Document KD477EyEQBX0kgJr4dkpB2aK
AR 426_ 3310
rd
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TRADE SECRET
Study Tie
H-25357: BiopersistenceScreening 10-Dose Oral Gavage Study in Rats
Laboratory Project ID: DuPont-11557
AR2RE 23/0
Dwupeonic1s55s7
AUTHOR: Carol Finlay, B.A.
STUDY COMPLETED ON: November 26,2003
~
PERFORMING LABORATORY: E.I du Pont de Nemours and Company
Haskell Laboratory for Health and Environmental Sciences
Elkton Road, P.O. Box 50
Newark, Delaware 19714-0050
---- TTT ---- ~~ Company Sanitized. Does not contain TSCA ca
H102-5D3o5s7e:OrBeiloGearvsiasgteenSceySericncFnaitnsg --
Dupont1557
CERTIFICATION
fWreo,mtthiesunsdtuedrys.igned, declare that this report provides an accurate evaluationofdataobtained
Reviewed by:
Tue byStudyDirector:
gResMVe.a acHhiTnodn iecro,loPgoD SafToia(yc.ooBgA
ZeMDeire ge Lb NDou.ue2607
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--_ Company Sanited. DossnotcontainTs cp,
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H1-02-5D3o5s7e:OraBiloGpearvsaigsteeSntcuedSycirneReanitnsg
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TABLE OF CONTENTS
Dupont 11557
Page
LCIESRTTIOFFITCAABTILOENS wood
LIST OF FIGURES.
nso EY
LIST OF APPENDICES STUDY INFORMATION css
so
SSUTUMDMYAPREYRw SONNEL tse
INTRODUCTION ssss 8
MATa BEeRsItALSSubAsNtDanMacEnedTHPoOsiDtiSve COMIIS....s..s..s.or
11 || ell
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dl dl el
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RESBrULTLSifAeNTDONDCIOSIOCRUYSSIcOrN er
RT ------------6
COFEUOW E DUR S oss L
16 16
RCEONCCOLRUDSSIAONNSD SAMPLE STORAGs E. ss
el? 18
TABLES FG RES
non ]9 sm 20
APPENDICES cs t s s 148
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--~ LIST OF TABLES
Duronti1557
1+ 2.
MEAN BODY MEANBODY
WEIGHTS... oe WEIGHTGAINS...............
Page A
3 4
MMEEAANNBBLOODOYDAFNDLLUIVEOR LWREVEIELSNI. EGHTS.rnwes2})
+ 6
MMEEAANNLBILVOEORDFLFULOUROIRNINEELECVEOLSNCovE.NNOTRMRALAIZETD ITODOOSNE
S-- rh
7 5
MMEEAANN LEIAVTEFRLFULOUROIRNIENLEEVCELOS..N. CENNOTRMRALIAZETDTIO ON
DOSE...
armen --
MEAN FAT FLUORINECONCENNOTRMRALIAZETDTIO OoNooDOSE...
SO" crm
--
LOIFFS IGUT RES
J 2:
MEANBODY WEIGHTS... CCOONMTPARROILSONr OF MEAN RELATIVE LIVER WEIGHTS:
TEST
SUBS
TANCE
p
oy
NE
Page
cern 28 GATIVE
3 CCOONMTP`RAORLISSONr OF MEAN REm LATIVE LIVEo R WEe IGHTm S: TESTe SUBSTANCE ans PNOESOITAITVEIVE 29
4 5
\MOIDRCAMRYAOLMOIORZLAEALGDRA5E.VQ25UA3I5GV7AEALNEDNTPSOSIINTRIAVETCONTROLBBLLOOODO.D..AUCINFI>
OVE 30 sm) RESULTING ROMA
MEANLIVERFLUORINECOw NCo ENNTOr RRMALAIZs TEDIT0Ot N DOSS... 7 COMPARISON OF RELATIVE LIVER
ROM
wenn
MCEANOFAN T FLCUORIFENOERCN12O5T3N57ARCNDEA WNEENIGGTNAHTOTTRIAMVI RNAEDCLAIOOMZNETETADRNNITOoLLIO.VENRo FLUORINe E
35
5 CCOONMCPEANRTIRSAOTNIOOFNMNEOARNMABLLIOZOEDD,TMOEAN LIVER,DOSE. AND MEcANoFoATnFLOposOt...RE - 3367
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Company Sanitzed. Does not contain 7ccar
H1-02-5D3os5e7:OrBailopGearvsaigsteeSntcueSdcyrieneRnaitnsg
--_ LIST OF APPENDICES
Dupont-11557
Page
2 1
IINNDDIIVBCOLIIDVNYIDWCIAELUIOGDBAHSTELU SRVAATIOL o NS... se
39
TAENRAMLSYSANIDS Cc ALCUFLACTAs ORTSIINFLOUENNCISNs G INTERPREesTOos FAKTINIEOTINC 63
1D: INDI FLUV ORINIELEDVELUSINAL BLOOD...
E. INDIVIDUAL FLUORINELEVELSIN LIVER
oo.
67 SA.
F- INDIVIDUAL FLUORINELEVELS INFAT coo 18
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`Company Sanitized. Donots contsain TSCA
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Test Substance
STUDY INFORMATION
Bi
H-25357 1
Submiter's Notebook NumbersT ) --
Haskell Number: 25357
CAS Reise Nose [NIN
|
Duon11357
Positive Control
Substance Tested; Potassium perfluoroalkyl sulfonate
SsmonymsCodes; H.24019
jl
Haskell Number: 24019
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Company Sanlize. Doss no contain 75 cor
1H0ADS3o5s7e:OrBsioGpaenviesnSceyScrneeRnaineg
Duranti1557
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STUDY INFORMATION(Continued)
.
Composition:
|
Known Impurities]
Positive Control
Swmonms/Cades, + H.24020 ) Substance Tested: Octanoic acid, pentadecafluoro-, ammoniumsalt
- C8
~
+
+
Perfluorooctanoate,
APFO
ammonium
salt
. Ammonium perfluorooctanoate
Haskell Number: 24020
Known ImpurT e --
1)
Usa. Sponsor: E.L du Pont de Nemours and Company Wilmington, Delaware 19898 Study. Initiated/Completed: October 10,200/2 (see report cover page)
Company Sanilzsd. Dos not cantain TSCA O81
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Dupont11557
STUDY PERSONNEL
Study Director:
Management:
Primary Technician:
Carol Finlay, B.A.
Judith C. Stadler, Ph.D., D.AB.T. Scott E. Loveless, Ph.D. James C. Mackay II
Fluorine Data Analysis: Paul M. Hinderliter, Ph.D.
Management: Matthew S. Bogdanfy, Ph.D., D.AB.T.
Toxicology Report Preparation: Scan M. Callaghan, B.A.
Management: NancSy. Selzer, M.S.
Laboratory Veterinarian: Thomas W. Mayer, D.V.M., A.C.LAM.
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ized. Docs nLSONY78CACBI Company San
Gompany Saniized. Does not contain TS r--r----------i----------a ----------------------
2105-3D5os7e:OrBailoGpeasviasgteenScteudSyeiennRiantsg ~~
DuPont 11557
SUMMARY
The objectiveofthis study was to evaluate `accumulate in a mammalian system. Two
the potential for groups of5 mal
H-25357tobe rats each were
absorbed dosed by
and to gavage
with
t1h0e0o0tmhegr/kggr/oduapywoafsHm-a2i5n3t5ai7nefodrw1i0thcoountsedcoustiinvgefdoarysa.n aOdndietigornoaulp8w4adsayssa.criBflioceoddownasDacyoll1e0,ctaendd
oanndtecsltindiacyals s1i,g5n,s 1w0e,r1e3r,e2c4o,r5d2e,datnhdro9u4.ghoLuitvetrhse adnosdifnagt awnedrereccoolvleecrtyedpeartiosdasc.rifAidcde.itiBoondalylyw,eiaghts
Hne-g2a4t0iv2e0 c(o2n0trmogl/okfgd/deaiyo)n,izweedrewatteesrteadnads 2depsocsriitibveed cfoonrtrHo-l2s5,3H5-72.40B1lo9o(d1,0lmivge/r,kga/nddayfa)t asnadmples
were analyzed for total fluorine content to determine test substance absorption and retention in
these tissues.
No deaths occurred, and no clinical signs attributed to the test substance were observed. The
mduerainngbtohdeydwoesiignhgtagnadinrseocfovreartys pdeorsieoddsw.itMheHa-n25b3o5d7y wweeirgehthiggahienrsotfhranatshednoesgeadtiwviethcotnhreoplosriattisve
control materials were lower during the dosing period than the weight gainsofras dosed with
the test substance. During the recovery period, the mean body weight gainofras dosed with the
positive control substance. The
material F-24019 was lower than the mean body weight gainofrats dosed
weight gainofrats dosed with with the other positive control
the test material,
H-
PS
24020, Was higher than the weight gainofrats dosed with the test substance.
For the purposeofcomparing absorption and retentionofthe test substance to the positive
ccoonntsriodlesr,eadlladsoasepserwceernetangoeromfaltihzeefdluoonrianmeodlealirvebarseids.inTthheeatdotmailniflsutoerriendedionsec,acahntdisalslueunwiatss were
expressed as pM cquivalents. As a measureofotal dose in the blood, an arca under the curve:
(estimated to infinity) was calculated for the test substance and positive controls. The
AUCINF/D for the fluorine component of H-25357 was 861x107, compared to AUCINED +
valuesof
indicated
a
5.22x10 and 8.15x10 for H-24019
total dose in blood that was much
and
less
fHo-r2H4-022503,5r7e,sptehcetitveeslty.subTshtainscpea,rtahmaentefror
the
positive with the
controls. There test substance.
was
no
detectable
fluorine
in
the
blood
on
days
52
and
94
in
rats
dosed
`tThhaen mteheannergealtaitvievecolinvterrolweriatgshton(ldiavyer1/0b.odyBywediagyh9)4o,ftrhaetmsedaonserdelwaittivheHl-i2ve5r3w5e7igwhatso2fr4a%tshidgohseerd
with with
H-25357 H-24019
wwaasssi4m1i%lahritgohetrhaenndegfaotriHve-2c4on0t2r0olw.aTsh9e3m%ehainghreerlaotinvedaliyve1r0wtehiagnhttohefrnaetgsatdiovseed
c2o4n0t2ro0lwgerroeups.imiBlyardtaoyt9h4e,ntehgeatmievaencornetlratoilvegrloiuvpe.r wTehiegrhetfsoorfer,altisvedrowseeidghwtistohfHr-a2s40d1o9seadndwiHt-h the
stiesmtilsaurbsttoatnhceenweegraetihviegchoenrtrtohlasnatthethneegeantdiovfetchoentrreoclsovaetrtyhpeeerinoddo.fthe dosing period but were
~
`The concentrationoffluorine in the livers from rats dosed with H-25357 was 114.94 uM
equivalents on day 10 and 6.96 uM equivalents on day 94. On the last day of dosing, the mean
`Company Santtized. Doesnotcontain TSCA CBI
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11.02-5D3o5s7e:OrBailoGpearviasgteenScte ySreinenRiansg
Duport11557
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BM equivalent concentrationsoffluorine in the liversofrats dosed with the positive control
`materialswere approximately 42-fold (H-24019) and 8-fold (H-24020) greater than values in rats
atrpepartoexdiwmiattheltyhe1t8e6sxt asunbds2taxncteh.e Bflyudoraiyne94c,ontcheenftlruaotriionne icnonractesnttrreaattieodnswiitnhpHM-2e5q3u5i7v.aleTnhtesrewfeorree,
rats treated with H-24019 or H-24020 absorbedand retained considerably more fluorine in the
liver than rats treated with the test substance, H-25357.
`The fluorine concentration in the fat from rats dosed with the test substance was 107.79 mw
equivalents on
equivalentsof
day 10
oneoft
and 13.59 pM
he positive con
equivalents on
trol materials,
day 94. The fluorine concentration in
H-24019, was approximately 2x higher
wm
than
H-25357 on day 10. The
approximately 2x higher
ofnludoariyne10cotnhcaennttrhaetfilounoorfitnehceontecsetnsturbasttiaonncofe,thHe-2o5t6h5e7r,pwosaistive
control
material, H-24020. By day 94, the fluorine concentrationofthe positive control, H-24019, was
similar to the fluorine concentration in rats treated with the test substance, H-25357. There was
no detectable fluorine by day 94 in the fat from rats dosed with the positive control H-24020.
Under the conditionsofthis study, fluorine was evident in the blood during the periodofdosing
`with H-25357, but was quickly eliminated. The amountsoffluorine in the livers and fat from
rats dosed with the test substance were higher than levels in the blood, and the results indicate
that there was evidence ofsome retention of fluorine in the liver and fat. Fluorine levels in the
blood and liver were lower than levels in rats dosed with the positive controls, H-24019 and H-
24020. Fluorine levels in the fat were lower at day 10 than levels in rats dosed with thepositive
~
control H-24019 but higher than
fat were similar to or higher than
the positive control H-24020.
levels in the positive controls.
At
day
94,
fluorine
levels
in
the
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Company Santizeq, Dos"ot contain 7504 oy
L11020D5-oD3o5ss7ce:OOrnBailloGpGeoarvvsaiagsgteeenSSctueuddSyyeriicnncRnRaiatnssg --_
DuDounPeotnits11s55y7
INTRODUCTION Tbihoeacobcjuemcutliavteoefinthaismasmtumdaylwiaasn tsoysdteefmi,neasthiendpoitceantteidablyofanHa-ly2t5i3ca5l7dteotebremaibnsatoirobneodfatnodtatlo fluorine: miantbelroioadl,s lpirveevr,ioaunsdlyfast.hoTwhnettoesbtisouabcsctuamnucleatweasincmoammpmaarlesd.toT2heposdiatiilvyedcoosnatgreoolsft1ha0t0w0emrge/kg for the test substance was selected based on existing toxicity information.
MATERIALS AND METHODS
A. Test Substance and Positive Controls `coTnhtertoelsst,sHu-bs2t4a0n1ce9,aHn-d25H3-52470,2w0a,swseurpeplsiuepdplbiyedthbeystphoensspoornassoraansamwbhietrelsioqluiidds.. TThheeptoessittive seuvbisdteanncceeofanidnsptoasbiiltiitvye, csouncthroalssaacppheaanrgeeditnocboelosrtaobrlpehuynsdicearltshaetceo,nwdiatsioonbssoefrvtehde. study. No
--
B. Test Species
Male Crl:CD(SD)IGS BR rats were received from Charles River Laboratories, Inc., Raleigh,
wNiotrhththCiasrostlrianian. anTdheitsCrsuli:taCbDi*li(tSyDw)iItGhSreBsRpecrtattwoalsonsgeelveicttye,dhoanrdtihneesbsa,siasnodfelxotweinnsciivdeenecxepeorfience spontaneous diseases.
C. Animal Husbandry
:
I. Housing Environment
ARnatismawlerreohoomussweedrseinmgaliyntinaisnteaidnloenssanstaeeplp,rwoixriem-amteesh12c-ahgoeusr sluigshpte/nddarekd caybcolvee(fclaugoerebsocaerndts.light) and ata temperatureof23 1C and a relative humidityof50 + 10%
2. Feedand Water
`Tap water was providedadlibitum. All rats were fed PMI Nutrition International, LLC
Certified
specified
RnuotdreitnitonLaalbrDeiqeuti"re5m0e0n2tschaonwd.toTbheeffreeeeodfisspgeucairfainetdeecdonbtyamtihneanmtasn.ufacturer
to
meet
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cMPany Sanitized. Doss not contain TscA Te
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~
3. Mdentification
DuDuoPmonlti11s5s57]
Ethaecchagrea.t wTahseaslassitg3neddigaitusniofquteheidneuntmibfeicratwieornentuamtbteooredwhoincthhewatasilroefcocradcehdroatn. a card affixed to
4. Health Monitoring Program
AfosllsopweicinfgipedroicnetdhuereHsasakreelpleLrafboorrmaetdorpyerainoidmicaalllhyeatlotehnasnudreenthvaitrocnomnetnatmailnamnotniltevoerlisngarperboeglroamw, the those that would be expected to impact the scientific integrity ofthe study:
+ `Waantdeorthsearmcpolnetsamairneanatnsa.lyzed for total bacterial counts, and the presenceofcoliforms, lead,
+ Feed samples are analyzed for total bacteria, spore, and fungal counts
Sabmyptlheecsagferwoamshferressh.ly washed cages and cage racks are analyzed to ensure adequate sanitation
rCeerqtuiifrieemdeanntismaanldfneoetd tiso uesxecde,edgusatraatnetdemeadbxyimtuhemmcaonnucfeancttruarteirontsoomfekeetyscpoecnitfaimeidnannuttrsi,tiionncalluding
sppreecsiefniceed ohfeathveysemectoanlts,amaifnlaatnotxsinb,eclholwortihneatmeadxhiymdruomcacrobnocnesn,traantdioonrgstaantoepdhobsypthhaetemsa.nufTahceturer
~~
`would not be expected to impact the integrity of the study.
`lTahbeoraantiomraylanhieamlatlhvaentedriennavriirano.nmeEnvtaalluamtoinoinotofrtihnegsperdoagtraadmidisnaodtmiinndiisctaetreeadnbyyctohnediattitoennsditnhgat affected the validity ofthe study.
D. Quarantine and Pretest Ufopro6ndaaryrsi.valThate HraastskewlelreLawbeoriagthoerdy,3 tthiemreastsduwreirneg rtehme opvreetdesftrpoemrisohdipapnidngexcaarmtionnesdadnadilqyuafroarnatniyned csliignniscoaflillylanpepsasr,einntjusriyg,nsoorfadbinsoeramsaelobrehianjvuiroyr.. The rats were observed daily for mortality and dOinsetahseeboarseinsojufrya,ctcheeptraatbslewebroedyrewleeaisgehdtfgraoinmsqaunadrafntrieneedobmy fthreomdecsliigninceaelloyfatphpearleabnotrsaitgonrsy oafnimal Veterinarian.
Company Sanilized. Does not contain TSCA cy --_--mT-- e ------
H1-02-5D3o5s7e:OBriaolpeGrasviasgteenScteuSdcyrienenRiatnsg
DuPont 11557
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E. Study Design
Substance Negative Control
Deionized water| Positive Controls
H-24019 H-24020 Test Substance H-25357
Vehicle
Dosage [Number of gkg)| Animals
Not applicable
10
Acetone/Com Oil| 10 10 Acetone/Com Oil| 20 10
None 1000 | 10
F. Assignment to Groups and Study Start
After the quarantine period, the rats were selected on the basesofadequate body weight gain, and freedom from any clinical signsofdisease or injury. The selected rats were arbitrarily assigned to each group.
After assignment to groups, each rat was housed individually. The rats were 7 weeks ofage at the timeof dosing. Dosing began on test day 1.
~
Rats that were not assigned to the study were released for other laboratory purposes, or were
sacrificed by carbon dioxide asphyxiation and discarded without pathology evaluation.
G. Dosing Material Preparation and Administration
1. Test Substance
H-25357 was administered neat. The amount of est substance each rat received was based on
the sir
body plate
weight collected on cach dayofdosing. The throughout the dosing procedure to maintain
test substance homogeneity.
was
stirred
on
a
magnetic
2. Positive Controls
Iotilw.aTshneecreatsisoaorfyatcoedtiosnseoltvoecHo-r2m4o0i1l 9waasnd20H:-820.40T2h0einamacoeutnotneeabcehforraet rseucsepievneddinwgasthbeamseidn ocnotmhe body weight collected on each dayofdosing and the suspension concentration. The rats were dosed atavolume 1 mL/100 g ofbody weight. The dosing preparations were stirred on a `magnetic stiplate throughout the dosing procedure to maintain homogeneity.
3. Negative Control
--~
Deionized water was chosen as the negative control. The rats were dosed at a volume of | mL/100 g ofbody weight. These rats were dosed in a separate room from the rats dosed with the
t"est substance opr espositive control*
Company Saniized. Does not contain TSCA
TTT
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DuPont11557
~~
H. Body Weights
All rats were weighed on each dayof dosing and weekly during the recovery period.
LI Mortality and Clinical Observations aCamgoen-sgitraetes xwaemrienactoinodnuscttoeddeattelcetamstoornicbeunddaiolry dtehardourgahtos uatntdhaebsntourdym.alAbteehvaevriyorweaingdhianpgp,eacraacnhcerat was individually handled and examined for abnormal behavior and appearance.
J. Collection and Analysis of Blood, Livers, and Fat
Attime points selected for blood sampling other than sacrifice days, approximately 1 mL of
blood was collected into EDTA tubes from the orbital sinus ofeach rat. Ras designated for
sacrifice fat were
were euthanized by collected according
carbon dioxide anesthesia and to the following schedules:
exsanguination
and
blood,
livers,
and
Group| Dosing Days| Tissue Collected
Sampling Time
1 1-10 |Blood 1 1-10 Blood
Test day 1 (2 hours post dosing) Test day 5 (2 hours post dosing)
1 1-10 |Blood, Liver, and Fat| Test day 10 at sacrifice (2 hours post dosing)
~~
min
1-10 Blood
1:10 |Blood
Test day 13
Testday 24
im 110 {Blood
Testday 52
m 110 | Blood, Liver, and Fat| Test day 94
wAesigmhuecdh. bTlhoeodfaatswpeoisgshitbslewwearse cuosleldecftoerdtihnetcoalEcDulTaAtiotnuboefsfaltuosarcirniefilceev.elsT.heThleivelrisvearnwdeifgathtwsere
twoetralebuosdeyd wfeoirgthhte.caTlhcuelabtliooondoffrfolmuoarlilnaetlsevwealssarnefdrifgoerrtahteedcaalncdultahteiolnivoerfslaivnedr fwaetiwgehrtereflraotzievne. to
"The blood, livers, and fat were appropriately packagedandshipped to Jackson Laboratory,
Deepwater, New Jersey where they remained frozen during shipping.
were
analyzed
for total
fluorine.
The
liver
and
fat
samples
`tTohrechtoctoalmbfulsuotriionne mceonttheondt,offtohlleowbeldoobdyaanndaltyississuewistahmp2lfelsuowraisdedieotnersemliencetdivueseilnegctaroWdiec.kbTohled
samples were decomposed or volatlized in the presenceofwet oxygen and swept through an
aoxqyu-ehoyudsraobgseonrbfilnagmesoilnuaticolnoasnedd qaunaarltyzzeadppwairtahtuas.flTuohreidceoimobnussetlieocntipvreoedlueccttrsodwee.reKcionlelteiccteadnailnysains
ofthe data evaluation
recived (ppm F in cach sample) of fluorine biopersistence.
was
performed
by
Haskell
Laboratory
personnel
for
--~ COTBARY An15a8 Mth mnt montain Tenn pe
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11.02D5o3s5e7;OrBailopGearvsiasgteenScteudSyrisnnRinsg ~~ K. Treatment of Fluorine Data
Dupont11557
Sadimnicneitshteertaeustnisufbosrtamncmeeakngd pdoossietifvoercalolnttreostlsmaheardiadlisf.ferPenrtopteorxliycictoynpdruofcitleeds,ikinwetaisc ncootmppaosrsiisbolnesto winassitcuoantdiuocnstewditihn vpamroileadrdounsietssrteoqauicrceodmtmhoeduasteeotefastnmoartmearliailzemdoldeosceu.larThweeidgohste-dniofrfemraelniczeastiaonnd was adjusted to an arbitrary normalized dose of 0.1 mmoles'kg.
nHe-g2a4t0iv1e9caonndtroHl-.24T0h2e0pweerrceenutosefdflausoproisnietiavnedcmoonltreocluslaarndweaidgohstionfgtdhieluteenstt swuabsstuasnecdeaasntdhepositive croencteriovlesdw(eprpemuFs)edfraosmpJroavcikdseodn bLyabtohreatsoproyn.sorF.orTthhee Wmeiacskubroelddttootraclhfmlueotrhionde,vatlhueebsawcekrgerouusnedd as fflruoomrienaeclhevsealmpilse0..2Tphpem.limTihtiosfiqutahnetilfiimciattoifodnet(eLcOtQi)onfo(rLtOhiDs)omfettihosdmies t0.h5odppamn,dawnadsasnuybtvraalcuteesd listed as less than 0.5 ppm were excluded from further treatment.
Swienrceectohnevedrotseadgefsraomndammoalsescutloaar wmoeliagrhbafsoirs.posIintiavdedictoinotnr,otlhseadnadtatewsetrmeatsetrainadladridfifzeerdedt,otahesidnagltea: wreefreerefnircset dcoosnevetroteadllforwocmoampmaeroisfotnesbtemtawteeerniaclobmapsiosuntodsmoilfldiimfofleersinogffflluuoorriinnee.coRntaewntf,luTohriededoisoens dmaotlaar(pdposmaFg)ewaenrdentohremnalniozremdalcioznecdenttor.2at0i.o1n mwielrleimcoolmebdionseedoftoayciteilvde tchoempmoonlenatr. (3FMin)alelqyuitvhaelents -- eoqfuaicvtailveentcsomcpaonnbeentcoimnptahretdisascuer.ossDectoamilpeoducnadlscuplratoivoindsedcatnhebecofnsoiudnedraitniAopnspelnisdtiexd iCn. The uM. Appendix C are observed.
NHo-n2c5o3m5p7aarntdmetnhteaplosaintailvyesicsonwtaroslscounsdiuncgtWeidnoNnonflluionriVneerdsaitoand4e.r0ivseodftfwraorme r(aPthsardsoisgehdtwCiotrhp, MphoaurnmtaacionkiVnieetwi,c CpAar)a.meWtienrNsofnrloimnesxopfetrwiamreentparlovdiatdae.d aAlmleaannasloysficsowmapsutcailncguldaetreidvuesding the iM equivalent in blood data.
a`TshseesmsaedxibmyuqumanotbisfeyrivnegdtceornmciennatlrealtiimoinniantibolnoobdlowoadshaClmf-alixfe((uTMy;edqauyisv)a.lenTth)e. pBoiiontpserisnicsltuednecde iwnas deleitmeirnmaitniaotniownaosfatchheieTv.e;d.werIentseemlaelcteexdpmoasnuuraelwlyasanddetienrcmliundeeddboynclaylcpouilnattsinagfitrheapbplaoroednatrlcoag--linear uthnedemro-stthec-coumrmveon(AmUeCa).ns AfoUrCe,xpwrheisscihngisisnitmerpnlayl tdhoesei.nteWgirtalhotfhbelcoaoldcucloantceednhtarlaf-tliiofne,ovtheerAtiUmeC, cisan bnoememxatlriazpeodlattoeddotsoein(fAinUiCtyIN(FA/UDC)INcFa)n bteo ruesfeldecttotcheomeplaimrienatthieorneloafttihvee ecxopmopsouurneds,ofdAiUffCeIreNnFt compounds and dosages.
L. Statistical Analyses
~~
Descriptive statistics (e.g. mean, standard deviation) were used.
CompanySanltzed. Does nol conlain TSCA CAL ATE
L0 H1o:02D-5Do3o5s7e:OOrBniaollpGGeroasvviaasgtgeeenScSettuuSddcyyrienennRaiatnsgs DuDoumpoenitis15s5y7 --~
RESULTS AND DISCUSSION
A. In-Life Toxicology (Tables 1-2, Figure 1, Appendices A-B)
iNnociddeeanttahlsaonccdunrortedt.estHasiubrsltoasnsceo-brseelratveedd.inTthweomreaatsndbuordinygwtehiesgthtudgyaiwnasosfcroantssiddoesreedd twoitbhethe test substance were higher than the negative control during the dosing and recovery periods. The t`hmeeadnosbiondgypweeriigohdttghaainntshoefwtehieghrattsgadionsoefdrawtisthdotsheedpowsiitthivtehecotnetsrtoslumbasttearnicael.s wDeurreinlgotwheerrdeucroivnegry period, the mean body weight gainofrats dosed with the positive control material H-24019 was rTaotwsedrotsheadnwtihtehwtehiegohtthgearipnoosfitriavtescdoonsterdolwmiatthertihael,teHst-2s4ub0s2t0a,ncwe.as hTihgehemretahnanbothdeywweeiigghhttggaaiinnooff rats dosed with the est substance.
B. Liver Weights (Table 3, Figures 2, 3, and 7)
~~
I. Test Substance
`tThhaen mteheannergealtaitvievecolinvierrolweriatgshton(ldiavyer1/0b.odyBywediagyht9)4,oftrhaetsmedaonserdelwaittivheHl-i2ve5r3w5e7igwhatsof2r4a%tshidgohseerd
with H-25357 was similar to the negative control.
2. Positive Controls
`The mean relative liver weightofrats dosed with oneofthe positive controls, H-24019, was 12%
higher on days 10 than the liver weightof ats dosed with the test substance, H-25357. 94, the weights were similar.
By day
`hTihgehemreaatndraeyla1t0ivtehlainvetrheweliigvehrtwoefirgahtts odfosraetds wdiotshedthweiotthheHr-2p5o3si5t7i.veBcyonidraoyl,94H,-2th4e02w0e,igwhatss w5e2r%e similar.
n`Tehgeatmievaencornetlraotlivgerloiuvpe.r wBeyigdhatyo9f4r,attshedomseeadnwrietlhatHiv-e24li0v1er9wweaisgh3t8of%ahtisghderosaetddawyit1h0Ht-h2a4n0t1h9e w24a0s2s0imwialsar8o8%thehingehgeartiovnedcaoynt1r0olthgarnoutph.e nTehgeatmieveancornetlraotlivgeroliuvpe.r wBeyigdhatyo9f4,rttshedwoesiegdhwtistwheHr-e similar
--_
t`Thhaenretfhoeren,egtahteirveelcatoinvterollisveartwtehiegehtnsdooffrtahtesddoossiendgwpietrhiotdhebuttestwesruebsstiamniclea,rHt-o2t5h3e5n7e,gawteirvee hciognthreorls
at the endof the recovery period.
CompanySanitized. Das,not contain TSCA cBy
-
L110.02D.5Do3o5ss7ee:OOrrBailloGGpeaarvvsaasgtgeeenScSteuuSddcyryieinennRaiRtnasgs --~ C. Fluorine Data
(Tables 4-9, Figures 4-9, Appendices C-F)
DuDuoPmolntis115s57
1. Factors Influencing Interpretation of Analysis
c`aTvheeadtastaanudsecdonisnitdheeraktiinoentsicaarneailmypsoirstwaentr.e dAerciovuepdlfeorfomcaonlsiimdietreadtisocnrseeonf, paanrdtitchuelraerfiomreposretvaenracle are (1)asingle dose level was used and kinetics may or may not be linear, (2) the kinetics apply `omnalyy itompbalcotodc,al(c3u)lsatteiaodnoy-fsttahtee tmearyminnoatl hhaalvf-elibfee.enAacmhoireveecdoamnpdle(t4e) tlihsetosfamcpolnesisdiezreatiisolnoswisansdh.own in Appendix C.
2. Positive Controls
`eTqhueivpaolseinttisveicnornattrbollosowdercoenHti-n2u4e0d1t9oarnisde Ht-h2r4o0u2g0h.outThthee Hd-o2si4n0g19pearnidodHa-n2d40m2a0ynnoortmahlaivzeerdepacMhed
steady-state (Figure (mean + $.D.)with
4A and 4B). The Cmax for H-24019 a terminal half-lifeof 42.2 days. The
was 1043.08 = 54.57 uM Cmax for H-24020 was
equivalents
t5h4e1.p4os5itiv5e0.c3o7nturoMls,eqbuliovoadlewnatss (smaemapnle=d5a.tD7.)tiwmiethpoaitnetrsmtihnraoluhgahlof-ultifteheofst1u5d.y1,dwaiyts.h oFnolry 4caocfh of
them occurring post-dose. The small sample size and analytical variability should be taken into
~~ aexcpcoosuunrtewrheesnultuisnigngfrtohemdaenroirvemdaltiezremdindaolshealwfa-lsifdeesfocrricboemdpabryaAtiUvCeIpNuErp/oDseasn.dTwhaesttohtealbianstiesrnfaolr
comparison between positive controls and the test substance. The AUCINF/D for the fluorine
component was 5.22 x 10 for H-24019 and 8.15 x 10 for H-24020.
"The concentrationsoffluorine in the livers on day 10 from rats dosed with the positive control materials were 4802.15 and 866.67 uM equivalents for H-24019 and H-24020, respectively. By day 94, the concentrations were 1292.92 and 17.10 uM equivalents.
"The concentrationsoffluorine in the fat on day 10 from rats dosed with the positive control `materials were 194.46 and 57.25 iM equivalents for H-24019 and H-24020, respectively. By day 94, the concentrationoffluorine in the fat from rats dosed with H-24019 was 15.38 pM equivalents. There was no detectable fluorine by day 94 in the fat from rats dosed with H-24020.
3. TestSubstance
`The H-25357 normalized uM equivalents in rat blood rose rapidly and appears to have reached
reach steady-state (Figure 4C). The Cmax for H-25357 was 15.74: 0.88 jtM equivalents (mean
94 SwDe)r.e aTbeorvmeintahle hlailmfi-tloiffeqcuoaunltidfincoattiboen.accBulroaotedlwyacsalscualmaptleeddbaetcasuesveennotismaemppolienstsonthdraoyusgh5o2utand
the study, with only four of them occurring post-dose. The small sample size and analytical
variability should be taken into account when using the derived terminal half-life for comparative
--_
purposes. The total internal exposure resulting from a AAUCINF/D and was the basis for comparison between
normalized dose was described H-25357 and positive controls.
by The
AUCINF/D for the fluorine component of H-25357 was 8.61x10% as compared to AUCINF/D
Company Saniized. Does not contain TSCA Ci -_--
202105D-3oD5os7see:OOrBaliloCpGeuarvvsaaiggsteeeSnStctueuddSyycirienneRRnaaittnssg
00000
DuDbuPoonneti1i1s55s7y
~~ dveatleucetsaobfle5f.l2u2oxr1i0ne ianndth8e.b1l5oxo1d0*onfodraHy-s254201a9nda9n4d Hin-2r4at0s2d0o,sreedspweictthivtehley.tesTthseurbestwaansce.no
Levelsoftotal than the levels
fluorine in livers
in livers from rats dosed from rats dosed with the
with the positive
test substance, H-25357, were lower control materials. The total fluorine
concentration in the liver from rats dosed with H-25357 was 114.94 uM equivalents at day 10
awenrde6.a9p6pr1oxMimeaqtueilvyal4e2ntxshaitgdheary(94d.ay F1o0r) tahnedpaopsiptriovxeicmoantterloyl 1H8-62x40h1i9g,hetrhe(elnidvoefrsctouncdeyn)trtahtainonHs-
25357. For H-24020, the liver concentrations were approximately 8x higher (endof dosing) and
2x higher (endof study) than H-25357.
sLiemviellasroofntodtaayl 9fl4uooritnheeilnefvaetlsfrinomfartatfsrodmosreatdswdiotshetdhewittehsttshuebpsotsaintcievewceornetrloolwemartoenridaalyH-1204b0u1t9. "The levels in fat from rats dosed with the test substance were higher than levels in fat from rats dosed with the positive control material H-24020. The fluorine concentration in the fat from rats dosed with the test substance was 107.79 uM equivalents on day 10 and 13.59 pM equivalents on day 94. The fluorine concentrationof oneofthe positive control materials, H-24019, was approximately 2x higher than H-25357 on day 10. The fluorine concentrationofthe test substance, H-25357, was approximately 2x higher than the fluorine concentrationofthe other positive control material, H-24020. By day 94, the fluorine concentration of H-24019 was similar to the fluorine concentration in rats treated with H-25357. There was no detectable -- fluorine by day 94 in the fat from rats dosed with H-24020. "The JM equivalents in the liver and fat were higher than levels in the blood.
CONCLUSIONS
Rats dosed for 10 consecutive days with 1000 mg/kg H-25357 exhibited no mortality, no test substance-related clinical signs, and no body weight effects. Liver weights were affected in rats dosed with the test substance.A steady-state for fluorine in the blood appeared to be achieved during the 10-day dosing period with the test substance. Dose-adjusted areas under the curve (AUCINF/D) for positive controls, H-24019 and H-24020, were approximately 600x and 95x the AUCINF/D for the test substance.
Under the conditionsofthis studs, there was limited absorption and no retention of fluorine in
the blood following dosing with H-25357. Administrationofthe test substance, H-25357, to
male rats for 10 consecutive days resulted in some absorption and retentionoffluorine in the
liver and fat. However, levels in blood and liverinrats dosed with H-25357 were generally
Tower than the fluorine levels in rats dosed with the positive control materials, H-24019 and
H-24020. Levels in fat in rats dosed with H-25357 were lower than at day 10 but similar to the
levels at day 94 in rats dosed with the positive control H-24019. Levels in fat from rats dosed
with the test substance were higher than levels in fat from rats dosed with the positive control
--~
H-24020.
Company Seized.DossnotcontainTSCA EY
Tis:
O H1-02-5D3D o5s7e: OBo riaolpGes arvsaigse eenScteuOdSycrienennRiantgs,iGavageS0 udyinDDuR uPoomnaiti11ss5s57y
~
RECORDS AND SAMPLE STORAGE
SNpeewcairmke,nDs(eliafwaaprpel,icoarblaet),IrroanwModautnat,aainndRtehceofridnsalMraenpoargtewmielnltb,eWrieltmaiinnegdtoatn,HaDseklealwlarLaeb.oratory,
--
~~
Com;"PEnY Sanltized. Daes notcontain Tsp,cay
-
H1-02-5D3o5s7e:OrBaioGpearviasgteenScteudSycrienenRiantgs,
DuPont11557
PN
TABLES
--~ -
Companyhw Saucon.+ woOSe tos Cin 4SUA CB) 20
H1-02-5D3o5s7e: OrBailopGearvsaigsteenScteudSycrieneRnaitnsg --
DuPont 11557
TABLE 1
MEAN BODY WEIGHTS
Negative Control DAYS ON TEST Deionized Water
MEAN BODY WEIGHTS (g) Positive Controls
__H-24019 H-24020
Test Substance H-25357
1
189.6
1844
184.1
1928
2
1955
1892
187.8
199.1
3
2046
1995
197.8
208.0
4
211.7
206.4
204.8
2173
H
21
2162
2125
230.1
6
2250
220
2160
236.6
7
2352
2294
236
2450
8
2423
2337
2269
253.0
9
248.3
2404
2342
260.1
10
257.0
246.5
243.0
2668
17
2033
290.1
297.4
311.4
2
3255
3133
338.6
3458
~
31
3593
348.4
3819
377.1
38
3809
370.8
404.9
406.2
45
407.4
403.2
4344
4422
52
420.5
428
460.6
468.1
59
436.4
439.6
483.1
486.7
66
-
-
-
-
67
4528
455.6
502.7
503.9
73
4726
480.1
525.6
520.7
80
489.6
496.5
542.1
536.8
87
491.7
5122
546.2
5392
94
S117
524.6
570.5
551.9
~ Indicates the animals were not weighed
~ -
CompanySanitized.Doesnotcontain TSCA CBI
IA 10Doose OrDs CawvescSud--yoin atns _lGuagsSuyinRoDwuoawn1n1is5s5s7y --~
TABLE 2
MEAN BODY WEIGHT GAINS
DOSING
MEAN BODY WEIGHT GAINS (g)
Negative Control
Positive Controls
DAYS ON TEST_ Deionized Water H-24019
H-24020
Test Substance H-25357
1-5
325
31.8
284
373
5-10
349
303
30.5
36.7
1-10
67.4
62.1
58.9
74.0
RECOVERY
~
MEAN BODY WEIGHT GAINS (g)
Negative Control
Positive Controls
Test Substance
DAYS ON TEST_ Deionized Water H-24019
H-24020
H-25357
10-17 17-24 24-52 5294
36.3 322
95.0 91.2
43.6 232 109.5 101.8
544 412 1220 109.9
44.6 34.4 1223 83.8
10-94
254.7
278.1
321.5
285.1
--_
Campa Sanzed. ows not contain TSCA CB
-- =
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TABLE 3
DAYS ON TEST 10 9%
MEAN BODY AND LIVER WEIGHTS
NEGATIVE CONTROL - DEIONIZED WATER
WEIGHT (2)
Body WeightAbsolute Liver Weight
Mean Relative Liver Weight (Liver/Body Weight)
2588 sig
10814 17.868
0042 0035
DAYS ON TEST
POSITIVE CONTROL - H-24019 WEIGHT (g)
Absolute
Mean Relative Liver Weight
Body Weight Tiver Weight (Liver/Body Weight)
~
10 9%
239 52456
14205 19.296
0038 0037
DAYS ON TEST 10 9
POSITIVE CONTROL - H-24020 WEIGHT (3)
Absolute
`Mean Relative Liver Weight
Body Weight Liver Weight (Liver/Body Weight)
243.1 5705
19.174 19.59
0079 0.034
DAYS ON TEST
TEST SUBSTANCE - H-25357
WEIGHT (g)
Body WeightAbsoluteTiver Weight
`Mean Relative Liver Weight (Liver/Body Weight)
10 9
2662 5519
13851 19.681
0052 0036
PN
CompanySanilized. Doesnot contain TSCA CBI
-=
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000
DDuuPeomntu1s15s57
TABLE4
DAYS ON TEST
MEAN BLOOD FLUORINE LEVELS
MEAN FLUORINE LEVELS (ppm)
Negative Control
Positive Controls
Test Substance
Deionized Water __ H-24019
H-24020
H-25357
1
5
0.60"
=<
2.60 (0.1)
3132 (L)
9.40 (2.4)
7492 (1.0)
LIL (0.1)
319 02)
10
110
6800 35) 6176 (55) 287 (03)
13
-
5398 (12) 2952 (49) 227 (03)
2 52
0s
3962 34) 1118 29) 228 (06)
*
256 (2.1) 226 (Ly *
94
=
12.60 (1.2)
0.85 (0.1)
:
=
b OStnaendoafrSd vdaelvuieast.ioFno(u5ro.fDtih)se ivnaplaureesntwheerseesb.elow the lit of quantification (LornOondG etect) able,
--
4 MAelal nvaolufe2sowfertheebSevlaolwuetsh.eTLhOrGeeoofnothne-vdaeltucetsawbeerebelow theLOQ.
TABLE 5
MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE
DAYS ON TEST
MEAN FLUORINE CONCENTRATION (uM F Equivalents)
Positive Controls
Test Substance
H24019
F-24020
H-25357
1
3692 (LI)!
6667 (17.5)
479 (0.6)
5
478.77 (17.6)
541.45 (50.4)
1574 (09)
10
1043.08 (54.6)
446.09 (39.7)
1407 (1.4)
13
827.38 (19.0)
212.46 (35.6)
10.87 (1.4)
2
606.46 (53.1)
79.57 (20.8)
1097 (32)
52
35938 (327)
1493 (1.7)
2
%
190.77 (19.2)
471 0.5)
-
-
ba MSteaanndaorfd2doevfitahteioSnv(alSuDes.. isThinrepaeroefntthheesevsa.lues wre below the limitofquantification (LOQ). All values were below the LOQ.
Company Sanitized, Dogs notcortainTSCA CBF ----------
10 H10:0D2-5Do3os5s7ee:OOrrBaailloGpGeuarvvsaiasggteeenSctueudSycirineeRntaitsnsg DDuuoPmotnits11s55y7 --
TABLE 6
MEAN LIVER FLUORINE LEVELS
MEAN FLUORINE LEVELS (ppm)
Negative Control DAYS ON TEST Deionized Water
Positive Controls __H-24019 H-24020
Test Substance H.25357
10
090 (02 31234 (19.7) 11980 (35) 2204 28)
9%
078 (00) 8424 (14) 256 (13) 152 02)
a Sundard deviation ($0) is in pareieses.
TABLE 7
MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
MEAN FLUORINE CONCENTRATION (uM F Equivalents)
--_
Positive Controls
Test Substance
DAYS ON TEST
H24019
24020
H25357
10 9
480215 (303.8) 120292 (114.1)
866.67 (25.5) 17.10 98)
114.94 (14.9) 696 (L1)
& Standard deviation (S.0.) i in parentheses.
-- -
Company Sanlzsd. Boss not conscacnag
=
0 20105D-3oD5os7see:OOrraBailloGpGeuarvvsaiasggteeenSSctueuddSyyeiiennnRRiaantsgs DDuuePmonnti11s5s5y7 --_
TABLE 8
DAYS ON TEST
MEAN FAT FLUORINE LEVELS
MEAN FLUORINE LEVELS (ppm)
Negative Control
Positive Controls
Test Substance
Deionized Water __H-24019 H-24020
H-25357
10
+
12.84 (1.7) 8.10 (LI) 21.06 (3.8)
9%
+
120 (0.3)
=
2.78 (08)
ab ASltlanvdaalrudesdewveiraetiboenl(o5w.thD.i)limiintpoafrqeunatnhteisfeisc.ation (LOQ) or non-detectable.
TABLE 9
MEAN FAT FLUORINE CONCENTRATION NORMALIZED TO DOSE
MEAN FLUORINE CONCENTRATION (uMF Equivalents)
~~
Positive Controls.
Test Substance
DAYS ON TEST H-24019
24020
H-25357
10
19446 (6.8)
5725 (1.8)
109.79 (19.8)
9
1538 (4.1)
>
13.59 (42)
a ASlulnvdaalrudesdewveiartiboenl(owS.t)heisliimnitopafreqnutahnetsiefsi.cation (LOQ) onondetectable
-
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LH1o-02-D5D3oo5s7e:OOnrBaiiloOGpeanrvasagigseetSnScuteuddSyycriiennenRRiaantgss, --~
DDuuPonto. 11s557
--_
FIGURES
--_ -
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~ 3g
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--_
APPENDICES
-
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1120-5D3o5s7e:OrBailopGearvsaigsteenScteudSycrieneRnisng --
Dupont 11557
--
APPENDIX A
Individual Body Weights
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H1-02-5D3o5s7e: OrBailoGpearvsaigseenScteudSycrieneRnaitnsg --
INDIVIDUAL BODY WEIGHTS
ABBREVIATIONS: SD - sacrificed by design
EXPLANATORY NOTES
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DuPont11557
--
APPENDIX B
Individual Clinical Observations
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~
APPENDIX C
`Terms and Calculations Factors Influencing Interpretation of Kinetic Analysis
--~ ------
CompanySanitized.Doesnotcontain TSCACE rr
H1205-3D5os7e: OBriaolpGeasviasgteenScteuSdcyrienenRaitnsg --
Dupont 11557
TERMS AND CALCULATIONS
Terms:
Active
Fluorine containing compound
9% Active
`The %offormulation that is made upoffluorine containing components
Mol Wt Active,
`The molecular weight ofthe fluorine containing components (g/mole)
Formulation Dose: `The mgof formulation given per kg ofanimal body weight
%F in Active
`The % fluorine in the fluorine containing components of the formulation (weight basis)
Mol WtE
`The molecular weight of fluorine g/mol
~~ Compound Calculations:
Dose Active (mgkg)
The mgoffluorine containing compound administered per kg of animal body weight. = (% active/100) x Formulation Dose
Dose Active (mmole/kg) The mmole of fluorine containing compound administered per kg of animal body weight = dose [mg/kg] / Mol Wt Active [mg/mmol]
Dose F (mg/kg)
`The mg Fluorine administered per kg ofanimal body weight =(%F in active/100) x Dose Active [mg/kg]
Dose F (mmol/kg) =`ThDeomsemoFl[emgo/fkfgl]uo/riMnoeladWmtinFis[tmerge/dmmpoerl]kg ofanimal body weight
Molar Ratio (Active/F) The molesoffluorine containing compound per mole of fluorine: = Dose Active [mmol/kg] / Dose F [mmol/kg]
Formulation Dose: The formulation dose that would be required to administer the amount
Normalization Factor
o=fac(tNiovremnaeleidzeedd
tdoosaecohifevAecttihveen[omrmmoall/ikzegd]
dose / Dose
Active
[mmolkg])
--_
x Formulation Dose
Company Sanitizod. Docs not contain TSCA CBI
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H1205D3o5s7e: OrBailopGearvsaigsteenScteudSycrieneRnisng --_
TERMS AND CALCULATIONS
Individual Animal Measurement:
ppm F
`The ppm fluoride measured
Dupont. 11557
Individual Animal Calculations:
ppm F minus
Bkg 0.2 ppm
`The ppm fluoride measured minus the background fluoride measured
in control animal. In this case the value was established at 0.2 ppm.
ppm F
normalized to 0.1 mmol/kg Dose
`The ppm fluoride minus background that would be expectedifthe
active dose was 0.1 mmol/kg insteadof the actual active dose. This assumes linearity between administered dose and blood fluorine levels, but is needed because different dosesofactive were used in the
study.
= (0.1 [mmol/kg]/ Active dose [mmol/kg]) x (ppm F in blood `minus background)
~
pmolar equivalents of The pmolar [nmol/L] concentration of fluorine containing compound
active
based on the ppm fluorine normalizedto 0.1 mmol/kg active dose.
`This assumes that all fluorine is derived from the fluorine-containing
component in the formulation. Note: 1 ppm -- I mg/L. = (Normalized ppm [mg/L] fluorine/Mol WF [mg/mmol]) x
`molar ratio active/F [mmol active/mmol F] x 1000 pmol/mmol
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11.02-5D3o5s7e:OrBailopGearvsaigsteeSntceudSyerieneRnaiinsg --~
DuPont-11557
FACTORS INFLUENCING INTERPRETATION OF KINETIC ANALYSIS
Considerations:
- The data used for kinetic analysis was from a limited screenand extrapolation should be done cautiously.
- Sample size is low - Analytical data used without validation - Steady-state not reached - Terminal phase maynotbe reached - Some compounds are mixtures of fluorinated compounds - Different active and formulation doses were sed - Different vehicles were used to deliver formulations - Each compound may have very different potency for producing toxicity
Assumptions: (May or may not bejustified in all cases) - Fluorine concentrations are linear with respect to dose ~ - Analytical method is appropriate for all typesof compounds - Elimination kinetics can be determined based on total fluorine rather than on concentrations of - iBnadcikvgidruoaulncdoFmlpuoonreinnetsis 0.2 ppm - %F data is the % Fluorineofthe active (Fluorine containing component(s) in the formulation) - Molecular weight is the molecular weightofthe active component in the formulation
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11.02-5D3o5s7e:OBriaolpGerasviasgteenScteuSdcyrneenRaitnsg
DuPont11557
--_
APPENDIX D
Individual Fluorine Levels in Blood
-- -
Company SankDoics snoetcodn.anTSCAcay
11205-D3o5s7e: OrBailoGpearvsaigsetnScteudSycrieneRnaitnsg
~~
Data for H-24019
DuPon-11557
Given:
Mol Wt. Active (g/mole):
497
%F in Active:
65
Formulation Dose (mg/kg):
10
Mol Wt. F (g/mol):
19
% Active (F Containing) in Formulation: 100
Calculated Values: Dose Active (mg/kg):
Dose Active (mmole/kg):
Dose F (mmol/kg):
10
0.020
0.342
Molar Ratio (Active/F): ~~ 0.059
Dose F (mg/kg):
65
Test Rat Day
Number _ Sample
ppmF in
Blood
ppm Fin
Blood Minus Bkg
0.2 ppm.
ppm F in Blood
Normalized to 0.1 mmoles/kg
Dose
pmolar
Equivalents of Active in
Blood
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1
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11.43 11.93 11.93
36.92 38.46
35.38 36.92 36.92
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646466991110
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5
322
5
327
10
7s
10
70.5
10
66.9
10
62.5
10
68.6
32091.9
311 320 325
71.3 70.3 66.7 62.3 68.4
114498..6600
154.57 159.04 161.53
354.36 349.39 331.50 309.63 339.95
446630..0080
478.46 492.31 500.00
1096.92 1081.54 1026.15 958.46 1052.31
CompanySentined.Sesnotconta Ts coy
-
11.02-5D3o5s7e:OrBailopGearvsaisgteenScteudSycrienenRiantgs,
Dupont 11557
~~
ppm Fin ppm Fin Blood molar
Rat
Test ppmF Blood
Normalized to
Day in MinusBkg ~~ 0.Lmmoleskg
Equivalents of Active in
Number Sample Blood 0.2 ppm
Dose
Blood
Group III
646915 13 550
548
646916 13 553
55.1
27236
843.08
27385
847.69
646917 13 522
520
258.44
800.00
646918 13 538
536
646919 13 536
534
26639 265.40
824.62 821.54
Group III
646915 24 389
387
19234
595.38
646916 24 438
436
21669
670.77
646917 24 376
374
185.88
575.38
646918 24 354
352
174.94
541.54
646919 24 424
22
209.73
649.23
Group Ill
~
646915 52 232
23.0
646916 52 203
201
646917 52 259
257
646918 52 249
27
646919 52 235
23
11431
35385
99.90
30923
127.73
395.38
12276
380.00
11580
358.46
Group III
646915 94 133
13.1
65.11
201.54
646916 94 117
11s
57.16
176.92
646017 94 129
127
63.12
19538
646918 94 110
108
53.68
166.15
646919 94 141
139
69.08
21385
--
Company Sanitized. Dos not contain TSCA CBI
oo
1120-5D3o5s7e:OrBailoGpearnsgissenScteudSycrieneRnaitnsg
Duron 11557
~
Data for H-24020
GiveMno:l Wt. Active (gimole):
26
F9%orAmcutliavtei(oFn CDoonsteai(nmign/gk)g)i:n Formulation: 21000
%FinActive
Mol Wt. F (g/mol):
19
CalcDuolsaeteAdctViavleue(sm:g/kg): Dose Active (mmole/kg):
Dose F (mmol/kg):
2
Molar Ratio (Active/F): 0.065
0047 Dose F (mgke):
138
0.726
Test Rat Day
Number _ Sample
ppmF in
Blood
ppm Fin
Blood Minus Bkg
0.2 ppm_
ppmF in Blood
Normalizedto 0.1 mmoles/kg
Dose
pmolar
Equivalents of Active in
Blood
Group I
646921
1
106
10.4
--~
646922
1
10.7
10.5
646923
1
92
9.0
646924
1
53
5.1
646925
1
1.2
11.0
22.15 237 19.17 10.86 23.43
75.36 76.09 65.22 36.96 79.71
Group I 646921 646922 646923 646924 646925
Group
646921 646922 646923 646924 646925
5
78.7
5
832
5
77.0
5
66.1
5
69.6
10
63.0
10
69.1
10 60.3
10
62.5
10
539
85 83.0
76.8 65.9 69.4
62.8 68.9
60.1 623 537
167.21 176.79 163.58 140.37 147.82
133.76 146.76 128.01 132.70 114.38
568.84 601.45 556.52 477.54 502.90
455.07 499.28 435.51 451.45 389.13
~--
CompanySane,0008notcontainTc cg
To
H1205-D3o5s7e: OrBailoGpeanviasgteenScteudSycrieneRnaitnsg
DuPont11557
--~
ppm Ein ppm Fin Blood molar
Rat
Test ppmF Day in
Blood
Normalizedto
MinusBkg ~~ 0.Immoleskg
Equivalents of Active in
Number Sample Blood 0.2 ppm
Dose
Blood
Group III
646926 13 348
346
73.70
250.72
646927 13 300
298
63.47
21594
646928 13 237
25
5006
17029
646929 13 337
35
7136
24275
646930 13 254
22
53.68
182.61
Group 11
646926 24 119
17
24.92
8478
646927 24 104
102
2173
7391
646928 24 81
79
1683
5725
646929 24 157
155
3.02
1232
646930 24 98
96
2045
69.57
Group IIT
~~
646926 52 25
23
646927 52 17
Ls
646928 52 13
11
646920 52 40
38
646930 52 18
16
490
16.67
320
1087
234
797
809
27.54
341
11.59
Group ITI
646926 94 08
06
646927 94 <05
*
646928 94 <05
646920 94 09
071
646930 94 <05
*
128
435
*
*
-
*
149
507
*
*
"Below
LOQ (Limit ofQuantification)
-- CompanySanitized, DogsnotconteleTSCAcg;
-__-- m--m_$kmmmy
H1205-3Do5s7e:OrBaioGpevrasigsetenScteudSycrieneRniinsg
DuPon11557
~
Data for H-25357
Given:
--
Mol Wt. Active (g/mole): Formulation Dose (mg/kg):
850000 %F in Active:
10
1000 Mol Wt. F (gimol): 19
9% Active (F Containing) in Formulation: 19
Calculated Values:
Dose Active (mg/kg):
DDoossee AFc(tmimvoel(/kmgm)o:le/kg):
190
21.20x0010*
Molar Ratio
(Active/F):
Dose F (mgkg):
22x10%
19.0
Test ppmF Rat Day in Number Sample _ Blood
ppm Fin ppm Fin Blood
Blood
Normalizedto
MinusBkg ~~ O.mmolesikg
0.2 ppm
Dose
pmolar Equivalents of Activein
Blood
Group 1
665500 1 128
11
483.16
568
~
665501 1 1.02
08
366.84
432
665502 1 113
09
41605
489
665503 1 102
08
366.84
432
665505 1 Ll
09
402.63
474
Group
665500 5 317
30
665501 5033s
32
665502 5 292
27
665503 5 33
31
665505 5 321
30
1328.68
15.63
140921
16.58
121684
1432
1386.84
1632
1346.58
1584
Group
665500 10 271
25
112289
1321
665501 10 331
31
1391.32
1637
66502 10 279
26
1158.68
13.63
665503 10 292
27
1216.84
1432
665505 10 264
24
1091.58
1284
--_--
Ex
escca
11.02-5D3o5s7e: OrBaiopGearvsaisgteenScuedSycrieneRnoitnsg
DuPont11557
--~
ppm Fin ppm Fin Blood mmolar
Rat
Test ppmF Blood Day in MinusBkg
Normalized to 0.0 mmoleskg
Equivalents of Activein
Number Sample _ Blood 0.2 ppm
Dose
Blood
Group III
665506 13 23
21
665507 13 221
20
939.47 89921
11.05 10.58
665508 13 244
22
1002.11
1.79
665509 13 252
23
1037.89
1221
665510 13 186
17
742.63
874
Group Il
665506 24 264
24
1091.58
1284
665507 24 2712
25
1127.37
1326
665508 24 133
11
505.53
595
665509 24 205
19
827.63
974
665510 24 268
25
1109.47
13.05
Group Il
665506 52 <5
*
*
*
~~
665507 52 <5
*
*
*
665508 52 <5
.
*
*
665509 2 <5
*
*
*
665510 52 <s
.
*
*
Group III
665506 94 <5
*
M
*
665507 94 <5
*
M
*
665508 94 <5
*
*
*
665509 94 <5
*
*
*
665510 94 <5
*
*
*
* BelowLOQ(LimitofQuantification)
-_----m--------
CompanySaniizad.DoesnotcontainTs cay
2105-3D5o7se: OrBailoGpearvsaigseenScteudSyreinenRiantsg --~
DuPont.11557
~~
APPENDIXE
Individual Fluorine Levels in Liver
~
Company.Sanitzoq,D0 notcontain ry cor
= -_--
H1-02-5D3o5s7e:OrBailopGearvsaigsteenScteudSycrieneRnaitnsg ~
Data for H-24019
DuPont 11557
Given:
Mol Wt. Active (g/mol):
497 9%F in Active:
65
Formulation Dose (mg/kg):
10
Mol Wt. F (g/mol): 19
% Active (F Containing) in Formulation: 100
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Dose F (mmol/kg)
10
Molar Ratio (Active/F): ~~ 0.059
0020 Dose F (mgke):
65
0342
Test ppmF Rat Day in Number Sample Liver
ppm Fin Liver MinusBkg 0.2 ppm
ppm Fin Liver Normalized to 0.1 mmoleskg
Dose
molar Equivalents of Activein
Liver
Group
646910 10 3209
3207
--_
646911 10 3340
3338
646912 10 3186 3184
646913 10 2816
2814
646914 10 3066
306.4
1593.88 1658.99 1582.45 1398.56 152281
4933.85 5135.38 4898.46 4329.23 471385
Group III
6461S 94 856
854
646916 94 759
757
646917 94 815
873
646918 94 780
738
646919 94 942
94.0
424.44 376.23 433.88 386.67 467.18
1313.85 1164.62 1343.08 1196.92 1446.15
--_
CompanySambcec.Does notcontaiTnscacay
-=
11.02-5D3o5s7e:OrBailoGpearvsaigsteenScteudSycrieneRnaitnsg ~
Data for H-24020
DuPont.11557
even:
Mol Wt. Active (g/mole):
26 %F in Active:
6
Formulation Dose (mg/kg):
20 Mol WLF (mol: 19
% Active (F Containing) in Formulation: 100
Calculated Values: Dose Active (mg/kg): Dose Active (mmol/kg): Dose F (mmolkg):
20 Molar Ratio (Active/F): 0.065
0047 DoseF (mgke):
138
0726
Test ppmF Rat Day in Number Sample _ Liver
ppmFin Liver MinusBkg 0.2 ppm
ppmFinLiver Normalized to 0.Ummoleskg
Dose
pmolar Equivalents of Activein
Liver
Group 1
6621 10 1183
181
251.55
855.80
G62 10 1227
1225
26093
887.68
~~
646923 10 1143
1141
646924 10 1216
1214
243.03 258.58
82681 879.71
66925 10 1221 1219
25965
883.33
Group Il
646926 94 18
16
66921 94 12
10
66928 94 22
20
646920 94 47
4s
646930 94 29
27
341
11.59
213
725
426
14.49
9.59
32.61
575
1957
~ --
`Company Sanitized.DosnotcontTSaCAiCBnI --
H1.02-5D3o5s7e:OrBailopGearvsaigsteenScteudSycrieneRnaitnsg
DuPont.11557
~~
Data for H-25357
Given:
--
Mol Wt. Active (g/mole):
850000
%F in Active:
10
Formulation Dose (mg/kg):
1000
% Active (F Containing) in Formulation: ~~ 19
Mol Wt. F (g/mol):
19
Calculated Values:
Dose Active (mg/kg): Dose Active (mmole/kg):
Dose F (mmol/kg):
190 22x10*
1.000
Molar Ratio
(Active/F): Dose F (mg/kg):
22x10% 19.0
Test ppmF
NRumabter SaDmapyle _ Liinver
ppm Fin
Liver
Mi0n2usppBkmg.
ppmF in Liver
Normalized to
0.1 mmDoolsees/kg.
pmolar
[Equivalents
of ALcitvievre in
Group
665500
10
222
220
~
665501
10
26.59
264
665502
10
20.43
202
666655550035 1100 2119.815
211879
9851.05 11806.05
9050.26
98648555..5236
115.89 138.89 106.47
19193..4975
Group II
665506 94
1.84
16
733.68
8.63
665507 94
1.49
13
577.11
6.79
666655550089 9944 11.3316
112
459168..5985
65.8141
665510 94
1.61
14
630.79
7.42
~
`CompanySankizod.Do nots contsainTSCAcay
eee
11.02-5D3o5s7e;OBriaolpGearsviasgteenScteuSdcyrienenRaitnsg --~
DuPont 11557
PN
APPENDIX F
Individual Fluorine Levels in Fat
~~
apySmitcot DossrtcentinVCE!
i
1120-5D3o5s7e:OriaolpGerasviasgteenScteudSycrieneRnaitnsg
~~
Data for H-24019
Dupont 11557
Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg):
% Active (F Containing) in Formulation:
Calculated Values:
Dose Active (mg/kg):
Dose Active (mmole/kg): Dose F (mmol/kg):
497 10
100
10
0.020 0.342
%Fin Active:
65
Mol Wt. F (g/mol):
19
Molar Ratio (Active/F): 0.059
Dose F (mg/kg):
6.5
Test ppmF
NRuambter SDaampyle Fiant
ppm Fin Fat
Mi0n2usppBmkg
ppmFin Fat Normalized to
0.1 mDmooslees/kg
pmolar Equivalents
of AcFtaitve in
Group I
646910
10
144
142
646911
10
14.9
14.7
rm
646912 10 109
10.7
646913 10 116
14
646914
10
124
122
70.57 73.06
53.18
56.66
60.63
218.46 226.15
164.62
17538
187.69
Gr6o4u6p1sINI 94 13
Li
646916
94
LI
09
646917
94
13
11
646466991189 9944 0L8s
01.36
547
1692
4.47
13.85
547
16.92
26.4968
290.2030
--_
-_--
BompanySanttized.Doesnotcontain vseacar
2105-3D5o7se: OrBailopGearvsaigsteenScteudSycrieneRnaitnsg
Dupont 11557
~
Data for H-24020
Given:
Mol Wt. Active (g/mole):
426
Formulation Dose (mg/kg):
20
% Active (F Containing) in Formulation: 100
--
%F in Active:
6
Mol WL F (mol: 19
Calculated Values: DDoossee AAccttiivvee ((mmgm/oklge)/:kg): Dose F (mmol/kg):
020047 MDoolsaerFRa(tmigo/k(gA)c:tive/F): 01.30865 0.726
Test ppmF Rat Day in Number Sample Fat
ppm Fin Fat MinusBkg 0.2 ppm
ppm Fin Fat Normalized to 0.1 mmoleskg
Dose
pmolar Equivalents ofActive in
Fat
Group I
646921 10 62
60
646922 10 85
83
2
646923 10 87
85
646924 10 88
86
646925 10 83
81
1278
43.48
17.68
60.14
18.11
61.59
18.32
23
1725
5870
Group Il
646926 94 ND
ND
ND
ND
646927 94 ND
ND
ND
ND
646928 94 ND
ND
ND
ND
646929 94 ND
ND
ND
ND
646930 94 ND
ND
ND
ND
ND Nondetecuble.
--~ --_--
CompanySanttized.Does notcontTSaCAiCBn}
H1-02-5D3o5s7e;OrBailoGpearvsaigsteenScteudSycrieneRnaitnsg
--~
Data for H-25357
DuPont11557
swe:
Mol Wt. Active (g/mole):
850000 %F in Active:
10
Formulation Dose (mg/kg):
1000 Mol WeF (gmol): 19
9% Active (F Containing) in Formulation: 19
Calculated Values:
Dose Active (mg/kg):
DDoossee AFc(tmimvoel(/mkmgo)l:e/kg):
190
21.20x0010
Molar Ratio
(Active/F):
Dose F (mgkg):
22x10%
19.0
Test ppmF Rat Day in Number Sample Fat
ppm Fin ppm Fin Fat
Fat
Normalizedto
MinusBkg ~~ O.mmoleskg
0.2 ppm
Dose
nmolar Equivalents ofActive in
Fat
Group
--_
663500 10 23.06
29
1022684
12032
665501 10 2436
242
10808.42
127.16
665502 10 183
18.1
8097.37
95.26
665503 10 1585
15.7
7001.32
8237
665505 10 23.73
235
10526.58
12384
Group III
665506 94 284
26
665507 94 314
29
665508 94 326
31
665509 94 328
31
665510 94 139
12
1181.05
1389
131526
15.47
1368.95
16.11
1377.89
1621
532.37
626
--~
BompenySantized,DoesnotconTtSaCAicBn;
-