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TRADE SECRET AR226-3161 DuPont-2931 Study Title H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Laboratory Project ID: DuPont-2931 A u t h o r : Carol Finlay, B.A. S t u d y C o m p l e t e d o n : August 29, 2000 P e r fo r m in g L a b o r a t o r y : E.I. du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 Page 1 of 83 Company Sanitised. Does not contain TSCA CBI H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. Gary W . Jepson, Ph-D. Senior Research Scientist Z S A uC 4 0 4 D ate R eview ed bv: C . Aj A / J I . U J u R jA I jA / J Judith C. Stadler, PhJD., D.A .B.T. (_/ D irecto r. G eneral T oxicology 2 $ -A U G -2 . O D ate Issued by Study D irector: LA iC . Carol Fifiay, B.A, Staff Scientist Y~ D a te -^ -2Company Sanitized. Does not contain TSCA CB1 H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 TABLE OF CONTENTS Page CERTIFICATION........................................................................................................................... .. LIST OF TABLES........................................................................................................................... .. LIST OF FIGURES......................................................................................................................... 4 LIST OF APPENDICES................................................................................................................. 4 STUDY INFORMATION................................................................................................................. STUDY PERSONNEL..................................................................................................................... 7 SUMMARY...................................................................................................................................... .. INTRODUCTION.......... ................................................................................................................. 9 MATERIALS AND METHODS....................................................................................................9 A. Test Substance and Positive Control..................................................................................... 9 B. Test Species........................................................................................................................... 9 C. Animal Husbandry.................................................................................................................9 1. Housing Environment....................................................................................................................................9 2. Feed and W ater........................................................................................................................................... .. 3. Identification............................................................... ......................................................... ; jq 4. Animal Health Monitoring Program........................................................................................................... JO D. Quarantine and Pretest.........................................................................................................10 E. Study Design........................................................................................................................... F. Assignment to Groups and Study Start............................................................................... 11 G. Dosing Material Preparation and Administration............................................................... 11 1. Test Substance................................................................................................................................. U 2. Positive Controls......................................................................................................................................... .... 3. Negative Controls....................................................................................................................................... .. H. Body Weights....................................................................................................................... 12 I. Mortality and Clinical Observations................................................................................... 12 J. Collection and Analysis of Blood and Livers..................................................................... 12 K. Treatment of Fluorine Data..................................................................................................13 RESULTS AND DISCUSSION............................................. 14 A. In-Life Toxicology............................................................................................................... 14 B. Fluorine D ata.................. 14 1. Factors Influencing Interpretation of Analysis............................................................................................14 2. Positive Controls............................................................................................................................................ 3. Test Substance........................................................................................................................................... 15 CONCLUSIONS............................................................................................................................ . RECORDS AND SAMPLE STORAGE......................................................................................16 TABLES................................................................................................................... 17 -3- Company Sanitized. Does not contain TSCA CIH H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 FIGURES....................................................................................................................................... 22 APPENDICES............................................................................................................................... 27 LIST OF TABLES Page 1. MEAN BODY WEIGHTS............................................................................................... .........................................] 8 2. MEAN BODY WEIGHT GAINS........................... ................................................................................................. 19 3. MEAN BLOOD FLUORINE LEVELS................................................................................................................... 20 4. MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DO SE................................................21 LIST OF FIGURES Page 1. MEAN BODY WEIGHTS........................................................................................................................................ 23 2. MICROMOLAR EQUIVALENTS IN RAT BLOOD............................................................................................ 24 3. MICROMOLAR EQUIVALENTS IN TEST COMPOUND AND POSITIVE CONTROLS............................26 LIST OF APPENDICES Page A. INDIVIDUAL BODY WEIGHTS.............................................................................................................................28 B. INDIVIDUAL CLINICAL OBSERVATIONS.........................................................................................................63 C. INDIVIDUAL FLUORINE LEVELS........................................................................................................................74 - 4 - Company Sanitized. Does not contain TSCA CB1 H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats STUDY INFORMATION TEST SUBSTANCE: Svnonvms/Codes: H-24042 DuPont-2931 POSITIVE CONTROL: Haskell Number: 24019 -5 C om pany S anitized. D oes noi co ntain T3CA CEI H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats STUD.Y INFORMATION (Continued) DuPont-2931 Perfluorooctanoate, ammonium salt PFOA Ammonium perfluorooctanoate Haskell Number: 24020 Known Impurities' 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 Initiated/Completed: June 13, 1999 / September 14, 1999 -6Company Sanitized. Does not contain TSC CBt H-24042: 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-2931 Sanft'*-e1d. c ^ H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 SUMMARY The objective of this study was to evaluate the potential for H-24042, when administered by gavage, to be absorbed and to accumulate in a mammalian system. Six groups of 5 male Crl:CD(SD)IGS BR rats each were given 100 mg/kg/day of H-24042. The test substance was administered to one group o f 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 of each rat from the 5-dose group. On selected days (5, 10, 13, 24, 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 of dosing and then approximately every other week 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-24042. No deaths occurred during the study. Transient alopecia, considered unrelated to test substance administration, was observed in two rats dosed with the test substance, H-24042. Rats dosed with H-24019 exhibited diarrhea, salivation, alopecia, black ocular discharge, and staining of various parts of the body during the dosing period. Rats dosed with H-24020 exhibited wet perineum and diarrhea during the dosing period. Alopecia was observed during the recovery period in rats dosed with the positive controls, H-24019 and H-24020. The negative control rats exhibited no clinical signs during the study. The mean body weights and mean body weight gains of the rats dosed with the test substance, H-24042, were comparable to the com oil negative controls and to the H-24020 positive controls. Comparison of body weights between the rats dosed with test substance and the com oil/acetone negative control and H-24019 positive control rats was complicated by the fact that there was a difference in age on test day 1 between the rats. Accounting for the age difference at study start and the expected rate of body weight gain, it appears that the mean body weights and mean body weight gains of the rats dosed with the test substance, H-24042, are comparable to the com oil/acetone negative controls and equal to or greater than the H-24019 positive controls. A steady-state for fluorine levels in whole blood was not achieved during 10 consecutive days of dosing with 100 mg/kg H-24042. An area under the curve (estimated to infinity) was calculated and normalized for fluorine content for the test substance and each positive control. The AUCINF/D for the fluorine component of the test substance, H-24042, was 6241.7, compared to AUCINF/D values of 566,479.1 and 70,789.6 for the positive controls, H-24019 and H-24020, respectively. Under the conditions of this study, administration of the test substance, H-24042, to male rats for 10 consecutive days resulted in a very low absorption and retention of fluorine in the blood. Dose-adjusted areas under the curve (AUCINF/D) for positive controls, H-24019 and H-24020, were approximately 90x and 1lx the AUCINF/D for the test substance. -8 - , not contain T9QA C o m p ly S anitized Doe H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 INTRODUCTION The objective of this study was to define the potential of H-24042 to be absorbed and to bioaccumulate in a mammalian system, as indicated by analytical determination of 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 100 mg/kg/day for the test substance was selected based on available toxicity data and the results of a rangefinding study. In the rangefinding study, a group of 5 male rats was dosed by oral gavage with H-24042 for 4 consecutive days at a dosage of 100 mg/kg/day. A group of 5 male rats was dosed with deionized water and served as controls. The rats dosed with H-24042 experienced an overall mean body weight gain of 16 grams. The control group had an overall mean body weight gain of 29 grams. All blood samples were analyzed for total fluorine content. This report contains the results of those analyses. Results from analyses of selected liver samples will be presented in a supplemental report. MATERIALS AND METHODS A. Test Substance and Positive Control The test substance, H-24042, was supplied by the sponsor as a pale amber waxy solid. 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, sensitivity, 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 o f 23 1C and a relative humidity of 50 10%. - 9 - Company iin TSCA CBl H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats 2. Feed and Water DuPont-2931 Tap water was provided ad libitum. All rats were fed PMI Nutrition International, Inc. Certified Rodent LabDiet 5002 chow. The feed is guaranteed by the manufacturer to meet specified nutritional requirements and to be free of specified contaminants. 3. Identification Prior to assignment to groups, each rat was temporarily identified by cage identification. After assignment to groups, an individual identification number was marked or tattooed on the tail of each rat. The information on the cage labels included the unique 6-digit Haskell animal number assigned to each rat. 4. Animal Health Monitoring Program As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to assure that contaminant levels are below those that would be expected to impact the scientific integrity of the study: Water samples are analyzed for total bacterial counts, and the presence 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 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. D. Quarantine and Pretest Upon arrival at Haskell Laboratory, the rats were removed from shipping cartons and quarantined for 6 days. The rats were weighed 3 times during the pretest period and examined daily for any clinically apparent signs of disease or injury. The rats were observed daily for mortality and signs of illness, injury, or abnormal behavior. On the bases of acceptable body weight gains and freedom from clinically apparent signs of disease or injury, the rats were released from quarantine by the laboratory animal veterinarian designee. - 10- contid T3CACBt ompany Sanitized. Does not  H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats E. Study Design DuPont-2931 Substance Negative Controls Com oil Com oil:acetone Positive Controls H-24019 H-24020 Test Substance H-24042 Vehicle Dosage (mg/kg) Number of Animals Not applicable 0 0 30 30 Com oil: acetone Com oil 10 20 30 30 Com oikacetone 100 30 F. Assignment to Groups and Study Start After the quarantine period, the rats were selected on the bases of adequate body weight gain, freedom from any clinical signs of disease or injury, and a body weight within 20% of the mean. The selected rats were divided by computerized, stratified randomization into 6 groups of 5 rats, so that there were no statistically significant differences among group body weight means. After assignment to groups, each rat was housed individually. The last 3 digits o f the animal number was marked or tattooed on the tail of each rat. The rats were between 7 and 9 weeks of age at the time of dosing. Dosing began on test day 1. Rats that were not assigned to the study were released for other laboratory purposes, or were sacrificed by carbon dioxide asphyxiation and discarded without pathological evaluation. G. Dosing Material Preparation and Administration 1. Test Substance It was necessary to dissolve H-24042 in acetone before suspending it in com oil. The ratio of acetone to com oil was 20:80. The amount of test substance each rat received was based on the body weight collected on each day of dosing and the suspension concentration. The dose volumes did not exceed 1 mL/100 g of body weight. The 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 of dosing and the suspension concentration. The dose volumes did not exceed 1 mL/100 g of body weight. The dosing suspensions were stirred on a magnetic stir plate throughout the dosing procedure to maintain homogeneity. -11 - Company Sanitized, Does not contain TSCA CSt H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats 3. Negative Controls DuPont-2931 Com oil and com oil:acetone (80:20) were chosen as the negative controls because they were the vehicles for the positive controls. Additionally, com oil:acetone was the vehicle for H-24042, the test substance. Each negative control rat received 1 mL of 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 of dosing. The rats were weighed weekly or every other week during the recovery period. I. Mortality and Clinical Observations Cage-site examinations to detect moribund or dead rats and abnormal behavior and appearance among rats were conducted at least once daily throughout the study. At every weighing, each rat 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 of blood was collected into EDTA tubes from the orbital sinus of 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 II III IV V VI Dosing Days Tissue Collected Sampling Time 1-5 Blood Test day 1 (2 hours post dosing) 1-5 Blood and Liver Test day 5 at sacrifice (2 hours post dosing) 1-10 Blood and Liver Test day 10 (2 hours post dosing) 1-10 Blood and Liver Test day 13 1-10 Blood and Liver Test day 24 1-10 Blood and Liver Test day 52 1-10 Blood and Liver Test day 94 Five to 10 mL of blood was collected into EDTA tubes at sacrifice. The livers were weighed. The blood from all rats was refrigerated and the livers were frozen. The blood was appropriately packaged and shipped refrigerated to Jackson Laboratory, Deepwater, New Jersey where it was analyzed for total fluorine. The total 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 of wet oxygen and swept through an oxyhydrogen flame in a closed quartz apparatus. The combustion products were collected in an 12 S5,, ,sconiato ISCACW Sanded- Oc Compaq H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 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 of fluorine biopersistence. K. Treatment of Fluorine Data Noncompartmental analysis was conducted on blood fluorine data derived from rats dosed with H-24042 using WinNonlin Version 3.0 software (Pharsight Corp, Mountain View, CA). WinNonlin software provided a means of computing derived pharmacokinetic parameters from data files including area under the curve (AUC1NF), Cmax and terminal half-life (Ti/2). The AUC1NF (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 of time. In all cases, doses were normalized to 0.1 mmole/kg for comparative purposes. The accumulation index (AI, l/(l-e'kt)) and bioaccummulation 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 of the analytical method, the background was set at 0.2 ppm fluorine. Since 0.2 ppm was the fluoride concentration limit of detection, any values listed as 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 of total blood fluorine were used as received (ppm F) from Jackson Laboratory. Fluoride ion was converted to micromolar (pM) equivalents o f active component for further comparisons. The data and descriptions of data manipulation and presentation are provided in Appendix C. - 13- Company Sanitized. Does no U U ^ i" TSCACB1 H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 RESULTS AND DISCUSSION A. In-Life Toxicology (Tables 1-2, Figure 1, Appendices A-B) No deaths occurred during the study. Transient alopecia, considered unrelated to test substance administration, was observed in 2 rats dosed with the test substance, H-24042. Rats dosed with H-24019 exhibited diarrhea, salivation, alopecia, black ocular discharge, and staining of various parts of the body during the dosing period. Rats dosed with H-24020 exhibited wet perineum and diarrhea during the dosing period. One rat dosed with H-24042 exhibited misshapen ears during the recovery 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. The mean body weights and mean body weight gains of the rats dosed with H-24042 were comparable to the com oil negative controls and to the H-24020 positive controls. Comparison of body weights between the rats dosed with the test substance and to the com oil/acetone negative control and H-24019 positive control rats was complicated by the fact that there was a difference in age on test day 1 between the rats. This difference resulted in differences in mean body weights on test day 1. The H-24042 rats were younger and lighter in weight than the com oil/acetone negative control and H-24019 positive control rats. Younger animals experience a period of rapid body weight gain. Older animals are expected to gain weight at a slower rate than younger animals. Accounting for the age difference at study start and the expected rate of body weight gain, it appears that the mean body weights and mean body weight gains of the rats dosed with the test substance, H-24042, are comparable to the com oil/acetone negative controls and equal to or greater than the H-24019 positive controls. B. Fluorine Data (Tables 3-4, Figures 2-3, Appendix C) 1. Factors Influencing Interpretation of Analysis The data used in the kinetic analysis were derived from a limited screen, and therefore several caveats and considerations are important. A couple of considerations of particular importance are (1) a single dose was used and kinetics may or may not be linear, (2) the kinetics apply only to blood, (3) steady-state may not have been achieved, and (4) the sample size is low and may impact calculation of the terminal half-life. A more complete list of considerations is shown in Appendix C. 2. Positive Controls The positive controls were H-24019 and H-24020. The H-24019 normalized pM equivalents in rat blood continued to rise throughout the dosing period and may not have reached steady-state - 14- Company Sanitized. Does not contain TSCA CBJ H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 (Figure 2A). The Cmax for H-24019 was 989.85 116.90 ppm (Mean SD) with a terminal half-life of 40.5 days. The H-24019 AI was 59.0 and the BI was 58382.2. The H-24020 normalized pM equivalents in rat blood peaked after 5 days of dosing and then decreased throughout the dosing period (Figure 2B). The Cmax for H-24020 was 518.12 44.89 ppm (Mean SD) with a terminal half-life of 8.3 days. The H-24020 AI was 12.5 and the BI was 6497.5. For each of 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-24042 normalized pM equivalents in rat blood continued to rise throughout the dosing period and did not reach steady-state (Figure 2C). The Cmax for H-24042 was 26.106 3.102 ppm (Mean SD) with a terminal half-life of 24 days. 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 H-24042 AI was 35.1 and the BI was 916.4. The total internal exposure resulting from a normalized dose was described by AUCINF/D and was the basis for comparison between H-24042 and positive controls. The AUCINF/D for the fluorine component of H-24042 was 6241.7 as compared to AUCINF/D values of 566,479.1 and 70,789.6 for H-21019 and H-24020, respectively. The data, calculations and equations are shown in Appendix C. CONCLUSIONS Rats dosed for 10 consecutive days with 100 mg/kg the test substance, H-24042, exhibited no mortality or test substance-related clinical signs o f toxicity and had mean body weights and mean body weight gains that were comparable to the negative control rats. However, the mean body weights and mean body weight gains o f rats were also comparable to the H-24020 positive controls. A steady-state for fluorine in the blood was not achieved during the 10-day dosing period. Under the conditions of this study, administration of H-24042 to male rats for 10 consecutive days resulted in a very low absorption and retention of fluorine in the blood. Dose-adjusted areas under the curve (AUCINF/D) for positive controls, H-24019 and H-24020, were approximately 90x and 1lx the AUCINF/D for the test substance. - 15 - Azed.Doe Sarfr Compaq patain TSC/k H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 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. -16- Compp.ry Sanife n contain 1B0A CBf H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 TABLES - 17- ss net coftlM TSCACB1 Company Sanitized. Do; H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 TABLE 1 MEAN BODY WEIGHTS (g) Test Days 1 2 3 4 5 6 7 8 9 10 .13 20 24 27 34 38 41 47 48 52 53 55 61 62 68 69 76 80 81 82 88 90 94 Negative Controls ComOil 229.8 234.1 241.4 250.4 259.3 266.8 271.2 281.9 285.2 295.9 321.1 350.5 378.3 407.8 - 434.5 454.9 464.7 - 487.0 505.1 - 515.4 - - - - 556.2 566.9 Com Oil:Acetone 297.6 299.6 309.4 314.3 321.5 326.0 334.9 339.2 345.2 351.7 350.7 369.8 401.0 - 411.4 - - - - 527.6 - - - -. - - 539.0 - - - - 562.2 567.8 ' - Indicates that the animal was not weighed. Positive Controls H-24019 291.5 291.5 298.3 304.1 308.6 312.7 317.5 317.3 318.4 318.9 329.1 359.7 387.9 393.9 416.9 - - - - 438.1 - - - 523.4 - - 563.4 570.7 - - 585.3 597.9 H-24020 227.5 232.4 242.0 248.9 252.4 259.8 263.3 269.8 278.5 283.9 289.1 311.3 340.9 - 402.9 - 425.0 438.2 - 465.6 - 452.3 465.8 - 470.9 - - - 499.2 - - 527.8 538.7 Test Substance H-24042 231.4 231.7 240.2 246.4 253.8 258.6 267.0 268.6 287.3 288.2 317.7 344.0 385.2 - 423.1 442.0 _ _ 467.8 480.1 _ 490.6 511.4 - _ 531.4 _ - - 531.4 578.7 - 592.0 -18 Company Sanitized. Does no- contain TSCA CBI H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats________________________________________________________ DuPont-2931 TABLE 2 MEAN BODY WEIGHT GAINS (g) Test Days 1-5 1-10 10-13 10-24 10-52 10-94 Negative Controls Com Oil Com OilAcetone 29.5 66.1 25.2 82.4 168.8 271.0 23.9 54.1 - 1.0 49.3 175.9 216.1 Positive Controls H-24019 H-24020 17.1 27.4 10.2 69.0 119.2 279.0 24.9 56.4 5.2 57.0 181.7 254.8 Test Substance H-24042 22.4 56.8 29.5 97.0 191.9 303.8 - 19- vontpan^ Sanitized, Dees not coniai 'rs c A c e i H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 TABLE 3 MEAN BLOOD FLUORINE LEVELS Test Days 1 5 10 13 24 52 94 Negative Controls Positive Controls Com Oil Com Oil:Acetone H-24019 H-24020 (PPm) (ppm) ____(PPm) (ppm) <0.2 <0.2 2.1 (0.9) 62.6 (3.2) <0.2 <0.2 48.8 (17.6) 71.7 (6.2) <0.2 0.3a (0.1 )b 61.7 (2.8) 54.2 (7.8) 0.2a (0.1) 0.6C(0.6) 64.5 (7.6) 26.6 (11.4) <0.2 0.2d 42.2 (2.8) 10.5 (3.0) 0.3a (0.1) <0.2 26.9 (2.6) 0.9 (0.2) 0.3a (0.1) <0.2 13.2 (2-1) 0.2C (0.1) Test Substance H-24042 (ppm) 1.8 (0.6) 15.6(1.2) 19.8 (2.3) 14.0(1.0) 5.3 (1.1) 2.6 (0.4) 0.9 (0.2) a Mean of 4 of the 5 values. One o f the values was below the level of detection (LOD). b Standard deviation is in parentheses. c Mean of 3 of the 5 values. Two o f the values were below the LOD. d One value. Four of the values were below the LOD. -20- Company Sanitise! I. D -=s not contain TSCA CBI H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 TABLE 4 MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE Test Days 1 5 10 13 24 52 94 Positive Controls H-24019 H-24020 pM F Equivalents pM 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) a Standard deviation is in parentheses. Test Substance H-24042 pM F Equivalents 2.16 (0.8) 20.59 (1.6) 26.11 (3.1) 18.38 (1.4) 6.80 (1.4) 3.15 (0.6) 0.90 (0.2) -21 - not co' lam t s c a c b i Company Sanitized- D3S H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 FIGURES -22- 'Coir.pany SanttfesdLEc? no? coni ,In TSCA CBI ; H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Oo T303 t03o). N<T> a. ao CcOn 3 Oroo3-f Wt 3* HC/> Mean Body Weights (g) 400 350 300 250 200 150 - 100 - 50 - % FIGURE 1 MEAN BODY WEIGHTS (g) DuPont-2931 T est Days 10 12 H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 FIGURE 2 MICROMOLAR EQUIVALENTS IN RAT BLOOD A. N o r ma l i z e d R a t Bl ood H-2401 9 |iM E q u i v a l e n t s Res u l t i n g fr om a 10- Day O ralGavage Micromolar (pM) 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 fiM 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 ral G avage Micromolar (pM) equivalents of H-24020 (positive control) in rat blood resulting from a 10-day oral gavage exposure. Values are means and error bars are standard deviation. -24- .C o m p a q SaniHz v o ss noj oonra:ri ISCA CB1 H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 FIGURE 2 (Continued) MICROMOLAR EQUIVALENTS IN RAT BLOOD C. Normalized Rat Blood H-24042 |iM Equivalents Resulting from a 10-Day O ral C avage Mean fiM Equivalents Micromolar (pM) equivalents of H-24042 (test substance) in rat blood resulting from a 10-day oral gavage exposure. Values are means and error bars are standard deviation. -25- . . . . -rtcon'.s-' i-''- , CBl c o m p a n y " ' 2" H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats_______________________________ DuPont-2931 FIGURE 3 MICROMOLAR EQUIVALENTS IN TEST COMPOUND AND POSITIVE CONTROLS -, J iS F S S F r ? - Mandj|j|?-.o:sti.v C on trol B l o o d AUCINF/D R e s u l t i n g from a 1 0 - D oes not contain TSC C! !! $3 jw i u> %*no5;. *J1 -26- H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 APPENDICES -27- Company Sanitized. Does not contain TSC A CBl H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 APPENDIX A Individual Body Weights not contain TOCACBl -28- Company Sanitized Doc H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats INDIVIDUAL BODY WEIGHTS ABBREVIATIONS: EXPLANATORY NOTES SD - sacrificed by design DuPont-2931 -29- Company S an ifesd . Doss no' contain TSCA CBI m H-24042: 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 I TEST DAYS DAY 3 DAY 4 DAY 5 627789 627801 627805 627810 627818 222.6 215.9 249.4 230.5 229.7 220.7 209.1 250.1 231.6 228.6 223.5 223.5 263.3 241.9 239.1 236.9 233.5 273.6 254.4 252.4 247.7 240.1 283.7 265.0 260.2 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 DuPont-2931 -30- Cotnpany Sanitized. D oes not c fimin TGGAC ffl H-24042: 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 270.6 303.9 280.2 312.0 303.6 274 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-2931 Company Sanitized. H-24042: 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 III TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627796 627806 627807 627809 627816 239.8 227.3 221.5 234.2 235.0 249.7 234.2 225.9 240.4 238.6 253.6 239.4 237.1 252.5 250.0 252.5 242.9 244.1 260.3 258.9 267.7 258.5 254.9 272.8 265.1 277.2 270.4 257.7 277.9 274.5 289.8 275.2 260.3 282.6 278.6 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS DAY 10 DAY 13 627796 627806 627807 627809 627816 285.9 282.8 270.7 297.9 291.8 290.1 285.8 274.7 300.2 296.4 300.0 302.8 280.7 311.9 305.7 322.7 320.3 305.2 336.2 330.2 SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13 DuPont-2931 -32- Company Sanitized. D oes not contain TSCA CB1 %% H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats_________________________ CORN OIL (NEGATIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S ANIMAL NUMBER DAY 1 DAY 2 GROU1 IV 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 D A Y 10 D A Y 13 DAY 2 0 285.0 295.4 278.1 294.3 294.6 _a 334.4 _a 377.4 _a 345.8 _a . 356.5 _a 368.7 DAY 24 365.6 416.7 378.1 388.4 407.3 SD test d ay 24 SD test d a y 24 SD test d a y 24 SD test d a y 24 SD test da y 24 # DuPont-2931 a Rat was not weighed. -33- t contain TSACBk VQpanxSanVasd. Do0 no' ANIMAL NUMBER 627792 627798 627813 627814 627815 ANIMAL NUMBER 627792 627798 627813 627814 627815 ANIMAL NUMBER 627792 627798 627813 627814 627815 DAY 1 DAY 2 CORN OIL IVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP V TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 235.8 241.1 214.8 217.5 230.1 240.8 253.4 219.2 220.5 242.2 244.3 257.6 220.5 223.7 243.8 247.9 266.1 233.2 225.2 255.7 252.5 272.9 239.8 233.8 265.0 264.4 281.9 243.2 236.7 270.0 268.1 286.2 246.8 240.6 274.1 DAY 8 DAY 9 TEST DAYS D A Y 10 D A Y 13 DAY 20 DAY 24 DAY 34 282.4 294.3 258.7 248.0 289.2 286.4 296.3 259.2 250.7 293.4 295.2 315.7 267.9 257.3 303.3 -a -a -a -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 DAY 41 DAY 47 TEST DAYS D A Y 52 456.5 470.7 395.0 358.7 462.6 482.3 496.9 407.2 372.7 487.3 496.8 517.3 416.8 386.9 505.9 SD test day 52 SD test day 52 S D t e s t .d a y 52 SD test day 52 SD test day 52 a Rat was not weighed. -34- Company Sanitised. Doe not contain TSCA CBI H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 CORN OIL (NEGATIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP VI TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627795 627811 627819 627820 627821 218.0 228.6 248.8 225.5 227.5 219.5 226.3 255.3 228.9 233.2 225.3 236.7 264.9 239.2 240.7 234.3 246.1 274.4 247.9 246.1 239.4 251.5 280.4 255.6 251.2 246.2 259.6 288.0 261.3 259.8 250.1 263.6 290.3 265.3 263.9 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS D AY 10 D A Y 13 DAY 20 D A Y 24 DA Y 34 627795 627811 627819 627820 627821 261.4 273.0 304.5 281.3 272.6 265.0 276.7 308.0 282.9 275.3 270.7 285.6 324.3 292.4 281.8 -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 ANIMAL NUMBER 627795 627811 627819 627820 627821 DAY 41 384.2 422.0 505.9 478.0 411.8 DAY 47 398.0 439.3 534.9 504.1 426.1 TEST DAYS DAY 52 DAY 55 _a 4 1 1 . 1 _a 4 5 5 . 4 _a 5 5 1 . 7 _a 5 2 9 . 7 _a 4 3 9 . 1 DAY 61 435.7 463.0 574.4 547.1 459.0 D A Y 68 440.7 473.6 588.6 558.6 463.3 # DuPont-2931 a Rat was not weighed. - 35 - Company Sanzad. Do no! con isto TSC A CSF H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER D A Y 90 D A Y 94 CORN OIL (NEGATIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S 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 S D t e s t day- 94 SD test day 94 SD test day 94 SD test d a y 94 SD test day 94 DuPont-2931 -36- Sanitized. Doe: ;not c or.btn fSCACSl Compatty H-24042: 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) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP I TEST DAYS DAY 3 DAY 4 DAY 5 337 278 299 291 302 6 4 9 5 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-2931 -37- 4P H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER' DAY 1 DAY 2 CORN OIL:ACETONE (NEGATIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S G R O U P II TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625355 625362 625367 625368 625378 280.0 290.3 301.5 312.3 309.6 282.0 294.1 307.8 318.0 306.4 293.0 303.5 315.6 326.0 327.3 297.9 308.9 320.1 336.4 328.4 306.1 313.8 327.7 343.7 333 .7 311.2 315.8 333.7 347.5 336.6 315.7 323.8 345.6 360.8 346.9 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS D A Y 10 625355 625362 625367 625368 625378 321.7 323.9 349.1 364.2 350.1 320 332 352 380 354 9 3 4 8 2 333.6 332.9 363.8 386.7 365.4 S D t e s t day- 10 SD test day 10 SD test day 10 SD test d a y 10 SD test d a y 10 # DuPont-2931 -38- not conta jn"TSCA CDl Company Sanitized. D es H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 CORN OIL:ACETONE (NEGATIVE Control) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP III TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625357 625358 625370 625384 625385 3 1 1 .9 2 8 5 .7 3 0 7 ,.9 2 9 4 .2 2 9 7 ..6 308.8 286.3 316.7 300.0 304.6 320.3 295.5 329.5 312.0 313.0 328.4 296.4 337.9 309.3 .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 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS D A Y 10 D A Y 13 625357 625358 625370 625384 625385 364.2 319.8 373.4 325.6 347.0 370.3 321.6 374.7 331.0 349.5 376.9 320.3 385.6 340.6 358.9 405.6 340.7 407.0 357.1 377.6 S D t e s t day- 13 SD test d a y 13 SD test d a y 13 SD test d a y 13 S D t e s t d a y 13 DuPont-2931 -39- Company Sanitized. Doe' not contain TSCA CSf H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 CORN OILACETONE (NEGATIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP IV TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625354 625365 625371 625376 625381 303.0 327.7 294.5 289.7 297.8 304.1 328.7 299.0 289.9 297.5 310.5 337.9 313.4 302.2 301.7 312.2 343.6 318.3 304.9 305.6 319.3 357.7 321.8 313.2 314.4 324.7 357.2 329.6 317.0 314.4 331.2 364.3 338.5 322.8 321.0 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS D A Y 10 D A Y 13 DAY 20 DA Y 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 da y 24 SD test da y 24 SD test day 24 SD test da y 24 SD test da y 24 DuPont-2931 -40- Company Sanitized. Coes no. conta. . H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER ' DAY 1 DAY 2 % C O R N O I L :A C E T O N E ( N E G A T I V E C O N T R O L ) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S 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 DAY 8 DAY 9 TEST DAYS DAY 10 D A Y 13 DAY 20 DA Y 24 DAY 27 625356 625359 625360 625372 625374 328. 8 339. 1 347. 9 344. 7 338. 0 334 . Y 346.2 354.3 348. 8 344. 6 341.3 353.6 363.4 355. 1 350.8 361. 9 372.9 381.7 373. 1 371.5 396.7 410. 0 419.8 395. 1 401. 3 _a _a _a _a _a 431.3 440. 9 465. 9 432. 1 447.2 ANIMAL NUMBER 625356 625359 625360 625372 625374 D A 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 S D t e s t day- 52 SD test d a y 52 SD test d a y 52 SD test day 52 SD test day 52 a Rat was not weighed. -41 - CowPanK. # DuPont-2931 H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats______________ CORN OIL:ACETONE (NEGATIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S ANIMAL NUMBER' DAY 1 DAY 2 GROUP VI 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 8 344.7 307.3 340.6 324.7 325.0 DAY 9 TEST DAYS DA Y 10 D A Y 13 352.7 311.9 348.2 336.0 333.7 358.1 317.2 352.6 336.9 340.7 371.7 331.1 371.5 350.1 353.5 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 D A Y 34 453.3 388.2 477.1 455.6 419.1 D A Y 52 _a _a _a _a _a TEST DAYS D A Y 76 DAY 90 D A Y 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 d a y 94 SD test d a y 94 SD t e s t d a y 94 SD test d a y 94 SD test d a y 94 DuPont-2931 a Rat was not weighed. -42- notcoHWtn -6GACBl Gompany Sanitize^. D ti H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 H-24019 (POSITIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP I TEST DAYS DAY 3 DAY 4 DAY 5 625322 625323 625336 625343 625349 290.3 285.0 316.5 288.2 303.6 283.7 285.5 313.5 281.9 295.9 291.5 290.2 320.1 286.8 308.2 298.9 290.9 327.1 291.0 310.1 298.0 294.0 329.0 293.7 318.1 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 DuPont-2931 -43 - no\1CUft|ainJ sa 4DOOS H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 H-24019 (POSITIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S G R O U P 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 D A Y 10 625320 625330 625332 625341 625350 308.5 314.0 324.1 332.4 279.8 306.3 312.6 321.8 320.3 282.5 312.1 310.1 318.3 325.6 284.3 S D t e s t day- 10 SD test d a y 10 SD test d a y 10 SD test day 10 SD test day 10 DuPont-2931 - 44- o.co n .a'.'U S C A C B l Company Sanitlzed. Does H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 H-24019 (POSITIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S 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 D A 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 S D t e s t day- 13 SD test d a y 13 SD test d a y 13 SD test d a y 13 SD t e s t d a y 13 DuPont-2931 -45 - Sanitized. D oes nul contain TSCA CBl Company H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 m H-24019 (POSITIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S 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 D A Y 10 D A Y 13 DAY 20 DAY 24 625325 625328 625338 625340 625352 318.6 352.0 287.4 347.0 316.9 321.9 351.7 291.3 352.2 322.3 ' 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 d a y 24 SD test d a y 24 SD test d a y 24 SD test d a y 24 SD test day 24 # DuPont-2931 eoniaimscftcgi - 4 6 - ponnpany. Sanitized. Dc ss noi ^% H-24042: Biopersistene Screening 10-Dose Oral Gavage Study in Rats________________________________ ANIMAL NUMBER. DAY 1 DAY 2 H-24019 (POSITIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S 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 ANIMAL NUMBER DAY 8 332.5 352.5 315.8 292.6 280.7 DAY 9 337.9 360.1 316.7 302.2 285.2 D A Y 34 D A Y 52 TEST DAYS DAY 10 D A Y 13 33 6 .1 357. 0 31 9 .3 30 5 .8 2 8 9 .3 299.6 364.3 325.8 312.0 295.8 TEST DAYS DAY 20 336.0 396.4 349.2 338.6 309.7 DA Y 24 _a _a _a _a _a DAY 27 380.3 423.3 375.2 368.8 330.4 625324 625329 625333 625334 625344 397.3 442.7 384.6 384.2 348.3 447.4 498.1 427.4 426.5 391.0 SD test day 52 SD test d a y 52 SD test day 52 SD test d a y 52 SD test day 52 # DuPont-2931 a Rat was not weighed. lTSCAC -47- ;zed . 0 o e s ^ t8nW C om paq SanU- H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER ' DAY 1 DAY 2 H-24019 (POSITIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP VI TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 # DuPont-2931 625326 625335 625346 625347 625351 313.2 301.0 290.2 266.0 310.6 317.1 303.6 293.4 275.6 310.9 325.5 302.3 300.2 287.7 321.1 330.9 310.4 309.5 300.0 329.6 336.2 315.1 313.5 308.5 338.2 336.0 299.6 318.6 316.6 341.6 293.6 326.0 326.9 340.7 ANIMAL NUMBER 625326 625335 625346 625347 625351 DAY 8 311.5 294.2 292.9 330.5 351.1 DAY 9 TEST DAYS D AY 10 D A Y 13 308.9 285.3 290.8 330.1 357.8 297.5 274.0 288.4 333.0 350.5 274.2 266.3 296.9 355.7 380.0 DAY 20 335.4 340.1 352.5 402.1 413.7 DA Y 24 _a _a _a _a _a D A Y 27 390.7 393.8 388.2 436.2 452.4 ANIMAL NUMBER 625326 625335 625346 625347 625351 D A Y 34 427.5 427.0 407.4 466.4 483.3 D A Y 52 _a _a _a _a _a TEST DAYS DAY 62 DA Y 76 497.5 506.0 485.8 568.6 559.0 540.0 538.6 523.7 617.8 596.8 D A Y 80 547.9 547.7 532.8 618.1 607.2 DA Y 90 565.2 562.1 542.4 632.6 624.0 D A Y 94 577.5 579.5 556.9 638.9 636.8 SD test d a y 94 SD test d a y 94 SD test d a y 94 SD test da y 94 SD test d a y 94 a Rat was not weighed. |tuonta>nTSCACB -48- id . DOSS w company SM2' H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627756 627767 627771 627773 627777 DAY I 227.2 227.0 219.5 246.8 225.4 DAY 2 226.4 231.8 214.7 244.4 221.4 H-24020 (POSITIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP I TEST DAYS DAY 3 DAY 4 DAY 5 233 237 226 252 232 4 9 1 7 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-2931 -49- Company Sanitized. Does not contain TSCA CBl H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats_____________________ H-24020 (POSITIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S ANIMAL NUMBER DAY 1 DAY 2 G R O U P II 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 D A Y 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 d a y 10 SD test d a y 10 SD test d a y 10 SD test d a y 10 SD test d a y 10 # DuPont-2931 TSCA CB - 5 0 - Company Samfcz H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 H-24020 (POSITIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP III 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 23 0 .8 25 4 .8 25 8 .6 24 7 .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 D A Y 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 d a y 13 SD test d a y 13 SD test d a y 13 SD test d a y 13 SD test d a y 13 DuPont-2931 -51 - % H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ____________________ ANIMAL NUMBER DAY 1 DAY 2 H-24020 (POSITIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S 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 627759 627761 627770 627779 627786 DAY 8 277.8 240.1 291.4 289.0 251.3 DAY 9 284.9 257.4 301.3 293.4 255.8 TEST DAYS DAY 10 D A Y 13 288.0 266.9 306.4 301.0 257.0 _a _a _a _a _a DAY 20 348.0 335.7 355.8 374.4 304.4 D A Y 24 380.1 359.4 379.8 406.2 326.1 S D t e s t day- 24 SD test da y 24 SD test da y 24 SD test da y 24 SD test da y 24 # DuPont-2931 a Rat was not weighed. -52- Company Sanitized. Doss not contain tS c a cal H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats__________ ANIMAL. NUMBER DAY 1 DAY 2 H-24020 (POSITIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP V TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627757 627760 627765 627772 627781 221.2 226.2 228.3 245.2 219.0 225.4 232.0 235.3 256.4 226.3 236.3 244.4 247.1 266.2 236.5 241.1 251.7 251.6 277.0 242.9 247.9 260.2 256.4 276.9 247.2 252.2 254.5 261.1 285.0 251.6 254.4 258.3 264.7 291.0 256.1 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS D A Y 10 D A Y 13 DAY 20 DA Y 24 DA Y 34 627757 627760 627765 627772 627781 269.1 262.6 271.5 300.9 258.1 276.7 280.3 282.4 307.5 266.8 279.7 287.3 288.1 317.0 271.2 -a -a -a -a 324.3 348.6 349.8 375.5 315.1 343.0 379.9 382.7 404.0 338.8 372.3 419.4 400.9 446.9 372.0 ANIMAL NUMBER D AY 41 DAY 47 TEST DAYS DA Y 52 627757 627760 627765 627772 627781 402.8 437.7 422.9 478.4 389.9 419 448 444 494 408 7 9 8 3 2 436.7 456.5 455.6 513.5 421.0 SD t e s t day- 52 SD test day 52 SD test d a y 52 SD test d a y 52 SD test day 52 DuPont-2931 a Rat was not weighed. -53- co m p an y S an itized . Do&frs e t -goplain .TSC A CB H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats __________________ H-24020 (POSITIVE CONTROL) ANIMAL NUMBER . DAY 1 DAY 2 I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP VI 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 627762 627769 627775 627778 627783 ANIMAL NUMBER 627762 627769 627775 627778 627783 DAY 8 DAY 9 285.9 302.0 286.6 244.8 256.6 299.1 309.6 296.0 250.8 259.2 DAY 41 DAY 4 7 438.7 479.7 433.2 356.8 409.6 439.9 474.6 451.1 373.5 426.9 TEST DAYS DA Y 10 D A Y 13 301.5 312.5 304.5 255.1 264.3 _a _a _a _a _a TEST DAYS DA Y 52 D A Y 55 _a 4 5 3 . 5 _a 5 1 2 .2 _a 4 6 0 . 8 _a 3 8 6 . 0 _a 4 4 9 . 0 DAY 20 356.5 386.6 353.3 294.0 311.3 DAY 61 473.0 511.4 477.4 393.3 473.8 D AY 24 381.5 414.4 377.4 320.0 340.9 DA Y 68 471.6 531.4 478.6 398.3 474.8 D AY 34 419.6 456.5 413.9 347.1 380.0 # DuPont-2931 a Rat was not weighed. - 5 4 - Com pany Sanitized. Do es noi onsn TSCA CB3  H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER D AY 81 D A Y 90 H-24020 (POSITIVE CONTROL) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S TEST DAYS D A Y 94 GROUP VI 627762 627769 627775 627778 627783 500.3 566.2 510.4 410.1 508.8 523 603 537 436 538 3 2 5 5 5 528.6 609.6 552.8 445.3 557.2 SD t e s t day- 94 SD test day 94 SD test d a y 94 SD test d a y 94 SD test d a y 94 # DuPont-2931 -55- contain ISCA CBfl Compsny Sanitized. D o-s  j* % H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats __________________________ ANIMAL NUMBER day 1 DAY 2 H-24042 (TEST SUBSTANCE) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP I TEST DAYS DAY 3 DAY 4 DAY 5 627295 627298 627300 627302 627311 256.4 218.6 225.9 244.5 238.5 257.2 215.9 225.3 237.5 236.0 265 228 237 240 240 8 6 4 8 7 271.4 232.7 246.7 247.2 247.8 278.0 241.9 259.6 257.0 257.9 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 # DuPont-2931 TSCACBl - 5 6 - ed. D oes > cPtriatn Com p-'s=""Be H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER . DAY 1 DAY 2 H-24042 (TEST SUBSTANCE) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S G R O U P II TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627283 627289 627292 627293 627309 213.3 225.3 243.9 224.9 238.8 211.7 224.4 244.8 226.8 241.8 224.3 229.7 253.6 237.9 249.0 223.4 240.2 255.4 240.3 255.3 235.3 242.6 264.8 246.0 267.3 240.2 253.1 269.3 246.6 274.8 248.1 255.7 278.0 258.4 285.5 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS D A Y 10 627283 627289 627292 627293 627309 250.3 255.4 280.4 260.3 290.1 262.1 276.3 296.9 274.4 305.8 264.4 277.6 308.6 274.2 306.6 SD test d a y 10 SD test d a y 10 SD test d a y 10 SD test d a y 10 SD test d a y 10 DuPont-2931 -57- C o m p = n ,S ^ i-D c = = H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 H-24042 (TEST SUBSTANCE) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP III TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627285 627288 627294 627301 627304 219.2 228.6 207.6 244.2 237.1 219.6 229.9 212.6 246.6 240.6 225.3 238.7 224.1 251.7 239.1 233.0 241.7 229.7 258.0 252.6 241.9 250.6 235.0 266.7 253.6 250.7 259.4 239.4 273.7 264.8 264.2 268.7 249.4 283.8 266.2 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS DAY 10 D A Y 13 627285 627288 627294 627301 627304 266.2 2-69.6 251.3 285.1 267.8 284.2 291.0 262.1 311.6 294.8 283.1 292.1 270.6 312.7 293.8 314.3 316.5 292.6 343.6 321.4 S D t e s t d a y 13 S D t e s t d a y 13 S D t e s t d a y 13 SD t e s t d a y 13 SD test d a y 13 DuPont-2931 -58- Com pany Sanitized. D o es not contain TSCA CBl H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats H-24042 (TEST SUBSTANCE) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP IV ANIMAL NUMBER DAY I DAY 2 TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627279 627282 627286 627287 627299 215.3 212.3 240.4 232.9 248.1 216.0 213.5 239.7 234.4 248.3 221.0 221.4 253.3 245.9 255.8 231.3 228.1 262.8 252.0 264.2 239.7 232.0 269.0 259.8 273.0 243.7 234.9 278.3 264.0 276.8 255.1 241.6 284.6 270.1 288.1 ANIMAL NUMBER DAY 8 DAY 9 TEST DAYS DAY 10 D A Y 13 DAY 20 DA Y 24 627279 627282 627286 627287 627299 258.0 242.9 284.0 274.1 289.5 272 258 310 294 307 6 5 6 6 2 272.3 261.0 309.8 297.8 309.3 _a _a _a _a _a 327 316 377 353 364 6 4 1 8 0 368.4 346.2 411.4 396.6 403.6 SD test day 24 SD test day 24 SD test da y 24 SD test day 24 SD test d ay 24 DuPont-2931 a Rat was not weighed. H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats % ANIMAL NUMBER 627290 627296 627306 627307 627310 ANIMAL NUMBER 627290 627296 627306 627307 627310 ANIMAL NUMBER H-24042 (TEST SUBSTANCE) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP V DAY 1 231.0 210.1 224.8 242.0 244.4 DAY 2 226.8 210.2 224.0 243.0 249.4 DAY 3 239.5 218.6 232.5 257.4 258.3 DAY 4 2 3 8 ,. 1 22 4 .9 23 9 .4 2 6 5 .4 26 0 .9 DAY 5 247.3 233.0 244.2 269.0 269.8 DAY 6 250.4 234.5 250.5 276.8 278.9 DAY 7 261.2 241.9 258.3 285.4 281.9 DAY 8 263.6 243.7 2 6 .0 285.8 282.6 DAY 9 275.0 252.8 285.3 307.1 305.8 TEST DAYS D A Y 10 D A Y 13 272.4 252.6 283.3 306.2 308.5 _a _a __a _a DAY 20 323.2 278.4 344.6 378.7 366.7 DAY 24 _a _a _a _a _a DA Y 34 385.7 360.2 445.4 462.1 454.3 DAY 38 DAY 48 TEST DAYS D A Y 52 627290 627296 627306 627307 627310 399.4 375.1 460.3 479.0 478.6 421.4 395.0 483.4 506.6 505.3 438.4 411.4 497.7 527.6 525.6 SD test d ay 52 SD test day 52 SD test d a y 52 SD test d a y 52 SD test da y 52 # a Rat was not weighed. Company SanUtact. nsl contain TSC H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 H-24042 (TEST SUBSTANCE) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP VI TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627281 627297 627303 627305 627308 243.1 221.8 236.6 254.5 216.6 237.0 219.8 242.9 255.2 220.3 247.6 229.5 244.5 266.0 228.4 247.7 228.2 251.9 278.5 244.3 251.2 241.8 259.9 279.4 246.5 255.8 244.0 26 0 ;1 293.6 251.3 267.1 250.8 268.6 302.7 259.1 ANIMAL NUMBER 627281 627297 627303 627305 627308 DAY 8 268.3 253.4 269.5 303.6 260.4 DAY 9 282.8 269.2 288.1 333.2 279.3 TEST DAYS D A Y 10 D A Y 13 282.1 268.8 289.5 327.0 281.0 _a _a _a _a _a DAY 20 333.3 310.9 320.4 424.3 341.0 DAY 24 _a _a _a _a _a D A Y 34 408.7 372.7 376.0 535.4 430.9 ANIMAL NUMBER 627281 627297 627303 627305 627308 DAY 38 432.4 393.7 392.9 559.1 449.0 DAY 48 466.2 419.2 411.7 591.6 477.4 TEST DAYS DAY 52 DAY 55 _a 480.1 _a 438.4 _a 431.3 _a 607.1 _a 495.9 D A Y 61 505.3 462.8 439.3 638.8 510.6 DAY 69 517.8 479.6 458.8 662.3 538.5 DuPont-2931 a Rat was not weighed. -61 - Compsnv Saralized. D sS u TS'AtBl H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER D A Y 82 DAY 88 H-24042 (TEST SUBSTANCE) I N D I V I D U A L B O D Y W E I G H T S (g) O F M A L E R A T S GROUP VI (Continued) TEST DAYS D A Y 94 627281 627297 627303 627305 627308 549.6 502.3 488.4 706.8 562.2 567.6 514.3 501.9 727.6 582.3 574.3 531.5 512.5 743.2 598.6 SD test SD test SD test S D ,t e s t SD test day day day day day 94 94 94 94 94 DuPont-2931 SiilatnTSr.ACBt -62- CtfapanySanttteeoj.. Doss n H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 APPENDIX B Individual Clinical Observations -63- Compsny Sanitized. contain TSCA CBl > H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Animal GROUP I N u m b e r ______ __________________ O b s e r v a t i o n ________________________ T e s t D a y 627789 627801 627805 627810 627818 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 627793 627797 627799 627800 627808 G R O U 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 lt<;otiflT6CACBl -64- CompanV S i * r f - 003snoi H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Animal GROUP IV 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 abnorma1itie s 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 -65- Company Saiv.t: ;2d. Doss net contain TSCA CSf H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Animal GROUP I N u m b e r ________________________ O b s e r v a t i o n __________ -__________________ T e s t D a y 625361 625363 625364 625380 625383 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 G R O U P II N u m b e r _________________________O b s e r v a t i o n _____________________________ T e s t D a y 625355 625362 625367 625368 625378 No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected 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 -66Compar.y Sanitized. Do ;3 no' contain TSCA C8I H-24042: Biopersistence Screening 10-Dose Orai Gavage Study in Rats DuPont-2931 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Animal GROUP IV N u m b e r _________________________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 -67- Comptny Sanitized. Dor - not contain TSCA CBI H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 H-24019 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Animal . Number 625322 625323 625336 625343 625349 GROUP I Observation No abnormalities detected No abnormalities detected No abnormalities detected NO abnormalities detected No abnormalities detected Test Day 1-5 1-5 1-5 1-5 1-5 Animal Number 625320 625330 625332 625341 625350 G R O U P 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 -68- Comp-ny Saniti 5,, -<g*contain TSC A CBt H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 H-24019 (POSITIVE 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 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 -69- .oieonMHTOt g . H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats H-24020 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS DuPont-2931 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 G R O U 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 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 H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats H-24020 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS DuPont-2931 Animal Number 627759 627761 627770 627779 627786 Animal Number 627757 627760 627765 627772 627781 Animal Number 627762 627769 627775 627778 627783 GROUP IV Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected GROUP V Observation No abnormalities detected No abnormalities detected No abnormalities detected Wet perineum No abnormalities detected Wet perineum No abnormalities detected GROUP VI Observation No abnormalities detected Diarrhea No abnormalities detected No abnormalities detected Alopecia perineum No abnormalities detected Alopecia both front paws Alopecia right front leg Test Day 1-24 1-24 1-24 1-24 1-24 Test Day 1-52 1-52 1, 3-52 2 1, 3-52 2 1-52 Test Day 1-8, 10-94 9 1-94 1-94 81, 90, 94 1-23, 94 24, 34, 41, 47, 55, 61, 74, 81, 90 -71 - contain TSCACB1 jnitizsd. Does not con Comply H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 H-24042 (TEST SUBSTANCE) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Animal GROUP I N u m b e r _________________________ O b s e r v a t i o n _____________________________ T e s t D a y 627295 627298 627300 627302 627311 No abnormalities detected No abnormalities detected No abnorma1ities detected No abnormalities detected No abnorma1it ies detected 1-5 1-5 1-5 1-5 1-5 Animal Number 627283 627289 627292 627293 627309 G R OUP 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 627285 627288 627294 627301 627304 GROUP III Observation No abnormalities detected Alopecia, abdomen No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-3, 5-13 4-10 1-13 1-13 1-13 1-13 H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 H-24042 (TEST SUBSTANCE) 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 627279 627282 627286 627287 627299 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 627290 627296 627306 627307 627310 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 627281 627297 627303 627305 627308 GROUP VI Observation No abnormalities detected No abnormalities detected No abnormalities detected Misshapen ears No abnormalities detected No abnormalities detected Alopecia right front leg Test Day 1-94 . 1-94 1-82 88, 94 1-94 1-34, 61-94 38, 48, 55 H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 APPENDIX C Individual Fluorine Levels -74Co OV'.!?""' 1SCA H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 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 Wi 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 o f Active [mmol/kg] / Dose Active [mmol/kg]) x Formulation Dose -75- Compsny Sanitise n - tot CO'r.tain TSCA C31 H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 TERMS AND CALCULATIONS Individual Animal Measurement: ppm F in blood The ppm fluoride measured in blood Individual Animal Calculations: ppm F in Blood minus The ppm fluoride measured in plasma minus the background fluoride Bkg 0.2 ppm 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/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) pmolar equivalents of active in blood The pmolar [pmol/L] concentration of fluorine containing compound in plasma based on the ppm fluorine in plasma normalized to 0.1 mmol/kg active dose. This assumes that all plasma fluorine is derived from the fluorine-containing component in the formulation. Note: 1 ppm - 1 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 pmol/mmol -76- Coc., -t H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 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 - 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 of individual components - Background plasma 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 -77- TSCACBl ,dccp net contain C o m p ly Sanii-S H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Data for H- 24019 DuPont-2931 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 pmolar Equivalents of Active in Blood 3.98 5.47 11.93 11.93 13.42 12.31 16.92 36.92 36.92 41.54 255.96 187.87 191.35 389.15 183.39 792.31 581.54 592.31 1204.62 567.69 325.04 302.67 299.69 312.61 287.76 1006.15 936.92 927.69 967.69 890.77 -78- COfOPEOVSSn lntS C ^ cSl r.c^c0 H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Rat Number Test ppm F Day in Sample Blood Group III 625321 625327 625342 625345 625348 13 13 13 13 13 77.2 61.5 64.6 57.0 62.4 Group IV 625325 625328 625338 625340 625352 24 24 24 24 24 40.3 46.3 43.2 39.1 41.9 Group V 625324 625329 625333 625334 625344 52 52 52 52 52 24.7 29.8 27.3 29.1 23.8 Group VI 625326 625335 625346 625347 625351 94 94 94 94 94 12.4 16.4 13.1 11.0 11.6 ppm F in Blood Minus Bkg 0.2 ppm 77.0 61.3 64.4 56.8 62.2 40.1 46.1 43.0 38.9 41.7 24.5 29.6 27.1 28.9 23.6 12.2 16.2 12.9 10.8 11.4 ppm F in Blood Normalized to 0.1 mmoles/kg Dose 382.69 304.66 320.07 282.30 309.13 199.30 229.12 213.71 193.33 207.25 121.77 147.11 134.69 143.63 117.29 60.63 80.51 64.11 53.68 56.66 DuPont-2931 pmolar Equivalents of Active in Blood 1184.62 943.08 990.77 873.85 956.92 616.92 709.23 661.54 598.46 641.54 376.92 455.38 416.92 444.62 363.08 187.69 249.23 198.46 166.15 175.38 ' H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Data for H- 24020 DuPont-2931 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 ppm F Day in Sample 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 pmolar 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 - 8 0 - conlsir.TSCA CSl C o m p ly Santi; ,d. Dec-' H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Rat Number Test ppm F Day in Sample 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-2931 pmolar 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 o f Detection) H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Data for H-24042 DuPont-2931 Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation: 531 100 100 % F in Active: Mol Wt. F (g/mol): 75 19 Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor: 100 0.188 53.1 Dose F (mmol/kg): 3.947 Molar Ratio (Active/F): 0.048 Dose F (mg/kg): 75 Rat Number Test ppm F Day in Sample Blood Group I 627295 627298 627300 627302 627311 1 1 1 1 1 2.1 2.1 2.1 2.1 0.7 Group I 627295 627298 627300 627302 627311 5 5 5 5 5 13.9 15.3 15.4 16.5 17.1 Group II 627283 627289 627292 627293 627309 10 10 10 10 10 20.6 22.5 19.7 16.1 20.0 ppm F in Blood Minus Bkg 0.2 ppm 1.9 1.9 1.9 1.9 0.5 13.7 15.1 15.2 16.3 16.9 20.4 22.3 19.5 15.9 19.8 . ppm F in Blood Normalized to 0.1 mmoles/kg Dose 1.01 1.01 1.01 1.01 0.27 7.27 8.02 8.07 8.66 8.97 10.83 11.84 10.35 8.44 10.51 pmolar Equivalents of Active in Blood 2.53 2.53 2.53 2.53 0.67 18.27 20.13 20.27 21.73 22.53 27.20 29.73 26.00 21.20 26.40 -82- H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 Group III 627285 627288 627294 627301 627304 13 13 13 13 13 15.5 13.0 14.5 13.3 13.6 15.3 12.8 14.3 13.1 13.4 8.12 20.40 6.80 17.07 7.59 19.07 6.96 17.47 7.12 17.87 Group IV 627279 627282 628286 627287 627299 24 24 24 24 24 6.4 5.8 6.0 4.0 4.3 6.2 5.6 5.8 3.8 4.1 3.29 8.27 2.97 7.47 3.08 7.73 2.02 5.07 2.18 5.47 Group V 627290 627296 627306 627307 627310 52 52 52 52 52 1.9 2.3 2.9 2.9 2.8 1.7 2.1 2.7 2.7 2.6 0.90 2.27 1.12 2.80 1.43 3.60 1.43 3.60 1.38 3.47 Group VI 627281 94 0.6 0.4 0.21 0.53 627297 94 0.9 0.7 0.37 0.93 627303 94 0.9 0.7 0.37 0.93 627305 94 1.1 0.9 0.48 1.20 627308 94 0.9 0.7 0.37 0.93 M -83 - Corn?