Document rLj9gpVVRa5BQBqXLmEoz1oq

--_-- 0 . 0 TRHesEearRchICoMrpMorUatiNonE AR226- 1906 | | 0 son 3M Corporate Toxicology | Cc Building 220-26-02, 3M Center | St. Paul, MN 55144-1000 C C FINAL REPORT 0 SuisTle Cell Proliferation Study with N-Ethyl Perfluorooctanesulfonamido Ethanol (N-EtFOSE; | o 3M T-6316.11), Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; 3M T-6295.16), and i NN-Ethyl Perfluoroctanesulfonamide (PFOSA 3M T-7091.1) in Rats i C Teg Ailes i| C N-EtFOSE C PFOS PFOSA C Authors: C Gary W. Wolfe, Ph.D., D.A.B.T. Kimberly A. Layton, B.S. C SCtoympletiDoaen: C May 2, 2000 | Performing Laborsiory: | c `Therlmmune Research Corporation | C 15 Firstfield Road | Gaithersburg, MD 20878 C TRCStudyNumber: C 1132-100 Cc CONTAIN NO Cp! | C | 3/5 ||| N-E{FOSE, PFOS, PFOSA TRC No. 1132-100 | C TABLEOFCONTENTS | C COMPLINCESTATEME+N1T1 sesso seeseseessesiasiseeneend | C STUDY IDENTIFICATION .......esuuesensenannnnnnnannnenns " reir STUDY PERSONNEL ++i 6 0 INTROD+U++C+eTtIe ON eeseee eases | TESTANDCONTROLARTICLES +++. sesasessniae snen snD | c TESTANIANMDHAUSBLANDSRY +. ooeeeaessnness cnn10 O MEGTuHnO,DASgene tSHs DRe E1L1At 1V+ISv viverensrmserererernes `TestArticle Formulation3nd AGRIGSEOn +++.++. 210 eeroeesines 1111 Cc ClinicalCheriseaadCompoundLevelAnsys + -.....-.10.o 1.o -11.3 o1 CP OolTl PRarGoiBfmeImoGnriwiaTrdeanisa eTCssoayelmiCeon- lslseonceidsC onI1m0do mAulnA ycesnhtsiers= porcaEvhhalneu~ ramteiieonec+aae. 1lr.ee.r.e. rrer1u.. n.r.s 1B16 | 0 TRiseCmolLlieirnnToRrgSEico+nMi-cros-copi+c Evaehoaetieorne ooo~~~... 11S6 Hiapabelogy e+1. LL C: FoodoydCWoeingmhmsapntdoBon1dy +Weig+h-tG-an+s+111... 1.0.11 ie e ! C ClTioniMcaaltOUaElTCBOORUSR +-+-+++1+111+ ve esrmsesrmesrrsinsinirniinisiis 16 TerminalBody WeighsadLives Weighs |. -.-...1...1 1111 || o SIGNATURBPAGE ++nesi sss 19 | C 1 SUMMARY OFBODYWEIGHTS (Gams)... .vosvesvsesssssnn2n0s C IA - SUMMARYOFBODYWEIGHTGAINS Gram) ..........o..oooroooers 2 | 2 - SUMMARY OFFEEDCONSUMPT(IGROINN) ........o.oo oovesssnnn 8 i C 5 = SUOM FCLIM NICAA LOBSER RVATY IONS ............o.oovoirirsnn25 C 3MCorporateToxicology 2 | 3/6 | t N-EtFOSE, PFOS, PFOSA "TRC No. 1132-100 i OT asso nso eros | C `TABLE OF CONTENTS (contd.) i `TABLES(Continued) C aA om i C 1 - MALES:INDIVIDUALBODY WEIGHTS (Grams) +. ++. +e ev vvvvnannnnns 32 | Im. INDBI ODYV WEII GHD TGAIU NS(A GramL s) +. + ove vnneennaaneenes. 35 1 C 2 . INDFI EEV DCOI NSUD MPTU IONA (GraL ms) ......vvvvnnnnnuuuanneenn3.7 oO 3 = INDIVIOBSEDRVAUTIONASL+.C..LveeIvreNervI erseCnseAsenL .40 5 4 INDIVIDUALTESTMATERIAL CONSUMPTIGpOaN) oe... 55 0 5. IWNEDGIVHITDRUAATLIAOBSSOLcUooTrELIVERWEIGHTS(Gams) ANI D ORGANTO Bs ODY | c || o | C || Cc | C :C || C C C rrr || C 7 C N-EFOSE, PFOS, PFOSA TRC No. 1132-100 COMPLIANCE STATEMENT C Cell Proliferation Study with N-ECFOSE, PFOS, and PFOSA in Rats C `This study was conducted in the spiritofthe Good Laboratory Practice Regulations as | o set forth in Title 21ofthe U.S. Code of Federal Regulations Part 58, issued December 22, 1978 (effective June 20, 1979) and was not reviewed by Quality Assurance. There vere no | o deviation from the aforementioned regulations which affected the quality or integrityofthe | c studyorthe interpretationof theresultsinthereport. 1 0 i C Study Director: C C Wl: shoo | Cc Gary {. Wolfe, Ph.D. /D.A.B.T./Date: | o | C || c : 3M Corporate Toxicology 3 - 3/8 ` | o N-EtFOSE, PFOS, PFOSA TRC No. 1132:100 i STUDY IDENTIFICATION O Cell Proliferation Study with N-E(FOSE, PFOS,andPFOSA in Rats C TRC Study Number: 1132-100 | 0 Test Articles: N-Ethyl Perfluorooctanesulfonamido Ethanol (N-ECFOSE) | PNe-rEftlhuyolroPoecrtfalnueorSoucltfaonneiscuAlcfoindaPmiodteas(sPiuFmOSSaAl)t (PFOS) i a `Sponsor: 0 3M Corporate Toxicology | Building 220-2E-02, 3M Center | St. Paul, MN 55144-1000 | c Sponsor's Representative: M3aMrvCionrpTo.raCtaeseT,oxDi.cVo.lMo.gy, Ph.D. St. Paul, MN 55144-1000 } C PFahxo:ne6:5615-713-37-3137-753180 In Study Director: o C TGahreyrlWm.muWnoelfRee,sePahr.cDh.,CoDr.pAo.rBat.iTo.n G1a5itFihresrtsfbiuelrdg,RoMaDd 20878 }i Phone: 301-330-3723 | C Study Monitor/Principal Investigator: SPaatnhdorlaoRg.y EAlsdsroicdigaet,esPIhn.tDe.rnational Phone: 301-663-2036. C Study Timetable Study Initiation: January 12, 1999 | C I4n8i-tiHaotuiornPoofsDtoDsoisneg:Sacrifice: FFeebbrruuaarryy 2235,, 11999999 7-Day Post-Dose Sacrifice: C 14-DayPostDose Sacrifice: March 2, 1999 March 9, 1999 i 1:Week Recovery, C 4-Wesk Recovery AMparriclh6,161,9919999 C Study Termination: April 6, 1999 || 3M Corporate Toxicology 5 | t | 3/9 C || Cc N-E(FOSE, PROS, PFOSA TRC No. 1132-100 i | Cc Cell Proliferation STUDY PERSONNEL Study with N-EtFOSE, PFOS, and PFOSAinRats | | C | Study Director: Gary W. Wolfe, Ph.D., D.A.B.T. | o | Study Pathologist: Carolyn Moyer, D.VM., A.C.V.P. | o Veterinarian: Edvard T. Greenstein, D.V.M., A.CLAM. | C Quality Assurance Director: E. Paige Lacy, B.S. 1| Cc HFaecailltihtyaMnadnSaagfeetry Officer/ Robert K. Blackford, A.A., LATG !| o Technical Supervisor: Patrick Benson, B.S., LATG | o Report Supervisor: Lori B. Kaiser, B.S. | Cc Technical Writer/Project Leader: Kimberly A. Layton, B.S. | 0 | o Laboratory Head Technician: C Technicians: C C Paula Davis, B.S. Sharron Stewart DKealnliyelMAu.ssJealcmkan, B.S. BFreeltetciCahBainsehyo,p,B.SA.,.A.LALTAGTG Francis Larissa NOenhwruebeemceknyie, B.S. JPaouAlnnMaMrtuirnp,hBy.S. c | C E 3M Corporate Te oxicology r5ste | r-- ee------------------el-- ---- ---------- ---- ------ 320 | C C N-BFOSE, PROS, PFOSA G SUMMARY | TRC No. 1132-100 | | C `This study was designed to assess cel proliferation and peroxisome proliferation in rats | administered N-Ethy1 Prfluorooctanesulfonamido, Perfluorooctane Sulforic Acid PotassiumSalt, | O N-Ethyl Perfluoroctanesulfonamide and Wy-14,643 i the diet. Animals in Groups 1, 2, and 3 | received the test articles in the feed for 48 hours, 7 days, and 14 days, respectively, and were | C necropsied immediately following completion of exposure. Animals in Groups 4 and received o the test articles in the feed for 14 days followed by a 1-week and 4- week recovery period, respectively, andwere necropsied following th recovery period. All Groups were divided into | O Subgroups. Subgroups 1, 2, 3,4, 5, 6, and 7 received 0, 300, 100, and30ppm of N-E(FOSE, | 20 ppm of PFOS, 100 ppm of PFOSA, and 100 ppm Wy 14,643 respectively. In Group 1, each | GC `Subgroupcontained 10animalswiththeexceptionofSubgroup 7withonly $animals. In Groups | 0 2,3, 4, and 5, Subgroup 1 contained 10 animals and received the control diet. The remaining | `Subgroups contained animals each.Criteriaevaluated for test article effect included mean body | C weights and body weight gains, feed ndtestmaterial consumption, clinical observations, clinical | pathology, organ weights, gross pathology, histopathology, cell proliferation, C immunobistochemistry, palmitoyl-CoA oxidase activity, and electron microscopy. { o `Therewerenotreatmreelantetfindingsforfeed consumption,testmateialconsumption, | and clinical bservations. However, there weretreatment.related effects found in the mean body Cc `weightsandmeanbodyweightgainsoftherecovery animals.Therewere decrseeeanisnmeeasn ! " bodyweiongSthudytDasy (SD) 15forthe 1-week recoveryanimalsinthe300 ppm N-EXFOSE, | C PFOSA, and Wy-14,643 groups. In addition, there were decreases seen in mean body weight | C gaoniSDn8-s15forthe1-weekrecoveryanimalsinthe 300and 100ppm N-EGFOSE, PFOSA, | and Wy-14,643 groups and for the 4-week recovery animals on SD 8-15 in the 300 ppm N- C EXFOSE group and on SD 22-29 in the 30 ppm N-EFOSE group. Treatment relate findings were also see in absolute andrelative(g liver weight body C weight) ivr weights. Increases were seen inthe absolut ver weights of the 48-hour post dose | C sacrifice animals inthe 100 ppm N-ECFOSE and 100ppm Wy-14, 643 graondauninpcreasse in ! o 3M Corporate Toxicology 7 i C ; ee rr ee------------------------ 32/ C NI PFOS, PFOSA TRC No. 1132-100 ! C the relative liver weight in the 100 ppm Wy-14,643 group. For the 7-day post-dose sacrifice | ! `animals, absoluteliverweightswereincreasedin the 100ppm PFOSAand 100ppm Wy-14,643 o groupsand relativeorganweightswereincreasedinthe 300ppm N-E(FOSE, 100 ppm PFOSA, | and 100 ppm Wy-14,643 groups. Absolute and relative liver weightsofthe 14-Day post-dose | C sacrificeanimalswereincreased ithe300ppm N-E(FOSE relativeonly), 100ppm PFOSaAn,d C 100 ppm Wy-14,643 groups. Terminal body weights of the one week recovery animals were decreased in the 300 ppm N-E(FOSE, 100 ppm PFOSA, and 100 ppm Wy-14,643 groups. | co Absoluteliverweightswereincreasedinthe300ppm N-EtFOSEgroupoftheseanimals. Also, | relativeliver weightswereincreasedinthe300 ppm N-E(FOSE,100ppm PFOSA, and100ppm i CO Wy-14,643 groups. In addition, absolute and relative liver weightsofthe four week recovery | 0 animalswereincreasedinthe 300ppm N-E(FOSE and100ppmPFOSA(relativeonly)groups. | Results of clinical pathology, histopathology, cell proliferation, immunohistochemistry, | I] palmitoyl-CoA oxidase activity, and electron microscopy will be reporied separately. i :0 || c C || Cc | Cc 3M Corporate Toxicology 8 | | Cc || o | Cc N-EFOSE,PF~ O~ S,PTF RCNO o.1S 132A -100 o INTRODUCTION GC `This study was designfeod assess cell proliferation and peroxisome proliferation in rats | administered N-E(FOSE, PFOS, PFOSA and Wy-14,643. The design of this study included o groups of animals. Each Group contained 7 Subgroups. Subgroups 1, 2, 3, 4, 5, 6, and 7 | received the following: Control (0 ppm), N-E(FOSE (300 ppm, 100 ppm, 30 ppm), PFOS (20 C ppm), PFOSA (100 ppm) and Wy-14,643 (1000 ppm), respectively. Dosing was initiated on o February 23, 1999 for all groups. Groups 1, 2, and 3 each received thetest diets for 48 hours, | 7 days, and 14 days, respectively and interim necropsies occurred on February 25, March 1, and | C March 8, 1999, respectively. Groups 4 and 5 received the same test diets for 14 days and | terminal necropsies occurred afer a 1 and d-week recovery period on March 16 and April 6, Em | 0 1999, respectively.InGroup 1, thetestdietswere administerteod 10 animals/Subgroupwith the | Cc excoefSupbgtrouip7owitnh5 animals. In Groups 2, 3,4, and 5,th testdiets were administered | 105 animals/Subgroup, with the exception of Subgroup 1 with 10 animals which received the 0 TEST AND CONTROL ARTICLES i t One 34.88 gsamploef N-E(FOSE T-6316 (Lot No. 30035, 30037,and30039 combined), | 0 a waxy solid, was received from Covance Laboratories, Inc., Madison, WI, on December 31, | 0 1998andstoredatambienttemperature. Thepurity was 98.1%andwassableforgreaterthan | 5 years. One 81.97 g sample of FxI2 Fuorad T-7091 (PFOSA) (Lot No. not provided), an | C amber waxy solid, and one 97.13 g sample of FC-95 Fluorad T6295 (PFOS) (Lot No. Not | provided), a white powder, were received from 3M, St. Paul, MN, onDecember 31, 1998 and C storedatambienttemperature.Bothtestartihacdalpueritsy assumtoebde 100 %andwereboth C stable for greater than 5 years. A 1 gram sample of Wy-14,643 (Lot No. 119904), a white powder, was reseived fromCaymanChemical, Ann Arbor, MI,on February 22, 1999and stored Cc at ambient temperature. The purity was greaterthan 98% and was stable for at least two years. C 3M Corporate Toxicology 9 | C | | C Cc N-EFOSE,PROS, PFOSA TRCNo. 132100 | ) Areservesample ofeachlot wastakenand storedatambienttemperature.Thesesamples o were transfered to the Sponsor after the completion of the n-lfe phase. Any remaining test [ C `material will be returned to the Sponsor' representative. { 0 TEST ANIMALS AND HUSBANDRY Rats were used because of the extensive historical data base, and FDA requirements for 0 a rodent species. Two hundred forty-cight male approximately five weeks old Crl:CD9(SD) IGS C BR ras were received from Charles River Laboratories, Raleigh, North Carolina on February 9, | 1999. The animals were assigned temporary animal numbers upon receipt. The rats were | Oo acclimatedtolaboratory conditions for thirteen days prior o initoifatrteaitmoennt.Eachrat was 0 identifiedbyaneartagandcagecardbearing auniqueanimalmumber. : Animalswerehousedoneper cage fromrectoeteriminpatiton. Dutrheistundy,gall C animalswerehoused instainlesssielsuspendedwirecages onstainless-steel racksequippedwith i plastic backed polyliners. Animals were provided with fitered tap water ad libitum via an C Edstrom automatic watering system or water bot. TekladTM 7012 Certified Rodent diet was . available ad libitum in glas jars with stainless steel lids and followers. Fresh food was provided C weekly. The water is analyzed at east two times per year for contaminants and specific microbes. o The feed s analyzed by the manufacturer for concentrationsofspecified heavy metals, aflatoxin, i chlorinated hydrocarbons, organophosphate, and specified nutrients. The results otfh feed and i a water analyses are on fileat Therlmmune Research Corporation. No contaminants were known | 0 10 be present inthediet or water at levels which might interfere with achieving the objectives of | : the study. C During the study period, the temperature and relative humidity of the study room were recorded twice daly. In addition,theanimalroomtemperature and humidity were continuously Cc monitored by a ReesTM Scientific Monitoring System. ~The animal room was set to maintain temperatures at 64 and 79Fand relative humiditybetween30%and 70%. A 12-hour light12- C hour dark cycle was maintained through the acclimation and study periods. C | oC 3M Corporate Toxicology 10 | 0 | 3IRY | C N-EtFOSE, POS, PFOSA TRC No. 1132-100 | METHODS | i UT] po L GArousp signandmDoeseLnevetls | Following examination by astaffveterinarian for physical condition, the rats were assigned to the study: | GrroiumpeNPuomibne)r|| Co[ ntrol[og eT~m10r0oppsms| 50 | | pros | op| PROSA | cooppm)| Wyld| 00 pom) TomiNo. | of Animals | Olde [oo[ofo m]>m [] 1 IPE CNIE ENHE CECN Cc Da be oo[oT Te] 0 (14 Days) te |"1 [oo [> Le] 0 frome [mim|" | 2| | [=[7[> [=] 4 wk recover 5 | | c c HEH HE EC a | 0 Computer-generated random numbers were used for assignment to groups. At the time a: owfeirgahntd,oamnidzatthieonm,eathnebwoedigyhwteviagrhiiastiofonoreftahchegarnoiumpaalsndusseedxdwiedrneontoexscteateidst+ic2allSy.dDi.foffetrhenet.meTahne | body weights at initiation of treatment ranged from 175.2 g 10 271.1 g. Extra animals were C removed and discarded without necropsy. C followiDnigeptraorcyedfuorrem:ulations ofth test articles and Teklad 7012C Feed were prepared using the || o For Group 1, the appropriate amount of feed was weighed into a plastic container and i C stored at ambient temperature and protected from light, For each dose level, the appropriate | 0 e-- 3S MeC-- rorp--or--a--te---- To--xic-- --oloEgEy--------I--n ------------eee || C || -- 328 | C || 0 N-EtFOSE, PFOS, PFOSA- TRC No. 1132-100 1 C QuantityofTeklad7012Cfeedwasaccurately weighed ntoplasticcontainers. Theproperamount oC apopfrotpheritaetsteaamrtoiuclnet owfaascewteoingehweda,s audsdiengd 0aasltoaiwntlheesstesstteemlatsepraitaulla0, gi0ntionao gslolaustsiobne.akeAr.dietTahrey | i C premix was prepared for each dose level of each test article by adding the appropriate amount of feed with the test article with a sinless steel spatula until no feed/chemical agglomerates | | . remained. Additional feed was added in increments that approximately doubled the amount of C c `premix until an adequate premix was achieved. Following each addition, the formulation was `mixedthroughlywithastainlesssteelspatula.When thetestarticle/feedmix wastransferredfrom | | `onecontainertoother,thecontainerwasrinsed atleastthreetimeswithpremixfeed. Allfeed | C used for rinsing and preparing the premix was taken from the preweighed feed in the plastic | o containers for each dose level. | From the preweighed feed, 10 kilograms was layered evenly into the Paterson-Kelly o Blender. The premix wasthenpoured in equal amounts into therightand left blender ports and | spread evenly. The premix container was then rinsed three times with the vehicle, from the | C preweighed feed. Bach rinse was poured evenly intothe blender. Theremainingpreweighedfeed | 0 was evenly poured into the blender. The blender was sealed and the dietary formulation was blended for approximately 30 mites. C Dietary formulationswerestoredin sealed plastic containersandwerestable for 21 days | at room temperature. The formulations were dispensed into glass jars with stainless steel i O followers and lids. Diets were prepared for the entire study in one Mix. C Two 100 g samples of each batch (per mix) of each dose level of the test article | | formulation and stored were stored in heat sealable foil bags protected from light at room C temperature. At the requestofthe Sponsor,sampleswil be retumed for analysis. Unless used | | 0 for analysis, sampleswillbediscaratdleeasdtonemonthafterthecompletionof the in-life phase. | 4 `Observations andRecords L Each animal was observed twice daily (a.m. and p.m.) for mortality and moribundity. ! | Cc Findings were recorded as they were observed. | o 3M Corporate Toxicology 12 | O _-- 00]| 324 | C | C N-EFOSE, PFOS, PFOSA TRC No. 1132-100 ! Individual body weights and physical examinations were recorded prior to treatment (at ! C randomization (physical examinations not reported) and weekly for Week 1 through 4 weeks of | C recovery, staring on Study Day (SD) 1. Body weights and physical examinations were also recorded prior to SD 1andnotusedo reportedbecauseofadelay inthestart ofthestudy. Food | o consumption was measured weekly for Week 1 through 4 weeks of recovery, starting on SD 1. i o Clin"icalChemis.tryand CompoundLevelAnalysi.s Cc `Samples were taken for clinical chemistry evaluation and compound level analysis from | all animals immediately prior to scheduled sacrifices. Blood was collected from thejugular vein | C into a serum-separator tube. Serum enzyme levels of alanine aminotransferase (ALT), alkaline | `phosphatase, asparatate aminotransferase (AST), cholesterol and triglycerides were determined. | cM | 0 `Serumsamples for clinical chemistry were setonPAtIinChevyChase, MD for analysis. Serum | o sample for compound level analysis are being stored in a freezer at approximately -80 C until | shipped to Dr. Kris J. Hansen, 3M E.T. & S., St. Paul, MN. The results will be reported o TR | oC Interim sacrifices were conducted aftr 48 hours, 7 days, and 14 days of exposure to the | test diets, following blood collection. The animals scheduled for interim sacrifices were | C anesthetized with CO,, weighed, and exsanguinated. The abdominal cavityofeach animal was " optehenliveerredmov,ed,weighedandliversamplescollected. Theanimalswerediscarded afer C liver collection. | c Terminal necropsies were conducted, following blood collection, on animals scheduled i for 1 and 4weekrecoveryafter 14daysofexposure10thetestdiets. Theanimalswere | c anesthetizedwithCO, weighed, exsanguinated,andnecropsied. Necropsiesinchudedexamination Ofthe external features of the carcass, all external body orifices, andthecranial, thoracic, and | tL abdominal cavities, organs and tissues. In addition, th liver was removed, weighed and liver Cc samples collected. | no 3M Corporate Toxicology 3 C ! 327 COcC oowommo00spomes Nemsww ||i OrganWeights ! 0 "The liver was weighed for all surviving scheduled necropsy animals | o | o Representative samplesofthe left lateral lobe of the liver and any microscopic lesions of the liver were collected and preservedi formalin. After fixation, the samples were delivered to | CL Dr. Sandra Eldridge at Pathology Associates Intemational, Frederick, MD. Proliferation cell | C nuclear antigen (PNCA) evaluation was performed on the samples. In addition, live sections | prepared fromthesame tissueblockwerestainedwithhematoxylinandeosinandexamined | Cc microscopically. The results will be reported separately. | | C `Pelimitovl-CoAOxidaseTissueCollection andAnalyses. | oc A sample (approximately 500 mg)ofthe right lateral lobeofthe liver was also collected | from select animals and flash-frozen in liquid itrogen. The liver tissue was stored frozen at i Cc approximately -80C until they were shipped on dry ice to Dr. Ron Markevitch, Covance | Laboratories, Madison, WI for palmitoyl-CoA Oxidase etivity. The liver samples analyzed | 0 inclulldsteaddy animals,withtheexceofpthetWyi-14o,6n43animalsandthe 4-weekrecovery | C Group. The results will be repored separately. | | C TissueCollection forElectronMicroscopicEvaluation | Sections of th lef lateral lobe of the lver from al animals were collected, minced to | approximately one millimeter cubes and placed in fixative spproprite for electron microscopy. i C The containers and fixative were provided by PAI, Frederick, MD. Samples were shipped to | Sharon Ambrose, Pathology Associates Intemational, Durham, NC. Electron microscopy was | Cc `performed on one animal per treatment group exhibiting the highest cell proliferative response as | 0 well as onecontrol animal atthediscretion ofthe Sponsor,fromonetimepointaswell as the4- | week recovery. Thus, EM will be performedonone animal from the control, N-EGFOSE (one | C dose only to be determined), PFOS, PFOSA, and the Wy-14,643 Subgroups at one of the time. a} 3M Corporate Toxicology In | ----------e-- ee e --e --e -- 328 EE -- cC N-E(FOSE, PFOS, PFOSA TRC No. 1132-100 | C points, as well as the 4-week recovery, for a otal of ten animals. The results will be reported | separately | RemainingLiver Tissue 0 The remaining liver issue was frozen and sored at approximately 80C at Pathology | | a Associates International, Frederick, MD in the long-term archive for possible future analysis. | C Histopathology | Livers from each animal that was examined for cell proliferation were stained with C hematoxylin and eosin, and examined microscopically for histopathological changes. The results | C will be reported separately. | C RecordRetention All raw data, documentation, records, protocol, specimens, and final report generated as | | C a result of tis study will be archived in the storage facilities of PAI for a period of one year | 0 following submissionofthe final report to the Sponsor. One yearafter submissionofth final | report, all of the aforementioned materials will be sent to the Sponsor and a return fee will be | [8] charged. All rawdatastoredonmagneticmediawill remain atPAL ! : c | | t | 0 | -_ 0 3M Corporate Toxicology 15 | | C | 32 | c | Cc N-EtFOSE, PFOS, PFOSA 0 } RESULTS TRC No. 1132-100 | BodyWeightsand BodyWeightGains | C Mean body weights are summarizedinTable 1andpresented individually inAppendix | o Table 1. Appendix Mean 1A. body weight gains are summarized in Table 1A and presented individually in | C Mean bodyweights and body`weight gains were comparable in all groups throughotuhte study with the exceptionofthe 1-Week recovery animals on SD 15. There wasa 14, 8, and 12% | C decrease in mean body weights in the 300 ppm N-E(FOSE, PFOSA, and Wy-14,643groups, | respectively. Mean body weight gains were decreased by 62, 32, 36, and 35 % in the 300 and | a 100 ppm N-E{FOSE, PFOSA, and Wy-14,643 groups, respectively on SD 8-15. In addition, | meanbody weightgainsweredecreased inthe 4-Weekrecovery animalsby 40%inthe300ppm | C N-E(FOSE group on SD 8-15 and by 38% in the30ppmN-EtFOSEgroup on SD 22-29. | tL EeedConsumption i C Mean feed consumption is summarized in Table 2 and presented individually in. Appendix | Table 2. | tL Mean feed consumption was comparable in all groups with the exceptionofdecreases of | C 16% inthe 14-Day PFOSAgroup animalson SD 14and 20 %and 14 % in the 1-Weekrecovery | 30 ppm N-EtFOSE and PFOSA groups, respectively on SD 15. C | TestMaterial Consumption | CCcL AppendiMxeTaanblteest4.material consumption is summarized in Table 4andpresented individually in ` Test article consumption averaged 31.6 mg/kgfor300 ppm N-E(FOSE, 11.1 `mg/kg for | i Cc 100 ppm N-EtFOSE, 3.3 ppm for 30 ppm N-E(FOSE, 2.2 mg/kg for PFOS, 10.8 mg/kg for | o PFOSA, and 10.9 mg/kg for Wy-14,643. | 00 || C 3M Corporate Toxicology 16 -- | 330 | o | C N-ECFOSE, POS,PROSA gig TRC No. 1132-100 i C Clinical observations are summariniTazblee3d,andpresentedindividuallyin Appendix | GC Table 3. | Notreatmentrelated clinical observations were noted, however the following clinical | C Observationswereseen during SD 2-15iamost ofthe Groups: tinmess, abrasions, alopecia, rough C haircoat, acrismoffaecets,aindodianrrh,ea. One 48-Hour PFOSAanimalhadparaphimosoins | : SD3. One 1-Weekrecoverycontrolanimal wasmoribundkilled due to a dislocated nasalbone C onsD21. | C `TerminalBodyWeightsandLiverWeights | C `Terminalbodyweightsandabsoluteandrelative liverweightsaresummarizedinTable 5, | and presented individually in Appendix Table 5. | C Terminalbodyweights ofthe48-hour, 7-day,and 14-daypostdosesacrificeand d-week | recoveryanimalswerecomparable othecontrols. Decreaseswereseen intheterminalbody | Cc weights in the 300 ppm N-E(FOSE (14%), 100 ppm PFOSA (9%), and 100 ppm Wy-14,643 i (15%) groupsofthe 1-Week recovery animals. | C Forthe48-hourpost-doseanimals,absoluteliverweightswereincreased by 13%and27% | C inthe 100ppm N-EFOaSnEd 100ppm Wy-14,643 groups; respectively. Relalivterwieivghtes i were also increased by 22% in the 100 ppm Wy-14,643 group. The 100 ppm PFOSA and 100 Cc `ppmWy-14,643groupsofthe7-daypostdoseanimalshadabsolute liverweightincreasesof20% | and90%,respectively. Relativeliverweightsfortheseanimalswereincreasedin the300ppm i 0 N-EWFOSE (20%), 100ppm PFOSA (16%), and 100 ppm Wy-14,643 (86%) groups. Increases | o wereseenintheabsolute iverweighisinthe300ppm N-EXFOSE (44%)and 100ppm Wy-14,643 | (1045) groupsofthe 14-day postdosesacrifice animals. Relative liver weights were increased i o 12-49%inthe 30,100,and300 ppm N-BFOSEgroups,22%inthe 100ppm PFOSAgroupand | 0 114% inthe 100ppm Wy-14,643group. Increoafs2e5%sand44%wereseeintheabsoluteand | relative iver weightsofthe 1-Weekrecoveryanimalsinthe300ppm N-EtFOSE group. Relative | C liver weight increasesof23-25% were seen in the 100 ppm PFOSA and 100 ppm Wy-14,643 | C 3MCorporateTosicology 7 | C _-- | BN 33/ TT C 0 N-E(FOSE, PFOS, PFOSA| TRC No. 1132-100 C groups. Forthe4-Weekrecoveryanimalsinthe300ppm N-EXFOSEgroup,increases wereseen intheabsoluteandrelativeliverweightsof34%and29%,respectively. Relativeliver weights | G `wereincreasedinthe 100ppmPFOSAgroupby27%. | | 0 rosObsersions | 0 No treatment-related:gross findings were seen. The following incidental findings were | C1 `nmoottelde:dlainveernilanrtghede2sp0lepepnminPFthOeS1g0r0ouppp,manWdY-a1s4m,a6l4l3riggrhotutpesotfsa1n-wdefeokcurseoconvterhye alneiftmaclasu,daa | | o epididymisinthe 100 ppm Wy-14,643group ofthe 4-weekrecovery animals. | ' | tC i : ` | | c C | : | | c C | 0 | CUm m 3MCorporate Toxicology 18 ||| G | --_-- - 332 0 0 N-E{FOSE, PFOS, PFOSA o SIGNATURE PAGE TRC No. 1132-100 | | C Study Director: 0 `Technical Writer: o WIJEL sthbo Fiotnog Qf ofco Gary jolfe, Ph.L), D.A.B.T./Date imberly A. Ldyton, B.S./Diie | c | o Report Supervisor: | | C` id wl | 0 Lori B. Kaiser,Espa | 0 | 0 i 0 | c | 0 | 0 | O i C i C 3M Corporate Toxicology 19 i ` | "333 | D [rp eo. 32100 | soma or SnYeh1ans eres Cc 0 mw TsGshe : ar Cell e PrE oBleifS eraE tionPStuedRy ewith aWB-wEFOa SE, PFOSS D , and PFB OE SA in RatE s QB | 0 iwm w BmewomWta owwe m mwi emmtoH omma3% aoews3 C mESTaVe; 1132-100.Sse:e.SEX: B88a WALE GROUP: 2 (7-Day Post Dose 8 Sacrifice) 0E 8 0&E 8 00a i|| C nwvea ooW29E.w2o W 2.4 oW26.8s 2W7.o1? 22o9.}9mo%2w.63 2o7.w3s | C ET aaw sSrhas E o(nf3TTREFo R EBs S Be & aa S &a o |! C3 rs iwwow Wmmeti Ewye omBeR3 mOsWi mEe3 omme3 omms3 | | oO w;sow. mBaano amndss woamse: 0m.7a9? 2m.3e1} fwoies3 modss3 Cc mEae TT oMsee: .S EoBBBSTER0e8gma 8@ 0a 9 0a9 |! 0 w wi w oemas B ms"4 OBom? mWree2 mTe? emmea3 mes 3 i o ore mwwoOEmRaTEm%eR mWam3 Wmsm3 moam? aomme$ oaus3 | | C 0 os eo noBwarRY mWms oWme3 mWee7 mo2w? wWrse3 woews7 ||| I oT Te RE Pr | Gc NOTE: Terminal body weights for all Groups were food-fasted weights and will be reported separately. | C SB @S& TiicL onhnroae0 rmm i Cc 7) = Uy-14,643 100 ppm o 3 corporate Toxcotoay | sd C | 0 esos, ros, ros nee, 131m | C soJns S-- E hs | r ow TSee e Cell S PrG H olifeS ratiE on Study G eewE ithrN-ELFtOSE, PFOS, and PFOSA in Rats 8em0s &we ooom i 0 wW : o E me5 Tmr: wwsas mwe7 ommr1 moew3 moem? || C ave weoOwamRe i i} W ma omms 3 : oomme 7 moam s wwee : momee : | | ons C a ison %w32a.9 : 30S5.E9 7W32.e8 R3.E0} 7 33R.5g s 30O7.W1 ?o319w.1 I| OB 0 wa mi omOaER3 sOeRet mWee2 ommes wome: moomee2 osms? 0 a w ; maOW3 ome s omma7 omme1 oowmse7 wosw: woem3 | 0 ore : gOMmE3 mSey7 wmae3 owsmy7 uwse2 omme3 ea gs i C FTF Tens than 05 Analysis of VarTance using DUNNETTS Procedure SS ---------- | NOTE: Terminal body weights for all Groups were food-fasted weights and will be reported separately. | g <B G@1) =rchonita eroel 0 pom o hosp Il| | FBIEAT ||| C | 0 3 Corporate Toxicology 21 i | | ) S -- - C M-Exrose, pros, PrOSA TRE No. 1132-100 i o TTT ctor taroemaSrry or eHotaKIiatecanBskccmprot nats GT (ow Fob Be po TEE EEE i Cc o mowe Gwe BOB 6 wmwooswr sonao moaN moem 008 oonm 0 e wo0e&8nh omah oso i wo 3373 3 ||| a mepean ToWeOE: .S EBTG 8E0{TR 8 8EE kaen0&0 x 0a | | C w iooeeahtH wW s Mwe: wm e? omsm } oso$ wosw? ons O nwiea oos2.8 ve3.s93 aCum2 aW s3 nS114 3E .92 o 4.0 i | o T mepe EMeawwe S sT B sGE S8 ma T8 R weI rE gy m8o m0s&4 , 0 e w&r nww ao i|| n woos Imo ow om om o& C ow 1s ww : w onmeEI eEms omws3 daa3 omsme3 aoea3 wosmt {|| c vz bey oSmoa5 msau eomne3 w5es mdGr3 awae1 obme3 | i C rm on ; moeRTsmoe moms?omeom7 mo1m3 om297 o0m7 |} | Cc C our 36 mw i oomma7mmi omme3 m ma3 omme} mna7 omme$ i|i RT mT C tSe:eAnaoyn Lin eGroupBs, l16-Hur PSot Stos E ScriFiRce) aA nd 20Sa lPost Dn oss ae cc)eers ot reported oe to || CC @B S=cEIoErE0eRle.mE BIBrNImEREATn.a were om | C 34 corporate Toxicology 2 | 0 wee vo see | Cc Tn CoLL protfaraP cie SantdwithT M-ESrot, FProe--s _anP-- FOinnte8ats 0 pe SeeBH 80&4 808 4 G m ps beb e m 8 0 STV: TIE SEX WALE_ GOW: 2 (7-Day Post DoreSacrTIce) | gT p seme in ox M T | 0 PeRICD. SUBGROUP: in 2H EX in Su oN TH bm4A | C ;sor wr7 3 pics2 5.753 mi} er1 0.822 || eT | C so. am saz wr Seo 11.64 68 C bose: a@ & @ @ 0 we 0 own m ts on rm nett mnrfS egem 1 gC Note = Control feed given to all Groups during the recovery period (SD 21-80 42). pimy mo, oC BZ Wrs10 tpom BHHEiLRbLS C B256 0rm I C 3M Corporate Toxicology 23 | GI | 337 -_-- 0 wars, ors, nom nee, 132.00 | C c E poSmyee n Col rsf ttes"tisoTonmAaSyrTTB7eEwh3 tCCE oinEetiIWnwshro ay r6c i pe wo i! -- T mmee _ mwyr a wH a e Gwe m0r&4 x w0s&8 mieasw 0 i5.0. ous % 19.09 :1.36 8553 6653 2.0s 5.7s 3 12.03 |I 0 im wmw o% mWeEs3 oWmw} wwme3 ommee1 wowes3 pomee2 i i a oz W iWmsW 3 wr3 Wwse3 omme] oomme3 ommr3 oemeee3 | || O are im wm ow s3 wwiy7 omEe? m om3 omme7 mwrr7 ow3 | C o oars im womoos3 aSeE$ omweee3 omsw7 yommee5 omeme} oammee3 C1 on iz m i Rme5 wwem3 E we3 dwwe3 m we1 omes3 oemse3 O sRoto=LrTxEdceoIrmummpatroeAsnT Eorw6aRdtoeDconf 0Be4a2r.sywiparStOesR0TS2P11e0e0r,s i || C GS B @ +Icoi nRtoE l 0m EpmE C B &(5) = I rPOES 2E 0 ppm.R C _ Ji C 3 Corporate Toxicology 22 | C { | T33 | o weose, ros, proms nes 1 to. 152-100 C Cott rotteeseoHayr oFwNiIhCAoLecescarTIosns rst te | o} ma ppugm eosseee:weer iaw a$ a fTES6 T,8 M Sw e8w o00w@ pAp-- || 0 [Noirma TBsoorok TB oower m 9TxETww er o rox fosworex 5 : ox o1 rNTsee:ractoantreKsaL JoTehly BT3 ooto TI R oswuorcwomtekx i dm Dw sowaemr w iuokrwJ8o'os s3oo ||| | o RJacehnairesat C [Larcrtimhation :: ;: : T:diwm oslu 8Se :fia: :Toxo: oo : Teo o || | te To 5 ` : o : FT TIoseE: S WoOE G@T CayTETPtSa er am C 0 W mYew. oo aervsd wewow arimnation fw fn Sn 1Tw ss oc Gs we S5 eer 8 Ss um e &5 n5000 w Lax Jum | | ws o : 3 5 3 Tao o ThYeoe.rraotmbasruisLd ith SBwo aoo sddum TwotE hZs omo Gd lSs iwm iE Sss wheo SsSlooow : us eew : | ! o mMe To ETsa EmeRewS E dw G e Sx nfaya Fe p8s ey8n &Q 0O |!! C NNoo.rmaabsarved r0ox sSer s dex 5Swe S5 wor sGrom a5Jowm | C oNrYoeor.maolservad Sort en PTnoaom dssom 3sSwe sS: um S35 w sS: um sJ3 um ||| C oaSrYToeor1rascrtoaulereKeHdL T0oor ss we Ps im S5 oo 5 wor J5 um 5Jum | !|| jj sSTfooftnt receesm 0i oSom0 som 0:diwEoo58sik wsTiwEix 5d3e%im 5o5em0000 |i C: @3@1) L=TCioneEtEtrtorloo0Sd1Hp0Eo0pmponmm {i| C @6 22Hhro0easntS0o8moTmE pee { || C -_ 0 SH carporate Toxicotony 2 | | [se on rem er. we C ET cot protonsosmom[S A--Nr-- LTy, oy ae St ro rot ote | 0 ome ER. BOR 80808 08 a | A3p-- wBoowsJu s JomsJum iJus 5Jue D3 ue || C C oa=N=ros. ,Cbserved --, PH0Bre oEwAJg5e om uA5Jm om dAJyom um lJ5e e ff5 agm D5feamm | o aA-- DAY 15 C EEen Bwuor sJum lyowsJu Jsum sfemslem || P HEOPEI T EtL a im C Ew=ratrond 0 J fs, PBTwuEoEs sLoJEiolm JIsjoWmx Jdps e umm sJoiwiuwms m olJuwmm lriuawm S pode8gm1optm b moym o O " TT mTR m RR eeB wm Rp--fmmer 4 2b 36 ef Pe gb ju | 0 ey Bun Jom lew Jum wm fom Drm | o oaro28eoipynens PJBPo earofbSeosm uasGf3ew um s Gf8e um sfiaammspSoes um f|8 ox | | C i. tml rs | o [oJ Eyert pPBtorwxoogJ5sussdd3em ex is l3m mwosJope e s lg1ehr emgl8 em gp wPB f F orii em Em sms 8 tw 8 | gp} BB L gimuIE EReEmE' | 3M Corporate Toxicology 26 | Cc | || oo EE img fossil d C wera, pros, orosa 1 bo, 1132100 | GC| ov oe Sol proarasStouiwToHOwFEinGh3UMCeNoEneGtroisnCeu,eod)s10t3,ian Ey pro in sats EE | || C We hNoE:ecroinerXvetd mew dw:Tee w fHo0 B.: 08o: e O0o:8 4o: 0o:9 C pwLaoezsaves oC Ih B': em S:s ux :sdum d:s um L:s ex 5fiaxmgS5 oo TNUooirmmseattetsnion .TTaSo: 8:; ::o s Tm 6:: 3:: C opneo2r3oxarved o! bhten [T:SE m fa Gi0 um Ss: om : s2 dum.sLex i: 5:wm : 8Js e 8 | Notmaation . wos: :: o ToeTmo8 :: || C oarg 3asrte o oe 'PeexgsJum Ss: om dsiemmo ls es us: m 3sJue ||! i EMeiedprhearcentaa iTiEoo 8:: o.Si :| 8:: ::: || C {acFimation 0 onoTare3tammser1e0s 0 Tao imo s[rIo Gwe s wm sSus sdum sdum d5 o | | 1 Reirttmien Aocia aE TmmOoeE noo sh 8: F imWomEITaE :em 0 iHiE w : oO SAerlwttn oo 0 Pr---- vo om oo 5 BC Eros en & INE wo || 0 Bf5 rhEioEzeogmiia | BOE C 0_co--rpor_ate--Tomxca--teay 27 | C ||| 0 ross oe ven en vim C a cu possotosn oEr 1L55 EAaeNEsScHoAoTr omy | Cc T me oBw BseoedeaE HHomsE momoOe0c 4mo&0s0e8 maaonswoa ee oopaoes 0D v me TE-SRES. Soh Eon GE Te eR B08 0&4 8 me aTEa | 9g wWw omee omms mr oscNsa Ea oma= omma || Cc o B me TT-GiwwSmwe. w0a 1e0T_P Tdm m8aeB5 w e Fo m0o iH5 r0s&r05 A aaaax35 0 e0w n45 ofoeo5 | 0 w7 oodswonB&H? oiH} m ma? owe} || o oAY 14 w iww oe m8Wms oWseoy osya| oaa? oaw} oome: |!|| 0 0] mefp--msw TIERB-E--3B RtB a G x am 8 T w s 8 F x----d--8w w------w--8a--3----6 ----4w----o ----a-- w Boeuem moemMoomma osse we ms me || wen k G4 e 2 oas m3 on} ;BodsS eoEmme as ey osse? oaaei saui omog? | Do i0-7_2--mcrmt e0m | c F S3) i= Wa-nnECnFL OenSE s1,00 pom OC 0) = Uy 14,643 100 ppm C| c [_-- p---- 2 | | | | 342 | C C vaso, ors, rom ete, 132100 C co rot arseotmieons Boutry aEewbh4 mEiniancmaoprici,onandoPmHS tn tts TO Ei 53 ok Tory yr er || C a r Saeem(ShgeSw f Te feeSf@ |i xe 0 oar 1s ewdmod0e.%0 B 2.7? oene3 3a.63 J2E.33 N 2.43 08ne3 |1! C wiowood0%0 aW1o? d0E23 3a.05 d2a0s W9.E83 010g.05 | i oC BBToTevtTree em | o fBB& iIAlESe.Te 0 || C ! r 0 Corporate Toicoteny 2 | | C 0. N-EXFOSE, FOS, PROS ET somEaL0SsuGEroeRsvTg rRoneniEeSsyAtceea 1 or eiennmics 18 Wo. 1132-100 | | 0 S=Sehe vor gn 0 Eg8E xB8&E 0B8 Ba6088wOoqfa C i;=h wFeOaMomEms oowmaOCE ovmCaR oommheE womrRg woew C ne pios Vso. 0u.6s3T4 ON0Eg.eR3m o03s8s5R3 R0a5m1o7 0ommeR 0ne%omem e0.s41s0ode || | 0 we cp=oV r wen ESETSEREsaw BseCwMMMEsEe eNaRmEEamoh esNioSw ||| Lo U Se =m ee e 0SB0H a8mB e8e H8 4 m a w r 88 80o0m 0 | 0 or fiaoVono waBOTooSmOaomoommeomy moawome oowwetey ws hy moemvy 0 er pnts iA) SLIToToSsM SgEscE Essemag msmeemoconumam oedy o ve c==g vem CSEwRBOaTWmTR CCsAaEe oNsiEm 2se%moby saeakg eusweolny Cc 0 fS=ereea e BBW OG&S Ba088T 8a 088 8a 00 |i||| C foF; d wTaBEoonEmggo oowwesRE oowmeeRg hmoems woywhg mwomyma J| oc) Ler @youswsnunes iso. O SWOEuS 0naanmeey nlieassTeg omsoenose omsumem sivenay | | 0 po=v C SEWE cCagm T oaNm ecWkaEm E sumoly w woiomn ocnuryaem | Cc m E m F TE EE RE EEm IANT E. a || - C Subgroup & = N-EXFOSE 30 ppm 1 o 3 Corporate Texicology 30 | | | | o wrest, ors, oron eo. 13200 | o Sao n of asor UTE LIVEy R LTEABTLTES Ce(CoyndtinAued)01S,RGaTt rsoyhae RATIOS ||| C RSoTixVa:n:TISET00 SON MALE SIIO8HEED& GROUP:4 (1-Week Recovery) 4wea 8we ow 1 0 [p--boeN F msaewms moWe8 Eweomms cm meocmane i HE ses : 3 | C3 ver @ooaowwsaunes TnaEm CcHusSs tw DnsReONneEs MmeEn Nnnm |!| i 17 To 33 0 Liver ct=ig=o~r ram) HsRaw eOHmERTo JaSm SmEoTSTsEw cNoExt ew 3 | C o SasT obsi:r: ha E oR @ R8 8w E a 8@ 0@ || son ra=Ar @ a} i Wwas3 wooWsnThBweROwWeHl 8m2s wWst owwr7 ||| o Liver iaos (G)(ABSOLUTE) smiamm3 cobumspTmVTikme mowuemsy neerr sLenae3 mnaem1 i C 0 ver pei=sson satan Gsims3 eCalimmToosaRe oamae7 osmm eoslss osnadr3 i || giSEirm aer 1 +m 0 T om cce nn trl) ErrEed aR. a. SSeienb7r=Wooy-1nu6,6pt43o1h00pen 1| C 3M Corporate Toxicology 31 0 8 oanan Leoann ! Ohm le | | go. - iad | 0 geziiz agrees ERENT | 0 cama| gan |S | c 5 BEEREs Of sma] gma | ER | O| =1gF ae e m | afn e | | | LEsgl gE2EEEE8EEE| gEfRiiEE dors. 0 | py pa| ga | EH *| ol : 0 EHEE fcoRnemdmeadcsnaadneyn [|p cRfnioeese 33g] 55 | Vin Ban TO | 0 SEER aERREEain eRgResss B0 cZEhAaRmEsAiRaAnRaNsS [B5 oRkemdid : Pm Suan o| mmm pl nie 4 H Cc TCY issno Hip 34 ] HE 1D FEE Hhiasas | 2FAA | Fini] Eb 3ckleadsaegs [Rfdalsnests To t FERERIEEE pgged i | sah og 04 : i | :0 eH | !] | ` dE i | ` Fig ; | o| ,4; HBAiEd :sl: Uli Jp on ; | :C| i |i Hagnun HHfoenime|:|: || i oo| & | pSaAg Terait |! "| o| ae|| jE | o| R8FE Lhg3iEsasEE cijagn i || c0 Pie i :. ] Ei :f Shamdaasaaasniess fa |, oh i5i ||| cll hae Eres i said hon fi ite P- o || C : i BPep i s p -- aF d 2 BTS a |iHsiuaninal Flinn Ei an P| Po ol siisen : | | 0 | oY 03 |i e |i c | C [i --EE HShioereis|| sSpaandues ! C 5qd glaasesveesn Rslhaennnsnde|| sRlpaanRasnde o | FEE | [gid EZEhmsEas OC | 88y e+ sEhoLzzEe: s383RE| zadadE saleeardne| [sspldoagaasn sRlEeLnaAsYa|| zelReEednd-s< | - Gl Oi omy o i aul, JERAARR| RAE | FDio | lw an Iz 5 5 5 o| BEEEECETRTRE FSIS sbi lLSe 0 l zfsciz 33ad | EAHARS | HSdRYE [o HEvdsR| 5: 8 fS8l3o4o3a%aeBoRaAs||[ tgoannnaessd ||[8 dRae-dede |RB sEloaEee- [3 || :i 3 ehhaniaEmisennenEaEy fGy ZRenoEne fo SEenRsorMy Hhaenneann [f2ab c 2 6 SfmEaininRnAaRaEnEy |[ fSueTns|ff fclianvees|[ sohdoandceed E(BooEoilEag| B | 3 CEfEomeaEnEgeEnss E [8 loE ennn [8 fEssaEnege [E 8 fiE neen CL[jEoCEEIIRZEENS | i2 DC8l [liadnlsiaanssseesaeneers [f3rusiansssavnsn [f3uleseesaenees [l-diieasgnasnan [(2H1E1H1E1|| & -_-- 03 oy #i | | i 1 | 0 Fr i = 3 aCl ls Pre jree n i` on FERE EH Fo m 2 i | BY Shnesn i C1 4 pun Fa : o| 5 bbs : BY | Jam i C Sus Hc E==Eas 2 o| Flin Hn ; Bed Sena i 0 ilps 25 eu i o| Ba... 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D or ortha a owxiroars | C os EeJ rhst wwwsii 0 [--ha oso hpoom owuiroms owty {| 0 Tem at ni 0 pSemraaeicnl1E2 m0sommcoRnIsRims | C eSRolreI &in peaS k, 108 pTm R | 7 eo eereeee--------------cp------ee--te--rererreyme 0 0 corporate Toxtcatoay 4 | - 0 J-- mse, vm o rT s Sar t (FI aortcepdsU3ATcEenn vy ts ||i oo ho+ ris To om xt in To mwwooeiTs | | 0 wee HweS aie wipos | o [ET ha ne wouysows | wo afrmr 4oun yous C wos iormh an wourivanes | 0 ewes lwmh xt wouivous 0 mt Tot xt EwoHsi 0 oo Treom tt wwosii ||| 0 wt j tEo -- e wwo4rii]s !|| Oo oRoh+TaEstedmourrmimonsx re LTo TThecwomaryosar 3 | o MoE errmn wwyi || C [ER BParaoghitnosets aowasi3 i| 0 os eiTnatt tt wwriis { 0] mToratt tt BowsHi C [rR na an woaysoars o a ehrma au Wouyroars o Sr SMheaalen1ld2r0lkpmaEe comnrR.t?E || 0 S e ShraEse iintom ii C 0 Corporate Totcaony 2 i [oss oe 16s, 13-0 C +TmTarioct ort erota T a rSyaiSS hleorny Toe So noEaehtssfd oro I cs | |i 0 Mids oTistaoiosn tt seen IR wwSEii | o won mETitt tt wwrtii C wor tmerhm an owuions 0 Bin +raTtefmrrmos Sevmei 1r5 TTE cowennytarsowmse | i Cc Ms Tostorarionna Kitt SOI oINS3 S C oom Toereminal Kitt EwoirH ony roars || a me Th a wy | R106 Nformeal in 0 J Yom xi wiDAY 1-DAY 3 owxyrons i !| 0 se emt Tom tt owwriis C wr rHmT xi owuyroars 0 [-- frp Wi--. R103 HT Normal xn wyOAY 1-DAY 3 |i 0 moo dtorosalm gi C Saran 120m const woaryour 3 | ! } C SHFreeere llaiigEnniIaRRE | | Sraend lenSon em { | L ee erre-------------- ||| C corporate eseteny - C wesross, pros, prssh eto, v32100 | a orm I vie 3 nin | C gp} S eTTETRTeSE--eme aGol potifaraE tiron Sntudy withLW-EEehFOSeE,oHwPOeySs,SandeE OSA in Rats ------------ 1 o Moz rmNTAolromopaelcmia xi wooowasriwd { || o0 vo wYn aesan wwwryi i i| i Todi eit wi 0} oT wroors +TtEoaTwremrmtear us r pe ies oe owowneyis T i!| [Tom m xi e 4 e or ort wr vows | 0 rh a We o mos oTerrmomalm xt wwourie1 ||| o wo ertha an oErHvows [Ee Hm xn wJia--, 0 ww rseam xi awarows 0 ost rt cn wouivous os erm oa vows | | 0 Yh an wo f ert p We owueyom i B woiss tNoermralm a moary10 8 | Cc se SJ vhered+ 4 kBe rios50e0p.om SS e nedh S A em 0 weve mn | | eee -------- ree ee -------- {| | C 0 carport Toten " = - | [ves ve ron a || C A TEE Sl rrTJ ea II --e S -- e ee ||| C ANIMAL # Togs an OBSERVATIONS Wornal SEVERITY LOC TIME wi OCCURRED DAY TORT 8. | | C aEn pwe e o wo iBt wwwiee | R10459 Eh Normal weDAY 1-DAY 8 I C 0 ows ee worm TmEEes aru rreSe T wmoayovpgans |i1 fe m[si ewe r C or pEome rwpi | o ws mHoth au owuafive || a ooEh wdipe 0 l ows ermu th LL ude Woryvows || ie ee 0 Tw xn we afe wa e | 0 ows hormat n monysroars || 0 ee eThma au iwirows | o or h pomn ofi i 0 E sSHnrzlenE libemR meeE, | 0 fE eoe S reerRe | go --me--m ----------is-------------- || | 0 wom ee oon m2 se, v0 cg o T hm a+ m armase Coll pre oliferaT tioop nAPsPtundEy NDIXwS JiTm tAhBaELAE-RE3XE TTOh(S SCeEoe ,nctiePnR HEunOeSt,d)syas nd L pe rOSA i-- e n Rats Se | || [Ep 0 vo mrtm xi we ownyvows on eYmth a owaeroars i C ore oHrmht x BonyEtour 8 C TE ae RIGS. rTNrormhale tu eT s se er coh wyaE DAY 1-0AY 8 ||| 0C e a TjorNmormal. e owwieeoonAYe8 ||| C R[IETRE Nhormaal ant waDAY 1-DAY 8 or vows || | o orm fTerrmienatl Kitt oouyarows sr mT { 0 ESeolslabo[swtrariiEonep sa hay tieasWrLe oEWerRsE | o [---- rm a o} res eTomma xi wonevows oWravows |i 0 vo efrtn owryyours emmt u oWuirows | C saharreean 21 r=C0Bomrs(,ContR3r0o0lE)pom !| | o See r arla e =E noEvrosE, 30hepom || C 7sh || | C i Toe ------------------------ i Corporate Toxicology. 46 i - 0 om moms | C al rit(oracSiSiAH3 SoSEnsnrnt,y 1 Oo m prate en pmmie-- a 1-- coEmeR--s --eeme C Etolmyen wwii TE eo 0 wes wm on ow1e 0 fe oi wo Th an rwiar | C on eTrhsta au ooa iron 1s | 0 eee eEmh oonu vow1s pom ov pe | Cc wpTTermhinal Kill a ooouAYiv15ows | | 0 we I Eehw ownuyyvows | oc 0 fm fErsTpO[-- r= GOa T CISmFtrSSe ern seenoiwT e wr yTo h oonn vo1w 0 wes tem on vow 0 pfomr. 0 E pom n 0} SEi rmeilm1i2r0tpI mmenmonEt)E 0 e A MEmn ihIed NEE. owryowe oqys Cc s------------------eereeeeeeeeieeen | 0 3M Corporate Toxicology 47 | EE 0 ems en Fp | C S TT catrootteoaecA hFFhnayEesiA re etSpSE --h pr I cs | C H+ e taTienmsxt ro 12 cnnwonyistS 0 wer mrtn in oonu vow 15 0 os rroma owuirow 5 | [ER Hn an owuyrow 5 | C o E --T-- Eonar u R p rm eT cwJ ouynt T i| et STeem an I wo o a Th x wJyar | C oo tomna woyyoe 15 { a oo emtha xn oouyyo 15 ! 0 ET oorTrEamermwthe E m pepe Te cooorynyso 1T 5 e Eh a T on a woz rormmta xn ooa n ow 5 | 0 os ETfeSmortmext WWwiEEye | o wos h ormt a ooaw ow 13 |i oO #10515 mh Normal au o fF ore)p bm--n, wy DAY 1-DAY 15. ii ii c e SSShhhrreuadne eslbiuieieiEWBorem i |i C [ji C | | C i ------------eeeeeaeseereee | 0 3M Corporate Toxicology 48 | co w-eerose, pros, prosh TRE No. 1132-100 LJ T Hive, Ses | C frSeTA. Cell proli(feCrahtiaTonpStmtudy saewitshLroN-EeCiFOeSeE,ccPoFOnSt,StsomndaPFOSA in Rats | C wTeotm wwsww !| 0 or L hdaert e wworiirows | o wots eTorotth Wouiron 1s wo e[rrtoc yen wouivow 15 C o wos TEeTiritmi si fra re TT RT i ay ivm sor eT Toth Lo 102 coonsts | i|| 0 ma W[ ormet . [---- ou Twhn TON TS woriawe | || o om Rero ou wouitow 1s o oa Terth kin wouirow 1s || 0 f om r rrreTra osmti ou rrrTot oohn ivow 15 Loc "Toe cia Soe | i|| o Hate Tom au wa wor Tdaortm iu Worisow 2 || O wos dTorsma ou oWwiow 2 i| 0] om fioTorrtna ea wWouiEvow 1s || C wo [errompe WoEo 2 C won am ou WoaErow [-- Terminal kit WEvow 22 C om Teotma sit WorEsow G wos pHeorta ei oWuErow 22 C} EoEsEsLTL heYS romemD cWaou wm EST Eaag:T ro amWdouysS ow 2 TW or C MINE RE WRIA || | 0 3 Corporate Toxicology. 49 0 ese 158, 200 | C TT ct poa tteorrTonceitaSe,3L(ScmtoiHa nsSsdprec Iancteer | i C] Ms mes+ soaiFpianria ts o Cn 1cs `oR awweeis in Tom itt wi C o oor hTreormeaml xi wwowariiavows | on rthm oO Terminal Kitt wowyton 15 NE ||| 0 eETmnotm au wWJnE-- || ROO rNormaml x oa 5oN 22 || C o RfSTOrOVs: 1132-- -10mTs0teaotionm x"GiROUP? (1-Weeok Rneciovery)u1eITTanGoRoewoe:w3ey |||Y R10562 Tom Normal win 0 oss orm WH DAY 1-DAY 22 owarirow 15 3i |i [LL-- WE | o os ertna xn owayrow 2 || o R10545 E-- TNrormahl x TE BRbDwAeYy1y-DAY 22. ||1 ]7 RoE NTormanl an = WE ORY 1-041 22 ---- || 0 R10547 Nformral.o [-- Hm xn wy DAY 1-0AY 22 WonEvow 2 1! | Cc oso oHrtm a ownb sour 2 || [PE -- C #10550 Normal 3 Terminal Kill DAY 1-DAY 22 DAY 22 || | a} SeFerioeibn5a=nrWE -TeoHOSuEn,R 1t00spom G ran | |] HT IR C | o | Corporate Toxicology 50 | | WE soma | oC ETE a rstson I eJn--e--rEeBemderPEo Ietes ||} | Tn Medetome eyo a eaten C tpKheerimmatioxn t wownzmz C oz i orm -- WonEvow 2 0 es jeme woryow 2 1 0 oe rm xs J wy em xi owryiow z | a1 o SBTOTeT T1 EmTaotoRmna xGiROUP: 4 T Ir WE (1-Week Recovery) "SUBGROUP: 6 or moeten wWWwhyew C Termine Kitt 0 eumtc - WE soy o5w 2 ; , #10859. ma Normal xis WE DAY 1-DAY 22 0 wi ow TEsromh a mene 1c SoRowRkvyeso z Sais t[mi=oan x sol ue "NNTeicEowa o oz YrTosmwt cit owwnyyztour 15 0 wos em rons | LL nz | Oo Roses Tdorosalm cit oWnyEtour 22 | o} or om woryvow 2 | 0 SE [ HrEpR E E120IpR R InEcnNE tE? | | 0 rforeesssinitonAm, || | pSipb7g=rWya-16u,64n3, 100 pre |i Cc WT = Ventral side of Neck i ge -- 51 | i: oi 0 MeEviose, bros, pros TRC No, 1132-100 C oa o Sen SE FFR ETTA SGeallrp]ral eC ratSiooSy ntnundy with_icke-EwSTFOoeSeE,odPtOSpo,aandFFOSA in Rats Op 2 ReeTeam rxt e--------mmwaeteemer. | o wo Mapoeieti Ton a woono oWareos n w we || C0 woe oTomme xt woresows || G} R10569 jp Normal o OT rEeimht wy DAY 1-DAY 43. war W3oshoa || Tom xe wa Ros i wo et Eh ot sows | | Cc pReTeddoenmed cit 6 wwDAYaa36 0 won EeTemntn x nowraA sow 2 || C ri0s7% Horanl x DWAYE1-DAY 43 Oo e R055 ETtEuNhornmaeleaa cwmniee e"ToeeSDneAYmyi1-sDAY 43. | | jul Terminal Kill 0 wom eHmitte xin ES rwyons | |i 10578 Tn Normal x we DAY 1-DAY 43. C HOSTS dTeorrasianlat itt . we emt aoharr 15oaY 43 wn ors | Cc a -- SSseavwsennsm 12LN0Taeo orEmlminaacloEnnx0ttrRo g id | OoLESR fEhrri i iineasr. EetRe ||| Co Bxm CRC= vai eeci sm ic of ck re es 5 Gime : | _--_-- | 0 3M Corporate Toxicology 52 a | - | C g N-EXFOSE, PROS, PROSA e i reo mviee3 cCaoilnnnee e TRC No. 1132-100 || 8 p o Trr TEeTrsh aCote pot C featicnt ey w withuleEbeSoTRoeiEow mtpeeseaa nd rE ain atntse r o os mrta in wfyypos os rrmm xt TC wom wm nyrows wr or ||| Cees ww ou rows Si+rtEeTenrnionanl Kill mene oc TDE AY 4e3s | c -- b Vorsal we BAY 1-07 wa Sg | Oo R10587 TNeorrmmianlal xitt we DAY 1-DAY 43 i| a oa orrt in wOwNsoSawn43 !| I} T-- eio em a La. 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