Document MzyK7y50yyz2DVYK43o12r8k

TRADE SECRET AR226-3165 DuPont-2926 Study Title H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Laboratory Project ID: DuPont-2926 AUTHOR: Carol Finlay, B.A. STUDY COMPLETED ON: September 5, 2000 PERFORMING LABORATORY; E.L du Font de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine ElktonRoad,P.O.Box50 Newark, Delaware 19714-0050 Page 1 of 93 Company Sanitized. Does not contain TSCA CM H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. Reviewed by: Gary W. Jepson, Ph.D. Senior Research Scientist Reviewed by; C-jfort^L C v^fcxg6^A 77JudJuidtihth (/ C.SSttaaddlleer, Ph.D., Director D.A.B.T. Issued by Study Director: ^;^u, C^LA^ Carol Finfay, B.A. Q Starf Scientist ^> S^fZ^c-^ Date o^-^er- 2.000 Date 6:)-^/lt-t6ffQ Date -2-oo^s^.o.--------------"' H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 TABLE OF CONTENTS Page CERTIFICATION........................................................................................................................! LIST OFTABLES........................................................................................................................4 LIST OF FIGURES ......................................................................................................................4 LISTOFAPPENDICES...............................................................................................................4 STUDY INFORMATION.............................................................................................................5 STUDY PERSONNEL.................................................................................................................. 7 SUMMARY.................................................................................................................................... 8 INTRODUCTION.........................................................................................................................9 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. Identification .......................................................................................................................................... 10 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 12 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 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.................................................................................................................................. 17 ^^nTSCACBl -3- s ;t;.Tffld. fw-n"P'-S,- "' Coinp^58^'-" H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 FIGURES..................................................................................................................................... 23 APPENDICES.............................................................................................................................28 LIST OF TABLES Page 1. MEAN BODY WEIGHTS................................................................................................................................... 18 2. MEAN BODY WEIGHT GAINS ........................................................................................................................20 3. MEAN BLOOD FLUORINE LEVELS................................................................................................................21 4. MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE................................................22 LIST OF FIGURES Page 1. MEAN BODY WEIGHTS...................................................................................................................................24 2. MICROMOLAR EQUIVALENTS IN RAT BLOOD..........................................................................................25 3. MICROMOLAR EQUIVALENTS IN TEST COMPOUND AND POSITIVE CONTROLS.............................27 LIST OF APPENDICES Page A. INDIVIDUAL BODY WEIGHTS.......................................................................................................................29 B. INDIVIDUAL CLINICAL OBSERVATIONS ....................................................................................................71 C. INDIVIDUAL FLUORINE LEVELS..................................................................................................................84 otconiainiaU^31 -4- SanW-0065" comply H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats STUDY INFORMATION TEST SUBSTANCE: Substance Tested: iMBBBBfl. Synonyms/Codes: H-24002 Haskell Number: 24002 Composition: Known Impurities:' POSITIVE CONTROL: Substance Tested: Potassium perfluoroalkyi sulfonate Synonyms/Codes: H-24019 DuPont-2926 Haskell Number: 24019 Composition Known Impurities: -5- Company Sanitized. Does not contain H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats STUDY INFORMATION (Continued) POSITIVE CONTROL: Substance Tested: Synonyms/Codes: H-24020 C-8 Perfluorooctanoate, ammonium salt PFOA Ammonium perfluorooctanoate Haskell Number: 24020 Composition DuPont-2926 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) m-Life Initiated/Completed: July 11,1999 / October 12,1999 ^QnialnTSCACBi -6- ^p,,ny SanCT...---- H-24002: 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-2926 -7^a^ed.13083' H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 SUMMARY The objective of this study was to evaluate the potential for H-24002, when administered by gavage, to.be absorbed and to accumulate in a mammalian system. Six groups of 5 male Crl:CD(SD)IGSBR rats each were given 75 mg/kg/day of H-24002. The test substance was administered to one group of 5 rats for 5 consecutive days and to 5 groups for 10 days. Approximately 2 hours after the first dose, blood was collected from the orbital sinus 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, 3 negative controls, deionized water, corn oil, and corn oil/acetone (80:20), and 2 positive controls, H-24019 (10 mg/kg/day) and H-24020 (20 mg/kg/day), were tested as described for H-24002. No deaths occurred during the study. No clinical signs associated with the test substance were observed in rats given H-24002. 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. The corn oil and corn oil/acetone 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-24002, were comparable to the deionized water and corn oil negative controls and greater than the H-24020 positive controls. Comparison of body weights between the rats dosed with the test substance and the corn 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-24002, are comparable to the corn oil/acetone negative controls and greater than the H-24019 positive controls. A steady-state for fluorine levels in whole blood may not have been achieved during 10 consecutive days of dosing with 75 mg/kg H-24002. 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-24002, was 7031.0 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-24002, to male rats for 10 consecutive days resulted in low absorption and retention of fluorine in the blood. Doseadjusted areas under the curve (AUCINF/D) for positive controls, H-24019 and H-24020, were approximately 81x and lOx the AUCINF/D for the test substance. -8- c^s------00""01^'"1 - H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 INTRODUCTION The objective of this study was to define the potential of H-24002 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 dosage of 75 mg/kg/day was chosen based on available toxicity data and the results of a rangefinding study. In the initial rangefinding study, 5 rats were dosed with the test substance for 4 consecutive days at a dosage of 700 mg/kg. The study was terminated because the rats experienced an overall mean body weight loss of 21 grams. In a second rangefinding study, 5 rats were dosed with the test substance for 5 consecutive days at a dosage of 100 mg/kg. The rats experienced an overall mean body weight gain of 6 grams. Based on the results of this rangefinding study, the dosage of 75 mg/kg/day for the test substance was chosen for the study. 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-24002, was supplied by the sponsor as an amber brown liquid. The positive controls, H-24019 and H-24020, were supplied by the sponsor as white solids. The test substance and positive controls appeared to be stable under the conditions of the study. No evidence of instability, such as a change in color or physical state, was observed. B. Test Species Male Crl:CD(SD)IGS BR rats were received from Charles River Laboratories, me., Raleigh, North Carolina. The Crl:CD(SD)IGSBR rat was selected on the basis of extensive experience with this strain and its suitability with respect to longevity, hardiness, sensitivity, and low incidence of spontaneous diseases. -?"^^'D;:;;^^ H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 C. Animal Husbandry 1. Housing Environment Rats were housed singly in stainless steel, wire-mesh cages suspended above cage boards. Animal rooms were maintained on an approximate 12-hour light/dark cycle (fluorescent light) and at a temperature of 23 1C and a relative humidity of 50 10%. 2. Feed and Water Tap water was provided ad libitum. All rats were fed PMI Nutrition International, 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 ofcoliforms, lead, and other contaminants. Feed samples are analyzed for total bacterial, spore and fungal counts. Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity of the study. The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. -10- Company Sanitized. Does not contain TSCA CBS H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 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. E. Study Design Substance Negative Controls Deionized Water Corn oil Corn oil:acetone Positive Controls H-24019 H-24020 Test Substance H-24002 Vehicle Not applicable Corn oil: acetone Corn oil Deionized Water Dosage (mg/kg) 0 0 0 10 20 75 Number of Animals 30 30 30 30 30 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-24002 was administered as mg test substance received per kg weight of each animal. The liquid test substance received was diluted with deionized water so an accurate amount could be administered at the selected dose level. The amount of dosing mixture (mL) each rat received 11Compa?"/ H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 was based on the body weight collected on each day of dosing and the dosing mixture concentration (7.5 mg liquid test substance/mL water). The rats were dosed at a volume of 1 mL/100 g of body weight. The dosing mixture 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. Corn oil was used as the vehicle for H-24019. It was necessary to dissolve H-24020 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 Deionized water was chosen as a negative control because it was the vehicle for the test substance. Corn oil and corn oil:acetone (80:20) were chosen as negative controls because they were the vehicles for the positive controls. Each negative control rat received 1 mL of corn oil or corn oil:acetone. These rats were dosed in a separate room from the rats dosed with the test substance or positive controls. H. Body Weights All rats were weighed on each day of dosing and then 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 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: Comply S"'"3"' ^.n^u^ H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 Group I I n m IV v VI Dosing Days 1-5 1-5 1-10 1-10 1-10 1-10 1-10 Tissue Collected Blood Blood and Liver Blood and Liver Blood and Liver Blood and Liver Blood and Liver Blood and Liver Sampling Time Test day 1 (2 hours post dosing) Test day 5 at sacrifice (2 hours post dosing) Test day 10 (2 hours post dosing) Test day 13 Test day 24 Test day 52 Test day 94 Five to 10 mL 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 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-24002 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 AUCDStF (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 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 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _- _13_- _ _ _C_o _m_p_a n_y_S_8." 1 . 1 ^no 1^1^ U n n ^ T S C A C B I H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 fluorine were used as received (ppm F) from Jackson Laboratory. Fluoride ion was converted to micromolar (pM) 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 1-2, Figure 1, Appendices A-B) No deaths occurred during the study. Alopecia, considered unrelated to test substance administration, was observed in 1 rat dosed with the test substance, H-24002. 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 deionized water and the positive controls, H-24019 and H-24020. The corn oil and corn oil/acetone 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-24002, were comparable to the deionized water and corn oil negative controls and greater than the H-24020 positive controls. Comparison of body weights between the rats dosed with the test substance and the corn 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-24002 rats were younger and lighter in weight than the corn 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-24002, are comparable to the corn oil/acetone negative controls and 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. -14- Company Sani&ed. Does not contain TSCA CBE H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 2. Positive Controls The positive controls were H-24019 and H-24020. The H-24019 normalized fiM 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 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 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-24002 normalized j^M equivalents in rat blood continued to rise throughout the dosing period and may not have reached steady-state (Figure 2C). The Cmax for H-24002 was 39.60 2.62 ppm (Mean SD) with a terminal half-life of 15.7 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-24002 AI was 23.1 and the BI was 916.0. The total internal exposure resulting from a normalized dose was described by AUCINF/D and was the basis for comparison between H-24002 and positive controls. The AUCINF/D for the fluorine component of H-24002 was 7031.0 as compared to AUCINF/D values of 566,479.1 and 70,789.6 for H-24019 and h-24020, respectively. The data, calculations and equations are shown in Appendix C. CONCLUSIONS Rats dosed for 10 consecutive days with 75 mg/kg H-24002 exhibited no mortality or test substance-related clinical signs oftoxicity and had mean body weights and mean body weight gains that were comparable to the negative controls. A steady-state for fluorine in the blood may not have been achieved during the 10-day dosing period. Under the conditions of this study, administration of H-24002 to male rats for 10 consecutive days resulted in 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 81x and lOx the AUCINF/D for the test substance. ""^np^^^^^ H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 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- Company Sanitized. Does noi contain TSCA CS) H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 TABLES 17- CompanySanlf.ed.DoosnotcontalnTSCACBI H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 TABLE 1 MEAN BODY WEIGHTS (g) Test Days 1 2 3 4 5 6 7 8 9 10 13 18 20 24 25 27 32 33 34 39 41 46 47 51 52 53 54 55 60 61 62 67 68 74 Negative Contn3ls Deionize d Corn Oil: Water Corn Oil Acetone 226.8 229.8 297.6 232.8 234.1 299.6 240.3 241.4 309.4 249.0 250.4 314.3 259.1 259.3 321.5 268.3 266.8 326.0 277.1 271.2 334.9 283.6 281.9 339.2 290.2 285.2 345.2 298.3 295.9 351.7 313.6 321.1 350.7 352.6 - - - 350.5 369.8 419.4 378.3 401.0 378.7 - - - - - 400.7 - - - - - - 449.5 - 463.5 - 407.8 - 434.5 - 454.9 411.4 - - - - 469.7 511.0 464.7 - 527.6 - - - - - 487.0 - 528.0 - - - 505.1 - - - - 547.7 - - - 515.4 - 558.0 Positive Controls Test Substance 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 - - 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 H-24002 234.6 239.3 248.4 256.1 264.8 271.2 274.2 288.6 294.3 301.9 322.1 - 364.7 371.9 - 416.0 - 444.9 - - 473.7 - 499.5 532.7 - - 506.6 - 525.9 - - - - -18. Company Samtizsd. Doss not contain TSCA Ci H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 TABLE 1 (Continued) MEAN BODY WEIGHTS (g) Test Days 76 80 81 82 88 90 94 Nesgative Contn3ls Deionized Water Corn Oil Corn Oil: Acetone - - 539.0 - - - 573.0 - - - - 589.5 - 584.6 - 556.2 566.9 - 562.2 567.8 Indicates the animal was not weighed. Positive; Controls Test Substance H-24019 563.4 570.7 - - - 585.3 597.9 H-24020 - - 499.2 - - 527.8 538.7 H-24002 562.3 - - 578.1 586.4 - 593.9 -19- ^npany Sanfed. Does not ccnfafn TS^ H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 TABLE 2 MEAN BODY WEIGHT GAINS (g) Test Days 1-5 1-10 10-13 10-24 10-51/52 10-94 Negative Controls Deionized Water Corn Oil Corn Oil:Acetone 32.3 29.5 23.9 71.5 66.1 54.1 15.3 121.1 25.2 82.4 -1.0 49.3 171.4 168.8 175.9 286.3 271.0 216.1 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-24002 30.2 67.3 20.2 70.0 230.8 292.0 "20' Company Sanitized. Does not contain TSCA CSf H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 TABLES MEAN BLOOD FLUORINE LEVELS Test Days 1 5 10 13 24 51/52 94 Nesgative Controls Deionized Corn Oil: Water Corn Oil Acetone (ppm) (ppm) (ppm) 0.2 0.2 0.2 0.2 0.2' 0.2 0.96 0.2 0.2 0.2 0.2s1 (0.1) 0.2 0.3s1 (Q.I) 0.3" (0.1) 0.2 0.2 OJ^O.!)" 0.6" (0.6) 0.2d 0.2 0.2 Positive 0 ontrols 1Fest Substance 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) H-24002 (ppm) 1.9 (0.4) 6.0 (0.4) 7.3 (0.5) 3.1 (0.2) 1.8 (0.2) 0.6 (0.1) 0.3 (0.0) Mean of 4 of the 5 values. One of the values was below the level of detection (LOD). Standard deviation is in parentheses. Mean of 3 of the 5 values. Two of the values were below the LOD. One value. Four of the values were below the LOD. Mean of 2 of the 5 values. Three of the values were below the LOD. -21- c.^^."".--"1^"' H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 TABLE 4 MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE Test Days 1 5 10 13 24 52 94 Positive Controls Test Substance H-24019 H-24020 H-24002 pM F Equivalents 28.92 (13.3)' pM F Equivalents___pM F Equivalents 89.28 (23.4) 9.35 (2.0) 747.69 (271.5) 518.12 (44.9) 32.26 (2.4) 945.85 (43.5) 391.01 (56.8) 39.60 (2.6) 989.85 (116.9) 191.45 (82.7) 16.13 (1.3) 645.54 (42.9) 74.35 (22.1) 8.90 (0.9) 411.38 (40.6) 4.64 (1.1) 2.00 (0.6) 195.38 (32.5)_____0.24 (0.4)_______0.45 (0.3) a Standard deviation is in parentheses. "22- ^nifcedDoesno^contalnTSCACBI Company Sanitized."" H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 FIGURES '23 " ^ ^ ^ i:f, -. ^ --- ,' ^ c-l -"^- Hzed. Dees nol contain TSCA CBt H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats 400 -i 350 -^ 300 -M 250 a I>> 200 -B 0 ea I 150 100 FIGURE 1 MEAN BODY WEIGHTS (g) --0--Negative Contr n Negative Contr A Negative Contr --^--Positive Contro --916--Positive Contro ----Test Substance 6 8 Test Days 10 12 -24- H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 FIGURE 2 MICROMOLAR EQUIVALENTS IN RAT BLOOD A. Normalized Rat Blood H-24019 pM Equivalents Resulting from a 10-Day Oral Gavage Micromolar (/iM) 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. NormalizedRatBIoo(lH-24020f(M Equivalents Resulting from a 10-Day 0 ralG avage Micromolar QiM) 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. -25- TSCACBl Company Samt^ ooes not contain H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 C. Normalized Rat Blood H-24002 pM Equivalents Resulting from a 10-Day Oral Gavage Micromolar (jiiM) equivalents of H-24002 (test substance) in rat blood resulting from a 10-day oral gavage exposure. Values are means and error bars are standard deviation. ftuioorfffl"'^088 26- co^--------.-. H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats FIGURES MICROMOLAR EQUIVALENTS IN TEST COMPOUND AND POSITIVE CONTROLS -27- .empany Sanitized H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 APPENDICES - 28 - company Sanitized. Does notconiam .^GBJ H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 APPENDIX A Individual Body Weights "5-----------------,,,O o.-"""-"""6*081 Comp"> Saniti""- H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats INDIVIDUAL BODY WEIGHTS ABBREVIATIONS: SD - sacrificed by design EXPLANATORY NOTES DuPont-2926 .Company Sanitized. Does not contain TSCA CB1 H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 632649 632650 632651 632652 632653 DAY 1 208.8 223.3 238.6 243.4 210.5 DAY 2 208.2 231.1 243.1 240.0 210.5 DEIONIZED WATER (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP I TEST DAYS DAY 3 DAY 4 DAY 5 219.8 239.3 253.6 253.0 217.6 225.1 243.7 260.8 257.3 223.0 240.4 261.7 276.7 272.4 236.0 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 .31- San,tU.d Coropaoy H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 632654 632655 632656 632657 632658 DAY 1 210. 1 234. 4 236. 4 251. 5 220. 8 DAY 2 217. 0 238. 1 243. 5 255. 0 227. 5 ANIMAL NUMBER 632654 632655 632656 632657 632658 DAY 8" DAY 9 282. 8 . 286. 6 295. 4 307. 1 286. 5 317. 0 274. 3 286. 1 324. 3 278. 2 DEIONIZED'WATER (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS TISST DAYS DAY 3 DAY 4 GROUP II DAY 5 DAY 6 DAY 7 227. 9 248. 1 250. 2 265. 0 235. 1 236.0 258.7 258.0 277.0 240.8 248. 5 265. 7 261. 9 292. 0 249. 3 259 .9 278 .0 272 .2 297 .3 256 .7 270.6 289.3 280.3 308.0 264.1 TEST DAYS DAY 10 303. 1 315. 8 294. 5 329. 6 286. 0 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 -32- Company Sanitized. H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 632659 632660 632661 632662 632663 Day 1 199. 9 232. 6 238. 1 248. 1 219. 4 Day 2 208. 0 238. 9 243. 1 255. 5 227. 9 DEIONIZED WATER (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS TEST DAYS Day 3 Day 4 GROUP III Day 5 Day 6 Day 7 211. 0 240. 7 247. 4 261. 5 229. 9 220.9 251.8 258.1 269.7 241.7 231.0 260.8 265.7 279.8 249.9 238.9 268.0 273.5 286.2 257.7 247.8 275.7 285.0 292.8 265.2 ANIMAL NUMBER 632659 632660 632661 632662 632663 Day 8 Day 9 254. 1 - 261. 5 279. 4 286. 1 291. 8 302. 4 297. 0 272. 0 302. 4 276. 4 . TEST DAYS Day 10 Day 13 270. 0 296. 3 304. 5 309. 2 285. 1 293.1 309.1 334.9 331.1 299.9 SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13 -33. Company Sanitized. H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 632664 632665 632666 632667 632668 ANIMAL NUMBER 632664 632665 632666 632667 632668 Day 1 208.2 228.3 245.8 254.3 218.7 Day 8 256.0 288.0 314.6 319.9 291.6 Day 2 213 .9 236 .6 251 .0 262 .3 226 .8 Day 9 262 .8 297 .9 326 .9 330 .0 301 .7 DEIONIZED WATER (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP IV TEST DAYS Day 3 Day 4 Day 5 Day 6 Day 7 219. 9 244. 9 263. 4 272. 0 238. 5 226.1 252.4 273.8 285.6 249.3 236. 6 264. 0 282. 8 293. 6 260. 3 242.9 274.3 297.4 300.6 270.1 252. 6 282. 1 310. 0 315. 2 282. 0 TEST DAYS Day 10 Day 13 273. 2 ^a 306. 5 a 334. 0 a 342. 1 a 314. 7 a Day 18 318. 2 367. 1 398. 1 414. 4 385. 7 Day 24 349.0 408.5 441.8 460.4 437.5 SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24 a Rats not weighed. -34- Company Sanitized. H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 632669 632670 632671 632672 632673 Day 1 194. 4 224. 5 226. 8 256. 3 217. 3 Day 2 197. 8 228. 6 230. 9 267. 1 224. 8 DEIONIZED WATER (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP V TEST DAYS Day 3 Day 4 Day 5 Day 6 Day 7 202 .5 237 .4 237 .2 272 .4 230 .8 209.5 246.7 243.5 281.3 241.3 215.1 251.9 249.0 295.1 248.2 221.4 259.9 256.9 304.6 258.6 228.1 268.8 262.0 315.4 265.7 ANIMAL NUMBER 632669 632670 632671 632672 632673 Day 8 Day 9 234. 3 - 232. 6 271. 0 268. 0 271. 0 273. 6 319. 4 328. 4 268. 9 276. 4 . TEST DAYS Day 10 Day 13 239 .6 a 280 .9 a 276 .0 a 334 .8 a 285 .2 a Day 18 278.1 328.3 308.4 389.8 335.6 Day 24 Day 25 -a 301.2 a 361.5 a 346.2 -a 441.1 -a 370.8 ANIMAL NUMBER 632669 632670 632671 632672 632673 Day 32 322. 8 389. 9 378. 5 377. 5 400. 9 Day 39 355. 5 415. 7 421. 9 517. 0 433. 8 TEST DAYS Day 46 Day 52 366 .6 434 .9 434 .6 542 .7 457 .3 392.4 449.1 456.4 566.6 484.2 SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52 a Rats not weighed. .35- S.nnUed.D Compa^ H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 632674 632675 632676 632677 632678 Day 1 197.0 228.8 238.3 238.1 211.3 Day 2 205.1 239.3 243.2 240.7 227.6 DEIONIZED WATER (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS TEST DAYS Day 3 Day 4 GROUP VI Day 5 Day 6 Day 7 214.1 243.1 252.0 248.2 233.9 221.7 255.3 259.8 255.9 244.4 232.7 264.9 270.3 261.7 253.6 242.0 271.8 280.9 276.0 262.6 250.9 278.0 289.4 282.0 266.0 ANIMAL NUMBER 632674 632675 632676 632677 632678 Day 8 Day 9 261.7 285.7 294.1 289.0 278.3 - 266.0 291.6 300.3 298.0 286.3 TEST DAYS Day 10 Day 13 276.7 a 296.7 a 309.8 a 302.7 a 291.4 a Day 18 336.2 352.9 368.3 356.9 351.4 Day 24 a a a a a Day 25 380.4 389.6 411.3 397.5 387.6 ANIMAL NUMBER 632674 632675 632676 632677 632678 Day 32 419.5 433.4 441.0 423.9 419.3 Day 39 465.7 482.3 484.3 458.8 460.1 TEST DAYS Day 46 Day 52 471.8 485.0 502.4 472.8 467.2 508.2 536.0 530.2 492.8 487.8 Day 53 529.6 540.7 552.8 514.7 502.0 Day 60 545.8 584.8 565.0 525.1 518.0 Day 67 566.2 592.2 571.8 536.4 523.5 a Rats not weighed. -36- Con.panysan^ H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 632674 632675 632676 632677 632678 Day 74 581.9 612.8 587.0 544.2 539.3 Day 81 DEIONIZED WATER (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS TEST DAYS Day 88 Day 94 GROUP VI 583.5 645.4 605.1 562.0 551.6 548.9 652.9 603.2 569.4 548.5 SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94 a Rats not weighed. -37- C.n,py8an,ze<.C-- H-24002: 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 TEST DAYS DAY 3 DAY 4 DAY 5 223.5 223.5 263.3 241.9 239.1 236.9 233.5 273.6 254.4 252.4 247.7 240.1 283.7 265.0 260.2 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 38- Company Ban^uoe.uu H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627793 627797 627799 627800 627808 ANIMAL NUMBER 627793 627797 627799 627800 627808 DAY 1 214. 8 239. 9 228. 9 246. 9 235. 6 DAY 2 224. 4 245. 9 231. 4 252. 8 241. 6 DAY 8 270. 6 303. 9 280. 2 312. 0 303. 6 DAY 9 274. 9 305. 1 284. 3 315. 4 305. 7 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP II TE ST r)AY1 DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 232 .1 257 .3 242 .3 265 .2 250 .1 243.1 267.5 246.2 279.3 262.1 TEST DAYS DAY 10 249 .9 280 .7 258 .9 283 .6 270 .4 257. 0 288. 0 261. 5 295. 5 284. 1 262 .0 290 .9 266 .4 300 .1 287 .4 283 .5 324 .2 294 .7 331 .3 321 .8 3D test day 10 3D test day 10 3D test day 10 3D test day 10 3D test day 10 -39- Company Sanitized. Doe H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627796 627806 627807 627809 627816 ANIMAL NUMBER 627796 627806 627807 627809 627816 DAY 1 239. 8 227. 3 221. 5 234. 2 235. 0 DAY 2 249. 7 234. 2 225. 9 240. 4 238. 6 DAY 8 285. 9 282-. 8 270. 7 297. 9 291. 8 DAY 9 290. 1 285. 8 274. 7 300. 2 296. 4 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP III TE ST r 1AYS 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 -40- Con-pany Sanfcd. Do H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627791 627794 627804 627812 627817 ANIMAL NUMBER 627791 627794 627804 627812 627817 DAY 1 231.1 224.4 224.7 221.9 233.5 DAY 8 274.0 286.-1 267.2 278.2 277.8 DAY 2 235.4 233.0 228.8 231.5 231.3 DAY 9 279.1 289.5 270.6 282.7 280.4 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP ,IV TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 241.2 238.1 230.6 236.3 229.0 246.8 247.8 243.0 245.7 244.8 TES':f DAYS DAY 10 DAY 13 255 .9 260 .0 251 .7 255 .5 255 .4 DAY 20 262 .6 267 .4 252 .9 264 .9 266 .4 DAY 24 268. 4 270. 1 259. 5 269. 5 270. 0 285.0 ^a 295.4 a 278.1 & 294.3 3. 294.6 a 334 .4 377 .4 345 .8 356 .5 368 .7 365 .6 416 .7 378 .1 388 .4 407 .3 SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24 a Rats not weighed. -41- S.nWa.Do ompa"y H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627792 627798 627813 627814 627815 ANIMAL NUMBER 627792 627798 627813 627814 627815 ANIMAL NUMBER 627792 627798 627813 627814 627815 DAY 1 235. 8 241. 1 214. 8 217. 5 230. 1 DAY 2 240 .8 253 .4 219 .2 220 .5 242 .2 DAY 8 282. 4 294= 3 258. 7 248. 0 289. 2 DAY 9 286 .4 296 .3 259 .2 250 .7 293 .4 DAY 41 456. 5 470. 7 395. 0 358. 7 462. 6 DAY 47 482 .3 496 .9 407 .2 372 .7 487 .3 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP V TEST I )AYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 244.3 257.6 220.5 223.7 243.8 247.9 266.1 233.2 225.2 255.7 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 34 295.2 ^a 315.7 a 267.9 a 257.3 a 303.3 a TEST DAYS DAY 52 360 .0 380 .2 323 .6 299 .3 368 .3 389 .2 403 .5 342 .3 319 .4 396 .5 426 .1 443 .1 367 .9 343 .7 434 .9 496.8 517.3 416.8 386.9 505.9 SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52 a Rats not weighed. -42- Company Sanitized. Does H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627795 627811 627819 627820 627821 ANIMAL NUMBER 627795 627811 627819 627820 627821 ANIMAL NUMBER 627795 627811 627819 627820 627821 DAY 1 218 .0 228 .6 248 .8 225 .5 227 .5 DAY 2 219 .5 226 .3 255 .3 228 .9 233 .2 DAY 8 261 .4 273 '.0 304 .5 281 .3 272 .6 DAY 9 265 .0 276 .7 308 .0 282 .9 275 .3 DAY 41 384 .2 422 .0 505 .9 478 .0 411 .8 DAY 47 398 .0 439 .3 534 .9 504 .1 426 .1 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TEST I 3AYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 225.3 236.7 264.9 239.2 240.7 234 .3 246 .1 274 .4 247 .9 246 .1 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 34 270.7 ^a 285.6 a 324.3 ^a 292.4 ^a 281.8 ^a TEST DAYS DAY 52 DAY 55 308 .0 337 .8 399 .7 367 .2 330 .1 DAY 61 329 .8 360 .6 431 .2 393 .0 352 .9 DAY 68 362 .0 396 .4 472 .5 445 .5 385 .6 a 411 .1 435 .7 440 .7 a 455 .4 463 .0 473 .6 ^a 551 .7 574 .4 588 .6 a 529 .7 547 .1 558 .6 a 439 .1 459 .0 463 .3 a Rats not weighed. - ^ -43- ^zed.Oo83 H-24002: 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 GROUP VI TEST DAYS 627795 627811 627819 627820 627821 474.6 503.6 638.1 608.6 509.0 485.0 511.6 653.1 618.0 521.5 SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94 "44' Company <SaWnritlsizs"'d1- D- H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 625361 625363 625364 625380 625383 DAY 1 322.6 273.7 291.1 289.4 304.7 DAY 2 325.0 271.4 290.9 286.2 299.7 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP I TEST DAYS DAY 3 DAY 4 DAY 5 337.6 278.4 299.9 291.5 302.7 340.3 281.7 306.0 300.1 310.7 349.7 286.7 312.0 305.5 313.1 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 "^--------------------c.n.panyS^^.00 H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 625355 625362 625367 625368 625378 ANIMAL NUMBER 625355 625362 625367 625368 625378 DAY 1 280 .0 290 .3 301 .5 312 .3 309 .6 DAY 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 TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 293.0 303.5 315.6 326.0 327.3 297. 9 308. 9 320. 1 336. 4 328. 4 TEST DAYS DAY 10 306 .1 313 .8 327 .7 343 .7 333 .7 311 .2 315 .8 333 .7 347 .5 336 .6 315. 7 323. 8 345. 6 360. 8 346. 9 333.6 332.9 363.8 386.7 365.4 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 .46- c.n-p^-'"^" H-24002: 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 8 364 .2 319 ;8 373 .4 325 .6 347 .0 DAY 2 308. 8 286. 3 316. 7 300. 0 304. 6 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 -47- Company Sanded. Ooes not c H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 625354 625365 625371 625376 625381 ANIMAL NUMBER 625354 625365 625371 625376 625381 DAY 1 303 .0 327 .7 294 .5 289 .7 297 .8 DAY 8 336 .2 370 .5 340 .3 331 .5 321 .6 DAY 2 304. 1 328. 7 299. 0 289. 9 297. 5 DAY 9 337. 0 379. 3 345. 9 339. 0 329. 1 ''^y CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP IV TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 310.5 337.9 313.4 302.2 301.7 312 .2 343 .6 318 .3 304 .9 305 .6 TEST DAYS DAY 10 DAY 13 319.3 357.7 321.8 313.2 314.4 DAY 20 324 .7 357 .2 329 .6 317 .0 314 .4 DAY 24 331.2 364.3 338.5 322.8 321.0 348.8 381.2 351.2 345.2 331.6 355 .8 407 .1 372 .6 363 .2 341 .2 377.7 438.2 413.0 399.7 358.2 396 .1 459 .6 447 .3 432 .9 381 .8 SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24 -48- Sanife^0035"01 Comp3^ H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OP 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 Rats not weighed. -49- Company Sanltl^d. Does no H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 625353 625369 625373 625375 625377 ANIMAL NUMBER 625353 625369 625373 625375 625377 ANIMAL NUMBER 625353 625369 625373 625375 625377 DAY 1 305.9 281.7 294.6 289.1 293.9 DAY 2 307.3 279.9 301.3 291.0 294.8 DAY 8 3 44 ..7 307.3 340.6 324.7 325.0 DAY 9 352.7 311.9 348.2 336.0 333.7 DAY 34 453.3 388.2 477.1 455.6 419.1 DAY 52 a a a a a CORM OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 316.8 289.7 312.7 298.0 302.9 325.0 286.9 317.0 307.0 312.0 TEST DAYS DAY 10 DAY 13 331. 7 292. 8 325. 4 309. 6 318. 0 DAY 20 330.1 295.3 329.0 314.2 317.4 DAY 24 342.5 303.8 334.6 323.5 325.0 DAY 27 358.1 371.7 399. 1 a 317.2 331.1 347. 6 a 352 .6 371.5 402. 3 ^a 336.9 350.1 387. 9 ^a 340.7 353.5 376. 3 a TEST DAYS DAY 76 DAY 90 DAY 94 427.7 374.9 444.6 432.3 405.2 544.9 483.8 628.8 567.3 470.3 562.8 505.3 661.3 589.8 492.0 565 .3 514 .8 673 .7 588 .8 496 .6 SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94 a Rats not weighed. .50- Company Sanifeed. Does not c H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 625322 625323 625336 625343 625349 DAY 1 290.3 285.0 316.5 288.2 303.6 DAY 2 283.7 285.5 313.5 281.9 295.9 H-24019 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP I TEST DAYS DAY 3 DAY 4 DAY 5 291.5 290.2 320.1 286.8 308.2 298.9 290.9 327.1 291.0 310.1 298.0 294.0 329.0 293.7 318.1 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 .51- Company Sanitized. Does H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 625320 625330 625332 625341 625350 ANIMAL NUMBER 625320 625330 625332 625341 625350 DAY 1 279. 3 286. 7 300. 0 304. 9 257. 1 DAY 8 308. 5 314: 0 324. 1 332. 4 279. 8 DAY 2 283 .0 286 .1 295 .9 309 .0 268 .5 DAY 9 306 .3 312 .6 321 .8 320 .3 282 .5 H-24019 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS GROUB II TE ST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 287 .7 291 .1 304 .1 317 .5 267 .3 288.4 296.5 308.8 320.0 272.2 TEST DAYS DAY 10 295 .9 304 .0 315 .0 325 .1 272 .6 299 .4 302 .3 322 .4 327 .5 276 .3 300 .6 306 .7 320 .7 327 .4 283 .6 312 .1 310 .1 318 .3 325 .6 284 .3 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 .52- Con,p Santod. ^ H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 62532.1 625327 625342 625345 625348 AMIMAL NUMBER 625321 625327 625342 625345 625348 DAY 1 307. 0 311.4 273. 7 291. 2 265. 5 DAY 8 337. 8 334, 3 304. 3 317. 3 302. 7 DAY 2 307. 8 306. 6 275. 5 291. 7 258. 6 DAY 9 339. 6 337. 0 305. 9 312. 9 306. 5 H-24019 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP III TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 311.4 312.5 282.3 297.3 268.0 319 .6 317 .8 285 .8 303 .3 275 .2 TEST DAYS DAY 10 DAY 13 322. 3 318. 3 290. 8 306. 4 280. 1 328. 4 319. 3 294. 2 310. 4 285. 2 335. 2 327. 6 326. 6 316. 1 290. 6 346.1 336.3 307.8 315.0 309.7 371 .2 355 .3 324 .4 336 .9 336 .4 SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13 .53- Coinpa"^ s,^."---- H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 625325 625328 625338 625340 625352 ANIMAL NUMBER 625325 625328 625338 625340 625352 DAY 1 282 .8 315 .6 264 .6 304 .0 285 .5 DAY 8 318 .6 352 .0 287 .4 347 .0 316 .9 DAY 2 285.9 315.2 261.9 309.2 283.9 DAY 9 321.9 351.7 291.3 352.2 322.3 H-24019 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS GROUP IV TE ST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 291 .7 323 .9 268 .5 316 .9 289 .1 295 .5 327 .7 272 .6 326 .0 299 .6 TEST DAYS DAY 10 DAY 13 303 .2 335 .0 275 .7 329 .8 307 .9 DAY 20 309. 2 340. 4 281. 9 334. 1 308. 2 DAY 24 308.3 340.1 284.4 338.4 312.4 327 .4 357 .5 290 .2 359 .2 321 .0 331 .6 367 .4 291 .1 368 .1 329 .6 355 .8 400 .2 320 .4 389 .3 355 .7 381. 3 423. 9 339. 9 419. 0 375. 3 SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24 -54- Company Sanitized. Does not contain H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER DAY 1 DAY 2 H-24019 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS GROUP V TES T DA'iirs 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 .1 326 .8 351 .6 313 .5 304 .2 - DAY 24 DAY 27 625324 625329 625333 625334 625344 ANIMAL NUMBER 332 .5 337 .9 336. 1 299 .6 336 .0 a 352 .-5 360 .1 357. 0 364 .3 396 .4 --a 315 .8 316 .7 319. 3 325 .8 349 .2 --a 292 .6 302 .2 305. 8 312 .0 338 .6 --a 280 .7 285 .2 289. 3 295 .8 309 .7 a DAY 34 DAY 52 TEST DAYS 380 .3 423 .3 375 .2 368 .8 330 .4 625324 625329 625333 625334 625344 397 .3 442 .7 384 .6 384 .2 348 .3 447 .4 498 .1 427 .4 426 .5 391 .0 SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52 a Rats not weighed. 55- Company Sanitized. Doss -^ con H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 625326 625335 625346 625347 625351 ANIMAL NUMBER 625326 625335 625346 625347 625351 ANIMAL NUMBER 625326 625335 625346 625347 625351 DAY 1 313 .2 301 .0 290 .2 266 .0 310 .6 DAY 2 317.1 303.6 293.4 275.6 310.9 DAY 8 311 .5 294 ;2 292 .9 330 .5 351 .1 DAY 9 308.9 285.3 290.8 330.1 357.8 DAY 34 427 .5 427 .0 407 .4 466 .4 483 .3 DAY 52 a a a a ^a H-24019 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TE ST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 325 .5 302 .3 300 .2 287 .7 321 .1 330 .9 310 .4 309 .5 300 .0 329 .6 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 27 297 .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 94 497 .5 506 .0 485 .8 568 .6 559 .0 540 .0 538 .6 523 .7 617 .8 596 .8 547 .9 547 .7 532 .8 618 .1 607 .2 565 .2 562 .1 542 .4 632 .6 624 .0 577.5 579.5 556.9 638.9 636.8 SD test d SD test d SD test d SD test d SD test d a Rats not weighed. -56- Company Sanstisad. Does not c H-24002: 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 TEST DAYS 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 .57- Coffipany Sans'.'ascL Dees not c H-24002: 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 8 272, 3 319. 8 246. 1 251. 0 260. 7 DAY 2 244 .1 261 .6 216 .3 228 .3 221 .7 DAY 9 291 .9 326 .3 252 .3 264 .0 268 .5 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP II TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 245.2 275.8 223.7 237.3 234.7 256.5 283.4 226.6 239.0 238.4 TEST DAYS DAY 10 256. 2 289. 3 229. 6 238. 8 241. 8 265 .5 301 .5 233 .7 244 .7 250 .5 271.4 303.2 236.9 246.7 255.6 293.5 338.2 254.4 268.2 267.9 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 .58. Company Sanitised. Does not H-24002: 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 8 280 .6 255 .-2 275 .8 221 .7 274 .1 DAY 2 240. 3 218. 3 235. 0 241. 0 222. 3 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 .59- Company Sanifeed. Does not H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627759 627761 627770 627779 627786 ANIMAL NUMBER 627759 627761 627770 627779 627786 DAY 1 226 .6 240 .7 235 .6 231 .5 211 .6 DAY 8 277 .8 240 .-1 291 .4 289 .0 251 .3 DAY 2 232.9 247.4 244.3 237.9 218.2 DAY 9 284.9 257.4 301.3 293.4 255.8 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS GROUP IV TE ST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 241 .4 257 .1 253 .6 252 .6 222 .5 250.9 262.5 260.1 261.4 230.4 TE ST 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 24 265.4 262.6 279.8 277.5 244.1 288 .0 ^a 266 .9 a 306 .4 a 301 .0 a 257 .0 a 348 .0 335 .7 355 .8 374 .4 304 .4 380 .1 359 .4 379 .8 406 .2 326 .1 SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24 a Rats not weighed. .60Sanji&r1'd, Qoss H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627757 627760 627765 627772 627781 ANIMAL NUMBER 627757 627760 627765 627772 627781 ANIMAL NUMBER 627757 627760 627765 627772 627781 DAY 1 221 .2 226 .2 228 .3 245 .2 219 .0 DAY 2 225 .4 232 .0 235 .3 256 .4 226 .3 DAY 8 269 .1 262 ;6 271 .5 300 .9 258 .1 DAY 9 276 .7 280 .3 282 .4 307 .5 266 .8 DAY 41 402 .8 437 .7 422 .9 478 .4 389 .9 DAY 47 419 .7 448 .9 444 .8 494 .3 408 .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 7 236.3 244.4 247.1 266.2 236.5 241. 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 34 279.7 ^a 287.3 a 288.1 a 317.0 a 271.2 a TEST DAYS DAY 52 324 .3 348 .6 349 .8 375 .5 315 .1 343 .0 379 .9 382 .7 404 .0 338 .8 372 .3 419 .4 400 .9 446 .9 372 .0 436.7 456.5 455-6 513.5 421.0 SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52 a Rats not weighed. .61- Company Sanitised. Doss H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627762 627769 627775 627778 627783 ANIMAL NUMBER 627762 627769 627775 627778 627783 ANIMAL NUMBER 627762 627769 627775 627778 627783 DAY 1 227 .2 231 .1 224 .7 213 .1 216 .4 DAY 2 235.0 241.1 235.7 217.4 218.2 DAY 8 285 .9 302 -.0 286 .6 244 .8 256 .6 DAY 41 438 .7 479 .7 433 .2 356 .8 409 .6 DAY 9 299.1 309.6 296.0 250.8 259.2 DAY 47 439.9 474.6 451.1 373.5 426.9 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TE ST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 248 .7 255 .9 246 .8 221 .3 226 .6 257.3 264.2 254.7 225.5 232.0 TE ST 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 34 301 .5 a 312 .5 a 304 .5 a 255 .1 a 264 .3 a. TE ST 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 a 453.5 473.0 471 .6 a 512.2 511.4 531 .4 a 460.8 477.4 478 .6 a 386.0 393.3 398 .3 ^a 449.0 473.8 474 .8 a Rats not weighed. .62- Company Sanitise H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627762 627769 627775 627778 627783 DAY 81 500.3 566.2 510.4 410.1 508.8 DAY 90 523.3 603.2 537.5 436.5 538.5 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 -63- Company SanEtizeci. Doss H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats AMIMAL NUMBER 628192 628195 628207 628211 628212 DAY 1 227.2 245.6 238.0 220.1 252.0 DAY 2 224.9 250.7 241.3 224.3 250.9 H-24002 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP I TEST DAYS DAY 3 DAY 4 DAY 5 236.5 261.4 253.4 233.4 267.8 244.2 265.9 261.0 239.6 271.0 251.3 279.5 269.9 250.9 281.1 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 -64- Company Sanitized. D H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 628187 628188 628199 628209 628217 DAY 1 240 .1 258 .1 253 .4 229 .5 218 .0 DAY 2 246. 4 261. 5 255. 3 238. 2 224. 4 H-24002 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS GROUP II TE ST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 258 .3 269 .2 263 .6 247 .6 234 .1 266.1 279.0 274.6 253.9 239.2 277 .4 292 .3 273 .6 259 .5 250 .6 284.5 299.3 284.1 268.7 256.5 287.8 302.6 289.4 272.5 260.1 ANIMAL NUMBER 628187 628188 628199 628209 628217 DAY 8 306 .-5 313 .4 302 .3 285 .3 270 .7 DAY 9 311. 2 320. 9 306. 6 291. 2 272. 5 TEST DAYS DAY 10 314 .4 328 .1 315 .3 299 .3 283 .4 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 -65- Company Sanitized. Dos H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 628190 628202 628204 628206 628214 DAY 1 230 .1 220 .2 255 .6 236 .8 239 .6 DAY 2 235. 0 223. 8 257. 2 238. 8 243. 7 H-24002 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP III TE ST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 241 .3 233 .7 267 .7 244 .6 249 .8 249 .5 238 .7 277 .4 254 .3 254 .2 256. 2 250. 6 283. 8 261. 5 262. 0 269. 3 252. 2 293. 9 267. 4 265. 1 273 .0 255 .3 296 .4 269 .6 268 .1 ANIMAL NUMBER 628190 628202 628204 628206 628214 DAY 8 281 :5 280 .4 318 .2 284 .9 275 .8 DAY 9 287. 1 283. 9 325. 6 290. 0 276. 7 TEST DAYS DAY 10 DAY 13 291 .3 294 .7 330 .8 296 .5 285 .4 314 .2 318 .6 361 .0 320 .0 296 .9 SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13 -66- Company Sanity. D^n H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 628197 628198 628201 628203 628216 DAY 1 229. 5 238. 3 216. 6 234. 0 223. 9 DAY 2 233. 5 239. 0 226. 1 239. 2 224. 9 H-24002 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP IV TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 240.7 247.1 233.5 251.0 231.9 249 .5 259 .0 239 .7 263 .7 238 .1 258.3 266.0 246.5 271.4 245.3 258. 5 277. 7 250. 5 275. 6 246. 2 260. 9 281. 1 254. 3 278. 1 249. 6 ANIMAL NUMBER 628197 628198 628201 628203 628216 DAY 8 273: 9 287. 8 266. 5 297. 6 263. 6 DAY 9 277 . 0 298. 0 269. 2 300. 9 267. 2 TEST DAYS DAY 10 DAY 13 283.0 a 302.7 a. 277.5 a. 311.3 a 271.2 a DAY 20 328.0 352.9 337.0 390.2 323.5 DAY 24 345. 6 378. 8 362. 8 423. 4 348. 9 SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24 a Rats not weighed. .67- 'Companx Sanitizad. Doss n H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 628191 628196 628208 628210 628215 DAY 1 222 .1 233 .7 253 .7 238 .8 224 .3 DAY 2 225 .8 239 .7 258 .5 244 .2 234 .3 H-24002 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP V TE ST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 233 .3 246 .0 264 .8 254 .6 242 .5 241 .8 260 .5 270 .8 263 .4 249 .0 249.6 266.8 279.9 274.5 259.2 253 .6 275 .0 288 .8 280 .8 266 .7 257 .3 276 .9 291 .5 283 .1 269 .4 ANIMAL NUMBER 628191 628196 628208 628210 628215 DAY 8" 275 .-0 299 .9 300 .2 298 .8 283 .3 DAY 9 283 .5 309 .9 304 .5 306 .8 293 .4 TEST DAYS DAY 10 DAY 13 291 .6 ^a 316 .6 a 316 .2 a 314 .5 a 301 .1 ^a DAY 20 352.6 403.0 394.1 389.4 367.0 DAY 24 --a a a a ^a DAY 27 396. 6 451. 0 437. 6 435. 2 404. 9 ANIMAL NUMBER 628191 628196 628208 628210 628215 DAY 3" 3 425 .3 479 .0 462 .2 470 .0 435 .2 DAY 41 457 .1 509 .5 490 .1 501 .1 469 .6 TEST DAYS DAY 47 DAY 51 482 .5 539 .6 516 .9 523 .5 493 .2 498 .3 565 .9 543 .3 542 .0 514 .0 SD test day 51 SD test day 51 SD test day 51 SD test day 51 SD test day 51 a Rats not weighed. 68Company San'stasd. Oo H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 628194 628200 628213 628218 628219 DAY 1 221. 3 222. 5 250. 9 236. 4 228. 5 DAY 2 229 .5 229 .3 259 .9 245 .1 232 .1 H-24002 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TE ST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 236 .4 238 .4 271 .6 256 .0 241 .0 242 .5 243 .8 280 .0 264 .6 248 .7 253 .2 251 .1 289 .9 274 .9 256 .0 262. 2 258. 5 297. 8 280. 9 266. 7 266.1 260.4 300.2 283.4 268.7 ANIMAL NUMBER 628194 628200 628213 628218 628219 DAY 8 282." 5 271. 3 315.4 303. 1 278. 0 DAY 9 287 .6 281 .8 322 .8 304 .7 285 .4 TEST DAYS DAY 10 DAY 13 292 .9 Q. 289 .6 a 332 .0 --a 313 .8 ^a 295 .3 a DAY 20 363 .1 348 .2 401 .1 374 .7 346 .0 DAY 24 a a a a ^a DAY 27 403.5 385.3 441.5 415.4 388.6 ANIMAL NUMBER 628194 628200 628213 628218 628219 DAY 33 434. 1 416. 8 458. 6 446. 7 420. 8 DAY 41 460 .6 444 .6 478 .3 472 .1 454 .1 TEST DAYS DAY 47 DAY 51 487 .0 --a 465 .1 a 501 .6 a 506 .8 a 478 .9 a DAY 54 501 .0 469 .5 525 .5 535 .6 501 .2 DAY 60 522. 8 488. 3 539. 5 552. 1 526. 8 a Rats not weighed. 69- a&i^a."^ 6ansu..c^. s^-ss H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 628194 628200 628213 628218 628219 DAY 76 556.5 521.9 584.2 586.6 562.4 DAY 82 567.5 534.2 597.3 610.6 581.1 H-24002 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TEST DAYS DAY 88 DAY 94 567.8 547.2 605.2 625.4 586.4 578.2 556.4 609.7 633.8 591.2 SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94 -70- Company Sanitized. D H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 APPENDIX B Individual Clinical Observations 71- Company Sanltizsd. Does not contain TSCA CBI H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 Animal Number 632649 632650 632651 632652 632653 DEIONIZED WATER (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 632654 632655 632656 632657 632658 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 632659 632660 632661 632662 632663 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 -72- ftUl^.TSCACBI Company Sam&ea .poss not H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 Animal Number 632664 632665 632666 632667 632668 DEIOWIZED WATER (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 632669 632670 632671 632672 632673 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 632674 632675 632676 632677 632678 GROUP VI Observation No abnormalities detected Hair Loss, Forelimb, Bilateral No abnormalities detected Hair Loss, Forepaw, Bilateral No abnormalities detected No abnormalities detected Hair Loss, Forepaw, Bilateral No abnormalities detected Test Day 1-88 94 ' 1-81 88-94 1-94 1-53 60-94 1-94 -73- .....,,, .^^^^<3chcw- H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 Animal Number 627789 627801 627805 627810 627818 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP I __________Observation__________________Test Day Mo 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 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 -74- onspany Sanstssd. Doss not contain TSCA CB5 H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 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 -75- 'o-r^eo-^-TSCACI H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 Animal Number. 625361 625363 625364 625380 625383 CORN OIL:ACETONE (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 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 -76- Companx Sanitized. Does not contain TSCA CBI H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 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 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 -77- ^^ffl%5anaized. Does sot contain TSCA CBi H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 Animal Numbe)- 625322 625323 625336 625343 625349 H- 24019 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP I Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-5 1-5 1-5 1-5 1-5 Animal Number 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 -78- Company Sanifeed. Does not cantein TSCA CBI. H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 Animal Number 625325 625328 625338 625340 625352 H-24019 (POSITIVE CONTROL) INDIVIDUAL 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 -79- Company Sanitized. Does not contain TSCA CBt H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats H-24020 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS DuPont-2926 Animal Number 627756 627767 627771 627773 627777 GROUP I Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-5 1-5 1-5 1-5 1-5 Animal Number 627768 627774 627776 627782 627785 GROUP II Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-10 1-10 1-10 1-10 1-10 Animal Number 627758 627763 627764 627787 627788 GROUP III Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Wet perineum No abnormalities detected Diarrhea Test Day 1-13 1-13 1-13 1-5, 7-13 6 1-8, 10-13 9 -80- ppropal^ Sanmzed. Does not contain is^CBl H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats H-24020 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS DuPont-2926 Animal' Number 627759 627761 627770 627779 627786 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 -81- C-ya^ws Sanste-s:^"- ^vfi..n-t contain TSCACBl H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 Animal Number 628192 628195 628207 628211 628212 H-24002 (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 1-5 1-5 1-5 1-5 1-5 Animal Number 628187 628188 628199 628209 628217 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 628190 628202 628204 628206 628214 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 -82- Company SanESized. Does noi conlaEn T8CA COS H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 Animal Number 628197 628198 628201 628203 628216 H-24002 (TEST SUBSTANCE) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP IV Observation___________________Test Day No abnormalities detected No abnormalities detected No abnormalities detected Alopecia right front paw No abnormalities detected No abnormalities detected 1-24 1-24 1-10 20, 24 1-24 1-24 Animal Number 628191 628196 628208 628210 628215 GROUP V Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-51 1-51 1-51 1-51 1-51 Animal Number 628194 628200 628213 628218 628219 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 H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 APPENDIX C Individual Fluorine Levels -84- Company Sanitised. Doss not contain TSCACBI H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 Terms: Active % Active Mol Wt Active Formulation Dose % Fin 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/I 00) 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/I 00) x Dose Active [mg/kg] Dose F (mmol/kg) The mmole of fluorine administered per kg of animal body weight = Dose F [mg/kg] / Mol Wt F [mg/mmol] Molar Ratio (Active/F) The moles of fluorine containing compound per mole of fluorine = Dose Active [mmol/kg] / Dose F [mmol/kg] Formulation Dose Normalization Factor The formulation dose that would be required to administer the amount of active needed to achieve the normalized dose = (Normalized dose of Active [mmol/kg] / Dose Active [mmol/kg]) x Formulation Dose "85" Company Sanitized. Does not contaHl TSCACM H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 TERMS AND CALCULATIONS Individual Animal Measurement: ppm F in blood The ppm fluoride measured in blood Individual Animal Calculations: ppm F in Blood minus Bkg 0.2 ppm ppm F in Blood normalized to 0.1 mmol/kg Dose 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. 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) fJimolar equivalents of active in blood The /imolar [/imol/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 /nnol/mmol -86- Company Sanitized. Doss not contain TSCA CBI H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2926 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 fluoridated 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 -S7- Cos'i-.pa;^ 3w^:^6. i-.^ nolcontaiR I3CACB1 H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Data for H- 24019 DuPont-2926 Given: Mol Wt. Active (g/mole): 497 Formulation Dose (mg/kg): 10 % Active (F Containing) in Formulation: 100 %F in Active: 65 Mol Wt. F (g/mol): 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 Day Sample ppmF in Blood Group I 625322 1.0 625323 1.3 62533(? 2.6 625343 2.6 625349 2.9 Group I 625322 625323 625336 625343 625349 51.7 38.0 38.7 78.5 37.1 Group II 625320 10 625330 10 625332 10 625341 10 625350 10 65.6 61.1 60.5 63.1 58.1 ppm F in Blood Minus Bkg 0.2 ppm 0.8 1.1 2.4 2.4 2.7 51.5 37.8 38.5 78.3 36.9 65.4 60.9 60.3 62.9 57.9 ppm F in Blood Normalized to 0.1 mmoles/kg Dose 3.98 5.47 11.93 11.93 13.42 255.96 187.87 191.35 389.15 183.39 325.04 302.67 299.69 312.61 287.76 /(molar Equivalents of Active in Blood 12.31 16.92 36.92 36.92 41.54 792.31 581.54 592.31 1204.62 567.69 1006.15 936.92 927.69 967.69 890.77 -88- Company Sanitized. Does not contain TSCA CBS H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Rat Number Test Day Sample ppmF in Blood Group III 625321 13 625327 13 625342 13 625345 13 625348 13 77.2 61.5 64.6 57.0 62.4 Group IV 625325 24 625328 24 625338 24 625340 24 625352 24 40.3 46.3 43.2 39.1 41.9 Group V 625324 52 625329 52 625333 52 625334 52 625344 52 24.7 29.8 27.3 29.1 23.8 Group VI 625326 94 625335 94 625346 94 625347 94 625351 94 12.4 16.4 13.1 11.0 11.6 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-2926 jxmolar 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 -89- Company Sanitized. Doss not contain TSCA CBI H-24002: Biopersistence Screening 10-Dose Oral Gayage Study in Rats Data for H-24020 DuPont-2926 Given: Mol Wt. Active (g/mole): 426 Formulation Dose (mg/kg): 20 % Active (F Containing) in Formulation: 100 %F in Active: 69 Mol Wt. F (g/mol): 19 Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor: 20 0.047 42.6 Dose F (mmol/kg): 0.726 Molar Ratio (Active/F): 0.065 Dose F (mg/kg):_____13.8 Rat Number Test Day Sample ppmF in Blood Group I 627773 13.2 627771 8.1 627767 16.5 627756 14.1 627777 10.7 Group I 627773 627771 627767 627756 627777 75.3 66.8 64.8 80.0 71.6 Group II 627768 10 627774 10 627776 10 627782 10 627785 10 56.3 51.0 54.8 43.6 65.1 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 [{.molar Equivalents of Active in Blood 27.69 16.83 34.72 29.61 22.37 94.20 57.25 118.12 100.72 76.09 159.96 141.86 137.60 169.97 152.08 544.20 482.61 468.12 578.26 517.39 119.49 108.20 116.30 92.44 138.24 406.52 368.12 395.65 314.49 470.29 -90- Sanil.'^6-' : r.Q2 co^s50 H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Rat Number Test Day Sample ppmF in Blood Group III 627758 13 627764 13 627787 13 627763 13 627788 13 43.5 20.7 13.2 30.8 24.9 Group IV 627759 24 9.2 627779 24 14.9 627770 24 11.6 627761 24 9.9 627786 24 6.7 Group V 627757 52 0.9 627781 52 0.6 627760 52 1.0 627765 52 0.9 627772 52 0.8 Group VI 627778 94 0.3 627783 94 0.2 627762 94 0.2 627775 94 0.2 627769 94 0.2 * = Below LOD (Level of Detection) 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 DuPont-2926 ^molar Equivalents of Active in Blood 92.23 43.67 27.69 65.18 52.61 313.77 148.55 94.20 221.74 178.99 19.17 31.31 24.28 20.66 13.85 65.22 106.52 82.61 70.29 47.10 1.49 0.85 1.70 1.49 1.28 5.07 2.90 5.80 5.07 4.35 0.21 * 0.00 0.00 * 0.72 * 0.00 0.00 * -91- Company Sanitized. Doas nol coniam TSCA CS! H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Data for H-24002 DuPont-2926 Given: Mol Wt. Active (g/mole): 570 Formulation Dose (mg/kg): 75 % Active (F Containing) in Formulation: 47 %FinA LCtive: 51 Mol Wt. F (g/mol): 19 Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor: 35.25 0.062 121.3 Dose F (mmol/kg): 0.946 Molar Ratio (Active/F): 0.065 Dose F (mg/kg):_____17.9775 Rat Number Test Day Sample ppmF in Blood Group I 628207 2.0 628195 1.6 628212 1.9 628211 2.4 628192 1.5 Group I 628207 6.1 628195 6.1 628212 6.0 628211 6.5 628192 5.3 Group II 628209 10 7.1 628187 10 8.1 628199 10 7.4 628188 10 6.9 628217 10 7.1 ppmF in Blood Minus Bkg 0.2 ppm 1.8 1.4 1.7 2.2 1.3 5.9 5.9 5.8 6.3 5.1 6.9 7.9 7.2 6.7 6.9 ppm F in Blood Normalized to 0.1 mmoles/kg Dose fimolar Equivalents of Active in Blood 2.91 2.26 2.75 3.56 2.10 10.01 7.79 9.46 12.24 7.23 9.54 9.54 9.38 10.19 8.25 32.82 32.82 32.26 35.04 28.37 11.16 12.77 11.64 10.83 11.16 38.38 43.94 40.05 37.27 38.38 -92- not contain tSCACBt Company Sanded. Does H-24002: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Rat Number Test Day Sample ppmF in Blood Group III 628202 13 3.3 628190 13 2.8 628206 13 3.3 628214 13 3.2 628204 13 2.9 Group IV 628201 24 1.8 628216 24 1.6 628197 24 2.0 628198 24 1.9 628203 24 1.7 Group V 628208 52 0.7 628191 52 0.4 628215 52 0.6 628196 52 0.6 628210 52 0.5 Group VI 628218 94 0.2 628213 94 0.3 628194 94 0.3 628200 94 0.3 628219 94 0.3 ppm F in Blood Minus Bkg 0.2 ppm 3.1 2.6 3.1 3.0 2.7 1.6 1.4 1.8 1.7 1.5 0.5 0.2 0.4 0.4 0.3 0.0 0.1 0.1 0.1 0.1 ppm F in Blood Normalized to 0.1 mmoles/kg Dose DuPont-2926 ^molar Equivalents of Active in Blood 5.01 4.20 5.01 4.85 4.37 17.24 14.46 17.24 16.69 15.02 2.59 2.26 2.91 2.75 2.43 8.90 7.79 10.01 9.46 8.34 0.81 0.32 0.65 0.65 0.49 2.78 1.11 2.23 2.23 1.67 0.00 0.16 0.16 0.16 0.16 0.00 0.56 0.56 0.56 0.56 -93- San^d.DoesnolconlainTSCACBl Company sar