Document JJXDgYxjJENJ13O9D2NbMBMG2
RARE - 3225
407
`TRADE SECRET
Study Title
H-24159; Biopersistence Screening
`Gavage Study in Rats.
Laboratory Project ID: DuPont6732
AR2z6 - 3225 Duron e72
AuTHOR: Gregory S. Ladics, PhD., DAB.
STUDY COMPLETED ON: January 24, 2002
-
PERFORMING LABORATORY: EI. du Pont de Nemours and Company
Haskell Laboratory for Health and Environmental Sciences
Elkton Road, P.O. Box 50
Newark, Delaware 19714-0050
WORK REQUEST None (SD)
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CERTIFICATION
We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study.
Reviewsay: 2 HPL arTa:?S 24-Za2seea
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Dupont6732
TABLE OF CONTENTS
Page
CERTIFICATION ssn
LIST OF TABLES corns
LIST OF FIGURES cosmos
LIST OF APPENDICES vcs
STUDY INEORMATION sssmmmmssrsssonssssasmssssmmmmsmmsnl
STUDL VERSOTE mmm
SUMMARY cosmos
TIRODUCTION sssonsmssmmsssssinmmmmammonsmmsssmmmpmmn
MATERIALS AND METHODS wcrc
1
A. TeSt SUBSIANCE rrr
m------rly
B. Test Specics .
en
ensmm--------------
C. A1. nimHoaulsiHnugsEbnavnidrroyn.ment wr"
------ C --e .
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2. Feed and Water.
5 Wenifcation...
ena---- -
1mn0
Animal HeathMonitoring Prograr........
S--T
D. QuaraanndtPirenteest .........
------------
1
E. StudyDESIgN cre
enmm--
12
FE. Assi(0GgrounpsamndSetudnySttart
nm------------k
G. D1 osTiEnSgSMUaStAerDiCaCl Preparation and AAMINISIEAON ..........o.I ovrossin oss 12
2. Negative Control
rrr.
B--
1
H. BOG WEIGHS ....creoseorrrsrsnsssmoneneeineeons
conn y
I. Mortality and Clinical ODSEIVAtONS rococo
wd
J. CollectionofBlood, Urine, and Feces for Total Fluorine Level Evaluation.
nd
K. AJ natomico al Pathology......--...--
m--------r-- er-- 133
2. Postdosing Phe L. FluorineAnalysis
-- --------
nm 1
M. Statistical Methods.
wem---------- enn
RESULTS AND DISCUSSION cerns15
A. I0-Life TOXICOI0gY rrr
--
nl
B. LI. iv"eTresWeSiugbhstasn.c.e...or.o-rroror
------ SLI
n1ed5s
C. Kidney Weights...
I
15
1D. FIUOMNEDAA rrr
'
SE
1s
-
CONCLUSIONSoevsmmsnmmsnmmsssssmmssssssssmsssssssss1n6
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RECORDS AND SAMPLE STORAGE .......covoenrrrssmsssssssssssssssssssssssssssssemsssssmsssssssssssss1se6s
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LIST OF TABLES
Page
1. MEAN BODY WEIGHTS...
S--
nd)
2. MEAN BODYWEIGGAINHS T ().......
S--
21
3. MEAN BODYANDLIVERWEIGHTS ()..
B--
BE
2s
4. MEAN BODY AND KIDNEYWEIGHTS (p.
--
S--
2
5. MEAN BLOODFLUORINELEVELS........... S--
cn 2]
6. MEAN BLOODFLUORINE CONCENTRATION EXPRESISNE4DM EQUIVALENTS......... 2
7. MEANLIVERFLUORINE LEVELS...........
BE
29
8 MEANLIVERFLUORINE CONCENTRATION EXPRESSED IN 4M EQUIVALENTS...
29
9. MEAN FAT FLUORINE LEVELS. ...........
SR
nO
10. MEAN FATFLUORINECONCENTRATIONEXPRESSED IN 4M EQUIVALENTS.
30
11. MEAN KIDNEYFLUORLIEVNELES...
SE
--
12. MEAN KIDNEY FLUORINE CONCENTRATION EXPRINkEMESQUSIVAELENDTS... 31
=
LIST OF FIGURES
1. MEANBODYWEIGHT(8S).
SE
2. FLU(O4MERQUIIVALNENTES) IN RAT BLOOD...
--
3. `CCOONCEMNTRPATOAIOFNRREFLOIARTHIS.V2E41OL5I9VNAENRWDNEEIGGAHTTIAVNEDCOMNETARNOLLI.V.E.RFLUORINE
4. CCOOMNPCAERNITSROANTOIOFNMNEOARNMALLIIVEZRE,DKTIODNDEOYSSE,.FAT, AND BSELOOD FLUORINE
Page
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LIST OF APPENDICES
Page
A INDIVBOIDYDWEUIGAHTLS
SE
38
B. INDIVIDUALCLINICAL OBSERVATIONS...
nd
C. ATNEARLMYSSAINSD CALCULATIONS FACTORS INFLa UENCING INTERPRETATIO-N OF KINETIC 5
D._ INDIVIDUALFLUORINELEVELS IN BLOOD...........
--
56
E._ INDIVIDUAL FLUORINE LEVELS INLIVER...
S--
o
F. INDIVIDUALFLUORINELEVELS IN PAT...
6]
G. INDFLIUORVINEILEVD ELSIUNKIADNELYS...
nT
H. URANDIFECN ESDAETA
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TEST SUBSTANCE:
STUDY INFORMATION
Substance Teste: (RNIN
me f --|
Haskell Number: 24159
-
awn(SY)
Sponsor: ton ------ E. I. du Pont de Nemours and Company
US.A.
SHR, Tow 100A morgen Lf ftom. Joe 15, 2001 / ottee 29,201
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STUDY PERSONNEL Study Director: GregorSy. Ladics, Ph.D., D.A BLT. Management: Judith C. Stadler, Ph.D., D.A.BT. Primary Technician: Robert E. Walker, Jr. Fluorine Data Analysis: Paul M. Hinderliter, Ph.D. Management: Matthew S. Bogdanffy, Ph.D., D.A.B.T. Toxicology Report Preparation: Wanda F. Dinbokowitz. Laboratory Veterinarian: William Singleton, D.V.M., A. CLAM
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SUMMARY
"The objective of this study was to evaluate the potential for H-24159, when administered by gavage, 10 be absorbed and to accumulate in a mammalian system following the attainment of
steady-state blood fluorine levels. Two groups of 10 male Crl:CD(SD)IGS BR rats each were:
exposed to 35 mg/kg/day of H-24159 or deionzied water for 52 consecutive days. Blood was collected from the orbital sinus of 10 rats approximately 2 hours after dosing (except on test day 53) on test days 0,4, 9, 14, 21, 28, 35, 42,49, and 53. Beginning on test day 50, animals were placed in metabolism cages and urine and feces were collected for total fluorine analysis for 3 days at 24 hour intervals from the first 5 males in the control and 35 mg/kg/day group. The urine and feces obtained from a particular dose group was pooled. After the collection of urine and feces, the first 5 males in each dose group were sacrificed on test day 53 and liver, kidney and fat were collected, weighed and stored frozen until fluorine analysis. Blood was also collected for total fluorine analysis at 3,7, 14, 21, 35, 56, and 84 days after the final dosing of each group. On postdosing day 84, the remaining rats were sacrificed and the liver, kidneys, and fat were collected, weighed and stored frozen until fluorine analysis. Body weights and clinical signs were evaluated twice per week.
No deaths occurred during the study. No test-substance-related clinical signs were observed. No
--
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weight gain compared to control were observed for the treatedgroupwith the exceptionof a
significant increase in mean body weight gain during the 95-98 and 102-105 test day intervals.
Mean liver and kidney weights relative to body weight were similar to control in the test
substance treated group.
"The levels of total fluorine in rat blood rose rapidly and reached steady-state in approximately 45 days with a maximum equivalent concentration (Cass) of 62.1 7.8 uM equivalents and a terminal elimination half-1ife of 38.0 days. Fluorine was present in each of the examined rat tissues with the relative ranking of liver > kidney > fat > blood at both the steady state and recovery time points. The ratio of tissue to blood fluorine wasnearlyequivalent at both time. points. Under steady-state conditions, fluorine was eliminated in urine and feces at a rate of S mmoles/kg body widay.
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INTRODUCTION
"The test substance, H-24159 i
[A 10-dose oral gavage
boifotpheirssiinsitteianlcestsucdrye,etnhiengadsmtiundiystrtaatsicoonnodfucHt-e2d4w1i5t9ht3o5mmalge/rdatas fyorH1-024c1o5n9s.ecuUtnidveerdtahyescroensduilttieodns
ifnlumooridneeralteveelasbsionrwpthioolneabnldoordetwenatsionnotofacflhuioerviendediunrtihnegbtlhoeod.10 cHoonwseevceutri,vae sdtaeyasdyo-fstdaotseifnogrwith
35 mg/kg H-24159. dose males with 35
Therefore, the objective mg/kg/day H-24159 until
ofsttheiasdsy.esctaotnedfboirofpleurosrisitneencleevselcsreiennwihngolsetubdlyowoads
to
was achieved. The potential of H-24159 o be absorbed and to bioaccumulate in a mammalian
swyasstetmh,enasevianlduiactaetd.ed by analytical determination of total fluorine in blood, iver, kidney, and fat
MATERIALS AND METHODS
A. Test Substance
"The test substance, H-24159, was supplied by the spo( nsor --
st
---
substance appeared to be stable under the conditions of the dy. No evidence of itability,
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,
wNiotrhththCiasrsotlrianian.anTdheitCsruli:taCbDili(tSyDw)iItGhSreBsRpecratttwoalsonsgeelveicttyedaonnd lthoewbiansciisodefnecxetoefnssipvoenteaxnpceoruisence diseases
C. Animal Husbandry 1. Housing Environment
RAantismawlerreohoomussweedrseinmgaliyntinaisnteadinloenssansteaeplp,rwoixriem-amteesh12c-ahgoeusr sluigshpte/nddaerkd caybcolvee(fclaugoerebsocaerndts.light) and ata temperature of 22 3Cand a relative humidity of SO 20%
2. Feed and Water `Tap water was provided ad libitum. All ats were fed PMI Nutrition International, Inc. Certified
Rodent LabDiet 5002 chowadlibitum.
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3.
Identification
Prreicoorrdteodasosniagncmaerndtatfofigxreoduptos,theeacchagrea.t wAaftsearsassisgingendmaenutnitqougeroiudepnst,iftihceatliasotn3nudimgbietsrowfhtihceh was
adindividual identification number were tattooed on the tail of each rat andrecordedon the cage
4. Animal Health Monitoring Program
As specified in the Haskell Laboratory animal health and environmental monitoring program, the
fthoolsleowtihnagt pwrooucleddubreeesxwpereectpe0rfoirmmpeadctpetrhieodsiiceatllfyi0c nenisueretthoaft choentsadmi:nant levels were below
+ aWnadteirhsramcpolmeasmairneaanntaslyzed for total bacterial counts, and the presence of coliforms, lead,
+ Feed samples are analyzed for total bacterial, spore, and fungal counts.
+ Sbyatmhpelecsgferaosmhferers.hly washed cages and cage racks are analyzed to ensure adequate sanitation
Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional
-
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opruelsedncneoofbteheesxepeccotnetdaminiamnptasctbehleowinttheegrmitayxoifmtuhemScuondc.entration stated by the manufacturer
"The animal health and environmental monitoring program is administered by the attending
alfafbeocrtaetdortyeanviamlaidlitvyetoefritnhaerisany. Evaluation of these data did not indicate any conditions that
D. `Quarantine and Pretest
Upon arial a Haskell Laborstory, the rats were removed from shipping cartons and quarantined
fo6r days. The rats were weighed 3 times during the pretest period and examined daily for any clinically apparent signs of disease or injury. The rats were observed daily for mortality and signsofillness, injury, or abnormal behavior. On the bases of acceptable body weight gains and freedom from clinically apparent signs of disease or injury, the rats were released from quarantine by the laboratory animal veterinarian or designee.
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E. Study Design
Negative Control Deionized water
Test Substance H-24159
Vehicle
Not applicable Deionized water
Dosage | Number of gg) | Animals
10
35
10
F. Assignment to Groups and Study Start
After the quarantine period, the rats were selected on the bases of adequate body weight gain and freedom from any clinical signs of disease or injury. The selected rats were distributed by computerized, stratified randomization into study groups as designated in the Study Design, so that there were no statistically significant differences between group body weight means.
After assignment to groups, each rat was housed individually. The rats were 7.5 weeks of age at the time of dosing. Dosing began on test day 0.
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
I. Test Substance
H-24159 was prepared daily as a solution in deionized water. The rats were dosed by intragastric intubation ata volume of5 mL/kg body weight until steady state was atained and urine and feces collected. The amount of test substance each rat received was based on the most recent body weight collected and the dose solution concentration. The mixture was stirred on a magnetic stir plate throughout the dosing procedure to maintain homogeneity.
2. Negative Control
Deionized water was chosen as the negative control. The control rats were dosed at a volume of 5 ml/kg of body weight.
H. Body Weights All rats were weighed twice per week at 3- to 4-day intervals.
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1 Mortality and Clinical Observations
`Cage-site examinations to detect moribund or dead rats and abnormal behavior and appearance `among rats were conducted at least twicedaily throughout the study. At every weighing, cach rat was individually handled and examined for abnormal behavior and appearance.
J. Collection of Blood, Urine, and Feces for Total Fluorine Level Evaluation
On test day 4 (pre-bleed) and test days 0,4, 9, 14, and weekly thereafter until attainment of
steady-state blood fluorine levels (i.. day 49), blood (approximately 0.6 mL) was collected from
the orbital sinus of animals while they were under light carbon dioxide anesthesia. On the day of
blood collection (except test da4y and 53), blood was collected from the animals 2 hours
i(c2e.30Fomirncuatcehs)blaefetedrindgo,sibnlgo.odThwaesblcoololdecwtaesd catolalpepcrtoexdiimnaptlealsytitchteusbaesmecotnitmaeinoifndgayE.DTBeAgiwnhniilnegon
on test day 50, the first 5 rats in the control and test groups were placed in metabolism cages and
urine and feces were collected daily fo3r days at 24-hour intervals. The urine and feces obtained
from a particular dose group was pooled. The exact time period of collection of urine and feces
was documented along with the total volume of pooled urine and weightofpooled feces
obtained. Urine and feces were stored frozen until analyzed for total fluorine. Blood was also
collected for total fluorine analysis each group and stored frozen.
at
3,
7,
14,
21,
35,
56,
and
84
days
after
the
final
dosing
of
K. Anatomical Pathology I. Dosing Phase
Following the attainment of steady blood fluorine levels and subsequent collection of urine and feces, the first 5 ats in the control and treated groups were euthanatized by carbon dioxide aKniedsntehyess,iaanadndfat.exsTahnegutiinsastuiesonwearned stthoerfeodlflroowzienngutnitsislueasnawleysriescoofllteotcatledflaunodriwneeilgehveelds:. liver,
2. Postdosing Phase cOanrbpoonstddioosxiindgedaanyes8t4h,esailla raenmdaiexnsiannggruaintaitniotnheacnodnttrhoelfaonldlotwrienagteidsgsruoeuspwsewreerceolcluetchtaenda,twieziegdhbeyd, and stored frozen until analysis of total fluorine levels: liver, kidneys, and fat.
L. Fluorine Analysis
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-
presence of wet oxygen and swept through an oxy-hydrogen flame in a closed quartz apparatus.
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`The combustion products were collected in an aqueous absorbing solution and analyzed with a
fHlausokreildle Liaonbosrealteocrtiyvpeeerlseocntnreolde.orKeivnaeltuiactainoanlyosfifsloufortihneepbipompFersiisnteeancceh.sample was performed by
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Laboratory. For the Wickbold torch method, the background fluorine level is 0.2 ppm. This is
the limitofdetection (LOD) of this method and was subtracted from each sample. The limit of
quantification (LOQ) for this methodis0.5 ppm, and any values listed as less than 0.5 ppm were
excluded from further treatment.
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experimental data.
`The maximum observed concentration in blood was Co (uM equivalent). Biopersistence was
assessed by quantifying terminal elimination blood half-life (Ts, days). The points included in
determination of the T; were selected manually and included only points after apparent log-linear elimination was achieved. Internal exposure was determined by calculating the blood area-
under-the-curve (AUC). AUC, which is simply the integral of blood concentration over time, is
the most common means for expressing internal dose. With the calculated half-life, the AUC can
~
be extrapolated to infinity (AUCINF) to reflect the elimination of the compound.
M. Statistical Methods Descriptive statistics (e.g. mean, standard deviation) were used for organ weights.
Significance was judged at p < 0.05.
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RESULTS AND DISCUSSION
A. In-Life Toxicology (Tables 1-2, Figure 1, Appendices A-B)
No deaths occurred during the study. No test-substance-related clinical signs were observed. No statistically significant differences in mean body weights compared to control were observed for the test-substance treated group. No statistically significant differences in mean body weight gain comparedto control were observed for the test-substance treated group with the exception ofa significant increase in mean body weight gain during the 95-98 and 102-105 test day intervals.
B. Liver Weights (Table 3) 1. Test Substance
`The absolute liver weight of rats dosed with the test substance, H-24159, was 9% lower on test ~. dcoanytr5o3lcaonmdptaerstedsutbosctoanntcreolt,rewahtieldeanthiemamlesawnerreelatthievesalimvee.r wAetigthhtese(nidvoefr/tbhoedryecwoeviegrhyt)peorfitohde(test
day 136), the absoluteliver weights of the H-24159 treated animals were 15% higher than control, while the mean relative liver weights were similar to control.
C. Kidney Weights (Table 4)
"The absolute and relative Kidney weights ofrats dosed with H-24159 were similar to control on atensitmdaalys w53e.reA2t4t9h%eheingdhoefrtthheanrceocnotvreorly, pwehriiloed,thaebsmoelaunterkeliadtnievye wkeiidgnhetyswoefigthhtesHw-e2r4e15si9mitrleaartteod control
D. Fluorine Data (Tables 5-12, Figures 2-4, Appendices C-H)
Total blood fluorine concentrations were converted to micromolar (4M, micromoles per liter)
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fluorine as presented in termsof the area under the blood curve extrapolated to infinity
(AUCINF, uM x days) was 4.24x10. The calculations and equations are shown in Appendix C.
`sThhoewcnonicnenAtprpaetnidoincoefsfEl.u-orGi.neTihnerartelbaltoiovde,rlainvkeri,ngfatofanflduokriidnneeiynartatsttuidsysudeasywsa5s3lainvde>r13k6iadren. e>y nfaeta>rlybleoqoudivaatlebnotthatstbuodtyh dtahyesdo5s3iangndan1d36re(cFoivgeurrye t4)i.meTphoeintrsa.tioFolfuotrisisnueectooncbelnotordatfilounosriinnetwhaes control group blood and tissues were generally below the limit of quantification.
`cTahveeadtastaanudsecdonisnitdheeraktiinoentsicaarneailmypsoirstawnetr.e dTehreisveedcofnrsoimdearaltiimointsedisnccrleuedne,tahnedlitmhietraetfioornessoefvesrinaglle: edsotsiemasttuidnigeeslwimhiennateixotnrakpionletaitcisn,ga1n0dotthheerldiomsietisn,gsomfalklinseatimcplaenasliyzsei,sltiomiotneldydtahteabplooiondts for compartment. A more complete list of considerations is shown in Appendix C.
CONCLUSIONS
Rclaitnsicdaolssedifogor rn5b2sodda,yyswweiitghht35efmfegc/tks.g/MdaeyanH-l2i4ve1r5a9nedxhkiibdinteeydwneoigmhotrstarleiltayt,ivteesttosubbosdtyanwceei-grhetlated. were similar to control in the test substance treated animals
-
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ttiesrsmuiensalwietlhimtihnearteiloantihvaelfr-alinfkeinogfo3f8l.i0vdeary>s.kiFldunore>iynefawta>s bplroeosednatt ibnoetahcthheofstteheadeyxsatmatienaenddrat
broetchovteirmyetpiomientpso.intUs.ndeTrhesteraatdiyo-sotfatteiscsounedtiotibolnoso,dfflluuoorriinneeweaqsuievlailmeinntastewdasinnuerairnley aenqudifveacleesntatata
rate of mmoles/kg body wilday.
RECORDS AND SAMPLE STORAGE
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Laboratory be retained
specificorsite-specific at the facility where the
raw data such as work was done.
personnel
files
and
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records
will
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REFERENCES
1. Draper, NR. and Smith, H. (1981). Applied Regression Analysis, 2% edition, pp 266-273.
Wiley, New York.
2. Selwyn, MR. (1995). The use of trend tests to determine a no-observable-effect level in animal safety studies. Journalof the American Collegeof Toxicology 14(2), 158-168.
3. Jonckheere, AR. (1954). A distribution-free K-sampl test against ordered alternatives. Biometrika 41, 133-145.
4. Levene, H. (1960). Robust test for equality of variances. Contributions to Probability and Statistics (1. Olkin, ed.), pp 278-292. Stanford University Press, Palo Alto.
5. Shapiro, $.5. and Wilk., M.B. (1965). An analysis of variance test for normality (complete samples). Biometrika 52, 591-611.
6. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6" edition, pp 246-248 and 349.352. The Towa State University Press, Ames.
7. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments
--~
with a control. J. Amer. Statist. Assoc. 50, 1096-1121
8. Kruskal, W.H. and Wallis, W.A. (1952). Use of ranks in one-criterion analysis of variance. J. Amer. Statist. Assoc. 47, 583-621.
9. Dunn, 0. (1964). Multiple contrasts using rank sums. Technomerics 6, 241-252.
ZS -- Company Sanity,ed. Doesnotcontain Tsp gy
1.24159: Biopesistence Srcening
Biman
TABLES
En Company Sanitized. Does notcontain TSC0A
1Go2a0g1e55SBuioipesrine Scrcring
won:
-
--_--
Test Days
0
47 1un
18
%221 53
39 42
456
56 &
67 70 74 m 81 84 88 91
095
102 105
1i110ns9
`TABLE 1
MEAN BODY WEIGHTS
Negative Control Deionized Water
Dosing 260.8
23802196 ws 3184
350.1
3346369.9 3i906308
4116 4213
4w3213s.1
"Test Substance H-24159
258.7
228008.41 3012623
3473
33366008.260 S38o6s8
400.1 409.1
42a1n382
Re5rco6yv0ery
4n9a6
is20
4503
456.8
485.6
463.7
499.0
467.5
504.8
4715
513.1
4794
519.0
485.8
524.1
488.0
529.4
490.1
537.0
449937.01
553590.52
504.1
558.8
506.3
568.2
SS5i01t60.a8
55o6796o.26
Company Sanilac, Dono econtsain Ts cay
`1G.a2v4a1g5e0:SwBdiyopienrsRiasttsence Screening.
TABLE I (Continued) MEAN BODY WEIGHTS
DuPont6732
Test Days 119 123 126 130 133 136
Negative Control
Deionized Water 5239 532.1 536.6 5425 545.7 5462
TestH-S2u4b1st5a9nce 587.8 5926 597.7 604.5 607.8 604.5
There were no statistically significant differences from vehicle control at p < 0.0.
-_--
=
Company Saniizec. Doss notcontain Tse cir
HGa2v4a1g5e9:SBtiyopeinrsRsattsenceScreening
DuPont6732
TABL2E
MEAN BODYWEIGHT GAINS (g)
Dosing and Recovery
Test Days
Negative Control Deionized Water
Test Substance H-24159
Day0-Day4
21 72010)
214 6510)
Day4-Day7
187 6.1010)
184 54(10)
Day7-Day 11
168 57010)
178 43010)
Day 1-Day 14
19.1
160
--
64010)
49010)
Day 14- Day 18
127 58010)
15.1 42010)
Day 18 - Day 21
138 46010)
127 3.0010)
Day 21 - Day 25.
n
86
8.1010)
7.2010)
Day25 -Day28
128 4100)
1s 39(10)
Day 28 - Day 32
84
66
10.710)
4410)
Day 32- Day 35
77
77
40010)
43010)
TagompanySaniized. Dos notcontain TSCA Ca
G12v4a1g5e9:SuBdiyopienrRsaitssence Screening
DuPon6732
TABLE 2 (Continued)
MEAN BODY WEIGHT GAINS (8)
Test Days
Negative Control Deionized Water
Test Substance H-24159
Day35 - Day 39
78 111310)
56 107010)
Day 39 - Day 42
98
34010)
9 34010)
Day 42 - Day 46
97 11210)
91 6310)
Day 46 - Day49
n2 3510)
102 4.1010)
Day 49 - Day 53
4
28
-
17.700)
18.3(10)
Day 53 - Day56.
02
02
4765)
5365)
Day 56 - Day 60.
51
635)
ns 6005)
Day 60 - Day 63
103
89
4405)
4065)
Day 63 - Day67
48
53
7465)
485)
Day 67- Day 70
69
685)
134 7565)
Day 70 - Day 74
39
59
346)
4205)
= -_-- `Company Sanitized. Doesnotcontain TSCACBI
HGa2v4a1g5e9:StuBdiyopienrRsasiisence Screening
DuPon6732
`TABLE 2 (Continued)
MEAN BODY WEIGHT GAINS (g)
Test Days
Negative Control Deionized Water
Test Substance H24159
Day 74-Day 77
10
82
3.165)
385)
Day 77 -Day81
18
59
925)
2165)
Day 84 - Day 88
22
53
7.065)
4005)
Day 81 -Day84
64
si
346)
1665)
Day 88 - Day 91
21
76
-
5565)
2265)
Day 91 - Day 95
3
21
495)
645)
Day95 - Day98
39
8965)
14@ 376)
Day 98 - Day 102
71
82
3265)
385)
Day 102- Day 105
22
95
4265)
2365)
Day 105 - Day 109
os
14
6505)
4765)
Day 109 - Day 112
43
66
6.15)
4065)
- `CompanySanltized. Doss not contain TSCACEL
1Ga2v4a1g5e9:SuBdiyopienrRsaissence Screening
Dupont6732
`TABLE 2 (Continued)
MEAN BODY WEIGHT GAINS (2)
-- Test Days
Negative Control Deionized Water
Test Substance H-24159
Day 112- Day 116
8
92
765)
5405)
Day 116 - Day 119
48
24
2465)
365)
Day 119- Day 123
82
48
5605)
406)
Day 123 - Day 126
46
52
615)
2205)
~
Day 12-Da6y 130
59
61
3265)
4165)
Day 13-Da0y 133
32
33
296)
4465)
Day 133 - Day 136
05
4565)
33 10.165)
Day 0-Day 53
1805 64.1(10)
1725 39.7010)
Day 53-Day 136
104 19.55 )
145.1 46205)
Dats summarized as: `MSetaanndard Deviation ()
@ NPaornapmaertarmiectcroimcpcaormipsaornitsocoonnttorcoolnt(rDolun(nDeurnnT'asm)bsairgnei-fDicuannntet) significant
we Company Sanitized. Does notcontain TSCA CB
1G2a4v1a5g9e:SuBdiyopienrRsaissence Screening
DuPon6732
Test Days n_ EI] Bs
TABLE 3
MEAN BODY AND LIVER WEIGHTS (g)
DEIONIZED WATER (NEGATIVE CONTROL)
Absolute
Body Weight Liver Weight
44638
15.192
5462
18379
Mean Relative, Liver Weight (Liver/Body Weight)
0.034 0.034
Test Days n 5s 136s
H-24159 (TEST SUBSTANCE)
Absolute
Mean Relative
Body Weight Liver Weight __ Liver Weight (Liver/Body Weigh)
4028
13794
0034
604.5
21219
0035
= `Company Sanitized. DossnotcontainTSCACBY
G1a.2v4a1g5e9:StuBdoypienrRsaisnce Srcning
Dupon732
TABLE4 MEAN BODY AND KIDNEY WEIGHTS ()
DEIONIZED WATER (NEGATIVE CONTROL)
TDeasyts n Body WeighAtbsoluKtiedney Weight_ Kidney WeigMheta(nKiRdelnaetyi/vBeody Weight)
53
5
446.8
3.153
0.007
136 5
546.2
6.382
0.012
TDeasyts n
53
5
136 5
H-24159 (TEST SUBSTANCE)
Body WeighAtbsolutKeidney Weight _ Kidney WeigMeha(nKiRcelnaetyi/vBeody Weight
402.8
3.178
0.008
604.5
7.937
0.013
EE
--
CompanySanitized. Doesnotcontain TSCA CBI
HGa2v4a1g5e9:StBuidoypeirnsRiasttsence Srcening
DuPon.6732
TABLE 5
MEAN BLOOD FLUORINE LEVELS
NegativeControl
TestSubstance:
Test
Deionized Water
Da=ys
+ (ppm F)
H24159 3(ppm F)
0
-
4
A
439 08)"
930 (1)
9
08402)
1037 27)
14
0.57 0.1)
1153 (17)
21
-
23
-
1108 (20) 1446 (1.8)
35
--
1154.0598
(16) (19)
9
:
1404 (13)
5
i:
1276 (19)
55
3
7.98 (13)
-
5696
:,
842 (0.9) 574 (06)
7
080(05)
474 (LO)
87
-
39 (03)
110386
0:.70 (0.1)
2157440(403))
ab SAtlalnvdaalrudesdewveiraetiboenlsoiwntphaerleinmtihteosfesq.uantification (LOQ < 0.5) MMeaenaofn73oooffhfhee 1100 vvaalluueess., STherveeenooff tthhee vvaalulesswweerreebbeellooww tthhee LLOOQQ. MMeeaannoof32foofftthehe5 vvaalluueess.. TThwiocoefotfhtehevavlauleuseswewreerebbeellowowthteheLOLQO.Q. ~ Indicates no fucine analysis performed on sample for this day Note: Only values tested or days 53 to 136 (recovery).
-=
Company Senitized. Doss not contain Tscace
1Ga2v4a1g5e9:SuBdiyopienrRsaissence Screening
DuPon.6732
TABLE 6
MEAN BLOOD FLUORINE CONCENTRATION EXPRESSED IN 4M EQUIVALENTS
Test Substance
Test
H24159
EDra)ys
1M Equivalents F :
0
4
1693 (3.35)
3677 (12.51)
9
41.09 (11.03)
14
4578 (699)
21
4396 (1.93)
28
5762 (1.25)
35 2
56.12 (6.59) 62.14 (1.80)
9
5592 (537)
53
5075 (1.51)
55
3143 (5.14)
-
EY
321 (381
66
2238 (2.30)
7
1834 (4.04)
87
15.19 (1.09)
108
9.45 (1.09)
136
622 (1.75)
ab ASltlanvdaalrudesdweeviraetbieonlowinthpearleinmtihteosfesq.uantification (LOQ, <0)
Note: Only values tested ordays 53to 136 (recovery).
-= `Company Sanitized. Boos not contain TSCACH"
1Ga2v4a1g5e9:SuBdiyopienrsRiasttsence Screening
Dupont6732
TABLE?
MEAN LIVER FLUORINE LEVELS
Negative Control
`Test Substance:
Test
Deionized Water
H24159
Days
(ppm F)
(ppm F)
53 136
0.60" 057_.1)
176.04 (17.6) 20.60 (5.7)
ab MSteaandnarodf 1dofehevivalaiunepst.ariFeohuocrsonsf.the valueswerebelow the limit ofquantification (L0G).
TABLES
MEAN LIVER FLUORINE CONCENTRATION EXPRESSED IN 4M EQUIVALENTS
-
Test Substance
Test
H24159
Days
4M Equivalents
53
136
781204426 ((2730..0977))
5 Standard deviations in parentheses.
Note: Only 5 values tested fordays 54 and 137 (recovery).
-
Company
Santized.
Does
not
contain
--
TsccA
2Ga4v1a5g9e:SuBdiyopienrRsaitssence Screening
Dupont6732
TABLE9
MEAN FAT FLUORINE LEVELS
Negative Control
Test Substance
Test
Deionized Water
H24159
Days
(ppm F)
(ppm F)
53
075 (0.4)
18.86 (16)
136
:
520 (09
ba SMteaanndaordf2doevfitahteion vialiunesp.arTchretsecso.fthe values were below the limit of quantification (LOQ). All valueswerebetlheoLOwQ.
TABLE 10
--
MEAN FAT FLUORINE CONCENTRATION EXPRESSED IN iM EQUIVALENTS
Test Substance
Test
H24159
Days
4M Equivalents
53
136
72503290 ((366557)
4 Sundard deviation is in penises Note: Orly5 values tested for days 54 and 137 recovery).
diiizes. Goes not Gna TSCA C=
2Ga4v1a5g5e:StuBdiyopienrRsiassence Screening
Dupont6732
TABLE 11 MEAN KIDNEY FLUORINE LEVELS
Negative Control
Test Substance
Test
Deionized Water
H24150
Days
(ppm F)
(ppm F)
5
056 (0.3)
76.08 (14.1)
136
090"
9.66 (29)
a SMuenadnaorfd doevfitahteionviasluiensp.arFcohuersoefsthe valuesweebelow the limit of quantification (LOG).
TABLE 12
-
MEAN KIDNEY FLUORINE CONCENTRATION EXPRESSED IN 4sM EQUIVALENTS
TestSubstance:
Test
H24159
Days
1M Equivalents
53
30659 (57.04
136
3822 (11.82)
a Standard deviation is in parentheses.
Note: Only5 values testedfor days 54 and 137 recovery)
3 CompanySanitized. Docs notcontalnTSCACZ
H24159: Biopersistence Screening. Gavage Study in Rats
DuPont.6732
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--
APPENDICES
-_-- Company Sanitzed. Does not contain Tsca ce:
H24159: BiopersistenceScreening Gavage Study in Rats
DuPont6732
APPENDIX A Individual Body Weights
3 Company Sanitized. Does not contain TSCA CBI
G1a2v4a1g5e9:StBuidoypienrRiastsenceScreening
INDIVIDUAL BODY WEIGHTS
ABBREVIATIONS: SD - sacrificed by design
EXPLANATORY NOTES
NOTE "The first 5 animals were sacrificed by design on test day 53.
DuPont6732
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53
2
3
3
~ 234
EH
L[I o
5=
u
x.
5
8
=TL=
CompanySwed. DossrotcomanTSCA"
3
i
3d
i,
8% gi
EEE 3 sex
gn yam 8. Im
`
858 fied,
Ea H2zagd
i100 hmm
. :
iy is 3 -~ i233Z)
o lfaiisiiigiiiilas Fadia i Ssssassdd
ii i d 3Ti=x
CompanySaid. Does ntcontTaSCiAn
H24159: BiopersistenceScreening Gavage Sudy in Rats
DuPont6732
APPENDIX C Terms and Calculations Factors Influencing Interpretation of Kinetic Analysis
5-- `Company Sanitized. Doosnotcontatn rms may
1G2a4v1a5g9e:SuBdiyopienrRsasttsence Screening
Dupon6732
Terms: Active % Active
Mol Wt Active 9% Fin Active
TERMS AND CALCULATIONS
Fluorine containing compound(s) "The % of formulation that is made upoffluorine containing components `The molecular weight of the fluorine containing components (g/mole) "The % fluorine in the fluorine containing components of the: formulation (weight basis)
Individual Animal Measurement:
ppm F
`The ppm fluoride measured
-
Individual Animal Calculations:
molar equivalents of active
"The umolar [mol/L] concentration of fluorine containing compound
based on the ppm fluorine measured minus the background fluoride
level (0.2 ppm). This assumes that all fluorine is derived from the
fluorine-containing component in the formulation.
Note: 1 ppm =1 mg/L
= (ppm [mg/L] fluorin/e Active [mg active/mmol
% F in active]
active x 1000
[mg active/mg ymol/mmol
F]
/
Mol
Wt
--
= Company Sanilized. Doe~s not containTSCAGp
FACTORS INFLUENCING INTERPRETATION OF KINETIC ANALYSIS
Considerations:
tlw - The data used for kinetic analysis was from a limited screen and extrapolation should be done cautiously.
~ Analytical data used without validation
~- 12015 Terminal sfphase elimination may not be reached
Assumptions: (May or may notbe justified in all cases)
- Fluorine concentrations are linear with respect to dose
a teen fmol - Elimination kinetics can be determined based on total fluorine rather than on concentrations of
a: - Background Fluorine is 0.2 ppm
Tea 8Eom momain --_
- 9% F data is the % Fluorine of the active (Fluorine containing component(s) in the formulation)
EE, Ge
Company Sanitized. Does notcontain TSCA C21
HGa2v4a1g5e9:SuBdiyoipnesRiassence Screening
DuPon6732
APPENDIX D Individual Fluorine Levels in Blood
36 `Company Sanitized. Does notcontain TSCA GAY
HGa2v4a1g5e9:StuBdiyopinerRsatsstnce Screening
~
Data for Negative Control
DuPont.6732
Test ppmF
Rat Day
in
Number Sample Blood
649293
"4
<05
649294
"4
<05
649295
"4
05
649296
4
<05
649297
4
<05
649298
"
<05
649299 "
<05
649300 "
<05
649301
"4
<05
649312
"4
<05
649293
4
<05
649294
4
0s
649295
4
<0s
649296
4
<05
649297
4
05
~
649298
4
<05
649299
4
<05
649300
4
<05
649301
4
05
649312
4
05
649293
9
07
649294. 9
<5
649295
9
05
649296
9
<05
649297
9
<05
649298
9
09
649299
9
08
649300
9
09
649301
9
Ll
649312
9
10
649293
14
<05
649294
14
<05
649295
14
<0s
649296
14
05
619297
14
<05
649298
14
<0s
649299
14
05
-
649300
14
05
-
"Pan Sanitizea. Does poy contain Tc gr
2Ga4v1a5g0e:SuBdioypeinrsRiasiesnce Sreening
Test ppmF
Rat Day
in
Number Sample Blood
649301
14
07
649312 14
05
649293
4
<0s
649294
9
<05
649295
ry
<05
649296
4
<05
649297
ry
<05
649298 49
<05
649299 4
<0s
649300 49
<0s
649301
ry
<05
649312 49
<05
649293 53
<05
649294 53
<05
649295 5
<05
649296 5
<05
649297
5
<05
-
649298 55
<05
649299 55
<05
649300 55
<05
649301
55
<05
649312
55
<05
649298 59
<05
649299 59
<05
649300 59
<05
649301 59
<0s
649312 59
<0s
649298
7
L4
649299 7
<05
649300 7
06
649301
7
04
649312 7
<05
649298 108
08
649299 108
<05
649300 108
<05
649301
108
<05
649312 108
06
649298 136
<05
649299 136
<0s
-
649300 136
<05
DuPon6732
CY Sizes, Dos not conan rac
HGa2v4a1g5e9:StuBdiyopienrsRiasttsence Sercring
Test ppm F
Rat Day
in
Number Sample Blood
649301
136
<0s
649312 136
<05
DuPont6732
50 Company Sanitzed. Does not conten 75, ca
HG2a4v1a5g9e:StBuidoypeinrsRaitssinceScreening
-
Data for H-24159
Given: Mol Wt. Active (g/mole): % Active(F Containing) in Formulation: % Fin Active:
DuPon6732
Test ppmF
Rat Day
in
Number Sample Blood
Equmiovlalaernts of Active in
Blood
649302
"4
<05
.
649303
"
<05
649304
"4
<05
*
649305
"4
<05
*
649307
"4
<05
*
649308 "4
<05
649309
"4
<05
*
649310
"
<05
*
-
649311
"
05
*
649313
"4
05
*
649302
0
45
1737
649303
0
26
9.70
649304
0
50
19.39
649305
0
42
16.16
649307
0
50
19.39
649308
0
36
13.74
649309
0
44
1697
649310
0
41
15.76
649311
0
53
2061
649313
0
52
2020
649302
4
48
18.59
649303
4
63
24.65
649304
4
102
4040
649305
4
54
2101
649307
4
85
3354
649308
4
17
46.46
649300
4
1.0
4364
649310
4
13.1
52.12
649311
4
86
33.94
649313
4
134
5333
-
649302
9
59
2.03
649303
9
140
55.76
EE
--
`Company Sanitized.Doesnotcontain Te =.
1G2o4v1g5e9:SuBdiyopienrRsaittsence Screening
-
Test
Rat
Day
Number Sample
649304
9
649305
9
649307
9
649308
9
649309
9
649310
9
649311
9
661499330123
194
649303
14
664199330045 1414
661499330087 1414
661199330190 1144
-
661199331113 1144
649302
21
649303
21
649304
21
649305
21
649307
21
649308
21
649309
21
649310
21
649311
21
649313
21
649302
28
649303
28
649304
28
649305
28
649307
28
649308
28
649309
28
649310
28
664199331113
238
649302
35
~~
649303
35
-
ppm F
in Blood
143 75 115 107 83 103 9.1
128.1 6
10.5
18375 112267 11248 1w2o6
9.0 107 8.8 98 11.8 9.9 145 11 1.0 14.2 10.9 145 16.2 15.5 128 15.0 16.8 132
1135.98
12.1 128
Equjipvmaollaernts
of Active in Blood
56.97 29.49 45.66 4242 3273 40.81 35.96
4383.9048
41.62
5334.3744 5500..5110 5502951 a50.n10
35.56 4242 34.75 38.79 46.87 39.19 57.78 44.04 43.64 56.57 4323 57.78 64.65 61.82 50.91 59.80 67.07 52.53
655..0335
48.08 50.91
Durone732
a omeanySuited. Does notcartan rs.
1Ga2v4a1g5e9:SuBdiyopienrRsaitssence Sexeening
-
Test ppmF
Rat Day
in
Number Sample Blood
649304 3s
16.1
649305 649307
35 35
163 126
649308 649309
35 35
158 155
649310 649311
3355
1133.21
649313 649302
35 pel
134 17
664499330034 aa2
156 189
649305 2
139
649307 2
165
649308 2
156
649309 2
152
649310 2
159
-
649311 2
151
649313 2
174
649302 9
12
649303 9
130
649304 4
19
649305 49
134
649307 9
134
649308 49
143
649309 9
154
649310 49
146
649311 49
141
649313 49
156
649302 3
145
649303 53
114
649304 53
138
649305 53
102
649307 53
139
649308 55
59
664499330190 5555
83 87
649311 55
78
649313 55
92
-
664499330089
59 50
84 71
Equpimvoallaernts of Active in
Blood 6424 65.05 50.10 6.03 61.82 522.1523 533 246.246 7555.3556 65.86 022 6061 6343 020 4694.4449 51.72 5039 5333 5333 5899 6La1 58.18 56.16 on 57.78 4525 54.95 4040 5535 23.03 273 33047314 36.36 B13 2788
Dupont6732
Te enim bommtcomamrsone
1G.u2a41g5e9:StuBdiyopienrRsaitsstnce Seeing
-
Rat
Test ppmF
Day
in
Number Sample Blood
649310 59
80
649311
59
91
649313
59
95
649308 6
sl
649309 6
57
649310 6
66
649311
6
59
649313 66
54
649308 73
38
649309 7
42
649310 7
64
649311
7
48
649313 7
as
649308
8
38
649309 87
36
649310 8
al
69311
8
43
-
649313
8
40
649308 108
21
649309 108
26
649310 108
28
649311 108
27
649313 108
25
649308 136
Ll
649309 136
17
649310 136
19
649311 136
17
649313 136
23
+ BelowLOQ (Limit ofQuanificsion)
molar Equivalents of ABcltoiovde in
3152 3596 3758 19.80 22 25.86 23.03 2101 1455 16.16 2505 1859 1737 1455 1374 1576 1657 1535 768 970 1051 10.10 929 364 606 687 606 848
Dupont6732
7 Company Sanlizsd. boos not contain sac;
`1G2a4v1a5g9e:StuBdiyopienrRsasttsenceScreening.
DuPont6732
_
APPENDIX E
Individual Fluorine Levels in Liver
--
ae Company Sanitized. Doesnotcontain TGA &
24150: Biopersistence Sereening GavageSudyioRas
000000000000 Dwowenz
-
Data for Negative Control
Test ppmF
Rat Day
in
Number Sample Liver
649293
53
05
649294 53
<05
649295
53
05
649296
53
05
649297
5
06
649298 136
05
649299 136
05
649300 136
07
649301 136
<05
649312 136
<05
I
ompany Sanlaad. Doss no cantinTSCAGS!
G1a2v4a1g5e9:SuBdiyopienrRsaitssence Screening
-
Data for H-24159
Given: Mol Wt. Active (g/mol): % Active (F Containing) in Formulation: % Fin Active:
Dupon6732
Rat Number
Test Day Sample
ppm F in
Liver
Equmiovlalaernts of Active in _Liver
649302
53
1898
766.06
649303
53
1693
683.23
649304
53
198.8
80242
649305
53
156.8
63273
649307
53
165.5
667.88
649308 136
137
5455
649309 136
193
77.17
649310
136
260
10424
649311
136
17.1
68.28
-
649313 136
269
107.88
- Company Sanftized. Doesnot containTSCACE
1Ga2v4a1g5e9:StuBdiyopienrRsitsstence Screening
DuPont6732
_
APPENDIX F
Individual Fluorine Levels in Fat
a
--
Company Sanltzed. Does not containTSCA Ca)
HGa2v4a1g5e9:StuBdiyopienrsRiasttsence Sreening
=
Data for Negative Control
Test ppmF
Rat Day
in
Number Sample Fat
649293
53
0s
649294
53
10
649295 53
05
649296 53
<05
649297 53
<05
649208
136
<05
649299
136
<05
649300 136
<05
649301 136
<05
649312 136
05
DuPont 6732
- [--
---- an2
HG:a2v4a1g5e5:StBaiypenrsRiatsstece Screening
Dupon.732
---
Data for H-24159
Given:
5
Mol Wt. Active (g/mole):
99%%FAcitnivAect(iFveC:ontaining) in Formulation:
Rat Number
Test
Day Sample
ppm F
in Fat
Equmiovlalaernts
of Active in Fat
649302
53
20.6
82.42
664499330043
5533
1197.51
976..9306
664499330075
553
210629
8607..8417
649308
136
56
21.82
649309
136
59
23.03
649310
136
59
23.03
649311
136
4.8
18.59
-_--
649313
136
38
14.55
pe
--------
CompanySanftized. Does not contain TSCAC5)
1G4a2r4a1g5e5:StByopnrastsstnc Screening
Durona732
--
APPENDIX G
Individual Fluorine Levels in Kidneys
--
=
Company SizDose snotdcon. ta TSCA CE!
HGa2v4a1g5e9:StBuidoypeinrsRsatsenceScreening
~
Data for Negative Control
Rat Number 649293 649294 649295 649296 649297 649208 649299 649300 649301 649312
Test Day Sample
53 53 53 53 5 136 136 136 136 136
ppmF in
Kidneys 08 12 09 0s 09 05 05 <05 <0s 09
DuPort6732
I Company Sanitized. Doos notcontaln-- TSCAC-- BI
1G.a2v4a1g5e0:StuBdiyopienrRsaitsstnce Screening
-
Data for H-24159
Given: Mol Wr. Active (g/mole): % Active (F Containing) in Formulation: % Fin Active:
DuPont6732
Rat Number
Test Day Sample
ppmF in
Kidneys
Equmiovlalaernts of Active in Kidneys
649302
53
934
376.57
649303 53
60.1
24202
649304 53
6.0
25374
649305 53
829
334.14
649307 53
810
32646
649308 136
60
2343
649309 136
103
4081
649310 136
84
33.13
649311
136
140
5576
-
649313 136
96
3798
"72" Company Sanllizod. DoesnotcontainTSCACEN
`1G.a2v4a1g5e0:SuBdiyopienrsRiasttsence Screening.
Dupon6732
APPENDIX H Urine and Feces Data
TT
7FOmPuny Sanlized, poggnotcontain Tscp cy
HG2a4v1a5g9e:StuBdiyopnerRsaissence Screening
Data for Negative Control Test Day _ppmF
Une SI 89 Une 52 102 Une 53 68 Feces 51 sl Feces 2 Ll Feces 53 LL
Dupont6732
~74= Company Sanitized. Doss notcontainTSCA C8!
HG2a4v1a5g9e:StByiopienrRsaitssence Screening
-
Data for H-24159
Given: Mol Wt. Active (g/mole): % Active (F Containing) in Formulation: % Fin Active:
DuPon6732
oo Une Une Une Feces Feces Feces
Test
pmole Equivalents
Day ppmF_gormijday pgFiday of ActiveDay
51 127 700 889.00 52 99 460 455.40 53 87 540 469.80 51 396 35 139.39 52 389 243 945.27 53 415 153 634.12
3591.11 1839.19 1897.37 56239 3818.46 2561.29
= `Company Sanilized. Does not contain TSCAGB