Document kYbDqne4e8Kq9yK9ee360Lrb

i-'..*PRIMEDICAArgus Division 905 Sheehy Drive,Bldg.A Tel2 15.443.8710 1 Fox 2 15.443.8587 @ Horshom, PA 19044 April13,2000 Marvin T. Case, D.V.M.,Ph.D. 3M ToxicologyServices 3M Center,Building220-2E-02 St.Paul,Minnesota 55144-1000 Telephone: (612)733-5180 Telefax: (612)733-1773 RE: FinalReport 418-008 - Dear Dr.Case: Combined Oral (Gavage) FertiliDteyv,elopmental and Perinatal/PostnataRleproductionToxicityof PFOS in Rats Sponsor'sStudy Number: 6295.9 Enclosed isone copy of the finalreportAmendment 1 tothe above-referenced report. Ifyou have any questions,please do not hesitateto contactme. Sincerely, RGY:kgp Attach. RayvmmoonnTYorYko.rk, Phh..DD, DABT Associated DirectorofResearch and Study Director P,;---dicaCorporat;on ww-,primedica.com JPRLMEDICA Argus Research Laboratodes,Inc. 905 Sheehy Drive,BuildihgA Horsham, PA 19044 Telephone:(215)443-8710 Telefax:(215)443-8587 REPORT AMENDMENT 1 13 APRIL 2000 PROTOCOL SPONSOR'S STUDY 418-008 NUMBER: 6295.9 COMBINED ORAL (GAVAGE) FERTILITY, DEVELOPMENTAL AND PERINATALJPOSTNATAL REPRODUCTION TOXICRFY STUDY OF PFOS IN RATS FINAL REPORT I. Page 1-9,paragraph 4 has been revisedto: Pregnancy occurredin 22 (95.6%),21 (84.0%) and 24 (96.0)of the23, 25 and 25 female ratsassignedto cohabitationin the 0 (Vehicle),0.1 and 0.4 mg/kg/day dosage groups, respectively.All pregnantdams deliveredlittersT.he gestationindex was comparable acrossthe threedosage groups. Viabilitaynd growth of the second generation offspring (F2 pups) to weaning were also unaffected by the highest dosage tested,0.4mglkglday. There were no toxicologicalliymportant differencesfrom the controlgroup values. No clinicalor necropsy observationsin theF2 generationpups were attributablteo dosages of the testarticleas high as 0.4 mg/ka.,/day. 2. Page I-10. paragraph 4 has been revisedto: The Fl ac@enerationreproductiveNOEL isgreaterthan a dosage of 0.4mg/kg/day; no effectson mating or fertiliotcycurred. The NOEL forviabilitaynd growth in theF2 generationoffspringisalso 0.4 mg/kg/day. There were no toxicologicalliymportant effectson pup survivalor growth at the highestdosage tested,0.4 mglkglday. 3. Page V-8, paragraph 3 has been revised to: The viabilityof the second generation offspring (F2 pups) was unaffected at the highest dosage tested,0.4 mglkglday. Small increases in the number of dams with stillbornpups and in the number ofpup deaths afterDL 2 in the 0.4 mglkglday dosage group were not toxicologicallyimportant because: 1) the values were not significantlydifferentfrom the control group values;2) the averagefor liveliuersizesdeliveredand surviving to DL 21 were greater than or comparable to the control group values;and 3) neitherthe viabilityor lactationindicesfor the 0.4 mglkglday dosage group remarkably differed from the controlgroup values. 4. V-8, paragraph4 has been revisedto: FINAL REPORT 418-008 AMENDMENT I PAGE 2 Pup body weightsof the second generation offspring(F2 pups) were unaffectedat the highestdosage tested,0.4 mglkglday. Small reductionsinpup body weightsin the 0.1 and 0.4mglkglday dosage groups were not toxicologicalliymportantbecause: 1)the small differencesbetween thepup body weightsfor the controland 0.1 mglkglday dosage groups were not statisticalsliygnificantand were associatedwith the largerlive littesrizesof the 0.1 mglkglday dosage group on DLs I through 4,as compared withthe controlgroup values,and the random selectionofpupsfor continued observationson DL 4; 2) the small reductionsinpup body weights inthe 0.4mglkglday dosage group were associatedwitha minimally largerlivelittesrizeatbirth(DL 1)and on DL 4 preculling,as compared with the controlgroup values,and the random selectionof pupsfor continued observationon DL 4; the statisticalsliygnificanrteductions(P-'50.05 andp-<D.01,respectivelyp)resent on DLs 7 and 14,as compared tothe controlgroup values,were transientand disappeared by DL 21. 5. Pa9e V-9: Revisionstoparagraph4 on page V-8 caused ittoextend ontopace V-9. These revisionswere made toclarifythe interpretationf theobservationsreportedand the NOEL forthesecond generationoffspring(F2 generation). R@o ond,G.York, .,DABT Date Ntcy @ ongliewski Date AssociateDirectorof4e eSsIeCarch QualityAssurance Managce@ r and Study Director 418-008:PAGE1-9 REVISED PAGE feedconsumptiovnalueswerereducedduringlactatiionnthe0.4mg/kg/day dosagegroup. Dosagesofthetestarticalsehighas 0.4mg/kg/daydidnotaffecttheaverage dayofvaginaplatencyintheFl generatiofnemalerats.Therewereno biologicailmlpyortandtifferenciensthevaluesforleamings,hort-terremtention, long-terrmetentioornresponseinhibitiontnheFl generatiofnemaleratsa,s evaluatebdy performanciena passiveavoidancoerwatermazeperformance paradigm. Dosagesofthetestarticalse highas 0.4mg/kg/daydidnotaffecatnymating and fertilpiatryameteresvaluateidntheFl generatiofnemalerats. AllnecropsyobservatioinnstheFl generatiofnemaler*atswereconsidered unrelatetdothetestarticle. Pregnancyoccurreidn22 (95.6%)2,1 (84.0%)and 24 (96.0o)fthe23,25 and 25 femaleratsassignetdocohabitatiionnthe0 (Vehicle0).,1and 0.4mg/kg/day dosagegroupsr,espectivelAyl.lpregnandtams delivereldifterTsh.e gestation indexwas comparableacrossthethreedosagegroups.Viabilaintdy growthof thesecondgeneratioonffspri(nFg2pups)toweaningwerealsounaffectebdy thehighesdtosagetested0,.4mg/kg/dayT.herewereno toxicologically importandtifferencfersomthecontroglroupvalues.No clinicoarlnecropsy observatioinnstheF2 generatiopnupswereattributatboldeosagesofthetest articalsehighas 0.4mg/kg/day 418-008:PAGE1-10 REVISED PAGE C. Conclusions On thebasisofthesedata,theFo generatiomnatemaland paternanloobservable-efefct-leve(lNOEL) ofPFOS is0.1 mg/kg/day (0.4mg/kg/day and higherdosages caused reductionsinbody weight gainand reduced feed consumption values). The Fo generationreproductiveNOEL isgreaterthan 3.2 mg/kg/day;no effects on mating,fertilityeqsrtrouscyclingoccurred.The NOEL forviabiliatnyd growth inthe Fl generationoffspringis0.4 mg/kg/day (1.6mg/kg/day and higherdosages caused preimplantatiolnossand reductionsinlinersize,pup viabilitgyr,owth and survival). The Fl generationmatemal and paternalNOEL of PFOS is0.1 mg/kg/day (0.4mg/kg/day dosage caused reductionsinbody weight gainand reduced feed consumption values). The Fl generationreproductiveNOEL isgreaterthan a dosage of 0.4 mg/kg/day;no effectson mating orfertiliotcycurred.The NOEL forviability and growth inthe F2 generationoffspringisalso 0.4 mg/kg/day. There were no toxicologicalilmyportanteffectson pup survivalor growth atthe highestdosage tested,0.4 mg/kg/day. -------------------- .. MildredS. ChristianP,h.D.,F-e-l-l-o-w-,A-T-S----D-a-t-e--- Exec tiveDirectorof Research - ----------- M. oberman, Ph.D.,DABT Date Directorf Research ---------------- Ray nd G. York, D., ABT Date AssociateDirector R earch and Study Director 418-008:PAGE V-8 REVISED PAGE B.8. NecropsV Observations (Summary- Table E18: IndividualData Table E34) Allnecropsy observationsinthe Fl generationfemale ratswere considered unrelatedtothe testarticlbeecause: 1)the observationsoccurredinratsinthe controlgroup;and 2) the observationcommonly occurs inthisstrainofrat. These observationsincludedrough and/orpittedcortexofthe kidneyswith calculinthe kidney and/orurinarybladderoftwo controlgroup rats.One of these ratsalsohad a tan granularmaterialinthe renalcortexand thickened wallsofthe urinarybladder.Necropsy observationsforthe 0.4 mg/kg/day dosage group dam thatdied as the resultof an intubatioenrrorwere described previously. B.9. Natural Deliveryand LifterObservations (Su'mmaries -Tables E19 and E20; IndividualData -Tables E35 through E38) Pregnancy occurred in22 (95.6%),21 (84.0%) and 24 (96.0%) ofthe 23, 25 and 25 female ratsassignedto cohabitatioinnthe 0 (Vehicle)0,.1 and 0.4 mg/kg/day dosage groups,respectivelyA.llpregnantdams deliveredlifterTsh.e gestation index(thepercentageof pregnantratswithliveoffspringw)as comparable across the threedosage groups. The viabiliotfythe second generationoffsprin(gF2 pups) was unaffectedatthe highestdosage tested,0.4 mg/kg/day. Small increasesinthe number of dams withstillbompups and inthe number of pup deaths afterDL 2 inthe 0.4 mg/kg/day dosage group were nottoxicologicalilmyportantbecause: 1)the valueswere not significantdliyfferenftrom the controlgroup values;2)the average forliveliftesrizesdeliveredand survivingto DL 21 were greaterthan or comparable to the controlgroup values;and 3) neitherthe viabiliotrylactation indicesforthe 0.4 mg/kg/day dosage group remarkablydifferedfrom the control group values. Pup body weightsofthe second generationoffsprin(gF2 pups)were unaffected atthe highestdosage tested,0.4 mg/kg/day. Small reductionsinpup body weightsinthe 0.1 and 0.4 mg/kg/day dosage groups were nottoxicologically importantbecause: 1)the smalldifferencesbetween the pup body weightsfor the controland 0.1 mg/kg/day dosage groups were notstatisticaslilgynificant and were associatedwiththe largerliveliftesrizesofthe 0.1 mg/kg/day dosage group on DLsl through4, as compared withthe controlgroup values,and the random selectionofpups forcontinuedobservationson DL 4;2)the small reductionsinpup body weightsinthe 0.4 mg/kg/day dosage group were associatedwitha minimallylargerlivelittesrizeat birth(DL 1)and on DL 4 precullinga,s compared withthe controlgroup values,and the random selection of pups forcontinuedobservationon DL 4; the statisticaslilgynificanrteductions 418-008:PAGE V-9 REVISED PAGE (p-<0.05and p-<0.01,respectivelyp)resenton DLs 7 and 14,as compared tothe controlgroup values,were transientand disappeared by DL 21. Administratioonfthe testarticlaetdosages as highas 0.4 mg/kg/day didnot adverselyaffectany otherparameter evaluated atnaturaldeliveryorduringthe 21-day lactatiopneriod(durationofgestation,averages forimplantationasnd live liftesrizes,numbers of dams withallpups dying duringlactationv,iabiliatnyd lactatioinndices,survivingpups per littearnd pup sex ratios). B.10. ClinicalObservations from Birthto Day 21 Postpartum and Necropsy Observations (Summaries -Tables E21 and E22; IndividualData -Tables E39 and E40 No clinicaolrnecropsy observationswere attributablteo dosages ofthe test articlaes high as 0.4mg/kg/day because: 1)the incidenceswere notdosagedependent; and/or2) the observationoccurred inonlyone ortwo pups. These clinicaolbservationsincludedone controlgroup pup thatwas not nestingor nursing,had decreased motor activitaynd was coldtothe touch,one pup in each ofthe controland 0.4 mg/kg/day dosage groups thathad a missingtipof tailand one 0.4 mg/kg/day dosage group pup thathad an umbilicalhernia. No milkinstomach occurredin2,4 and 4 pups thatwere found dead inthethree respectivedosage groups. One controlgroup pup had hydrocephalyand one 0.1 mg/kg/day dosage group pup had a raisedtan area on the median and left lateralobesofthe liveartnecropsy on DL 21.