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V 407 TRADE SECRET Study Title H-24159: Biopersistence Screening Gavage Study in Rats Laboratory Project ED: DuPont-6732 DuPont-6732 AUTHOR: Gregory S. Ladies, Ph.D., D.A.B.T. Study Completed on: January 24,2002 Performing Laboratory: E.I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 Work Request Number: Service Code Number Page 1 of 75 Company Sanitized. Does not contain TSCA CBS H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. Reviewed by: Reviewed by: Issued by Study Director: Paul Hinderliter, Ph.D. Postdoctoral Fellow Judith C. Stadler, Ph.D., D.A.B.T. Director Gregory S. Ladies, Ph.D., D.A.B.T. Senior Research Scientist Date h zo o 'z Date Date 2- __________ Company Sanitized, Does not contain TSCA S3" H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 TABLE OF CONTENTS Page C E R T IF IC A T IO N ................................................................................................................................. 2 LIST OF TABLES.................................................................................................................................5 LIST OF FIGURES...............................................................................................................................5 LIST OF APPENDICES...................................................................................................................... 6 STUDY INFORMATION.................................................................................................................... 7 STUDY PERSONNEL.......................................................................................................................... 8 S U M M A R Y .............................................................................................................................................9 INTRODUCTION................................................................................................................................ 10 MATERIALS AND M ETHODS...................................................................................................... 10 A. Test Substance...........................................................................................................................10 B. Test Species............................................................................................................................... 10 C. Animal Husbandry.................................................................................................................... 10 1. Housing Environment................................................................................................................................... 10 2. Feed and Water..............................................................................................................................................10 3. Identification.................................................................................................................................................11 4. Animal Health Monitoring Program............................................................................................................ 11 D. Quarantine and Pretest..............................................................................................................11 E. Study D esign.............................................................................................................................. 12 F. Assignment to Groups and Study Start................................................................................... 12 G. Dosing Material Preparation and Administration.................................................................. 12 1. Test Substance...............................................................................................................................................12 2. Negative Control............................................................................................................................................ 12' H. Body W eights.............................................................................................................................12 I. Mortality and Clinical Observations....................................................................................... 13 J. Collection of Blood, Urine, and Feces for Total Fluorine Level Evaluation...................... 13 K. Anatomical Pathology...............................................................................................................13 1. Dosing Phase.................................................................................................................................................13 2. Postdosing Phase.......................................................................................................................................... 13 L. Fluorine Analysis...................................................................................................................... 13 M. Statistical Methods.................................................................................................................... 14 RESULTS AND DISCUSSION........................................................................................................ 15 A. In-Life Toxicology.................................................................................................................... 15 B. Liver W eights.............................................................................................................................15 1. Test Substance...............................................................................................................................................15 C. Kidney Weights......................................................................................................................... 15 D. Fluorine D a ta .............................................................................................................................15 C O N C L U S IO N S .................................................................................................................................. 16 -3 Company Sanitized. Does noi contato TSCA CBI H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 RECORDS AND SAMPLE STORAGE......................................................................................... 16 REFERENCES..................................................................................................................................... 17 T A B L E S ................................................................................................................................................. 18 FIGURES...............................................................................................................................................32 APPENDICES...................................................................................................................................... 37 -4 Company Sanized Does noi contain TSCA CBI H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 LIST OF TABLES Page 1. MEAN BODY WEIGHTS.........................................................................................................................................19 2. MEAN BODY WEIGHT GAINS (g)........................................................................................................................ 21 3. MEAN BODY AND LIVER WEIGHTS (g )........................................................................................................... 25 4. MEAN BODY AND KIDNEY WEIGHTS (g)........................................................................................................ 26 5. MEAN BLOOD FLUORINE LEVELS....................................................................................................................27 6. MEAN BLOOD FLUORINE CONCENTRATION EXPRESSED IN x M EQUIVALENTS.............................28 7. MEAN LIVER FLUORINE LEVELS.......................................................................................................................29 8. MEAN LIVER FLUORINE CONCENTRATION EXPRESSED IN jtM EQUIVALENTS................................29 9. MEAN FAT FLUORINE LEVELS.......................................................................................................................... 30 10. MEAN FAT FLUORINE CONCENTRATION EXPRESSED IN p M EQUIVALENTS....................................30 11. MEAN KIDNEY FLUORINE LEVELS..................................................................................................................31 12. MEAN KIDNEY FLUORINE CONCENTRATION EXPRESSED IN /iM EQUIVALENTS.......................... 31 LIST OF FIGURES Page 1. MEAN BODY WEIGHTS (g).................................................................................................................................. 33 2. FLUORINE ( f i M EQUIVALENTS) IN RAT BLOOD...........................................................................................34 3. COMPARISON OF RELATIVE LIVER WEIGHT AND MEAN LIVER FLUORINE CONCENTRATION FOR H-24159 AND NEGATIVE CONTROL.................................................................... 35 4. COMPARISON OF MEAN LIVER, KIDNEYS, FAT, AND BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE................................................................................................... 36 c a m p is i Saniti* Does not contata TSCA CM H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 LIST OF APPENDICES Page A. INDIVIDUAL BODY WEIGHTS.............................................................................................................................38 B. INDIVIDUAL CLINICAL OBSERVATIONS....................................................................................................... 46 C. TERMS AND CALCULATIONS FACTORS INFLUENCING INTERPRETATION OF KINETIC ANALYSIS.................................................................................................................................................................. 53 D. INDIVIDUAL FLUORINE LEVELS IN BLOOD....................................................................................................56 E. INDIVIDUAL FLUORINE LEVELS IN LIVER......................................................................................................64 F. INDIVIDUAL FLUORINE LEVELS IN FAT..........................................................................................................67 G. INDIVIDUAL FLUORINE LEVELS IN KIDNEYS............................................................................................... 70 H. URINE AND FECES DATA......................................................................................................................................73 -6- Does noi contain TSe$ cm H-24159: Biopersistence Screening Gavage Study in Rats TEST SUBSTANCE: STUDY INFORMATION DuPont-6732 Haskell Number: 24159 Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: June 11, 2001 / (see report cover page) In-Life Initiated/Completed: June 15, 2001 / October 29, 2001 ,,V UuC(tW4l(iu.. ,_.fc H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 STUDY PERSONNEL Study Director: Gregory S. Ladies, Ph.D., D.A.B.T. Management: Judith C. Stadler, Ph.D., D.A.B.T. Primary Technician: Robert E. Walker, Jr. Fluorine Data Analysis: Paul M. Hinderliter, Ph.D. Management: Matthew S. Bogdanffy, Ph.D., D.A.B.T. Toxicology Report Preparation: Wanda F. Dinbokowitz Laboratory Veterinarian: William Singleton, D.V.M., A.C.L.A.M -8 iS fipaity SlffiHIzedf. Does no?contain TSCA GB! H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 SUMMARY The objective of this study was to evaluate the potential for H-24159, when administered by gavage, to be absorbed and to accumulate in a mammalian system following the attainment of steady-state blood fluorine levels. Two groups of 10 male Crl:CD(SD)IGS BR rats each were exposed to 35 mg/kg/day of H-24159 or deionzied water for 52 consecutive days. Blood was collected from the orbital sinus of 10 rats approximately 2 hours after dosing (except on test day 53) on test days 0, 4, 9, 14, 21, 28, 35, 42, 49, and 53. Beginning on test day 50, animals were placed in metabolism cages and urine and feces were collected for total fluorine analysis for 3 days at 24 hour intervals from the first 5 males in the control and 35 mg/kg/day group. The urine and feces obtained from a particular dose group was pooled. After the collection of urine and feces, the first 5 males in each dose group were sacrificed on test day 53 and liver, kidney and fat were collected, weighed and stored frozen until fluorine analysis. Blood was also collected for total fluorine analysis at 3, 7, 14, 21, 35, 56, and 84 days after the final dosing of each group. On postdosing day 84, the remaining rats were sacrificed and the liver, kidneys, and fat were collected, weighed and stored frozen until fluorine analysis. Body weights and clinical signs were evaluated twice per week. No deaths occurred during the study. No test-substance-related clinical signs were observed. No statistically significant differences in mean body weights compared to control were observed for the group treated with the test substance. No statistically significant differences in mean body weight gain compared to control were observed for the treated group with the exception of a significant increase in mean body weight gain during the 95-98 and 102-105 test day intervals. Mean liver and kidney weights relative to body weight were similar to control in the test substance treated group. The levels of total fluorine in rat blood rose rapidly and reached steady-state in approximately 45 days with a maximum equivalent concentration (Cmax) of 62.1 7.8 /M equivalents and a terminal elimination half-life of 38.0 days. Fluorine was present in each of the examined rat tissues with the relative ranking of liver > kidney > fat > blood at both the steady state and recovery time points. The ratio of tissue to blood fluorine was nearly equivalent at both time points. Under steady-state conditions, fluorine was eliminated in urine and feces at a rate of 5 mmoles/kg body wt/day. - 9 - ompany Santfzetf, Does no! coniato TSCA CBf H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 INTRODUCTION The test substance, H-24159 10-dose oral gavage biopersistence screening study was conducted with 35 mg/Kg/day H-24159. Under the conditions of this initial study, the administration of H-24159 to male rats for 10 consecutive days resulted in moderate absorption and retention of fluorine in the blood. However, a steady-state for fluorine levels in whole blood was not achieved during the 10 consecutive days of dosing with 35 mg/kg H-24159. Therefore, the objective of this second biopersistence screening study was to dose males with 35 mg/kg/day H-24159 until a steady-state for fluorine levels in whole blood was achieved. The potential of H-24159 to be absorbed and to bioaccumulate in a mammalian system, as indicated by analytical determination of total fluorine in blood, liver, kidney, and fat was then evaluated. MATERIALS AND METHODS A. Test Substance The test substance, H-24159, was supplied by the sponsor a: substance appeared to be stable under the conditions of the such as a change in color or physical state, was observed. IThe test lability, B. Test Species Male Crl:CD(SD)IGS BR rats were received from Charles River Laboratories, Inc., Raleigh, North Carolina. The Crl:CD(SD)IGS BR rat was selected on the basis of extensive experience with this strain and its suitability with respect to longevity and low incidence of spontaneous diseases. C. Animal Husbandry 1. Housing Environment Rats were housed singly in stainless steel, wire-mesh cages suspended above cage boards. Animal rooms were maintained on an approximate 12-hour light/dark cycle (fluorescent light) and at a temperature of 22 3C and a relative humidity of 50 20%. 2. Feed and Water Tap water was provided ad libitum. All rats were fed PMI Nutrition International, Inc. Certified Rodent LabDiet 5002 chow ad libitum. -10- Company S an iti* Does noi contain SCACBJ H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 3. Identification Prior to assignment to groups, each rat was assigned a unique identification number which was recorded on a card affixed to the cage. After assignment to groups, the last 3 digits of the individual identification number were tattooed on the tail of each rat and recorded on the cage card. 4. Animal Health Monitoring Program As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures were performed periodically to ensure that contaminant levels were below those that would be expected to impact the scientific integrity of the study: Water samples are analyzed for total bacterial counts, and the presence of coliforms, lead, and other contaminants. Feed samples are analyzed for total bacterial, spore, and fungal counts. Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity of the study. The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluation of these data did not indicate any conditions that affected the validity of the study. D. Quarantine and Pretest Upon arrival at Haskell Laboratory, the rats were removed from shipping cartons and quarantined for 6 days. The rats were weighed 3 times during the pretest period and examined daily for any clinically apparent signs of disease or injury. The rats were observed daily for mortality and signs of illness, injury, or abnormal behavior. On the bases of acceptable body weight gains and freedom from clinically apparent signs of disease or injury, the rats were released from quarantine by the laboratory animal veterinarian or designee. -11 - H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 E. Study Design Substance Negative Control Deionized water Test Substance H-24159 Vehicle Not applicable Deionized water Dosage (mg/kg) Number of Animals 0 10 35 10 F. Assignment to Groups and Study Start After the quarantine period, the rats were selected on the bases of adequate body weight gain and freedom from any clinical signs of disease or injury. The selected rats were distributed by computerized, stratified randomization into study groups as designated in the Study Design, so that there were no statistically significant differences between group body weight means. After assignment to groups, each rat was housed individually. The rats were 7.5 weeks of age at the time of dosing. Dosing began on test day 0. Rats that were not assigned to the study were released for other laboratory purposes, or were sacrificed by carbon dioxide asphyxiation and discarded without pathology evaluation. G. Dosing Material Preparation and Administration 1. Test Substance H-24159 was prepared daily as a solution in deionized water. The rats were dosed by intragastric intubation at a volume of 5 mL/kg body weight until steady state was attained and urine and feces collected. The amount of test substance each rat received was based on the most recent body weight collected and the dose solution concentration. The mixture was stirred on a magnetic stir plate throughout the dosing procedure to maintain homogeneity. 2. Negative Control Deionized water was chosen as the negative control. The control rats were dosed at a volume of 5 mL/kg of body weight. H. Body Weights All rats were weighed twice per week at 3- to 4-day intervals. - 12Company Sanitized. Does not contain Ts c a w H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 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 twice daily throughout the study. At every weighing, each rat was individually handled and examined for abnormal behavior and appearance. J. Collection of Blood, Urine, and Feces for Total Fluorine Level Evaluation On test day -4 (pre-bleed) and test days 0, 4, 9, 14, and weekly thereafter until attainment of steady-state blood fluorine levels (i.e. day 49), blood (approximately 0.6 mL) was collected from the orbital sinus of animals while they were under light carbon dioxide anesthesia. On the day of blood collection (except test day -4 and 53), blood was collected from the animals 2 hours ( 30 minutes) after dosing. The blood was collected in plastic tubes containing EDTA while on ice. For each bleeding, blood was collected at approximately the same time of day. Beginning on test day 50, the first 5 rats in the control and test groups were placed in metabolism cages and urine and feces were collected daily for 3 days at 24-hour intervals. The urine and feces obtained from a particular dose group was pooled. The exact time period of collection of urine and feces was documented along with the total volume of pooled urine and weight of pooled feces obtained. Urine and feces were stored frozen until analyzed for total fluorine. Blood was also collected for total fluorine analysis at 3, 7, 14, 21, 35, 56, and 84 days after the final dosing of each group and stored frozen. K. Anatomical Pathology 1. Dosing Phase Following the attainment of steady blood fluorine levels and subsequent collection of urine and feces, the first 5 rats in the control and treated groups were euthanatized by carbon dioxide anesthesia and exsanguination and the following tissues were collected and weighed: liver, kidneys, and fat. The tissues were stored frozen until analysis of total fluorine levels. 2. Postdosing Phase On postdosing day 84, all remaining rats in the control and treated groups were euthanatized by carbon dioxide anesthesia and exsanguination and the following tissues were collected, weighed, and stored frozen until analysis of total fluorine levels: liver, kidneys, and fat. L. Fluorine Analysis The blood, tissue, and urine and feces samples were shipped frozen to Jackson Laboratory, Deepwater, New Jersey where they were analyzed for total fluorine. The total fluorine content of the samples was determined by using a Wickbold torch combustion method, followed by analysis with a fluoride ion selective electrode. The samples were decomposed or volatilized in the presence of wet oxygen and swept through an oxy-hydrogen flame in a closed quartz apparatus. 13 ' Sanitized. Does hot contalo xgp& qbi H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 The combustion products were collected in an aqueous absorbing solution and analyzed with a fluoride ion selective electrode. Kinetic analysis of the ppm F in each sample was performed by Haskell Laboratory personnel for evaluation of fluorine biopersistence. The percent of fluorine and molecular weight of the test substance was used as provided by the sponsor. The measured total fluorine values were used as received (ppm F) from Jackson Laboratory. For the Wickbold torch method, the background fluorine level is 0.2 ppm. This is the limit of detection (LOD) of this method and was subtracted from each sample. The limit of quantification (LOQ) for this method is 0.5 ppm, and any values listed as less than 0.5 ppm were excluded from further treatment. Noncompartmental analysis was conducted on fluorine data derived from rats dosed with H-24159 using WinNonlin Version 3.1 software (Pharsight Corp, Mountain View, CA). WinNonlin software provided a means of computing derived pharmacokinetic parameters from experimental data. The maximum observed concentration in blood was Cmax (piM equivalent). Biopersistence was assessed by quantifying terminal elimination blood half-life (Ti/2, days). The points included in determination of the T>/2were selected manually and included only points after apparent log-linear elimination was achieved. Internal exposure was determined by calculating the blood areaunder-the-curve (AUC). AUC, which is simply the integral of blood concentration over time, is the most common means for expressing internal dose. With the calculated half-life, the AUC can be extrapolated to infinity (AUCINF) to reflect the elimination of the compound. M. Statistical Methods Descriptive statistics (e.g. mean, standard deviation) were used for organ weights. Significance was judged at p < 0.05. Parameter Body Weight Body Weight Gain Incidence of Clinical Observations Preliminary Test Test for lack of trend*11 Levene's test for homogeneity*45and Shapiro-Wilk test(5>for normality0 None Method of Statistical Analysis If preliminary test is not If preliminary test is significant significant Sequential application of the Jonckheere-Terpstra trend test Preliminary tests for pairwise comparison OR One-way analysis of variance*61followed with Dunnett's test*71 Kruskall-Wallis test*81 followed with Dunn's test*91 Cochran-Armitage test for trend*61 a If the Shapiro-Wilk test was not significant but Levene's test was significant, a robust version of Dunnett's test was used. Company Sanitized, g H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 RESULTS AND DISCUSSION A. In-Life Toxicology (Tables 1-2, Figure 1, Appendices A-B) No deaths occurred during the study. No test-substance-related clinical signs were observed. No statistically significant differences in mean body weights compared to control were observed for the test-substance treated group. No statistically significant differences in mean body weight gain compared to control were observed for the test-substance treated group with the exception of a significant increase in mean body weight gain during the 95-98 and 102-105 test day intervals. B. Liver Weights (Table 3) 1. Test Substance The absolute liver weight of rats dosed with the test substance, H-24159, was 9% lower on test day 53 compared to control, while the mean relative liver weights (liver/body weight) of the control and test substance treated animals were the same. At the end of the recovery period (test day 136), the absolute liver weights of the H-24159 treated animals were 15% higher than control, while the mean relative liver weights were similar to control. C. Kidney Weights (Table 4) The absolute and relative kidney weights of rats dosed with H-24159 were similar to control on test day 53. At the end of the recovery period, absolute kidney weights of the H-24159 treated animals were 24% higher than control, while the mean relative kidney weights were similar to control. D. Fluorine Data (Tables 5-12, Figures 2-4, Appendices C-H) Total blood fluorine concentrations were converted to micromolar (/xM, micromoles per liter) equivalents of active fluorine-containing component for use in kinetic analysis (Appendix D). The level of fluorine in rat blood rose rapidly and reached steady-state in approximately 45 days (Figure 2). The maximum fluorine concentration (Cmax) was 62.1 7.8 /xM equivalents (Mean SD). Under steady-state conditions, fluorine equivalents were eliminated in urine and feces at a rate of 5 mmoles/kg body wt/day. The fluorine in urine and feces on test days 51-53 are shown in Appendix H. The terminal elimination half-life was 38.0 days. The total internal exposure to - 15 - Company S anine. Does no!^ ^^ H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 fluorine as presented in terms of the area under the blood curve extrapolated to infinity (AUCENF, /tM x days) was 4.24xl03. The calculations and equations are shown in Appendix C. The concentration of fluorine in rat blood, liver, fat and kidney at study days 53 and 136 are shown in Appendices E - G. The relative ranking of fluorine in rat tissues was liver > kidney > fat > blood at both study days 53 and 136 (Figure 4). The ratio of tissue to blood fluorine was nearly equivalent at both the dosing and recovery time points. Fluorine concentrations in the control group blood and tissues were generally below the limit of quantification. The data used in the kinetic analysis were derived from a limited screen, and therefore several caveats and considerations are important. These considerations include the limitations of single dose studies when extrapolating to other doses, small sample size, limited data points for estimating elimination kinetics, and the limiting of kinetic analysis to only the blood compartment. A more complete list of considerations is shown in Appendix C. CONCLUSIONS Rats dosed for 52 days with 35 mg/kg/day H-24159 exhibited no mortality, test substance-related clinical signs, or body weight effects. Mean liver and kidney weights relative to body weight were similar to control in the test substance treated animals. The fluorine jaM equivalents in rat blood rose rapidly and reached steady-state in approximately 45 days with a maximum fluorine concentration (CTM*) of 62.1 7.8 fiM equivalents and a terminal elimination half-life of 38.0 days. Fluorine was present in each of the examined rat tissues with the relative ranking of liver > kidney > fat > blood at both the steady state and recovery time points. The ratio of tissue to blood fluorine equivalents was nearly equivalent at both time points. Under steady-state conditions, fluorine was eliminated in urine and feces at a rate of 5 mmoles/kg body wt/day. RECORDS AND SAMPLE STORAGE All original records will be retained at Haskell Laboratory, E. I. du Pont de Nemours and Company, Newark, Delaware or at Iron Mountain Records Management, 200 Todds Lane, Wilmington, Delaware. Laboratory specific or site-specific raw data such as personnel files and equipment records will be retained at the facility where the work was done. - 16Company Sanitized. Does not contain TSCACBI H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 REFERENCES 1. Draper, N.R. and Smith, H. (1981). Applied Regression Analysis, 2nd edition, pp 266-273. Wiley, New York. 2. Selwyn, M.R. (1995). The use of trend tests to determine a no-observable-effect level in animal safety studies. Journal o f the American College o f Toxicology 14(2), 158-168. 3. Jonckheere, A.R. (1954). A distribution-free K-sample test against ordered alternatives. Biometrika 41, 133-145. 4. Levene, H. (1960). Robust test for equality of variances. Contributions to Probability and Statistics (J. Olkin, ed.), pp 278-292. Stanford University Press, Palo Alto. 5. Shapiro, S.S. and Wilk., M.B. (1965). An analysis of variance test for normality (complete samples). Biometrika 52, 591-611. 6. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6th edition, pp 246-248 and 349-352. The Iowa State University Press, Ames. 7. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Statist. Assoc. 50, 1096-1121. 8. Kruskal, W.H. and Wallis, W.A. (1952). Use of ranks in one-criterion analysis of variance. J. Amer. Statist. Assoc. 47, 583-621. 9. Dunn, O.J. (1964). Multiple contrasts using rank sums. Technometrics 6, 241-252. 17 Company Sanitized. om no! com,, t s c a c b . H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 TABLES - 18Company Sanitized. Does no! contain TSCA CT H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 Test Days 0 4 7 11 14 18 21 25 28 32 35 39 42 46 49 53 56 60 63 67 70 74 77 81 84 88 91 95 98 102 105 109 112 116 TABLE 1 MEAN BODY WEIGHTS Negative Control Deionized Water Dosing 260.8 282.9 301.6 318.4 337.5 350.1 363.9 374.9 387.6 396.0 403.8 411.6 421.3 431.1 442.3 441.3 Test Substance H-24159 258.7 280.1 298.4 316.3 322.2 347.3 360.0 368.6 380.2 386.8 394.5 400.1 409.1 418.2 428.3 431.1 Recovery 436.0 441.7 452.0 456.8 463.7 467.5 477.5 479.4 485.8 488.0 490.1 493.1 497.0 504.1 506.3 506.8 511.1 519.1 459.6 471.4 480.3 485.6 499.0 504.8 513.1 519.0 524.1 529.4 537.0 539.2 550.5 558.8 568.2 569.6 576.2 585.4 -19Company Sanitized. Does not contain TSCA CBf H-24159: Biopersistence Screening Gavage Study in Rats____________ TABLE 1 (Continued) MEAN BODY WEIGHTS DuPont-6732 Test Days 119 123 126 130 133 136 Negative Control Deionized Water 523.9 532.1 536.6 542.5 545.7 546.2 Test Substance H-24159 587.8 592.6 597.7 604.5 607.8 604.5 There were no statistically significant differences from vehicle control at p < 0.05. -20Company SanfUzed. Does noi contain TSM H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 TABLE 2 MEAN BODY WEIGHT GAINS (g) Dosing and Recovery Test Days Negative Control Deionized Water Test Substance H-24159 Day 0 - Day 4 22.1 7.2(10) 21.4 6.5(10) Day 4 - Day 7 18.7 6.1(10) 18.4 5.4(10) Day 7 - Day 11 16.8 5.7(10) 17.8 4.3(10) Day 11 - Day 14 19.1 6.4(10) 16.0 4.9(10) Day 14 - Day 18 12.7 5.8(10) 15.1 4.2(10) Day 18 - Day 21 13.8 4.6(10) 12.7 3.0(10) Day 21 - Day 25 11 8.1(10) 8.6 7.2(10) Day 25 - Day 28 12.8 4.1(10) 11.5 3.9(10) Day 28 - Day 32 8.4 10.7(10) 6.6 4.4(10 ) Day 32 - Day 35 7.7 4.0(10 ) 7.7 4.3(10) Company Sanitized. Does not contain TSCA CBS H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 TABLE 2 (Continued) MEAN BODY WEIGHT GAINS (g) Test Days Negative Control Deionized Water Test Substance H-24159 Day 35 - Day 39 7.8 11.1(10) 5.6 10.7(10) Day 39 - Day 42 9.8 3.4(10) 9 3.4(10) Day 42 - Day 46 9.7 11.2(10) 9.1 6.3(10) Day 46 - Day 49 11.2 3.5(10) 10.2 4.1(10) Day 49 - Day 53 -1 17.7(10) 2.8 18.3(10) Day 53 - Day 56 0.2 4.7(5 ) 0.2 5.3(5 ) Day 56 - Day 60 5.7 6.3(5 ) 11.8 6.0(5 ) Day 60 - Day 63 10.3 4.4(5 ) 8.9 4.0(5 ) Day 63 - Day 67 4.8 7.4(5 ) 5.3 4.8(5 ) Day 67 - Day 70 6.9 6.8(5 ) 13.4 7.5(5 ) Day 70 - Day 74 3.9 3.4(5 ) 5.9 4.2(5 ) - 22Company Sanitized. Does not contain TSCA CB1 H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 TABLE 2 (Continued) MEAN BODY WEIGHT GAINS (g) Test Days Negative Control Deionized Water Test Substance H-24159 Day 74 - Day 77 10 3.1(5 ) 8.2 3.8(5 ) Day 77 - Day 81 1.8 9.2(5 ) 5.9 2.1(5 ) Day 84 - Day 88 2.2 7.0(5 ) 5.3 4.0(5 ) Day 81 - Day 84 6.4 3.4(5 ) 5.1 1.6(5 ) Day 88 - Day 91 2.1 5.5(5 ) 7.6 2.2(5 ) Day 91 - Day 95 3 4.9(5 ) 2.1 6.4(5 ) Day 95 - Day 98 3.9 8.9(5 ) n.4@ 3.7(5 ) Day 98 - Day 102 7.1 3.2(5 ) 8.2 3.8(5 ) Day 102 - Day 105 2.2 4.2(5 ) 9.5* 2.3(5 ) Day 105 - Day 109 0.5 6.5(5 ) 1.4 4.7(5 ) Day 109 - Day 112 4.3 6.1(5 ) 6.6 4.0(5 ) -23- Company Sanitized. Dees not contain TSCACOI H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 TABLE 2 (Continued) MEAN BODY WEIGHT GAINS (g) Test Days Negative Control Deionized Water Test Substance H-24159 Day 112-D ay 116 8 7.1(5 ) 9.2 5.4(5 ) Day 116-D ay 119 4.8 2.4(5 ) 2.4 3.6(5 ) Day 119-D ay 123 8.2 5.6(5 ) 4.8 4.0(5 ) Day 123 - Day 126 4.6 6.1(5 ) 5.2 2.2(5 ) Day 126 - Day 130 5.9 3.2(5 ) 6.7 4.1(5 ) Day 130-D ay 133 3.2 2.9(5 ) 3.3 4.4(5 ) Day 133 - Day 136 0.5 4.5(5 ) -3.3 10.1(5 ) Day 0 - Day 53 180.5 64.1(10) 172.5 39.7(10 ) Day 53 - Day 136 110.4 19.5(5 ) 145.1 46.2(5 ) Data summarized as: Mean Standard Deviation (n) @ Nonparametric comparison to control (Dunn's) significant * Parametric comparison to control (Dunnett/Tamhane-Dunnett) significant -24Company Sanitized. Does not contain TSCA CBi H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 TABLE 3 MEAN BODY AND LIVER WEIGHTS (g) DEIONIZED WATER (NEGATIVE CONTROL) Test Absolute Mean Relative Days n Body Weight Liver Weight Liver Weight (Liver/Body Weight) 53 5 446.8 15.192 0.034 136 5 546.2 18.379 0.034 H-24159 (TEST SUBSTANCE) Test Absolute Mean Relative Days n Body Weight Liver Weight Liver Weight (Liver/Body Weight) 53 5 402.8 13.794 0.034 136 5 604.5 21.219 0.035 -25 Company Sanitized. Does not contain TSCA CBI H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 Test Days 53 136 n 5 5 TABLE 4 MEAN BODY AND KIDNEY WEIGHTS (g) DEIONIZED WATER (NEGATIVE CONTROL) Absolute Body Weight Kidney Weight 446.8 3.153 546.2 6.382 Mean Relative Kidney Weight (Kidney/Body Weight) 0.007 0.012 Test Days 53 136 n 5 5 H-24159 (TEST SUBSTANCE) Absolute Body Weight Kidney Weight 402.8 3.178 604.5 7.937 Mean Relative Kidney Weight (Kidney/Body Weight) 0.008 0.013 - 26- eompany Sanitized Does not contain TSCA CBI H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 TABLE 5 MEAN BLOOD FLUORINE LEVELS Negative Control Test Substance Test Days -4 0 4 9 14 21 28 35 42 49 53 55 59 66 73 87 108 136 Deionized Water (ppm F) a a 0.84c (0.2) 0.57d (0.1) - a a a a - 0.80e (0.5) - 0.70f (0.1) a H-24159 (ppm F) a 4.39 9.30 10.37 11.53 11.08 14.46 14.09 15.58 14.04 12.76 7.98 8.42 5.74 4.74 3.96 2.54 1.74 (0.8)b (3.1) (2.7) (1.7) (2.0) (1.8) (1.6) (1.9) (1.3) (1.9) (1.3) (0.9) (0.6) (1.0) (0.3) (0.3) (0.4) a All values were below the limit of quantification (LOQ, < 0.5) b Standard deviation is in parentheses. c Mean of 7 of the 10 values. Three of the values were below the LOQ. d Mean of 3 of the 10 values. Seven of the values were below the LOQ. e Mean of 3 of the 5 values. Two of the values were below the LOQ. f Mean of 2 of the 5 values. Three of the values were below the LOQ. Indicates no fluorine analysis performed on sample for this day. Note: Only 5 values tested for days 53 to 136 (recovery). - 27- Company Sanitized. Does no, cornata TSCA o r H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 TABLE 6 MEAN BLOOD FLUORINE CONCENTRATION EXPRESSED IN /xM EQUIVALENTS Test Substance Test H-24159 Days_______________ juM Equivalents F -4 a 0 16.93 (3.35)b 4 36.77 (12.51) 9 41.09 (11.03) 14 45.78 (6.99) 21 43.96 (7.93) 28 57.62 (7.25) 35 56.12 (6.59) 42 62.14 (7.80) 49 55.92 (5.37) 53 50.75 (7.51) 55 31.43 (5.14) 59 33.21 (3.81) 66 22.38 (2.30) 73 18.34 (4.04) 87 15.19 (1.09) 108 9.45 (1.09) 136 6.22 (1.75) a All values were below the limit of quantification (LOQ, < 0.5) b Standard deviation is in parentheses. Note: Only 5 values tested for days 53 to 136 (recovery). -28Company Sanitized. Does not contain TSCACB H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 TABLE 7 MEAN LIVER FLUORINE LEVELS Negative Control Test Substance Test Deionized Water H-24159 Days_________________ (ppm F)__________________ (ppm F) ~53 060* 176.04 (17.6)b 136 0.57 (0.1)_______________ 20.60 (5.7) a Mean of 1 of the 5 values. Four of the values were below the limit of quantification (LOQ). b Standard deviation is in parentheses. TABLE 8 MEAN LIVER FLUORINE CONCENTRATION EXPRESSED IN ftM EQUIVALENTS Test Substance Test H-24159 _______ Days________________ /xM Equivalents 53 710.46 (70.97)a ________136___________________ 82.42 (23.07) a Standard deviation is in parentheses. Note: Only 5 values tested for days 54 and 137 (recovery). -29Company Sanitized. Does not contain TSCA C H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 TABLE 9 MEAN FAT FLUORINE LEVELS Negative Control Test Substance Test Deionized Water H-24159 Days (ppm F) (ppm F) ~~53 0.75 (0.4)b 18.86 (1.6) 136____________________ ' ______________________5.20 (0.9) a Mean of 2 of the 5 values. Three of the values were below the limit of quantification (LOQ). b Standard deviation is in parentheses, c All values were below the LOQ. TABLE 10 MEAN FAT FLUORINE CONCENTRATION EXPRES SED IN /xM EQUIVALENTS Test Substance Test H-24159 Pays________________ /xM Equivalents 53 75.39 (6.57)a 136___________________20.20 (3.65) a Standard deviation is in parentheses. Note: Only 5 values tested for days 54 and 137 (recovery). -30- Ss n! mti TSCA i H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 TABLE 11 MEAN KIDNEY FLUORINE LEVELS Negative Control Test Substance Test Deionized Water H-24159 Days_________________ (ppm F)_________________ (ppm F) 53 0.86 (0.3)a 76.08 (14.1) 136_______________ 0.90b______________________ 9.66 (2.9) a Standard deviation is in parentheses. b Mean of 1 of the 5 values. Four of the values were below the limit of quantification (LOQ). TABLE 12 MEAN KIDNEY FLUORINE CONCENTRATION EXPRESSED IN fiM EQUIVALENTS Test Substance Test H-24159 Days________________ M Equivalents 53 306.59 (57.04)a 136___________________ 38.22 (11.82) a Standard deviation is in parentheses. Note: Only 5 values tested for days 54 and 137 (recovery). -31 Company Sanitized. Does not contain TSCACO H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 FIGURES - 32- Company Sanitized. Does not contain TgCCBI ))) H-24159: Biopersistence Screening Gavage Study in Rats________________________________________________________________________________________________________DuPont-6732 FIGURE 1 MEAN BODY WEIGHTS (g) rs *o I tfi % HOQ, o O 03 3 0O5 - 33- H-24159: Biopersistence Screening Gavage Study in Rats FIGURE 2 FLUORINE (nM EQUIVALENTS) IN RAT BLOOD DuPont-6732 Micromolar ( i M ) equivalents fluorine in rat blood resulting from a 52 day oral gavage exposure. Values are means and error bars are standard deviation. -34Company Sanitized. Does not contain TSCA Ob ) H-24159: Biopersistence Screening Gavage Study in Rats ) ) DuPont-6732 FIGURE 3 COMPARISON OF RELATIVE LIVER WEIGHT AND MEAN LIVER FLUORINE CONCENTRATION FOR H-24159 AND NEGATIVE CONTROL Company Sanitized. Does not contain TSCAC81 Day 136 Day 53 Deionized Water (Negative Control) H-24159 (Test Substance) Day 136 -35- H-24159: Biopersistence Screening Gavage Study in Rats ) FIGURE 4 COMPARISON OF MEAN LIVER, KIDNEYS, FAT, AND BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE ) DuPont-6732 Company Sanitized. Does not contain T5CACH - 36- H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 APPENDICES - 37- Company Sanitized Does not contain TSCA CEI H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 APPENDIX A Individual Body Weights -38Company Sanitized. Does not contain TSCA CBi H-24159: Biopersistence Screening Gavage Study in Rats____________ INDIVIDUAL BODY WEIGHTS ABBREVIATIONS: EXPLANATORY NOTES SD - sacrificed by design NOTE: The first 5 animals were sacrificed by design on test day 53. DuPont-6732 - 39 Company Sanitized. Does not contain TSCA C9I Company Sanitized. Does H-24159: Biopersistence Screening Gavage Study in Rats ANIMAL NUMBER 649293 649294 649295 649296 649297 649298 649299 649300 649301 649312 Day 0 2 8 1 .5 265.3 2 7 5 .8 2 4 2 .7 2 6 5 .4 2 2 6 .8 2 9 3 .1 2 6 8 .9 2 4 6 .0 2 4 2 .8 ANIMAL NUMBER D a y 32 649293 649294 649295 649296 649297 649298 649299 649300 649301 649312 3 9 7 .0 438.2 450.0 3 4 6 .8 398.2 323.6 493.7 419.7 3 5 4 .8 338.2 3O o3 CD 3* CO 5 Day 4 304.3 2 8 7 .6 304.7 2 6 3 .6 289.2 2 4 1 .8 3 2 4 .4 2 9 8 .9 2 5 4 .1 2 6 0 .4 D a y 35 3 9 9 .6 4 5 0 .6 4 6 4 .8 3 5 0 .5 4 0 7 .2 328.7 501.5 4 3 0 .5 359.0 3 4 5 .1 DEIONIZED WATER (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS Day 7 GROUP I TEST DAY D ay 11 D ay 14 D ay 18 3 1 3 .1 3 0 6 .8 3 3 1 .2 278.2 3 0 4 .1 2 5 8 .1 354.7 3 1 6 .5 273.2 2 8 0 .3 3 2 4 .6 3 2 8 .1 3 5 3 .6 2 9 5 .5 3 1 8 .9 2 6 4 .7 380.3 3 3 6 .8 2 8 6 .1 2 9 5 .2 340.2 355.2 3 8 1 .1 3 1 0 .8 3 3 3 .4 2 7 2 .0 4 0 4 .8 354.7 304.2 3 1 8 .1 3 4 6 .5 3 6 8 .6 398.3 313.3 3 4 6 .8 2 8 3 .9 4 2 8 .7 3 7 0 .2 3 1 6 .3 3 2 8 .4 D ay 21 3 6 3 .6 3 8 5 .9 4 1 5 .6 3 2 6 .7 3 5 0 .6 2 9 3 .5 4 4 3 .4 3 8 2 .4 3 3 5 .6 3 4 1 .7 DuPont-6732 D ay 25 3 7 2 .5 4 0 4 .6 4 2 5 .2 3 2 3 .3 3 7 1 .6 3 0 3 .6 4 5 9 .4 4 0 3 .0 3 3 7 .7 3 4 7 .7 D ay 28 3 8 2 .3 4 2 3 .7 4 3 9 .0 3 3 5 .1 3 8 4 .9 3 0 9 .6 4 7 9 .1 4 1 5 .4 3 4 8 .7 3 5 8 .5 Day 39 4 1 6 .3 4 6 3 .9 4 7 6 .2 330.3 4 1 8 .0 340.9 520.6 4 3 6 .1 3 6 6 .5 347.0 TEST DAY D a y 42 D a y 46 4 2 8 .4 4 7 4 .8 4 8 5 .5 3 3 4 .1 4 3 0 .1 354.7 5 3 1 .5 446.2 377.3 3 5 0 .8 4 3 5 .3 4 8 9 .3 506.2 3 5 1 .8 4 4 6 .0 3 5 7 .7 5 4 5 .5 4 5 5 .0 3 5 9 .0 3 6 5 .0 D a y 49 4 4 4 .4 5 0 2 .8 5 1 5 .9 3 5 9 .8 4 5 2 .0 3 6 6 .6 5 6 0 .9 4 6 5 .5 3 7 4 .7 3 8 0 .0 D a y 53 D a y 56 D ay 60 4 3 7 .2 505.2 5 2 5 .8 312.2 4 5 3 .4 3 7 8 .0 5 7 1 .9 4 7 4 .1 3 8 1 .7 3 7 3 .5 SD t e s t d a y 53 SD t e s t d a y 53 SD t e s t d a y 53 SD t e s t d a y 53 SD t e s t d a y 53 3 8 0 .5 5 6 9 .8 4 8 0 .6 3 7 5 .6 3 7 3 .6 3 8 6 .9 5 8 1 .5 4 7 8 .8 3 7 5 .9 3 8 5 .5 H-24159: Biopersistence Screening Gavage Study in Rats ANIMAL NUMBER D ay 63 649293 649294 649295 649296 649297 649298 649299 649300 649301 649312 396.2 591.0 4 8 6 .4 393.8 3 9 2 .6 D a y 67 4 0 3 .5 583.7 4 9 5 .6 3 9 7 .1 4 0 4 .0 ) DEIONIZED WATER (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP I Continued) Day 70 TEST DAY Day 74 D a y 77 Day 81 D ay 84 407.3 598.4 504.1 4 0 7 .5 4 0 1 .0 4 0 7 .9 6 0 4 .9 5 0 4 .4 4 1 1 .5 4 0 9 .0 418.2 6 1 9 .4 514.9 420.2 4 1 5 .0 4 2 4 .2 6 2 5 .0 5 2 5 .0 4 0 6 .5 4 1 6 .1 4 2 6 .8 632.1 532.3 417.7 4 1 9 .9 ) DuPont-6732 Day 88 D ay 91 4 3 3 .3 6 3 0 .5 525.2 4 2 0 .3 4 3 0 .7 4 3 6 .5 6 3 6 .8 5 3 2 .8 4 1 4 .2 4 3 0 .3 ANIMAL NUMBER D a y 95 649293 649294 649295 649296 649297 649298 649299 649300 649301 649312 4 4 0 .8 640.2 528.0 4 1 7 .5 439.0 D ay 98 4 4 5 .0 6 4 8 .8 5 3 6 .5 4 2 7 .2 4 2 7 .5 D a y 102 TEST DAY D ay 105 D ay 109 D ay 112 D ay 116 Day 119 D ay 123 454.3 6 5 8 .1 544.2 4 3 5 .0 4 2 9 .0 4 6 0 .1 6 6 1 .6 546.3 4 3 0 .0 4 3 3 .5 4 5 0 .0 6 6 1 .4 552.3 431.3 4 3 8 .9 4 5 5 .7 6 5 5 .8 5 5 6 .4 4 4 2 .2 4 4 5 .3 4 5 9 .8 6 6 9 .9 569.3 4 3 9 .5 4 5 6 .8 4 6 4 .2 6 7 7 .1 5 7 2 .0 4 4 6 .9 4 5 9 .2 4 7 2 .2 6 8 3 .4 5 8 7 .6 4 4 7 .4 4 6 9 .8 Company Sanitized. Does not contain TSCACBi -41 - ) H-24159: Biopersistence Screening Gavage Study in Rats ANIMAL NUMBER Day 126 649293 649294 649295 649296 649297 649298 649299 649300 649301 649312 4 7 8 .9 682.0 585.2 4 5 8 .8 478.3 Day 130 4 8 2 .4 6 8 9 .0 5 9 6 .1 4 6 3 .0 4 8 2 .0 ) DEIONIZED WATER (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP I Day 133 TEST DAY Day 136 4 8 8 .6 692.1 597.7 4 6 2 .4 4 8 7 .9 4 9 4 .4 689.6 597.3 4 5 7 .5 4 9 2 .3 SD t e s t SD t e s t SD t e s t SD t e s t SD t e s t day day day day day 136 136 136 136 136 ________DuPont-6732 Company Sanitized. Does O3 30O ST 5` 1 toeJ -42 - ) H-24159: Biopersistence Screening Gavage Study in Rats ANIMAL NUMBER 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 Day 0 2 1 5 .0 2 6 7 .4 254.7 2 6 5 .4 2 5 9 .0 2 3 5 .7 2 8 0 .4 2 6 8 .8 2 3 5 .8 304.4 Day 4 2 2 8 .1 2 7 8 .5 2 8 1 .9 2 8 3 .2 2 8 5 .0 2 5 4 .9 3 1 0 .7 2 9 2 .5 2 5 4 .1 3 3 1 .8 ) H-24159 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP III Day 7 TEST DAY D ay 11 D a y 14 D a y 18 2 4 0 .4 2 9 3 .6 3 0 3 .4 2 9 5 .5 3 0 9 .5 2 6 6 .8 3 3 4 .5 314.7 2 6 9 .5 356.3 2 5 6 .9 3 0 5 .3 3 2 4 .3 3 1 4 .4 3 3 0 .1 2 8 5 .9 3 4 3 .4 3 3 4 .7 2 9 0 .0 3 7 7 .7 2 7 0 .2 3 1 6 .4 3 4 3 .0 324.3 350.2 3 0 0 .8 3 5 3 .9 3 5 6 .8 3 0 5 .7 4 0 1 .1 2 7 7 .0 3 2 6 .9 3 6 0 .6 3 4 4 .9 3 6 3 .6 3 1 3 .8 3 7 2 .6 373.2 3 2 0 .6 4 1 9 .8 D ay 21 2 8 5 .9 3 4 0 .7 3 7 4 .6 3 5 6 .9 378.2 3 2 2 .4 3 8 3 .8 383.7 3 3 6 .8 4 3 7 .3 ) DuPont-6732 D a y 25 2 9 0 .5 3 3 8 .0 3 8 9 .8 3 6 4 .8 3 8 6 .0 3 3 7 .9 3 9 4 .0 3 9 9 .5 3 5 1 .7 4 3 4 .0 Day 28 3 0 0 .6 3 4 9 .5 4 0 4 .0 3 7 2 .2 3 9 6 .1 3 5 0 .4 4 1 4 .0 4 1 3 .6 3 6 0 .2 4 4 1 .0 ANIMAL NUMBER D a y 32 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 300.2 363.5 409.6 374.4 405.4 356.6 4 2 6 .4 421.3 365.0 445.7 Day 35 3 1 0 .7 3 6 8 .8 4 1 9 .0 3 7 1 .9 4 1 1 .8 3 6 6 .5 4 3 4 .8 4 2 6 .7 3 7 6 .7 4 5 7 .8 D a y 39 3 2 0 .6 3 7 6 .8 431.3 3 7 8 .1 418.0 3 7 3 .9 443.2 4 3 7 .1 3 8 8 .4 4 3 3 .5 TEST DAY D a y 42 D ay 46 3 3 1 .2 3 8 7 .6 4 4 0 .1 3 8 7 .1 424.3 381.2 4 5 1 .2 4 4 2 .0 3 9 5 .2 4 5 0 .7 3 3 7 .9 3 9 7 .5 4 5 1 .6 390.2 422.2 3 9 6 .3 4 5 7 .8 452.2 4 0 4 .4 4 7 1 .4 D ay 49 3 4 7 .6 406.3 461.3 4 0 0 .4 434.3 4 0 5 .4 4 5 9 .9 4 6 2 .1 4 1 5 .8 4 9 0 .2 D a y 53 D a y 56 D a y 60 3 0 1 .5 4 0 9 .2 4 6 4 .0 4 0 0 .4 4 3 9 .1 4 1 0 .2 4 7 9 .0 4 7 5 .5 4 2 7 .7 5 0 4 .6 SD t e s t d a y 53 SD t e s t d a y 53 SD t e s t d a y 53 SD t e s t d a y 53 SD t e s t d a y 53 4 1 7 .1 4 8 2 .1 4 7 3 .4 4 2 0 .5 5 0 5 .1 4 2 1 .2 4 9 3 .0 4 8 3 .9 4 3 3 .3 5 2 5 .8 Company Sanitized, Does not contain TSCACB! - 43- H-24159: Biopersistence Screening Gavage Study in Rats ANIMAL NUMBER D a y 63 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 432.7 4 9 8 .0 4 8 8 .8 442.2 539.9 D a y 67 4 3 5 .9 509.5 4 9 4 .0 440.9 5 4 7 .8 1 H-24159 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP III (Continued) Day 70 TEST DAY D ay 74 D a y 77 D ay 81 D a y 84 4 5 0 .7 513.7 504.7 453.3 5 7 2 .5 4 5 2 .5 5 1 9 .0 5 1 2 .1 4 5 5 .9 5 8 4 .7 467.2 5 2 6 .6 5 1 7 .0 4 6 3 .2 5 9 1 .4 473.3 530.2 5 2 3 .0 4 6 7 .9 6 0 0 .6 4 7 9 .9 5 3 3 .8 526.2 473.2 607.3 DuPont-6732 D a y 88 D a y 91 4 8 3 .3 5 3 4 .7 5 3 4 .4 4 7 6 .7 6 1 8 .0 4 9 1 .5 5 4 3 .6 5 4 3 .6 4 8 0 .4 6 2 6 .1 ANIMAL NUMBER D a y 95 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 496.3 5 4 5 .9 540.9 4 7 5 .5 637.3 D ay 98 506.4 5 5 7 .5 5 4 6 .6 490.3 651.9 D ay 102 TEST DAY D ay 105 D ay 109 Day 112 Day 116 Day 119 D ay 123 5 1 6 .1 5 6 1 .5 554.5 4 9 6 .1 665.7 5 2 5 .4 5 7 4 .9 5 6 2 .1 5 0 3 .9 6 7 4 .9 5 2 0 .5 5 7 7 .1 5 6 0 .8 5 0 7 .5 682.3 5 2 8 .8 5 8 7 .6 563.9 5 0 9 .0 691.7 541.2 5 9 4 .0 5 6 8 .5 5 1 4 .6 7 0 8 .8 549.2 5 9 4 .8 5 6 6 .9 5 1 7 .5 7 1 0 .6 5 5 0 .2 6 0 1 .0 5 7 1 .0 519.2 7 2 1 .5 Company Sanitized, Does not contain TSCACBI -44- H-24159: Biopersistence Screening Gavage Study in Rats ANIMAL NUMBER Day 126 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 556.9 603.1 575.5 523.8 7 2 9 .4 Day 130 5 6 9 .1 6 0 5 .8 5 8 0 .1 5 3 3 .8 7 3 3 .6 ) H-24159 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP III (Continued) D ay 133 TEST DAY Day 136 570.3 6 1 1 .8 578.3 535.5 7 4 3 .0 567.3 613.7 5 8 5 .9 5 3 2 .1 7 2 3 .4 SD t e s t d a y 136 SD t e s t d a y 136 SD t e s t d a y 136 SD t e s t d a y 136 SD t e s t d a y 136 ) DuPont-6732 Company Sanitized. Does not contain TSCACy* -45- H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 APPENDIX B Individual Clinical Observations Company Sanitized. Does not contain TSCACr - 46- 'Iw Sfffl tfot )) H-24159: Biopersistence Screening Gavage Study in Rats Sex Group A nim al MI 649293 MI 649294 MI 649295 MI 649296 DEIONIZED WATER (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS O b servatio n GROUP I G en era l o b s e rv a tio n , No A b n o rm a lity D e te cte d Eye O b s e rv a tio n s, E n op hthalm us, R ig h t Eye O b se rva tio n s, B le d v ia O r b ita l fo r C lin Path, Eye O b se rva tio n s, B le d v ia O r b ita l fo r C lin Path, D isch arg e, Eye b ila t e r a l, B la c k D isch arg e, Eye r ig h t, B la c k H a ir Loss, Face, R ig h t S a c r if ic e d by d e sig n L e ft R ig h t G e n e ra l o b s e rv a tio n , No A b n o r m a lity D e te c te d Eye O b servatio n s, B le d v ia O r b it a l fo r C lin Path, Eye O b servatio n s, B le d v ia O r b it a l fo r C lin Path, Eye O b servatio n s, B le d v ia O r b it a l fo r C lin Path, H a ir Loss, Fo re lim b , B ila t e r a l H a ir Lo ss, Forepaw, B ila t e r a l S a c r if ic e d by d e sig n B ila te ra l L e ft R ig h t G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d Eye O b se rva tio n s, B le d v ia O r b ita l fo r C lin Path, Eye O b se rva tio n s, B le d v ia O r b ita l fo r C lin Path, D isch arg e, Eye le f t , B la c k D isch arg e, Eye r ig h t, B la ck S a c r if ic e d by d e sig n L e ft R ig h t G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d Eye O b se rva tio n s, Exophthalm us, L e ft Eye O b servatio n s, B le d v ia O r b it a l fo r C lin Path, B ila t e r a l Eye O b servation s, B le d v ia O r b ita l fo r C lin Path, L e ft Eye O b servation s, B le d v ia O r b ita l fo r C lin Path, R ig h t D isch arg e, Eye b ila t e r a l, B la c k D isch arg e, Nose, B la c k D isch arg e, Eye le f t , B la c k M isshapen O b s e rv a tio n s, Ear, R ig h t S a c r if ic e d by d e sig n Days 0-7 21-53 9 ,14,28,42,49 0 -4 ,2 1 ,3 5 21 1 1 -1 4 ,2 5 1 8 ,2 8 -3 5 53 0 35 9 ,1 4 ,4 2 ,4 9 0 -4 ,2 1 ,2 8 4 -7 ,1 1 -5 3 18-53 53 0 -7 ,1 1 -1 4 ,3 5 -5 3 9 ,1 4 ,3 5 0 -4 ,2 1 ,2 8 ,4 2 ,4 9 21-32 18 53 0-4 7 ,1 1 35 9 ,1 4 ,4 2 0 -4 ,2 1 ,2 8 ,4 9 25 18-46 1 8 -2 1 ,2 8 -4 6 14-53 53 ' VQ&l U&iUQQ 1j - 47- ) DuPont-6732 >) ) H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 Sex Group A n im a l MI 649297 MI 649298 jjj M ! 649299 DEIONIZED WATER (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS O b servatio n GROUP I (Continued) Days G e n e ra l o b s e rv a tio n , No A b n o r m a lity D e te c te d Eye O b servatio n s, B le d v ia O r b ita l fo r C lin Path, Eye O b servatio n s, B le d v ia O r b ita l fo r C lin Path, D ischarge, Nose, B la c k D isch arg e, Eye rig h t, B la c k H a ir Loss, Face, R ig h t Wound, S u p e r f ic ia l, Face S a c r if ic e d by d e sig n L e ft R ig h t G e n e ra l o b s e rv a tio n . No A b n o r m a lity D e te c te d Eye O b se rv a tio n s, Enop h th alm u s, R ig h t Eye O b s e rv a tio n s, Opague, R ig h t Eye O b servatio n s, B le d v ia O r b ita l fo r Eye O b servatio n s, B le d v ia O rb ita l fo r Eye O b servatio n s, B le d v ia O rb ita l fo r Eye O b servatio n s, Dark, R ig h t D isch arg e, Nose, B la c k D ischarge, Eye r ig h t, B la c k S a c r ific e d by d e sig n C lin C lin C lin Path, B ila t e r a l Path, L e ft Path, R ig h t G e n e ra l o b s e rv a tio n , No A b n o r m a lity D e te c te d Eye O b servatio n s, B le d v ia Eye O b servatio n s, B le d v ia Eye O b servatio n s, B le d v ia S a c r if ic e d by d e sig n O rb ita l O rb ita l O rb ita l fo r fo r fo r C lin C lin C lin Path, B ila t e r a l Path, L e ft Path, R ig h t 0 -7 ,1 1 ,1 8 ,3 2 -3 5 ,4 9 -5 3 9 ,1 4 ,4 2 0 -4 ,2 1 ,2 8 ,3 5 ,4 9 14 39-46 28 21-25 53 0 -7 ,1 1 -3 2 ,3 9 -5 3 ,5 6 ,6 0 -6 3 ,6 7 -7 0 , 7 4 ,1 2 6 -1 3 3 7 7 -8 4 ,8 8 -1 0 5 ,1 0 9 -1 2 3 136 42 9 ,1 4 ,6 6 0 -4 ,2 1 ,2 8 ,3 5 ,4 9 ,5 5 ,5 9 ,7 3 ,8 7 ,1 0 8 7 7 -8 4 ,8 8 -1 0 5 ,1 0 9 -1 2 3 35 109 136 0-7,11 -53 ,56 ,6 0-63 ,6 7-70 ,7 4-84 , 8 8 -1 0 5 ,1 0 9 -1 3 6 108 9 ,1 4 ,4 2 ,6 6 ,7 3 0 -4 ,2 1 ,2 8 ,3 5 ,4 9 ,5 5 ,5 9 ,8 7 136 Sanitized. Does not contain TSCA -48- H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 DEIONIZED WATER (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Sex Group A n im al MI 649300 MI 649301 MI 649312 GROUP I (Continued) O b servatio n G e n e ra l o b s e rv a tio n , No A b n o rm a lity Eye O b servatio n s, B le d v ia O r b ita l Eye O b servatio n s, B le d v ia O rb ita l Eye O b servation s, B le d v ia O rb ita l Eye O b servatio n s, Dark, R ig h t D isch arg e, Eye r ig h t, B la c k H a ir Loss, Fo re lim b , B ila t e r a l D etected for C lin for C lin for C lin Path, B ila t e r a l Path, L e ft Path, R ig h t H a ir Loss, Forepaw , B ila t e r a l H a ir Lo ss, S h o u ld e r, L e ft S a c r if ic e d by d e sig n G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te c te d Eye O b servatio n s, B le d v ia Eye O b servatio n s, B le d v ia Eye O b servatio n s, B le d v ia D isch arg e, Nose, B la c k D isch arg e, Eye r ig h t, B la c k H a ir Loss, Face, R ig h t S a c r if ic e d by d e sig n O rb ita l O rb ita l O rb ita l fo r fo r fo r C lin C lin C lin Path, B ila t e r a l Path, L e ft Path, R ig h t G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te cte d Eye O b servatio n s, B le d v ia O r b ita l Eye O b servatio n s, B le d v ia O rb ita l Eye O b servatio n s, B le d v ia O r b ita l D isch arg e, Eye b ila t e r a l, B la c k D isch arg e, Nose, B la c k D isch arg e, Eye le f t , B la c k S a c r if ic e d by d e sig n fo r fo r fo r C lin C lin C lin Path, B ila t e r a l Path, L e ft Path, R ig h t Days 0 87 9 ,1 4 ,4 2 ,6 6 0 -4 ,2 1 ,2 8 ,3 5 ,4 9 ,5 5 ,5 9 ,7 3 ,1 0 8 6 0 ,8 8 -9 1 74 4 -7 ,1 1 -5 3 ,5 6 ,6 0 -6 3 ,6 7 -7 0 ,7 4 -8 4 , 8 8 -1 0 5 ,1 0 9 -1 3 6 1 8-53 ,56,60-63,67-70,74-84, 8 8 -1 0 5 ,1 0 9 -1 3 6 112-136 136 0 ,2 1 -5 3 ,5 6 ,6 0 -6 3 ,6 7 -7 0 ,7 4 -8 4 , 8 8 -1 0 5 ,1 0 9 -1 3 6 0 -4 ,4 9 9 ,1 4 ,4 2 ,5 9 ,6 6 ,7 3 ,8 7 ,1 0 8 2 1 ,2 8 ,3 5 ,5 5 14-18 4-7 7 ,1 1 -1 8 136 0 -7,11-14,28,49-53,56,60-63, 6 7 -7 0 ,7 4 -8 4 ,8 8 -1 0 5 ,1 0 9 -1 3 6 35 9 ,1 4 ,4 2 ,5 9 ,6 6 ,7 3 0 -4 ,2 1 ,2 8 ,4 9 ,5 5 ,8 7 ,1 0 8 32-46 18,32 18-25 136 H-24159: Biopersistence Screening Gavage Study in Rats DEIONIZED WATER (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Sex Group M III A n im al 649302 M III 649303 M III 649304 M III 649305 M III 649307 GROUP III O b servatio n G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te cte d Eye O b servatio n s, B le d v ia O r b it a l fo r C lin Path, Eye O b se rv a tio n s, B le d v ia O r b it a l fo r C lin Path, S a c r if ic e d by d e sig n Le ft R ig h t G en eral o b s e rv a tio n , No A b n o rm a lity D e te cte d Eye O b serva tion s, B le d v ia O r b ita l fo r C lin Path, Eye O b servatio n s, B le d v ia O r b it a l fo r C lin Path, Eye O b se rv a tio n s, B le d v ia O r b it a l fo r C lin Path, S a c r if ic e d by d e sig n B ila te ra l Le ft R ig h t G e n e ra l o b s e rv a tio n , No A b n o rm a lity D e te cte d Eye O b servatio n s, B le d v ia O r b it a l fo r C lin Path, Eye O b servatio n s, B le d v ia O r b ita l fo r C lin Path, S a c r if ic e d by d e sig n Le ft R ig h t G e n e ra l o b s e rv a tio n , No A b n o r m a lity D e te c te d Eye O b servatio n s, B le d v ia O r b it a l fo r C lin Path, Eye O b serva tion s, B le d v ia O rb ita l fo r C lin Path, Eye O b se rv a tio n s, B le d v ia O r b it a l fo r C lin Path, D isch arg e, Eye r ig h t, B la c k D is c h a rg e , Eye r ig h t , Brown S a c r if ic e d by d e sig n B ila te ra l Le ft R ig h t G e n e ra l o b s e rv a tio n , No A b n o r m a lity D e te c te d Eye O b se rv a tio n s, Exophthalm us, L e ft Eye O b serva tion s, B le d v ia O rb ita l fo r C lin Path, Eye O b serva tion s, B le d v ia O rb ita l fo r C lin Path, Eye O b se rv a tio n s, B le d v ia O r b it a l fo r C lin Path, Eye O b servation s, Dark, L e ft H a ir L o ss, Abdomen, V e n tr a l H a ir Loss, Nose Wound, S u p e r f i c i a l , Nose S a c r if ic e d by d e sig n B ila te ra l Le ft R ig h t Days 0 -7 ,1 1 -5 3 9 ,1 4 ,4 2 0 -4 ,2 1 ,2 8 ,3 5 ,4 9 53 0 -7 ,1 1 -5 3 9 ,1 4 42 0 -4 ,2 1 ,2 8 ,3 5 ,4 9 53 0 -7 ,1 1 -5 3 9 ,1 4 ,4 2 0 -4 ,2 1 ,2 8 ,3 5 ,4 9 53 0 ,1 1 -2 8 ,4 2 -5 3 28 9 ,1 4 ,4 2 0 -4 ,2 1 ,3 5 ,4 9 4-7 32-39 53 0-4 49-53 42 9 ,1 4 0 -4 ,2 1 ,2 8 ,3 5 ,4 9 49-53 7 ,1 1 -4 9 35-49 42-46 53 DuPont-6732 iiiompanySanitized. Does notcontain TSCAt -50- ))) H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 DEIONIZED WATER (NEGATIVE CONTROL) Sex Group A n im a l M III 649308 M III 649309 M III 649310 M III 649311 INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP III (Continued) O b servatio n Days G e n e ra l o b s e rv a tio n , No A b n o r m a lity D e te cte d Eye O b servatio n s, B le d v ia O r b ita l fo r C lin Path, Eye O b se rva tio n s, B le d v ia O r b ita l fo r C lin Path, D isch arg e, Eye r ig h t, B la c k D isch arg e, Eye rig h t, Red M isshapen O b se rv a tio n s, T a il Le ft R ig h t S a c r if ic e d by d e sig n 0 -7 ,1 1 -1 8 9 ,1 4 ,4 2 ,5 9 ,6 6 ,8 7 0 -4 ,21 ,28,35,49,55,73,108 109 5 6 ,6 0 -6 3 ,6 7 -7 0 2 1 -5 3 ,5 6 ,6 0 -6 3 ,6 7 -7 0 ,7 4 -8 4 , 8 8 -1 0 5 ,1 0 9 -1 3 6 136 G e n e r a l o b s e r v a t io n , No A b n o r m a lit y D e te c te d Eye O b se rv a tio n s, En op h th alm u s, R ig h t Eye O b se rv a tio n s, Opaque, R ig h t Eye O b servatio n s, B le d v ia O r b ita l fo r C lin Eye O b servatio n s, B le d v ia O r b ita l fo r C lin Eye O b servatio n s, B le d v ia O r b ita l fo r C lin D isch arge, Nose, B la c k D isch a rg e , Eye r ig h t, Red H a ir Loss, Forepaw, B il a t e r a l H a ir Loss, Face, R ig h t S a c r if ic e d by d e sig n Path, B ila t e r a l Path, L e ft Path, R ig h t 0 -7 ,3 9 -4 2 ,4 9 11-35 1 1 -3 5 ,7 0 ,7 4 -8 4 ,8 8 -1 0 5 ,1 0 9 -1 3 6 9 ,2 1 ,2 8 14,4 2,59 ,6 6,7 3,87 ,1 08 0 -4 ,3 5 ,4 9 ,5 5 1 4 -2 1 ,2 8 -3 5 ,4 6 18-25 5 3 ,5 6 ,6 0 -6 3 ,6 7 -7 0 ,7 4 -7 7 28 136 G e n e ra l o b s e rv a tio n , No A b n o r m a lity D e te c te d Eye O b servatio n s, B le d Eye O b servatio n s, B le d S a c r if ic e d by d e sig n v ia v ia O rb ita l O rb ita l fo r C lin fo r C lin Path, Path, L e ft R ig h t 0 -7 ,1 1 -5 3 ,5 6 ,6 0 -6 3 ,6 7 -7 0 ,7 4 -8 4 , 8 8 -1 0 5 ,1 0 9 -1 3 6 9 ,1 4 ,4 2 ,5 9 ,6 6 ,8 7 0 -4 ,21 ,28,35,49,55,73,108 136 G e n e ra l o b s e rv a tio n , No A b n o r m a lity D e te c te d Eye O b servatio n s, B le d v ia Eye O b servatio n s, B le d v ia D isch arg e, Eye le f t , B la c k S a c r if ic e d by d e sig n O rb ita l O rb ita l fo r C lin fo r C lin Path, P a th , Le ft R ig h t 0 -7 ,1 1 -5 3 ,5 6 ,6 0 -6 3 ,6 7 -7 0 ,7 7 -8 4 , 8 8 -1 0 5 ,1 0 9 -1 3 6 9 ,14,42,59,66,73,87 0 -4 ,2 1 ,2 8 ,3 5 ,4 9 ,5 5 ,1 0 8 74 136 Sanitized. Does not contain TSCA -51 - H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 Sex Group A nim al M III 649313 DEIONIZED WATER (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP III (Continued) O b servatio n Days G e n e r a l o b s e r v a tio n , No A b n o r m a lit y D e te c te d Eye O b se rv a tio n s, Enop h th alm u s, R ig h t Eye O b se rva tio n s, Exophthalm us, L e ft Eye O b servatio n s, B le d v ia O r b ita l fo r C lin Path, B ila t e r a l Eye O b servatio n s, B le d v ia O r b it a l fo r C lin Path, L e ft Eye O b servatio n s, B le d v ia O r b ita l fo r C lin Path, R ig h t Eye O b servatio n s, Dark, L e ft D isch a rg e , Nose, B la c k S a c r if ic e d by d e sig n 0 -7 ,1 1 -2 5 ,3 2 -5 3 ,5 6 ,6 0 -6 3 ,8 4 ,8 8 -1 0 5 109-136 6 7 -7 0 ,7 4 -8 1 9 ,14,21,28,49,55,73 4 2 ,5 9 ,6 6 ,8 7 0 -4 ,3 5 ,1 0 8 6 7 -7 0 ,7 4 28 136 Company Sanitized. Does not contain TSCAf H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 APPENDIX C Terms and Calculations Factors Influencing Interpretation of Kinetic Analysis - 53- Company Sanitized. Does nor confab TSPfl r m H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 Terms: Active % Active Mol Wt Active % F in Active TERMS AND CALCULATIONS Fluorine containing compound(s) The % of formulation that is made up of fluorine containing components The molecular weight of the fluorine containing components (g/mole) The % fluorine in the fluorine containing components of the formulation (weight basis) Individual Animal Measurement: ppm F The ppm fluoride measured Individual Animal Calculations: /molar equivalents of active The /molar [/imol/L] concentration of fluorine containing compound based on the ppm fluorine measured minus the background fluoride level (0.2 ppm). This assumes that all fluorine is derived from the fluorine-containing component in the formulation. Note: 1 ppm = 1 mg/L = (ppm [mg/L] fluorine / % F in active [mg active/mg F] / Mol W t Active [mg active/mmol active] x 1000 /imol/mmol -54Company Sanitized. Does not contain TSCA CMI H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 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 - Terminal phase elimination may not be reached - H-24159is Assumptions: (May or may not be justified in all cases) - Fluorine concentrations are linear with respect to dose - Analytical method is appropriate for all types of compounds - Elimination kinetics can be determined based on total fluorine rather than on concentrations of individual components - Background Fluorine is 0.2 ppm - % F data is the % Fluorine of the active (Fluorine containing component(s) in the formulation) - Molecular weight is the molecular weight of the active component in the formulation - 55Company Sanitized. Does not contain TSCA GSI H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 APPENDIX D Individual Fluorine Levels in Blood -56Company Sanitized. Does not contain TSCA CjE H-24159: Biopersistence Screening Gavage Study in Rats Data for Negative Control Test ppm F Rat Day in Number____ Sample______ Blood 649293 649294 649295 649296 649297 649298 649299 649300 649301 649312 649293 649294 649295 649296 649297 649298 649299 649300 649301 649312 649293 649294 649295 649296 649297 649298 649299 649300 649301 649312 649293 649294 649295 649296 649297 649298 649299 649300 -4 -4 -4 -4 -4 -4 -4 -4 -4 .4 4 4 4 4 4 4 4 4 4 4 9 9 9 9 9 9 9 9 9 9 14 14 14 14 14 14 14 14 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 0.7 <0.5 0.5 <0.5 <0.5 0.9 0.8 0.9 1.1 1.0 <0.5 <0.5 <0.5 0.5 <0.5 <0.5 <0.5 <0.5 DuPont-6732 - 57Companjr Sanffeea. Does not contain TSCA H-24159: Biopersistence Screening Gavage Study in Rats Test ppm F Rat Day in Number____ Sample_______Blood 649301 649312 649293 649294 649295 649296 649297 649298 649299 649300 649301 649312 649293 649294 649295 649296 649297 649298 649299 649300 649301 649312 649298 649299 649300 649301 649312 649298 649299 649300 649301 649312 649298 649299 649300 649301 649312 649298 649299 649300 14 14 49 49 49 49 49 49 49 49 49 49 53 53 53 53 53 55 55 55 55 55 59 59 59 59 59 73 73 73 73 73 108 108 108 108 108 136 136 136 0.7 0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 1.4 <0.5 0.6 0.4 <0.5 0.8 <0.5 <0.5 <0.5 0.6 <0.5 <0.5 <0.5 DuPont-6732 - 5 8 - Company Sanitizea. Does noi contamTSCAC H-24159: Biopersistence Screening Gavage Study in Rats Test ppm F Rat Day in Number_____ Sample______ Blood 649301 649312 136 136 <0.5 <0.5 DuPont-6732 - 59- Company Sanitized. D o e s not contain TSCACBJ H-24159: Biopersistence Screening Gavage Study in Rats Data for H-24159 Given: Mol Wt. Active (g/mole): % Active (F Containing) in Formulation: % F in Active: Test ppm F Rat Day in Number_____ Sample______ Blood 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 649302 649303 -4 -4 -4 -4 -4 -4 -4 -4 -4 _4 0 0 0 0 0 0 0 0 0 0 4 4 4 4 4 4 4 4 4 4 9 9 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 4.5 2.6 5.0 4.2 5.0 3.6 4.4 4.1 5.3 5.2 4.8 6.3 10.2 5.4 8.5 11.7 11.0 13.1 8.6 13.4 5.9 14.0 molar Equivalents of Active in Blood * * * * * * * * * * 17.37 9.70 19.39 16.16 19.39 13.74 16.97 15.76 20.61 20.20 18.59 24.65 40.40 21.01 33.54 46.46 43.64 52.12 33.94 53.33 23.03 55.76 DuPont-6732 -60Company Sanitized. Does not contain TC ' " H-24159: Biopersistence Screening Gavage Study in Rats____________ Rat Number 649304 649305 649307 649308 649309 649310 649311 649313 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 649302 649303 Test Day Sample 9 9 9 9 9 9 9 9 14 14 14 14 14 14 14 14 14 14 21 21 21 21 21 21 21 21 21 21 28 28 28 28 28 28 28 28 28 28 35 35 ppm F in Blood 14.3 7.5 11.5 10.7 8.3 10.3 9.1 12.1 8.6 10.5 13.5 8.7 12.7 12.6 11.4 12.8 11.9 12.6 9.0 10.7 8.8 9.8 11.8 9.9 14.5 11.1 11.0 14.2 10.9 14.5 16.2 15.5 12.8 15.0 16.8 13.2 13.9 15.8 12.1 12.8 /molar Equivalents of Active in Blood 56.97 29.49 45.66 42.42 32.73 40.81 35.96 48.08 33.94 41.62 53.74 34.34 50.51 50.10 45.25 50.91 47.27 50.10 35.56 42.42 34.75 38.79 46.87 39.19 57.78 44.04 43.64 56.57 43.23 57.78 64.65 61.82 50.91 59.80 67.07 52.53 55.35 63.03 48.08 50.91 DuPont-6732 -61 - '* '* * " * * > not conte,,, T sc u H-24159: Biopersistence Screening Gavage Study in Rats____________ Rat Number 649304 649305 649307 649308 649309 649310 649311 649313 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 649308 649309 Test Day Sample 35 35 35 35 35 35 35 35 42 42 42 42 42 42 42 42 42 42 49 49 49 49 49 49 49 49 49 49 53 53 53 53 53 55 55 55 55 55 59 59 ppm F in Blood 16.1 16.3 12.6 15.8 15.5 13.2 13.1 13.4 11.7 15.6 18.9 13.9 16.5 15.6 15.2 15.9 15.1 17.4 11.2 13.0 14.9 13.4 13.4 14.8 15.4 14.6 14.1 15.6 14.5 11.4 13.8 10.2 13.9 5.9 8.3 8.7 7.8 9.2 8.4 7.1 - 62 limolar Equivalents of Active in Blood 64.24 65.05 50.10 63.03 61.82 52.53 52.12 53.33 46.46 62.22 75.56 55.35 65.86 62.22 60.61 63.43 60.20 69.49 44.44 51.72 59.39 53.33 53.33 58.99 61.41 58.18 56.16 62.22 57.78 45.25 54.95 40.40 55.35 23.03 32.73 34.34 30.71 36.36 33.13 27.88 DuPont-6732 Soni"ied not contato TSCAc H-24159: Biopersistence Screening Gavage Study in Rats____________ Rat Number Test Day Sample ppm F in Blood 649310 649311 649313 649308 649309 649310 649311 649313 649308 649309 649310 649311 649313 649308 649309 649310 649311 649313 649308 649309 649310 649311 649313 649308 649309 649310 649311 649313 59 59 59 66 66 66 66 66 73 73 73 73 73 87 87 87 87 87 108 108 108 108 108 136 136 136 136 136 8.0 9.1 9.5 5.1 5.7 6.6 5.9 5.4 3.8 4.2 6.4 4.8 4.5 3.8 3.6 4.1 4.3 4.0 2.1 2.6 2.8 2.7 2.5 1.1 1.7 1.9 1.7 2.3 Below LOQ (Limit of Quantification) /molar Equivalents of Active in Blood 31.52 35.96 37.58 19.80 22.22 25.86 23.03 21.01 14.55 16.16 25.05 18.59 17.37 14.55 13.74 15.76 16.57 15.35 7.68 9.70 10.51 10.10 9.29 3.64 6.06 6.87 6.06 8.48 DuPont-6732 63 - Company Sanitized. Does not contain TSQA CL H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 APPENDIX E Individual Fluorine Levels in Liver -64Company Sanitized. Does not contain Q H-24159: Biopersistence Screening Gavage Study in Rats Data for Negative Control Rat Number 649293 649294 649295 649296 649297 649298 649299 649300 649301 649312 Test ppm F Day in Sample_______ Liver 53 <0.5 53 <0.5 53 <0.5 53 <0.5 53 0.6 136 0.5 136 0.5 136 0.7 136 <0.5 136 <0.5 DuPont-6732 -65 - jM -T-- Sanitized. Does notoontwISgACff H-24159: Biopersistence Screening Gavage Study in Rats____________ Data for H-24159 Given: Mol Wt. Active (g/mole): % Active (F Containing) in Formulation: % F in Active: Rat Number 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 Test Day Sample 53 53 53 53 53 136 136 136 136 136 ppm F in Liver 189.8 169.3 198.8 156.8 165.5 13.7 19.3 26.0 17.1 26.9 /molar Equivalents of Active in Liver 766.06 683.23 802.42 632.73 667.88 54.55 77.17 104.24 68.28 107.88 DuPont-6732 -66Company Sanitized. Does not contain TSCA CBi H-24159: Biopersistence Screening Gavage Study in Rats____________ DuPont-6732 APPENDIX F Individual Fluorine Levels in Fat -67Company Sanitized. Does not contain TSG GBl H-24159: Biopersistence Screening Gavage Study in Rats Data for Negative Control Rat Number 649293 649294 649295 649296 649297 649298 649299 649300 649301 649312 Test Day Sample 53 53 53 53 53 136 136 136 136 136 ppm F in Fat 0.5 1.0 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 DuPont-6732 - 68- H-24159: Biopersistence Screening Gavage Study in Rats____________ Data for H-24159 Given: Mol Wt. Active (g/mole): % Active (F Containing) in Formulation: % F in Active: Rat Number 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 Test Day Sample 53 53 53 53 53 136 136 136 136 136 ppm F in Fat 20.6 19.1 17.5 20.2 16.9 5.6 5.9 5.9 4.8 3.8 /imolar Equivalents of Active in Fat 82.42 76.36 69.90 80.81 67.47 21.82 23.03 23.03 18.59 14.55 DuPont-6732 -69<Sompany SanHfced. Does nof contain TSCA COI H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 APPENDIX G Individual Fluorine Levels in Kidneys -70noi contain TfCAttftl Gompany Saniiized. Does H-24159: Biopersistence Screening Gavage Study in Rats Data for Negative Control Rat Number 649293 649294 649295 649296 649297 649298 649299 649300 649301 649312 Test Day Sample 53 53 53 53 53 136 136 136 136 136 ppm F in Kidneys 0.8 1.2 0.9 0.5 0.9 <0.5 <0.5 <0.5 <0.5 0.9 DuPont-6732 Company Sanitized, Does not contain TSC CB8 H-24159: Biopersistence Screening Gavage Study in Rats Data for H-24159 Given: Mol Wt. Active (g/mole): % Active (F Containing) in Formulation: % F in Active: Rat Number 649302 649303 649304 649305 649307 649308 649309 649310 649311 649313 Test Day Sample 53 53 53 53 53 136 136 136 136 136 ppm F in Kidneys 93.4 60.1 63.0 82.9 81.0 6.0 10.3 8.4 14.0 9.6 /molar Equivalents of Active in Kidneys 376.57 242.02 253.74 334.14 326.46 23.43 40.81 33.13 55.76 37.98 DuPont-6732 72 - Company Sanitized. Does not contain TSCA CB1 H-24159: Biopersistence Screening Gavage Study in Rats DuPont-6732 APPENDIX H Urine and Feces Data - 7f 0lPany Sanitized. Does not contain T SC A cei H-24159: Biopersistence Screening Gavage Study in Rats Data for Negative Control Test Day ppm F Urine Urine Urine Feces Feces Feces 51 8.9 52 1 0 . 2 53 6 . 8 51 5.1 52 1 .1 53 1 .1 DuPont-6732 - 7 4 - Company Sanitized. Does not contain TSCACBS H-24159: Biopersistence Screening Gavage Study in Rats Data for H-24159 Given: Mol Wt. Active (g/mole): % Active (F Containing) in Formulation: % F in Active: DuPont-6732 Urine Urine Urine Feces Feces Feces Test /mole Equivalents Day ppm F g or mL/day fig F/day of Active/Day 51 12.7 52 9.9 53 8.7 51 39.6 52 38.9 53 41.5 70.0 46.0 54.0 3.5 24.3 15.3 889.00 455.40 469.80 139.39 945.27 634.12 3591.11 1839.19 1897.37 562.39 3818.46 2561.29 - 75Company Sanitized, Does not contain TSOACBf
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CUNY - The Graduate CenterColumbia University Mailman School of Public Health - Sociomedical Sciences