Document ByNGBwzdEe79bGJEmgxKOmQYk
TRADE SECRET
Study Title H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Laboratory Project ID: DuPont-2924
AR226-3156
DuPont-2924
AUTHOR: CarolFinlay,B.A.
STUDY COMPLETED ON: August 3, 2000
PERFORMING LABORATORY: E.I. du Font de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050
fadnr
WORK REQUEST NUMBER.fLj SERVICE CODE NUMBER--n i
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
CERTIFICATION
We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study.
Reviewed by:
Gary W. Jepson, Ph.D.
Senior Research Scientist
Reviewed by::
C^^^C (]. Mojoiie.^
^fJudith C. Stadler,lti.D., D.A.B.T.
(/
Director, General Toxicology
Issued by Study Director:
^i&^ ^SL/lb^ Carol Ffalayy,, B.A. 9 Staff Scientist
2. ft*6 <2oot>
Date
S-^UG '20QQ
Date
<? - fi ULr . 'tOO ft
Date'
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H-24001: Biopersistence Screening 10-DoseOralGavage Study in Rats
DuPont-2924
TABLE OF CONTENTS
Page
CERTIFICATION........................................................................................................................^
LiliS 1 Of 1 ABLEo ..........................................................................>..............>...........>............>.4
LISTOFFIGUKES.......................................................................................................................4
LIST OF APPENDICES...............................................................................................................4
STUDY INFORMATION .............................................................................................................5
STUDY PERSONNEL...................................................................................................................?
SUMMARY ....................................................................................................................................8
INTRODUCTION..........................................................................................................................9
MATERIALS AND METHODS ..................................................................................................9
A. Test Substance and Positive Control...................................................................................^ B. Test Species .........................................................................................................................9 C. Animal Husbandry.............................................................................................................10
1. HousingEnvironment..............................................................................................--.--........................lO 2. Feed and Water.......................................................................................................................................10 3. Identification..........................................................................................................................................10 4. Animal Health Monitoring Program.......................;......--...................................................................... 10
D. Quarantine and Pretest.......................................................................................................11 E. Study Design.;....................................................................................................................ll F. Assignment to Groups and Study Start..............................................................................11 G. Dosing Material Preparation and Administration..............................................................11
1. Test Substance........................................................................................................................................11 2. Positive Controls....................................................................................................................................12 3. Negative Controls...................................................................................................................................12
H. BodyWeights.....................................................................................................................l2 I. Mortality and Clinical Observations..................................................................................12 J. Collection and Analysis of Blood and Livers ....................................................................12 K. Treatment of Fluoride Data...............................................................................................13
RESULTS AND DISCUSSION ......................................................................'............................14
A. In-Life Toxicology............................................................................................................. 14 B. Fluorine Data .............................................>...........-......................-........................-.......14
1. Factors Influencing Interpretation of Analysis.............................................................................. ...--...14
2. Positive Controls....................................................................................................................................14 3. TestSubstance........................................................................................................................................l5
CONCLUSIONS ..........................................................................................................................15
RECORDS AND SAMPLE STORAGE ....................................................................................15
TABLES........................................................................................................................................16
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
rlGLri<ES <,...................................<,......................................................<,..........................................21 APPENDICES ..............................................................................................................................26
LIST OF TABLES
Page
1.
TABLE
1
MEAN
BODY
WEIGHTS
17 ..................................................................................................................
2.
TABLE
2
MEAN
BODY
WEIGHT
18 GAINS........................................................................................................
3. TABLE 3 MEAN BLOOD FLUORINE LEVELS............................................................................................... 19
4. TABLE 4 MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE ...............................20
LIST OF FIGURES
Page
1. MEAN BODY WEIGHTS................................................................................................................................... 22 2. MICROMOLAR EQUIVALENTS IN RAT BLOOD..........................................................................................23 3. MICROMOLAR EQUIVALENTS IN TEST COMPOUND AND POSITIVE CONTROLS .............................25
LIST OF APPENDICES
A. INDIVIDUAL BODY WEIGHTS.......................................................................................................................27 B. INDIVIDUAL CLINICAL OBSERVATIONS ....................................................................................................61 C. ANALYSIS OF BLOOD FLUORIDE DATA .....................................................................................................72
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY INFORMATION TEST SUBSTANCE;
Substance Teg
Synonyms/Codes: 1
DuPont-2924
Known Impurities: Unknown
POSITIVE CONTROL;
Substance Tested:
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Known Impurities: Unknown
POSITIVE CONTROL;
Substance Tes
DuPont-2924
Known Impurities: Unknown
Sponsor:
E. I. du Font de Nemours and Company Wilmington, Delaware 19898
U.S.A.
Study Initiated/Completed: April 30,1999 / (see report cover page)
In-Life Initiated/Completed: May 30,1999 / August 30,1999
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Company
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY PERSONNEL
Study Director: Management:
Primary Technician:
Carol Finlay, B.A. Judith C. Stadler, Ph.D., D.A.B.T. Richard P. Mathena
Blood Fluorine Data Analysis: Gary W. Jepson, Ph.D. Management: Matthew S. Bogdanffy, Ph.D., D.A.B.T.
Toxicology Report Preparation: Wanda F. Dinbokowitz
Laboratory Veterinarian: Wanda L. West, D.V.M., A.C.L.A.M.
DuPont-2924
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
SUMMARY
The objective of this study was to evaluate the potential for H-24001, when administered by gavage, to be absorbed and to accumulate in a mammalian system. Six groups of 5 male Cri:CD(SD)IGSBR rats each were exposed to 1000 mg/kg/day of H-24001. The test substance was administered to one group of five rats for 5 consecutive days and to 5 groups for 10 days. Approximately two hours after the first dose, blood was collected from the orbital sinus of each
rat from the 5-dose group. On selected days (5,10,13,24,52, 93/94) 5 rats per group were
euthanized and the blood and livers were collected. Body weights and clinical signs were recorded on each day of dosing and then approximately every other week during the recovery period. Additionally, 2 negative controls, corn oil and corn oil/acetone (80:20), and 2 positive controls, H-24019 (10 mg/kg/day) and H-24020 (20 mg/kg/day), were tested as described for H-24001.
No deaths occurred during the study. No compound-related clinical signs oftoxicity were observed in the rats dosed with H-24001. Rats dosed with a positive control material, H-24019, exhibited diarrhea, salivation, alopecia, black ocular discharge, and staining of various parts of the body during the dosing period. Rats dosed with H-24020, the other positive control substance, exhibited wet perineum and diarrhea during the dosing period. Alopecia was observed during the recovery period for rats dosed with H-24001, H-24019, and H-24020. The negative control rats exhibited no clinical signs during the study.
Comparison of body weights was complicated by a difference in age on test day 1 between the rats dosed with the test substance and those dosed with the positive or negative controls. Accounting for the age difference at study start and the expected rate of body weight gain, the mean body weights and mean body weight gains of the rats dosed with H-24001 were comparable to the negative controls and equal to or greater than the positive controls.
A steady-state for fluorine levels in whole blood was not achieved during 10 consecutive days of dosing with 1000 mg/kg H-24001. An area under the curve (estimated to infinity) was calculated and normalized for fluorine content for the test substance and each positive control. The AUCINF/D for the fluorine component of H-24001 was 1750, compared to AUCINF/D values of 566,479.1 and 70,789.6 for H-24019 and H-24020, respectively.
Under the conditions of this study, administration of H-24001 to male rats for 10 consecutive days resulted in limited absorption and retention of fluorine in the blood. Dose-adjusted areas under the curve (AUCINP/D) for positive controls, H-24019 and H-24020, were approximately 320x and 40x the AUCINP/D for the test substance.
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
INTRODUCTION
The objective of this study was to define the potential of H-24001 to be absorbed and to bioaccumutate in a mammalian system, as indicated by analytical determination of total fluorine in blood and liver. The test substance was compared to two positive controls that were materials previously shown to bioaccumulate in mammals.
The daily dosage for the test substance was selected based on available toxicity data and the results of a rangefinding study. In the rangefinding study, a group of 5 male rats was dosed by oral gavage with H-24001 at a dosage of 2000 mg/kg for 5 consecutive days. A group of 5 male rats was dosed with deionized water for 5 consecutive days and served as controls. The rats dosed with H-24001 experienced an overall mean body weight gain of 13 grams. The control group had an overall mean body weight gain of 27 grams.
A dosage of 1000 mg/kg was selected for the limit dosage for this project. The limit dosage of 1000 mg/kg was chosen for the main study and was expected to produce less than a 10% difference in mean body weight over 10 days when compared to controls.
All blood samples were analyzed for total fluorine content. This report contains the results of those analyses. Results from analyses of selected liver samples will be presented in a supplemental report.
MATERIALS AND METHODS
A.
Test Substance and Positive Control
The test substance, H-24001, was supplied by the sponsor as an amber-brown liquid. The positive controls, H-24019 and H-24020, were supplied by the sponsor as white solids. The test substance and positive controls appeared to be stable under the conditions of the study. No evidence of instability, such as a change in color or physical state, was observed.
B.
Test Species
Male Cri:CD(SD)IGS BR rats were received from Charles River Laboratories, me., Raleigh, North Carolina. The Crl:CD(SD)IGSBR rat was selected on the basis of extensive experience
with this strain and its suitability with respect to longevity, hardiness, sensitivity, and low incidence of spontaneous diseases.
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
C.
Animal Husbandry
1.
Housing Environment
Rats were housed singly in stainless steel, wire-mesh cages suspended above cage boards. Animal rooms were maintained on an approximate 12-hour light/dark cycle (fluorescent light) and at a temperature of 23 1C and a relative humidity of 50 10%. Occasional excursions outside the accepted ranges were minor and did not affect the study.
2.
Feed and Water
Tap water was provided ad libitum. All rats were fed PMI Nutrition International, Inc. Certified
Rodent LabDiet 5002 chow. The feed is guaranteed by the manufacturer to meet specified nutritional requirements and to be free of specified contaminants.
3.
Identification
Prior to assignment to groups, each rat was temporarily identified by cage identification. After assignment to groups, an individual identification number was marked or tattooed on the tail of each rat. The information on the cage labels included the unique 6-digit Haskell animal number assigned to each rat.
4.
Animal Health Monitoring Program
As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to assure that contaminant levels are below those that would be expected to impact the scientific integrity of the study:
Water samples are analyzed for total bacterial counts, and the presence ofcoliforms, lead, and other contaminants.
Feed samples are analyzed for total bacterial, spore and fungal counts.
Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers.
Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity of the study.
The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian.
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
D. Quarantine and Pretest
Upon arrival at Haskell Laboratory, the rats were removed from shipping cartons and quarantined for 6 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 signs of illness, 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.
E.
Study Design
Substance Negative Controls
Corn oil Corn oil:acetone Positive Controls H-24019 H-24020 Test Substance H-24001
Vehicle
Dosage (mg/kg) Number of Animals
Not applicable
0
30
0
30
Corn oil: acetone
10
30
Corn oil
20
30
None
1000
30
F.
Assignment to Groups and Study Start
After the quarantine period, the rats were selected on the bases of adequate body weight gain, freedom from any clinical signs of disease or injury, and a body weight within 20% of the mean. The selected rats were divided by computerized, stratified randomization into 6 groups of 5 rats, so that there were no statistically significant differences among group body weight means.
After assignment to groups, each rat was housed individually. The last 3 digits of the animal number was marked or tattooed on the tail of each rat. The rats were between 7 and 9 weeks of age at the time of 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 pathological evaluation.
G. Dosing Material Preparation and Administration
1.
Test Substance
H-24001 was dosed as received. The amount of test substance each rat received was based on the body weight collected on each day of dosing and the test substance density of 1150 mg/mL. The test substance was stirred on a magnetic stir plate throughout the dosing procedure.
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
2.
Positive Controls
The solid positive control materials were suspended as emulsions in their respective vehicles. Corn oil was used as the vehicle for H-24020. It was necessary to dissolve H-24019 in acetone before suspending it in corn oil. The ratio of acetone to corn oil was 20:80. The amount each rat received was based on the body weight collected on each day of dosing and the suspension concentration. The dose volumes did not exceed 1 mL/100 g of body weight. The dosing suspensions were stirred on a magnetic stir plate throughout the dosing procedure to maintain homogeneity.
3.
Negative Controls
Corn oil and corn oibacetone (80:20) were chosen as the negative controls because they were the vehicles for the positive controls. Each negative control rat received 1 mL of corn oil or
corn oil: acetone. These rats were dosed in a separate room from the rats dosed with the test substance or positive controls.
H. Body Weights
The rats were weighed on each day of dosing and then weeMy or every other week during the recovery period.
I.
Mortality and Clinical Observations
Cage-site examinations to detect moribund or dead rats and abnormal behavior and appearance among rats were conducted at least once daily throughout the study. At every weighing, each rat were individually handled and examined for abnormal behavior and appearance.
J.
Collection and Analysis of Blood and Livers
Approximately 2 hours after the first dose, 1-2 mL of blood was collected into EDTA tubes from the orbital sinus of each rat from Group L At all other selected time points, 5 rats/group were
euthanized by carbon dioxide anesthesia and exsanguination and blood and livers were collected according to the following schedules:
Group I I n m
IV
v
VI
Dosing Days 1-5 1-5 1-10 1-10 1-10 1-10 1-10
Tissue Collected Blood
Blood and liver
Blood and Liver Blood and Liver Blood and Liver Blood and Liver Blood and Liver
Sampling Time Test day 1 (2 hours post dosing) Test day 5 at sacrifice (2 hours post dosing) Test day 10 (2 hours post dosing)
Test day 13 Test day 24 Test day 52 Test day 94
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
Five to 10 mL of blood was collected into EDTA tubes at sacrifice. The livers were weighed.
The blood from all rats was refrigerated, and the livers were frozen. The blood was appropriately packaged and shipped refrigerated to Jackson Laboratory, Deepwater, New Jersey where it was analyzed for total fluorine.
The total ffuorine content of the blood samples was determined by using a Wickbold torch combustion method, followed by analysis with a fluoride ion selective electrode. The liquid blood was decomposed or volatilized in the presence of wet oxygen and swept through an oxyhydrogen flame in a closed quartz apparatus. The combustion products were collected in an aqueous absorbing solution and analyzed using a fluoride ion selective electrode. The analytical data (ppm P in each sample) was supplied to Haskell Laboratory for evaluation of fluorine
biopersistence.
K. Treatment of Fluoride Data
Noncompartmental analysis was conducted on blood fluorine data derived from rats dosed with H-24001 by using WinNonlin Version 3.0 software (Pharsight Corp, Mountain View, CA). WinNonlin software provided a means of computing derived pharmacokinetic parameters from data files including area under the curve (AUCINP), Cmax and terminal half-life (Ti/z). The AUCINF (concentration x time) represents the area under the blood concentration curve from the time of dosing extrapolated to infinity. The maximum observed concentration was Cmax (concentration). The points included in determination of the terminal half-life were selected manually and given in units of time. Since the dosages and fluorine content for each positive control and the test material varied, all doses were normalized to 0.1 mmole/kg for comparative
purposes. The accumulation index (AI, l^l-e'^)) and bioaccumulation index (BI, Cmax x AI)
were calculated and reported but not further use.
H-24019 and H-24020 were used as positive controls. Dosing diluents were used as negative controls, but because of variability and limited sensitivity of the analytical method, the background was set at 0.2 ppm fluorine. Since 0.2 ppm was the fluoride concentration limit of detection, any values listed as <0.2 ppm were excluded from further treatment.
The percent of fluorine and molecular weight of the test substance and positive controls were used as provided by the sponsor. The measurements resulting from analysis of total blood fluorine were used as received (ppm P) from Jackson Laboratory. Pluoride ion was converted to micromolar QxM) equivalents of active component for further comparisons. The data and descriptions of data manipulation and presentation are provided in Appendix C.
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
RESULTS AND DISCUSSION
DuPont-2924
A. In-Life Toxicology (Tables 1 and 2; Figure 1, Appendices A and B)
No deaths occurred during the study.
No compound-related clinical signs of toxicity were observed in the rats dosed with H-24001. Rats dosed with H-24019 exhibited diarrhea, salivation, alopecia, black ocular discharge, and staining of various parts of the body during the dosing period. Rats dosed with H-24020 exhibited wet perineum and diarrhea during the dosing period. Alopecia was observed during the recovery period for rats dosed with H-24001, H-24019, and H-24020. The negative control rats exhibited no clinical signs during the study.
Comparison of body weights was complicated by the fact that there was a difference in age on test day 1 between the rats dosed with the test substance and those dosed with the positive or negative controls. This difference resulted in differences in mean body weights on test day 1. The rats dosed with the test substance, H-24001, were older and heavier in weight than the corn oil negative control and H-24020 positive control rats, but younger and lighter in weight than the corn oil/acetone negative control and H-24019 positive control rats. Accounting for the age difference at study start and the expected rate of body weight gain, the mean body weights and mean body weight gains of the rats dosed with H-24001 was comparable to the negative controls and equal to or greater than the positive controls.
B.
Fluorine Data
(Tables 3 and 4; Figures 2 and 3; Appendix C)
1.
Factors Influencing Interpretation of Analysis
The data used in the kinetic analysis were derived from a limited screen, and therefore several caveats and considerations are important. A couple of considerations of particular importance are (1) a single dose was used and kinetics may or may not be linear, (2) the kinetics apply only to blood, (3) steady-state may not have been achieved, and (4) the sample size is low and may impact calculation of the terminal half-life. A more complete list of considerations is shown in Appendix C.
2.
Positive Controls
The positive controls were H-24019 and H-24020. The H-24019 normalized /xM equivalents in rat blood continued to rise throughout the dosing period and may not have reached steady-state (Figure 2A). The Cmax for H-24019 was 989.85 116.90 ppm (Mean SD) with a terminal half-life of 40.5 days. The H-24019 AI was 59.0 and the BI was 58382.2. The H-24020
normalized ^M equivalents in rat blood peaked after 5 days of dosing and then decreased
throughout the dosing period (Figure 2B). The Cmax for H-24020 was 518.12 44.89 ppm (Mean SD) with a terminal half-life of 8.3 days. The H-24020 AI was 12.5 and the BI was
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
6497.5. For each of the positive controls, blood was sampled at seven time points throughout 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 normalized dose was described by AUCINF/D. and was the basis for comparison between positive controls and the test material. The AUCINF/D for the fluorine component was 566,479.1 for H-24019 and 70,789.6 for H-24020.
3.
Test Substance
The H-24001 normalized fiM. equivalents in rat blood continued to rise throughout the dosing period and did not reach steady-state (Figure 2C). The Cmax for H-24001 was 9.188 1.917 ppm (Mean SD) with a terminal half-life of 46.9 days. Blood was sampled at seven time points throughout the study, with only four of those 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 H-24001 AI was 68.1 and the BI was 625.4. The total internal exposure resulting from a normalized dose was described by AUCINF/D and was the basis for comparison between H-24001 and positive controls. The AUCINF/D for the fluorine component of H-24001 was 1750 as compared to AUCINF/D values of 566,479.1 and 70,789.6
for H-24019 and H-24020, respectively. The data, calculations and equations are shown in
Appendix C.
CONCLUSIONS
Rats dosed for 10 consecutive days with 1000 ing/kg H-24001 exhibited no mortality or clinical signs of toxicity and had mean body weight gains that were comparable to the negative control rats. A steady state for fluorine in the blood was not achieved for H-24001 during the 10-day dosing period.
Under the conditions of this study, administration of H-24001 to male rats for 10 consecutive days resulted in limited absorption and retention of fluorine in the blood. Dose-adjusted areas under the curve (AUCINP/D) for positive controls, H-24019 and H-24020, were approximately 320x and 40x the AUCINP/D for the test substance.RECORDS AND SAMPLE STORAGE
Specimens (if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware.
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
TABLES
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
TABLE 1 MEAN BODY WEIGHTS (g)
Test Days 1 2 3 4 5 6 7 8 9 10 13
20 24 27 34 41 47 48
'
52 55 61 62 68 69 75 76 80 81 89 90 93 94
Neg;ative Controls
Corn Oil 229.8 234.1 241.4 250.4 259.3 266.8 271.2 281.9 285.2 295.9 321.1 350.5 378.3
Corn Oil'-Acetone 297.6 299.6 309.4 314.3 321.5 326.0 334.9 339.2 345.2 351.7 350.7 369.8 401.0
-
-
407.8 434.5 454.9
411.4
-
-
-
464.7 487.0 505.1
527.6
-
-
-
515.4
-
-
-
-
-
539.0
-
-
-
-
-
556.2
566.9
-
562.2" '
-
567.8
Positive Controls
H-24019 291.5 291.5 298.3 304.1 308.6 312.7 317.5 317.3 318.4 318.9 329.1 359.7 387.9 393.9 416.9
-
H-24020 227.5 232.4 242.0 248.9 252.4 259.8 263.3 269.8 278.5 283.9 289.1 311.3 340.9
-
402.9 425.0 438.2
-
-
438.1 523.4
465.6 452.3 465.8
-
470.9
-
-
'563.4 570.7
-
-
499.2
-
-
585.3
527.8
-
-
597.9
538.7
The rats were sacrificed a day early because of a laboratory event on test day 94. Indicates that the animal was not weighed.
Test Substance H-24001 245.3 251.4 260.4 267.9 277.6 286.3 291.1 298.6 305.5 309.4 321.3
.
388.5
-
416.8
-
-
466.4 483.2
-
-
506.8
517.6 533.2
-
-
-
543.5
-
570.5'1
-
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
TABLE 2 MEAN BODY WEIGHT GAINS (g)
Test Days 1-5 1-10
10-13 10-24 10-52 10-93/94
Negative Controls
Corn Oil
29.5 66.1
Corn Oil:Acetone 23.9 54.1
25.2 82.4 168.8 271.0
-1.0 49.3 175.9 216.1
Positive Controls
H-24019
17.1 27.4 10.2 69.0 119.2 279.0
H-24020 24.9 56.4 5.2 57.0
181.7 254.8
Test Substance
H-24001 32.3 64.1 11.9 79.1 173.8
261.1
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
TABLES MEAN BLOOD FLUORINE LEVELS
Test Days
1 5 10 13
24 52 93/94
Negative Controls
Corn Oil
ppm <0.2 <0.2 <0.2
0.2'(0.1) <0.2
0.3 (0.1)
OJ^O.l)
Corn OiLAcetone
ppm <0.2 <0.2
O^O.l)"
0.6 (0.6)
0.2d
<0.2 <0.2
Positive Controls
H-24019
ppm 2.1 (0.9) 48.8 (17.6) 61.7 (2.8)
64.5 42.2 26.9
(7.6) (2.8) (2.6)
13.2 (2.1)
H-24020
ppm 62.6 (3.2) 71.7 (6.2) 54.2 (7.8) 26.6(11.4) 10.5 (3.0)
0.9 (0.2) 0.2s (O.I)
Mean of 4 of the 5 values. One of the values was below the LOD.
Standard deviation is in parentheses. Mean of 3 of the 5 values. Two of the values were below the LOD. One value. Pour of the values were below the LOD. Mean of 4 of 5 values. Tube of blood for one rat was missing or broken.
Test Substance
H-24001 ppm
'4.1 (0.7)
n^aj)
19.5 (4.0) 6.3 (1.0) 2.6 (0.2) 1.8 (0.2) 1.1 (0.2)
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H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
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TABLE 4
MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE
Test Days
1 5 10 13
24 52 7^/7^
Positive Controls
H-24019
{JIM F Equivalents
28.92 (13.3)"
747.69 (271.5)
945.85 (43.5)
989.85 (116.9)
645.54 (42.9)
411.38 (40.6)
195.38 (32.5)
,,
-
H-24020
pM P Equivalents
89.28 (23.4) 518.12(44.9) 391.01 (56.8) 191.45 (82.7)
74.35 (22.1) 4.64 (1.1) 0.24 (0.4)
a Standard deviation is in parentheses.
b Mean of 4 of the 5 values. No data for one rat.
Test Substance
H-24001 I^M F Equivalents
1.85 (0.3) 6.28" (0.7) 9.19 (1.9) 2.88 (0.5) 1.16 (0.1) 0.74 (0.1) 0.41 (0.1)
.20-
Company Sanitized. Does not contain TSCA CBl
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
FIGURES
i
-21-
Company Sanitized. Doss not contasn TSCA CBl
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
400 -i 350 -\
300 -^
250 ^
i
S
|"<^
n
150 -\ 100 d 50
FIGURE 1 MEAN BODY WEIGHTS (g)
---- Negative Con --S--Negative Con --A-Positive Cont --<--Positive Cont --9K--Test Substanc
Test Days
10
12
.22-
Companysanifeed.
Does not conta
H-24001: Biopersistence Screening IQ-Dose Oral Gavage Study in Rats
DuPont-2924
FIGURE 2
MICROMOLAR EQUIVALENTS IN RAT BLOOD
A. Normalized Rat Blood H-24019 fiM Equivalents Resulting from a 10-Day Oral Gavage
1200 -i
Micromolar (fiM) equivalents ofH-24019 (positive control) in rat blood resulting from a 10-day
oral gavage exposure. Values are means and error bars are standard deviation.
B. Normalized Rat Blood H-24020 pM Equivalents Resulting from a 10-Day Oral Gavage
80
100
Micromolar (^M) equivalents of H-24020 (positive control) in rat blood resulting from a 10-day oral gavage exposure. Values are means and error bars are standard deviation.
-23-
Company Sanitized. Does not contain TSCA CBI
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
C. Normalized Rat Blood H-24001 fiM Equivalents Resulting from a 10-Day Oral Gavage
a
8 -{
70
80
90
Micromolar (pM) equivalents of H-24001 (test substance) in rat blood resulting from a 10-day
oral gavage exposure. Values are means and error bars are standard deviation.
Company Sanitized. Does not contain TSCA CBI
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
HGURE3 MICROMOLAR EQUIVALENTS IN TEST COMPOUND AND POSITIVE CONTROLS
B3||||Di*ih:'RatsResulti
-25-
Company Sanitized. Does not conta
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
APPENDICES
-26- co^san.--------------.--------
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
APPENDIX A Individual Body Weights
-27-
CompaBy SasEBzed. Doss not contain TSCA CBI
H-24001: B iopersistence Screening 10-Dose Oral Gavage Study in Rats
INDIVIDUAL BODY WHGHTS
ABBREVIATIONS: SD - sacrificed by design
EXPLANATORY NOTES
DuPont-2924
-28-
Company Sanitized. Doss not contain TSCA CBI
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats .
ANIMAL NUMBER
627789 627801 627805 627810 627818
DAY 1
222.6 215.9 249.4 230.5 229.7
DAY 2
220.7 209.1 250.1 231.6 228.6
CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP I
DAY 3
DAY 4
DAY 5
223.5
223.5 263.3 241.9 239.1
236.9 233.5 273.6 254.4 252.4
247.7 240.1 283.7 265.0 260.2
SD test day 5 SD test day 5 SD test. day 5 SD test day 5 SD test day 5
-29-
Company Sanitized. Does not c
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
627793 627797 627799 627800 627808
ANIMAL NUMBER
627793 627797 627799 627800 627808
DAY 1
214 .8 239 .9 228 .9 246 .9 235 .6
DAY 2
224 .4 245 .9 231 .4 .252 .8 241 .6
DAY 8
270 .6 303 .9 280".2 312 .0 303 .6
DAY 9
274 .9 305 .1 284 .3 315 .4 305 .7
CORN OIL (NEGATIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP II
TEST E)AYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
232.1 257.3
242.3 265.2 250.1
243.1 267.5 246.2 279.3 262.1
TEST DAYS DAY 10
249 .9 280 .7 258 .9 283 .6 270 .4
257 .0 288 .0 261 .5 295 .5 284 .1
262.0 290.9 266.4
300.1 287.4
283.5 324.2
294.7 331.3 321.8
SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10
-30-
^apany SanHtesd. Does not conta
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
627796 627806 627807 627809 627816
ANIMAL NUMBER
627796 627806 627807 627809 627816
DAY 1
239 .8 227 .3 221 .5 234 .2 235 .0
DAY 2
249 .7 234 .2 225 .9 240 .4 '238 .6
DAY 8
285 .9 282-. 8 270 .7 297 .9 291 .8
DAY 9
290 .1 285 .8 274 .7 300 .2 296 .4
CORN OIL (NEGATIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP III
TE,ST I )AYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
253 .6 239 .4 237 .1 252 .5 250 .0
252 .5 242 .9 244 .1 260 .3 258 .9
267.7
258.5 254.9 272.8 265.1
277 .2 270 .4 257 .7 277 .9 274 .5
289 .8 275 .2 260 .3 282 .6 278 .6
TEST DAYS
DAY 10
DAY 13
300 .0 302 .8 280 .7 311 .9 305 .7
322 .7 320 .3 305 .2 336 .2 330 .2
SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13
-31-
Company Sanded. Does not contain
H-24001: B iopersistence Screening IQ-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
627791 627794 627804 627812 627817
ANIMAL NUMBER
627791 627794 627804 627812 627817
DAY 1
231.1 224.4 224.7 221.9 233.5
DAY 2
235.4 233.0 228.8 231.5 231.3
DAY 8
274.0 286.1 267.2 278.2 277.8
DAY 9
279.1 289.5 270.6 282.7 280.4
CORN OIL (NEGATIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP IV
TEST E)AYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
241.2
238.1 230.6
236.3 229.0
246.8
247.8 243.0 245.7 244.8
TEST DAYS
DAY 10
DAY 13
255 .9 260 .0 251 .7 255 .5 255 .4 DAY 20
262.6 267.4
252 ..9
264.9 266.4
DAY 24
268.4 270.1 259.5 269.5 270.0
285.0
^a
295.4
a
278.1
^a
294.3
a
294.6
a
334 .4 377 .4 345 .8 356 .5 368 .7
365.6 416.7 378.1 388.4 407.3
SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24
a Rat was not weighed.
-32-
company san(ti2ed- Does not conta
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
DAY 1
DAY 2
CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS
GROUP V
TEST r 1AYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
627792 627798 627813 627814 627815
ANIMAL
NUMBER
235 .8 241 .1 214 .8 217 .5 230 .1
DAY 8
240 .8 253 .4 219 .2 220 .5 242 .2
DAY 9
244.3 257.6 220.5 223.7 243.8
247.9 266.1 233.2
225.2 255.7
TEST DAYS
DAY 10
DAY 13
252 .5 272 .9 239 .8 233 .8 265 .0 DAY 20
264 .4 281 .9 243 ..2 236 .7 270 .0 DAY 24
268.1 286.2 246.8 240.6 274.1
DAY 34
627792 627798 627813 627814 627815
ANIMAL NUMBER
282 .4 294 .3 258 .7 248 .0 289 .2 DAY 41
286 .4 296 .3 259 .2 250 .7 293 .4
DAY 47
295.2
a
315.7
a
267.9
a
257.3
^a
303.3
a
TEST DAYS DAY '52
360 .0 380 .2 323 .6 299 .3 368 .3
389 .2 403 .5 342 .3 319 .4 396 .5
426.1 443.1 367.9
343.7 434.9
627792 627798 627813 627814 627815
456 .5 470 .7 395 .0 358 .7 462 .6
482 .3 496 .9 407 .2 372 .7 487 .3
496.8 517.3 416.8 386.9
505.9
SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52
a Rat was not weighed.
-33.
Company Sanifeed. Does not contain
w -.
H-24001: Biopersistence Screening
10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
DAY 1
DAY 2
CORN OIL (NEGATIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP VI
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
627795 627811 627819 627820 627821
ANIMAL NUMBER
218 .0 228 .6 248 .8 225 .5 227 .5
DAY 8
219.5 226.3 255.3 228.9 233.2
DAY 9
225.3 236.7 264.9 239.2 240.7
234.3 246.1 274.4 247.9
246.1
TEST DAYS
DAY 10
DAY 13
239 .4 251 .5 280 .4 255 .6 251 .2
DAY 20
246 .2 259 .6 288 .0 261 .3 259 .8 DAY 24
250.1 263.6 290.3 265.3 263.9
DAY 34
627795 627811 627819 627820 627821
ANIMAL NUMBER
261 .4 273 .0 304 .5 281 .3 272 .6 DAY 41
265.0 276.7 308.0 282.9 275.3
DAY 47
270.7
^a
285.6
^a
324.3
^a
292.4
a
281.8
^a
TEST DAYS
DAY 52
DAY 55
308 .0 337 .8 399 .7 367 .2 330 .1 DAY 61
329 .8 360 .6 431 .2 393 .0 352 .9
DAY 68
362.0 396.4 472.5
445.5385.6
627795 627811 627819 627820 627821
384 .2
398.0
a
411.1
435 .7
440 .7
422 .0
439.3
a
455.4
463 .0
473 .6
505 .9
'534.9
a
551.7
574 .4
588 .6
478 .0
504.1
a
529.7
547 .1
558 .6
411 .8
426.1
a
439.1
459 .0
463 .3
a Rat was not weighed.
-34-
Company Sanitized. Does not cont
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats '
ANIMAL NUMBER
DAY 90
DAY 94
CORN OIL (NEGATIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
TEST DAYS
GROUP VI
627795 627811 627819 627820 627821
474.6 503.6 638.1
608.6 509.0
485.0 511.6 653.1 618.0 521.5
SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94
-35-
Company Sanitized. Does not conta
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
625361 625363 625364 625380 625383
DAY 1
322.6 273.7 291.1 289.4 304.7
DAY 2
325.0 271.4 .290.9 286.2 299.7
CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP I
DAY 3
DAY 4
DAY 5
337.6 278.4 299.9 291.5 302.7
340.3
281.7 306.0 300.1 310.7
349.7 286.7 312.0 305.5 313.1
SD test day 5 SD test day 5
SD test. day 5
SD test day 5 SD test day 5
-36-
^"^""'"^"o.c.n^TSC
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
625355 625362 625367 625368 625378
ANIMAL NUMBER'
625355 625362 625367 625368 625378
DAY 1
280 .0 290 .3 301 .5 312 .3 309 .6
DAY 2
282 .0 294 .1 307 .8 318 .0 306 .4
DAY 8
321 .7 323.. 9 349 .1 364 .2 350 .1
DAY 9
320 .9 332 .3 352 .4 380 .8 354 .2
CORN OIL:ACETONE (NEGATIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP II
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
293.0
303.5 315.6 326.0 327.3
297.9 308.9 320.1 336.4 328.4
TEST DAYS DAY 10
306 .1 313 .8 327 .7 343 .7 333 .7
311 .2 315 .8 333 .7 347 .5 336 .6
315.7
323.8 345.6 360.8 346.9
333.6 332.9 363.8 386.7
365.4
SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10
.37-
^'"^""-^no.c^
w
..
H-24001: Biopersistence Screening
10-Dose Oral Oavage Study in Rats
ANIMAL NUMBER
625357 625358 625370 625384 625385
ANIMAL
NUMBER
625357 625358 625370 625384 625385
DAY 1
311. 9 285. 7 307. 9 294. 2 297. 6
DAY 2
308 .8 286 .3 316 .7 300 .0 304 .6
DAY 8
364. 2
319.. 8
373. 4 325. 6 347. 0
DAY 9
370 .3 321 .6 374 .7 331 .0 349 .5
CORM OIL:ACETONE (NEGATIVE Control)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP III
TE:ST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
320 .3 295 .5 329 .5 312 .0 313 .0
328 .4 296 .4 337 .9 309 .3 320 .4
TEST DAYS
DAY 10
DAY 13
340. 5 306. 0 346. 9 316. 3 331. 9
343 .3 302 .7 349 .8 314 .1 334 .0
361 .1 309 .2 364 .1 321 .4 345 .4
376 .9 320 .3 385 .6 340 .6 358 .9
405 .6 SD test day 13 340 .7 SD test day 13 407 .0 SD test day 13 357 .1 SD test day 13 . 377 .6 SD test day 13
-38-
Company Sanitised. Does not cont
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
625354 625365 625371 625376 625381
ANIMAL
NUMBER
625354 625365 625371 625376 625381
DAY 1
303.0 327.7 294.5 289.7 297.8
.DAY 2
304.1 328.7 299.0 289.9 297.5
DAY 8
336.2 370..5 340.3 331.5 321.6
DAY 9
337.0 379.3 345.9 339.0 329.1
CORN OIL:ACETONE (NEGATIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP IV
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
310.5 337.9
313.4 302.2 301.7
312.2
343.6 318.3 304.9 305.6
TEST DAYS
DAY 10
DAY 13
319 .3 357 .7 321 .8 313 .2 314 .4 DAY 20
324 .7 357 .2 329 .6 317 .0 314 .4 DAY 24
331.2 364.3
338.5 322.8 321.0
348.8 381.2 351.2 345.2 331.6
355.8 407.1 372.6 363.2
341.2
377 .7 438 .2 413 .0 399 .7 358 .2
396 .1 459 .6 447 .3 432 .9 381 .8
SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24
.39-
Company Sanitized. Does not co
H-24001: Biopersistence Screening' 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
DAY 1
DAY 2
CORN OIL-.ACETONE (NEGATIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP V
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
625356 625359 625360 625372 625374
ANIMAL
NUMBER
291.7 297.9 296 .8 294 .8 295 .9
DAY 8
291.2 303.3 300.7 298.8 302.2
DAY 9
304.5
314.0
308.5 310.6 312.1
307 .0 315 .0 312 .7 317 .4 321 .7
TEST DAYS
DAY 10
DAY 13
316 .9 323 .5 319 .1 324 .0 323 .4
DAY 20
319 .8 323 .5 332 .2 329 .0 328 .3 DAY 24
323. 9 333. 9 339. 5 335. 6 337. 2
DAY 27
625356 625359 625360 625372 625374
ANIMAL NUMBER
625356 625359 625360 625372 625374
328 .8
334.7
341.3
361 .9
396 .7
^a
339 .1
.346.2
353.6
372 .9
410 .0
^a
347 .9
354.3
363.4
381 .7
419 .8
a
344 .7
348.8
355.1
373 .1
395 .1
a
338 .0
344.6
350.8
371 .5
401 .3
^a
DAY 34 466 .2 467 .7
484 .1 454 .7 466 .8
DAY 52
533.7 530.3 555.4 506.2 512.3
TEST DAYS
SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52
431 .3 440 .9 465 .9 432 .1 447 .2
a Rat was not weighed.
-40-
<=P"S.n,,,,,.Don,
^y
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
625353 625369 625373 625375 625377
ANIMAL NUMBER
625353 625369 625373 625375 625377
ANIMAL NUMBER
625353 625369 625373 625375 625377
DAY 1
305 .9 281 .7 294 .6 289 .1 293 .9
DAY 2
307 .3 2.79 .9 301 .3 291 .0 294 .8
DAY 8
344 .7 307. .3 340 .6 324 .7 325 .0
DAY 9
352 .7 311 .9 348 .2 336 .0 333 .7
DAY 34 453 .3 388 .2 477 .1 455 .6
419 .1
DAY 52
a a a a a
CORN OIL:ACETONE (NEGATIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP VI
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
316.8 289.7
312.7 298.0 302.9
325. 0 286. 9 317. 0
307. 0 312. 0
TEST DAYS
DAY 10
DAY 13
331.7 292.8 325.4 309.6 318.0
DAY 20
330.1 295.3 329.0 314.2 317.4
DAY 24
342.5 303.8 334.6 323.5 325.0
DAY 27
358.1
371. 7
399.1
a
317.2
331. 1
347.6
a
352.6
371. 5
402.3
-a
336.9
350. 1
387.9
340.7
353. 5
376.3
--a
TEST DAYS
DAY 76
DAY 90
DAY 94
427.7 374.9 444.6
432.3. 405.2
544.9 483.8 628.8
567.3 470.3
562 .8 505 .3 661 .3 589 .8 492 .0
565.3 514.8 673.7 588.8 496.6
SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94
a Rat was not weighed.
-41-
Company Sanitized. Does not co
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
625322 625323 625336 625343 625349
DAY 1
290.3 285.0 316.5 288.2 303.6
DAY 2
283.7 285.5 313.5 281.9 295.9
H-24019 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP I
DAY 3
DAY 4
DAY 5
291.5 290.2
320.1 286.8 308.2
298.9
290.9 327.1 291.0 310.1
298.0 294.0
329.0 293.7 318.1
SD test day 5 SD test day 5 SD test. day 5 SD test day 5 SD test day 5
.42-
3. Does not cont
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
625320 625330 625332 625341 625350
ANIMAL NUMBER
625320 625330 625332 625341 625350
DAY 1
279 .3 286 .7 300 .0 304 .9 257 .1
DAY 8
308 .5
314 ,0
324 .1 332 .4 279 .8
DAY 2
283 .0 286 .1 295 .9 309 .0 268 .5
.
DAY 9
306 .3 312 .6 321 .8 320 .3 282 .5
H-24019 (POSITIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP II
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
287.7
291.1 304.1 317.5 267.3
288.4 296.5 308.8 320.0 272.2
TEST DAYS DAY 10
295 .9 304 .0 315 .0 325 .1 272 .6
299 .4 302 .3 322 .4 327 .5 276 .3
300 .6 306 .7 320 .7 327 .4 283 .6
312.1
310.1 318.3 325.6 284.3
SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10
-43-
Company Sanlfaed. Does not c
H-24001: B iopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL
NUMBER
625321 625327 625342 625345 625348
ANIMAL NUMBER
62532.1 625327 625342 625345 625348
DAY 1
307 .0 311 .4 273 .7 291 .2 265 .5
'DAY 2
307 .8 306 .6 275 .5 291 .7 258 .6
DAY 8
337 .8 334 .3
304 .3 317 .3 302 .7
DAY 9
339 .6 337 .0 305 .9 312 .9 306 .5
H-24019 (POSITIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP III
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
311.4 312.5 282.3 297.3 268.0
319.6 317.8 285.8 303.3 275.2
TEST DAYS
DAY 10
DAY 13
322.. 3
318.3 290.8 306.4 280.1
328 .4 319 .3 294 .2 310 .4 285 .2
335 .2 327 .6 326 .6 316 .1 290 .6
346.1 336.3 307.8 315.0 309.7
371.2 355.3 324.4 336.9 336.4
SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13
-44-
Company Saiu-feed. Does not c
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL
NUMBER
625325 625328 625338 625340 625352
ANIMAL
NUMBER
625325 625328 625338 625340 625352
DAY 1
282.8 315.6 264.6 304.0 285.5
DAY 2
285 .9 315 .2 261 .9 309 .2 283 .9
DAY 8
318.6 352.0 287.4 347.0 316.9
DAY 9
321 .9 '351 .7 291 .3 352 .2 322 .3
H-24019 (POSITIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS
GROUP IV
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
291.7
323.9 268.5 316.9 289.1
295 .5 327 .7 272 .6 326 .0 299 .6
TEST DAYS
DAY 10
DAY 13
303 .2 335 .0 275 .7 329 .8 307 .9 DAY 20
309 .2 340 .4 281 .9 334 .1 308 .2 DAY 24
308.3
340.1 284.4 338.4 312.4
327.4 357.5 290.2 359.2
321.0
331 .6 367 .4 291 .1 368 .1 329 .6
355 .8 400 .2 320 .4 389 .3 355 .7
381 .3 423 .9 339 .9 419 .0 375 .3
SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24
45. Company Sanitized. Does no
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL
NUMBER
DAY 1
DAY 2
H-24019 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP V
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
625324 625329 625333 625334 625344
ANIMAL NUMBER
303 .0 318 .9 292 .4 274 .6 262 .9
DAY 8
298.5 316.3 .291.2 277.0 262.2
DAY 9
305.8
326.5 297.8 286.4 269.0
312 .1 335 .4 304 .1 290 .6 273 .5
TEST DAYS
DAY 10
DAY 13
320 .1 338 .3 307 .7 292 .0 274 .5 DAY 20
322.8 346.7 312.0 300.1 284.1
DAY 24
326 .8 351 .6 313 .5 304 .2 DAY 27
625324 625329 625333 625334 625344
ANIMAL NUMBER
332 .5
337.9
336.1
299 .6
336 .0
^a
352 .5
360.1
357.0
364 .3
396 .4
a
315 .8
316.7
319.3
325 .8
349 .2
^a
292 .6
302.2
305.8
312 .0
338 .6
a
280 .7
285.2
289.3
295 .8
309 .7
a
DAY 34
DAY 52
TEST DAYS
380 .3 423 .3 375 .2 368 .8 330 .4
625324 625329 625333 625334 625344
397 .3 442 .7 384 .6 384 .2 348 .3
447.4 498.1 427.4 426.5 391.0
SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52
a Rat was not weighed.
46Company Sanitized.
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
625326 625335 625346 625347 625351
ANIMAL NUMBER
625326 625335 625346 625347 625351
ANIMAL NUMBER
625326 625335 625346 625347 625351
DAY 1
313.2 301.0 290.2 266.0 310.6
DAY 2
317.1 303.6 293.4 275.6 310.9
DAY 8
311.5 294.2 292.9 330.5 351.1
DAY 9
308.9 285.3 290.8 330.1 357.8
DAY 34
427.5 427.0 407.4 466.4 483.3
DAY 52
a a
^a
a a
H-24019 (POSITIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS
GROUP VI
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
325.5 302.3 300.2 287.7 321.1
330.9 310.4 309.5 300.0 329.6
TEST DAYS
DAY 10
DAY 13
297.5 274.0
288.4 333.0 350.5
274.2 266.3 296.9 355.7
380.0
TEST DAYS
DAY 62
DAY 76
336.2 315.1 313.5 308.5 338.2
DAY 20
335.4 340.1 352.5 402.1 413.7
DAY 80
336.0 299.6
318..6 316.6 341.6
DAY 24
a a
^a
a a
DAY 90
293.6 326.0 326.9 340.7
DAY 27
390.7 393.8 388.2 436.2 452.4
DAY 94
497.5 506.0 485.8 568.6
559.0
540.0 538.6 523.7 '617.8
596.8
547.9 547.7
532.8 618.1 607.2
565.2 562.1 542.4 632.6 624.0
577.5 579.5 556.9 638.9
636.8
SD test da SD test da SD test da SD test da SD test da
a Rat was not weighed.
.47-
Company Sanitized. Do
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
627756 627767 627771 627773 627777
DAY 1
227.2 227.0 219.5 246.8 225.4
DAY 2
226.4 231.8 214.7 244.4 221.4
H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP I
DAY 3
DAY 4
DAY 5
233.4 237.9 226.1 252.7 232.9
238.6 245.8
233.5 263.8 239.4
237.5 248.6 239.6 262.3 236.0
3D test day 5 SD test day 5 SD test. day 5 SD test day 5 SD test day 5
-48-
Company Sanitized.
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
627768 627774 627776 627782 627785
ANIMAL NUMBER
627768 627774 627776 627782 627785
DAY 1
236 .9 258 .6 212 .0 221 .6 220 .3
DAY 2
244 .1 261 .6 216 .3 228 .3 221 .7
DAY 8
272 .3 319...8 246 .1 251 .0 260 .7
DAY 9
291 .9 326 .3 252 .3 264 .0 268 .5
H-24020 (POSITIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP II
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
245.2 275.8 223.7 237.3 234.7
256.5
283.4 226.6 239.0 238.4
TEST DAYS DAY 10
256 .2 289 .3 229 .6 238 .8 241 .8
265.5
301.5 233.7
244.7 250.5
271 .4 303 .2 236 .9 246 .7 255 .6
293.5 338.2 254.4 268.2
267.9
SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10
-49-
Company Sanitized. Does not con
H-24001: Biopersistence Screening . 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
627758 627763 627764 627787 627788
ANIMAL NUMBER
627758 627763 627764 627787 627788
DAY 1
235 .1 212 .1 230 .0 235 .1 219 .4
DAY 2
240 .3 218 .3 235 .0 241 .0 222 .3
DAY 8
280 .6 255 .2 275 .8 221 .7 274 .1
DAY 9
283 .6 261 .2 '281 .9 235 .7 276 .9
H-24020 (POSITIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP III
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
248.6
226.5 246.1 250.1 232.2
255 .8 234 .3 251 .3 257 .2 239 .6
TEST DAYS
DAY 10
DAY 13
261. 2 230. 8 254. 8 258. 6 247. 6
272.0
235.5 261.7 237.6 256.7
276 .1 238 .0 264 .7 240 .3 257 .9
295.8 272.5 288.0 234.7 284.8
308 .7 285 .8 306 .7 234 .9 309 .4
SD test day 13 SD test day 13 SD test day 13 'SD test day 13 SD test day 13
-50-
Company Sanitized. Does n
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
627759 627761 627770 627779 627786
ANIMAL' NUMBER
627759 627761 627770 627779 627786
DAY 1
226.6 240.7 235.6 231.5 211.6
DAY 2
232.9 247.4 .244.3 237.9 218.2
DAY 8
277.8 24Q.1 291.4 289.0 251.3
DAY 9
284.9 257.4 301.3 293.4 255.8
H-24020 (POSITIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP IV
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
241.4 257.1
253.6 252.6 222.5
250.9 262.5
260.1 261.4 230.4
TEST DAYS
DAY 10
DAY 13
288.0
a
266.9
a
306.4
^a
301.0
a
257.0
^a
254.2 266.7 267.7 262.3 230.6
DAY 20
348.0 335.7 355.8 374.4 304.4
262.1 259.2
277..3 273.8 240.6
265. 4
262. 6
279. 8 277. 5 244. 1
DAY 24
380.1 359.4 379.8 406.2 326.1
SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24
a Rat was not weighed.
-51-
Company SanEfeed. Does n
H-24001: B iopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
DAY 1
DAY 2
H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP V
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
627757 627760 627765 627772 627781
ANIMAL NUMBER
221.2 226.2 228.3 245.2 219.0
DAY 8
225.4 232.0 235.3 256.4 226.3
DAY 9
236.3
244.4 247.1 266.2 236.5
241.1 251.7 251.6 277.0 242.9
TEST DAYS
DAY 10
DAY 13
247.9 260.2 256.4 276.9 247.2
DAY 20
252 .2 254 .5 261 .1 285 .0 251 .6 DAY 24
254.4 258.3 264.7 291.0 256.1
DAY 34
627757 627760 627765 627772 627781
AMIMAL NUMBER
269.1 262.6 271.5 300.9 258.1
DAY 41
276.7 280.3 282.4 307.5 266.8
DAY 47
279.7
a
287.3
a
288.1
a
317.0
a
271.2
^a
TEST DAYS DAY 52
324.3 348.6
349.8 375.5 315.1
343 .0 379 .9 382 .7 404 .0 338 .8
372.3
419.4 400.9 446.9 372.0
627757 627760 627765 627772 627781
402.8
437.7 422.9 478.4
389.9
419.7
448.9 444.8 494.3
408.2
436.7 456.5 455.6 513.5
421.0
SD test day 52 SD test day 52 SD test day 52 SD'test day 52 SD test day 52
a Rat was not weighed.
-52-
Company Sanitized. Does not
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
DAY 1
DAY 2
H-24020 (POSITIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP VI
TEST DAYS
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
627762 627769 627775 627778 627783
ANIMAL NUMBER
227 .2 231 .1 224 .7 213 .1 216 .4
DAY 8
235 .0 241 .1 235 .7 217 .4 218 .2
.
DAY 9
248.7 255.9 246.8 221.3 226.6
257.3
264.2 254.7 225.5 232.0
TEST DAYS
DAY 10
DAY 13
263 .0 272 .3 265 .7 230 .1 238 .0 DAY 20
275.1 286.3 276.7 236.9 243.9
DAY 24
279 .7 289 .9 280 .2 240 .4 247 .6 DAY 34
627762 627769 627775 627778 627783
ANIMAL NUMBER
285 .9 302. .0 286 .6 244 .8 256 .6 DAY 41
299 .1 309 .6 296 .0 250 .8 259 .2
DAY 47
301.5
a
312.5
^a
304.5
a
255.1
^a
264.3
a
TEST DAYS
DAY 52
DAY 55
356 .5 386 .6 353 .3 294 .0 311 .3 DAY 61
381.5 414.4 377.4 320.0 340.9
DAY 68
419 .6 456 .5 413 .9 347 .1 380 .0
627762 627769 627775 627778
627783
438 .7
439 .9
a
479 .7
474 .6
a
433 .2
451 .1 .
a
356 .8
373 .5
a
409 .6
426 .9
a
453.5 512.2 460.8 386.0 449.0
473 .0 511 .4 477 .4 393 .3 473 .8
471.6 531.4 478.6 398.3
474.8
a Rat was not weighed.
-53-
Company Sanitized. Does not con
H-24001: Biopersistence Screening 10-Dose Oral Oavage Study in Rats
ANIMAL
NUMBER
627762 627769 627775 627778 627783
DAY 81
D'AY 90
500.3
566.2 510.4 410.1 508.8
523.3
603.2 537.5 436.5 538.5
H-24020 (POSITIVE CONTROL)
INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
TEST DAYS DAY 94
GROUP VI
528.6 609.6 552.8 445.3 557.2
SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94
.54-
collipafly ^"'^ Does
H-24001; Biopersistence Screening 10-Dose Oral Gavage Study in Rats
AMIMAL NUMBER
626904 626905 626915 626923 626930
DAY 1
265.0 232.8 249.6 255.6 234.7
DAY 2
265.1 241.6 249.4 261.0 239.3
H-24001 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP I
DAY 3
DAY 4
DAY 5
279.7 249.0
260.5 265.6 245.9
286.5 258.5
265.6 273.5 252.8
300.9 274.2 275.4 280.5 258.8
SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5
55. Company Sanitized. Does n
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
626900 626909 626912 626919 626921
DAY 1
251 .0 231 .0 245 .6 242 .9 260 .1
DAY 2 259 .5
234 .8 25S .7 248 .5 271 .0
H-24001 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP II
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
270 .3 244 .5 262 .4 260 .9 284 .5
276.1 252.1 274.6 267.2 292.6
288.6 262.2
281.3
278.7 303.4
294.3 270.9 293.7 288.7 307.8
302.0
278.1 298.1 291.8 316.8
ANIMAL NUMBER
626900 626909 626912 626919 626921
DAY 8
312 .1 287 .5 309 .5 298 .2 323 .2
DAY 9
320 .0 295 .2 316 .1 306 .2 329 .4
DAY 10
331 .0 298 .2 322 .2 307 .6 335 .5
3D test day 10 3D test day 10 SD test day 10 SD test day 10 SD test day 10
-56-
Company Sanitized. Does not con
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
626901 626907 626910 626913 626914
DAY 1
235.1 248.7 257.0 225.7 240.0
DAY 2
239.7 254.0 260.3 229.5 246.2
H-24001 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS
GROUP III
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
254.3
268.0 267.3 235.2 257.1
254.8 272.2 279.4 241.9 266.6
264.9
289.3 288.8 250.9 280.7
268.4 300.6
293.8
255.1 288.2
274.5 299.0 297.4 258.4 295.0
ANIMAL NUMBER
626901 626907 626910 626913 626914
DAY 8
280.5 313.1 305.8266.5 305.9
DAY 9
292.4 320.1 310.2 269.7 314.4
DAY 10
294.3 321.4 318.3 272.8 319.4
DAY 13
DAY 24
DAY 34
301.9
345.5 334.4 282.7 342.1
SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13
DAY 48
-57-
Csmpany Saniliz.sd. Does not contain
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
626897 626903 626916 626925 626926
DAY 1
234.4 249.3 245.1 230.2 262.7
DAY 2
238.9 253.4 256.4 239.0 265.6
H-24001 (TEST SUBSTANCE) INDIVIDUAL 60DY WEIGHTS (g) OF MALE RATS
GROUP IV
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
247.4 261.7 259.5 249.9 279.3
254.9
273.6
272.1 258.0 281.0
261.7 286.9 282.2
268.8 292.8
271.7 296.3
289.1 275.3 299.5
283.0 305.8
294.5 282.8
301.5
ANIMAL NUMBER
626897 626903 626916 626925 626926
DAY 8
283.4 312.4
298.7-
294.5 305.8
DAY 9
295.4 318.8 303.5 296.2 311.6
DAY 10
303.0 321.3 310.5 303.8 319.4
DAY 13
a a a a
^a
DAY 24
DAY 34
DAY 48
379.3 404.0 382.7 390.7 385.7
SD test day 24 3D test day 24 SD test day 24 SD test day 24 SD test day 24
a Rat was not weighed.
-58-
Ccmpany Sanitized. Does not cont
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
626898 626902 626908 626918 626922
DAY 1
251 .4 268 .6 250 .7 232 .6 227 .3
t
DAY 2
261.5 276.7 256.9 235.8 234.1
H-24001 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS
GROUP V
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
266 .3 286 .4 266 .2 243 .4 240 .4
274.8 290.9
276.1 249.1 249.0
283.7 301.5 285.7 252.8 253.3
294 .6 307 .3 294 .3 263 .9 261 .5
296.4 310.0
298.9 261.4 265.5
ANIMAL NUMBER
626898 626902 626908 626918 626922
DAY 8 300 .3
316 .8 308 .7265 .6 271 .9
DAY 9
307.7 322.1 312.6 279.8 283.2
DAY 10 310 .2
322 .4 319 .0 276 .3 279 .4
DAY 13
--a
a a a a
DAY 24
a a a a a
DAY 34
406. 6 436. 3 452. 4 369. 6 381. 9
DAY 48
450.2 486.3 503.5 418.5 422.4
ANIMAL NUMBER
626898 626902 626908 626918 626922
DAY 52
DAY 62
DAY 69
467 .6 500 .1 523 .4 433 .2 433 .6
SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52
DAY 75
DAY 83
DAY 89
DAY 93
a Rat was not weighed.
-59-
Company Sanitized. Does not contain TS
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
626906 626911 626920 626924 626927
DAY 1
260 .8 229 .5 239 .0 244 .4 257 .1
DAY 2
262 .7 238 .1 246 .9 255 .0 265 .9
H-24001 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS
GROUP VI
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
274.7 246.2 250.9 260.8 274.5
282.9 248.5 260.5 271.6 280.3
290.4
257.9
267.4 280.6 283.5
305 .6 271 .7 280 .3 289 .5 295 .2
311 .8 271 .4 282 .5 296 .8 303 .3
ANIMAL NUMBER
626906 626911 626920 626924 626927
DAY 8
313 .9 280 .6 292 .9303 .4 313 .1
DAY 9
323 .5 286 .3 298 .4 310 .8 312 .7
DAY 10
326.6 286.6 295.4 322.6 318.4
DAY 13
a a a
^a
a
DAY 24
a a a
--a
a '
DAY 34
484. 4 381. 7 397. 8 433. 9 422. 9
DAY 48
550. 4 429. 9 448. 8 478. 6 475. 5
ANIMAL NUMBER
626906 626911 626920 626924 626927
DAY 52
572 .8 439 .6 467 .9 494 .7 499 .2
DAY 62 597 .0 446 .3
471 .0 503 .8 516.1
DAY 69
613.8 455.2 484.7 516.8
DAY 75
627.4 475.8 493.1 527.5 542.4
DAY 83
645.0 479.0 501.8 531.4 560.1
DAY 89
659 .1 500 .1 521 .5 540 .6 578 .9
DAY 93
674 .6 506 .9 527 .1 549 .5 594 .5
SD test day 93 SD test day 93 SD test day 93 SD test day 93 SD test day 93
a Rat was not weighed.
.60- CompanySan.t.ed.Doe
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
APPENDIX B Individual Clinical Observations
61 -
-
Company Sanded. Does not contain TSCA CM
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
Animal Number
627789 627801 627805 627810 627818
CORM OIL (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS
GROUP I
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-5 1-5 1-5 1-5 1-5
Animal
Number
627793 627797 627799 627800 627808
GROUP II
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-10 1-10 1-10 1-10 1-10
Animal
Number
627796 627806 627807 627809 627816
GROUP III
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-13 1-13 1-13 1-13 1-13
-62-
Company Sanitized. Does not contain TSCA CB!
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
Animal Number
627791 627794 627804 627812 627817
CORN OIL (NEGATIVE CONTROL)
INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS
GROUP IV
Observation
Mo abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
____Test Day
1-24 1-24 1-24 1-24 1-24
Animal Number
627792 627798 627813 627814 627815
GROUP V
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-52 1-52 1-52 1-52 1-52
Animal
Number
627795 627811 627819 627820 627821
GROUP VI
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-94 1-94 1-94 1-94 1-94
-63-
CompanySanitized. Does "ot contain TSCACSI
H-24001: Biopersistence Screening 10-DoseOral Gavage Study in Rats
DuPont-2924
Animal
Number.
625361 625363 625364 625380 625383
CORN OIL: ACETONE (NEGATIVE CONTROI.)
INDIVIDUAL CLINICAL OBSERVATIONS IN MAIjE RATS
GROUP I
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-5 1-5 1-5 1-5 1-5
Animal Number
625355 625362 625367 625368 625378
GROUP II
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-10 1-10 1-10 1-10 1-10
Animal
Number
625357 625358 625370 625384 625385
GROUP III
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-13 1-13 1-13 1-13 1-13
- 64 - Company Sanitized. Does not contain TSCA CBI
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
Animal
Number
625354 625365 625371 625376 625381
CORN OIL:ACETONE (NEGATIVE CONTROL)
INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS
GROUP IV
_ J^bservation _ _ _
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
_______Test Day
1-24 1-24 1-24 1-24 1-24
Animal
Number
625356 625359 625360 625372 625374
GROUP V
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-52 1-52 1-52 1-52 1-52
Animal Number
625353 625369 625373 625375 625377
GROUP VI
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-94 1-94 1-94 1-94 1-94
-65 Company Sanitized. Does not contain TSCA CB8
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
Animal Number.
625322 625323 625336 625343 625349
H-24019 (POSITIVE CONTROL)
INDIVIDUAL CLINICAL OBSERVATIONS IN MAI,E RATS
GROUP I
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-5 1-5 1-5 1-5 1-5
Animal
Number
625320 625330 625332 625341
625350
GROUP II
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Diarrhea No abnormalities detected
Test Day
1-10 1-10 1-10 1-4, 6-10
5
1-10
Animal Number
625321
625327 625342 625345 625348
GROUP III
Observation
No abnormalities detected Diarrhea
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-4, 6-13 5 1-13 1-13 1-13 1-13
-66-
Company Sanitized. Does not contain TSCACBJ
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
Animal Number
625325 625328 625338
625340 625352
H-24019 (POSITIVE CONTROL)
INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS
GROUP IV
__ __Observation
Ho abnormalities detected No abnormalities detected No abnormalities detected
Salivation No abnormalities detected No abnormalities detected
__________Test Day
1-24 1-24 1-6, 8-24
7
1-24 1-24
Animal Number
625324 625329
625333
625334 625344
GROUP V
Observation
No abnormalities detected No abnormalities detected
Salivation No abnormalities detected
Salivation No abnormalities detected No abnormalities detected
Test Day
1-52 1-6, 8-52
7
1-6, 8-52 7 1-52 1-52
Animal Number 625326
625335 625346
625347 625351
GROUP VI
Observation
No abnormalities detected Salivation
Alopecia both front legs Alopecia abdomen
No abnormalities detected Salivation
Black ocular discharge Yellow-stained perineum
Red-stained chin Brown-stained chin No abnormalities detected No abnormalities detected
Salivation
Test Day
1-6, 9-76, 77-94 7-8
76 7, 8, 9, 10, 13,
20, 27
1-6, 11-94 7-8
8 8 8
9-10 1-94 1-6, 8-94
7
-67- Company Sanitized. Does not contain TSCA CBI
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
Animal Number
627756 627767 627771 627773 627777
H-24020 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS
GROUP I
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-5 1-5 1-5 1-5 1-5
Animal Number
627768 627774 627776 627782 627785
GROUP II
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-10 1-10 1-10 1-10 1-10
Animal
Number
627758 627763 627764 627787
627788
GROUP III
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Wet perineum No abnormalities detected
Diarrhea
Test Day
1-13 1-13 1-13 1-5, 7-13
6
1-8, 10-13 9
-68-
Company Sanitized. Does not contain TSCA CBI
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
Animal Number
627759 627761 627770 627779 627786
H-24020 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS
GROUP TV
Observation _ __________Test Day
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
No abnormalities detected
1-24 1-24 1-24 1-24 1-24
Animal
Number
627757 627760 627765
627772
627781
GROUP V
Observatican
No abnormalities detected No abnormalities detected
-N..o- a--b-n-Wo-.re-mt apleitriienseudmetected
-N-o a--bnWoremt apleitriienseumdetected
No abnormalities detected
Test Day
1-52 1-52 1, 3-52
2
1, 3-52 2 1-52
Animal Number
627762
627769 627775 627778 627783
GROUP VI
Observation
No abnormalities detected Diarrhea
No abnormalities detected No abnormalities detected
Alopecia perineum No abnormalities detected Alopecia both front paws
Alopecia right front leg
Test Day
1-8, 10-94 9
1-94 1-94 81. 90, 94 1-23, 94 24, 34, 41, 47, 55, 61, 74, 81, 90
-69- Company Sanitized. Does not contain I'SCA CBi
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
Animal
Number
626904 626905 626915 626923 626930
H-24001 (TEST SUBSTANCE) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS
GROUP I
__ No No No No No
Observation
__
_____________Test Day
abnormalities detected
1-5
abnormalities detected
1-5
abnormalities detected
1-5
abnormalities detected
1-5
abnormalities detected
1-5
Animal Number
626900 626909 626912 626919 626921
GROUP II
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-10 1-10 1-10 1-10 1-10
Animal
Number
626901 626907 626910 626913 626914
GROUP III
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-13 1-13 1-13 1-13 1-13
-70- Company Sanitized. Does not contain TSCA CBI
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
Animal Number
626897 626903 626916 626925 626926
H-24001 (TEST SUBSTANCE)
INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS
GROUP IV
Observation
Mo abnormalities detected tSo abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-24 1-24 1-24 1-24 1-24
Animal
Number
626898 626902 626908 626918 626922
GROUP V
Observation
No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected
Test Day
1-52 1-52 1-52 1-52 1-52
Animal
Number
626906 626911
626920 626924 626927
GROUP VI
Observation
No abnormalities detected No abnormalities detected
Alopecia perineum Alopecia both front paws Alopecia both front legs No abnormalities detected No abnormalities detected No abnormalities detected
Alopecia underbody Alopecia chest
Alopecia right side
Test Day
1-93 1-48
52
62, 69, 75 89, 93 1-93 1-93 1-24
34, 48, 52, 62 69, 75,83
89, 93
-71-
Company Sanitized. Does not contain TSCACBi
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2924
APPENDIX C Analysis of Blood Fluoride Data
72-
Company Sani'dzed. Doss no* contain TSCA CBI
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Terms: Active . % Active
Terms and Calculations
Mol Wt Active
Formulation Dose % F in Active
Mol Wt P
The molecular weight of fluorine g/mol
DuPont-2924
Compound Calculations:
Dose Active (mg/kg)
The mg of fluorine containing compound administered per kg of animal body weight.
= (% active/100) * 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 of animal body weight = (% P in active/100) * Dose Active [mg/kg]
Dose F (mmol/kg)
The mmole of fluorine administered per kg of animal body weight
= Dose P [mg/kg] / Mol Wt F [mg/mmol]
Molar Ratio (Active/F)
The moles of fluorine containing compound per mole of fluorine = Dose Active [mmol/kg] / Dose P [mmol/kg]
Formulation Dose Normalization Factor
The formulation dose that would be required to administer the
amount of active needed to achieve the normalized dose = (Normalized dose of Active [mmol/kg] / Dose Active [mmol/kg]) * Formulation Dose
-73-
Company Sanitized. Does not contain TSCA CBS
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Individual Animal Measurement:
ppm F in blood
The ppm fluoride measured in blood
DuPont-2924
Individual Animal Calculations:
ppm F in Blood minus Bkg 0.2 ppm
The ppm fluoride measured in plasma minus the background fluoride measured in control animal blood. In this case the value was established at 0.2 ppm.
ppm F in Blood
The ppm fluoride minus background that would be expected if the
normalized to 0.1 mmol/kg active dose was 0.1 mmol/kg instead of the actual active dose. This
Dose
assumes linearity between administered dose and blood fluorine
levels, but is needed because different doses of active were used in
the study.
= (0.1 [mmol/kg] / Active dose [mmol/kg]) * (ppm F in blood
minus background)
jMnolar equivalents of active in blood
The /imolar [pnol/L] concentration of fluorine containing
compound in plasma based on the ppm fluorine in plasma normalized to 0.1 mmol/kg active dose. This assumes that all
plasma fluorine is derived from the fluorine-containing component in the formulation. Note: 1 ppm - 1 vag/L
= (Normalized ppm [mg/L] fluorine in blood / Mol Wt F
[mg/mmol]) * molar ratio active/F [mmol active/mmol P] *
1000 ^mol/mmol
-74-
Compaxly SaaitizedL Does not contain TSCA CB!
H-24001: Biopersistence Screening 10-Dose Oral Gavage Stuctyin Rats
Factors Influencing Interpretation of Kinetic Analysis
DuPont-2924
Considerations:
The data used for kinetic analysis was from a limited screen and extrapolation should be done cautiously.
Sample size is low Analytical data used without validation Steady-state not reached Terminal phase may not be reached Some compounds are mixtures of fluorinated compounds Different active and formulation doses were used
Different vehicles were used to deliver formulations The kinetics apply only to plasma, not to specific tissues or the whole body Each compound may have very different potency for producing toxicity
Assumptions: (May or may not be justified in all cases)
- Plasma fluorine concentrations are linear with respect to dose - Analytical method is appropriate for all types of compounds - Elimination kinetics can be determined based on total fluorine rather than on concentrations of
individual components - Background plasma Fluoride is 0.2 ppm
- % F data is the % Fluorine of the active (Fluorine containing component(s) in the formulation - Molecular weight is the molecular weight of the active component in the formulation
-75-
Carepan,^ SaaiAizad. Does not contain TSCA.CB8
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H- 24[Q19
Given:
MolWt. Active (g/mole):
Pormiilation Dose (mg/kg): %Acti ve (F Containing) in
Ponnul ation:
497
% F in Active:
10
MolWt.F(g/mol):
100
CalculatedI Values: Dose A .ctive (mg/kg): Dose A .ctive (mmole/kg): Pormuliation Dose Normalization Factor:
10
0.020
49.7
Dose P (mmol/kg): Molar Ratio (Active/]F): Dose P (mg/kg):
DuPont-2924
65 19
0.342 0.059 6.5
Rat#
Test Day Sample
ppm F in
blood
Group I
625322
1
1.0
625323
1
1.3
625336
1
2.6
625343
1
2.6
625349
1
2.9
Group I
625322
5
625323
5
625336
5
625343
5
625349
5
51.7 38.0 38.7 78.5 37.1
Group II
625320
10
625330
10
625332
10
625341
10
625350
10
65.6 61.1 60.5 63.1 58.1
ppm Fin
blood ixunus Bkg
0.2 ppm
0.8 1.1 2.4 2.4 2.7
51.5 37.8 38.5 78.3 36.9
65.4 60.9 60.3 62.9 57.9
ppm F in blood Normalized to 0.1 mmoIes/Kg
Dose
3.98 5.47 11.93 11.93 13.42
255.96 187.87 191.35 389.15 183.39
325.04 302.67 299.69 312.61 287.76
/xmolar equivalents
of active in
blood
12.31 16.92 36.92 36.92 41.54
792.31 581.54 592.31 1204.62 567.69
1006.15 936.92 927.69 967.69 890.77
.76- Company Sanitized. Does not contain TSCA CBi
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Rat#
Test Day Sample
ppmF
in
blood
Group m
625321
13
625327
13
625342
13
625345
13
625348
13
77.2 61.5 64.6 57.0 62.4
Group IV
625325
24
625328
24
625338
24
625340
24
625352
24
40.3 46.3 43.2 39.1 41.9
Group V
625324
52
625329
52
625333
52
625334
52
625344
52
24.7 29.8 27.3 29.1 23.8
Group VI
625326
94
625335
94
625346
94
625347
94
625351
94
12.4 16.4 13.1 11.0 11.6
ppmF in
blood minus Bkg
0.2 ppm
77.0 61.3 64.4 56.8 62.2
40.1 46.1 43.0 38.9 41.7
24.5 29.6 27.1 28.9 23.6
12.2 16.2 12.9 10.8 11.4
ppm F in bllood
Normalize<ito
0.1 mmoles/Kg
Dose
382.69 304.66 320.07 282.30 309.13
199.30 229.12 213.71 193.33 207.25
121.77 147.11 134.69 143.63 117.29
60.63 80.51 64.11 53.68 56.66
DuPont-2924
^molar equivalents of active in
blood
1184.62 943.08 990.77 873.85 956.92
616.92 709.23 661.54 598.46 641.54
376.92 455.38 416.92 444.62 363.08
187.69 249.23 198.46 166.15 175.38
-77-
Company Sanitized. Doss not contain TSCA CBi
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-24020
Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (P Containing) in
Formulation:
426
% F in Active:
20
Mol Wt. F (g/mol):
100
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization
Factor:
20 0.047
42.6
Dose P (mmol/kg): Molar Ratio (Active/.F): Dose F (mg/kg):
DuPont-2924
69 19
0.726 0.065 13.8
Rat #
Test Day Sample
ppmF
in blood
Group I
627773
1
13.2
627771
1
8.1
627767
1
16.5
627756
1
14.1
627777
1
10.7
Group I
627773
5
627771
5
627767
5
627756
5
627777
5
75.3 66.8 64.8 80.0 71.6
Group II
627768
10
627774
10
627776
10
627782
10
627785
10
56.3 51.0 54.8 43.6 65.1
ppmF in
blood iminus Bkg
0.2 ppm
13.0 7.9 16.3 13.9 10.5
75.1 66.6 64.6 79.8 71.4
56.1 50.8 54.6 43.4 64.9
ppm F in blood Normalized to 0.1 mmoles/Kg
Dose
27.69 16.83 34.72 29.61 22.37
159.96 141.86 137.60 169.97 152.08
119.49 108.20 116.30 92.44 138.24
^imolar equivalents of active in
blood
94.20 57.25 118.12 100.72 76.09
544.20 482.61 468.12 578.26 517.39
406.52 368.12 395.65 314.49 470.29
-78-
Company Saratized. Does not contain TSCA CES
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Rat#
Test Day Sample
ppmF
in blood
Group HI
627758
13
627764
13
627787
13
627763
13
627788
13
43.5 20.7 13.2 30.8 24.9
Group IV
627759
24
9.2
627779
24
14.9
627770
24
11.6
627761
24
9.9
627786
24
6.7
Group V
627757
52
0.9
627781
52
0.6
627760
52
1.0
627765
52
0.9
627772
52
0.8
Group VI
627778
94
627783
94
627762
94
627775
94
627769
94
0.3 <0.2 0.2 0.2 <0.2
* = Below LOD (Level of Detection)
ppmF in
blood minus Bkg
0.2 ppm
43.3 20.5 13.0 30.6 24.7
9.0 14.7 11.4 9.7 6.5
0.7 0.4 0.8 0.7 0.6
0.1
*
0.0 0.0
*
ppm F in blood Normalized to 0.1 mmoles/Kg
Dose
DuPont-2924
/imolar equivalents of active in
blood
92.23 43.67 27.69 65.18 52.61
313.77 148.55 94.20 221.74 178.99
19.17 31.31 24.28 20.66 13.85
65.22 106.52 82.61 70.29 47.10
1.49 0.85 1.70 1.49 1.28
5.07 2.90 5.80 5.07 4.35
0.21
*
0.00 0.00
*
0.72
*
0.00 0.00
*
-79- c^Sao^00""01"""1"^"'
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H- 24001
Given:
MolWt. Active (g/mole):
Ponnplation Dose (mg/kg): %Actrve (P Containing) in
Fonnul ation:
60 1000
35
% F in Active:
MolWt.F(g/mol):
Calculated1Values: Dose A .ctive (mg/kg): Dose A ctive (mmole/kg):
Formul.ation Dose Normalization Factor:
350 0.583
171.4
Dose F (mmol/kg): Molar Ratio (Active;'F): Dose F (mg/kg):
DuPont-2924
60
19
11.053 0.053 210
Rat#
Test Day Sample
ppmF
in blood
Group I
626904
1
3.3
626905
1
4.2
626915
1
3.9
626923
1
3.9
626930
1
5.1
Group I
626904
5
626905
5
626915
5
626923
5
626930
5
12.8 13.3 11.9
#
15.5
Group II
626900
10
626909
10
626912
10
626919
10
626921
10
15.2 18.5 20.8 25.7 17.3
ppmF in
blood ininus Bkg
0.2 ppm
3.1 4.0 3.7 3.7 4.9
12.6 13.1 11.7
# 15.3
15.0 18.3 20.6 25.5 17.1
ppm F in blood Normalized to 0.1 nunoles/Kg
Dose
0.53 0.69 0.63 0.63 0.84
2.16 2.25 2.01
#
2.62
2.57 3.14 3.53 4.37 2.93
jxmolar equivalents of active in
blood
1.48 1.90 1.76 1.76 2.33
6.00 6.24 5.57
#
7.29
7.14 8.71 9.81 12.14 8.14
-80-
Coaipany Sanitized. Does not contain TSCA CBi
H-24001: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Rat#
Test Day Sample
ppmF
in blood
Group ffl
626901
13
7.7
626907
13
5.5
626910
13
6.8
626913
13
5.7
626914
13
5.6
Group IV
626897
24
2.4
626903
24
2.8
626916
24
2.7
626925
24
2.5
626926
24
2.8
Group V
626898
52
1.8
626902
52
2.0
626908
52
1.4
626918
52
1.7
626922
52
1.9
Group VI
626906
94
0.8
626911
94
1.0
626920
94
1.2
626924
94
1.2
626927
94
1.1
ppmF in
blood
minus Bkg 0.2 ppm
7.5 5.3 6.6 5.5 5.4
2.2 2.6 2.5 2.3 2.6
1.6 1.8 1.2 1.5 1.7
0.6 0.8 1.0 1.0 0.9
# = Tube of blood for this rat was missing or broken.
ppm F in I ilood Normaliztdto 0.1 mmoles/Kg
Dose
1.29 0.91 1.13 0.94 0.93
0.38 0.45 0.43 0.39 0.45
0.27 0.31 0.21 0.26 0.29
0.10 0.14 0.17 0.17 0.15
DuPont-2924
inmolar equivalents
of active in blood
3.57 2.52 3.14 2.62 2.57
1.05 1.24 1.19 1.10 1.24
0.76 0.86 0.57 0.71 0.81
0.29 0.38 0.48 0.48 0.43
.81-
CoiapasySaw^28^ Boss-BKEEeosiiam TSCA CBI