Document Qk5j0nqn9kvBbYmpYxkNx2wr4

TRADE SECRET Study Title H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Laboratory Project ID: DuPont-2920 DuPont-2920 AR226-3159 Author: Carol Finlay, B.A. Study Completed on: August 29,2000 performing laboratory: Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 W ork Request Number: Service Code Number: industrial Medicine Company Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation o f data obtained from this study. Reviewed by: Gary W.Jepson, PhD . Senior Research Scientist Reviewed by: Judith C. Stadler, P h J J , D.AB.T. Director Issued by Stndy D irector:------------- ( ( Staff Scientist 000 Date ?K-Aa0'2o&> Date 7 *\ - - "2600 Date ^ Company Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 TABLE OF CONTENTS CERTIFICATION........................................................... LIST OF TABLES........................................................... LIST OF FIGURES......................................................... LIST OF APPENDICES.................................................. STUDY INFORMATION................................................ STUDY PERSONNEL.................................................... SUMMARY....................................................................... INTRODUCTION........................................................... MATERIALS AND M ETHODS.................................. A. Test Substance and Positive Control.................... B. Test Species........................................................... C. Animal Husbandry................................................ 1. Housing Environment..................................................... 2. Feed and W ater................................................................ 3. Identification.................................................................... 4. Animal Health Monitoring Program.............................. D. Quarantine and Pretest.......................................... E. Study Design......................................................... F. Assignment to Groups and Study Start......... ...... G. Dosing Material Preparation and Administration 1. Test Substance................................................................. 2. Positive C ontrols............................................................. 3. Negative Controls............................................................ H. Body Weights........................................................ I. Mortality and Clinical Observations.................... J. Collection and Analysis of Blood and Livers...... K. Treatment of Fluorine D ata................................. RESULTS AND DISCUSSION.............................. . A. In-Life Toxicology................................................ B. Fluorine Data........................................................ 1. Factors Influencing Interpretation of Analysis............ 2. Positive Controls............................................................ 3. Test Substance................................................................ CONCLUSIONS............................................................. RECORDS AND SAMPLE STORAGE..................... TABLES..................... ...................................................... Page 2 4 4 ,4 ,5 ,7 .8 .9 .9 .9 .9 .9 ..9 10 10 10 10 11 11 11 11 .11 .12 12 12 12 13 14 14 14 .14 .14 .15 15 15 16 -3 ompan^ Sanitized. Does not contain TSCA ClS FIGURES ......... APPENDICES LIST OF TABLES 1. MEAN BODY W EIGHTS......................................................................................... 2. MEAN BODY WEIGHT GA IN S............................................................................. 3. MEAN BLOOD FLUORINE LEVELS.................................................................... 4. MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE LIST OF FIGURES 1. MEAN BODY W EIGHTS......................... 2. MICROMOLAR EQUIVALENTS IN RAT BLOOD....................................................... MICROMOLAR EQUIVALENTS !N TEST COMPOUND AND POSITIVE CONTROLS 3. LIST OF APPENDICES A. INDIVIDUAL BODY W EIGHTS....................... B. INDIVIDUAL CLINICAL OBSERVATIONS... C. INDIVIDUAL FLUORINE LEVELS................. 21 26 Page ....17 ....18 .... 19 .20 Page 22 23 25 Page ......27 ......61 ......72 Company Sanitized. Does no! contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats STUDY INFORMATION TEST SUBSTANCE: Substance Tested Svnonvms/Codes: H-23926 Haskell Number: 23926 Composition Known Impurities: None POSITIVE CONTROL: Substance Tested DuPont-2920 Known Impurities: Unknown -5 - Company Sanitized. Does not contain TSCA CBB H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats STUDY INFORMATION (Continued) POSITIVE CONTROL: DuPont-2920 Haskell Number: 24020 Sponsor: E. I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: April 30, 1999 / (see report cover page) In-Life Tnitiated/Completed: May 16, 1999 / August 17, 1999 -6sspams? Sanitized. Doe noeontain TSCACBfl H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats STUDY PERSONNEL Study Director: Carol Finlay, B.A. Management: Judith C. Stadler, Ph.D., D.A.B.T. Primary Technician: 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-2920 -7 Gompany Sanitised. Does not contain TSC CBl H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 SUMMARY The objective of this study was to evaluate the potential for H-23926, when administered by gavage, to be absorbed and to accumulate in a mammalian system. Six groups o f 5 male Crl:CD(SD)IGS BR rats each were given 1000 mg/kg/day o f H-23926. The test substance was administered to one group of 5 rats for 5 consecutive days and to 5 groups for 10 days. Approximately 2 hours after the first dose, blood was collected from the orbital sinus o f each rat from the 5-dose group. On selected days (5 ,1 0 ,1 3 ,2 4 , 52, 94) 5 rats per group were euthanized and the blood and livers were collected. Body weights and clinical signs were recorded on each day o f dosing and then weekly, every other week, or every 3 weeks during the recovery period. Additionally, 2 negative controls, com oil and com 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-23926. No deaths occurred during the study. No clinical signs o f toxicity were observed in rats dosed with the test substance, H-23926. Rats dosed with H-24019 exhibited diarrhea, salivation, alopecia, black ocular discharge, and staining of various parts o f 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 in rats dosed with the positive controls, H-24019 and H-24020. The negative control rats exhibited no clinical signs during the study. Comparison o f 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. Accounting for the age difference at study start and the expected rate o f body weight gain, it appears that the mean body weights and mean body weight gains o f the rats dosed with the test substance, H-23926, are comparable to the negative controls and equal to or greater than the positive controls. A steady-state for fluorine levels in whole blood was achieved during 10 consecutive days of dosing with 1000 mg/kg H-23926. 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 o f the test substance, H-23926, was 312.5, compared to AUCINF/D values o f 566,479.1 and 70,789.6 for the positive controls, H-24019 and H-24020, respectively. Under the conditions o f this study, administration of the test substance, H-23926, to male rats for 10 consecutive days resulted in minimal absorption and retention o f fluorine in the blood. Doseadjusted areas under the curve (AUCINF/D) for positive controls, H-24019 and H-24020, were approximately 1813x and 227x the AUCINF/D for the test substance. -8Company Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Pose Oral Gavage Study in Rats DuPont-2920 INTRODUCTION The objective o f this study was to define the potential o f H-23926 to be absorbed and to bioaccumulate in a mammalian system, as indicated by analytical determination o f total fluorine in blood and liver. 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/day for the test substance was set based on the limit dosage for the project and was selected based on available toxicity data and the results o f a rangefinding study. In the rangefinding study, a group o f 5 male rats was dosed by oral gavage with H-23926 for 5 consecutive days at a dosage o f 2000 mg/kg/day. A group o f 5 male rats was dosed with deionized water and served as controls. The rats dosed with H-23926 experienced an overall mean body weight gain of 26 grams. The control group had an overall mean body weight gain of 27 grams. No effects on body weight were expected dining the study. All blood samples were analyzed for total fluorine content. This report contains the results of those analyses. Results from analyses o f selected liver samples will be presented in a supplemental report. MATERIALS AND METHODS A. Test Substance and Positive Control The test substance, H-23926, was supplied by the sponsor as a opaque tan 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 o f the study. No evidence o f 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 o f extensive experience with this strain and its suitability with respect to longevity, hardiness, sensitivity, and low incidence o f 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) -9 Company Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 and at a temperature o f 23 1C and a relative humidity o f 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 o f 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 o f 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 o f the study: Water samples are analyzed for total bacterial counts, and the presence o f 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 o f key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence o f these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity o f the study. The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. 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 o f disease or injury. The rats were observed daily for mortality and signs of illness, injury, or abnormal behavior. - 10Company Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 On the bases o f 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 designee. E. Study Design Substance Negative Controls Com oil Com oiltacetene Positive Controls H-24019 H-24020 Test Substance H-23926 Vehicle Dosage (mg/kg) Number o f Animals Not applicable 0 0 30 30 Com oil: acetone Com oil 10 20 30 30 None 1000 30 F. Assignment to Groups and Study Start After the quarantine period, the rats were selected on the bases o f adequate body weight gain, freedom from any clinical signs o f disease or injury, and a body weight within 20% of the mean. The selected rats were divided by computerized, stratified randomization into 6 groups o f 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 o f the animal number was marked or tattooed on the tail o f 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-23926 was dosed as received. The amount o f test substance each rat received was based on the body weight collected on each day o f dosing and the test substance density o f 1120 mg/mL. One rat (626461) was inadvertently not dosed on test day 8. The test substance was stirred on a magnetic stir plate throughout the dosing procedure to maintain homogeneity. 2. Positive Controls The solid positive control compounds were suspended as emulsions in their respective vehicles. Com oil was used as the vehicle for H-24019. It was necessary to dissolve H-24020 in acetone before suspending it in com oil. The ratio o f acetone to com oil was 20:80. The amount each rat received was based on the body weight collected on each day o f dosing and the suspension -11 - Company Sanitized. D oes not contain TSCA CBi H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 concentration. The dose volumes did not exceed 1 mL/100 g o f body weight. The dosing suspensions were stirred on a magnetic stir plate throughout the dosing procedure to maintain homogeneity. 3. Negative Controls Com oil and com oil:acetone (80:20) were chosen as the negative controls because they were the vehicles for the positive controls. Each negative control rat received 1 mL o f com oil or com oil:acetone. These rats were dosed in a separate room from the rats dosed with the test substance or positive controls. H. Body Weights All rats were weighed on each day o f dosing (with the exception o f rat 626461 on test day 8). The positive and negative control rats were weighed weekly or every other week during the recovery period. The rats dosed with H-23926 were weighed weekly, every other week, or every 3 weeks 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 and Livers Approximately 2 hours after the first dose, 1-2 mL o f blood was collected into EDTA tubes from the orbital sinus o f each rat from Group I. 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 Five to 10 mL o f 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. -12- ewpassy ianled. D oes n8eonafn TSC& CBS H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 The total fluorine content of the blood samples was determined 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 o f 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 F in each sample) was supplied to Haskell Laboratory personnel for evaluation o f fluorine biopersistence. K. Treatment of Fluorine Data Noncompartmental analysis was conducted on blood fluorine data derived from rats dosed with H-23960 by using WinNonlin Version 3.0 software (Pharsight Corp, Mountain View, CA). WinNonlin software provided a means o f computing derived pharmacokinetic parameters from data files including area under the curve (AUCINF), Cmax and terminal half-life (T1/2). The AUCINF (concentration x time) represents the area under the blood concentration curve from the time o f 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 o f 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, 1/(1-e_kt)) and bioaccumulation index (BI, Cmax x AI) were calculated and reported but not further used. H-24019 and H-24020 were used as positive controls. Dosing diluents were used as negative controls, but because of variability and limited sensitivity o f 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 less than 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 o f total blood fluorine were used as received (ppm F) from Jackson Laboratory. Fluoride ion was converted to micromolar (p M ) equivalents o f active component for further comparisons. The data and descriptions of data manipulation and presentation are provided in Appendix C. -13@o9pany Sanitized. Does not contain TSCA CBS H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 RESULTS AND DISCUSSION A. In-Life Toxicology (Tables 1-2, Figure 1, Appendices A-B) No deaths occurred during the study. No clinical signs of toxicity were observed in rats dosed with the test substance, H-23926. Rats dosed with H-24019 exhibited diarrhea, salivation, alopecia, black ocular discharge, and staining o f various parts o f the body dining the dosing period. Rats dosed with H-24020 exhibited wet perineum and diarrhea during the dosing period. Alopecia was observed during the recovery period in rats dosed with the positive controls, 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-23926, were older and heavier in weight than the com oil negative control and H-24020 positive control rats, but younger and lighter in weight than the com oil/acetone negative control and H-24019 positive control rats. Accounting for the age difference at study start and the expected rate o f body weight gain, it appears that the mean body weights and mean body weight gains o f the rats dosed with the test substance, H-23926, are comparable to the negative controls and equal to or greater than the positive controls. B. Fluorine Data (Tables 3-4, Figures 2-3, Appendix C) 1. Factors Influencing Interpretation o f 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 o f 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 /tM 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 o f 40.5 days. The H-24019 AI was 59.0 and the BI was 58382.2. The H-24020 normalized [iM 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 o f 8.3 days. The H-24020 AI was 12.5 and the BI was - 14psffif SanRbed. Oo meseenSata TiC OBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 6497.5. For each o f the positive controls, blood was sampled at seven time points throughout the study, with only four o f 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-23926 normalized fiM equivalents in rat blood rose rapidly and appeared to reach steadystate (Figure 2C). The Cmax for H-23926 was 1.14 1.04 ppm (Mean SD) with a terminal half-life o f 16.1 days. Blood was sampled at seven time points throughout the study, with only four o f 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 H-23926 AI was 23.7 and the BI was 27. The total internal exposure resulting from a normalized dose was described by AUCINF/D and was the basis for comparison between H-23926 and positive controls. The AUCINF/D for the fluorine component o f H-23926 was 312.5 as compared to AUCINF/D values o f 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 mg/kg H-23926 exhibited no mortality or clinical signs o f toxicity and had mean body weights and mean body weight gains that were comparable to the negative controls. A steady-state for fluorine in the blood was achieved during the 10-day dosing period. Under the conditions of this study, administration o f the test substance, H-23926, to male rats for 10 consecutive days resulted in minimal absorption and retention of fluorine in the blood. Doseadjusted areas under the curve (AUCINF/D) for positive controls, H-24019 and H-24020, were approximately 1813x and 227x the AUCINF/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. -15Compamy SanWsed. Does not c o n ta i TSCA CBl H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 TABLES 9 i i " -16- Company Sanitized. Does not contain TSC CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 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 66 68 76 80 81 83 89 90 94 Negative Controls Com Oil Com Oil:Acetone 229.8 297.6 234.1 299.6 241.4 309.4 250.4 314.3 259.3 321.5 266.8 326.0 271.2 334.9 281.9 339.2 285.2 345.2 295.9 351.7 321.1 350.7 350.5 369.8 378.3 401.0 - 407.8 434.5 454.9 - 411.4 - - - 464.7 487.0 505.1 - 527.6 - - 515.4 - 556.2 566.9 - 539.0 - 562.2 567.8 . Positive Controls H-24019 H-24020 291.5 227.5 291.5 232.4 298.3 242.0 304.1 248.9 308.6 252.4 312.7 259.8 317.5 263.3 317.3 269.8 318.4 278.5 318.9 283.9 329.1 289.1 359.7 311.3 387.9 340.9 393.9 - 416.9 402.9 - 425.0 - 438.2 - 438.1 - 523.4 563.4 570.7 -' 585.3 597.9 - 465.6 452.3 465.8 - 470.9 499.2 527.8 538.7 Test Substance H-23926 276.9 280.2 288.4 294.0 301.6 305.4 312.6 318.7 324.9 330.2 347.8 377.9 401.4 - - 482.5 509.8 - - 515.0 529.3 544.9 '- 557.3 564.8 574.9 - Indicates the animal was not weighed. -17- Gompoqr SanRbed. eonMn TSC C ii H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 Test Days 1-5 1-10 10-13 10-24 10-52 10-94 TABLE 2 MEAN BODY WEIGHT GAINS (g) Negative Controls Com Oil Com OilrAcetone 29.5 23.9 66.1 54.1 25.2 - 1.0 82.4 49.3 168.8 175.9 271.0 216.1 Positive Controls H-24019 H-24020 17.1 24.9 27.4 56.4 10.2 5.2 69.0 57.0 119.2 181.7 279.0 254.8 Test Substance H-23926 24.7 53.3 17.6 71.2 179.6 244.7 ! -18Company Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats m TABLE 3 MEAN BLOOD FLUORINE LEVELS DuPont-2920 Test Days 1 5 10 13 24 52 94 Negative Controls Com Oil Com Oil:Acetone (ppm) (ppm) <0.2 <0.2 <0.2 <0.2 <0.2 0.3a (0.1 )b 0.2a (0.1) 0.6C(0.6) <0.2 0.2d 0.3a (0.1) <0.2 0.3a (0.1) <0.2 Positive Controls H-24019 H-24020 (ppm) (ppm) 2.1 (0.9) 62.6 (3.2) 48.8 (17.6) 71.7 (6.2) 61.7 (2.8) 54.2 (7.8) 64.5 (7.6) 26.6 (11.4) 42.2 (2.8) 10.5 (3.0) 26.9 (2.6) 0.9 (0.2) 13.2 (2.1) 0.2C (0.1) Test Substance H-23926 (ppm) 0.6 (0.2)e 1.2 (0.2) 1.2 (0.5) 1.3 (1.0) 0.6 (0.2) 0.3 (0.1) 0.2 (0.0) a Mean of 4 o f the 5 values. One o f the values was below the level o f detection (LOD). b Standard deviation is in parentheses. c Mean o f 3 o f the 5 values. Two o f the values were below the LOD. d One value. Four o f the values were below the LOD. e Mean o f 4 o f the 5 values. The tube o f blood for one rat was missing or broken. # - 19ampara^ SarafcsdL 0@@raottGrattateTS&CIS H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 TABLE 4 MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE Test Days 1 5 10 13 24 52 94 Positive Controls H-24019 H-24020 fiM F Equivalents liM F Equivalents 28.92 (13.3)a 89.28 (23.4) 747.69 (271.5) 518.12 (44.9) 945.85 (43.5) 391.01 (56.8) 989.85 (116.9) 191.45 (82.7) 645.54 (42.9) 74.35 (22.1) 411.38 (40.6) 4.64 (1.1) 195.38 (32.5) 0.24 (0.4) Test Substance H-23926 fiM F Equivalents 0.375 (0.2)b 1.02 (0.2) 1.04 (0.5) 1.14 (1.0) 0.4 (0.2) 0.14 (0.1) 0.02 (0.0) a Standard deviation is in parentheses. b Mean o f 4 o f the 5 values. The tube o f blood for one rat was missing or broken. -20ompany Sanitized. D oes not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 FIGURES -21 i MBpsffiSPSamfeecL 0@s im8sM k TI Ci H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 400 -I 350 - 300 - J'+VOZ*)f 250 - *3 *fofol. 200 - 1 150- 100 - 50 - 0 -1---------------------r 02 FIGURE 1 MEAN BODY WEIGHTS (g) --O--Negative Cont rol (Corn Oil) Negative Control (Corn OihAcetone) A Positive Control H-24019 X Positive Control H-24020 x Test Substance H-23926 -I----------------- 1------------------ 1------------------ 1------------------ 1 4 6 8 10 12 Test Days -22otnpany Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 FIGURE 2 MICROMOLAR EQUIVALENTS IN RAT BLOOD A. N o r m a l i z e d R a t Bl o o d H - 2 4 0 1 9 jxM E q u i v a l e n t s R e s u l t i n g f r o m a 1 0 - Da y O r a l G avage Micromolar (ftM) equivalents of 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 r m a l i z e d R a t Bl o o d H - 2 4 0 2 0 i M E q u i v a l e n t s R e s u l t i n g f r o m a 1 0 - D a y O r a l G avage Micromolar (fiM) 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. -23Company Sanitized. Does not contain TSCA CB H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 C. Normalized Rat Blood H-23926 fiM Equivalents Resulting from a 10-Day O ra lG avage Micromolar (fiM) equivalents of H-23926 (test substance) in rat blood resulting from a 10-day oral gavage exposure. Values are means and error bars are standard deviation. -24- OBmpaisy Sanitized. Samefieomafra TSS GBi 0> H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats m # DuPont-2920 FIGURE 3 MICROMOLAR EQUIVALENTS IN TEST COMPOUND AND POSITIVE CONTROLS i l l ' AUCINF/D in Rats Resulting 25 CwnPa"ySanttbedL Does not contain TSCa car H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 #' APPENDICES -26Contpaisy Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 APPENDIX A Individual Body Weights - 27- B@mnog MSafe tsca CBi H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats INDIVIDUAL BODY WEIGHTS EXPLANATORY NOTES ABBREVIATIONS: SD - sacrificed by design DuPont-2920 - 28- M M t a M m h , tsc* cbi H-23926: 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 BO DY WEIGHTS (g) OF MA LE RATS GROUl? I TEST DAYS 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 DuPont-2920 - 29Company Sanitized. Does not contain TSCA CBI H-23926: 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 II TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627793 627797 627799 627800 627808 214.8 239.9 228.9 246.9 235.6 224.4 245.9 231.4 252.8 241.6 232.1 257.3 242.3 265.2 250.1 243.1 267.5 246.2 279.3 262.1 249.9 280.7 258.9 283.6 270.4 257.0 288.0 . 261.5 295.5 284.1 262.0 290.9 266.4 300.1 287.4 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS DAY 10 627793 627797 627799 627800 627808 270.6 3'03.9 280.2 312.0 303.6 274.9 305.1 284.3 315.4 305.7 283.5 324.2 294.7 331.3 321.8 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 DuPont-2920 -30essspamy Sanitized. Does ortalto TSS CBS H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats 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 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP III TEST DAYS 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 ANIMAL NUMBER 627796 627806 627807 627809 627816 DAY 8 285.9 282.8 270.7 297.9 291.8 DAY 9 TEST DAYS DAY 10 DA Y 13 290.1 285.8 274.7 300.2 296.4 300.0 302.8 280.7 311.9 305.7 322.7 320.3 305.2 336.2 330.2 SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13 DuPont-2920 -31 - Company Sanitized. Does not contain TSCA CBI %,~ ......................................... H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats_______________________________________ CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WE IGHTS (g) OF MALE RATS GROUP IV ANIMAL NUMBER DAY 1 DAY 2 TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627791 627794 627804 627812 627817 231.1 224.4 224.7 221.9 233.5 235.4 233.0 228.8 231.5 231.3 241.2 238.1 230.6 236.3 229.0 246.8 247.8 243.0 245.7 244.8 255.9 260.0 251.7 255.5 255.4 262.6 267.4 252.9 264.9 266.4 268.4 270.1 259.5 269.5 270.0 ANIMAL NUMBER 627791 627794 627804 627812 627817 DAY 8 274.0 286.1 267.2 278.2 277.8 DAY 9 279.1 289.5 270.6 282.7 280.4 TEST DAYS DAY 10 DA Y 13 285.0 295.4 278.1 294.3 294.6 _a __a _a _a _a DAY 20 334.4 377.4 345.8 356.5 368.7 DAY 24 365.6 416.7 378.1 388.4 407.3 SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24 DuPont-2920 a Rats not weighed. -32- Osmpany SainilteBiL 0em i eofFramTSGAGil H-23926: 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 V TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627792 627798 627813 627814 627815 235.8 241.1 214.8 217.5 230.1 240.8 253.4 219.2 220.5 242.2 244.3 257.6 220.5 223.7 243.8 247.9 266.1 233.2 225.2 255.7 252.5 272.9 239.8 233.8 265.0 264.4 281.9 243.2 236.7 270.0 268.1 286.2 246.8 240.6 274.1 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS DA Y 10 DA Y 13 DAY 20 DAY 24 D A Y 34 627792 627798 627813 627814 627815 282.4 2 94.3 258.7 248.0 289.2 286.4 296.3 259.2 250.7 293.4 295.2 315.7 267.9 257.3 303.3 -a -a 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 ANIMAL NUMBER DAY 41 DA Y 47 TEST DAYS DAY 52 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 DuPont-2920 a Rats not weighed. -33Consparty Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL. NUMBER 627795 627811 627819 627820 627821 ANIMAL NUMBER 627795 627811 627819 627820 627821 ANIMAL NUMBER 627795 627811 627819 627820 627821 DAY 1 218.0 228.6 248.8 225.5 227.5 DAY 2 219.5 226.3 255.3 228.9 233.2 DAY 8 261.4 2.73.0 304.5 281.3 272.6 DAY 9 265.0 276.7 308.0 282.9 275.3 DAY 41 DAY 47 384.2 422.0 505.9 478.0 411.8 398.0 439.3 534.9 504.1 426.1 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL B O DY WEIGHTS (g) OF MALE RATS GROUP VI TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 225.3 236.7 264.9 239.2 240.7 234.3 246.1 274.4 247.9 246.1 239.4 251.5 280.4 255.6 251.2 246.2 259.6 288.0 261.3 259.8 250.1 263.6 290.3 265.3 263.9 TEST DAYS DAY 10 D A Y 13 DAY 20 DAY 24 DAY 34 270.7 285.6 324.3 292.4 281.8 _a __a _a _a _a 308.0 337.8 399.7 367.2 330.1 329.8 360.6 431.2 393.0 352.9 362.0 396.4 472.5 445.5 385.6 TEST DAYS DAY 52 D A Y 55 DAY 61 DA Y 68 --a 411.1 435.7 440.7 _a 455.4 463.0 473.6 _a 551.7 574.4 . 588.6 _a 529.7 547.1 558.6 _a 439.1 459.0 463.3 DuPont-2920 a Rats not weighed. -34CompajBy SanHUzed. Doss m i conflato TSC CBE H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 90 DAY 94 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WE IGHTS (g) OF MALE RATS GROUP VI TEST DAYS 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 DuPont-2920 -35Comparty Sanitized. Does not contain TSCA CBI H-23926: 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 TEST DAYS 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 DuPont-2920 -36- Samltted Does not contain T3CACBG H-23926: 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 34-9.1 364.2 350.1 DAY 9 320.9 332.3 352.4 380.8 354.2 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF M A LE 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 DuPont-2920 -37Company Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 625357 625358 625370 625384 625385 ANIMAL NUMBER 625357 625358 625370 625384 625385 DAY 1 311.9 285.7 3 07.9 294.2 297.6 DAY 2 308.8 286.3 316.7 300.0 304.6 DAY 8 364.2 3-19.8 373.4 325.6 347.0 DAY 9 370.3 321.6 374.7 331.0 349.5 CORN OIL:ACETONE (NEGATIVE Control) INDIVIDUAL BODY WE IGHTS (g) OF MALE RATS GROUP III TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 320.3 295.5 329.5 312.0 313.0 328.4 296.4 337.9 309.3 320.4 340.5 306.0 346.9 316.3 331.9 343.3 302.7 349.8 314.1 334.0 361.1 309.2 364.1 321.4 345.4 TEST DAYS DAY 10 DA Y 13 376.9 320.3 385.6 340.6 358.9 405.6 340.7 407.0 357.1 377.6 SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13 DuPont-2920 -38 - osnpany Sanitized. Does not contain TSCA CBI m ------------------------------ H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 625354 625365 625371 625376 625381 ANIMAL NUMBER 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 DAY 9 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 7 310.5 337.9 313.4 302.2 301.7 312.2 343.6 318.3 304.9 305.6 319.3 357.7 321.8 313.2 314.4 324.7 357.2 329.6 317.0 314.4 331.2 364.3 338.5 322.8 321.0 TEST DAYS DAY 10 D A Y 13 DA Y 20 DAY 24 625354 625365 625371 625376 625381 336.2 370.5 340.3 331.5 321.6 337.0 379.3 345.9 339.0 329.1 348.8 381.2 351.2 345.2 331.6 355.8 407.1 372.6 363.2 341.2 377.7 438.2 413.0 399.7 358.2 396.1 459.6 447.3 432.9 381.8 SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24 DuPont-2920 -39Company Sanitized. Does not contain TSCA CBI H-23926: 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 M A LE RATS GROUP V TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625356 625359 625360 625372 625374 291.7 297.9 296.8 294.8 295.9 291.2 303.3 300.7 298.8 302.2 304.5 314.0 308.5 310.6 312.1 307.0 315.0 312.7 317.4 321.7 316.9 323.5 319.1 324.0 323.4 319.8 323.5 332.2 329.0 328.3 323.9 333.9 339.5 335.6 337.2 ANIMAL NUMBER 625356 625359 625360 625372 625374 DAY 8 328.8 339.1 347.9 344.7 338.0 DAY 9 334.7 346.2 354.3 348.8 344.6 TEST DAYS DA Y 10 DA Y 13 341.3 353.6 363.4 355.1 350.8 361.9 372.9 381.7 373.1 371.5 DAY 20 396.7 410.0 419.8 395.1 401.3 DAY 24 _a DAY 27 431.3 440.9 465.9 432.1 447.2 ANIMAL NUMBER 625356 625359 625360 625372 625374 DA Y 34 466.2 467.7 484.1 454.7 466.8 D A Y 52 TEST DAYS 533.7 530.3 555.4 506.2 512.3 SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52 DuPont-2920 a Rats not weighed. -40Gempansf Sanitized. Does not contain TSCA CBS H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats_________________________________________ CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WE IGHTS (g) OF MALE RATS GROUP VI ANIMAL NUMBER DAY 1 DAY 2 TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625353 625369 625373 625375 625377 305.9 281.7 294.6 289.1 293.9 307.3 279.9 301.3 291.0 294.8 316.8 289.7 312.7 298.0 302.9 325.0 286.9 317.0 307.0 312.0 331.7 292.8 325.4 309.6 318.0 330.1 295.3 329.0 314.2 317.4 342.5 303.8 334.6 323.5 325.0 ANIMAL NUMBER 625353 625369 625373 625375 625377 DAY 8 344.7 3-07.3 340.6 324.7 325.0 DAY 9 352.7 311.9 348.2 336.0 333.7 TEST DAYS DA Y 10 DA Y 13 358.1 317.2 352.6 336.9 340.7 371.7 331.1 371.5 350.1 353.5 DAY 20 399.1 347.6 402.3 387.9 376.3 DAY 24 _a _a _a _a _a DAY 27 427.7 374.9 444.6 432.3 405.2 ANIMAL NUMBER 625353 625369 625373 625375 625377 DAY 34 453.3 388.2 477.1 455.6 419.1 DAY 52 --a _a _a _a _a TEST DAYS DA Y 76 DAY 90 . DAY 94 544.9 483.8 628.8 567.3 470.3 562.8 505.3 661.3 589.8 492.0 565.3 514.8 673.7 588.8 496.6 SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94 DuPont-2920 a Rats not weighed. -41 Company Sanitized. Does not contain TSCA CBI H-23926: 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 M A LE RATS GROUP I TEST DAYS 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 DuPont-2920 -42Company Sanitized. Does not contain TSCA CBI H-23926: 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 II TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625320 625330 625332 625341 625350 279.3 286.7 300.0 304.9 257.1 283.0 286.1 295.9 309.0 268.5 287.7 291.1 304.1 317.5 267.3 288.4 296.5 308.8 320.0 272.2 295.9 304.0 315.0 325.1 272.6 299.4 302.3 322.4 327.5 276.3 300.6 306.7 320.7 327.4 283.6 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS DA Y 10 625320 625330 625332 625341 625350 308.5 3.14.0 324.1 332.4 279.8 306.3 312.6 321.8 320.3 282.5 312.1 310.1 318.3 325.6 284.3 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 DuPont-2920 -43- ompany Sanitised. Does not contain f SCA CIBI H-23926: 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 III TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625321 625327 625342 625345 625348 307.0 311.4 273.7 291.2 265.5 307.8 306.6 275.5 291.7 258.6 311.4 312.5 282.3 297.3 268.0 319.6 317.8 285.8 303.3 275.2 322.3 318.3 290.8 306.4 280.1 328.4 319.3 294.2 310.4 285.2 335.2 327.6 326.6 316.1 290.6 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS DAY 10 DA Y 13 625321 625327 625342 625345 625348 337.8 334.3 304.3 317.3 302.7 339.6 337.0 305.9 312.9 306.5 346.1 336.3 307.8 315.0 309.7 371.2 355.3 324.4 336.9 336.4 SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13 DuPont-2920 -44Comparty Sanitized. Does not contain TSCA CBI list,**e& H-23926: 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 IV TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625325 625328 625338 625340 625352 282.8 315.6 264.6 304.0 285.5 285.9 315.2 261.9 309.2 283.9 291.7 323.9 268.5 316.9 289.1 295.5 327.7 272.6 326.0 299.6 303.2 335.0 275.7 329.8 307.9 309.2 340.4 281.9 334.1 308.2 308.3 340.1 284.4 338.4 312.4 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS DA Y 10 DAY 13 DAY 20 DAY 24 625325 625328 625338 625340 625352 318.6 3.52.0 287.4 347.0 316.9 321.9 351.7 291.3 352.2 322.3 327.4 357.5 290.2 359.2 321.0 331.6 367.4 291.1 368.1 329.6 355.8 400.2 320.4 389.3 355.7 381.3 423.9 339.9 419.0 375.3 SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24 DuPont-2920 -45- Company Sanitized. Does not contato TSSA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 H-24019 (POSITIVE CONTROL) INDIVIDUAL BODY WE IGHTS (g) OF MALE RATS GROUP V TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625324 625329 625333 625334 625344 303.0 318.9 292.4 274.6 262.9 298.5 316.3 291.2 277.0 262.2 305.8 326.5 297.8 286.4 269.0 312.1 335.4 304.1 290.6 273.5 320.1 338.3 307.7 292.0 274.5 322.8 346.7 312.0 300.1 284.1 326.8 351.6 313.5 304.2 - ANIMAL NUMBER 625324 625329 625333 625334 625344 DAY 8 332.5 352.5 315.8 292.6 280.7 DAY 9 337.9 360.1 316.7 302.2 285.2 TEST DAYS DAY 10 DA Y 13 336.1 357.0 319.3 305.8 289.3 299.6 364.3 325.8 312.0 295.8 D A Y 20 336.0 396.4 349.2 338.6 309.7 DAY 24 _a __a _a _a _a DAY 27 380.3 423.3 375.2 368.8 330.4 ANIMAL NUMBER DAY 34 DA Y 52 TEST DAYS 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 DuPont-2920 a Rats not weighed. -46Company Sanitized. Does not contain TSCA CBI # H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats 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 H-24019 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 325.5 302.3 300.2 287.7 321.1 330.9 310.4 309.5 300.0 329.6 336.2 315.1 313.5 308.5 338.2 336.0 299.6 318.6 316.6 341.6 _ 293.6 326.0 326.9 340.7 DuPont-2920 ANIMAL NUMBER 625326 625335 625346 625347 625351 DAY 8 311.5 294.2 292.9 330.5 351.1 DAY 9 308.9 285.3 290.8 330.1 357.8 TEST DAYS DA Y 10 DAY 13 297.5 274.0 288.4 333.0 350.5 274.2 266.3 296.9 355.7 380.0 DAY 20 335.4 340.1 352.5 402.1 413.7 DAY 24 _a DAY 27 390.7 393.8 388.2 436.2 452.4 ANIMAL NUMBER 625326 625335 625346 625347 625351 DAY 34 427.5 427.0 407.4 466.4 483.3 DA Y 52 _a _a _a _a _a TEST DAYS DA Y 62 DAY 76 497.5 506.0 485.8 568.6 559.0 540.0 538.6 523.7 617.8 596.8 DAY 80 547.9 547.7 532.8 618.1 607.2 DAY 90 565.2 562.1 542.4 632.6 624.0 DAY 94 577.5 579.5 556.9 638.9 636.8 SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94 a Rats not weighed. - 47Company Sanitized. Does not contain TSCA CBS H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WE IGHTS (g) OF MALE RATS GROUP I TEST DAYS DAY 3 DAY 4 DAY 5 627756 627767 627771 627773 627777 227.2 227.0 219.5 246.8 225.4 226.4 231.8 214.7 244.4 221.4 233.4 237.9 226.1 252.7 232.9 238.6 245.8 233.5 263.8 239.4 237.5 248.6 239.6 262.3 236.0 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 DuPont-2920 - 48Company Sanitized. Does not contain TSC CBI u......wf{aslai..aei m #- H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats__________________________________________________________________________________________ DuPont-2920 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WE IGHTS (g) OF MALE RATS GROUP II ANIMAL NUMBER DAY 1 DAY 2 TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627768 627774 627776 627782 627785 236.9 258.6 212.0 221.6 220.3 244.1 261.6 216.3 228.3 221.7 245.2 275.8 223.7 237.3 234.7 256.5 283.4 226.6 239.0 238.4 256.2 289.3 229.6 238.8 241.8 265.5 301.5 233.7 244.7 250.5 271.4 303.2 236.9 246.7 255.6 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS DAY 10 627768 627774 627776 627782 627785 272.3 319.8 246.1 251.0 260.7 291.9 326.3 252.3 264.0 268.5 293.5 338.2 254.4 268.2 267.9 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 - 49Compansf Sanitized. Does not contain TSCA CB! / * ..-- m H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats________________________________________________________________________ H-24020 (POSITIVE CONTROL) INDIVIDUAL BO DY WE IGHTS (g) OF MA LE RATS GROUP III ANIMAL NUMBER DAY 1 DAY 2 TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627758 627763 627764 627787 627788 235.1 212.1 230.0 235.1 219.4 240.3 218.3 235.0 241.0 222.3 248.6 226.5 246.1 250.1 232.2 255.8 234.3 251.3 257.2 239.6 261.2 230.8 254.8 258.6 247.6 272.0 235.5 261.7 237.6 256.7 276.1 238.0 264.7 240.3 257.9 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS DAY 10 D A Y 13 627758 627763 627764 627787 627788 280.6 255.2 275.8 221.7 274.1 283.6 261.2 281.9 235.7 276.9 295.8 272.5 288.0 234.7 284.8 308.7 285.8 306.7 234.9 309.4 SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13 DuPont-2920 -50Company Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF M A LE RATS GROUP IV TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627759 627761 627770 627779 627786 226.6 240.7 235.6 231.5 211.6 232.9 247.4 244.3 237.9 218.2 241.4 257.1 253.6 252.6 222.5 250.9 262.5 260.1 261.4 230.4 254.2 266.7 267.7 262.3 230.6 262.1 259.2 277.3 273.8 240.6 265.4 262.6 279.8 277.5 244.1 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS DA Y 10 DA Y 13 DAY 20 DAY 24 627759 627761 627770 627779 627786 277.8 240.1 291.4 289.0 251.3 284.9 257.4 301.3 293.4 255.8 288.0 266.9 306.4 301.0 257.0 _a _a _a _a _a 348.0 335.7 355.8 374.4 304.4 380.1 359.4 379.8 406.2 326.1 SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24 DuPont-2920 a Rats not weighed. -51 Company Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627757 627760 627765 627772 627781 DAY 1 221.2 226.2 228.3 245.2 219.0 DAY 2 225.4 232.0 235.3 256.4 226.3 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF M A LE RATS GROUP V TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 236.3 244.4 247.1 266.2 236.5 241.1 251.7 251.6 277.0 242.9 247.9 260.2 256.4 276.9 247.2 252.2 254.5 261.1 285.0 251.6 254.4 258.3 264.7 291.0 256.1 ANIMAL NUMBER 627757 627760 627765 627772 627781 DAY 8 269.1 262.6 271.5 300.9 258.1 DAY 9 276.7 280.3 282.4 307.5 266.8 TEST DAYS DAY 10 DA Y 13 279.7 287.3 288.1 317.0 271.2 -a -a -a DA Y 20 324.3 348.6 349.8 375.5 315.1 DAY 24 343.0 379.9 382.7 404.0 338.8 D A Y 34 372.3 419.4 400.9 446.9 372.0 ANIMAL NUMBER DAY 41 DAY 47 TEST DAYS DAY 52 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 _ _ . ....................DuPont-292() a Rats not weighed. -52- (Sosipai S anitized. Does not contain TSCA CBS ... ............................................ --------------------------------------------------- H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats___________________________________________________________________________________________ DuPont-2920 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI ANIMAL. NUMBER DAY 1 DAY 2 TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627762 627769 627775 627778 627783 227.2 231.1 224.7 213.1 216.4 235.0 241.1 235.7 217.4 218.2 248.7 255.9 246.8 221.3 226.6 257.3 264.2 254.7 225.5 232.0 263.0 272.3 265.7 230.1 238.0 275.1 286.3 276.7 236.9 243.9 279.7 289.9 280.2 240.4 247.6 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS DAY 10 DAY 13 DAY 20 DAY 24 DAY 34 627762 627769 627775 627778 627783 ANIMAL NUMBER 285.9 3G2.0 286.6 244.8 256.6 DAY 41 299.1 309.6 296.0 250.8 259.2 DAY 47 301.5 312.5 304.5 255.1 264.3 -a -a -a TEST DAYS DA Y 52 DA Y 55 356.5 386.6 353.3 294.0 311.3 DAY 61 381.5 414.4 377.4 320.0 340.9 D A Y 68 419.6 456.5 413.9 347.1 380.0 627762 627769 627775 627778 627783 438.7 479.7 433.2 356.8 409.6 439.9 474.6 451.1 373.5 426.9 _a _a __a _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 Rats not weighed. -53Compaeisr Sanitized. Does not contain TSCA CBI ! :: m H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 81 DA Y 90 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TEST DAYS DA Y 94 627762 627769 627775 627778 627783 500.3 566.2 510.4 410.1 508.8 523.3 603.2 537.5 436.5 538.5 528.6 609.6 552.8 445.3 557.2 SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94 DuPont-2920 -54- Com pany Sanitised,, D oes eomam TSG CB8 H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL. NUMBER 626448 626450 626453 626457 626460 DAY 1 294.5 267.3 280.2 259.5 288.4 DAY 2 295.4 267.6 284.6 264.5 292.5 H-23926 (TEST SUBSTANCE) INDIVIDUAL BODY WE IGHTS (g) OF MALE RATS GROUP I TEST DAYS DAY 3 DAY 4 DAY 5 304.7 273.8 295.1 271.2 297.9 311.8 278.0 298.9 274.8 309.7 318.6 285.7 311.4 283.4 323.1 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 DuPont-2920 -55Compasiy Sanitized. Does not contain TSCA CBI ........................... -- %-- ------------------------------------------------------------------------ i H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL. NUMBER 626430 626433 626444 626449 626452 DAY 1 272.0 274.2 257.9 290.5 268.4 DAY 2 275.2 284.8 257.0 292.3 270.0 H-23926 (TEST SUBSTANCE) INDIVIDUAL BODY WE IGHTS (g) OF MA LE RATS GROUP II TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 282.1 294.1 262.8 300.8 281.5 285.7 303.2 271.2 311.1 282.0 295.1 310.1 273.9 316.4 290.1 298.6 318.0 279.7 325.0 292.8 306.1 322.8 287.5 333.7 300.9 DuPont-2920 ANIMAL NUMBER 626430 626433 626444 626449 626452 DAY 8 311.7 329.1 292.2 343.5 303.3 DAY 9 TEST DAYS DA Y 10 314.2 338.4 304.6 351.6 311.3 320.7 344.4 307.8 356.6 319.7 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 -56Gampamg Sanitized. Does no contain TSCA CBS > .... -- - m # H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats___________________________________________________________________________________________ DuPont-2920 H-23926 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP III ANIMAL NUMBER' DAY 1 DAY 2 TEST DAYS . DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 626435 626436 626445 626459 626572 247.2 272.0 292.5 280.7 275.7 247.4 276.9 300.3 276.3 278.3 254.1 285.6 310.1 284.3 290.3 258.7 291.4 320.0 290.6 296.6 264.8 300.2 331.4 302.1 3 03.0 268.3 303.2 338.7 309.3 307.2 272.0 310.7 348.0 316.9 315.0 ANIMAL NUMBER 626435 626436 626445 626459 626572 DAY 8 273.6 34.7 358.1 322.6 314.3 DAY 9 TEST DAYS DAY 10 DA Y 13 282.9 323.9 363.0 327.6 322.1 289.9 327.9 371.4 336.6 330.7 301.4 348.4 392.4 358.0 346.7 SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13 -57Company Sanitized. Does not contain TSCA CBf .fatti H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 626437 626438 626443 626456 626458 DAY 1 268.6 257.2 280.6 306.5 288.3 DAY 2 270.9 260.9 286.8 313.5 284.1 H-23926 (TEST SUBSTANCE) INDIVIDUAL BODY WE IGHTS (g) OF MALE RATS GROUP IV TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 277.0 270.9 294.3 325.5 290.6 279.0 277.2 296.3 323.8 294.2 285.1 286.8 304.5 334.0 298.8 288.3 293.5 304.5 338.2 303.9 294.7 304.6 316.8 349.1 311.2 ANIMAL NUMBER 626437 626438 626443 626456 626458 DAY 8 29'9 .4 310.1 315.8 352.0 316.5 DAY 9 303.4 317.9 322.3 359.4 319.7 TEST DAYS D A Y 10 DAY 13 306.7 324.7 334.2 363.6 321.3 320.6 346.8 341.2 383.4 337.9 DA Y 20 345.8 382.7 371.5 413.8 362.1 DAY 24 366.5 410.1 399.5 445.2 385.9 SD test day 24 SD test d a y 24 SD test day 24 SD test day 24 SD test day 24 DuPont-2920 -58Company Sanitized. Doss not contain TSCA CBB H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL. NUMBER 626429 626432 626439 626442 626461 DAY 1 281.9 268.4 293.6 268.4 293.2 DAY 2 276.8 270.4 299.8 275.0 297.1 H-23926 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP V TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 286.7 280.6 312.1 279.5 298.7 296.0 285.0 317.0 282.5 309.5 299.4 295.1 327.6 288.7 310.6 304.9 294.9 333.5 289.9 316.8 309.5 303.0 339.8 294.9 323.5 ANIMAL NUMBER 626429 626432 626439 626442 626461 DAY 8 318.3 314.1 346.4 297.9 327.5 DAY 9 324.5 318.6 355.1 301.4 335.6 TEST DAYS DAY 10 DAY 13 329.8 325.4 359.1 309.0 333.4 349.3 340.1 381.6 316.5 357.4 DA Y 20 376.2 373.5 422.6 348.9 385.9 DAY 24 _a _a _a _a _a DAY 48 478.4 491.8 526.5 446.1 487.5 ANIMAL NUMBER 626429 626432 626439 626442 626461 DA Y 52 TEST DAYS 513.4 522.8 547.9 459.7 505.0 SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52 DuPont-2920 a Rats not weighed. -59Company Sanitized. Does not contain TSCA CBI % H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats________________________________________ H-23926 (TEST SUBSTANCE) INDIVIDUAL BODY WE IGHTS (g) OF MALE RATS ANIMAL NUMBER' DAY 1 DAY 2 GROUP VI TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 626434 626441 626446 626447 626455 268.6 272.3 288.5 297.4 253.3 274.7 271.3 288.4 312.4 261.2 284.0 280.9 296.6 313.2 272.4 288.0 285.4 301.2 323.3 278.1 298.8 287.5 307.2 328.9 286.5 304.7 287.9 312.6 333.9 286.8 306.4 298.0 312.0 340.2 298.3 DuPont-2920 ANIMAL NUMBER 626434 626441 626446 626447 626455 DAY 8 317.8 300.8 322.9 347.2 _a DAY 9 324.3 307.4 330.6 353.3 309.1 TEST DAYS DAY 10 DA Y 13 330.4 307.1 331.7 358.2 313.6 352.8 327.1 350.0 374.2 329.5 DA Y 20 384.9 346.0 384.5 409.0 360.9 DAY 24 DAY 48 _a 486.6 _a 431.5 _a 486.9 _a 503.4 _a 486.4 ANIMAL NUMBER 626434 626441 626446 626447 626455 DA Y 52 _a _a _a _a _a DAY 62 522.8 477.8 514.1 527.4 533.0 TEST DAYS DA Y 66 DAY 76 536.8 492.2 533.6 538.4 545.6 555.0 499.7 547.7 555.3 566.8 D A Y 83 574.9 505.6 558.1 570.0 578.1 DAY 89 588.4 514.4 563.2 571.0 587.2 DA Y 94 601.3 532.3 571.8 575.3 593.6 SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94 a Rats not weighed. -60- mpmaSanitized. Does not contain T1GBU H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 APPENDIX B Individual Clinical Observations -61 - Company Sanitized. Does not contain TSCA CBi H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Animal Number 627789 627801 627805 627810 627818 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 GR OU P 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- Sanitized. Does m l eonflaSnSC ca H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP IV Animal N u m b e r _________________________O b s e r v a t i o n _____________________________ T e s t D a y 627791 627794 627804 627812 627817 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 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 -63Conipany Sanitized. Does no! contain TSCA CSI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Animal Number 625361 625363 625364 625380 625383 GROUP I ___________ O b s e r v a t i o n _____________________ T e s t D a y No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected 1-5 1-5 1-5 1-5 1-5 Animal 625355 625362 625367 625368 625378 GROUP II 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- fflpaR Sarstissdl. Doss eefSaira TSG C8 H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Animal Number GROUP IV O b s e r v a t i o n _____________________________ T e s t D a y 625354 625365 625371 625376 625381 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 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 -65Company Sanitized. Does not contain TSCA CBt H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 H-24019 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Animal Number GROUP I ______________________ O b s e r v a t i o n _____________________________ T e s t D a y 625322 625323 625336 625343 625349 No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected 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- Qfflpaf afiisketl D ees soi Malis TSCA CB6 H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 H-24019 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Animal Number GROUP IV Observation Test Day 625325 625328 625338 625340 625352 No abnormalities detected No abnormalities detected No abnormalities detected Salivation No abnormalities detected No abnormalities detected 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 -67Company Sanitized. Does not contain TSCA CBl H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats H-24020 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS DuPont-2920 Animal Number 627756 627767 627771 627773 627777 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 -68Company Sanitized. Doe* not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats H-24020 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS DuPont-2920 Animal Number 627759 627761 627770 627779 627786 GROUP IV O b s e r v a t i o n _____________________________ T e s t D a y 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 # Animal Number 627762 627769 627775 627778 627783 GROUP V Observation No abnormalities detected No abnormalities detected No abnormalities detected Wet perineum No abnormalities detected Wet perineum No abnormalities detected Test Day 1-52 1-52 1, 3-52 2 1, 3-52 2 1-52 GROUP VI . O b s e r v a t i o n _____________________________ T e s t D a y No abnormalities detected Diarrhea No abnormalities detected No abnormalities detected Alopecia perineum No abnormalities detected Alopecia both front paws Alopecia right front leg 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- (g@mps? Sssllsed, 0@s sunSsto YS<A C1 H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 H-23926 (TEST SUBSTANCE) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Animal Number 626448 626450 626453 626457 626460 GROUP I 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 Animal Number 626430 626433 626444 626449 626452 GR O U P II 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 Animal Number 626435 626436 626445 626459 626572 GROUP III 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 -70Company Sanitized. Does not contain TSCA C5I H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 H-23926 (TEST SUBSTANCE) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Animal Number 626437 626438 626443 626456 626458 GROUP IV O b s e r v a t i o n ___________;__________________ T e s t D a y No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected 1-94 1-94 1-94 1-94 1-94 Animal Number 626429 626432 626439 626442 626461 GROUP V 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 Animal Number 626434 626441 626446 626447 626455 GROUP VI O b s e r v a t i o n ___________________ __________ T e s t D a y No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected 1-94 1-94 1-94 1-94 1-94 f -71 - O o m p m a SanH lM d. Doe no eootaim TS S C H H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 APPENDIX C Individual Fluorine Levels $ -72Company Sanitized. Does not contain TSCACBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats_______________________________________________________DuPont-2920 t TERMS AND CALCULATIONS Terms: Active % Active Mol Wt Active Formulation Dose % F in Active Mol Wt F Fluorine containing compound The % o f formulation that is made up o f fluorine containing components The molecular weight o f the fluorine containing components (g/mole) The mg o f formulation given per kg o f animal body weight The % fluorine in the fluorine containing components o f the formulation (weight basis) The molecular weight of fluorine g/mol Compound Calculations: # Dose Active (mg/kg) The mg o f fluorine containing compound administered per kg of animal body weight. = (% active/100) x Formulation Dose Dose Active (mmole/kg) The mmole o f 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 o f animal body weight = (% F in active/100) x Dose Active [mg/kg] Dose F (mmol/kg) The mmole o f fluorine administered per kg o f animal body weight = Dose F [mg/kg] / Mol Wt F [mg/mmol] Molar Ratio (Active/F) The moles of fluorine containing compound per mole o f fluorine = Dose Active [mmol/kg] / Dose F [mmol/kg] Formulation Dose Normalization Factor The formulation dose that would be required to administer the amount o f active needed to achieve the normalized dose = (Normalized dose o f Active [mmol/kg] / Dose Active [mmol/kg]) x Formulation Dose . SamfeedL Does not eomtaisn T lO A OBa H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 TERMS AND CALCULATIONS Individual Animal Measurement: ppm F in blood The ppm fluoride measured in blood 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 normalized to 0.1 mmol/kgDose The ppm fluoride minus background that would be expected if the active dose was 0.1 mmol/kg instead o f the actual active dose. This assumes linearity between administered dose and blood fluorine levels, but is needed because different doses o f active were used in the study. = (0.1 [mmol/kg] / Active dose [mmol/kg]) x (ppm F in blood minus background) /xmolar equivalents of active in blood The p,molar [/xmol/L] concentration o f 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 mg/L = (Normalized ppm [mg/L] fluorine in blood / Mol Wt F [mg/mmol]) x molar ratio active/F [mmol active/mmol F] x 1000 /rmol/mmol -74Company Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2920 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 o f 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 bejustified 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 o f individual components - Background plasma Fluorine is 0.2 ppm - % F data is the % Fluorine o f the active (Fluorine containing component(s) in the formulation - Molecular weight is the molecular weight o f the active component in the formulation -75ossupany Sanitised. Does not eositairo TSCA O il H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats D ata for H- 24019 DuPont-2920 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): Formulation Dose Normalization Factor: 10 0.020 49.7 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 625322 625323 625336 625343 625349 1 1 1 1 1 1.0 1.3 2.6 2.6 2.9 Group I 625322 625323 625336 625343 625349 5 5 5 5 5 51.7 38.0 38.7 78.5 37.1 Group II 625320 625330 625332 625341 625350 10 10 10 10 10 65.6 61.1 60.5 63.1 58.1 ppm F in Blood Minus 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 mmoles/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 /molar 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 -76Company Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats_____________________________________________ DuPont-2920 Rat Number Test Day Sample ppm F in Blood ppm F in Blood Minus Bkg 0.2 ppm ppm F in Blood Normalized to 0.1 mmoles/kg Dose /imolar Equivalents of Active in Blood Group III 625321 625327 625342 625345 625348 13 13 13 13 13 77.2 61.5 64.6 57.0 62.4 77.0 61.3 64.4 56.8 62.2 382.69 304.66 320.07 282.30 309.13 1184.62 943.08 990.77 873.85 956.92 Group IV 625325 625328 625338 625340 625352 24 24 24 24 24 40.3 46.3 43.2 39.1 41.9 40.1 46.1 43.0 38.9 41.7 199.30 229.12 213.71 193.33 207.25 616.92 709.23 661.54 598.46 641.54 Group V 625324 625329 625333 625334 625344 52 52 52 52 52 24.7 29.8 27.3 29.1 23.8 24.5 29.6 27.1 28.9 23.6 121.77 147.11 134.69 143.63 117.29 376.92 455.38 416.92 444.62 363.08 Group VI 625326 625335 625346 625347 625351 94 94 94 94 94 12.4 16.4 13.1 11.0 11.6 12.2 16.2 12.9 10.8 11.4 60.63 80.51 64.11 53.68 56.66 187.69 249.23 198.46 166.15 175.38 -77- Osmpariy Sanitized. Does n8contain TSCA COS H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Data for H- 24020 DuPont-2920 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): Formulation Dose Normalization Factor: 20 0.047 42.6 Dose F (mmol/kg): 0.726 Molar Ratio (Active/F): 0.065 Dose F (mg/kg): 13.8 Rat Number Test Day Sample ppm F 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 75.3 627771 5 66.8 627767 5 64.8 627756 5 80.0 627777 5 71.6 Group II 627768 627774 627776 627782 627785 10 10 10 10 10 56.3 51.0 54.8 43.6 65.1 ppm F in Blood Minus 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 /i m o la r 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 -78Company Sanitized. Does not contain TSCA CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Rat Number Test Day Sample ppm F in Blood Group III 627758 627764 627787 627763 627788 13 13 13 13 13 43.5 20.7 13.2 30.8 24.9 Group IV 627759 627779 627770 627761 627786 24 24 24 24 24 9.2 14.9 11.6 9.9 6.7 Group V 627757 627781 627760 627765 627772 52 52 52 52 52 0.9 0.6 1.0 0.9 0.8 Group VI 627778 627783 627762 627775 627769 94 94 94 94 94 0.3 <0.2 0.2 0.2 <0.2 ppm F 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 92.23 43.67 27.69 65.18 52.61 19.17 31.31 24.28 20.66 13.85 1.49 0.85 1.70 1.49 1.28 . 0.21 * 0.00 0.00 * DuPont-2920 /t m o la r Equivalents of Active in Blood 313.77 148.55 94.20 221.74 178.99 65.22 106.52 82.61 70.29 47.10 5.07 2.90 5.80 5.07 4.35 0.72 * 0.00 0.00 * * = Below LOD (Level of Detection) -79- tanfSSzedL 0g contain SCAGBS H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Data for H-23926 DuPont-2920 Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation: 2500 1000 25 % F in Active: Mol Wt. F (g/mol): 40 19 Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor: 250 0.100 1000.0 Dose F (mmol/kg): 5.263 Molar Ratio (Active/F): 0.019 Dose F (mg/kg): 100 Rat Number Test ppm F Day in Sample Blood Group I 626448 626450 626453 626457 626460 1 1 1 1 1 0.5 0.5 0.9 0.4 a Group I 626448 626450 626453 626457 626460 5 5 5 5 5 1.4 1.4 1.0 0.9 1.4 Group II 626430 626433 626444 626449 626452 10 10 10 10 10 1.7 0.5 0.9 1.4 1.7 ppm F in Blood Minus Bkg 0.2 ppm 0.3 0.3 0.7 0.2 a 1.2 1.2 0.8 0.7 1.2 1.5 0.3 0.7 1.2 . 1.5 ppm F in Blood Normalized to 0.1 mmoles/kg Dose 0.30 0.30 0.70 0.20 a 1.20 1.20 0.80 0.70 1.20 1.50 0.30 0.70 1.20 1.50 /imolar Equivalents of Active in Blood 0.30 0.30 0.70 0.20 a 1.20 1.20 0.80 0.70 1.20 1.50 0.30 0.70 1.20 1.50 -80- Companjf Sanitized. Does not eontaln TSC CBI H-23926: Biopersistence Screening 10-Dose Oral Gavage Study in Rats_______________________________________________________DuPont-2920 Rat Number Test Day Sample ppm F in Blood ppm F in Blood Minus Bkg 0.2 ppm ppm F in Blood Normalized to 0.1 mmoles/kg Dose p m olar Equivalents of Active in Blood Group III 626435 626436 626445 626459 626572 13 13 13 13 13 0.9 0.9 0.9 3.2 0.8 0.7 0.7 0.7 3.0 0.6 0.70 0.70 0.70 0.70 0.70 0.70 3.00 3.00 0.60 0.60 Group IV 626437 626438 626443 626456 626458 24 24 24 24 24 0.4 0.3 0.8 0.8 0.7 0.2 0.1 0.6 0.6 0.5 0.20 0.20 0.10 0.10 0.60 0.60 0.60 0.60 0.50 0.50 Group V 626429 626432 626439 626442 626461 52 52 52 52 52 0.4 0.3 0.4 0.3 0.3 0.2 0.1 0.2 0.1 0.1 0.20 0.20 0.10 0.10 0.20 0.20 0.10 0.10 0.10 0.10 Group VI 626434 626441 626446 626447 626455 93 93 93 93 93 0.2 0.2 0.2 0.2 0.3 0.0 0.0 0.0 0.0 0.1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.10 0.10 a = No data because tube of blood was missing or broken ! -81 - ompaffisv Sanifeed. 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