Document J3Lyyw0p1wYjNYGaDqrqLX8ke

3M MEDICAL DEPARTMENT TOXICOLOGY SERVICES To: GeodeanAdams 290-4-01 cc:John Butenhoff 220-2E-02 From: Marv Case 220-2E-02 Subject:FC 95 and 143 Teratology Date: 26 May 1998 John passed on to me your requestforsomeone to review and writean analysison the eye lensdefectthatwas reportedintheoriginaFlC 95 ratteratologystudy. I have reviewed the toxicologystudy fileosn FC 95 and FC 143. Attached are my review comments and conclusions.You willnotethatthe lensdefectreportedwas subsequentlyshown to be a sectioningar-tifaacntd was not observed inlatterteratologystudiesdone atother laboratoriesT.o date,teratogeniceffecthsave not been shown with eithercompound at doses which are not maternallytoxic AdditionalFC teratologystudiesareto be startedsoon. A FC 95 rabbitteratologystudy (we have no rabbitdata),a ratFC 10 teratologystudy(we need to determinean NOEL level)a,nd a rabbitFC 10 teratologystudy(we have no rabbitdata)have been contracted and should startinJune/July. ReviewofFC 95 & 143TeratologSytudies FC 95 A ratFC 95teratologsytudy(studnyo.0680TROO08)was conductedatRiker Laboratoriesand the studyreportisdatedDec. 1980. Dose levels(oral)givento the pregnantratdarnswere 0, 1,5,and 10 mgfkg. Matemal toxicit(yreducedweight gain) occurredatthe high dose of 10 mgfkg. Evidence of fetaltoxicitwyas not found atany dose level.No skeletaland softtissueteratogenichanges were found atany dose level with one exception.A change inthe lensofthe eye was found inaU dose groups including thecontrolbut the incidenceinhighdose group was significanthliygher.This change was reportedout as developmentaleye abnormalityand the summary of thereportstatesthe compound was teratognic. Another ratFC 95 teratologystudy(studyno. 154-160)was done atHazleton Laboratoriesand the studyreportisdatedNov. 1983. Dose levels(oral)givento the pregnantdams were 0, 1,5, and 10 mg/kg (same dose levelsasinthe previousrat teratologystudy).Matemal toxicitwyas found atthehighertwo dose levels- 5 & 10 mg/kg. Signsof matemal toxicitwyere reduced weightgain,anorexia,thinness,and death of two of thehigh dose (10 mg/kg) dams. Fetaltoxicit(yincreaseudterinelossof pups at 10 mg/kg and reduced pup weightsat5 & 10 mglkg) which was relatedto thematemal toxicitwyas observed atthe highertwo dose levels.Pup examinationrevealeddelayed ossificatioantthe high dose as wellas visceralanomaliesofcleftpalateand crytorchism. The studyconcluded thatthe compound did not appeartobe teratogenicatdose levels lessthan or equal to 5 mg/kg. An importantfindingwas no eye or lensabnormalityatany dose level. I can not findany record ofa rabbiteratologystudybeingdone on FC 95. (Note we have justcontractedfora rabbitFC 95 teratologystudy;shouldhave databy the end of 1998.) FC 143 A ratFC 143 teratologystudy(studyno. 068 1TRO I10)was conducted atRiker Laboratoriesand the studyreportisdatedDec. 198 1. Dose levels(oral)givento the pregnantratdams were 0,0.05,1.5,5,and 150 mg/kg. Matemal toxicit(yreducedweight gainand threedeaths)occurredatthehigh dose of 150 mg/kg. Evidence of fetaltoxicity was not found atany dose level.Although delayedossificatiownas found inthe high dose pups (relatedtomatemal toxicity)n,o skeletaland softtissueteratoger@changes were found atany dose level.As was the caseinFC 95 ratteratologystudy,a change inthe lensof the eye was found inalldose groups includingthecontrolbut theincidenceinhigh dose group was significanthliygher.However, inthisstudyreportthisfindingis attributetdo an artifacctreatedby sectioninogf theeye. The studyconclusionisthatthe compound was notteratogenic. An outsideconsultantand teratologeyxpert,Dr E. Marsha Johnsonfrom Jefferson Medical College,visite3dM and reviewedthemt pup eye specimensinquestionfrom the two Rikerratteratologystudies.He concurredthattheeyellencshangeswere, infact, sectioninagrtifactasnd not compound relatedteratologyabnormalities. A rabbitFC 143 teratologsytudy(studyno.06SITBO398) was conductedatRiker Laboratorieasnd thestudyreportisdatedFeb. 1982. Dose level(soralg)ivento the pregnantrabbitdams were 0, 1.5,5,and 50 mg/kg. Maternaltoxicit(yreducedweight gain)occurredatthehighdose of 50 mglkg. True fetaltoxicitwyas notfound atany dose levelbut highdose pups had slightliyncreasedincidenceof ribvariationwshich was attributetdo embryotoxicityN.o skeletaalnd softtissueteratogenichangeswere found atany dose levelT.he studyconclusionisthatthecompound was not teratogenic. Staplesand co-workersatDuPont HaskellLaboratorieshave done additionarlat teratologsytudieson FC 143. In one study,pregnantratdams were dosed orallyat0 and 100 mg/kg (reportdatedJan.1982).In otherstudy,pregnantratdams were exposedto inhalatiodnosesof 0, 0,1,1.0,10 and 25 mg/m' (reportdatedJan,1982).These repeat studiesdidnot revealany eye or lensabnormalitieisnratpups. Thiswork has been publishedand thereferenceis:StaplesRE, Burgess BA, Kerns VM: The embyro-fetal toxicitaynd teratogenipcotentiaolf ammonium perfluorooctanoa(tAePFO) intherat. Fund Appl Toxicolo4:429440, 1984. Conclusion Thus, theweightof theevidenceindicatetshatneitherFC 95 nor FC 143 causes teratogeniecffectisnanimalswhen dosed atlevelswhich arenot maternallytoxic.Even atmaternallytoxicdoses,effectseen inthepups were thosegenerallyassociatedwith matemal toxicityT.he lenschange observedinratpups inRikerLaboratoriestudieswas a sectioninagrtifacatnd was notfound upon repeatstudiesatindependentlaboratories. I 764,.o- Marvin T. Case,DVlvt PhD CorporateScientist 3M ToxicologyServices --,@-& -z,f--loe Date