Document 1QGVrpZEj2NVXY0mBRM08Z4JE

Summary PFOS Rat Cross-Fostering StudyNumbers:3M T-6295.13,Argus418-014 Compound & Lot: PFOS (Perfluorooctanesulfona-teL)ot 217,98.4% pure(SMD AnalyticalRequest 53030) C.A.S. RegistryNumber: 275-39-3 Study Title:Oral (Gav@oe) Cross-Fosterin-Study of PFOS in Rats ReportDate: 23 July 1999 (in-lifeI)I;February2000 (serum analysis) Studv Year and GLP status:1998 - 2000 and GLP study Procedures:Groups of female rats(25/group)were administeredPotassium Perfluorooctanesulfona(tPeFOS) by dailyoralintubationatdose levelsof 0 or 1.6 mc,/ka/day.Dos'nL,startedwhen the females were approximately70 days old. The female ratswere dosed for42 days priorto ii-iatitnocu,ntreatedmales.Afteriii@LtinE. dosincrcontinuedin thefemales throu-hout aestationand the 21 days of lactation. At parturitiotnh,econtroland treatedcroups were subdividedintoadditional-rolipsfor cross-fosterino-f litterasnd forobtaininep,harmacokineticsamples. For cross-fostering thelitterwsere transferretdo anotherdam,%x,hichhad delivered- no dam was allowed to raiseitsown litteTrh.e foursuboroups were as follows:controldams with litterfsrom controldams (ne-ativecontrol);treatedams withlitterfsrom treatedams (positive control);controldams with litterfsrom treateddams; and,treateddims with litterfsrom controldams. On day of lactatio4n,litterwsere culledto 10,with equalnumbers per sex where possible. On lactatiodnay one (day of birth)lun0- and liversamples were collectedfrom selected pups of controland treatedlitternsot used forcross-fosterZiDngT.hese tissuesamples were fixedforelectronmicroscopicevaluation. In additiontothe cross-fosterelditteresi,ghtcontroldams and litterasnd two exposed dams and litterwsere assignedtopharmacokineticsample collectionon day 14 of lactationS.amples of milk,serum, liverand milk secretingglandswere obtainedfrom the dams. Pup serum and liversamples were obtainedand pooled from thelitters correspondingtothe dams. All samples were frozenand sentto the3M Envirotunental AnalyticalLaboratoryforpossiblefutureanalysis. On days of lactation2'1and 22,-serum ind liversamples were obtainedatten-nfrom dams and littersU.ttersamples were pooled. All samples were frozenand shippedtothe3M EnvirorunentalLaboratoryforpossiblefutureanalysis. ResultsM:ean bodyweightswerereducedinthetreate(d1.6mg/kg/dayf)emaledsuring thepre-matinagndgestatipoenriodsT.hesebody weighteffectcsorrelatweidthreduced foodconsumptionR.educedpup survivaolccurreidntwo ofthefoursub-groupass shown by thefollowindgata.Controdlams X Controplupshad3/191(1.6%)pupdeaths (singldeeathinthreelittersT)r.eatedarnsX Treatedpupshad 34/177(19.2%)pup deaths(deathisn8 of12littersC)o.ntrodlams X Treatedpupshad 16/166(9.6%)pup deaths(deathisn10ofII littersT)r.eatedams X Controlpupshad2/181(1.1%) pup deaths(sinoldeeathintwo littersT)h.esedataindicattehatreducedpup survivawlas a resulotfpup exposureinitteraondnota resulotfeffectosn thedam fromexposure. I Electronmicroscopy of theday-oldratpups' lun-sshowed no compound-relatedchances on Type 11pneumocvtes nor on thelamellarbodies or lunorsurfactantE.lectron microscopy of the liverdid reveala compound relatedeffectintheday-oldratpups. The liverof the pups from treateddams had increasednumber (2 to3 X) ofperoxisomes. Peroxisome proliferatiiosna known PFOS livereffectinrats.This findingindicates compotind-relatedliverchan-e,;inthe new-born ratpup deliveredfrom dams treatedwith PFOS at 1.6ma/kLy/da@-. Oiil@-the anal%-siosf serum S@IIIIPItC@SikcidiLii-lnt,h-e stud@,is complete. 01 lactitioidia)14,controldams (ii=S)and theirlitter(.n@=@S) demonstrited low backcrrotiiliedn,elosf PFOS, with seven of the eiahtpairs(dams and littersh)avinc,senim concentrationosf PFOS below thelower limitof quintitatio(n< 0.05ppm). The eiglitchontrolpair(dam and litterm)easured 0.08ppi-nforthe dam and 0.1 ppm forthe pooled pup serum. The two exposed dams had serum PFOS levelsof 98 and 218 ppm. For the dam with the98 ppm value,thepooled pup serum was at89 ppm PFOS. There was insufficienstample volume todetermine theserum PFOS concentrationfrom the pups associatedwith the dai-nhivinszthe218 ppm serum PFOS. From serum samples takenon days 21 and 22 of lactationi,tisevidentthatexposure of pups can occurafterbirthvia themilk. Pooled serum from pups inlitterbsorn from untreateddams and cross-fosterewdith treateddams (onlyexposed viamilk)had ')4 ppi-n PFOS on average(n = 4) compared totheirtreatedfoster-damserum values,which averacred72 ppm. Serum from litterbsom to treateddams and cross-fosteretdo untreateddams (onlyexposed initteroh)ad 54 ppm PFOS on average(n = 6) compared totheiruntreatedfoster-damserum PFOS values,which averaaed 2.54 ppm. The singledigitppm PFOS levelsobserved intheseuntreatedfoster-damsismost likelyfrom exposure tocontaminatedpup urineand feces,sincealluntreateddams which fostered pups from untreateddams had serum PFOS valuesator below the lower limitof quantitatioonf 0.05 ppm. Littersfrom treateddams which were cross-fosteretdoother treateddams (exposed inuteroand via milk)had the highestserum PFOS values, averaging88 ppm (n = 6). In-thilsattecrase,thepooled littesrerum PFOS conc*6ntratibns were in therangeof foster-damsewm values(88 ppm on averageforlittervss.98 ppm on averagefortheirrepectivefoster-dams)I.tshould be noted thatthesesamples arefrom theend of thelactatiopneriod(days21 and 22),and thatpups have likelystartedon feed around lactatiodnays 14 and 15. Theironly exposure would be inuteroor viamilk from treateddams. Theseanalysecslearldyemonstrattehatexposuroeccursbothinuteroand viamilk. ConclusionsR:educedpup survivaolbserveidnthePFOS ratreproductisotnudy(seeT- 6295.9)was a resulotfpup exposurienuteroandnota resulotfeffectosn thedam from exposure.In-utereoxposuroefPFOS (damtreateadt1.6mg/kg/dayc)anresulitnliver effect(sincreaspeedroxisomesb)eingpresenitnthenew-bom pup.The productioonf pulmonarysurfactabnytpupsdoesnotappeartoaffect6bdy exposurteoPFOS inittero. Pupscanbe exposedtosionificalnetvelosfPFOS frominittereoxposuraendviamilk from exposed dams. NOTE: Althou-h samples of liver,urine,feces,milk, and milk-producin,.G,lands were taken forpossibleanalysisof PFOS, thesesamples have not been analyzed. Two additionalpharmacokineticstudieswere undertakentobettercharacterizdeispositionof PFOS during pre2nancy and lactationT.he firssttudyexamines thedispositioonfbod), burden ifterpreornanevand throu-h-estation.The second studyeximines the dispositionthrou-hpre-nancv and lact@it*loIn.-lifiescomplete on thesestudies'. however, anal3-siissnot coiiipleteR.eports areexpected by ALI-LIST 1.--'000.111 addition.@,i,ia,-chiiiistic isplanned to start1,.t-l,,csecoiioia!ll'oi' 2000. The objecti%-eosf tliis.t@l;id%a'i-L-I: tot)ctteurnderstandthe possiblemec@aiiistioif toxicitytothe pups; 2)more precisel@d-efinethe no-effectlevelforreduced %,iibilit@,: and,3) obtainadditioniplharinLicok-iiideattia,.:These threeadditionilstudieswill enhance our complete understandingof thepotentialperinataleffectsof PFOS asthe%- relateto senim and tissuePFOS coliciitrationasnd potentialmechanisticendpollits.