Document NG8yY3p6MOp8amwJRVkj2q648

AR226-3161 TRADE SECRET Study Title H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Laboratory Project ID: DuPont-2931 AUTHOR: Carol Finlay, B.A. STUDY COMPLETED ON: August 29, 2000 PERFORMING LABORATORY: E.I. du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 Company Sanitized. Doss not contain TSCA CBi 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 Cr Reviewed by: ^b^A^L yfclxU^, L Judith C. Stadler, PhJO., D.A.B.T. Director. General Toxicology ZS A^< ^<3<1 Date ^-^t/g-Z^O^ Date Issued by Study Director: 1^(-^ ^SLA^C Carol Fifiay, B.A. 1 Staff Scientist ^__^(/_<_^06 nDaalie^-^ -2- ;ompany Sanitized. Does not contain TSCA CBJ H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 TABLE OF CONTENTS Page CERTIFICATION.........................................................................................................................2 LIST OF TABLES .........................................................................................................................4 LIST OF FIGURES .......................................................................................................................4 LIST OF APPENDICES...............................................................................................................4 STUDY INFORMATION.............................................................................................................5 STUDY PERSONNEL...................................................................................................................? SUMMARY ....................................................................................................................................8 INTRODUCTION.........................................................................................................................^ MATERIALS AND METHODS..................................................................................................9 A. Test Substance and Positive Control...................................................................................^ B. Test Species .........................................................................................................................9 C. Animal Husbandry..............................................................................................................^ 1. Housing Environment.............................................................................................................................. 9 2. Feed and Water...................................................................................................................................... 10 3. 10 Identification.......................................................................................................................................... 4. Animal Health Monitoring Program ...................................................................................................... 10 D. Quarantine and Pretest.......................................................................................................10 E. Study Design......................................................................................................................11 F. Assignment to Groups and Study Start..............................................................................! 1 G. Dosing Material Preparation and Administration..............................................................11 1. Test Substance ....................................................................................................................................... 11 2. Positive Controls....................................................................................................................................11 3. Negative Controls.................................................................................................................................. 12 H. Body Weights.....................................................................................................................12 I. Mortality and Clinical Observations..................................................................................12 J. Collection and Analysis of Blood and Livers ....................................................................12 K. Treatment of 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.................................................................................................................................... 14 3. Test Substance ....................................................................................................................................... 15 CONCLUSIONS ..........................................................................................................................15 RECORDS AND SAMPLE STORAGE ....................................................................................16 TABLES........................................................................................................................................17 -3- Company Sanitized. Does not contain TSCA DBS H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 FIGURES......................................................................................................................................22 APPENDICES ..............................................................................................................................27 LIST OF TABLES Page 1. MEAN BODY WEIGHTS............................................................................................;...................................... 18 2. MEAN BODY WEIGHT GAINS..........................;............................................................................................. 19 3. MEAN BLOOD FLUORINE LEVELS............................................................................................................... 20 4. MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE ............................................... 21 LIST OF FIGURES Page 1. MEAN BODY WEIGHTS...................................................................................................................................23 2. MICROMOLAR EQUIVALENTS IN RAT BLOOD......................................................................................... 24 3. MICROMOLAR EQUIVALENTS IN TEST COMPOUND AND POSITIVE CONTROLS ............................ 26 LIST OF APPENDICES Page A. INDIVIDUAL BODY WEIGHTS.......................................................................................................................28 B. INDIVIDUAL CLINICAL OBSERVATIONS....................................................................................................63 C. INDIVIDUAL FLUORINE LEVELS.................................................................................................................. 74 -4- Company Sanitized. Does not contain TSCA CBI H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats STUDY INFORMATION TEST SUBSTANCE: Synonyms/Codes: H-24042 Haskell Number: 24042 DuPont-2931 POSITIVE CONTROL: Substance ^ Tested: I Synonyms/Codes: H-24019 Haskell Number: 24019 -5- Company Sanitised. Does noS conlsin T3CA CBl H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats STUDY INFORMATION (Continued) Composition! DuPont-2931 Known Impurities :H POSITIVE CONTROL: Substance Tested:^ Synonyms/Codes: e H-24020 C-8 Perfluorooctanoate, ammonium salt PFOA Ammonium perfluorooctanoate Haskell Number: 24020 Composition Known Impurities' Sponsor: E. I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: April 30, 1999 / (see report cover page) In-Life Initiated/Completed: June 13, 1999 / September 14, 1999 -6- Company Sanitized. Does not contain TSCA CBt 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. -1-nCo^WP^3^ '-00^' H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 SUMMARY The objective of this study was to evaluate the potential for H-24042, when administered by gavage, to be absorbed and to accumulate in a mammalian system. Six groups of 5 male Crl:CD(SD)IGSBR rats each were given 100 mg/kg/day of H-24042. 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, 2 negative controls, 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-24042. No deaths occurred during the study. Transient alopecia, considered unrelated to test substance administration, was observed in two rats dosed with the test substance, H-24042. Rats dosed with H-24019 exhibited diarrhea, salivation, alopecia, black ocular discharge, and staining of various parts of the body during the dosing period. Rats dosed with H-24020 exhibited wet perineum and diarrhea during the dosing period. Alopecia was observed during the recovery period in rats dosed with the positive controls, H-24019 and H-24020. The negative control rats exhibited no clinical signs during the study. The mean body weights and mean body weight gains of the rats dosed with the test substance, H-24042, were comparable to the corn oil negative controls and to the H-24020 positive controls. Comparison of body weights between the rats dosed with 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-24042, are comparable to the corn oil/acetone negative controls and equal to or greater than the H-24019 positive controls. A steady-state for fluorine levels in whole blood was not achieved during 10 consecutive days of dosing with 100 ing/kg H-24042. An area under the curve (estimated to infinity) was calculated and normalized for fluorine content for the test substance and each positive control. The AUCINF/D for the fluorine component of the test substance, H-24042, was 6241.7, compared to AUCINF/D values of 566,479.1 and 70,789.6 for the positive controls, H-24019 and H-24020, respectively. Under the conditions of this study, administration of the test substance, H-24042, to male rats for 10 consecutive days resulted in a very low absorption and retention of fluorine in the blood. Dose-adjusted areas under the curve (AUCINF/D) for positive controls, H-24019 and H-24020, were approximately 90x and 1 Ix the AUCINF/D for the test substance. -8- Company.5 ^8"11' n o ^ ^ H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 INTRODUCTION The objective of this study was to define the potential of H-24042 to be absorbed and to bioaccumulate in a mammalian system, as indicated by analytical determination of total fluorine in blood and liver. The test substance was compared to 2 positive controls that were materials previously shown to bioaccumulate in mammals. The daily dosage of 100 mg/kg/day for the test substance was selected based on available toxicity data and the results of a rangefinding study. In the rangefinding study, a group of 5 male rats was dosed by oral gavage with H-24042 for 4 consecutive days at a dosage of 100 mg/kg/day. A group of 5 male rats was dosed with deionized water and served as controls. The rats dosed with H-24042 experienced an overall mean body weight gain of 16 grams. The control group had an overall mean body weight gain of 29 grams. All blood samples were analyzed for total fluorine content. This report contains the results of those analyses. Results from analyses of selected liver samples will be presented in a supplemental report. MATERIALS AND METHODS A. Test Substance and Positive Control The test substance, H-24042, was supplied by the sponsor as a pale amber waxy solid. The positive controls, H-24019 and H-24020, were supplied by the sponsor as white solids. The test substance and positive controls appeared to be stable under the conditions of the study. No evidence of instability, such as a change in color or physical state, was observed. B. Test Species Male Crl:CD(SD)IGS BR rats were received from Charles River Laboratories, Inc., Raleigh, North Carolina. The Crl:CD(SD)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. 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%. TSCACB) -9- Company Sanded. Does n ot contain H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats______________________ 2. Feed and Water DuPont-2931 Tap water was provided ad libitum. All rats were fed PMI Nutrition International, Inc. Certified Rodent LabDiet 5002 chow. The feed is guaranteed by the manufacturer to meet specified nutritional requirements and to be free of specified contaminants. 3. Identification Prior to assignment to groups, each rat was temporarily identified by cage identification. After assignment to groups, an individual identification number was marked or tattooed on the tail of each rat. The information on the cage labels included the unique 6-digit Haskell animal number assigned to each rat. 4. Animal Health Monitoring Program As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to assure that contaminant levels are below those that would be expected to impact the scientific integrity of the study: Water samples are analyzed for total bacterial counts, and the presence 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. D. Quarantine and Pretest Upon arrival at Haskell Laboratory, the rats were removed from shipping cartons and quarantined for 6 days. The rats were weighed 3 times during the pretest period and examined daily for any clinically apparent signs of disease or injury. The rats were observed daily for mortality and signs of illness, injury, or abnormal behavior. On the bases of acceptable body weight gains and freedom from clinically apparent signs of disease or injury, the rats were released from quarantine by the laboratory animal veterinarian designee. -10- S.n^.Doe.no.oon^^11' Coinpany H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 E. Study Design Substance Negative Controls Corn oil Corn oil: acetone Positive Controls H-24019 H-24020 Test Substance H-24042 Vehicle Not applicable Dosage (mg/kg) Number of Animals 0 30 0 30 Corn oil: acetone 10 30 Corn oil 20 30 Corn oiLacetone 100 30 F. Assignment to Groups and Study Start After the quarantine period, the rats were selected on the bases of adequate body weight gain, freedom from any clinical signs of disease or injury, and a body weight within 20% of the mean. The selected rats were divided by computerized, stratified randomization into 6 groups of 5 rats, so that there were no statistically significant differences among group body weight means. After assignment to groups, each rat was housed individually. The last 3 digits 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 It was necessary to dissolve H-24042 in acetone before suspending it in corn oil. The ratio of acetone to corn oil was 20:80. The amount of test substance each rat received was based on the body weight collected on each day of dosing and the suspension concentration. The dose volumes did not exceed 1 mL/100 g of body weight. The test substance was stirred on a magnetic stir plate throughout the dosing procedure to maintain homogeneity. 2. Positive Controls The solid positive control compounds were suspended as emulsions in their respective vehicles. 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. Company Sgnili:rs.'J, Dcss no' nonSain TSCA C21 H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 3. Negative Controls Corn oil and corn oiLacetone (80:20) were chosen as the negative controls because they were the vehicles for the positive controls. Additionally, corn oiLacetone was the vehicle for H-24042, the test substance. Each negative control rat received 1 mL of corn oil or corn oiLacetone. These rats were dosed in a separate room from the rats dosed with the test substance or positive controls. H. Body Weights All rats were weighed on each day of dosing. The rats were weighed weekly or every other week during the recovery period. I. Mortality and Clinical Observations Cage-site examinations to detect moribund or dead rats and abnormal behavior and appearance among rats were conducted at least once daily throughout the study. At every weighing, each rat was individually handled and examined for abnormal behavior and appearance. J. Collection and Analysis of Blood and Livers Approximately 2 hours after the first dose, 1-2 mL of blood was collected into EDTA tubes from the orbital sinus of each rat from Group I. At all other selected time points, 5 rats/group were euthanized by carbon dioxide anesthesia and exsanguination and blood and livers were collected according to the following schedules: Group I I II III IV V VI Dosing Days 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 - 12- Oossn-, contain TSCACB1, Compa1^ Sani^d. H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 aqueous absorbing solution and analyzed using a fluoride ion selective electrode. The analytical data (ppm F in each sample) was supplied to Haskell Laboratory personnel for evaluation of fluorine biopersistence. K. Treatment of Fluorine Data Noncompartmental analysis was conducted on blood fluorine data derived from rats dosed with H-24042 using WinNonlin Version 3.0 software (Pharsight Corp, Mountain View, CA). WinNonlin software provided a means of computing derived pharmacokinetic parameters from data files including area under the curve (AUCINF), Cmax and terminal half-life (Ti/z). The AUCINF (concentration x time) represents the area under the blood concentration curve from the time of dosing extrapolated to infinity. The maximum observed concentration was Cmax (concentration). The points included in determination of the terminal half-life were selected manually and given in units of time. In all cases, doses were normalized to 0.1 mmole/kg for comparative purposes. The accumulation index (AI, l^l-e"1")) and bioaccummulation index (BI, Cmax x AI) were calculated and reported but not further used. H-24019 and H-24020 were used as positive controls. Dosing diluents were used as negative controls, but because of variability and limited sensitivity of the analytical method, the background was set at 0.2 ppm fluorine. Since 0.2 ppm was the fluoride concentration limit of detection, any values listed as less than 0.2 ppm were excluded from further treatment. T h e percent of fluorine and molecular weight of the test substance and positive controls were used as provided by the sponsor. The measurements resulting from analysis of total blood fluorine were used as received (ppm F) from Jackson Laboratory. Fluoride ion was converted to micromolar (uM) equivalents of active component for further comparisons. The data and descriptions of data manipulation and presentation are provided in Appendix C. CBi- -- ----------c--o--m----p--a--n--y--S--a--^--.--D--o--e--s--n--o--^.c-O-l-^-'"^^ RESULTS AND DISCUSSION A. In-Life Toxicology (Tables 1-2, Figure 1, Appendices A-B) No deaths occurred during the study. Transient alopecia, considered unrelated to test substance administration, was observed in 2 rats dosed with the test substance, H-24042. Rats dosed with H-24019 exhibited diarrhea, salivation, alopecia, black ocular discharge, and staining of various parts of the body during the dosing period. Rats dosed with H-24020 exhibited wet perineum and diarrhea during the dosing period. One rat dosed with H-24042 exhibited misshapen ears during the recovery period. Alopecia was observed during the recovery period in rats dosed with the positive controls, H-24019 and H-24020. The negative control rats exhibited no clinical signs during the study. The mean body weights and mean body weight gains of the rats dosed with H-24042 were comparable to the corn oil negative controls and to the H-24020 positive controls. Comparison of body weights between the rats dosed with the test substance and to the 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-24042 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-24042, are comparable to the corn oil/acetone negative controls and equal to or greater than the H-24019 positive controls. B. Fluorine Data (Tables 3-4, Figures 2-3, Appendix C) 1. Factors Influencing Interpretation of Analysis The data used in the kinetic analysis were derived from a limited screen, and therefore several caveats and considerations are important. A couple of considerations of particular importance are (1) a single dose was used and kinetics may or may not be linear, (2) the kinetics apply only to blood, (3) steady-state may not have been achieved, and (4) the sample size is low and may impact calculation of the terminal half-life. A more complete list of considerations is shown in Appendix C. 2. Positive Controls The positive controls were H-24019 and H-24020. The H-24019 normalized uM equivalents in rat blood continued to rise throughout the dosing period and may not have reached steady-state -14- Company Sanitized. Does not contain TSCA CBf H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 (Figure 2A). The Cmax for H-24019 was 989.85 116.90 ppm (Mean SD) with a terminal half-life of 40.5 days. The H-24019 AI was 59.0 and the BI was 58382.2. The H-24020 normalized uM 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 for H-24019 and 70,789.6 for H-24020. 3. Test Substance The H-24042 normalized uM equivalents in rat blood continued to rise throughout the dosing period and did not reach steady-state (Figure 2C). The Cmax for H-24042 was 26.106 3.102 ppm (Mean SD) with a terminal half-life of 24 days. Blood was sampled at seven time points throughout the study, with only four of them occurring post-dose. The small sample size and analytical variability should be taken into account when using the derived terminal half-life for comparative purposes. The H-24042 AI was 35.1 and the BI was 916.4. The total internal exposure resulting from a normalized dose was described by AUCINF/D and was the basis for comparison between H-24042 and positive controls. The AUCINF/D for the fluorine component of H-24042 was 6241.7 as compared to AUCINF/D values of 566,479.1 and 70,789.6 for H-21019 and H-24020, respectively. The data, calculations and equations are shown in Appendix C. CONCLUSIONS Rats dosed for 10 consecutive days with 100 mg/kg the test substance, H-24042, exhibited no mortality or test substance-related clinical signs oftoxicity and had mean body weights and mean body weight gains that were comparable to the negative control rats. However, the mean body weights and mean body weight gains of rats were also comparable to the H-24020 positive controls. A steady-state for fluorine in the blood was not achieved during the 10-day dosing period. Under the conditions of this study, administration of H-24042 to male rats for 10 consecutive days resulted in a very low absorption and retention of fluorine in the blood. Dose-adjusted areas under the curve (AUCINF/D) for positive controls, H-24019 and H-24020, were approximately 90x and 1 Ix the AUCINF/D for the test substance. -'5- Do5 ^ sanl.',.,-eed. Compa^ TSCAC^i v,Aam H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 RECORDS AND SAMPLE STORAGE Specimens (if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, Delaware, or at h-on Mountain Records Management, Wilmington, Delaware. -16- 'Compp.ry SanHizs'c', Po^s "c" .'cnfain TSCA CB! H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 TABLES -17- Sanitized. Doss T^i tuHU-.l I'UCACBl Compaq H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 TABLE 1 MEAN BODY WEIGHTS (g) Test Days 1 2 3 4 5 6 7 8 9 10 .13 20 24 27 34 38 41 47 48 52 53 55 61 62 68 69 76 80 81 82 88 90 94 Negative Controls Corn Oil 229.8 234.1 241.4 250.4 259.3 266.8 271.2 281.9 285.2 295.9 321.1 350.5 378.3 Corn Oil Acetone 297.6 299.6 309.4 314.3 321.5 326.0 334.9 339.2 345.2 351.7 350.7 369.8 401.0 - - 407.8 411.4 - - 434.5 - 454.9 - - - 464.7 527.6 - - 487.0 - 505.1 - - - 515.4 - - - - 539.0 - - - - - - - 556.2 566.9 - 562.2 567.8 Indicates that the animal was not weighed. Positive Controls H-24019 291.5 291.5 298.3 304.1 308.6 312.7 317.5 317.3 318.4 318.9 329.1 359.7 387.9 393.9 416.9 H-24020 227.5 232.4 242.0 248.9 252.4 259.8 263.3 269.8 278.5 283.9 289.1 311.3 340.9 - 402.9 - - - 425.0 - 438.2 - - 438.1 465.6 - - - - 523.4 - 452.3 465.8 - 470.9 - - 563.4 570.7 - - 499.2 - - - 585.3 597.9 - 527.8 538.7 Test Substance H-24042 231.4 231.7 240.2 246.4 253.8 258.6 267.0 268.6 287.3 288.2 317.7 344.0 385.2 - 423.1 442.0 - - 467.8 480.1 - 490.6 511.4 - - 531.4 - - - 531.4 578.7 - 592.0 -18- net contain TSCACB1 Company SaniUzec3... Does TABLE 2 MEAN BODY WEIGHT GAINS (g) Test Days 1-5 1-10 10-13 10-24 10-52 10-94 Negative Controls Corn Oil Corn Oil Acetone 29.5 66.1 25.2 82.4 168.8 271.0 23.9 54.1 -1.0 49.3 175.9 216.1 Positive Controls H-24019 H-24020 17.1 27.4 10.2 69.0 119.2 279.0 24.9 56.4 5.2 57.0 181.7 254.8 Test Substance H-24042 22.4 56.8 29.5 97.0 191.9 303.8 -19- .Comparyf Sanitize;?. Qces no? cor;?a;R TSCA CSi TABLE 3 MEAN BLOOD FLUORINE LEVELS Test Days 1 5 10 13 24 52 94 Negative Controls Corn Oil Corn OiLAcetone Positive Controls H-24019 H-24020 Test Substance H-24042 (ppm)_____(ppm)______(ppm)_____(ppm)______(ppm) <0.2 <0.2 2.1 (0.9) 62.6 (3.2) 1.8(0.6) 0.2 0.2 0.2'(0.1) <0.2 0.3'(O.I)13 0.6" (0.6) 48.8 61.7 64.5 (17.6) (2.8) (7.6) 71.7 54.2 26.6 (6.2) (7.8) (11.4) 15.6(1.2) 19.8(2.3) 14.0(1.0) 0.2 OJ-^O.!) 0.2'1 0.2 42.2 (2.8) 10.5 (3.0) 26.9 (2.6) 0.9 (0.2) 5.3(1.1) 2.6(0.4) 0.3''(0.1) 0.2_______13.2 (2.1) 0.2 (0.1)____0.9 (0.2) a Mean of 4 of the 5 values. One of the values was below the level of detection (LOD). b Standard deviation is in parentheses. c Mean of 3 of the 5 values. Two of the values were below the LOD. d One value. Four of the values were below the LOD. " ^ , . ^ 0 ^CommnpaannyySan- sitee'-"-5 not contain TSCA CB1 TABLE 4 MEAN BLOOD FLUORINE CONCENTRATION NORMALIZED TO DOSE Test Days 1 5 10 13 24 52 94 Positive Controls H-24019 H-24020 uM F Equivalents 28.92 (13.3)' uM F Equivalents 89.28 (23.4) 747.69 (271.5) 518.12 (44.9) 945.85 (43.5) 391.01 (56.8) 989.85 (116.9) 191.45 (82.7) 645.54 (42.9) 74.35 (22.1) 411.38 (40.6) 4.64 (1.1) 195.38 (32.5) 0.24 (0.4) a Standard deviation is in parentheses. Test Substance H-24042 uM F Equivalents 2.16 (0.8) 20.59 (1.6) 26.11 (3.1) 18.38 (1.4) 6.80 (1.4) 3.15 (0.6) 0.90 (0.2) -21 - --Sa--n--U.izstH1-nDon^CU.^.nTSCACBl Compa"'/ FIGURES _,,-,e------.dr''-":-t'.^COniainTSCAC51 .C,, orr-p^y baiilt;-'-1--1---~ "- H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats 400 -i 350 ^ 300 en 250 If t 200 CO I '50 100 FIGURE 1 MEAN BODY WEIGHTS (g) Test Days -23- Negative Contr Negative Contr Positive Contro Positive Contro Test Stubstance 10 H-24042: Biopersistence Screening 10-DoseOral Gavage Study in Rats DuPont-2931 FIGURE 2 MICROMOLAR EQUIVALENTS IN RAT BLOOD A. Normalized Rat Blood H-24019 p M Equivalents Resulting from a 10-Day 0 ralC avage Micromolar (uM) equivalents of H-24019 (positive control) in rat blood resulting from a 10-day oral gavage exposure. Values are means and error bars are standard deviation. B. Normalized Rat Blood H-24020 uM Equivalents Resulting from a 10-Day Oral Gavage Test Days Micromolar (uM) equivalents of H-24020 (positive control) in rat blood resulting from a 10-day oral gavage exposure. Values are means and error bars are standard deviation. .24- Comps/ij,- Ssniiizcc, Dasa nsi contain TSCA C8J H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 FIGURE 2 (Continued) MICROMOLAR EQUIVALENTS IN RAT BLOOD C. Normalized Rat Blood H-24042 uM Equivalents Resulting from a 10-Day Oral Gavage Micromolar (uM) equivalents of H-24042 (test substance) in rat blood resulting from a 10-day oral gavage exposure. Values are means and error bars are standard deviation. -25- - p.^^tcon^' Compan^11^-1-' H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats FIGURE 3 MICROMOLAR EQUIVALENTS IN TEST COMPOUND AND POSITIVE CONTROLS -26- H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 APPENDICES -27- Sanitized. Does < Conipany H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 APPENDIX A Individual Body Weights --------------...dDoosno^0"^00 - zo - Company. San^d.D^ H-24042: Biopersistence Screening 10-DoseOral Gavage Study in Rats INDIVmUAL BODY WEIGHTS ABBREVIATIONS: SD - sacrificed by design EXPLANATORY NOTES DuPont-2931 '29' Company Sa.R-sd, Do- no- con^n TSCA CBE ^ H-24042: 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 9 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 ----------^n.t.zedDo Company Sanilizeo. uu H-24042: 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 8 270 .6 303 .9 280 .2 312 .0 303 .6 DAY 2 224. 4 245. 9 231. 4 252 . 8 241. 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 TES T DAYS 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 TE:ST DA1fS DAY 1 0 249 .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 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 .31 Sanded. Does Company H-24042: 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 DJ\YS 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 T EST 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 -32- D Conipany Sanitized. H-24042: 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 GROU1 IV TE,ST D;\.YS 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 T EST DJ^YS 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 .0 295 .4 278 .1 294 .3 294 .6 334 .4 365 .6 SD test day 24 -a 377 .4 416 .7 SD test day 24 345 .8 378 .1 SD test day 24 -a . 356 .5 388 .4 SD test day 24 -" 368 . 7 407 .3 SD test day 24 a Rat was not weighed. -33- w^S^.. .-,^uo 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 8 282 .4 294 .3 258 .7 248 .0 289 .2 DAY 41 456 .5 470 .7 395 .0 358 .7 462 .6 DAY 2 240 .8 253 .4 219 .2 220 .5 242 .2 DAY 9 286 .4 296 .3 259 .2 250 .7 293 .4 DAY 47 482 .3 496 .9 407 .2 372 .7 487 .3 CORN OIL (I^BTIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP V TE ST 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 Rat was not weighed. .34- Compa"Y Sanded. Dc^no H-24042: 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 (9) OF MALE RATS GROUP VI TEST r)AYS 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 13 270.7 a 285.6 a 324 .3 a 292.4 a 281.8 a TEST DAYS DAY 52 DAY 55 239 .4 251 .5 280 .4 255 .6 251 .2 DAY 20 308 . 0 337 .8 399 . 7 367 .2 330 . 1 DAY 61 246 .2 259 .6 288 .0 261 .3 259 .8 DAY 24 329 .8 360 .6 431 .2 393 .0 352 .9 DAY 68 250 .1 263 .6 290 .3 265 .3 263 .9 DAY 34 362 .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 Rat was not weighed. -35- Cewpany Sar^fese!. D H-24042: 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 ^------------------c^s ^ H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 625361 625363 625364 625380 625383 DAY 1 322.6 273.7 291.1 289.4 304.7 DAY 2 325.0 271.4 290.9 286.2 299.7 e 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 ------------ .37- ^ ^ ^ D OTOP3"^ H-24042: 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 GROU? II TEE,ST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 293 . 0 303 .5 315 .6 326 .0 327 .3 297 .9 308 .9 320 .1 336 .4 328 .4 TEST DAYS DAY 10 306 . 1 313 . 8 327. 7 343 . 7 333 . 7 311 .2 315 .8 333 .7 347 .5 336 .6 315. 7 323 . 8 345. 6 360. 8 346 . 9 333.6 332.9 363 .8 386.7 365.4 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 .38- co.np^.n.*-^-00 H-24042: 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 TES T DAY 3 D.AYS DAY GROUP III 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 D!\YS 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 -39- Company Sanitiz H-24042: 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 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP IV TE,ST D!WS 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 TE;ST D!vys 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 3D test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24 -40- Company Sanitized. D H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL ' NUMBER DAY 1 DAY 2 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (9) OF MALE RATS GROUP V TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625356 625359 625360 625372 625374 ANIMAL NUMBER 291 .7 297 .9 296 .8 294 .8 295 .9 DAY 8 291 .2 303 .3 300 .7 298 .8 302 .2 DAY 9 304.5 314. 0 308.5 310 . 6 312.1 307 .0 315 .0 312 .7 317 .4 321 .7 TEST DAYS DAY 10 DAY 13 316 . 9 323 .5 319 .1 324 .0 323 .4 DAY 20 319 .8 323 ,5 332 .2 329 .0 328 .3 DAY 24 323. 9 333. 9 339. 5 335. 6 337. 2 DAY 27 625356 625359 625360 625372 625374 ANIMAL NUMBER 625356 625359 625360 625372 625374 328 .8 334 .Y 341.3 361 . 9 396 .7 a 339 .1 346 .2 353 .6 372 .9 410 .0 a 347 .9 354 .3 363 .4 381 .7 419 .8 a 344 .7 348 .8 355.1 373 .1 395 . 1 a 338 . 0 344 .6 350 .8 371 . 5 401 .3 a DAY 34 466 .2 467 .7 484 .1 454 .7 466 .8 DAY 52 533 .7 530 .3 555 .4 506 .2 512 .3 TEST DAYS SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52 431 .3 440 .9 465 .9 432 .1 447 .2 a Rat was not weighed. -41 - Sa Compa^-.0-- H-24042: 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 8 344 .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 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TES!T 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 13 358. 1 317. 2 352. 6 336. 9 340. 7 371 . 7 331 . 1 371 . 5 350. 1 353 . 5 TEST DAYS DAY 76 DAY 90 544 .9 483 .8 628 .8 567 .3 470 .3 562 .8 505 .3 661 .3 589 .8 492 .0 331. 7 292 . 8 325. 4 309. 6 318. 0 330.1 295.3 329'. 0 314.2 317.4 342. 5 303 . 8 334. 6 323. 5 325. 0 DAY 20 399. 1 347. 6 402. 3 387. 9 376. 3 DAY 24 a a a a a DAY 27 427 .7 374 .9 444 .6 432 .3 405 .2 DAY 94 565 .3 514 .8 673 .7 588 .8 496 .6 SD test day 94 SD test day 94 SD test day 94 SD test day 94 SD test day 94 a Rat was not weighed. S a -42- Cpmpany. H-24042: 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 -43- Sant' it &f"S]SS^ H-24042: 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) OF MALE RATS GROUP II TES T D1\YS 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 TES T DAYS DAY 1 0 295 .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 .44- Con.panySan H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 625321 625327 625342 625345 625348 ANIMAL 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 TE,ST D.AYS 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 DJ^.YS 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 H-24042: 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 IV TE,ST D1\YS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625325 625328 625338 625340 625352 ANIMAL NUMBER 282 . 8 315. 6 264. 6 304 . 0 285. 5 DAY 8 285 . 9 315. 2 261. 9 309. 2 283. 9 DAY 9 291 .7 323 .9 268 .5 316 .9 289 .1 295. 5 327. 7 272. 6 326. 0 299. 6 TEST D1WS 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 625325 625328 625338 625340 625352 318 .6 352 .0 287 .4 347 .0 316 .9 321 .9 351 .7 291 .3 352 .2 322 .3 327.4 357.5 290.2 359.2 321.0 331.6 367.4 291. 1 368.1 329.6 355 .8 400 .2 320 .4 389 .3 355 .7 381 .3 423 .9 339 .9 419 .0 375 .3 SD test day 24 SD test day 24 SD test day 24 SD test day 24 SD test day 24 -------------- -46- pompany.^^ H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER. DAY 1 DAY 2 H-24019 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP V TES T DK\'S DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 625324 625329 625333 625334 625344 ANIMAL NUMBER 625324 625329 625333 625334 625344 ANIMAL NUMBER 303 .0 318 .9 292 .4 274 .6 262 .9 DAY 8 332 .5 352 .5 315 .8 292 .6 280 .7 DAY 34 298 .5 316 .3 291 .2 277 .0 262 .2 DAY 9 337 .9 360 .1 316 .7 302 .2 285 .2 DAY 52 305. 8 326. 5 297. 8 286. 4 269. 0 312 .1 335 .4 304 .1 290 .6 273 .5 TEST DAYS DAY 10 DAY 13 336. 1 357. 0 319. 3 305. 8 289. 3 299 .6 364 .3 325 .8 312 .0 295 .8 TEST DAYS 320 .1 338 .3 307 .7 292 .0 274 .5 DAY 20 336 .0 396 .4 349 .2 338 .6 309 .7 322 .8 346 .7 312 .0 300 . 1 284 .1 DAY 24 a a a a a 326 .8 351 .6 313 .5 304 .2 - DAY 27 380 .3 423 .3 375 .2 368 .8 330 .4 625324 625329 625333 625334 625344 397 .3 442 .7 384 .6 384 .2 348 .3 447 .4 498 .1 427 .4 426 .5 391 .0 SD test day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52 a Rat was not weighed. -47- Com?81^ Sa^cd H-24042: 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 TEST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 325.5 302.3 300.2 287.7 321.1 330 .9 310 .4 309 .5 300 .0 329 .6 TEST 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 TEST 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 SD test SD test SD test SD test a Rat was not weighed. -48- C^nY??"" H-24042: 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 Company Sani^ H-24042: Biopersistence Screening 10-Dose Oral Oavage 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 TE:ST D!^YS 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 TES T DAYS DAY 1 0 256 .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 50- ^ Company53"11'2 H-24042: 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 TES.T DJ\YS 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 DJYYS 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 .51 - .ompani^""1 H-24042: 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) OF 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 TEST DAYS DAY 10 DAY 13 288 .0 a 266 .9 a 306 .4 a 301 .0 a 257 .0 a 254 .2 266 .7 267 .7 262 .3 230 .6 DAY 20 348 .0 335 .7 355 .8 374 .4 304 .4 262 .1 259 .2 277 .3 273 .8 240 .6 265. 4 262. 6 279. 8 277. 5 244 . 1 DAY 24 380 .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 Rat was not weighed. .52- Company Sanit H-24042: 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 TE ST 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 Rat was not weighed. .53- CUHlpdHi!1 SdiiitLLtcL H-24042: 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 DAY 9 285 .9 302 .0 286 .6 244 .8 256 .6 299 .1 309 .6 296 .0 250 .8 259 .2 DAY 41 . DAY 47 438 .7 479 .7 433 .2 356 .8 409 .6 439 .9 474 .6 451 .1 373 .5 426 .9 H-24020 (POSITIVE CONTROL) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TE,ST D1YYS 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 TEST DAYS DAY 52 DAY 5.5 356 .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 Rat was not weighed. 54- COOT Q^6-Do % H-24042: 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 """^r'------------_Sa_ni_tized fCnommopaannyy; H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627295 627298 627300 627302 627311 DAY 1 256.4 218.6 225.9 244.5 238.5 DAY 2 257.2 215.9 225.3 237.5 236.0 H-24042 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP I TEST DAYS DAY 3 DAY 4 DAY 5 265.8 228.6 237.4 240.8 240.7 271.4 232.7 246.7 247.2 247.8 278.0 241.9 259.6 257.0 257.9 SD test day 5 SD test day 5 SD test day 5 SD test day 5 SD test day 5 -56- c^^^-3" H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER . 627283 627289 627292 627293 627309 ANIMAL NUMBER 627283 627289 627292 627293 627309 DAY 1 213 .3 225 .3 243 .9 224 .9 238 .8 DAY 8 250 .3 255 .4 280 .4 260 .3 290 .1 DAY 2 211 .7 224 .4 244 .8 226 .8 241 .8 DAY 9 262 .1 276 .3 296 .9 274 .4 305 .8 H-24042 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROU7' II TE ST D!\YS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 224 .3 229 .7 253 .6 237 .9 249 .0 223 .4 240 .2 255 .4 240 .3 255 .3 TES.T DAYS DAY 1 0 235 .3 242 .6 264 .8 246 .0 267 .3 240 .2 253 . 1 269 .3 246 .6 274 .8 248 .1 255 .7 278 .0 258 .4 285 .5 264. 4 277 . 6 308. 6 274. 2 306. 6 SD test day 10 SD test day 10 SD test day 10 SD test day 10 SD test day 10 .57- Coinpany. Sanded-Do H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627285 627288 627294 627301 627304 ANIMAL NUMBER 627285 627288 627294 627301 627304 DAY 1 219. 2 228. 6 207. 6 244. 2 237. 1 DAY 8 266 .2 2-69 .6 251 .3 285 .1 267 .8 DAY 2 219. 6 229. 9 212. 6 246. 6 240. 6 DAY 9 284 .2 291 .0 262 .1 311 .6 294 .8 H-24042 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS TEST DAY 3 D!YYS DAY GROUP III 4 DAY 5 DAY 6 DAY 7 225. 3 238. 7 224. 1 251. 7 239. 1 233 .0 241 .7 229 .7 258 .0 252 .6 TEST D;^YS DAY 10 DAY 13 241. 9 250. 6 235. 0 266. 7 253. 6 250. 7 259. 4 239.4 273 . 7 264 . 8 264. 2 268. 7 249. 4 283. 8 266. 2 283 . 1 292 . 1 270.6 312.7 293 .8 314 .3 316 .5 292 .6 343 .6 321 .4 SD test day 13 SD test day 13 SD test day 13 SD test day 13 SD test day 13 .58- Company Sanitized. D H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627279 627282 627286 627287 627299 ANIMAL NUMBER 627279 627282 627286 627287 627299 DAY 1 215. 3 212 . 3 240. 4 232 . 9 248 . 1 DAY 8 258. 0 242. 9 284 . 0 274. 1 289. 5 DAY 2 216. 0 213 . 5 239. 7 234. 4 248. 3 DAY 9 272. 6 258. 5 310. 6 294. 6 307. 2 H-24042 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP IV TE ST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 221 .0 221 .4 253 .3 245 .9 255 .8 231 .3 228 . 1 262 .8 252 . 0 264 .2 TEST DAYS DAY 10 DAY 13 239 .7 232 .0 269 .0 259 .8 273 .0 DAY 20 243 .7 234 .9 278 .3 264 .0 276 .8 DAY 24 255. 1 241. 6 284. 6 270 . 1 288. 1 272 .3 a 327 .6 368 .4 SD test day 24 261 .0 a 316 .4 346 .2 SD test day 24 309 .8 a 377 . 1 411 .4 SD test day 24 297 .8 a 353 .8 396 . 6 SD test day 24 309 .3 a 364 . 0 403 .6 SD test day 24 a Rat was not weighed. -59- CoW^"^ H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627290 627296 627306 627307 627310 ANIMAL NUMBER 627290 627296 627306 627307 627310 ANIMAL NUMBER 627290 627296 627306 627307 627310 DAY 1 231 .0 210 .1 224 .8 242 .0 244 .4 DAY 2 226 .8 210 .2 224 .0 243 . 0 249 .4 DAY 8 263 .6 243 .7 260 .0 285 .8 282 .6 DAY 9 275 .0 252 .8 285 .3 307 .1 305 .8 DAY 38 399 .4 375 .1 460 .3 479 .0 478 .6 DAY 48 421 .4 395 .0 483 .4 506 .6 505 .3 H-24042 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP V TE ST DAYS DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 239 .5 218 .6 232 .5 257 .4 258 .3 238. 1 224. 9 239. 4 265. 4 260. 9 TEST DAYS DAY 10 DAY 13 272 .4 a 252 .6 a 283 .3 a 306 .2 a 308 .5 a TEST DAYS DAY 52 247 .3 233 .0 244 .2 269 . 0 269 . 8 DAY 20 323 .2 278 .4 344 .6 378 .7 366 .7 250 .4 234 .5 250 .5 276 .8 278 .9 DAY 24 a a a a a 261 .2 241 .9 258 .3 285 .4 281 .9 DAY 34 385 .7 360 .2 445 .4 462 .1 454 .3 438 .4 411 .4 497 .7 527 .6 525 .6 SD best day 52 SD test day 52 SD test day 52 SD test day 52 SD test day 52 a Rat was not weighed. .60- ..-.O^ complysankusc' H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627281 627297 627303 627305 627308 ANIMAL NUMBER 627281 627297 627303 627305 627308 ANIMAL NUMBER 627281 627297 627303 627305 627308 DAY 1 243 .1 221 .8 236 .6 254 .5 216 .6 DAY 2 237 .0 219 .8 242 .9 255 .2 220 .3 DAY 8 268 .3 253 .4 269 .5 303 .6 260 .4 DAY 9 282 .8 269 .2 288 .1 333 .2 279 .3 DAY 38 432 .4 393 .7 392 .9 559 .1 449 .0 DAY 48 466 .2 419 .2 411 .7 591 .6 477 .4 H-24042 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI TE ST DAYS DAY 3 'DAY 4 DAY 5 DAY 6 DAY 7 247 .6 229 .5 244 .5 266 .0 228 .4 247 .7 228 .2 251 .9 278 .5 244 .3 TEST DAYS DAY 10 DAY 13 282 .1 a 268 .8 a 289 .5 a 327 .0 a 281 .0 -a TEST DAYS DAY 52 DAY 55 251 .2 241 .8 259 .9 279 .4 246 .5 DAY 20 333 .3 310 .9 320 .4 424 .3 341 .0 DAY 61 255 .8 244 .0 260 .1 293 .6 251 .3 DAY 24 a -a a a a DAY 69 267 .1 250 .8 268 .6 302 .7 259 .1 DAY 34 408 . 7 372. 7 376. 0 535. 4 430 . 9 a 480 . 1 505 .3 517 .8 a 438 .4 462 .8 479 .6 a 431 .3 439 .3 458 .8 a 607 . 1 638 .8 662 .3 495 . 9 510 .6 538 .5 a Rat was not weighed. -61 - Compa^ Sanded. Co  rH-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats ANIMAL NUMBER 627281 627297 627303 627305 627308 DAY 82 549.6 502.3 488.4 706.8 562.2 DAY 88 567.6 514.3 501.9 727.6 582.3 e H-24042 (TEST SUBSTANCE) INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP VI (continued) TEST DAYS DAY 94 574.3 531.5 512.5 743.2 598.6 SD test day 94 SD test day 94 SD test day 94 SD.test day 94 SD test day 94 APPENDIX B Individual Clinical Observations -63~-'---------------------------__c_on_t_ai_n_T_S_CA CBI Company Sanitized. Doss n^- H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 Animal Number 627789 627801 627805 627810 627818 CORN OIL (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP I Observation___________________Test Day No abnormalities detected 1-5 No abnormalities detected 1-5 No abnormalities detected 1-5 No abnormalities detected 1-5 No abnormalities detected 1-5 Animal Number 627793 627797 627799 627800 627808 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 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 ^co^SCACm, -64- SanU^d.O^5 Coinpa"y H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 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 v SSaanr.'tf---d^-Dl-o"ss not contain TSCA C3t Company H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 Animal Number 625361 625363 625364 625380 625383 CORN OIL:ACETONE (NEGATIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP I __ Observation_________________Test Day No abnormalities detected 1-5 No abnormalities detected 1-5 No abnormalities detected 1-5 No abnormalities detected 1-5 No abnormalities detected 1-5 Animal Number 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 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 Company Sanitized. Doss not contain TSCA C81 H-24042: Biopersistence Screening 10-DoseOral Gavage Study in Rats DuPont-2931 Animal Number 625354 625365 625371 625376 625381 CORN OILiACETONE (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 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 Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-94 1-94 1-94 1-94 1-94 -67- contain TSCACBl Compsany San,i-tize^-nl3o0"-J3^. H-24042: Biopersistence Screening 10-Dose Oral^Gavage Study in Rats DuPont-2931 Animal . Number 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 Observatic>n N0 abnormalities detected Diarrhea No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Tes t Dcy 1-4, 6- 13 5 1 -13 1 -13 1 -13 1 -13 -68- Sanit^ o.''. Co Comps^ H-24042: Biopersistence Screening 10-DoseOral Gavage Study in Rats DuPont-2931 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 1, 8, 9, 10, 13, 20, 27 1-6, 11-94 7-8 8 8 8 9-10 1-94 1-6, 8-94 7 con^5^-' --- ------------------. --n---s--^--c--o--n--ia--"--' ^.iTGG---'^^ H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats H-24020 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS DuPont-2931 Animal Number 627756 627767 627771 627773 627777 GROUP I Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-5 1-5 1-5 1-5 1-5 Animal Number 627768 627774 627776 627782 627785 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 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 70- y^py;";";' pi.s. -r.-,",1'' '^rfa!?' ^c.c.h H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats H-24020 (POSITIVE CONTROL) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS DuPont-2931 Animal Number 627759 627761 627770 627779 627786 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 N0 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 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 ^,-^.-.--------"lai"TSCACBl LiOis'f--"^ H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 Animal Number 627295 627298 627300 627302 627311 H-24042 (TEST SUBSTANCE) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP I Observation__________________Test Day No abnormalities detected 1-5 No abnormalities detected 1-5 No abnormalities detected 1-5 No abnormalities detected 1-5 No abnormalities detected 1-5 Animal Number 627283 627289 627292 627293 627309 Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-10 1-10 1-10 1-10 1-10 Animal Number 627285 627288 627294 627301 627304 Observation No abnormalities detected Alopecia, abdomen No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-3, 5-13 4-10 1-13 1-13 1-13 1-13 72- QW^^I Sar.ite^.. " H;./? contain 'E' aCA H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 Animal Number 627279 627282 627286 627287 627299 H-24042 (TEST SUBSTANCE) INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS GROUP IV Observation ___ No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-24 1-24 1-24 1-24 1-24 Animal Number 627290 627296 627306 627307 627310 Observation No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected No abnormalities detected Test Day 1-52 1-52 1-52 1-52 1-52 Animal Number 627281 627297 627303 627305 627308 Observation No abnormalities detected No abnormalities detected No abnormalities detected Misshapen ears No abnormalities detected No abnormalities detected Alopecia right front leg Test Day 1-94 1-94 1-82 88, 94 1-94 1-34, 61-94 38, 48, 55 ^ST,U^- 73Ccn"'?--1 '. DC; rfa'.n rsc ^GOWri APPENDIX C Individual Fluorine Levels ^^"^^ /t -- fs.,. -^.' .",,,"...', . . "''" eow:^'"^. -i'-"""" 6 H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats DuPont-2931 Terms: Active % Active Mol Wt Active Formulation Dose % F in Active Mol Wt F TERMS AND CALCULATIONS Fluorine containing compound The % of formulation that is made up of fluorine containing components The molecular weight of the fluorine containing components (g/mole) The mg of formulation given per kg of animal body weight The % fluorine in the fluorine containing components of the formulation (weight basis) The molecular weight of fluorine g/mol Compound Calculations: Dose Active (mg/kg) The mg of fluorine containing compound administered per kg of animal body weight. = (% active/100) x Formulation Dose Dose Active (mmole/kg) The mmole of fluorine containing compound administered per kg of animal body weight = dose [mg/kg] / Mol Wt Active [mg/mmol] Dose F (mg/kg) The mg Fluorine administered per kg of animal body weight = (% F in active/100) x Dose Active [mg/kg] Dose F (mmol/kg) The mmole of fluorine administered per kg of animal body weight = Dose F [mg/kg] / Mol 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 - /j - p^-^csr.ta'.nTSCACSi Compsny . Sanded. D------^ 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) umolar equivalents of active in blood The umolar [umol/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 umol/mmol 76- Coc.-ny ,,i;i,,^ -r''' .-. i .-;-^/> "-?' wi^t; _____FACTORS INFLUENCING INTERPRETATION OF KINETIC ANALYSIS_____ Considerations: - The data used for kinetic analysis was from a limited screen and extrapolation should be done cautiously. - Sample size is low - Analytical data used without validation - Steady-state not reached - Terminal phase may not be reached - Some compounds are mixtures of fluorinated compounds - Different active and formulation doses were used - Different vehicles were used to deliver formulations - The kinetics apply only to plasma, not to specific tissues or the whole body - Each compound may have very different potency for producing toxicity Assumptions: (May or may not 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 component(s) in the formulation - Molecular weight is the molecular weight of the active component in the formulation -77- Company,..S.3,,->,,.i.--..". D^-o'-131"^"1 H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Data for H- 24019 DuPont-2931 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 ppm F in Blood Group I 625322 1 1.0 625323 1 1.3 625336 1 2.6 625343 1 2.6 625349 1 2.9 Group I 625322 5 51.7 625323 5 38.0 625336 5 38.7 625343 5 78.5 625349 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 umolar 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 .,-rSC^ ^IQ.11- 78- TYCiC01' ColftP^ SSW^ H-24042: 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 12.4 625335 94 16.4 625346 94 13.1 625347 94 11.0 625351 94 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 BIlood Normalizelito 0.1 mmolefi/kg Dose 382.69 304.66 320.07 282.30 309.13 199.30 229.12 213.71 193.33 207.25 121.77 147.11 134.69 143.63 117.29 60.63 80.51 64.11 53.68 56.66 DuPont-2931 umolar 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 -79- eoi--^"^^:!^'.^'-' .^cor^TSC.---- H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Data for H- 24020 DuPont-2931 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 ppm F 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 27.69 16.83 34.72 29.61 22.37 159.96 141.86 137.60 169.97 152.08 119.49 108.20 116.30 92.44 138.24 umolar Equivalents of Active in Blood 94.20 57.25 118.12 100.72 76.09 544.20 482.61 468.12 578.26 517.39 406.52 368.12 395.65 314.49 470.29 -80- ,,.rQ^*"!-nTSOAC^l Comply S, a"1,,.1_",---! -"nc'"-'; '''^c- -w--" --- H-24042: 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 Bflood Normalize dto 0.1 mmole s/kg Dose 92.23 43.67 27.69 65.18 52.61 19.17 31.31 24.28 20.66 13.85 1.49 0.85 1.70 1.49 1.28 0.21 * 0.00 0.00 * DuPont-2931 umolar Equivalents of Active in Blood 313.77 148.55 94.20 221.74 178.99 65.22 106.52 82.61 70.29 47.10 5.07 2.90 5.80 5.07 4.35 0.72 * 0.00 0.00 * 81- ------------,.^ DO^0^111" ^p^a^- H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats Data for H-24042 DuPont-2931 Given: Mol Wt. Active (g/mole): 531 Formulation Dose (mg/kg): 100 % Active (F Containing) in Formulation: 100 % F in Active: 75 Mol Wt. F (g/mol): 19 Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor: 100 0.188 53.1 Dose F (mmol/kg): 3.947 Molar Ratio (Active/F): 0.048 Dose F (mg/kg):_____75_ Rat Number Test Day Sample ppm F in Blood Group I 627295 1 2.1 627298 1 2.1 627300 1 2.1 627302 1 2.1 627311 1 0.7 Group I 627295 5 627298 5 627300 5 627302 5 627311 5 13.9 15.3 15.4 16.5 17.1 Group II 627283 10 627289 10 627292 10 627293 10 627309 10 20.6 22.5 19.7 16.1 20.0 ppm F in Blood Minus Bkg 0.2 ppm 1.9 1.9 1.9 1.9 0.5 13.7 15.1 15.2 16.3 16.9 20.4 22.3 19.5 15.9 19.8 ppm F in Blood Normalized to 0.1 mmoles/kg Dose 1.01 1.01 1.01 I.01 0.27 7.27 8.02 8.07 8.66 8.97 10.83 II.84 10.35 8.44 10.51 umolar Equivalents of Active in Blood 2.53 2.53 2.53 2.53 0.67 18.27 20.13 20.27 21.73 22.53 27.20 29.73 26.00 21.20 26.40 82- ----------CS--a---n.nr--t^.zZ---^o--.- C--O--S5--W,^---"--'1^-n T5i/a ^"' Company Group III 627285 13 15.5 627288 13 13.0 627294 13 14.5 627301 13 13.3 627304 13 13.6 Group IV 627279 24 6.4 627282 24 5.8 628286 24 6.0 627287 24 4.0 627299 24 4.3 Group V 627290 52 1.9 627296 52 2.3 627306 52 2.9 627307 52 2.9 627310 52 2.8 Group VI 627281 94 0.6 627297 94 0.9 627303 94 0.9 627305 94 1.1 627308 94 0.9 15.3 12.8 14.3 13.1 13.4 6.2 5.6 5.8 3.8 4.1 1.7 2.1 2.7 2.7 2.6 0.4 0.7 0.7 0.9 0.7 8.12 6.80 7.59 6.96 7.12 3.29 2.97 3.08 2.02 2.18 0.90 1.12 1.43 1.43 1.38 0.21 0.37 0.37 0.48 0.37 20.40 17.07 19.07 17.47 17.87 8.27 7.47 7.73 5.07 5.47 2.27 2.80 3.60 3.60 3.47 0.53 0.93 0.93 1.20 0.93 - 8 3 - ,con^^ ,^-^ "" . i - ^ 0 - " " " .^SCA^