Document 30goVy07G5gNNgJLX8kmzLLy

AR 826_ 0656 POSF Ongoing - { 000279 Tosmr200 PHARMACOKINETIC STUDY OF POSF IN RATS - STUDY OUTLINEPOSF PK aSntdudcyaOlbjcelcetairvaen:ceTahnedobbijoelcotgiivcealofptehrississtteundcyeiosftoerafslsueosrotohcetpaonteenstuilaflonfyolr oflauloraibdseor(pPtOioSnF,)uirninary male Sprague Dawraltsaeferya sngl ora dos. The POSF compound i the starting material SpfotururdptyhoesweislyolnftpthrheiossviissdtoeuddfayatwsaitfdooeuvpnardroeipreetsrytoarnfidspketchrehfalrruaaotcertoeoorfcimzteaattniaeobsnooullffioPsnOmaoStFef-(PPOFSOFS)tobaPsFeOdSmabteyrtihals.lveT.heThis d(eGfLiPneSdtaptruost:ocTohliasnsdtucdlaysswiilfliebdeapear"fColramsesdBinStthued3y'MasSterxaptleagiicneTdorinicToOloXgySLOaPbo0r9a5t0o,rySturnadteegric Toxicology Lab GLP Program Procedure. "Test Animals: Mal, Sprague-Dawrltesy, 150-250 g, obtained from Harlan [GDroosewGroups: 0[aPndowemg/kg accord[ingNtothe following[scEheduale:ts [sm To5 ms ghs5 TTaiyojpmdam || = [sSmmgkse [[55 TTdannd2ppeorsdcmdeoe || h"Tiegsht-pAurrtiitcylPeODSaF.n Hakes, Proust Responsibility Lisison 3M Chemicals Division, will furnish `Compound Administration: Oral gavage. Clinical Observations: Once dil. `dSaaymsp1l,e2,Co4l,le1c5taionnd:2U0r-iponsetadnodsef.eceTshewsilelabneimcaollslewcitleldbtehrpeelascpeeciifnicmertatasboflriosmmgcraoguepss f3oran2d46hoounrs Kfoirdneeaycsh, fsorrse,ascuhbccoultleacnteioonu.s faNtecarnodpwsiheoslewiclalrcoacscsurcoolnledcatyison1w.illaondcu2r9paotsntecdroospes.y.Liver, `rSaampilveerA,naulryisniesa:nTdhfee3csMfEornvtihreopnamreennttacloLmapboournadt,orPyOwSiFll,maandnatgseptrheeseuxmteradctmieotnabaonlditaen,lPyRsOiSs.of `EnAvliirsosnmaesnatmapllLeasbowrialtlobreyroertaiisneddesfiognpeoesswioblueldfupteurrefoarnmalsyuscsh oafn taontaallyosrisgiafndieeflmueordinnee(ceTsOsFa)ry3bMy the Study Director wDialtlabeAnaanlaylsyizse:dDfaotratocxoillceocktiendetoinc tpiasrsaumeelteevreslsnodf pfaorresnttaticsotimcpalolyunsdiganinfdicdaennttidfiifsfbelreenmceetsabboeltiwteeesn groups using Students T-test andlor ANOVA. `EstimatATeand-aLlTiyiftmeieclSatilanrCeso:(mAJpsalsneuutamirioynn|g:1tEMhHa,rS1c&9h9R922a1pdp,ro1v9al99on JanFT.oi-n5La"il)f:ReeEpnodr:tF:eAbprruialr1y9thh,,19199999 Study Director: AndreMw Sescat PhD. 000280 T172079380.918 3M MEDICAL DEPARTMENT, CORPORATE TOXICOLOGY POSF PK Protocol for Study No. T-7098.1 PHARMACOKINETIC STUDY OF POSF IN RATS Study Objective: `The objectiveofthis study is to assess the potential for oral absorption, urinary and fecal clearanceand biological persistence ofperfluorooctane sulfonyl fluoride (POSF) in male Sprague Dawley rats aftera single oral dose. The POSF compound is the starting `material for the synthesis ofawide varietyofperfluorooctane sulfonate (PFOS) based `materials. The purposeofths study is to understand the rate of metabolismofPOSF to PFOS by the liver. This study will provide data for proper risk characterization ofPOSF. Research Client: 3M Specialty Chemicals Division 3M Center, Building 236 Saint Paul, MN 55133-3220 Sponsor: 3M Specialty Chemicals Division 3M Center, Building 236 Saint Paul, MN 55133-3220 Study Location: 3M Strategic Toxicology Laboratory 3M Center, Building 270-35-06 room SB314 Saint Paul, MN 55133-3220 Study Director: Andrew M. Seacat, Ph.D. Sr. Research Toxicologist 3M Medical Dept. / Corporate Toxicology 3M Center, Building 220-2E-02 Saint Paul, MN 55133-3220 Ph: 651-575-3161 FAX: 651-733-1773 Study Toxicologist. Deanna Nabbefeld, MS Advanced Research Toxicologist 3M Medical Dept. / Corporate Toxicology 3M Center, Building 220-2E-02 Saint Paul, MN 55133-3220 Ph: 651-737-1374 FAX: 651-733-1773 ProposedStudy Timeline (Assuming EHS&R approval on Jan. 5*): In-Life Start Date: January 11th, 1999 In-Life End Date: February 9th, 1999 Analytical Completion Date: March 22nd, 1999 Final Report Completion Date: April 19th, 1999 000281 r5o05m% Regulatory Compliance: `This study will be performed in the 3M Strategic Toxicology Laboratory under a defined protocol and classified as a "Class B Study" as explained in TOX SOP 0950, Strategic Toxicology Lab GLP Program Procedure. purty POSE Test Material: Dan Hakes, Product Responsibility Liaison 3M Chemicals Division, will furnish high- Identification: Name: Perfluorooctane Sulfonyl Fluoride Molecular Formula: To be provided. Lot Number: The lot numbers will be maintainedinthe raw data. Purity: Documentation will be kept in on file. Stability: porate. Documentation will be kept on file. Storage Conditions: Upon receipt, test material will be stored tightly sealed at room Characteristics: Information on synthesis methods, composition or other characteristics that define the test material will be kept on file. Animals: Species: Strain: Rat Sprague Dawley Source: Harlan Age at initiationoftreatment: 6-8 weeks Weight at initiation of treatment: approximately 150-250g Number and sex: 30 males [1"GTarbolew1 - Dose[[GDro[oomusgpNeshe_--[E5 utb[udynIpowsdosse n|| [5 2 T[oommgghhee [[55 T[adnydpposoiddoose || s [S[Smmeolkee [[55 [Iddwippoossiddoussee || fe"ai groupTs S13mwoilhbee aed c[o5ncamTanTays cToairnanipmaolss sdolc sJ T0712, Phatramnacokinetic Studyof M556 in Rats, and T-7099.1, Pharmacokinetic StudyofFX-845 Identification: ea tag with animal number or unique il mark ' 000282 P1O2S7E30P9K8 AUANumber: 2154 Husbandry: Housing: Three specific rats from groups 3 an6wdill be housed individually in metabolism cages for portionsofthe study (see Table 2). When notin metabolism cages, theseratswill be group housed in standard cages. All other rats will be group housed in standardcagesthroughout the study. Diet/Water: Harlan Teklad LM-485 Mouse/Rat Sterilizable Diet, supplied by Harlan `Teklad, Madison, WI,andtap water will be providetdo all rats ad libitum throughout the study. Environment; Environmental controls fortheanimal room will be set to maintaian temperature of 72 + 3F, humidity of 30-70%, a minimum of 10 `exchangesofroom air per hour and a 12 hour light/dark cycle. Dose and Dosing Procedures: Method of administration/Dose preparation: A single Sme/kg dose of POSF will be administered via oral gavage to rats in groups 4-6 on day zeroofthe study. The POSF will be prepared as a 1% (1 mg/ml) uniform suspension in 2% Tween 80 using a 15 mi tissue grinder. A volume ofS mi suspensio/n kg body weight will be administered toeachrat. Re-suspension of solids will be performed with 5 strokesofthe tissue grinder pestelbeforeeach sample is drawn-up in the sAyrsiinnggelefoSrmdlos/ikngg. body weight doseof 2% Tween 80 will be administered via oral gavage to rats in groups 1-3 on day zeroofthe study. ObservationofAnimals: Clinical Observations: Each animal will be observed daily for morality and morbidity and notable findings will be recorded. Additional findings will be recorded as they are observed. Body Weights: Each animal wil be weighed immediately prior to dosing, weekly thereafier and immediately prior to euthanasia Specimen Collection: Frequency (sce Table 2): Urine and feces collections will be made on days 1,2, 4, 14 and 29 post dose. Necropsies will be performed on days 1, 4 and 29 post dose. 3 000283 P1O2S7F30P9K8. `Table 2 - Schedule Tdeaiyl0]| daGyanPiD]| dagy2mPD]| damy3iPiD]| daJym4iPsD]| dadySmPcD DOSING | Collection | Dy IPD| CoSlwlieccthiioon|| mSewtciacghest.o|| CSolwlieccthitoon Dy4PD | arTearlo|arGno]| asJsameid]|aygoms]n|aymtodrs|avis|a nvTm daynIZ3iP|D| dayJ1a4nPZD|| day 1Jm536D| | dayJ16wP]D | dayJ1am7aPsD] | dayJ1e8 dP]D| dayJ1a9nPDo. metcages.| Switchto LanS2S0T%Lay3R17T0arre5s0]0a5F7S0|an207 |ay2F5eb7s5||ar2F6e7e0 Feb7| Fens] FebS msewticcahgieos|| cDoyll2ec9tPioDn sae Methodof Specimen Collection: Urine and feces will be collected from each metabolism cage at the designated times. The initial volume of urine will be recorded, the sides of the urine collection apparatus will be washed with 10-20 mi deionized water and the final volumeofurine wilbe brought to 45 ml with additional deionized water. Daily feces weight will be recorded for cach animal. At the designated times, animals will be euthanized by CO, and gross necropsy performed. During necropsy, blood (6= ml) will be collected via the abdominal aorta and transferred to blood collection tubes without anticoagulant. Blood samples will be allowed to clot for a period of 15 10 30 minutes at room temperature, and the clot will be spun down in a centrifuge at 1100 xg for 5 minutes. The serum willbe transferrteod labeled 1.5 ml microfuge tubes and centrifuged again at 2000 x g to remove any remaining red blood cells. Each sera sample will then be transferred to a separate labeled polypropylene microfuge tube and flashfrozen in liquid nitrogen. Liver, kidneysand subcutaneous fat from each animal will be removed, weighed, flash frozen in liquid nitrogen and placed individually into labeled sterile sample bags. The remainder of each carcass will be placed in a labeled ziplock bag and frozen (-70 C) until analysis Specimen Handling: 4 0002354 osums Specimens will temporarily be stored in a freezer set to maintain -60 to - 80C. For metabolite analysis, these specimens willbepacked in dry ice and shipped to: Kris Hansen, Ph.D. 3M Environmental Technology and Safety Services 935 Bush Avenue St. Paul, MN 55133-3331 Ph: 612-778-6081, FAX: 612-778-6176. "The 3M Environmental Laboratory will managetheextractionand analysis of sera, liver, urine and feces fortheparent compound, POSF, and its presumed metabolite, PFOS. All tissue samples will be retained for possible future analysisoftotal organic fluorine (TOF)ifdeemed necessarybythe Study Director. 3M Environmental Laboratory or its designee would perform this analysis. All results will be provided for inclusion in the final report. "The number, type and dateofcollectionofspecimentso be generated for analysis are as follows: Table 3 - Specimens SSpeecimemns lQaty1 d[apyt? |[dpoasyd [[dpaoys [|pdoawy29| Toul [[veearm TT[ dooose dose Twdoose--0 [dose TTi1doo0se_TT330|] [[SRuibdenweaynesows fa [1 10 0 [10 | 0 TT11003300]] [[COomees 0 fo To TTe1T0o1T0e 3 [5]| [ees To To Te Jo Je Tw] Data Analysis: Data collected on tissue levelsofparent compound and identifiable metabolites will be analyzed for toxicokinetic parameters and for statistically significant differences between groups using Students T-test and/or ANOVA. Responsibilities: Deanna Nabbefeld and Andrew Seacat will be responsible for dotshei anin malgs, collecting in-life specimens, performing the necropsy and collecting and sending tissue samples for analysis. Kris Hansen, 3M Environmental, will be responsible for analytical analysis. 5 GLOSS P1O2S7F30P9K8 Andrew Seacat will drafta final report and ensure the report receives appropriate 3M review before a final report is issued. Signatures: Dr. Andrew Seacat Date Senior Research Toxicologist Study Director Deanna Nabbefeld, MS Date Advanced Toxicologist Study Toxicologist Sponsor Representative. Date 6 Lu286