Document O3oKvgg24kr8aJBeqx2bm82xM

COVANCE.> Sponsor St Pal TMMinnesota FINAL REPORT Study Tite 26Week Capsule Toxicity Study with Prfluoroocan Sufi Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys Author Peter Thomond, PHD Study Completion Date Jamary 11,2002 Testing Facly C5o5v0a1neKeinLsambaonraBtooruileessalrnd Madison Wisconsin 37042595 Laboratory Study Identification Counce 6320223 Sponsor Study dentiication SM Study No. T2957 Volume Ff Page1 of 1086 118811188.8.0.000000111 EExxhiibtit 18188 State of Minnesota v. 3M Co., Court File No. 27-CV-10-28862 3M_MN03278834 CovancTe 2630295-2723 COMPLIANCE STATEMENT 26-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys. All aspeocftthiss study were in accordance with the Environmental Protection Agency Good Laboratory Practice Regulations, 40 CFR 792, with the exception tha the analysis of fecal samples for urobilinogen at the Mayo Clinic were not done in compliance with Good Laboratory Practice Regulations. Study DFiAricgtroorrd PhD Covance Laboratories fe. Andrew M_Seacat, PRD. Study Monitor 3M eatin Date 2 111888111888..0.00000000222 3M_MN03278835 Comreseassasn QUALITY ASSURANCE STATEMENT ITnhci.sirnepcocrtorhdaasnbceeenwirtehvtiheeweEdnvbiyrtohnemeQnutaaliltPyrAostscutriaonncAegUenntcyof(CEoPvAa)nGcoeoLdabLoarbaotroartioersy rPerpaoirtieed Sotatnhdearsdtsu,dy40diCreFcRtor79a2n.d sTthuedyfodlilroewcitonrgmiansnpaegcetimoennstwere conducted and findings Trapection Dato Repored to "T06F9D8ate esOTRIom 0GT Tes ArlePrePphaarsaetion 01812245/9988 0182/5249988 BPordotyocWoeliRgehvtiew. 00340039/09999 0034//0132999 PrAontsoyctioclalALmaebnodrmaetonrtyReIvnsipeewction 009522731/9999 00951/22739999 PrPorottooccooll AAmmeennddmmeennttRReevviieeww 110022020099 11002275//9999 DDaattaaRReevviieeww 00321161//0000 0032/11361/0000 PPrroottooccooll AAmmeennddmmeennttRReevviieeww 00341034/0000 0043//02430000 PDraottaocRoelvAiemwendment Review 0043113//0000 005S//0351/0000 PrRoetpoorctolReAvmieenwdmentReview 110221380011 11022138/0011 PRreoptoorctolRAemvieenwdmentReview StudySDtiurdey0c8tDio0rr6ecM0ta8onraagnedment 01822549988 004310230909 00592237909 11002277959 00/1136/0000 0034203410000 00/53019/0000 1101283/0011 fh A ReQpurielsicyofAastsiuvreance Unik 4 Jen 200 Bue 3 118811888..0.00000033 3M_MN03278836 CovancTe 2630295-2723 STUDY IDENTIFICATION 26-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys. Test Material Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) Sponsor 3M Toxicology Services Building 220-26-02, 3M Center St. Paul, Minnesota. 55144-1000 Study Monitor Andrew M. Seacat, PD 3M 651.575.3161 Alternate Study Monitor MarvinT. Case, DVM, PhD. 3M Toxicology Services 651.733.5180 Study Location Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595 Study Director PeteJr.Thomford, PhD. Covance Laboratories Inc. PO Box 7545 Madison, Wisconsin 53707-7545 608.241.7207 Study Timetable Study Initiation Date In-Life (Experimenta) Start Date In-Life Termination Date Experimental Termination Date August 20, 1998 August 26, 1998 March, 2000 December21, 2001 4 11188181818.8.00.000000404.4 3M_MN03278837 CovanScMe 5T2e9.s2273 KEY PERSONNEL 26-WePeoklaCsaspisuumleSaTlotxi(cPitOySStTu-d6y2w9i5t)hiPneCryfnlouomroolocgtuasneMoSunlkfeoryisc Acid Study Director Study Toxicologist Study Coordinator Manager, Large Animal Toxicology Supervisor Dose Formulation AsMseodciicaitneeDirector, Laboratory Animal Clinical Pathologist Supervisor, Clinical Pathology Anatomic Pathologist Supervisor, Anatomic Pathology Supervisor, Anatomic Pathology Consultant Consultant Consultant Consultant Consultant PeterJ. Thomford, PHD Dale Aldridge, BS Elizabeth A. Disch, BA Sharon Dunn, LATG, AT Disie Bushee, BS, LATG DDoipnlnoamaJteC,leAmCoLnsA,MDVM, MS RDoibpelrotmaLt.e,HaAllC,VDPVM(C,linPihcaDl Pathology) Ronald Markevitch, BS, MT (ASCP) RDoibpelrotmaAt.e,LeAeCdlVe,PDVM, PhD Laurie). Schuller, BA, LAT Kimberly W. Durland, BS, HT Stephen |. Bistner, DVM DVieptelroimnaatrey,OAphCtVhaOlmologist DArn.iLSyatriocjsDnacs. Sandra R_ Eldridge, PHD DPiavtihsoiloong.yAAsCshoacrilaetsesRiNvoerrthCoCmarpoalniyna SPhaatrhoolnoAaymbArsososceiates North Carolina Division, A Charles River Company MDra.yJooeClMinciCc.onnell 5 111888111888..0.00000000555 3M_MN03278838 VOLUME 10F It CONTENTS ABSTRACT. PURPOSE REGULATORY COMPLIANCE, TEST MATERIAL, VEHICLE, AND SOLVENT VeThesitclMaeterial SoGlelvaetnitn Capsules. Reserve (Archive) Samples Disposition TAEnSiTmaAlNsIMALS AND HUSBANDRY. Idenifcation HJuusstbifaincdatriyon . Acclimation PROCEDURES. `Group Designations and Dosage Levels DDoossienAgnParloycseedsures Observation of Animals CBllionoicdalHoPramthoonleogDyetermination. SAdedriutmioPnaFlOSSeLreuvmelCoDlelteecrtmiionnation UArdidnietoannadlFFeecceaslPSFaOmpSleLsevel Determination ner Liver Biopsy Samples TAenmamtionmailcLPiavtehroBlioogpys-yTSearmmpilneasl. Sacrifice Anatomic Pathology - Recovery Sacrifice SRteactiosrtdicaRletAennatliyosnes 6 111888111888..0.00000000666 CovancSMe 5T2e9.s2273 Page nu 1 in 1 114 i1ss 1s 15 11s5 16 116 1" 17 I 118 1 221 22 22 2 22 2% 2287 3M_MN03278839 CovancSMe 5T2e9.s2273 VOLUME 10F It CONTENTS (Continued) Page RESULTS AND DISCUSSION 28 OClbisneircvaaltPiaotnhoofloAgnyimals. 2580 BPallomoidtoHyol mCoonAeOxDeitdearsmeinDaettieornm.ination 3311 Anatomic Pathology 31 CONCLUSION 5 SIGNATURES 54 REFERENCES. 35 OPHTHALMOLOGY REPORT 36 PATHOLOGY REPORT. 37 COMMENTS ON THE DATA as CODES. ABBREVIATIONS, AND UNITS. 4 `CGoedneersalfoCroCdleinsicaanldPAabtbhroelvoigatyions. aWo AAbbbbrreevviiaattiioonnss aanndd UUniittss ffoorr CClliinniiccaall HCheemmaitsotrlyo.gy 5521 Abbreviations and Units for Clinical Urinalysis 56 Codes for Anatomic Pathology 57 FIGURES 21 MMeeaann BBooddyy WWeeiigghht DDaataa ((kkge)) -- MFaelmeasl.es 59 TABLES 1 SummaryofClinical Observations - Treatment ol 32 SSuummmmaarryyooff CClliinniiccaall OObbsseerrvvaattiioonnss-- RReeccoovveerryy ((DDaayyss 316866 tthhrroouugghh 3S6615)). 665 45 SSuummmmaarryyooffOOpphhtthhaallmmiicc OObbsseerrvvaattiioonnss--TrReecaotvmeeryn.t w 76 SSuummmmaarryyooff BBooddyy WWeeiigghhttDDaattaa ((kkgg))-T- rReecaotvmeeryn.t 77 98 SSuummmmaarryyooff CClliinniiccaall HHeemmaattoollooggyy DDaattaa --DDaayy -3277 5884 1110 SSuummmmaarryyooffCClliinniiccaall HHeemmaattoollooggyy DDaattaa -- DDaayy 9621. 92% 7 111888111888..0.00000000777 3M_MN03278840 CovancTe 2630295-2723 VOLUM1OEF Il CONTENTS (Continued) Page TABLES 12 SummaryofClinical Hematology Data -Day 153 100 13 Summary ofClinical Hematology Data -Day 182 104 14 SummaryofClinical Hematology Data - Day 217 108 15 SummaryofClinical Hematology Data- Day 245 nz 16 SummaryofClinical Hematology Data -Day 274 16 17 SummaryofClinical Hematology Data - Day 322 120 18 SummaryofClinical Hematology Data - Day 364 124 19 SummaryofClinical Hematology Data -Day 456 128 20 SummaryofClinical Hematology Data - Day 546 132 21 SummaryofClinical Chemistry Data - Day -27. 136 22 SummaryofClinical Chemistry Data - Day 37 132 23 SummaryofClinical Chemistry Data - Day 62 148 24 SummaryofClinical Chemistry Data - Day91 154 25 SummaryofClinical Chemistry Data - Day 153 160 26 SummaryofClinical Chemistry Data - Day 182 166 27 SummaryofClinical Chemistry Data - Day217 2 28 SummaryofClinical Chemistry Data - Day 245 178 29. Summaryof Clinical Chemistry Data- Day 274 184 30 Summaryof Clinical Chemistry Data - Day 322 190 31 SummaryofClinical Chemistry Data - Day 364 196 32 Summaryof Clinical Chemistry Data - Day 456. 202 33 SummaryofClinical Chemistry Data - Day 46. 208 34 Summaryof Clinical Urinalysis Data- Day -27. 214 35 Summaryof Clinical Urinalysis Data - Day 37 216 36 SummaryofClinical Urinalysis Dat-a Day 62 218 37 Summaryof Clinical Urinalysis Dat-a Day 91 20 38 Summaryof Clinical Urinalysis Data - Day 153 22 39 SummaryofClinical Urinalysis Data - Day 182 24 40 SummaryofClinical Urinalysis Data - Day 217 26 41 SummaryofClinical Urinalysis Data - Day 245 28 42 SummaryofClinical Urinalysis Data-Day 274 230 43 SummaryofClinical Urinalysis Data- Day 322 32 44 SummaryofClinical Urinalysis Data - Day 364 234 45 Summary ofClinical Urinalysis Data - Day 456 236 46 SummaryofClinical Urinalysis Data- Day S46 238 47 SummaryofPalmitoy] CoA Oxidase Determinations - Terminal Sacrifice...... 240 48 SummaryofOrgan Weight Data - Terminal Sacrifice 202 49 Incidenceof Macroscopic Observation-s Terminal Sacrifice. m 50 IncidenceofMacroscopic Observations- Recovery Sacrifice 25 8 111888111888..0.00000000888 3M_MN03278841 VOLUME 1 OF Il CONTENTS (Continued) TABLES 51 IncidenceofMicroscopic Observations - Terminal Sacrifice. 52 Incidence of Microscopic Observations- Recovery Sacrifice APPENDIX | Protocol Deviations. Protocol Protocol Amendment No. 1 Protocol Protocol Amendment Amendment NNoo.. 32 Protocol Amendment No. 4 APPENDIX 2. Individual Animal Fate Data, Individual Clinical Observations. Individual Ophthalmic Observations APPENDIX 3 Individual Body Weight Data (ke). CovancTe 2630295-2723 Page 276 286 287 288 203 31 33280 34 336 337 339 81 49 497 VOLUME 11 OF Il APPENDIX 4. si Individual Clinical Hematology Data si2 Individual Clinical Chemistry Data. 614 Individual Clinical Urinalysis Data 78 APPENDIX 5 sis Individual Palmitoy] CoA Oxidase Determinations. 819 Individual Anatomic Pathology Data. 823 APPENDIX 6. 907 Anilyics Inc. Quality Assurance Statements 908 Summary and Individual Blood Hormone Determination. 17 APPENDIX 7. 963 Cell Proliferation Report 964 APPENDIX . o17 Electron Microscopic EvaluationofLiver in Cynomolgus Monkeys. 978 0 111888111888..0.00000000999 3M_MN03278842 VOLUME 11 OF Il CONTENTS (Continued) APPENDIX 9. Urobilinogen Analysis Report APPENDIX 10 Dose Confirmation Analysis Report `Compound Stability Report Analytical Laboratory Report Certificate of Analysis Quality Assurance Statement CovancTe 2630295-2723 Page 1069 1070 1072 1073 1078 1080 1083 1086 10 111888111888..0.00000111000 3M_MN03278843 ABSTRACT CovancSMe 5T2e9.s2273 "The purposeofthis study was 0 assess the effect ofthe test material, Perfluorooctane Sulfonic Acid Potassium Salt [PFOS; T-6295 (hereafter refered to as PFOS)] on ical enzyme levels, hormones, nd other selected biochemical parameters when administered aly by oral capsule to cynomolgus monkeys for at leas 26 weeks. The treatment period was followed by an approximate S2-weck recovery period. Male and female cynomolgus monkeys were assigned to four groups (six animalssex in Groups 1,3, and 4 four animals'sex in Group 2). Each group received dose preparations containing the vehicle, lactose, or 0.03, 0.15, or 0.75 mg of PFOS/kgofbody weight/day (mufkg/day). Two animalsigroiupn Groups 1,3, and 4 were ina recovery period and were not trated for at least 52 weeks Following the 26 week treatment period. Food was provided ad ibitum, except when animals were fated. Water was provided ad iim, The animals were observed twice daily (am. and pm)for mortality and moribundity. Atleast once daily, animals were examined for abnormalities and signs of tonicity, and food consumption was assessed qualitatively. Ophthalmic examinations were done before initiationof treatment and during Weeks 26 and 52. Body weight data were recorded weekly before initiation oftreatmenot,n Day-s1 and 1, and weekly thereafer. Blood and urine samples were collected for clinical hematology, clinical Chemisty, and urinalysis tests before initiation of treatment and at specified intervals during treatment and recovery. Blood was also collected for blood hormone and PFOS level determination before, during. and afer treatment at specified intervals Feces and Viver samples were also collected at specified intervals. On Day 155 (Week 23), one male given 0.75 mk/day did, and on Day 179 (Week 26), one male given 0.75 mukg/day wassacrificed due o poor health. On Days 134 and 185 (Week 27), four animalsisex/aroup (Groups | through 3) and four females and two males (Group 4) were anesthetized, weighed, exsanguinated, and necropsied. At necropsy at the scheduled and unscheduled sacrifices, a serum sample was collected, macroscopic observations were recorded, selected organs were weighed, and selected tissues were collected and preserved. Microscopic examinations were done on tissues fiom cach animal in the control and high-dose groups and selected issues from animals i the Tow-and mid-dose groups. Tissues were also collected fo palmitoy] CoA oxidase. detemination, cel proliferation evaluation, PROS determination, and electron microscopy. Additionally, the bile was collected from the gallbladder, and the gallbladder was preserved. At the recovery sacrifice on Day 549, the remaining Group 4 un 11188811188.8.00.0000111111 3M_MN03278844 CovancSMe 6T32e9-s2273 animals were anesthetized, weighed, exsanguinated, and necropsicd. Macroscopic observations were recorded and specified tissues and serum were collected. Remaining animals in Groups 1 and3 were transferred to Covance stock or transferred 10 a follow-up study, Covance 6329-268 Atall dose levels, clinical observations, ophthalmic observations, and palmitoyl CoA oxidase determinations do not appeartobe affected by treatment with PFOS Two males given 0.75 mg/kg/day did not survive to scheduled termination. These deaths were preceded by some adverse clinical observations (constricted pupil, pale gums, abnormal feces, excessive salivation, labored respiration. dehydrated appearance, hypoactiv, ataxic, recumbent, low food consumption) and appeared to be related to the administration ofPFOS. When compared with animals given the control material, covariate adjusted mean bodyweights (CAM) for males given 0.75 ma/kg/day were, lightly lower beginning at Week 21, and for females given 0.75 mg/kg/day CAM body weights were, in general, significantly lower beginning at Week 11. Similar decreases were not seen in the other treated groups; therefore, this finding is likely test material-related. Test material-rlated effects on body weights were not apparent during recovery. Low food consumption was noted sporadically for animals in the groups given the control material and 0.03 mg/kg/day throughout treatment. The incidence of low food consumption was generally higher in the groups given 0.15 or0.75 mg/kg/day as `compared to animals given thecontrol material and appeared to be test material-related During recovery, effects on food consumption were reversed. Estradiol values were generally lower on Days 62, 91, and 182 in males given 0.75 my/ke/day, although becauseof the variation inthe data only the Day 182 value was significant. Estrone values were generally higher in alofthe treated females on Days 37, 62,and 91, although because ofthe variation in the data noneofthese values were significantly different, and this difference was not apparent on Day 182. Triiodothyronine values were notably lower in both males and females given 0.15 and 0.75 my/kg/day on Days 91 and 182. With the single exception of males given 0.15 mg/kg/day on Day 91, all values were significantly lower. During recovery were `occasional instances in which the hormone values in treated groups differed slightly from thoseof controls, but those differences were not consistentover ime or between sexes, were not clearly dose-related, and did not appear to be clearly related to the adminisiration ofthe test material Apparent differences in the sexual maturityof both males and females used in this study complicates the interpretationof the hormone data 2 111888111888..0.00000111222 3M_MIN03278845 CovancTe 2630295-2723 "The only clinical pathology parameters considered related to the test material were lower total cholesterol for animals given 0.75 mg/kg/day and lower high density lipoprotein cholesterol foranimalsgiven 0.15 or 0.75 mg/kg/day. These effects were reversed within the firs 5 and weeksof recovery, respectively. Atthe terminal sacrifice, increased liver weights, macroscopic observationsof mottled liver, hepatocellular hypertrophy, and hepatocellular vacuolation in animals given 0.75 mu/kg/day were considered related to PFOS treatment, However, the microscopic. examination liver biopsies taken during recovery did not indicate any test material-related findings and noneof the macroscopic observations made at the recovery sacrifice were considered test material-elated. There were no microscopic findings in the liver from the animals in the high-dose recovery group. This indicates thatthe hepatic test materiahrelated effects were reversible. "Treatment with PFOS by oral capsule for at least 26 weeks isgenerally well-tolerated in male and female cynomolgus monkeyast doses up (0 0.15 mg/kg/day. Clinical and pathological findings considered to be associatedwith the treatment of PFOS afer at least 26 weeksoftreatment were found to be reversible durinag S2-weck recovery period. Based on the data presented in this report, the no-observable-adverse-effect level i 0.15 mg/kg/day. Dose analyses (provided by the Sponsor), fecal analysis results (provided by the Mayo Clinic) and electron microscopy results (provided by Pathology Associates North Carolina Division, A CharlesRiver Company), were provided for inclusion in the final report. 5 111888111888..0.00000111333 3M_MN03278846. PURPOSE CovancTe 2630295-2723 "The purpose ofthis study was to assess the effectof thetest materialoncritical enzyme levels, hormones, and other selected biochemical parameters when administered daily by capsule to cynomolgus morikeys for at least 26 weeks. The treatment period was followed by an approximate S2-sweek recovery period. REGULATORY COMPLIANCE All aspects ofthis study were done in accordance with the Environmental Protection `Agency Good Laboratory Practice Regulations, 40 CER 792, with the exception that the analysisoffecal samples for urobilinogen at the Mayo Clinic were not done in compliance with Good Laboratory Practice Regulations TEST MATERIAL, VEHICLE, AND SOLVENT Test Material The test material, Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295), Lot No. 217 (expiration date: August 31, 2001),i a white to off-white powder and is 86.9% pure. It was received at Covance on September 4, 1997. The test material was stored at room temperature. Information on synthesis methods, composition, or other characteristics that define the test material is onfilewith the Sponsor. Vehicle "The vehicle was lactose (Spectrum, New Brunswick, New Jersey), Lot No. NN0192. (expiration date February 13, 1999). It was received at Covance on March 30, 1998 "The vehicle was stored at room temperature. Information on synthesis methods, purity, stability, composition, or other characteristics that define the vehicle is on file with the manufacturer. in 11188181818.8.00.000101414,4 3M_MN03278847 CovancTe 2630295-2723 Solvent "The solvent was acetone (Spectrum, Gardena, California), Lot No. LH0253, (expiration date June 2000). It was received at Covance on June 23, 1997. The solvent was stored at room temperature. Information on synthesis methods, composition, or other characteristics that define the solvent is on fle with the manufacturer. Gelatin Capsules Gelatin capsules, Size Nos. 2 (Lot No. 122932, expiration date June 12, 2003) and 4 (Lot No. 544043, expiration date August 1, 2002) were manufactured by Torpac Inc., (FairfNeiweJelrsdey,). Lot No. 122932was received at Covanceon June 12, 1998, and Lot No. 544043 was received on September 1 and November 10, 1995. The capsules were stored at room temperature. A copyofthe Certificate of Analysis provided by the manufacturer is maintained in the data Reserve (Archive) Samples Ateserve sample (1g) ofeach lot of the test material, vehicle, and each test materialactose dilution was taken and stored at room temperature. These samples were transferred to the Sponsor ater completionofthe treatment phase (see Protocol Deviations). Disposition Remaining test material will be retained at Covance for use in possible future studies. TEST ANIMALS AND HUSBANDRY Animals `Young adult to adult cynomolgus monkeys were obtained fiom Covance Research Products Inc. (Denver, Pennsylvania) on June 30, 1998. The animals weighed 2.4104.4 kg at initiationoftreatment Is 111888111888..0.00000111555 3M_MN03278848 CovancTe 2630295-2723 Identification Each animal was assignead permanent number upon arrival and identified witha collar tag before initiationoftreatment. All data for an animal are recorded under this number Justification PFOS is a known hepatic peroxisomeproliferator (PP) in therat. When exposed to a PP, nonhuman primates (such as the cynomolgus monkey) respond similarly to humans (i, Tow 10 no hepatic response) and therefore are an appropriate human surrogate. species. Husbandry AnimalRooms 251, 258, 259, and 527 were used for this study. Environmental controls for the animal rooms were set to maintain 18 to 29C,a relative humidityof30 to 70%, and a 12-hour light/12-hour dark cycle. Variations from these conditions are documented in the data and are considered to have had no effect on the outcomeof thestudy. "The animals were housed individually in suspended, stainless-steel cages Centfiedprimatediet (#8726, Harlan Teklad) was provided once or twice daily, unless otherwise specified. The lot numbers are recorded in the data. The diet i routinely analyzed by the manufacturer for nutritional componentsand environmental contaminants. Resultsofspecified nutrient and contaminant analyses are on file with Covance-Madison. Fruits or additional supplements were provided, but did not require. analysis Water was provided ad libitum. Samplesofthe water are 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 16 111888111888..0.00000111666 3M_MN03278849 CovancTe 2630295-2723 Acclimation Twenty-four males and 24femaleswere received on June 30, 1998, and acclimated in Animal Room 251 for 57 days before initiationoftreatment. In general, animals in this shipment appeared healthy. During acclimation, the animals were examined for abnormalities indicoaftheiavlteh problems. In addition, three tuberculosis tests, a physical examination, anda fecal flotation for parasites were performed on each animal PROCEDURES "This study was conducted in accordance with the Protocol dated August 20, 1998, and Protocol Amendment Nos. 12,3, and 4. The protocol, protocol amendments, and protocol deviatioanrse in Appendix | Group Designations and Dosage Levels Selectionof animals for the study was based on data collected during acclimation Animals were assigned to treatment groups usinag computerized blocking procedure designed to achieve body weightbalancewith respect to treatment group. Dose Lovel Total Material Dose Level_ Number of Animals. Group (my/kuday)" (my/kg/day) Males Females T 0 30 6 2 003 1s" 4 4 3 01s & 6 4 075 30 6 @ Tschleatcionntcraoplsgulreosupas(tGhreotuoptal1)marteecreiiavledadtmhieneiqsutievraeldenttoGarmoouupnt4of lactosien b The low-dose (Group 2) received the test material diluted with lactose T(1h4e9m9i,dw-dwo)se (Group3) and high-dose (Group4) groups received the test `material diluted withlactose (1:39, ww). d Two animals in Groups 1, 3, and 4 designated as recovery animals were treated for at least 26 weeks, then treatment was discontinued, and the animals were observed for reversibility, persistence, or delayed occurrence oftoxic effects for at least 52 weeks postireatment 7 111888111888..0.00000111777 3M_MN03278850 CovancTe 2630295-2723 Dosing Procedures Vehicle. Dose levels were based on the vehicle as supplied for Group 1. For Group | dose preparations, the specified amountoflactose was weighed, transferred into gelatin `capsules, and the top and bottom halvesofeach capsulewere joined. Capsules were prepared atleast once weekly. Test Material. The test material/lactose preparations for Groups 2 through 4 were. diluted once before initiationoftreatment; capsules were prepared atleast once weekly. A specified amountoftest material was weighed, placed intao labeled mixing container, and the appropriate volumeofacetone was added. Afr stirring manually until the test material was dissolved, the required amount of lactose was weighed and transferred to the container. The components were mixed thoroughly using a spatula. The prepared test material dilution was stirred periodicallywhileallowed to stand exposed to the air until the acetone had evaporated. Preparations were diluted to facilitate capsule preparation. `Samplesof the finished mixture for dose analyses were taken directly from the container. "The dose preparations were stored at room temperature between capsule preparations. The appropriate amount ofprepared test material was weighed and transferred into Size 2 (Days 1 through 8) or 4 (Day9s through 134) gelatin capsules and the top and bottom halvesofeach capsule werejoined. Size 4 capsules were used insteadofSize 2tobetter facilitate dose administration. Individual daily doses were based on the most recently recorded body weight, with the exceptionofdoses given on days when body weight measurements were performed; on those days, the previous body weight was used. All capsulepreparationswere stored at room temperature until used for dosing Method of Administration. Gelatin capsules were used to facilitate comparison with data fromprevious toxicology studies that usedtheoral route. Also, oral is the most likely routeofexposure in humans. Partial or intact capsules were noted in the vomitus. ofseveral animalsonoccasion; however, this s not considered to have adversely affected the resultsofthe study. "The dose preparations were administered orally in gelatin capsules once daily 7 daysisweek for at least 26 weeks (see Protocol Deviations for exceptions). 18 111888111888..0.00000111888 3M_MN03278851 CovancSMe 6T32e9-s2273 Dose Analyses Homogeneity and stability analyses were th responsibiltyofthe Sponsor Samples (approximately | geach) were taken from the top, middle, and bottomofthe test materiallactose preparations on Day -15 for homogeneity analysis. Samples collected from the middleofthe preparations were also designated for prestudy stability analysis. A set ofsamples (approximately 1 each) were taken from the low- and high-dose fest materiallactose preparations at the endof the treatment phase for test material content analysis. All samples were stored a room temperature until sent under ambient conditions to the Sponsor for analysis. Resultsofdose analyses were provided for inclusion in the final report Observationof Animals Clinical Observations. The animals were observed twice daily (a.m. and p.m)for mortality and moribundity. Animals were also observed at least once daily (a.m) for signsofpoor health or abnormal behavior, and food consumption was assessed qualitatively, only abnormal findings were recorded. Once weekly and on the day of scheduled sacrifice, each animal was observed; abnormal findings or an indication of normal was recorded (see Protocol Deviations for exceptions). Additionally, postdose observations were recorded during treatment approximately 30 to 90 minutes afer the last dose administration; only abnormal findings were recorded. Ophthalmology. Ophthalmic examinations were done on each animal before initiation oftreatment, before the scheduled terminal sacrifice during Week 26, and during Week 52 (see Protocol Deviations). The pupils were dilated with 1% Mydriacy1 and the anterior portionof the eye, optic media, and ocular fundus were examined with an indirect ophthalmoscboypae board-certified ophthalmologist Body Weights. Individual body weight data were recorded weekly before initiation of weament, on Day -1, on th first day of treatment, and weekly thereafter 1 111888111888..0.00000111999 3M_MN03278852 CovancSMe 6T32e9-s2273 Clinical Pathology Blood and urine samples were collected from cach animal once before initiation of treatment (Day -27), on Days 37, 62, 91, 153, and 182of treatment; and onDays217, 245, 274, 322, 364, 456, and 546 duringrecovery (see Protocol Deviations). Animals were fasted overnight, and urine was collected overnight on wet ce before blood sampling; water was provaidldibeitudm. Blood was collected from the femoral vein Potassium EDTA was the anticoagulant used for hematology tests no anticoagulant was used for the chemistry tests. Blood samples were collected from the animal that was. sacrificed at an unscheduled interval. Arima were bled in sequential order onDays 37, 62,and 91 and in random order at all other scheduled collections; tis is not expected to have an impact on the clinical pathology results. The following were evaluated (see Protocol Deviations for exceptions) red blood cell (erythrocyte) count Hematolodgiyfferential blood cell count hheemmaotgolcorbiitn sleygmmpehnotceydtenecuoturnotphil count ``mmeeaann ccoorrppuussccuullaarr vheomlougmleobin meoosnioncoyphtiel ccoouunntt `mean corpuscular hemoglobin basophil count pcloantecleenttcroautniton breltoiocdulcoeclyltmeocropuhnotlogy `white blood cel leukocyte) count gulruecaonsietrogen crteotaatlinpironteein gallobbuumliinn ctohtoallesbtielriorlubin wiglycerides aallkaanliinneeapmhionsopthraantsafseerase aspartate aminotransferase. `gammaglutamy lransferase Clinical Chemsiosrbtirtyol dehydrogenase creatine kinase calcium isnoodriguamnic phosphorus potassium cbihlleoraicdieds amylase lpiapnacsreeatic-specific amylase High density lipoprotein (HDL) (effectivewith collection on Day 153) 20 111888111888..0.00000222000 3M_MIN03278853 vspoelcuifmiec (graapvpirtoyximately 16 hours) ha gplruoctoeisne ketones CovancSMe 5T2e9.s2273 Urinalysbiislirubin burlooboidlinogen amipcpreoasrcaonpciec examinationofsediment Blood Hormone Determination Blood samples (approximately mL) were calected from each anima tree imes before initiationoftreatment (Days -50, 40, and -27), on Days 3, 62,91, and 182 oftreatment; and on Days 217, 245, 274, 322, 364, 456, and 546 during recovery (se Protocol Deviations). Animals were fasted overnight. Bloodwascollected fra foemomral vein without using an anticoagulant. Samples were allowed 10 clot and centrifuged within 1 hour afte collection: serum was harvested. The serum was divided into two approximately equal aliquots and sored ina freezer, st 0 maintain 60 to 80C, unl packed on dry ice and shipped to AniLytics Inc. for analoyfcosrtiissol testosterone, estradiol, estrone, estriol thyroid simulating hormone, total ifodothyronine, and total thyroxin. Beginning with the collection on Day 322 the samples were also analyzed for free iodothyronine and fee thyroxin Serum PFOS Level Determination Blood samples (approximately 2 mL) were collected from each animal once before initiationoftreatment (Day -27) during Weeks | (Day 7), 2,4, 6,8, 12, 16,20, 24, and 26, and 27 (Day 183) oftreatment; and duringWeeks 27 (Days 184, 185, and 187), 28 (Day 190),29 (Day 198), 30 (Day 204), 31 (Day 211), 35, 39,43, 47,51, 33, 57.61, 65.69,73, 77, and 79 (see Protocol Deviations). Animals werefastedovernight and water was provided adlibitum. Blood was collected from 2 femoral vein without using an anticoagulant. Samples were centrifuged within | hour afte collection and serum was Harvested. Serum samples were sored ian freezer, set to maintain 60 to 80C, unl packed on dry ice and shipped tothe Sponsor for analysis. Results will reported separately 2 11188811188.8.00.0000222111 3M_MN03278854 CovancSMe 6T32e9-s2273 Additional Serum Callection Atthe scheduled terminal necropsy and the necropsy of Animal No. 105506 (Group 4 male), blood samples (approximately 20 mL) were collected from the vena cavaat the timeof exsanguination. Samples were collected without usinang anticoagulant and centrifuged within | Hourof collection. Serum was harvested and stored ina freezer, set to maintain -60 10 80C. until packed on dry ice and shipped to the Sponsor for possible future analysis. An aliquot (0 mi) ofthe additional serum collection samples collected from all animals from Groups 1,2. 3, and 4 sacificed at the terminal necropsy were sent on dryiceby the Sponsor to AniLtics for total triiodothyronine, total thyroxin, fe triiodothyronine, and free thyroxin determinations. Additional serum samples collected at the terminal and recovery sacrifices were transferred by the Sponsor to Anilytics for analysisofesradiol, follicle stimulating hormone (FSH), and lutenizing hormone (LH) for females, and estradiol in males Results were provided for inclusion in the fina report Additionally, samples were transferred by the Sponsor to the Mayo Clinic for analysis of wiiodothyronine (T3), total thyroxin (T4), fre thyroxin (fee T4), and thyroid stimulating Hormone (TSH). Additional reserve samplesofserum were transferred for possible future anlaysis for estradiol. Any unused serum will be returned o the Sponsor. Results were provided for inclusioni the inal report Urine and Feces POS Level Determination Urine fat least 2 ml. (see Protocol Deviations) and feces (at east ) were collected overnight on the first dayofrecovery (Day 184) and on Days 189, 216, 275, 321, and 366 during recovery. Tn addition, a 24-hour sample of urine and feces was collected before the completionof 52 weeksofrecovery. Except for the first dayofrecovery, animals were not fasted. Samples were stored in a feezer set to maintain -1t0o -30C, until they were packed on dry ice and shipped tothe Sponsor. The samples willbeanalyzed for PFOS. Results will be reported separately 2 111888111888..0.00000222222 3M_MIN03278855 CovancSMe 6T32e9-s2273 Additional Fecal Samples During Week 23,a fresh fecal sample (up 10 5 2) was collected from all animals in the control and high-dose groups. Samples were collected in white polypropylene containers aftr pans were cleaned in the morning to ensure that the fecal samples were not more than 6 hours old (see Protocol Deviations). Samples were packed on dry ice and shipped tothe Mayo Clinic for analysisofurobilinogen using a routine, standardized, colormeric assay. Resultswere provided for inclusion in th final report. Interim Liver Biopsy Samples A sample of liver (approximately 1 102 g) was collected by biopsy from animals in Group 4 only during recovery [Week 57 (Day 393),on the same day as the serum PFOS. blood collection]. This sample was divided into four portions as follows. One subsample was preserved in 10% neutralbuffered formalin, embedded in paral, sectioned, stained with hematoxylin and eosin (duplicate slides were prepared), and examined microscopically. The second subsample was flash-frozen in liquid nitrogen and stored in a freezer, st to maintain -60 to -80C, unl shipped to the Sponsor for analysis (see Protocol Deviations). Resultswill be reported separately. "The third subsample was processed to block stage for electron microscopic evaluation. "The tissue blocks and a hematoxylin and eosin-stained slide for light microscopy were transferred to Pathology Associates. Tissues were processed and evaluated by electron microscopy by Pathology Associates. A report was provided by Pathology Assoicates for inclusion in the inal report "The fourth subsample was flash-frozen in liquid itrogen and sored in a freezer, set 10 maintain -60 to -80C, unl transferred 0 the Sponsor or possible future analysis. Terminal Liver Biopsy Samples A sample of liver (approximately 1 g) was collected by biopsy from all animals in Group 3 during recovery [Week 80 (Day 554), one week aftr the serum PFOS blood collection (see Protocol Deviations) This sample was flah-frozen in liquid nitrogen and stored ina freezer, set to maintain -60 to -80C, until shipped to the Sponsor for analysis. Results wil be reported separately 3 111888111888..0.00000222333 3M_MIN03278856 CovancSMe 6T32e9-s2273 Anatomic Pathology- Terminal Sacrifice Necropsy. A necropsy was done on Animal No. 105509 (Group 4 male) tht died on Day 155 (Week 23) and Animal No. 105506 (Grou4p male) that was sacrificed in a moribund condition on Day 179 (Week 26). During Week 27 (Days 184 and 185) four animals/sexgroup (Groups1 through 3) and four females and two males (Group 4) were: fasted overnight, anesthetized with ketamine and xylazine, weighed. bled for required tests, exsanguinated, and necropsied. Animals were necropsid in random order The necropsy included a macroscopic examinationof the external surfaceofthe body: all orifices: the cranial cavity: the extemal surface ofthe brain; the nasalcavity and paranasal sinuses; cervicaltissuesand organs, and the thoracic, abdominal, and pelvic cavities and viscera Organ Weights. At scheduled and unscheduled sacrifices, th followingorgans (when present) were weighed: paired organs were weighed separately. braadriennal (2) Keipdindeiydy(m2i)s (2) liver opavnacrryea(s2.) ttehsytriosi(d2)(2) with parathyroid Organ-to-body weight percentages and organ-to-brain weight ratios were calculated. Palmitoyl CoA Oxidase Determinations. Representative samples of the right lateral Tobe of fiver were collected from cach animal at the scheduled sacrifice, weighed, fash-frozen in liquid nitrogen, and stored ian freezer, set to maintain -60 to -80C, until analyzed for palmitoy CoA oxidase activity. Cell Proliferation Evaluation. Representative sampolfethse left lateral lobeofthe liver, left and right testes, and pancreas were collected and preserved in zinc formalin. A second set of issues (representative samplesof the lef lateral lobe ofthe fiver, lef and righ testes, and pancreas) preserved in formalin without zinc were also prepared. Afier fixation, samples were embedded in paraffin and shipped to Pathology Associates North Carolina Division, A Charles Riser Company (Pathology Associates) for proliferation cell nuclear antigen (PCNA) evaluation, including the examination ofslides stained with 2 11188181818.8.00.000202424.4 3M_MIN03278857 CovancSMe 6T32e9-s2273 hematoxylin and cosin (sec Protocol Deviations). Results were provided by Pathology Associates for inclusion in the final report (Appendix 7) Liver PFOS Determination. A sectionof iver (approximately 20 g) was collected from each animala the scheduled sacrifice, weighed, lash-frozen in liquid nitrogen, and stored ina freezer, st to maintain -60 to -80C, until shipped with plasma samples o the Sponsor. Results will be reported separately. Gallbladder and Bile Collection. At the scheduled terminal sacrifice for each animal, bilewas collected from the gallbladder, measured, transfered into acryovial, and fashefiozen in liquid nitrogen. The gallbladder, once emptied, was weighed, and a section (approximatel4y to mm) from the mid-portion was collected. The remaining gallbladder was placed ina cryovial and flash-frozen in liquid nitrogen. The bile and sallbladder samples were stored on dry ice unil transferred oa freczer set to maintain 6010 -80C. Samples were packed on dry ice and shipped to the Sponsor for possible ture analysis "Tissue Preservation. The followingtissues (when present)orrepresentative samples were collected and preserved in 10% neutral-buffered formalin, unless otherwise specified (see Protocol Deviations) aaodrrteanal (2) brcaeicnum cervix dcuoolodnenum eepsiodpihdaygmuiss (2) eyfeisxa[t(i2v)epfroersaelrvesadcriinfDicaevdidasnoinma'lss] femur with bone marrow (articular galslubrlfaadcdeoerfth distal end) ilheeaurmt jKeijdunneuym(2) llievseirons umnagm,mary gland mesenteric lymph node opavnacrryea(s2.) ppirtousittaatrey rectum sscailaitviacrynegrlvaend [mandibular (2)] sskeemlientaall mveussiccllee ((2t)high) sspkiinnal cord (cervical, thoracic, and spllueemnbar) 25 111888111888..0.00000222555 3M_MN03278858 sstteormnaucmhwith bone marrow testis (2) preserved in Bouin's solution thfyomruasll sacrificed animals] Comm Ni9t2s3 trhaycrhoeida 2) with parathyroid urinary bladder uvtaegriunsa Histopathology. Tissues (as appropriate) were embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined microscopically from exch animal inthe control and high-dose aroups see Protocol Deviations for exceptions). In addition, liver and thymus or al animals inthe ow and mid-dose groups and spinal cord gray mater from females inthe low- and mid-dose groups ere embedded in paraffin, sectioned. stained with hematoxylin and cosin, and examined microscopically. Othertissues, a5 appropriate, will be retained for possible future examination. Bone marrow smears from the sternum ofeach animal at scheduled and unscheduled sacrifices were prepared, tained with Wright's stan, and retainedfo possible examination Electron Microscopy. A sample ofthe iver was collected from each animal at the scheduled terminal sacrifice Tisues were processed ino blocks and, along witha hematoxylin and cosinstained lide, were shipped o Pathology Associates for analysis Results were provided for inclusion inthe final report. Anatomic Pathology - Recovery Sacrifice Termination. Remaining animals in Group | were transfered to Covance stock on Day 549 and remaining animals in Group 3 were transferred to Covance 6329-268 on Day 561. On Day $49, remaining anima in Group 4 were fased overnight, anesthetized with ketamine and xylazine, weighed, exsanguinated, and necropsed. `eTxhteernneaclrsouprsfyoacfetohfethaenibmoadlys, ianlGorroifuipce4s.itnhcelucdraendiaalmcaacvriotsycotphiecexetxearmnianlastuirofnaocfetohfethe brain; he nas cavity and paranasal sinuses; cervial tissues and organs, and the thoracic, abdominal, and pelvic cavities and viscera Liver Samples. Samplesofliver were collected from animals in Group 4 as follows. 2 118811888..0.00002266 3M_MN03278859 CovancSMe 6T32e9-s2273 One sample was preserved in 10% neutal-bulred formalin, embedded in paraffin, sectioned, sained with hematoxylin and eosin (duplicate slides were prepared), and examined microscopically. "The second sample was flash-frozen in liquid nitrogen and stored ina freezer, set to maintain -60 to -80C, unil shippedtothe Sponsor for analysis. Results will be reported separately. The third sample was processed to block stage or electron microscopic evaluation. The tissueblocksand a hematoxylin and eosin-stained side for light microscopy were transferred to Pathology Associates. Tissues were processed and evaluated by electron microscopy by Pathology Associates. A report was provided by Pathology Associates for inclusion in the inal report Additional Tissue and Serum Samples. Samplesoflung. kidney, spleen, thyroid. brain, abdominal fa, hear, (approximately 3g each, ifpossibe), and bile and serum (each as much as possible) were collected. These samples were flash-rozen in liquid nitrogen and stored ina freezer, set to maintain -60 to -80C, until shippedto the Sponsor for possible future analysis Statistical Analyses Levenc's test (Levene, 1960) was done to test for variance homogeneity. In the case of heterogeneityof variance at p.< 0.05, transformations were used to stabilize the variance. Comparison tess took variance heterogeneity into consideration One-way analofyvasriiansce [ANOVA (Winer, 19712)] was used (ifapplicable) to analyze initial body weights, organ weights, plmitoyl CoA oxidase activities, continuous clinical pathology values, and blood hormone determinations. Ifthe ANOVA was significant, Dunnetts -test(Dunnett, 1964) was used for control versus treated group comparisons. One-way analoyfscoivasriance [ANCOVA (Winer, 19711)] was used to analyze body weights, with inital body weights as thecovariate. If the ANCOVA was significant covariate-adjusted means were used for control versus trated group comparisons. 27 111888111888..0.00000222777 3M_MIN03278860 CovancTe 2630295-2723 Group comparisons (Groups2 throug4h versus Group 1) were evaluated at the 5.0%, two-tailed probability level. Only data collectedonor afer the first day of treatment were analyzed statistically. Statistical analyses were not performed on data collected during recovery. Record Retention All raw data, documentation, records, protocol, andspecimensgeneratedas a result of this study wil be archived in the storage facilitesof Covance-Madison foar periodofat least 1 year, At least one year afer the submissionofthe final report, theSponsorwill determine the final dispositionof the materials. All raw data stored on magnetic media and the protocol, study correspondence, and an original copyofthe final report will be retained by Covance-Madison Within | year afer submissionofthe final report,a ofthe aforementioned materials from the Sponsor's designees (Anil ytics Inc., 3M E. T. & , Mayo Clinic, and Pathology Associates) will be sent 0 the Sponsor (Andrew Seacat, PhD, 3M) by the Sponsor's designees. RESULTS AND DISCUSSION Observationof Animals Clinical Observations. Clinical observationsaresummarized in Tables 1, 2, and 3; individual data are presented in Appendix 2. Individual animal fate data are also presented in Appendix 2. Animal Nos. 105506 and 105509 given 0.75 mg/kg/day (Group 4 males) did not survive othe scheduled terminal sacrifice. All other animals survived to the scheduled sudy termination. No clinical observations noted in the animals that survived to the terminal sacrifice or recovery were atributable to the administrationofPFO. Animal No, 105509 (Grou4p male) died after dosing on Day 155 (Week 23). On Day 154 (Week 22) observationsofconstricted pupil in both eyes and pale gums were noted. Observations noted on Day 155 prior todosing included few, mucoid, liquid, and black-colored feces and low food consumption. Approximately 15 minutes after dosing, the animal was observed as hypoactive with labored respiration and pale gums. This 2 111888111888..0.00000222888 3M_MN03278861 CovancTe 2630295-2723 animal also appeared dehydrated and was cold 10 the touch. These observations persisted uniil approximately 30 minutes postdose when the animal was also noted as recumbent Shortly thereafter, the animal died during an examination by a laboratory animal veterinarian. An enlarged liver was detected by palpation. The causeofdeath was determined to be pulmonary necrosis with severeacute inflammation. On Day 179 (Week 26), Animal No. 105506 (Group 4 male) was sacrificed in a moribund condition. Low food consumption was noted on Day 178 (Week 26) and at the a.m. observation interval on Day 179. Approximately $ to 10 minutes postdose on Day 179, the animal had excessive salivation, labored respiration, and hypoactive and ataxic behavior. With the exceptionofexcessive salivation, these findings continued to be observed approximately 3 hours postdose. The causeofthe moribund condition was not determined. "Two additional animals had noteworthy observations during treatment. One female in the group given the control material, Animal No, 105529, was examined by a laboratory animal veterinarian on Day (Week 1)due to observationsof dehydration, thin appearance, clear oral and nasal discharge, excessive salivation, and audible respiration. "This animal was diagnosed with peumonia and treated with Lactated Ringer's solution andantibiotics. This animal had recovered by Day 14 (Week 2). Animal No. 105534 (Group 4 female) was diagnosed witha tapeworm infection during Week 23 and was treated with praziquantel. Neither infection was test materialrelated Clinical observations during recovery were typicalof laboratory primates. Ophthalmology. Ophthalmic observations are summarized in Table4s and 5; individual data are presented in Appendix 2. There were no ophthalmic observations at the Week 26 or Week 52 examinations that were test material-related. Animal No. 105520 (Group 1 female) was noted as having increased myelination ofthe right optic nerve at the baseline and Week 52 ophthalmic: examinations. Because this is a permanent, congenital condition, it was noted at the baseline and recovery examinations only and is not related to treatment with PFOS Body Weights. Body weight data are illustrated in Figures | and 2 and summarized in Tables6 and 7; individual data are presented in Appendix 3. 2 111888111888..0.00000222999 3M_MN03278862 CovancTe 2630295-2723 Covariate-adjusted mean (CAM) body weights were slightly lower in males given 0.75 mg/kg/day when compared with males given the control material beginning at Week 21; the difference was significant at Weeks 23 and 27. In females given 0.75 mg/kg/day, CAM body weights were significantly lower at Weeks 11 through 16, 19through 23, and 25 through 27 when compared with females given the control material. These decreases were likely test material-related. Differences in body weights were not apparent during the recovery period. Food Consumption. Food consumption data are summarized in Tables 1, 2, and 3 (SummaryofClinical Observations), individual data are included in the individual clinical observatioinsn Append 2. Low food consumption was noted sporadically for animals in the groups given the control material and 0.03 mg/kg/day. The incidence of low food consumption was `generally higher in the groups given 0.15 and 0.75 my/kg/day as compared to animals given the control material and appeared to be test material-related. During recovery, instancesoflow food consumption were sporadic and were similar for animals in the control and treated groups. Clinical Pathology Hematology, clinical chemistry, andurinalysisdata are summarized in Tables through 46; individual dataarepresented in Appendix 4. Administration of PFOS was associated with moderately to markedly lower total cholesterol for males and females given 0.75 mg/kg/day and high density lipoprotein cholesterol for males and females given 0.15 or 0.75 mg/kg/day. During the treatment period, the effect on total cholesterol became progressively worse over time. The effect on cholesterol was reversed within 5 weeksofthe endoftreatment, and the effect on high density lipoprotein cholesterol was reversed within 9 weeksofthe endof treatment. OF uncertain relationship to administrationof PFOS was lower total bilirubin concentration for males given 0.75 mg/ke/day and higher serum bile acid concentration for males given 0.75 my/kg/day. These potential effeocftthse test material were very mild, and neither was considered adverse. 30 111888111888..0.00000333000 3M_MN03278863 CovancTe 2630295-2723 Palmitoyl CoA Oxidase Determination Palmitoy] CoA oxidase determinations are summarized in Table 47, individual data are presented in Appendix 5 Resultsofpalmitoy] CoA oxidase determinations were not considered to be related to the test material Blood Hormone Determination `Summary and Individual Blood Hormone Data are presented in Appendix 6 Estradiol values were generally lower onDays 62, 91, and 182 in males given 0.75 my/ke/day, although becauseofthe variation in the data only the Day 152 value was significant. Estrone values were generally higher in allof the treated females on Days 37, 62,and91, although becauseof the variation in the data noneof these values were significantly different, and this difference was not apparent on Day 182. Triodothyronine values were notably lower on Days 91 and 182 in both males and females given 0.15 or 0.75 mg/kg/day. Withetsinhgle exception on Day 91 of males given 0.15 me/kg/day, all values were significantly lower. There were several other instances in which the hormone values in treated groups differed from those ofcontrols, but these differences were not consistent over time or between sexes, were not clearly dose-related, and did not appear to be related to the administrationof the test material During recovery were occasional instances in which the hormone values in treated groups differed slightly from thoseof controls, but those differences were not consistent over time or between sexes, were not clearly dose-related, and did not appear to be clearly related to the administrationofthe test material, Apparent differences in the sexual maturity ofboth males and females used in this study complicates the interpretationof the hormone data Anatomic Pathology Terminal body weights, absolute organ weights, rgan-to-body weight percentages, and organ-to-brain weight ratios are summarized in Table 48; incidencesof macroscopic and microscopic observatioarnes summarized in Tables49 through 52. Individual data are presented in Appendix 5 3 11188811188.8.00.0000333111 3M_MN03278864 CovancSMe 5T2e9.s2273 Twoof four males receiving 0.75 me/kg/day (high dose) did not survive tothe scheduled terminal sacrifice a Week 27. At the terminal sacrifice, females in the group receiving 0.75 mykgiday had increased absolute iver weight, liver-to-body weight percentages, and ivr-to-brain weight ratios. In males, lver-10-body weight percentages were increased inthe high-dose group compared to the control group. Absolute and relative liver weight increases were regarded as test mateial-related. Amon the macroscopic observations,only"mottled liver was considered test material related. "Mottled" livers were observed n the to high-dose males andi one high-dose female. Ofthe two males not surviving uni the scheduled terminal sacrifice, one had "mottled" and "large" liver Microscopic examinationofanimals sacificed at Week 27 andofthe two males sacrificed at an unscheduled interval yielded test mateial-related observations in the tiver In fouroffour high-dose males there was hepatocellular hypertrophy, occurring either centrlobullary or without regard to location within hepatic lobules. Hypertrophy, as described in the males, was observed in al high-dose females. The microscopic obserovfaheptatioceollnulasr hypertrophy were reflected i higher iverweights in the high-dose females. Hypertrophy was regarded us test materal-dependent in high-dose animals. Centrilobular or difuse hepatocellular vacuolation was also test material-dependent in High-dose animals, occurring in two of four females and twooffour males. Multifocal hepatic vacuoles were not regarded as est material-dependent because they were found in oneof four low-dose males, and ina conrol and a low-dose female. Microscopic examination offiver takena biopsy on Week 57 from the high-dose animal did not have any test material related findings. Atthe recovery sarifce, one of two males and one of two females did not have macroscopic observations. The observations inthe other animals wereofadhesions on the lungs or liver and nodules in the thoracic cavity. None ofthese observations was considered test material-related. Only livers were examined microscopically. and no test materiabelated observations were made. The hepatic vacuolation observed in terminal sacrifice and unscheduled death animals was not presen, indicating that the hepatic test materia related effects were reversible. 2 111888111888..0.00000333222 3M_MN03278865 CONCLUSION CovancSMe 5T2e9.s2273 Treatment with PROS by oral capsule for at least 26 weeks is generally well-tolerated in male and female cynomolgus monkeys at doses up 0 0.15 mykg/day. Clinical and pathological findings considered 0 be associated withh treatment of PFOS aftr at least 26 weeksof treatment were found to be reversible during a S2-weck recovery period. Based on the data presented in this report, he no-observable-adverse-ffect evel 5.0.15 mg/kg/day. Dose analysis results (rovided by the Sponsor), fecal analysis resus (provided by the Mayo Clini), and electron microscopy results (provided by Pathology Associates), were provided for inclusion in the final report 5% 111888111888..0.00000333333 3M_MN03278866 SIGNATURES Coanree632s92s25 Sh Tosbelh AdDir sh. BAft Study Coordinator Sub geLaboratories lnc. eel PCSetotuvedaryn)c.e LabDoeironafordt, orPichh nc. r[y{atav scn iy DV 4 0 118811888..0.00003344 3M_MN03278867 CovancTe 2630295-2723 REFERENCES Dunnett, C. W., "New Tables for Multiple Comparisons witha Control," Biometrics, 20:482-491 (1964). Levene, H., "Robust Tests for EqualityofVariances," ContritobPurobtabiiliotynansd Statistics, (eds)I Olkin et al, Ch. 25, pp. 278-292, Stanford University Press: Stanford, California (1960). Winer, B. J, "Design and AnalysisofSingle-Factor Experiments," Statistical Principles in Experimental Design, Second Ed., Ch. 3, pp. 149-260, McGraw-Hill: New York, NewYork (19712). Winer, B. J, "AnaolfCyovsariiansce." Statistical Principles in Experimental Design, Second Ed., Ch. 10, pp. 752-812, McGraw-Hill: New York, New York (1971b). 35 111888111888..0.00000333555 3M_MN03278868 OPHTHALMOLOGY REPORT Coanree632s92s25 Ophtanic examinations were done before ntationofresent and during Weeks 26 and 52. There were no ophthalmic observations at the Weck 26 or Week 52 neoxtaemdinaastihoanvsintghaitnwcerreaesetdestmymealtierniaatli-orneolaftetdh.e rAinghitmaopltiNco.ne1r0v5e5a2t9t(hGerboauspeli1fneemaanlde) was Week 52 ophthalmic examinations. Because this sa perma, congenital condition, it was noted athe baseline and recovery examinations only and is no elated to treatment with PROS. There werneo test tera relted observations at an ofthe examinations. SSStTTepEhCen.hUBAoeDDr,GsDUdmNTeAlNWMW eevvoe Diplomat. ACVO Veterinary Ophthalmologist RDWaeLe ponnddia (1i8f,220010/ 118811888..0.00003366 3M_MN03278869 PATHOLOGY REPORT CovancSMe 6T32e9-s2273 SUMMARY "The purpose ofthe study was toassess th effectofth test material, Perfluorooctane. Sulfonic Acid Potassium Salt (PFOS), on critical enzyme levels, hormones, and other selected biochemical parameters when administered daily by capsule to cynomolgus monkeys for at least 26 weeks. The est material was administered at dose levels of 0.03,0.15, and 0.75 mg/kg/day. One male given 0.75 mg/kg/day died on Day 155 after dose administration and one male given 0.75 mg/kg/day was sacrificed on Day 179 due. to poor health. The treatment period was followed by an approximate 52-wee recovery period. Administration of PFOS was associated with moderately to markedly lower total cholesterol for males and females given 0.75 mg/kg/day and high density lipoprotein cholesterol for males and females given 0.15 or 0.75 mg/kg/day. During the treatment period, he effect on total cholesterol became progressively worse over time. The effect on cholesterol was reversed within 5 weeks ofthe endoftreatment, and the effect on high density lipoprotein cholesterol was reversed within 9 weeks oftheend of treatment. OF uncertain relationship to administrationof PFO was lower total bilirubin concentration for males given 0.75 mg/kg/day and higher serum bile acid concentration for males given 0.75 mg/kg/day. These potential effectsofthe test material were very mild, and neither was considered adverse. "Twoof four males receiving 0.75 mg/kg/day did not survive to the scheduled terminal sacrifice at Week 27. At the terminal sacrifice, females in the group receiving 0.75 mg/kg/day had increased absolute liver weight, iver-to-body weight percentages, and iver-to-brain weigh ratios. In males, liver-1o-body weight percentages were increased in the high-dose group compared to controls. These absolute and relative liver weight increases were regarded as test material-related. Among the macroscopic observations,only "mottled liver was considered test material-related. "Mottled" livers were observed in the two high-dose males and in one high-dose female. Of the two males not surviving uni the scheduled terminal sacrifice, one had "mottled" and "large" liver, 37 111888111888..0.00000333777 3M_MIN03278870 CovancTe 2630295-2723 Microscopic examinationofanimals sacrificed at Week 27 and the two unscheduled sacrifice males yielded test material-related observations inthe fiver. In four of four high-dose males there was hepatocellular hypertrophy, occurringeither centilobullary or without regard to location within hepatic lobules. Hypertrophy, as described in the males, was also observed in four of four high-dose females. The microscopic observationsof hepatocellular hypertrophy were reflected in higher iverweightsin the high-dose females. Hypertrophy was regarded as test material-dependent in high-dose animals Centrlobular or diffuse hepatocellular vacuolation was also test material-dependent in high-dose animals, occurring in two of four females and twoof four males. Multifocal hepatic vacuoles were not regarded as test material-dependent because they were found in oneoffour low-dose males, and in a control and a low-dose female. Microscopic examinationofliver taken at biopsy on Week 57 from the high-dose animal did not have any test material-related findings For the recovery sacrifice at Week 79, only high-dose animals were necropsied. One of two males and oneof two females did not have macroscopic observations. The observations in the other animals were of adhesions on the lungs or liver and nodules in the thoracic cavity. Noneofthese observations was considered test material-related. Only livers were examined microscopically. No test material-related observations were made. The hepatic vacuolation observed in terminal sacrifice and unscheduled death `animals was not present, indicating that the hepatic test material-related effects were reversible. METHODS Four groupsofmale and female cynomolgus monkeys were administered the test materia dailyby capsule at a dose levelof 0 (control group; received capsules containing lactose), 0.03, 0.15,or0.75 mg/kgofbody weightiday (mg/ke/day). There were six animal/sex in the control group andthe groups given 0.15or0.75 mg/kg/day: two animal/sex in these groups were designated as recovery animals to be observed for approximately 26 weeks posttreatment. The recovery period was later extended an additional 26 weeks. There were four animals/sex in the group given 0.03 mg/kg/day. 38 111888111888..0.00000333888 3M_MN03278871 CovancSMe 5T2e9.s2273 One male given 0.75 mg/kg/day did on Day 155 following dose administration, and one male given 0.75 myke/day was sacrificed on Day 179 due to poor health Blood and urine were collected for hematology. clinical chemistry, and urinalysis tests once befor initiationof treatment (Week 4), on Days 37, 62,91, 153, and 182 and on Days 217, 245, 274, 322, 364, 456, and 546 (recovery animals). High density lipoprotein cholesterol was not measured at the clinical pathology intervals before Day 153, The terminal sacifice and necropsy occurred on Days 134/185; macroscopic observations were recorded, organ weights were obtained, and tissues were placed in fixative as specified by the protocol. Samples ofthe ight lateral lobe ofthe iver from each animal were frozen for analysis of palmitoyl CoA oxidase activity. Sectionofliver from each animal were processed to block fo electron microscopy and shipped to the Sponsor's designe for ultrastructural evaluation. Samplesofliver from each animal were frozen and shipped to the Sponsor for PFOS determination. The galbladders and bile from each animal were collected, frozen, and shipped 10 the Sponsor. Samples of pancreas, left and ight testes, and the left lateral lobe ofthe iver were preserved for ell proliferation evaluation by the Sponsor'sdesignee using proliferation cell nuclear antigen. Light microscopic examinations were done on collected tissues rom control animals and animals given 0.75 mkg/day. In addition, liver and thymus from all animals given 0.03 or 0.15 mg/kg/day and spinal cord gray matter from females ven 0.03 or 0.15 mg/kg/day wereexamined by light microscopy. During Week 57, liver biopsies were performed on th recovery animals tht had been given 0.75 my/ke/day. The tissue was divided into four samples. Three ofthe samples were used for light microscopic examination, ultrasiructural examination by the Sponsor's designee, and PFOS analysis by the Sponsor, respectively. The fourth sample was frozen and shipped tothe Sponsor for posible analysis. At the end of the recovery period (Week 79). he control animals were returned 10 he Covance stock colony. the animals that had been given 0.15 mg/kg/day were transferred 0 a subsequent study for the Sponsor (Covance 6329-268) following liver biopsy for PFOS alysis by the Sponsor, and theanimals that had been given 0.75 mg/kg/day were sacrificed and necropsied. At this recovery necropsy, macroscopic observations were recorded, and three samplesof liver were collectedfo ight microscopic examination, ultrastructural examinationby the Sponsor's designee, and PFOS analysis by the Sponsor, respectively 3 111888111888..0.00000333999 3M_MN03278872 CovancSMe 5T2e9.s2273 Statistically significant differences cited inthe Results and Discussion are based on comparisons between the control and treated groups RESULTS AND DISCUSSION Morality Twoof four males receiving 0.75 makg/day (high dose) of the test material did not survive to the scheduled terminal sacrifice at Week 27. One was found dead on Day 155. "The otherwas sacrificed on Day 179 due t poor health. The causeofdeath in the animal found dead was judged to be pulmonary necrosis with severe acute inflammation. Microscopically, the pulmonary lesion appeared obe an acute exacerbation ofa chronic lesion. The causeof death in the moribund animal was not determined. All other animals survived to ther scheduled sacrifices Clinical Pathology Week -4. Results ofclinical pathology tests indicated no obvious group or individual Health abnormalities Several animals, however, had mildly elevated alanine aminotransferase activities at Week 4. These animals were primarily females and were dispersed among allofth groups. By Day 37, thei alanine aminotransferase activites were no longer elevated. The transient increase in tis fiver enzymewas considered Tikly due to subclinical infection with Hepatitis A virus, a common infection in cynomolgus monkeys, and did not negatively impact evaluation ofthe test material Days 37,62,91, 153, and 182. Although there were several statistically significant or otherwise notable differences for clinical pathology test results between the control and treated animals, most ofthe differences were inconsistentover time or similar to differences present before initiation oftreatment ic. Week 4). The only differences. considered to represent effectsof the test material were lower total cholesterol for males and females given 0.75 m/ky/day and lower high density lipoprotein cholesterol for males and females given 0.15 or 0.75 mg/kg/day. The effect on total cholesterol became progressively worse over time. At Day 182, the mean total cholestrol concentrations for the males and females given 0.75 mg/kg/day were approximately 68% and 49% lower, respectively, than those fo the control males and females. The effect on high density Vipoprotein cholesterol, measured only at Days 153 and 182, was proportionately greater than that or total cholesterol At Day 182. the mean high density lipoprotein cholesterol a 111888111888..0.00000444000 3M_MN03278873 CovancTe 2630295-2723 concentrations for the males and females given 0.75 ma/kg/day were approximately 79% and 62% lower, respectively, than those for the control males and females. Ofuncertain relationship to administrationof PFOS was lower total bilirubin concentration for males given 0.75 mg/kg/day (statistically lower on Days 91, 153, `and 182) and higher serum bile acid concentration for males given 0.75 mg/kg/day (statistically higher on Day 182 only). These potential effectsof the test material were very mild, and neither was considered adverse. Statistically significant differences for other testresultswere considered incidental and unrelated to administrationof the test material. These differences were inconsistent over time or were similar to differences that existed before the initiationoftreatment Unscheduled sacrifice Animal No. 105506, a male given 0.75 mg/ke/day, was sacrificed on Day 179. The most notable findings for this animal were a moderate neutrophilic leukocytosis, mildly increased serum bile acid and globulin concentrations, and moderately to markedly decreased total cholesterol and high density lipoprotein cholesterol Days 217, 245,274, 322, 364, 456, and $46 (Recovery animals). The effect on cholesterol was reversed by Day 217, and the effect on high density lipoprotein cholesterol was reversed by Day 245. There were no other findings considered to represent persistentor delayed occurrenceoftoxic effects. Anatomic Pathology Organ Weights. At the teminal sacrifice (Week 27) females in the group receiving 0.75 ma/ka/day (high-dose) had increased absolute liver weight, liver-to-body weight percentages, and liver-to-brain weight ratios. This increase was regarded as test material-related. In females the absolute pancreas weights were higher in animals receiving 0.03 mg/kg/day (low-dose) than in those receiving 0 mg/kg/day (contro). Increased pancreatic weights were not regarded as test material-related. In males, iver-to-body weight percentages were increased in the high-dose group `compared to controls. The increase was regarded as test material-related. Left adrenal-to-body weight percentages were also increased in high dose males compared to controls. The significanceofthe increase lef adrenal weight percentage was not known. a 11188811188.8.00.0000444111 3M_MN03278874 Organ weights were not taken at the recovery sacrifice at Week 79. CovancTe 2630295-2723 Macroscopic Observations. Twenty oneof 30 animalast the terminal sacrifice had at least one macroscopic observation. Oneofthe observations was obesity, it was not regarded as pathologic. Thus, 20 animals had macroscopic observations. OFal the macroscopic observations, only "mottled" iver was considered test material-related. "Mottled liver was observed in the two high-dose males and in one high-dose female. The other observations included adhesions and dark or red foci in anyofseveral organs, Among high-dose females, each had at least one observation ofa dark or red focus. In addition, adrenal corticesofthe two high-dose males and twoof four high dose females. were recorded as dark. In one high-dose female (Animal No. 105540), the red focus in the lung correlated microscopically with hemorrhage. There were no microscopic. correlates for the other observations. Hence, dark or red foci were considered t00 non-specific to be considered test material-related. Additionally, dark and red foci were observed in animals in other dose groups. Dark adrenal cortices did not havae microscopic correlate; they, 100, were not considered test material-related. Ofthe two males not surviving until the scheduled terminal sacrifice, one did not have any macroscopic observations. The other (Animal No. 105509) had several observations OFthese observations, those in the liver were considered test material-related. The liver observations were "mottled" and"large" For the recovery sacrifice at Week 79, only high dose animals were necropsied. One of two males and oneof two females did not have macroscopic observations. The observations in the other animals wereof adhesions on the lungsorliver and nodules in the thoracic cavity. Noneofthese observations was considered test material-related. Microscopic Observations. Af the terminal sacrifice, all tissues from the control and high dose groups were examined. All tissues were examined on the two high-dose males not surviving until the termina sacrifice; the microscopic data were grouped with that of the terminal sacrifice animals. Liver, thymus, and spinalcord (females only) were `examined from animalsin the low and intermediate dose groups. In fouroffour high-dose males there was hepatocellular hypertrophy, occurringeither centrilobullary or without regard to location within hepatic lobules. Hypertrophy, as described in the males, was observed in four offourhigh-dose females. The microscopic observations of 2 111888111888..0.00000444222 3M_MN03278875 CovancSMe 6T32e9-s2273 hepatocellular hypertrophy were reflected in higher liver weights n the high-dose females. Hypertrophy was regarded as est material-dependent in high dose animals Centrilobular or diffuse hepatocellular vacuolation was also test material-dependent in High-dose animals, occurring in twooffour females and twoof four males. Multifocal hepatic vacuoles were not regarded as test material-dependent. Multifocal hepatic vacuoles were found in one offour low dose males, and in a control and a low-dose. female "Two other observations were suggestiveofpossible test material effects upon examinationofonly control and high-dose animals. When tissues were examined fiom the low and intermediate dose groups as wel, test material-dependency was not supported. In females, thymic atrophy was more pronounced in dosed animals than in controls. However, there is no clear dose-dependent pater and thus, thymic atrophy `cannot be considered test materiakdependent. Intraneuronal pigment was observed in the. spinal cord gray matter oftwo offour high dose, four of four mid-dose, three of four low-dose and oneof four control females. And thus, spinal cord pigment was considered unrelated to the test material. Microscopic examination ofliver taken at biopsy on Week 57 from the high-dose animal did not have any test material related findings Atthe recovery sacrifice, livers were examined from high-dose animals. No test material-related observations were made. The hepatic vacuolation observed in terminal sacrifice and unscheduled death animals was not presen, indicating that the hepic test material-related effects were reversible. In those animals from which all tissues were examined, the width ofthe femoral growth plates were assessed asa general indication of thematurity oftheanimals. Based on this indicator, males were less mature than females. 5 111888111888..0.00000444333 3M_MIN03278876 CouncNe i320t.2s23 f Roweri d atS, DVMZ.UPLD E (CDliinpilcoama,PabAoCloYgPy) RB DoibpleormaV tAe-.ToAaM CdVeP LFID 2Bu1e Mocomde 2001 Bw " 118811888..0.00004444 3M_MN03278877 CovancSMe 5T2e9.s2273 COMMENTS ON THE DATA dVaatraioiunsthmiosdsetuldsy.of Bcaelccauulasteordsi,ffceormenptutmeordse,lasnrdocuondmpoutfeofrr ptrroungcraatmesnwuemrbeerusseddif0feraennatllyy.ze vslailguhetslyinfrsoommethtoasbeleisn (o.t5h.e,r mteaabnss,, rstoamndairnddidveivdiuaatliloyncsa,locruliantdeidviddautaal, ovralfureos)m smtaatyisdtiifcfaelr adniaflfyesriesncdeasta. Neither the integrity no the interpretation ofthedata was affectedby these. Some tabular data were compiled using Excel Version 7.0 software The units fr the dose levels onthdata collection system (PTS) summary tables are mgkg/day. The numberof animals sted in theheading ofthe summary table for clinical ostbusdeyr.vations reflects the number of animals assigned to each group at the tatofthe "cTohnedistuimonmawrays taabbsleerfvoerdcwliintihcoaultorbesgearrvdatoiontsheinsdpieccaitfeisc tahteurneu,mbseevreoriftya,nriemvaelrssibfiolritwyh,ich a number ofncidences/animal, or the lengthof ime the condition persisted. Only observations other than normal are indicated on the summary ofclinical observations table. "iTnhdeicsapteecdifwicidtehaa"iCs"focrancobemfmoeunndtiasnt tthhee iennddivoifeduaaclhclgirniocuapl foobrseeravcahtisoexn.s tables that are "thTehesdaaryooffainisttiuadtyiowneoefktr(e2a.tmeantboisdy"Dwaeyigh1,tWreeecokrd1e.d" oBnodDyayw|eiisghtcodnastiadearreedenatWereeedkat| body weight, abody weight recorded on Dayis considered a Week 2 body weight. Differences inthe populationsize (N) on the summary ablesfo clinical and anatomic pathology are explainedon the individual data tables. Rinetseurlvtasloafpcpleianricoanl pthaethionldoigviydsuaalmpclliensiccaolllpeacttheodlofogryatnaibmleaslsfosractrhiefinceexdtascahneduunlsecdheindtuerlveadl. a"nTahleysseesr.esults are not on the summary tables and are not included in th statistical Statistical analyses were not done when there were to or fewer values for a parameter. as 111888111888..0.00000444555 3M_MN03278878 CovancTe 2630295-2723 COMMENTS ON THE DATA (continued) Bile volume is located on the individual anatomic pathology table under the heading of "absolute organ weight (srams)". The value listed for bile is not aweight and is designated with a unitofmL. `Some clinical observations discussed in the report were documented on the Request for Veterinary Services form and will be archived with the raw data, but they do not appear onthe individual clinical observations tables. 46 111888111888..0.00000444666 3M_MN03278879 `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 Uits for Clinical Urinalysis Codes for Anatomic Pathology CovanScMe 5T2e9.s2273 Note: The following lists of codes abbreviations, and units are used by Covance. Some, but not necessarily allof his information may be needed for his report. a 111888111888..0.00000444777 3M_MN03278880 General Codes and Abbreviations CovanScMe 5T2e9.s2273 WK NMean, MEAN cam SDS.TSAD.NDSATRADNDDEVD.EVs.d . NA v c UNSCHED DISPATCH T# BW AVEMTOEBXSAM 30:90 0B FLSHi fi) 2F)REE T4 TSH Week NAvuimtbhemertoifc mmeeaasnurements ina group. Covariate-adjusted mean Standard deviation Group mean is significantly different from the meoaftnhe control group (Group 1)at pNo=0va0l5ue; not applicable; not present Present `foCroemamcehntsefxound at the endofeach group Unscheduled Ombosdeurlveatoiftonhsetdraatnasfcearleedstfiroonmstyhseteimn-(i0fethe necropsy module for reference during ntehcerloapsstyn.-iOfbeseorbvsaetrivoantsioanrse duplicates of TNeurmmbienral body weight OVbesteerrivnaatriyonesxarmeicnoartdieodnduring the daily, Ombosmeirvnagtioobnsserrveactoirodnedindteurrvianlg the 30 1090 mEsitnruatdeioplostdose observation interval FLoultleincilzeisntgimhuolramtionngehormone Tritodothyronine. TForteaelthtyhryorsoixnin "Thyroid simulating hormone a 111888111888..0.00000444888 3M_MN03278881 NQss/oNs NisR SsHc H SLL s1t NuF oDBTDOT m1 RE SEEE rc PPlD [a PcAo HPBLASMO NFRO AGG uNtOpCOAG CovanScMe 5T2e9.s2273 Codes for Clinical Pathology GENERAL CODES QNuoanstaimtpylneot sufficient NFiobrrienpesattan(dssample volume not sufficient for repeat analysis) SSlaimgphtlleychleomnoeldyzed Hemolyzed SLliipgehmtilyc lipemic Setlegrhiicly icteric AUnnsicmhaeldnuoltedf/asmtoerdibund biced DAineidmadlurdiinegd bolneeedsitng TTeecchhnniiccailanejruodrgimnesnttruomernetpeoratteecthnician eror hat results in supnialclcede,pteanbtlreyodfatian,val.i,d duantaac)ceptable instrument output, sample sRpeeclolridnginegrreorr,roirn(croercreocrtdeddatien)correct data, eg. wrong number, ESnatmrpylienrrgorer(rionrcorrect keyboard entry) Platelets clumped PPllaatteelleettss dienccrreeaasseedd Platelets large CPloaltoerleitnstaerpfpeeraers waidtehqutaestte PHelianszmobdoiduiems observed NFroacatgigoruesgation NUnoabcloeagtuoladteitoenrmine a 111888111888..0.00000444999 3M_MN03278882 Comersas2s92:3 `Codes for Clinical Pathology (Continued) RESULTS NOT INCLUDED IN STATISTICAL ANALYSES SHaemmpolleyszefdrocmlianniciamlaclhseamtiwstsrcyhoerducloeagduleatvioanlamples PAcrtoitvhartoemdbipnattailmetsh(rPoTmb)ogprleaastteirnthiamnes50(sPeTcTo)ndgsrate than 10 sons Bleed times (BLETIV) greser than 30 mites CODES FOR BLOOD CELL MORPHOLOGY Tpohlekifloolclyotowsiinsg (sPaOIlK)w,aspoulssecdh0rommaecaiasu(rPOtLheY)d,eghryepeoocfhraosmoassyiaos(iHsYP(OA)N,TSaOn)d,oxic Reattapils (FOXNEUT) TaTe Nomibratwewes Pee Nope 251 SlMMioaghdkteam RTMaoordweerate 4 Not applicable Many URINE APPEARANCE Ta a e Violen A B Siw P FABwowen TE PBBleEgeen JCK eHuyr MD0 Faees m CDYDdulrokywellow HGRGereden QRBOhraenge L Clow 0 118811888..0.00005500 3M_MN03278883 Codes for Clinical Pathology (Continued) CovancTe 2630295-2723 URINE CHEMISTRY MULTISTIX STRIP Urine Glucose TT Negative + 100 mg/dL +++++ 255000mmgg//ddLL +s aries 1,000 mg/dL 22000mgdl Urine Ketone, Negative + ++ S15mmag/ddL +++ 40 mg/dL +++ <+ 80 mg/dL 160 mg/dL Urine Blood ~ Negative +++ SMmoadlelrate "++ Large Urine Urobilinogen TC onal + mgldL ++ 2mgldl +++ 4myidL +S mld (mg = approximately 1 Eich uni) Urine Bilirubin + SNmeaglaltive ++ Moderate +++ Large URINE SEDIMENT Calls, Crystals, Casts, and Comments A Amorphousuraies Q Sperm B Amorphousphosphates R Fecal contamination DC TrUirpilcaecpihdosphates TS PPiniwonrmwloavroavfaroeufmnodund E Calciumoxalate U Paraovsaifotuned F_ Calcium carbonate GGranular casts 0 Not present H Hyalinecasts 1 perfield I Cellularcasts 26-10per field J Waxy casts 311-20 perfeld K Unknowncrystal 4 >20perfield P_ Mucous threads Bacteria 0 Not present I Few 23 MMoadneyrate si 11188811188.8.00.0000555111 3M_MN03278884 ConSeM T32e0-s2273 Abbreviations and Units for Clinical Hematology TReesdtblood cell count HHeemmaotgolcorbiitn MMeeaann ccoorrppuussccuullaarr vheomlougmleobin MPleaatenlectocropuunstcular hemoglobin concentration Meanplateletvolume ARebtsiocluultoecyrteeticcouulnotcyte count HeEriynthzrboocdytyecsoeudnitmentation rate APcrtoitvhartoemdbipanrttiiamlethromboplastin ime Thrombin time FiAbcrtiivnaotgeedncoagulation ime Fibrinfbrinogen degradation products PClaotlelleatgaegngregation AlpAhdaen2o-sainntepldaispmhionsphate BMleetehdeimnoggtliombein Plasma hemoglobin MEysetliomiadt/eedrymytehlrooiidd/reartyitohroid ratio White blood cel count DifNfuerceknatitaeldbrleododblcoeoldccoeullntcount CSoergrmeecntteeddwhnieutterboplhoiold ccoelulntcount BLyamnpdhnoecuytrtoephciolunctount Monocyte count BaEsoospinhoiplhicloucnoutnt APnailsyocchyrtoomsaissia Paikilocytosis ARbBbCre(vEiGat/iUoLnoUr nX1i0)7meL) HHCGTB ((%G)IDL) MMCCHV ((FPLG)) MPLCTH(CE3(/%U)L or X10/meL) MPV (FL) RREETTIICC ((%E)3/UL or X10%imeL) HEESIRN(ZM(M%H)R) PPTTT(S(ESCE)C) TT SEC) FABCRT ((MSEGC/)DL) FDP (UG/ML) PPAAGGGGI/CAODLP ((%%)) ANTIPLAS (%) MBLEETHTIGMBE((%S)EC) PLA HGB (MG/DL) MESET RMAETIROATIO WBC (E3/UL or X10VmeL) CNORRBCW(B/C100(EW3B/CU)L or X10VimeL) N-SEG (ESor/X10UiLmc.)and % LN-YBMAPNHD((EES3//UULLororXX101'0i"mmeeLl..))aanndd%% MONO (E3/UL or X10"meL.) and % BEAOSSOIN((EE33//UULLoorrXX1100""m/emeLl..))aanndd%% ANISO (1.2.3) PPOOILKY((11.223.3)) 2 111888111888..0.00000555222 3M_MN03278885 CovancTe 2630295-2723 Abbreviatioands Units for Clinical Hematology (Continued) Test Hypochromasia Abbreviation (Units) HYPO (1.2.3) HBaoswoeplhli-lliocllsytibpopldiinegs. HBAISBTOIDPY(-(1+,21.233) 4) Toxic neutrophils TOXNEUT (-123.4) Atypical lymphocytes ATYPLYM (123.4) Aqueous `Aqueous white white bblloooodd cceellll ccoouunntt ((rlifgthteyeey)e) ~~ RL EEYYEE ((WWBBCC//UULL)) 5 111888111888..0.00000555333 3M_MN03278386 Comm Ni9t2s3 Abbreviationsand Units for Clinical Chemistry GTiensctose UrUreeaa nitrogen CTroenaatlipnrionteein GAllobbuumliinn AToltbaulmibni/ligrluobbiunlin ratio IDnidriercetctbibliirluubbiinn TChroilgeyscteerriodle TUorteaalnliitpirdosgen/reatinine ratio PHhiogshp-hdoelnispiitdyslipoprotein cholesterol LUroiwc-daecnisdity lipoprotein cholesterol Ansipanrteateamaimniontortarnasnfsefrearsaese GASolarkbmailmtioanlegdplehuhotysadpmrhyoalgtetarnsaaensseferase CLraecattaitneedekihnyadsreogenase ALimpyalsaese CPaallmciituomyl Co oxidase Toorrigzaendiccaplhciousmphors SPootdaisusmium Chloride AGbLbUre(viMaGtIiDoLn)(Units) UUNRE(AMG(MDGL/)DL) CTRPERAOTG(IMDGL/)DL) GALLBOB(G(IGD/LD)L) TABGILRIAMTGIOIDL) 1DBBIILLI((MMGGI/DDLL)) TCRHIOGL((MMGG//DDLL)) TULNIIPCIRDESA(TM(GR/ADTLI)O) PHLDILPI(DMSG/(DMLG)/DL) LUDAL(M(MGGDILD)L) AALSTTIISSGGPOTT ((IUUL/L)) GASGDLHTK (P(UHULOL)S) (IU/L) LDH (UI) AcKMYaLuAnS)E (U1) LPICPOAASOE ((IUU//GL)) CTOANMCGAD(LM)GIDL) N1AP(HMOMSO(LMIGL/D)L) CKL((MMMMOOLLIILL)) ZSMtiarngoennteiusmium Tron ZSMNRG(((MGMGIE/LQL/ooLrr oPPrPPMA)G)/DL) FE (UG/DL) st 118811888..0.00005544 3M_MN03278887 CovancSMe 6T32e9-s2273 Abbreviations and Units for Clinical Chemistry (Continued) TEexsctess ron UTnotbaoluinrodnibrionndbiinngdcianpgaccaiptaycity PPelracsemnat cihroolninseasttuerraatsieo:n Red blood cell cholinesterase Bra`iCnaucdhaotleipneusttaemreasne HiFpropnotaclacmoprtuesx. BicCaerrbcobnealtleum SSeerruumm hbielmeoagcliodbsin FAevcearlabgelefeaccaildsweight FOescmaollabliilteyacids (calculation) EAlelcbturompihonresis AAllpphhaa-21--gglloobbuulliinn `BeGtaamgmlaobgulloibnulin High-density lipoprotein LVeorwy--dleonws-idteynsliiptoyprloitpeoipnrotein Insulin CoArdtriensooclorticotropic hormone. GTrliuicoadgotohnyronine TChryeraotixnienekinase isoenzymes. BB MMBM AEbbXrEevi(aUtGiIoDnL()Units) TUIIBBCC ((UUGGIIDDLL)) CFEHESPA(TMU(M%)L) CHER (MUL) CCHAEUBD(PMUUTM(LU)MOLG) HF ICPOPROTCEAXM((UUMMOOLL//GG)) CEREBELL (UMOL/G) BICARB (MMOLIL) SSEBRA H(UGMBO(LM/GL/oDrL)MG/DL) FFBCAC W(UGGT/M(LG)) SFBMAO(M(GM/DOaSyM)/KG) EEAA-L1B((GG/IDDLL)) EEAB-E2T(AG(/DGLI)DL) EE-GHADLMM(%A) (G/DL) EE--LVDLLDL(%()%) INSULIN (UUML) CAOCRTTHI(SPOGLIM(LU)G/ML) GTSL(UNCGADGLO)N (PG/ML) T4 (UGIDL) CK-BB (UL) CCKK-MMMB ((UUILL)) 5 111888111888..0.00000555555 3M_MN03278888 CovancTe 2630295-2723 Abbreviations and Units for Clinical Urinalysis Test Urinevolume 8 hour urine volume Specific gravity Urine osmolality Quantitative urinary/cerebrospinal uid protein Urine protein excretion Urine chemistry Multistix strip Urine pH Urine protein UUrriinnee gkleutcoonsees Urine bilirubin Urine blood Urine urobilinogen Urinereducing substances Microscopic examination ofurine sediment Red blood cells per high-power field White blood cells per high-power field Epithelial cells per high-power field Bacteria per high-power field Casts per low-power field Crystals per low-power field Urine appearance Comments Abbreviation (Units) UVOL (ML) $SPHGRRVOL (ML) UOSMO (MOSMKG) QUAN PRO (MG/DL) PRO EXC (MG) uPH UUPGRLOY (MG/DL) UKET UBILI UBLOOD UROBILI URE SUB RBC (PER HPF) WBC (PER HPF) EPITH (PER HPF) BACT (PER HPF) CASTS (PER LPF) CRYSTALS (PER LPF1 or URPIENRELAPFP2P)I or URINE APP COMMENTS Miscellaneous Codes and Abbreviations for Clinical Pathology Fecal ocault blood Not applicable Fecal parasite detection Not applicable Hemolytic potential Not applicable 56 111888111888..0.00000555666 3M_MN03278889 CovancTe 2630295-2723 Codesfor Anatomic Pathology Code Definition ANIMAL DEATH CODES uT Terminal sacrifice Recovery sacrifice D Found dead M Moribund Pio Transferred to Covance stock 6 Transferred to Covance 6329-268 MACROSCOPIC CODES EX Indicates that organ weight is excluded from calculations NOT TAKEN Organ weight not taken; explanation given in necropsy notes. MISSING Organ missing or lost UNSUITABLE ~~ Organ technically unsuitable for weighing AUTOLYTIC Organ autolyzed and could not be weighed EXCLUDE Weight was taken, but was excluded from all calculations. MICROSCOPIC CODES Codes Prefacing Neoplastic Findings B- Primary, benign neoplasm M- Primary, malignant neoplasm No Metastatic neoplasm I Locally invasive neoplasm x- Other neoplasm FDoicsatlribution of Findings Diffuse Multifocal 57 111888111888..0.00000555777 3M_MN03278890 CovancTe 2630295-2723 Codes for Anatomic Pathology (Continued) Code Definition Grades for Severity or Amount ' Minimal -the least amountofchange that can be observed with the light microscope 2 Slight - less than average amountof change, but readily discernible as abnormal 3 Moderate-the average amountofchange that isexpected for a lesion 4 Moderately severe (marked) - a marked amountofchange with possible loss of function of the affected cells or organs 5 Sever-e a great amountofchange with probable lossoffunction of the affected cell o organs and frequently involves large areas of the organ bOuther Microscopic CoTdoetsa.l .3 FFiinnddiinngg pnroetspernetsent Abbreviation LF RT LN GL STOMACH, GL STOMACH, NONGL. SALIV GL, MANDIB LN, ANT MES/PANC AUDITORY SEB GI. LACRIMAL GLAND, EX HEMATO NEOPLASIA LACRIMAL GL, INT CAVITY, ABDOM SALIV GLPAROTID LN, TRACHEOBRON THYROID/PARA `TISSUE ABBREVIATIONS Definition Left Right Lymph node Gland Glandular stomach `Nonglandular Mandibular salivary gland Anterior mesenteric/pancreatic lymph node Auditory sebaceous gland Exorbital lacrimal gland Hematopoietic neoplasia Internal lacrimal gland APbadoroimdinsaallivcaarvyitgyland `Tracheobronchial lymph node Thyroid with parathyroid 58 111888111888..0.00000555888 3M_MN03278891 nFes sata icnoms Go mmmEmSRosemmoR mTOsA eET r re SAA W -- Ea i e=f 7A Te Ee esion l ahdeGh ALAA = . -- 11881188..0.00000555999 Hoan BodyWeigfhitgDuaetzs (kg) - Females. pre ERE sel oo Fa Conrrcosetzrsa . t= ---- Cme oactamsr| | Sones) | M_MN03278893 111888111888..0.00000666000 a 3M_MN03278894 111888111888..00.0000666111  3M_MN03278895 111888111888..0.00000666222 Py 3M_MN03278895 111888111888..0.00000666333 o 3M_MN03278897 11188181818.8.00.000606464.4 os 3M_MN03278898 111888111888..0.00000666555 P 3M_MN03278899 111888111888..0.00000666666 @ 3M_MN03278900 111888111888..0.00000666777 o 3M_MN03278901 111888111888..0.00000666888  3M_MN03278902 111888111888..0.00000666999 n 3M_MN03278903 111888111888..0.00000777000 p---- 1188111888..0.00077111 p-- 118811888..0.00007722 u [p-- 118811888..0.00007733 i wns 118811888..0.00007744 [p-- 118811888..0.00007755 7s 3M_MN03278909 111888111888..0.00000777666 " 3M_MN03278910 111888111888..0.00000777777 ES 3M_MN03278911 111888111888..0.00000777888 my ot3sig cas 3M_MN03278912 111888111888..0.00000777999  3M_MN03278913 111888111888..0.00000888000 5 3M_MN03278914 111888111888..00.0000888111 = 3M_MN03278915 111888111888..0.00000888222 my ot3sig cas 5 3M_MN03278916 111888111888..0.00000888333 " 3M_MN03278917 11188181818.8.00.000808484.4 Shen oF BE Ee Tr ST By TO Sn ss 3M_MN03278918 111888111888..0.00000888555 5% 3M_MN03278919 111888111888..0.00000888666 Shen oF BE Ee Tr ST By TO Sn 3M_MN03278520 111888111888..0.00000888777 MN 3M_MN03278921 111888111888..0.00000888888 Shen oF BE Ee Tr ST By TO Sn 3M_MN03278922 111888111888..0.00000888999  3M_MN03278923 111888111888..0.00000999000 Shen oF BE Ee Tr ST By TO Sn on 3M_MN03278924 111888111888..00.0000999111 2 3M_MN03278925 111888111888..0.00000999222 Shen oF BE Ee Tr ST By TO Sn % 3M_MN03278926 111888111888..0.00000999333 % 3M_MN03278927 11188181818.8.00.000909494.4 Shen oF BE Ee Tr ST By TO Sn os 3M_MN03278928 111888111888..0.00000999555 9% 3M_MN03278929 111888111888..0.00000999666 Shen oF BE Ee Tr ST By TO Sn 9 3M_MN03278930 111888111888..0.00000999777 os 3M_MN03278931 111888111888..0.00000999888 Shen oF BE Ee Tr ST By TO Sn % 3M_MN03278932 111888111888..0.00000999999 100 3M_MN03278933 111888111888..0.00111000000 Shen oF BE Ee Tr ST By TO Sn 101 3M_MN03278934 111888111888..00.0111000111 2 3M_MN03278935 111888111888..0.00111000222 Shen oF BE Ee Tr ST By TO Sn 103 3M_MN03278936 111888111888..0.00111000333 104 3M_MN03278937 11188181818.8.00.101010404,4 Shen oF BE Ee Tr ST By TO Sn 10s 3M_MN03278938 111888111888..0.00111000555 106 3M_MN03278939 111888111888..0.00111000666 Shen oF BE Ee Tr ST By TO Sn 07 3M_MN03278940 111888111888..0.00111000777 10s 3M_MN03278941 111888111888..0.00111000888 Fri) sree 111888111888..0.00111000999 bo ro) mrss 111888111888..0.00111111000 bo ro) mrss 11188811818.8.00.01111111 n 3M_MN03278945 111888111888..0.00111111222 cr ot Stem tos tn ws 3M_MNo3278945 111888111888..0.00111111333 cr of Stem wots tn ns 3M_MNo3278947 111888111888..0.00111111444 cr of Stem wots tn us 3M_MNo3278948 111888111888..0.00111111555 ne 3M_MN03278949 111888111888..0.00111111666 Fitna) srs 111888111888..0.00111111777 cr of Stem tes tn us 3M_MN03278951 111888111888..0.00111111888 cr of Stem tes tn in 3M_MNos278952 111888111888..0.00111111999 m 3M_MN03278953 111888111888..0.00111222000 Frit) mrss 11188811188.8.00.0111222111 bo yo) res 111888111888..0.00111222222 bo yo) mrss 111888111888..0.00111222333 14 3M_MN03278957 11188181818.8.00.101212424.4 A. 5. mrss 111888111888..0.00111222555 IN... mrss 111888111888..0.00111222666 cr of Stem tos ta w 3M_MNo3278960 111888111888..0.00111222777 ns 3M_MN03278961 111888111888..0.00111222888 Fran) sre: 111888111888..0.00111222999 IN. as. res 111888111888..0.00111333000 IN. as. res 11188811188.8.00.0111333111 m2 3M_MN03278965 111888111888..0.00111333222 Fr) res 111888111888..0.00111333333 cr of Stem tos ta us 3M_MNo3278967 111888111888..0.00111333444 cr of Stem tos tn us 3M_MNo3278968 111888111888..0.00111333555 16 3M_MN03278969 111888111888..0.00111333666 w 3M_MN03278970 111888111888..0.00111333777 ns 3M_MN03278971 111888111888..0.00111333888 1 3M_MN03278972 111888111888..0.00111333999 0 3M_MN03278973 111888111888..0.00111444000 1 3M_MN03278974 11188811188.8.00.0111444111 2 3M_MN03278975 111888111888..0.00111444222 5 3M_MN03278976 111888111888..0.00111444333 14 3M_MN03278977 11188181818.8.00.101414444.4 15s 3M_MN03278978 111888111888..0.00111444555 He 3M_MN03278979 111888111888..0.00111444666 w 3M_MN03278980 111888111888..0.00111444777 14s 3M_MN03278981 111888111888..0.00111444888 w 3M_MN03278962 111888111888..0.00111444999 150 3M_MN03278983 111888111888..0.00111555000 1s 3M_MN03278984 111888111888..00.0111555111 12 3M_MN03278985 111888111888..0.00111555222 15 3M_MN03278985 111888111888..0.00111555333 15 3M_MN03278967 11188181818.8.00.101515454.4 15s 3M_MN03278988 111888111888..0.00111555555 156 3M_MN03278989 111888111888..0.00111555666 15 3M_MN03278990 111888111888..0.00111555777 15s 3M_MN03278991 111888111888..0.00111555888 1 3M_MN03278992 111888111888..0.00111555999 100 3M_MN03278993 111888111888..0.00111666000 161 3M_MN03278994 111888111888..00.0111666111 1 3M_MN03278995 111888111888..0.00111666222 16 3M_MN03278995 111888111888..0.00111666333 16 3M_MN03278997 11188181818.8.00.101616464.4 16s 3M_MN03278998 111888111888..0.00111666555 166 3M_MN03278999 111888111888..0.00111666666 16 3M_MN03279000 111888111888..0.00111666777 16s 3M_MN03279001 111888111888..0.00111666888 1 3M_MN03279002 111888111888..0.00111666999 m 3M_MN03279003 111888111888..0.00111777000 m 3M_MN03279004 11188811188.8.00.0111777111 m 3M_MN03279005 111888111888..0.00111777222 m 3M_MN03279005 111888111888..0.00111777333 ms 3M_MN03279007 11188181818.8.00.101717474.4 17s 3M_MN03279008 111888111888..0.00111777555 ms 3M_MN03279009 111888111888..0.00111777666 m 3M_MN03279010 111888111888..0.00111777777 m 3M_MN03279011 111888111888..0.00111777888 TM 3M_MN03279012 111888111888..0.00111777999 0 3M_MN03279013 111888111888..0.00111888000 1s 3M_MN03279014 111888111888..00.0111888111 2 3M_MN03279015 111888111888..0.00111888222 5 3M_MN03279016 111888111888..0.00111888333 18 3M_MN03279017 11188181818.8.00.101818484.4 15s 3M_MN03279018 111888111888..0.00111888555 16 3M_MN03279019 111888111888..0.00111888666 wr 3M_MN03279020 111888111888..0.00111888777 18s 3M_MN03279021 111888111888..0.00111888888 1 3M_MN03279022 111888111888..0.00111888999 190 3M_MN03279023 111888111888..0.00111999000 1 3M_MN03279024 11188811188.8.00.0111999111 2 3M_MN03279025 111888111888..0.00111999222 103 3M_MN03279026 111888111888..0.00111999333 194 3M_MN03279027 11188181818.8.00.101919494,4 195 3M_MN03279028 111888111888..0.00111999555 196 3M_MN03279029 111888111888..0.00111999666 7 3M_MN03279030 111888111888..0.00111999777 108 3M_MN03279031 111888111888..0.00111999888 1 3M_MN03279032 111888111888..0.00111999999 20 3M_MN03279033 111888111888..0.00222000000 om 3M_MN03279034 11188811188.8.00.0222000111 m 3M_MN03279035 111888111888..0.00222000222 n 3M_MN03279036 111888111888..0.00222000333 0 3M_MN03279037 11188181818.8.00.202020404.4 205 3M_MN03279038 111888111888..0.00222000555 206 3M_MN03279039 111888111888..0.00222000666 wm 3M_MN03279040 111888111888..0.00222000777 08 3M_MN03279041 111888111888..0.00222000888 29 3M_MN03279042 111888111888..0.00222000999 210 3M_MN03279043 111888111888..0.00222111000 mn 3M_MN03279044 11188811188.8.00.0222111111 pr 3M_MN03279045 111888111888..0.00222111222 0 3M_MN03279046 111888111888..0.00222111333 pm 3M_MN03279047 11188181818.8.00.202121414.4 21s 3M_MN03279048 111888111888..0.00222111555 216 3M_MN03279049 111888111888..0.00222111666 w 3M_MN03279050 111888111888..0.00222111777 as 3M_MN03279051 111888111888..0.00222111888 2100 3M_MN03279052 111888111888..0.00222111999 =m 3M_MN03279053 111888111888..0.00222222000 =m 3M_MN03279054 11188811188.8.00.0222222111 =m 3M_MN03279055 111888111888..0.00222222222 om 3M_MN03279055 111888111888..0.00222222333 En 3M_MN03279057 11188181818.8.00.202222424.4 as 3M_MN03279058 111888111888..0.00222222555 26 3M_MN03279059 111888111888..0.00222222666 om 3M_MN03279060 111888111888..0.00222222777 EY 3M_MN03279061 111888111888..0.00222222888 = 3M_MN03279062 111888111888..0.00222222999 0 3M_MN03279063 111888111888..0.00222333000 = 3M_MN03279064 11188811188.8.00.0222333111 =m 3M_MN03279065 111888111888..0.00222333222 = 3M_MN03279065 111888111888..0.00222333333 ns 3M_MN03279067 11188181818.8.00.202323434.4 zs 3M_MN03279068 111888111888..0.00222333555 26 3M_MN03279069 111888111888..0.00222333666 m 3M_MN03279070 111888111888..0.00222333777 Py 3M_MN03279071 111888111888..0.00222333888 29 3M_MN03279072 111888111888..0.00222333999 210 3M_MN03279073 111888111888..0.00222444000 0 3M_MN03279074 11188811188.8.00.0222444111 pr 3M_MN03279075 111888111888..0.00222444222 EN 3M_MN03279076 111888111888..0.00222444333 204 3M_MN03279077 11188181818.8.00.202424444.4 21s 3M_MN03279078 111888111888..0.00222444555 216 3M_MN03279079 111888111888..0.00222444666 27 3M_MN03279080 111888111888..0.00222444777 21 3M_MN03279081 111888111888..0.00222444888 20 3M_MN03279082 111888111888..0.00222444999 20 3M_MN03279083 111888111888..0.00222555000 x 3M_MN03279084 111888111888..00.0222555111 = 3M_MN03279085 111888111888..0.00222555222 ES 3M_MN03279085 111888111888..0.00222555333 250 3M_MN03279087 11188181818.8.00.202525454.4 255 3M_MN03279088 111888111888..0.00222555555 256 3M_MN03279089 111888111888..0.00222555666 21 3M_MN03279090 111888111888..0.00222555777 2s 3M_MN03279091 111888111888..0.00222555888 2 3M_MN03279002 111888111888..0.00222555999 0 3M_MN03279003 111888111888..0.00222666000 01 3M_MN03279004 111888111888..00.0222666111 Pe 3M_MN03279095 111888111888..0.00222666222 26 3M_MN03279095 111888111888..0.00222666333 264 3M_MN03279007 11188181818.8.00.202626464.4 265 3M_MN03279098 111888111888..0.00222666555 266 3M_MN03279099 111888111888..0.00222666666 27 3M_MN03279100 111888111888..0.00222666777 268 3M_MN03279101 111888111888..0.00222666888 2 3M_MN03279102 111888111888..0.00222666999 m 3M_MN03279103 111888111888..0.00222777000 m 3M_MN03279104 111888111888..00.0222777111 m 3M_MN03279105 111888111888..0.00222777222 ns 3M_MN03279106 111888111888..0.00222777333 m 3M_MN03279107 11188181818.8.00.202727474.4 zs 3M_MN03279108 111888111888..0.00222777555 6 3M_MN03279109 111888111888..0.00222777666 m 3M_MN03279110 111888111888..0.00222777777 m 3M_MN03279111 111888111888..0.00222777888 m 3M_MN03279112 111888111888..0.00222777999 0 3M_MN03279113 111888111888..0.00222888000 = 3M_MN03279114 111888111888..00.0222888111 = 3M_MN03279115 111888111888..0.00222888222 = 3M_MN03279116 111888111888..0.00222888333 Fn 3M_MN03279117 11188181818.8.00.202828484.4 25s 3M_MN03279118 111888111888..0.00222888555 56 3M_MN03279119 111888111888..0.00222888666 APPENDIX 1 Protocol Deviations Protocol Protocol Amendment No. 1 Protocol Amendment No. 2 Protocol Amendment No. 3 Protocol Amendment No. 4 CovancTe 2630295-2723 287 111888111888..0.00222888777 3M_MN03279120 Protocol Deviations CovanScMTe 5e29s.2723 Protocol. Reserve (Archive) Samples. "These samples wil be transferred tothe Sponsor afer completionofthe nif phase." Actual Procedure. These samples were shipped tothe Sponsor afer the dosing phase was competed, which was prior to the endof the inlife phase Protocol. DosingProcedures. MeotfAdmhinisotratdion. "Obry gaelatlincalpsulyes, daily(7 daysfveek) for at least 26 weeks" Actual Procedure. OnDay3, Animal Nos. 105520 (Group |male)and 105529 (Group | female) did not receivae dose administration due to bleeding and iation in the throat Dosing was discontinued for Animal No. 05530 (Group | female) from Days 10 through 14 due to. sore inside its mouth Protocol. ObservoafAtniimaolsn. Clinical Observations. "Once weecakchlanyim,al will be observed, abnormal findings or an indication that the animal was norma will be recorded" Actual Procedure. During the course ofthe study, several animalsdid not have a weekly observationof normalof abnormal recorded on various scheduled days. Protocol. ObservoafAtniimaolsn. Ophthalmic Examinations. Before initiationof treatment and before each scheduled sacrifice: the anterior potion ofthe ye, optic media and ocular fundus wil be examined using an indirect ophthalmoscope bya boardcertified ophthalmologist. Actual Procedure. An ophthalmic examination was completed during Week 2 instead ofprior tothe recovery sacrifice during Week 79, 28 111888111888..0.00222888888 3M_MN03279121 Protocol Deviations (Continued) CovancTe 2630295-2723 Protocol. Clinical Pathology. Frequency. Scheduled Collections. "Once before initiationof treatment; after at least 30, 60, 90, 150, and 180 daysoftreatment (before the daily dose); and after at least 30, 60, 90, 135, 180, 274, and 365 daysofrecovery" Actual Procedure. On Day 184, urine samples were collected for several animals; however, these samples were not required by the protocol and were discarded. `Samples were collected on Days 273 and 363ofrecovery. Protocol. Clinical Pathology. Tests. Hematology. Eleven hematological parameters were o be tested at all intervals Actual Procedure. In addition to the required hematology tests at the pretreatment interval, mean platelet volume, red blood cell distribution width, platelet distribution width, and platelterit were also inadvertently tested for. Protocol. BloodHomoneDetermination. Frequency. "Three timesbefore initiatioofn treatment; afte atleast 30, 60, 90, and 150 daysoftreatment; and afte at least 30, 60, 90, 135, 180, 274, and 365daysofrecovery." Actual Procedure. Samples were collected on Days 273 and 363ofrecovery. Protocol. Serum PFOSLevel Determination. MetofCholloectidon. "Animalswill be fasted overnight, blood (approximately 2 ml) will be collected from a femoral vein without an anticoagulant." Actual Procedure. Animals were not fasted overnightfor the scheduled collection on Day 197; however, animalswere fasted the following night and collection was done on Day 198. 280 111888111888..0.00222888999 3M_MN03279122 Protocol Deviations (Continued) CovancTe 2630295-2723 Protocol. Urine and Feces PFOS Level Determination. Methodof Collection. "Animals will not be fasted (exceptforth first dayof recovery); urine (at least 2 mL) and feces (at least 5 2) will be collected overnight" Actual Procedure. The amountofurine collected was not documented at the ime of each collection and therefore cannot be verified Protocol. Additional Fecal Samples. "The samples will be collected in the early afternoon after pans are cleaned in the morning to ensuretha they are no more than 6 hours old." Actual Procedure. On Day 160, some fecal samples were collected inthelate morning. rather than theearly afternoon Protocol. Interim Liver Biopsy Samples. "KriJs. Hansen or her alternate will be norified regarding the shipment of the samples. Actual Procedure. The phone call made to notifyKrisJ. Hansen prior to shipment of these samples was not documented and therefore cannot be verified. Protocol. Terminal Liver Biopsy Samples. "A sample of iver (approximately 1g) will be collectedby biopsy from all animals in Groups3 duringrecovery (Week 79, within 1 dayofthe serum PFOS blood collection)." Actual Procedure. These sampleswere collected during Week 80, and were not collected within one dayof the serum PFOS blood collection. Protocol. Postmortem Procedures Cell Proliferation Evaluation. "After fixation, samples for proliferation cell nuclear antigen (PCNA) evaluation willbe embedded in paraffin and shipped to." 200 111888111888..0.00222999000 3M_MN03279123 Protocol Deviations (Continued) CovancTe 2630295-2723 Actual Procedure. PCNA analysis was not done for Animal No. 105509 (Grou4p male) Protocol. Termination. Postmortem Procedures. Additional Lung Tissue Samples. "At the terminal necropsy, a sampleof lung (approximately 5 g) will be collected from an animal in the high-dose group. Thissamplewil be weighed. flash-rozen in liquid nitrogen, and storedin afreezer, st to mainta-i6n0 to -80C, until shipped. Thisfrozen sample, and a sample oflung (approximately 1 g, stored in formalin) from Animal No. 105509 (Group 4 male, died January 27, 1999) will be sent separately under appropriate conditions (ambient or packed on dry ice) to KriJs.Hansen, PhD IME T&S Bldg. 23-09 935 Bush Avenue St.Paul,Minnesota $5106 TFaeclseipmhiolnee:: 665511..777785..66101786. Kris J. Hansen or her alternate willbe notified regarding the shipmentofthesamples." Actual Procedure. This procedure was inadvertently not done at the terminal sacrifice; thus no samples were available for shipment to KriJs. Hansen, PhD. Protocol. Termination. Postmortem Procedures. Tissue Preservation. "The following tissues (when present) from each animal wil be preserved in 10% neutral-buffered formalin, unless otherwise specified, for possible future microscopic examination." 1 11188811188.8.00.0222999111 3M_MN03279124 Protocol Deviations (Continued) CovancTe 2630295-2723 Actual Procedure. Femoral bone marrow from Animal Nos, 105517, 105519, 105527 (Group 1 males), 105507, 105509, 105512 (Grou4p males), 105531, 105535 (Group | females), 105536, 105540, and 103551 (Group 4 females), mammary gland from Animal Nos. 103508, 103519 (Group 1 males), and 105512 (Group 4 male); and parathyroid from Animal No. 105544 (Group 1 female) were insufficient. These tissues, therefore, were not examined microscopically. Additionally, one ovary ofa possible two was examined from Animal No. 105536 (Grou4p female). Missingtissues are listed with appropriate `comments in the pathology data sheets for individual animals. Summary tables do not include them as having been examined. `These deviations are not expected to have affected the resuolftthse study. 2 111888111888..0.00222999222 3M_MN03279125 COVANCE. Sponsor St.Paul Misnnnis PROTOCOL Sty Title: 26 WeFeokaCsahposumleSTlo(rPiFOiS,STt6y3w5i9thiPn eCyfmloomralogtuaseMoSunlkfeonyisc Acid Date: Aue 20, 1998 PestrmingLaboratory CoS3v0a1ncKeiLnasbmoarantBoroilesovnrcd. Mado, Wicondin $37042595 LaboStrudyadtentoficratiyon: Proposal No. S0545B Covance 329.223 SponsorProject entfication 3M Sud No. 762957 Ey 118811888..0.00229933 3M_MN03279126 Comeps ii9F2ue2 S2t6u-dWyeek Capsule Toxiity Study with Pefluoroncane Slfonic Acid Porassiom Salt (PROS: T-6295i)nCynomalgus Monkeys P"Tuorapsoesses the effect ofthe test material on rial enzyme vel, hormones, nd other smeolnekcteeydsbfioorchatemliecaatl2p6arwaemeektesrs when sdministerd duly by capa 0 cynomolgus SEptonsor TBouxilidcionlgog2y0S2e6r.vi0c2e,s 3M Center St Pan, Mimnesoa 55144-1000 SAtnuddryewMoMn.itSoerss, PhD. Taelephone No. 651.575.3161 Facsimile No. SLITS AMlatrervniaTtne SCatsued,yDMoVr,itoPrhD 3TeMleTpohxoinceolNogoy S6e8r1vi.c7e3s3.5150 Facsimile No: 651.733.1773 SC3to30uv1daynKcLieoncLsaambtaoinroanBtooruivesarnds. Madison, Wisconsin 537042595 Mailing Address: PMaOdiBsooxn,75W4i5sconsin S3707-7545 29 118811888..0.00229944 3M_MN03279127 _-- Study Director Peter J. Thomford, PhD. Covance Laboratories Inc. Telephone No.: 608.241.7207 Facsimile No.: 608.242.2736 CovanScMe 6T39295.273 Pm Study Toxicologist Dale Aldridge, BS `Covance Laboratories Inc. PExrpoeproismeedntSatluSdtyarTtiDmaette:ablAeugust 26, 1998 Inife Start Date: August 26, 1998 Ine Termination Date: Tobe determined Audited Draft Report Date: Tobe determined Experimental Termination Date: To be determined Regulatory Compliance "`TGhoiosdstLuadbyorwaitllorbye PcroancdtuicceteRdegiunlcaotmipolnsiaancesetwiftohrtthheinETniviero4n0meonfttahle PUrSoteCcotdioen oAfgFeendceyral wRietghulaantyioanpsp,liPcaantbl7e92a,meinsdsmueendtNso.vember 29, 1983 (ffcetve December 29, 1983), and Animal Care and Use Statement All procedures in this protocol are in compliance with the Animal Welfare Act Regulat9orCFsR, 1-4. In the opinion of the Sponsor and study director, the study docs notunnecessarily 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 evaluation data and report. will be audited by the QAU of Pathology Associates International. The dose analysis and serum and liver PROSanalysisand report will be audited by the QAUof 3M Environmental Laboratories. The blood hormone determinations and report will be audited by the QAUofAni Lytics Inc. 205 111888111888..0.00222999555 3M_MN03279128 Test Material CovanScMe 6T32209.52273 Puget Identification Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) L"Tohte Nloutmnbumebrer wil be maintained inthe aw data. Purity Responsibility ofthe Sponsor Stability Responsibilityofthe Sponsor S`Attorroaogme Cteomnpdeirtaitounrse CInhfaorramcatteiroinstoincssynthesis methods, composition, orother characteristics that define the test material is on fle with the Sponsor. Vehicle Identification Lacwose Lot Number "The lot number will be maiotained inthe rw data. Purity On fle with the manufacturer Stability On file with the manufacturer Storage Conditions Atroom temperature. 206 111888111888..0.00222999666 3M_MN03279129 Covance 6T32692-295 Pages Gelatin Capsules Capsules (Size No. 2) obtained from Torpac, nc. (Fairfield, New Jersey); lot umber will be supplied by the manufacturer. Gelatin capsules willbestored at oom temperature, A dcaotpayofthe Certificate ofAnalysis provided by the manufacturer will be maintained inthe RAerseesrevreve(Asracmhpilveeo)feSiacmhplleotsoftest material, vehicle, and each test materialactose dilution (1g cach) will be taken and stored at room temperature. These samples wil be transferteod the Sponsorafer completion of th inife phase. DAinsyporseimtaiionnoinfgTteessttmaMtaetreirailawlil be retained at Covance for use in possible Future studies Animals SCpyencoimeoslgus monkey Source. `Covance Research Products Inc. AYgoeunagt IandiutlitaatdiuolntofTreatment `Weight at InitiationofTreatment Approximately 210 5 kg Number and Sex 22 males and 22 females Identification Collar ag. Husbandry Housing Individual; animals wibehlousled in suspended, sinless seel cages 207 111888111888..0.00222999777 3M_MN03279130 CovanMceT6239255.273 Paes Diet Certified primate dict (#726C. Harlan Teklad) once or tics daly. The diet is croonuttaimneilnyanatnsa.lyzReedsublytsthofespmeacniuffiaecdtnureufotr naurntrdicitoinonteaalmncionmatpnotnaennatlsysaensdareenvoinroinlmeanttal Covance-Madison. Frit, vegeotrotahebrsulppelemsen,tsmaybeprovided but will not require analysis. AWdatleibritum. Samples of the water are routinely analyzed fo specified microorganisms and environmental contaminants. The results are on fie at Covance-Madison. Contaminants "hTihsersetuadrye.no known contaminants in the diet or water at levels that might interfere with EEnnvviirroonnmmenetnatl controls for the animal room will be set to maintain 18 10 29C, a relative humidoift3y0 70%, anda 12-hour light/12-hou dark cycle. The dark cycle maybe interrupted to accommodate in-lif procedures. Acclimation Minimumof 4 weeks Randomization Animals will be weighed, suatified by body weight, andallocated tothe numbeorf blocks equal to the numberofanimals 0 be selected for each group. Animalsin each block wil then be asigned to groups using computer generated random numbers. Justification PFOSisaknown hepatic peroxisome prolifeator (PP) in the rat. When exposed t PP, nonhuman primates (sucha the cynomolgus monkey) respord similarly to humans i. Tow 10 00 hepatic response) and therefore ar an appropriate human surrogate species. 208 111888111888..0.00222999888 3M_MN03279131 `Group Designations and Dosage Levels CovMe 6T329s223 Parc TDGTrooup wLe(mwghghiay) ToLeuvlelM(amrkagldaDoyse MNaulmebserofAFemmamlaes T 2 003 w1x 4F&F4 31 007155 Eoa <3 @ = eDqouisvalleevnetlsamwiolulnbteofpraovcidteod.inThgeelactionncalpsgurloeuspa(sGtrhoutpoa1l) wmialtlereialcadmiannistered 0 b TGhreoulpow4,-dose (Group 2) willreceivethe est material died with lactose T1h:e49m9i,dw-dwo)s.e (Group 3) and high-dose (Group 4) groups will ceive the test @Tmwatoeriaanlimialluseidn Gwriothuplsact1o.s3e,a(n1d394,dewsei)g.nate a recovery animals wbiereled for oabtlseearsvte2d6fowreerkevse,rstihbeilnitryc,atpemresnitstweinlcle,beordidsecloanyteidnuoecdc,urarnedtnchee ofatnoixmialcsewfiflelctbsefor at lpeaatsh:ol1o3gwyefeiknsdipnogss,urtehaetmreenctov.erByasmeadyobneprleadsumcaedesortcxmaiteenrdieald,leavteltshaenddiscclrientiicoanl of he studydirector andaterconsulaton with the Sponsor. Dosing Procedures MOeltlhyodboyfgeAladtmiinnciasptsrulaetsi,odnily 7 daysheeek) fora leas 26 weeks "RTeoacsoomnpafroreDwaistihndgatRaofurtoem provious toxicology studiesusingthe oral route, which is the most likely routeofexposure `DCoaspesuPlresepwailrlatbieopnrepared at east weekly. The size and numberofcapsules will depend omonntkheey.physIincdailvicdhuaarlacdtaeirliystdiocssesofwitlhl beestbamsaetdcroinlthtehemodsotserelcoevnet,iandnidvitdhueawlebiogdhyt of the wweeiigghhtts,viwliltbhehueseedx.cDeoptsieonolefveblosdwyillwebiebghatsceodlloencthioenvdeahyisclwehasestuhpeplpireedvifoorusGrbooudpy |. 209 111888111888..0.00222999999 3M_MN03279132 CovanMce 3T292s21 _-- he For the Groups 2 thro4udogshe preparation, the test material wil be dissolved in ainciettioatnieonaonfd wdeialuttmeedntw.ithDillaucttioosnew(i1t:h49a9c,t1o:s39,isannedce1s:s3a9r,ywtwo,facrielsipteatceticvaeplsyu)leonce before preparation. All dose preparations will be stored at room temperature until dosed. Dose Analyses Dose analyses wilbedone by the Sponsor Homogeneity OSfamtpheletsest(mapaptreorxiiamlaltaecltyose1 gprceapcahr)awtiilolnbefocrotlhleecltoedwfarnodm htihgeht-odpo,smegirdoduipesaannddbottom aunnallyazneadlyfzoerd.test material content. Al samples willbe stored at room temperature SHtoamboigleitnyeity samples collected from the middieofthe preparations willbe used for the prestudy stability analysis. One set of samples (approximately 1 ach) wil be taken from the low- and high-dos? test materialactose preparations at the end of the inelife phase and analyzedfo test material content. `Sample Shipping Samples willbe shippedunderambient conditions t: Kis J. Hansen, PHD. IMET.&S 9Bi3d5g.Bu2s-h35A-v0e9nue St. Paul, Minnesota 55106 Telephone: 651.778.6018 Facsimile: 651.778.6176 Kis1. Hansen orhr ahiemate willbenotified regarding the shipment ofthe samples. Analysis of for test material content will be done on the samples. Results willbe provided for inclusion in the ina report. Observationof Animals CElaicnhicaanlimOablsewrivllatbieoonbsserved twice daily (1m. and p.m.) for mortality and moribundity; findings will be recordedatheyae observed. 300 111888111888..0.00333000000 3M_MN03279133 CovanTce2392952273 eee Each animal will be observed daly and food consumption will be asscssed qualitatively; abnormal findings willbe recorded. Once weekly, each animal will be observed: abnormal findings, ora indication tht the animal is normal will be recorded. During ueatment, cach animalwill beobserved for signsof poor health or abnormal behavior approximately 30 0 90 minutes ater the lust ania on test has been dosed; abnormal findings will be recorded. `Additional findings willbe recorded astheyare observed. B`WoedeyklWyebiegfhotresinitiationof eatment, 0 the firs dayofuesumen, and weekly thereaiter. An additional bodyweightwill be recorded on Da-y1fortheDay 1 dose. calculations. OBepfhotrheailnmitiicatEioxnaomfintraetaitomnesnt and before ach scheduled sacrifice; the anterior portion Ofthe cy, optic media, and ocular fundus willbe examined using an indirect ophthalmoscope by a board-certified ophthalmologist Clinical Pathology Frequency U`Wnhsecnhepdosuslieblde,Cobllloeocdtiowinlsl.be collect for clinical pathology tests from animals sacrificed at unscheduled intervals S`OcnhceedubelfeodreCoilnilteicattiioonnsoftreatment;and (before the dily dose) afer at last 30, 60, 90, and 180 days of treatment; ndafte at least 30, 60, ad 90 days of recovery `MAentihmaolds woifllCoblelefcatstieodnovernight; bloodwillbecollected frafoemomral vein. r`AenqtuiicroeadgfuolracnltinwiiclallbcehpeomtiasstsriyutmestEs.DTUArifnoerwhiellmabteocloolglyectteesdtso.veNroniagnhtticoonagwueltancte:is 301 11188811188.8.00.0333000111 3M_MN03279134 CovanMceT392952273 Page 10 Tests Hematology red blood cell (erythrocyte) count platelet count hemoglobin white blood cell leukocyte) count hematocrit differential blood cel count `mmeeaann ccoorrppuussccuullaarr vhoelmuomgel.obin breltoiocdulcoeclyltmeocropuhnotlogy `mean corpuscular hemoglobin concentration Clinical Chemistry glucose `aspartate aminotransferase gamma curreeaatinniitnreogen lsourabmityollidaenhsyfderrosgseenase Toul protein creatine kinase albumin calcium looublulbiilnirubin sinoodriguamnic phosphorus direc bilirubin Gf total bilirubin is potassium chgorleeastteerrotlhan2.0 mg/dL) cbhilleoraicdieds wiglycerides amylase aallkaanliinneeapmhionsoptrhaantsafseerase plainpcasreeaticspecific amyhase Urinalysis appearance ucose vspoelcuifmiec (graapvpirtoyximately I6 hours) Kbeitliounbeisn oH blood protein microscopic examinationofsediment urobilinogen Blood Hormone Determination F"Trherqeeuetnimceys before initiation of teament; aftr at least 30, 60,90, and 150days of reament; and after at east 30, 60, an9d0 days of recovery 302 111888111888..0.00333000222 3M_MN03279135 Covance 3T2a92s23 Fase 11 aNumberof Animals MAneitmhaoldsowfiClolbleefcatsiteodnovernight; blood willbe cllcted rom a femoral vein c`lAoptprfoorxismeartuemlysa3mmplLeso.f blood will be caleted without anticoagulant and allowsd to SSaammpplleesfHoandslcirnugm willbe centrifuged within 1 hour afte collcion, nd serum wil be harvested. Serum willbe divided into two proximately equal aliquots nd swtored inafreezersettomaintain-60 to -80C until packed on dry ic and shipped DArn.i SLayrisDnaes. 2Ga0i0thGeirrsabrudrgS.teMeta,rySluaintde 22000877 FTaeclseipmhiolneeNoNo:.: 33010.199727.100413638 Ani Lytes Tn. will be pote reading shipmentof samples. TSeasmtpsles will be analyzed by An Lyte Inc, for conisl estosterone, estradiol, etshtyrroonxei,nes1tr4i)ol, thyroid sumulting hormone, iodathyrorine (T3), and Serum PFOS Level Determination FBrefeoqrueenicnyationofueamaendnutsi,ng Weeks 1 (Day 7.2,4.6.8, 12, 16,20, 24, 26,28,30.32. 34, 04 39. ANlumber of Animals MAneitmhaoldswofiClollbleefcatsitoednovecnigh;blod (approximately 2 mL) will be collected from femoral vein without an anticoagulant. 303 111888111888..0.00333000333 3M_MN03279136 CovanNce 6T320s223 -_-- hen `Sample Handling `haSravmepslteesd.wilSlbereucmenstarmipfliegesdwwililthbien s1ohroeudrnafaerfrceoelzleerctsieotn,toamnadinsteariunm-w6i0lltobe-80C. `Sample Shipping Serum samples will be packed on dry ice and shipped to Kis J. Hansen, PAD SBldMg.ET23.E&.0S9 935 Bush Avene TSetl.Peapuhlo,neM:inn63e1s.o7t7a5.565011056 Facsimile: 651.778.6176. KrisJ. Hansenofher alienate wilbe notificd ganding the shipment ofthe samples ATonraliynscilsusoifonsienrtuhmeffoirnaPlFrOepSorw.ill be done on the samples. Results will be provided ``AAtddsicthieodnualledSearndumunCsoclhleedcutlieodnnectopsics, blood (as much as possible, up to 20 mL) vil be collected from the vena cava without an anticoagulant from animals at the time of ebxeshaanrgvueisnteadt.on.SerSaummplfersomwcialchbeacneinmtarlifwuigleldbewittrhainnsfIerhroeudrianttoaencaopllpercotpironi,at1edcosnetrauinmerwill and storedi a freezer set 0 maintain -60 to 80C until shipped to the Sponsor (Kris J. Hansen) for possible future analysis. Urine and Feces PFOS Level Determination Frequency On the first day of recovery and afer at least 6, 30,and90 daysof recovery Numberof Animals Al `Method of Collection (Aanpipmraolxsiwmialtlelnyot5bgerafmuss)edw;ilrlibneeco(lslpepcrtoexdimoavteerlnyig2hmtL)andfeces 304 11188181818.8.00.303030404.4 3M_MN03279137 _-- `SSaammpplleesHwailnldbleinsgtored ina freeze st to maintain 10 t0 30C. CovanTcee63w29s22?3 een `SSaammpplleesSwihlilpbpeinpgacked on dry ice nd shipped to Kris J. Hansen, PAD IBldMg.E 2T3.5.&0S9 9St3.5PaBuuls,hMAivnenneuseo:ta 55106 TFaeclseipmhiolen:e: 6655117.777586.1670618 Kis J. Hansen or hr altemate wilbenotified regathresdhiipmnengt of the samples. ApnraolvyisdiesdoffourriinncelausnidonifecetshefofrinPalOrSepowriltlbe done on the samples. Results will be Termination UNencsrcohpesdieuslewdillSbacerdiofincee.s aAnnidmDaelastthbse sacrificed wil be anesthetized with ketamine and xylazine, weighed, bled for required tests, and exsanguinated. ``ASfctheredautlleedasSta2cr6ifwieceekss of eatnent four animalssex/group will be asiedovernight, then anesthetized withketamineand xylazine, weigh, cxsanguinated, snd neeropsied. rAfelmiaeriantinTgeaasnti2m6alwseweiklslobfe fraesatuedmeonvtearnnidgahtt,letahsenta1n3eswteheetkiszewditwhiotuhtkterteaamtmiennet,antdhe xylasine, weighed, exsanguinaed, and necropsied. Postmortem Procedures Necropsy The necropsy wil include examination of: alorfices cerxatneiranlalcasvuirtfyaceofthe brain; the extemal surfoaftche spinal cord ard cut surfaces of the brain and spinal cord wilbe examined when tissue rimming is performed. corvieal issues and organs 305 111888111888..0.00333000555 3M_MN03279138 CovNe 2T92s23 Fase 1d ehxotremaasl,saubrfdaocmeinoaftlh,aenbdopdeylviccavesand viscera nasal cavity and paranasal sinuses OFrrogmaneaWcehiagnhitmsal at scheduled and unscheduled sucificetsh, Following organs (when present) wil be weighed; paired organs willb weighed separately abrdariennal 2) cKpiiddniedyy@mi)s 2) liver ovary 2) epasnicsre2a)s thyroid (2) with prahyroid Organ-t-bods weight percentages and organto-brsn weight ratios willbe calculated. PRaeplrmeisteonyt]atCivoeAsaOmxpildeasseofDtehteeirgmhitnaetriaonlslobe ofver will becollected from each aanfiemcaelerasttohte oscmhaeidnutlaeidns-ac6r0if0ice8, 0weiCghuendti,l faansahl-yfzreodsfeonrianllmiiqutiodylniCtrooAgeno,xiadnadsestaocrteidvitiyn. RCeeplrlePsreonltiafteirvaetsioanmpElveasloufatthieonleft ateral lobe of th Liver, eftandright estes, and pancreas will be collected and preserved in zie formalin. After fixation, sumpls orproliferation cl uckar angen (PCNA) evaluation willbe embedded in paraffin and shipped SPaatnhdorlaoRg.y EAlsdsroicdigaet,esPAnDe.rmational S1u5itWeo1man's Mil Court "FrTeedleerpihcokn,e:Ma3r0y1la.n6d632.17106e14xt4. 2036. Facsimile: 301.663.8994 PPaCtNhoAloegvaylAuastsioocniatweilslIbnetedmoanteioonnalthweilsabmpelneost.ifiReedsruelgsarwdiilnlgbsehpirpomveindtedoffosramipnlcelsu.sion in the final report. 306 111888111888..0.00333000666 3M_MN03279139 CovanScoe 3T2299.25275 Pagels Liver PROS Determination Ascation (proximately 20.2)ofliver wil be collected from each animal at the scheduled sacrifice, weighed, flash-firnol7iqeuind nitrogen, and storedinafreezer set to maintain -60 to -80C unil shipped withplasma samples 0 3M (Kris Hansen) for analysis. Results will be provided for inclusion in the final report. Tissue Preservation "The following issues (when presen) from each arimal willbe preserved in m1i0c%ronsecuotpriacl-ebxualmlienraetdiofno;rmalin, unless otherwise specified, for posible future adrenal (2) aorta bcreaciunm cervix cdouloodnenum epididymis (2) esophagus ye (2) 0 be preserved in Davidson's fefmiuxartiwvietfhorbsoancerimfaicrerdoawn(iamratlicsuloanrly] surfaceofthe distal end) ghaelalrbtladder eum jKeijdunneuym(2) lesions lilvuengr mammary gland ovary 2) `mesenteric lymph node. pancreas ppriotsitaatrey rectum saslciiavtaircyngelravned (mandibular 2)] sskeemlienaall mveussiccllee 2(h)igh) skin splinuamlbacro)rd (cervical thoracic, and sSptleeremnum with bone marrow stomach testis (2)10bepreseirnBvoueinds' thSyomluutsion for sucrificed animes ony) thyroid (2) with parathyroid turraicnahreya bladder erus vagina Bone Marrow Smear From the stemumof cach animal at unscheduled and scheduled sacrifices (made and eld for possible future examination). 307 111888111888..0.00333000777 3M_MN03279140 Cove 6T32a92]23 Pages Histopathology Tissues from cach animal in the control and high-dose groups will be embedded in `Tpiasrsauffeisn,fsreocmtiaollneodt,hsetraainniemdawlisthwihlelmbaetorxeywliinnedanfdoeropsoisns,ibalnedfuetxuaremienxeamdinmaictrioosnc.opically. Reports LAeltetteerrRreeppoorrttwil be prepared followin the tenia sacrifice FAindaralftRerpepoorrtt that includes the folowing information will be prepared and submitid: Experimental Design and Methods Rmeosrualltisty clinical cbservations bfoooddycwoenisguhtmsption colpihntichaallmpiactheoxlaomgiynartesiuolntss hpaolrmmiotnoyelaCnaolAysoexsid(parsoevaicdteidvibtyesAni Lytics) Sceerllumpr,oulriifneer,atifeocneesv,aalnuadtliiovnesr P(pRrOovSidleedvbelysP(aptrhoolvoigdybeyAdss3oMc)iates International) dose analyses (provided by 3M) organ weights oorrggaann-ttoo--bbroadiyn wweeiigghhttpreatricoesntages macroscopic observations microscopic observations SLteavteisntei'catlesEtvwaillulabteiodnone 0 tesforvariance homogeneity. Inth case of hvaertiearnocgee.neCitoympoafrviasroianntceestastpwil5l 0a.k0e5,vtarrainasnfcoermhaettieornosgewnieliltbyeuinsteodco0nssiadberialtzieotnhe 308 111888111888..0.00333000888 3M_MN03279141 CovanTce26392592723 Pet? bOondey-wwaeyighatnasl,yspiasmoiftovya]riCanocAe o(xAiNdiOsVeAa)ctiwviiltliebse,uasneddco(ifnatpipnuloiucsacbllineti)coalanpaaltyhzoelongiyal vtraelauteesd. gIrFtohuep cAoNmpOarViAsoniss,significant, Dunnett test willbeused for control versus `wOintchesineiatyiaalnbaolydsyiwseoifgchotvsaarsiatnhceec(ovAarNiCatOe.VA1)f twhiellAbNeCuOsdVA0iansailgynzifeibcaondty, cwoeviagrhitast,e: adjusted meanswillbe used for control versus treated group comparisons. G5r.o0u%ptwcoo-mtpaairliedsopnrsob(abGirliotuyp2lsevetl. hOrnloy4dvuaetrgascuohlslGerctoeudpo1n)owilalfbeer etvhealfuiastteddaayt otfhe reament will be analyzed statistically. Aintstthruecetinodnsofto1fyineaalrizaefhtaeviesshueaenncecoofmmtuhneiacuadtiteeddbdyratfhterSeppoornts,oirf,ntoherneqtuheesatueddirteevdidsriaofnts or arenpdorstubwimlilttbeedctoonstihdeeSrpeodnsfoinra.l' and issued as the final report, signed by the study director, `Any wil bmeodpiefrifcoartmioendsoatracddhiatnigoensal0cotshte autdhieteSdpodnrsafotr.report requested I year afer issuance Record Retention All raw data, documentation, records, protocol, specimens, and final report generated asa rCeosvulatncofetfhiosarstpuedryiogdenocfra1tyeedabryfoClolvoawnicnge swiulblmibsesairocnhiovftehdeinfitnhaelsrteoproargtetfoactihleitSipesonosfor. `One year afer submission of the final report, ll ofth aforementioned materials will be sent io the Sponsor, and a rerum fee will be charged. The Sponsor may elect to have the `materials retaineindtheCovance archives for an additonal periodof time, and Covance will charge a storage fe. Ifthe Sponsor chooses 1 have Covance dispose of the materaidiaspolsa,l feewill be charged. All aw data sored on magnetic mdia willbe retained by Covance. WthiethSipnon1syoerasrdaefseirgnseuebsmi(sAsniionLyotfitsheInficn,al3rMepoEr.t,T.al&l ofS,thandafPoartehmoelnotgiyonAesdsomcaitaetreisals from International) wil bsent tothe Sponsor (Andrew Seacat, PhD, 3M) by the Sponsor's designees. 300 111888111888..0.00333000999 3M_MN03279142 PROTOCOL APPROVAL [-- traets 9 MO Linder VI Senet SMAtnuddryeMwoMn.itSoeracat, PhD 29 k2 Date Stud7y DiTrhloarn, Covance Laboratories nl I= 510 118811888..0.00331100 3M_MN03279143 COVANCE PROTOCOL AMENDMENT NO. 1 CoMvTe.239295-7223 26: WePcoktCssaapmsSaTtos(PkRcOyS;STa-y62w05i)liPneCfylmaoomrooolcetuasnsoSrllkosie Ack BE STetsiyngMaFnaoyr,: AConvdarnecweML.abSoraacto,riePsADLn. Madson, Wisconsin StyDicior,_ Pee JThomforPdA,D This meinen modifies the following portionsofthe protocol Effective August 20,1998 PLacgem4a,rViehaiceler,sStonrasge CwoinlhittohnsL.osTeo,nachudtehtfeolslowlisenngthusredt1hisdssecltvioen the Solvent Aecnetioinastion "LToot Noutmmbaetrser will b manained inth ra dt. pOunrittly with the mantactrer aOoblietwith he mafactuer Storroaogem Ctoendmiptieornas sn 118811188.8.0.033111111 3M_MN03279144 ProtosCAonnndSceiMn63a2T9N2o2.31 --_-- ho Cfhoarrmaactteiroinstoincssynhesis methods, composition, or ther characteristics that defn the solvent i on fle withthe manufacturer 2 cPoamgeeet,aGnrroou,p dDeesliegtntahtiisoennseannced.Dosage Levels, Footnote, Sentence 1. To Effective September 2, 1995 3. cPaapgseulse,s,GkelattinthCiaspssuelens,tSaenndternecpela1c.e wTiothchthaengfelotwhisnigzof he elasin nCaupmsbuelreswi(llSibee sNousp.pli2eodrb4y tohbetmaainnuedfafcrtoumreT,orpa, In (Fai, New Jersey): lot Effective December 15, 1998 4 PPaargaeg1r4a,phPo3s,tSmeonrttenecmeP2r.ocTeoduirensc, hCecllPursoliiofneroaftisoindeEsvasltuaaitneidonw,ith hwielmhatthoexyfionloawingc.osin inthe PCNAevaluation, delet this scence and reps: cPoOsN)Aweilvllbuenidoonne(ionncthhiensgamepxlaem.ination ofsds stained with ematoxyhs and Effective January 21,1999 5 aPdadgieio1n0s,l cClliinniiccaallcPhaetmhiotloygyt,s,Teasds,tChleinfoilclaolwiCnhge.mistry. To inch an High density lipoprotein (HDL) Elective January 21 and 28 and February 2,1999 Phaegree1q2u,isUorfitnheeanSpdonFsecoersoPcFoOlSleLtevaeddliDteontaelrmeicnlatsiaomnp,leSsamepflzeciSvheipping. At JJaannuuaarryy2218,a1d999F)ebarunard0y 2c,la1ri9f9y9)h,eadsdamtphleeFcoollloewiinognarfeeqrutihrismesnotsn(.effective sn 111888111888..0.00333111222 3M_MN03279145 CormnMcNs 6T3.2692-925273 Prooon Amendment No.| -_-- we ADdudriitnigoWnealekFe2c3a,laSafrmepslhefsecal sample ofat east g,ifpossible, wible collected pferrommit6tinmga.lesThaends6amfpelmeaslewsilclabcehcionllheectcedonitnrtohleaneadrlhyigahf-ideorsmeoognroaufpesr,psaunrsviavrael clseamapnleedsinwiltlhebemcoomlilencgtetdoiennwshuirteethpaotlytphreoypyrleen1e0cmoontraeintehrasna6ndhosuernstoodn.drTyhice to: Joe McConnell PMoarypohyCrliinnicand Nutritional Chemistry Group. 200 First Steet SW RTeolcehpehsotneer:, M5i0n7n.c2s8o4t.a21$550905 Lab Telephone: 507.284.3232 Dr. MeConnel wil be contacted before shipping th samples. EffectiveJanuary 21 and February 12and 16, 1999 7. Page, Clinical Pathology, Frequency, Scheduled Collections. To reflect the d1e5c0isdiaoynsofotfhueeaStpomnesnor(aefnfdetcthivee SJtaunduyarDyi2r1e,ct1o99190),2010deaxcioelnldectthieonleinngttehrvoalfafter r(eeceocvteirvye(Feeffbercutairvey F1e2b,r1u9a9r9y),12d,el1e9t9e9t),hatnedxttoincthils setachteicoionllafencdtyiroenplraecqeuwiirtehmetnhte Dollowing. Oofnctreeabtemfeonrte i(bnetfaotrieontohfe dtarielaytdmenot;saanendd)aaftte;r aattlleeaasstt3300,,6600,,9900,,115305,, aanndd180 days 180 daysofesovery Effective February 10 and 16, 1999 8 Page 12, Urine and Feces PFOS Level Determination, MethodofCollection. Ttoopmeordmiitfycotlhleecatmioonunotfosfasmpalmepslefrtoombefcasotleldecatneimdal(esffoencttihvee fFiersbtrduaaryyof10r,ec1o9v9e9r)y.and (foclfleocwtiinvge. February 16, 1999), delete the text tis section and replace with the A2nmim)alsanwdilflencoetsb(eat flaestaesdt()exwcielpltfboercotlhleecftiestddoavyeornfigrhte,coveruyr)e; (st least 31 111888111888..0.00333111333 3M_MN03279146. ProcolCoAvmanecSaeHdn6Te3.2n259.N52o.2.131 Fused Effective February 12,1999 9. Pdeacigseio,n oGfrtohuepSpDoenssiogrnaatnidontsheaSntdudDyosDairgeectLoervetlost,eFonodtntohteelde.ngtThoofrreeflceocvtetrhye, delete the ext in thisfootnoteand replace with the folowing. 4 "Two animals in Groups 1, 3, and 4 designateda recovery animals will be tarneiamtaedlwfiolrlatbleoabsse2r6vewdeefkosr,retvheresitbirleiatym,enpetrswiisltlebnecdei,socrondteilnauyeedd,ocacndurttheeres of oxi eects for at least 26 weeks postreatment. Effective February 12 and 15, 1999 10. Page 11, Serum PFOS Level Determination, Frequency. To reflect the d(eccfifscitoinveofFtehbreuSaproyn1s2o,r1n99d9)tahne dSttuodyreDviirseectthoerr1eqeuxitremnednthsefloerntghtehsoef rceolckoevteiroyns dreiplnagcerweictohvetrhye f(foflelcotwiivneg February 15, 199), delete the text in this section and 2B6e,f3onredi2n7it(iDoany o1f8t3r)eadtumreinntg;redautrimnegatW;eeankdsG1u(iDnagyW7e)ek2s,42,76(,D5,ay1s2,18146,,21085,,24a,nd S1517a),nd2853(.Day 190), 29 (Day 197), 30 (Day 204), 31 (Day 211), 35,39, 43, 47, 11. Page 13, Termination, Scheduled Sacrifices. To relect the decisionofthe `FSepbornusaorrya1n2d, t1h9e99S)tuadnydD(i0repctroritoo ertxhiteentnudimtbhzeeekreonfgtahniofmraelcsdoevseirgyn(atceldctfiovrerecovery (fcoflfoewcitnigv.e February 15, 1999), delet the text inthis section ad eplace with he Afsttleasrt26weoeftrekaumesnt, up fo four snimalsisexgroup willbe fisted oavnedrnniegchrto,pstihede.n anesthetized with ketamine and xylazine, weighed, cnsanguinaed, Atfwtoeranatimlaalssts2ex6/wgrouepowfeiltrbekeatfmasestnetd aovneardnigehat,s t2h6enweaeneksstwhicttzheodutwtirtehaKmeetnatm,ine and xylaine, weighed. exsanguinated, and necropsied. 314 11188181818.8.00.303131414.4 3M_MN03279147 CovanMcNe 6T3.2a9:925273 -_-- Protocl AmendmenteNos.1 Effective February 12 and 16, 1999 12. oPfagthee 1S0p,onBsloorodanHdotrhemoSntuedyDeDtierremcitnorat0ioenx,teFnrdeqthueenlceyn.gthToofrreefcleocvterthyeedfefcecitsiovne dFeelbertueatryht12e,xt1i9n99t)hisansdec0tiocnlaarnitdyrtehpelarceequwiirtehmetnhtesfcofleocwtiinvge February 16, 1999), tTrheraetemetnitm;esanbdefaofreerinaittikaatsitono30f,t6r0e,at9m0e,nt1;35a,fatnrdat1l8e0asdta3y0s,of60r,e9c0o,venryd 180 days of 13. tPhaegdeec1i2s,ioUnroifnethaenSdpoFnescoersaPnFOtSheLSetvuedlyDDeitreercmtionra0tieoxnt,enFdretqhueelnecnyg.th Tofo reflect Freecborvuearryy (1e6f,fe1c9t9i9v)e,Fdeeblreutaerythe12t,ex1t99in9)thasndsetcoctliaorniafnydtheeplrecqeuiwrietmhentthse (feoflclotwiivneg:. Orencotvheerfyrst dayofrecovery and aftr at leas 6, 30,90, 135, and 150 days of Effective February 15, 17, and 18, 1999 14. Ptraagnesfe1r3,saPmoplsetsmoofrtaenmgPtriosscueedu(erfefse.ctiTveoFfebrauaryia15rteaqnudees1t8,by1t9h9e9)Sapnodnsor to gallbladder and bike (effective February 17, 1999), add the following. A`dAduitthiotenramlinLaulnngecTriospssyu,easSaammpplleesof lun (approximately Sg) willbe collected ifnrloimquaindanintiromgaeinl, tahnedhsitgohr-eddosiengrforuepe.r,"Theits staommpalientwaiillnb-e6w0etiogh8e0d,C,fausnht-iflrozen sfhoirpmpaeldi.n)TfhriosmfArnoizemnalsaNmop.le10a550a9nsa(mdpGlero4ofmulinepg,(daipepdroJxainmuaatreyly27,1 81,9s9o9r)ewdililnbe sent separately under appropriate conditions (ambient o packed on dry ie) to: KMriEs J.THan&seSn, PAD B9l3d5g.Bu2s3h6A-v0e9nue STte.lPeapuhlo,neM:im6e5s1o.7t7a8.565011086 Facsimile: 6517786176 315 111888111888..0.00333111555 3M_MN03279148 ConeTs6322952273 Protocol AmendmentPuNcoe| Kris J. Hansen of her altemate will be notified regarding the shipment of the samples AAdtdtihteisocnhaeldGulaeldlbnleacdrodpesricasn,dthBeilgeaSlbalmapdldeesr and bike will be collected and stored aiclceosradmipnlgets0wailslpebceiaplaccokleldecotniodnraynidcefiaxnadtitornapnrsofceerdruerdeo.: Frozen gallbladder and Kis). Hansen, PRD IBldMg.E 2T3.-&0S9 9St3.5PaBuuls.hMAivnneensuoeta 55106 TFaeclseipmhiolnee::65615.177778.866107168 sKaimspleJ.s.Hansen or her altemate will be notified regarding the shipment of the Effective February 24 and March 9, 1999 15. Page 13, Postmortem Procedures. To facilate request by the Sponsor to spruemppalreso(feffvecrtivfeorFeeblreuctarroyn2m4i,c1r9o9s9c)opayndantdratnosfperre(peafrfeecatnivdetMraanrscfhor9h,em1a9t9o9x)ylin and cosin-stained sides for light microscopy (effective March 9, 1999), add the following. Electron Microscopy sAtuagtehefotreremliencatlronnecmriocprsoys,cospaimcpleevsaloufatiiovnr. wTilhlebiscsoulelebcltoecdkasnadndpr4ocheesmsaetdox1y0lbilnock andcosin-stained side for lightmicroscopywillbe transferred to: SDihsairsoinonADmibrreocsteo.r Pathology Associates International 4915 D. Prospectus Drive DTeulreaphno,neN:or9t1h9C.a5r4o4l.i5n2a57_27713 Facsimik: 919.544.3218 316 111888111888..0.00333111666 3M_MN03279149 CovancSeh 6T.36229952.723 Protec AmendmentPuNgos.?| "ATsissoscuiesawtiesllIbneterpnraotcieosnsaled(PaAnDd).evaAluraetpeodrbtywielllecbterpornomviidcerdosbcyopPyAIbyfoPratinhcolluosgiyon in mthaeinftineanlarnecpeoortf.anPyAIraiswrdeastpaonosribslpeecfoirmetnhes qpuraoldiutyceadssbuyraPnAcLe auditing and `SharonAmbroseor samples. he alterate will be notified regarding the shipment of the Effective April 22,1999 16. Page 16, Reports, Statistical Evaluation, Paragraph 2, Sentence 1. To add rsteaptliastciecawlitanhatlyhseifsoolfloorwignagn. weight and hormone values, delete thi sentence and iOnniteia-lwbaoydaynawleyisgihstso,f vpaarlimaintcoeyl(CAoNAOVoxAi)dawsielltbievuitsieesd,Giacopnptliincuaobulse)clitnoicaanlalyze: pathology values, hormone values, and organ weight data. Effective April 26, 1999 17. PPaagreag1r4a,phPo1.stmTooratdedmaPsreoccoenddurseest,ofCetlislsPuresolfiofrercaetliopnroElivfaelruaatitoinonev,aluation, add the following 0 this paragraph A second set of tissues (representative samples of th lft lateral lobe of the lve, leftand right testes, and pancreas) preservedinformalin without zine will lo be. prepared. Effective April 28, 1999 18. Page, Dose Analyses, Stability, Sentence 2. To change the schedule for the retumofthesamples, delee this sentence and replacewiththe following, One setof samples (approximately 1g cach) willbe taken from the low- and whiillgbeh-adnoaselytezset dmaftoerritaesltlamcattoesreiaplrceopanrtaetni.onsa the endofthe treatment phase and 17 111888111888..0.00333111777 3M_MN03279150 Effective May 6, 1999 Conhni 6T36229952.23 Preocol Amendment No. | a 19. Page16, Reports, Letter Report. To change the kite report 0 an interim report, delete the txt in this section and replace with the following, IAnntienrtiemriRnepreoprortt, includingatl ems from the final report as appropriate, will be prepared folowing the terminal sacifice. Effective May 17,1999 20. Page 16, Postmortem Procedures, Histopathology, Sentence 2. To include: traerpgleatceorwgiatnhsthfoerfaonlilomwailnsg.inthelow. and mid-dose groups, delete (hs sentence and In addition. iver and thymus for ll animals i the low- and mid-dose groups and eSpmibnealddcoerddingrpaayramfaitnt,ersefcrtoiomnfede.maslteasiniendtwhietlhohwe-m1a0tdoxmyildi-ndnosde cgorsionu,psanwdilexbaemined microscopically. Other tissuesas, appropriate, will be retained for possible future examination. Effective May 18, 1999 21 Page3, Proposed Study Timetable. To include proposed dates for incite ttehremtienxattiionnt,htsheseucntaiuodniatnedd rdreapfltacientweirtihmtrheepofrotl,oawnindgt.he audited draft report, delete EIxnpdeireimSetnatralDaSttea:rt ADuagtu:stA2u6g,us1t99286, 1998 IUnn-aiufdeiTteerdmiDrnaafttioInntDeartiem:ReApuogrutstDa2te,: 1M99a9y 11, 1999 `Audited Draft Report Date: December 28, 1999 Experimental Termination Date: To be determined 318 111888111888..0.00333111888 3M_MN03279151 sor[en--lyo--, - re AMENDMENTe APPROVAL d AC)irdiid ImN.CSaul RSboolyooMiESreon, BD _ fSuA Diroso4 (Lol , pt -- os 3 2/555 wo 118811888..0.00331199 3M_MN03279152 COVANCE PROTOCOL AMENDMENT NO. 2 CovTan0c2e 30250.223 26-WePeoktaCsaspisuumleSaTtox(icPiFtOyS,StTu-d6y2w9i5t)hinPeCryfnlouromrooolcgtuasneMoSunlkfeonyisc Acid Sewer MSP Mme STetsutdiyngMoFnaictiolry:: AConvdarnecweML.abSeoarcsaotr,ePshIDnc. Madison, Wisconsin Study Director: __ PeteJr. Thomford, PhD This amendment modes the following portions ofthe protocol Effective February 19, 1999 I. SPeangteen,ceOb2s.erTvoataidodnaonfoAbsneirmvaaltsi,onCloinnichael dOabyseorfvastchieodnusl,edPasracargifriacep,hde2l.ete hs somence and replace wit he following. aOnncoermwaelekfliyndainndgsoonrhaen idnadyiocfatsicohnehdautlethd saicmriafilce,5enaocrhmaanlimwialllwbiellrbeecobrsdeedrvd; Effective June 11,1999 2 APraogdeot1h1,yrBolnoiondeH(o1r5maonndefDiectteyrrmoixnaitni(o7n4,)Teestt,s dTeloetaeddthieceet i his section and replace with he Following Seaxmppleesewislrbe SaonploztedmabylAantigLyetveeiIonncsoerhcoratnisdole, mtesEtovsetecrtonger,osnrnei(,79, and toal an fee thyroxin (T4) 20 118811888..0.00332200 3M_MN03279153 CovancNeT5299.s2273 Protocol AmcndnentPNaog.e2? 5. Page 16, Reports, Final Report, Statistical Evaluation. To add repeated madedastuhreefsotlaltioswtiincagltaonathleyseinsdooffcthholeesstecetriooln.and total and fee wiodothyronine (13), Cmheoalseusrteesroalnaalnydsitsootfalcoavnadrfiraenecteri(iAodNoCthOyrVoAni)nepr(o1c3e)dwuirlel wbiethanaavleyrzaegdebpyrerterpeeaattmeednt moreaAsNurCeOmeVnAtspfroorctehdeurpeasrawmileltebreseavsalcuovaatreidataets.p Tr0e.a0t5mleevnetl.effAlcltspousntd-ehrocANOVA creocnotvreorly-)vewrislulsb-erecaotneddu-gcrtoeudpumseinagnDcuonmnpeatrti'ssomnsan(yi-ncolnud-ionnge{vparlouceesdudrurei.ng. Abontahlyses will be carried out with SAS procedure PROC MIXED or BMDP, or Effective August 24, 1999 4 Page, Group Designations and Dosage Levels, Footnote d. To reflec the ddeelceitseiotnheoftetxhteinSptohinssofrooatnndottehaenSdturdeyplaDcierewcittohr t0heexftolelnodwtihnge.length of recovery, d Two animals in Groups 13, and 4 designated as recovery animals will be atnreiamtaeldsfwoirlaltbeeasotbs2e6rvweedafk,o rtehveenrstirbeilaittmye.ntperwsiillstbeneced,isocorndteilnauyede,d aoncdcutrhreence oftoxic effects for at leas 52 weeks postireatment 5. dPeacigsei,onColfitnhiecalSpPoantshoorloagnyd,tFhreeSqtuuednycDy,irSecchtedotuorleexdtCeonldltehcetiloenngst.h Toofrreefcloevcetrtyh,e delete the text in this section and replace with the following. Otrnecaetmbeenftor(ebeifnoirteiatthieondaofiltyredaotsmee)n:ta;nadfaefreart aetaesats3t0,306,0,6,909,0,1501,35a,nd1801,8027d4a,ysanodf 365 daysofrecovery Page 10, Blood Hormone Determination, Frequency. To reflec the decison of ttheextSipnotnhsisosreacntdiotnheanSdturdeyplDaicreewcittohr ttoheexftoelnldowtihneglength ofrecovery. delete the o"Tfhtrreeeattimmeenst;baefnodreafienriatiatlieoansotf30t,re6at,me9nt,; a1t35e,r 1a8t0,le2as7t4,30a,nd603,6950,daaynsdo1f8r0ecdoavyesry a 11188811188.8.00.0333222111 3M_MN03279154 Comm Ni9t2s3? Procol AmendmentPaNroe 2 7 Page 11, Serum PFOS Level Determination, Frequency. To elect the ddeelceitseiotnohfttexhteinSptohinssosercatniodntahnedStruepdlyacDeirweictthorthteo feoxltleonwdintgh.e length of recovery, Before ntatonof rcatment; during Weeks 1 (Day 7). 2, 4,6, 5, 12, 16,20, 24, 251683,7,)5a,n72d,8621(7,D6(a5Dy,a6y1990,1)87,332),0d7u(7rD,ianaygndt1r97e79a)t.me3n0t;(Daanyd 2d0u4r)i,ng31We(Dcakys 22171)(,Da3y5,s3198,4,431,8457,, a5n1d. Effective August 24, 1999, and January 12 and 21, 2000 8. S`PApauoggneusso1t3r2,a4T,nedr1m9t9hi9en)aS.tt1iu0odynre,fDliSerccethcettdhoeurldteeodceixSstaiceornnidfoitfhctehse.leSnTpgoothnrseoofflrerctetoctochavenecrdeyelc(iteshfieeonrteiocvfotevheery (enfefcercotpisvye(Jfaencuatriyve21J,an2u0a0r)y,1d2.el2e0t0e0t)h,eatnedxttionshuibssesqeucetnitolnyacnldarriefpyltahcee rweiqtuhirtheement following Aoveerrniagthte,astthe2n6awneesetkhsetoifzerdcawtimtehntk,etuapmitnoefaonurd axyilmazailnse,sewxegigrhoeudp,weixlsabnegfuaisntaeedd, and necropsied. eAfmtierniatnegasatni2m6alwseweiklsobfetrreemaatmveendt farnodmatthleassttud5y2 awseefkolslwoiwtshout reatment the Two animalgsex in Group | will be returned tothe Covance stock. Two animals/sex in Group 3 will be transferredto a subsequent study (Covance 6329-268). "KTewtoamainniemaanlds/xsyxlaizninGer,owuepig4hweidl,l ebexsfaansgtueidnoaveedm,igahntd,etchreonpasnieesdthetized with Effective August 24 and September 22, 1999 5 JPiavgeres1a2m,pAldedsibtyiobniaolpsFyec(aelTeScatmipvleeAsu.guAstth2e4,re1q9u9e9s)taonfdthtoemSpoinsorth0e pcrololceecdtures (effective September 22, 1999), ad the followin afer thi section m 118811888..0.00332222 3M_MN03279155 CovancNeT63929s-2273 Protocol Amendment[No3.2 Interim Liver Biopsy Samples AanismaamlpsleinoGflriovuepr 4(aopnplryoxdiumraitneglyrec1 o0ve2ry)(Wwielelkbe7,colwlietchtiend1bydabyoiofpstyhefrsoemrum PfoFlOloSwsblood collection). This sample will be divided into four portions as pOanreaflsiunb,ssaemcptlieonweidl,l sbteaipnreedsweirtvhedheinma1t0ox%ylnieuntraanld-beuofsfienre(ddufpolrimcaaltiens,leidmebsewdidlledbein prepared). and examined microscopically "The second subsample will be flash-frozen in liquid nitrogen, and stored ina freezer, set to maintain -60 0 80C, unil shipped for analysis to Kris J. Hansen, PhD SBlMdgET2.3-&0S9 935 Bush Avenue TStelePapuhlo,nMeiNnon.-eso6t5a1.$757180.66018 Facsimile No. 651.778.6176 KsarmiplJse.s.HanRseesunoltrshweilrlalbteerpnraotveidweildfl obreinnoctliufsiiedonreignatrhdeinfgintalheresphoirptmentofthe "evTahleutahtiirodn.subTshaemtpilsesuweibllobcekspraoncdesasehdemtaotbolxoyclkinstaangde efoorsienl-escttarionnedmisclriodesfcoorpliicght microscopy wil be transferred to SDihvairsoinonAmDbirreocsteor 4P9at1h5olD.ogPyrAossspoeccitautseDsrIinvteemational TDeulrehpahmo,neNoNrot.h Ca9r1o9l.i5n4a4.257275713 Facsimile No. 919.544 3218 AissssouceisawtiesllInbteempartoicoensasled(PaAnDd.evaAluraetpeordtbwyilellebcetrpornovmiidcerdosbcyoPpyAIbyfoPraitnhcolluosgioyn in tshheipfmineanltroefpotrht.e sSahmaplreosn.Ambrose or her alternate will be notified regarding the 323 111888111888..0.00333222333 3M_MIN03279156 CovanNceT5299.s2273 Protocol AmcndnentPaNgoe.23 "The fourth subsample willbe flash-frozen in liquid nitrogen and sored in a ffroeteuzreer,ansaltys0is.maintain 60 080C, and transferred (0 the Sponsor for possible Effective January 12 and21, 2000 10 Page 12, Interim Liver Biopsy Samples. At the request ofthe Sponsor 0 collect Hsiuvbesresqaumepnltesstbuydyb(ioeplseyc,titvheenJatneuramrinya12,th20e00st)uadnydantod mtoradnisffyertthheeraenqiumiarlemse0nta (effective January 21, 2000), add the following ate his section ATesrammipnlaelofLifvievrerB(iaopppsryoxSiammaptelleys 1 8) will be collected by biopsy from all animals in Groups 3 during recovery (Week 79, within 1 day ofthe serum PFOS blood collection). This sample will be lash-frozen in liquid nitrogen and stored in a freezer, set to maintain -6010 -80C, until shipped for analysis to: KrisJ Hansen, PhD MBidEg T2-3&E-S09 9St5.5PaBuuls,hMAivnneensuoeta 55106 FTaeclseipmhiolneeNoNo.. 665511..777788..66107168 KsaimpslJes.HanRseesunlotsrhweirllableteprrnaotveidweildlfboer niontcilfuiseidonreignatrhdeinfginatlheresphoritp.ment ofthe Effective January 21, 2000 11 aPnaagleyz1e2,adAddidtiitoniaolnaslerSuemrsuammpClolelsecfotriosnp.eciTfoieedftlhcytrotihdehdoremconiesso,ifaotdhdnefSoplolnowsionrgto othe endofthis section. An aliquot (0 mi) ofthe additional serum collection samples collected from all aonnidmraylsicferboym tGhreouSpposns1.o2r t3o aDrn.d 4SarsoajcriDfaisc,edAanti tLhyettcersmionralfrneeecrTo3p,syfrweilTl4,be sent total 3, and total T4 determinations 24 111888111888..0.00333222444 3M_MN03279157 CovancTe 2630295-2723 Protocol AmendmentPNaog.es2 12. Page 12, Urine and Feces PFOS Level Determination, Frequency. To reflect the decision ofthe Sponsor to collect a 24-hour urine and fecal sampleafter one year of recovery, delete the text in this section and replace with the following On the firs dayofrecovery andafterat least 6, 30, 90, 135, and 180 days of recovery. In addition,a 24-hour sample ofurine and feces wil be collected before the completion of 52 weeksofrecovery. 13. Page 16, Postmortem Procedures, Histopathology. To define the postmortem procedures for recovery animals in the high-dose group, add the following afier his section. Postmortem Procedures for Recovery Animals in the High-Dose Group Atnecropsyofthe recovery animals inthe high-dose group, procedures e(ixnacmliundaitnigoonr)gdaenscwreiibgehdtspraenvdiocuoslllyecatrieonnoofttriesqsuuireesd.forThhiestfooplaltohwoilnoggipcraolcedures willbe done. Necropsy "The necropsy will include examination of all orifices cranial cavity external surface ofthe brain; the external surface of the spinal cord and cut surfucesofthe brain and spinal cord will be examined when tissue trimming is performed cervical tissues and organs thoracic, abdominal, and pelvic cavities and viscera external surfaceofthe body nasal cavity and paranasal sinuses Liver Samples A sample of liver (approximately 1 t0 2 g) will be collected. This sample will be divided into three portions a follows. One subsample wil be preserved in 10% neatral-buffered formalin, embedded in paalln, sectioned, stained with hematoxylin and eosin (duplicateslides will be prepared). and examined microscopically. "The second subsample will be flash-frozen in liquid nitrogen and stored in a freezer, set to maintain 60 to -80C, until shipped for analysis to: 325 111888111888..0.00333222555 3M_MN03279158 CovancTe 2630295-2723 Protocol AmendmentPNaog.e?2 Kris J. Hansen, PhD SBlMdgE 2T-3.E&-S09 935 Bush Avenue St. Paul, Minnesota 55106 Telephone No.: 651.778.6018 Facsimile No.. 651.778.6176 KriJs.Hansen or her alternate will be notified regarding the shipmentof the samples. Results will be providedforinclusion in the final report. "The third subsample will be processed to block stage for electron microscopic evaluation. The tissue blocks and a hematoxylin and eosin-stained slideforight microscopy willbe transferred to Sharon Ambrose Division Director 4P9at1h5olD.ogPyrAossspoeccitautseDsrIinvteemational Durham,NorthCarolina 27713 Telephone No.. 919.544 5257 Facsimile No. 919.544.3218 "Tissueswill be processed and evaluated by electron microscopy by Pathology Associates Intemational (PAI). A report wil be provided by PAI for inclusion in the final report. Sharon Ambrose or her alternate will be notified regarding the shipmentofthe samples. Additional Tissue and Serum Samples `Samplesof lung, kidney, spleen, thyroid, brain, abdominal fe, heart, bile, (approximately 3 g each), and serum (as much as possible) will be collected. These samples will be flash-frozen in liquid nitrogen and stored ina freezer, set to `maintain -60 to -80C, nil shipped for possible future analysis to KriJs Hansen, PhD SME. T.&S Bldg 2-3E-09 935 Bush Avenue St. Paul, Minnesota 55106. Telephone No.: 651.778.6018 Facsimile No.. 651.778.6176 32 111888111888..0.00333222666 3M_MN03279159 oocAompmarpiiaaavn) Kris. Harsn orher alternate wil be notified regain he shipment ofthe samples. Efective February 11 30d 15,2000 14 FLPaeegarer3m,yaPnr1o5pe.o2s0ee0d0n,StdueFdtyeeTihmbeeta1b1le,i.30hT0io0ccathniadonngoeeapnirdopdeosledaedatweeshpfoohrroinl(-llaiTofeewtiinveg ETxpoerimSenntalDoStear sDatte A2u0g1us0t9826,1998 dEUInrx-ilapieufeeidiTemedDermrnDilanraaTtReieroempnironDaamttDei:oeRneMupaeNor.ncyhDiT27,co5.2,b02e00M00d0ymi1n1,e1d999 AMENDMENT APPROVAL TSooCsovnodSennas b0). Sspeat" Si Ceoov+e taman ris Ba3 [30/200 Lelelonr . 118811888..0.00332277 3M_MN03279160 SOvANCETM PROTOCOL AMENDMENT NO.3 Covance 6329.23 IMT-6295.7 26-Week Capsule Toxiciy Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295)inCynomolgus Monkeys Sponsor: 3M, St. Paul, Minnesota ---- Study Monitor: Andrew M. Seacat, PD. Testing Facility: Covance Laboraiorics Ic. Madison, Wisconsin Study Director: _ PeteJr.Thomford, PhD. `This amendment modifies the following portionsofthe protocol. Effective August 20, 1998 I. Pcagoe 1ma6,noRemeipsocsritsot,n,FiandadltRheepforotl, lStoatwitsittinchgael eEvnadloufatthieons,ecPtiaorn.agraph 4. To sDaamtpalceolsliezce.ted during recovery will not be analyzed statistically du to the small Effective January 21, 2000 2 Protocol Amendment No. 2, Item 13. To correct a typographical error, change the font to bold on the following heading. Postmortem Procedures for Recovery Animals in the High-Dose Group Effective February 18, 2000 3. SPeangteen12c,eS3e. rTuomiPndOicSateLtehvaeltDeetreersmuisnaotfitohnes,SpSoanmsoprl'esSahnialpypsiinsg,ofPsaerraugmraph 3, `wsiatmhpltehse ffoorllPowFiOngS. will be reported separately, delete his sentence and replace Results wil be reported separately. 328 111888111888..0.00333222888 3M_MN03279161 CovncSeM 6T3629925273 Protocol Amendment No. 3 erm 4. Phaagteth1e2,reIsnulttesroifmtLhievSeproBnisoorp'ssyaSnaamlpysliess,ofPtahreaignrtaerpihm 3l,ivSeernbtieonpcsey s2.amTpoleisndwiiclalte be reported separately, delete this sentence and replace with the following Results will be reported separately. 5. Pinadgiecat12e,tThaetrhmienraelsuLltisvoefrtBhiopSspoynSsaomrp'lseasn,alPyasrisagofrtahpeh2te,rmSiennatlelnicveer2b.ioTposy sfoalmlpolweisngw.il be reported separately, delet this sentence and replace with the Results will be reported separately. 6. P"Taogiend1i5c,atPeotshtamtothreteremsPulrsoocefdtuereSsp,oLnisvoerr'sPaFnOalSysDisetoefrtmhienlaitvierosnasm,pSleenstweinlcleb2e. reported separately, delete this sentence and replace with the following. Results will be reported separately. 7. Preamgoev1e6,reRpeepaotretds,meFaisnuarleRsetpatoirstti,caSltaatniasltyisciasloEfvcahloulaetsitoenr,olPaanrdagtortaalphan4d. fTreoe triiodothyronine (Ta3t t)he requestofthe Sponsor,deleteth following. Cmehaoslueresstaenranolydlsifsooafl caonvdafrieaencweio(dAoNthCyOrVonAi)nepr(oTc3e)dwuirlel wbietahnaavleyrzaegdebpyrerterpeeaatmeednt moreaAsNurCeOmeVnAtspfroorctehdeurpeasrawmileltebreseavsaclouvaatreidataet.p =Tr0e.0a5tmleenvetl.effAelcltspousntd-ehrocANOVA croenctorvoelrvye)rwsiulls-beecaotnedd-ugcrtoeudpumsienagnDcuonmnpeaurti'ssomnasniyn-colnud-ionngetvaplruoecsedduurrei.ng. Abontahl.yses will be carried out with SAS procedure PROC MIXED or BMDP, or Effective February 18 and 22, 2000 8. P`Sapgoens1o6r,'sReanpaolryissi,soFfitnahl sReerpuomrta,ndResluilvters,saTmopliensdi(ceaftfeectthiavtetFheebrreussurltys1o8f,t2h0e00) saenpdaruartienley,anddefeecetshesafmopllloewsin(ge,lective February 22, 2000) will be reported serum, rine, feces, and liver PFOS levels (provided by 3M) 329 111888111888..0.00333222999 3M_MN03279162 ConSeN 6T3929s2273 Procol AmendmentPaNog.e 3 9. GPraoguep1,6,LPivoesrtSmaomrptleems.PrTocoeidnudriecsatfotrhaRtetchoevreersyultAsnoifmtahlesSipnotnhseorH'igahn-alDyossies of t`hmeodliifvyertsheamapmloeusnwtilolfblvrepcoorltleedctseedpaatranielcyro(pesfyfe(ctfievcetFievberFueabrryu1a8r,y22020.0)20a0n0d).to delete the text in tis section and replace with the following. `Samplesof iver will becollsteads follows. Opanreaffsianm,psleectwiiolnlebd,e spariesneerdvewditihn h1e0m%atopreuytlrianb-abunffceorseidnf(odrmuaplliinc,ateemsblieddeds ewdiilnble prepared), and examined microscopically s"eTthe0smeacionntdasianm6pl0etwoil0lbe,fluansthi-lfsrhoizzpnpeidn floirquaindamlyistiosgteon: and stored ina freczzr, KIiMs)E. TH.an&sSe.n, PhD 9Bl3d5g.Bu2s3hE-A0ve9nve TStepPahual,neMiNnon.e:so6t5a1.5757180.66018 Facsimile No. 651.778.6176 sKarmipslJe.sH.anRseseunltosrwhielrlabeereaptoeriwidllsebpearnaotteilfyi.ed regarding the shipment of the e"vTahleutahtiirodn.samTphleetwisllebbelporcokcseasnseddatboebmlaotcoksyslaignefaodreeloescitnr:sotnaimniecdrosscioepifco ght microscopy will be transfered to: `DSihvairsoinonAmDbirreocsteor P4a9t1h5olDo.gyPrAossspoeccitautseDsrIinvteemational DTeulrehpahmo,neNoNrot:h Ca9r1o9l.i5n4a4.257275713 Facsimile No. 919.544.3218 "ATsissoscuieastweisllInbteempartoicoensasled(aPnAdD.evaAluraeptoerdtbyweilllebcetrpornovmiidcerdosbcyoPpyAIbyfoPraitnhcolluosigoyn in hsheipfmineanltreofpiortc. sSahmaprloens.Ambroseo her akerate wil be notified regarding the 330 111888111888..0.00333333000 3M_MIN03279163 CovanScMe 6T362299252)3 Prtacal AmendmentPNaog.e3s Effective February 22, 2000 10. PPaargaeg1r3a,pUhri2,neSeanndteFnecc3ee.s PTFoOiSndiDceatteetrhmaitntahteiorne,sSuasmpoflethSehSippopnisnogr,'s analysis of the urine and feces samples will be reported separately, delet this sentence and eeplace with the following. Results will be reported separately. 11. P`Gargoeup1,6,APddoisttimoonratleTimsPsruoecaenddureSserfuormSRaemcpolveesr,yPAanriamgarlaspihn 1t.heTHoigmhod-iDfoysethe afomloluonwitnogf. issue collected at necropsy, delet thi paragraph and replace with the `(aSpparomxiopmfaltueelnygs,3 kgideaaecyh,, isfplpeosesni,btlhey)r,oaidn,dbbaiilen,anadbdsoemriunmal(efaact,hhaesarmtu,ch as paonsdsisbolre)edwiilnl befrceoelzleerc,tesde. 10Thmeasinetsaaimnp-l6e0stwoil8l0beC,fluansthi-lfsrhoizpenpeid floirqupiodssiitblceo:gen future analysis to: Kis J. Hansen, PhD. MBlEdg., T2.3&8S.0.9 S9t3.5PaBuuls,hMAinvneensuotea. 55106 Telephone No.: 651.778.6018 Facsimile No. 651.778.6176 KsraimsplJ.esHansen or her alternate wil be notified regatrhedshiipnmegntofthe Effective April 6, 2000 12. Pfeacgael3a,naRlyesgiusldaotnoreyaCothmeplMiaaynoceC.liTnioc,idenletcathlceomtuepxltdiiannetcheisesxeccetpitoinonanfdorretphleace. with the folowing. 331 11188811188.8.00.0333333111 3M_MN03279164 ProtocolCAomnennScdemNe2Tnt9229No52. 733 Pages "ATghiesnsctyudGyoowidllLbaebocroantdourcytPerdacitniccoemRpelgiualnacteiownisthstsheetEfnovritrhoinnmTeanlteal40Prooftetchteion DUeSceCmobdeero2f9F,ed1e9r8a3l),Reagnudlawtiitohnsa,nyPaaprpl7i9c2a.bliessaumedenNdomveenmtbsewri2t9h,th1e98f3ol(leoffweicntgive. ebxecedpotnieoni.n cAonmapllyisainscoefwfietchalGsLaPmsples for urobilinogen at the Mayo Clinic will not 13. Patagthee3M,aQyuoalCiltiyniAcs,saudrdantchee,foTloloiwnicnlgudteotahneexncedpotfitohn sfeorcttihoenf.ecal analysis doe cAnoamlpylsiiasncoef wfeictahlGsLamPpslaensdfowrilulronboitlbienaougdeintaetdthbe yaMaQyuoalCiltiyniAcsswuilrlanncoet bUenidtone in 14. Preaqgueir1e2m,eAndtdsifotiofneaclalFaencaallysSiasm.paldeds.theTofoclllaorwiifnygantaoltyhseisenandodfretphiosrtsiencgtion. "cTohleorsmaemtprliecsaswsialyl.beThanearleyszueldtsfoofrthureosbeilainnaolgyesnesuswiinllg aberopurtoivniedesdtafndoaridniczleudsion in the final report 15. Preaqgueir1e7m,enRtescoforrdRfeoctaelnatniaolny,sPs,ardaeglertaepthhis2.paTraogriancplhuadentdhererpelcaocredwrietthetnhteion following. m`Waittehriinal1s yferaormatfhterSspuobnmsiosrs'iodnesoifgtuchesfi(naAlnireLpyotrti,csallcof. tSheMEaf.orTe.m&ent5,ioMnaedyo C(lAinnidcr,eawnSdePacaatth,olPohgDy.A3sMso)cbiyattehseISnptoenrnsaotrio'rsald)eswiiglnleebse.ent tthe Sponsor Effective April 7, 2000 16. sPecatigo2en,anPdurpraepslea.ceTwoitmhatihfyfotlhleopwuirngp.ose ofthe study, dekee te text n this "oTtohearssleescstthedebfifoecctheomfitchaeltpesatrammaetetreiraslwohnecnriatdicmailneinstzeyrmeed dlaeviellys,byhocramposunlees, and cfyolnloomwoeldgbuysamnonapkperyosxifmorataetl5e2as-twe26ekwereekcso.veTrhyeperrieoad.ument period will be BY 111888111888..0.00333333222 3M_MIN03279165 CovanSchei6T32a9.2s23 Protocol AmendmentFNuos.e3s Effective Apri 17, 2000 17. Panaagleyz1e2,adAddidtiitoinaolnaslerSuemrusammpCloellsecfotriosnp.eciTfoieedftlhcytrotihdehdoercmisoinoensoaftnhde Sponsor to lipoprotein, add following tothe end ofthis scetion. r`Aonmadsdpietciiofniaeldaalniiqumoatls(1s.a0crmilf)icoedtfaht haedditteiromnianlalsearnudmrceoclolveecrtyionnecsraomppslieesscwoillllebceted sent on dy ice by the Sponsor Dr. Saoj Das, Ani Lytcs, for thyroid. sltiipmouplroatteiinng (hLorDmLo)nteot(aTlSHli)p,ophriogthe-idne,nsaintdy clailpcouplraotteedivne(ryHDlLo)w,-dleonws-idteynlsiiptoyprotein fdientaelrrmeipnoartti.ons. Resultsofthese analyses will be provided for inclusion in the AMENDMENT APPROVAL (ni, ts 7] Sania?+ StudywMoMn.itSocracat, PD M StuGdey.Director rd. PhD. Covance Laboratories Tc. --dfee Due Dae ; Va 33 111888111888..0.00333333333 3M_MN03279166 COVANCE PROTOCOL AMENDMENT NO. 4 CovaSnMceT66232995-7223 26-Week Capsule Toxisity Study with Peflorooctane Sufonic Acid PotassiumSalt (PFOS; T-6205) in Cynomolgus Monkeys "SSptoundsyorMo.nitor: A3Mn,drSt.ePMa.ul,SeMiantn,esPohtDa trem STetsutdiyDngirFeaccitliotry:,_ PCeotvearn).ceThLoimbfooartodr,icAsDIn. Madison, Wisconsin "Tis amendment mais the folowing portions ofthe protec, Effective 24 May 2001 1 oPcacguerr13e,ncPeosstofmo"rPtatehmoPlroogcyeAdsusroecsi,atEelsecItnrtoenrnMaitciroonsaclo"pyT,oaenldecatl aotchhearnge in Iinheernmaamieonosfl"theinstuhbcopnrtortaocctoolr,snddelreetplaalcleocwciuhretnhecefsololfow"iPnagthology Associates Pathology Associates North Carolina Division, A Charles River Company Bifectiv2e7August 2001 2 aPdadgietio1n2a,lAhddoirtmioonnealanSselyrsuems aCtolAlnectLiyotneT,oInl.eotn stchreuSmposnasmoprl'es,eacdidstohne 0do following totheendof taesection. Aretctohveerryeqsuuecsitfiocfetshewisllpobnesotrr,asnsefreurmedsabmyplthes scpoolnsloert10stAtnheLtyetrmei,naIl .andfor a(nLaHl)ysfiosroffemesatlread,iola.ndfocltiacdisailmmulamatliensg. hRoersmaolntseo(fFtSHh)s.eaanndaluytsensiziilngbheormone onded for ction he oe pe. 4 118811888..0.00333344 3M_MN03279167 a oeyn te 17 Spe2r00 5. Page 13, AiSern um Colt lcton Tore berio he Somers etcomno do Att ptoth spor sod sama piveny femrety ai Li a dieo -- AMENDMENT APPROVAL P Fiiaat l litorerin = =LOH dao) as 118811888..0.00333355 3M_MN03279168 APPENDIX 2 Individual Avimal Fate Data Individual Clinical Observations Individual Ophthalmic Observations CovancTe 2630295-2723 336 111888111888..0.00333333666 3M_MN03279169 37 3M_MN03279170 111888111888..0.00333333777 a3 3M_MN03279171 111888111888..0.00333333888 339 3M_MN03279172 111888111888..0.00333333999 0 3M_MN03279173 111888111888..0.00333444000 0 IM_MN03279174 111888111888..00.0333444111 sa 3M_MN03279175 111888111888..0.00333444222 ss 3M_MN03279176 111888111888..0.00333444333 sa 3M_MN03279177 11188181818.8.00.303434444.4 sss 3M_MN03279178 111888111888..0.00333444555 246 3M_MN03279179 111888111888..0.00333444666 1 3M_MN03279180 111888111888..0.00333444777 sa 3M_MN03279181 111888111888..0.00333444888 309 3M_MN03279162 111888111888..0.00333444999 350 3M_MN03279183 111888111888..0.00333555000 8 3M_MN03279184 111888111888..00.0333555111 m= 3M_MN03279185 111888111888..0.00333555222 ss 3M_MN03279185 111888111888..0.00333555333 as 3M_MN03279187 11188181818.8.00.303535454.4 ass 3M_MN03279188 111888111888..0.00333555555 356 3M_MN03279189 111888111888..0.00333555666 a1 3M_MN03279190 111888111888..0.00333555777 ss 3M_MN03279191 111888111888..0.00333555888 3% 3M_MN03279102 111888111888..0.00333555999 0 3M_MN03279193 111888111888..0.00333666000 s61 3M_MN03279104 111888111888..00.0333666111 0 3M_MN03279195 111888111888..0.00333666222 se 3M_MN03279196 111888111888..0.00333666333 64 3M_MN03279107 11188181818.8.00.303636464.4 ses 3M_MN03279198 111888111888..0.00333666555 266 3M_MN03279199 111888111888..0.00333666666 61 3M_MN03279200 111888111888..0.00333666777 se 3M_MN03279201 111888111888..0.00333666888 0 3M_MN03279202 111888111888..0.00333666999 am 3M_MN03279203 111888111888..0.00333777000 m 3M_MN03279204 11188811188.8.00.0333777111 m 3M_MN03279205 111888111888..0.00333777222 ES 3M_MN03279206 111888111888..0.00333777333 Ea 3M_MN03279207 11188181818.8.00.303737474.4 ws 3M_MN03279208 111888111888..0.00333777555 76 3M_MN03279209 111888111888..0.00333777666 om 3M_MN03279210 111888111888..0.00333777777 ES 3M_MN03279211 111888111888..0.00333777888 am 3M_MN03279212 111888111888..0.00333777999 30 3M_MN03279213 111888111888..0.00333888000 mn 3M_MN03279214 111888111888..00.0333888111 = 3M_MN03279215 111888111888..0.00333888222 EY 3M_MN03279216 111888111888..0.00333888333 ss 3M_MN03279217 11188181818.8.00.303838484.4 ass 3M_MN03279218 111888111888..0.00333888555 386 3M_MN03279219 111888111888..0.00333888666 El 3M_MN03279220 111888111888..0.00333888777 as 3M_MN03279221 111888111888..0.00333888888 8 3M_MN03279222 111888111888..0.00333888999 El 3M_MN03279223 111888111888..0.00333999000 mm 3M_MN03279224 111888111888..00.0333999111 m 3M_MN03279225 111888111888..0.00333999222 03 3M_MN03279226 111888111888..0.00333999333 04 3M_MN03279227 11188181818.8.00.303939494.4 05 3M_MN03279228 111888111888..0.00333999555 396 3M_MN03279229 111888111888..0.00333999666 37 3M_MN03279230 111888111888..0.00333999777 a8 3M_MN03279231 111888111888..0.00333999888 399 3M_MN03279232 111888111888..0.00333999999 "00 3M_MN03279233 111888111888..0.00444000000 "ol 3M_MN03279234 111888111888..00.0444000111 wo 3M_MN03279235 111888111888..0.00444000222 a0 3M_MN03279236 111888111888..0.00444000333 a 3M_MN03279237 11188181818.8.00.404040404.4 0s 3M_MN03279238 111888111888..0.00444000555 "0s 3M_MN03279239 111888111888..0.00444000666 wor 3M_MN03279240 111888111888..0.00444000777 0s 3M_MN03279241 111888111888..0.00444000888 "0 3M_MN03279242 111888111888..0.00444000999 an 3M_MN03279243 111888111888..0.00444111000 an 3M_MN03279244 111888111888..00.0444111111 an 3M_MN03279245 111888111888..0.00444111222 an 3M_MN03279246 111888111888..0.00444111333 a 3M_MN03279247 11188181818.8.00.404141414.4 as 3M_MN03279248 111888111888..0.00444111555 ame 118811888..0.00441166 an 3M_MN03279250 111888111888..0.00444111777 a 3M_MN03279251 111888111888..0.00444111888 a 3M_MN03279252 111888111888..0.00444111999 rE 3M_MN03279253 111888111888..0.00444222000 en 3M_MN03279254 111888111888..00.0444222111  3M_MN03279255 111888111888..0.00444222222 3M_MN03279255 111888111888..0.00444222333 en 3M_MN03279257 11188181818.8.00.404242424.4 as 3M_MN03279258 111888111888..0.00444222555 es 3M_MN03279259 111888111888..0.00444222666 ao 3M_MN03279260 111888111888..0.00444222777 EY 3M_MN03279261 111888111888..0.00444222888 w 3M_MN03279262 111888111888..0.00444222999 "0 3M_MN03279263 111888111888..0.00444333000 wl 3M_MN03279264 111888111888..00.0444333111  3M_MN03279265 111888111888..0.00444333222 El 3M_MN03279265 111888111888..0.00444333333 a 3M_MN03279267 11188181818.8.00.404343434.4 ws 3M_MN03279268 111888111888..0.00444333555 we 3M_MN03279269 111888111888..0.00444333666 " 3M_MN03279270 111888111888..0.00444333777 wo 3M_MN03279271 111888111888..0.00444333888 " 3M_MN03279272 111888111888..0.00444333999 "0 3M_MN03279273 111888111888..0.00444444000 wr 3M_MN03279274 11188811188.8.00.0444444111 ww 3M_MN03279275 111888111888..0.00444444222 aw 3M_MN03279276 111888111888..0.00444444333 a 3M_MN03279277 11188181818.8.00.404444444.4 as 3M_MN03279278 111888111888..0.00444444555 wo 3M_MN03279279 111888111888..0.00444444666 wr 3M_MN03279280 111888111888..0.00444444777 ws 3M_MN03279281 111888111888..0.00444444888 ww 3M_MN03279282 111888111888..0.00444444999 "0 3M_MN03279283 111888111888..0.00444555000 wt 3M_MN03279284 111888111888..00.0444555111 a 3M_MN03279285 111888111888..0.00444555222 as 3M_MN03279285 111888111888..0.00444555333 ass 3M_MN03279287 11188181818.8.00.404545454.4 ss 3M_MN03279288 111888111888..0.00444555555 so 3M_MN03279289 111888111888..0.00444555666 ws 3M_MN03279290 111888111888..0.00444555777 as 3M_MN03279291 111888111888..0.00444555888 a 3M_MN03279202 111888111888..0.00444555999 "0 3M_MN03279203 111888111888..0.00444666000 wl 3M_MN03279204 111888111888..00.0444666111 ww 3M_MN03279205 111888111888..0.00444666222  3M_MN03279205 111888111888..0.00444666333 a. 3M_MN03279207 11188181818.8.00.404646464.4 0s 3M_MN03279208 111888111888..0.00444666555 wo 3M_MN03279209 111888111888..0.00444666666 wr 3M_MN03279300 111888111888..0.00444666777 ws 3M_MN03279301 111888111888..0.00444666888 "wo 3M_MN03279302 111888111888..0.00444666999 mn 3M_MN03279303 111888111888..0.00444777000 an 3M_MN03279304 111888111888..00.0444777111 mn 3M_MN03279305 111888111888..0.00444777222 mn 3M_MN03279306 111888111888..0.00444777333 a 3M_MN03279307 11188181818.8.00.404747474.4 a 3M_MN03279308 111888111888..0.00444777555 we 3M_MN03279309 111888111888..0.00444777666 mn 3M_MN03279310 111888111888..0.00444777777 an 3M_MN03279311 111888111888..0.00444777888 a 3M_MN03279312 111888111888..0.00444777999 " 3M_MN03279313 111888111888..0.00444888000 irons agin,wots wl 3M_MN03279314 111888111888..00.0444888111 irons agin,wots 3M_MN03279315 111888111888..0.00444888222 irons agin,wots a 3M_MN03279316 111888111888..0.00444888333 irons agin,wots a 3M_MN03279317 11188181818.8.00.404848484.4 irons agin,wots as 3M_MN03279318 111888111888..0.00444888555 irons agin,wots wo 3M_MN03279319 111888111888..0.00444888666 irons agin,wots " 3M_MN03279320 111888111888..0.00444888777 a 3M_MN03279321 111888111888..0.00444888888 [Ee -- oo. 0 3M_MN03279322 111888111888..0.00444888999 naan ay mis . smarag Wh, TU UTES sensmawesse., 0 a_unoszrss23 111888111888..0.00444999000 naan ay mis . smarag Wh, TU UTE sensmawess., aM_unoszrss2e 11188811188.8.00.0444999111 vi etc eric - " 3M_MN03279325 111888111888..0.00444999222 vi etc eric - ws 3M_MN03279326 111888111888..0.00444999333 naan ay mis smarag Wh, TN UVES sensmawess., on a_unoszrssr 111888111888..0.00444999444 0s 3M_MN03279328 111888111888..0.00444999555 APPENDIX Individual Body Weight Data (kg) Coane 6329225 496 118811888..0.00449966 3M_MN03279329 rinagsove - wr 3M_MN03279330 111888111888..0.00444999777 rinagsove - as 3M_MN03279331 111888111888..0.00444999888 rinagso ve _ wo 3M_MN03279332 111888111888..0.00444999999 rinagsove - S00 3M_MN03279333 111888111888..0.00555000000 rinagso ve _ on 3M_MN03279334 111888111888..00.0555000111 rinagso ve _ wo 3M_MN03279335 111888111888..0.00555000222 0 3M_MN03279336 111888111888..0.00555000333 04 3M_MN03279337 11188181818.8.00.505050404.4 sos 3M_MN03279338 111888111888..0.00555000555 S06 3M_MN03279339 111888111888..0.00555000666 07 3M_MN03279340 111888111888..0.00555000777 sos 3M_MN03279341 111888111888..0.00555000888 COVANCE. Sponsor St PaulaMwinnesota Study Tite: 26-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295)in Cynomolgus Monkeys. Petr. Thomond, PID Study Completion Date Jamary 1, 2002 Testing Fac MadCiSos5v0oa1nnKeWsiinsLcsaombnaosrnianBtooru3il7ees0v1Ir2nd595 Laboratory Study dentition Spoor Study Wemfenion: IM Study No. T6295 7 Page 50901086 118811888..0.00550099 3M_MN03279342 VOLU1M1OEF Il CONTENTS APPENDIX 4. Individual Clinical Hematology Data. Individual Clinical Chemistry Data. Individual Clinical Urinalysis Data APPENDIX s. Individual Palmitoy] CoA Oxidase Determinations. Individual Anatomic Pathology Data. APPENDIX 6. Aniytics Inc. Quality Assurance Statements Summary and Individual Blood Hormone Determination. APPENDIX 7 Cell Proliferation Report APPENDIX 8. Electron Microscopic EvaluationofLiverin Cynomolgus Monkeys. APPENDIX 9. Urobilinogen Analysis Report APPENDIX 10 Dose Confirmation Analysis Report `Compound Stability Report Analytical Laboratory Report Certificate of Analysis Quality Assurance Statement CovancTe 2630295-2723 Page si 512 614 8 818 819 823 907 908 o17 963 964 977 978 1069 1070 1072 1073 1078 1080 1083 1086 S10 111888111888..0.00555111000 3M_MN03279343 APPENDIX 4 Individual Clinical Hematology Data Individual Clinical Chemistry Data Individual Clinical Urinalysis Data CovancTe 2630295-2723 si 11188811188.8.00.0555111111 3M_MN03279344 a 2 3M_MN03279345 111888111888..0.00555111222 BE TeTEBUF Me oe ss 3M_MN03279346 111888111888..0.00555111333 BE of Me We Ren Rend pI FE Buss masserinss super py wm un si M_Noazrsas 111888111888..0.00555111444 BE Pe He WlTRl on Eo wi sis 3M_MN03279348 111888111888..0.00555111555 Grow3s oree018 one hisssaharty ste. 3M_MN03279349 111888111888..0.00555111666 a si 3M_MN03279350 111888111888..0.00555111777 BE TeTEBUF Me oe ss 3M_MN03279351 111888111888..0.00555111888 BE of Me We Ren Rend pI FE Buss mesmerinss. semper spy wm un st M_oazrsas2 111888111888..0.00555111999 BE Pe He WlTRl on Eo wi so 3M_MN03279353 111888111888..0.00555222000 Grom3 oree018 one hisssaharty 2 3M_MN03279354 111888111888..00.0555222111 a 2 3M_MN03279355 111888111888..0.00555222222 BE TeTEBUF Me oe 2 3M_MN03279355 111888111888..0.00555222333 BE of Me We Ren Rend pI FE Buss marmerinss spies spy wm un Pn M_oazrsas? 111888111888..0.00555222444 BE Pe He WlTRl on Eo wi as 3M_MN03279358 111888111888..0.00555222555 Grow3s oree018 one hisssaharty 6 3M_MN03279359 111888111888..0.00555222666 a 21 3M_MN03279360 111888111888..0.00555222777 BE TeTEBUF Me oe as 3M_MN03279361 111888111888..0.00555222888 BE of Me We Ren Rend pI FE AT AP A wm un 2 M_oazrsae2 111888111888..0.00555222999 BE Pe He WlTRl on Eo wi 0 3M_MN03279363 111888111888..0.00555333000 Grom3 oree018 one hisssaharty 1 3M_MN03279364 111888111888..00.0555333111 a = 3M_MN03279365 111888111888..0.00555333222 BE TeTEBUF Me oe = 3M_MN03279365 111888111888..0.00555333333 BE of Me We Ren Rend pI A Buss mareerins. sumer py wm un a M_Moazrsa6 111888111888..0.00555333444 BE Pe He WlTRl on Eo wi ss 3M_MN03279368 111888111888..0.00555333555 Grow3s oree018 one hisssaharty ss 3M_MN03279369 111888111888..0.00555333666 a 7 3M_MN03279370 111888111888..0.00555333777 BE TeTEBUF Me oe ss 3M_MN03279371 111888111888..0.00555333888 BE of Me We Ren Rend pI FE Buss mesrerins. spies spy wm un a M_oazrsar2 111888111888..0.00555333999 BE Pe He WlTRl on Eo wi si0 3M_MN03279373 111888111888..0.00555444000 Grom3 oree018 one hisssaharty sa 3M_MN03279374 111888111888..00.0555444111 a sa 3M_MN03279375 111888111888..0.00555444222 a ss 3M_MN03279376 111888111888..0.00555444333 BE of Me We Ren Rend pI FE Buss mempeninss. swe spy wm un " M_Moazrsa7 111888111888..0.00555444444 BE Pe He WlTRl on Eo wi ss 3M_MN03279378 111888111888..0.00555444555 Grow3s oree018 one hisssaharty sis 3M_MN03279379 111888111888..0.00555444666 a sa 3M_MN03279360 111888111888..0.00555444777 BE TeTEBUF Me oe ss 3M_MN03279381 111888111888..0.00555444888 BE of Me We Ren Rend pI FO Buss smaseninst. spies py wm un "w M_oazrsas2 111888111888..0.00555444999 BE Pe He WlTRl on Eo wi sso 3M_MN03279363 111888111888..0.00555555000 Grom3 oree018 one hisssaharty ssi 3M_MN03279364 111888111888..00.0555555111 a = 3M_MN03279385 111888111888..0.00555555222 BE TeTEBUF Me oe BY 3M_MN03279385 111888111888..0.00555555333 BE of Me We Ren Rend pI FE Buss masperinsts spies spy wm un = M_Moazrsas 111888111888..0.00555555444 BE Pe He WlTRl on Eo wi sss 3M_MN03279368 111888111888..0.00555555555 arom 3 ton orks as nntis sar ss IM_MN03279388 111888111888..0.00555555666 a 1 3M_MN03279390 111888111888..0.00555555777 a ss 3M_MN03279391 111888111888..0.00555555888 BE of Me We Ren Rend pI FE Buss messes spies spy wm un = M_oazrsas 111888111888..0.00555555999 BE Pe He WlTRl on Eo wi 60 3M_MN03279303 111888111888..0.00555666000 Grom3 oree018 one hisssaharty so 3M_MN03279304 111888111888..00.0555666111 a 3M_MN03279395 111888111888..0.00555666222 BE TeTEBUF Me oe 3M_MN03279395 111888111888..0.00555666333 BE of Me We Ren Rend pI FE Buss marries. sumer spy wm un or M_Moazrsas? 111888111888..0.00555666444 BE Pe He WlTRl on Eo wi ses 3M_MN03279398 111888111888..0.00555666555 ca + nm ssoin saat + min. PA M_MNO3Z75399 111888111888..0.00555666666 a 1 3M_MN03279400 111888111888..0.00555666777 BE TeTEBUF Me oe ses 3M_MN03279401 111888111888..0.00555666888 BE of Me We Ren Rend pI FE Buss mesrerins series spy wm un w M_Moazrseo 111888111888..0.00555666999 BE Pe He WlTRl on Eo wi sm 3M_MN03279403 111888111888..0.00555777000 Grom3 oree018 one hisssaharty sn 3M_MN03279404 111888111888..00.0555777111 BE oe We TH HST Me a < 3M_MN03279405 111888111888..0.00555777222 BE Pe He WlTRl on Eo wi 5 3M_MN03279406 111888111888..0.00555777333 Ea 3M_MN03279407 11188181818.8.00.505757474.4 BE oe We TH HST Me a os 3M_MN03279408 111888111888..0.00555777555 BE Pe He WlTRl on Eo wi 6 3M_MN03279408 111888111888..0.00555777666 sn 3M_MN03279410 111888111888..0.00555777777 BE oe We TH HST Me a ES 3M_MN03279411 111888111888..0.00555777888 BE Pe He WlTRl on Eo wi sm 3M_MN03279412 111888111888..0.00555777999 so 3M_MN03279413 111888111888..0.00555888000 BE oe We TH HST Me a 1 3M_MN03279414 111888111888..00.0555888111 BE Pe He WlTRl on Eo wi = 3M_MN03279415 111888111888..0.00555888222 = 3M_MN03279416 111888111888..0.00555888333 BE oe We TH HST Me a Fn 3M_MN03279417 11188181818.8.00.505858484.4 BE Pe He WlTRl on Eo wi sss 3M_MN03279418 111888111888..0.00555888555 ss 3M_MN03279419 111888111888..0.00555888666 BE oe We TH HST Me a 1 3M_MN03279420 111888111888..0.00555888777 BE Pe He WlTRl on Eo wi ss 3M_MN03279421 111888111888..0.00555888888 0 3M_MN03279422 111888111888..0.00555888999 BE oe We TH HST Me a so 3M_MN03279423 111888111888..0.00555999000 BE Pe He WlTRl on Eo wi on 3M_MN03279424 111888111888..00.0555999111 wo 3M_MN03279425 111888111888..0.00555999222 BE oe We TH HST Me a 3M_MN03279426 111888111888..0.00555999333 BE Pe He WlTRl on Eo wi so 3M_MN03279427 11188181818.8.00.505959494.4 sos 3M_MN03279428 111888111888..0.00555999555  mp BE ae Me TR BN fe ins ; k= ) a 1 we "ea #3 5H We 3 2 wo aM_wNos2rsezs 111888111888..0.00555999666  mp BE lhe He BeBom Ronde oR JJ w aM_wNos27s430 111888111888..0.00555999777 sw con Rit sos 3M_MN03279431 111888111888..0.00555999888  BE ae Me TR BN fe mp We aM_wNos27ses2 111888111888..0.00555999999  mp BE lhe He BeBom Ronde Togs wareionrs agesior wo aM_wNos27s4s3 111888111888..0.00666000000 sw con Rit on 3M_MN03279434 11188811188.8.00.0666000111  BE ae Me TR BN fe mp We w@ aM_Nos27s43s 111888111888..0.00666000222  mp BE lhe He BeBom Ronde oR:J I J ws aM_Nos27s43s 111888111888..0.00666000333 sw con Rit 0 3M_MN03279437 11188181818.8.00.606060404.4  BE ae Me TR BN fe mp We ws aM_wNos27sess 111888111888..0.00666000555  mp BE lhe He BeBom Ronde oR: J ws aM_wNos27s4ss 111888111888..0.00666000666 sw con Rit Pr 3M_MN03279440 111888111888..0.00666000777  BE ae Me TR BN fe mp We ws aM_wNos27seat 111888111888..0.00666000888  mp BE lhe He BeBom Ronde oR. A w aM_wNos27sssz 111888111888..0.00666000999 sw con Rit so 3M_MN03279443 111888111888..0.00666111000  BE ae Me TR BN fe mp We an aM_Nos27ssss 111888111888..00.0666111111  mp BE lhe He BeBom Ronde Togs weirs wipes rior a aM_Nos27ssss 111888111888..0.00666111222 sw con Rit os 3M_MN03279446 111888111888..0.00666111333 mn 3M_MN03279447 11188181818.8.00.606161414.4 ois 3M_MN03279448 111888111888..0.00666111555 oie 3M_MN03279449 111888111888..0.00666111666 or 3M_MN03279450 111888111888..0.00666111777 Ct 4b on a smn FALE as IM_MN0G279451 111888111888..0.00666111888 69 3M_MN03279452 111888111888..0.00666111999 a 3M_MN03279453 111888111888..0.00666222000 a 3M_MN03279454 111888111888..00.0666222111 @ 3M_MN03279455 111888111888..0.00666222222 @ 3M_MN03279455 111888111888..0.00666222333 Crete oan oa nsmtg Cre at 2 en emit as 3M_MNo3279457 111888111888..0.00666222444 as 3M_MN03279458 111888111888..0.00666222555 as 3M_MN03279459 111888111888..0.00666222666 ar 3M_MN03279460 111888111888..0.00666222777 os 3M_MN03279461 111888111888..0.00666222888 a 3M_MN03279462 111888111888..0.00666222999 pe3 oee h801 Son iessat rp 3 oe rah 018 aa ies wu 0 3M_MN03279463 111888111888..0.00666333000 @1 3M_MN03279464 11188811188.8.00.0666333111 2 3M_MN03279465 111888111888..0.00666333222 a 3M_MN03279465 111888111888..0.00666333333 5 3M_MN03279467 11188181818.8.00.606363434.4 as 3M_MN03279468 111888111888..0.00666333555 pe3 oe eh S01 Son ieseat rp 3 on rah 018 aa ies wu oo 3M_MN03279469 111888111888..0.00666333666 a1 3M_MN03279470 111888111888..0.00666333777 os 3M_MN03279471 111888111888..0.00666333888 0 3M_MN03279472 111888111888..0.00666333999 0 3M_MN03279473 111888111888..0.00666444000 0 3M_MN03279474 111888111888..00.0666444111 Sotto nb oan ge ns mtg FATA on 3M_MN03279475 111888111888..0.00666444222 os 3M_MN03279476 111888111888..0.00666444333 4 3M_MN03279477 11188181818.8.00.606464444.4 ois 3M_MN03279478 111888111888..0.00666444555 oo 3M_MN03279479 111888111888..0.00666444666 1 3M_MN03279480 111888111888..0.00666444777 pO psn et 15 ont icsmaha os 3M_MN03279481 111888111888..0.00666444888 0 3M_MN03279482 111888111888..0.00666444999 oso 3M_MN03279483 111888111888..0.00666555000 6st 3M_MN03279484 111888111888..00.0666555111 652 3M_MN03279485 111888111888..0.00666555222 os 3M_MN03279485 111888111888..0.00666555333 Ct4 nb on. oa ns ng 3 tts 058 nape is att ee 3M_MNo3279487 111888111888..0.00666555444 ass 3M_MN03279488 111888111888..0.00666555555 56 3M_MN03279489 111888111888..0.00666555666 a1 3M_MN03279490 111888111888..0.00666555777 oss 3M_MN03279491 111888111888..0.00666555888 ao 3M_MN03279492 111888111888..0.00666555999 pe3 oe eh S01 Son ieseat pes net15 ont icsmaha 0 3M_MN03279493 111888111888..0.00666666000 a1 3M_MN03279494 11188811188.8.00.0666666111 FE Buss smmsreninss spies py w M_Moazrsess 111888111888..0.00666666222 os 3M_MN03279495 111888111888..0.00666666333 64 3M_MN03279497 11188181818.8.00.606666464.4 ass 3M_MN03279498 111888111888..0.00666666555 pe3 oee h801 Son iessat rp 3 on rah 018 aa ies wu 6 3M_MN03279499 111888111888..0.00666666666 a1 3M_MN03279500 111888111888..0.00666666777 FE Buss series spies PY M_Moazrss01 111888111888..0.00666666888 wo 3M_MN03279502 111888111888..0.00666666999 on 3M_MN03279503 111888111888..0.00666777000 on 3M_MN03279504 111888111888..00.0666777111 Soret nb on. nsmpg Core ot 2 en te wy on 3M_MNo3279505 111888111888..0.00666777222 a 3M_MN03279506 111888111888..0.00666777333 FE Bugss smmeninss spies on M_Moazrsso 111888111888..0.00666777444 as 3M_MN03279508 111888111888..0.00666777555 oe 3M_MN03279509 111888111888..0.00666777666 on 3M_MN03279510 111888111888..0.00666777777 pe3 oee h801 Son ieseat pes nt15 ont icsmaha os 3M_MN03279511 111888111888..0.00666777888 on 3M_MN03279512 111888111888..0.00666777999 rop3e So eth $01 oan Sitspy Srp3 oan h438 maw ins ay 0 3M_MN03279513 111888111888..0.00666888000 os 3M_MN03279514 111888111888..00.0666888111 2 3M_MN03279515 111888111888..0.00666888222 os 3M_MN03279516 111888111888..0.00666888333 Crt4 nb on ns ng Cte at 2 en ewig os 3M_MNo3279517 111888111888..0.00666888444 ass 3M_MN03279518 111888111888..0.00666888555 TM 3M_MN03279519 111888111888..0.00666888666 or 3M_MN03279520 111888111888..0.00666888777 oss 3M_MN03279521 111888111888..0.00666888888 oo 3M_MN03279522 111888111888..0.00666888999 0 3M_MN03279523 111888111888..0.00666999000 wo 3M_MN03279524 111888111888..00.0666999111 0 3M_MN03279525 111888111888..0.00666999222 os 3M_MN03279526 111888111888..0.00666999333 os 3M_MN03279527 11188181818.8.00.606969494.4 os 3M_MN03279528 111888111888..0.00666999555 ws 3M_MN03279529 111888111888..0.00666999666 1 3M_MN03279530 111888111888..0.00666999777 os 3M_MN03279531 111888111888..0.00666999888 0 3M_MN03279532 111888111888..0.00666999999 0 3M_MN03279533 111888111888..0.00777000000 om 3M_MN03279534 111888111888..00.0777000111 mn 3M_MN03279535 111888111888..0.00777000222 0 3M_MN03279536 111888111888..0.00777000333 EY 3M_MN03279537 11188181818.8.00.707070404.4 0s 3M_MN03279538 111888111888..0.00777000555 06 3M_MN03279539 111888111888..0.00777000666 01 3M_MN03279540 111888111888..0.00777000777 08 3M_MN03279541 111888111888..0.00777000888 9 3M_MN03279542 111888111888..0.00777000999 WE OWE Wh AF IE mp I ME of JE JR WE Togs sweden ies roy no aM_wNos27sses 111888111888.00.0777111000  FT mp mn M_oazrssas 111888111888..00.0777111111 es epi Sirs meer pm gar awwnoczresss 111888111888..0.00777111222 WE OWE Wh AF IE mp I ME of JE JR WE Togs sweceont ies arviog ns aM_wNos27ses 111888111888.00.0777111333  mp ns aM_wNos27seT 111888111888.00.0777111444 es epi Sirs gees mgr us awwnoczrssse 111888111888..0.00777111555 WE OWE Wh AF IE mp I ME of JE JR WE Togs swesbeontTM iretog ne aM_wNos2rsses 111888111888.00.0777111666  mp w aM_wNos27ssso 111888111888.00.0777111777 es epi Sirs wipers mgr aw noszrest 111888111888..0.00777111888 WE OWE Wh AF IE mp I ME of JE JR WE Togs sweat peesog ks aM_wNos2rsss2 111888111888.00.0777111999  mp an 3 kd HW Es Hn wn af Be aM_wNos27ssss 111888111888.00.0777222000 es HE ad E23 I] a fe Sirs mie imma epi = aw nocaresse 111888111888..00.0777222111 WE OWE Wh AF IE mp I ME of JE JR WE Togs sweden ees Sing p aM_wNos27ssss 111888111888.00.0777222222  mp ns aM_wNos27ssss 111888111888.00.0777222333 es epi Sirs mieers mgr je awnoczress? 111888111888..0.00777222444 WE OWE Wh AF IE mp I ME of JE JR WE Togs aweennt pees Sri ns aM_wNos2rssss 111888111888.00.0777222555  mp an 3 kd we ra a # # #3 ns aM_wNos2rssss 111888111888.00.0777222666 es epi Tors mien mgr m awwnoczreseo 111888111888..0.00777222777 ers wt goin tn oa ies = M_MNO9279561 111888111888..0.00777222888 m 3M_MN03279562 111888111888..0.00777222999 Gros 3 son ares oan ona hissmaha 0 3M_MN03279563 111888111888..0.00777333000 = 3M_MN03279564 111888111888..00.0777333111 Bt rms met =m M_Moazrsses 111888111888..0.00777333222 = 3M_MN03279565 111888111888..0.00777333333 Gro 3 Son are oan ona hissmaha ns 3M_MN03279567 11188181818.8.00.707373434.4 reso veh 0.5 mer iessaat 7s 3M_MN03279568 111888111888..0.00777333555 eis wt goin in om ies g 6 M_MNO9279560 111888111888..0.00777333666 w 3M_MN03279570 111888111888..0.00777333777 Gros 3 on are oan ona hissmaha EY 3M_MN03279571 111888111888..0.00777333888 7 3M_MN03279572 111888111888..0.00777333999 2 So eh S00 Sa Sts ry 0 3M_MN03279573 111888111888..0.00777444000 3M_MN03279574 11188811188.8.00.0777444111 Gro 3 on are oan ona hissmaha 0 3M_MN03279575 111888111888..0.00777444222 i 3M_MN03279576 111888111888..0.00777444333 2 So eh S00 Sa Sts ry 4 3M_MN03279577 11188181818.8.00.707474444.4 24s 3M_MN03279578 111888111888..0.00777444555 Gros 3 on are oan ona hissmaha 46 3M_MN03279579 111888111888..0.00777444666 LP" [O-- rt +o veh 0.5 comer ies saat wr 3M_MN03279580 111888111888..0.00777444777 ois wt goin tn oa ies ns M_MNO9279S61 111888111888..0.00777444888 9 3M_MN03279562 111888111888..0.00777444999 Gros 3 Son ares oan oan hissmaha 0 3M_MN03279583 111888111888..0.00777555000 i 3M_MN03279584 111888111888..00.0777555111 eis ws goin tn oiea s = M_MNoo2795ES 111888111888..0.00777555222 ES 3M_MN03279585 111888111888..0.00777555333 Gros Son are oan ona hissmaha 8 3M_MN03279587 11188181818.8.00.707575454,4 ss 3M_MN03279588 111888111888..0.00777555555 2 So eh S0. Sa Sts ry 756 3M_MN03279589 111888111888..0.00777555666 2 3M_MN03279590 111888111888..0.00777555777 Gro 3 Son ares 018 ona hissmalhartr 8 3M_MN03279591 111888111888..0.00777555888 9 3M_MN03279592 111888111888..0.00777555999 rr2 So eh S0. San Sts ry 0 3M_MN03279593 111888111888..0.00777666000 1 3M_MN03279594 11188811188.8.00.0777666111 Gros 3 on are oan ona hissmaha 0 3M_MN03279595 111888111888..0.00777666222 6 3M_MN03279595 111888111888..0.00777666333 ois wt goin tn oiea s 0s M_MNOo279557 111888111888..0.00777666444 765 3M_MN03279598 111888111888..0.00777666555 Gro 3 Son ares oan ona hissmaha 6 3M_MN03279599 111888111888..0.00777666666 1 3M_MN03279600 111888111888..0.00777666777 2 So eh S0. Sa Sts ry 8 3M_MN03279601 111888111888..0.00777666888 3 3M_MN03279602 111888111888..0.00777666999 Gros 3 Son ares 018 ona hissmaha mm 3M_MN03279603 111888111888..0.00777777000 m 3M_MN03279604 111888111888..00.0777777111 ave rT gis agente op ts wn sens aie spe m M_MNO3279605 111888111888..0.00777777222 mTM 3M_MN03279606 111888111888..0.00777777333 Gro 3 Son ares 018 ona hissmaha TM 3M_MN03279607 11188181818.8.00.707777474.4 ns 3M_MN03279608 111888111888..0.00777777555 76 3M_MN03279609 111888111888..0.00777777666 m 3M_MN03279610 111888111888..0.00777777777 TM 3M_MN03279611 111888111888..0.00777777888 m 3M_MN03279612 111888111888..0.00777777999 0 3M_MN03279613 111888111888..0.00777888000 TM 3M_MN03279614 11188811188.8.00.0777888111 TM 3M_MN03279615 111888111888..0.00777888222 TM 3M_MN03279616 111888111888..0.00777888333 EY 3M_MN03279617 11188181818.8.00.707878484.4 755 3M_MN03279618 111888111888..0.00777888555 6 3M_MN03279619 111888111888..0.00777888666 1 3M_MN03279620 111888111888..0.00777888777 ES 3M_MN03279621 111888111888..0.00777888888 El 3M_MN03279622 111888111888..0.00777888999 Ed 3M_MN03279623 111888111888..0.00777999000 m 3M_MN03279624 11188811188.8.00.0777999111 m 3M_MN03279625 111888111888..0.00777999222 ES 3M_MN03279626 111888111888..0.00777999333 EY 3M_MN03279627 11188181818.8.00.707979494.4 5 3M_MN03279628 111888111888..0.00777999555 6 3M_MN03279629 111888111888..0.00777999666 7 3M_MN03279630 111888111888..0.00777999777 8 3M_MN03279631 111888111888..0.00777999888 ES 3M_MN03279632 111888111888..0.00777999999 sw con Rit Gti3 So ath 7 Soe ts ary 0 3M_MN03279633 111888111888..0.00888000000 -- DE Liman minnie cg it wo M_oazrse3s 11188811188.8.00.0888000111 sw con Rit mgt fr 3 fom of & = 3M_MN03279635 111888111888..0.00888000222 sw con Rit Gis So th 7 Swe ts ry 0s 3M_MN03279636 111888111888..0.00888000333 sree latin | wainnni cay 42 0s M_MNO3279637 111888111888..0.00888000444 sw con Rit mgt fb 1 0 fe EO 0s 3M_MN03279638 111888111888..0.00888000555 sw con Rit Sti3 So th 57 Sue ts ary 06 3M_MN03279639 111888111888..0.00888000666 ns DE Lmcrin minnie ug psw_woszr9so 118811888..0.00880077 sw con Rit os 3M_MN03279641 111888111888..0.00888000888 sw con Rit Gis So teh 570 Sue ts ary 9 3M_MN03279642 111888111888..0.00888000999 jes SE Dwain minnie Ee] aw_umoszrssss 118811888..0.00881100 sw con Rit sn 3M_MN03279644 11188811188.8.00.0888111111 es epi Toit may ape awwnocarsess 111888111888..0.00888111222 ns DE Lmcrin minnie ug sw_woszrosis 118811888..0.00881133 sw con Rit se 3M_MN03279647 11188181818.8.00.808181414.4 sw con Rit Gis So th 57 Sue its ary sis 3M_MN03279648 111888111888..0.00888111555 ns DE Lwin minnie ug sw_woszrosas 118811888..0.00881166 sw con Rit mgt of 3 3 im of BE: sr 3M_MN03279650 111888111888..0.00888111777 APPENDIX Individual Palmitoy] CoA Oxidase Determinations Individual Anatomic Pathology Data CovancTe 2630295-2723 sis 111888111888..0.00888111888 3M_MN03279651 so te2 maiemmateey so 3M_MNos279652 111888111888..0.00888111999 so 3M_MN03279653 111888111888..0.00888222000 2 So eh S08 oa Ses ry = 3M_MN03279654 11188811188.8.00.0888222111 = 3M_MN03279655 111888111888..0.00888222222 -- 111888111888..0.00888222333 . w_mcszrsost 118811888..0.00882244 " -- 111888111888..0.00888222555 HE Se Bn BT SeR mae ws mares 118811888..0.00882266 sr 3M_MN03279660 111888111888..0.00888222777 asm 118811888..0.00882288 A-- 111888111888..0.00888222999 wo w_mcszrsess 118811888..0.00883300 mares 1188111888..0.08833111 -- 111888111888..0.00888333222 -- 111888111888..0.00888333333 fo Soi kBoede p B kgR te Er BR, 4 M_MNO3279667 111888111888..0.00888333444 A 111888111888..0.00888333555 HE BnHe SR aligree me w _ncszrsess 118811888..0.00883366 n LE a anIT RAE T w M_MNO3279670 111888111888..0.00888333777 111888111888..0.00888333888 HE SN nn NO SR [Eo Sin wmcszrsor2 118811888..0.00883399 wo am 118811888..0.00884400 " 111888111888..00.0888444111 , 111888111888..0.00888444222 " Sones 111888111888..0.00888444333 ; -- 111888111888..0.00888444444 " 111888111888..0.00888444555 " -- 111888111888..0.00888444666 " -- 111888111888..0.00888444777 -- 111888111888..0.00888444888 " Sane 111888111888..0.00888444999 " -- 111888111888..0.00888555000 " -- 111888111888..00.0888555111 " -- 111888111888..0.00888555222 . -- 111888111888..0.00888555333 BBPEn EI SET " -- 111888111888..0.00888555444  Sane 111888111888..0.00888555555 " Sane 111888111888..0.00888555666 " Sane 111888111888..0.00888555777 Saar 111888111888..0.00888555888 " Sane 111888111888..0.00888555999 " -- 111888111888..0.00888666000 Ea me so M_MN3Z73694 111888111888..00.0888666111 semen 111888111888..0.00888666222 w aw neszrsess 111888111888..0.00888666333 Saar 111888111888..0.00888666444 " semen 111888111888..0.00888666555 BI,JW eni J TR aw neszrsess 111888111888..0.00888666666 " -- 111888111888..0.00888666777 ErginBr mESE ss 111888111888..0.00888666888 " -- 111888111888..0.00888666999 - 111888111888..0.00888777000 ER,BYEnET SRR swmaszroea 111888111888..00.0888777111 " aw neszrsros 111888111888..0.00888777222 HE ST enEeGT SR BE sire, ra mrs 118811888..0.00887733 -- 111888111888..0.00888777444 BIJ, en iJ TR aw neszrsros 111888111888..0.00888777555 -- 111888111888..0.00888777666 BIJ, en iJ TR w aw meszrsrio 111888111888..0.00888777777 . 111888111888..0.00888777888 BEJ, en iJ TR " aw meszrsriz 111888111888..0.00888777999 " 111888111888..0.00888888000 BI,JT enBR fT TR aw eszrsrie 111888111888..00.0888888111 - 111888111888..0.00888888222 BIJ, en ifT TR I. aw meszrsris 111888111888..0.00888888333 , 111888111888..0.00888888444 BI,JT eni J TR ws aw meszrsris 111888111888..0.00888888555 Eh RS 556 M_MNoo791T9 111888111888..0.00888888666 " -- 111888111888..0.00888888777 -- 111888111888..0.00888888888 BI,JT eni J TR aw neszrsrzz 111888111888..0.00888888999 Sane 111888111888..0.00888999000 " aw neszrsrze 111888111888..00.0888999111 SRlan nm me a wn M_MNooz79725 111888111888..0.00888999222 ECE v -- 111888111888..0.00888999333 . -- 111888111888..0.00888999444 Sane 111888111888..0.00888999555 HE ST EERSe SR a mcszrsrzs 118811888..0.00889966 -- 111888111888..0.00888999777 -- 111888111888..0.00888999888 . -- 118811888..0.00889999 BI,JW enBR fT TR 2 aw neszrsrss 111888111888..0.00999000000 HeSW En NO SRR " wmoszrsrss 1188111888..0.09900111 RE Ls Bra AT 2 M_MNoo79735 111888111888..0.00999000222 U SET RH ELL TE Sa In: CREME nT H FaiaEyTa iRRE Ha E Fl E eT a l"RBi nTpFT Ta Rel llylF EeEeBg 01 on 3M_MN0s279736 111888111888..0.00999000333 U SET RH ELL TE Sa fe e Ri n a SERENE BL occor ei Tei RETR Rie ar so ro ss TRIce, sr me owe, E R t See E EiESSaE.EeB Ty BE R AE elHeE a on 3M_MNos279737 111888111888..0.00999000444 U SET RH ELL TE Sa fe ed EE EE Si Fa TR aR 0s 3M_MNos279738 111888111888..0.00999000555 U SET RH ELL TE Sa nL CERES me FB H aia EE yTiR R 81, SSFE ETP a TReoSrriTReFT l eke l(iadF HeR,tBnyd001 oe 3M_MN0s279739 111888111888..0.00999000666 CovancTe 2630295-2723 APPENDIX 6 AniLytics Inc. Quality Assurance Statements Summary and Individual Blood Hormone Determination Note: Thisappendixcontains information supplied and audited by Anilyics Inc. 907 111888111888..0.00999000777 3M_MN03279740 CATYATLICES mosmaosasosrmosamisussseanoznom hEcngeTEr50eSTS TSHee tndpeoBraee slton,atrlcoinepigans socieLty STETEoRa a,SiTtonsletSyrheestnho at Cs5 eddtoireene SPONSOR: CYVANCE L465 summa mT, ) 3.63, TH TEST, 77, TH mess 9-07% stv: (321-223 msmeses wk 94-78 7565! " teAYar I" 118811888..0.009990088 3M_MN03279741 ne 1B0E0 S12T37I0R0 Stheo5 BSa9to0r ue mvetioedotFoosnacogrpgs es SbeEenEFeThhe he ee re or ET HL Re Franklin 5.Newsan SPONSOR: Cova. LAB Ie smn cree Eee B57, 159 swnum Warig stv: (927-723 sewrssmn | sme aectte fn 97 os) wo 1188111888..0.00990099 3M_MN03279742 Comm Ni9t2s3 INCORPORATED sorssronss ss0asrasts dtSahatebacFIrwhaDeetroeGrroyeorpdeoPvrriatLcesatwbieoicdrseaste.oodrryTabbhceeelruoarwfcaitcvniyasos]ssnxzadaepvvodGireetn.ewioscldshsn.cdfeocnsrhsleylcSooaomskpdsleidcacoihnneescteeSdiwnikrtiuhnngs were Teportas to mamgenent. adaoccmeeshTtadhanettem,cletytaphT]oadfLsianoccuetssewdittvhheersdShaetthaeFOmN"eahtenhroaedtsEoErAdeerGsocorCdhiebbeLad,abSarrnaedtdeitnohyge Seeprogrt SPONSOR: COVE 4p Report Tres: TEes, cof 450 23,73, 5m ADIT oars: 1227-9% hatater5:Newman stv: 327-223 maRow To won: arr a FE efi 910 118811888..0.00991100 3M_MN03279743 ConTea3n20s-22?3 GLINYCOTRPOIRACTESD o soramrors es soss oroassrcomso. s mmana Ldtaahteb3orETwhaDeeXtroarzGye0ep3oPvrriaLeocasntbeioTsdrieaestrf.oeorrdybTahcePeclruoarcwfaticniveyca]esssnrsdeaonpvcdoioronwtvsieitdashntdfeocnrahcieylcSoaaEmoRbpdtieiSocminihmseae.teeEdwinittrihanwgs Gas Toporied th mansgements oaccrurTeahteelmcyehatphsotedfasinacuatsneldtyiheordeattsh:oo nm"eSCthRhaAovdeEsfoRrdee;oscortdhiebreEsda,vaesnroedadtietnrhsye Sroelpsort SPONSOR: CoypuE ABS Repos ves: CREST E55 5 73,7, 731 ADIT DATE: 30.7 Lahtetr aeee stor: (329-329 REPORT To aim. awit 8: 3.5277 29-727 GMEoT_ TE on 118811188.8.0.099111111 3M_MN03279744 ConTea3n20s-22?3 INCORPORATED soiesraies &eosorists GLtahibetorFTvahDeteAroeGrroyesopedoPvrriatLcoasbtwoieTrcdiaeetstfo.oarrdy,abThcabeclruoarswfaticinwcyaaelssarrndaeepnvcodiorentwwsieitdashncdfeocnarhcieylc5oaa5msnphsalodicsotnichecdaeteFdwinirdtaihnwgs Vere Feported io mansgenent. PaSrcnaccutTriIhacneteescml:oyltahapoTttilsaanscueessewditwtheehretd:ahtetah:eFomneTt3hhedogdesEfoorhdee,GsocortdhievreLsd,aboascnedsadtiotenhsye wreerpeort : TarFaaniuindiiidntor.AL,Fomin SENSOR: COMME 4465 sev 4337-223 Report Ties: corr TESS, 3, 3, 73,7, 757 AIT DATE: #-25-77 Reso: Towanms Youn AIT 4: 97-73% RCKiE on 118811888..0.00991122 3M_MN03279745 CovanScMTe 5e29s.2723 CLYTICS cnosssens ans openvor INCORPORATED o0roiotes s0020mams TTGhohooe.d'rfeLipanobaroltrsarteolprioyscttePdraancbdteilcoaewlslwaaSnsadsrowecivitiahetweEsdPdAxfmGoerooddcaotmLspalbiowarenarcteeoriwyeivtPihreawtcehtdeicFfeoo:rr HAeccaugreancaynt.and consistency and the findings Lora reporied i TTGhoeedunremaetttahlioyndesrefulWssIeetdthscwhteehree7Ddaatthase.aameTth9he8oredGfsooorned,ebsacbtrhoierbraestdorsytsunPddriaecstthiweeeersereSpoonret f Ga Ada ttor ke SENSOR: CoygucE LHS Ie srw: G329-223 REPORT TIVE: con, Tess 1 PE AUDIT DATE: REPORT TO MAWAGHMENT: AUDIT b: Feber 2.577 7-509 fe ARGRa H TTT] ons 111888111888..0.00999111333 3M_MN03279746 Comreseassasn REGRESS SRE euThtetaaraEe'poertaaStnLeoirrsiyteeeseSdnet"abslneaaialvboeuwwnaict)aysn`e"datsnoeaweviiiiaethhrweee.SddhaffeiaoSunr.uticcdnoagmsTspaalbivwrsaeanrrtcaeeenwSyToiertPpihoamrcmtvkehedeedrFtsoEo:nAr Sagem Ie She La sethIov ts ueed wyeraatlhe seB tvheoetrsModaeL scvroiabgeldiemitTthge resort GA udizor svomson: covpues sas we Mok: TRE. coma, m81 EEL 13,7 73, Fry, FY ADI DATE. nan sor. eu9-223 RAORTTo MNMGBNT. ADIT eam? 79-947 SaNbe o ots 118811888..0.00991144 3M_MN03279747 The seport Listed below vas seviored tox compliance ) with the mn Loa EEE RE CHET SOE RR nTonb s n SPONSOR: CoVAVCE 4ABS we Rano rus: 73,7 TH, ,3, 3, aa, 5705 arroars: Ha-0s STUDY: 379-233 Razomvaomoss Auer 5: 7-300 00-737. = Na 118811888..0.00991155 3M_MN03279748 - ooooOoOoOoO@ @O@O@O@O@0@0@C0ov@awn0cer@52e90.w2@23 [IS NCOR5 V)O(RNO7 TESDJ Sorstiorse sanierao-- rs ooFhrRaea.ufrfaEeilEpnyRaoIlrEtaaend1pdaiosystsetoFdnraaibncseat.tlieovawnelcslwyans`sd"earnsedicvetiiehtswhteeeBddPAffaioGemroaotcddnoaGmtTspaalbiowwraeeanrrtceoseryTw.seievtFpihreerewtisehehdeserfFs2oD:t%A Hh TTheeruTrmteHetlhoTdsFasuIisvEecdRkehwTeehreeeaRstthahe. ame"TtPohhnuordGasatcohrdee;Lsacbtrhoierrbaset.delsytsumdPdiraecstehimeseerssr.eHpoenrs ofan Ratio svosoR: CovvEE 4ad5 we NEPOKE TYPE: Frs, Fra AUDIT DATE: pono sxove: C329. 333 RMPOR TO MNAGHNENT, ADIT #4 or700 00-335 RAA1sT TTTE0 916 111888111888..0.00909111666 3M_MIN03276749 rie ontots 01 onan ni may on 3M_MN03279750 111888111888..0.00999111777 rp mie en tarts oe ic mtatte ois 3M_MN03279751 111888111888..0.00999111888 ares rin3 untots 073 onan nb may on 3M_MN03279752 111888111888..0.00999111999 rp ie ontots 01 onan ni may on 3M_MN03279753 111888111888..0.00999222000 rp mie en tarts oe ic hatte ol 3M_MN03279754 111888111888..00.0999222111 ares rnin3 untots 073 onan nb may om 3M_MN03279755 111888111888..0.00999222222 rp ie ontots 01 onan ni may os 3M_MN03279755 111888111888..0.00999222333 rp mie en tarts p---- oa 3M_MN03279757 11188181818.8.00.909292424.4 ares rnin3 untots 073 onan ni may os 3M_MN03279758 111888111888..0.00999222555 rp ie ontots 01 onan nb may 02 3M_MN03279759 111888111888..0.00999222666 rp mie en tarts oe ic hatte on 3M_MN03279760 111888111888..0.00999222777 ares rin3 untots 073 onan ni may os 3M_MN03279761 111888111888..0.00999222888 rp ie ontots 01 onan ni may o 3M_MN03279762 111888111888..0.00999222999 rp mie en tarts oe ic rtatte 950 3M_MN03279763 111888111888..0.00999333000 ares rnin3 untots 073 onan nb may 1 3M_MN03279764 111888111888..00.0999333111 rp ie ontots 01 onan nb may 0x2 3M_MN03279765 111888111888..0.00999333222 rp min en tarts p---- 053 3M_MN03279765 111888111888..0.00999333333 ares rnin3 untots 073 onan ni may 954 3M_MN03279767 11188181818.8.00.909393434.4 rp ie ontots 01 onan ni may 35 3M_MN03279768 111888111888..0.00999333555 rp pies tn ors fo ---- 956 3M_MN03279769 111888111888..0.00999333666 ares rnin3 untots 073 onan nb may 057 3M_MN03279770 111888111888..0.00999333777 Tops sens ot soon preg as M_oazrsT71 111888111888..0.00909333888 pits ints amissaos M_MNooz7eTT2 111888111888..0.00999333999 AT JE A 90 3M_MN03279773 111888111888..0.00999444000 oul 3M_MN03279774 111888111888..00.0999444111 on 3M_MN03279775 111888111888..0.00999444222 oss 3M_MN03279776 111888111888..0.00999444333 ou 3M_MN03279777 11188181818.8.00.909494444.4 oss 3M_MN03279778 111888111888..0.00999444555 ony sa iisBs br Sein ous. 3M_MN03279779 111888111888..0.00999444666 or 3M_MN03279780 111888111888..0.00999444777 oss 3M_MN03279781 111888111888..0.00999444888 ow 3M_MN03279782 111888111888..0.00999444999 50 3M_MN03279783 111888111888..0.00999555000 ost 3M_MN03279784 111888111888..00.0999555111 052 3M_MN03279785 111888111888..0.00999555222 053 3M_MN03279785 111888111888..0.00999555333 051 3M_MN03279787 11188181818.8.00.909595454.4 nr 3 ote take Sap ts ny oss 3M_MN03279788 111888111888..0.00999555555 rg i + ote Saad 0.7 eta iss shy 956. 3M_MN03279789 111888111888..0.00999555666 J-- ge rin 3 So eee 563 Sage ts cng ia 3 So ana $58 Soap ts Rn 951 3M_MN03279790 111888111888..0.00999555777 J-- oss 3M_MN03279791 111888111888..0.00999555888 ree Reo os 3M_MNosz79752 111888111888..0.00999555999 EE NT oe 3M_MNosz79793 111888111888..0.00999666000 ei di Be 961 3M_MN03279704 11188811188.8.00.0999666111 EE NT a 3M_MNosz79795 111888111888..0.00999666222 APPENDIX 7 Cell Proliferation Report CovancTe 2630295-2723 Note: Thisappendix contains information supplied and audited by Pathology Associates International (PAI) 963 111888111888..0.00999666333 3M_MN03279796 CovancTe 2630295-2723 PATHOLOGY ASSOCIATES CELL PROLIFERATION REPORT 26.WAECEIKDCPAOPTSAUSLSEITUOMXSIACLITTY(PSFTOSU;DYT-W62I9T5)HIPN ECRYFNLOUMOORLOGOUCSTAMNOENKSUELYFSONIC COVANCE STUDY NUMBER 6329-223 PREPARED FOR: TOXICOLOaGmY SERVICES BUILSDTI.PNAGUL2,202ME-N025,5134M4-C10E0N0TER PREPARED BY: PATHOLOGY ASSOCIATES-A CHARLES RIVER COMPANY 15 WORMAN'S MILL COURT, SUITE I FREDERICK, MD 21701 TWSormMaUCnour,sSoe 1 Fredaryel r0i70c(k01),G631604G01) 65 FAX 964 11188181818.8.00.909696464.4 3M_MN03279797 Coane 6329225 TABLE OF CONTENTS --_ Comes Namie 0000000 \Section Tate Sana Page w Qty AsurneStems Ww Agent V 965 118811888..0.00996655 3M_MN03279798 CovancTe 2630295-2723 CoFnoel SCltlyPNourmesro6n29Re.p2or3t Pusch I. CELL PROLIFERATION REPORT 26-WAECEIKDCPAOPTSAUSLSEIUTMOXSIACLITTY(PSFTOUS;DYT-6W2I95T)HIPN ECRYFNLOUMOORLOGOUCSTAMNOENKSUELYFSONIC COVANCE STUDY NUMBER 6320-223 PURPOSE "nTohremopunrepso,seanodf otthehesrtusdeylecwtaesd tboioacshseesmsictahle pefafreacmteotfertshewhesetnmaatdemriinailsoenrecdritdiaciallyebnyzycmaepsluelveel(s, exnomolgus monkeys foart least26weeks. "STphoisnsroerp,or3t,M.subrmeiptrteseedntbsy tPhaethcoelllogpyroAlsisfoecriataitoens f-iAndiCnhgasrlaensdRiinvieerprCeoimatpiaonnyfo(rPACIo)vtaonctehe Ssttudyy NAcuimdbeProta6s3s2i9u-m223Saletnt(itPlFeOdS;"26T--W62e9e5k)CianpsCuylneomToosligcuistyMSotnukdeyysw"i.th APlelrflausopreocotsctaonfetShuelftoansikcs aEsnsvoicrioanimeedntwailthProPtAeTct'isonpAorgteinocny oGfootdhisLabsotruadtyorywePrreacciocned(uGctLePd) Riengulcaotmipolnisanacsestwiftohththien "DTeilcee40mbofe2t9rh,e1U98S3)C.ondedowfitFhedaenryalapRpelgiuclaabtlieonasm,enPdamrten7t9s2,. issued November 29, 1983 effective MATERIALS AND METHODS Tissue Collection for Cell Proliferation SFaomuprlaeniomfaltshepelirvesre,xtienstgesro(umpasle1s-o4nlyw)eraendsacprainfcirceeadsafftreorm26eawcehekasniomanlstwuadys. fiAxedreipnrefsoernmtaaltiinv.e wpreorceteshseendsahnidppeemdbe1d0dPeAdTofo pasreacftfiinonbilnogcaknbdysCtaoivnianngc.eFpreormpreoatcocholblsopcekc,ifaicsaltiidoensw.asTpirsespuaerbeldocfkosr (HPACENA)e,vaalumaatrikoneraofndcelimpmruolniofheirasttioonshemica detection of proliferating cel nuclear antigen Immunohistochemistry for Cell Proliferation (SeScuipoenrsosotf pPalursa,fiFni-sheemrbeSdcdieendtitfiiscs,uePsiuwsebruergcuht, aPtA)j1m0 eannsdurpelaaceddheosniopnosciutrivienlgy pcrhoacregsesdinsglifdeosr SPtCaNnAd.ard SOtpaenrdaatridngimPmruoncoebdiusrteocfohremIimcmaulnomheitshtoodcshewmeircealusSetdintionsgta(inSOtPiss#u7e0s7)f.or PBrNieAl.(sPAuI'es saevcitdiionnsbiowteirnepienrcouxbiadtiesde wmietthhoadmofonroctlhoenadleteacntiibonodoyf(thePaCnNtiAgeunn-dantriebaogdeyntscormepqlueixr.ed fPorCNthAe Seexcptrieosnssiowneriencoceulnltserwstaasinelodcawliitzhedherbaytotxhyelicn.hromagen 3.3-diaminabenzicine (DAB). Tissue 966 111888111888..0.00999666666 3M_MIN03279799 Covance 6329-223 ----------------------------------------------------O CovFamos SCeellyPNroubss63R9e.pe3n3t Pel Cell Proliferation Measurements "3T0h0e0pehrecpeanoteaygeteosf hinepa1t0ocfyiteeds ionfS-fipvehra.seT(haebelLiInginintdheex,teLsIt)esw(amsaldeesteornmliyn)edwabsy sdceotreirnmgiantedleabsyt laSbceolriinngg ithnedenxuimnbtehre poafncPrCeaNsA-wapsossicotreedLseuybdjeicgticvaelllys waimthon4gbeaitnglebasotth1a0c0inaLreaynddiiscleells.staiTnheed Hienacvliuldyedainndth3e sbteaiinnginpgrreudnomainndancotnssitsatiendinogfisntutdhyeiascsiunearthraetgiwoans. nAoniengcautbiavteedcowriitrholtheslpidreimwaarys antibody. qFuoarlcietlyl opfrosluifienriantgi,onpervoacleusastiinogns,snsdlisdeecstwioenriengf.isptoptecrnuisaled paatltoewmsmaogfniceflilcualtaironpr(o1l0e0rXs)itoojnu, dagned Hfoirstiovmeorrpahnodlopgainccrcehaasn,geasn.d 4Ce0l0lXprfoolrifterateioanssadtsestcshreinb)eqduanstbiovfei.ed aHihsitgohmeorrmpahganliofgiycatwiaosn f(u0th0eXr aesvsaelsusaetdedbfyorecvoallupartoilnigfertahteioHn A slide prepared from the sume tissue block for cach animal Statistical Analysis "LTIhebeSttwuedeenntcsontHreosltan(do-tsrieadtemde.ntugnreoquupasl uvsairniganMciec)rwosaosftusEexdce1l vteesrtsifoonr $st0a.tisAtiPcvalalsiugenioffic0an0c5e oinF Tesswas judged be statistically sigrifican. RESULTS Cell Proliferation Individual animal prolifeaon in the cell proliferation lve, testes and data are presented in pancreas of control and teSsetctmiaotneraIIlt(rTeaabtleed a[nL1i)m.als Cwealsl similar Histopathology Sweictthihonesmaftrooxmyltihne asnadmecoisisnsu(eHblEo)cksfousheidsofpoartphroelpoagriactieovnaloifarPiCoNnAt-osftaainleadteslitdheesiwneterreprsettaaitnieodn of the immunostained alides. Individual animal findings are presented ir Appendis | lSiivnegrleasndectpainoconrfseaisvefr,ropmanc1r6e.asa,dualntd feesmtaelsefrmoomnk16eyadsultremparelseenmtoinngkecyosntraonld, silnoglwe-dsoescetio(n0s.0o3f emvgaklguiadtaeyd)h.ismtioldo-gdiocsaelly(.0.15Esmcyhkitgisdseuye)seacntdiohnigwha-sdossteai(n0e.d75wmitfhheF/edmaayt)oxeylaitnneaantd gerosoiunp.s wTehree ipnurtphoessee otfitshsiuessewvhaliucahtimoanywaasletro odretceornmfionuenwd hthee tspoehcienfiorctitymoorfphtohleoPgiCcNcAhasntgaeisniwngeroebsoecrcvuerdinign thse animals. 967 111888111888..0.00999666777 3M_MIN03279800 CovancTe 2630295-2723 CorFinrss CSllurNtenuio6n33e5p.5s5 tTehseticruelasrustissshueoswefdrotmhamamloe smiognnikfeicyasntocrhtahnegeisvewreraendobpsaenrcvreedasintiesfsuteesrftrhoemlifveemr,alpeanmcorneakse,yso,r `which would se the interpretation of the PENA staining in hi study DISCUSSION Imnotnhkeeypsr,esaenntdstthuedy,ivceeslanpdropalnicfreears oafsfemmeaalseumroednkweiytshinfrtohem cloivnert,roelst(e0smng/dkgpAalncyr)e,ssowo:f mdaolsee w(0e.e0k3smognlksgt/uddayy)1,0 amsisde-sdsotshee (e0f.f1e5ctmoefktehiedteeys)maatnedrihailghondocsreiic(a0l.7e5nzmyg/mkeg/ldevaeyl)s,ghroorumposnaefse,rs2n6d othe selected biologi! parameters, including cel proliferation. Tphanecrreeadsi,dansotdestpepremsisnetdo bbey alcaeblellinpgroilnidfiecreas,tivwehirceshpoenrsee tsoimtihlearteisntamlataenriimaallsi. the lier, testes or SUMMARY Iinnctrheeasperdesienntthestluidvye,r, ctell eproorlsifpeartcatrieosna,s aosf dmoentkeerymsi.ned hy measuring the labeling index, was not 968. 111888111888..0.00999666888 3M_MN03279801 CovancTe 2630295-2723 ILTABLE Legend ND, not determined due to suboptimal staining. NP, slide not present PLiavnecrrelaasbellaibnegliinngdeixn:dePx:ercSecnotraegdesoufbhjeecptaitvoeclyyewsitihn4S-=phisalseets and acinar staining heavily; 3 = Staining more abundant in acinar cells than sles Testes labeling index: Percentage of PCNA positive Leydig cells 969 111888111888..0.00999666999 3M_MN03279802 CovancMeT6632299-52273 TABL1E.CEL FROUTRNAMOTHOOYNS comesuono ePomta oom: Hrarrber [T r Fraregaoe Comer -- ---- ---- -- es lomarae (Core) . CHoe ssre [Jo0essmm oan y tdoowwcnees #1752 smeeast llooocsammaarreiyaacnyAoowwaacsse)y| f1z2 Mtoowsssdsro I 018ry sco Fs soionrs [(r0011e53mmaanaggpraoacnsydMMaedasoroyes) Ff#a3s lipoossssisss Toeineete ---- aor omot ooooinns oar te orwys aa0no2u0et ccGooismna ponctonasae TeTaogesan oT53 JI bia 3s i'hy 03i --y 3a3 E|l :5 (6e 28aay rgonan L Fi ros ss aGsiosorwna:33 | (0077sragnpgyroomey:Gingihnocomo)) ati liosossslsi0 ooaom. 33 | I oon omnes. 0 JJloeommmaaamggpiiiaaannn,yyCcCaoorrrrtreooynp TM M L ss -- s ooines. "33 im w50i0% manaConteh Mesa om 3 ozs sSaanng oGloovvaasoee WWEZ saOOnWSEI SOoommneeensn. 533 Tjieerr Sesosrmoangairoea(owawnee) M2Ma lHo0o8os1na6r omooemanen.n Css3e Eavrawosl 0o1r5smmoggrRaonrE((rcsose) MMsA s101n0S1Ts oomomemnee,r aa3 w Zahroue, 15Tmsgrhgngg/icscs; tarsaece)| MMsp 00ss meen ooiucesn mm i3 oFsre as ss 07Tsmianggrhoney(tinscoem MMed 010880087 0du0rs 33 aTie O7SmroamnogOOau sohm,es)MWEAIOSjIORS13 Fo - I]5 0J [5 . massessrcatsornysn o-- om otha [vP[eoavnrecrpreoecnrocSrocornooerpeedwrsmooapeotsecwyisinnsssehsje0onudGir inA ed ayGAD SeedsSor E8% 970 111888111888..0.00999777000 3M_MIN03279803 AR,o ---- ee k Coipal Ttm--Sty--ioFeaernSsoyleaA En -- Pots ee EeehHy = 2-02 sets sie Gg hr Carolyn Moyr, D.V.M., Diplomate, A.C.V.P. Js Date. on 118811188.8.0.099777111 3M_MN03279804 Coane 6329225 IV. QUALITY ASSURANCE STATEMENT om 118811888..0.00997722 3M_MN03279805 Comreseassasn --< PATHOLOGY ASSOCIATES Cott rtiteration Repors 26-WeFckoCsapssaulSeaTlox(iFiOyS,StudTy4w2i9th5i)nPeCfylnoroomolcitsneMSounfkoenyisc Acid ConesSudy No 329223 QUALITY ASSURANCE STATEMENT UU1oh,ScAolFDpoimoiennebprcoatchieaoGsnogBdeen,LnpaTcrSC,iR)PanTdcheascie(dCPLbIyoiheomPAYnsGloysmAeranseby ePctorof ta h eendhdeaaAUTh lowing bl i+ ond oF esto se SDuinah maces rEr Siasn tbi haoyDs ts we EnEe mReNiEnER Wa11E00 iwam Zi 8rnBtuel Quit Aare Offer iajoose fe 15milCou. Ske der MD 21761 301 GG31648 FAX 30163350 + spiro on 111888111888..0.00999777333 3M_MN03279806 Coane 6329225 APPENDIX I om 118811888..0.00997744 3M_MN03279807 CoTmrmians LWEEK GOTaApSSsIUTNONSCAILTTYI(nPrdFiOvuSid:euaTleaAsn)imaIlNEAFCiRUndNLiOnLgMOsORLOOOUESTAMoMNSkuELTgOSNICeMIaC sAiACeIDs.t Ql voor wirotooie rams wv ge Pw r v wma PEHrEanEccreanasE-NS-- F -- wo 0aI wane LEDi EEEElhiE,S---- J J ws ea E EEEldEE .A-- RE Fe I fe A JEE p---- --tr---- [E Ei Ee rr wwaowwf EEfeeRte wesw wen fEEE E BeyEEe tn , we wa EBEEmEErE Ll I co ames NSF 0ss21 2 wows E( HLiver ENiSs E md as 118811888..0.00997755 3M_MN03279808 ati Iadividual Animal Findings Eat, coRimroi Jur rosso -- ssn wo. EEE LE M ` Facress NSF eEE Edanr ar invoryshowsblocs oom TER, 70 118811888..0.00997766 3M_MN03279809 CovancTe 2630295-2723 APPENDIX Electron Microscopic EvaluationofLiver in Cynomolgus Monkeys Note: Thisappendix contains information supplied and audited by Pathology Associates International (PAI) 077 111888111888..0.00999777777 3M_MN03279810 JIT ranorooy assccimes mtornationst CovancTee52n9.s22)3 SRE eRxmGoLoGy Repu BOETCLVTR TOe NNCIRNTOOSOCLOGELSYASLAOTNISON SSUELEFKONCCAABCILD EFOTTOANSCIUToAYLSkTTUD(iYPOWSIT4H0r5t) oYAsMoS CpTSTY NER [-- Jas od DY 1 Pilot, AC try es tenons in Scent 1300 PREPAEREND 10T8 8S CIORAPTORAhTE sTOXICOLOGY ors 118811888..0.00997788 3M_MN03279811 Quy Asanese Soames CovancTe 2630295-2723 w 79 111888111888..0.00999777999 3M_MN03279812 Coane 6329225 980 118811888..0.00998800 3M_MN03279813 00000000000CCom0 rm e90 2w3 rA ooSkrrokT MLECVTRROE NICNRCOR sICOMMI C ENLOORNA A ZEELK CAAPSURLETEONIACITMYSTkUihDY sWI TRI On KO s TSE caursrtoy sem ss ok Ba pEm ve swne HASnte tT o ceh eLei o c em 0 t amans o rte soe e mpeeaee be fH-- anos a a i e--e --ta--Spe "hemee ecobeepefy TTetpoucpsmrprenisiteeAgntracti oems aeyAedeAnrRscTfoePohOiedirn128 Jeutetmmre ie oinsa vy oecSweapeeteie oChonm3onic ee ee 81 11188811188.8.00.0999888111 3M_MN03279814 0000000000C0 owmers0 aeswan EEr Em , c p innr gatreasliseo saBooeadssenon uSnte hae dnrcehodoe fori aheeers ePOas teen os ny ac poe mn? me re i ma l e ei teeene haed ApneEkee aaatorrs a e esere SLE mesE,A1te I ---------- Eon mm = f= R ea igem eu opensem msek moteeses ml n n e iope Dig Wes et a imhsdspeeeyroityse wr midb s rrlp at 0 ttt e tes posi fehem hain aot eee ecto setmmdstyAosmainit.eoeSepoeseebowap oiaeattonnd on 111888111888..0.00999888222 3M_MN03279815 CovancMeT6632299-52273 Siceeisefn(f20h%priaosctoochstseexldaomRween6e.4ifnTasooesdsvaetnnpchst0t1 op5gnsmnicgEeKaemovsnky'ss lSFdian otnamebH1lame0sdtoTnnbsiwsroo edaenr tTIoAEef)orsebtnhSdceisoh,ti ieonasofoePmnes esh AE TT Week er hg se343.79 Work rmIaioe os le [ TT S-- e a | T0Ciraneemcoanhtsxcmaoppecroo$ncshone5d00)wiRorh5 A nEtpocn cbsaetudnSiroient.woeCeoRuYtn,Olmoenedn iRECPtiienctsineacelroscircolnavhyetee camco ero1gfvooofeIapehesoPw.te awehcetoFnd illlnocnsx2d Fpocbsiohacsroccaoplhoye AbSkedeHs eSCmEotafPo.soTplo uetebsdopbscrsee, er ogy ere rn 2 Sn fons wer od AB RESULTSAND Discussion anrirtaelnsFneoew,en sSihiceidnoo2nfdH1.itRaSohsaootSnvyosSncce eodAcFhs kironmseirgrcgescoivoenefosxchhe marge sul the osap LMistiran SAEFsuhm1a0crocfsute chard.cwinhTsedsttsTsrokise 3dfTsgherae ssoesr,ce epGciannogenEineibcspoasdttooitglhayn rGcvipa vpinmin..ocnmeetdsaanogne2 ccompr0ovFbeh SeTaWeoekm ohpaeor0pn ctkorlems,acnnhers 083 111888111888..0.00999888333 3M_MIN03279816 ConeMs 6T320-s223 G J TR p-- ep-- fmm -- oe ------ TR TIE Ten enED Fis [P wea -- rT T |en nese nope mom 2 |1 | niint nonsh pemkeme ama||| 21| 2: = CDheneg.ntxipmni.eeooniisn|| - -i isnMmm Elm necetora micrscodepoiscvm ninas obfet,s STo3 enepk baypmrdpTepceeetlcomemyd osv8nsion Em eprertr aeeydfn ne. mTeessao nimtoA l(etsidneBY nSnSey Ose nTeresnaoiseeeaeccsaonmeaoppssfo reresdog eress.eTTitest TTR Som Tce FR A TOOr7u0cNe s TGoSuvpteagrazyise,_A0EsmISie CNNommope 00O7795T Nem aSeonye eemn NSNaoomt 000777859FFFeeemmmi.k Toomkeky apyy _S 2_st1 D prNfovma}d | 98a 111888111888..0.00999888444 3M_MIN03279817 0000000000C0 owmers0 aeswan r ime at id i e nas eps Ci, TT eo rng" Ere LiE pton me iTce BenoonooHsmenoen coomieo teetrse csd frie rent oma Bee STey me SonaTOREOF THOR SpremB eA Em TieneBs.Nol. DVM. PRD. goto Jove Dae - ons 111888111888..0.00999888555 3M_MN03279818 CovancTe 2630295-2723 1. Litt Msc and Tomsedvicn con Fnonrmda xmtscofpeeof gridon ds bts ings. 986 111888111888..0.00999888666 3M_MN03279819 Commra9n2s3: Lot werosconcEvaLATION pire cent Taw tie ein cspte Yo , 3.0.84 nin I RR _} Eh See ee Tv wae iSE it 987 111888111888..0.00999888777 3M_MN03279820 CovanMceT63e2592723 THANSMISSION ELECTRON SICROGRAPI INTERPRITATION Sty No 29.123 EM Speke Caomign otk TJ imsa Grows ISSamicacfrodese) Toe tive coment , Swe [R-- SantenLoos nck) Yo xs cin Felgen Ed S360 FnFieclasrasicneZssEdETEohn TrreilTi eopbeeossleaHn en4bc9i0nThg miaorxigodaatodbuso0Sotdomlso,ot i| ru Fiiotnasna orSee,li Tah ecahB pob,on tpsrifneoTcuaepdooe1ic5) eC ZIsSEiREsr eLvetoi u103o30%le.m d aoarrispoene einopfcrhtos ecssol. STreas,.tTcehiglrsi t woepub srites | CiaoieansnmeeereenResspnccoknr]aon oyoPl EoTEFtsnr dPieRaa yn. OAlorn Tpsle1r03y || e oSrtaiaemn eheeexep icgbau.naaOrdet 3dior hTBsenysCeaeenrebycmisa1 || {B Rralionroafceeesnhowsinrgmaetmop e s nThte siee tes ee. | T2li1e8cs8r3so3psLi.vreTooueendereoynopi1c0a3o3p0cKio.anTaoonsashtumeseprtpahs eoofcrp opiwita hn3osaobt lcr, || SB Ereydnefeoentaonages,sedse otymedsenh osroarpreo,nawhsceh. oTowetyowfo3) nZIeRrEd, eLpesHespaeocype.ps03s30K.eThoskpdreyedbd853 ys xls Craocegeiiseescesneegrnam.rt.ShTehse cean1dnh]1p4r1oinakedotccoorteoend cu.n Sve oss 111888111888..0.00999888888 IM_MN03279821 CovanMceT6a3229-52273 [mc --| IMT bis fepace 03. Aare ud clo srs mah cvs | | e en gr ni || [fs So Fe | 980 111888111888..0.00999888999 3M_MN03279822 CovanMceT63e2592723 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION So So:e221NT) Spe: Cm Monks Nest _tiescotis sss Gg: Sma ies Bk Non:_22628_ Seve PreNegaine Soo 218822 SinanLevon hkonc vox ramen Frogs gre nd S16aMarlon 20 rVepotrnpieheAZSeItTeeSkWHtI.eArAeTTYOTNT EKKR eo l1i RYp aR edPo 0C | Tns na Son cg on | onubhrnsdRscEoaRumn)aedocBodeJcaekpaensincsbesle25sn0cve Boe erps0edo ZCSISup30na,nLiero.sbeHnoeepaftopi10c5n3t08Ti.eTsohenciesco svoeonnsnoocdssoogtng Aenixd cpsaedlle. iionn Tao tormi certnee copofci oocis 8d3 A 7 | 8Sa8m3ee0d.iivStrevepau1n)eep.Te.n10sD3i3of0c%naemTs oeea s s epeist c4cos Tntioesns | ia echoniSnE.R. Aeimhs pmeoposfikslvof eKER ss eosfs,tpoeolfcowerdoe ||| eSocpiiiiTiiaeppThreounsc3uofognslcdsrbioessse<ipesep.ensbTca1mdho(rs3la1olwperneidsgse.orneAlsyde S| eZiImSEprRLoFZsIiSvEe2Sp.TiTnuectoorph i1m03ac2n0do5fTnoesfmoeubcomcornf oeosopcscereoep,vssey lo soe on"tsofhe,Sv psrt, rt. 990 111888111888..0.00999999000 3M_MN03279823 oan |i -- deri pane rn i ee | em Fo s | J I---------- creer | . 118811188.8.0.099999111 3M_MN03279824 Coimrmiass suns am ann Teorey Soa PR co Coma Wate ty ee Soin eTteeP ETTrg oeeid:gSO eorenFBS a S| R H T moT n TSe eok sh eeSspisoste | Ce te TS et mute ts ni | TT er FT i r e r eeLemIae es SAT It ty sg ions [E REe e me e eg | marginof thssection rograph.The Hghieendroshe-liaslcealisnpreisentalgong.| CE TT] o 111888111888..0.00999999222 3M_MN03279825 Shin Aneepreting Patologis (signaeoreanddate): mint May 29.2000 Features: ZIRT Liver. Wepatocyie [0.330% ThishepaFtoeoa curgye reousnd Si a re al Thee lhe tation of Gra asm clon Pca ov ros `lectronmicrograph.Theysapsutiastassueallayr.Theyex-miud bilaissciton. | | echoesan oct pn rolesed sgtbodes Pesabomesire sal | ESSe LEe en EE BEEmrR E pe n L | " 118811888..0.00999933 3M_MN03279826 Covance 6329-223 ----------------------------------------------------O TRANSMISSION ELECTRON MICKOGRAPH INTERPRETATION Sten Noe In Species pong Mkes om Toso: oeit Tarn Gro 5n3g ids Sef Bock No 275.3s5.ss Preaeprie No) ZI8EL Sent Less checkenes Ver X_N Ietr elopt(sgn SimMisa B20. FcFeTatIuroesrZmTbEgrCeerbsaTtniaplisryltTOlSoL0e%eTeoness ptaahsesm orwsrll oeGE eaormbntnctTbloocccuabsnoosuar rionsesservcoecaatrtheostio,a.rimdene.obTescnydarSpeempsmo0t | Zieliaya,ieeLispneeTnHieoE psa(4)HpSIn rN aTncaema reet nc net gd eodbpba { | paesofis"Sco soope acnodmseis,pe rcs ebosr isndets re |E1FL5i8Sn8o,1f sLitieongsohapheronlhsesyTpotbsia.iTidpcesrabyiiFsoncr(3o9)Poireigsfosorgsunbcho1m0, F21i8l8e4s6TLoieteipunnnexi1a03n20%cTooincmoarnrdobn e ps b cosendm gaonydo.t F lpiraoi fgp e3vnots epc nascors.c pTieytuebeheeht GSoE)hRe orss edrRoErgRe.hsGorosirve.otfSiherpeoxhvoeThhe BZoIpRlaaa]ncvoehnenToipardpounntnerSEWROOhSN.ayTcokchnhg daonecindtcproregdopspseshsevtt,isnenvlddet0 1p3o8s3s1lAeoshsereomriah.Tinetiooto(n4e)dportsaicoa:tne. poe RT ma mee.Fonds weeBA 904 11188181818.8.00.909999494.4 3M_MIN03279827 Commra9n2s3: TRANSMISSION 1 ECTRON MICKOGRAP INTERPRETA TION Sioa nos SmsCmts sks a ----vi= res Toe Lis ne ree Foi Soto S12 Santen ts X_N Ics Pe a S0gn84230 erTE TeyTh [rm areetrr ri o e oi ee dy | [Ena a DI Teroebenn ne | reel Tn ie, | [EERRE | ZeaB IRtEeeToaR cTthe em ip,n, 1a39% DTrtappdosrreeam yi SseaeS ussp s oS nr: ni a cERrsetnTh pmcrenasy e sph hu o omntn pcs sbofeSi hoe vent || ee po= } Comin a ge an e ST | 95 111888111888..0.00999999555 3M_MN03279828 000 CTomwmr9e2w3 TRANSMISSIONFLECTRONMICROGRAH IN HRFRFTIOAN Soo 35 Ee SpecCsmtstne sep Tae tir sont Termeni meh ck ot seam Praocpsnenos Bee Samoans @koner te X_N ningaio edssYen84 0300 Va eeaturem cs: ZIoSe SsETtLinemoor kTeinoep,anwocme yseoe n1h0a3o30b XpThissbeegywopiepe daoosensposyroiuirdeed | Str ieanesh SS cn oed pa. mI B etLcynastae npaauaTrnRia aShhSsiaknews7i1S8a55odTeoee sssdiiamts stnof | EPrEiirfe etyeonvcbseie6S3ark 5S T e98y sspe e aLimsn.e5 ei eo en cops AiiSsi crenenAnaia0.chP pdefrevooeps t eene cciPsnr r rgemebs sof E rTetsTnok tHasporeb 10330% Se out nar s cmg d a rinaoee ene est p sere |Conclusions: Normalbepwiocyien Peroavweragre 7a30spermBepeaioesyie 996 111888111888..0.00999999666 3M_MN03279829 [r--e--n orn, soem, nano-- sSRmT tn a A ------ ova ima I Sev Female PhonoNeparive Note). 718862 loterpeting Pathologist (signaruie anddae) Hp Miy2e.200 Ft0eaotunrneast:ionZgIeTcSiSo.plt Caisvserco oiempasiom cpaybieae.nsde oon1so0S.sE3R3m.0 ceThsehhoefeegthpmeoesgaeint.s 3omraoccohpodyncientes.nnea|| o EE S a ne i m Sr t R p eT amorspmaetst multi areasofgiyeoge: raneaccumulation.Theseare lighilystained ress with || | E ESlm I oe mr Se enwA p s ome i es togae tS oE ngrioT iL , em || n r EEdh See i a EeTo emB Lifer sbeaa te oTeTReit E i a ee ei os Aer [rm Concluskons: Normal hepatoyS--------__] ics Feioniomessera 15.2per Iopwoevie. o07 118811888..0.00999977 3M_MN03279830 Coane 6329225 98 118811888..0.00999988 3M_MN03279831 [---- L sB on iRE e ihR we STCIlOl ReSET pSmSe O EtRaReL EaSa a RN ree ERE S oSCEnaL l Rb R ePE N RG NCiEgSaeI es e C S aReR i d Re ien RLaCl DE Rr EL bWTe Sai A a idS t A fGiG gDIaE TaTE lONESE Rr CA N e ES Se GaN REY, L 4 eiagrArD Taie ne"aCCUISUIeNdl Sd EE et| MYE INNE ae e ae HEE FR oe LS o iw g e aBr eGe Ra a BREE ERS CAR bo Wan FG ARNEL 0 118811888..0.00999999 3M_MN03279832 Troe lee 0 FeSdE SAE AEE 1S BET GOREEAESEhGx * Flin Ely EtBD er Sov OELig cal Land opte IERTR A, ak SNe WC F Ba ee a i aet d y1Bg aaeM " E konaoHm pSeEeEs RWEECEh 5 i Bhsco SRG a DR Rea eT T EL d onOSRi Oe E aa e NSEaEa gR SeBa S na a vs der Cor BRONCO ETogtes U"aReE HAOSRRSOR lnPL FS aeeT iade Gdea T 3eeBl SSge ] BN Ton. Nl NB WAR ono 118811888..1.110000000 3M_MN03279833 REL TREE SEE fe a kehse Gay. it LL I on Pas hTeHoaEmR oAao eete s sO.ERsWhoee C Sao memte Bos ofitls eaie ELSE ae Seger lB Re SErr a EgaTte (Oe UBy eaPE be TBVOieRoEosomesB esUC oCo iL rJSER ELSI E ed ns ee SS r a R P Ra E RgAe RRSCIR OSEeFeel on 1188811818.8.1.1000000111 3M_MN03279834 a Eo Sram FUE Lr an LU ahSRR SCEE peMinee sa apBy SEG Raiden Pe ET Fda8 N e Ge I e Foeoln: JUOYdeiane e SaElR RNCyos; a, Bse Si e han WE Ts Ne Tol ale EABROwLeSearen e Soi e AR CRITI SRT aS SE TR SEER ee on 118811888..1.11000022 3M_MN03279835 CovanMceT63e2952273 frei [rr EMigAoiiScatano.fPh r nssnicaior n dpciso0 bicik of0c0h0 t The ti Eaoros,nosift vehart,dceeipeb nn socorno re npd cv cpreyoki pekshioe.s genAnint.doSofrSea4c5t52,075 hay 5 dn) Saeki, 030K ion Bw aie2. Lie. Bm eto. laytco"penscuSmlaHoeEtse07do7wms.gGshhenet FeeI, SLitvear HeopsFocye sa hoo orEmUexop4araiciiciWE,TS.hAe sAight TSSE21073 mig ihn era 7 nk rm 0 mescton BEEiE5d510.L7oem. yep teghshdorweinfgesre,l9yowapck scoog03n0K migNe m 1003 111888111888..1.11000000333 3M_MN03279836 CovancTe6630295-2273 Abition = : vfKio = Index LaloUtrssncrs Strate sane Nockaremvlope Lael RKRoesehoeentygin ican freemen 1004 111888111888..1.11000000444 3M_MN03279837 Coane 6329225 1005 118811888..1.11000055 3M_MN03279838 CovancTe 2630295-2723 QUALITY ASSURANCE STATEMENT AssuranTcheisUenlietcaisrornemqiuicrreodscboyptyhestGuodyodhaLsabboereantoirnyspPercatcetdicaensdReaguudliatteidobnys pthreomQuulaglatied QbuyaltihteyUA.Ss.suFroaondceaUnnditDrwuhgicAhdmrienpiosrttrsatdiionr.ectPlAlyIo mhaansaagefmunecntti,oniTngheanfdolroewsipnognssivea.record of inspections/autits and ther resuling reports: DInastpeecotfion PhaseInspected DfaMotaenFaigndeimnegsnRteported and Study Pathologist an.299 Data Audit a9 m0 Draft Report Audit 4299 nase Audit of Data from Adional Groups. mee 7319 Final Report Audit M399 525.3000 DReactoavaenrdyDArnaifmtaRlesport Audit 513000 91100 Final Report Audit 9/1100 sfuhaitay AGsmesWuarradn_ceBSSpeciRaOliAsPt-GLP. -- fer Sponsor. 3M Corporate Toxicology. Test Article: PFOS. Study Number: 6329-223, PAI Study EM-99.76 1006 111888111888..1.11000000666 3M_MN03279839 (B PAz L FPaatthmoclosyAshssoscoicaatteess mIentremrantaitoionnaasl S= REp TR fron Ra E Ca T ---- ErrE SSA wr 1188111888..1.11000077 3M_MN03279840 LMgerMicerosecopyisndnTrafsomrsmieon Econ Tonsaision Becton Mcrognhs Quit Assn Senet CovancTe 2630295-2723 u w w 1008 111888111888..1.11000000888 3M_MN03279841 Coane 6329225 1009 118811888..1.11000099 3M_MN03279842 CovancMeT6302952273 CTBE PAANTCHIOLLLOAGRYYRSETPUODYR,T LOEFCLTIIVOERNIMNICCYRNOSOCMOOPLIGCUESVMAOLNUAKTEIYOSN S2U6LWFEOENIKCCAACPISDUPLOETTAOSNSIICUIMTYSASLTTU(DPYOWSIITT.H42P5E5)RFILUCOYRNOOOMCOTLAGNUES MONEYS CLPIAEINSTTSUTDUYDNYUNMBOERMEAB192E95.7.R621 suanniRy eSreplcoiactmoa1f cdyvnyoapmoeclrugouposhmsyowdesrBepspewriiinoe0g7yy5bcymggshPoRcOoSgcioyrfioeHn2j6oeweaepnkds aidsuviadyfian in{icdhceaeeadap0dddsaderlvoepslrebctserwtaiwnteeheanaboeddpuiaoetnso.faIosrc.egdhUl<pAksdncdeuormaglssy.esdexweparemwsrenetorbodl bieypoFtnohicilcucodppivnoyggaesndcowwanischpsceedsewtinehhedepefmignpwrosienhtcuiipghwhederaghc.dionveTihaeec.id Tm recoa oifPRnOSi (onibddeen vocp).vcsaion (hp ropeecsmisiony wach15 Qe muaanPiaRtim OonSof.ei soUislobriel esssveewisote tfpreeevee cesssi cbedllreascrmsonsescridoowsniphoyGf0m1iic0nch1don5ei1r2i70a 5 AE ntdsermblbecwee como 0d eed rns he samples varied PROCEDURES seTIlnoeesctieod nteii1nn0ao3lsfpritenraaa2l6qdwueewakaispaceleoinnneoicrblyotreodiyfcwriemhciePssRoObsSoowipeyhnecrvoneessssfnodm,eesnse.d paenparli,ichseemsnbdmeoedcemdiavleassanacndsdoponmnstiwschthsasuleudor.oigeopfesetosscssoLsgewimincetocrpy lFoorttehtouchytsitalt,o2e2 dlle2fo0r2ael2e6wceyemkslgcoorimnagsks6v4eeTgeiv1eth st 1010 111888111888..1.11000111000 3M_MIN03279843 - ooooOoOoOoO@ @O@O@O@O@0@0@C0o@uwn0sr@63e2092w2@5 TeTe Gn DesiBnr Ln SE EE TEE ee gm ASEE RT ne ULI ronS3 ntRS et me st rT r ets. Aptro tafcoedeprionddnd5vyahsetcpoeadreos weecing SIIepprarcap.aAbKdamomo reaoefnI e(10%cacrthsomnsd e.h3Tpoaoosrtiee Fett py rEpoanioodifsedntciteneeHme otschkxem HbsAEotrwaei thSsrhshoens iusosoisnmieCenEs,Attaeslypoexnag5sso5wmd4rma5imnss0fdceaoehnSd(Gedstgoh oesr3 nkTsodo ieeotenrCosaoaiofetlescinstoeh nf.ri nnsF,pob gehA toee fI iE on reprees tmomess denvi. p nd seasncsokI ote Tee. mtSd erm ETSRoorttne To[r mre |OEeons || TcoS ins Ciaacmtsspporm$sn 90a)hfo5m% eSnpoe. cetseesvRestcu.scoltns 1011 11188811188.8.11.1000111111 3M_MN03279844 Cones ar2e9s2s3 Ee oene aid oaelieye Ep COunEo ipo ase EmaHav.esaEusEe 1s03nr le s e BEh eo ecoe secdeSo ss op e eseydbS epeneogshy ee - ee eer RasuLTS AD DISCUSSION i n Sae ei g t phS mmca ee a T itsl mas og, eg i Mens T a E F T te Ee oe ee spat Ea o me e r a R e T e s a e, ste oT. oe withhepatocellular hypertrophy. Styof svns : Toi2 118811888..1.11001122 3M_MN03279845 Comfsariniazes [EE -------- --a -- a a Tz Pel eC E te n a e nigr E P I eee e we mYme , Sr -- T-- e-- er -- ee)) paBF I rrEEeIaILsIReST r neaer ei y 013 111888111888..1.11000111333 3M_MN03279846 cofrmisot (P77) PapnecsltoongRAessspoictseemoonm.a.r..SREe:ASPE, SEE e BNEo DB Eo ABEE BE wn te p EEeeme me-- BE ---- SEBEseeL m T a mE ms 0 EBBEEEEBOEE E OEESem e T H eS Tm1p 500 teers 1b0e3r 4sptT eT pesepelCo flfa.aeFo R e pC eTei r r e T , 01s 111888111888..1.11000111444 3M_MN03279847 covmaas I -- pr FEES = i pr | g------ B Ie n tertt eT ene ssTrTeeee epoti ece n tetne g t oto 7325 EE E TrSeeL maedItrn S a ee eel, E FB TEREEe TL -- ioese R pebe mmemeE eH e mt S peoT rrr en 150 ine Tsa ors 111888111888..1.11000111555 3M_MN03279848 CovanIcMTe 66302952273 IRENE dDiofsfearnendcecsotecinceso, Mondocnbsfomceoanssse wegephscieenreibdre1eSNiTgh Terabe Brees ATE (gre 5 10. meL arkae roeh(e0n0dw 30m01wgimhs afcgo.dnecyFsioufsnPgE.OSLciidepdoosctoeeni cypnaramytymnpsiiid scsnoramsseoeim sEceuumiaotcayiosns(ditmn aboNosdo0e551l4esangd 5p1s5)0 hHaovemSeH:ENinEcesedd gdUprlolee t SSchimiettironewaasct1 sec thCeowhwodsose esawlas olehd peosscaisida.d males. fbaoctligoni,c visssom2dacslmpsheeag.adAas oprdicdlr,oppldeteiespics.2 aFogl 1.cs llsres bao fom he low-dose$505. Foeslseddon(1s0ifoer,frtihess eTegx nTabbleer5of eonsomes pe besos ws 75 fo DRoeseep0d.1gmsgea)s.Tahee wsbech ssofe edasdoceokeevideynceesnof 015 PmROSeetgodf cFafOcS oTfhcseaedcepeelt015dgscy cclaiooen tcisocliaivoen) he akheed rveenP1RONsoCpe fr: Aedcail No JtObSeS. hdd sfenedsgceuraisnse,d t3 Froiremnisddos3e vFiralfsltee aTrexaTuablem5.ofbipuiep12erl s esu bepeps t wiso167r0 fthse radose oun. coxcusion EURlOsSncidrylfeovr2alaaiohnsofeenrfsiefdomcscyenodmoUlgismderospkleetsswistiedowipht07y5 mg eIeremuedmidnfg isp eidgxphdisvsweetrtrees.eeTdthep3sbeotreaesresdcpiroklgSsuerxgeiwsanoprsi0ned8w5ihfo eeproceaignpoaeogreytshsedHiVgeh-dlosrenalsc.dbyTheLh ectrovpesfhoadewaith ceere.d acuta Quntiaion opfpdedrsoploetseiciun )Ftwat 1b3y p lon g ocfhFoRsOeS(sa miidct gr) mmghsgfieny fUenlcestSure sCceirecsealal4meedasUnfstseeodrwiriohc0ab0o3r.cd01a3weere0s275k eral ta conn 204 eed wis hesaps xsd 1016 111888111888..1.11000111666 3M_MIN03279849 CovancTe 2630295-2723 SIGNAOFTAUUTRHOER Fr2n] t Diora. ACV en13 14s REFERENCES CrBeosirsseK-rLsiighAmhtImaigcSersooAsfcoa pic1m5o8rpbn ametiocvet rbleskoafa npeeDrAoBig amebsy ooti.nHicstocmhaeme Rteye, UnN parT.heLsoeesst.sdSsp0eci1es d,ie1n8e8s ine discuosfse 07 111888111888..1.11000111777 3M_MIN03279850 CovancTe 2630295-2723 I LighNtiMcetorgsnohpiysenedaTiorniocmine L eee kyO -- 1018 111888111888..1.11000111888 3M_MN03279851 Covance 529.223 -_-- raw LIGHT MICROSCOPIC EVALUATION Study No. 129:223 (EM 99.76) SpecicyStsin: CymamolzusMonkeys Animal No:_see below Tse: Liver Sex: seebelow Interpreting Pathologist signature and date) enn 210 DeCsrcnfgGhrsoe|p NTuRmECesr TT Toe aMicrposcophic aFidingss ainmd iCaonmdments - (CVoiemra) [10T50881178 | 11 . Infirtuee,. mymphpabihsiocmtoicf,omommliinnfetdocal, TREE 221 ClgIslnnogn,,cybtotrpolcakpsmie.mchmoamsnmtoiloiibomcucinl,yimrnoea,li,l . Cmoentgos |E_I0TSS30T2__I|._InCnflliasbtne,vqppabh,aocntonmimimunslia,iiocicodmmmicaienyalte Fersie LTeET|Z Cnriag,p rphhss aoys,i ulo. aml mmei 18512 aifaarn pcohscgointte smalaoons.mitola. tight Gmigndyons OST 21 nVaec.uuhm paupertteon, modelsree ae" [GEE 3. Clinepceroptp, ipaetceo,nvco.msiani dt GDiroe:| WES 2. 2 IHVyapeecnurl,oapihyom .n eheppatp oecelelula,r.i codemiarielcm. buSlmharh,minimal Foie" |[T6_55_6 |1 Vyaeineipo,, pstocoeclcuacconnmnotro.mbmoimrntanel vee [LRoES.2. Tp21 eVaorcas,sa,bhpoprcnicceoetcmSoeonltooi,mmomldeenre! 5 Ching opincmon,igh [GEST | 231. iHVaycpeseirouono,phpty.chieepe:t,oceebllooaoa,c,enmrmiilinloisbmualar, 3 Cura cope. cenit te 1019 111888111888..1.11000111999 3M_MN03279852 - Cones 6320-223 00 MTems7 DDo0xcGerkouep | NTumIeErNT2 ITaflFuminonp.MiccroooisscooeppitclyiFcinrdminongksoscaln,dmCaofomcmamle,nmtinsimal (onde) 130 LTOSL S 1 ClnPeslrtian,gn, choetophpolecslmhiscr,e,s,menamibaot,ro.nc,loimgnhttioll, wii Mites TOSIE a1 Vahia,cbpbetoacyi,comnoiscs, imirm 1 | 05521112. 12 Coiktiineg,. ywupphloboimsiticcyeten,omlao.)igmhinal_ Pigment hep, mula, emis sight 155. VCilueoel.ionc,rpopts.ee,saltfa.c,sighmtains! Gorge| TRE (owdosey | GESHTT 12.11 Ciakalrtaineg,,coyapplhaoueniiscth,ocs,eyn,imbmauelsk,faio.gahmlimilv -- Fels LTS21. TG it, ynppbiest,ocyes.rmilesm,imnieid _ L | ToT La1 3 piIsartianegb,,myepalofmioicl,sme,irliReAR,Em,iAlA Time|| TESI0 |1.3. mVbaicats,ion,phpobisaceyit, mmiko aio,smmi,mls (Middoey L[oe TTL12. CToausnss,crtpophtsomitc,oasf,,mmoinne,d_ml Mates loo [TS1T21 CCleon,gccorpao,ctoommnu smignhal [| ssa 12 Cnioenn,g cmveopblissmiiocc.yiiee..muslilghat , mina OOTiSo;ey|| EI0553I 8 1 anefsl.hyampplhooltiusteicctytee, mmulktofsocsalLmminimmaml fami L [70552 881 G lneae, ppcxeptihsmoico.nceirtsomoioylkgsosshm,hal | 2 Clee. repiounc ceviche sig Interpreting Pataologist (signature and date):Pell Lotti 1020 111888111888..1.11000222000 3M_MIN03279853 Coners aa2s92:3 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Sud No: 20233 (E076 [I PE. Treatment Group: 0 mg'ks(Control). Speci: ConamelgsMonkey Tow Ling 436-1 p. FBlocrk Noo(s)e. sNoeteor48i1053. - Sic Lesons Ceckonss Yes X_N mg Poi is nd oe: Yo 0.04031 E53 CCFeooastitunreess:nhyToEcw.eriLivteri.dHpodehipeisanex oocfitnheoge Teayrgrgsotcsetn.tesraallio.sltBocTcpheoclyaptlyaom Soonr0ti.5onS ooffmhle ce l1.0 PMcv okhosrinpdi erlnsepse oprropwor l:spse,rpFlevt,,(9)Pm pororsmsee oeornd hN0ie:cmoTaisrS,toHantosonuplmitiopfDos.ilycevtdileseatw,pdbtmdehrsgomeltppcrhofceotsvooro5fcc5hoi0ncKh F942 ciS2in2neLsieedcelRseprosretdteowwiiithhbiiseoscmnae.ss.hFNesvo(o5owtpogehs.ooOsldy seomewdsclto neRicabuToieicHautbe,anNoioneeieOhnos.omcCalsuesodeueindchleamnd sarys adnBdooGmos, RSo1ri0isi.er.c HHoerpaaarna ntcaiotmlhesins fwteamilo.alBfetvsoenme(of1m)mepesrrceodhan.eioSedves-nr | etreeeon an so pA onso rp Conclusions: Normal hepatocyte. Average7.5perocxouintesd oorhempae tocsyte. | 1021 118811188.8.1.100222111 3M_MN03279854 00000000000CCom0 mre90 2w3 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No: 6320-223 (EM 99.76) Ail No: 105511 Treen Grog:0mekGol Sov Mite Tose: Line `Species/Sirain: CynomolgusMonkey PBhltocokNeNgoasi:ve No_s_9_i97463e24 SiLensionsa@hsknarer Yes _X_ No IncPlrogpiensinddg Won S20 MR 31 153 SFmeoatnuories ncSIhE0ho6awveLiravaeirghTteandnppdp osiohruameirieinds.oyofTcehlrlER.r4aThrmeysseeRemnveeerloop eeSpsoielvedsie.iOhnlyncoeuplceomslthcelmesapr iprdipnsFevi(e8.prSsevseerssill | cStouwnRteod.sLiverofHpepiooeoytpe.witAhpBiee crnsshiesloicpreosvclnltosnboedhtvidmeilien logwi eofhrt |SiCeHoleo n isvoernn,aHceupa lmsltorcn efw.ihFSoiuoerdi(cosysraBndargndscrcyomp tniaercsvs e3th.rO.e rA lsidon | Sepisona rmansdosiamome.onfRhaenldEoRmiasprpelealrsycmsplrTesiedniteGade.otsEto1eeets(ao1n1dt) pF ilee nrpauslsolmeies. "XieriLeivveisthHmeapwcohyotncdonatnad smuaosFRdeSseonsaoammeaseanadripserrosisooneis {d38e1no0 iLiTvpeoirscEpanehlosarirnoeggrea(dp9np).phAreotusgoeohfshpmecitoaoacnghpoeendhriFa iTeenuittfofcc,hhaoseencaldruspstnereselds arsenal oo. Ther my bid Staion of hs ER he pte. a Nom bepiocye Aves T235e-- masm-- es po- repocy-- e . 1022 111888111888..1.11000222222 3M_MN03279855 Comm 923 00000000000C0 re0 w TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study Noi 6329-223 (M9076) Avimal No: _ 105510 Specie: Cunomolgus Monkes Tiss: Live . `Treatment Group: 0mg/kg(control) Sex: Male Block No(s): 1 ___99.76-3 is, Photo/Negative No(s).:_43431 SignificansLesions (beck one: Yo X_N Interpreting Pathologist (signatureand ate):Sowa 2 MR31i FoeraitnugrecesllT1ALcellL)icvoenr.taiTneipngiornuymee,rouAstlonwgercleefaliippriodmdrionpleentst.Tpheeriennntoeireddl Ta HeenpvaetloocpyetaencdoEntRainis ominldllyardgielacteld.s MpoidderdarotpelentumanbderssevoefragllymcaoglenlgornaensdesThpernese.at "2S3ec4ra2yn2ed:risetdLiinrvcee.rs.idGulMaylictdooigcehenosnidnncioyattaon.sodlF.souMuro(u4i)ndpteirnoosciytscooasmpoephlseaacnoodeusnEnetRpe.iddaMlelrmybmrioarnaaels.oLaEmRfianra onfck Iintcomcohroannedsr.and sae appr parallel. Several normal granules in he maui of the i32a3i, nLiovefr,Et.MitMoocchhonodnrdiiai,aSspapmeeavrieowrsls.43A4p2e2rbooxtilsigohmtelyslepsrsesmeangtnifictahtiolno.wesSoemfe o3Sf2tta2hl4el!rphLaoitvnoegr,srapHwhie.tphaitnoccyyttoewsoiltansdevreoraulndmeEdiRanav-p+ipzeetdoabarned loyncolgiesnepclaerarlpeidordroplets | 4i3Sb: oLiavesnrd. pooHleyprmaitboocesyotmesess.urrFoouurnd4bzpydeortohxershaeepsatcoocuyntteesda.nSda siinugsouidthoafiloowsyer.right. Sever Sropiet ble nll in pre inth vide: between bepato hepatocyte. Four (4) cpyoerso.visAomseisngcloeumneieddi.umA-sciozeudpecoefrrpgiedr | dSoe3un3c1ne lcToyvnetrsa,inoTaahnsleysocdoeiindstmetenirteienfdipsehdedpsdorcopylteetsi. oAblfoenwg dpiiadgodnraolpllyetis haree sphroteoagraipha,dajancdent vhepeatokcyaics.saThcerie knomtiel,d dTiwloa(t2o)ifothpneerLoRysoamnedsnouuclneadr.envelope. Onlya few [ns FNoromalrFepmatoseie.TAevermageS3p3 epersonepr epaioye | 1023 118811888..1.11002233 3M_MN03279856 oo Comm 923 wrew TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No: 620.223 (EM 90.76) Avimal No: 105927 Tresiment Grou: _0 mg (contol So Mae SpecisStin: Cxpomls Monkey Tio: __ Liver BlockNot): 9076342 PhotoNeguive Not) 43420 SignificantLesions checkone _X_ Yes No Incrvting Paologis gnats and da:YM eon@02R 4 L 1339 (Taepaptraorxeism:atTe3l0y3260.TvTeheraTecpattoclyowsewriJhfseepvseoreystoelslhowds soigmnific7a2nt8dTadtioonpoifeits `ESR.omeArteosipduealfboadnidesringohttemd.arTwee,nthye-oenxet2c1e)lpurlorxinseorsnteisioonuhnasdsomecollagen bers. So3r27l rLiavenr.sViptreoscehnatndmiaat,.MemSbormaeneo,cgrhstER parnedsmeattaeascparfoomirclch.onSdervieral L3y4s3o5somLeivperr.esHeeptastolcyfteof.ceTnhterrenftomocihdonldaiotn iofothne ER id mica cavelope. eSesaktdeurledbosdiesmtnootmaede.dTilwme-ntslyaeficee(29p)ipderroonlkeomse(sacopupntredo.val 15). Seaseed C3ol4l.25T:heLiEveRr.ismHielpdaltyoietec.dB.iSlccaanraleicdulacrleavpiiddderoapntltehttes aleoweevridgenhtt. aAdbuonpdaonftte Tuhmibneyr(s0)ofpdeernosxeisoodmiesec(oupnteedr.oxissosmoes ad residual bodies ar present. 3C4aSt)e:redLisvmearl.l H0epeaodcyiie aeppeacresasiildahoospbeosv.edeSsocmreibreesdicdeulal,odThieererare psreosmeet Fiften (13) peroxisomes counted CCoonmcplruseidonwsh:l Noobremralcoenptaoiloscpyie.es.AApverpagbeee22c7ar5eaptseerdoimsrobmeerspseorfheerpiotxoscyctmeis 1024 118811888..1.11002244 3M_MN03279857 Comm Ni9t2s3 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Stody No: _6320:223 (M9970 Avimal No: _lossor SpeciesSiin Cynomlgus Monkey Tue: Li Treatment Group: 025make(hi-dose) Sexi . Block Nos): PhotoNegaive No9(.97_a6.493.r415 SignificantLesions (Check one _X_ Yes No nerpsing Polposewg s nsnda do: YW eaSR 02s IfT 333 STnorteuarne:y melEo.n edLivenr, HSoiohsspcromoipnsg.wTehereveayppTaagre0ebaaTomrosse Ttheeawnaoirofsloygoon rnsnedtpegarmsleosn.eSnovred.a fNoiteof(9E)Rpaoppsareimsceclauryddled 5r3o3p1e2sLnivtehr.ecyHteopsaotlocpytreocxonitimn alal1a2e5,nmuomsbtebreoifngsmvaelrly 0smamlle.diAb.unsdzaendtcllyecoppiend vTHcEuEr:eeLtieesw, gBaegeanoone cymoapn.wrTweenvtyssie (s2o0 pneUrpmSspictorntde ny JmoanlerlIdfrooplfettse. phSootomgraephr.itSaolmeoisdoocloBnodsieis pseomeer.collMaagneyn bEecroisprseserntcthe T23e1a4r: Lioerr, eSmcv,erdTomgs ( itraoesphocwnmwhhichoappnaedsenaily noma, Sore poreatlndoervmerIantmhesaeotpraesenteirhsramiulnedtSmhaellcirdt dndpsv,elolpiyng erbrae SS4n1o5u,ndievdberfaHeedpeoseeyserrwuiltehsabgikocogmoicbsosomhees)h. sm margin and a rsa ySoenon|pF reriscromessiCcpoundtepeid r(17e0).,RaTdhonpssiitbtiasm pesca. x6 ne Coscnocsehnt.onAsveragEe c110opmoonn,sodpeerhpocyvea.r, Feposl. Trees 1025 118811888..1.11002255 3M_MN03279858 Comm 923 00000000000C0 re0 w TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No: _6329:223 (M9976 Animal No: _10ss12 Trcstment Group: 075 mek ticdose) Soo Mle SpociesSain: Cynomolgus Menkes Tiss Live Block No(s): 076T.i1l0e PhotoNegative Not): 4320 SignificantLesions checkone): X__ Yes No nereing Pathologist ignatre and duc renGAA WROD 7 mFeaaltlurcels:eSp3k16dropTlveetrs., MPhoostopgreaaphredsthoeunpdoc10y0eaTms Bimcdilacmteetedratndhocuognhtinfmewanayre Jalrragpelretasnadpopnesisoabbeouft e1w.i7tmhiicnrotnhescnyiodsioalmeatnedrsTrhneoytsimem0br0anaeu-mbeoiuonuds.foNcionuen,(9)The p5e4r1o7n:isoLmievse.couHnetpeadt.ocyte contains maple medium sized cle lipid droplets {paeprporiosxoimmaetse.lyF9o0ry)-iTveh(4a5)eepsebrruonxdieasnotmensucmboeurts.ofdense primary lysosomeosr rS0o1p8e:sLwiivtehr.in Htehepactytoocsyotl.e cTohnetyaairnegtonoumaeurmoeursowsmsatolclo0utm,edTiwuemlvseiz(e1d2)leperropxidsomes co3u8n1t9ed.Liver Hepatocyteadjscenttoacetal vin. Mictonilousbord nthe STeirdsidnrusoopisda1s0panteuamnedernodutostohceouuntm. aAndmceryitcruombcaerryovtfiepdresi.aryCellylscoosnotmaeinssosdmaolrl D2e5r2o2n0i.soLmievsear eMietvoicdheonnt.driTaw.entMyi-tfoicvheon(d2r5i)apeaprpoeiasroemseesntcaolulnytehdorn. Numerous smal {iiddroapelpreesetntsthe surounding<stosol |ConduossioomnessTaipsp ncresmed.lavemraiogdeeSri2pehoreopsimnsoocme,els.peNr eupamoeoiybfep.eeroxrsonses Frew ie 1026 118811888..1.11002266 3M_MN03279859 00000000000CCo0 rmesea0 swan TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION StudyNos _6320.223 EM99760 Animal No: 105530 Specie: Conomelgus Monkey Tio: __Liver. Treatment Group: 0mg/kg(control) Sex: Female Block Nos). 99.L7i6r5se- Photo/Negative No(s)..__L4760 Significan Lesions (heckone) Yeo XN Inset Pang gms sn: menG0 MRILEES CFaeantaulriecsl:atLIhTe56o,pLiigvhetratHteeoptat,ocytaendcaopmeaiisnisnruesredsellmlipcodvirloopsebsordeTrhearetahbre e oNuomme.rouTshmeincucchleoanrdeinavesleoppereasnedn.ERFisvheo(w5s)spoemroexwiislodmeasrciofuanctetda. (fat) dilation. d4e7n5e7,graLinvuelre.s sMiptpoecnhonnodnrimal., HEiRghbereemeangmintoichfonoidfrcSiavoi msiitgochhtonddriitae..Maris and m"eEn7d5otihvlear clelp.stoFcoyuie(. AmesdiiausmoiidziesdprTeisedntdrsotphleetsoap fprtehseepnhonogirsapesl,.inTehdeby mcilccrhoenndvieilorpee aprenseEdnR.shFoowurssompeermoiwlidsosmtefsaccotuanlte(d.tion) dilation. Numerous (p"p47r3o.vimLaisveelyHe1p4s)tocSyetstoecroendtapinaingrscyasroseodmsemsalalnd0ormepdeiruomx-issiozmeeds pprietd.ropTleetsr s STCopeotryimfuivseod(2l9)mpiecrroonisloomenbsorcdoeurrtaed he top henethan endothelial cll nd sinusoid. Ti2p7id60dropLlievtesr.. SReevpeanoteceynie(1c7 pneronxisosmpepsrocsomuantteedly nin (9) snl io medivm sized Conclusions: Normal Bepioeye. Avergs TE75 peroniomes per Bepaoeic 1027 118811888..1.11002277 3M_MN03279860 ConeSsMT6e320s-2723 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No: _6320.22% (EM9976 AnimaiNo: 10S Treamen:Group:0mghs (consol) Sexi Femme i Speier: Canons Monkey Tissue: Liver wade ' BlockNog): __ goLaeesl- 0n 47 PhotoNegtive No(o:___Lazas Signin Lesions heckonc: Yo XN nots Pa sigma g nddn: mets PR IT E85 Fieraiturees:dgeLd76by1:heLigvreird bTar. Aefewpwsmiaulltocgmeecdecineaslyzmeedckc. Teowsoigmaharigyinsshaadreed iid dorouplegtshachperecseonntsa,pprAoxoimdaetrelsye3n2u).mbEeRropf rrmoaafndiya5ll0csoe0gmeesns ograneulepsaereoxicsaotmeersed n14o7d6:3NLiinvee.(9)MpietroocxhisoonmdeisacOonsao.valsnd one cubsbmaichpeen d pes. Boh Svppressesmoomraallwdietnhterissraam,lemsemabnrdanseos,mahe hti.dilatTedhrcilsaeb,-hparpoebdabolnyeactoisoinnearta LS7i6n5e:RELiRvearn,dHseopoactehytEeRs(uSarEmeebRvyoid)enurt ninhemdccoonetsaiding some collgen bers. Yi[Cionltlshcesl.iFgouhr (G4)peerdoExiRsoamnedscnocued.envelope. & sige srl id rope is present Lbo7di6es8inLtih vercytTohpilsahsmo,ptFocto(c1t)huaswsrlsolrepddltronoopfarleEReeavndtdenss.eveNrualmeFranoeullsi sceasrdeudsl Ls7h6c5o:genLigvrear.nuHiespasteocpyrteesencto.ntaEiingihntg (3)spmearloxlisommesecdouriicaclmeavr p-ididroepledts. Bile RcanaliiEcuplriesRsrentidnetnhte ltohweer oewheirdleetofatnhdetoopcciugh,tofSohmeeellalrgmearrdgoirkns A lusterof PIeyrsoosxoommeespceoruonXtSeodma ar preset amongsomeof he mto<hondri, THY.four (34) [Fr eNormmal epost wAveera [1-- 78 eros por bepaioyie 1028 111888111888..1.11000222888 3M_MIN03279861 0000000000TCo0 nresea0 2w923 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Sut No: 6325.23 (M2076 Amo: _gssis Tse Group: Ons arto Sov Fumie Spc: CommolasMonkex Tie Liss ~ BPohcokoNeogtat:e_9N0o3o6E1747r70 SinnLesionsGc on Yo xe neeing Paboein Gnn nd d: YrnaBtit RITES EFenevnealortpes1aTRSprT eandtaTatoi,pshooOwicnsgohmeoifnpcsnosimtdliSmarisoovinikloocTsaboirade,cr,e1v0es eCLo7em6m7ienTgiir,abmMioeidehwosordnyteisn tiofesrn.etOgn.)speTeuaneioetmemlcoooimaentnrflss,honorl TrLemtnpl,Lei.veT,oMeHeEoaRprseoonse.fyToahseleaislaoldysddareao oTto,f oSEeReadndaGeiFlSlsos pttoepr.adnd iciecsaetehlon'-opesensnpihd grtoiartreievhsCdsooe1endso.. | ee DipeR everw.ite psmmTihooieclpsti.nsdThoyanpn) pdmomnos mcdeunnctsllir peoint oo |"i iroolToedest seaHrepdeons.eovtiN ssaiti n1o9)vpiroce nipineglson cpootaiseLn.pATsi.on5.x6N)oe Peon um eCnoomnmeie oral epaony Swopimal Ton Rompe Topo | 1029 18181029 11881188.1.1002299 3_MN03279862 Comm 923 -_-- raw TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study Nos _6320.223 M9076 Avimal No: 108s Trssment Group: _0 mk cont seFemle SpecenSiin: Camm Mkey Tie: __ Live Block Not): _L_9i07m63i PhotoNegaive Noto): LATIS signicanLesions checkone: Ye X_N Interpreting Pathologist (ignaur and date: MAR 31 955 cFeaaltaugreens:iesL.IZIHLepLaitvoecrycNoconngtaeints ampipnrgoximoaTtheleyp1a7osemaylisteonmtediiurm-ssized alnadr pid ErRo.pitsFi.ghtA(f9e)wperreosixdiusaolmbes ocoudnarteidveidse. Thor s some minimal 1 mild dilationof LUTT7725 LLiivveer.. EHnelpaartgoecdytpehvoittohgroanpehohfugtehaendmsietvocrhaolndsrmiaal.l oNmoesdinumo.sirzeed niedd r"oEp72e5sTivnehr.e cHyteopptloecmy.eEwiigthhtp(r9)ofpenreonxtismoimcersocvoiulroucdbord lon hoo sinusoid mAendsinandostihzeldaccleelsmpoildedsroipslevtis.eTnthelEoRndohiessosrhoew.soImnetheledpdialattioonarcendysevttehreeael are bEiignhd8u) pgehrycoongseonmegsrcaonunuted the cytoplasm, Several dar residual bodiics preset. mL7d25t:t aLirveir,n.HepNaotoicydtedwriotplhestisnpurseosiedntonntcheetriegrhtdanhd peromianenttcanoliunlus monetodpi uStednotpmiucdhoSElR, pepssrblsy poorppoartsaclenetpahtoecype.a.RanCdoomlpermoxiosoimess inodirr RER pry sosomes ned. Sescnicen (17) perosisomes counted | | S Norm epA ost Avene 038prowessperbepaoeye. | 1030 118811888..1.11003300 3M_MN03279863 Cones 6320-223 wesw TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No: 612E9M92963). Animal No: 105534 Treament Group 75make(hisdoss) Sov __Fomde SpeciesSinin: CypomolzusMonkey Tiss: " Block Noto): 907L6:798 PhotoNegativeNo(s): Ls02 Significant Lesions (check onc: X__ Yes ___ No Imcrpreng Pog gna snd due eee MR 32 10g aFebautnudraenst:nmLbeOrsofLmiivetro,chHoenpdarioacyaendsERr. mThoeruebynamdjialecdeddnitlbeaptaatootyfiiohenes ncucolenaran eronpctviseaevnliddoeofntp.soFmeeouErR.(4S)cpeartoexriesdormeessidcuoaulnbtedodreipreesesnt. Just oneisin lipid 14709: Jorma. LSievvee.ralEdennsle garvairneuwgloeferievdperemsietnotchionndtrhiea.matMs.iTtheoccrishtaaeopanendedismsirteinings rmuecmkbursa.nes appear normal. AtheTsEeNsiYdenitihre mildly ied ulcer enlope an the TLh8er0e0srLailvesro.abHuenpdaatonctytgel.ycAogefnewgrsamnaulllesleintaherclytpoipdlraopslmet.sarAe pnresuetomnfthcbelecayretorpelraassm" imartghienc,ytTopwloas(2m)apperpoasis0omceosntcaoinungtleydcogen granules without iinet iid droplet L"SpBocOkLetLsiv"e:ntheHyteapplaa(,ppTrhoexeiarre aac5lr7y1.eSsosmlecoonm tain e somde d wdhiri ildamelglar t Gerroapll.erasendosto4msesghlayrpcloygednefairnaendlaesscalpepaeaoruonbsdipsidedrospplaecetss.usTuhaelymsarrg.insFoouftre(s4)s Je 17% peLr8o0xi2soLmievsecrouHretpeadtocyte appears similarfoL480]withsome small10media-ized Siodmedrcoopnltetasinasnodmoetwhierf dgidlarreas mwaitterhiagl.lyTchoegreen airnehaelscoyatboupnldaasnmt(galpypcroogxemnaigcrlyul2e9s) rougthhecyotopulastm. Twelve {12 peroxisomes counted. CAovnecrlaugsei-o4n3s:pceeroaxsiesodmegslypcrogheenpaTtnoTchyte.mmal. creased numberof glycogen gramies <5 Ez 1031 11188811188.8.11.1000333111 3M_MIN03279864 - Cones 6320-223 wre TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No. 6329223 (EM99.76) Animal No: 105536 Treatment Group: JSmk hidoss) Sex Femie SpeciedStran: Cunomolaus Monkey Tissues Liver Block No(s): __99.76L.a12go-s PhotoNegatve Noto). LAs0S__ SignificantLesions checkone): __ X__ Yes No Ineeing Puhoogh(gnu 1d 6) oenR1d WRS100 FTehaetrueraerse:mLuZlEi0pLl,eLlinvegr.cleHaerpaptiocdytder.oplOetsnialtshmeaySlylteoplsge. oNrfuhmeeernouucstlesalils ve idrcopelets a1hcpypetaorpalaslme.s dTisrtinect (d3i)pleartoixoisniosnmehseccoyutonstoeld. Therear abundant glycogen granules in Foiu50r5;(4 pLeivreorxiHseopmaetsoccyoteu.n.Mosmalll l lrgecelea pddroipnclyteopltassm. Lde8f0i6e;d iLnivheir.s pEhnoltaorggreadphm, baut mgatni,iogrfafnuclilesucaendoafoumttietroiclhiomonidtirnniga.memCbrraneiaaeps1pe0takrweall normal LAS Live. Hepatosyte. Molipl small 0 arg cer iiddroplets in toplasin p4(ea8rpo0pxr8io:sxiomLmaietvseec.loyuHn1e2t3pe)a.di.osTyhteer coanetainasbumnudlatnitplgelyscmoaglelnosrlragmelleipiindthderocplyettosp.lDarsomp.leTcsieare(3) 1co0u0nnteudm.erous 10 count. Several dense residual bodies present. Five(5) peroxisomes Cmiotnocclhuosnidornisa:appMeosdeereastseenltyisalelvyesriemipladr 1acccountmruollas.tioAnvienraFgeepa3o.c7y5tepse.roxMiesmobmreasnpeesrad hepatocyte. 1032 111888111888..1.11000333222 3M_MIN03279865 Cones 6320-223 wesw TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No._632023 (EVL9976 Animal No: __103540 "Treament Groups 75make(hidoss) Sexi Female SpeciesSuain: Conomolius Moakey Tier Live Block No(s): 99.7L6i.s1309 PhotofNegative No(9)_LISL3 Significant Lesions check one): _X_ Yes No Interpreting Pathologist (signature and date):Yeo8044 HAR 3113 Fpheoattougrressp:i.L4A5b3u,ndaLnivterE,RHsoapdagtoleyyctoegenOngrlaynualsemsaalrlesperegsemnte.notTfhceleeaurse s1cparreseedntsintlhis dtouclkarrge leipisdbdoridoipeldseatr,uebuetaviodtlrtt.ooFimfatneeynn(1h)spehreopxaitsoocmyets c(oauppnrtoexdi.mately 15). A few CLy4t1o0p;lasLimvecro.ntaEinnlsarssoemdepEhoRtoagnrdasphcaofrseedvegrallycmotgoesnhogrrdaniuilae.s.No sbaormlites noted L(a4p8p1r:oximLiavteerl.y H4e1)p.atTohceyrtse cionatbauinndsanmtalstlpylceogmeendiinutmhtocyltaorgpeasclte.arFliivpied(d5r)oppleertosrisomes cLoAuGn1t2ed:. Liver. Hepatocyte. SimilartoLASI1. Hepatocyte contains mulipe smal `0 cLyaiogplcalsamr.lTipoiedndtryo-plceitgsh,t1(0208)upoeruoxissoomesouctou.nieTdhere is abundant glycogen inthe LJAiiSdTSd:ropLlievtesrreHeppraetseoncty.teAconnteandiontshealbiuanldcalnltmisiptreosecnthaonthineadt0EpRo.ftOhenphaoltoeygwrapchl.ear | Tbohdeiressiasrmeipnriemsaenlt.toTmwilod(d2i)lapteiroonxiosfotmheesEclReaarnldy niduecnlteiafrieednvelope. Scattered residual Ciovnecolguesnioinnsm:osNt dhepfaotmocoydteosr.teAvineerraegssee12n.3cypteoropxliassommepspderdpraoptloetcsy.teIncreased 1033 111888111888..1.11000333333 3M_MIN03279866 Cones 6320-223 en FILE TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study Noi _6320(E:M929726)3. Animal No: __10553 Trestmen Group: (7h5miaxfdose) Sex: Fogle SpeciesStsin: CynomolgssMonkey Tisue ne Block Not): __9L9,i16s: la PhoofNegaiveNo(s) LISI SignificantLesions check one): _X_ Yes _____No a HR 31 189 hFeeathuerpeust:oeyeA8.1I4n, thLeivceyrtoNpelpsamtotcythsaeTehmeurlretiispel4ediraarteefdcieadndairccsultihast maoishtleyoapppieagrho0tf cisonSitgihntsdyilcaotzateinongorafnuhleesc. lHeowaeveenvre,lopfewanhdavERe.soSmoemleamreelsliadruamlatbeordiiaelsirnetphreem.senTth.erNeo ddriosptlietnsliinpitdhderoppelretssiuasrosidparleseantt-satorhiinshgecpealtotcytcel,lh)oawetvehr,tptheefrte. arNisneeer(9a)l lipid oTe4t8o1n5i:soLmievesrc. oEunldagenncatof cluster of mitochondria, These organs appear eLs8s1en6t:ialLliyvneorr.miHle.pstoeyte contasiinnglse medium-sized clear iid drople. rThte e 8cytoppelraosxmicsoonmteasincsleaarbluyniddaennttifliyedc.ogSeenvegrraalnuslemsa.l Sdeavrekrablodrieessidpupaleabordifeosbeprepsseno.f Four mi4t8o1c7:honTdvreira.. HepappteasoiiclytoLt48e1. Therissbundan glycogenin he cOyFtRopElRaspmr,esoefnitc.n Omniensgmacllealripaidrderaopcloettapnreisnengt.usFtogulrycceonge(n14)grapneurleosx.isoSmeevsecroucnlucsdters p"i4d818d;ropLlievtesr.preHseepnat.toEclyetveecnont(a1i1)nspemruolixpilseomerasrecfoiuendte"dpockets" ofglycogengranules. No Trcreased Fycogen. Average r 5peroxir pesr oepmatoecys] 1034 111888111888..1.11000333444 3M_MIN03279867 Comm Ni9t2s3 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No:_G120223 EM 0976) Animal Noi_ss14 Trssment Gon: _03 mk lon-dose Sexe Mie Species: ComomolgusMonks Tosser Liver _ Block Noto: 99761Z5i6_3_2 PaotoNegaine Noto. ZI6236 SignificantLesions checknek __X__ Yes No InterpretingPathologist (signature and. 0 dpe 8h oo MA2Y01830 sFeiadturpesd: dZropIleGts scCitveerredHenpomuogchyoeu.t 5Hecpyettoospyltaesm.coAmlitnhemtoip mlaergina5llimedio `emiicarlovuimlo(usSEbRo)rdaenrdaonudgshomeendcooplllaasgmenicfirbeerisuilnutmhe(sEpRac)e osfeDipsrsees.entSmthoooutghheonudtophlcasmic | taodpclraiatne,wigrtahnualeasyanmdim tocha aoenclhetaorltyhrcovudgehonutt.. SMeviecrcalhornedgrus aedwkeliprneisnergved 2ve1s6i2d5u3s,l boLdiiveesr.arHeegparteosceyns.. OAnemo(1d)erpaetreonnomue comunstmebda.lteomerdiuomifsd lid droplets onroprersenteifntbhoerceyrtsoisahaonw,maiswcreovlil2lsasnedvceroalllpgreonminenrts raedsjiadcueanltb0od3iesn. Tghesuoprper lf pS2e1ar6o2r3il4s.ovminLe.isecTrohuenHtReepEdmRocfyotremsCodniereetd hpelpatcoecy0e shobwstmminiofmtahleficxlat.ionNainie (t9 with moemdeiumi.gsihzeddiliatdiodnroopfleStEsRpreensdent.heFuocuira6r)empvelroopes,omTshceoeusrrteafew small to || CZIa6n23d5o. pLiidverd.ropHleetpsmaoncdyme iCeel sappeuars i bodies. Fihvm eoe(9d)espcerrioo bseodsmheasrceo,uTrhiecrears | Sh21e62cy3t6o,plLainve.r. OHnelpyatsociyntae. cMlletarlepsmralliso0evmifededntnmn-sdasc6ceplldEropves11r)eeprsovenaibtlne pres 1Co0nchhoaimoinds:crTeiavsoinsapmpbewreolflTpeidddTrooplletsa. oAnsrng]s 6cx0ampirnioixosno.meTsheprre seas hepsocye. 1035 111888111888..1.11000333555 3M_MN03279868 Cones a2923 ----------------------------------------------------O TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Sty Noi 320223 EM9976) AniaNo: oss Trent Grou: 08 mga dose sev Me Secs: Cones Monkey Toor Lime FBloak Naotes: No_t_0o7.6T.1i261e6241 Siaifican Lesions checkone): _X_ Yes x Iting Pts ges nr gor 014 HAY 20 BS Features ZIG, Tver Topoeye A melvn per 1 op rin and ciJogenhttabyiendsnaielerdrgeesamhhioesuipnsto.coyfacsoi.lloanghaeenieeenxt.droacpSlmeuvilercrya.eltpcAklhuidlme ocradramlaocceulpuspsre<essenptr.ecseoPnrtroomeinntehnet | vZ1c6o2f35e.n gLiavemeHespucpyreisee.nt dABrolugchtacmoippae. nTawoherop od(Ge2)rPwriohNsaommeos,r pEeapatosisco.raOnneduoevsmodesecveer,smtalilenr,pwiddrroalnlsreTruesy.0Mi3o)chponediers if2o35s.isLivehri.dTGreopplnesa.spLeargsenc.nTroreesis nfsaiscatsGac0osen ormfgve1KdEKaples.he3 Cotemrecela. Seer kin dis pro, Fouten (1) presses 7p2i62n4.otLi.ver,ThHrepeatiocmytea. dThGilearantieondoiepeaRtcEyRtencdotsoimnaseesr!eccioo.sAirbeidle ciunneiucpupelriigphr,esenTteon (1h0) pJfromasrgeinsofshoisicl and xis colon vide CZErAoLneF.iverT, oHReEpRaatnd:uFcpatogcteolcooanrse itewod.grTeHpeinplmnndhsoewnsd Croailnslboraisoneoxntnh13em ncduanedecdl5tdhaek bGoerom.sA.promEiinegnt(b3le roxio ome pCeohenptaooesye STEN Soci meee Ge Aves eee 1036 118811888..1.11003366 3M_MN03279869 Covance 529.223 - ooooOoOoOoO@ @O@O@O@O@0@0@0@w0r@e0w@ TRANSMISSION ELECTRON MICKOGRAPH INTERPRETATION Study No: 6220223 (EM9976) Avimal No: __ 103516 Treatment Group: _03 mule Gonos) Sex: Mile SpesesSuain: Conomols Mores Tie: Lise Block Not): __07Z76i:1e7n PhotoNegaNtovte 216246 Significant Lesions check ane): Ye _X No Interpreting Pathologist ine 046) Men, O00 MAY 20 099 Flaeragteurliepsi:d dZrIoGle8,LprLoibvearblyFeppmeorcsyirneu_sidaFletp-asotocryiingaela(lco ce1l0.7 cTlhleceopamteoeiynteag Cboodnietsi.nSnmuoroctrhouasndnoRrEmaRlaarpepperaersienng: mtihtroocuhgohnodurtihaeancdytsopclaasrme.d Odanrek(i1)eepgroublarblreesidual ZpeIroGxi.somLeivecro,unHeecpatoyie. Hepatocyte has a bile cndliclas present long is right mInearrgoinuisthmiatnocahoncdiea, heApaftoecyrteesiduTahlebcoyditeosrosrlecornesaeets.bTawnoda(2)rpoertohxinsodmeRsEsRn.and o16p2l4u1s.i Liverr,etiHuelpaanttocayntde.suceHsespaetolcoyptee,exhGiliyscovgeerny glriagnhutldeislastaxtipornesofenhethroughout "dheenyitoepdlasn, and scored resiual bodiesar presen. To (2)probable peroxisomes ZI62l3f5t,ofLtihveesnucHleepuastoocfytthee.heApcatlcesycv,acTuohlieswaitphesseattorbaelcryotuondpldaesnsmiitcy iismpargeisneanttio1n0 cryoompltahaem.plaAsmfaemwermbersaunes.boNdoiersmaaleapprpeseeanrti.ng Foilcenh(15o) peaoeisroemsneenst c(oounutgedht the ZS1h6o2v4e6-.deLsirveirb.dceHlelpsa.toTcyhtee aTnhscgelnytcoegreendghreapnautleoscyttehraoupgehsoutshseectyitlopylassimm.iSliatvoricen 16)prosisomes couned. ComTustons: Eoscralynormal Bepatocyes. Avera TZ peroxiposeopamtoeeyss 1037 111888111888..1.11000333777 3M_MN03279870 Coners aa2s92:3 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No: _6329223 EA9276 Speci Soi: CynomoMolroess AnimalNo: 103521 Tieumen Group: 00imghg Gowdose) Sev ae Tissue: Liver Block Noto __ 9976Z.1i8er ProtoNegaie Not. 21625 SgnanLesions check one: Yo X_N Irn Plo: Sena and da: Bien 8-04MAY 20 El FSeonltewsets:erZeLsGtHn LhievecrenHteedpheesp.atSoooannd ThersbTjeggeamdepaeoryec.emTsoheeSsEmRlad lbloeuaeghnotheilaoptppeeassghesisiaedl Aloen,gwtihthmhieeicthedenSSEdRp.trnA fhowgShmalwloillaen. oZIpRiEeLivperrese.piFoouertteeen C(1ruososfftteagmcoeurtesdoatalblycsogen,, re present hceopoocyps,theTheep tit.oTdheacoaoppEsR is polyldyodedned. dSoeevepres rSEl.lnpihdfdropnlers a0e1)rpomraon.sonTewsocs ome. hocghk of he ps hnegph Elven ZSiilnlLtide.r cHoepraeiorntew.ithThserReERs,oacmeraiextv:eloSpeevearanld sSmEaRllipntihde dhoapetd.ire | etthse alowteeehs,eepreesent. s.yendosthceglmienneolf.3Speereinsim1s0o)dlpefrcnsmescelsnedrt T7Sh1r6i3o5u0gc.hoduLtuiseTr.andHh1ce3prppuror.veisSoevplerrsocissmeaesllssrpcirsosuopmoeelr.aepTassoER SihgehhayptGoceydt | CZCIlGa3ag5e1dt, LoOivneort,hsHeefpatatottnhaeyoebgphuTothuore.es'Mssimmoiecdrhoodvnialdtlaionohsnasfbohreael,reuwmlietahxaenaalddoepyenaendd Shoelly | 10)perovi isomestomie.od. ik ben in ovr i. Tn CraotneaTOn pBerenoiomeas polepTsBooregg. Som waa Sg Fo sat. | 1038 118811888..1.11003388 3M_MN03279871 - Cones 6320-223 wre TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No: 6320.23(EM99.76 Avimal No: __108537 Treatmers Group: _03 mek low-dose) Sex: Female Species: Cynomolgus Monkey Tissue @ Block Noto): 99.76.21196352 Phoo/Negative No(s). 216256 SignificantLesions (check me) Yo X_N Interpreting Palos gnstur nddot Syn, 8.0) ot AY 20 183o8 HFeeaptautroecsy:tei7s1a62c5e2.raLivveeri.n oHrepuatsocydte.reaF.iaSteivoenraalppmeeadrisugmo-soidz.edDioirdsdforatoplelrs see pAreesesnttinothse ciystopprleassemn.t Fhien glolwyecrogleenfgmraarnguilneswairetcahnataedrjeadcenhteoheupgahtooctythe.e cTyetonpl(a1s0e)n, pZeIr6o2xi5s3o,mesLcivoeur.ntHeedp.atocyte. Hepatocyteshows veryslight diofeo ndopln asmic ceyttcouplluasnm.. TAhebrilecisaonne alarlgeiliispupirdeldsreounptlaset ahned(0sepverriaglhtsmmalladrrooplgehtesicweinltlh.iFnitvhee (5) pZ1e6s2o5n4i,somLeisecro.unHteepdatocyte. Thiscell spearsessentisiamlillayr 10 ZI6253, although pHreseeantrronetseherlenfutmabnedrsrioghftlsiipdied odrfoptlheetsn.uclTewuso. rTehgeuloanredornkt-hseaingihntgisressoimdeuawlhabotdies sre vacuolated. Heven (11) perosisomes cocred mZeal1ts6ee2rw5ih5ael.reiLiipvnreterhs.ecocHtyettpooapttlhoaecsymit.geh.tToArfemetehdenidumomup-cllsaeiuszsme.idlJriudpseitdudlfrueompwlsietlnciglohtlnTyidtdilaartseoodip.mleneAlsLiamaherneellpbgaorrteosm aisrethperemseinsto.vSiilxou(s9)bporrodbearbelexipesrioxnistoometshceousnptaceedofDisse. A fe small residual bodies SZoImeGw,hatLisvweorl.lenH.epaTthoecyrteet. apInpetahirshneoprmaatlo.cyTteewloemi(t12o)chporonbdarbiiaeappepreoaxripsaolmeersacnodunted eCxopneccltautsiioonnss.: AEssventei8al.l3rypenroaormxaiglsohmeepeastpoceyhteepsa.toQcytue. aofpnd sppeas wit moral | 1039 111888111888..1.11000333999 3M_MN03279872 ConeSsMT6e320s-2723 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No:_6320223 EM9976 Animal Noi: 10541 Treatment Group: 03 mgs low-dose) Se Pome SpeciesSirsin: Cynomolgas Monkey tissue se Block Noto: 9976Zi2o0a_sPhotoNegative Nots)_21626 Signiican Lesions eheckonek ____Yes _X_ No Irrein Patologia nd du Mums Bt HAY 20 7980 FJeeataunresu:pp7e1r6F2g5h7:.maLirvgeirn.s oHfephmoicyhteepa,tecMyctreo.viAlabriebocradnedrlsicsurlopsriessepnretsselntonag 0the Tloowweerr inguhctl.eus.LamTehlelraerimsataebruinadlanwtiStERhltiiphnidrdroopuettghishcplorelsueanntt othtehReEvRearppreiaghrtsolfigthhtelcyentral dZiIl6a2te5dK., SLeivveern.(7H)eppratoobcaybtlee.peSreovxeirsaolmmeesdciouurmtseidz.e piddroplers avepresen, a well as | mapipcrrooxvilmlaotueslyboeridgerh,t raesnaibddibodciacsa,liicutlhse cisytporpelsaesnmt.nTthhee mliodwenrdeftupmpaerrgriinghits maargins o2f1t6h2i3s0h.epLaitvoecr.yteH.epEaitgohctyt(e5.) pTehriosscilsolmiessscuouonutenddebdy seovtheerhrepataocytles, and Saormaounnadpp1rooxviamatreesliydutanl bmoeddiiesoanr sipzreedselntpatdrtohpeloetpsoif ttshccyeltlo.plaSsemv.eraSledvaerrakl very pmeirtooxcihsoonmdersi.aFnooutretd:eetnhe(s1e4a)rpe eofrteon xdiifsfcouomutnoeedsidfferentiate from Iysosemeosr | 21Sh6o2e6.0T,Lwiovelri.pidHdepratoopcyltnee.otHesd.eThepreaiaphtpgehaorislecsasteynatitaelolfyntshenlendooplthaossmeicdersectiibcueldum | a71n6d26n1u,cavreern.velHoeppea.tocTywteen.tyCotlhleceo(n2t3a)ipnearpopxriosxoimmeastecloyuntesdm.all 10 medium-sized lipid tdrhoepcleitrsc.ulaAtivon.ebAonrottorherissianussioniudsaolidmacrognitaniannindgmaicleoviallooturssbelogrmdeeerntiopfregsreanntulottchyetoep.in "here issighdijataoftthieeondnoplasmicreticulum. Eight (9)peroxisomes counted. nCoornmcalulseixopnesc:tatiEosnssenfotialhleypanioocrymiaels,hepAavteorcaytgees.12S.0opmeeroTsidsodmreosplpeetrs hneoptaetdo.cyhtaet. win 1040 111888111888..1.11000444000 3M_MN03279873 CovancTe 2630295-2723 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION StudyNo: 6320.23 (EM90.76 Animal No: _105547. Treatment Group: 0.3 mak (low-dose) Sex: Fomiles `Species/Stain: Cynomoleus Monkey Tissue ve Block No(s): 99.76.21 Photo/NegativeNos) 716_Z21662266 `Significant Lesions (check ore: Yes X No Incrprting Pathologist gir nddue: Sema 0.04 HAY 20 1659 Fsmeaaltlurneusc:leZar16p2ro6f2il.e.LiAverm.icHreopvaitloocuysteb.ordePr ishproesestnahtoowthseagtohperrpiaghiato.esptSeoimheharjtuifsa+tctual || skmnailfle mlaiprikddsroarpeleptrsesaeent.evSiedveenrtalindtahrekcryetsoipcluaaslm.bodAicbsunacraenptreSseEnRt,aannddKoEnlRy aabrotuhrsoiuxgkout te cytoplasm intermixed with numerous mitochondria. Fou (4) pronisomes identified. Z16263, Liver. Hepatocyte. Numerous collagenfibersaepreselonntgthedorsal | etxhtersapcealcleuloafrDmiasrsgei.n.ThAetrethies soiwgehtrdeiflathaitisonheopfatthoecyntuec'lseamricernovveillolpoeusabnodreenrdoepxltaesnmdiscin rareeticcualunmd. orSevsecraatlerreesditduharloubgohdoiuets tahnedelyitpoipdldarsomp.letSsixa(r6e)ppreesreonxt.isoFmienseclgelayrcloygeindegnrtiafniueldes Znu1c6l2e6a4r,enLvievleorp.e.HeApabtioclyctaen.alTiecurleusisispirgehstendtialattatthieondoofrtsahleriegnhdtompalragsimnicofretthieccullu,m aanndd asinmoitlhaerroheepatodcoytveeisdepsrcersiebntedailosn.g thOenlveyntornael mpairdgidn,oThiesgencexriadleatmonrpihsoloegly. isSov || ZrIes6i2d6u5a.l boLdivieers. arHeepevaitdoecn:y.teFouArcteenetnr(a1l4)verionabanbdlseipmesroxissuormeosuniddenttiisfibedo.stocytc on | the lower <nd upper left margins. Erythroarcyprteseenst in the vascular lumens `Within the hepatocyte there i slight dilatation of the endoplasmicreticulumand nuclear e2n1v6e2l6o6p,e. LiTvewro. sHmeaplaltolcipyitde.droHpleeptastoacryetpereaspepneta.rsNiesnseen(t9i)alpleyrsoixmiisloarmetsocceolulrstdede.scribed alabrogvee.ireTghuelrreliys-sslhiaghpteddirleastaitdiuoanl obftodhyeiesnpdroepslenatsmoicthreetliocwuelrumLeaftndorfutchleenaurclaevuse.lope. A Sevenieen (17) probableperoxisomes counted. `Conclusions: Essentially rormal hepatocytes. Average 10.0 peroxisomes per hepatocyte. 1041 11188811188.8.11.1000444111 3M_MIN03279874 Comm Ni9t2s3 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION StodyNo: 6320223 EMS) Animal Noi__105550___ Sposa: Cena Menkes Tose: Liver Treatment Group: _03mg/kg (low dose) sei Fame Block Nos). PhoroNeguive Not9o9)7Z6i-6222216672 7 2 Significant Lesions Check one: Veo X_N IncsingPaologis signe and ne. Sfrni@1o21t20e5l0d ouFewgaetrhurloeestu:mZhaegIit.GeApTiraereofdTtkoceypatbeoiyntNb.oTdBlsIe crmuetiso2eaSecogx tObnSopht emsgehas.trhneodp NKioitt:boocSeheveopnedoassvhplosrrsseocroeaulnn.tBbiineg car,spaosheeaymospafnhdCromaemdmPaenpw.ocFyee (5) Fa0th0ie8on.cnedoeovpedanuhnTaenTegse.tilePr.omCiTzheyen:ntleeaorbcasepoaesllioomisesrscetmaparkeiongsthohanythpdieateded.duTesohtwoeseelsaiageFhgadhcacietaelina Zhm1i6ar3a6di., nLNivoesrI,codHseeonppgatatsm.sesCroilm.hsFeppiceowns,i(m19)Ap1m2r1c6o36rsdceePosouednrestvreedd Pover, Toherr aapptears 0 Doghpotemxitstnd.miangrFiom.sishT-eanesvpaancreCoTo)fnDyoiedla,kewhmipleerbcwloehnasesmhsciocroaher idenlongHehermloiwterefotmnd 1co6s7p1t.lmiivnerc,heaHdepwnoicrdyde.waeTotahnlil:yhcanedewooaaapsptophysieoetesbcaehemypleTeeery.doOrAhan eoftxrscocale.nelTholleins TIaTpTe.r.TeDrallHeyp,mohceyem.iseTwlwoungsebaonrddmexlteendssomtihlre pid gcoflDeee.asendtocies10 FSreneumnsodiall sael-l.riVnaglcllaarde 38sjlloseeDnepohfe,pTiwemoy-onne =31,) pprroovbaabblley SCTpsoi.nnsAavtehrneagoevEa17lraprmrpoomsrs eeortgeHpoEtCsosoetsmhsoIorewlasAaoCnTxPcid oTryd 1082 111888111888..1.11000444222 3M_MN03279875 ConeSsMT6e320s-2723 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No: 6320(E2M929763). Avimal No: _10ss10 Trcamen: Group: LSmgfke(mid-dose) Sew Mie SpecievSiain: CynomolzusMonkey. Tse: Liver Block No(s 976.Z2i3ons PhotoNegative Not) ZIT Significant Lesions (check re): Yo _X No rreing Paholgi grus and dr) on Gd MY 20 1898 Faenatduroers: th2r1o6u2g7h3o.utLtihveeSrEHKepaantdoceyyttossol.NuFmiexraotiuosn gplpyecaorgsengosorda.nleOsneaespwraellseennt"barell dsahrakperde"simduiatlocbhodoinedsriaareispprreesseetn.t, bTuhtiratleleont(h1e3)miptroocshiosndormieasacpopueratredn.ormal. Seated 2h1e62c74y,oLpivleo.afstHhemepahteopcayttoec.ytSee.veArlaolnsgmatls gtohtmemdiaurm-esitzsemdilcrdovidlorusoboparrdleperfeatsceessnt ia cmyottohpelrashmepiastofciyllteed. wiAthpSooErRl,y-RdEeRf,inmeidtboiclheocndarinalanidcsisucpolrgeuesenstgtrahielslotwherroeugth.ouTthe p|eSroomxeispoemersocoxunitsedro. nmoetes. Scdakrresidrualboediesdar presen. Ten(10) 2{1se62b7o5t.omLiivsesc.enlterpaaltovceyitne.strCreonutnedreedd beypaainoeensdcohtahseollicyeallsnmadlla modleersasteprnofuimleb.erAtof ehxteraecellludlardrcoopllleagsepnrietseern. Atnheecnydtoothpellaisaml.ceTlhiis easnl(i1g)hptesrhoaxdiesdomceeslcaoutnthedt.op ight S21m6a2l76to.mLienerd. iHeapastocpyited.drTohpilsetcslalreapprepsesntsiinlhae c1y0t2o1p6l2a7s3m.. NAuppmreorxoiumsatgellyyco1g0en hgreaneullles Faroeuretveiednen(t14in) tpheercoyxtiossoolm.es cAouLarmeedl.lar body is presen at the btom margin of | 2G1r6o2p7t7r,s aLeivper.eseHnetpanttochytec.ytopAlapsmp.rTohxeihmisatstodroesolefysS sdmraolpetto matedtiheumf-tsriizgehdtalniepidin | baondoitehserarceel.notTedh,eTchyeteop(l3s)epcroonbtaabilnepsearbouxnidsaonmtefsince ogluycdogen granules. Several residual CceolnlcsluNsiuonsm: boEsfseenprtiidaldlryoprlorrsmaalppeepraetsoncyeims.. MoAdervate3emopruenrnasofigslogymceosgeeenrin several hepatocyte te ow 1043 111888111888..1.11000444333 3M_MIN03279876 CovancMeT6302952273 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6320.23(EM 9936) Animal No: ___I0SS18 Treatment Group:_15 mele (mid-dose Sex Male Species/Srein: Cynomolgus Monkey Tissue: ___ Liver Block No(s): __99.7261:264278Photo/Negative Nts): ZIG282 SignificantLesions checkone): Yes x No Iovrpreing Pathologist (sigandndiee: Nore G1 4 HAY 20 1983 Features: ZIG27S. Liver. Hepatocyte. Al theop right this hepatocyteisborderbeyda pliepriidsidnursoiodaplarfletp-erieotsreinsntginceltlhecohnetpaaitnoicnygtes.eveArablilpercoamnianleicnutlulisp,idaddjraopcleentts.0 Faoluarrgsemall |rensucildeuaarlebnovdeyl.opieparnedseenndoonpltahsemliectrmeatricguilnumo.ftMheulcielpl.leTihrerergeuliasrslriegshitdudaillbaotdiioensorfethe e2v1i6d2e7nt9.. TLhiiverrt.eenHe(p1a3t)ocpyetreo.xiTshomeecsenctleearreldyhiedpeantiofciydt.e is borderedby adaskerhepatocyte oenndtohpelarisgmhit.creOtnictuslulmftabeaslnighdtlyofdiilattede. rSaevceorlallageennd.ocTyhteotncucvleesaircleensvaerleoppreesaenndt along the right cellular membrane. Sixieen (16) probable peroxisomes counted. 216250, Liver. Hepatocyte. Hepatocyte has prominent bile canaliculi along its right `Maintdolecfhtonmdarrigainssaiwnitshotmheewahdajtacmeantreheppaalteociyntethsi.sceOllneansdmaclolnlisptid dwriotphldeatrnkoetredp.eroxisomes. ZMIu6l2t8i1p,le cLliuvsetre.rsoHefpaRtEoRcyteev.idTehnti.shTweelvep(12aa)pppeetraorxsoifsoobcmeebsyicnouuctnlteeaedt:e. At the op let is iann tehreytchyrtoocpyltaesmw.ithTihnertehiscesnitgrhalt vteoimnoodrersaintuesodiidl.ataSteivoenroaflthsmealelndlioppildasdrmoipclertestairceuplruemsaenndt nuclear envelope. Some shrunken mitochondrairea difficult odifferentiate from ZlAyRso2s8o2m,esLiovrerp.erHoexpiastoomceyst.e. ThGiernteyr-atlwcoe(l3l2u)laprromboarbplheolpoegryoxiisssomeis comtuonctieedl:lldesacrirbed above. There is slight dilstatior. of the endoplasmic reticulum and clear envelope. Nineteen (19) peroxisomes counted. `Conclusions: Essentially normal hepatocytes. Only small numbersof Tpid oroples | seen. Average 13.4 peroxisomesper hepatocyte. 1044 111888111888..1.11000444444 3M_MN03279877 ConeSsMT6e320s-2723 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No:_6320223 (EM9976) Avimal No: 105524 Treument Group: _L3my (mid-dose) Sei Mie SpeciesStain: Cynomolgas Monkey Tissue: Liner BlockNots): 9276.Z25io: Photo/Negative Noto, _ZI6287 Significant Lesions (check ane): _X_ Yes No Irring Patologia a0:Sm Be. HAY 20 11899 Fdreoaptluertes.s: TZhIeGn2uRc3l.earLievnerv,eloHpeepastnodcyetned.opHlasmeic rpeticcaounltuatmiznseovsolcigmhetdyliy udmitlieide.zedAtlpthie aorperiprgehstenitaabrioluencdatnhaelciancalliscbuelutsw.eenTthihritsycoenlea(n3d1)apneardojvaicseontmeespactouonstsetde.. Desmosores || 2he1p6a2t8o3c.yteLsivoern.alHlempaartgoicnystei.n tThhiisspcheonttoegrreadphh.epBailteoccaynitalseicsulaur ruevnibdeycnotteha:edrthe op et aanndd bSoEtRtoampplefsttmnaoirnmasl.. NTowelnitpiyd-idrnoepl(e2t9s rperonesvbidleenptenrosthiissocmeels. cMouirecde.bondrRcER, Z{e1f6t 2o8f5t,hisLihveepra.tocHyetpea.tocCyotel.leTnwfoibeerrylroecyptreesserte nptrheseenstpianchoef sDiinssucs.oidAaldojancetnte 0ighthte ims aprerseognftitihnnitshicselclells.aTpwreonmtiyn-esnetvbeinle(c27a)ndplecruolxuiss.omAesscionugnlteemd.edium-sized iid droplet 2"16A28t6,ett oLinvpedr.boHtetpoatmorciygthet.aeCeerlyltharpopceyatresseswsietnhtiinalsliynussoiidms.i1Nlcoealilrss idenscliibpeidddarbooplveets rneucplreeasreenntveilnotphei.s cSeel.veraTlhdearrk rsesiigdhuadliblaotdaiteisonaoefptrheeseennt.dopTlwaesnityc-eotniec(u2l1u)m and pe2r1o6v2i8s7omLeisvecro.untHeedp.atocyte. Cell has wo large and several sale iid droplets present icnnvteslocpyet.opSleavsem.raTlhdearrek rieliidgahtlbdoildaiteastioanreofptrehseeen.ndoGpIlyacsomgiecnrgetirculaumn, arunedplrnecesleesnste | throuthgechytoopulats. Eight (5) peroxisomescounted. [C|poenrcohxuissoimoenss.: NEovvnecrnelasyenionrpmadl hneepadt.ocytAes.vSIeg2h3t2rnepreaeraosxgeis1oemaevsepreegheenpautmobeeyrieof. | | 1045 111888111888..1.11000444555 3M_MN03279878 Covance 6329223 ----_---------------------------------------- TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No:_6320.223 (EM 09.76 Animal No: 10528 Treatment Groups _15 mglkg (mid-dose Sev Mie Species/Strain: CsnomolgusMonkey Tissue: Liner Block No(s): __99.731662625-5 Photo/Negative Nots):__ 216202 SignificantLesions (checkone): Yes XN Interpreting Padhologit (signature a Bow MAY 2078 [sTizeedoanrd apZpErEoxEi,mateTloyrfifteeenssmoallslipidTdiroopt lets in ie s cytopm lasmd.oMi ticerovlilc loius | biolredecranbaeinceualtuhsesnudrortoiuenldieadeblysdaersmeovsiodmenetsaitstphreeuspepnetrartihgehtlaonwedrlroiwgehrt lmeatrgmianr.gins. A |diSlcaattatterieodndoafrtkhsetaeinndionpglarsemsiidcuarletbiocduileusmaarndptrheesennucilnsahre encvyeelpolpaes.m.FivTehe(r5)episeriogxhitsomes | lZ1e6a2r8y9,enLiiiveire.d.Hepatocyte. Thishepatocytes microvillousborder extends nfo the ppecrseinoufsDoiiscsaefaatrtshtoruinpgpecrelllft(imoarcegli)n. oTfhteheepshotsloiggrhatphi.lataAttihoneolfotwheereenfdtop1l:a2smic reticulum and the nucle envelope. Two small lipid dropletsare evident. Sixteen (16) p1e6ro2x9i0s,omLeisvecro.unHteepda.tocyte, This cellis a ile darker ssining thanprevious cells. At p{eorwiesrineustoaidaglrafnautl-oscoyrtiengscperles(etnotcnetlh)e spriesenntu.osrSceoevneirtarldalsmveainl. liAp:idtdhreo0plpetisgahrteaprs enntdhoeplhaespmaitcocryetteicaulunmfadenwdtrhesinduucallebar enovelroepiee.vidsNenitn.cieTehner(e1i9s) psleirgohtxidsiolamteasticoonuorftetdh.e ZCIo6m2p9o1s.edLoifverS.ER,Hepgaltcocoygteen. grMaunculheos,fatnhdecpryobtabloe phyatlossaakdeeesinasmlecgormapnounleanrtasp.pearance, `pArpopbraobxliemapteerloyxicsiogmhetscecnousnimead.ltlo medium-sized lipid roplets are present. Nineteen (19) l2i1p6id29d2r.oplLeitvser.preHseepnattnoctyhteec.ytHoeplpaastmo.eyiFoauprpteeaeensprsoimbialbalre0(7114)6p2e91r,oxiTshomreescaroeunsteveedrsl Cexopnecetlaursiionosn.s_: AEvsesreagnetiall1y4.n6poremraolxihsepoamteocsypteers.hepLaitopciydtedroplet sumbers wil, normal 1046 111888111888..1.11000444666 IM_MN03279879 Comm Ni9t2s3 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study Nos _6320223 EM9976) Animal No: __10ss2 Treatment Group: 1Smee(iddose) Sex Femute SpeceuStin: Cxnamsigus Monkey Tiss: _Lines . Block Noto; 997Z63i7en PhotoNegative Nos)_216297 Significant Lesion check ne): Yo XN Inrsing Pang ss nd 040 Steen. Ce HY 20 888 (FheHeaottouerlea.sr:eo2at1li6n2i9thi3i.s lhiLepipivadetrdo.rcoyHpteleeptastTowhceyrhteei.aTarrcehiimhsonpseanrhoauodsjatlcsencotohgpgaeesrnrasgciarenanutnspelcredheasdlnhtaethptaeotorccyiytntoegs.ocleAlt Miintteoscmhiovneddriwailahphpeesemmgoonpnl.asiTcheeyicsehlouwm:fineTocoirtve,essomae griapnnudldesrsonldefaoepgsana mZIa6x00.3,FoLuivrer(. pHeepratooextei.soAcmlseiaenrglslyeldaergneieldi.d droplet is present n he cytoplasm `Sheincehtsptpheesnaocuvs,lySciomgreno rZ1a6m2i9.3,Ttoeesr(a3rspmeannyisfienesgermasinitnhehciystoplasm h1e6p2a9c5e,yte.Liver, Hepatocyte Severs medium-sized lipid ropsreepressat in his ffiebpeirso.cyMtoed.erAattehamuopupnetrsiogfhtglsycaogPe*nsrheappreedssexnuicnehleuacroparleaascmoonfntihngnecpotlolcaygteen. S2e1v6e2r9a6l, reLsivieura.l bHeopiatsocsyrte,alCoernetseernetd.beFatios(y3i)epraopbpaebalresspiemriolxairstoomehsosceoudnetecdried | Gove. `Toes lid ropar evidse i s ctoplsm. At the oto is. longitudinal || Spriosfciolesoefn ra bailne csanaralicruelsuesnatndtharocugrhouot sSisxo(-f)aspceaernoaxlciisctoumlueissacottohnnetteop margin. Fine S2h1o6ve2.97TwLoivme.ediHeupmaatiozcyetde.andCsmeiveerraeldsobmeailopedtedraopppleeatrsspSresienr, oTothtohseeseigshctisbaend renadoohfeilnstceelr. iTmhacsoent(3iingpesroonmsocmeosllcaoguenntefdi.bers. Th niles probly belongs to an TCoocnkehcseltso.nsL:ipEidverrotpaeltynoumrbaerlseappipoaeryirsa.mao. dAVeETrAgee 4v.2aproonfSooemoegsepnerpoem n hepucyt. 1047 111888111888..1.11000444777 3M_MN03279880 ConeSsMT6e320s-2723 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION StudyNo: _6320.223 (EM 99.76 Anil No: 105538 Treament Group: _15mek (mid-dose) Sex: Femsie SpecieSta: ConomlzusMonkey Ties Liver Block No(s): __99.76:25 PhotoNegaive No(s) Z_i21o6302 Significant Lesions (check ones _X_ Yes Xo InerpretingPathologist (signature and date): Spree aly MAY 200% F`seaantsucrteisn:gZthLeGc2el0l8beLnieveart,h tHheepnautcolceyutse. NSuecmteiroonuasslycoorogmeinnegntrsiangalueeklpfreecsemsanrkin the cayptpoepalrasnmo.rmaAl.siFnigvlees(m5)alplelriopxidisdorompelsectouisntperdes.et. Mitochondria and ther orgalles 2Gr1o6p2l9e9t,s. Livesri.nuHseopiadtioscpyrtees.enHt tethpeauptpheoarsceafytsimtnagrelgeilnarwgheearnedthseevmeircarlovsimlalloulsibdorder eSxotmeendsminttoochtohnedrsipaacaeroeDliigshte.r stTahienirnegaarenabtuhnedmanatjgolrycoogfednargkrearnuolnees.inThtehsecylliogphtlasm. mEiigthotceheonnd(r1i3a)srprobsaobmleewpheartoxdiisfocmuessctooudinfefedrentiate from lysosomes oF peroxisomes | S2p1a6c3e0s0.orLpiovcekre,tsHeipnatthoecyctyteo.solC.elAl cosnintgaliensliapbidunddraonptleltycopgreesnenotf.teTnhrineerr(s3ulparroscissromes | ZiIde6n3t0i1f,iedLiver. Hepatocyte. This centered epatocyic basadjacent hepatocyte dorsally || n`mudltvipelnetrialluy asnd apomcikcertosviolflsouyscsoigneusnoigdraanlulbeso.rdOeatrhetheortgapnerliglhets. apIpsecayrtsoopmleaswmhactontains c21l6u3m0p2e.d bLievterw.enHetphatgoclyytceo.geTnhpiosckceltsl.apNpienaers(9s)mipleerox0is2o1me6s30co1nanletdh.oughit has mors | ppopcekaertsclofumgplyecdogbeentwgreannutlheesgalnydcohgaenarnaovnersa.l lOignht (sp1p)epasearnocxei.soOmrebcelreaorrlgyandeelnleised. || hCoenscelubespieotnosc:yteEss.scaAfalvly em7or2raplearhoenpgaitsoocemyetseps eThheepraetoicyntec.reased yogi some oF || 1048 111888111888..1.11000444888 3M_MIN03279881 Comm Ni9t2s3 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No_632023(EM9926) Ania Noi __tossas Treameot Group: 1S mph (mide) Sexi Female Speedin: Cypmotgus Monkey Tove: Live Block Not: _907Z62i0 o ProtrNegaiveNot). Z1G07 SimianLesions check oer Yes _X_ No psi Plog(esndedi:Seah0dHAY201000 Tiegahttaarneds,oZtIoGg.htTvnedrbyaMenporcyse.aThmsacrliln anbotredelrfe.d Prohmeipnaeonetyebseoncohnedocupl arreetiecvulduemnanhdecelnaadjavceelnotph.epaNtocyicisd. dThrereospssilghvteidditel.atSieovneorfalhae kendmopelasgmic cZIhGEaOLl, bDoivdeer.neHeppartvoicy.te.SmCe(6n)crradsheapapteorcoyxtsieosres coounubtynepadocyiesondsl engt.lBnidecciasnealcnaerloepvdaerensighehiitteda.nd bSeoveormalmeardgiun.lhis SsndaoeplPermesiecnt N1o6l3i0pi5d dLrinoepr.leHtreespaptoecys. HFeopuartotccyete(1s4p)ppersoevsabsleiemrso21s630c3ousnhotveed. Aco tic Nconipad dvenr, oinpaendleveeyviatdnesnntdiontthbilslhpcalocuyned.coSenvetna7i)SpnerigmaneingsceofsoncclyyhrHoceymei. e21a6t3o05c,ycsTi,vrl,ioHuegphathoceyem.icTchihsoclnldwrilsaoameewhsaitnihngghtierysadirny.anCeplrlevoiotuhs fi ZighIt aGyLbiveear.n aHneopaateolcyitle.cl.AllTmwietlovceho(n1d2r)iar. oltheis eelrreodasilycosniensg.. Ther is ign sation of te ndoplsTe sesh, Six (6) pero somes deni Conclusions: Evenly oral epocyies No evidence a mereased Fd Gopi. Average 9.0 perosisomes por hepatocyte 1049 111888111888..1.11000444999 3M_MN03279882 Comreseassa:n TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Stay No: 6320-223 (EM 9076) Avimal No: 105548 SpeciesSrin: Cynamolaus Monkey Tova: Line TreatmentGroup: __.15mg/kg(mid-dose) Sex ___ pene PBlhoocrkofNNoe(sg)a:ive_ZN9oit9):n.722161663.019130 Zin SiriicontLosions heckone Yo X_N Inerpreing Pathologist (signature and date)S: peena M2!201959 I Ty ee ee {ipr tleftygansdrin ghPtmaparnlngiainps.tcO.nstashhSieoriugehSateniRaSpp eparihnooelmsbnriiyt loencansneapslimnclualtucpns.tTSAshomoeimmcsparoolsuvitalNloosudsobso:ordrleeresisetsvaoidenatt.k TZarineedhosL..ivetOaayprsgine.CoTvams eterers otihmaosttued.h0gholatikoFno hee doepaidcrts s5re SeerednmeniTSprooTrsoeeesaldleeaPlpasehtpaendoreafkiscoeerogan +Ahe oi rcnot.e ns FZiHIRR6nT0Y1i0 ii:vvere.Y eTpesoorn..a COanreegm udtoamndnevpa irtsehscaolnemaiichocsnldss, rnpcs nicflinags. SoETHmtAeToSnhige,STanednmibi eTeokparhaeee heboorSend.ey taSnehep,10)RaoSmoeDc Pmat:e oSovl. SHRM aapatsrpmoteeneote tpmeeaa .rca noen mee wsrsostnBlestgedr motos wars pls xen LeeEntR.mavpaeeBaro misreloefi. AegTaoohesi esanetasttionnooftlSoegreaiBsp.101riPleocldoiSlpecsialy a ey CiomrteeEscnnalymeoms ys Ne SR rt TR Fes Aree 1050 111888111888..1.11000555000 3M_MN03279883 Coane 6329225 0 Tomisimo 1051 118811188.8.1.100555111 3M_MN03279884 CovancMeT6632299-52273 [-- Meiegneon.iProicnhtP s sioRn diOcfeodF soonotheFcikof0c0ac0h1po.togat, The rueeeL nLivesrt.dcHehepeuocdye shoowinrgcaad,lVteos 0smrilcss.bSoeresporosces e mitend pe. AN 17.0 EA on 0. 193 SSEurni,aitvteihreoeHnerpsoafocsyoiee.301S0heesddoiAppdadcee oprnle.etaeAp.ecasSioecv.tehTlxolres osl aSincgheg eT03a38 imggaSacsosm feonee11 240cKorperaofcbeec.opa. Aneto. mCF iincscThaomsiiroann.tsArwainnNeor 1r519.i0 mcheiecoorllmt.-- 1s1t31000of gnicsion raFiienes4veLS iyveormNHesaltEcyeSvsroFngien.gmcSaevhease(iisdddodroBnploemtisdswcserp0mrie5ssie2on%n.. PLiodses FFeiacgoanLnivsee LFeedp.ocyAersihonNionTnOTS,c075pimdgrodpnesinpd pdroeoap)s,. 1S09v30e8 ipErioN.neLiTv0ew.5e5l3Ha5eb,ps0a.75 Dpewthaislaataansshsandoosbleeasarger.soi1sn2er0oKepvease.nhtRsseee.Fsabes iEnitftuhteic7,eeLpisvae.. HAonpisma NoxiHS550l,i0t17e5 pge yropes(sigdh dsoiendfeelg)l,yco1ge2n0g0% s 1F5i55z1,,0.L7ivem s. Hepa ato(ciygtehg cosen taes)um|e2r0%pemcktofsgegen. Ania So 1052 111888111888..1.11000555222 3M_MIN03279885 0000000000Co0 mwesra0 e92w3 fREomraaLnin, oHempopen,s essoiieocp T fbese,sE irsterd aot Ba AULID Lim n p5u50r8e. EMion mimt teeeaso0r7tw, tsbs F eS a--ld--ee--Hh--Sa-- ta a pois pong i, iv. py het ee oc totsaohe psisro oseoenimasSoo iid E fem 11e 300% pron. ebBESoho`dn 1053 111888111888..1.11000555333 3M_MN03279886 oo TCowanre 6e329w225 [R----R s&&c -- hGair -- 8i SEee 5 om og3x SfLipidigdronplet Ww free inA= m Reve acyne ion los 118811888..1.11005544 3M_MN03279887 Eas Cee eg 3 raEr LotoyelmwY MRELsiy | & Bl eh g gnBl siya B bo o oo a t ot gAe E | B 2 Ge in SaE ECN geE h W nReORLS E uaa Cd nY | Nfeu edna e Badin aaa EPa eERaeESs REAy , ieRys EAhgRCaASGRl R 5 Be Tien oe, 85 Bo l0e 0ST d L E OLe R ANESMoggSEa!yn IbRrS en FEBgyEeS LtOhSIS a I e e CREs AR WTAE 1188111888..1.11000555555 3M_MN03279888 UE # |8g, aaePme > ob Wig 2 > [pf aSeS Te SET SR ET i | FRee ew 8 EC ey | SDoineea S .w algaee bm Ael l | BAN EC SES SER wf os NR | G Bw N ia NWasheJe E g ah t Set ansAal as AtReSaEEL R RYa geRBEe PEs Cm Ae be i& sA l eAl D NERSS eC es Pha INASERC RE 2 ag PA ATTEN LEE 056 118811888..1.11005566 3M_MN03279889 | " ARE Ce pm Ey GE TED Spreeara O SRER Y 4 ry B Bh 2 Ruy| RX Sa i && eRe, ear |Sadie. wh | iErE x HR SE EEA hs Oeages A BA eT NEE ee Uae bn $0) ABERINE foh SR SCRE,J Fs pe L:o eRx co SEE ARE GE age liaRNCeS LaSe E | ala GESTS aed Sede EEE Ny,kiVU : EAR = ET =f SRSA, os? 118811888..1.11005577 3M_MN03279890 Coireva fh SRE Se LLNd ae SEr VIRS.w. ESTEOeebaors of SRSI ty |5 BE w OY bs. . FR 274 Es fo ky' oi B PEEOaSeEe S il fa RIN BTiael A HE ae IhEo" Wy 0 pT rec LdJ 5 oS pra)paRenARZeEYSN Ziia)d aed 95) hal, W Ea Yh TRYX CLHodPRTCEEAESE HR Rens al, PEt RE RETR p: HOU at Rl re AETC ei RBECUR AERRCEe,R BROT ER 058 118811888..1.11005588 3M_MN03279891 pa afon a 3 L4 SO aoe olS RER a Saee loCaTneSReV9 L fC ond Ea se FRE Wg EY "fCOyg OTRNSTEETREDo SE g We aea oae 1 foiiraD2n I REoNol, eT S o) 0 Elli me Tg E Woreay aMn E ey BR os TR oagRhOeeaERK SR HSaE nRw S eRe e 118811888..1.11005599 3M_MN03279892 Pade. E v eel SY ' RT vy ikAE 2 . we~ AA oi Rr .e * 1 Bel, a SHEEN Wk QL, - yooh... 2s oin, SHA Woh Gri, Beayo RR elar I egNoo RVeI ~ S A HBeTEASSEGeTPR gsA BEXAa EN WT ytSr RO NC eR SN ve TY A h, LE bg MayT: ge Ge g SR C n BR eIEAES He oe BWI FH 0)'o -- 118811888..1.110066000 3M_MN03279893 *fe0 lm a gEx L ChaR EamyeA l ares SSN A C eya e ORP T ape SS Ceien ; Ba eS RT W | BPR e a EON a [Emeosin, 8 aMath i"4 i ard SS H R$E a SN aSlhal pita Fi Lo Bw CAm TEa N IOA NA EaE n ea [on Uni Seman CG E*CiTp eo NF 5 Niheali aSE T Eo He ae LAN emily 118811188.8.1.100666111 3M_MN03279894 CR Wag 8 WHR LL foe B 2.y0. 5sofie SL en 0 sk x oLs E iFergAEA EE8 R, SGNSE NBORePFT oh aN 5 t , Fae Pe fac f f) ofo t"3in.<r iB]era3 ro Lox RN, gS UR io EbBooo}ebha | Ell og JTB HEA LRRAGYES kREE B0E0= Prantgl argaRgeheee tyBl : FY ? %s etl afi 118811888..1.11006622 3M_MN03279895 rans . osa * = EaEgR Rka El BBL. ara | Es kde 2 Fn Pr GEN RS(CkSEAHECaBg Ji =JRE | RL ln NT g :FO. RIT. . et on Lh Pp i 2J Rr oO SRE SE+ ~3 KNEE J. NE 7 EAR , . Op Ooo J ; dR JER. | SE A TE, 4 TRA - RENEEREO CR EY BE SORRCS & 3.5, ens ERENT PS AER SE N Po EY WwRKeIy N 1063 118811888..1.11006633 3M_MN03279896 [s--e | F : Ci & Loma | E Fa e r RTE nTE leaae Fee yal al See ERT a as Lo BPRNCEEE aeat BSaE. USTE.ESeTaT mminR aaarE | GEoRsRs. AIOENEEDa [BetE o llidgRC Na aeR" RS 2 Ba Ee | Te eS AT | CE TnT ReR RE Bae nTaadnA SUiE FT AE a TL ty nga TEE CE 064 118811888..1.11006644 3M_MN03279897 iRno C wie EeeN hT e)A beTEleeeman SFLOEoET sLGloAySE RODae SlaN eB y DEr AN OyNd Tea B ovs r LRSaanEDoe CBElCr a REE RYFpLaEiAdS SEEkT SN Fe a Re Vs i bo REEECN avn a pArYaRried BaLpNe EC gageT SEP clasWig ns Tl NPR oCAs RRTS egtraeg v togt Na LAAT RMTRTe, woos 118811888..1.11006655 3M_MN03279898 A SEA T TRfa pyl La aeT XFe a dr BRLRe e 5h ee ra WT ENG CI CA wi ah ie cdSeIE hEvgyaan LaSAETEA{TLE4L 8R y fE on NRIEETNgFEoy TO HAO ENrast daST SES wAi L oo Sa oak e Si oay E Roars =N Te eEe RS aR Ri eRe REE TE elaa oss 118811888..1.110006666 3M_MN03279899 Coane 6329225 1. Qty Are Sse 1067 118811888..1.11006677 3M_MN03279900 (FF Patnology associates ternattionnal Covance 5T2a9n.2s2?3 S= HE Guru AssuRaNGE STATEMENT P faeyrAe irliecr ntroUenntins co elossnsyybGratsreee sgacgder .rdTco tli ooneoenC3/ue0l655 aa iee. pDuinaes esis E COulEioE stpcr wan oma wn wm oanmea wn Tam pment mem SPleisavmin mBS sFON2E G4 Sos, Capa Toons To cn pr0S Suc mor 529220,9 uy4070 Sr SrToT Gr TS eR 1068 118811888..1.11006688 3M_MN03279901 APPENDIX 9 Urabilinogen Analysis Report CovancTe 2630295-2723 Note: The report in this appendix was supplied by the Sponsor, based on data supplied by the Mayo Clinic. The analysis a the Mayo Clinic was not done in compliance with Good Laboratory Practice Regulations and was not audited by a Quality Assurance Unit, 1069 111888111888..1.11000666999 3M_MN03279902 ConeSsM 6T32e0-s2273 PeUrrfolbuoirloioncotgaennesAunlafloynsiicsARceipdorPtotfaosrsSituumdySatlitle(:PF2O6S-)WeienkCyCnaposmulleguTsonMieointkyeSytsudCyowviatnhce 6320.223, (3M Medical Dept number: T- 6295.7) Author: Andrew M. Seacat Final Report Date: 3/1/01 IInntrodeufcftoirotnto understand the loweringofbilirubin in the blood of thc PFOS high dose: e(v0a7lu5atmegd.kgTihdeayh)ypCoytnheosmioslbgeuisngmotneksecyds, htheatpiontcernetiaasledexfcercealtiwoonbosfluirnoobgielnineoxgcerentviaonsis r"Tehsepomnusllibhlyepfootrhetshiesobwsoeurlvdedstlatoewetrhiangtohfebiislniorusbiignniifnictahnet bdliofofderiennctehebehtigwheednosteheanciomnatlrso.l and high dose fecal urobilinogen values MSeitxh-hoodursufmecmalarsaymples were collected from the cages otfh conte and high dose male wanodbifleimnaolgeenmoannakleyysissa(n1d).wer sen 0 Dr. Joc McConnell a Mayo Clinic for fecal Results s"iTghneiufriocabnitlliynodgieffnerveanltuebsetowbetaeinntehdefcroonmtrtohleasnidx hhioguhrdfoecsaelgsraomupplseosfcomlalleecatenddwefermeanloet Cwryonboimloinlogguesn mvoanlukeesyswe(rTeabwlieth1i)n. Tthheraesfsoaryedtehteecutliolnhlyipmoittsh,esbiustcwaenrneotvbeeryreljoecwtecdo.mTpahreed `phoytshieoltoypgiiccaallhsupmciaensrdainfgfeorefnucreoboirlpionsosgieblnyvdauluces. Tahnailsytciocuallddbiefdiuceu0ltaetnrcoeuntered With a new mattis. R1 eferenUcreobilinogen (UB) Analysis Results fromDrJoseph P. MeConelL. Porphyins aMnadyonuCiltionni,alRoBcihoecshteemrisMtNr.y lab, DeptofLaboratory Medicine and Pathology. 1070 111888111888..1.11000777000 3M_MIN03279903 i pe EEE pee oa Harr ee Bs rame ro o e eEe---p E repa C er] Presses] on ran aw_uosz7s904 118811188.8.1.100777111 APPENDIX 10 Dose Confirmation Analysis Report `Compound Stability Report Analytical Laboratory Report Certificateof Analysis Quality Assurance Statement CovancTe 2630295-2723 Note: Thisappendixcontains information supplied and audited by the Sponsor. 1072 111888111888..1.11000777222 3M_MN03279905 CovancTe 2630295-2723 Dose Confirmation Analysis Report fo Study ttle: 26-Week Capsule Toxicity Study with PerfluorooctanesulfonicAcidPotassium Salt (PFOS) in Cynomolgus Monkeys Covance 6329-223, (3M Medical Dept number: T- 6295.7), Author: Andrew M. Seacat Final Report Date: 3/1/01 Introduction Dose confirmation analysis were performed on samples of pefluorooctanesulfonic acid poowtadsossieumgrsaolutp((K0P.F03OSm)g/tkrgi/udraatyedofinPlOaSct)osereactediivleudti1o5nsmofp1:d49o9fatnhde 11:34999wwiwo.w dTihluetion imnghgegliadtianyc)apgsruoluesp.s rTehecemiid-6vdaeonsde 3(00.m2g5/mkgg//kdga/ydraeyspPeFctOiSv)elayondftthhee hig1:h39-dwooswe d(0i.l7i5on in gelatin capsule. Samples from the top, middle and bottom of exch mixture were collected Eonnvdiaryon-m1e5nptrailorlabo. Sthaempinl-elsfccoplhlaesceteodfftrhoemstthuedymifdordlheoomfotgheenepirteypaarnaatliyosnisswsenrdesceonltl1e0ct3edM cproemsptouduyndansdtaabtitlhiteyeinndtohfedtohseintgreavtehmiecnlte.phase for material content analysis to gssess. "MTehtehoddosseucmonmfairrmyation data were collected according t0 a method described fully in the. Athneallyatcitcoasle LdaobsoersaetmorpylReespo10r0t-(f1o).lBdrwiieftlhyM,dilolsie-Qcwoantfeirr,mawthiiocnhwwaserpetrhfeonrmexetdrabcyteddiulustiinngg the (1). iTohn-epeaxitrrraecatsgefnrtotmetthsea1b1u4t9y9mmanodnithuem 1h:y3d9driolguetniosnuslfwaetreeactchoerndidnigluttoedth 1:5 praoncded1u:r5e0:, sraempslpe,ec(1topi,tvmoebidrldiylne,gatnhde bPoFtOtoSm)l,evhelesaivnethreagleinPeFarOSrasnpgieokfedthmeariinxstreuxmternatc.t vFaolruecawcsh aunsaeldyazsedcovrerrescutsioannfuancteoxrtrfaocrtceadlccuulravteinugsitnhge HpePrLceCn-tErSecMoSve/rMy.S.In all cases, samples were. Results 8T6h+e 4re9s%uoltfstihneditcaartgeedttchoantcetnhtera1t:i4o9n9,dainlduttihoantutsheed1f:o3r9tdhiel0u.ti0o3n umsge/dkgf/odatyhedo0s.7e5garnoudp0.w1a5s.. mg/kg/day dose groups were 11+3 31 %ofthe target concentration (Table 1) The stability samples were obisicd fron the middleofeach mixture and were received on 5-07-99. The stability sample or the1:499 was 100+ 1 % ofthe target concentration, and the stability sample for the 1:39 was 69.20 % ofthe target concentration (Table 2), 1073 111888111888..1.11000777333 3M_MIN03279906 Covance 6329-223 ----------------------------------------------------O Conner 12023 Dose Amis Kept Reference: S1tudy wiHtahnsPeenrKfl.uoJ.roAoncatlayntciscaallfLoanboArcatiorPyotRaespsoirutmfSraolmt(hPeFO2S6)-WieneCkynCoapmsoullgeuTsoxicity MPeornfkleuoyrsooocntatnhcesuDleftoenramtiena(tPiFoOnSo)ftihneLiPvreerseanncdeSnedruCmonSacmepnltersa,tiPornojoefct deotification: FACoCvTancTeOX6033209,.3321,L63a20b.2o23r,rae3qtMueosMtreNdyoi.caUl22D7e,pt21numpbper:20T0-06295.7, Anata su. 107 11188181818.8.11.010707474.4 3M_MIN03279907 ---- a a CNET Ll 118811888..1.11007755 ms TI To = TET=] Tron Toe at 118811888..1.11007766 wn Pum iotuier [-- Clos(e1rMgsy BEnMGtcDieMscxWoOmMoec) cas onsmr1t 3000 S2h0s0) "son esCoorse 2a015s08 Cm R Imnye-En OEn E dRea <R21w T aT.r i100ydha tea r n are s d in2s wo Comme many 3M_MN03279910 111888111888..1.11000777777 CCCoooprrierbteaRsiomspeeds Ssbe September, 2000 M350e5os v036008 CouncNe i320t.2s23 SPettyrD.iTehtomaf,orTdo,xPchlD.ogy C53o01neKsiLmaboarsntoiris Io Sion WT 53708 Re. CCoovmapnocuen6d7S20u.b22s(TR6e2po9r5), 6329223 (162957), Pefuroocinesuonte per CTohveapnecsei6uo3r2o0o1ta2n2es3i2f5o.ni2c7,acbidaspomtais dsslabl(ePFfoOrS,htFCt9i5eLodtu2r17o) woefdhcin study. A Cerificate of Analy C of A) diedMisch, 2000 (1. died the compound asbeing 90.49% C8F17S03-K+ by a combination of LC/MS, 'H-NMR, sF.iNNMoMRRn,awnawdesseledenmet0nitaacllhaonralhyisiCssaf teFcCAhn9ei3quneost. 2P1r7evsinoadursdlyr,heoindsDyteehctremhbeerom1e*r1.997, `Additionally, "*F-NMR and IH NMR conductoend August 24 2000 (3) were i{`hcneotrmespvaewraaeisdntngoot3ihgeidf'i*cFabn-atNlMiyRfeccaontmciplemeestpendrcoen,DcTeocmkep,omsbiePtrRiOo1Sn*,o1fFi99Cs7.9aon5tdootifnPd2i1Oc7atSsedostvhweaatrls siblefo ratehre ie period din which thes sic were condcid. Sic, Ch2 orinpes MTH.M. SSLpeal ATorxiecoeloMg.y SSpeecisaliPshtD, 1078 118811888..1.11007788 3M_MN03279911 PPeatgeer2Thomford, Ph.D. September 6, 2000 CovanScMe 5T2e9.s2273 References: 1. PDiavyifseironR.MM.arCceh 9r,t20i00OffiAcnaalytsies FC-95, Lot 217. 3M Specialty Chemicals 2. KFeCs-t9n5e,rloTt.21F7luAonraolcyhteimcialcaRleqIuseosmter53Di0s3t0r.ibuStiAo&n CbyAn'aFly-tNicMaRl LSapbe.ctrDoesccoepmyb.er 1,1997 3. KFe-stNeMrRT.SpCehcetmriocscaolpCyh.aCraocmtpearriizastoinontoofFCP-F9O5S/2(1F7C-an9a5l,ysoits 2f1r7o)mbRyeq"H#5-3N0M3R0-& Request No. 61886. 3M SA&C Analytical Lab- 236-2811. August 24, 2000. 107 111888111888..1.11000777999 3M_MN03279912 Soca Doportrer Sh: T2067 Coane 6r32e9s22s5 tccReBepaosFmACoT T0O0533703 ANALYTICAL LABORATORY REPORT rome 26-Week Capsule Toxicity Study with Perfluorooctanesulfonic Acid Potassium Salt (T-6295) in Cynomolgus Monkeys ome DetermoifnPaetrifolnuoorfotohcetaPnreessuelnfcoenaatned(CPoFnOcSe)ntirn ation Liver and Serum Samples Project dentiication aMCMoevdiacnacleDiepnarftmSetnctyS.t#a0y3:27662220357 aAMnalLyatricaatloSrtyuyR:eqFuAeCsTt NToO.XU.202370 Study Completion Date Atsigning Total NumbEeYr of Pages MEmiomentltabontoy 1080 118811888..1.11008800 Front 3M_MN03279913 Cotevnias J to------ -- T[ E-- S Ee -- J SS E moee ieSLLoPYeA mnrse A TTT r BIB a I rT mA ------I-- EE Se Carfmpeot ancsA erarpsyry i hyoc mt. eI nLL nial t r ERI CTa n e Sm nET e EmiI ger B SE O E ecES Lsy eWhgorr waeldtie) 1 Seal gon Pon . Billrdolf 19 seor seco Sse om eens FO-- 08 118811188.8.1.100888111 a fuse: 3M_MN03279914 hems sonaTR:nFERNS EE wo pp EEErsm A--ee ----rn aT Brm m rer N e om e Ioor | vem |_| om| [ o -- m EE n||oweemE || || Ter CE aRC Te = -- T.. oz cNtT Ube foo ---- reno srr 118811888..1.11008822 " "oe 3M_MN03279915 INTERIM CERTIFICATE OF ANALYSIS -Swpir : r -- I tyr rmrrer----t _ Seo 5. Nickel 5. <0001 wim| a"To&Implurity (WR) ST E C e 3 T ResidualSolvents(TGA)| ---- oneDetected 1Eo 1 Ei I[ETY 31 001m0mmm 118811888..1.11008833 3M_MN03279916 CovancSMe 5T2e9.s2273 CenItNreTAEnaRlyItiMcalCLEaRboTraItoFriIeCs ACOTAEROeFfeAreNnA#c:eLY0S23I0S184 Date of Last Analysis: 0/31/00 Expiration Date: 0853101 Storage Conditions: Frozen 10C Reassessment Date: 08/31/01 FPluuorriidte=y, 01.0509%%+- sNuMmRoifmpmuertiatlieis.mpu1r.i9t3i%es,so1r.g4a5n5c+aLcCd/iMmSpuirmipturiiets0i,es3.885.-41+5P%OIAnAo.rganic 033%) otal impurity from al tests = 13.09% Purity = 100%- 13.09% = 86.9% Potassium is expected in this salt form and is therefore not considered sn impuiy. a"bPsuerrviebtdyfoDrStChisissgeanmeprlaelly not applicable to materials of ow purity. No endotherm vas Sinuolrfguarniicnatnhieosnammepltehoadppceoanrdsittconbse. coTnhveeratneidon1reSsuOltaangdreheesnwceeldewtietchtetdheussiunlfgutrhe odnettehremirneastuison, itnhhSeOcleismennottaclonansaildyesriesd, nendiimnpgunciotnyfidence to this interpretation. Based SHTFFABA TaHelpuaofrlousocroebtucyarciicdacid PNFEPAA NPoennoifalluuoorrooppernotpaannoiocn aaccidd "heorctical value calculations base on th empirical formula, CFO K' (MW=535) "This work wasconducted under EPA Good Laboratory Practice Standards (40 CFR 160). conmaisa 1084 111888111888..1.11000888444 Pagezots 3M_MN03279917 CovancTe 2630295-2723 INTERIM CERTIFICATE OF ANALYSIS Centre Analytical Laboratories COA Reference #: 023-0184 LC/MS Purity Profile: CL Wm [3 purTy wwe 23 ccss a133 a Total sLaits Ncoutrev:es.TrheespCe4ctiavnedlyC.6TvhaeluCeSs wvealrueecwaalcsulcaatlecduluastiendgustihnegC4theanadveCr6agsetarnedsaprodnscealfiabcrtaotrison afvreormagtheerCeispaonnsdeCf6acsttoarsndfarrodmcutrhveesC.6 LainkdewCi8ses,tatnhdeaCrd7cuvravleuse.was calculated using the Prepared By: Davids~. Bell ems FEDate Scientist, Centre Analytical Laboratories Reviewed By: John Flaherty-- =Date Laboratory Manager, Centre Analytical Laboratories connotea 1085 111888111888..1.11000888555 Pogo 3of3 3M_MN03279918 Coanree632s92s25 Spon BrCaeoteNSooFyANCoTs-T0C5R3I0D1N8 QUALITY ASSURANCESTATEMENT oLCootnit1ee71uthwayessNraevmwibaerewsredvb02oy3w-Ce0o1dn,veoctoASinloa,pya"aaChoLararbsotrratzoa0roCinooSQruuedayryofsePuFrsOaSn,cLLeaobtUnoi2tr1.7atanod PSraanctdincedSOupnedraatei.ng ArNoconudirneg,swteherSeupdorireodtfoslh, aSnuddalDargoirlaendGtooomdanLaagboomrteners Pac IpDiuees CDoSunyeeDRMeipeoerect itdSuooenerMporoapremeens | roikenew 3190 sia nave t2liancyhes is 00 Pending 5FpSiruenitbeydds"obion G"a0i2n00 6a3m0 TThains iGRoawDuaReovew TiO 7130 renting rh5 Saiannidtsouion 71400 0m Feat FeSiantnwisouion T6i3d0e0s0 2i0e0 F1o4t0o0s s7 Roptneien 00 sno Fein T rmRepo_ een T sono renting } Fliers $900 GgaulyaAsoc Officerfr bwe 1 ORGINAL BOT Cones Anya Lborsorion re. 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