Document qdvbmM2y3namoEBo1yOq0M7ok

Summary PFOS Rat Two-GenerationReproductionStudy StudyNumbers:3M T-6295.9,Argus418-008(in-lifFeA)C,T-TOX-012 (analytical). Compound & Lot: PFOS (Perfluorooctanesulfona-teL)ot 217,98.4% pure(SMD AnalyticalRequest 53030). CAS No. 2795-39-3 Study Title:Combined Oral (Gavage)FertilitDye,velopmental and Perinatal/Postnatal ReproductionToxicityStudy ofPFOS inRats. ReportDate: 10 June 1999 (in-life1)9;April1999 (analytical). Study Year and GLP status:1997-1999 and GLP study Procedures:Groups of male and female rats(35/sex/groupw)ere administered(dailyoral intubationP)FOS atdose levelsof 0,0.1,0.4,1.6,and 3.2 mg/kg/day. Dosing started when the animalswere = 70 days old. The male and female rats(Fo generation)were dosed for42 days priorto mating. Aftermating,,dosingcontinuedin themated females throuc,houat station.At day 10 of gestationC,aesarean sectionwas done on 10 females/grouptocheck forany effectsinearlygestation.The remaininc,25 females/groupwere allowto delivertheirlittersD.osing of thefemalescontinuedduring the21-day lactatiopneriod.At weaning, 2 males and 2 femalesper littewrere randomly selectedforcontinuationon the study(Fl generation).Note: Because of post-natal effectsathicyhdoses (seebelow fordetailso)nly threegroups of F, animalscontinued thestudy,namely 0,0.1 and 0.4mgtkg/day. Dailydosin-be-an intheF, pups theday afterweaninorand continuedthrou-houttheir growth tosexualmaturity.At 24 days of acretheF, ratswere testedina passive avoidanceparadiccm. The animals were alsotestedin a water-filleMd-maze when they were 70 davs old. Cohabitationformatincybeoranwhen the F, animals were 90 days old littermatmeatincrswere avoided. Dosinc,continuedinthe females throu-h gestationand 21-day lactatioanfterdeliveryof F2 pups. The study ended upon weaningC)of theF2 PUPS- Results:No deathsoccurredin any of theFo animals and therewere no compound relatedclinicalsigns.Dose relatedreduced weiaht body weiorhtsoccurredinboth male and femalesatthehighertwo dose levels(3.2& 1.6mg/kg/day). Reduced food consumption correlatedwiththesebody weight effects.The 0.4 mg[kg/day males also had a slightb,ut statisticalsliygnificantr,educed body weight gain duringthepre-matinc, period.Dosing of PFOS as high as 3.2 mg/kg/day had no effecton estrouscycling;all mating and fertiliptayrametersof theFo ratswere unaffected.There were no siornificant differencesatany dose levelinrecardtolittearveragesforcorporalutea,implanations, viableembryos or nonviableembryos from theday 10 of gestationCaesarean section females. Upon litterinpcoys,t-nataslurvivalwas reduced atthehiorhetrwo dose levels(1.6& 3.2 mg/kg/day).The post-nataslurvivaleffectwas manifestedby increasednumber of apparentstill-birtahnsd increasedpup deathsduringthe firs2t4 to72 hours afterbirth. Necropsy of dead pups revealedmany had not nursed- no milk curd inthe stomach. Reflex and physicaldevelopment (surfacenghting,pinna unfolding,eye opening, acousticstartlreeflexa,irrightreflex,pupilconstrictionw)as not affectedinthe0.1 & 0.4 mglkg/day F, pups. Some oftheseparameterswere slightlydelayedinthe 1.6 mg/kg/day F, pups and theywere not evaluatedatthe high dose (3.2mg/kg/day) as no pups survivedbeyond fourdays post-natal. Because of adverseeffectsinthehighertwo dose levels(1.6& 3.2mg/kg/day) F, pups, reduced survivaland/orreduced growth,thedecisionwas made, inconjunctionwith the attendinglaboratoryveterinarian,ot tocontinuethesetwo dose levelsintothe second generation.Ithad been determinedthatdose of 1.6mglkg/day or higherproduced compound toxicity.Continuanceof thesedose levelswould not resultin any additional usefulinformationand would subjectthe animalstounnecessarystress. Death did not occur post-weaningintheF, animalsnor were thereany compound related clinicasligns. The male and female F, ratsinthe0.4 mglkg/day group had somewhat reducedbody weight and food consumption;atsome pointsintime (weeks of growth)the differencefsrom controlswere statisticaslilgynificantT.he appearanceof external evidenceof sexualdevelopment (preputiasleparationinmales & vaginalpatency in females)was not affectedateitherdose level.Also,the passiveavoidance and water maze testincdyid not revealany differenceisn regardtolearning,short-termretentionnor Iona-termmemory. Likewise,none of themating orreproductiveperformance measurements (parameters)were adverselyaffectedinthe 0.1 & 0.4 mg/kg/day F, male and female ratswhen they were mated and allowed todeliverlittersT.here were no significandtifferencesinregardtoF2 PUP survivalorpup weights atweaning. Conclusions:The resultosf the studyindicatedthefollowingN,OEL levels. The Fo matemal and paternalNOEL is0.1 mgfkg/day. [hiZD-herdose levelshad reduced body weight and food consumption] The Fo reproductiveNOEL is> 3.2 mg/kg/day. [no effecton reproductiveperformance even athighestdose level] The F, post-nataNlOEL is0.4 mg/kg/day. [higherdose levelshad reducedpup viability and ,growth] The F, matemal and paternalNOEL is0.1 mgikg/day. [0.4mg/kg/day animals had reduced body weicht and food consumption] The F, reproductiveNOEL is> 0.4 mg/kg/day. [no effecton reproductiveperformance ateither0.1 or0.4 mglkg/day] The F2 post-natalNOEL is0.4 mglkg/day. [no importanttoxicologicaelffecton pup survivalor growth ateither0.1 or0.4 mg/kg/day] Compound Level Sami)les:At theterminalsacrificoef theFo males (aftemrating was completed),serum and liversamples were collectedfrom 5 males ineach ofthe dose groups. Serum samples were collectedfrom 5 Fo femalesinallthedose groups except 3..2mg/kg/day group atthe terminalsacrificteheday afterweaning theF, litterLsi.ver samples were collectedfrom the same Fo femalesand liversamples were alsocollected from theweaned F, pups of thesame dams. Analysisof thesamples forPFOS (3M AnalyticalReportTOX012) yieldedthefollowing mean PFOS concentrations. Male Fo Serum: control7 0.024 ppm, 0.1 mg/kg/day - 10.5ppm, 0.4mglkg/day - 45.4 ppm, 1.6mg/kg/day - 152 ppm, 3.2mg/kg/day - 273 ppm. Male Fo Lver: control- 0.665 ppm, 0.1 mg/kg/day - 84.9ppm, 0.4 mg/kg/day - 176 ppm, 1.6mg/kg/day - 323 ppm, 3.2 mglkg/day - 1357 ppm. Female Fo Serum: control- 0.037 ppm, 0.1 mg/kg/day - 5.28 ppm, 0.4 mg/kg/day - 18.9 ppm, 1.6mg/kg/day - 82.0ppm. Female Fo Liver:control- 0.171 ppm, 0.1 mglkg/day -14.8 ppm, 0.4 mglkg/day - 58.0 ppm, 1.6mg/kg/day - 184 ppm. Pup F, Liver:control- 0.051 ppm, 0.1 mg/kg/day - 6.19ppm, 0.4 mg/kg/day - 57.6 ppm, 1.6mg/kg/day - 70.4ppm. Note: Serum and liverreflectPFOS concentrationosfFo dams and F, pups attheend of 21-day lactationi,.e.when thesamples were collected.Compound levelsatparturition when reduced pup survivalwas observed could differand thosearebeing measured ina follow-upPK study. Data Evaluation:A well conductedGLP studyfollowingestablishetdestingguidelines (OECD 416). Study evaluatedreproductiveparametersand post-nataplup development includingneurologicalparameters.The studyestablishevdalidNOEL values. LaboratoryReportFACT-TOX-012 SerumandliverSamples:At theterminaslacrifiocfetheFo males(aftemratingwas completed),serum and liversamples were collectedfrom 5 males ineach of thedose groups. Serum samples were collectedfrom 5 Fo females inallthedose groups except 3.2 mg/kg/day group attheterminalsacrifictehe day afterweaning theF, litter(sday 21 of lactation)T.iver samples were collectedfrom thesame Fo females.Liver samples were alsocollectedfrom theweaned F, pups (livesramples were pooled by littero)f the same dams. NfilkCurd SamRLeE. On day 4 of lactationa,lllitterass, statedin theprotocol,were reducedto 8 pups per litterA.t thistime stomach contents(milkcurd)samples,pooled by littewre,re collectedfrom 4 or 5 litterfsrom threedose groups - control,low dose (0.1 mg/kg/day)and highdose (3.2mg/kg/day).A validatedanalyticamlethod formilk curd matrix has not been developed and thesesamples have not been analyzed.