Document e7JV0nn1xL27rzBoJnkrqOQeg
oDupwonte. 13s267
Study Title
Ammonium PerfPlouosrto-oWcetaannoiantge:RatAsgeFoElflfoewcitnognOtrhael PGlaavsamgaeConcentration in
AUTHOR: Xing Han, Ph.D.
STUDY COMPLETED ON: December 15, 2003
PERFORMING LABORATORY: HELa.skdelulPoLanbtodreatNoerymofuorrsHeaanldthCaonmdpaEnnvyironmental Sciences Elkton Road, P.0. Box 50
Newark, Delaware 19714-0050
LABORATORY PROJECT ID: DuPont-13267 [-6859.(0
`WORK REQUEST NuMBER: 14762
SERVICE CODE NUMBER: 1389
Sponsor: EWLi.lmdiungPtoonnt,dDeeNleawmaoruers19a8n9d8Company USA.
and
3M Company 3M Cente Building St Paul, MN 55144-1000
TT
heew
APmimoConntPeenrtfiuoonro:ocanPoossttcW,aAnpge EfRfeactt aFonlhloewing Os Gavage
Duron 13267
GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT TLhaibsorsattuodryywParsacctoicneduScttaenddairndsc.ompliance with U.S. EPA TSCA (40 CFR part 792) Good
Study Director:
= ReYsieanrgchFTaoviPohlo.gist EL. du Pont de Nemours nd Company
S15-hDecw-2e007
T
PAlmamsomaniCounmcePnetrrlautoiroonocitnPanoosatteW:eanAigneg EfRfaetcst Foonltlhoewing Oral Gavage QUALITY ASSURANCE STATEMENT
Haskell Sample Number(s): 24921
Dates of Inspections: Protocol: Conduct:
Records, Reports:
June 18, 2003 July 8,9,21,28,30, 2003 October 27-30, 2003
Dates Findings Reported to: Study Director: June 18, 2003; November 3,11, 2003 Management: November 3,11,2003
DuPont 13267
Reported by:
mda k Lally ely Quality Assurance Auditor
15-Dec-2003 Date
oe
PAlmamsomaniCuonmcePnetslastoiroonosintaPnoossteW:eaAngiengEfRfaetcstoFnoltlhoewing Oral Gavage
DuPone13267
CERTIFICATION
We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study.
Approved: 20.
prc
Tao.nds = ra Dec-roes
AppearedT: akViosi,o Boga. PoE] ART Resch Marge
r2-pe=c-2e8d
[ER
Toot POD.
(-D3ec-2203
Rete Toucobogs
Ee
APlmamsomnaiCuonmcePnetrrlautoiroonoicntPaonsota-eW:eaAngiengEfRfaetcst oFnoltlhoewing Oral Gavage
DuPont13267
TABLE OF CONTENTS
Page
QGUOAOLDITLYABAOSRSAURTAONRCYEPSRTAACTTIECMEENCTOMcPrLIsANCE STATEMENT ovr 3
A
LA IST OF TABLES comsesssmimsmmmismmmO mmmmS mmo-- mmnm-- onim-- osmm-- mnin-- nss
SLITSUTDOYFIANPFPOERNMDAITCIEOSN.......orccoroeonernesnneemssssnmesnsssssmmmssssnsessssssssssssssssssssssssisnsnos.T
SSUTMUMDAYRPYEc RSONNEL woroe rcresrenrsrmmenr esssesn sions s).10
A. AgeEffect.
--------------------
B. Sox Corpaiionummmmmmmmmmmm--------
10 10
MIATN ERIT ALSRANO D MrD ErTHrUODSCc TIr ONeams |1
Ae Tet SOR mnmsmmmmme------------ B. TOR Sm grmmmmm----------------
1 nse]
C. A1 RiMAnailmaHlUHSouDsiAnRg.I.Y. er mn rs
A; ----
23. FEenevdiraonndmeWantaelr.C.o.n.d.i.tions
eremm--
w----i
NE3 F Animal Y Health and Environmental M----onitoring Program...
1 emermmmm----
21. ADnoismaPlrseparation, pArnalyansdRi-- ass,
rm-- I1H
4F Experimentaly ProceduSree. ---- r-------------- 13
E. A1n. alyVteicraliMfEtoihfOcDdoaSsetSiluoionn...r.o-r
tam-- m-- --r "
25. EIxntsrarcutmieonnaotfioPnF.O.A...fromPlasmafor LOMS Tali...
m-- in
4. Chuomatographic Methods er----
1s
F. Satistical Analysis
----------------------------_
RESULTS AND DISCUSSION crcernensmsmrnonssmssssssssssssmnsosssnons 15
A. Dose Verificatio.n
" smmm------------------5
F 1. MaleRats. S cmmmm-- mm----_
23. CFoemmpaalreisRoansb..e.een Male-and Female Ras
re--
A-- 16
A RECORDS AND SAMPLE STORAGE crore-- s 16
REREREROE Suwrssssmprmmmsmmmmmmmmmmimomsmimmisnir 17
TABLES cnmmmmmmismrmtsmmemseimtmmmmmmmmmmmmm------------
A
A
APlmamsomaniCounmcePnetrrlautoiroonocinanPooast-eW:eaAngiengEfRfaetcst oFonltlhoewing Oral Gavage
Dupont13267
LIST OF TABLES
Page
1.
Plasma concentration 10 MEK PFOA.
in
rats 24 hours post-dose errs
following
oral
gavage with smn)
LIST OF FIGURES
Page
1. P1l0amsmagconPcFeOnAt.ration in ma-- le rats 24-- hours po-- st-dose following oral gavage with
n
2. Plasma concentration in female rats 24 hours post-dose following oral gavage with
10 MEE PFOA. corns
mmsm--
3. Plaaasgmea cWointchen1t0rMatEioEn inPFmOalAe.ancd fermaloe ratrs 24ehousrs post-dose following oral
2
LIST OF APPENDICES
A. Dose Verification Data B. Plasma CONCENtEation Data...
Page mm-------------3F
mmm
_--
APlmamsomaniCuonmcsPnerrfautoiroonocitnaPnoosatteW:eanAigneg EfRfaetcst Foonltlhoewing Oral Gavage
Dupont13267
STUDY INFORMATION
9th Collective Nomenclature: Octanoic acid, pentadecafluoro-, ammonium salt
Synonyms/Codes:
+ +
FACm-m1o4n3iFuLmUpOerRfAluDorBoroactnadnoFaltueorochemical Surfactant
(3M Company, Specialty Materials)
. +
cPesrfluorooctanoate, ammonium salt
+ PFOA
H20921
Lot 332 (3M Specialty Materials) (Lot No.)
Haskell Number: 24921
CAS Registry Number: 3825-26-1
Purity: 9St5r.a2ig%ht9c7h.ai9n:9%77.6%
Branched:
12.6% intemal monomethyl 9% isopropyl
(on-alpha)
00.21%% gteemrt--dbiumtyelthyl
0.1% alpha monomethyl
Known Impurities: Ca(C;F,COy' NH), 0.01% C5(C4FsCO;" NHL), 0.03%
CCoo((CCesFFiusCCOO;y NNHHLL)),, 00.5473%% CMso(nCoehFyCdrOo APNFHOL,)0,.00.91%6% MUondneofuinnseadtu(rpaotsesidblAyP)FsOu,bst0i.t7u2te%d perfluorocyclo species, 0.2% cyclopentyl, and 0.1% cyclohex!
Physical Characteristics: White solid Stability: The test substance appeared to be stable under the conditionsofthe study; no evidence of instability was observed.
52
APlmamsomnaiCuonmcePnetrrfautoiroonociinaPnoosatt-cW:eaAngiengEfRfaetcst oFonltlhoewing Oral Gavage
Sponsor;
E.1. du Pont de Nemours and Company. Wilmington, Delaware 19898
USA.
and
3M Company 3StM. PCaeunl,teMrNBui5l5d1i4n4g-1000
Experimental Start/Completion: June 30, 2003 / August 7, 2003 `Study Initated/Completed: June 27, 2003 / (see report cover page)
DuPont 13267
- ----
APlmamsomaniCounmcePnetrrlautoiroonoicntaPnoostte-:WeaAngiengEfRfaetcst Foonltlhoewing Oral Gavage
Dupont13267
STUDY PERSONNEL Study Director: Xing Han, Ph.D. Primary Technicians: LaRue A. Manning, B.A. Management: BMraitatnhPe.wSSh.erBtozg,dAa.nAf.ly, Ph.D., D.ABT.
Gary W. Jepson, Ph.D. Toxicology Report Preparation: Lisa G. Burchfield, A.A.
Management: NancSy. Selzer, M.S. LaboratoryMVaenteargienamreinant:: JTahnoimceasL.WC.onMnaeylelr,,MDS..V,.MB..A,.,DCi.pLlHom.ate A.C.LAM.
= --_--
APlmamsomaniCounmcePnetrrfautoiroonoicanPooast-eW:eaAngienEgffReacstoFnotllhoewing Ora Gavage
DuPont13267
SUMMARY "(TPhFeOrAel)atiinornasthsiphabsetbweeeennianvgeestaingdatpeldaisnmathcisonscteudnyt.ratMiaolneoafnadmfmeomnaileumratpserbfeltuwoereonoc4taannodate weeks oPlFdOwAeraet a2d4mihnoiusrtseproesdt-1d0omseg/wkagsomfePasFuOrAedbbyysLinCg/leMSor.alTghaevargees.ultTshsehpolwaesdmathactontcheenptlraatsimoan of concentration of PFOA in rats was dependent on the age and sexof the rats. A AgeEffect wInasbootbhsmeravleedabndetfwemeaeln4e raantds,5thweegerkesatoefsatgaeg.e-rTehleatSed-wdeieffkeroelndcemailnePrFatOsAhapdlaPsFmOaAcopnlcaenstmraation cpolnacsemnatrcaotnicoennstrtahattiownesrien St.h4e-f5o-lwdeheikghoelrd tfheamnalteher4at-swweeerkeo2l.d4-mfaolled rlaotsw.erInthcaonntirnastth,et4h-ewePeFkOoAld wraetsr.e PolFdOerAthlaenve5lswienepklsa(stmharowuegrhesntoudlyontgeerrmisniagtniiofincaatntlyweaefkfse)c.ted by age in atsofeither sex that B. Sex Comparison Afetmalwese.ekTshoefaPgFe,OAmaplleasramtas choandcePnFtrOaAtiopnlsasimna5-cotnoc8en-twreaetkioonlsdtmhaatlewerrates2w.e7r-feol3d4.hi7g1h0er65t.h1a-nfoilnd higher than that in the females of the same age.
o
FAlmiomrCiomncPeenurrtooncninPaost: cAagnea ERfatoFnlhieng Ol Gage
Dupent3267
INTRODUCTION
`Ammonium perfluorooctanoate (PFOA) is perfluorinated octanoic acid salt used as an
industrial surfactant. Elimination of PFOA in rats is sex-dependent and hormone regulated. PFOA elimination is much faster in female rats than in male rats," down-regulated by testosterone in both female and castrated male rats," and up-regulated by estradiol in the male
r"amtas.le anHdofweemvaelre,ptohsetsewesatundiinegs wraesrestcodinfdfuecrtenetdaognessewxeuraelldyomsaetduwrietrhatPs.FOIAn,thaencdurtreenptlsatsumday, concentration of PFOA.at24 hours pos-dosingwere compared.Thispost-dtoismepioningt
`was chosen because 24 hours after dosing, the sex difference in PFOA elimination in mature rats can be easily distinguished via the plasma concentration of PFOA.) The objectiveofthis study
was to determine if immature male and female rats eliminate PFOA from blood at rates different than those observed in mature rats. This study was not designed tofully characterize the
GpheanrimtaicvoekilniemtiicnsaioofnPrFaOeAcoinnstiamnmtsa.ture rats, and was not designed for use in determining
A TestSubstance MATERIALS AND METHODS
ParniFdtOyaA,si(cgoanmmepmdoosHinatisiukoemnl,lpceLorafnlbtuoaormraiotnooacrtnyatn,Nouastmyenb,oenFryCa-Ht1-s42,34,h9a2zL1aortudsp3,3o2na)nrdwecaFesiapto,dbtoaAuivnaseidlmaafbtrleoermiia3nlfMaors(msSatit.iePoaanutloo,nnMt(hNse) was provided by the vendor and documented n he study records and report. CAS Registry Number: 335-67-1 Molecular Weights 414.1
Molecular Formula:
CsFisOH
B. Test System
Male and female Crl:CD*(SD)IGSBR rats were obtained from Charles River Laboratories, Inc., Raleigh, North Carolina. The Sprague-Dawley rat was chosen for this study becauseof the
extensive experience with this strain and its suitability with respect to longevity, sensitivity, and
low incidenceofspontaneous diseases. Furthermore, the Sprague-Dawley rat has been used previously for toxicokinetic testing of PFOA and other fluorinated test materials. **
At the timeofdosing, rats were 4, 5, 6, 7, and 8 weeksof ageand the weight variation did not `exceed 20%ofthe mean weight by dose group and sex. Information on the cage labels
----------TP -- ---- ------
[2
PPAllmaamssmomaanCioConuncmceenPntetrcralatutioiorononoicinntaPPnooossta-eWW:eeaaAnngiiennggERfRufatctstPoFlnolotlwhoeiwinnggOOrlalGGaavvaaggee______ DuDPupoonnce1133226677
TinhceluidneddivtihdeuaHlasidkeenltlifainciamtiaoln
number number
awnadsapnlaicndeidvoidnuatlheidteanitioffeicaactihonrant.umber
assigned
to
each
at,
C. Animal Husbandry
1. Animal Housing
aUppporonprariraitvealcaatgeHsasakceclolrdLianbgortaotSotrayn,daatrsd wOpeerreartienmgovPerodcefdruormess.hipApniinmgaclasrtwoenrseamnadinhtoauisneeddiunnder d`eqtueacrtaendt.ineAfftoerratthleeqausartahnrteindeaypse,rihoadd, artatslewasetreonseelreecctoerddefodrwsetiudgyh.t gain, and no abnormalities `apTphrroopurgihaotuetctahgeedsoascicnogrpdeirnigodtowtihtehStOePst.substance, the rats were housed individually in
2. Environmental Conditions
Arenliamtiavle hruomoimd(ist)ywoefre30m-ai7n0t%ai(nteadrgaetteadtteom4p0e-r6a0t%u)r.e ofAn1i8m-a2l6rCoo(tmasrgweetreed taort2i2fi-c2i4allCy)iallnudmianated
d(iuroercetosrceorntthleiglhatb)oornataonryavpeptreorxiinamraitaen t1o2 hhaovuersliiggnhitf/idcaarnktlcyyacflef.ecUtneldetshsejrudegseduoblfytthtshee ssttuuddyy, the
relative the final
hruempiordti.ty
and
temperature
ranges
in
the
housing
rooms
was
recorded
but
not
included
in
3. Feedand Water
CAelrltaifniiemdalRsodweenrte LparboDviiedetd" t5a0p0w2aatedrlaibditluimb.ituAmnainmdalfsedwPerMeIfaNsuttedriotvieornnIingthetrnfaotrioanpaplr,oxLiLmCately
12 hours dose.
before
dosing with
test
substance.
Food
was
returned
approximately
two
hours
post-
4. Animal Health and Environmental Monitoring Program AfosllsopweciinfgiepdroicnetdhuereHsasakreelpleLrafboorrmaetdorpyerainoidimcaalllhyeatlothenasnudreenthvaitrocnomnetnatmailnamnotnilteoverlisnagrperboeglroamw, the those that would be expected to impact the scientific integrity of the study: + aWnadteorthsearmcpolnetsamairneaanntsa.lyzed for total bacterial counts, and the presenceof coliforms, lead,
+ Feed samples are analyzed for total bacterial, spore, and fungal counts. + sSaanmiptalteisonfrboymthferecsahglyewwaasshheerds cages and cage racks are analyzed to ensure adequate
rCeerqtuiifrieemdeanntismaanldfneoetd tiso eusxecde,egdusatraatnetdemedaxbiymtuhemmcaonnucfeancttruartieorntsoo fmekeetyscpoenctifaimeidnannuttrsi,tiionncalluding
-_--
Tae
APmummoaniCuomncPneefvliooronocnPoossttsW;eaArgiengEfReacttso Ptlhlewin Or Gavage
Dupont 13267
sppreecsiefniceedohfeathveysemectoanltsa,maifnlaatnotxsinb,eclholwortihneamteadxhiymdruomcacrobnocnesn,traantdioonrsgtaantoepdhboyspthhaetemsa,nufTahceturer
Would no be expected o impact the integrityofthe study.
"lTahbeoraantiomraylamheiamlatlh vaentdereinnavriiraonn.meEnvtaalluamtoinointoorfitnhgesperdoagtraamdidis nadomiinndiisctaetreedanbyyctohnediattieonndsitnhget affected he validity ofthe sty.
D. In-Life Methods
I Animals The experimental groups were as shown below:
Group weeks Daye
I| w
`5 5
32s a
wvv
:7
5
Fisadioclusmewneterd1in GhaeysToymsecorndgs 2
Mate Fema
1w00 1
10 10
Ii
10
eof Ging, The Seal eg dog
2. Dose Preparation, Analysis, and Rates
Tbehceautesset isutbsstthancreouwtaesmaodsmtinciosmtmeorendltyouascedhforat taosxiasciitnyglsteudoiraels ogafvPaFgeO.A.ThPiFrOoAutweawsasmicxheodsewnith
HPLC grade water t0 achieveth target dose concentrations. For al experiments, a single dose
laepvpelrowxaismuasteedl4yeqmuivLalenbtotdoy1w0eimgght use and sored in a 4C refrigerator
.pPrFiDOoroAst/oekugssoeb.luotdiyonwseiwgehrte,
parnedpatrheeddoosnee
dvoalyubmeefowraeshe
d
a
y
of
LMeCt/hModSs.methods that were used for dose verification are described in Section E, Analytical 3. Sacrifice and Blood Sampling
Rats were sacrificed by CO; asphyxiation and exsanguinated by cardiac puncture.
4. Experimental Procedure
aRdamtisnwiesrtaetaidomni,nriasstewreedrePsFaOcrAiafiscead sainndglwehoorlael bdolsoeodofsa1m0plmegs/kwge.reTwcoelnlteyc-tfeodubryhcoaurrdsiaacftpeurnPctFuOrAe cBsealnmotporlidefsusagwametpirloeenspalwnaedcreefdraoilznletcnooalEtlDe<cT-t1Ae0dtwuCibteuhsninaln2da0nmamlaiyinsnuitsta.eisneodfothnewdeetsiircee.d sPalmapslmeatwimaes. seWphaorlateedblboyod
--_--
PAlmamsomaniCuomncPeenflaaiooronocitnaPnooast-eW:eaAngiengEfRfaetcst Foonltlhoewing Ors Gavage
DuPont13267
aKti.d<n-e6y0sCanfdorlpiovesrssibwleerefutcuorlelebcitoecdhaemsiaccarlifaincaelaysnidswere flash frozen in liquid nitrogen and stored
E. Analytical Methods
I. VerificationofDose Solution
dPoFsOeAsosltutainodnarwdass(1d.i0l,u0t.e5d,b0y.2,100,.010,0a-nfodl0d.pr0i5orptg/omtLh)e wanearleyspirsepbayreLdCi/nMHSPLmeCt-hgorda.de water. The
2. Extraction of PFOA from Plasma for LC/MS Analysis
pPrleacsimpiatsataimopnlceoslwuemrnes p(rJoocneesssCehdrboymaptrootgerianphprye,ciLpaiktaetwioonod(,PPCTO)).usiAng0.I5soplugt/emALrrsaoyluptriootneoifn apenrifnltueomraolnosntaannodiacrdacfiodr q(uAalndtriitcahtiCohnemoifcPaFlOsA,.MilPwlaauskmeaes,aWmIpl)eisnwaecreetotnhitaiwleed,(AanCdN)22w0asuuLsedas aadldiingqoafupeporaocpthrisaatempdlieluwtiaosn arpatpeliveodltuomtehseoPfPATCNar;riany.terTahle sptlaansdmaardssaomlpulteisonwetorethperePcPiTpitarartaeyd.by sDitlauntdiaornd rsaotleust,iorna)n,giwnegrefruotimli1z:e4d(i6n0ourdLeroftoinctaeprtnuarlestthaendsaarmdplsoeluctoinocne)nttroa1t:i5o0ns(w9i8t0hpinLtohfeinternal pSltaatned,acredntcruirfvuegepdaraatme~t3e0r0s0. rTphmefaorrraymiwnaustessl,oawnlydleuxtteradctusndweerrevaacnauluymzeidntboyaL9C6/-MweSl,l receiver
3. Instrumentation
System:
h`eWaatteerr,sa2n7d90awLaisqaumidplCehrromatograph, equipped with quaternary pump, column
DMeotdeec:tor:
QMuRaMt.io Micro Mass Spectrometer
SourcMe:1 resolution
[10r0 e --
fHoMnen| crregsyol|uion
11000
CEonltlriasnicoen
2s
LExMit2 esotion
5In
oHnM2enerregsoylu2t: ion:
210
CMaapliilpllriyr((kVV))::
200
CExotnreac(tVo)r: (V):
0is
SRoFurlcenest(eVm)perature 0Boe
MS MDeetshoolvdaton temperature: 350C.
TMiomdee
M0-R1M0,0 m2iannions
cn
D4u1l3l00536900 02550
T-
APlmamsemnaiCuonmcPeenrtfrlaotriooonciinaPnoosatteW:eaAngiengEfReacttsoFnotllhoewing Oral Gavage
on
C4o6l3li0s0ion e4n1er9g.y0:0 15eV
DCoulelli:sion energy: 012556V50
4. Chromatographic Methods
CoMletuhmo:d:
PWaltaesrmsaXciornrcaenMrSaiCo1n8a,naly2si.s1x302.mumm,
CNoobliulmenptheamspeesrature: AA:mbi5e0nmtM Ammonium Aceiate
B: Acctonirile
Gradient
[Time nim)
5B
eo
0
es 70
e1i0o9o. Tee10ee
FStloopwtaimee:: Injection volume:
01205mmiUnmin sul
Dufont13267
F. Statistical Analysis vGarroiuatpiodna.taiStatriestpirceaslesnitgendifbiycamnecaenw,asstaansdsaersdseddevbiyattihoen,Stsutdaenndta'rsdte-rtresotr., aRnedjepcetricoennotfcdoaetfaficiisebnatsoefd on Chauvenet's criterion."
RESULTS AND DISCUSSION A. Dose Verification
(Appendix A) d`TehsecrciobnecdenitnraMtaitoenrsioalfstahnedteMsettshuobdsst,anSceectiinotnheE.doSsteansdoalurtdisonfsorwdeorseevveerriiffiiecdatbiyonLaCn/dMtShemdeotsheod as sthoeludtoisonesswoleurteiopnrsepwaerreedabllywdiitfhfienre2nt0p%erosfontnheel.tarTgehteeddectoencremnitnreadtimoena(n2.P5FmOgA/mcLo,ncAepntpreantdiionxsAo)f.
-_--
DimsOCon-- cent Foe-- an Ro Following Or Gigs B. P(Tlaabslmea1C,oFnicgeunrtersat1i3o,nAopfpePnFdOiAx B)
--_--
I MaleRas
`W7T3hi2e.tp2lha1s0amg]apcogofon/cmeeLntmr(aamlteilaornnst.soSfsDPp)FliOnoAdt-iwnetehkFesimoarllsdem1r. altseTharrete.PshFoIOnwcnpoiannseTosabs,lceoh1n.icgeThmheestiaPriForOenlAawtaisonship cm5oe.na1cn9enPgtr/FamOtiLAo,np(lw3ha9is.ci2ha4,c1bo.an3se.ee8d9nroiannitlohn.s)rnowasssaoobfusdenrpvae8dv-eiwndehc1ek oplkdasma9l9eo%faeStovnwefecrdkeenoilned8mmaanelgeraotsfl, 3eT7.h1ea3o1t0
significantly different from the plasma concentration of PFOA in the S-week old male rats.
2 FemaleRas Teihctekptlahladsamfaegmcoaoflnecetheernttrsfaewtmiaaolsnes2r.o6a8ft.PF0lO.A6oiign/thmienLfF,eimWgahrlieec3hr. tTwsahasregpslhaiosmwfan citonnTcaehbniltgerhae1t.rio(Tnpho<efi0P1rFe)lOtaAthinnonhs4he.ip PFOA concentrations (mean ranged rom 0.510 1.18 pnt) in he ldr omnes that were 3 to
8 weeks old.
3. Comparison tatwesn Mate snd Pele Rs cPoFnOcAeiprluiaonnascwonecrenhtirgahteironisn ihnemamlaelasnthfnonatlhrafsemaarelesshfoowrnalinaFgigugrreou3p.s.PFThOeArpoolm s
dramatic sex-dependent difference in PFOA concentration was observed for rats that were 5
weeks and older. The ratios of PFOA concentrations between male and female rats that were 5 to 8 weeks old were all greater than 34, whereas the ratio was only 2.7 for the 4-week old rats.
CONCLUSIONS
TAcogolenlochvaeistngaioosrinaglnsidfoioscaiwnntgepwfirfteohcnto1ou0nnmteghle/fpgolaPasFmOaA.tconaTcehenetrdsaotesiroentseohfdP5dFwiOefArrekin,ncbweoittihhn PmaaEllOseAaFnprdlfbaemsialne rats PFOA plasma levels more han 4-1old higher tha femal as
RECORDS AND SAMPLE STORAGE SNpeewcairmke,nDseliaFwaaprliecoarbla),roan Mdoautsn,aainndRheecofirndalMraenpoargtewmielnltb,eWrietmaiinngedloatn,HaDskeealwliLea.boratory,
eeec ee m----
7
FPAllmaasmsmomaanCiCoounnmcceePnnettrrrfaalttuiiooornonoiicnntPaPnooossattteW-:eWeaanAniginenggERfRafaettcsstFFooonllltlohoewwiinnggOOrlal GGaavvaeggee _____ REFERENCES
DuDuPPoonnee-1133226677
1. tOohxmiocorkiinKe.t,icKsudboe,twHe.e,nKpaetrafylaumoaro,caK.r, baoxnydliKcaawciadsshwiitmhaYd,.iff(e2r0e0n3t).carCboomnpacrhaiisnonleonfgtht.he Toxicology 184, 135-140.
2. oVfapnedreflnuoHreouovcetaln,oiJ.cP.,aDcaidviins,maJl.W.e, Sraotsm:mienrhisb,itRo.,ryaefnfdecPtetoefrstoesnt,osRteEr.on(e1.99J.2)BiRoecnhaelm.excTroextiicoonl. 7.3136.
3. KCuodmop,arNi.s,oSnuozfuktih,e Ee.l,iKmaintaatkiuorna,beM.t,wOehemnopreirf,luKo.r,inNaotsehdirfoa,ttyR.a,ciadnsdwKiatwhadsihffiemrae,ntYc.ar(b2o00n1c)hain length in rats. Chem. Biol. Interact. 134, 203-216,
4. Ythleinuerni,naMr.y,eHxacnrheitjiaornovif,pHe.r,flJuaoarkoooncathaon,oJi,c aanciddPienurtah,e mP.al(e19r8at9.)PShtairmmualcaotlio.nTobxyicooels.tra6d5i,ol27o4f277.
5.
DuPont Haskell Laboratory (2003). Unpublished report, DuPont-7473.
Perfluorooctanoic Acid:
Toxicokinetics in the Rat.
6. dViasntrdiebnutiHoenu,vemle,taJb.oPl,isKmu,slaiknids,elBi.Lm,inVaatinonoRaffpeelrgfhleumo,roMo.cJ.t,anoaincdaPceitderisnonm,alRe.Ea.nd(1f9e91m)a.leTriastss.ue J. Biochem. Toxicol. 6, 83-92.
7.
Taylor, LR. (1982). University Press.
In
An
Introduction
to
Error
Analysis.
E.D. Commins, Editor, Oxford
_------ TI ------
APlmamsomaniCounmcePnetrrfautoiroonocitnaPnoosatteW:eaAnignegEfRfaetcst Foonltlhoewing Oral Gavage
DuPont 13267
TABLES
_--
Tie
FPAllmaasmsmomaanCiCoounnmcceePnnettsrrfaauttoiirooonnoicintnaPPnooossattteWW:eeaannAiignnegg ERfRafaettcsstFFooonllltlohoewwiinnggOOrlal GGaavvaaggee __
-_--
TTAA BLEsS
ABBREVIATIONS:
EXPLANATORY NOTES
sD
standard deviation
DDuuPPoonntt1133226677
ees
Ammonium Pefluoroocanons: Age Eft anthe Table 1: P10lamsgm/akcgoPncFeOnAtr.ation in rats 24 hours post-dose following oral gavage with
Group n3ee
Sean Siaes 55
1!
`5
02 52
iIr
wWw v
758
8s1i
30779
35s Sa
Siean Females 5
2[E6H8
o0s3s6
oLs is
00522
ose oa
D{uR26ee6xcpWorEermeLdtopCwhaasnvoetnent' drieroiohn" tchaelcvulaaltioonfPoFftOheAmpelnasmaandcotnecSen.aion a-- bsined rom rat 51
ET
APlmamsomaniCounmcePnetsrlautoiroonociinaPnoosatteW:eanAigneg EfRfaetcst oFonltlhoewing Oral Gavage
DuPon-13267
FIGURES
-
Ammen, ge tse igure 1: iPlasmTaocmoanchentPraFtOio.n in male rt 4 hours pst dose falling ora nage
$0
wl
E
2
|
5i
|
|
o
|
o se as rn ut
DPAalmsamsmomaanCiCoounmncecPnetosrfanutooirononaiicnnaPPnooosssttteWW:eeaanAniignnggERfRtfaestcstFFooonllltlohoewwiinnggOOrrstGGaavvagee
_DDuupPoonnte13267
Figure2: wPiltahsm1a0 cmogn/ckegntPraFtOiAo.n in female rats 24 hours post-dose following oral gavage
Eo 3
3Z 25
3HE!
|
s
8
8
[5
o 4 0s 8 1 8 Age weeks)
-
APlmamsomaniCounmcePnetsrfautoiroonocitnaPnoosit-eW:eaAnigneg EfRaftcstoFnoltlhoewing Or Gvage
Dupont 13267
Figure3: Plasma concentration in male and female rats 24 hours post-dose following oral gavage with 10 mg/kg PFOA.
--o--Male --O-Female op
3 :2% gfw 8i 0
ss 6 1 a Age (weeks)
--_--
PAlmamsomaniCounmcePnetrrfautoiroonocitnaPnoosstteW:eaAnignegEfRfaetcst Foonltlhoewing Oral Gavage
DuPone 13267
APPENDICES
-
PAlmamsomaniCuomncPeenrfiuioornooicntaPnoost-eW:eaAngiengEfRfactts FonotlhelowiOnrg Gavage
APPENDICES
EXPLANATORY NOTES
ABBREVIATIONS:
sLD0Q
slitmaintdoafrdqudaenvtiiattaitoinon
wSEey
psetracnednatrdcoeerfrfoircientof variation
DuPont 13267
e--e--e----r------T-- e ------teeer er:
APlmamsomnaiCounmcePnetrrfaltaicornooicnaPnoosntteW:eaAngiengEfRfeactt oFonltlhoewing Oral Gavage
DuPon-13267
APPENDIX A Dose Verification Data
-
APlmamsomaniCounmcePnetrrfaltuoiroonocitnaPnoosstte-:WeaAngiengEfRfaetcst oFonltlhoewing Oral Gavige
ReNpulmcbaetresof Description
mg/mL.
Doss Solution - Group |
21
2200mnygmmLL ddiiltaiioonn-33A4 230614
5
2200ngmmmL ddiillaaiioonn3-38A 228730
6s
225500nngimgl_ddiilluuiioonn -3388 228600
7
250mg dilwion-3C 280
5
20ngml dilwion-3C 275
5
ong dilwion-3C 278
MesaDn
2o172
nseev
0044s
Dose Solu'tion 1 - Grou2p0ImTgmLdiwion-34 229
23
22500nnggm/LmdLidliuilount-i33o4An 210963
hl
250 ng/mL dilution - 38 220
s
250 ng/mL dilutio-n 38 22
6
250 ng/ml diluion -38 187
s7
225500nngg/imlm.Lddiliuliuonio--n33CC e18d6
5
250 ng/mL dilution - 3 18s
MseDan
200109
SneEv
094076
Dose Solu'tion 1 - Gro2u0pmIgll.mLdiluion-34 269
2
20ngmL dilwion 3A 265
3
225o0mnggm/Lmdlidliuliuoion-n-33A8 226520
6s
225500nnggiimml_L ddiilluiuotn-i-o33n88 225m5
75
225500 nngg//mmll ddiilluuiioo--nn 33CC 226m0
9
250 ng/ml diluion - 3C 276
MesaDn
020697
sweey
03033
=
Dupo 13267
APlmamsomnaiCuonmcPeenrtfrlaotriooonctinaPnoosatt-eW:eaAngienEgfRfacttsoFnotlhloewing Oral Gavage
ReNpalmibaetreosf Description
mg/mL.
Dose Solu1tion IV ~ Gro2u0p I0Vml dilsion 3A 249
23
22o0ngmmLmdidliwwiioonn-33AA 224372
3
250ml dilwion-38 251
5
20ngmL ditsion 38 251
67
2200nnggmmLL ddiillwwiioonn--338C 22.6433
20nymLdilaion-3C 262
9
20ngmL dilsion -3C 256
Mea0n
020590
SwEey
03043
Dose Solution V - Group V
2'
2200nmgmmL ddiitsiioonn3-3AA 222189
53
22500nnggmmLL ddiillwwiioonn3-38A 221118
s5
22500nngg/mmLL ddiillsuitoino-n3388 210778
7 8
22550 0ngm/mmL ddiiluttiioonn- 3-C3.C 212805
9
20nymL dilwion-3C 221
Mesaon
2o1n0
SwEey
080163
Dose Solutions 1-V
MesaDn
023414
wSeEy
1o4n19
DuPon-13267
5
PAlmamsomaniCounmcePnetrrlautoiroonocitnaPnoosatteW:eaAnignegEfRfaetcstoFnotllhoewing Oral Gavage
DuPont 13267
APPENDIX B Plasma Concentration Data
Tos
APlmamsomaniCuonmcePnetrrfautoiroonocitnPanoosntteW:eaAngiengEfRfaetcst oFonltlhoewing Oral Gavage
Males
Animal Number pgml___
Group 101
601
110023
683210
1100s8
6s3e8t
110067
2s2s
110098
s2it
1
874
MesaDn
7L3ol2
S"Eev
1033826
Grow It 0
340
0203
360.043
202084
11879
220076
3S723654
22098
4350191
210
3645
MesaDn
3395294
S"Eev
915203
Group 11 01
31s
002
3290905
330084
4153281
330067
32436
300 8
S009494
310
200
MseaDn
13799
nSeev
817270
ois
Dupo.13267
PAmimnoiniCounmcePnetrrfaotrioonociinnPoosstic:WeaAngiengEfRfactts oFnoltlhoewing Oral Gage
Males (continued)
Amal Number ____pgml
Group IVan rl
3310248
aao0e
pwi n
00s6
3361746
aa0
33750%
walno
3289336
Me0an SE
nano 129
wey
1097
Grow V son 2
33216963
5S0034
6m7a8
5s0086
33890954
sS0o8
3a80s3
550190
s39s16
MeEYa)n
8S5445
sneev
114710
Dupont13267
ee
=
APmmhoniCuamnPceTiuoornooncaPnoosstcW:eaAngiengERfaetcstFooltlhoewing Ors] Gavage
Females
"imal amber gl
Grow m1
saos
11
i3a
11s6
p3r5e
iins
2Ir 0
112
Sp5r0
Me>n
2G6e
s5ev
aa7i
Group aau
oTsse
m33ss
oiJarr
i21n6
av7o
aaEhY
ooieas
Me>an
oLiss
wsve
a01ns
Group iat3n
0L3o
S2m1nise
0d1599
S3ie
1To3s
S30i1e9
oo2sse
SM>een
ooLsrs
nev
a
ED
Dupone13267
APlmamsomaniCounmcePnetrrfaltuioornooicntaPnoosatteW:eaAngiengEfRaftcstoFnoltlhoewing Oral Gavage
Females (continued)
Anima Number
pgimL
Group IVsu
066
aan
002710
pairs
00371s
aiasr
014039
ai19s
oLoqg
a
023
MesaDn
005279
"seev
5010.090
Group V sue
266
s1i
008673
ssiis
019356
stsie
008674
sissi
008590
0
0
MesaDn
008217
S"Eev
30.0197
DuPont 13267
+ AinccclourddeidnfgortothCehacaulvceunlaet'isoncorfittehreimoen"antahnvdaltuheeoSfD.PFOA plasma concentration obtained fromra S11 ws not
as