Document R26p3GRRBkZaQyV311qmDLJZV

Argus PK Outline 5/03/2000 One Generation ReiproductionStudy of PFOS in Rats Pharmacokinetic Analysis Study Outline Study Objectives:This studywillserveas a follow-upstudytoCombined Oral(gava2e) FertiliiDye.velopmentaland Perinatal/PostnaRteaplroductionToxiciiyStudyof PFOS i Rats(ArgusProtocol418-008,3M studynumber T-6295.9).The objectivoef thestudy isto gainadditionaplhannacokinetc(PK) dataon PFOS inpregnantratsand theirpups. GLP Status:A GLP studywithappropriatQeA auditsa; signedQUA statementtobe includedinthefinalreport. Animals: Female HarlanCD rats. Dose Groups: Six:VehicleControl;0.1 mg/kg PFOS; 0.4mg/kg PFOS; 0.8 mg/kg PFOS; and 1.6mg/kg PFOS. Number Per Group: 36 pergroup = 150 total Test Article:Compound willbe fumished by theSponsor who isresponsiblefor compound identitaynd purity.Reservesample tobe retained. Compound Administration:Females only,dailyoralintubationd,ose volume 5ml/kg. The vehicle(0.5% Tween 80 indeionizedwater)willbe preparedweekly.PFOS win be prepareddailyas a suspensionindeionizedwaterwith 0.5% Tween 80.Compound administratiownillstar6t weeks priortomating and continuethroughday 21 of lactation. Samples of dosingpreparationwsillbe collecteodnce duringthesixweeks priorto mating,once duringgestatioannd once duringthepostnatapleriod.A portionof each of thesesampleswillbe frozenand shippedtotheSponsorforpossibleanalysisA. backup sampleofeach willbe retainebdy thetestinfgacilityR.ecordswillbe maintainedon how dosingpreparationwsere made. ClinicalObservations:Twice daily- approximatelyone hour afterdosingand again4-6 hours later. Body Weights: Weekly exceptwhen femalesarecohabitingwith males duringmating. Food Consumption: Weekly exceptwhen femalesarecohabitingwith males during mating. Mating: After6 weeks of compound administrationo,ne male (Argusbreedercolony) willbe co-inhabitewdith eachfemale.A femalewillbe determinedasmated upon the presenceof sperm positivveaginalsmear. The day of mating shallbe considereday 0 of gestation. Page 1 of4 D.J.Luebker Argus PK Outline 5/03/2000 Day Zero of Gestation Sacrificeand Exandnation: On day zeroof gestation6, pregn*antfemales ineach group willbe sacrificebdy CO, asphyxiation.A terminalbody weight foreach dam willbe obtainedand recorded.Animals willbe necropsiedand any grosslesionswillbe describedand recorded.Serum and liversamples willbe taken from each dam. AU specimens willbe frozen(-20'C)and shippedon dry icetoKrisJ. Hansen, Ph.D.,3M EnvironmentalTechnology and SafetyServices,935 Bush Avenue, Building2-3E-09,St Paul,MN 55133-333 1.Upon receipts,erawillbe analyzedfor PFOS and liverswillbe storedforpossiblefutureanalysis. Day 15 of Gestation Sacrificeand Examination: On day 15 ofgestation6, pregnant femalesineach group willbe sacrificebdy CO, asphyxiationand cesarean-sectiownillbe performed.A terminalbody weight foreach dam and a pooled terminalbody weight for each littewrillbe obtainedand recorded.Dams willbe necropsiedand any grosslesions willbe describedand recorded.Serum, liverand milk samples win be takenfrom each dam. Dam sera,liverm,ilk and whole pups willbe frozen(-20'C)and shippedon dry ice toKrisJ.Hansen, Ph.D.,3M EnvironmentalTechnology and SafetyServices,935 Bush Avenue, Building2-3E-09,SL Paul,MN 55133-3331. Upon receipts,era,milk and whole pups willbe analyzedforPFOS and liverswillbe storedforpossiblefutureanalysis. Pre-Birth Sacrificeand Examination: Justpriortodelivery(moniing ofday 21 of gestation6) pregnantfemalesin each group willbe sacrificebdy CO, asphyxiationand cesarean-sectiownillbe performed.A terminalbody weight foreach dam and a pooled terminalbody weight foreach littewrillbe obtainedand recorded.Animals wW be necropsiedand any grosslesionswillbe describedand recorded.Serum and liversamples willbe takenfrom each dam and her pups (pup samples pooled by litterM)i.lk samples willbe collectefdrom each dam. Allspecimenswillbe frozen(-20*C)and shippedon dry icetoKrisJ.Hansen, Ph.D.,3M EnvironmentalTechnology and SafetyServices,935 Bush Avenue, Building2-3E-09,St Paul,MN 55133-333 1.Upon receipts,eraand milk willbe analyzedforPFOS and liverswillbe storedforpossiblefutureanalysis.A-FAY ADD ADDITIONAL DAMS IN SOME DOSE GROUPS SO WHOLE PUP PFOS LEVELS CAN BE EXAMINED OR MAY SAVE REMAINDER OF EACH PUP AFTER LIVER AND SERA ARE COLLEC7ED. Female Parturition:Remaining ratswillbe allowedtodelivertheirlitters. Pup Examinations:Pups willbe counted,sexed,weighed and observedfor moribundity/mortalitoyn postnataldays 0, 1,2,3 and 4,7, 14 and 21. Rats Found Dead or Moribund: Rats thatdieor are sacrificebdecause of moribund conditionor abortionwillbe exwnined forcauseof deathormoribund conditionon the day theobservationismade. Aborted fetusesand/orin-uteropups willbe examined to the extentpossibleW.hen possiblet,he followingspecimens willbe collectedand analysis performed: Rats willbe necropsiedand any grosslesionswillbe describedand recorded.Serum and Ever samples willbe taken (individuallfyoreach darn and her pups - pup samples pooled by litterM)i.lk samples willbe collectefdrom each dam. All specimenswillbe frozen(- Page 2 of 4 D.L Luebker Argus PK Outline 5/03/2000 20'C) and shippedon dry icetoKrisJ.Hansen, Ph.D.,3M EnvironmentalTechnology and SafetyServices,935 Bush Avenue, Building2-3E-09,St.Paul,MN 55133-3331. Upon receipts,eraand milk willbe analyzedforPFOS and liverswillbe storedfor possiblefutureanalysis. Lactation Day 7 Sacrificeand ExarWnation: Six dams ineach dose group and allof theirpups willbe sacrificebdy CO, asphyxiationon lactatiodnay 7. A terminalbody weight foreach dam and a pooled terminalbody weight foreach littewrillbe obtained and recorded. Animals willbe necropsiedand any grosslesionswillbe describedand recorded.Serum and liversamples willbe taken from each darnand her pups (pup samples pooled by sex foreach btter)M.ilk samples willbe collectedfrom each dam. All specimens willbe frozen (-20"C)and shippedon dry iceto KrisJ.Hansen, Ph.D.,3M EnvironmentalTechnology and SafetyServices,935 Bush Avenue, Building2-3E-09,SL Paul,NIN 55133-3331. Upon receipts,eraand milk willbe analyzedforPFOS and livers willbe storedforpossiblefutureanalysis. Lactation Day 14 Sacrificeand Exandnation: Six dams ineach dose group and allof theirpups willbe sacrificebdy CO.,asphyxiationon lactatiodnay 14. A terminalbody weight foreach dainand a pooled terminalbody weight foreach littewrillbe obtained and recorded.Animals willbe necropsiedand any grosslesionswillbe describedand recorded.Serum and liversamples willbe takenfrom each dam and her pups (pup samples pooled by sex foreach litterM)i.lk samples willbe collectedfrom each dam. AR specimens willbe frozen(-200C)and shippedon dry iceto KrisJ.Hansen, Ph.D.,3M EnvirorunentalTechnology and SafetyServices,935 Bush Avenue, Building2-3E-09,SL Paul,MN 55133-3331. Upon receipts,eraand milk willbe analyzedforPFOS and livers willbe storedforpossiblefutureanalysis. Lactation Day 21 Sacrificeand Examination: Six dams ineach dose group and allof theirpups willbe sacrificebdy CO, asphyxiationon lactatiodnay 2 1. A terminalbody weight foreach dam and a pooled terminalbody weight foreach littewrillbe obtained and recorded.Animals willbe necropsiedand any grosslesionswillbe describedand recorded.Serum and liversamples willbe takenfrom each dam and her pups (pup samples pooled by sex foreach litterM)i.lk samples willbe collectedfrom each dam. AU specimenswillbe frozen(-20'C)and shippedon dry icetoKrisJ.Hansen, Ph.D.,3M EnvironmentalTechnology and SafetyServices,935 Bush Avenue, Building2-3E-09,St. Paul,NW 55133-333 1.Upon receipts,eraand milk willbe analyzedforPFOS and livers willbe store@fdorpossiblefutureanalysis. Page 3 of 4 D.J.Luebker Argus PK Outline 5/03/2000 Table 1 - Scheduled Sacrifices (N d grou *fice) Grp 1 2 3 4 5 Group Name > co Ei 0 boo 00 Dy 0 ofgestation 6 6 Dy 15 ofgestation Pre-Bir(tdhy-1) 6 6 LactatioDny 7 LactatioDny 14 LactaiioDny 21 66 66 1 66 TOTAL N 30 30 6 6 6 1 I 6 6 6 6 6 6 6 6 6 6 6 6 1 1 30 30 30 Study Director: Deanna J. Luebker, M.S. 3M CorporateToxicology 3M Medical Department 3M CenterBldg.220-2E-02 SaintPaul,MN 55144-1000 Telephone 65in37.1374 FAX 651/733.1773 AlternativeStudy Director: John Butenhoff,Ph.D.,DABT, CHi 3M CorporateToxicology 3M Medical Department 3M CenterBldg.220-2E-02 SaintPaul,MN 55144-1000 Telephone 651/733.1962 FAX 651n33.1773 In-LifePhase Investigator: Argus AnalyticalPhase Investigator: KrisJ.Hansen, Ph.D., 3M Envirommental Technology and Safety Services, Bldg.02-3E-09 935 Bush Avenue, Building2-3E-09, St.Paul,MN 55133-3331 Telephone 651/778.6018 FAX 651n78.6176 Page 4 of 4 D.J.Luebker