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AR226-3155 TRADE SECRET Study Title H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Laboratory Project ID: DuPont-2923 DuPont-2923 AUTHOR: Carol Finlay, B.A. STUDY COMPLETED ON; July 27,2000 PERFORMING LABORATORY: E.I. du Font de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 t^^^l WORK REQUEST NUMBER: I--------| J "<A SERVICE CODE NUMBER:B--------I Page 1 of 80 Company Sanitized. Does not contain TSCA CB{ H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. Reviewed by: Gary W. Jepson, Ph.D. Senior Research Scientist yi Tu. L i-ooo Date Reviewed by: A^dJ^-. Q^ctc^jL C. /Judith C. Stadler, Ph.D., D.A.B.T. y Director, General Toxicology ^-^UL-iOoo Date Issued by Study Director; ^ / ^ j / ^ ^ Caroiyinlay, B.A. ([ Staff Scientist ^LJ^LL^^ 3ate -2- Company SaiiiEiZbti. Lioes i.ot contain 'i SCA CB( H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 TABLE OF CONTENTS Page CERTIFICATION........................................................................................................................^ LIST OF TABLESLIST OF FIGURES. LIST OF APPENDICES...............................................................................................................4 STUDY INFORMATION .............................................................................................................5 STUDY PERSONNEL...................................................................................................................? SUMMARY ....................................................................................................................................8 INTRODUCTION..........................................................................................................................? MATERIALS AND METHODS ..................................................................................................9 A. Test Substance and Positive Control....................................................................................9 B. Test Species .........................................................................................................................9 C. Animal Husbandry.............................................................................................................10 1. Housing Environment............................................................................................................................10 2. Feed and Water.......................................................................................................................................10 3. 10 Identification.......................................................................................................................................... 4. Animal Health Monitoring Program....................................................................................................... 10 D. Quarantine and Pretest.......................................................................................................11 E. Study Design......................................................................................................................11 F. Assignment to Groups and Study Start..............................................................................11 G. Dosing Material Preparation and Administration..............................................................11 1. Test Substance........................................................................................................................................11 2. Positive Controls.................................................................................................................................... 12 3. Negative Controls...................................................................................................................................12 H. Body Weights.....................................................................................................................12 I. Mortality and Clinical Observations..................................................................................12 J. Collection and Analysis of Blood and Livers ....................................................................12 K. Treatment of Fluoride Data................................................................................................ 13 RESULTS AND DISCUSSION ................................................................................................14 A. In-Life Toxicology.............................................................................................................14 B. Fluorine Data .....................................................................................................................14 1. Factors Influencing Interpretation of Analysis .......................................................................................14 2. Positive Controls.................................................................................................................................... 15 3. Test Substance......................................................................................................................................15 CONCLUSIONS ..........................................................................................................................15 RECORDS AND SAMPLE STORAGE ....................................................................................15 TABLES........................................................................................................................................16 Company Sanitized. Doss not ccnSasn TSCA CB( H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 FIGURES......................................................................................................................................21 APPENDICES ..............................................................................................................................25 LIST OF TABLES Page 1. MEANBODY WEIGHTS...................................................................................................................................17 2. MEAN BODY WEIGHT GAINS ........................................................................................................................ 18 3. MEAN BLOOD FLUORINE UEVELS......................................................................................,.........................19 4. MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE................................................20 LIST OF FIGURES Page 1. MEANBODY WEIGHTS ...................................................................................................................................22 2. MICROMOLAR EQUIVALENTS EN RAT BLOOD..........................................................................................23 LIST OF APPENDICES Page A. INDIVIDUAL BODY WEIGHTS .......................................................................................................................26 B. INDIVIDUAL CLINICAL OBSERVATIONS....................................................................................................60 C. ANALYSIS OF BLOOD FLUORIDE DATA.....................................................................................................71 -4- Coirspany Sanitized. Does not contain TSCA CSE H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats STUDY INFORMATION TEST SUBSTANCE; Synonyms/Codes,^ H-23961 DuPont-2923 Haskell Number: 24019 a^i,^. -5Comp^y Doss ,-.ot contain 73CA CBE H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Composition Known Impurities: Unknown POSITIVE CONTROL: ( Substance Tested: DuPont-2923 Haskell Number: 24020 Compositio: Known Impurities: Unknown 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: May 30, 1999 / August 30, 1999 0P, S,,,,, ^ ^^ ^ ^ clp"' ""------ - ------------ .... CS, H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats STUDY PERSONNEL Study Director: Management: Primary Technician: Carol Finlay, B.A. Judith C. Stadler, Ph.D., D.A.B.T. Richard P. Mathena Blood Fluorine Data Analysis: Gary W. Jepson, Ph.D. Management: Matthew S. Bogdanffy, Ph.D., D.A.B.T. Toxicology Report Preparation: Wanda F. Dinbokowitz Laboratory Veterinarian: Wanda L. West, D.V.M., A.C.L.A.M. DuPont-2923 -7- Company Sanitized. Does not contain TSCA CBi H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 SUMMARY The objective of this study was to evaluate the potential for H-23961, 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 exposed to 1000 mg/kg/day of H-23961. The test substance was administered to one group of five rats for 5 consecutive days and to 5 groups for 10 days. Approximately two hours after the first dose, blood was collected from the orbital sinus of each rat from the 5-dose group. On selected days (5,10,13, 24, 52,93/94) 5 rats per group were euthanized and the blood and livers were collected. Body weights and clinical signs were recorded on each day of dosing and then approximately every other week during the recovery period. Additionally, 2 negative controls, corn oil and corn oiVacetone (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-23961. No compound-related clinical signs of toxicity were observed in the rats dosed with H-23961. Rats dosed with a positive control material, H-24019, exhibited diarrhea, salivation, alopecia, black ocular discharge, and staining of various parts of the body during the dosing period. Rats dosed with H-24020, the other positive control substance, exhibited wet perineum and diarrhea during the dosing period. Alopecia was observed during the recovery period for rats dosed with H-24019 and H-24020. The negative control rats exhibited no clinical signs during the study. Comparison of body weights was complicated by a difference in age on test day 1 between the rats dosed with the test substance and those dosed with the positive or negative controls. Accounting for the age difference at study start and the expected rate of body weight gain, the mean body weights and mean body weight gains of the rats dosed with H-23961 were comparable to the negative controls and equal to or greater than the positive controls. The H-23961 normalized fiM equivalents in the rat blood were highly variable and near the limit of detection. Due to the variability of the data and the small sample size, no terminal half-life, AI, BI, or AUCINP could be determined. However, the H-23961 Cmax was very low (1.5 ppm) when compared to the H-24019 (990 ppm) and H-24020 (518 ppm) positive control values.Under the conditions of this study, administration of H-23961 to male rats for 10 consecutive days resulted in minimal absorption and retention of fluorine in the blood. ^=^%^^, H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 INTRODUCTION The objective of this study was to define the potential of H-23961 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 two positive controls that were materials previously shown to bioaccumulate in mammals. The daily dosage for the test substance was selected based on available toxicity data and on the results of a rangefinding study. In the rangefinding study, a group of 5 male rats was dosed by oral gavage with H-23961 at a dosage of 2000 mg/kg for 5 consecutive days. A.group of 5 male rats was dosed with deionized water for 5 consecutive days and served as controls. The rats dosed with H-23961 experienced an overall mean body weight gain of 24 grams. The control group had an overall mean body weight gain of 27 grams. A dosage of 1000 mg/kg was selected for the limit dosage for this project. The limit dosage of 1000 mg/kg was chosen for the main study and was expected to produce less than a 10% difference in mean body weight over 10 days when compared to controls. All blood samples were analyzed for total fluorine content. This report contains the results of those analyses. Results from analyses of selected liver samples will be presented in a supplemental report. MATERIALS AND METHODS A. Test Substance and Positive Control The test substance, H-23961, was supplied by the sponsor as an 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 of the study. No evidence of instability, such as a change in color or physical state, was observed. B. Test Species Male Cri:CD(SD)IGS BR rats were received from Charles River Laboratories, 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. -9- Company Sanitized. Does not contain TSCA CB! H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 C. Animal Husbandry 1. Housing Environment Rats were housed singly in stainless steel, wire-mesh cages suspended above cage boards. Animal rooms were maintained on an approximate 12-hour light/dark cycle (fluorescent light) and at a temperature of 23 1C and a relative humidity of 50 10%. Occasional excursions outside the accepted ranges were minor and did not affect the study. 2. Feed and Water Tap water was provided ad libitum. All rats were fed PMI Nutrition International, me. 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 of coliforms, lead, ' and other contaminants. Peed 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. -10- Company Sanitized. Does not contain TSCA CSi H-23961: B iopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 D. Quarantine and Pretest Upon arrival at Haskell Laboratory, the rats were removed from shipping cartons and quarantined for 6 days. The rats were weighed 3 times during the pretest period and examined daily for any clinically apparent signs of disease or injury. The rats were observed daily for mortality and signs of illness, injury, or abnormal behavior. On the bases of acceptable body weight gains and freedom from clinically apparent signs of disease or injury, the rats were released from quarantine by the laboratory animal veterinarian or designee. E. Study Design Substance Negative Controls Corn oil Corn oihacetone Positive Controls H-24019 H-24020 Test Substance H-23961 Vehicle Not applicable Dosage (mg/kg) Number of Animals 0 30 0 30 Corn oil: acetone 10 30 Corn oil 20 30 None 1000 30 F. Assignment to Groups and Study Start After the quarantine period, the rats were selected on the bases of adequate body weight gain, freedom from any clinical signs of disease or injury, and a body weight within 20% of the mean. The selected rats were divided by computerized, stratified randomization into 6 groups of 5 rats, so that there were no statistically significant differences among group body weight means. After assignment to groups, each rat was housed individually. The last 3 digits of the animal number was marked or tattooed on the tail of each rat. The rats were between 7 and 9 weeks of age at the time of dosing. Dosing began on test day 1. Rats that were not assigned to the study were released for other laboratory purposes, or were sacrificed by carbon dioxide asphyxiation and discarded without pathological evaluation. G. Dosing Material Preparation and Administration 1. Test Substance H-23961 was dosed as received. The amount of test substance each rat received was based on the body weight collected on each day of dosing and the test substance density of 1050 mg/mL. The test substance was stirred on a magnetic stir plate throughout the dosing procedure. -11- Company Sanitized. Does not contain TSCA CBi H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 2. Positive Controls The solid positive control materials were suspended as emulsions in their respective vehicles. Corn oil was used as the vehicle for H-24020. It was necessary to dissolve H-24019 in acetone before suspending it in corn oil. The ratio of acetone to corn oil was 20:80. The amount each rat received was based on the body weight collected on each day of dosing and the suspension concentration. The dose volumes did not exceed 1 mL/100 g of body weight. The dosing suspensions were stirred on a magnetic stir plate throughout the dosing procedure to maintain homogeneity. 3. Negative Controls Corn oil and corn oihacetone (80:20) were chosen as the negative controls because they were the vehicles for the positive controls. Each negative control rat received 1 mL of corn oil or corn oihacetone. 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 positive and negative control rats were weighed weekly or every other week during the recovery period. The rats dosed with H-23961 were weighed 3 weeks after the beginning of the recovery period and then weekly or every other week thereafter. I. Mortality and Clinical Observations Cage-site examinations to detect moribund or dead rats and abnormal behavior and appearance among rats were conducted at least once daily throughout the study. At every weighing, each rat were individually handled and examined for abnormal behavior and appearance. J. Collection and Analysis of Blood and Livers Approximately 2 hours after the first dose, 1-2 mL of blood was collected into EDTA tubes from the orbital sinus of each rat from Group 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: -12- Company Sanitized. Does ^t contain TSCA CBi H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 Group I I n ffl 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 93/94 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 by using a Wickbold torch combustion method, followed by analysis with a fluoride ion selective electrode. The liquid blood was decomposed or volatilized in the presence of wet oxygen and swept through an oxyhydrogen flame in a closed quartz apparatus. The combustion products were collected in an aqueous absorbing solution and analyzed using a fluoride ion selective electrode. The analytical data (ppm P in each sample) was supplied to Haskell Laboratory for evaluation of fluorine biopersistence. K. Treatment of Fluoride Data Noncompartmental analysis was conducted on blood fluorine data derived from rats dosed with H-23961 by using WinNonlin Version 3.0 software (Pharsight Corp, Mountain View, CA). WinNonlin software provided a means of computing derived pharmacokinetic parameters from data files including area under the curve (AUCINF), Cmax and terminal half-life (Ti/z). The AUCINF (concentration x time) represents the area under the blood concentration curve from the time of dosing extrapolated to infinity. The maximum observed concentration was Cmax (concentration). The points included in determination of the terminal half-life were selected manually and given in units of time. Since the dosages and fluorine content for each positive control and the test material varied, all doses were normalized to 0.1 mmole/kg for comparative purposes. The accumulation index (AI, l^l-e'^)) and bioaccumulation index (BI, Cmax x AI) were calculated and reported but not further 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 <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 form analysis of total blood fluorine were used as received (ppm F) from Jackson Laboratory. Fluoride ion was converted to -13- Company Sanitised. Does hot contain TSCA CBt H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 micromolar (juM) equivalents of active component for further comparisons. The data and descriptions of data manipulation and presentation are provided in Appendix C. RESULTS AND DISCUSSION A. In-Life Toxicology (Tables 1 and 2; Figure 1, Appendices A and B) No deaths occurred during the study. No compound-related clinical signs oftoxicity were observed in the rats dosed with H-23961. One rat exhibited alopecia of the leg during the dosing period. This clinical sign is not considered to be test substance-related since it was only seen in one animal. Another rat dosed with H-23961 exhibited staining around the eye and broken or chipped teeth on test day 34. These clinical signs were probably caused by the rat's teeth becoming caught on the cage. Rats dosed with H-24019 exhibited diarrhea, salivation, alopecia, black ocular discharge, and staining of various parts of the body during the dosing period. Rats dosed with H-24020 exhibited wet perineum and diarrhea during the dosing period. Alopecia was observed during.the recovery period for rats dosed with H-23961, 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 I 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-23961, were older and heavier in weight than the corn oil negative control and H-24020 positive control rats, but younger and lighter in weight than the corn oiVacetone negative control and H-24019 positive control rats. Accounting for the age difference at study start and the expected rate of body weight gain, the mean body weights and mean body weight gains of the rats dosed with H-23961 was comparable to the negative controls and equal to or greater than the positive controls. B. Fluorine Data (Tables 3 and 4; Figure 2; 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. -14- Company Sanitized. Does not contain TSCA CBg H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 2. Positive Controls The positive controls were H-24019 and H-24020. The H-24019 normalized juM equivalents in rat blood continued to rise throughout the dosing period and may not have reached steady-state (Figure 2A). The Cmax for H-24019 was 989.85 116.90 ppm (Mean SD) with a terminal half-life of 40.5 days. The H-24019 AI was 59.0 and the BI was 58382.2. The H-24020 normalized (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 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 of them occurring post-dose. The small sample size and analytical variability should be taken into account when using the derived terminal half-life for comparative. purposes. The total internal exposure resulting from a normalized dose was described by AUCINF/D and was the basis for comparison between positive controls and the test material. The AUCINF/D for the fluorine component was 566,479.1 and 70,789.6 for H-24019 and H-24020, respectively. 3. Test Substance The H-23961 normalized juM equivalents in rat blood were highly variable and near the limit of detection (Figure 2C). The Cmax for H-23961 was 1.464 0.787 ppm (Mean SD). Due to the variability of the data and the small sample size, no terminal half-life, AI, BI, or AUCINF could be determined. However, the H-23961 Cmax of 1.464 0.787 ppm was very low when compared to the H-24020 and H-24019 positive control values of 518 44 ppm and 990 117 ppm, respectively. The data, calculations and equations are shown in Appendix C. CONCLUSIONS Rats dosed for 10 consecutive days with 1000 ing/kg H-23961 exhibited no mortality or clinical signs of toxicity and had mean body weight gains that were comparable to the negative control rats. Due to the variability of the blood fluoride data and the small sample size, no terminal halflife, AI, BI, or AUCINF could be determined. However, the H-23961 Cmax was very low (1.5 ppm) when compared to the H-24019 (990 ppm) and H-24020 (518 ppm) positive control values. Under the condition of this study, administration of H-23961 to male rats for 10 consecutive days resulted in minimal absorption and retention of fluorine in the blood. 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. - 15- Company Sanitized. Does not contain TSCA CBi H-23961: B iopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 TABLES -16- Company Sanitized. Does noi contain TSCA CBi H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 TABLE 1 MEAN BODY WEIGHTS Test Days 1 2 3 4 5 6 7 8 9 10 13 20 24 27 34 41 47 48 52 55 61 62 68 69 75 76 80 81 83 89 90 93 94 Negiitive Controls Corn Oil 229.8 234.1 241.4 250.4 259.3 266.8 271.2 281.9 285.2 295.9 321.1 350.5 378.3 Corn OiLAcetone 297.6 299.6 309.4 314.3 321.5 326.0 334.9 339.2 345.2 351.7 350.7 369.8 401.0 - - 407.8 434.5 454.9 411.4 - - - 464.7 487.0 505.1 527.6 - - - 515.4 - - - - - - 539.0 - - - - - - - 5j0.^ - ^5u6-2w..2jj 5^6\j\6j..^9 ^56^7...8- Positive Controls H-24019 291.5 291.5 298.3 304.1 308.6 312.7 317.5 317.3 318.4 318.9 329.1 359.7 387.9 393.9 416.9 - - H-24020 227.5 232.4 242.0 248.9 252.4 259.8 263.3 269.8 278.5 283.9 289.1 311.3 340.9 - 402.9 425.0 438.2 - - 438.1 - - 523.4 - 465.6 452.3 465.8 - 470.9 - - - 563.4 570.7 - - - 499.2 - - 585.3 -- -- - - 527.8 597.9 538.7 a The rats were sacrificed a day early because of a laboratory event on test day 94. Indicates that the animal was not weighed. Test Substance H-23961 241.0 247.3 255.9 262.1 270.2 277.9 283.8 290.9 297.6 304.3 336.7 - 381.7 - 415.8 - - 473.4 482.8 - - 495.7 - 513.2 529.4 - - - 541.0 551.5 - 561.7' - - 17- Company Sanitised. Does not conia.n TSCA CBi H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 TABLE 2 MEAN BODY WEIGHT GAINS Test Days 1-5 1-10 10-13 10-24 10-52 10-93/94 Negative Controls Corn Oil Corn OihAcetone 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 17.1 27.4 10.2 69.0 119.2 279.0 H-24020 24.9 56.4 5.2 57.0 181.7 254.8 Test Substance H-23961 29.2 63.3 32.4 77.4 178.5 257.4 10 _ Company Sanitized. Does noS contain TSCA CB? H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 TABLES MEAN BLOOD FLUORINE LEVELS Test Days 1 5 10 13 24 52 94 Negative Controls Corn Oil ppm <0.2 <0.2 <0.2 0.2s (0.1) <0.2 O.S^O.l) OJ'CO.l) (^om OihAcetone ppm <0.2 <0.2 0.3^0.1)'' 0.6 (0.6) 0.2'1 <0.2 <0.2 Positive Controls H-24019 ppm 2.1 (0.9) 48.8 (17.6) 61.7 (2.8) 64.5 (7.6) 42.2 (2.8) 26.9 (2.6) 13.2 (2.1) H-24020 ppm 62.6 (3.2) 71.7 (6.2) 54.2 (7.8) 26.6 (11.4) 10.5 (3.0) 0.9 (0.2) 0.2 (0.1) a Mean of 4 of the 5 values. One of the values was below the LOD. b Standard deviation is in parentheses. c Mean of 3 of the 5 values. Two of the values were below the LOD. d One value. Pour of the values were below the LOD. e Mean of 2 of the 5 values. Three of the values were below the LOD. Test Substance H-23961 ppm 1.8 (0.9) 0.7 (0.1) 1.5 (0.4) 0.5 (0.2) 0.3 (0.1) 0.3 (0)6 0.5 (0.1) -19- Company Samtized. Does not contain TSCA CBI H-23961: B iopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 TABLE 4 MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE Test Days Positive Controls Test Substance H-24019 ^M F Equivalents H-24020 pM F Equivalents H-23961 jitM F Equivalents 1 5 10 13 24 52 93/94 28.92 (13.3)2 747.69 (271.5) 945.85 (43.5) 989.85(116.9) 645.54 (42.9) 411.38 (40.6) 195.38 (32.5) - - , 89.28 (23.4) 518.12(44.9) 391.01 (56.8) 191.45 (82.7) 74.35 (22.1) 4.64 (1.1) 0.24 (0.4) 1.46 (0.79) 0.47 (0.08) 1.16 (0.32) 0.24" (0.14) 0.07 (0.08) OW (0.00) 0.25 (0.08) a Standard deviation is in parentheses. b Mean of 3 of the 5 values. Two of the values were below the LOD. c Mean of 2 of the 5 values. Three of the values were below the LOD. Company Sanit-zed. Does not contain TSCA CB( H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 FIGURES -21- Company Sanitized. Does not contain TSCA CB( H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats 400 350 -\ 300 -\ I 250 -^ I 200 -\ n 150 -} 100 -^ 50 ^ FIGURE 1 MEAN BODY WEIGHTS ----Negative Control (Co --B-- Negative Control (Co --A--Positive Control H-2 --x--Positive Control H-2 --a^-Test Substance H-23 TestDays 10 12 -22- Company Sanitized. Does not contain TSC H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 FIGURE 2 MICROMOLAR EQUIVALENTS IN RAT BLOOD A. Normalized Rat Blood H-24019 ftM Equivalents Resulting from a 10Oral Gavage Micromolar OaM) 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. Normalized Rat Blood H-24020 (iM Equivalents Resulting from a 10-Day 0 ralG avage Micromolar (^iM) equivalents ofH-24020 (positive control) in rat blood resulting from a 10-day oral gavage exposure. Values are means and error bars are standard deviation. -23- Company s.. ^.-.".""^""""^08' H-23961: B iopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 C. Normalized Rat Blood H-2 3961 ftM Equivalents Resulting from a 10-Day 0 ralG avage 10 20 30 40 60 70 80 90 Micromolar QxM) equivalents ofH-23961 (test substance) in rat blood resulting from a 10-day oral gavage exposure. Values are means and error bars are standard deviation. .24- Company Sanitised. Does not contain TSC-A CB1 H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 APPENDICES -25- Company Sanitized. Does noS contain TSCA CBI H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 APPENDIX A Individual Body Weights -26- Company Sanitized. Does nolcositeiEl TSCACBI H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats INDIVIDUAL BODY WEIGHTS ABBREVIATIONS: SD - sacrificed by design EXPLANATORY NOTES DuPont-2923 -27- Company Sanitized. Does not contain TSCA CB1 H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats' ANIMAL NUMBER 627789 627801 627805 627810 627818 DAY 1 222.6 215.9 249.4 230.5 229.7 DAY 2 220.7 209.1 250.1 231.6 228.6 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP I DAY 3 DAY 4 DAY 5 223.5 223.5 263.3 241.9 239.1 236.9 233.5 273.6 254.4 252.4 247.7 240.1 283.7 265.0 260.2 3D test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 -28- Companysanifeed.ooes no{ contain H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS GROUP II TEST E1AYS DAY 3 DAY 4 DAY 5 DAY 6 . DAY 7 627793 627797 627799 627800 627808 ANIMAL NUMBER 627793 627797 627799 627800 627808 214 .8 239 .9 228 .9 246 .9 235 .6 DAY 8 270 .6 303 .9 280 .2 312 .0 303 .6 224 .4 245 .9 231 .4 252 .8 241 .6 DAY 9 274 .9 305 .1 284 .3 315 .4 305 .7 232.1 257.3 242.3 265.2 250.1 243.1 267.5 246.2 279.3 262.1 249 .9 280 .7 258 .9 283 .6 270 .4 TEST DAYS DAY 10 283.5 324.2 294.7 331.3 321.8 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 257 .0 288 .0 261 .5 295 .5 284 .1 262.0 290.9 266.4 300.1 287.4 -29- Company Sanitized. Does not contain TSCA H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627796 627806 627807 627809 627816 ANIMAL NUMBER 627796 627806 627807 627809 627816 DAY 1 239 .8 227 .3 221 .5 234 .2 235 .0 DAY 2 249 .7 234 .2 225 .9 240 .4 238 .6 DAY 8 285 .9 282 .8 270 .7 297 .9 291 .8 DAY 9 290 .1 285 .8 274 .7 300 .2 296 .4 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS GROUP III TE;3T r )AYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 253 .6 239 .4 237 .1 252 .5 250 .0 252 .5 242 .9 244 .1 260 .3 258 .9 267.7 258.5 254.9 272.8 265.1 277. 2 270. 4 257. 7 277. 9 274. 5 289 .8 275 .2 260 .3 282 .6 278 .6 TEST DAYS DAY 10 DAY 13 300 .0 302 .8 280 .7 311 .9 305 .7 322 .7 320 .3 305 .2 336 .2 330 .2 SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13 .30- Company Sanitized. Does not contain TSCA H-23961: 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 IV TEST r )AYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627791 627794 627804 627812 627817 ANIMAL NUMBER 627791 627794 627804 627812 627817 231 .1 224 .4 224 .7 221 .9 233 .5 DAY 8 274 .0 286 .1 267 .2 278 .2 277 .8 235 .4 233 .0 228 .8 231 .5 231 .3 'DAY 9 279 .1 289 .5 270 .6 282 .7 280 .4 241.2 238.1 230.6 236.3 229.0 246.8 247.8 243.0 245.7 244.8 TEST DAYS DAY 10 DAY 13 285.0 a 295.4 a 278.1 a 294.3 --a 294.6 -a 255.9 260.0 251.7 255.5 255.4 DAY 20 334.4 377.4 345.8 356.5 368.7 262 .6 267 .4 252 .9 264 .9 266 .4 268.4 270.1 259.5 269.5 270.0 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 a Rat was not weighed. -31- Company Sanitized. Does not contain TSC H-23961: 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 E>AYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627792 627798 627813 627814 627815 ANIMAL NUMBER 235 .8 241 .1 214 .8 217 .5 230 .1 DAY 8 240 .8 253 .4 219 .2 220 .5 242 .2 DAY 9 244.3 257.6 220.5 223.7 243.8 247.9 266.1 233.2 225.2 255.7 TEST DAYS DAY 10 DAY 13 252 .5 272 .9 239 .8 233 .8 265 .0 DAY 20 264 .4 281 .9 243 .2 236 .7 270 .0 DAY 24 268.1 286.2 246.8 240.6 274.1 DAY 34 627792 627798 627813 627814 627815 ANIMAL NUMBER 627792 627798 627813 627814 627815 282 .4 294 .3 258 .7 248 .0 289 .2 DAY 41 456 .5 470 .7 395 .0 358 .7 462 .6 286 .4 296 .3 259 .2 250 .7 293 .4 DAY 47 482 .3 '496 .9 407 .2 372 .7 487 .3 295.2 a 315.7 a 267.9 a 257.3 a 303.3 a TEST DAYS DAY 52 360 .0 380 .2 323 .6 299 .3 368 .3 496.8 517.3 416.8 386.9 505.9 3D test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52 389 .2 403 .5 342 .3 319 .4 396 .5 ' 426.1 443.1 367.9 343.7 434.9 a Rat was not weighed. -32- Coinpany Sanitised. Does not contain TSC H-23961: Biopersistence Screening' 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TEST ElAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627795 627811 627819 627820 627821 ANIMAL NUMBER 218 .0 228 .6 248 .8 225 .5 227 .5 DAY 8 219.5 226.3 255.3 228.9 233.2 DAY 9 225.3 236.7 264.9 239.2 240.7 234.3 246.1 274.4 247.9 246.1 TEST DAYS DAY 10 DAY 13 239.4 251.5 280.4 255.6 251.2 DAY 20 246.2 259.6 288.0 261.3 259.8 DAY 24 250.1 263.6 290.3 265.3 263.9 DAY 34 627795 627811 627819 627820 627821 ANIMAL NUMBER 261 .4 273 .0 304 .5 281 .3 272 .6 DAY 41 265.0 .276.7 308.0 282.9 275.3 DAY 47 270.7 a 285.6 a 324.3 a 292.4 a 281.8 a 308.0 337.8 399.7 367.2 330.1 TEST DAYS DAY 52 DAY 55 DAY 61 329.8 360.6 431.2 393.0 352.9 DAY 68 362.0 396.4 472.5 445.5 385.6 627795 627811 627819 627820 627821 384 .2 398.0 a 422 .0 439.3 a 505 .9 534.9 ^a 478 .0 504.1 a 411 .8 426.1 ^a 411.1 455.4 551.7 '529.7 439.1 435.7 463.0 574.4 547.1 459.0 440.7 473.6 588.6 558.6 463.3 a Rat was not weighed. -33- CsBipany Saniffeed. Dees no( conlain TSCA H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 90 DAY 94 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS TEST DAYS GROUP VI 627795 627811 627819 627820 627821 474.6 503.6 638.1 608.6 509.0 485.0 511.6 653.1 618.0 521.5 3D test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94 -34- Company Sanitized. Does not contain TSC H-23961: Biopersistence Screening 10-DoseOral Gavage Study in Rats ANIMAL NUMBER 625361 625363 625364 625380 625383 DAY 1 322.6 273.7 291.1 289.4 304.7 DAY 2 325.0 271.4 290.9 286.2 299.7 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP I DAY 3 DAY 4 DAY 5 337.6 278.4 299.9 291.5 302.7 340.3 281.7 306.0 300.1 310.7 349.7 286.7 312.0 305.5 313.1 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 -35. Caaapany Siuiiiized. Does not contain TS H-23961: Biopersistence Screening 10-DoseOralGavage 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 8 321 .7 323 .9 349 .1 364 .2 350 .1 DAY 2 282 .0 294 .1 307 .8 318 .0 306 .4 DAY 9 320 .9 332 .3 352 .4 380 .8 354 .2 CORN OIL-.ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP II TE:ST 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 -36- Coinpany SamSze^L Does not contain TS H-23961: 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 .7 307 .9 294 .2 297 .6 . DAY 2 308 .8 286 .3 316 .7 300 .0 304 .6 DAY 8 364 .2 319 .8 373 .4 325 .6 347 .0 DAY 9 370 .3 321 .6 374 .7 331 .0 349 .5 CORN OIL:ACETONE (NEGATIVE Control) INDIVIDUAL BODY WEIGHTS (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 TEST DAYS DAY 10 DAY 13 340. 5 306. 0 346. 9 316. 3 331. 9 343.3 302.7 349.8 314.1 334.0 361 .1 309 .2 364 .1 321 .4 345 .4 376.9 320.3 385.6 340.6 358.9 405 .6 340 .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 -37- Company Sanifeed, Does no* contain TSC H-23961: B iopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP IV TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 . DAY 7 625354 625365 625371 625376 625381 ANIMAL NUMBER 625354 625365 625371 625376 625381 303 .0 327 .7 294 .5 289 .7 297 .8 DAY 8 336 .2 370 .5 340 .3 331 .5 321 .6 304 .1 328 .7 299 .0 289 .9 297 .5 DAY 9 ,337 .0 379 .3 345 .9 339 .0 329 .1 310.5 337.9 313.4 302.2 301.7 312 .2 343 .6 318 .3 304 .9 305 .6 TEST DAYS DAY 10 DAY 13 348.8 381.2 351.2 345.2 331.6 355 .8 407 .1 372 .6 363 .2 341 .2 319 .3 357 .7 321 .8 313 .2 314 .4 DAY 20 377 .7 438 .2 413 .0 399 .7 358 .2 324.7 357.2 329.6 317.0 314.4 331.2 364.3 338.5 322.8 321.0 DAY 24 396.1 459.6 447.3 432.9 381.8 SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24 -38- CoiHpany Sanitized. Does not contain TS i ^v^1^-^' ^^-^laal H-23961: Biopersistence Screening 10-Pose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP V TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625356 625359 625360 625372 625374 ANIMAL NUMBER 291 .7 297 .9 296 .8 294 .8 295 .9 DAY 8 291.2 303.3 300.7 298.8 302.2 DAY 9 304.5 314.0 308.5 310.6 312.1 307.0 315.0 312.7 317.4 321.7 TEST DAYS DAY 10 DAY 13 316 .9 323 .5 319 .1 324 .0 323 .4 DAY 20 319.8 323.5 332.2 329.0 328.3 DAY 24 323. 9 333. 9 339. 5 335. 6 337. 2 DAY 27 625356 625359 625360 625372 625374 ANIMAL NUMBER 625356 625359 625360 625372 625374 328 .8 334.7 341.3 361.9 396 .7 a 339 .1 346.2 353.6 372.9 410 .0 -a 347 .9 354.3 363.4 381.7 419 .8 a 344 .7 348.8 355.1 373.1 395 .1 a 338 .0 344.6 350.8 371.5 401 .3 a DAY 34 466 .2 467 .7 484 .1 454 .7 466 .8 DAY 52 533.7 530.3 555.4 506.2 512.3 TEST DAYS SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52 431 .3 440 .9 465 .9 432 .1 447 .2 a Rat was not weighed. -39- Coropany Sanitoed. Does noloontain TSC H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625353 625369 625373 625375 625377 ANIMAL NUMBER 305 .9 281 .7 294 .6 289 .1 293 .9 DAY 8 307.3 279.9 301.3 291.0 294.8 DAY 9 316.8 289.7 312.7 298.0 302.9 325.0 286.9 317.0 307.0 312.0 TEST DAYS DAY 10 DAY 13 331. 7 292. 8 325. 4 309. 6 318. 0 DAY 20 330.1 295.3 329.0 314.2 317.4 DAY 24 342.5 303.8 334.6 323.5 325.0 DAY 27 625353 625369 625373 625375 625377 ANIMAL NUMBER 344 .7 352.7 358.1 371.7 399. 1 a 307 .3 311.9 317.2 331.1 347. 6 a 340 .6 348.2 352.6 371.5 402. 3 a 324 .7 336.0 336.9 350.1 387. 9 a 325 .0 333.7 340.7 353.5 376. 3 a DAY 34 DAY 52 TEST DAYS DAY 76 DAY 90 DAY 94 427.7 374.9 444.6 432.3 405.2 625353 625369 625373 625375 625377 453 .3 a 388 .2 a 477 .1 & 455 .6 a 419 .1 a 544.9 483.8 628.8 567.3 470.3 562.8 505.3 661.3 589.8 492.0 565 .3 514 .8 673 .7 588 .8 496 .6 SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94 a Rat was not weighed. -40- COBli PanySaniiize&naes "otsotKamTSCA H-23961: B iopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 625322 625323 625336 625343 625349 DAY 1 290.3 285.0 316.5 288.2 303.6 DAY 2 283.7 285.5 313.5 281.9 295.9 H-24019 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP I DAY 3 DAY 4 DAY 5 291.5 290.2 320.1 286.8 308.2 298.9 290.9 327.1 291.0 310.1 298.0 294.0 329.0 293.7 318.1 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 -41- Company Sanitized. Does noS contain TSC H-23961: 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 ANIMAL NUMBER 625320 625330 625332 625341 625350 279 .3 286 .7 300 .0 304 .9 257 .1 DAY 8 308 .5 314 .0 324 .1 332 .4 279 .8 283 .0 286 .1 295 .9 309 .0 268 .5 DAY 9 306 .3 312 .6 321 .8 320 .3 282 .5 287.7 291.1 304.1 317.5 267.3 288.4 296.5 308.8 320.0 272.2 TEST DAYS DAY 10 295 .9 304 .0 315 .0 325 .1 272 .6 312.1 310.1 318.3 325.6 284.3 3D test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 299.4 302.3 322.4 327.5 276.3 300.6 306.7 320.7 327.4 283.6 -42- '?1 contain TSCA H-23961: 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 ANIMAL NUMBER 307 .0 311 .4 273 .7 291 .2 265 .5 DAY 8 307 .8 306 .6 275 .5 291 .7 258 .6 DAY 9 311.4 312.5 282.3 297.3 268.0 319.6 317.8 285.8 303.3 275.2 TEST DAYS DAY 10 DAY 13 322.3 318.3 290.8 306.4 280.1 328 .4 319 .3 294 .2 310 .4 285 .2 335.2 327.6 326.6 316.1 290.6 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 -43- Company Sam-feed. Does not contain TS H-23961: 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 ANIMAL NUMBER 625325 625328 625338 625340 625352 282 .8 315 .6 264 .6 304 .0 285 .5 DAY 8 318 .6 352 .0 287 .4 347 .0 316 .9 285 .9 315 .2 261 .9 309 .2 283 .9 DAY 9 321 .9 351 .7 291 .3 352 .2 322 .3 291.7 323.9 268.5 316.9 289.1 295 .5 327 .7 272 .6 326 .0 299 .6 TEST DAYS DAY 10 DAY 13 327.4 357.5 290.2 359.2 321.0 331 .6 367 .4 291 .1 368 .1 329 .6 303 .2 335 .0 275 .7 329 .8 307 .9 DAY 20 355 .8 400 .2 320 .4 389 .3 355 .7 309 .2 340 .4 281 .9 334 .1 308 .2 308.3 340.1 284.4 338.4 312.4 DAY 24 381 .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 -44- CoHipany SaamSssS. Qses not eontaEn T8C H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 H-24019 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP V TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625324 625329 625333 625334 625344 ANIMAL NUMBER 303 .0 318 .9 292 .4 274 .6 262 .9 DAY 8 298.5 316.3 291.2 277.0 262.2 DAY 9 305.8 326.5 297.8 286.4 269.0 312 .1 335 .4 304 .1 290 .6 273 .5 TEST DAYS DAY 10 DAY 13 320 .1 338 .3 307 .7 292 .0 274 .5 DAY 20 322 .8 346 .7 312 .0 300 .1 284 .1 DAY 24 326.8 351.6 313.5 304.2 - DAY 27 625324 625329 625333 625334 625344 ANIMAL NUMBER 332 .5 337.9 336.1 299 .6 336 .0 a 380.3 352 .5 360.1 357.0 364 .3 396 .4 a 423.3 315 .8 316.7 319.3 325 .8 349 .2 a 375.2 292 .6 302.2 305.8 312 .0 338 .6 a 368.8 280 .7 -285.2 289.3 295 .8 309 .7 a 330.4 DAY 34 DAY 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 a Rat was not weighed. .45- antain TSCA CB H-23961: 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 VI TE,ST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625326 625335 625346 625347 625351 AMIMAL NUMBER 313 .2 301 .0 290 .2 266 .0 310 .6 DAY 8 317.1 303.6 293.4 275.6 310.9 DAY 9 325 .5 302 .3 300 .2 287 .7 321 .1 330.9 310.4 309.5 300.0 329.6 TE ST DAYS DAY 10 DAY 13 336 .2 315 .1 313 .5 308 .5 338 .2 DAY 20 336 .0 299 .6 318 .6 316 .6 341 .6 DAY 24 293 .6 326 .0 326 .9 340 .7 DAY 27 625326 625335 625346 625347 625351 ANIMAL NUMBER 311 .5 294 .2 292 .9 330 .5 351 .1 DAY 34 308.9 285.3 290.8 330.1 357.8 DAY 52 297 .5 274 .0 288 .4 333 .0 350 .5 274.2 266.3 296.9 355.7 380.0 TE;ST DAYS DAY 62 DAY 76 335 .4 340 .1 352 .5 402 .1 413 .7 DAY 80 a ^a a a. a DAY 90 390 .7 393 .8 388 .2 436 .2 452 .4 DAY 94 625326 625335 625346 625347 625351 427 .5 a 497 .5 540.0 547 .9 565 .2 577 .5 SD test day 427 .0 a 506 .0 538.6 547 .7 562 .1 579 .5 SD test day 407 .4 a 485 .8 523.7 532 .8 542 .4 556 .9 SD test day 466 .4 a 568 .6 617.8 618 .1 632 .6 638 .9 SD test day 483 .3 a 559 .0 596.8 607 .2 624 .0 636 .8 SD test day a Rat was not weighed. I contain T8CAC81 -46- ^ " " - - ^ Lc'on"tain^TS^ftW H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627756 627767 627771 627773 627777 DAY 1 227.2 227.0 219.5 246.8 225.4 DAY 2 226.4 231.8 214.7 244.4 221.4 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP I DAY 3 DAY 4 DAY 5 233.4 237.9 226.1 252.7 232.9 238.6 245.8 233.5 263.8 239.4 237.5 248.6 239.6 262.3 236.0 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 -47- Company Sanitized. Does not contain TSCA H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627768 627774 627776 627782 627785 ANIMAL NUMBER 627768 627774 627776 627782 627785 DAY 1 236 .9 258 .6 212 .0 221 .6 220 .3 DAY 2 244 .1 261 .6 216 .3 228 .3 221 .7 DAY 8 272 .3 319 .8 246 .1 251 .0 260 .7 DAY 9 291 .9 326 .3 252 .3 264 .0 268 .5 H-2402.0 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP II TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 245.2 275.8 223.7 237.3 234.7 256. 5 283. 4 226. 6 239. 0 238. 4 TEST DAYS DAY 10 256 .2 289 .3 229 .6 238 .8 241 .8 265. 5 301. 5 233. 7 244. 7 250. 5 271 .4 303 .2 236 .9 246 .7 255 .6 293.5 338.2 254.4 268.2 267.9 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 .48- Company Sanitized. Does not contain TSCA C H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627758 627763 627764 627787 627788 ANIMAL NUMBER 627758 627763 627764 627787 627788 DAY 1 235 .1 212 .1 230 .0 235 .1 219 .4 DAY 2 '240.3 218.3 235.0 241.0 222.3 DAY 8 280.6 255.2 275.8 221.7 274.1 DAY 9 283.6 261.2 281.9 235.7 276.9 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP III TE;ST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 248 .6 226 .5 246 .1 250 .1 232 .2 255.8 234.3 251.3 257.2 239.6 TEST DAYS DAY 10 DAY 13 261.2 230.8 254.8 258.6 247.6 272 .0 235 .5 261 .7 237 .6 256 .7 276 .1 238 .0 264 .7 240 .3 257 .9 295.8 272.5 288.0 234.7 284.8 308.7 285.8 306.7 234.9 309.4 SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13 .49- Company Sanitized. Does not contain TSCA H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP IV TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627759 627761 627770 627779 627786 ANIMAL NUMBER 226 .6 240 .7 235 .6 231 .5 211 .6 DAY 8 232 .9 247 .4 244 .3 237 .9 218 .2 DAY 9 241.4 257.1 253.6 252.6 222.5 250 .9 262 .5 260 .1 261 .4 230 .4 TEST DAYS DAY 10 DAY 13 254 .2 266 .7 267 .7 262 .3 230 .6 DAY 20 262.1 259.2 277.3 273.8 240.6 DAY 24 265. 4 262. 6 279. 8 277. 5 244. 1 627759 627761 627770 627779 627786 277 .8 284 .9 288.0 a 348 .0 380.1 SD test day 24 240 .1 257 .4 266.9 a 335 .7 359.4 SD test day 24 291 .4 301 .3 306.4 a 355 .8 379.8 SD test day 24 289 .0 293 .4 301.0 a 374 .4 406.2 SD test day 24 251 .3 '255 .8 257.0 a 304 .4 326.1 SD test day 24 a Rat was not weighed. -50- Company Sanitized. Does not contain TSC H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP V TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627757 627760 627765 627772 627781 ANIMAL NUMBER 221 .2 226 ,2 228 .3 245 .2 219 .0 DAY 8 225 .4 232 .0 235 .3 256 .4 226 .3 DAY 9 236.3 244.4 247,1 266.2 236.5 241.1 251.7 251.6 277.0 242.9 TEST DAYS DAY 10 DAY 13 247 .9 260 .2 256 .4 276 .9 247 .2 DAY 20 252 .2 254 .5 261 .1 285 .0 251 .6 DAY 24 254 .4 258 .3 264 .7 291 .0 256 .1 DAY 34 627757 627760 627765 627772 627781 ANIMAL NUMBER 269 .1 262 .6 271 .5 300 .9 258 .1 DAY 41 276 .7 280 .3 282 .4 307 .5 266 .8 DAY 47 279.7 a 287.3 a 288.1 a 31-7.0 a 271.2 ^a TEST DAYS DAY 52 324 .3 348 .6 349 .8 375 .5 315 .1 343 .0 379 .9 382 .7 404 .0 338 .8 372 .3 419 .4 400 .9 446 .9 372 .0 627757 627760 627765 627772 627781 402 .8 437 .7 422 .9 478 .4 389 .9 419 .7 448 .9 . 444 .8 494 .3 408 .2 436.7 456.5 455.6 513.5 421.0 SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52 a Rat was not weighed. -51- Ccropany Sanitised. Does not contain TSC H-23961: B iopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 627762 627769 627775 627778 627783 ANIMAL NUMBER 227 .2 231 .1 224 .7 213 .1 216 .4 DAY 8 235 .0 241 .1 235 .7 217 .4 218 .2 DAY 9 248.7 255.9 246.8 221.3 226.6 257.3 264.2 254.7 225.5 232.0 TEST DAYS DAY 10 DAY 13 263 .0 272 .3 265 .7 230 .1 238 .0 DAY 20 275 .1 286 .3 276 .7 236 .9 243 .9 DAY 24 279 .7 289 .9 280 .2 240 .4 247 .6 DAY 34 627762 627769 627775 627778 627783 ANIMAL NUMBER 285 .9 302 .0 286 .6 244 .8 256 .6 DAY 41 299 .1 309 .6 296 .0 250 .8 259 .2 DAY 47 301.5 a 312.5 a 304.5 a 255.1 a 264.3 a TEST DAYS DAY 52 DAY 55 356 .5 386 .6 353 .3 294 .0 311 .3 DAY 61 381 .5 414 .4 377 .4 320 .0 340 .9 DAY 68 419 .6 456 .5 413 .9 347 .1 380 .0 627762 627769 627775 627778 627783 438 .7 439 .9 a 453.5 473 .0 471 .6 479 .7 474 .6 a 512.2 5.11 .4 531 .4 433 .2 451 .1 a 460.8 477 .4 478 .6 356 .8 373 .5 a 386.0 393 .3 398 .3 409 .6 426 .9 a 449.0 473 .8 474 .8 a Rat was not weighed. -52- Company Sanitised. Does not contain TSCA H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627762 627769 627775 627778 627783 DAY 81 DAY 90 500.3 566.2 510.4 410.1 508.8 523.3 603.2 537.5 .436.5 538.5 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TEST DAYS DAY 94 528.6 609.6 552.8 445.3 557.2 SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94 -53- Company Sanitized. Does not contain TSCA ^^^:%^ - ^ r " a.t.^^^^^iaateBhia H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER I 626876 626877 626885 626889 626890 DAY 1 DAY 2 236.4 253.3 223.3 247.2 248.0 237.8 260.2 225.7 249.1 246.3 H-23961 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP I DAY 3 DAY 4 DAY 5 247.5 272.2 234.2 258.1 254.9 255.2 272.3 236.9 262.2 259.9 262.6 278.2 245.9 268.9 268.9 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 -54- Company Sanitized. Does not contain TSC H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 626871 626872 626875 626882 626888 ANIMAL NUMBER DAY 1 250. 6 251. 6 247. 3 249. 0 224. 8 DAY 2 259 .4 261 .0 256 .2 257 .0 226 .4 DAY 8 DAY 9 H-23961 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS GROUP II DAY 3 DAY 4 DAY 5 DAY 6 . DAY 7 266 .3 268 .3 265 .6 265 .6 233 .6 275.2 277.2 270.9 272.8 238.3 285 .2 280 .3 283 .0 285 .1 243 .4 288 .8 289 .9 291 .2 297 .1 247 .5 295 .9 294 .2 298 .2 301 .4 249 .5 DAY 10 626871 626872 626875 626882 626888 297. 5 300. 5 301. 3 309. 6 258. 2 305 .2 309 .9 310 .5 314 .4 260 .7 309 .0 318 .1 315 .1 325 .1 264 .8 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 -55- Company Sanitized. Does not contain TSCA H-23961: B iopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 626868 626879 626886 626887 626891 ANIMAL NUMBER 626868 626879 626886 626887 626891 DAY 1 255 .0 231 .4 237 .1 246 .2 249 .7 DAY 2 '265 .4 242 .2 243 .2 253 .0 256 .2 DAY 8 323 .0 280 .4 290 .9 295 .6 310 .3 DAY 9 328 .3 290 .1 296 .3 302 .5 321 .8 H-23961 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP III DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 . 279 .9 248 .9 251 .5 260 .0 265 .1 288.0 255.2 259.4 268.7 275.8 300.4 260.8 265.1 275.0 283.8 308. 8 267. 3 270. 0 283. 1 294. 9 311 .6 271 .7 280 .8 288 .3 300 .8 DAY 10 338 .0 297 .8 302 .1 307 .9 318 .8 DAY 13 366.9 320.6 319.9 329.9 346.3 SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13 -56- Company San,t,-ze<.. Does notcontain TSC H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 626864 626865 626873 626894 626895 ANIMAL NUMBER 626864 626865 626873 626894 626895 DAY 1 248 .7 232 .9 248 .9 225 .8 233 .9 DAY 2 256 .1 241 .4 261 .8 231 .4 238 .9 DAY 8 289 .1 276 .8 311 .4 274 .7 278 .2 DAY 9 294 .9 280 .5 318 .1 ,282 .6 280 .3 H-23961 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP IV DAY 3 260. 7 245. 9 268. 2 244. 3 247. 3 DAY 4 268.3 255.4 280.1 250.0 249.5 DAY 5 271. 4 263. 4 290. 1 258. 8 262. 0 DAY 6 277. 8 266. 2 300. 1 263. 9 262. 7 DAY 7 280 .8 270 .8 303 .8 268 .9 271 .2 DAY 10 300. 8 283. 8 328. 4 292. 7 287. 6 DAY 13 a a a a a DAY 24 390. 7 351. 8 424. 7 380. 8 360. 6 SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24 ' Rat was not weighed. -57- Company Sanitized. Does not contain TSC H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 626867 626880 626881 626884 626892 ANIMAL NUMBER DAY 1 249.0 228.9 233.4 243.5 236.6 DAY 2 257.1 235.7 238.4 251.1 243.0 DAY 8 DAY 9 H-23961 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP V DAY 3 263 .1 239 .6 247 .1 261 .0 255 .8 DAY 4 270 .8 244 .2 253 .7 269 .7 262 .9 DAY 5 274 .2 255 .5 264 .6 275 .0 273 .5 DAY 6 281 .2 261 .5 278 .0 283 .9 281 .5 DAY 7 . 286 .9 269 .3 284 .1 290 .1 292 .3 DAY 10 DAY 13 DAY 24 DAY 34 DAY 4; 626867 626880 626881 626884 626892 ANIMAL NUMBER V 626867 626880 626881 626884 626892 294.1 299.6 308 .7 a 275.5 284.5 290 .3 a 293.6 300.5 307 .7 a 300.5 305.4 316 .0 a 299.8 309.1 318 .0 a a 407 .1 455 .1 a 399 .1 454 .0 a 444 .6 517 .9 a 429 .0 489 .7 a 440 .9 498 .8 DAY 52 DAY 62 DAY 69 478.7 470.8 533.9 507.8 518.8 SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52 DAY 75 ' DAY 83 DAY 89 DAY 93 '' Rat was not weighed. -58- ^'"^ySan.&ed.Doesnol contain TS H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 626866 626869 626874 626893 626896 ANIMAL NUMBER VI 626866 626869 626874 626893 626896 ANIMAL NUMBER VI 626866 626869 626874 626893 626896 DAY 1 240 .1 255 .2 223 .8 246 .3 233 .2 DAY 2 242.5 259.0 232.2 253.8 237.5 DAY 8 275 .9 295 .6 282 .6 278 .4 279 .0 DAY 9 277.3 302.8 290.0 283.1 290.9 DAY 52 469 .9 458 .2 535 .2 454 .7 466 .1 DAY 62 485.6 475.8 568.4 471.8 476.8 H-23961 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI DAY 3 251.9 266.5 244.0 259.2 250.7 DAY 4 252 .2 270 .4 249 .9 260 .5 258 .0 DAY 5 257.2 279.6 260.4 267.6 265.3 DAY 6 266.0 286.7 269.0 271.9 258.7 . DAY 7 270.6 290.8 277.3 273.8 270.7 DAY 10 284.4 304.8 295.0 287.9 a DAY 13 a a a a a DAY 24 a a a a a DAY 34 398.4 400.1 444.4 389.5 405.1 DAY 48 461.3 446.4 519.5 441.7 449.6 DAY 69 500.9 481.0 593.8 488.3 502.0 DAY 75 514 .9 493 .2 616 .5 501 .5 521 .1 DAY 83 541.3 496.4 625.3 519.1 523.1 DAY 89 555.6 505.8 640.4 527.8 527.8 DAY 93 565.5 507.0 654.5 539.5 541.8 SD test day SD test day SD test day SD test day SD test day a Rat was not weighed. -59- Company Sanitized. Does not contain TSC H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 APPENDIX B Individual Clinical Observations -60- Company Sanitized. Does not contain TSCACB1 H-23961: B iopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 Animal Number 627789 627801 627805 627810 627818 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP I Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-5 1-5 1-5 1-5 1-5 Animal Number 627793 627797 627799 627800 627808 GROUP II Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-10 1-10 1-10 1-10 1-10 Animal Number 627796 627806 627807 627809 627816 GROUP III Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-13 1-13 1-13 1-13 1-13 .61- Company Sanitized. Does not contain TSCA CBI H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 Animal Number 627791 627794 627804 627812 627817 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP IV ___'______Observation___________________Test Day No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected 1-24 1-24 1-24 1-24 1-24 Animal Number 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 Company Sanitized. Does not contain TSCA CS( H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 CORN OIL:ACETONE (NEGATIVE CONTROL) Animal Number 625361 625363 625364 625380 625383 INDIVIDUAL CLINICAL OBSERVATIONS IM MALE RATS GROUP I Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected __ Test Day 1-5 1-5 1-5 1-5 1-5 Animal Number 625355 625362 625367 625368 625378 GROUP II Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-10 1-10 1-10 1-10 1-10 Animal Number 625357 625358 625370 625384 625385 GROUP III Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-13 1-13 1-13 1-13 1-13 -63- Company SanKized. Does noS contain TSCA CB8 H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 Animal Number 625354 625365 625371 625376 625381 CORN OIL-.ACETONE (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP IV Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected __Test Day 1-24 1-24 1-24 1-24 1-24 Animal Number 625356 625359 625360 625372 625374 Animal Number 625353 625369 625373 625375 625377 Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected GROUP VI 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 Test Day 1-94 1-94 1-94 1-94 1-94 -64- Company Sanitized. Does not contain TSCA CBE H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 H-24019 (POSITIVE CONTROL) Animal Number 625322 625323 625336 625343 625349 INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP I Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-5 1-5 1-5 1-5 1-5 Animal Number 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 -65- Company Sanitized. Does not contain TSCA CB1 H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 Animal Number 625325 625328 625338 625340 625352 H-24019 (POSITIVE CONTROL) I :NDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP IV Observation Test Day 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 -66Company Sanitised. Does not coatain TSCA CB1 H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 Animal Number 627756 627767 627771 627773 627777 H-24020 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP I ___'______Observation___________________Test Day No abnormalities detected 1-5 No abnormalities detected 1-5 No abnormalities detected 1-5 No abnormalities detected 1-5 No abnormalities detected 1-5 Animal Number 627768 627774 627776 627782 627785 GROUP II Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Mo 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 -67- Company Sanitized. Does not contain TSCA CBI H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 H-24020 (POSITIVE CONTROL) Animal Number 627759 627761 627770 627779 627786 INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP IV Observation __ No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected __ __ __ Test Day 1-24 1-24 1-24 1-24 1-24 Animal Number 627757 627760 627765 627772 627781 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 Animal Number 627762 627769 627775 627778 627783 GROUP VI Observation No abnormalities detected Diarrhea No abnormalities detected No abnormalities detected Alopecia perineum No abnormalities detected Alopecia both front paws Alopecia right front leg Test Day 1-8, 10-94 9 1-94 1-94 81, 90, 94 1-23, 94 24, 34, 41, 47, 55, 61, 74, 81, 90 -68- Company Sanitized. Does not contain TSCA CBI H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 Animal Number 626876 626877 626885 626889 626890 H-23961 (TEST SUBSTANCE) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP I Observation __ __ No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day __ 0-5 0-5 0-5 0-5 0-5 Animal Number 626871 626872 626875 626882 626888 GROUP II Observation No abnormalities detected No abnormalities detected No abnormalities detected Alopecia left front leg Mo abnormalities detected Test Day 0-10 0-10 0-10 1-10 0-10 Animal Number 626868 626879 626886 626887 626891 GROUP III Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 0-13 0-13 0-13 0-13 0-13 -69- Company Sanitized. Does not contain TSCA CBi H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 Animal Number 626864 626865 626873 626894 626895 H-23961 (TEST SUBSTANCE) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP IV __ Observation No abnormalities detected. No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 0-24 0-24 0-24 0-24 0-24 Animal Number 626867 626880 626881 626884 626892 GROUP V Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 0-52 0-52 0-52 0-52 0-52 Animal Number 626866 626869 626874 626893 626896 GROUP VI Observation No abnormalities detected Alopecia both front legs No abnormalities detected Stain periocular both black Teeth broken or chipped No abnormalities detected Test Day 0-93 52, 62, 69, 75 0-93 34 34 0-93 -70- Company Sanitizsd. Does not contain TSCA C81 H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 APPENDIX C Analysis of Blood Fluoride Data -71- Company Sanitised. Does not contain TSCACB1 H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Terms: Active % Active Terms and Calculations Mol Wt Active Formulation Dose % F in Active MolWtF DuPont-2923 Compound Calculations: Dose Active (mg/kg) The mg of fluorine containing compound administered per kg of animal body weight. = (% active/100) * Formulation Dose Dose Active (mmole/kg) The mmole of fluorine containing compound administered per kg of animal body weight = dose [mg/kg] / Mol Wt Active [mg/mmol] Dose F (mg/kg) The mg Fluorine administered per kg of animal body weight = (% F in active/100) * Dose Active [mg/kg] Dose F (mmol/kg) The mmole of fluorine administered per kg of animal body weight = Dose F [mg/kg] / Mol Wt F [mg/mmol] Molar Ratio (Active/F) The moles of fluorine containing compound per mole of fluorine = Dose Active [mmol/kg] / Dose F [mmol/kg] Formulation Dose Normalization Factor The formulation dose that would be required to administer the amount of active needed to achieve the normalized dose = (Normalized dose of Active [mmol/kg] / Dose Active [mmol/kg]) * Formulation Dose .72Company Sanitized. Does not contain TSCA CBi H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Individual Animal Measurement: ppm F in blood The ppm fluoride measured in blood DuPont-2923 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 Dose mmol/kg 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]) * (ppm F in blood minus background) pmolar equivalents of active in blood The jumolar [/unol/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]) * molar ratio active/F [mmol active/mmol F] * 1000 ^mol/mmol -73- Company Sanitized. Does not contain TSCA CBI H-23961: B iopersistence Screening 10-Dose Oral Gavage Study in Rats Factors Influencing Interpretation of Kinetic Analysis DuPont-2923 Considerations: The data used for kinetic analysis was from a limited screen and extrapolation should be done cautiously. Sample size is low Analytical data used without validation Steady-state not reached Terminal phase may not be reached Some compounds are mixtures of fluorinated compounds Different active and formulation doses were used Different vehicles were used to deliver formulations The kinetics apply only to plasma, not to specific tissues or the whole body Each compound may have very different potency for producing toxicity Assumptions: (May or may not be justified in all cases) - Plasma fluorine concentrations are linear with respect to dose - Analytical method is appropriate for all types of compounds - Elimination kinetics can be determined based on total fluorine rather than on concentrations of individual components - Background plasma Fluorine is 0.2 ppm - % F data is the % Fluorine of the active (Fluorine containing components) in the formulation - Molecular weight is the molecular weight of the active component in the formulation -74- Compavy SaciffeEagL Does not contain TSCShCBS H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Data for H-24019 Given: MolV\It. Active (;g/mole): Fonnulation Doss; (mg/kg); %Active (F Containing) in Formulation: 497 % F in Acti ve: 10 Mol Wt. F (:g/mol): 100 Calculateld Values: Dose^active (mg/kg): Dose /active (mmole/kg): Formuilation Dose Normalisaticm Factor: 10 0.020 49.7 Dose F (nurlol/kg): Molar Ratioi (Activ(;/F): Dose P (mg/kg): DuPont-2923 65 19 0.342 0.059 6.5 Rat# Group I 625322 625323 625336 625343 625349 Group I 625322 625323 625336 625343 625349 Group II 625320 625330 625332 625341 625350 Test Day Sample ppmF in blood ppmF in blood minus Bkg 0.2 ppm 1 1.0 0.8 1 1.3 1.1 1 2.6 2.4 1 2.6 2.4 1 2.9 2.7 5 51.7 5 38.0 5 38.7 5 78.5 5 37.1 51.5 37.8 38.5 78.3 36.9 10 . 65.6 65.4 10 61.1 60.9 10 60.5 60.3 10 63.1 62.9 10 58.1 57.9 ppm F in bllood Normalize!ito 0.1 mmolesi/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 umolar equivaleiits 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 -75- Company Sanif'zed. Does not contain TSCA CBS H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Rat# Group ffl 625321 625327 625342 625345 625348 Test Day Sample 13 13 13 13 13 ppmF in blood 77.2 61.5 64.6 57.0 62.4 Group IV 625325 24 625328 24 625338 24 625340 24 625352 24 40.3 46.3 43.2 39.1 41.9 Group V 625324 52 625329 52 625333 52 625334 52 625344 52 24.7 29.8 27.3 29.1 23.8 Group VI 625326 94 625335 94 625346 94 625347 94 625351 94 12.4 16.4 13.1 11.0 11.6 ppmF in blood minus Bkg 0.2 ppm 77.0 61.3 64.4 56.8 62.2 40.1 46.1 43.0 38.9 41.7 24.5 29.6 27.1 28.9 23.6 12.2 16.2 12.9 10.8 11.4 ppm F in b lood Normalizedto 0.1 mmoleii/kg Dose 382.69 304.66 320.07 282.30 309.13 DuPont-2923 umolar equivalents of active in blood 1184.62 943.08 990.77 873.85 956.92 199.30 229.12 213.71 193.33 207.25 616.92 709.23 661.54 598.46 641.54 121.77 147.11 134.69 143.63 117.29 376.92 455.38 416.92 444.62 363.08 60.63 80.51 64.11 53.68 56.66 187.69 249.23 198.46 166.15 175.38 -76- Company Sanitized. Does not contain TSCA CB( H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 Given: MoPiVt. Active (^^mole): Formulation Dose: (mg/kg): %Ac;tive (F Contiaining) in Pormulation: Data for H- 7A1020 426 % P in Active: 20 MolWt.F(g/mol): 100 Calculateed Values: Dose Active (mg/1kg): Dose Active (mm<ole/kg): Formulation Dose Normalization Factor: 20 0.047 42.6 Dose F (mmol/kg): Molar Ratio (Active/F): Dose F (mg/kg): 69 19 0.726 0.065 13.8 Rat# Test Day Sample ppmF in blood Group I 627773 1 13.2 627771 1 8.1 627767 1 16.5 627756 1 14.1 627777 1 10.7 Group I 627773 5 75.3 627771 5 66.8 627767 5 64.8 627756 5 80.0 627777 5 71.6 Group II 627768 10 627774 10 627776 10 627782 10 627785 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 umolar 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 -77- Company Sanitized. Does not contain T3CA CBI H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Rat# Test Day Sample ppmF in blood ppm F in blood minus Bkg 0.2 ppm ppm F in hilood Normalizeid to 0.1 mmoles/kg Dose DuPont-2923 umolar equivalents of active in blood Group ffl 627758 13 627764 13 627787 13 627763 13 627788 13 Group IV 627759 24 627779 24 627770 24 627761 24 627786 24 Group V 627757 52 627781 52 627760 52 627765 52 627772 52 Group VI 627778 94 627783 94 627762 94 627775 94 627769 94 43.5 20.7 13.2 30.8 24.9 9.2 14.9 11.6 9.9 6.7 0.9 0.6 1.0 0.9 0.8 0.3 <0.2 0.2 0.2 <0.2 * = Below LOD (Level of Detection) 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 * 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 * 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 * -78- Company SartSijsed. Does net contain TSCA CBI H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2923 Given: Mol Wt. Active (g/mole): Formulation Dose (mg/kg): % Active (F Containing) in Formulation: Data for H-23961 27500 1000 28 % F in Active: Mol Wt. P (g/mol): Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor: 280 0.010 9821.4 Dose P (mmol/kg): Molar Ratio (Active/F): Dose F (mg/kg): 40 19 5.895 0.002 112 Rat# Group I 626876 626877 626885 626889 626890 Group I 626876 626877 626885 626889 - 626890 Group II 626871 626872 626875 626882 626888 Test Day Sample ppm F in blood 1 3.4 1 1.6 1 1.4 1 1.3 1 1.5 5 0.8 5 0.7 5 0.6 5 0.7 5 0.8 10 1.2 10 1.1 10 1.8 10 1.5 10 1.9 ppm F in blood minus Bkg 0.2 ppm 3.2 1.4 1.2 1.1 1.3 0.6 0.5 0.4 0.5 0.6 1.0 0.9 1.6 1.3 1.7 ppm F in blood Normalized to 0.1 mmoles/kg Dose 31.43 13.75 11.79 10.80 12.77 5.89 4.91 3.93 4.91 5.89 9.82 8.84 15.71 12.77 16.70 umolar equivalents of active in blood 2.86 1.25 1.07 0.98 1.16 0.54 0.45 0.36 0.45 0.54 0.89 0.80 1.43 1,16 1.52 -79- Company Sanitised. Does noi cci'itain TSCA CBS H-23961: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Rafr# Test Day Sample ppmF in blood ppm F in blood minus Bkg 0.2 ppm ppm F in blood Normalized to 0.1 mmoles/kg Dose DuPont-2923 umolar equivalents of active in blood Group III 626868 13 0.5 0.3 626879 13 0.6 0.4 626886 13 <0.2 * 626887 13 0.3 0.1 626891 13 <0.2 * Group IV 626864 24 0.2 0.0 626865 24 0.3 0.1 626873 24 0.4 0.2 626894 24 0.2 0.0 626895 24 0.3 0.1 Group V 626867 52 0.3 0.1 626880 52 <0.2 * 626881 52 <0.2 * 626884 52 <0.2 * 626892 52 0.3 0.1 Group VI 626866 93 0.6 0.4 626869 93 0.4 0.2 626874 93 0.5 0.3 626893 93 0.4 0.2 626896 93 0.5 0.3 * = Below LOD (Level of Detection) 2.95 3.93 * 0.98 * 0.00 0.98 1.96 0.00 0.98 0.98 * * * 0.98 3.93 1.96 2.95 1.96 2.95 0.27 0.36 * 0.09 * 0.00 0.09 0.18 0.00 0.09 0.09 * * * 0.09 0.36 0.18 0.27 0.18 0.27 -80- Conipany SanffizacL Doss nol contain TSCA CBI