ppmwere not considered to be biologically adverse. 10805 10 _ CovawnMcTer-6633e2194-.2125 PURPOSE `The purposeofthis study was to assess the toxicityofthe test material, N-Methy! Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) when administered in the diet to rats for at least 13 weeks. REGULATORY COMPLIANCE All aspectsofthis study wereinaccordance with the Food and Drug Administration Good Laboratory Practice Regulations as set forth in Title 21ofthe US Code of Federal Regulations, Part 58, issued December 22, 1978 (effective June 20, 1979), and with any applicable amendments. TEST MATERIAL `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. `The test material was stored at room temperature. Information on synthesis methods, stability, purity, composition, or other characteristics that define the test material is on file with the Sponsor. Reserve (Archive) Sample A reserve sample (approximately 5 g)ofthe test material was taken and stored at room temperature. This sample will be transferred to the Sponsor after authorization from the Sponsor. Disposition Remaining test material wil be retumed after authorization from the Sponsor. 1 10806 ANIMALS AND HUSBANDRY CovanMce 6T329-L225 Test Animal `fMacailleitayonfdCfheamralleesCRri:vCeDrL(aSboDr)atIorGiSesB,RInrca.t,sowneAreugoubsttai1n7e,d 1f9r9o8m. tThehePoarntiamgael,sMwiecrhieg3a9n,to 45daysold at initoiftaretatimeontn. The males weighed from 184 to 236 g, and the females weighed from 140 to 179 g at initiationoftreatment. Identification Each animal was assigned a temporary number upon arrival. Before initiation of treatment, a microchip identification device was implanted into cach animal. After randomization for placement on test, each animal was assigned a permanent number, and the microchip was coded with that number. All dataforan animal are recorded under these numbers. Acclimation Ninety-twomales and 92 females were received on August 17, 1998, and acclimated in Animal Room 348 for 15 days before initiationoftreatment. In general, animals in this shipment appeared healthy. During acclimation, the animals were examined for abnormalities indicative of health problems, an ophthalmic examination was done, and body weights were recorded for all animals at randomization. Housing and Maintenance Animal Room 348 was used for this study. Environmental controls for the animal room were set to maintain 18 to 26C, a relative humidity of 30 to 70%, and a 12-hour light/12-hour dark cycle. "The animals were housed individually (except for the first7 days of acclimation when animals were group-housed) in stainless steel, screen-bottom cages. 10507 12 CovanMcTe-6633219-42.215 Certified rodent diet #5002 meal, (PMI Nutrition International) was provided (see Protocol Deviations for exceptaidloibnitsum), except when animals were fasted. The diet is routinely analyzed by the manufacturer for nutritional components and environmental contaminants. The results are on fle with Covance-Madison. `Water was providedad libitum. Samplesofthe water are routinely analyzed for specified `microorganisms and environmental contaminants. The results are on file with Covance-Madison `There were no known contaminants in the diet or water at levels that would have interfered with this study. Animals not selected for the study (12 males and 12 females) were removed from the study room and used for training procedures. Justification Historically rats 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 August 27, 1998, and Protocol Amendment Nos. 1, 2, and 3. The protocol, protocol amendments, and protocol deviations are in Appendix 1 Group Designations and Dose Levels `The animals were examined by a laboratory animal veterinarian on August 31, 1998, and found to be suitable for study consideration. Selectionofanimals for the study was based on clinical observations, body weights, ophthalmic examinations, and other data as appropriate. 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, the weight variationof the animals for each sex used did not 10808 13 CovanMcTe-6633291-42.215 aenxacleyezde4d2ussitnagndLaervdedneev'iatteisotnfsoorfhtohmeogmeenaenitwyeiogfhtv.ariGarnocuepattmheean5.b0o%dypwreoibagbhitlsitwyelreevel and found to be homogeneous. Animals were assigned 10 the study according to the following design: Group `MNaulmeber ofAnFiemmaalles (DpipemtaMreyFLOevSeEl)s* 1 (Control) 2 (Low) 20 20 20 20 0 3 34 ((HMiigdh)) 2200 2200 30 100 a b TDohseecolnetvreolsl waenirmeaelxsprreecsesievdedasthpepbmasoafl MdieeFt OonSlEy.. Dose Preparation Dietary concentrations were based on the test material as supplied. Before initiation of treatment, diets of 1,3, 30, 100, and 500ppmconcentrations were mixed. Diets were prepared for stability analyses at the1-ppmand 500-ppm concentrations and for homogeneity analyses at the 3, 30, and 100 ppm concentrations. Diets were prepared once every 4 weeks for use in the in-life phase. PreparationofDiet for Group 1. The appropriate amount of diet was weighed into a lcaobnecleendtrcaotnitoani.neTrhaendcoamcbeitnoanteiownasoafdtdheeddiaett tahnedsaacmeetocnoencweanstrtahteinonmiaxsetdhefohrig1h5-dmoisneutes. Pinrdeeppaernadtenitolnyo.fDAiestpseciffoiredGraomouupnst2oftdhireotuwghas3.weEiagchheddoisnetoleavellabwealsedcporneptaarienderand a tspheecfifeieeddianmtoheunmtioxfidnigebtowfo]raGnrdotuhpe4amwoausnwteoifghdieedt ffoorr eGarcohudpie4t.waAsttrreanncshfewraresdftoortmheed in trench. The contents of the mixing bowl were thoroughly mixed for 1 minutes. Preparation of Diet for Group 4. A specified amountof det was weighed into a labeled cloanbtealiendecro.ntTahineerr.equAiprperdoaximmoautnetloyf5mtesLtomfatearcieatlowneaswawseiagdhdeeddatnodtthreacnosnftearirnederianntodamixed `manually. Increments of approximately 5 mL acetone wereaddedas necessary until the test material had dissolved. To prepare apremix, the dict was transferred into a labeled 14 C0809 -_ Tr CovanMe cTe 66332a 10-42215 Hobart" mixing bowl. The test material and acetone were added to the mixing bowl, overlaid with a portion of diet fromthe mixing bowl, and thoroughly mixed. A portion of direectofvreormrteshiedmuialxitensgt bmaotwelriwaal,s tarnadnsrfeetrurrendetdotoatsheecfoinsdtmmiixxiinnggbboowwll.,mTihxeedcmoantneunatlsloyfttohe `mixing bow] were thoroughly mixed. Samples for dose analyses were taken directly from the `mixing bowl. The prepared test diets were stored at room temperatureincovered containers until dispensed into feeding jars. Retention Samples During the in-life phase, samples (approximately 100 g) were taken from each dose preparation for doseanalysesand stored at room temperature. These samples were discarded on May 11, 1999 (see Protocol Deviations for exceptions). Method of Administration Dietary admixture was used because the potential route ofexposure in humansis oral. The dose preparations were administered ad libitum for at least 13 weeks, unless otherwise specified. Dose Analyses Analyses for the concentrationoftest material in the dose preparations were done by Covance using an analytical method, MP-M324-MA, supplied by the Sponsorand validated by Covance. `Homogeneity was determined for the 3-ppm, 30-ppm, and 100-ppm dose preparations once pretest. One sample (approximately 100 g) each from the top, middle, and bottom of the dose preparations mixed for homogeneity analyses were collected, divided into three subsamples for extraction and analysis, and analyzedfortest material content. All `samples were stored at room temperature until analyzed within 7 days of mixing. 10320 15 CovanM ce 63T 29-225 Fcoonucrenstarmaptlieosno(fapdpireotxipmreaptaerlayti1o0n0sgmiexacehd)pwreetreestt.akOennefsraommptlheew1a-spapnmadloyzseedloevnelthe day of mJeiaxsitn1g9adnadysu,setdheanstahnealbyazseedl.inAe vtahliured.saOmnpelesawmapslestwoarsedstaotrreodoamttreomopemrtaetmupreerfaotruartefloerasatt 3120datyos-,3t0heCn faonralyzweede.ksT,htehernemaanianliynzgeds.amIpnlaeddwiatsiosnt,otrwedoinsaampflreesez(erapspertotxoimmaatienltyai1n00g. each) were takenfromthe 500-ppmdose preparation mixed pretest. One sample was analyzed on the at least 32 days, dayofmixing. then analyzed. The second sample was stored at room temperature after Two additional samples (approximately 100 geach) were taken from the 3-ppm dose preparation mixed for Weeks 9 through 12. One sample was stored at room temperature for at least 19 days, then analyzed. The second sample was stored at room temperature for at least 32 days, then analyzed. The sample collected for dose confirmation analysis was used as the baseline sample. During the in-life phase, samples (approximately 100 g)fromall dose preparations were collected and analyzed for dose confirmation. Allsamples were stored at room temperature until analyzed. Clinical Observations "The animals were observed twice daily (a.m. and p.m. for mortality and moribundity (sce Protocol Deviationsfor exceptions). Signs ofpoor health or abnormal behavior were recorded as they were observed. At least once weekly, cach animal was removedfromits cage and examined. Any unusual or abnormal findings were recorded. BInoddivyidWueailgbhotdsy weight data were recorded on the first day of treatment, and weekly thereafter. Food Consumption Individual food consumption data were recorded weekly during treatment. Food consumption was not measured during Week 5 for animals scheduled for sacrifice during Week 5. 1034% 16 Covance 6329-225 --- wre Ophthalmology Ophthalmic examinations were done before initiationoftreatment and during Week 14. `The pupils were dilated with 0.5% Mydriacy!, and the eyes were examined bya Veterinarian with an indirect ophthalmoscope. Clinical Pathology Blood samples were collected from 10 animals/sex/group during Weeks S and 14, Urine samples were collected from 10 animals/sex/group during Week 14. Animals were fasted overnight, (see Protocol Deviations for exception) and urine was collected chilled (approximately 16 hours before blood sampling); water was provided ad libitum. Blood was collected from ajugular vein. Potassium EDTA was used as the anticoagulant for hematology tests. No anticoagulant was usedforthe clinical chemistry samples. Animals were bled in random order. The following were evaluated: Hematology red blood cell (erythrocyte) count hemoglobin white blood cell (leukocyte) count differential blood cell count hematocrit * mean corpuscular volume segmented neutrophil count Iymphocyte count mean corpuscular hemoglobin mean corpuscular hemoglobin monocyte count eosinophil count concentration basophil count platelet count blood cell morphology Reticulocyte count smears were made and held for possible future examination. glucose urea nitrogen creatinine total protein albumin globulin total bilirubin cholesterol triglycerides Clinical Chemistry aspartate aminotransferase alanine aminotransferase `gamma glutamyltransferase: calcium inorganic phosphorus sodium potassium chloride 10812 17 Covance 6329-225 -- we, Urinalysis volume specific gravity bilirubin blood pH protein `umriocbriolsicnoopgiecnexamination of sediment glucose appearance ketones DSureirnugm PWeerefklsuo5roaoncdta14n,efSiuvlefaonniicmaAclisd/sLeevxe/lg(rwPeoFruOepS)fasDteetdeorvmeirnniagthito,n(see Protocol Deviations for exception) anesthetized with carbon dioxide, and blood (approximately 4 mL) was collected from ajugular vein.Allsamples were collected without anticoagulant, allowed to clot at room temperature, and centrifuged. Serum was harvested and stored ian freezer set to maintain -60 to -80C until packed on dry ice and shipped to the Sponsor for analyses. The samples were analyzed for PFOS. Results of analyses will be reported separately by the Sponsor. Necropsy A necropsy was done on the Group 2 female that was sacrificedatan unscheduled interval. During Week 5, five animals/sex/group were fasted overnight (see Protocol Deviations for exception), anesthetized with carbon dioxide, bled for serum PFOS samples, weighed, and exsanguinated. Theseanimals were discarded without necropsy. The liver was removed from these animals, weighed, and collected for palmitoyl CoA oxidase and PFOS analysis. During Weck 14, the remaining animals were fasted overnight, anesthetized with carbon dioxide, bled for clinical pathology tests (10 animals/sex/group with the exception of Group 2 female) and serum PFOS samples (five animals/sex/group), weighed, exsanguinated, and necropsied. Liver samples were collected for palmitoyl CoA oxidase, PCNA, and PFOS analysis. Animals were necropsied in random order. aTlhleexnteecrrnaolpsbyodinycolruidfeidceas;mtahceraobsdcoompiincale,xatmhionraatciico,noafndthceraenxiatlercnaavlitfieeast;uorregsaonfs;thaencdartcisassuse;s. 10843 18 CovanMcTe.6632391-42215 Organ Weights After 13 weeksoftreatment, the following organs (when present) were weighed; paired organs were weighed together: adrenal brain (2) kidney (2) liver ovary 2) tsepslteisen(2) thymus thyroid (2) with parathyroid `Organ-to-body weight percentages and organ-to-brain weight ratios were calculated. Cell Proliferation Tissue Collection and Immunohistochemical Evaluation At the terminal sacrifice, representative sampolfethse lef lateral lobe of the liver were collected from five animals/sex/group and preserved in zinc formalin. After fixation, samples were embedded in paraffin and shipped to Pathology Associates International (Frederick, Maryland) for proliferation cell nuclear antigen (PCNA) evaluation. In addition, liver sections were stained with hematoxylin and cosin and examined `microscopically. Results of the evaluationarein Appendix 7. Palmitoyl-CoA Oxidase Tissue Collection and Analyses At the scheduled sacrifices, the right lateral lobeofthe liver was collected from each animal, flash-frozen in liquid nitrogen, and storedin a freezer set to maintain -60 to -80C until analyzed by Covance for palmitoyl CoA oxidase activity. Liver PFOS Analyses At the scheduled sacrifices, a portionofthe liver fromeachanimal was flash-frozen in liquid nitrogen and stored in a freezer set to maintain -60 to -80C until packed on dry ice and shipped to the Sponsor for PFOS and metabolites analyses. Results of these analyses. will be reported separately by the Sponsor. C0814 19 CovanMceT63E292L25 TTihsesufeolPlroewsiengrvtaitsisuoens (when present) from the animal that was sacrificed at an unscheduled interval, or fromeachanimal sacrificed atthe terminal sacrifice were collected and preserved in 10% neutral-buffered formalin, unless otherwise specified: adrenal (2) aorta brain cecum cervix colon duodenum epididymis (2) esophagus eye 2) femur with bone marrow (articular surfaceofthe 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) pancreas pituitary prostate rectum salivary gland [mandibular (2)] sciatic nerve, seminal vesicle (2) skeletal muscle (thigh) sspkiinnal cord (cervical, mid-thoracic, and lumbar) ssptleerennum with bone marrow stomach testis (2) thymus thyroid (2) with parathyroid trachea urinary bladder uterus vagina Zymbal's gland Histopathology Tissues (as appropriate) were embedded in paraffin, sectioned, stained with hematoxylin and cosin,and examined microscopically from each animal in thecontroland high-dose: `groupsand from the low-dose animal that was sacrificed at an unscheduled interval. Due to microscopic findings noted in the high-dose group, theliverand stomachfromanimals in the mid-dose group, and the liverfromanimals in the low-dose group were also embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined microscopically. 2 40845 -_-- CovwanMcTeT6633291-42215 Macroscopic lesionsfromanimals in the low- and mid-dose groups were embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined microscopically. Bone marrow smears from the feofm cachuanir mal were prepared at the scheduled sacrifice after 13 weeks of treatment, stained with Wright's stain,andretained for possible examination. Statistical Analyses Levene's test (Levene, 1960) was done to test for variance homogeneity. In the case of heterogeneity of variance at p < 0.05, transformations were used to stabilize the variance. `Comparison tests took variance heterogeneity into consideration. One-way analysisofvariance [ANOVA (Winer, 1971a)] was used to analyze body weights, body weight changes, food consumption, continuous clinical pathology values; `organ weights, organ-to-body weight percentages, and organ-to-brain weight ratios. If the ANOVA was significant, Dunnett's t-test (Dunnett, 1964) was used for control versus treated group comparisons. Group comparisons (Groups 2 through 4 versus Group 1) were evaluated at the 5.0%, two-tailed probability level. Only data collected on orafterthe fist day of treatment was analyzed statistically. RECORD RETENTION All raw data, documentation, records, protocol, and specimens generated as a result of this study will be archived in the storage facilitiesofCovance-Madison for a periodofat feast 1 year. At least 1 yearaferthe submission of the 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 wil be retained by Pathology Associates International. 10816 21 CovanMcTe-6362391-24215 Liver andserumsamples sent to the Sponsor and analysis data generated from these: samples will be retained by the Sponsor. RESULTS Dose Analyses Resultsofthe homogeneity, stability, and dose preparation analyses arein Tables 1 through 3. Mean valuesofthe homogeneity analyses ranged from 74.0-78.0%, 84.0-96.7%, and 77.5-84.2%ofthe theoretical concentrations for the diets containing 3, 30, and 100ppm N-MeFOSE, respectively. These results indicate that the mixing procedure `produced a homogeneous distributionofthe test material in the dose preparations; although variability generally appeared slightly greater at the 3 and 30-ppm dietary concentrations. Resultsof stability analyses of samples stored for 19 and 32 days at room temperature and 8 weeks under frozen conditions indicated that the mean concentrations ranged from 54.4-62.5%ofthe initial concentrationsof 1 ppm for diet mixed pretest. Samples stored for 32 days at room temperature indicated that the mean concentration was 98.4% of the initial concentrations of500 ppm. Results of stability analysesofsamples stored for 19 and 32 days at room temperature indicated that the mean concentrations ranged from 9s3to.r2e-d94fo.r0%1o9fdtahyes aintitrioalocmontceemnpterraattiuornes ionfdi1cpatpemd tfhoartdtiheet mmiexaendcaotncWeenetrkat4i.oSnawmapsle8s9.0% ofthe initial concentrations of3 ppm. The mean concentrations of the dose preparation analyses for all levels ranged from 63.7 to 110.0%ofthe theoretical concentrations. Inherentvariabilityand lack of sufficient sensitivity at low levels in the analytical method for measuring N-MeFOSE orfestuhletesdtainndhaormdogliemnictistoyf,+s/t-ab1i5li%t.y aTnhdersoeutrienseulatnsawliylslisbedarteaevtahaltuawteerdeinincmonajnuynccatisoenswoiutthsitdhee analytical results from the blood and liver level determinations whenthey are provided by the sponsor. 10847 2 CovanMcTe-663321942.215 Clinical Observations and Survival Clinical observations are summarizedin Table 4; individualdataare in Appendix 2. Individual animal fate data are also in Appendix 2. One female given 3 ppm N-MeFOSE was sacrificed on Day 59 due to severe laceration of the tail. There were no macroscopic or microscopic changes to indicate that its moribund condition was test material-related.Allotheranimals survived to the scheduled sacrifice. No clinical observations were noted that were considered effectsofthe test material. Ophthalmology `Ophthalmic observations are summarized in Table 5; individual data are in Appendix 2. `The Ophthalmology Report contains a discussionofthe data. `Animals selectedforthe study had no lesions at the prestudy examination. No test `material-related ophthalmic observations were noted at the Week 14 examination. Body Weights Body weight and body weight change data are summarizedin Tables 6 and 7; individual body weight data are in Appendix 3. Testmaterialrelated lower body weights were noted for males given 30 and 100ppmand formales and females given 100 ppm. Statistically significantly lower mean body weights were noted beginning at Week 4 and continuing through the end of study for males and females given 100 ppm. Statistically significantly lower mean body weights were noted beginning at Week 7 and continuing through the end of study for males given 30 ppm. Body weight changes were statistically significantly lower in a sporadic manner for males given 30 ppm and for animals of both sexes given 100 ppm. Overall body weight changes (Weeks 1-14) were statistically significantly lower for all groups given N-McFOSE. Food Consumption Food consumption data are summarized in Table 8; individual data are in Appendix 4. 10318 CovanIcMeT6-36239-124215 Although statistically significant onlyatWeek 13 for males given 100 ppm, food consumption was lower for males given 30 and 100 ppm when compared to those of controls for mostof the study. Females given 100 ppmhad statistically significantly lower foodconsumption than thoseof controls at Weeks 3, 4, 6, 7, 11, and 12. The overall mean food consumption for females fed the 100-ppm concentration was significantly lowerby 17.5% when compared with that of the controls. `Test Material Consumption Test material consumption data are summarized in Table 9; individual data are in Appendix 4. Animalswere fed diets containing 3, 30, or 100 ppm N-MeFOSE, T-6314. The mean `amountsof test material consumed by the animalsin these groups were 0.148 to 0.304 mg/kg/day; 1.390 to 3.094 mg/kg/day; and 5.054 to 10.291 mg/kg/day for males, respectively. Values for females were 0.184 to 0.319 mg/kg/day: 2.204 to 3.395; and 6.494 to 10.378, respectively. The overall mean test material consumpfotrimaolens fed diets containing 3, 30, or 100 ppm N-MeFOSE, T-6314 were 0.203, 2.041, and 6.844 mg/kg/day, respectively. The overall mean test material consumption for females fed diets containing 3, 30, or 100 ppm N-McFOSE, T-6314 were 0.240, 2.588, and 7.702, respectively. Clinical Pathology Hematology, clinical chemistry, and urinalysis data are summarized in Tables 10 through 14; individualdataare in Appendix 5. The Pathology Report contains a discussion of the data. Dietary administration of N-MeFOSE was associated with lower hematocrit for males and females fed 100 pp; higher urea nitrogen formalesand females fed 100 ppm; higher albumin for males fed 100 ppm; lower globulin for males fed 30 or 100 ppm; lower cholesterol and triglycerides for males fed 30 or 100 ppm and females fed 100 ppm; higher alanine aminotransferase for males fed 100 ppm; and higher hepatic palmitoyl CoA oxidase for males and females fed 100 ppm. The effects were relatively mild with the exception of those on cholesterol and triglycerides for the high-dose males; those effects C0319 2% _-- CovawnMcrTe-6e6323n91-42a215 `were considered to be of moderate severity. All ofthe test materialrelated clinical pathology findings were more prominent at Week 14thanat Week 5. Serum Perfluorooctane Sulfonic Acid Level (PFOS) Determination Resultsof serum PFOS level determination will be reported separatelybythe Sponsor. Cell Proliferation Tissue Collection and Immunohistochemical Evaluation Resultsofcell proliferation and immunohistochemical evaluation provided by Pathology Associates International are in Appendix 7. Liver PFOS Determination Resultsofiver PFOS level determination will be reported separately by the Sponsor. Anatomic Pathology `Terminal body weights, absolute organ weights, organ-to-body weight percentages, and organ-to-brain weight ratios are summarized in Tables 15 and 16; incidences of macroscopic and microscopic observations are summarized in Tables 17 and 18; the incidence of severity of microscopic observations is summarized in Table 19. Individual data are in Appendix 6. The Pathology Report contains a discussionofthe data. Statistically significant and test material-related changes in terminal body weights and liver `weights were seen in males and/or females in the two highest dose groups. Statistically significant decreases were seen in the terminal body weights ofmales fed 30 ppmand in both males and females fed 100 ppm of N-MeFOSE. Statistically significant increases were seen in the mean liver-to-body weight percentage and mean liver-to-brain weight ratio in males fed 30 ppm, in mean absolute liver weight and mean liver-to-body weight percentage in females fed 30 ppm, and in all liver weight parameters in males and females fed 100 ppm. 103820 25 CovanMcTe66332194-2.215 Test material-related macroscopic findings were noted atalow incidencein theliverand glandular stomachofmales and females in the 100ppmdose group only. Liver findings included organs that were large and diffusely dark. In the glandular stomach, darkfocior areaswere sometimes seen in the gastric mucosa. Testmaterialrelated microscopic findings were seen in the liverofanimals fed 30and 100 ppm of N-MeFOSE and in the glandular stomach of males and females in the . 100 ppm group only. No test material-related changes were seeninanimals fed 3ppmof N-MeFOSE. Intheliver, one or more testmaterial related findings affected all animals fed 100 ppm and included slight-to-moderate centrilobular or diffuse hepatocellular hypertrophy, minimal-to-slight coagulative necrosis, minimal hepatocellular pigment, and `minimal-to-slight centrilobular to midzonal or diffuse hepatocellular vacuolation. In `animals fed 30 ppm, centrilobular hepatocellular hypertrophywasalso seen, although the incidence and severity was decreased atthisdose. In addition, a low incidenceofminimal hepatocellular vacuolation occurred in 30 ppm dose group males, and the liofvaseingrle female fed 30ppmhad minimal coagulative necrosis. A possible test material-related change in the glandular stomachofanimals fed 100 ppm was arelatively low incidence of mucosal erosions. The erosions wereofminimal to slight severity and involved a very smal portionof themucosalsurfaceinal cases. CONCLUSIONS Based on anatomic pathology, clinical pathology, and body weight effects at 30 and 100 ppm the no-observable-adverse-effect level was determined to be less than 30 ppm `when N-MeFOSE is administeraetd concentrations of 0, 3, 30 and 100 ppm to. Cr:CDY(SD) IGS BR rats for at least 13 weeks through dietary administration. Based on the body weight effects at 3, 30, and 100 ppm, the no-observable-efect level was determined to be less than 3 ppm when N-MeFOSE is administered at concentrations of 0, 3,30 and 100 ppm to Crl:CD*(SD) IGS BR rats for at least 13 weeks through dietary administration. In the absence of correlative changes in anatomic pathology and clinical pathology the body weights effects at 3ppmwere not considered to be biologically adverse. 1082% 2% SIGNATURES cme Mud Nii Van Bruce-Konuah Study Coordinator Covance Laboratories Inc. LL ns Study Director Covance Laboratories Inc. 20 Tus 2 poo Date $0 ne ooo 10322 27 CovanMceT683219-42125 REFERENCES Dunnett, C. W., "New Tables for Multiple Comparisons with a Control," Biometrics, 20:482-491 (1964). Levene, H., "Robust Tests for Equality of Variances," Contributions to Probability and `CSatlaitifsotrincsi,a ((e1d9s6.0)).I. Olkin et al., Ch. 25, pp. 278-292, Stanford University Press: Stanford, Ex`Wpienreri,meB.ntJa,l"DDeessiiggnn,aSnedcoAnnadlEyds.i,soCfhS.in3g,lpep-.Fa1c4t9o-r26E0x,pMecrGirmaewn-tHsi,lSlta:tisNteicwalYPorrinkc,iples in New York (1971a). n0823 28 -_-- Covance 6329-225 M3MTT-e631M4.11 OPHTHALMOLOGY REPORT Ophthalmic examinations were done before initiationoftreatment and during Weck 14. Animals selectedfor the stuhdayd no lesions at the prestudy examination. No test `material-related ophthalmic observations were noted at the Week 14 examination, Donna J. , DVM, MS iplomate, Ag 19 200 10824 29 PATHOLOGY REPORT CovanMceT683219-42125 SUMMARY "PTehrefpluuorrpoooscetoafntehsiuslfsotnuadmyiwdoasEtthoaansosle(ssN-thMeetFoOxSicEi)ty,owfthheen atedsmtinmaitsetreiraeld, iNn-Mtheethdiyelt to rats forat least 13 weeks. The test material was administered at doselevels of3, 30, and 100 ppm. Dietary administration of N-MeFOSE was associated with lower hematocrit for males and females fied 100 ppm;higherurea nitrogen for males and females fed 100 ppm; higher albumin for males fed 100ppm; lower globulin for males fed 30 or 100 ppm; lower cholestearnodl triglycerides for males fed 30 or 100 ppm and females fed 100 ppm; higher alanine aminotransferase formalesfed 100 ppm; and higher hepatic palmitoyl CoA oxidaseformalesandfemalesfed 100ppm.Theeffectswererelativelymildwiththe exceptionofthose on cholesterol and triglycerides for the males fed 100 ppm; those effects were considered to be of moderate severity. Allofthe test material-related clinical pathology findings were more prominent at Weck 14thanat Week 5. Statistically significant and test material-related changes in terminal body weights and liver weights were seen inmalesand/or females in the two highest dose groups. Statistically significant decreases were seeninthe terminal body weightsofmales fed 30ppmand in bothmalesand females fed 100 ppm. Statistically significant increases were seen in the `mean liver-to-body weight percentage and mean liver-to-brain weight ratio in males fed 30 ppm, in mean absolute liver weight and mean liver-to-body weight percentage in females fed 30 ppm, andinall liver weight parameters in males and females fed 100 ppm. Testmaterialrelated macroscopic findings were noted at a low incidenceinthe liver and `ignlcalnuddueldarosrtgoamnsacthhaotfwmearleeslaarngde afnemdadliefsfuisneltyheda1r0k0. pIpnmthdeosgleagnrduoluaprosntloym.acLhi,vedrafrikndfioncigsor areas were sometimes seen in the gastric mucosa. Testmaterialrelated microscopic findings were seen in the liverofanimals fed 30 and 100 100 ppm ppm ofN-MeFOaSndE in the glandular stomachofmales and females in the group only. No test material-related changes were seen in animals fed 3 ppm of C0825 30 - Covance 6329225 Te N-MeFOSE. In the liver, one or more test material-relatedfindingsaffected all animals fed 100 ppm, and included slight-to-moderate centrilobuloarr diffuse hepatocellular hypertrophy, minimal-to-slight coagulative necrosis, minimal hepatocellular pigment, and minimal-to-slight centrilobular to midzonal or diffuse hepatocellular vacuolation. In animals fed 30 ppm, centrilobular hepatocellular hypertrophy wasalso seen, although the incidence and severitywasdecreased at this dose. In addition, a low incidenceofminimal hepatocellular vacuolation occurred in 30ppmdose group males, and the liver oaf single female fed 30 ppm hadminimal coagulative necrosis. A possible test material-related change in the glandular stomachofanimals fed 100ppmwas a relatively low incidence of `mucosal erosions. The erosions were ofminimal to slight severity and involved a very small portion of the mucosal surface in all cases. METHODS Four groups of Crl:CD*(SD) IGS BR rats (20 animals/sex/group) were fed diets containing the test material at a dose level of0 (control group; fed basal diet only), 3, 30, or 300 ppm. During Week 5, five animals/sex/group were sacrificed to obtain liver samples for determination of hepatic palmitoyl CoA oxidase activity (by Covance) and analysisforPFOS and metabolites (by 3M). One female fed 3 ppm was sacrificed and necropsied during Week 9 because of poor health (unscheduled sacrifice). The remaining animals were sacrificed and necropsied during Week 14 (terminal sacrifice). Blood was collected for hematoloagndy clinical chemistry tests during Weeks 5 and 14. Urine was collected for urinalysis tests during Week 14. At necropsy, macroscopic observations were recorded, organ weights were obtained (terminal sacrifice only), and tissues were placed in fixativeasspecified by the protocol. In addition, samplesofliver were collected at the terminal sacrifice for evaluationofproliferation cell nuclear antigen (PCNA; by Pathology Associates International; five animal/sex/group), and both scheduled sacrifices for determination of hepatic palmitoyl CoA oxidase activity (by Covance) and analysis for PFOS and metabolites (by 3M). Microscopic examinations were done on protocol-required tissues from all control and high-dose animals sacrificed during Week 14 and the 3 ppm dose group female sacrificedin a moribund condition during Week 9 (unscheduled sacrifice). In addition, livers, stomachs, and macroscopic 10826 31 Covance 6329-225 MT.63141 lesions were examined from all terminal sacrifice animals fed 30 ppm, and macroscopic lesionsand liversonlywereexamined romanimalsfed 3 ppm. `Statistically significant differences citedinthe ResultsandDiscussion section are based on `comparisons between the control and treated groups. RESULTS AND DISCUSSION Mortality One female fed 3 ppm (Animal No. C96016) was sacrificed during Wee9k (Day 59) because of poor health. All other animals survived to the respective scheduled sacrifice. CWleienikcsal5Paantdho1l4o.gyThere were several statistically significant or otherwise notable differences for clinical pathology results between control and treated animals. Differences considered to be effects of the test material were lower hematocritformalesand females fed 100ppm;higherureanitrogenformalesandfemalesfed 100ppm;higheralbumfionr males fed 100 ppm, lower globulin for males fed 30 or 100 ppm; lower cholesterol and `tamriniotrganlsfefyroarcsmeaeflorersmfiaelddes3ef0eosdr101000pppmp; aannddfhiegmhear lhfeepeasdti1c0p0alpmpimt;oyhligChoeAraloaxniidnaes:e for malesand females fed 100 ppm. The effects were relatively mild with the exception of those on cholesterol and triglycerides for the males fed 100 ppm those effects were considered to be of moderate severity. Al of the test material-related clinical pathology findings were more prominent at Week 14 than at Week 5. The mild effects on hematocrit and globulin were consistentwithanimals failing to gain weight appropriately. Although mildly higher ureanitrogenand albumin suggested a relative dehydration for animals given 100 ppm, there were no effects on urine volume or urine specific gravity consistent with dehydration. The mildeffecton alanine ahempiantoitcrapnaslfmeirtaosyelwCaosAinodxiicdaatsievewoafsthiendhiecaptaitvoeceolfluplearroxdiegseonmearlatprioolni,fearnadtiomni.ldlTyhheiegfhfeercts on cholesterol and triglycerides were the most prominent findings, and suggested lipid metabolism by the liver was altered. 010088227 -_-- CovwanIcMreT663e329124n215 Ofuncertain relationship to administrationofthe test material was statisticallylowermean corpuscular volume for females fed 100 ppm. The difference for mean corpuscular volume became smaller over time (ic., from Week 5 to Week 14). Other statistically significant differences were considered incidental and unrelated to administrationofthe test material Anatomic Pathology Unscheduled Deaths. The one female fed 3 ppm that was sacrificed in a moribund condition on Day 59 (Animal No. C96016) had no macroscopic or microscopic changetso indicate that its moribund condition was test material-related. Terminal Sacrifice `Terminal Body Weights and Organ Weights. Test material-related changes were seen in the terminal body weights andin absolute and relative liver weights in animals fed 30 and 100 ppm N-MeFOSE. Mean terminal body weights were statistically significantly decreased in males and females that were fed 100 ppmofN-McFOSE and in males only fed 30 ppm. The decreased mean `body weights at both dose levels were considered to be testmaterialrelated. Statistically significant and test material-related increases were seen in the mean liver-to-body weight percentage and the mean liver-to-brain weight ratio in males fed 30 ppm, in mean absolute liver weight and mean liver-to-body weight percentage in females fed 30 ppm, andinall liver weight parameters inmalesand females fed 100 ppm. `The liver weight increases correlated macroscopically with large livers in 3 of 15 males in the 100 ppm dose group and microscopically with the presenceofhepatocellular hypertropihny all males and femalesinthe high-dose group. 10828 33 CovanIcMeT6-36239-124215 Additional statistically significant absolute or relative organ weight changes affected several other organs in both sexesand in multiple dose groups. Because there were no `macroscopic or microscopic findings that correlatedwiththe weight changes, the remaining organ weight variations were considered to be within the rangeofnormal biologic variation or were attributed to the lower body weights in treated versus control animals. Macroscopic Findings. Test material-related macroscopic findings were noted at a low incidenceinthe liver and glandular stomach ofmalesand females fed 100 ppm N-MeFOSE.Liversthat were large wereseenin 3of 15malesandin 0femalfeesd 100 ppm,anddiffuselydarkliversoccurredin 2 of 15malesand 1of 15 females fed 100 ppm. Noliverchanges occurred in animals fed the controlmaterialor in animals fed lowerdoses of N-MeFOSE. The large and diffusely dark livers correlated microscopically with hepatocellular hypertrophy in the affected animals. In the glandular stomachs, dark fociorareasoccurreadtanincidofe0nofc15e, 1 of15,0 0f 15,and 2 of 15inmales, andatanincidenceof 0 of 15,0 of 14, 0of 15, an3dof 15infeminathelcoentrsol, 3 ppm, 30 ppm, and 100 ppm groups respectively. The dark foorcareias generally correlated microscopically with small erosions in the glandular mucosa. Diffuse reddening and mottling of the thymus and mandibular lymphnodesas well as red foci or areas in the thymus were relatively common findings and frequently correlated `microscopically with hemorrhage in the affected organs. Because these findings did not occurinadose-relatedmannerand because rats in multiple dose groups, including control `males, were sometimes affected, the findings were considered to be agonal changes that `were not associated with test material administration. All remaining macroscopic findings. were considered to be spontancous andincidentaland not related to test material administration. Microscopic Findings. Testmaterial related microscopic findings wereseenin the liver of animals fed 30 and 100 ppm of N-MeFOSEand in the glandular stomach of males and females in the 100 ppm group only. There were no test material-related findingsin the liversofanimals fed 3 ppm. C1089 3 -_-- CovwanMTceTe683i219a-42r125 `Test material-related findings in the liver included hepatocellular hypertrophy, coagulative necrosis, hepatocellular pigment, and hepatocellular vacuolation. The incidence and severity ofthese findings tended to begreaterin 100 ppmanimals. The incidence of pertinent liver findings is presented in Text Table 1. Text Table | Incidence of Selected Microscopic Findings in the Liver Group Number/Sex Number Examined IM 2M 3M 4M IF OF 3F 4F 15 15 15 15 15 14 15 IS Hypertrophy, hepatocellular, diffiss. Hypertrophy, hepatocellular, 0 0 0 0 Centrilobular Necrosis, coagulative 0 0 14 15 0003 Pigment, hepatocellular Vacuolation, hepatocellular, 0002 centrilobular tomidzonal Vacuolation, hepatocellular, diffise 0 0 0 0 2 2 7 2 0001 0 0 7 14 00 1 0 0007 0002 0000 As noted in the above table, hepatocellular hypertrophy generally affected centrilobular areasoftheliverin animals fed 30 and 100 ppm, but theliver was more diffusely hypertrophicd in one female fed 100 ppm. The hypertrophic hepatocytes were enlarged with abundant cytoplasm that often had a granular to globular cosinophilic appearance. Tn some animals in the high-dose group (two males and seven females), the cytoplasm of hepatocytes also contained minimal amounts ofabrown granular pigment at the periphery ofthe cell. In addition, liver cells frequently were vacuolated (se Text Table 1), particularly in males given 100 ppm, with the vacuolation generally affecting hepatocytes incentrilobular and midzonal areas. Diffuse hepatocellular vacuolation was also seen in two males in cach of the 30 and 100 ppm dose groups, but in no other animals. Lastly, minimal to slight coagulative necrosis seen in 3 of 15 males fed 100 ppm and 1 of 15 females fed 30 ppm was likely related to dietary administrationofthe test material since no control or 3 ppm dose group animals were similarly affected. A possible test material-related change in the glandular stomach was the presence of mucosal erosions. The erosions wereofminimal to slight severity and involved a very small portionofthe mucosal surface in all cases. The erosions were seen with an C10330 35 CovanMcTe-6632391-24215 incidence of0 of 15, 0of 15, and 2 of15 in males, and atanincidence of0 of 15, 0 of 15, and 3of 15 infemalesinthecontrol, 30ppm,and 100ppmgroupsrespectively. The presence of erosions microscopically generally correlated with the dark fo oracrei as seen' in the gastric mucosa at necropsy. One male fed 3 ppmalso hada slight gastric erosion that was collected as agross lesion at necropsy. Since no erosions were seen in anyofthe animals'stomachs examinedfromanimalsfed 30ppm,thelesioninthe 3ppmmale was considered unlikely to be test material-related. All remaining microscopic findings were considered to be spontaneous and incidental changes and tyopfraitsocfthaisalge and strain. (GP AUN Robert L. Hall, DVM, PhD Diplomate, ACVP (Clinical Pathology) foo We A ie J. Eig y MS iplomate, ACVP Diplomate, ABT Vine /9, 2000 ite v/a foo Date 1083% 36 Covance 6329-225 -_ wMTem COMMENTS ON THE DATA Various modelsofcalculators, computers, and computer programs were used to analyze dvaatlaueisnitnhissosmteudtya.blBesec(ac.ugs.,e mdeifafnesr,ensttmaonddaerldsdreovuiantdioofnfso,rortirnudnicvaitdeuanlumvableuress)dmifafyerdeintflfye,r aslniaglhytsliysfdraotma.thNeoistehienrtothheerinttaebglreist,yfnroormtihnediivnitdeuraplrleytactailocnuloafttehdeddaatat,a owrafsroafmfsetcatteidstbiycatlhese differences. `reTfhleecntusmtbheernofuamnbiemroaflasnliimstaeldsianstshiegnheedadtiongeoafcthhgerosuupmamtatrhye tsatbarltesoffotrhcelisntiucdayl.observations `cTohnedistuimonmawraystoabbsleerfvoerdclwiintihcaolutobrseegravradtitoontshiensdpieccaitfeitchneatnuurme,besrevoerfiatyn,imraelvserfsiobrilwihtiy,ch a number of incidences/animal, or the lengthoftime the condition persisted. Only observations tables. other than normal are indicated on the summary clinical observations Ecaocmhmeannitma"lAnwiimtahlohbassernvoatsiiognnsifriceacnotrdfienddiansgs""Noirndmiacla"tetdhoronutghheouitndtihveidsutauldcylihnaiscatlhe `observations tables. i`Tnhdeicsapteecdifwiictdhetaai"lCs"fcorancobmemfeonutnsd iant tthhee iennddiovifdeuaalcchlignricoaulpobfosrerevaacthiosnexs.tables that are `The day of initiationoftreatment is "Day 1, Week 1." Bodyweightdata are entered at the `stwaeritgohtf, aa sbtouddyywweeicgkht(r.eg.c,oradbeoddoynwDeaigyh8t irseccoonrsdieddeornedDaayWe1eiks c2obnsoiddyerweedigahtW).eeBko1dybody `twheeifghotllcohwainnggedstautdayawreeeckal(cc.ugl.a,teWdeferkom| tvhaelufeisrstardeaycaolfcutlhaetesdtufdryowmeDeakyto| tthherofuirgsht d7)ayanodf (aree.gi.nWdieceatkedIivnatlhueestaabrleesinwdiitchattehde adsay"Dbaeiyn8g."t)h.e fWiesetkdlayyoffotohdecofnoslulmopwitnigonweaenkd test `tmhaetefroilallocwoinngsusmtputdiyowneaerke (cca.lgc,ulWateeedkfr|ovmatlhueesfiarrstedcaalycoufltahteedsftruodmyDwaeyek1 ttohtrhoeugfhirs7t).day of s`iTghneifviaclaunetsffiogrurseusmtmhaarnyisaanpdprionpdriivaitdueaflotretsthemadtaetraiadluecotnosluimmpittaitoinonasroef trehpeordtaetdawciotlhlemctoiroen and reporting software. 10832 37 CovanMcTe -638291-42215 (COMMENTS ON THE DATA (Continued) c`Foonosdumcpotnisounmvpatliuoensvtaolouensearpelarceeptoortthederiingwhhtoolfethnuemdbeecrism;alhfoowrefvoero,dePfTfiSciceanrcryieasnfdotoedst `material consumption calculations. The differences in values generated do not influence the interpretationofthe calculation. The comment "SPILLED" on individual foodconsumptiondata tables indicates that food `consumption was not recorded du to spillage during the interval. `The comment "NOT TAKEN" on individual food consumption data tablesindicatesthe animaldied before the end of the food consumption interval. Dpiaftfheorleongcyesairnetehxeplpaoipnueldaotinotnhseiziend(iNvi)douanltdhaetasutambmlaesryortatbhleescofdoersclsihneiectasl.and anatomic: The calculation for individual test material consumption is: Test material consumption = Fond Comper er FDiitrBCodoy cWeiighntaof iraCoen(sDmuilyonBoyWegGuanFo] where: Daily Body Weight Gain = roLitBBokyyWWeieghgtooff teervaFaisytBof yFtWBeyiWgehigthteodf icv and: Day Factor = (FoodConsumptionStDayeDay Fis Body Weightof ral) +200Compton er and: Food ConsumFpotoidoCnonIunmtpeirovnaEln=dDey odCommon SrDey 710833 38 CODES, ABBREVIATIONS, AND UNITS General Codes and Abbreviations Codes for Clinical Pathology Abbreviations and Units for Clinical Hematology Abbreviations and Units for Clinical Chemistry Abbreviations and UnitsforClinical Urinalysis Codes for Anatomic Pathology CovanMcTe.6632391-24215 Note: The following listsof codes, abbreviations, and units are usedby Covance. Some, but not necessarily all,ofthis information may be needed for ths report. 4083 3 CovanMcTe-6362391-24215 General Codes and Abbreviations WK N Mean; MEAN SD; $.D; STAND DEV; STANDARD DEV; sd * NA P c UNSCHED DISPATCH TBW # co WNeuemkb.er of measurements in a group. Arithmetic mean. Standard deviation. Grtohuepmemaeanonfisthseigcniofnitcraonltlgyrdoiuffper(eGnrtofurpom1) atp s 0.05. No value; not applicable; not present. PCroesmemnte.nt found at the end of each group for each sex. Unscheduled. Observations transferred from the in-life: `module of thedatacollection system to tnheecrnoepcsryo.psOybsmeordvualteiofnosr arerfedruepnlciecadtuersinogf. the last in-life observations. Terminal body weight. Number. Clinical observation. Animal Death Codes: 1 T M Interim sacrifice 1. Terminal sacrifice. Sacrificed at an unscheduled interval. 108335 " NS QS/QNS NR FS sc SH H SL L st 1 NF u DT/DOT DB i] TE RE EE SE PC PD Pl PL PA co HB PLASMO NO AGG FR UTD NO COAG CovanMceT8633210-42215 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. Ieteric Animal not fasted Unscheduled/moribund bleed Animal died on test Died during bleeding `Technician judgment to repeat test `uTneacchcneipctaalbelrerodrat(ai,ns.tgr.u,meunntacocreptteachbnlieciiannsterrurmoerntthaotutrpeustu,ltssaimnple spilled, entry ofinvalid data) Recording error (recorded incorrect spelling error, incorrect date) data, e.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 10826 4 Covance 6329-225 MT8141 Codes for Clinical Pathology (Continued) RESULTS NOT INCLUDED IN STATISTICAL ANALYSES Hemolyzed clinical chemistry or coagulation samples ``SamP plesrfrootmiamnetism(alPhsT)atgrruenaso tcehretdmhualneb d50instieercvoan nlsds `Activated partial thromboplastin times (PTT) greater than 110seconds. Bleed times (BLETIME)greaterthan 30 minutes. CODES FOR BLOOD CELL MORPHOLOGY Tpohiekifloolclyotwoisinsg (sPcaOlIeK)w,aspoulsyecdhrtoommaesaisau(rePOtLhYe)d,eghryepeoocfhraonmiasosciyato(sHiYsP(OA)N,ISoOr)b,asophilic stippling (BASTIP) or the presence of Howell-Jolly bodies (HJBODY), toxic neutrophils (TOXNEUT), or atypical lymphocytes (ATYPLYM): Scale Degree - Normal for the species 1 Slight 2 Moderate 3 Marked 4 Not applicable Presence `Not present Rare Few Moderate Many URINE APPEARANCE F Color L Clarity Miscellaneous APale B Straw EAmber 1 Black F Bown P Bluelgreen 7 Clear K Hazy M Debris O Feces C Yellow G Red Q Blue L Cloudy D Dark yellow H Green R Orange n0337 2 -_-- CovawncMeTr63E2e19422n15 Codes for Clinical Pathology (Continued) URINE CHEMISTRY MULTISTIX STRIP _ UrineGluoose "Negative + ++ 215000mmgg//ddLL +++ +++ 1,S0000m0gm/gd/LdL He 22000mg/dl __UrincKetone "Negative + ++ S15mmgg//ddLL +++++++ 4800mmgg//ddLL. +s 160 mgidl UrmeBlood ~ + Negative Small ++ +++ MLaordgeerate Urine Urobilinogen +~ 0m2gmgd/dL ++ 2mg/dL +++++++ 4Bmmgg/lddLl (1mg =approximately | Ehrlich unit) Urine Bilirubin + NSemgaaltive ++ Moderate +++ Large URINE SEDIMENT Cells, Crystals, Casts, and Comments A B AAmmoorrpphhoouussuprhaotsepshates Q R Sperm Fecalcontamination CD UTrriipclaecpihdosphates S T PPiinnwwoorrmmolvaravafeoufnodund E Cacium oxalate F Calciumcarbonate U. Paraovsaifotuned G Granular casts H1 CeHlylaullianreccaassttss 011N-o5tpperrefsieenltd J Waxycasts K. Unknowncrystal 32 161--1200peprefrifeiledld Se P_ Mucoy us threads 44 W>20pperfield Bacteria 0 1 Not present Few 2 3 MMoadneyrate 10338 a --e--r-- eeenererees eeeeeneesirmmnieConnnceeC63An29E-L2e2,5 Abbreviations and UnitsforClinical Hematology Test RHeemdobgllooobdicnell count Hematocrit MMeeaann ccoorrppuussccuullaarr vheomlougmleobin Mean corpuscular hemoglobin concentration Platelet count Mean platelet volume Reticulocyte count AHbesionlzubtoedryetciocuunlotcyte count Erythrocyte sedimentation rate PArcotitvhartoemdbipanrttiiamle.thromboplastin time Thrombin time Activated coagulation time FiFbirbirinno/gfeinbrinogen degradation products Platelet aggregation CoAldleanogseinne diphosphate Alpha 2-antiplasmin Bleeding time Methemoglobin Plasma hemoglobin MEysetliomiadt/eedrymtyherlooiidd/reartyitohroid ratio `DiWfhfietreenbtlioaoldbcleololdcoceulnltcount `Nucleated red blood cell count Corrected white blood cell count Segmented neutrophil count Band neutrophil count Lymphocyte count Monocyte count Eosinophil count AnBiassoopchyitlosciosunt Polychromasia Abbreviation (Units) RBC (E6/UL or X10%4L) HGB (G/DL) HCT (%) MCV (FL) MCH (PG) MCHC (%) PLT (E3/UL or X10/uL) MPV (FL) RETIC (%) RETIC (E3/UL or X10%uL) HEINZ (%) ESR (MM/HR) PT (SEC) PTT (SEC) TT (SEC) ACT (SEC) FBR (MG/DL) FDP (UG/ML) PAGGICOL (%) PAGG/ADP (%) ANTIPLAS (%) BLE TIME (SEC) METHGB (%) PLA HGB (MG/DL) M/E RATIO EST ME RATIO WBC (E3/UL or X10/L) NRBC (/100 WBC) COR WBC (E3/UL or X10/uL) N-SEG (E3/UL or X10"/4L) and % N-BAND (E3/UL or X10%uL) and % LYMPH (E3/UL or X10%uL) and % MONO (E3/UL or X10%/uL) and% EOSIN (E3/UL or X10%4L) and % BASO (E3/UL or X10*/uL) and % ANISO (1,23) POLY (11.2.3) 10329 a" -_-- CovawnMcTer.663e2391-24215 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 bloodcellcount (left eye) Abbreviation (Units) POIK (12,3) HYPO (1.2.3) HIBODY (12.3.4) BASTIP (12.3) TOXNEUT (-,1,23,4) ATYPLYM (-12.3.4) REYE (WBC/UL) LEYE (WBC/UL) 503:10 45 CovanIcMeT6632391-42215 Abbreviations and Units for Clinical Chemistry 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 Tonized calcium Inorganic phosphorus Sodium Potassium Chloride: Magnesium Zinc Strontium Tron Abbreviation (Units) GLU (MG/DL) UN (MG/DL) UREA (MG/DL) CREAT (MG/DL) TPRO (G/DL) ALB (GIDL) GLOB (G/DL) A/G RATIO TBILI (MG/DL) D BILI (MG/DL) 1BILI (MG/DL) CHOL (MG/DL) TRIG (MG/DL) UN/CREAT (RATIO) T LIPIDS (MG/DL) P LIPIDS (MG/DL) HDL (MG/DL) LUDAL((MMGG//DDLL)) AST/SGOT (IU/L) ALT/SGPT (IUL) ALK PHOS (TUL) GGT (IU/L) SDH (IU/L) LDH (IU/L) CK (UL) AMYLASE (IU/L) LIPASE (IUL) PCOAO (IU/G) CA (MG/DL) ION CA (MG/DL) PHOS (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) 30321 46 CovanMceT631294-2125 Abbreviations and Units for Clinical Chemistry (Continued) Test Excess iron Total iron binding capacity Unbound iron binding capacity Percent ron saturation Plasma cholinesterase Red blood cell 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 (MU/ML) CHEB (MU/ML) CAUD PUT (UMOL/G) HIPPOCAM (UMOLIG) F CORTEX (UMOLIG) CEREBELL (UMOL/G) BICARB (MMOL/L) SER HGB (MG/DL) SBA (UMOL/L or MG/DL) FBA (UG/ML) FCC WGT (G) FBA (MG/Day) SMO (MOSM/KG) EALB (G/DL) EA-1 (GDL) EA2 (GDL) 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 (U/L) CK-MB (U/L) CK-MM (UL) 10842 a CovanMcTe-6362391-24215 Abbreviations and Units for Clinical Urinalysis Test Urine volume 8hoururine volume Specific gravity UQurainnteitoastmiovlealuirtiynarylcerebrospinal fluid protein Urine protein excretion Urine chemistry Multistix strip Urine pH Urine protein Urine glucose Urine ketones Urine bilirubin Urine blood Urine urobilinogen Urine reducing substances Microscopic examinationofurine sediment `RWehditbelboloodocdelclesllpspererhhigihg-hp-opwoewrefrieflideld Epithelial cells per high-power field Bacteria per high-power field Casts per low-power field Crystals per low-power field Urine appearance Comments UAbbVrOevLia(tMiLo)n (Units) 8 HR VOL (ML) SPGR U OSMO (MOSM/KG) QUAN PRO (MG/DL) PRO EXC (MG) UPH U PRO (MG/DL) UGLU UKET UBILI U BLOOD UROBILI URESUB RBC (PER HPP) `WBC (PER HPF) EPITH (PER HPP) BACT (PER HPF) CASTS (PER LPF) CRYSTALS (PER LPF1 or PER LPF2) URINE APP! or URINE APP2 COMMENTS Miscellaneous Codes and Abbreviations for Clinical Pathology Fecal occult blood Fecal parasite detection Hemolytic potential Osmolality Not applicable Not applicable SNoMt aOppl(iMcaObSleM/KG) I" 10313 Codes for Anatomic Pathology CovanMcTe.6632391-24215 Code Definition ANIMAL DEATH CODES 1 Interim sacrifices 1 T `Terminal sacrifice M Sacrificed at an unscheduled interval EX NOT TAKEN MISSING UNSUITABLE AUTOLYTIC EXCLUDE MACROSCOPIC CODES OInrdgiacnatweseitghhatt onrogtatnakweeni;gehxtpilsaenaxtciloundegdivfernoimncnaelccruolaptsiyonnsotes Organ missing or lost Organ technically unsuitable for weighing Organ autolyzed and could not be weighed `Weight was taken, but was excluded from all calculations MICROSCOPIC CODES BC-odes Prefacing NeoplParsimtaircyF,ibnedniinggnsneoplasm mM N- Primary, malignant neoplasm Metastatic neoplasm I Locally invasive neoplasm X- Other neoplasm Code Definition Distribution of Findings Focal Diffuse Multifocal 90314 4 CovanMceT6633291-42215 Codes for Anatomic Pathology (Continued) G1rades for Severity MoirnAimmoauln-ttheleastamountof changethatcanbeobservedwiththe 2 lSilgihgthtm-iclreosssctohpaen average amountof change, but readily discernible 3 aMsodaebrnaotrem-althe average amount of change that is expected foar 4 Mleosdieornately severe (marked) - a marked amountof change with 5 `Speovsesirbele- laosgsroefaftuanmcotuinotnoofftchheanagfefewctietdhcperlolsbaobrloerlgoasnssof function of the affected cellor organs and frequently involves large areasofthe organ Other Microscopic Codes bo P Total Finding present - Finding not present MN Mean 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 TISSUE ABBREVIATIONS Definition Lymph node Gland Glandular stomach Nonglandular MAantnedriibourlamersseanltievraircy/gplaancnrdeatic lymph node Auditory sebaceous gland Exorbital lacrimal gland Hematopoietic neoplasia Internal lacrimal gland Abdominal cavity TParraocthiedobsraolinvcahriyaglllayndmph node 10875 50 _-- CovanuMcTer3613e249.-1225 Table 1 Resultsof Homogeneity Analyses (ppm) Mixed 8/20/98 13-WEEK DIETARY TOXICIETYTHSATNUODLY (WNI-TMHeFNO-SME,ETT6H3Y1L4)PIENRRFALTUS.OROOCTANESULFONAMIDO Samples Location _ Replicate 3 T6314 (ppm) 30 Top 1 2.19 337 2 2a 3 209 27.8 256 Mean 224747) 290067) Middle 1 224 252 2 22; 32 253 25.1 Mean 222(740) 252(34.0) Bottom 1 203 27 2 3m 276 3 Mean 1.94 234(780) 24 269897) a Each value in parenthesisi the percentoftheoretical 100 79.4 76.5 767 77.5(77.5) 750 797 895 81.4(814) 832 816 87.8 842(84.2) 03:6 51 CovanMcTe-362391.42.215 Table 2 Results ofMSitaxbeildit8y/A2n0a9l8yses (ppm) 13:WEEK DIETARY TOXICIETYTHSATNUODLY (WNI-TMHeFNO-SME,ETT6H3Y1L4)PIENRRFALTUSOROOCTANESULFONAMIDO T6314 (ppm) Storage Conditions Replicate 1 3500 Initial 21s 0954 415 468 Mean 142(142) 442 (884) 19rdoaoym, temperature 21007 811 - Mem 077272) - 32rdoaoy,m temperature 2r-Mean - a4 425 4357.0) 32day, 10709 . `room temperature" Me2an 0.0875800(780) -- 8 week, frozen 210m09m5 - Mean 0887 (887) - "2 Each value in the parenthesis i the percentoftheoretical b Reinjected He84E7 52 -_ CovwanMcrTe 663e3219-42215 `Table 2 (Continued) Results of Stability Analyses (ppm) Mixed 9/24/98 13-WEEK DIETARY TOXICIETYTHSATNUODLY (WNI-TMHeNFO-SMEE,TTH63Y1L4)PEINRFRALTUSO.ROOCTANESULEONAMIDO T6314 (ppm) Storage Conditions Replicate 500 T Initial 12- Mean - 0.788 0.656 0.722(722)" 19 day, room temperature 1 - 2Mean - 0.707 0.651 0.679 (67.9) 32 days, room temperature 1 2Mean - 0.688 0.657 0.673 (67.3) `a Each value in the parenthesis is the percent of theoretical. 10318 53 CovanMcTe -638291-42215 Table 2 (Continued) ResultsofStability Analyses (ppm) Mixed 10/22/98 13-WEEK DIETARY TOXICI"TEYTSHTAUNDOYL (WNI-TMHeFNO-SME,ETTH63Y1L4)PIENRRFALTUSOROOCTANESULFONAMIDO T6314 (ppm) Storage Conditions Replicate 3 Initial 1 224 2 249 Mean 2379.0 19 day, 18 room temperature 2 233 Mean 2.11 (70.3) a Eachvalueintheparenitsthheepsericesnt oftheoretical. 10819 54 Covance 6329225 - MTeM Table 3 ResultsofDose Preparation Analyses (ppm) 13-WEEK DIETARY TOXICITY STUDY WITH N-METHYL PERFLUOROOCTANESULFONAMIDO ETHANOL (N-MEFOSE, T-6314) IN RATS Week Replicate 03 T-6314 (ppm) 30 100 14 1a 216 297 873 2 a 212 270 852 Mean - 214(713) 28.4(947) 863 (863) 14 1. ass - - 2-1 - 5 Mean - 191(637) - - 14 1-248 - . 2. 2m - - Mean - 238(193) - - 58 1a ass 279 893 2 a 305 270 823 Mean a 330(110) 27.5(917) 858(858) oz 1a 2: 276 89.7 2 a 249 268 872 Mean a 237(790) 27.2(90.7) 885(88.5) 13014 1a 2s 262 98.1 2 a 24 264 987 Mean a 247(823) 263(87) 98.4(98.4) a Below the limitof quantitation (<0.5 ppm). b Each value in parenthesis is the percentoftheoretical Retest. d Retention 450850 ss FE i HE. i 8] (Bg emreem eo oo PE igicg meee oe ooo AB ee cee ee en PePlead Pietiiesi emec oe oo oo 2 SE iii. cw coon eo oo JH] eel ww oo SBEh gl He | BEE Dr3 gBad aa iiniipn a wii ehli Poa 8 ig ii n0851 FFI oi |: hoi PEgE! Eis.a ooo PH ims coe sBiiHbibpees eoene = CFHhL ed.eg en ceo i] es ii : Bi i |[:3 giiB Ehiiindi : te : C0352 To Por i Pais aig ee phi oe PPighiiglime > - iggi E i T | T FE g H ag gi i HH i i i Cr | aff, Bf Ho PL iiast fb 5 ' 10353 f 22% Sed 5g Aun spe und ses i | oh 837 834 884 RF =gR mags ag VE Bl Ht] oh ag? a nd asd al ad DHE EEE PELL. LLL C0851 gop : | al 2g? upd ngd agf 283 azd and J zis 1 EL 5 28 1 iecEl age ape ugd age 3gd apa age 1g 3 i Biel 2 {iMRI a RES ad AER aed ARR ned AgR med RR nd GER nel AER Le 20 i Pd Lo 21 lak) nad uaF 233 aid age ogf wi ig } | onE] asd 257 2g8 252 253 Pe 258 [ok] ad gd vg ng ng mgd md DEE pn BBE LELE Po OBL. ozs os oan. C1855 PFooig ba 85% ge 2h ged oof ped aod : 23% gas 82% gas aed aad aed E 2g | eek! aad sed rad get net ged aed 15, i Hoi vai as" 3% 23% aid aad mad mad 3% ! inal 25% ase asd ges and min uxt Lt 26 597 ged gat mat aed ne OEE EEE PB rororor aos 10556 Lal PPI ES Pe :: i 1 i I| fue5 gedwm ggoedd 357% 3 gnedod wyes ed oifS] "3 5 3Fe: Ri RoLTaRAwoTaAndAgod 5 pel po ge3d a POE lar mde nt 2 dae nl Bly ] i i ins] 25% nov nod 239 023 ad 234 CHEE dE dE i SE A PE FEaElYloa"t|h BaEsRd Sagnnd NoEaEd SEY wCeT" aOaEdR onVF? i i {EL ue ant upd and os gd a 23 i | imeB| ag? nad and nad ned apd aed gS Pea PEaH ag a an? aed a H Bt o aed ned eed ned mad ad msl B | [7RR| SRW m7 223 Rd apn aad nd Pig THE BER E EEE HA PoE ene ees ca0a58 ; gh nzd nad odd aid xpd odd 5 jf) gd opd nad apd mgm ag og 5g i ~Bl mgd amd ogd sags aged ops vgd Sg1HEEhL : . if i | {of 3% a3% apd 23% ag and ogd i a Lo HER REEE I Pe PTEI ealimat mnt aiW t giB d poeEon LRH gs fiE EE immense ifodg l smo omomom a #5 i i ! ig 496 25 39S 3dd nds ned un TPRE iCl i " Pigg aEs osm oomee oaee a a ea alon =me ; Ee 273 275 gis gid zis gas wie | yl 22,888 5 EEE CHE BeBe EE 90850 Pasi SEER) 3 : 0 ! al ommozsomy ans eds gee oR ged omg gs ER ate 8 iPEBi lary] 8a5n 5=352 230% 388% at8%a 2| 30 BE i o33 3} EE ORR OAR os3m | re i o3 gid gid mie gis 4 yl SaEERR Lig ge EEE coos pi 3 gi - - ~ Ee 1ihi *PRofEp oEfaGfia FR i $ip iDe gage2e gofns i b: . 52 gfe A Ny 20352 ) 7 } fg eg cz 2 ' gir i boa = Je Pla a a i | gNe 82 g- a 372 5 2 ; dg elg eiz v2 BoE 1.7 : : o8g 32 32 of $18 a oe me EO H i EI : ae "882g ffez =Rfa Po- g k2. o3eg oERz %% 1CgBokB. BB! 82 . 2 5 2g ie 00863 o : ; al = pd mse gms rl Foo oe Jiu EEE BE . i$1f, EiH {zea 3aa edexee swtf 2 FE op. oe wT gg sig 7 H Lo che giz ode of i gi 5 52 i gl wi of wie gk Io, BoE OER B=i| . - 2= 38 1085 : ~'g 8 "8% "8 ELL . i weg whiz wen weg ! gi se gv siz ss fof i5 o:EEs EE BLE a a em am SEER if, si of Be Sa od Sia Bo PPgde oo i go ded : 8 "fy af wf: ei i! $f rie ode ok Jd "3B a R 34 E34 =3 Bi. - = 3 = 10565 F 3 : i | gam gee 52 3 ; &| og fe oe F2 oR ogi1 2os92 o=fa Sszdnfs PoE dif aa FE Ee Lees : 3 gE i iz i3 i| f mfgoagBy agfhs wfi=g i od i a2 ge= hl 35% IFE o, BOB ORE B3io - = 2 103G66 = | Tg og or Te i i| : | sg az =z 7% iy . 1 wig nig edg wdg ii i- 2%e whe gh ste ii, 8 gi 82 8x 8a og Popa Rh i gt & Co i gi He yh i gi fz giz Ro gle l= +z fs ! sf gi oh ook , BBB gi Ls g | Bg io - 2 2 C0867 3 v| 9 gt of she ; i ol Fe i th LE . ii i ge a an EF S&F LF Pal 5P Tddg BGe osgi i gi EEE i] Fof f8: a02 giz zhe ad ols I iynBORa OowH OomR 8y ia - 8 10868 i . i wig edn ndg weg ! g| gg Loh PoE AE Ta EzEy B F8EJ,EiE8g LOEBBSu P I gE ofl Ee3l i 1 I gi RoR ek Be ofr of ma me oe oe oo ste oie Tem EEE aT aR of of od a3 . nf of die gle go gl Pz fn ok ole 0 BOER gfii. - s= 82 = C0869  $ - - -a of | ss dz gsxr ges #8 | . gi 282 232 322 Im 3 i5iaEs | wlyRamopd Gyaks edn=z . i a TE Pe Ee i i: : i gal 3 Ih ooh oR = s3 Ef 7 on. wm us i iER u#ng 1 083 ez Bz Bs i i i ats mdz mde ate i fea ee Z 8 | 7% FER ogRR gms , BOB OE BR ge | g ag ie - 2 2 50370 i 41 g's ge ge Bo, of ol gf % pdr Eos sk og ge sis fpiEpo gois wEig Eofp Eofe JET a a a I i a a a en g 5 ads avs sts sve PF : Belo sis gia siz Toad 3 BORO. Bi. . = 3 ) C1037 # $ - a - - of| B% ESR ROR se ES i fn \ 8 siz siz ve ads I ` : gi 1.2 ome om am Blof gr om fee om SEE gpd Lp 82 32 Bz ee f | ads ads mz vg 2Po5 giffFT gh ogi RTF ie J i 6 Be = he. sw 10872 # + 1] 3% f2g= of=33 =o f + Tog pr ope ifa.g ga| 3 2% gfe FN Be 5 2 od iE 8 | LC :i Fioggy oJ:esctr whoe rsie !Pi {sdH s E avs I Bti. . 2 10873 F : i i dhe : BE 3ihE } . fan ae a bg , BOEOBE OE tiP gagiHS -~ 2 2 f 10374  8 s ! I ge LI TT Bi. - 8 10875 | siz siz sdz nem | i [EERE EE i i) aly a2 ada ada i i # sr of 8a SE di i Fe fe fr fa ir gl Pe Pee ' PHEdai ne aly 8g Sz =8z i5 ane avs Eve ane E5 os fe i i yk EE Bi. - = 2 C0876 EERE EIR Ee ose oh oh oor ghe of i gh i i i ge| 30% fe fe gfe T.a Ric Aik ooo sie 3a oie H:jo E 8EE oe I gt y | siz wiz se sam 3 BB. OB. B gi. os C0877 # t # giz gin pe3 gsm iiEE ! 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DEEom rsd s Boo w Pg oH : i1 Eel i A gPriiR egl E 0RR iso g i: o Lowm iiwE Go Pom PE ETE PEELD EEd 5 C0885 i F BN i: eEllm1s55 | E e50l3m} CoeElle a iRa iad| An Eat Pini iel al EEE CED hh | giriaPo iEm Ee E TrPyhahl TiEsdE imio03m%i| iegd!| ; E EB o HelE laEU s ElA m oy HE Ge ee ` Vomiwlialial pom LR on] ais Plog ia] geomom om PET 1g i Lied PELE LEE C0886 0 Fog mdEom PTPOiE im |C1 EE`gm SEF ETBio N if pli 2h3%eB d LpTictEE * TiEgs cfodmged PDoLmEe im DLaobe dE PED JEEEEiEg Eied h n0837 Fog Eee Ee El nim lee ie ol EER TER SIifh a" i " 5ain . TrFy yhl Bee Cuslimlomlim| 2i1 E!E D es feL d | me d Bomdimioomigl PEER add add | add LE me Pg org i i. Pai lmtEt if Ef rege | `wan | `wed | 10838 EFoly mByo om PDoOlEl ieem HIgRoEr Jdegowe el H fr E E I v8 N BE Fry gd BFlB Tiaugsl E raEm PgR 1iio 08 o=m Pom am PoE LE PPaEo sbo LE Ca wHoows Erg 3 ; 20639 Ipo 3) ElEiglipliy] DEE eee 5h I EAEEIrY dows EE Iq SHER Lid El Eerglieiaied Til iq etn 8 FRIED fm igtoisloised 1 BREE S1 owBee BIy LEe OE PRET Lh E Es Dell EaE E aE PEALE LY C0890 Fogo A Pog el ls I: | He jets | SE ig Hio E8 tii 5 rl dio a Deal nidh| Linh gh by EE RR B Bl OE ml a im | DO o EEiw : gm CLE TE PBEl wm Phe EL RE PE eh } en | wiiwliimiiml CEE EE i deleig dri meade i I PIII] Bo age Pogo EEE 2yi2% 2 Ei gCEiBE fEurE deEgE 5 Pg ES ee Tiyle Csligiigmlog ag | yn i! i i's i 1 Fe E888 gd oT oC COU22 i ded ded Foi HE |CFed i aE | jh gir HPEoSw re PoEa o HE Tryodei md Ed Pg Eo 1 Ee DE ie PLE oe EE EE a PE pl ET ; n0323 EEE igo. boemlnmB iimEliR nl i gf ELT PT kiwislial Ploheieieeliae gi EVE Bi hdd gP p E 0og3g dE E igpldaigeEE tgaiigal EgE iaaggE sb ig PRICES forg dme } TpEgE CiEE BOOERE Boom POD 0 bi DE ee a PEEVE CEE las les les | EEE 2 eens  i i gHrE ig] = ir || tf g ; ii bo ji Ha i 0 a] i =e~ed we u- # i ire E iE pod Co ies l idot : 10395 ST LEE limelig gE EEE PLEoDg (iEsige sa gEss | Pe Bi alii p 33 fh BgL ogoR LPyedET ioE]ogmE Lgi i i 25 Tig ofel Tkediaiimloimi qyog EESSSSS TRBLf lecEl ei AE PEER 30 asl asd go db hdd {POB REIREadiTmgTd | Y lngd | PORE le DPEEELglLadE laGd ElieGd cones Foy Eo Po I im Com wl i BE gl Bom om gi EY gi P iBogo glo iE 21% BLS ad phil PR TRE Til iE P BoE lo H88 2i: Bei E eeE Pom iB |by BiEdE eOo S PERT {Of E%sl ads| PRC LEE EE DEE a wi PEL TE 10897 Py mes Eo. won wooT ES C Foi m LE hod i Bi Com PoE I limilela BT Ld2 RARE Doles Dee |e | S pidU gERo Eh : tig tml iw 5B)ooRE ElmE oomE ik pee a CLE EE | i181 E moEmR owE PH glAea Efi i, AI HI Pon POE PLoomle SEOgEle gio i 3 Lo " sgirpaB gEe t Rid . hie ob 2 TrypE fmt gB oiwH om we gii FEElE ieeE PCo l Ly PCa ERC EE oj] WEE '3 g Po: Ejle ibmo lbiio ns3 POE ea Comms n Poon Pom aa cEgl E h Te T Pi o 25 [ F | E J E |LI ESpEhaE dEL ptCpnHtTyEtEgRnoLTEahi 3: Ti iih TLialliEmaitiboaabll Holle ws BHe OEel EEE b DEgE,ma ET ma PRET mE PEt i. i nceo0 Fog oe PT im POE oe PPoEmE a Po a gi HOT ogBi gl gpfagl pres Bora Frpyd FhgRil om Fl\iatg! g=8e8d 2 ml isl BoD kmi ami DCoLmE a PRBEE Ena REE g nego r i i HE te | les a Pole limi Pol ee Poh ihgi Ei} i4 Ri$ay Bai Poon FE vod le boveee bree | Lo " LL mvase t mn d d mEemd E TRE R I SE z Fe Qimdomiimlia Ea sell lal lia ge EEL 083 1 8818. 8 EE DCp E m a Fete PE RUmE img ak 5 creg02 EO wml om pogo Eo Powel imi iPoEETC ee Pom gl EE EE aElo ia Bio Ld i PoBa ta EE si Bl ops oe gig Bend vgyi BSoEi Bfiongeedl EognEi ig file oe EE oe = ul i a i | sz | Bohr ii EEE CCloEE loyv PELL PE age H | EE Ee a {3 Eis 8 i g 10803 jl iltmememm mn gPgf iiplrimmrnenmnaeanaes g3 dBihlE 4B888g 5 i= di Fi F2 bg E8 TE PCy hyg in, | eCo CE EEE ii Hy Bi By lied 10304 GIT bins mnan PE hnTnnno iba HERE i B Blli il ii smmmm enoi %i . id GE | voEd i :ii BBB Po 1 ao | oo } : : d Pg EH,e falHd PEPER PoE [Tiassa i: fonmpmmnnonn- flidesien arose glia ememane Po oE L gin. = 3 Simp iSpF oBdogtghss i og o8 8 CE EE b PE Pl : i: h2 | iIE : i E : Ee Poof E PolglEsin= | dpb DE gC i 33% *1B biggf EE Eg @- gf [EE C1030 Poa jliitumomm mm IEILI EERE 2 fon pjesme cbi BBEillciiasme mg z ge n wz sEg gsmeom6 sf Bi "REG OM oo Hood a PvBE LEETREEEE BE Pog Ebi . i Poh bE FI CE PP ly E 0 E ES PPoEHoEeg EBLrF Lf,Lug OII A PEE LE Ce C0907 LE pan II II giilem ag ouen m2 an gn neegemeee Ela eee en oe ge commen A igEE UE RR 2o 3 fl BE BEE 3 f o5 e |PL i i 3 gd2 Eo Bek Cog diE CEE gl ln eg Ea: EE Be Pog AR 1 TY 10508 P8od5 Tie [2] aay ame ee emmmnceooe oo [28ay ammo coos mmo me om Pliiemmomem ab hed wan ohouiEE nus 2 sI oE E EREA iop filor iEi PPEE BEE CCoo Elo |PHg3IeL| PORE rG fPiooggpE g :Ro: :: D Ddofnooahm o C0329 ppraTIIIIIn Popnow Blinn iPDFonbPooOggL fHipEEH EETe Beaoe eHdl T# 2 Pd ik EB OB dl 3| gl PPEoEr : i EEE FE Bld L Epift Ha! DOB BC 5. fis fg Gu. PERE ET C0010 Pops IaE y meD en oe noe ane Prifpmmomem mm EE Pogi ieee iid we meonre i Bimmer mem spi laBoagTpHEE8RBBEEEL # : BE BE BREE gE EE i : so : Boo : 4 Pio bd gi Pi : i: Ei |i Po I Po i PE POZE eitc BC 4 ! <z Pee a d By for Pan lhe EL 10521 [ ifs Pipa eee Piiiases 53 owe 5% me oan oun og VE sang cs i Bitiimm Bg omex3 omg wm am =ifi BoPgRsR RAEoE on go H = u 12 | 7BE BhEE CEE A [i I g gi PiSiEd EAHElEo i EN PL ig 1 I L i Po i : i : PogEdiE l BE o Lag wm PPEEERREoTgTgIog 10312 P hd fS: ie jliiinm mmm [Thames sores meee PiBgmmym memes mene Bln sip babo odMgpeaEndno HHiEH 2z - i058 bgd el& 2BEgE D ig o E iES 3 [AE : PooL Pde e yd COREE gr ES PPIoonRsEbeEeSE PEsEFe"8RgCEiTEgEEE Parle i 10953 FA 3 go Gmrnooioo : i : i " = = am mmo ax oan am ig HERE E RE e Fh iE BoE 0a Is sod BE EEE BE EE PT Po FH PEE Ed 3 PL Bgli PLE o Poy oi, Eo CER Pogd ogi E01 8 ii PPRo EEE CE CPTa PogeE Bll 3 8 EE : Pr PSE NI WE ET 57g Fy 130344 Fat gan go en mn um oma oe 3i BBliililia weeHO =a Ha2 E- . geo t g i BEB b I b | Lo a [I 8 PPooga gl PEt o PCEH CoLo heEsI: " om hE ~ CH03L5 Foci 8 0 : . : : i : ~ aon aeag es oe Pol nmEmna IE Tp pi : i | : { + 2 meeng mesg es rE i Hy ; ji 908 "aE eed tas s HEPo1n 4 HE i | ) oA ooRa Cor iLoeg Eb Eo Da i :: POE | I ; FE h051g RE Poi pg i nmEemes {5 Bo sy macons meeny mens 2oong I ilpummman ID 574s; macong enemy meng weeny } Bina 2g SF Ege TAA a TR a igCH * PoE Hi j eh a Pe : Hi E a ii a i i DPhiee os [18 CEE ioREE Eliz E g FTE Cee? i fi i : i 4 8} #8n3 meng aseens [2g ag mmmeag ag meee : 2 : | 4 8} 2aeon3 acay mmeens 5 3: | . | 4 8} 2noean meng an~eay { Bis ; 4 8} maveny aay macens 3; 0274 Ry mmceny meng vom EBay mmcens meng mzeexs = BE: i 55 El gTeanE tang gaan R iPod TRE i 8 [ a8 gE ii f f fog Fd Poa Pi : 5 8| i! : g af | {ii Rab fo Eg EEE Poi ig i: II Ci ih LLEECEU CT Pos fo, caeszs APPENDIX 1 Protocol Deviations Protocol Protocol Amendment No. 1 `Protocol Amendment No. 2 Protocol Amendment No. 3 CovanceT52e9.225 124 npas9 Protocol Deviations CovanMMcTe.T66332s19-42.215 Protocol. Housing. Diet. "Certified Rodent Dict #5002, meal (PMI Nutrition International)adlibitum,unlessotherwise specified." Actual Procedure. The animals were given Teklad 8728C pelleted food from August 17, 1998 to August 23, 1998. Protocol. Dose Preparation. Retention Samples. "During the in-life phase, samples (approximately 100 g) will be taken from each dose preparation sampled for dose analyses and stored at room temperature. Unless used for analyses, these samples will be discarded approximately 1 month after completion of the in-life phase." Actual Procedure. Retention samples were discarded after approximately 1 monthofthe completionofthe in-lfe phase. Protocol. ObservationofAnimals. Clinical Observations. "Eachanimal wil be observed twice daily (a.m. and p.m.) for mortality and moribundity, recording findings as they are observed." Actual Procedure. On Days 16 through 30, the a.m. and p.m. mortality and moribundity checks were not documented. Protocol. Termination. Scheduled Sacrifices. "After at least 4 weeksof treatment, five animals/sex/group will be fasted overnight, bled for serum samples, anesthetized with carbon dioxide, weighed, and exsanguinated." Actual Procedure. Fastingofanimals at the Week $ scheduled sacrifice was not documented. 10320 125 CovanMcTe-6633291.42.215 Protocol Deviations (Continued) Pprroesteoncto)l.orErxepperreismenetnattailveDessaimgpnl.esPowisltlmboerctoelmlePcrtoecdefdurroemse.ac"hTahneimfaolllaonwdingprteissesruvesed(winhen 10% phosphate-buffered formalin, unless otherwise specified." hAicsttuoaplatPhroolcogeidcureexa.miSnoatmieont.issMuiess,sirnegqutiirsesduebsyatrheelipsrtoetdowciolt,h awpeprreopnroitataveaciloabmlme efonrtisn the pathology data sheets for individual animals. Summarytablesdo not includethemas having been examined. "These deviations are not expected to have affected the resultsofthe study. neond 126 COVANCE.> `Sponsor: 3M St. Paul, Minnesota PROTOCOL Study Title: 13-Week Dietary Toxicity Study with N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) in Rats Date: August 27, 1998 Performing Laboratory: Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595 Laboratory Study Identification: Proposal No. 90545D Covance 6329-225 `Sponsor Project Identification: 3M T-6314.1 127 10922 Covance 6320.225 Pea S1t3u-dWyeek Dietary Toxicity Study with N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) in Rats Purpose To assess the toxicoiftthy test matwheenardmiinisaterled in the diet 10 ratsforat least 13 weeks Sponsor M Toicology Services Building 220-2E-02, 3M Center St. Paul, Minnesota 55144-1000 Study Monitor | Andrew M. Seacat, PhD 3M Toxicology Services Telephone No.: 651.575.3161 Facsimile No.: 651.733.1773 Alternate Study Monitor Marvin T. Case, DVM, PhD 3M Toxicology Services Telephone No.: 651.733.5180 Facsimile Nos: 651.733.1773 Study Location Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595 Maling Address: POBox 7545 Madison, Wisconsin 53707-7545 cn0323 128 _--m-- Study Director Peter J. Thomford, PhD Covance Laboratories Inc. Telephone No.: 608.241.7207 Facsimile No.: 608.242.2736 ee Covance 6h32P0ea-g2e235 `Toxicologist `Thomas E. Ryan, BS Covance Laboratories Inc. Proposed Study Timetable In-Life Start Date: September 1, 1998 In-Life End Date: December 3, 1998 Audited Draft Report Date: May 26, 1998 Regulatory Compliance `This study will be conductedin compliance with the Food and Drug Administration Good Laboratory Practice Regulations as set forth in Tile 21ofthe US Code of Federal Regulations, Part 58, issued December 22, 1978 (effective June 20, 1979), and with any applicable amendments. Animal Care and Use Statement All procedures in thisprotocolare in compliance with the Animal Welfare Act Regulations, 9 CFR 1-4. In the opinionofthe Sponsor and study director, the study does not unnecessarily duplicate any previous work. Quality Assurance `The protocol, study conduct, and final report will be audited by the Covance Quality Assurance Unit (QAU). The proliferation cell nuclear antigen (PCNA) evaluation, data, and report will be audited by the QAU ofPathology Associates International. Liver and `serum analyses, data, and report wil be audited by the QAUof3M Environmental Technology and Safety Services. 10524 129 Test Material Covance 6329-225 Paged Identification N-Methyl Perfluorooctanesulfonamido Ethanol (MeFOS, T-6314) Lot Number "Thelot numberswilbemaintainedintherawdata. Purity Responsibilityofthe Sponsor Stability Responsibility of the Sponsor Storage Conditions At room temperature: CIhnafroarcmtaetriiosntoincssynthesis methods, composition, or other characteristics that define the test material is on file with the Sponsor. Reserve (Archive) Samples Areserve sample (approximately 5 g)ofeach lot will be taken and stored at room temperature. These samples will be transferred to the Sponsorafter completion ofthe in-life phase. Dispositionof Test Material After authorization from the Sponsor, any remaining test material will be returned to: Andrew M. Seacat, PhD 3M Toxicology Services Building 220-26-02, 3M Center St. Paul, Minnesota 55144-1000 Telephone No.: 651.575.3161 Facsimile No.: 651.733.1773 10975 130 Animals Species. Rat Strain Cri:CD?(SD) IGS BR Covance 632P9a-g2e2s5 Source Charles River Laboratories, Inc., Portage, Michigan Age at InitiationofTreatment Preferably less than 6 weeksof age but not more than 8 weeksofage `Weight at Initiationof Treatment 10010300 g Number and Sex 80 males and 80 females Identification Implantable microchip identification device Husbandry Housing Individual (maybe group-housed during acclimation). Animals will be housed in suspended, stainless steel cages. Diet Certified Rodent Diet #5002, meal (PMI Nutrition International)ad libitum, unless otherwise specified. The diet is routinely analyzedbythe manufacturfeor nutritional components and environmental contaminants. Specified nutrient and contaminant analyses are on file at Covance-Madison. 1092 131 Covance 632P9a-g2e25s Water Ad libitum. Samplesofthe water are routinely analyzed for specified microorganisms. `and environmental contaminants. The results are on file at Covance-Madison. CThoenrteamarienanontksnown contaminants in the diet or water at levels that might interfere with this study. Environment Envicor ntroo lsfonrthemaniemalnroot m wilalbelset to maintain 18 to 26C, a relative humidity of 30 to 70%, and a 12-hour light/12-hourdark cycle. The light/dark cyclemaybe interrupted to accommodate in-life procedures. Acclimation Atleast1 week Randomization Selectionofanimals for the study will be based on clinical observations, ophthalmic examinations, and other data as appropriate. Animals will be assigned to treatment groups using a computerized blocking procedure designed to achieve body weight balance with respect to treatment groups. At the timeof randomization, the weight variationof the animalsofeachsex used will not exceed +2 standard deviationsofthe `mean weight, and the mean body weight for cach groupofeach sex will not be statistically different at the 5.0% probability level. JRuasttsifhiisctaotriiocnally have been used in safety evaluation studies and are recommended by appropriate regulatory agencies. 10927 132 Covance 6329225 --_-- Per `Group Designations and Dietary Levels : Group --NomberofAnimals Male Female 1 (Control) 20 20 23 ((MLiodw)) 2200 2200 4 (High) 20 20 a Dose levels are expressed as pop fMeFm OS. Dictary Levels (ppm MeFOS)* 0 330 100 b The control animals will receive the basal diet only. Dosing Procedures Method of Administration bDieeftoarreyn,e7crdoapyssy/.week for at least 13 weeks. Treatment will continue through the day Reason for Dosing Route "The potential routeof exposure in humans is oral. Dose Preparation All dose preparations will be mixed according to the study-specific mixing procedure developed by Covance. Dose concentrations will be based on the MeFOS content as supplied. All dose preparations will be stored at room temperature. Before initiation of treatment, dose preparations of1 ppm, 3 ppm, 30 ppm, 100 ppm and 500 ppm will be mixed. Dose preparations will be mixed at least once every 4 weeks during the in-life phase. Retention Samples `During the in-life phase, samples (approximately 100 g) will be taken from each dose `preparation sampled for dose analyses and stored at room temperature. Unless used for analyses, these samples will be discarded approximately 1 month after completionofthe in-life phase. 10928 133 Covance 6329-225 Pages Dose Analyses By Covance, using amethod supplied by the Sponsor and validated by Covance Homogeneity Homogeneity will be determined for 3-ppm, 30-ppm, and 100-ppm dose preparations once pretest. One sample (approximately 100 g) each from the top, middle, and bottom ofthe dose preparations mixed for homogeneity analyseswillbe collected, divided into three subsamples for extraction and analysis, and analyzedfortest material content. All samples will be stored at room temperature until analyzed withi7n days after mixing. Homogeneity analysis will be repeatedifbatch size changes by more than 30%. Stability `Four samples (approximately 100g each)willbe taken from the 1-ppmdose level concentration of dict preparations mixed pretest. One sample will be analyzed on the dayofmixing and used as the baseline value. One sample will be stored at room temperature for at least 19 days, then analyzed. A thirdsamplewill be stored at room temperatureafterat least 32 days, then analyzed. The remaining sample wil be stored inafreezseert tomaintain -10to -30Cfor 8weeks,thenanalyzed. In addition, two samples (approximately 100 g each) will be taken from the 500-ppm dose preparation mixed pretest. One sample will be analyzed on the dayofmixing. The second sample will be will be stored at room temperature after at least 32 days, then analyzed. Dose Confirmation During the in-life phase, samples (approximately 100 g)fromall dose preparations will be analyzed. All samples will be stored at room temperature until analyzed. 10929 134 Observation of Animals Covance 6329-225 Pages Clinical Observations `Eachanimalwillbeobservedtwicedaily (a.m.andp.m.)formortanadmolriibuntdityy, recordingfindingsastheyare observed.Atleastonceweekly,eachanimalwillbe observed (cagewillbeopened,andtheanimalwillberemoved); abnormal findingsor anindoifnocrmaalwitllbeirecoordned. Additionalfindingswillberecordedasthey are observed. Body Weights Eachanimalwillbeweighedatleast oncepriortotreatment, onthefistday of treatment, and weekly thereafter. Food Consumption Food consumption wil be recorded weekly during treatment. Food consumption wil not be measured during Week 5foranimals scheduled for sacrifice during Week 5. Ophthalmic Examinations Ophthalmic examinations will be done for each animal before initiationoftreatment and. befthoeWreeek 14scheduledsacrifice.Theeyesofeachanimalwillbeexaminedby a veterinarian using an indirect ophthalmoscope. A mydriatic agent will be instilled into the eyes prior to examination. Clinical Pathology Frequency Hematoloagndy clinical chemistry during Weeks 5 and 14; urinalysis during Week 14 Number of Animals `Ten animals/sex/group (the same animalswillbe used at each interval,ifpossible) Method of Collection Animals willbe fasted overnight; blood will be collectedfroma jugular vein. The anticoagulant will be potassium EDTA for hematology tests. Urinewillbe collected chilled overnight (approximately 16 hours). e950 135 Covance 63P2a9g-e22150 Tests. Hematology red blood cell (erythrocyte) count hemoglobin `hematocrit `mean corpuscular volume `mean corpuscular hemoglobin `mean corpuscular hemoglobin concentration platelet count `white blood cell (leukocyte) count differential blood cell count `blood cell morphology reticulocyte smear (made, but not examined) Clinical Chemistry glucose urea nitrogen creatinine total protein albumin globulin cholesterol wiglycerides total bilirubin alanine aminotransferase gamma glutamyltransferase aspartate aminotransferase calcium inorganic phosphorus sodium potassium chloride Urinalysis appearance volume specific gravity PH pruorotbeiilninogen glucose ketones bilirubin blood `microscopic examination of sediment `Serum Perfluorooctane Sulfonic Acid (PFOS) Analyses Frequency and Number of Animals `Five animals/sex/group after at least 4 and 13 weeks of treatment. Samples after 4 weeks of treatmentwillbe collectedfromanimals selected for the interim sacrifice. e35E 136 Covancee 63ePa2ge9-n22151 Method of Collection Animals will be fasted overnight; blood (approximatel4y mL) will be collected from ajugular vein. Samples will be collected without anticoagulant. Sample Handling Blood samples will be allowed to clot atroomtemperature and centrifuged. Serum samples will be harvested and stored in a freezer set to maintain ~60 to -80C. Samples will be packed on dry ice and shipped to: Kris J. Hansen, PhD 3M Environmental Technologyand Safety Services 935 Bush Avenue Building 2-3E-09 St. Paul, Minnesota 55133-3331 Telephone No.: 651.778.6018 Facsimile No.: 651.778.6176 Serum samples will be analyzed for PFOS and metabolites by the Sponsor. Results will be reported separately by the Sponsor. Termination Unscheduled Sacrifices and Deaths Necropsies will be done. Animals to be sacrificed will be anesthetized with carbon dioxide, weighed, and exsanguinated. Scheduled Sacrifices After at least 4 weeksoftreatment, five animals/sex/group will be fasted overnight, bled for serum samples, anesthetized with carbon dioxide, weighed, and exsanguinated. The `abdominal cavityof each animal willbe opened, the liver will be removed and weighed, and liver samples will be collected for palimitoyl CoA and PFOS analysis. Animals will be discarded after liver collection. 10532 137 Covance 62P9a.ge22152 After at least 13 weeksoftreatment, all surviving animals will be fasted overnight, bled afonresstehretuimzesdamwpiltehsc(avrbeonandiimoaxlisd/es,ewxe/igrgohuepd), aenxdsacnlgiuniicnaaltpead,thaonldognyectreostpssi(e1d0./seLxi/vgerroup), sampleswillbe collected for palimitoyl CoA, PCNA, and PFOS analysis. Postmortem Procedures Necropsy "The necropsy will includean examinatoiftohne external featuresofthe carcass; all external body orifices; the abdominal, thoracic, and cranial cavities;organs;and tissues. Organ Atthe Weights scheduled sacrifice after 13 weeks of treatment, the following organs (when presen) wil be weighed; paired organs will be weighed together: adrenal (2) bkriadinney (2) loivvearry @) spleen testis (2) tthhyyrmouisd (2) with parathyroid Organ-to-body weight percentages and organ-to-brain weight ratios wil be calculated. Bone Marrow Smear Fromthe femur of each animal at the scheduled sacrifice after 13 weeks of treatment only; made but not examined CAetltlhPersoclhifeedrualteidosnacTriisfsiucee aCfotlelre1c3tiwoeneaknsodfItmrmeuantomehnitst, orcephreemsienctaaltiEvveaslaumaptlieosnofleft lateral lobe of the liver from cach animal willbe collected and preserved in zinc: formalin. After fixation, each sample of liver will be embeddedinparaffin, and the paraffin blocks will be shipped to: ne9s3 138 _-- Covancee63Pe2a9g-en22153 Sandra R. Eldridge, PhD Pathology Associates Intemational 15 Worman's Mill Court, SuitIe Frederick, Maryland 21701 Telephone No.: 301.663.1644, ext. 2201 Facsimile No: 301.663.8994 Proliferationcellnuclear antigen (PCNA) evaluation will be done on the samples. Results will be provided for inclusioninthe final report. Palmitoyl-CoA Oxidase Tissue Collection and Analyses At the scheduled sacrifices, the right lateral lobe of theliverwill be collectedfromeach animal and flash-frozen in liquid nitrogen. The liver tissue wil be stored ina freezer set to maintain -60 to -80C until analyzed by Covance for palmitoyl-CoA oxidase activity. Liver PFOS Analysis At scheduled sacrifices, the remaining portion of the liver from each animal after other required collections wil be stored ian freezer set to maintain -60 to -80C. Samples will be packed on dry ice and shipped toKrisJ. Hansen, PhD, 3M Environmental Technoloagnyd Safety Services. Liver samples will be analyzed for PFOS and `metabolites by the Sponsor. Results will be reported separately by the Sponsor. Tissue Preservation `The following tissues (when present) from cach animal that is found dead, sacrificed at an unscheduled interval, or sacrificed at the scheduled sacrifice after 13 weeks of treatment will be preserved inl0% neutral-buffered formalin: C1083 139 terres ree Covance 6329-225 --------reeteeEE1, adrenal (2) aorta brain cecum cervix colon duodenum epididymis (2) esophagus efyeemu(r2)with bone marrow (articular surface ofthe of the distal end) Harderian gland heialerutm with Peyer's patch (lymphoid aggregate) jejunum leksiidonneys (2) liver lluynmgphwintohdmeasi(nmsetseemntberroincchaind mandibular) `mammary glands (females only) ovary (2) pancreas pituitary prostate. rectum salivary gland (mandibular (2)] sciatic nerve seminal vesicle (2) skeletal muscle (thigh) sspkiinnal cord (cervical, mid-thoracic, and Tumbar) spleen sternum with bone marrow stomach testis (2) tthhyyrmouisd (2) with parathyroid trachea urinary bladder uterus vagina Zymbal's gland Histopathology Tissues (as appropriate)fromeach animal in the control and high-dose groups and each asneicmtaiolntehda,tdsitaeisnoerd iwistahcrhiefmiacteodxaytlainnaunndscehoesdiun,leadnidnteexravmailnweidllmbiecreomsbcoepdidcealdliy.nparaffin, Mpaarcarffoisnc,ospeicctiloenseido,nsstfarionmedawniitmhalhseimnattohxeylloiwn-aannddemosiidn-,daonsde gerxoaumpisnweidllmbiceroesmcbopeidcdaelldyin `Suspected target organs noted at the high dose will be examined microscopically from each animal (at the Sponsor's request and added by amendment). Reports One copy of the draft reportwillbe sent to the Sponsor. The report will include the following information: 10935 140 Experimental Design and Methods Covance 6329-225 Page 15 Results dose analyses mortality clinical observations body weights body weight changes food consumption test material consumption ophthalmic findings clinical pathology results `palmitoyl CoA oxidase activities `macroscopic observations `microscopic observations cell proliferation assessments (provided by the Sponsors designee) Statistical Evaluation Levene's test will be done to test for variance homogeneity. In thecase of heterogeneity ofvariance atp 0.05, transformations will be used to stabilize the variance. Comparison tests will take variance heterogeneity into consideration. One-way analysisofvariance (ANOVA) will be used (if applicable) to analyze body weights, body weight changes, food consumption, continuous clinical pathology values, and organ weight data. If the ANOVA is significant, Dunnett' t-test will be used for control versus treated group comparisons. Ifthe ANOVA shows significance for body weights at Week 1, one-way analysis of covariance (ANCOVA) will be used to analyze body weights, with initial body weights as the covariate. If the ANCOViAs significant, covariate-adjusted means will be used for control versus treated group comparisons. Group comparisons (Groups 2 throug4h versus Group 1) will be evaluated at the 5.0%, two-tailed probability level. Only data collected on or afte the first day of treatment wil be analyzed statistically. 10926 141 Covance 63P2a0g-e22156 At the end of 1 year after issuanceoftheauditeddraft report,ifno requested revisions or instructions to finalize have been communicated by the Sponsor, then the audited draft reportwillbe cons`ifindalaendrisesudedasthefinalreport,signedbythestudydirector, and submitted to the Sponsor. Any modifications or changes to the audited draft report requested 1 year after issuance willbeperformedatadditional costtotheSponsor. Two copiesofthe signed final report (one unbound and one bound) will besentto the client. Record All raw Retention data, documentation, records, protocol, specimens, and final report generatedas a resultofthis study will be archived in the storage facliiesofCovance-Madison for a period o1f year following submissionof the final report to the Sponsor. One year after submissionofthefinalreport, the aforementioned materials will be sent to the Sponsor, `and a return feewil be charged; al raw data stored on magnetic media, protocol, study c`moaryreeslpeoctndteonhcea,veatnhdetmhaeteorriiagilnsalreftianianlerdepinortthweiClolbveanrceetaairncehdibvyesCfoovraanncea.ddiTthioenaSlpopnersioord of time, and Covance will charge a storage fee. If the Sponsor chooses to have Covance disposeofthe materials, a disposal fee will be charged. PCNA antigen evaluation data will be retained by Pathology Associates International. Liver and serum samples sent to the Sponsor and analysis data will be retained by the Sponsor. C0937 142 PROTOCOL APPROVAL CovanceP6a32g9e-22175 LAdodregw M.oSeascat, PhMD1 Suis?" Study Monitor 3M Date7/31/23 SPtliuedry).DirGrorfd, PAD Covance Laboratories Inc. date 10028 143 COVANCE. PROTOCOL AMENDMENT NO. 1 Covance 6329-225 FE -- 13-Week Dietary Toxicity Study with N-Methyl Perfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) in Rats `Sponsor: 3M, St. Paul, Minnesota Study Monitor: `Andrew M. Seacat, PhD Testing Facility: ~ Covance Laboratories Inc., Madison, Wisconsin Study Director: Peter J. Thomford, PhD "This amendment modifies the following portion of the protocol: Effective August 27, 1998 1 Pag3e, Proposed Study Timetable. To correct the audited draft report date, delete the text inthissection and replace with the following: In-Life Start Date: September 1, 1998 In-Life End Date: December 3, 1998 Audited Draft Report Date: May 26, 1999 Effective October 1, 1998 2. Page 12, Postmortem Procedures, Cell Proliferation Tissue Collection and Immunohistochemical Evaluation, Paragraph 1. To reflect the decision to `perform proliferation cell nuclear antigen evaluation for five animals/sex/group. only, delete this paragraph and replace with the following: At the scheduled sacrifice after 13 weeksoftreatment, representative samples of the left lateral lobeofthe liver from five animals/sex/group will be collected and preserved in zinc formalin. ness 144 _-- Procol CAeomvenencedem65e2hung5et.251 AMENDMENT APPROVAL ;lnditir Andrew M. Seacat, PhAD Study Monitor 3M vSenn 1//5_/93 Date A Study Dipor rd, PhD Covance Laboratories Inc. 0 Date Cregg 14s COVANCE PROTOCOL AMENDMENT NO. 2 Covance 6329-225 o TeETrEr r-- 13-Week Dietary Toxicity Study with 'N-Methyl Perfluorooctanesulfonamido `Ethanol (N-MeFOSE, T-6314) in Rats Sponsor: 3M, St. Paul, Minnesota Study Monitor: Andrew M. Seacat, PhD Testing Facility: Study Director: Covance Laboratories Inc., Madison,`Wisconsin Peter J. Thomford, PhD. This amendment modifies the following portionofthe protocol: Effective October 21, 1998 1 Page 8, Dose Preparation, Dose Analysis, Stability. To reflect the decision to `perform additional stability analysis, add the following to this section: Two additional samples (approximately 100 g each) `will be taken from the 3-ppm dose preparation mixed for Week 9 through 12. One room temperature for at least 19 days, then analyzed. sample will be stored at The second sample will be stored at room temperature for at least 32 days, then analyzed. The sample collected for dose confirmation analysis will be used as the baselinesample. Ceo 146 Protocol CAomveanndcmee6n3t29N-o2.225 _-- Pe? Effective December 4, 1998 2. Page 13, Postmortem Procedures, Liver PFOS Analysis, Sentence 1. To clarify collectionofliver sections for PFOS analysis, delete this sentence and replace with the following: Aotthsecrhreedquulierdedsaccorlilfeiccteiso,ntshweirllembaeinfilansghp-forrotzieonnoifntlhiqeuildivneirtrforgoemn eaancdhasntoirmeadlianftaer freezer set to maintain -60 to -80C. Effective December 15, 1998 3. Page 13, Postmortem Procedures, Cell Proliferation Tissue Collection and Immunohistochemical Evaluation, Paragraph 3. To include examination of liver sections wil be stained with hematoxylin and eosin as partofthe cell proliferation evaluation, delete this paragraph and replace with the following: Proliferation cell nuclear antigen (PCNA) evaluation will be doneonthe samples. In addition, liver sections will be stained with hematoxylaindn eosin and examined microscopically. Results will be provided for inclusion in the final report. Effective January 25, 1999 4. Page 14, Postmortem Procedures, Histopathology, Paragraph 3. Liver and stomach were identified as target organs in animals in the high-dose group and will be examinedinanimals from the mid-dose group. Therefore delete this paragraph and replace with the following: Liver and stomach fromcachanimal in the mid-dose group will be embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined microscopically. 10922 147 ProtocslCAomvaenncdem6e3n2t9N0o225 ------------------------teereeeeamsacimnetEdE Effective February 8, 1999 5. Page 14, PostmortemProcedures, Histopathology, Paragraph 3. Liver and was identified as target organ in animals inthemid-dose group and will be examinedinanimalsfromthe low-dose group. Therefore delete this paragraph and replace with the following: Liverand stomach from each animal in the. mid-dose group and liver from cach animal inthelow-dose group will be embedded in paraffin, sectioned, stained with hematoxylin and eosin,andexamined microscopically. AMENDMENT APPROVAL 77) 4 J $ 1 Andrew M. Seacat, PhD. Study Monitor 3M / /oi f Date Ped TThyfogra,PhD, Study Dirdotor Covance Laboratories Inc. 2 o% 148 C1033 COVANCE> PROTOCOL AMENDMENT NO. 3 Covance 6329-225 13-Week Dietary Toxicity Study with N-MethylPerfluorooctanesulfonamido Ethanol (N-MeFOSE, T-6314) in Rats `Sponsor: 3M, St. Paul, Minnesota Study Monitor: Andrew M. Seacat, PhD ST tuyDison,o Parl nd eo --e `Testing Facility: Study Director: Covance Laboratories Inc., Madison, Wisconsin Peter J. Thomford, PhD This amendment modifies the following portionofthe protocol: Effective August 28, 1998 3 Page 4. To include the vehicle used to dissolve the test material before mixing with the diet, add the following section. Vehicle Acetone Identification Lot Numbers The lot numbers will be maintained in the raw data. Purity On file with the manufacturer Stability On file with the manufacturer 109:4 149 Comeesnazs _(]) Protocol Amendment No2= 3 te BREE S`Attorroaogem Ctoenmpdeirtaitounrse Characteristics Information on synthesis methods, composition, or other characteristics that define the vehicle is on file with the manufacturer. AMENDMENT APPROVAL (ochaTdN Sos Andrew M. Seacat, PhD Dat Study Monitor 3M Peter 1. , PhD Day Study Direbfor Covance Laboratories Inc. 'E777 Zz @ Yo Corre on "Or C1095 150 - APPENDIX 2 Individual Animal Fate Data Individual Clinical Observations Individual Ophthalmic Observations CovanIcT MeT6-3e 6239-124r215 Cease 151 Fe || BJyE | Fanaa ARIAL || 8#! canasnnassansARRRRRIRRREAERRRAIAA EASE annS ate Bi EEE ore . i EB FE B10 ell laminae o 2 Ti5o SE gC issmsEsil itunsmaii ERicissicn ansennng iE 5 i i +S . | B5asaasaeenasee asnsnatsneannany t ! Bfcenmmmuninnmnens oes : on i 513888808000005000688858858058080888 ! Prd a i Ji | "rrrmmzzama anes IIT i|BEg nnn08aRRRREREREAAAAASARRSSEREREEE HE HIRES 2! |aseens ar ces s cs Ree sor REEs DE . i Dele sense v5i1o ibl EpiEmESiinercnaanRmRRcgrpiercosaaiaaiiadeigc B20 Bf EEE a= 23 5 [Emm i iiSSR| E assasnannsnei E annsnnsniaans 193588 # Bi reeerennnnn teen Bo [EERIE | 3H 5 aasi nasaan nnsasa ssanaasananaanaznses } esis Por |: afy enon manmsmss aa RR | 88 | cnsnrnnassRansaRasasRRARRERRRESER iE 1, sssssmsmmmmmmmsssassessessazaaa Ha. gs i i faseina = POOREBE E s smsl sssagsa ansann aa nnsnsannasnnang * : Bgl ern e Cnn i, gunn anaannnansangy | 35igeznozsecencasazsssagaaazasazasay 10329 gPooE es i BE FERRI IRAE RRIIII QFi 58 | 8550200095998 588888RRRRRREARAR ES . E Pal aamme nee ppb pUGmpeneEngs ~E Z| giEEREREAdaEaa RENEEEE nanant 3 3 OR mmm : [na = 2TOEi3 SelS Emv EsEmRiEunEenEnEse sssssssnnsens 4 | Bl emertennmeeon CHEE Ei {238sasannanu sana nanaay gua Es 1eoL0 Pi PoE | .i mmm eee LE| 88|cennnnansssassasansassan sie i] cBi dBL m opmnim namia anan Toh Cn iFOHR .msma msemui sensan neanse senss i sR |El EE gmsammauns FEREEETTL] | %218853808088080805000808588 i . 103%d Bd . LE |[EgE iPghs oLHE e2g1! ogEia Pagid i PEG 3 : SE ELC 2 3 HE HA EL : 5 DEE PBiy o FTiirf adm } gies Bak fess f Ppa 330s El am zrygd | Hie " Eee oe 10352 Foil : 2 OE DDeEel iI oe]s yl fH ao0g H CESE d fE rap EB .is:= 2 gr FEE aes osnrnny PERE iin Phriday | sles: fzzzsszzs Peflzzzaiazzaigy (8 1EEER 5533333 PEE ores [I 0353 P Foogrg | Bi LE sla 1 EEiog i edi : Sin igi ils i 3 2 PEG TpE o, fain gfairi aof EYRE qiEE CE rinaia PEE in iE EEEEENEEETEI CE eee CEE 10951 hpLE oa Ei o [PIEE L ` : : 3 iPEad PaHoi,l ibieiranir 1i1 Toning iE PH igi rEEeEEYei s TfiEd eRisEE | dyno oRae Leen ee Poggigp3z3a3s% : 10855 Tiong Li og i Fgoiyf od sll E d BOEEG L 2 Po, SEE i FE 13 30 E1 id z i: Bio - id Tg fig i TgEiI ,1 ofgiri8:1 f8 Hi Dogrriiiifite Poadl BB3832332083it8. FR | Wrz znann as [Bee rene en 10958 i i gi[IhHi og SoH PrEn E fed EF boat JED TE igi iIE,REpTeYlTiiIiTaIiTiInYg EFEFEEEIEEEY i[efgilezzzszsaszzzeaszsiegg:s P18 1 232%%2%333332 LC Bran DBE semen Po Rglereeeee i 28388 EEEEEED = 10957 y LE oai EG 3 LEsBa i: Dboail El :i gir t3TIB gS1 R:8 RETEITEY Bo iEiEi, Edd Topo bEpias EH ilflgiiezszsrszszsaggie P8 cs R0, OTE | fivEEaaaa PR eee {ggigzsissag 109:8 LIELE PE HE HH a0 gE i hig i : * i: Hig 0 = JE T HiiE sg| nn Bo, 1 fRERiigs i g2 8 Beseszsia f | E ESL TBEEiEEiRiEiEiRiERiSit| LGre on nee PE mee IE HEEREEEEEEEEE] 0959 | i{ag [a a g2o0ag t B Eiog A3PoE8z81D. 1 i: B33 a81 ,80 z= 8 3S PR HEB;C ITTY T Bi, R BEEE 2nHn: EE { d 5 steesE ce Ezz DE ENT iaia Pdr mamazoazas Pe DE cece wenn sr ioai iii 10560 Boy Potig LE bioag an ER PE dEdEL jie fl 2FR8E3glegrrrensge , ERERERERiS P07 (GEiiipai: i siezezssgsges E PE I iaEgEiN EaEiEiE EiRaEy (EF diirEiiEaai [imenrraaas PR eee 109s PE |5B fh HHH . B Fg k wo | EB! gi ELE FH iE 2 PPEEFIiarrrasriEiigs Bi iERfrEiiEEiiig | glesessesszeses PRES 33d gg iEiiiiaiaagg IEEEEEEEEEERE BEALL ELELL Rie cecvriineaan 10952 OE - | Hi 1 Pa JB Pa siPahliss i OEE! i 7 L TLGE, rT 1 fai: TEBio fl 1i3 PY i | glee gs fsa ILEiHEFAEF EE i3 Lg res PE oe ee {ogIERiRzgEs] i g i8 s88 e - 10963 PH CB | ogxl slaET g BEosEt LPTE RIRL21 AEE Pa e i2& $3000 8 fF fF oe 2 P3EE8s = i i if leggy 3 P0L0gEliigiei tairy i CPEaElriripragil gii igl ii; ne FERRER i fags Pagirrear oz oan = PE eee ee |PEiRIEi88E88sg 5 883% 8 C1096 Fig EELLEa PaE | all 8o EPOeEliooond FE nnn Hipoirnnaninieg S18 |EEEEEEEEEESL PY oRngiiiiaiid i giezassszggee faghi 23333228234 (BE assiiiaaaid 1d 1EZzEziiaaaa IEEE EEEE En 109S5 | | i} kg . . al : sog8 :: EBLE 1dr i4 PE : jSigEEfi @ g Poot E Boag iFE oigrEggguess i. ge inna E10 igEEigE: i Pi elgilzzr2zzeizzgzsgisBadifisz pS 1r2riEEaE A 33 {irEEEzaaa x a= i EE - Ddfisziisss:i os: C0858 | pid PE HH HE HE al 0 gE $i EY PER LEE jie 3FE Eig| ya gi BT dEiEiEREC laieEgegs S18 [EEEEEEEEE i gieegszezge Pail g22iggiig IRIEEEREERRE (5 j1iiiEREAA [lonvmzzzss : (30957 I APlb PTSE5h1s i; hin Ch, (ERIEEREinii ilafgiigs2e2g2s32s3s2s2s3g3z3s5s3e3e3 IHEiiiiiiiiiiiag (8 lRiiiziiEiiiii Dmigssressssiiz: 109G8 Foo 8x ah i sh by Eg BTie oil] LB [ogi Defi 38 isi FEE i %EI 88 10959 Fog i 0 PE LE EEREE :i IHEYS i s = HBIOEE,i f HEi Ig RETTFR TERIY Bi, (128F ErERii: BR {osls 22e 22z s8e % lai sdrgfliozrzzzz: 8 1223238 IEEEERE] C0570 dPEh El P E EL n TEH.EHTH 1B1g 1431888 [IsEiEeEg]e VEE (81233 i E288E chos7L gy PEL ELI Hii . - ; = TEEH nn TRE, PEEEERIEIGE 8t BC ORREiEiiagieg i gissezezezjsuss PDaBpEiil g3i2i2 gi3i3i3 si3g3Ht8yi iS i iz aiiial Z 305772 Fi HE eh i BEL Wey PE g EEi gi, iif Ha Bag i gi} peopERE PERI BES : = 10973 gon i LEE PE Poggi PED fPaE EghgdelB 2. -2 B aiE i;| TE i nn TE, EEEEEEE iii | SIA iPhIaEiirii33i3%aiabENiTtE iiae3 {5 iREIARiE iiaz Ces Fi PE Pl CEE sci Bi HE H fEfiri FBEi| t iPeEsE LAER EEE {LBeEnRia33a% PE EEE PEI EEE 2- CHoETs FF o3l Po Eo E iE l og = jd' 139i} = : BE8i8gilssssassgenes CIR i P iEfEiEiEeEiEiREEE iErEEEiEiE:R li efsiiszszszzzeziezsgzaeigsizigasge PER IIa iEIEAILS {8 iiizzziiiziaiz | igrIIEIEEIEINE i Hii3iiE883888483C057 io BE odd i rPefbaRlloga 8 thin FgEERiEd THa i8= g a oi Po ty EL iogag . iSne g k oB 2 Si5R01 nn BR FREI Bi (fffigzaagEae l{ egfiie3s3z2s2z3g3es3g8g3s3g%s4s3g Pilpiiiiiiiiig EEEEEREEEE EEE Dpsssiszsziaziag 1e378 Ti BE LPEg G fan Eri d PiEn Tai, Ed BC iE LLoegniie (BEsue qi Paee 2 40579 dR a. gi PEL Eadl | 1PF0aElYirpgrrinnnias Fgh EEBriaiEiiiie: PHliagiaaaaiiaa |legfiiegs2s2z3s3z3sz3z2z2z2z3z3a3z (8 jdFrzediiazraz a 000930 I Poor (tBgO Aaa HIN PBhEiE EH30 B8 E3|ET TH. 3 E21 PEE Eo IRE] {aoigl e2e3 |BBEg 8213 PH Cob i %B1 8% 2: 109381 FPoo:E sid PE PE 1 dpi zi THE . 2 Pll (BRRioiiriiig PRiiariaiiiiii i glisseesessazzs Paailgagzzzaiziigd (3 jrziiziiiaazaz 109582 i i, PE hg a 1 3 3S%EF3 L| E i iILiREeg HB1iigTcofitt BoE [oglas HE (8 123 PEE z = ! 30383 oo APPENDIX 3 Individual Body Weight Data (g) Covancer63e29i-225 10984 189 i5 ~ EEeF F booygy ol PB 33588E3E3R5E5E5s3E geass s$e2g8s3 $$E3S8E3333I I gees 9NNEEH r{Byy 5g3I3a5g3a8s5E9e5R5s s3a8s5s% 9 853E3 3EE i Eo FUE gasses sie SNE go s Bi S PEo F Fceno mmmeod WE EOE EE . SED i 13 d 5 e i Bl suneaoseRxEgmaMuundgsnuancaagnEsEassRs RRERZRERZIREARRR - if i i DE senses EEE i Ur mmmmsspns BREE i i | sreRARNASRRRARANARE | RAARRRRR r sem | SAE i 5 5B } ssmssmmnnIIas BBBE37esBEEEcotecEes CERNE ousoTne 90985 8 LB os mu mmm 3 I PE ow sum ssensme 3 TFs Bo SF om mem mamma mem mmm ith s PHF os mm measn ia f PHF 2 EZ Hel ns sms a }i ] ; i bg CE zeuameseEss Bo RnasAgananEE Ago| i e s%sse zazan dsss m 3aEBNm ERSNSm uIEAS [Fi RRAARARANAER , WRANSERNCRRNESER HFLG nn : amma DsHl msssinnznassians i R$39O323R33R334E050E08 109388 I gFiEd opams wasn GSE Hi i i FEL Pp 0 ome amas aE mm cosssannn Ro LR i i i : S838 FARRAR | g i i Ey EREAAZERRARARARRERE Dipl Bases seman 5 C0937 Por i py c |FiTl i ReRRERRRRR" 3833883882 WBORRETE -- RERR-- IER 3398 sooEmIER Fl sARRRARE BREE naa i CED mean mem man i Ef! Fl gmaeaaaass GREET IRRAREER (i:EE8L p . ssngnzs & r hHF saan ones i iP|oFl covemnamens meen i LF crmsmmena BERS EE g oi 3 GEERASREIARRERERAZAS p GSIAERES '| sssssnsmonesnnnians aman CH mEanRRRE mann 1303838 {IE io id ii u | ii| I 2RRRASANEERY -- NERRARRR-- ARRRRRRR 2 i EE Hl essoesmemasn AaRdGSIRISRSARER gi i | [REE iy i 2gagnzngneag 33R348REsREARAEE C0589 Fi i"0:- Foun ween we PE em seman mem Po r WR Rl Re s EER 11i PEF mm OWEEE WR I semen mE i i i Fi BEE SREIIMTIIIRINNANE = PEL i fg : sE8% ERSASRIASBEREEAZNANE wREaE zeae | smsmenmuanenenas | i {rem i SHBSRIRANERNEEE PPHEBE EEEEREREER Coseo Foi BE iE 1H 23 EL o 2 22 2! i He 2 EE i i Eo |EeB sgsoepssszsaegnssnrneisnennns | S3S3R8R33G3e3SRRIERIRAEY | Fi Gensassssanaen | RANTING Pah 388i engasEee BEEBE oon gi s EL 8 ire 2 HEfq ssn smn ie I PFDs samme sen EF pF p SIE geszaeess | E 5 3 sssmnnazasass ssn i i3 3 3 i; i 333323333855502 i 333333532 10592 HE Bd VHC ERE RR ae HrEg ifihd : i igioVB Hi t30o% see aumssesEng smammmuEs REARMBNRRINREEA Pe FEL anne seeneanReR bar Fame {BR 333%insaRE sisssasassneny BBBESTIENELIE 30934 Po or Po PihE SPHEEER 18: ygi"o B: LE i i | ; 3523RAZERARNRE AINSRRANRARARAS a basse g 109935 Covance 6329-225 re APPENDIX 4 Individual Food Consumption Data (g) Individual Test Material Consumption Data (mg/kg/day) 10596 201 E P# oL ogrF i i PI madi smmmmer mm sme mms mesa PE io Eb msds asssdenss aml fee 23338 SREARES 3 Eid PE Bol oemsmnmser ozs sass P1OR5IF comms oma sam]: 3 1g | : g | El Bio DF HEE eS ssamanealanazanansds cesses saezages wee 8 LVFE sesssssnedeans ssn FL smemnsssseens J sansa C| 3H8; m zagza ssRaa sasfa mIocn azas H SRGNE SERR C0927 . : Bi se sams smEemIERE OR Por Co . So des mem | Ain PED a mem mmm 3 iPioheiditbl OoRp sme wmmmm 8 . oR i : i so mam omEsEE J : i r selosamena LE Tir ems i SnsESRERRSEREAS meses i 2 i : ERGEREARREEE : 233REZIRARINIAL |i v2 ! :4 sErE5A3S6E3A3ARR9A5R3A8Y :3 2M3A2R2R3R3RaAERnS3EaRARRLIEEER 10593 Por E gooL g F me spasm omm DB em ssmnssnan ams ; Fl ome meses aE Bo o3 0 Eman momen uERmE Bi SEL 3 BL i san ARIaERRER ERR JHE 5 iBgHib| am ames wes 1i3i1i7B]i 3u33n8 3SGoRIuRRnRGsSEeARRSaORnENeREsS 1 [I i TE mm sssssne8lensanen ! i SEE p BSEAREIORASERSNEEN PFEoE ses i ssmemneseasnassa i 281 gsi BELETEITEEIoITRnnee cn0899 og eT go bd PF alenl ddelnli en | E magma aie ees BLBEE Ea! i a & & :5 gPpr endEedenole mele i ILE :e i Ur T leadedBEfeElls |PoCE lms bFE ale UE omnia Beeld RAE RE onrenganinanazad 3 Tasendns LCiHeC r Em ns a | aanin 004090 ETE # - Bl 38 233% GGIARRIARE g how fem bealnl | Fos ale male BF LLd adEF e GFTaElElEE: i TH ds sands H$E i TLIC ag 5 BElEelie a : ale ; delle g ig i ;3 aagEE EEAREEA i il i i EAERAAARAEAY spasiiaantann BoE Agi| iFl SGcReGdEoRsRnNaOnNnEnLsN sasRaRzRaglRzmannoaizneannaesns Ui Sosemnenzes 1 oonldelinses | r iamsesaanee] i feeadamnennions DarEt Ferenamns o sustmessaenssannis EH 11001 Foro iio B.lo8f8 ssesasemaseianz smmlpn PB alk mmm ssh Dil ames sh Bo ELE gE 0TEER sal8 a mmm PEE all seas am EEL B h leo8 semen om 8 ig 3od7 ed ET UI EE apseEgneeemstsauanfsmniesaEnRiAnEinasd |P Bal EWEE Eg std E emededeadnen Eee | smelemmanen VH.C foEeEsC i 3R39E35s35a323n40h8 5a83a53n8 C1002 0fo tPE5 . HPdy: Pa | 1 LE senseless mnomeeenEEns - ElComdlnmansldss $as7ssmamsness E bln ssmammmantens Di 2H3 C28H57m38p88m8mntC GuneaEl Foi hi SLEEL th dE 2 iE PE |Pokl Fl aainEsAITERNERE |p EEE BRNEZEECR zzezsins ! g li :33z 4: sasEsEggsAlReNsRnEzRnNzAzRaEg :4 RSA2SESCRLERSARSR PaRbCs bmn | name e 11001 Poi PPEaL (I jdiE d -g Tg iH Pl | #LLe e sass sm8.e 88.8 aLom. Bo Re I i & |g SERED REIMERSRANESY = H 4 po -- S 28 f HED 2 1thae HBoiol, { Fo chelels Bo I ma emse : Fl i sheskpmss | smeslinialonsy Ua|e 391 sgurnanzsasaaanasass | SsEoEnEnEaEmEnSGaSnsneeayd {BB BEREREIREY cocasscooEcisEs C11008 Fi i CB pPhEe "8 ER H|ien8 : Bl t yeep Ei : vamvanhh i | r smilie mmm il sabEE ! PPE pl mmeenisalssBhe mmm Del mmeseBBen moe RAEI Ep PoErlip smeengBaglfo mas iq iPhiiPlH p selprfs mn i id poodle wenn 8 PE Hi P 3 iELE L cSessassscagguaeasnseanss F meEeRn i 4 IRIE es BF Bl ] pa : sp | 3 3 3%333332323333333 : 233m HE 3 DIH Raa HNES . 11008 i | Ee oie omen PT 5585 ' I Cpl offen sanshd iek Dp offen oon dEE LEE sh PjPoEgrpl 4PioPpU emlm e nTaim f sonasatles moonshess ifi Dele mile son 3 i i PT mms BEES E i El mmm e mmm & ? ARNNaNNANNaN TRESS pd Dp mm smn C} gedl J mn i| PO CHAU ERRREE Rania 11909 iFo lp oan mi l mf Fel PF] mm Fg U fene Rispom HpE ple iE un lla Pip mm omni fal Possum i i i PT i mmm f iid Leos pemgelifoe 8 { i| ; g Eo oEEbE 3 ii ix3! pli om ppm TR PEE : :fi| igF, mm mFoeFoeFcIaTIIISN I RCplEdEoCodFEn E e a na Ly sees smzssszasmanznseans nNi0290 # Lp savin [A piss EH ! : Cpi mmenBee POLE EB games gs naan amos l{gpel FY FEfle : gl ezorerirafnifflioengseg wsoameenas Bom i smpmenifBiIfEeEsEoese souaarmnegenn Hn Php weeds son ii ! HI H i Del sri se 5 HERE gE 3 ii | iFH4 Lp ii i 8 5 8855 mmm 88% smns Lrg mp p amg : Hy i rp i FE Cap smn | ssn 11021  Fo0goip : PLE p omldl BTaemm ed LPopl FPialilty PE r2I iGid ii: ggiel iid pl PEL EEL nTiemeneE of Tom TmoaEomEfEfmEEEn.I.I.S oH Tom rennnee 18: i 4i Vp T sia i El pg e ETTr [L3a | ssn 5 cats c$eE TE ig 1Poii . tBag PHD PTOHLIF SEdls vBeInoRmTs EL lel sme mm i wef po ii Tg wy 1 f 11013 CF i: TE Pal 18 i iTEdD BE PEHao I Ppl aElEeE sonnnnnneshdiEEE Toit Tom CDegEpIEHmTsam : smartpitwh bylpl elif asn omaHlh PTE ae : Dn i BHi mBEm EaEEEEm: i GpEnIR Ce For i2 FE PEL RB P iiEdD 3PiEEl PE 2 E32! 8 ] PE Pp mm Bit DPorEel mmemn, FETT DE Pid {oPnliEB 5Er5e7s3s2 ooeniiifee EER sm ee n8555. 38 ETE en eB i OE sssessessas m zogmssszsn ssnnasesas 5 945 [EL i: in sg Ei:EgLi _8 3 uk! 3 PE EiEE i 4 Lp 0 mmeniBien Ea oom (pFyE emeeiBEiEen 2 mons EORerers pe iT FoR BE al i 2333EAEARAREAARInang J N1526 Eo gor I} oaElld PE PhPalo (PPaE IHfoIl FI BE cl 1a! i ii Lp nTimlte |PPFgog NOTRRaRmEmEINNfC Cp nie POE mE IEE 233302203288 8 1a9017 APPENDIX 5 Individual Clinical Hematology Data Individual Clinical Chemistry Data. Individual Clinical Urinalysis Data CovanIcMeT6-362391-42.215 191028 23 Do= oim. mmmndssie ogumameem=asseie 3 kEL po} p EcEelEl LN| s a Fer rl] . I ik Bg I $ smn i {i 1i .3 4i go! Pgaecmedsedmngns s+ sdgesesa e; hg #8 o FEsRRaERa OLRi E I EE Ci N SInamdeds nee nEEAMMRMRG G00 heea CADE  i Fi ARZAIAARRINR 3 [RARZZIANR 3 3 i wg FER 2 EE TUE bm bn rEg oe mE i i i : HER : EEE Eo! mameme obe mam 2Po TEE &. CNL50 oEER ) H:= + a8a anennnnenn Sg B iiyH gl vemos E"E| C i EFe regen FwEeT) Pragg y | mgm oF Loman gop f i 2 SR3330883% 3d. BBRRREEES C1152 ii . i | vervengnee ody erevconnnn wig : g| IE sesame 37% sazsIsRssr Iva 5 i oi emeeemesnn aly ngeecgpeng edz Togs $i (IEE ewvevrese of reeves of _ ii, 8 gy, verre lr eer fn 8 sh id i HI J PO BRE EE i Ei gg;l 8 ea emneaconn oFfEg n5e3aSa3a3eEnScEeRe oAfFg i Bi, ae i 0 onneencn 03 nema ETT cio F 8 : LB Pod i SiH i . PEaE . SP oH EEL : E PL . C1193 i 5 8 Le , shit : gfhoimg,ef i . EEE i 3PogB FE Ea iidg i 38 3 svsiessiss ageIEEeses : [HERES I han Cao 5 gl sddndodddd 27 Azaguandds AC sep EERE, mmm Pm EE Ee PEogEm Big8 oonsiemmamssasaes sfng z Boasnsanancs dia = Had hmm ee lama " IE 5FplGF 88)Li _ wodneumaamdanmaadnds 4c7de adaosndoamdoandaand o2 f CPd oy] rm onbi| mame o:b 2 Hii i gi sgazassang gggzesssss A915 8i x : l HOSEN BC EEANEREEE BO i ti Aefndnefes 8 gfsgasssis 1 : h = nRssassRas | g sffgagddan @ fog 1 Pomme 2 1 npn ot pHEgE By vonemmeR og mmm _ B3o.B8 | P oceananenrennods d aanvsmnovnens <3 a i i 18] a SRE I EE Pay aFzEasRssRssEia EsEs3eRnzaEeas ofa " . C1526 3 | emcsescses oy essseasses oy i i gi mms og mmeeennnne og gi . . : 1 | Soevanmane wrg mveamemeee vsig 3 Bpg i Po| E | FUoTTTTTT ont ; eemvewwezzocng ; i 3 s wl i" a1eaqeeqee of tevmeerie ofg & i 4 Bennneninnn ofa B aneaannnnn og i gi i J333TAIF(WC IF [APRN IF : gl grrvanne <fg ; warmers oie ob ommnemnens 28 frnsaenen 5a Can? i; gi| oooccee og sescmceccs og . i : wesnmins wig senvpseanc sdg IRE 5 hi i vegrwenegs svg mregweegey eg dBioEgg .2 smevrrvery of. ) i iE gli , wrrreeet 8s reer <3 8 33 i Big i TEER i iE Euir B oSnAnAnSaNnSeAnArAsS vSiOnF F5 uAoGnNmEmEmAmAaSnSeS wOiFs i anmenerns wig aveseonwe ofg = v1 . E3i3g RIEMENI R f SIELn EE 383 YRIA25E32 3 5333535238 11078 8 : 5 5, i! k SEoGa,E"id :i P$3SiIeEl2d, ` sree . rrr Te # i Hyd i PEELE boa} smn sn N1529 i 8 8bo PLobsyi:t 3: SFgiiEozEEf een : een 3 Fs rEL pi : HI FOE. : B iE & 3020300238 & 2333338338 2 n1520 F : pl RE Pam i k " gp SHAT dE PEO wt ; slE pfE Egin s . BE E00 ONE i] mas et FRE i Yo, vom am ;BHog eof g 3 i naeeannsendadgagdeds gIF is iiyp swdAisdgigieaedsee vie 11031 7 Di mmmnnst mama fr bs pl g ER Py EE TET i Tarps Eamenien oa Bonen 2g tH ST H iEgl e e}i menrl emenm s 28a 5 wn vevamn ecan doeg a Tow EEEERT EET [PE og mmm ooo C3 amma o"e 5 & . . 11532 i 2 } ; i | eRTR : oi seeeszemse de ressessses oie iE 1 L i | FUDARIACER AYR WINANNRUSG 909 like . BoBC . $28 I aco9meses e8y . eoosessese of i:spaBalad4t; nwrrererm dEnyi verve: ole# ] : 5 i & wre: +58 aerieneys Ry Ig dommes fom Fug eeegmer of pppoe of & i edeadaian 4 i Srraddgnan d 1933 ;i i } . ii:el sesszamers ave Erazeemese ee 13 B gi cceessnss oF TE Lr errr ofa vivian oS 8 Top nr beeen te Bonnin a8 i 8 angmagen oF meng ad f i | reer ana . i sims oe amr of Bye 3- 11934 TT 8 ii SHiogug,y db ; PPEhyl i PERLE EL i BE! GEBRRRREAE J BRRERERRER C1535 # 5 be s hoi! t Pap diA fiet FiL 1,8, . & EEE PERE EL y uHOpLE3 sevyesens 3iHIePynnsesets 11936 iI i # sinaddd 4 drduiadds 4 i bp gm SEER PB3Lo8IEEolSLoom 2at; damn . 32 BE I } mn i i S339%uded g EEE og gp lrommo l--a--me P2:o%i.i i . * gg } oman, SIREN 11037 & : . gl 2538238387 857 gagsEasmas ga pl EmEEE ET EEE F 1 fi gel; p s ddesn ddia add a87e, gp mssodamidmadadn o2 5F%Ea5 14 %Eosscdensan ais xBovnevenens 80 -1% i ge} 3 dansaten og ddnasdiad = i: i # oF EENEG S nnn i i # : dedzaddddd 4 : cifdddidds 3 Eg)yg y sssdeneesaodmaaasnen s3af7e g aSsEseRnsIaEgoSs oSfYfs 57g i Eo . 11528 Fog i - " iIE wsagsesses xi: savssgsRs Foe i : i 3 E cinennnnny og B acennanas ogo i Bl aaeanmnee 2% famed Loir frome ote i roe oe 11929 Fog gi gi .g Nene mig . wosewniAve Beh mmnneenns "= wwnvonwnme 22 | ; gRERzsesgR $92 SESSIESHeT 8% FH | 222922R5 SR INECRSIAR 39 FE, 8 0, womens 8a envmnmens 5a & fipad { i H 3 amenaneenn 22 E aenenenn oie PEE i 5i gEai | oGaAmReAmRn0aCnEeSsE oIEfFa oGnaRsnEsEenNenEs AoE2g Eg emaananess oz vesennuaue fz Eooi oom ok fi ampnenes 119520 F |HE : Hl 11,8 BE ;A : Boghzig ; PR iBen 38 ; szsssssss 3 1951 i8x iPh Trg 1d diff . 1,8. 3 i gid BoE LE : . 5 gg! a 3333885383 33SE3IIfEE CGR i 5 og} SARSIEAATS giz saRIRneRss ade Bgl ; # BHEIVIAELAT an2 RARBLRALST |N2 2Pu5 gl SRI Fe mmm Pe . i i B xl 1 Winaa ds 3 Ra 2 . T3 E B anencrnsen os anceacnmen ods i i: 4 Es: SRRSRISEIS ITF p SAGER OF 3i iy BEE al| d oveneernen ]ofa3 neeneveses .oSg i al A ezzgmeense ag ~EEERS EERIE] U8 crmmesenns o% | opsasmnans oe BOG8E) 2g nTToTmR RT 2gg menRemRRRR 119723  - - # TT me . i ssssemesag 33s ReszIaamAs Tim ; [kI yl FETT mmm Te i ! annannannn 03g aaannnnnnn 08g I nenen nln tmmanens oi : i i BE # t Seseeeeeee t "eeeueeeea . 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PlFotEs,Eommmmn ote b: rmon oe 3 PFOEE8HuiisE oanammannen 282 i neenanens o3e HE i . i sotemmuman ave sesaasan ane Lm 0 | oom A TE N1959 # 8 ~ i 4 | Hg og mEmmm SE mam figrEaE385 slig ay momma T.R,i smu g.h i sTg EBf ,gl;& cmaneoeesm nan o%zRR cmvvemnenm ane fORz & 5E378Ti0s,i i Faenonnens wioniioanenenenen o.f i iBi i ) HsE Ri nenanannen ade 5: sasmnasgan aoe g g4al+d RaEzCeNaEmSnEaRnnRsR EaR e i sRangAsRsNganSzReRs Yoo I$5i5i SINE, ELEIEEN 1950 i i nr crm 1 ononmmness ofa smesnaaae ofa : % 4 g: E2mma)| g aWneEwoIwwRonDs aORf mmmmammmamne Re F583 EE # PEER bee on Bonin on ii, i si Teese Eg meee & i i fi RamARAghes 342 saRsssvas see PE 3 . 5 foi eesezsees zde 3 "gasERgey ER Ii C1195 4of somimumEd BR SEESEEEEN BR ir . i noemnunmn nfa sousmnawss oI Lig memsm aa mmmsm 8 EGI B ogg p SUURINENN BOR RAINE F 2080 i PLIE aor oto Bannan oa . =: i 1 SRSNARIARZ 34% BARINAIAST 39% :PiFid :i ] dy i zasusegess gic avessensss sf2 E 2} UE T , E HIRI 11062 i i5 8io t E 8 3 8i%2 o i iE 3 BE of vamnzmageanaes ata PPogi i ii i C1953 Id 8 s iio i i gi I i i Ei GE ifFi: i52 " . 8 2 3 BE gi savmmmmmmmgvess adn PE I YWo3nA ia E n, i 11964 # 8 8 i2 E 2 EAit PEO sliile 28 Fir ene oh g PE h B gi & 333333303383288 ga. i 21065 F gPog i I g=i 53 H] 3! mammeszanaanang 2% ' 3 35: sisIsssanescens i C56 "5 3 g i1 g iLE, lif . iT Bi ' 35 & spasesasessssas i C1967 pH 5 8 gId ioe HPoI ifaigE . i i Bi 3 : i xl : Eesountatssonsiingy "5 #5 SEINE i I nnn, 8. 110G8 " i5 iy :z 9 | FI] 33 := ity 5 111k FjrEg 5! i: vEgeegnedteRERe "N-t iigoi BE oi mmnananna: i 11069 ; gPod |! iFEEET scene cn iE RE i C070 i i5 8io : : : i ge : : i 0 ommemnenn of oennaan fre i . $M 3{ i ggE o: |. 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PERE oR iBi.idg BE ; 8 33 i BBiil d econ i onsen Colel. : BE O82! s 3Hi03Csamshnsnan EimniNnEeE 197g FF 8 i: i: i i i ; Jom om fmm pi d piia5 ;|e saeisisaisiaziais 3ae0. dnmdmnsisisieim 2gd & i E Ea! i SnggvgNgee of 5 Aeieggnne dg 5 : C107? = i5 85 3 2 2 3 2 SBY ee| f3 eunsemanem nes of o | senu enoun ese oOims PBEyiEizc, wi sEezEzssRssEen ,aE ammazsmssEasss ode . 5 PEE); men of | eg PHoEggo .i 4 Fn,. Hmm i 10mg | [I IE . 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Po ite. ii 8 . 5 131337 gf gh al gPooth; Li || toER gEEjIEa,E | Bh! oh PDgPhp go EsCiiERRE gWBhEEey pi oBlIyL d Lw eolu n 2 Booms o ToooHk E HL gai Eiatiln 2 iIRgCh iEeeR fTrE ed Bohai nas #0 nnd ad 3! i i3ed558 3.g520aE aELal Bia Bike ffah e dls Hale |Bhs EHe HE mer LE ' 11338 FPo oil mmmPo p Hpeaimn e |g : | gBhlt i I. :. | Bhgia, PECs : ABE IE Rag , EBEoE E E[iEsEs : PPOgLhE LaEaEt SBoodfaEsg og Fe ig Rn Baeer BED I PPloaEn TIEE E a GE iLo t ngE hgee PPPgaEREtEel fe1oami |i hIHybea HpEE philCoEgealn LE LER 3 Mi389 EE rg Chefs igEE PPDEERElER agdpEe odBllErC al RE Sh LE gait | HERE = Bi Hdd von Bel Ly pnGliE EL Cama e Gadd SPOoEh npatpeelihaen i gi i Brags dude : iFooggH leEte, S0ightt 0Cdogrtlslh EE i hss 8; 5 ZRCSL.| E | BES, Bgt08 FE ESHECE | |Eespggnileefeee]n ne ElEtN |[g IG ETHEE R Re LEaomePY | EERE | " : nase APPENDIX 7 Cell Proliferation Report CovanMceT-636291-42215 Note: This appendixofthe report contains information supplied by Pathology Associates International and has been reviewed by the Quality Assurance Unit of Pathology Associates Intemational. 137d 546 CovanMce T329S.225 Fi7z7 & A CommppanaynyPaotfhSoclioegnycAesAsepoppcliicaatteisonIsntIenrtneamtaitoionnaaalll CorCpoorrpoartaition ==3. _--ehwomwomay FINAL CELL PROLIFERATION REPORT 13-WEEK DIETARY TOXICITY STUDY WITH N-METHYL PERFLUOROOCTANESULFONAMIDO ETHANOL (N-MeFOSE, T-6314) IN RATS COVANCE STUDY NUMBER 6329-225 PREPARED FOR: 3M `TOXICOLOGY SERVICES BUILDING 220-2E-02, 3M CENTER ST. PAUL, MN 55144-1000 PREPARED BY: PATHOLOGY ASSOCIATES INTERNATIONAL 15 WORMAN'S MILL COURT, SUITEI FREDERICK, MD 21701 MAY 12, 2000 ToS rmaMnlCtourts,Sute +Frederic,Maryiand71701 (00) 663-1684 G00) 658990 FRX sa C1342 CovanIcMeT6633219-42.215 CovaFinncael CSetluldyPrNoluimfberearti6on32R9e-p2o2r5t Page2 TABLE OF CONTENTS IL CELL PROLIFERATION REPORT WL. TABLES ML. SIGNATURE PAGE IV. QUALITY ASSURANCE STATEMENT V. APPENDIXI CAGES 548 CovanIcMe 6T3-26391-42.215 CovFainncael SCetluldyPrNoulimfberearti6on32R9e-p2o2r5t Page3 CELL PROLIFERATION REPORT PERFLUOR1O3O-CWETEAKNEDSIUELTAFROYNATMOXIIDCOITEYTHSATUNDOYLW(IN-TMHeFNO-SME,ETT-H6Y31L4) IN RATS COVANCE STUDY NUMBER 6329-225 PURPOSE `The diet purposeofthe study 10ratsforat least 13 was to weeks. assess the toxicity of the test material when administered in the r`Tehpirsesreenptosrtt,hesucbemllitptreodlifbeyraPtaiotnhofliondgiyngAsssaoncdiaitnetserIpnretteamtaitoinonfoarl C(oPvAaIn)cteoStthuedystNuudymbSeporn6s3o2r,9-32M2,5 (enNt-itMleedFO*S1E3,-WTe-e6k31D4i)etIanryRatTso"x.icitAyllSatsupdeyctwsitohf Nth-eMettashkyslaPsesrofcilautoerdoowcittahnePsAuIl'fsonpaomritdioonEtohfatnhoils Psrtaucdtyicweer(eGLcPo)ndRuecgtueldatiinoncsomapslsieatncfoertwhitinh TtihteleFo21odofantdheDUrSugCAoddmeinoifstFreadteiroanl Good Laboratory Regulations, Part 58, issued December 22, 1978 (effective June 20, 1979), and with any applicable amendments. MATERIALS AND METHODS Tissue Collection for Cell Proliferation hFeipvaetoacneilmlaullasr pperrolisfeexratpieorn.grAouspecitniongroofupthse 1 through lef lateral l4obweeorfethseacrliifviecrefdrodumreiangchwoefe5k 13 rats for per group (groups specifications. T1i-s4s)uewbalsockfsixweedreansdhipppreodcetsosPedAItoforpasreacftfiionninbgloacnkd sbtyainCiongv.anFcreompeeracphrobtlooccokl, a slide was cell nuclear apnrteipgaerne(dPfCoNrAH),&Ea maevrakleuraotifocnelalnpdroilmifmeurnaotihoins.tochemical detection of proliferating Immunobistochemistry for Cell Proliferation (SSeucpteirofnrsoosftpaPrluasf,fiFni-sehemrbeSdcdieendtitfiiscs,uePsitwtesrbeurcguht, at 5 PA) um to eannsdurpelaaceddheosniopnosdiutriivenlgy charged slides processing for PCNA. SOP for Sitmamnudnaorhdisitmomcuhneomhiissttroyc)h.emBirciaelflym,etthiossduse were used to stain tissues for sections were incubated with PCNA (PAT's a monoclonal paenrtoixbioddaysteo (PACBNCAK(itD,AlKotO,#PlKot-6#100160,, PPAAIINNoo..AK1732234))amnedtrheoadgenftors rtheequdierteedctfoironthoefatvhiediann-tbiigoetni-n wanatsibloodcyalciozmepdlebxy. tPhCe NcAhreoxmpargeessnion3,i3ndcialmsinionbaelnlzpihdaisnees (ofDAthBe;ceSlligcmycaleC(hGe,m,iSc,alG,Coa.n,d M) lot w#1a8sHi8n2c0l1u)d.ed Tiinstshuee ssteacitniionngs rwuenraencdoucnotnesrissttaedinoedf swtiutdhyhteimsastuoexythlaitn.wasAnnoetgaitnicvuebactoendtrwoilthsltihdee. primary antibody. 549 C1374 CovanMcTe.6633219-42.215 `CovFainncaelSCteuldyPrNoulimfberearti6on32R9e-p2o2r5t Paged Cell Proliferation Measurements For cell proliferation evaluations, slides were first perused at low magnification (100X) to judge quality of staining, processing and sectioning, pattem of cell labeling (c.g., centrilobular or panlobular, extrahepatocellular proliferation, such as Kupffer cells, bile duct epithelium, endothelium), and histomorphologic changes. Cell proliferation was then quantified at higher `magnification (200X). The percentage of hepatocytes in S phase of the cell cycle (labeling index, LI) was determined by scoring at least 3000 hepatocytes in 10 randomly selected fields per animal. Histomorphology was further assessed by evaluating the serial H&E slide for cach animal evaluated for cell proliferation. Statistical Analysis The Student's t-test (two-sided, unequal variance) was used to test for statistical significance in LI between control and treatment groups using Microsoft Excel version 5.0. A P value of less than 0.05 was judged to be statistically significant. RESULTS Cell Proliferation ITnhdeivpiedrucaelnatnaigemaolfapnrdoligfreoruaptinmgeahenpacteollcyptreosl,ifaesradteitonerdmaitnaedarbeyprtehseenltaebedliinngSiencdtieoxn(ILI)(,Twabalse n1o)t. significantly increased in treated groups compared to that of controls in either male or female rats. The LI was significantly less than controls in female rats from groups 3and 4, Histopathology Sections from the same issue blocks used for preparation of PCNA-stained slides were stained with hematoxylin and eosin (H&E) for histopathologic evaluation to facilitate the interpretation of the immunostained slides. Individual animal findings and group summaries are presented in Appendix The results showed no changes in the liver tissue of male and female rats that would alter the interpretation ofthe PCNA staining in this study. C135 550 SUMMARY CovanIcMeT6-36239-124215 CovaFinncael SCteuldyPrNoluimfberearti6o3n2R9e-p2o2r5t Pages Ifnrotmhecopnrtersoelnt(0stpupdmy),,cellolwpdroolsiefe(r3atpipomn)w,amsimdedaossuere(d30wiptphmi)n athned lhiivgehr doofsmeal(e10a0npdpmfe)maaflteerra1t3s `weeks on study. No statistically significant increases in cell proliferation, as determined by the pPeCrfNlAuolraoboecltianngesiunldfeoxna(mLiId)oweertheanoobls.erAvletdhoinugmhalceelolr pfreolmiafleerartaitosn after was 13 weeks ofN-methyl statistically less than rceolnattreodl,s ainndmtihde dionsdeivi(d3u0alppamn)imaalndvahliugehsdwoesree(1w0i0thpinpmt)hefreamanlgees,obtsheervdeecdreiansceonwtarsolnaotnimdaolsse.- Therefore, this decrease was not considered to be biologically relevant. 376 551 CovanIcMeT6-362391-42.215 CovFainncael CSetluldyPrNoluimfbereartio6n32R9e-p2o2r5t Pages II TABLES Legend + SEM = Standard Error of the Mean 552 mMa37 Table I1-1. Cel Profferaton n Rat Liver CovSanMceT6.362301-42.215 Covance Study No. 6329-225 }T T| fmt |[FvOaNbeiing (C(onCtornotlDro-ol00spepppmmG))roup | SoMeT]x Number | index (%) Ces005 |0.248| [- 1ContO rol ppm) | w_| Cosov6 | 0227 71 (CoCnotnrt-or00lopplppm) ITMM C[os0 te | 005.18833 2 ow-3 | TW Mseaenm | 03oo1r9e cesoza | 01s Es [2lCiono3ppwo m) m WM CCoasss52275|| 00220385 [22 L(oLwow-=33ppppmm) TM"CM | eosss||ea00s 02r 6324| TR ----] = [s3(iMida -3300pp ppm) sem oost WMMT GoCs95a94r7 | 0.0.11662_ 0| 33((MMiidd-3300 opoomm) "TMM 1IGGeossoeass0| [001.0088|5| (Wd. -30pp [C MIT TWcsesasnss ||oi0.r160 [4pFeigh--100ppm) J(High 100ppm) |W TTT || |Cseesmeez00.021130| Cases |0.163 4 E (H-ri100gp) phm) TTMMTceCsesooee7s as0s09ts 4 +igh 100 pom a TMT csserr nex TT Mean 0.286 -- 1 _SEm 0.149 Page ll-1 553 11318 Table II-1. Cell Proliferation in Rat Liver CovanMcTe-6362194-2.215 Covance Study No. 6326-225 r ro | Animal | Labeling (CoCntornaD-t-o00rsppoeomGml)roup TSFeFxT~Nccuomsboaesr s|| oIn00de11ex1603 r| 7T1(C(ConoCtnrotolnr-ot0r0rpp-popp0pml) |TF __FF | | CcCoeo5ss9so8oo8r0 00|_.2o2.1198s81 Men 0208 lz Cow 3 pom) TTFTT TsCeoeomtz o02o [2[2((CCooww-=-33ppppmm)) 1 TFF_C|eCe0o0s|so0o0278e85 || [[22CCooww==33 ppoomm)) FCF[oCsoosootso || _0o20.51232 | S-- TT Tr sMeeamn [oosdmes| [3 (M-3i0ppdm) [3(M-3i0ppdm) OF Co6021 | 0.088 TF Co6023 | 0.063 _| 3(Mia-30 ppm) F Coos 00% [3[(3M(iMda--3300ppppmm)) TF TFT| g Cosposs|Lo 0082 ---- --T SMeaan 0o.o09m9 la igh foam) | __Coeo|ds oom la(High l[e4(Fiigghh - 100 ppm) 1f0oo0ppopmm)) -- | CF Co6046 TTF TF| ceCooodass || 0.128 ooiiaetz| (HiT0g0pphm) IF CoMeasn |os0o.s2a0t TTT TT sem oat Page ll2 554 11319 FCoonunCcehaTinonarzdsson fepr (Covance Study Number Fer 6329-225 TIL SIGNATURE PAGE Submitted by: Project Manager: Sandra R. Eldridge, Ph.D. - Date Project Pathologist: AO Carolyn Moyf, D.V.M., Diplomate, A.C.V.P. 555 sles Date 11350 `Covance 6329-225 Final 3CeMlTl-P6r3ol1i4f.er1ation Report Covance Study Number 6329-225 Page8 IV. QUALITY ASSURANCE STATEMENT 31351 556 EH ------------ Pathology Associates International ACompofaScnienyce ApplicationsIntemational Corporation CovanScMeT.6633291-42125 SNE AnbremeOnto Cell Proliferation Report Perfluoro1c3ta-nWeeseuklfDoineatmairdyoToExtihcaintoylS(tNud-yMewiFtOhSEN-,MTe-t6h3y1l4) in Rats Covance Study Number: 6329-225 QUALITY ASSURANCE STATEMENT AThsissurcaenlcle pUrnoiltife(rQatAiUo)n apsrorjeeqcutirheads bbyeethne iGnosopedctLeadboarnadtorayudPirtaecdticbey (tGhLeP)PArIeguQluaatliiotnys promulgated by the U.S. Food and Drug Administration (FDA). The cellproliferation report is an accurate reflectionofthe recorded data. The following table is a record ofthe inspections/audits performed and reported by the QAU. Date of Inspection 1223/98 04/03/00 04/03/00 05/12/00 Phase Inspected Microtomy Study Data and Supporting Documentation Draft Cell Proliferation Report Final Cell Proliferation Report Date Findings Reported to PAI Management/Project Manager 1212398 04/03/00 04/03/00 05/12/00 x 2 RH Karen E. Butler Quality Assurance Officer 5/12 foo Date 1352 --_-- 15 Worman's Mil out, Suit | + Frederick, 557 Maryand 21701 + G01) 653-1644 + (307) 603-3994 FAX Covance 6320-225 Final CIeMlTl-6Pr3o1l4i.f1eration Report Covance Study Number 632P9a-g2e259 APPENDIX I 11353 558 : Individual Anim Finogs CCOovVaAnMcNeTCgE.az#1n3a13ns9225 Perfuorou1c3t-aWneeesklDoineatmariydoTEothsaenolSt(udMy weitOh -,etT-h43y14) in Rate Ties Liver ANAL sEX posE Grour HISTOLOGIC FINDINGS --N0 omcoe0 setr00 r 0030000 NoSigni0 ficant F0 indings0 cons F 3 coon r : No Significant Findings No Significant Findings cons v 5 cons F 3 NoSignificant Findings No Significant Findings coma Mm : com wm 5 NNooSSiiggnniiffiiccaannttFFiinnddiinnggss ose om 3 ose Mm 3 No Significant Findings NoSignificant Findings cons wm comes wm 3 ` NNooSSiiggnniiffiiccaanntt FFiinnddiinnggss come om ` ee . NoSignificant Findings No SignificantFindings ome mM ` om ` No Significant Findings No Significant Findings Conon v . cososs s NoSignificant Findings NoSgnifcnFindings conse cosner r . ` NNooSSiiggnniiffiiccaanntt FFiinnddiinnggss conse v cosons F . | NNooSSiiggnniiffiiccaannttFFiinnddiinnggss Coser : cosoms v : NoSignificant Findings No Significant Findings cosa? v : cos v : NoSignificantFindings NoSignificant Findings ome om osm \ : NoSignificantFindings NoSignificant Findings ome om oss wm : ) NoSignificant Findings No Significant Findings oss wm : NoSignificant Findings - 31354 NmUMaBlER Cosmas cose Cosmas Cosmas cose costo coon cooon2 cooons coons cosas cosanz coon Costus IndividualAnimalFindings ConeTs 3E25I.225 COVANCE#6329.225 Perfuo1r3a:nWceiekaDniceetaurlyoTnoEssimiaindoolSt(u4d:yMwieth NF-MeOt6i3y1S4)iEnRa,ts Tiosue: Liver sex DosE GrouP HISTOLOGIC FINDINGS M 2 M 2 u 2 M 2 2 r 2 r 2 r 2 E 2 E 2 E 2 r 2 x 2 r 2 NoSignifant Findings No Significant Findings No Significant Findings NoSignificantFindings No Significant Findings No Signifan Findings No Significant Findings NoSignificant Findings NoSiniian Findings NoSignifiant Findings NoSignificantFindings No Significant Findings No SignificantFindings NoSignificant Findings 11335 560