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Study Title H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Laboratory Project ID: DuPont-11557
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DuPont-11557
Author: Carol Finlay, B.A.
Study Completed on: November 26,2003
Performing Laboratory: E.I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
CERTIFICATION
We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study.
Reviewed by:
Paul M. Hinderliter, PhD . Research Toxicologist
Issued by Study Director:
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CaroliFinlay, B.A. f
Staff Toxicologist
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Date
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Date
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
TABLE OF CONTENTS
DuPont-11557
Page
CERTIFICATION....................................................................................................................... 2
LIST OF TABLES....................................................................................................................... 4
LIST OF FIGURES......................................................................................................................4
LIST OF APPENDICES.............................................................................................................. 5
STUDY INFORMATION............................................................................................................ 6
STUDY PERSONNEL.................................................................................................................. 8
SUMMARY......................................................................................................
9
INTRODUCTION....................................................................................................................... 11
MATERIALS AND METHODS............................................................................................... 11
A. Test Substance and Positive Controls............................................................................... 11
B. Test Species...................................................................................................................... 11
C. Animal Husbandry............................................................................................................ 11
D. Quarantine and Pretest................................................
12
E. Study Design..................................................................................................................... 13
F. Assignment to Groups and Study Start............................................................................. 13
G. Dosing Material Preparation and Administration..............................................................13
H. Body Weights..........................................................................................
14
I. Mortality and Clinical Observations................................................................................. 14
J. Collection and Analysis of Blood, Livers, and Fat..........................
14
K. Treatment of Fluorine Data............................................................................................... 15
L. Statistical Analyses........................................................................................................... 15
RESULTS AND DISCUSSION................................................................................................. 16
A. In-Life Toxicology............................................................................................................ 16
B. Liver Weights...............
16
C. Fluorine D ata.................................................................................................................... 17
CONCLUSIONS......................................................................................................................... 18
RECORDS AND SAMPLE STORAGE.....................................
19
TABLES....................................................................................................................................... 20
FIGURES..................................................................................................................................... 27
APPENDICES............................................................................................................................. 38
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
LIST OF TABLES
Page
1. MEAN BODY WEIGHTS.................................................................................................................................................21 2 . MEAN BODY WEIGHT GAINS................................... ........................................................ ........................................ 22 3. MEAN BODY AND LIVER WEIGHTS........................................................................................................................ 23 4 . MEAN BLOOD FLUORINE LEVELS.......................................................................................................................... 24 5 . MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO D O SE ................................................... 24 6 . MEAN LIVER FLUORINE LEVELS............................................................................................................................. 25 7. MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO D O SE ..................................................... 25 8. MEAN FAT FLUORINE LEVELS................................................................................................................................. 26 9. MEAN FAT FLUORINE CONCENTRATION NORMALIZED TO DOSE........................................................... 26
LIST OF FIGURES
Page
1. MEAN BODY WEIGHTS..................................................................................................................................................28
2 . COMPARISON OF MEAN RELATIVE LIVER WEIGHTS: TEST SUBSTANCE AND NEGATIVE CONTROL................................................................................................
3. COMPARISON OF MEAN RELATIVE LIVER WEIGHTS: TEST SUBSTANCE AND POSITIVE CONTROLS...........................................................................................................................................................................30
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4 . MICROMOLAR EQUIVALENTS IN RAT BLOOD.................................................................................................. 31
5 . NORMALIZED H-25357 AND POSITIVE CONTROL BLOOD AUCINF/D RESULTING FROM A 10-DAY ORAL G AVAG E........................................................................................................................
6. MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO D O S E .......................................................34
7. COMPARISON OF RELATIVE LIVER WEIGHT AND MEAN LIVER FLUORINE CONCENTRATION FOR H-25357 AND NEGATIVE CONTROL........................................................................35
8. MEAN FAT FLUORINE CONCENTRATION NORMALIZED TO DOSE.............................................................36
9. COMPARISON OF MEAN BLOOD, MEAN LIVER, AND MEAN FAT FLUORINE CONCENTRATION NORMALIZED TO DO SE...........................................................................................................37
33
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
LIST OF APPENDICES
Page
A. INDIVIDUAL BODY WEIGHTS.................................................................................................................................... 39 B . INDIVIDUAL CLINICAL OBSERVATIONS.............................................................................................................. 49 C. TERMS AND CALCULATIONS FACTORS INFLUENCING INTERPRETATION OF KINETIC
A N A L Y S IS ............................................................................................................................................................................63 D. INDIVIDUAL FLUORINE LEVELS IN BLOOD.........................................................................................................67 E. INDIVIDUAL FLUORINE LEVELS IN LIVER........................................................................................................... 74 F. INDIVIDUAL FLUORINE LEVELS IN FA T............................................................................................................... 78
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY INFORMATION Test Substance
Substance Tested Svnonvms/Codes^ H-25357
DuPont-1155 7
Positive Control Substance Tested: Potassium perfluoroalkyl sulfonate Synonvms/Codes: \ H-24019
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY INFORMATION (Continued)
DuPont-11557
Positive Control Substance Tested: Octanoic acid, pentadecafluoro-, ammonium salt
Perfluorooctanoate, ammonium salt APFO Ammonium perfluorooctanoate Haskell Number: 24020
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Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A.
Study Initiated/Completed: October 10, 2002 / (see report cover page)
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
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STUDY PERSONNEL
Study Director: Carol Finlay, B.A. Management: Judith C. Stadler, Ph.D., D.A.B.T. Scott E. Loveless, Ph.D.
Primary Technician: James C. Mackay II
Fluorine Data Analysis: Paul M. Hinderliter, Ph.D. Management: Matthew S. Bogdanffy, Ph.D., D.A.B.T.
Toxicology Report Preparation: Sean M. Callaghan, B.A. Management: Nancy S. Selzer, M.S.
Laboratory Veterinarian: Thomas W. Mayer, D.V.M., A.C.L.A.M.
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
SUMMARY
The objective of this study was to evaluate the potential for H-25357 to be absorbed and to accumulate in a mammalian system. Two groups of 5 male rats each were dosed by gavage with 1000 mg/kg/day of H-25357 for 10 consecutive days. One group was sacrificed on Day 10, and the other group was maintained without dosing for an additional 84 days. Blood was collected on test days 1, 5,10, 13,24, 52, and 94. Livers and fat were collected at sacrifice. Body weights and clinical signs were recorded throughout the dosing and recovery periods. Additionally, a negative control of deionized water and 2 positive controls, H-24019 (10 mg/kg/day) and H-24020 (20 mg/kg/day), were tested as described for H-25357. Blood, liver, and fat samples were analyzed for total fluorine content to determine test substance absorption and retention in these tissues.
No deaths occurred, and no clinical signs attributed to the test substance were observed. The mean body weight gains of rats dosed with H-25357 were higher than the negative control rats during the dosing and recovery periods. Mean body weight gains of rats dosed with the positive control materials were lower during the dosing period than the weight gains of rats dosed with the test substance. During the recovery period, the mean body weight gain of rats dosed with the positive control material H-24019 was lower than the weight gain of rats dosed with the test substance. The mean body weight gain of rats dosed with the other positive control material, H24020, was higher than the weight gain of rats dosed with the test substance.
For the purpose of comparing absorption and retention of the test substance to the positive controls, all doses were normalized on a molar basis. The total fluorine in each tissue was considered as a percentage of the fluorine delivered in the administered dose, and all units were expressed as pM equivalents. As a measure of total dose in the blood, an area under the curve (estimated to infinity) was calculated for the test substance and positive controls. The AUCINF/D for the fluorine component of H-25357 was 8.61xl02, compared to AUCINF/D values of 5.22xl05and 8.15xl04 for H-24019 and H-24020, respectively. This parameter indicated a total dose in blood that was much less for H-25357, the test substance, than for the positive controls. There was no detectable fluorine in the blood on days 52 and 94 in rats dosed with the test substance.
The mean relative liver weight (liver/body weight) of rats dosed with H-25357 was 24% higher than the negative control rats on day 10. By day 94, the mean relative liver weight of rats dosed with H-25357 was similar to the negative control. The mean relative liver weight of rats dosed with H-24019 was 41% higher and for H-24020 was 93% higher on day 10 than the negative control group. By day 94, the mean relative liver weights of rats dosed with H-24019 and H24020 were similar to the negative control group. Therefore, liver weights of rats dosed with the test substance were higher than the negative controls at the end of the dosing period but were similar to the negative controls at the end of the recovery period.
The concentration of fluorine in the livers from rats dosed with H-25357 was 114.94 pM equivalents on day 10 and 6.96 pM equivalents on day 94. On the last day of dosing, the mean
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
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pM equivalent concentrations of fluorine in the livers of rats dosed with the positive control materials were approximately 42-fold (H-24019) and 8-fold (H-24020) greater than values in rats treated with the test substance. By day 94, the fluorine concentrations in pM equivalents were approximately 186x and 2x the fluorine concentration in rats treated with H-25357. Therefore, rats treated with H-24019 or H-24020 absorbed and retained considerably more fluorine in the liver than rats treated with the test substance, H-25357.
The fluorine concentration in the fat from rats dosed with the test substance was 107.79 pM equivalents on day 10 and 13.59 pM equivalents on day 94. The fluorine concentration in pM equivalents of one of the positive control materials, H-24019, was approximately 2x higher than H-25357 on day 10. The fluorine concentration of the test substance, H-25657, was approximately 2x higher on day 10 than the fluorine concentration of the other positive control material, H-24020. By day 94, the fluorine concentration of the positive control, H-24019, was similar to the fluorine concentration in rats treated with the test substance, H-25357. There was no detectable fluorine by day 94 in the fat from rats dosed with the positive control H-24020.
Under the conditions of this study, fluorine was evident in the blood during the period of dosing with H-25357, but was quickly eliminated. The amounts of fluorine in the livers and fat from rats dosed with the test substance were higher than levels in the blood, and the results indicate that there was evidence of some retention of fluorine in the liver and fat. Fluorine levels in the blood and liver were lower than levels in rats dosed with the positive controls, H-24019 and H24020. Fluorine levels in the fat were lower at day 10 than levels in rats dosed with the positive control H-24019 but higher than the positive control H-24020. At day 94, fluorine levels in the fat were similar to or higher than levels in the positive controls.
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
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INTRODUCTION
The objective of this study was to define the potential of H-25357 to be absorbed and to bioaccumulate in a mammalian system, as indicated by analytical determination of total fluorine in blood, liver, and fat. The test substance was compared to 2 positive controls that were materials previously shown to bioaccumulate in mammals. The daily dosage of 1000 mg/kg for the test substance was selected based on existing toxicity information.
MATERIALS AND METHODS
A. Test Substance and Positive Controls
The test substance, H-25357, was supplied by the sponsor as an amber 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 Crl:CD(SD)IGS BR rats were received from Charles River Laboratories, Inc., Raleigh, North Carolina. The Crl:CD(SD)IGS BR rat was selected on the basis of extensive experience with this strain and its suitability with respect to longevity, hardiness, and low incidence of spontaneous diseases.
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%.
2. Feed and Water
Tap water was provided ad libitum. All rats were fed PMI Nutrition International, LLC Certified Rodent LabDiet 5002 chow. The feed is guaranteed by the manufacturer to meet specified nutritional requirements and to be free of specified contaminants.
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1 3. Identification
Each rat was assigned a unique identification number which was recorded on a card affixed to the cage. The last 3 digits of the number were tattooed on the tail of each rat.
4. Health Monitoring Program
As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure 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 of coliforms, 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. Evaluation of these data did not indicate any conditions that affected the validity of the study.
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 designee of the laboratory animal veterinarian.
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
E. Study Design
Dosage Number of
Substance
Vehicle
(mg/kg) Animals
Negative Control
Deionized water Not applicable
0
10
Positive Controls
H-24019
Acetone/Com Oil 10
10
H-24020
Acetone/Com Oil 20
10
Test Substance
H-25357
None
1000
10
DuPont-11557
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 arbitrarily assigned to each group.
After assignment to groups, each rat was housed individually. The rats were 7 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 pathology evaluation.
G. Dosing Material Preparation and Administration
1. Test Substance
H-25357 was administered neat. The amount of test substance each rat received was based on ' the body weight collected on each day of dosing. The test substance was stirred on a magnetic stir plate throughout the dosing procedure to maintain homogeneity.
2. Positive Controls
It was necessary to dissolve H-24019 and H-24020 in acetone before suspending them in com oil. The ratio of acetone to com 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 rats were dosed at a volume 1 mL/100 g of body weight. The dosing preparations were stirred on a magnetic stir plate throughout the dosing procedure to maintain homogeneity.
3. Negative Control
Deionized water was chosen as the negative control. The rats were dosed at a volume of 1
mL/100 g of body weight. These rats were dosed in a separate room from the rats dosed with the
test substance or positive controls.
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
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H. Body Weights
All rats were weighed on each day of dosing and weekly 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 was individually handled and examined for abnormal behavior and appearance.
J. Collection and Analysis of Blood, Livers, and Fat
At time points selected for blood sampling other than sacrifice days, approximately 1 mL of blood was collected into EDTA tubes from the orbital sinus of each rat. Rats designated for sacrifice were euthanized by carbon dioxide anesthesia and exsanguination and blood, livers, and fat were collected according to the following schedules:
Group Dosing Days Tissue Collected
Sampling Time
I 1-10 Blood
Test day 1 (2 hours post dosing)
I 1-10 Blood
Test day 5 (2 hours post dosing)
I , 1-10 Blood, Liver, and Fat Test day 10 at sacrifice (2 hours post dosing)
III 1-10 Blood
Test day 13
III 1-10 Blood
Test day 24
III 1-10 Blood
Test day 52
III 1-10 Blood, Liver, and Fat Test day 94
As much blood as possible was collected into EDTA tubes at sacrifice. The livers and fat were weighed. The fat weights were used for the calculation of fluorine levels. The liver weights were used for the calculation of fluorine levels and for the calculation of liver weight relative to' total body weight. The blood from all rats was refrigerated and the livers and fat were frozen. The blood, livers, and fat were appropriately packaged and shipped to Jackson Laboratory, Deepwater, New Jersey where they were analyzed for total fluorine. The liver and fat samples remained frozen during shipping.
The total fluorine content of the blood and tissue samples was determined using a Wickbold torch combustion method, followed by analysis with a fluoride ion selective electrode. The samples were decomposed or volatilized in the presence of wet oxygen and swept through an oxy-hydrogen flame in a closed quartz apparatus. The combustion products were collected in an aqueous absorbing solution and analyzed with a fluoride ion selective electrode. Kinetic analysis of the data received (ppm F in each sample) was performed by Haskell Laboratory personnel for evaluation of fluorine biopersistence.
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
K. Treatment of Fluorine Data
DuPont-11557
Since the test substance and positive controls had different toxicity profiles, it was not possible to administer a uniform mg/kg dose for all test materials. Properly conducted kinetic comparisons in situations with varied doses required the use of a normalized dose. The dose-normalization was conducted in pmolar units to accommodate test material molecular weight differences and was adjusted to an arbitrary normalized dose of 0.1 mmoles/kg.
H-24019 and H-24020 were used as positive controls and a dosing diluent was used as the negative control. The percent of fluorine and molecular weight of the test substance and positive controls were used as provided by the sponsor. The measured total fluorine values were used as received (ppm F) from Jackson Laboratory. For the Wickbold torch method, the background fluorine level is 0.2 ppm. This is the limit of detection (LOD) of this method and was subtracted from each sample. The limit of quantification (LOQ) for this method is 0.5 ppm, and any values listed as less than 0.5 ppm were excluded from further treatment.
Since the dosages and molecular weight for positive controls and test material differed, the data were converted from a mass to a molar basis. In addition, the data were standardized to a single reference dose to allow comparison between compounds of differing fluorine content. The doses were first converted from a mg of test material basis to millimoles of fluorine. Raw fluoride ion data (ppm F) were then normalized to a 0.1 millimole dose of active component. Finally the molar dosage and normalized concentration were combined to yield the pmolar (pM) equivalents of active component in the tissue. Detailed calculations can be found in Appendix C. The uM equivalents can be compared across compounds provided the considerations listed in Appendix C are observed.
Noncompartmental analysis was conducted on fluorine data derived from rats dosed with H-25357 and the positive controls using WinNonlin Version 4.0 software (Pharsight Corp, Mountain View, CA). WinNonlin software provided a means of computing derived pharmacokinetic parameters from experimental data. All analysis was calculated using the pM . equivalent in blood data.
The maximum observed concentration in blood was Cmax (pM equivalent). Biopersistence was assessed by quantifying terminal elimination blood half-life (T/,,days). The points included in determination of the Ty2were selected manually and included only points after apparent log-linear elimination was achieved. Internal exposure was determined by calculating the blood areaunder-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. AUCINF normalized to dose (AUCINF/D) can be used to compare the relative exposures of different compounds and dosages.
L. Statistical Analyses /`"S
Descriptive statistics (e.g. mean, standard deviation) were used.
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
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RESULTS AND DISCUSSION
A. In-Life Toxicology (Tables 1-2, Figure 1, Appendices A-B)
No deaths occurred. Hair loss observed in two rats during the study was considered to be incidental and not test substance-related. The mean body weight gains of rats dosed with the test substance were higher than the negative control during the dosing and recovery periods. The mean body weight gains of the rats dosed with the positive control materials were lower during the dosing period than the weight gain of rats dosed with the test substance. During the recovery period, the mean body weight gain of rats dosed with the positive control material H-24019 was lower than the weight gain of rats dosed with the test substance. The mean body weight gain of rats dosed with the other positive control material, H-24020, was higher than the weight gain of rats dosed with the test substance.
B. Liver Weights (Table 3, Figures 2, 3, and 7)
1. Test Substance
The mean relative liver weight (liver/body weight) of rats dosed with H-25357 was 24% higher than the negative control rats on day 10. By day 94, the mean relative liver weight of rats dosed with H-25357 was similar to the negative control.
2. Positive Controls
The mean relative liver weight of rats dosed with one of the positive controls, H-24019, was 12% higher on days 10 than the liver weight of rats dosed with the test substance, H-25357. By day 94, the weights were similar.
The mean relative liver weight of rats dosed with the other positive control, H-24020, was 52% higher at day 10 than the liver weight of rats dosed with H-25357. By day 94, the weights were similar.
The mean relative liver weight of rats dosed with H-24019 was 38% higher at day 10 than the negative control group. By day 94, the mean relative liver weight of rats dosed with H-24019 was similar to the negative control group. The mean relative liver weight of rats dosed with H24020 was 88% higher on day 10 than the negative control group. By day 94, the weights were similar.
Therefore, the relative liver weights of rats dosed with the test substance, H-25357, were higher than the negative controls at the end of the dosing period but were similar to the negative controls at the end of the recovery period.
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H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
C. Fluorine Data (Tables 4-9, Figures 4-9, Appendices C-F)
DuPont-11557
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 level 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 FI-24019 and H-24020. The FI-24019 and H-24020 normalized pM equivalents in rat blood continued to rise throughout the dosing period and may not have reached steady-state (Figure 4A and 4B). The Cmax for H-24019 was 1043.08 54.57 pM equivalents (mean S.D.) with a terminal half-life of 42.2 days. The Cmax for H-24020 was 541.45 50.37 pM equivalents (mean S.D.) with a terminal half-life of 15.1 days. For each of the positive controls, blood was sampled at 7 time points throughout the study, with only 4 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 substance. The AUCINF/D for the fluorine component was 5.22 x 105 for H-24019 and 8.15 x 104 for H-24020.
The concentrations of fluorine in the livers on day 10 from rats dosed with the positive control materials were 4802.15 and 866.67 pM equivalents for H-24019 and H-24020, respectively. By day 94, the concentrations were 1292.92 and 17.10 pM equivalents.
The concentrations of fluorine in the fat on day 10 from rats dosed with the positive control materials were 194.46 and 57.25 pM equivalents for H-24019 and H-24020, respectively. By day 94, the concentration of fluorine in the fat from rats dosed with H-24019 was 15.38 pM equivalents. There was no detectable fluorine by day 94 in the fat from rats dosed with H-24020.
3. Test Substance
The H-25357 normalized uM equivalents in rat blood rose rapidly and appears to have reached
reach steady-state (Figure 4C). The Cmax for H-25357 was 15.74 0.88 pM equivalents (mean SD). Terminal half-life could not be accurately calculated because no samples on days 52 and 94 were above the limit of quantification. 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 H-25357 and positive controls. The AUCINF/D for the fluorine component of H-25357 was 8.61xl02as compared to AUCINF/D
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H-25357: Biopersistence Screening 1Q-Dose Oral Gavage Study in Rats
DuPont-11557
values of 5.22x 105and 8.15x104 for H-24019 and H-24020, respectively. There was no detectable fluorine in the blood on days 52 and 94 in rats dosed with the test substance.
Levels of total fluorine in livers from rats dosed with the test substance, H-25357, were lower than the levels in livers from rats dosed with the positive control materials. The total fluorine concentration in the liver from rats dosed with H-25357 was 114.94 pM equivalents at day 10 and 6.96 pM equivalents at day 94. For the positive control H-24019, the liver concentrations were approximately 42x higher (day 10) and approximately 186x higher (end of study) than H25357. For H-24020, the liver concentrations were approximately 8x higher (end of dosing) and 2x higher (end of study) than H-25357.
Levels of total fluorine in fat from rats dosed with the test substance were lower on day 10 but similar on day 94 to the levels in fat from rats dosed with the positive control material H-24019. The levels in fat from rats dosed with the test substance were higher than levels in fat from rats dosed with the positive control material H-24020. The fluorine concentration in the fat from rats dosed with the test substance was 107.79 pM equivalents on day 10 and 13.59 pM equivalents on day 94. The fluorine concentration of one of the positive control materials, H-24019, was approximately 2x higher than H-25357 on day 10. The fluorine concentration of the test substance, H-25357, was approximately 2x higher than the fluorine concentration of the other positive control material, H-24020. By day 94, the fluorine concentration of H-24019 was similar to the fluorine concentration in rats treated with H-25357. There was no detectable fluorine by day 94 in the fat from rats dosed with H-24020.
The pM equivalents in the liver and fat were higher than levels in the blood.
CONCLUSIONS
Rats dosed for 10 consecutive days with 1000 mg/kg H-25357 exhibited no mortality, no test substance-related clinical signs, and no body weight effects. Liver weights were affected in rats dosed with the test substance. A steady-state for fluorine in the blood appeared to be achieved during the 10-day dosing period with the test substance. Dose-adjusted areas under the curve (AUCINF/D) for positive controls, H-24019 and H-24020, were approximately 600x and 95x the AUCINF/D for the test substance.
Under the conditions of this study, there was limited absorption and no retention of fluorine in the blood following dosing with H-25357. Administration of the test substance, H-25357, to male rats for 10 consecutive days resulted in some absorption and retention of fluorine in the liver and fat. However, levels in blood and liver in rats dosed with H-25357 were generally lower than the fluorine levels in rats dosed with the positive control materials, H-24019 and H-24020. Levels in fat in rats dosed with H-25357 were lower than at day 10 but similar to the levels at day 94 in rats dosed with the positive control H-24019. Levels in fat from rats dosed with the test substance were higher than levels in fat from rats dosed with the positive control H-24020.
.Company Sanitized Does no! contain TSCACBf
- 18-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
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.
company --
- 19-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
TABLES
Company
woes iut GOUii 'iwA CBi
-20-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats_____________________________
DuPont-11557
TABLE 1
MEAN BODY WEIGHTS
Negative Control DAYS ON TEST Deionized Water
MEAN BODY WEIGHTS (g)
Positive Controls
H-24019
H-24020
1
189.6
184.4
184.1
2
195.5
189.2
187.8
3
204.6
199.5
197.8
4
211.7
206.4
204.8
5
222.1
216.2
212.5
6
225.0
222.0
216.0
7
235.2
229.4
223.6
8
242.3
233.7
226.9
9
248.3
240.4
234.2
10
257.0
246.5
243.0
17
293.3
290.1
297.4
24
325.5
313.3
338.6
31
359.3
348.4
381.9
38
380.9
370.8
404.9
45
407.4
403.2
434.4
52
420.5
422.8
460.6
59
436.4
439.6
483.1
66 - - -
67
452.8
455.6
502.7
73
472.6
480.1
525.6
80
489.6
496.5
542.1
87
497.7
512.2
546.2
94
511.7
524.6
570.5
Test Substance H-25357
192.8 199.1 208.0 217.3 230.1 236.6 245.0 253.0 260.1 266.8 311.4 345.8 377.1 406.2 442.2 468.1 486.7
-
503.9 520.7 536.8 539.2 551.9
Indicates the animals were not weighed
Company Sanitized. Does not contain TSCACBI
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
TABLE 2
MEAN BODY WEIGHT GAINS DOSING
MEAN BODY WEIGHT GAINS (g)
Negative Control
Positive Controls
Test Substance
DAYS ON TEST Deionized Water H-24019
H-24020
H-25357
1-5 32.5 31.8 28.4 37.3 5-10 34.9 30.3 30.5 36.7
1-10 67.4 62.1 58.9 74.0
RECOVERY
MEAN BODY WEIGHT GAINS (g)
Negative Control
Positive Controls
Test Substance
DAYS ON TEST Deionized Water H-24019
H-24020
H-25357
10-17 17-24 24-52 52-94
36.3 43.6 54.4 44.6
32.2 23.2 41.2 34.4
95.0
109.5
122.0
122.3
91.2
101.8
109.9
83.8
10-94
254.7
278.1
327.5
285.1
f g j m j ^ M f b e a . Does no! contain TSCA CBI -22-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
TABLE 3
MEAN BODY AND LIVER WEIGHTS
DAYS ON TEST
NEGATIVE CONTROL - DEIONIZED WATER
WEIGHT (g)
Absolute
Mean Relative Liver Weight
Body Weight
Liver Weight
(Liver/Body Weight)
10
258.8
10.814
94
511.7
17.868
0.042 0.035
DAYS ON TEST
10 94
POSITIVE CONTROL - H-24019
WEIGHT (g)
Absolute
Mean Relative Liver Weight
Body Weight
Liver Weight
(Liver/Body Weight)
243.9 524.6
14.205 19.296
0.058 0.037
DAYS ON TEST
10 94
POSITIVE CONTROL - H-24020
WEIGHT (g)
Absolute
Mean Relative Liver Weight
Body Weight
Liver Weight
(Liver/Body Weight)
243.1 570.5
19.174 19.590
0.079 0.034
DAYS ON TEST
10 94
TEST SUBSTANCE - H-25357
WEIGHT (g)
Absolute
Mean Relative Liver Weight
Body Weight
Liver Weight
(Liver/Body Weight)
266.2 551.9
13.851 19.681
0.052 0.036
Company Sanitized. Does not contain TSCA CUI
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
TABLE 4
MEAN BLOOD FLUORINE LEVELS
MEAN FLUORINE LEVELS (ppm)
Negative Control
Positive Controls
Test Substance
DAYS ON TEST Deionized Water H-24019
H-24020
H-25357
1
0.60a
2.60 (0.1)b
9.40 (2.4)
1.11 (0.1)
5
C
31.32 (1.1)
74.92 (7.0)
3.19 (0.2)
10
1.10a
68.00 (3.5)
61.76 (5.5)
2.87 (0.3)
13
c
53.98 (1.2)
29.52 (4.9)
2.27 (0.3)
24
0.5a
39.62 (3.4)
11.18 (2.9)
2.28 (0.6)
52
c
23.56 (2.1)
2.26 (1.1)
C
C
94
c
12.60 (1.2)
0.85 (0.1)d
c
c
a One o f 5 values. Four o f the values were below the limit o f quantification (LOQ) or non-detectable. b Standard deviation (S.D.) is in parentheses, c All values were below the LOQ or non-detectable. d Mean o f 2 o f the 5 values. Three o f the values were below the LOQ.
TABLE 5
MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE
MEAN FLUORINE CONCENTRATION (pM F Equivalents)
_____________Positive Controls_________________Test Substance
DAYSONTEST
H-24019
H-24020
H-25357
1
36.92 (l.l)a
66.67 (17.5)
4.79 (0.6)
5
478.77 (17.6)
541.45 (50.4)
15.74 (0.9)
10
1043.08 (54.6)
446.09 (39.7)
14.07 (1.4)
13
827.38 (19.0)
212.46 (35.6)
10.87 (1.4)
24
606.46 (53.1)
79.57 (20.8)
10.97 (3.2)
52
359.38 (32.7)
14.93 (7.7)
C
94
190.77 (19.2)
4.71 (0.5)b
c
a Standard deviation (S.D.) is in parentheses. b Mean o f 2 o f the 5 values. Three o f the values were below the limit o f quantification (LOQ). c All values were below the LOQ.
Company Sanitized. Does not cortsta TS0A 081 -24-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
TABLE 6
MEAN LIVER FLUORINE LEVELS
MEAN FLUORINE LEVELS (ppm)
Negative Control
Positive Controls
Test Substance
DAYS ON TEST Deionized Water H-24019
H-24020
H-25357
10
0.90 (0.2)a 312.34 (19.7) 119.80 (3.5)
22.04 (2.8)
94
0.78 (0.0)
84.24 (7.4)
2.56 (1.3)
1.52 (0.2)
a Standard deviation (S.D.) is in parentheses.
TABLE 7
MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
DAYS ON TEST
MEAN FLUORINE CONCENTRATION (pM F Equivalents)
Positive Controls
Test Substance
H-24019
H-24020
H-25357
10
4802.15 (303.8)a
866.67 (25.5)
114.94 (14.9)
94
1292.92 (114.1)
17.10 (9.8)
6.96 (1.1)
a Standard deviation (S.D.) is in parentheses.
Company Sanitized. D n a a n o i o ^ ^ ^
-25 -
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
TABLE 8
MEAN FAT FLUORINE LEVELS
MEAN FLUORINE LEVELS (ppm)
Negative Control
Positive Controls
Test Substance
DAYS ON TEST Deionized Water H-24019
H-24020
H-25357
10
a
12.84 (1.7)b
8.10 (1.1)
21.06 (3.8)
94 a 1.20 (0.3) a 2.78 (0.8)
a All values were below the limit o f quantification (LOQ) or non-detectable. b Standard deviation (S.D.) is in parentheses.
TABLE 9
MEAN FAT FLUORINE CONCENTRATION NORMALIZED TO DOSE
DAYS ON TEST
MEAN FLUORINE CONCENTRATION (pM F Equivalents)
Positive Controls
Test Substance
H-24019
H-24020
H-25357
10
194.46 (26.8)a
57.25 (7.8)
109.79 (19.8)
94 15.38 (4.1)
b 13.59 (4.2)
a Standard deviation (S.D.) is in parentheses. b All values were below the limit o f quantification (LOQ) or non-detectable.
C0Wpany Sanit,'2ed- Does not contain TSCA CB -26-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
FIGURES
Company Sanitized. Does not contain TSCA CBS -27-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 1 MEAN BODY WEIGHTS
DuPont-11557
Company Sanitized. Does not contain TSCA CM
- 28-
)
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
>
FIGURE 2
COMPARISON OF MEAN RELATIVE LIVER WEIGHTS: TEST SUBSTANCE AND NEGATIVE CONTROL
) DuPont-11557
Company Sanitized. Does not contain TSCAuBl
- 29-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 3 COMPARISON OF MEAN RELATIVE LIVER WEIGHTS:
TEST SUBSTANCE AND POSITIVE CONTROLS
DuPont-11557
m v o s i u muootou
10 94
Test Days
- 30-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
FIGURE 4 MICROMOLAR EQUIVALENTS IN RAT BLOOD
A. N o rm a lize d Rat B lood H -2 40 1 9 pM E q uiva len ts Resulting from a 10 -D a y O ra l G a v a g e
Micromolar (pM) equivalents o f H-24019 (positive control) in rat blood resulting from a 10-day oral gavage exposure. Values are means and error bars are standard deviation.
B. N o rm a liz e d R a t B lood H -2 4 0 2 0 p M E q u iv a le n ts R e sulti ng from a 10- Day Oral G a v a g e
Micromolar (pM) equivalents o f H-24020 (positive control) 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 CE
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
C. Normalized Rat Blood H-25357 uM Equivalents Resulting from a 10-Day Oral Gavage
Micromolar (pM) equivalents o f H-25357 (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 nf
tco* cr
-32 -
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
600000
FIGURE 5
NORMALIZED H-25357 AND POSITIVE CONTROL BLOOD AUCINF/D RESULTING FROM A 10-DAY ORAL GAVAGE
500000
400000
z Z<urr3aei 300000 Ois'
200000
100000
DuPont-11557
Company Sanitized. Does not contain TSCA CBt
B A U C IN F /D
H-24019 5.22E+05
H-24020 8.15E+04
-33-
H-25357 8.61 E+02
) H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
)
FIGURE 6 MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
) DuPont-11557
Company Sanitized. Does not contain TSCA CBI
Day 10
Test Days
-34-
Day 94
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
FIGURE 7
COMPARISON OF RELATIVE LIVER WEIGHT AND MEAN LIVER FLUORINE CONCENTRATION FOR H-25357 AND NEGATIVE CONTROL
25.00
"O Co c(Q
05
>G>
> tVozS sc(00)
Day 10
Test Day
D a y 94
oc 20.00
u uco ^
co Ea
o3 ^
a>>
15.00
10.00
c(00) 5.00
0.00
Day 10
Test Day
Day 94
Deionized Water (Negative Control) H H-25357 (Test Substance)
Company Sanitized. Does not contain fSCA GB1
-35-
) H-25357: Biopersistence Screening
10-Dose Oral Gavage Study in Rats
)
FIGURE 8 MEAN FAT FLUORINE CONCENTRATION NORMALIZED TO DOSE
) DuPont-11557
IH-24019 (Positive Control) IH-24020 (Positive Control) I H-25357 (Test Substance)
All values for H-24020 (Positive control) were non-detectable.
.Company Sanitized. Does not contain TSCA CSI
Day 10
Test Day
-36-
Day 94
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 9 COMPARISON OF MEAN BLOOD, MEAN LIVER, AND MEAN FAT FLUORINE
CONCENTRATION NORMALIZED TO DOSE
DuPont-11557
Company SwW*ed. Dom not contain TSCA CBI
-37-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
APPENDICES
Company Sanitized, Poes not contain TSCA CBi
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
APPENDIX A Individual Body Weights
Company SsnHit#4t DofS flftt 9RtTi TSH 88!
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats___________________________________________________________ DuPont-11557
INDIVIDUAL BODY WEIGHTS EXPLANATORY NOTES
ABBREVIATIONS: SD - sacrificed by design
-40-
)) H-25357: Biopersistence Screening
10-Dose Oral Gavage Study in Rats_______________________________________________
ANIMAL NUMBER
Day 1
Day 2
D E IO N IZ E D WATER {N EG A TIV E CONTROL)
IN D IV ID U A L BODY W EIG H TS (g ) OF MALE RATS
Day 3
GROUP I
TEST DAY
Day 4
Day 5
Day 6
646932 646933 646934 646935 646936
197.1 191.9 182.6 203.0 196.8
202.1 195.4 188.9 208.9 201.4
212.9 205.0 195.4 218.0 208.6
221.5 213.2 207.0 228.1 204.0
233.6 226.5 213.9 239.7 216.7
234.1 219.3 215.9 243.0 218.6
Day 7
242.4 232.9 224.2 257.2 229.9
ANIMAL NUMBER
Day 10
646932 646933 646934 646935 646936
264.7 254.4 248.6 278.0 248.1
SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10
TEST DAY
) DuPont-11557
Day 8
251.1 239.5 230.9 265.7 234.9
Day 9
256.1 246.4 238.1 270.5 240.3
1HBU0JOiGfl
v->!
u
om
-41 -
))
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats____________________________________________
D E IO N IZ E D WATER (N EG A TIV E CONTROL)
IN D IV ID U A L BODY W EIG H TS (g ) O F MALE RA TS
ANIMAL NUMBER
Day 1
Day 2
Day 3
GROUP I I I
TEST DAY
Day 4
Day 5
Day 6
646937 646938 646939 646940 646941
184.5 163.7 193.3 191.5 191.6
186.8 173.8 204.2 197.1 195.9
199.0 180.9 214.6 203.8 207.9
205.9 189.3 221.1 209.8 216.8
213.6 200.6 234.4 218.5 223.1
221.0 204.1 240.7 222.1 231.2
Day 7
229.6 215.9 248.9 229.3 241.3
ANIMAL NUMBER
Day 10
646937 646938 646939 646940 646941
249.8 237.2 277.9 244.5 266.3
Day 17
282.6 270.4 329.7 271.5 312.4
Day 24
322.3 296.5 372.8 291.3 344.8
TEST DAY
Day 31
Day 38
366.1 325.8 415.2 317.9 371.6
395.0 342.9 443.2 332.8 390.7
Day 45
425.0 367.5 475.2 356.3 412.8
Day 52
443.9 373.7 484.1 367.0 433.6
ANIMAL
I
NUMBER
Day 73
I 646937
504.3
646938
417.4
646939
540.1
O3
646940 646941
407.3 493.7
Day 80
520.5 431.0 568.9 424.0 503.5
Day 87
533.7 432.1 578.1 430.8 513.8
TEST DAY Day 94
545.7 450.6 586.9 449.4 525.8
SD test day 94 SD test day 94 SD test day 94 SD test day '94 SD test day 94
DuPont-11557
Day 8
238.7 221.8 259.2 232.0 249.1
Day 9
241.4 228.3 267.3 237.5 257.0
Day 59
461.7 378.7 505.7 380.3 455.8
Day 67
478.7 401.3 516.4 392.5 475.3
contain TSCA CSI
-42-
) H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
646910 646911 646912 646913 646914
Day 1
184.3 184.4 180.5 186.4 185.5
Day 2
185.3 187.1 185.9 189.7 189.6
.) )
_________________________________________________________ DuPont-11557
n-z4ui!3 (rubiiiviL v_wiNJ.KUijyr r o / i n - i o
/ n A H T n i T T m "i/- \7 T m T D /O T \
IN D IV ID U A L BODY W EIG H TS (g ) OF MALE RATS
Day 3
GROUP I
TEST DAY
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
197.3 195.7 195.9 198.1 198.8
204.8 202.0 202.5 205.7 203.8
212.7 211.7 211.9 221.8 215.4
216.3 217.2 217.7 225.0 222.7
226.4 225.2 227.2 228.6 226.7
232.3 225.6 232.4 238.4 231.5
237.5 231.9 238.5 245.8 238.8
ANIMAL NUMBER
Day 10
Q 646910
s 646911
646912
1
646913 646914
I %
!Ut
I
3
,**
5'
H(ft 5 om
241.1 236.6 241.9 257.0 243.0
SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10
TEST DAY
- 43 -
)1
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats___________________________________________________
H - 2 4 0 1 9 {P O S IT I V E C O N TR O L ) IN D IV ID U A L BODY W EIG H TS (g ) OF MALE RATS
ANIMAL NUMBER
Day 1
Day 2
Day 3
GROUP I I I
TEST DAY
Day 4
Day 5
Day 6
646915 646916 646917 646918 646919
182.7 185.0 187.8 175.5 192.0
188.3 192.7 194.3 181.9 196.9
200.1 205.5 205.8 189.8 207.9
206.3 211.6 210.4 197.6 218.9
211.1 220.0 221.8 207.0 228.3
220.6 226.9 227.5 212.4 234.0
Day 7
225.8 239.5 233.9 220.2 240.8
) DuPont-11557
Day 8
231.1 240.1 235.8 224.1 245.8
Day 9
236.8 249.3 244.3 228.2 252.9
ANIMAL NUMBER
Day 10
646915 646916 646917 646918 646919
240.4 257.0 250.2 237.1 260.2
Day 17
283.4 310.0 280.3 270.6 306.1
Day 24
302.9 334.4 308.2 292.7 328.5
TEST DAY
Day 31
Day 38
326.7 383.2 339.7 323.2 369.2
337.9 411.9 362.8 350.8 390.4
Day 45
371.1 450.3 387.9 379.4 427.3
Day 52
399.7 469.8 409.0 396.7 439.0
Day 59
412.5 494.8 420.0 418.8 451.7
Day 67
433.1 511.8 441.5 433.8 457.6
ly Sanitized. Doe not coni
ANIMAL NUMBER
Day 73
646915 646916 646917 646918 646919
m S'
H0o)
> o
00
461.2 544.2 457.5 448.1 489.5
Day 80
475.0 565.5 464.7 472.5 504.8
Day 87
498.1 578.5 479.5 480.8 524.2
TEST DAY Day 94
513.3 590.9 495.7 500.3 522.9
SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94
-44-
) H-25357: Biopersistence Screening
10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
646921 646922 646923 646924 646925
Day 1
204.5 178.3 185.9 188.7 172.2
Day 2
204.9 180.9 185.1 194.6 176.0
..)
uj._ou/inonw /DriCTi*TVT4_7i vr_>,rwr-tP-X'nriTAi/
IN D IV ID U A L BODY W EIG H TS (g ) OF MALE RATS
Day 3
GROUP I
TEST DAY
Day 4
Day 5
Day 6
215.7 188.9 196.0 209.5 183.9
222.2 197.4 202.3 212.6 193.4
233.3 197.7 203.5 230.4 202.7
238.8 202.4 204.9 225.9 202.7
ANIMAL NUMBER
Day 10
646921 646922 646923 646924 646925
262.6 218.6 240.6 259.1 234.8
SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10
TEST DAY
Day 7
244.3 202.4 219.1 236.2 215.1
) DuPont-11557
Day 8
244.9 204.0 224.9 236.5 221.5
Day 9
252.2 207.7 231.7 250.9 228.7
Company Sanitized. Does not contain TSCA CBI
-45 -
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
646926 646927 646928 646929 646930
Day 1
182.0 172.2 190.4 178.6 187.9
ANIMAL NUMBER
Day 10
646926 646927 646928 646929 646930
250.8 243.3 254.1 225.5 240.3
ANIMAL NUMBER
Day 73
646926 646927 646928 646929 646930
535.3 551.2 540.3 502.6 498.5
Day 2
187.8 178.8 195.3 182.5 191.6
Day 17
297.2 306.2 310.6 280.9 292.3
Day 80
551.9 574.5 557.0 509.6 517.6
H -2 4 0 2 0 (P O S IT IV E CONTROL)
IN D IV ID U A L BODY W EIG H TS (g ) OF MALE RATS
Day 3
GROUP I I I
TEST DAY
Day 4
Day 5
Day 6
197.0 191.1 204.5 190.7 201.0
203.6 195.1 212.3 198.3 210.4
206.0 206.6 222.1 203.5 219.6
213.2 213.2 230.1 204.2 224.4
Day 7
222.9 218.2 236.1 214.6 226.7
Day 24
349.3 355.1 349.4 323.2 316.2
TEST DAY
Day 31
Day 38
383.8 404.0 392.8 376.0 352.7
412.1 424.8 422.4 396.8 368.4
Day 45
432.1 463.2 443.5 426.4 406.8
Day 52
467.8 484.0 464.8 450.2 436.0
Day 87
564.4 541.3 568.3 526.7 530.3
TEST DAY Day 94
580.6 602.5 581.9 544.0 543.4
SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94
DuPont-11557
Day 8
229.9 228.7 235.8 210.3 232.6
Day 9
239.7 233.1 243.4 219.2 235.3
Day 59
493.2 511.7 492.2 463.8 454.7
Day 67
509.5 527.2 518.6 484.2 474.2
I. Does not contain TSCA CBI
-46-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
Day 1
Day 2
665500 665501 665502 665503 665505
203.3 194.1 196.4 180.3 195.0
ANIMAL NUMBER
Day 10
205.2 197.0 202.2 189.8 201.1
665500 665501 665502 665503 665505
273.5 266.1 275.7 258.5 257.1
SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10
n-ziDoo/ (xiiiOi buco xAi'jt-.Ci)tt orn r~ '~i /m^nm cttdr r m \ . umrp\
IN D IV ID U A L BODY W EIG H TS (g ) OF MALE RA TS
Day 3
GROUP I
TEST DAY
Day 4
Day 5
Day 6
212.7 210.3 212.6 198.0 209.8
223.3 219.0 221.0 206.0 218.6
234.2 235.2 236.3 219.3 230.9
242.8 242.0 241.7 223.2 230.8
TEST DAY
Day 7
250.4 244.5 251.1 238.1 238.9
DuPont-11557
Day 8
256.5 256.4 259.3 247.2 245.0
Day 9
265.0 265.4 268.9 249.1 252.0
990(3 p2!U!U,*S
83
e.
tO>o o
)
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
ANIMAL NUMBER
Day 1
665506 665507 665508 665509 665510
ANIMAL NUMBER
191.0 190.7 187.3 196.3 193.7
Day 10
665506 665507 665508 665509 665510
ANIMAL NUMBER
273.5 263.9 251.5 265.4 283.0
Day 73
665506 665507 665508 665509 665510
532.2 478.2 446.6 519.0 627.7
Day 2
201.7 199.1 194.3 199.4 201.5
Day 17
314.5 305.7 285.8 303.4 347.4
Day 80
555.6 488.1 463.3 532.6 644.4
)
H -2 5 3 5 7 (TE ST SUBSTANCE)
IN D IV ID U A L BODY W EIG H TS (g ) OF MALE RATS
Day 3
GROUP I I I
TEST DAY
Day 4
Day 5
Day 6
208.9 205.0 199.1 210.1 213.1
Day 24
213.8 216.1 211.7 220.4 223.0
225.9 224.4 220.7 234.3 239.9
TEST DAY
Day 31
Day 38
238.8 236.2 227.7 238.7 243.7
Day 45
342.9 337.8 314.0 334.6 399.7
Day 87
377.0 366.6 332.3 363.0 446.4
410.8 388.2 351.3 397.0 483.7
TEST DAY Day 94
455.5 414.8 374.3 432.1 534.3
558.9 488.9 470.5 530.2 647.6
576.0 495.6 483.1 539.0 665.7
SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94
Day 7
242.3 245.0 234.7 249.3 255.6
Day 52
487.4 437.5 395.9 454.6 564.9
) DuPont-11557
Day 8
253.7 247.4 242.3 255.1 266.7
Day 59
501.0 450.3 416.9 477.1 588.2
Day 9
261.3 251.8 248.2 261.2 277.7
Day 67
515.4 462.0 431.7 504.7 605.6
gd p*!!u*S insdlUO
3
Os s3.
"5 Og> O
OB
-48-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
APPENDIX B Individual Clinical Observations
Sanitised-Pees,notcontain.TSCA CBt
-49-
Does not contain TSCA CSt
)
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats______________________ ______
')
D E IO N IZ E D WATER {N EG A TIV E CONTROL)
IN D IV ID U A L C L IN IC A L O BSERV A TIO N S IN MALE RATS
GROUP I
A n im al
O b se rv a tio n
D ays
646932
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1
E ye O b s e rv a tio n s , E x o p h th a lm u s, L e ft
2 -9
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft
1 ,5
D isc h a rg e , E ye l e f t , B la c k
10
S a c rific e d by d e sig n
10
646933
G e n e ra l o b s e rv a tio n . No A b n o rm a lity D e te c te d
1 -5
E ye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft
1 ,5
Eye O b s e rv a tio n s , D ark, L e ft
6 -1 0
D isc h a rg e , E ye l e f t , B la c k
6 -7
S w o lle n O b s e r v a tio n s , M o u th
10
S a c rific e d by d e sig n
10
646934
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -5 ,1 0
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft
1 ,5
D isc h a rg e , E ye l e f t , B la c k
6 -9
S a c rific e d by d e sig n
10
-50-
)
DuPont-11557
) H-25357: Biopersistence Screening
10-Dose (Oral Gavage Study in Rats
)> __________ ______________________________________________ DuPont-11557
A n im al 646935
646936
D E IO N IZ E D WATER (N EG A TIV E CONTROL)
IN D IV ID U A L C L IN IC A L O B SER V A TIO N S IN MALE RA TS
GROUP I ( C o n tin u e d )
O b se rv a tio n
D ays
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -1 0
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft
1 ,5
S a c rific e d by d e sig n
10
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -1 0
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft
1 ,5
S a c rific e d by d e sig n
10
Company Sanitized. Does not contain TSCA C$f
-51 -
iso v a g i uiBiuoaiou 8o 'pezntws itwduioa
)
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
)
nU rHiTXAW>-DJTXTnJ. ZriiUn tV-tva/ i n1 rnn V/WrT-Cnj'CrJ<.M7X\mX Tv t.rhp ^/'U''k'\1AnTJrT.JVAP.Of'`\ITJ 7 \
IN D IV ID U A L C L IN IC A L O BSERV A TIO N S IN MALE RATS
GROUP I I I
A n im al 646937
O b se rv a tio n G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
D ays 1 -1 0 ,1 7 -9 4
Eye O b se rv a tio n s, Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , L e ft B le d v ia O r b ita l fo r C lin P a th , R ig h t
13 2 4 ,5 2
646938
S a c rific e d by d e sig n G e n e ra l o b s e rv a tio n . No A b n o rm a lity D e te c te d Eye O b s e rv a tio n s , E n o p h th a lm u s, R ig h t Eye O b s e rv a tio n s , E x o p h th a lm u s, R ig h t
94 1 -1 0 ,1 7 -4 5 8 0-94 5 2-73
Eye O b s e rv a tio n s ,
B le d v ia O r b ita l f o r C lin P a th , B ila te r a l
1 3 ,5 2 .
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , R ig h t
24
Eye O b se rv a tio n s , C o rn e a l O p a c ity , R ig h t
8 0-94
D isc h a rg e , E ye r i g h t, B la c k
59
S a c rific e d by d e sig n
94
646939
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -1 0 ,1 7 -9 4
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , L e ft
13
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , R ig h t
2 4 ,5 2
S a c rific e d by d e sig n
94
-52-
DuPont-11557
)
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats_______
)
T V G , T r \ - M " r r 7 'G ' T \ T.77V m - p D
/'N T T p r , S r n T t 7 p r~>/^TtTfTV D /^\T \
U i h X W 1 V -L Z j H i L J VV.tt.-L u r< . \ I X j l l i V j A X JL V l l i
X X \O x j )
IN D IV ID U A L C L IN IC A L O B SER V A TIO N S IN MALE RATS
A n im al 646940
646941
GROUP I I I ( C o n tin u e d ) O b se rv a tio n G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft Eye O b s e rv a tio n s , B le d v ia O r b ita l fo r C lin P a th , R ig h t D isc h a rg e , N ose, B la c k S a c rific e d by d e sig n G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , B ila te r a l Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft Eye O b s e rv a tio n s , B le d v ia O r b ita l fo r C lin P a th , R ig h t S a c rific e d by d e sig n
D ays 1 -1 0 ,1 7 -8 0 ,9 4 13 2 4 ,5 2 87 94 1 -1 0 ,1 7 -9 4 52 13 24 94
)
DuPont-11557
Sanitized. Does not contatti
HWO>
0 1
-53 -
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
H -2 4 0 1 9 (P O S IT IV E CONTROL)
IN D IV ID U A L C L IN IC A L O B SERV A TIO N S IN MALE RATS
A n im al
O b se rv a tio n
GROUP I
D ays
646910
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -1 0
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft
1 ,5
S a c rific e d by d e sig n
10
646911
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 ,1 0
E ye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft
1 ,5
Eye O b s e rv a tio n s , D ark , L e ft
2 -9
S a c rific e d by d e sig n
10
646912
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -1 0
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft
1
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , R ig h t
5
S a c rific e d by d e sig n
10
646913
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -1 0
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft
1 ,5
S a c rific e d by d e sig n
10
646914
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -1 0
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft
1 ,5
S a c rific e d by d e sig n
10
DuPont-11557
Xueduioo
)
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
)
A n im al 646915
646916
646917
3 1.
H -2 4 0 1 9 (P O S IT IV E CONTROL)
IN D IV ID U A L C L IN IC A L O BSERV A TIO N S IN MALE RATS
GROUP I .II
O b se rv a tio n
D ays
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 ,1 7 -3 8 ,7 3
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft
1 3 ,2 4 ,5 2
D isc h a rg e , Eye r ig h t, Red
2 -1 0
H a ir L o ss, F o re lim b , R ig h t
80
H a ir L o ss, F o rep aw , R ig h t
4 5 -6 7 ,8 7 -9 4
S a c rific e d by d e sig n
94
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -1 0 ,1 7 -9 4
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , B ila te r a l
24
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , L e ft
13
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , R ig h t
52
S a c rific e d by d e sig n
94
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -1 0 ,1 7 -9 4
Eye O b s e rv a tio n s ,
B le d v ia O r b ita l f o r C lin P a th , L e ft
1 3 ,2 4
Eye O b se rv a tio n s ,
B le d v ia O r b ita l f o r C lin P a th , R ig h t
52
S a c rific e d by d e sig n
94
9>. 5
03
o>
-55-
DuPont-11557
)
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
)
H -2 4 0 1 9 {P O S IT IV E CONTROL) IN D IV ID U A L C L IN IC A L O B SERV A TIO N S IN MALE RATS
A n im al 646918
646919
GROUP I I I ( C o n tin u e d )
O b se rv a tio n
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , L e ft
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , R ig h t
S a c rific e d by d e sig n
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
Eye O b se rv a tio n s, Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , L e ft B le d v ia O r b ita l f o r C lin P a th , R ig h t
S a c rific e d by d e sig n
D ays 1 -1 0 ,1 7 -9 4 1 3 ,2 4 52 94 1 -1 0 ,1 7 -9 4 1 3 ,2 4 52 94
)
DuPont-11557
Company Sanitized. Does not contain TSCA CBI
-56-
)
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
)
H -2 4 0 2 0 (P O S IT IV E CONTROL)
IN D IV ID U A L C L IN IC A L O BSERV A TIO N S IN MALE RATS
GROUP I
A n im al 646921
O b se rv a tio n G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
D ays 1 ,5 -1 0
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft
1 ,5
Eye O b s e rv a tio n s , D ark, L e ft
2 -4
S a c rific e d by d e sig n
10
646922
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -1 0
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , L e ft
1
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , R ig h t
5
646923
S a c rific e d by d e sig n G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
10 1 ,7 -1 0
E ye O b s e rv a tio n s , E x o p h th a lm u s, L e f t
4 -6
Eye O b s e rv a tio n s ,
B le d v ia O r b ita l f o r C lin P a th , L e ft
1
Eye O b s e rv a tio n s ,
B le d v ia O r b ita l f o r C lin P a th , R ig h t
5
Eye O b s e rv a tio n s , D ark , L e ft p. S a c r i f i c e d b y d e s i g n
2 -6 10
)
DuPont-11557
Does not contain TSCA CB1
-57-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
A n im al 646924
646925
H -2 4 0 2 0 (P O S IT IV E CONTROL)
IN D IV ID U A L C L IN IC A L O BSERV A TIO N S IN MALE RATS
GROUP I ( C o n tin u e d )
O b se rv a tio n
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
Eye O b s e rv a tio n s ,
B le d v ia O r b ita l f o r C lin P a th , L e ft
D ays
1-10
1
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , R ig h t
S a c rific e d by d e sig n
5
10
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
Eye O b s e rv a tio n s ,
B le d v ia O r b ita l fo r C lin P a th , L e ft
1-10
1
Eye O b s e rv a tio n s ,
B le d v ia O r b ita l f o r C lin P a th , R ig h t
S a c rific e d by d e sig n
5
10
DuPont-11557
-58-
Company SanRte*. Doe
))
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats___________________________________________
A n im al 646926
646927
646928
H -2 4 0 2 0 (P O S IT IV E CONTROL)
IN D IV ID U A L C L IN IC A L O BSERV A TIO N S IN MALE RATS
GROUP I I I
O b se rv a tio n
D ays
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -1 0 ,1 7 -9 4
Eye O b se rv a tio n s,
B le d v ia O r b ita l fo r C lin P a th , B i la te r a l
52
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , L e ft
1 3 .2 4
S a c rific e d by d e sig n
94
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -1 0 ,1 7 -9 4
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , B ila te r a l
52
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , L e ft
1 3 .2 4
S a c rific e d by d e sig n
94
G e n e ra l o b s e rv a tio n . No A b n o rm a lity D e te c te d
1 -1 0 ,1 7 -9 4
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , L e ft
1 3 ,2 4 ,5 2
S a c rific e d by d e sig n
94
i
(o>0
-59-
)
DuPont-11557
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
H -2 4 0 2 0 (P O S IT IV E CONTROL)
A n im al 646929
646930
IN D IV ID U A L C L IN IC A L O B SE R V A T IO N S IN MALE RATS
GROUP I I I ( C o n tin u e d )
O b se rv a tio n
D ays
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -1 0 ,1 7 -3 1
Eye O b se rv a tio n s,
B le d v ia O r b ita l f o r C lin P a th , L e ft
1 3 ,2 4
Eye O b s e rv a tio n s ,
B le d v ia O r b ita l f o r C lin P a th , R ig h t
52
H a ir L o ss, F o re lim b , B i l a t e r a l
5 2-73
H a ir L o ss, N eck, L e ft
73
H a ir L o ss, N eck, V e n tra l
3 8 -6 7 ,8 0 -9 4
W ound, S u p e r f ic ia l, F ace
59
S a c rific e d by d e sig n
94 .
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -1 0 ,1 7 -9 4
Eye O b s e rv a tio n s ,
B le d v ia O r b ita l f o r C lin P a th , L e ft
Eye O b s e rv a tio n s ,
B le d v ia O r b ita l f o r C lin P a th , R ig h t
S a c rific e d b y d e sig n
1 3 ,2 4 52 94
DuPont-11557
SanitttXL D8not contain T
tO* -
-60-
w
)
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats____________________
)
A n im al M
M
M
H -2 5 3 5 7 (T E ST SUBSTANCE)
IN D IV ID U A L C L IN IC A L O BSERV A TIO N S IN MALE RATS
GROUP I
O b se rv a tio n
665500
G e n e ra l o b s e rv a tio n . No A b n o rm a lity D e te c te d
Eye O b s e rv a tio n s , B le d v ia O r b ita l fo r C lin P a th , R ig h t
S a c rific e d by d e sig n
665501
E ye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , R ig h t
H a ir L o ss, V e n tra l body, V e n tra l
S a c rific e d by d e sig n
665502
G e n e ra l o b s e rv a tio n . No A b n o rm a lity D e te c te d
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , R ig h t
S a c rific e d by d e sig n
M
665503
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , R ig h t
S a c rific e d by d e sig n
M
665505
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
Eye O b s e rv a tio n s , B le d v ia O r b ita l fo r C lin P a th , R ig h t
S a c rific e d by d e sig n
D ays
1-10
1 .5
10
1 .5
1-10 10 1-10
1 .5
10
1-10
1 .5
10 1-10
1 .5
10
)
DuPont-11557
8iOp?lU03i|!fS8fJ
-61 -
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
A n im al 665506 665507 665508 665509
665510
H -2 5 3 5 7 (T E ST SUBSTANCE)
IN D IV ID U A L C L IN IC A L O B SER V A TIO N S IN MALE RATS
GROUP I I I
O b se rv a tio n
D ays
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -94
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , R ig h t
2 4 ,5 2
S a c rific e d by d e sig n
94
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -9 4
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , R ig h t
2 4 ,5 2
S a c rific e d by d e sig n
94
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -94
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , R ig h t
2 4 ,5 2
S a c rific e d by d e sig n
94
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -2 4 ,3 8 -9 4
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , R ig h t
2 4 ,5 2
H a ir L o ss, F o rep aw , B i l a t e r a l
31
S a c rific e d by d e sig n
94
G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d
1 -9 4
Eye O b s e rv a tio n s , B le d v ia O r b ita l f o r C lin P a th , R ig h t
2 4-52
S a c rific e d by d e sig n
94
-62-
DuPont-11557
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
APPENDIX C Terms and Calculations Factors Influencing Interpretation of Kinetic Analysis
jCompwqfSanitized. Does not contain TSCACB;
-63 -
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
Terms: Active % Active
Mol Wt Active Formulation Dose % F in Active
Mol Wt F
TERMS AND CALCULATIONS
Fluorine containing compound The % of formulation that is made up of fluorine containing components The molecular weight of the fluorine containing components (g/mole) The mg of formulation given per kg of animal body weight The % fluorine in the fluorine containing components of the formulation (weight basis) The molecular weight of fluorine g/mol
Compound Calculations:
Dose Active (mg/kg)
The mg of fluorine containing compound administered per kg of animal body weight. = (% active/100) x Formulation Dose
Dose Active (mmole/kg) The mmole of fluorine containing compound administered per kg of animal body weight = dose [mg/kg] / Mol Wt Active [mg/mmol]
Dose F (mg/kg)
The mg Fluorine administered per kg of animal body weight = (% F in active/100) x Dose Active [mg/kg]
Dose F (mmol/kg)
The mmole of fluorine administered per kg of animal body weight = Dose F [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 F [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])
x Formulation Dose
Company Sanitized. Does not contain ISCA CBS
-64-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
TERMS AND CALCULATIONS
Individual Animal Measurement:
ppm F
The ppm fluoride measured
Individual Animal Calculations:
ppm F minus Bkg 0.2 ppm
The ppm fluoride measured minus the background fluoride measured in control animal. In this case the value was established at 0.2 ppm.
ppm F normalized to 0.1 mmol/kg Dose
The ppm fluoride minus background that would be expected if the active dose was 0.1 mmol/kg instead of the actual active dose. This assumes linearity between administered dose and blood fluorine levels, but is needed because different doses of active were used in the study. = (0.1 [mmol/kg] / Active dose [mmol/kg]) x (ppm F in blood
minus background)
/'"'"n p molar equivalents of The pmoiar [pmol/L] concentration of fluorine containing compound
active
based on the ppm fluorine normalized to 0.1 mmol/kg active dose.
This assumes that all fluorine is derived from the fluorine-containing
component in the formulation. Note: 1 ppm - 1 mg/L
= (Normalized ppm [mg/L] fluorine / Mol Wt F [mg/mmol]) x
molar ratio active/F [mmol active/mmol F] x 1000 pmol/mmol
Doesnotoontain T$CA6il
-65 -
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
FACTORS INFLUENCING INTERPRETATION OF KINETIC ANALYSIS
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 - Each compound may have very different potency for producing toxicity
/ ''"""v
Assumptions: (May or may not bejustified in all cases)
- 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 Fluorine 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
Company Sanitized. O o a j n o t c o n i a t o t s c a C 8 -66-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats____________________________________________
DuPont-11557
APPENDIX D Individual Fluorine Levels in Blood
-67-
Compaq? S a n n & Does not contain tsca cat
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-24019
DuPont-11557
Given:
Mol Wt. Active (g/mole):
497
Formulation Dose (mg/kg):
10
% Active (F Containing) in Formulation: 100
% F in Active: Mol Wt. F (g/mol):
65 19
Calculated Values:
Dose Active (mg/kg):
10
Dose Active (mmole/kg):
0.020
Dose F (mmol/kg):___________________0.342
Molar Ratio (Active/F): 0.059
Dose F (mg/kg):
6.5
Rat Number
Test ppm F Day in Sample Blood
Group I 646910 646911 646912 646913 646914
1 1 1 1 1
2.6 2.7 2.5 2.6 2.6
ppm F in Blood
Minus Bkg 0-2 ppm
2.4 2.5 2.3 2.4 2.4
ppm F in Blood Normalized to 0.1 mmoles/kg
Dose
pmolar Equivalents of Active in
Blood
11.93 12.43 11.43 11.93 11.93
36.92 38.46 35.38 36.92 36.92
Group I 646910 5 30.1 646911 5 30.3 646912 5 31.3 646913 5 32.2 646914 5 32.7
29.9 30.1 31.1 32.0 32.5
148.60 149.60 154.57 159.04 161.53
460.00 463.08 478.46 492.31 500.00
Group I
646910 10 71.5
646911
10 70.5
646912
10 66.9
646913
10 62.5
646914 10 68.6
71.3 70.3 66.7 62.3 68.4
354.36 349.39 331.50 309.63 339.95
1096.92 1081.54 1026.15 958.46 1052.31
nokcontaialSCACBi
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Test ppm F Rat Day in Number Sample Blood
Group III 646915 646916 646917 646918 646919
13 13 13 13 13
55.0 55.3 52.2 53.8 53.6
ppm F in Blood
Minus Bkg 0-2 ppm
54.8 55.1 52.0 53.6 53.4
ppm F in Blood Normalized to 0.1 mmoles/kg
Dose
272.36 273.85 258.44 266.39 265.40
DuPont-11557
pmolar Equivalents of Active in
Blood
843.08 847.69 800.00 824.62 821.54
Group III 646915 646916 646917 646918 646919
Group III
646915 646916 646917 646918 646919
24 24 24 24 24
52 52 52 52 52
38.9 43.8 37.6 35.4 42.4
23.2 20.3 25.9 24.9 23.5
38.7 43.6 37.4 35.2 42.2
23.0 20.1 25.7 24.7 23.3
192.34 216.69 185.88 174.94 209.73
114.31 99.90 127.73 122.76 115.80
595.38 670.77 575.38 541.54 649.23
353.85 309.23 395.38 380.00 358.46
Group III 646915 646916 646917 646918 646919
94 94 94 94 94
13.3 11.7 12.9 11.0 14.1
13.1 11.5 12.7 10.8 13.9
65.11 57.16 63.12 53.68 69.08
201.54 176.92 195.38 166.15 213.85
COflfifljf Sanitized. Does not contain TSCA CBi -69-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-24020
DuPont-11557
Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation:
426 20 100
% F in Active: Mol Wt. F (g/mol):
69 19
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Dose F (mmol/kg):
20 0.047 0.726
Molar Ratio (Active/F): 0.065
Dose F (mg/kg):
13.8
Rat Number
Test ppm F Day in Sample Blood
Group I
646921
1 10.6
646922 1 10.7
646923 1 9.2
646924 1 5.3
646925
1 11.2
ppm F in Blood
Minus Bkg 0.2 ppm
10.4 10.5 9.0 5.1 11.0
ppm F in Blood Normalized to 0.1 mmoles/kg
Dose
22.15 22.37 19.17 10.86 23.43
pmolar Equivalents of Active in
Blood
75.36 76.09 65.22 36.96 79.71
Group I
646921 5 78.7
646922 5 83.2
646923 5 77.0
646924 5 66.1
646925
5 69.6
78.5 83.0 76.8 65.9 69.4
167.21 176.79 163.58 140.37 147.82
568.84 601.45 556.52 477.54 502.90
Group I
646921
10 63.0
646922 10 69.1
646923
10 60.3
646924 10 62.5
646925 10 53.9
62.8 68.9 60.1 62.3 53.7
133.76 146.76 128.01 132.70 114.38
455.07 499.28 435.51 451.45 389.13
aoitked. 0 ^ "i contain TSCACBI
-70-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Test ppm F Rat Day in Number Sample Blood
Group III 646926 646927 646928 646929 646930
13 13 13 13 . 13
34.8 30.0 23.7 33.7 25.4
ppm F in Blood
Minus Bkg 0.2 ppm
34.6 29.8 23.5 33.5 25.2
ppm F in Blood Normalized to 0.1 mmoles/kg
Dose
DuPont-11557
pmolar Equivalents of Active in
Blood
73.70 63.47 50.06 71.36 53.68
250.72 215.94 170.29 242.75 182.61
Group III 646926 646927 646928 646929 646930
24 24 24 24 24
11.9 10.4 8.1 15.7 9.8
11.7 10.2 7.9 15.5 9.6
24.92 21.73 16.83 33.02 20.45
84.78 73.91 57.25 112.32 69.57
Group III 646926 646927 646928 646929 646930
52 52 52 52 52
2.5 1.7 1.3 4.0 1.8
2.3 1.5 1.1 3.8 1.6
4.90 16.67 3.20 10.87 2.34 7.97 8.09 27.54 3.41 11.59
Group III 646926 646927 646928 646929 646930
94 94 94 94 94
0.8 <0.5 <0.5 0.9 <0.5
0.6 * *
0.7 *
1.28 4.35 ** **
1.49 5.07 **
* Below LOQ (Limit o f Quantification)
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-25357
DuPont-11557
Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation:
850000 1000 19
% F in Active: Mol Wt. F (g/mol):
10 19
Calculated Values:
Dose Active (mg/kg): Dose Active (mmole/kg): Dose F (mmol/kg):
190 2.2 x 10'4 1.000
Molar Ratio (Active/F): Dose F (mg/kg):
2.2 x 10"4 19.0
Test ppm F Rat Day in Number Sample Blood
Group I
665500 1 1.28
665501
1 1.02
665502 1 1.13
665503 1 1.02
665505 1 1.1
ppm F in Blood
Minus Bkg 0.2 ppm
1.1 0.8 0.9 0.8 0.9
ppm F in Blood Normalized to 0.1 mmoles/kg
Dose
483.16 366.84 416.05 366.84 402.63
pmolar Equivalents of Active in
Blood
5.68 4.32 4.89 4.32 4.74
Group I 665500 665501 665502 665503 665505
5 5 5 5 5
3.17 3.35 2.92 3.3 3.21
3.0 3.2 2.7 3.1 3.0
1328.68 1409.21 1216.84 1386.84 1346.58
15.63 16.58 14.32 16.32 15.84
Group I
665500 10 2.71
665501
10 3.31
665502
10 2.79
665503
10 2.92
665505
10 2.64
2.5 3.1 2.6 2.7 2.4
1122.89 1391.32 1158.68 1216.84 1091.58
13.21 16.37 13.63 14.32 12.84
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Rat Number
Test Day Sample
ppm F in
Blood
ppm F in Blood
Minus Bkg
___ -2.PPm____
ppm F in Blood Normalized to 0.1 mmoles/kg
Dose
DuPont-11557
pmolar Equivalents of Active in
Blood
Group III 665506 665507 665508 665509 665510
Group III 665506 665507 665508 665509 665510
13 13 13 13 13
24 24 24 24 24
2.3 2.21 2.44 2.52 1.86
2.64 2.72 1.33 2.05 2.68
2.1 2.0 2.2 2.3 1.7
2.4 2.5 1.1 1.9 2.5
939.47 899.21 1002.11 1037.89 742.63
1091.58 1127.37 505.53 827.63 1109.47
11.05 10.58 11.79 12.21 8.74
12.84 13.26 5.95 9.74 13.05
Group III
665506
52
<.5
*
*
*
665507 52 <.5
*
*
*
665508 52 <.5
*
*
*
665509 52 <.5
*
*
*
665510 52 <.5
*
*
*
Group III
665506 94 <.5
*
*
*
665507 94 <5
*
*
*
665508 94 <5
*
*
*
665509 94 <5
*
*
*
665510
94
<5
*
*
*
Below LOQ (Limit o f Quantification)
Com ply & ***,. <x* O te la tscacb,
-73 -
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
APPENDIX E Individual Fluorine Levels in Liver
anltked. Does
not contain TScA CBI -74-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-24019
DuPont-11557
Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation:
497 10 100
% F in Active: Mol Wt. F (g/mol):
65 19
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Dose F (mmol/kg):
10 0.020 0.342
Molar Ratio (Active/F): 0.059
Dose F (mg/kg):
6.5
Rat Number
Test ppm F Day in Sample Liver
Group I 646910 646911 646912 646913 646914
10 10 10 10 10
320.9 334.0 318.6 281.6 306.6
ppm F in Liver
Minus Bkg 0.2 ppm
320.7 333.8 318.4 281.4 306.4
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose
1593.88 1658.99 1582.45 1398.56 1522.81
pmolar Equivalents of Active in
Liver
4933.85 5135.38 4898.46 4329.23 4713.85
Group III 646915 646916 646917 646918 646919
94 94 94 94 94
85.6 75.9 87.5 78.0 94.2
85.4 75.7 87.3 77.8 94.0
424.44 376.23 433.88 386.67 467.18
1313.85 1164.62 1343.08 1196.92 1446.15
contain TSCA CBj -75-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-24020
DuPont-11557
Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation:
426 20 100
% F in Active: Mol Wt. F (g/mol):
69 19
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Dose F (mmol/kg):
20 0.047 0.726
Molar Ratio (Active/F): 0.065
Dose F (mg/kg):
13.8
Test ppm F Rat Day in Number Sample Liver
Group I
646921
10 118.3
646922
10 122.7
646923
10 114.3
646924
10 121.6
646925
10 122.1
ppm F in Liver
Minus Bkg 0.2 ppm
118.1 122.5 114.1 121.4 121.9
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose
251.55 260.93 243.03 258.58 259.65
pmolar Equivalents of Active in
Liver
855.80 887.68 826.81 879.71 883.33
Group III 646926 646927 646928 646929 646930
94 94 94 94 94
1.8 1.2 2.2 4.7 2.9
1.6 1.0 2.0 4.5 2.7
3.41 11.59 2.13 7.25 4.26 14.49 9.59 32.61 5.75 19.57
/""""N
Company Sanitized. Does not contain TSCA CBJ -76-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-25357
Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation:
850000 1000 19
% F in Active: Mol Wt. F (g/mol):
Calculated Values:
Dose Active (mg/kg): Dose Active (mmole/kg): Dose F (mmol/kg):
190 2.2 x 10'4 1.000
Molar Ratio (Active/F): Dose F (mg/kg):
DuPont-11557
10 19
2.2 x 104 19.0
Rat Number
Test ppm F Day in Sample Liver
Group I 665500 665501 665502 665503 665505
10 22.22 10 26.59 10 20.43 10 19.1 10 21.85
Group III 665506 665507 665508 665509 665510
94 94 94 94 94
1.84 1.49 1.36 1.31 1.61
ppm F in Liver
Minus Bkg 0.2 ppm
22.0 26.4 20.2 18.9 21.7
1.6 1.3 1.2 1.1 1.4
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose
pmolar Equivalents of Active in
Liver
9851.05 11806.05 9050.26 8455.26 9685.53
115.89 138.89 106.47 99.47 113.95
733.68 577.11 518.95 496.58 630.79
8.63 6.79 6.11 5.84 7.42
Company SanH tad Doaa notcontain TSCA CBI -77 -
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-11557
APPENDIX F Individual Fluorine Levels in Fat
/ '""'N no*wtufaW l i l l
-78-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-24019
DuPont-11557
Given:
Mol Wt. Active (g/mole):
497
Formulation Dose (mg/kg):
10
% Active (F Containing) in Formulation: 100
% F in Active: Mol Wt. F (g/mol):
65 19
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Dose F (mmol/kg):
10 0.020 0.342
Molar Ratio (Active/F): 0.059
Dose F (mg/kg):
6.5
Rat Number
Test ppm F Day in Sample Fat
Group I 646910 646911 646912 646913 646914
10 10 10 10 10
14.4 14.9 10.9 11.6 12.4
ppm F in Fat
Minus Bkg 0.2 ppm
14.2 14.7 10.7 11.4 12.2
ppm F in Fat Normalized to 0.1 mmoles/kg
Dose
70.57 73.06 53.18 56.66 60.63
pmolar Equivalents of Active in
Fat
218.46 226.15 164.62 175.38 187.69
Group III 646915 646916 646917 646918 646919
94 94 94 94 94
1.3 1.1 1.3 0.8 1.5
1.1 0.9 1.1 0.6 1.3
5.47 16.92 4.47 13.85 5.47 16.92 2.98 9.23 6.46 20.00
**tc o m TSCA CSI -79-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-24020
DuPont-11557
Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation:
426 20 100
% F in Active: Mol Wt. F (g/mol):
69 19
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Dose F (mmol/kg):
20 0.047 0.726
Molar Ratio (Active/F): 0.065
Dose F (mg/kg):
13.8
Rat Number
Test ppm F Day in Sample Fat
Group I 646921 646922 646923 646924 646925
10 10 10 10 10
6.2 8.5 8.7 8.8 8.3
ppm F in Fat
Minus Bkg 0.2 ppm
6.0 8.3 8.5 8.6 8.1
Group III 646926 646927 646928 646929 646930
94 94 . 94 94 94
ND ND ND ND ND
ND ND ND ND ND
ND Non-detectable.
ppm F in Fat Normalized to 0.1 mmoles/kg
Dose
12.78 17.68 18.11 18.32 17.25
ND ND ND ND ND
pmolar Equivalents of Active in
Fat
43.48 60.14 61.59 62.32 58.70
ND ND ND ND ND
Company Sanitized. Dees not contain TSCA CB|
V
-80-
H-25357: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-25357
Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation:
850000 1000 19
% F in Active: Mol Wt. F (g/mol):
Calculated Values:
Dose Active (mg/kg):
190
Dose Active (mmole/kg):
2.2 x 10'4
Dose F (mmol/kg):_____________________ 1.000
Molar Ratio (Active/F): Dose F (mg/kg):
DuPont-11557
10 19
2.2 xlO"4 19.0
/ " `'N
Rat Number
Test ppm F Day in Sample Fat
Group I
665500
10 23.06
665501
10 24.36
665502 10 18.3
665503
10 15.85
665505
10 23.73
Group III 665506 665507 665508 665509 665510
94 94 94 94 94
2.84 3.14 3.26 3.28 1.39
ppm F in Fat
Minus Bkg 0.2 ppm
22.9 24.2 18.1 15.7 23.5
2.6 2.9 3.1 3.1 1.2
ppm F in Fat Normalized to 0.1 mmoles/kg
Dose
10226.84 10808.42 8097.37 7001.32 10526.58
1181.05 1315.26 1368.95 1377.89 532.37
pmolar Equivalents of Active in
Fat
120.32 127.16 95.26 82.37 123.84
13.89 15.47 16.11 16.21 6.26
Sanitized.Doesnot contain TSCACBI
