Document Qknr7MLmOqEogmqaz40dXzR1E
AR 226 _ 3276
Duwpoonmt 1155
AR R26_ 3276
~
TRADE SECRET
Study Tite H-24743: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Laboratory Project ID: DuPont-11558
AuTHOR: Carol Finlay, B.A.
STUDY ComPLETED ON: April 7, 2003
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PERFORMING LABORATORY: E.I. du Pont de Nemours and Company
EHlakstkeolnlRLoaabdo,raP.t0o.ryBfooxr
Health 50
and
Environmental
Sciences
Newark, Delaware 19714-0050
Company Sani# Dos not contain rcp ogy
--_ --re ------------Pag-- e Tor-- s ------------
~ CERTIFICATION
`We, the undersigned, declare that this report provides an accurate evaluationofdata obtained from this study.
rin DaSl LR i r orldeen
etm
Cadnast ER_-- IE
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mpgs ----
2104-7D4o3se;OBriaolpGearsviasgteenScteuSdcyrienenRiatnsg
DuPont11558
--_ TABLE OF CONTENTS
Page
CERTIFICATION conned
LIST OF TABLES corms
LIST OF FIGURES worms
LIST OF APPENDICES wcrtonsnrasmsssssssossssnsssssssssssssonsS
STUDY INFORMATION coms
STUDY PERSONNEL cosas
SUMMARY cvnmsrmmmmmensssssmsummmmmsssssmssmmnd
INTRODUCTION csr
1
MATA.ERTIesAtLSSubAstNanDceManEdTHPOOSIDtISVEc COMIOIS.....vev vrnrrersvenrens sensnsrerne 1111
Bu C..
TAEDSISLPECHIUESSDc AIYv oo rn s et rs
11 11
--_
DD. E.
QSEUYADTESAAIgNd.HcPIvRNrIErGSrtnrsr rossnssesssssmn smossmsmssmsnss msmsosmsnennr11n23
F. ASSIGAMEN 10 GrOUDS A SIUAY SI... G.Dosing Material Preparationand AMnISUAON................ocer
13 rere13
LO I. Mortalityand Clinical ODSGIVAHONS ves
1 14
J. Collectionand AnaloyfsBIi00sd, LIVers,ad Fat K. TreaOftFImUOeNEnt Dat.
......u.cucureceremeeo1n4 15
L. Statistical ABLYSCS vrs smmnemsrsmsnssemsenosennren 16
RESAUr LTLSIAfeNTDOXDICIOSICOBUYSc SION cc o s rreo1111
Be C..
LIVE WEBS FIUOINE Data
cvo orrsssr sssssr snsnemo mssnons snsnsi nsososo eneonn eo
1 18
CONCLUSIONS ocrmrmemmsssmsssssmmmssmssssssnsmmsasssanss 19
RECORDS AND SAMPLE STORAGE cvs 2)
TABLES corms21
FIGURES ccrsmssrmrmemmssssmmssmsmmssssssssssssssssss3n8
APPENDICES ocrmsmammssssmssmmmsmsmssssssssssssansssssn3n9
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`Company Saniized. Does not contain TSCA CBI 3
H1-02-4D7o4s3e;OBriaolpGearsviasgteeSntcuedSycrienenRiantgs
DuPont-11558
--_ LIST OF TABLES
Page
I. MEAN BODYWEIGHTS...
wemmm--
A
2
2. MEANBODY WEIGHT GAINS... c----------
conmndlh
3. MEANBODYANDLIVERWEIGHTS.d.........
s---- SE
2
4. MEANBLOODFLUORINE LEVEL..... sm--
smn
5. MEANBLOOD FLUORINE CONCENNTORMRALAIZTEDTIOODONSE cc
25.
6. MEANLIVER FLUORINELEVELS............
----
oni
ltl
7. MEANLIVER FLUORINECONCENNTORMRALAIZTEDITOODONSE ... communi
8. MEAN FAT FLUORINELEVELS .........cooo.
commit
cri
27
9. MEAN FATFLUORINECONCENNTORMRALAIZTEDITOODOSNE...
mn
LIST OF FIGURES
Page
~
I. MEAN BODYWEIGHTS.......
crmem--
commmmmmmm--
2. CCOONMTRPOALR..I.SON OF MEAN RELATIVE LIr VER WE-- IGHTS-- : TEST-- SUBSTANCE AND NwEGoArTImVsE
3. CCOOMNPTARROILSSO.N OF MEAN RELATIVE LIVER WBEIG--HTS: TEST SUBwSTsANC--E AND POSB ITIVE T
4. MICROMOLAREQUIVALENTSIN RAT BLOOD...
hm
32
5. N10O-RDMAAYLOIRZAELDGHA-2V4A7G43EA.N..D. POSITIVE CO--N--TROL BLOODenAaUCINF/D RESULarTenING FROM A 3
6. MEANLIVER FLUORINECONCENNOTRMRALAIZETDTIODOOSEN .....
comm 2S
7. C COMPOARINSONCOFFE REOLRAN HT-I2V4T E74L3IAVRENRDWNAEEIGGATHTTIAVIENCDOO MNETARNNOLLIVERvFLUcORrINE
36
8. MEAN FAT FLUORINE CONCENNOTRMRALAIZTEDTIOODOSNE.
women
37
9. CCOONMCPEANRTIRSAOTNIOOFNMNEOARNMABLLIOZOEDD,TMOEDAONSELI.V.E.R, A.N...D. MEAN FApT FrLUOmRINmE. sm--
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`Company Sanitized. Donotecontsain TSCA CBI
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1H02.4D7o4s3e:OraBilopGearvsaigseteSntcuedSyeirn eRnaitnsg
DuPont11558
LIST OFAPPENDICES
Page
A. INDIVBOIDYDWEUIGHATS.L..
em
"0
B._ INDCILINV ICALIOBD SERVUATIAONSL...
wmm----
wn
C._ TANEARLMYSSIAS.ND CALCULATIONSwFnACpTOrRmS --INFLUENCING INTERA PRETATION OF KINETIC 6
D._ INDFILUOVRINIELEDVELUSINABLOLOD.
--
mn 8
E. INDIFLUV ORINIELEDVELUSINAL LIVER......
swan
I
F. INDIVIDUALFLUORINELEVELSIN FAT .
cml
19
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Company Sanitized. Does not contain TSCAcel
pr
Ivonne owas
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STUDY INFORMATION
Test Substance
nlsonce,YN
Ssnonm Codes: (SMD, H-24743
Submiter's Notebook Numbers: [SENN]
HaskellNumber: 24743
J -- Stns Tests --
Synonyms/Codes: + H-24019
yl
Haskell Number: 24019
D i EroSpomrw sons ell ea es
~
rosin Conn
STUDY INFORMATION (Continued)
Synonyme/Codes: + H-24020
Haskell Number: 24020
~
(--
Spon oELaaPo de Neos nd Conga Wilmington, Delaware 19898
StudyIntiated/Completed; October 10, 2002/(see report cover page)
~
conpny Send cs conn TSCA
H1-02-4D7o4s3e;OrBailoGpearvsaigseenScteuSdcyrienenRaitnsg
DuPont 11558
--_ STUDY PERSONNEL
Study Director: Carol Finlay, B.A. Management: Scott E. Loveless, Ph.D. Primary Technician: James C. MackaIyI Fluorine Data Analysis: Paul M. Hinderlter, Ph.D. Management: Matthew S. Bogdanffy, Ph.D., D.AB.T. Toxicology Report Preparation: Sean M. Callaghan, B.A. Management: Nancy S. Selzer, MS. Laboratory Veterinarian: Thomas W. Mayer, D.V.M., A.CLAM.
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CompanySanitized. Does not contain TSCA CBI
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11204-D7o4s3e;OrBailoGpearvsaigsteenScteudSyrcinenRiatnsg
Dupont 11558
-- SUMMARY
`aTchceumobujleactteivienofatmhaimsmsatluidaynwasyssttoeme.vaTluwaotegtrhoeuppostoefnt5ialmafloer Hra-t2s4e7a4c3h twoebree adbossoerdbbeyd aganvdatgoe with
t3h0e0omtgh/erkgg/rdoauypowfaHs-m2a4i7n4t3aifnoerd1w0itchoonustecduotsiivnegdfaoyrsa. nOandedigtrioonuaplw8a4sdasyacsr.ifBilceododonwaDsayco1l0l,ecatnedd
owenitgehsttsdaaynsd 1cl,i5n,ic1a0l,s1i3g,ns24w,e5r2e,raencdor9d4e.d Ltihvreorusghaonudtftahtewdeorseincoglalnecdterdecaotvsearcyripfeircie.odsB.ody
Amdgd/iktgi/odnaayll)ya,nadnHeg-a2t4i0v2e0co(n2t0romlgo/kfgd/ediaoyn)i,zweedrweatteers,teadnads 2depsocsriitibveed cfoonrtrHo-l2s4,7H4-32.40B1lo9o(d1,0liver,
and and
fat samples retention in
were these
analyzed tissues.
for
total
fluorine
content
to
determine
test
substance
absorption
`Nmoeadneabtohdsyowcecuirgrhetd,gaainndsonforacltisnidcoaslesdigwnisthatHt-r2i4b7u4t3teodwetrhee tseismtilsaurbsttoatnhceenweegraetiovbesccrovnetdr.ol rTahtse dcounrtirnogltmhaetedroisailnsgwaansd lroewceorvedruyripenrgiotdhse.doMseinagnpbeordioydwtehiagnhtthgeawienoigfhrtagsaidnoosfedrawtsitdhotsheedpwoistihtitvhee pteosstitsiuvbestcaonncter.olDmuarteirnigaltshewraescohviegrhyerpetrhiaond,thtehewemiegahnt gbaoidnoyfweriagtshtdogasiendowfirtahtsthdeotseesdt swuibtshtatnhcee.
~ Fcoonrtrtohles,puarilpodsoeseosfcweormepanroirnmgalaibzseodroptnioanmaonldarrebtaesnist.ionTohfethtoetatlesftlusourbisnteanincecatochthteispsouseitwivaes.
ceoxnpsriedsesreeddaassuaMpeerqcueivnatlaegnetosf.thAesfalmueoraisnuerdeeloifvteorteadlidnotsheeiandtmhienibsltoeorde,dadnosaer,caaunnddaelrl uthneitcsuwrevree
(estimated to infinity) was calculated for each test material. The AUCINF/D for the fluorine
component of H-24743 was 1.07x 10, compared to AUCINF/D valuesof 5.22x10 and
8.15x10* for H-24019
that was much less for
and H-24020, respectively. This parameter
H-24743 than for the positive controls.
indicatead
total
dose
in
blood
Tthhaen mteheannergealtaitvievecolnivterrolweriatgshton(ldiavyer1/0b.odyBywediagyht9)4o,ftrhaetms edaonserdelwaittivheHl-i2ve4r7w4e3igwhatsof3r1a%tshidgohseerd wdiotshedH-wi2t4h74H3-2w4a0s1911w%ahsi4gh1e%rhtihgahnertahendnefgoartiHv-e2c4o0nt2r0olw.asTh9e3%mehainghreerlaotnivdealyiv1er0 wtehiagnhtthoe.frats annegdaHti-v2e4c0o2n0trwoelrgerosuipm.ilaBrytodatyhe9n4e,gtahteivmeecaonntrreollatgirvoeulpi.verThweeriegfhotrseo,flriavetrswdeoisgehdtswoifthaHts-2d4o0s1e9d pweirtihotdhaentdesattstuhbesteanndcoeftwhereerheicgohveerrtyhpaenritohde. negative controls at both the endofthe dosing
e`qThueivcaolnecnetnstroantidoanyof1f0luaonrdi2n.e26inktMheclqiuviervsalfernotms roantsddaoys9e4d.wiOtnhtHh-e2l4a7st4d3awyaosfd2o7s.i5n2g,uMthe mean HmaMtereiqaulisvawleernet acpopncreonxtirmaattieolnys o17f4f-lfuoolrdin(eH-in24t0he19l)ivaernsdof31r-aftoslddo(sHe-d24w0it2h0)thgerepaotseirtitvheancovnatlruoels in -- r5a7t2sxtraenadte8dxwitthhe tfhleuotreisntescuobnsctaenncter.atBioyndianyra9t4s,ttrheeatfelduowriitnhe Hc-on2c4e7n4t3r.atTihoenrsewfeorree,arpapsrotxriemaatetdelwyith
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Company Sanitized. Does not contain TSCA CBI
H1-02-4D7o4s3e:OrBailopGearvsaisgteenScteudSycrienenRiantgs,
DuPont11558
~
Htr-e2a4te0d1w9iotrhHH--2244704230.absorbed and retained considerably more fluorine in the liver than rats
e`Tqhueivfallueonrtisneocnondcaeynt1r0atainodn1i0n.t8h7eufaMt ferqouimvraaltesntdsosoenddwaiyth94t.heTthesetfsluubosrtiannecceonwcaesnt4r9a.t1i0onuoMfone
ofthe positive control materials, H-24019, was approximately 4x higher than H-24743 on day
10. day
The fluorine concentrationofthe other positive control material, H-24020, 10 to the fluorine concentration of the test substance, H-24743. By day 94,
was the
similar fluorine
on
c`TohnecreentwraastinoonodfetHec-t2a4b0le19flwuaorsinseimbiyladratyo9t4heinfltuhoerifnate cfornocmenrtatrsatdioosnedinwriatths ttrheeapteodsiwtiitveh cHo-n2t4r7ol43,
H-24020.
UwintdherH-t2h4e7c4o3n,dibtuitonwsaosftqhuiiscksltyuedlyi,mfilnuaotreidn.e wTahseeavmioduennttsionftfhleubolroionde dinurtihnegltihveerpsearnidodofaftdforsoimng rtahtast dthoesreedwwaisthevtihdeetnecsteosfubssotmanecerewteernetihonioghfefrltuhoarninleevienltshienltihveerbalnooddf,ata.ndFltuhoerirenseulltesveilnsdiicnatthee tfhatewbelroeodgeannedrallilvyerswliegrhetlcyohnisgihdeerraobrlsyimliolwaerrtothtahnelpeovseiltsiivne rcaotnstrdoolsemdatweiritahlst.heFplousoirtiinvee cloenvterloslisn, H-24019 and H-24020.
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`Company Sanitized. Dos not contain TSCA CBI --~
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2104-7D4os3e;OrBailopGearvsaigseenScteuSdcyrienenRiatnsg
DuPont11558
--~ INTRODUCTION
`The objectiveofths study was to define the potential of H-24743 to be absorbed and to bioaccumulate in a mammalian system, as indicated by analytical determinationoftotal fluorine in blood, liver, and fat. The test substance was compared to 2 positive controls that were materials previously shown to bioaccumulate in mammals. `The daily dosage of300 mg/kg for the test substance was selected based on existing toxicity information and the results ofa rangefinding study. Groupsoffive rats were dosed at 0 (control) or 300 mg/kg for 6 consecutive days. The rats dosed with the test substancehad an overall body weight gainof24 grams compared to 28 grams for the control rats. The dosage of 300 mg/kg was chosen for the study andwas expected to produce less than a 10% difference in `mean body weight over 10 days when compared to the negative control.
MATERIALS AND METHODS
A. Test Substance and Positive Controls
--~
p`oTshiettievset scounbtsrtoalnsc,e,H-H2-420417943a,ndwaHs-2s4up0p2l0i,edwebryetshuepspploinesdobryatshae cslpeoanr,socrolaosrlwehsistelisqouliidd.s.ThTehe test
substance and positive controls appeared to be stable under the conditionsofthe study. No
evidenceof instability, such as a change in color or physical state, was observed.
B. Test Species Male Crl:CD(SD)IGS BR rats were received from Charles River Laboratories, Inc., Raleigh, NwoitrhththCiasrsotlrianian.anTdheitsCrsuli:taCbDi*li(tSyDw)iItGhSreBsRpecrtattwoalsonsgeelveicttye,dhoanrtdihneebsass,iasnodfleoxwteinnsciivdeenecxepeorfience spontaneous diseases.
C. Animal Husbandry 1. Housing Environment
RAantismawlerreohoomussweedrseinmgaliyntinaisnteadinolenssanstaeeplp,rwoixriem-amteesh12c-ahgoeusr sluigshpte/nddaerkd caybcolvee(fclaugoerebsocaerndts.light) and ata temperatureof23 + 1Cand a relative humidity of 50 + 10%
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`Company Sanltized. Does not contain TSCA C8
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L2104D7o04s3e:OO-rnBailloDGGpaeorvvsoaaigsgteeeSsSntcuueddSeyyeiirnnceRRnaaittnssg
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2. Feedand Water
DuDubPoonti11s558
`CTearptiwfaiteedrRwoadesnptroLvaibdDeideta"d5l0ib0i2tucm.howA.ll Trahtes wfeeerdeifsegduParMaInteNeudtrbiytitohne Imnatneurfnaatcitounrael,r LtoLmCeet specified nutritional requirements and to be freeofspecified contaminants.
3. Identification
tEhaecchagraet.wTahseaslsasitgn3eddigaitusnoifqtuheeidneuntmibfeicratwieornenutamtbteooredwhoincthhewatasilroefcocracdhedroant a card affixed to
4. Health Monitoring Program
Athse sfpoelcliofwiiendginprtohceeHdausrkeeslalreLapbeorrfaotromreydapneirmiaoldihceaallltyhtaonednseunrveirtohnamtecnotnatlammionnainttorlienvgelpsraorgerabme,low those that would be expected to impact the scientific integrityof the study:
+ Water samples are analyzed for total bacterial counts, and the presenceofcoliforms, lead, and other contaminants.
+ Feed samples are analyzed for total bacterial, spore, and fungal counts.
--~
+ Ssaanmiptlateisonfrboymthferecsahgleywwaashsehresd. cages and cage racks are analyzed to ensure adequate
rCeerqtuiifrieemdeanntismaanldfneoetd tioseuxsceed,edgusatraatnetdemead xbiymtuhemmcaonnucfeancttruarteirontsoomfekeetyscpoecnitfaimeidnannuttrsi,tiionncalluding sppreecsiefniceedofhtehaveysemectoanltsa,maifnlaantotxsinb,eclholwortihneamteadxhiymdruomcacrobnocnesn,traantdioonrgstaantoepdhobsyphtahetemsa.nufTahceturer would not be expected to impact the integrityofthe study.
`lTahbeoraantiomraylahneiamlatlhvaentdereinnavriiraonn.meEnvtaalluamtoinoinotofrtihnegsperdoagtraadmiidsnaodtmiinnidisctaetreedanbyyctohnediattitoennsditnhgat~~ affected the validity ofthe study.
D. Quarantine and Pretest
Upon arrival at Haskell `quarantined for6 days.
Laboratory, the rats were The rats were weighed 3
removed from shipping times during the pretest
cartons and period and examined
mdoaritlaylfiotryaannydcsliignincsoalflyilalpnpeasrs,enitnjsuirgyn,soorfadbinsoeramsealorbeihnajvuiryo.r.The rats were observed daily for
dOinsetahseeboarseinsjoufray,ccteheptraatbslewebroedyrewleeiagsehdt fgraoinmsqaunadrafnrtieneedobmy ftrheomdecsliinginceaelolyftahppearleabnotrsaitgonrsy oafnimal --_ Veterinarian.
Company Sanitized. Does not contain TSCA C8! --_--Te------
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DuPont 11558
--
E. Study Design
Substance
Vehicle
Dosage | (mgkg)|
Negative Control
Deionized water| Not applicable
Positive Controls
H-24019 Acctone/Com Oil| 10
H-24020 Acetone/Com Oil| 20
Test Substance
H-24743
Deionized water| 300
[Number of Animals
10 10 10 10
F. Assignment to Groups and Study Start
Affrteeerdothmefqruoamraanntyincelipneirciaolds,itghnesorfatdsiwseearseesoelreicntjeudryo.ntThheebasseleescotfeaddreatqsuwaetreebaordbiytrwaeriilgyhtasgsaiignn,ed to cach group.
Athfetetriamesosfigdnomseinntg.to Dgorosuipnsg,beeagcahnraotnwtaessthdoauys1e.d individually. The rats were 7 weeksofage at
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sRaactrsiftihcaetdwbeyrecanrobtoansdsiiogxnieddetaostphheysxitautdiyownearnedrdeilsecaaserddefdorwiotthhoeurtlapbaotrhaotloorgyypeuvraplousaetsi,ono.r were
G. Dosing Material Preparation and Administration 1. Test Substance
Ham-o2u4n7t4o3ftweasstmsiuxbesdtawnictehedaecihonraitzerdewcaeitveerdswoasanbaacsceudraotne tvhoelbuomdeycwoeuilgdhtbecoaldlmeicntiesdteorneeda. chTdhaey obfoddoyswienigghatn.d Tthheemmiixxttuurreecwonacsensttriarteiodno.n aThmeagrnaetstiwcersetrdpolsaetdeattharovuoglhouumtetohef1domsLi/n1g0p0rogceodfure: to maintain homogeneity.
2. Positive Controls oIitlw.aTshneecreatsisoaorfy taocedtiosnseoltvoecHo-m24o0il19waasnd20H:-802.40T2h0einamaoceutnotnecabcehforraet rseucsepievneddiwngasthbeamseidnocnotmhe. bdoosdeydwaetaighvtocloulmleect1 emdLo/n1e0a0chgodfabyoofdydowseiignhgt.andThtheedsoussipnegnpsrieopnacroantcieonntsrawteirone.stiTrhreedroantsawere magnetic stir plate throughout the dosing procedure to maintain homogeneity.
--_ Company Sanitized. Does not contain TSCA C81
-YY
LH1o-02-D4D7oo4s3e;OOrnBailloGGpeuarvasagigseteSetnScuteuddSyycirinenReRnaitsnsg
DDuubPoonti1s1558
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3. Negative Control
mDLei/o1n0i0zegdofwabtoedrywawesicghhto.seTnahessteheratnsegwaetrievedcoosnetdroiln. aTsheeparraattsewreoroemdofsreodmathte rvaotsludmoeseodfw|ith
the test substoraponsictivee controls.
H. Body Weights All rats were weighed on cach dayofdosing and weekly during the recovery period.
IL Mortality and Clinical Observations Caamgoen-sgitraetsexwaemrienactoinodnuscttoeddeattecletasmtoornicbeunddalory dtehraodurgahtosuatntdhaebsntoudrym.alAtbeehvaevriyorweaingdhianpgp,eacraacnhcerat `was individually handled and examined for abnormal behavior and appearance.
J. Collection and Analysis of Blood, Livers, and Fat
bAltotoidmweapsoicnotlslescetleedctiendtofoErDblToAodtusbaemsplfirnogmotthheeorrtbhitaanlssaicnruisfoicfe dcaaycsh,raatp.prRoaxtismadteesilgyna1 tmedLfoofr
--~
asancdriffaitcweewreerecoelultehcatneidzaecdcobrydcinagrbtoontdhieofxoildleoawniensgtshcehseidaulaensd: exsanguination and blood, livers,
Gop 1
1-10
Tissue Collected
Sampling Time
[Blood
Test day 1 (2 hours post dosing)
1 1
1-10 1-10
|Blood |Blood,
Liver,
and
Fat
|
Test Test
day day
$ (2 hours post dosing) 10 at sacrifice (2 hours
post
dosing)
m 1:10 {Blood
Test day 13
m 110 {Blood mt 1-10 {Blood
Test day 24 Testday 52
im 1-10 |Blood, Liver, and Fat Test day 94
Awesigmhuecdh. bTlhoeodfaatswpeoisgshitbslewweares ucosleldecftoerdthientcoalEcDulTaAtiotnuboefsfaltuosracirniefilceev.elsT.heThleivlerisvearnwdeifgathtwsere wtoetralebuosdeyd fweoirgthhte. caTlhcuelabtliooondoffrfolmuoarlilnreatlsevwealss arnefdrifgoerrtahteedcaalncdultahteiolniovefrlsiwveerrewferiogzhetn.relTahteive to Dlieveeprwsaatnedr,faNt ewewreJearpsperyowprhiearteeltyhpeyacwkeargeedanaanldyzsehdipfopredtortealfrfilgueorraitneed.toThJeaclkisvoenr aLnadbofraattsoraym,ples remained frozen during shipping.
t`Tohrechtoctoalmbfulusotriionne mcoenttheondt,offtohlleowbeldoobdyaanndaltyississuewistahmpalfelsuowraidsedieotnersmeliencetdivueseilnegctaroWdiec.kbTohled ~ soaxmyp-lheysdrwoegreendfelcaomempionsaecdloosrevdoqluaatrltizzeadppianrtahteusp.reTshenecceoomfbwuesttiooxnypgreonduacntdsswweerpetctohlrloeucgthedainn an
TT ---- Company Sanitized. Does not contain TSCA CAI
LH1o-02-D4D7oo4s3e;OOnrBaiiloGGpeaorvvsaiagsgteeenSScteuudSdycyriienenRnaRitnasgs
DDuPuoneo-11s555
aqueous absorbing solution and analyzed with a fluoride ion selective electrode. Kinetic
~
paenarlsyosninseolftfohreevdaaltuaarteicoenoivfedfl(uporpimneFbiinopeearcshisstaemnpcel.e) was performed by HaskellLaboratory
K. Treatment of Fluorine Data
tSoinacdemitnhiestteesrt asuubnsitfaonrcme magn/dkpgosdiotsiveefcoornatlroltessthamadtedriifaflesr.entPtrooxpiecriltyy cproonfdiulecst,edit kwiansetnioct possible cnoormmpaalriizsaotnisoninwsaistucaotnidonusctweidthinvaurmioeldadrosneistsrteqouiarcecdotmhmeoudsaetoef taesntomramtaelriizaledmdoolseec.ulTarhewediogshetdifferences and was adjusted to an arbitrary normalized dose of 0.1 mmoles/kg,
nHe-g2a4t0iv1e9caonntdroHl-.24T0h2e0pweerrceentuosfedfalsuoproisnietiavnedcmoonltreocluslaarndweaidgohstoinfgthdieluteenstt swuabsstuasnecdeaasndthe puosseidtaisvereccoentirvoelds(wpeprmeuFs)edfarosmpJraocvkisdoendLbaybotrhaetsoproyn.soFro.r tThheeWmiecaksbuorleddttoortaclh fmleutohroinde,vatlhuees were bwaacsksgurboturnadctfelduforrionme eleavcehlsiasm0p.l2ep.pmT.heTlhiimsitoisftqhueanltimiifticoaftdieotnec(tLiOonQ)(LfOorDt)hoifs tmheitshmoedtihso0d.5apndpm, and any values listed as less than 0.5 ppm were excluded from further treatment.
Swienrceectohnevedrotseadgefsroamndammoalsescutloaar mwoeliagrhtbfaosrisp.osIintiavdedictoinotnr,otlhseadnadtatewset rmeatsetrainadladridfifzeerdedt,otahesidnagtlae
--~
droefseersenwceeredofsiersttocoanlvleorwtceodmfpraormisaomngboeftwteeesnt mcaotmerpioaulnbdassiosftdoimffielrliinmgolfelsuoorfinfelucoornitneen.t.RaThwe
fFliunoarlildyetjhoenmdoaltaar(dpopsmagFe)awnedrenotrhmeanlinzoerdmacloinzceednttraoati0o.n1wmeirlelicmoomlebidnoesde toofayciteilvdethceomppmoonleanrt(.1M)
eAqpupievnadleinxtsCo. faTchteivueMcoemqupiovnaelnenttisnctahne bteisscuoe.mpaDerteadilaecdrcoaslscucloamtpioounsncdasnprboevfioduenddthien
considerations listed in Appendix C are observed.
NHo-n2c4o7m4p3aarntdmetnhteaplosaintailvyesicsonwtaroslscounsdiuncgtWeidnoNnonflluionriVneerdsaitoand4e.r0ivseodftfwraorme r(aPthsardsoisgehdt wCiotrhp,
Mountain View, `pharmacokinetic
CA). WinNonlin software provided parameters from experimental data.
a meansofcomputing derived All analysis was calculated using
the
JM
equivalent in blood data.
`aTshseesmsaedxibmyuqumanotbisfeyrivnegdtceornmciennatlrealtiimoinniantibolnoobdlowoadhsaClm-alfxe((uT;M;,edqauyisv)a.lenTth)e. pBoiionptesrisnicsltuednecde iwnas ldienteearrmeilniamtiinoantoiofnthweasT;acwheierveeds.elecIntteedrmnaalnueaxlploysuarnedwiansclduedteedrmoinnleydpobiyntcsalacfutleartaipnpgatrheentbllooogdatirmeea,-uinsdtehre-tmhoes-tcucrovemm(AoUnC)m.eaAnsUCfo,r wehxpircehssisinsgiminptleyrntahle dionstee.graWloitfhbltoheodcaclocnucleantterdahtailof-nliofvee,rthe AAUUCCIcNaFn nboeremxatlriazpeodlattoeddotsoein(fAiUniCtIyN(FA/UDC)INcaFn)bteo uresfeldecttotchoemeplaimrienatthieorneolfattihvee ecxopmopsouurnesd.of ~~ different compounds and dosages.
times Company Sanitized. Does notcontain TSCA CB
S H1:02-4D7D o4s3e;OroBailoGpeawrvsaigsteO enScteudu SycrieneRl naitnsg GevegeSudyinDkDuuPaobntos11s558
--
L. Statistical Analyses
Descriptive statistics (e.g. mean, standard deviation) were used.
--~
--~
CompanySanitized.Does not contain TSCA car
TT
--
H24743: Biopenistence Screening
A0DowOnl_GevigeSudyinpRwea mnssss
--~
RESULTS AND DISCUSSION
A. In-Life Toxicology
(Tables 1-2, Figure 1, Appendices A-B)
No deaths occurred. Hair loss observed in one rat during the recovery period was not considered to be test substance-related because it was. only seen in one rat. The mean body `weight gainsofrats dosed with H-24743 were similar to the `negative control rats during the
dosing and recovery periods. Mean body weight gain of rats dosed with the positive control
`materials was lower during the dosing periodthan the weight gainofrats dosed with the test substance. During the recovery period, the mean body `weight gain ofrats dosed with the positive control materials was higher than the weight gain ofrats dosed with the test substance.
B. Liver Weights (Table 3, Figures 2, 3, and 7)
1.
`Test Substance
`The mean relative liver weight (liver/body weight) ofrats dosed with H-24743 was 31%higher
~
than `with
the negative control rats on day 10. H-24743 was 11%higherthan the
By day negative
94, the control,
mean
relative
liver
weightofrats
dosed
2
Positive Controls
`The mean relative liver weightsofrats dosed with one of the positive controls, H-24019, were similar on days 10 and 94 to the liver weightsofrats dosed with the test substance, H-24743.
`The mean relative liver weightofrats dosed with the other `positive control, H-24020, was 44% `higher at day 10 than the liver weightofrats dosed with H-24743, By day 94, the weights were similar.
`The mean relative liver weight of ratsdosed with H-24019 was 38% higher at day 10 than the
`wnaesgsaitmivielacornttorotlhegrnoeugpa.tiBveycdoanytr9o4l,gtrhoeupm.eaTnheremlaetaivne rleilvaetrivweeilgivhetrowfreaitghstdoofseradtswidtohseHd-2w4it0h19H-
24020 was 88% higohnedary 10 than the negative control group. By day 94, the weights were `similar.
pTtehhreairnoedtf.hoeren,egtahteirveelactoinvterollisveartwbeoitghhttsheofernadtosftdohseeddowsiitnhgtpheertieosdt asnubdsattantchee,eHn-do24f74th3e,rweecroevehriygher
Pa
SompanySaniized. Doss not contain TSCA ay
a
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C. Fluorine Data
~
(Tables 4-9, Figures 4-9, Appendices C-F)
1. Factors Influencing Interpretationof Analysis
ca`vTheeadtastaanudsecdonisnitdheeraktiinoentsicaarneailmypsoirstwanetr.e dAerciovuepdleforofmcoansliidmeitreadtisocnrseoenf,paarntdictuhlearerfiomrpeosretvaenracle
a10rebl(1o)oad,s(i3n)glsetedaodsy-eswtaatse umsaeyd naontdhkaivneetibcesenmaacyhioervmeda,yannodt(b4e) ltihnecasra,m(p2l)ethseizkeinisetliocswaapnpdlymaonyly
impact calculationof Appendix C.
the
terminal
half-life.
A
more
complete
listofconsiderations
is
shown
in
2. Positive Controls
`eTqhueivpaolseinttisveincornattrbollsoowdecroenHti-n2u4e0d1(90ainsdeHt-h2r4o0u2g0h.outThtheeHd-o2si4n0g19pearnidodHa-n2d40m2a0ynnoortmhaalivzeed uM
erqeuaicvhaeldensttsea(dym-esatnat+e (SF.iDg.u)rwei4tAahantedr4mBi)na.lThahlef-Climfae xoffo4r2.H2-d2ay4s0.1TwhaesC1m0a4x3.f0o8r4H-5244.50720uwMas
o5f4t1h.e45po+si5t0i.v3e7cuonMtroelqsu,ivballoeondtswa(smseaam+nple5d.0a.t) 7wittihmeatpeorimnitnsatlhrhoalufg-hloifuetotfhe15s.t1uddya,ysw.itFhoornelayc4hof
tachceomunotccwuhrreinnguspionsgt-tdhoesed.erTivheedstmearlmlinsaalmhpallef-sliifzee faonrdcaonmaplayrtiactailvevapriuarbpiolsietsy.shTohueldtobtealtainkteenrnianlto
~~
cexopmopsaurriesornesbulettiwnegefnrpoomsiatinvoermcaonltirzoeldsdaonsdetwheastedsetsscurbisbteadncbey.ATUhCeIANUFC/IDNaEn/dDwafosr tthheebfalsuiosrifnoer
component was 5.22 x 10 for H-24019 and 8.15 x 10 for H-24020.
Tmahteercioanlcsenwterraeti4o8n0s2o.f15flaunordin8e66i.n6t7heulMiveerqsuiovnaldeanyts10fofrrHo-m2r4a0ts19doasneddHw-i2t4h0t2h0e,proessipteicvteivceolnyt.rolBy day 94, the concentrations were 1292.92 and 17.10 uM equivalents.
m`Tahteercioanlcsenwterraeti1o9n4s.o4f6 falnudor5i7n.e2i5nWthMe feaqtuoivnadleanyts10fofrrHom-2r4a0ts1d9oasnedd Hw-i2th40t2h0e,porseistpeicvteivceolnyt.rolBy
day 94, the equivalents.
concentration of fluorine in the fat There was no detectable fluorine
from rats by day 94
dosed in the
with H-24019 was fat from rats dosed
15.38 with
uM
H-24020.
3. Test Substance
`stTahteeH(-F2ig4u7r4e34nCo).rmaTlhiezeCdmuaMx efoqruiHv-a2le4n7t4s3iwnarsat4b.l3o9od+ro5s.e66raupiMdleyquainvdalaepnptesar(sMteoarnea#chSsDte)adwyi-th
awittehrmoinnlaylfhoaulrfo-lfitfeheomf 9.o5ccduaryrs.ingBplosoto-ddowsea.s saTmhpelsemdaaltlsseavmepnletismiezepoainndtsantahlryotuigcahlouvtartihaebisltiutdyy,
should be purposes.
taken into The total
account when using the derived internal exposure resulting from
terminal half-life for comparative a normalized dose was described by
AUCINF/D and was the basis for comparison between H-24743 and positive controls. The
+i
a
Company Sanitized. Does not contain TSCA cal
AoF1-0D2-4Do7o4sw3e:OOBrnialoGpGeuarvvsoiasggteeenSSctteuoSdcdyryieinennRaiRtnasgs
DuDuPpoonmin-1i1s5s55
~ vAaUlCueIsNoEf/5D.2f2oxr1t0he afnludor8i.n1e5cxo1m0pofonrenHt-o2f40H1-92a4n7d43H-w2a4s0210.,0r7exs1p0ectaisvceloym.pared to AUCINF/D
Ltheavneltshoeflteovtealls ifnluloirvienres ifnrloimverrastsfdroosmerdatwsidtohstehde wpiostihttihvee cteosnttrsoulbsmtaatnecrei,alHs-.24T7h4e3t,otwaelrfeluloorwienre acnondce2n.t2r6autiMoneiqnuitvhaelleinvtesr aftrdoamy9ra4ts.dFoosredthweitphosHit-i2v4e7c4o3ntwroalsH2-72.45021u9,Mtehqeuliivvaelrecnotnscaetntdraayti1o0ns w2e4r7e43a.ppFroorxiHm-a2t4e0l2y0,17t4hxe lhiivgehrecro(ndcaeynt1r0a)tiaonnds awpeprreoaxpipmraotexliyma5t7e2lxy h3i1gxhehrig(heenrdo(fensdtoufddyo)stihnagn)Hand 8x higher (endofstudy) than H-24743.
Levelsoftotal fluorine similar to the levels in
in fat
fat from rats dosed with from rats dosed with the
the test substance were slightly positive control materials. The
higher than fluorine
or
`dcaoync1e0ntarnadtio1n0.i8n7thueMfaetqfuriovamlreanttssdoonseddaywi9t4h. tThheetefsltuosruibnsetcaonncceewnatrsat4i9o.n1o0fuonMeeoqfutivhaelepnotssitoinve
ccoonntcreonltrmaattieornioalfst,hHe-2ot4h0e1r9,powsiatsivaepcpornotxriomlamtaetleyri4axl,hiHg-h2e4r02th0a,nwHa-s24si7m4i3laornodnadyay10.10Tthoethfeluorine
fHl-u2o4ri0n1e9cwonacsenstirmaitliarontooftthheefltueostrisnuebcsotnacnecen,trHa-t2i4on74i3n.ratBsytrdeaayte9d4,witthhe fHl-u2o4r7i4ne3.coTncheenrterawtaisonnoof
detectable fluorine by day 94 in the fat from rats dosed with H-24020.
`The uM equivalents in the liver and fat were higher than levels in the blood. --~
CONCLUSIONS
sRuabtsstadnocsee-drefloarte1d0ccloinnsiceaclutsiivgnesd,aaynsdwniothbo3d0y0 wmegi/gkhgtHe-ff2e4ct7s4.3Leixvheirbiwteeidghntosmwoertraeliatfyf,ecntoedteisnt rats dduorsiendgwtihteh1t0h-edtaeystdsousbisntganpceer.iodAwsittehadtyh-esttaetste sfuobrstfalnucoer.ineDionsteh-eadbjluosotdedapaprecaarseudndtoerbethaecchuirevveed (thAeUACUICNFI/NDE)/Dforfoprostihteitveestcosnutbrsotlasn,ceH.-24019 and H-24020, were approximately 490x and 75x
tUhnedbelrotohdefcoolnldoiwtiinognsdoosftihnigswsittuhdyH,-2th4e7r4e3w.asAdlmiimniitsetdraabtsioornpotfiotnheantedstnosurbestteanntcieo,noHf-f2l4u7o4r3i,netoin
mliavlere. rTathsefroerw1a0scosnosmeecuatbisvoerpdtaiyosnraensdulrteetdeinntisoonmoefafblusoorripnteioinn tahnedfraet.tenLteivoenlsofinfltuhoerifnate iinn rtahtes
dmaotseeridalwsi.thHtohweetvesetrs,ublesvtealnscienwbelroeodslainghdtllyivheirgihnerratthsadnoosredsiwmiitlharHt-o2l4e7v4el3swienrtehecoponssiitdievreabcloyntrol
lower than H-24020.
the
fluorine
levels
in
rats
dosed
with
the
positive
control
materials,
H-24019
and
~~ Company Sanitized. Does not contain TSCA CBI
P TT e TT re
H1-0D2-4De7o4se3e;OOnrBaGilooGpvaeravsagigseeeSnSucteuddSyycirienneRRnaietnssg
--
RECORDS AND SAMPLE STORAGE
DDuuPPoomnnts11s55s8
SNpeewcairmke,nDs(eliafwaaprpel,icoarblaet),IrroanwModautnat,aainndRtehceofridnsalMraenpaorgtemwielnltb,eWrieltmaiinnegdtoatn,HaDseklealwlarLea.boratory,
Company Saniized. Dossnotcontain Tscacar -_--
F1-02-4D7o4s3e;OrBailoGpearvsaigsteenScteudSycrieneRnaitnsg --~
DuPont-11558
--~
TABLES
--_ -_--
`Company Sanitized. Does notcontainTSCACBI ie
L11O.02-D4Do7os4s3ce:OOrnBalilGoGpaeavrvsaaiggsteeeSnScuteuddSyycirienneRRnaaitnssg ~
TABLE 1
Dwupeontn15s58
MEAN BODY WEIGHTS
--DADYAYSSOONNTTEESSTT_DeNDieeoginaotiniizvzeeeddCWoWnaatttreeorlr
MEAN BODY WEIGHTS (g)
HH--224400Po11s99it_i_ve_C_onHt-rHo2-l42s0402200 __TeHsoHto-S24u4b77s44t33ance
1
189.6
184.4
184.1
192.9
2
195.5
189.2
187.8
196.0
3
204.6
199.5
197.8
205.5
4
211.7
206.4
204.8
216.3
5
222.1
216.2
2125
2294
6
225.0
2220
216.0
2339
7
235.2
2294
223.6
2442
8
2423
233.7
2269
250.3
9
2483
240.4
2342
258.8
10
257.0
246.5
243.0
264.6
w
293.3
290.1
297.4
306.2
24
325.5
3133
338.6
3389
31
3593
348.4
381.9
360.7
~ 38 3809 3708 4049 3833 45
407.4
403.2
4344
409.8
52
420.5
4228
460.6
4299
59
436.4
439.6
483.1
449.9
67
452.8
455.6
502.7
-
66
-
-
-
463.7
73
472.6
480.1
525.6
4825
80
489.6
496.5
542.1
500.2
87
497.7
5122
546.2
504.7
reen Ind-- icae te t-- he e anim-- alswer--no w-- eighed-------------------- 94
S17
5246
570.5
515.8
~~
-
`Company Sanlized. Doss not contain TSCA cB
H1-240743;O-rBaiolDpGearvsoaisgteeSsntcuedSeyricnenRiatnsg
Dupont 11555
--_ TABLE 2
MEAN BODY WEIGHT GAINS
DOSING
Negative
Control
MEAN
BODY WEIGHT GAINS Positive Controls
(g
Test Substance
--DADAYYSSOONNTTEESSTT DeDeiioonnizeeddWater HF2-24400199~~HH2-244002200_ HH--2247433_
15 510
325 349
318 303
284 305
365 352
1-10 _--
674
621
589
77
RECOVERY
m
Negative
Control
MEAN
BODY WEIGHT GAINS Positive Controls.
(g)
Test Substance
--DADAYYSSOONNTETESSTT DeDieioonniizeddWaatteerr H_-_H2-42040119_ H-244002200___ HHo2d477433
1017 1724
363 322
436 22
544 412
416 327
24-52 52.94
95.0 912
109.5 1018
1220 1099
910 859
10.94 _----m
2547
278.1
3275
2512
~ -
CompanySanitized. Does not contain TSCA Cal
H1-02-4D7o4s3e; OrBailopGearvsaigsteenScteudSycrieneRnaitnsg
DuPont 11558
-- TABL3E
DAYS ON TEST 10
--_-- 94
MEAN BODY AND LIVER WEIGHTS
NEGATIVE CONTROL - DEIONIZED WATER
WEIGHT (g)
`Absolute Body Weight Liver Weight
Mean Relative Liver Weight (Liver/Body Weight)
25838
10814
si?
17.868
0.042 0.035
DAYS ON TEST
POSITIVE CONTROL - H-24019
WEIGHT (g)
Absolute Body Weight Liver Weight
Mean Relative Liver Weight (Liver/Body Weight)
~~ --_-- 91%0 25423496 1149..220956 00..003578
DAYS ON TEST 10 9%
--_--m
POSITIVE CONTROL - H-24020
WEIGHT (g)
`Absolute Body Weight Liver Weight
Mean Relative Liver Weight (Liver/Body Weight)
243.1 5705
19.174 19.590
0079 0.034
DAYS ON TEST 10 9
_-- ~~
-
TEST SUBSTANCE - H-24743
WEIGHT (g)
Body WeightAbsoluteLiver Weight
Mean Relative Liver Weight (Liver/Body Weight)
260.7 5158
14333 20212
0.055 0.039
Company Sanitized. Does not contain Tara cay
-- ES ------
oH1L02-4De7o4s3e:OOrmBaiClouGpeagsviaesgSteeunScdetySciiurnenRdeRanityensgs ~~
TABLE 4
DouwPoonmtn1s15s5s8
MEAN BLOOD FLUORINE LEVELS
--DDAAYYSSOONNTTEESTTDeNDieeogiaontniiizveeddCoWnattreorl
1
5
0.60
+
10
L10*
13
=
2
0s
52
-
94
-
-_--
MEAN FLUORINE LEVELS (ppm) Positive Controls
_H_-_2H-420401199 H-H-224402200
2.60
332
(0.1)
(LD)
68.00 33)
$398 (12)
3962 34)
2356 (2.1)
12.60 (1.2)
9.40
7492
(2.4)
(70)
61.76 (5.5)
20.52 (49)
ILI 29)
226 (LI)
085 (0.1)
"Test Substance H-H2-24477433 _
9.07
9152
(4.23)
(1152)
91 (41)
6.4 (1.36)
3.536 (0.54)
0.58
=
4b OSntaenodfardS vdaelvuieast.ioFno(u5roDf)tiheivnaplaureesntwheerseesb.elow the limit of quantification (LOG). 4 AMlelavnaloufes2woertfehbeSlovawluetsh.e LTOhGr.eeofthevalueswerebelowtheLOQ.
TABL5E
MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE.
DAYS ON TEST
MEAN
FLUORINE CONCENTRATION Positive Controls
(uM
F Equivalents) Test Substance
H-24019
H-24020
H-24743
1 5 10 13 24 52
94
_--
3692 (1.1) 478.77 (17.6) 1043.08 (54.6) 827.38 (19.0) 606.46 (53.1) 35938 (32.7)
190.77 (19.2)
66.67 (17.5) 541.45 (50.4) 446.09 (39.7) 21246 (35.6) 79.57 (20.8) 14.93 (1.7)
471 (05)
435 (208) 439 (5.66) 437 2.0) 3.04 (067) 1.64 (0.27)
019
.
ba
MOStneaeanndoaforSdfd2veoavlfiuaetsth.eionFov(uaSrl.ouDe.fs)t.shieTvhnipcaaereonlfwttheheureseevbseae.lluesoswwtehreeLbOeGl.ow the limit ofquantification (L0Q)
--~
All valueswerebelow the LOQ,
Company Sanitized. Does not contain Tsca rar
-------------- ------I------------
1w 1024D7o4s3ec :OnBliGoapo veargeiSntem udSyeeinenRiaG tneg esbyintoe Dwuros e15s56 --_
TABLE 6
MEAN LIVER FLUORINE LEVELS
--DAYSONTESTDeionizedWater F209 1.24000 DAYS ON TEST
MEAN FLUORINE LEVELS(ppm)
Negative Control
Positive Controls
Deionized Water H-24019
H-24020
Horas -- Test Substance H-24743
7 5_--S_t--andard deviion (5. sin par7 entheses. 7 9140 00..7980 ((00..20))" 38142.3244 ((71.94.)7) 1129..5860 ((13..35)) 564..8215 ((02.28.96)4)
TABLE 7
MEAN LIVER FLUORINE (CONCENTRATION NORMALIZED TODOSE
--DAYSONTEST HOOD Woios mows MEAN FLUORINE CONCENTRATION (UM F Equivalents)
~~
DAYS ON TEST
Positive Controls
H-24019
H-24020
`Test Substance H-24743
-- 9140 41820922..1952 ((131043..18)) 86167..6170 ((92.58.)5) 272..5226 ((01.14.41)2)
a Standard devinion (5.0) is in parentheses.
TT
~ -Y
Company Saniize, Dosnos contin v5 cay
--------
H1-02-4D7o4s3e: OrBailopGearsgisetenScteudSycrieneRnaitnsg
DuPont 11558
DAYS ONTEST 190
TABLE $
MEAN FAT FLUORINE LEVELS
MEAN FLUORINE LEVELS (ppm)
Negative Control
Positive Controls
Test Substance
Deionized Water F-24019 H-24020
H-24743
4
1284 (17 810 (11) 100.21 (55.64)
ES
120 03)
+
2234 (1043)
a ASltlanvdaalrudedsewvieartiboenl(o5w.t0h)eiliimnitpoafrqeunaensifciscarion LOQ) onondcctabe
TABLE
MEAN FAT FLUORINE CONCENTRATION NORMALIZED TO DOSE
MEAN FLUORINE CONCENTRATION (uMF Equivalents)
--_~
Positive Controls
Test Substance
DAYS ON TEST
H24019
F-24020
H-24743
10
194.46 (26.8)
57.25 (18)
49.10 (2732)
94
1538 (4.1)
>
10.87 (5.12)
ba ASltlanvdaalrudesdewveiraetiboenl(oSwD)theilsimiintpoafrqeunatnhteisfesi.cation (LOQ) or non-detetable.
--~
Company Sanitzed. Doesnotcontain Tc car
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--
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APPENDICES
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Dupont 11558
PN
APPENDIX A
Individual Body Weights
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INDIVIDUAL BODY WEIGHTS
ABBREVIATIONS: SD - sacrificed by design
EXPLANATORY NOTES
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APPENDIX B
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H1-02-4D7os4e3:OrBailoGpearvsaigsetSentcuedSycirneeRnaitnsg. --_
DuPont-11558
APPENDIX C Terms and Calculations Factors Influencing Interpretation of Kinetic Analysis
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1120-4D7o4s3e;OraBilopGearvsaigsteenScte uScdirynseRnaitnsg
DuPont-11558
-- TERMS AND CALCULATIONS
Terms: Active % Active
Mol Wt Active Formulation Dose % Fin Active
Mol WF
Fluorine containing compound `The %of formulation that is made upoffluorine containing components `The molecular weightofthe fluorine containing components (g/mole) `The mg of formulation given per kg ofanimal body weight `The% fluorineinthe fluorine containing components ofthe formulation (weight basis) `The molecular weightoffluorine g/mol
Compound Calculations:
--
Dose Active (mgkg) The mgoffluorine containing compound administeredperkg 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)
`The mmole of fluorine administered per kgofanimal body weight = Dose F [mg/kg] / Mol Wt F [mg/mmol]
Molar Ratio (Active/F) The moles of fluorine containing compound per moleoffluorine = Dose Active [mmol/kg] / Dose F [mmol/kg]
Formulation Dose `The formulation dose that would be required to administer the amount
Normalization Factor ofactive needed to achieve the normalized dose
= (Normalized doseof Active [mmol/kg] / Dose Active [mmol'kg])
--_
x Formulation Dose
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H.24743: Biopersisence Screening
2c0c0 cOilcCnAtnIiAmRsgppmamanemmierppeeenDreSmELmLnS,
--~ TERMS AND CALCULATIONS
Individual Animal Measurement:
ppm F
`The ppm fluoride measured
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 nomalized to 0.1 mmol/kg Dose
Theppm fluoride minus background that would be expected ifthe active dose was 0.1 mmol/kg insteadofthe actual active dose. This `assumes linearity between administered dose and blood fluorine levels, but is needed because different doses of active were used in the study. = (0.1 [mmolkg] / Active dose [mmol/kg]) x (ppm F in blood
`minus background)
~
molar equivalents of The wmolar [umol/L] concentrationoffluorine containing compound
active
based on the ppm fluorine normalized to 0.1 mmol/kg active dose.
"This assumes that all fluorine is derived from the fluorine-containing
component in the formulation. Note: 1 ppm ~ 1 mg/L
= (Normalized ppm [mg/L] fluorine / Mol WtF _[mg/mmol]) x
`molar ratio active/F [mmol active/mmol F] x 1000 ymol/mmol
--
-
`Company Sanitized. Does not contain Tara cay
11.02-4D7o4s3e; OrBailoGpearvsaigteenScteudSycrieneRnaitnsg
DuPont-11558
PN FACTORS INFLUENCING INTERPRETATION OF KINETIC ANALYSIS
Considerations:
- The data used for kinetic analysis was from a limited screen and extrapolation shouldbe done: cautiously.
- Sample size is low. - Analytical data used without validation - Steady-state not reached - Terminal phase may not be reached - Some compoundsare mixtures of fluorinated compounds - Differentactiveand formulation doses were used - Different vehicles wereusedto 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 respecttodose
-- - Analytical method is appropriate for all typesof compounds
- Elimination kinetics can be determined based on total fluorine rather than on concentrations of
individual components
- Background Fluorine is 0.2 ppm
-
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H-24743: Biopersstence Screening 10-Dose Oral Gavage Study in Rats --~
DuPont-11558
APPENDIX D --~
Individual Fluorine Levels in Blood
--~
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H120-4D7o4s3e:OrBailoGpearsviseenScetSycxinenRinsg
Dupont1558
--
Data for H-24019
Given:
Mol Wt. Active (g/mole):
497
% Fin Active:
65
Formulation Dose (mg/kg):
10
Mol Wt. F (g/mol):
19
9% Active (F Containing) in Formulation: 100
Calculated Values: Dose Active (mg/kg):
DDoossee FAc(tmimvoel(/mkmgo)l:e/kg):
10
Molar Ratio (Active/F): 0.059
00.304220 Dose F (mg/kg):
65
~~
rr
Test
Rat Day
Number _ Sample
Group 1
646910
1
646911
1
646912
1
646913
1
646914
1
ppm F
in
Blood
26 27 25 26 26
Group I
646910 646911
646912
646913 646914
5
30.1
5 303
5
31.3
5
322
5
327
Group I
646910 646911 646912
646913 646914
10
71.5
10 70.5
10 66.9
10 62.5
10
68.6
ppm Fin Blood
Minus Bkg
0.2 ppm
24 25 23 24 24
299 30.1 3L1 320 325
713 70.3 66.7 623 68.4
ppm F in Blood Normalized to
0.1 mmoles/kg.
Dose
11.93 1243 11.43 11.93 11.93
148.60 149.60
154.57 159.04 161.53
354.36 349.39 331.50 309.63 339.95
pmolar Equivalents
ofActive in
Blood
36.92 38.46 35.38 36.92 36.92
460.00 463.08 478.46 492.31 500.00
1096.92 1081.54 1026.15 958.46 1052.31
Company Santtized. Does not contain TSCA cai
eee ri
----------
2104-7D4o3se; OrBailopGearvsaigsteenSctsudSyeicnnRiantsg
DuPont11558
ppm Fin ppmFin Blood molar
~~
Rat
Test ppmF
Day in
Blood
Normalized to Equivalents
MinusBkg ~~ O.1mmoleskg ofActivein
Number Sample Blood 0.2 ppm
Dose
Blood
Group IN
6469s 13 550
548
27236
843.08
646916 13 553
55.1
273.85
847.69
66917 13 522
520
258.44
800.00
646918 13 538
536
266.39
82462
646919 13 536
534
265.40
821.54
Group Il
6469s 24 389
387
646916 24 438
36
646917 24 376
374
646918 24 354
352
646919 24 424
22
Group ITI
--_
646915. 52 232
2.0
646916 52 203
201
646917 52 259
257
646918 52 249
247
646919 52 235
23
19234
595.38
21669
670.77
185.88
575.38
174.94
541.54
209.73
64923
11431
353.85
99.90
309.23
127.73
395.38
122.76
380.00
11580
358.46
Group IIT
646915 94 133
13.1
646916 94 117
15
65.11 57.16
201.54 176.92
646917 94 129
127
63.12
195.38
646918 94 110
108
53.68
166.15
646919 94 141
139
69.08
21385
Company Sanitized. Does not contain TSCA C81 -------------------- Toe ------------------
2104-7D4o3se;OrBailopGearvsaigsteenScuedSycrieneRnaitnsg
DuPont. 11558
~~
Data for H-24020
Given:
Mol Wt. Active (g/mole):
426
Formulation Dose (mg/kg):
20
% Active (F Containing) in Formulation: 100
9%F in Active:
6
Mol WL F (ghmol: 19
Calculated Values:
Dose Active (mg/kg):
Dose Active (mmole/kg): Dose F (mmol/kg
20
0.047
MDoolsaerFRa(tmigok(gA)c:tive/F): 01.30865
0.726
Test ppmF Rat Day in Number _ Sample Blood
ppm Fin Blood Minus Bkg 02 ppm
ppm Fin Blood Normalizedto 0.1 mmoleskg
Dose
molar Equivalents of Active in
Blood
Group I
646921 1 106
104
646922 1 10.7
10.5
215 237
7536 76.09
~
646923 1 92
90
19.07
6522
646924 1 53
si
646925 1 n2
10
10.86 2.43
36.96 7971
Group I
646921 5 ma
785
6692 5 82
8.0
646923 5 710
7638
64624 5 66.1
659
646925 5 696
69.4
167.21
568.84
176.79
601.45
163.58
556.52
140.37
477.54
147.82
502.90
Group I
646921 10 630
628
646922 10 69.1
689
646923 10 603
60.1
646924 10 625
623
646925 10 539
537
133.76
455.07
146.76
499.28
12801
43551
13270
451.45
11438
380.13
--_ _-- mm
`Company Saniized. Doss not contain TSCA CBI En
J10120D-4oD7os4s3ce;OOBwrialolpGGeoarvsvieasggteeeSnStctueuSddcyyriienneRnRaaittnssg
0000 DuDuePownut1s15s5s8
--_
Test ppmF
ppm Fin Blood
ppmF in Blood Normalizedto
molar Equivalents
Rat Day in Number Sample Blood
Minus Bkg ~~ O.1mmoleskg
0.2 ppm
Dose
of Activin Blood
Group III
646926 13 348
346
64697 13 300
2938
7.70
250.72
63.47
21594
646028 13 27
235
646929 13 337
335
50.06 7136
17029 24275
646930 13 254
22
53.68
182.61
Group Il
64696 24 119
1.7
646927 24 104
102
2492 2173
84.78 7391
646928 24 8.1
79
646929 24 157
15.5
1683
57.25
33.02
112.32
646930 24 98
96
2045
69.57
Group IIT
--~
646926 52 25
23
646927 52 17
15
646928 52 13
11
646929 52 40
38
646930 52 18
16
490
16.67
320
1087
234
797
809
2754
341
1.59
Group Il
646926 94 08
06
646927 94 <05
M
128
435
*
*
646928 94 <05
*
646929 94 09
07
. 149
* 507
646930 94 <0
.
.
*
--
* BelowLOQ (LimitofQuantification)
~~
Company Sanitized. Does notcontain TSCA CBI
TT
H1-02-4D7o4s3e:OBriaolpGearvsiasgteenScteuSdcyrienenRiatnsg
Dupont 11558
~
Data for H-24743
Given:
Mol Wt. Active (g/mole): Formulation Dose (mg/kg):
3641 %Fin Active:
679
300 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):
300 Molar Ratio (Active/F): 0.077
0.824 Dose F (mghke):
2037
10.721
Test ppmF Rat Day in Number Sample _ Blood
ppm Fin Blood Minus Bkg 0.2 ppm
ppm Fin Blood Normalized to 0.1 mmoleskg
Dose
molar Equivalents of Activein
Blood
Group 1
665511 1 874
85
663512 1 427
al
1.04 049
4.19 200
--
665513 1 7.19
7.0
665514 1 15.77
15.6
085 1.89
343 7.64
665515 1 9.38
92
Lil
451
Group I
665511 5 438
42
663512 5 336
32
051 0.38
205 155
665513 5 3.06
29
663514 5 5.26
5.1
035 0.61
140 248
665515 5 27
295
3.58
14.48
Group 1
66511 10 687
67
665512 10 531
5.1
081 062
321 251
665513 10 662
64
665514 10 1505
149
0.78 1.80
315 7.29
665515 10 1165
ins
139
562
--_
Company Sanitized. Does not contain Sma Amt
-
A0H1-D02-o4D7so4se3e;OOnrBaiiloGpGeaarvvsaaiggsteeeSnStctoeuddSyycirienneRnRaiaentgss,
DuDubPoomntn.i1s15s58s
--
ppm Fin ppmF in Blood molar
Rat
Test ppmF Day in
Blood MinusBkg ~~
Normalized to 0.Immoleskg
Equivalents ofActive in
Number_Sample Blood 0.2 ppm
Dose
Blood
Group III
665516 13 522 665518 13 612
50 59
061 072
246 291
665519 13 503
48
665520 13 797
78
0.59 0.94
237 381
66521 13 766
75
091
3.66
Group 11
665516 24 416 665518 24 376
40 36
048 043
1.94 175
665519 24 276
26
66520 24 375
36
031 043
126 1.74
665521 24 325
31
037
1.50
Group IIT
--_
665516 52 <5
*
665518 52 058
04
* 0.05
* 0.19
665519 52 <s
*
665520 52 <5
*
* *
* *
665521 52 <5
*
*
*
Group II
665516 94 <s
*
665518 94 <s
*
* *
. *
665519 94 <5
.
665520 94 <5
*
* *
. *
66521 94 <5
.
.
_--
* Below LOQ (Limit ofQuantification)
PN `Company Sanitized. Does not contain TSCA CB
-
H1D-02-o4D7o4se3e;OOrnBailCoGpaearvgsasgeteeSnScuteuSddcyyrieinennRkiaentgss
DuDPuPoomntl-i11s5s58s
--
APPENDIX E
Individual Fluorine Levels in Liver
CompanySanitized. Doesnot contain TSCA GR)
-_--
he
L0 H10-02D-4Do7o4sw3e;OOnrBaiiloGGparevrasagigeseeSnSuctdeuydSyicrineneknRaianstgss, DuDuoPmonnt.i1s15s5s8
--
Data for H-24019
Given:
Mol Wt. Active (g/mole): Formulation Dose (mg/kg):
497 10
% Fin Active:
65
Mol Wt. F (g/mol): 19
9% Active (F Containing) in Formulation: 100
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Dose F (mmol/kg):
10 0020
Molar Ratio (Active/F): 0.059
Dose F (mghke):
65
0342
Rat
Test ppmF Day im
Number Sample _ Liver
ppm Fin ppm Fin Liver
Liver MinusBkg ~~
Normalized to O.1mmoles'kg
0.2 ppm
Dose
molar Equivalents of Active in
Liver
Group
646910 10 3209
3207
~
646911 10 3340 646912 10 3186
3338 3184
646913 10 2816 646914 10 3066
2814 306.4
1593.88 1658.99 1582.45 1398.56 152281
4933.85 5135.38 4898.46 4320.23 4713.85
Group III
6469s 94 856 646916 94 759
854 757
424.44
1313.85
376.23
116462
646917 94 875 646918 94 780
873 738
433.88
1343.08
386.67
1196.92
646919 94 942
940
467.18
1446.15
eee
~~ -_--
CompanySanitized. Does not contain TSCA CBI Tes
H1-02-4D7o4s3e:OrBailoGpaevrsaigseenScteudSycrieneRnaitnsg
DuPont-11558
--
Data for H-24020
Given:
Mol Wt. Active (g/mol):
426
Formulation Dose (mg/kg): %Active (F Containing) in Formulation:
20 100
%F in Active:
69
Mol We F (mol): 19
Calculated Values: Dose Active (mg/kg):
Dose Active (mmole/kg):
Dose F (mmol/kg):
20 Molar Ratio (Active/F): ~ 0.065
0.047
0.726
Dose F (mg/kg):
138
Test ppmF Rat Day in Number Sample _ Liver
ppm Fin ppm Fin Liver
Liver
Normalized to
MinusBkg ~~ O.Ummoleskg
0.2 ppm.
Dose
molar Equivalents of Active in
Liver
Group1
646921 10 183
118.1
646922 10 1227
1225
251.55 26093
855.80 887.68
~~
646923 10 1143
1141
64624 10 1216
1214
243.03 258.58
82681 879.71
646925 10 1221
1219
259.65
88333
Group IIT
646926 94 18
16
646927 94 12
10
341 213
11.59 725
646928 94 22
20
646920 94 47
4s
426
14.49
9.59
3261
646930 94 29
27
575
19.57
------ e-- i------------------------
--_ Company Sanilized. Dossnotcontain TSCA CRI -- -- -- e-- e T-- e eee -- ------
A0H1-0D2-o4D7os4s3ce:OOrvBailoGGpoearvvsaaiggseteeSnStctueuddSyycirineeRRnaitnsg
00
--_
Data for H-24743
DuDbuoPnoentii1s15s58s
Given:
Mol Wt. Active (g/mole): Formulation Dose (mg/kg):
3641 %Fin Active:
679
300 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)
300 0.824 10.721
Molar Ratio (Active/F): 0.077
Dose F (mgke):
2037
Test ppmF Rat Day in Number Sample Liver
ppm Fin ppm Fin Liver
Liver
Normalized to
Minus Bkg ~~ 0.Immoleskg
0.2 ppm
Dose
molar Equivalents of Activein
Liver
Group 1
665511 10 4468 445
5.40
21.84
~~
665512 10 4146
413
665513 10 3384
336
501 4.08
2026 1651
665514 10 8231
82.1
665515 10 7898
7838
9.97 9.56
4031 3867
Group IIT
665516 94 543
52
665518 94 595
58
063 0.70
257 282
665519 94 394
37
66520 94 475
46
0.45 0.5
184 223
665521 94 397
38
046
185
-- ee -------------- ------ ----e --
_ _--
Company Sanitized. Does not contain TSCA CBI ee
H1o-0D2-o4D7wo4sc3e:OOBrmiaolOpGevarvsvioasggteeenSSctueuSddcyyreiinennRRiaantgss ~~
DuDPuPoomnil-i1s15s58
~
APPENDIX F
Individual Fluorine Levels in Fat
~~ _--_--
`Company Sanitized. Does not contain TSCA CBI 5
F1-02-4D7o4s3e;OrBailoGpaevrsaigseenScteudSycrieneRnaitnsg
--_
Data for H-24019
Dupont 11555
Given:
Mol Wt. Active (g/mole): Formulation Dose (mg/kg):
497 10
%F in Active: Mol Wt. F (g/mol):
65 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
0.020 DoseF (mgke):
65
0342
Test ppmF Rat Day in Number Sample Fat
ppm Fin ppmFin Fat
Fat
Normalizedto
Minus Bkg ~~ O.Ummoles'kg
0.2 ppm
Dose
pmolar Equivalents of Active in
Fat
Group
646910 10 144
142
64691 10 149
147
70.57 73.06
218.46 226.15
--
646912: 10 109
10.7
646913 10 116
114
53.18 56.66
164.62 175.38
646914 10 124
122
60.63
187.69
Group III
646915 94 13
11
646916 94 11
09
547
1692
447
13.85
646917 94 13
Ll
646918 94 08
06
547
1692
298
9.23
646919 94 Ls
13
646
20.00
FS --
--_ -
Company Sanitized. Does not contain TSCA CBI ws
H1-02-4D7o4s3e:OrBailoGpaervsaigteenScteudSycrieneRnaitns:g
--_
Data for H-24020
DuPont 11558
Given:
Mol Wt. Active (g/mole):
426
Formulation Dose (mg/kg): 9% Active (F Containing) in Formulation:
2 100
% F in Active:
6
Mol WEF (g/mol): 19
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Dose F (mmol/kg):
20
Molar Ratio (Active/F): 0.065
0.047 Dose F (mgkg):
138
0.726
Test ppmF Rat Day in Number Sample Fat
ppm Fin Fat Minus Bkg 0.2 ppm
ppm Fin Fat Normalized to O.mmoleskg
Dose.
molar Equivalents of Active in
Fat
Group
646921 10 62
60
646922 10 85
83
--~
646923 10 87
85
646924 10 88
86
646925 10 83
8.1
12.78
43.48
17.68
60.14
18.11
61.59
18.32
6232
1725
58.70
Group III
646926 94 ND
ND
646927 94 ND
ND
ND ND
ND ND
646928 94 ND
ND
646929 94 ND
ND
ND ND
ND ND
r--r 64-- 6930 ---- 94 --Ni D erNDtalm ND eeeNe Dame en
ND Nondetectable.
-- -_--
Company Sanitized. Does not contain TSCA C81 Te
LDH1-02o-4D7ow4s3e;OOrnBailCoGpoaevvresaiggseeeSnSctteuudSdycyriienenRnRaitens:gs ~
Data for H-24743
DDuuoPmonnti11s5s58s
Given:
Mol Wt. Active (g/mole): Formulation Dose (mg/kg):
3641 %Fin Active:
679
300 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):
300 Molar Ratio (Active/F): 0.077
0824 Dose F (mk) 10721
2037
Rat
Test ppmF Day in
Number Sample Fat
ppm Fin ppm F in Fat
Fat
Normalized to
MinusBkg ~~ 0.Immoleskg
0.2 ppm
Dose
pmolar Equivalents ofActive in
Fat
Group
665511 10 97.26 665512 10 3549
97.1 353
1.78
47.65
428
17.32
~
665513 10 65.62
654
665514 10 12164 1214
7.94 14.74
32.12 59.62
665515 10 181.03
18038
2195
88.77
Group Il
665516 94 29.18
200
665518 94 34.66
345
352 418
14.23 16.92
665519 94 972
9.5
665520 94 2436
242
116 293
4.67 11.86
665521 94 1377
136
1.65
6.66
---
--
`Company Sanlized. Does notcontain TSCA CBI
eT
TT --
