Document NG1bDER075GD7D0rEw60qXo2y

Medicine,Health Physics IndustriaHlygiene,Toxicology 3M Medical Department 3M Center,Building220-2E-02 PO Box 33220 St.Paul,MN 55133-3220 612733 1110 Oral Developmental Toxicity(Teratology)inRats and Rabbits An oralteratologsytudyinratswithpotassiumperfluorooctanesulfonwaatse conducted atRiker Laboratorie(sRikerPharmaceuticaPlathology/ ToxicologyLaboratory). Dose levels(oral)giventothepregnantratdams were 0, 1,5,and 10 mg/kg. Matemal toxicit(yreducedweightgain)occurredatthehighdose of 10 mg/kg on days 6 through15 ofgestation.Evidenceoffetaltoxicitwyas not foundatany dose level. No skeletaalnd softtissueteratogenicchangeswere found at any dose levelwithone exception.A change inthelensof theeye was found inalldose groupsincludingthe controlbut theincidenceinhighdose group was significanthliygher.This change was reportedas a developmentaleye abnormalityand thesummary of thereportstatesthe compound was teratogenicA.n outsideconsultanatnd teratologeyxpert,Dr. E. MarshallJohnson from JeffersonMedicalCollege,visited3M and reviewedtheratpup eye specimensin question.He concludedthattheeye/lenschangeswere, in fact, sectioninagrtifactasnd not compound relatedteratologaybnormalitie(sseeenclosed letter)A. repeatstudywas conductedatHazletonLaboratorieAsmerica (seebelow) which revealedno effectson thelens. Inthesubsequentstudymentioned above,potassiumperfluorooctanesulfonate (suspendedincom oil)was administeredon gestationadlays 6-15by oralgavage to groupsof 25 pregnantSprague-DawleyCD ratsatdosesof 0 (control)1,,5,and 10 mg/kg/day (HazletonLaboratorieAsmerica).Severematemal toxicitoyccurredinthe5 mg/kg and 10 mg/kg dose groups,as evidencedby significanrteductionsinmean body weightgain,terminalbody weightminus graviduterineweightand food conswnption compared tocontroldams, actuallossesinbody weight on commencement of treatment among numerous dams and deathintwo dams inthe 10 mg/kg dose group priorto gestationadlay 20. Mean body weightgains(days0-20)at5 and 10 mg/kg were 104 35 (S.D.)and 34 73 (S.D.)r,espectivelays,comparedto125 24 (S.D.)inthecontrol group. Mean foodconsumptionvalues(days0-20)at5 and 10 mg/kg were 363 60 (S.D.)and 264 90 (S.D.)r,espectivelays,compared to421 28 forthecontrolgroup. Mean terminalbody weightminus graviduterineweightat5 and 10 mg/kg was 293 28 (S.D.)and 241 60 (S.D.)r,espectivelays,comparedto321 23 (S.D.)inthecontrol group. Clinicaslignsinsurvivingdams includedhunching,lowerbody weight,alopecia, rough haircoata,norexia.Gastrointestinanld kidneylesionswere notedinthehighdose dams. Treatment-relatefdetaleffecttshatwere attributetdo matemal toxicitiyncluded: increasedresorptionasnd fetaldeath,decreasedfetalbody weight,delayedskeletal I Medicine,Health Physics IndustriaHlygiene,Toxicology 3M MedicalDepartinent 3M Center,Building220-2E-02 PO Box 33220 St.Paul,MN 55133-3220 612733 1110 ossificatiocnl,efptalate,subcutaneousedema and cryptorchism(undescendedtesticles). These effectsoccurredprimarilyinthehigh-dosegroup. The matemal and fetal NOAELs forthisstudywere both Img/kg/day. An oraldevelopmentaltoxicit(yteratologsyt)udyinrabbitswas conductedatArgus Laboratories.In thisstudy,dose groupsof 22 pregnantnew zealandwhiterabbitswere dosed on days 7 through20 of gestatiownith either0,0.1,1.0,2.5,or 3.75 mg/kg/day PFOS. Matemal toxiceffectsincluded:1)decreasedbody weight atthehighestthreedose levels witha minimal effectatthe 1.0mg/kg dose;2) decreasedfood consumptionatthe highesttwo doses;3) frequentscantfecesatthehighestdose,and 4) increasedabortions atthehighesttwo doses. Fetaltoxiceffectsincludedreducedfetawleightand an increaseindelayedossificatiaotn thehighesttwo doses.No teratogeniecventswere observedinthestudy. Based on thisstudy,PFOS was notteratogeniucnder conditionsofthestudyand the matemal and fetalNOELs are0.1 mg/kg/dayand 1.0mg/kg/day,respectively. Thus, theweightof theevidenceindicatetshatperfluorooctanesulfonadtoees notcause teratogeniecffectsinratsand rabbitswhen dosed atlevelswhich arenotmaternally toxic.The lenschange observedinratpups intheRikerPharmaceuticalstudywas a sectioningartifacatnd was not found upon repeatstudiesatan independentlaboratory. 2