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AR226-2803 DuPont-5207 TRADE SECRET Study Title H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period Laboratory Project ID: DuPont-5207 A u t h o r : Susan A. MacKenzie, V.M.D., Ph.D., D.A.B.T. St u d y C o m p l e t e d o n : August 9,2001 P er fo r m in g L a b o r a t o r y : E.I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 Page 1 of 65 , s an\ti*ed*DoSnocontstnnTS1 t e s i Company H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. Reviewed by: Matthew S. Bogdanffy, Director, Biochemical Toxii Reviewed by: Shawn A. Gannon, B.S. Senior StaffScientist Date/ ( // }Reviewed by: \ / m L Judith C. Stadler, Ph.D,, D.A.B.T. Director, General Toxicology eft-gO G -Z oof Date Issued by Study Director: Susan A. MacKenzie, V.M.D., Ph.D., D.A.B.T. Senior Research Scientist Date - 2 - qooPaoV Saa1>Vw-"ed.* stat.o *tSG'acbi H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 TABLE OF CONTENTS Page CERTIFIC ATIO N......................................................................................................................................2 LIST OF T A B L E S......................................................................................................................................5 LIST OF FIG U R E S................................................................................................................................... 5 LIST OF APPENDICES............................................................................................................................5 STUDY INFORM ATION..........................................................................................................................6 STUDY PERSO NNEL............................................................................................................................... 8 SUM M ARY................................................................................................................................................... 9 INTRO DUCTIO N......... ........................................................................................................................... 10 M ATERIALS AND M E T H O D S..................................... A. Test Substances................................................... B. Test Species......................................................... C. Animal Husbandry.............................................. 1. Housing Environment.................................................... 2. " Feed and Water.............................................................. 3. Identification................................................................. 4. Animal Health Monitoring Program............................. D. Quarantine and Pretest........................................ E. Study Design............. .......................................... F. Assignment to Groups and Study Start............... G. Dosing Material Preparation and Administration 1. Test Substance............................................................... 2. Control........................................................................... H. Body Weights...................................................... I. Mortality and Clinical Observations................... J. Collection and Analysis of Blood....................... K. PFOA Data Analysis........................................... L. Statistics............................................................... 10 10 10 11 .11 .11 .11 .11 12 12 12 13 .13 .13 13 13 14 14 15 RESULTS AND D ISC U SSIO N .............................................................................................................16 A. Body Weight and Body Weight Gain...................................................................... ..........16 B. Clinical Observations and Mortality......-........................................................................... 16 C. PFOA Data............................................................................................................. 16 1. Factors Influencing Interpretation of Analysis..........................................................................................16 2. Test Substances.......................................................................................................................................... 17 C O N C L U SIO N S......................................... 18 RECORDS AND SAMPLE STORAGE 18 R E F E R E N C E S ............................................ -3 - -CiTlVSan'W- c-d. U oe*-- 19 r.ontain tsca CB H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period_____________________________________ DuPont-5207 T A B L E S.......................................................................................................................................................20 FIG U R E S.................................................................................................................................................... 27 A PPEN D IC E S........................................................................................................................................... 31 oniain IS p aeS.naie' - 4 - s a ^ vj H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 LIST OF TABLES Page 1. MEAN BODY WEIGHTS FOR MALES................................................................................................................21 2. MEAN BODY WEIGHTS FOR FEMALES............................................................................................................22 3. MEAN BODY WEIGHT GAINS FOR MALES.................................................................................................. 23 4. MEAN BODY WEIGHT GAINS FOR FEMALES................................................................................................ 24 5. PFOA CONCENTRATION IN RAT PLASMA..................................................................................................... 25 6. RESULTS OF KINETIC ANALYSIS OF PFOA DATA.......................................................................................26 LIST OF FIGURES Page 1. PFOA CONCENTRATION IN MALE RAT PLASMA.......................................................................................28 2. PFOA CONCENTRATION IN FEMALE RAT PLASMA....................................................................................29 3. AUCall IN RAT PLASMA RESULTING FROM A 20-DAY ORAL GAVAGE............................................... ,.30 LIST OF APPENDICES Page A. INDIVIDUAL BODY WEIGHTS........................................................................................................................... 32 B. INDIVIDUAL CLINICAL OBSERVATIONS....................................................................................................... 40 C. ANALYTICAL METHODS.....................................................................................................................................54 D. INDIVIDUAL PFOA PLASMA CONCENTRATION DATA...............................................................................56 H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 STUDY INFORMATION Test Substance No. 1 9th Collective Nomenclature: Octanoic acid, pentadecafluoro-, ammonium salt . APFO Haskell Number: 24648 CAS Registry Number: Known Impurities: Physical Characteristics: Colorless liquid Stability: The test substance appeared to be stable under the conditions of the study; no evidence of instability was observed. Test Substance No. 2 9th Collective Nomenclature: Octanoic acid, pentadecafluoro-, ammonium salt , Svnonvms/Codes: Perfluorooctanoate, ammonium salt . C-8 Haskell Number: 24020 CAS Registry Number: fi -6- Goi ,,.-,1 CO' 036 ^ :--- TSc k cl H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period STUDY INFORMATION (Continued) Composition: DuPont-5207 Known Impurities: Physical Characteristics: White solid Stability: The test substance appeared to be stable under the conditions of the study; no evidence of instability was observed. Sponsor: Daikin Industries, Ltd. 1-1, Nishi-Hitotsuya, Settsu-shi Osaka 566-8585 Japan Study Initiated/Completed: November 16, 2000 / (see report cover page) In-Life Initiated/Completed: November 20, 2000 / March 5, 2001 Do,1ss no,'\coOi\ato C$V -7- % H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 STUDY PERSONNEL Study Director: Susan A. MacKenzie, V.M.D., Ph.D., D.A.B.T. Management: Judith C. Stadler, Ph.D., D.A.B.T. Primary Technician: Nita B. Baker Biochemical Toxicologist: Shawn A. Gannon, B.S. Management: Matthew S. Bogdanffy, Ph.D., D.A.B.T. Blood 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. Wanda L. West, D.V.M., A.C.L.A.M. -8- H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 SUMMARY The purpose of this study was to compare plasma concentrations of perfluorooctanoic acid (PFOA) in rats exposed to either H-24648 or H-24020. These test substances represent different isomeric mixtures of perfluorooctanoate ammonium salt (APFO). H-24648 ^ o n ta in s |p m i^ f i M N l B V 9 while H-24020 c o n t a i n s ^ H H H H H H H B H B H H H ^ Three groups of 5 male and 5 female Crl:CD(SD)IGS BR rats each were exposed by oral gavage to 20 mg/kg/day of either H-24648 or H-24020 in deionized water, or to deionized water (control). Rats were weighed daily during the 20-dose exposure phase, then once a week during the recovery phase. Clinical signs of toxicity were evaluated weekly. Blood was collected from each rat on test days -3 (pretest), 1, 5, 10,15, 18, 20, 24, 30, 37, 51, and 106, for evaluation of plasma concentration of PFOA. During the exposure phase, blood was collected approximately 2 hours after dosing. PFOA was extracted from the plasma by solid phase extraction, then the concentration of PFOA was determined by HPLC-MS. Mild reductions in body weight and body weight gain (compared to control) were observed in male rats exposed to H-24648 or H-24020. The magnitude of effect was similar with both test substances, although more complete reversal (recovery) from effects occurred in the males exposed to H-24648. Body weights in female rats were not affected by exposure to either test substance. No compound-related deaths or clinical observations resulted from exposure to either test substance. Effects on body weight gain were not considered to have affected interpretation of pharmacokinetics. No PFOA was detected in plasma collected prior to the start of test substance administration. Kinetic analysis of PFOA plasma levels demonstrated no significant differences between the two test substances in plasma biopersistence. Terminal half-life in male rats was 9.6 1.5 days and 10.4 1.6 days for H-24648 and H-24020, respectively. Terminal half-life in female rats could not be calculated (< 1 day) for either test substance. There was a statistically significant difference in the plasma concentrations achieved in the male and female rats during dosing with the two test substances. In males the total internal exposure to H-24020 was higher compared to H-24648. In females the total internal exposure to H-24648 was higher compared to H-24020. Under the conditions of this study, in rats of the same gender dosed with the two test substances, no difference in biopersistence (half-life) of PFOA was observed. Differences in internal exposure were observed between compounds for males and females, although these differences were not consistent. In males, dosing with H-24020 resulted in greater exposure to PFOA, compared to dosing with H-24648. In females, dosing with H-24648 resulted in greater exposure to PFOA compared to dosing with H-24020. Differences between genders were observed in the pharmacokinetics of PFOA in rats dosed with the two test substances. Female rats dosed with either test substance had lower peak plasma levels and total internal dose, and a shorter half-life of PFOA than males dosed with the same test substance. 9- Sar.ttiz .'d. poroPany rl0tf.Qr-la'inTSCA-^ _ H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 INTRODUCTION The objective of this study is to compare the internal exposure to and biopersistence of perfluorooctanoic acid (PFOA) in rats with test substances containing straight-chain ammonium perfluorooctanoate (APFO) or a mixture of APFO isomers. The rat was selected for these comparisons because of its use in related toxicity studies and the oral route of exposure was selected because it is relevant for human health risk extrapolation. Internal exposure was determined by measuring plasma area-under-the-curve (AUC) of total PFOA. AUC, which is simply the integral of plasma PFOA concentration over time, is the most common means for expressing internal dose. Biopersistence was assessed by quantifying terminal elimination plasma half-life (T/2). A dosage of 20 mg/kg was selected for each test substance. This dosage was expected to produce less than a 10% difference in mean body weight over 20 days of exposure (when compared to vehicle control) for both test substances based on previously reported data from studies conducted with H-24020/1' MATERIALS AND METHODS A. Test Substances The test substance, H-24648, was supplied by Daikin Industries, Ltd. as a colorless liquid consisting of a 10% solution in water. The test substance, H-24020, was supplied by DuPont Chemical Solutions Enterprise as a white solid. The test substances 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 and female Crl:CD(SD)IGS BR rats, with an assigned birth date of October 2,2000, were received from Charles River Laboratories, Inc., Raleigh, North Carolina. The Crl:CD(SD)IGS BR rat was selected on the basis of extensive experience with this strain and its suitability with respect to longevity, hardiness, sensitivity, and low incidence of spontaneous diseases. eoiripW nTSCACBl H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 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. 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 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 ensure that contaminant levels are below those that would be expected to impact the scientific integrity of the study: Water samples are analyzed for total bacterial counts, and the presence o f coliforms, lead, and other contaminants. Feed samples are analyzed for total bacterial, spore and fungal counts. Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity of the study. The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Data are maintained separately from study records and will not be included in the final report. Evaluation of these data did not indicate any conditions that affected the validity of the study. ,,at ccnt.vamintSCAcal Dos5 -11 - Company*"*1 H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 D. Quarantine and Pretest Upon arrival at Haskell Laboratory, the rats were removed from shipping cartons and quarantined for 7 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 on test day -4 by the laboratory animal veterinarian designee. E. Study Design The study design is as follows: Group Male Female Animal Numbers3 Male Female #/Grouo Dose (mg/kg/day) Dose Solution Concentration (me/mli I n 101-105 201-205 5 0 (control) m IV 301-305 401-405 5 20 V VI 501-505 601-605 5 20 0 2 2 Test Substance Deionized water H-24648 H-24020 a Each rat was assigned its own Haskell animal number. Study Parameters Body Weight and Clinical Observations Blood Collection for PFOA analysis Dosing Frequency Daily during dosing. Weekly during recovery Test days-3, 1, 5, 10, 15,18, 20, 24, 30, 37, 51, and 106 Daily for 20 days Recovery 86 days after last dose 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 distributed by computerized, stratified randomization into 3 groups n0l c o n t ^ SC^ id. Boas -12- Q om P an ^ ^ a n `l H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 of 5 male rats and 3 groups of 5 female rats, so that there were no statistically significant differences among group body weight means for each sex. After assignment to groups, each rat was housed individually. The last 3 digits of the animal number were tattooed on the tail of each rat. The rats were approximately 7 weeks of age at the start 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 pathology evaluation. G. Dosing Material Preparation and Administration 1. Test Substance H-24648, a 10% solution of active ingredient in water, as received, was diluted with deionized water to a concentration of 2 mg active ingredient/mL in the dosing solution. H-24020, a solid test substance, as received, was dissolved in deionized water to a concentration of 2 mg active ingredient/mL in dosing solution. Both test substances were dosed at a volume of 10 mL/kg body weight. The amount of test substance each rat received was based on the body weight collected on each day of dosing and the dosing solution concentration of 2 mg/mL. The dosing solution was stirred on a magnetic stir plate throughout the dosing procedure to maintain homogeneity. 2. Control Deionized water was administered to the control groups because it was the vehicle for the test substance. Each control rat received 10 mL/kg dose volume. H. Body Weights All rats were weighed on each day of dosing during the dosing phase of the study and weekly during the recovery phase. 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. After the final blood sample was drawn on test day 106, all rats were sacrificed by carbon dioxide overdose and discarded without necropsy. -13- post, not contain TSCACBl Qornpany Sar..v BO H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 J. Collection and Analysis of Blood Blood samples (approximately 0.25 ml) were collected via orbital sinus bleeding while the rats were under carbon dioxide anesthesia. Blood was collected on the following test days: -3 (pretest), 1, 5,10,15,18,20, 24, 30, 37, 51, and 106. Test day 1 was defined as the first day of dosing. Blood was collected approximately 2 hours after dose administration during the dosing phase and at approximately the same time of day during the remainder of the in-life phase of the study. Blood was collected into EDTA tubes and stored on ice, then separated by centrifugation into plasma and packed red blood cells. Plasma was removed and refrigerated until analysis. Red blood cells were stored until the end of the study, but were not analyzed. To prepare the plasma samples for solid phase extraction (SPE) a 100 ptl aliquot of each plasma sample was transferred to a single well in a deep-well format 96-well microtiter plate. A 4 fi\ aliquot of internal standard (tridecafluoroheptanoic acid, initial concentration: 200 mg/ml) was added to each well followed by 96 fi\ 5M sulfuric acid. The plate was shaken to precipitate the plasma proteins. A 96-well format SPE plate (Waters Oasis HLB 5 mg) was prepared by conditioning with 500 /u.1 0.5% sulfuric acid in acetonitrile followed by 500 fx1of 0.5% sulfuric acid in water. Water (800 n\) was added to each well followed by an aliquot (50 - 100 fxl) of the plasma sample described above. The samples were loaded onto the SPE bed and washed with 500 x\ of water. The samples were then eluted from the SPE bed with two aliquots of acetonitrile (250-500 /xl). Following elution, the samples were analyzed for PFOA by LC-MS using a Waters 2690 HPLC Alliance HT connected to a Micromass Quattro Ultima with an electrospray source set in negative mode. A standardization function was calculated from the internal standard and a known linear PFOA standard (Aldrich Chemical). Since branched standards were not available, the MS detector response was assumed to be equal across PFOA isomers. The standardization function converted MS detector area counts into PFOA concentrations. Samples that contained a concentration of PFOA greater than the highest standard were diluted further and then reanalyzed. Details of analytical method are reported in Appendix C. K. PFOA Data Analysis Plasma concentration data for branched and straight-chain PFOA were combined to yield total PFOA. Noncompartmental analysis was conducted on total plasma PFOA data using WinNonlin Version 3.1 software (Pharsight Corporation, Mountain View, CA). WinNonlin software provided a means of computing derived pharmacokinetic parameters including terminal elimination half-life (Ty,), maximal concentration (Cmax), time of maximal concentration (Tmax), and area under the curve (AUC). Two means of expressing AUC were calculated: area under the curve for all points (AUCall); and AUC measured from time 0 and extrapolated to infinity (AUCINF). -1 4 - Sav.;u-,."" 5 a s w * wnlain't s <* c H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 L. Statistics The following methods were used to conduct statistical analysis of the data. Significance was judged atp < 0.05. Body weight and body weight gain data from each test group was compared to the control group of the same gender using the following statistical methods. Levene's test(2) and Shapiro-Wilk test(3) were run to evaluate homogeneity and normality, respectively. If the preliminary tests were not significant, data were analyzed using a one-way analysis of variance,(4) followed with Dunnett's test.(5) If the preliminary tests were significant, data were analyzed using a KruskalWallis test(6) followed with Dunn's test.(7) If the Shapiro-Wilk test was not significant but Levene's test was significant, a robust version of Dunnett's test was used. Comparisons of derived plasma kinetic parameters (Cmax, AUCall, and T/,) between the two substances, within the same gender, were analyzed using Student i-test.(4) - 15 - OfilpaT^ San'l` tsgacsi \Gonte`tn D oc^ H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 RESULTS AND DISCUSSION A. Body W eight and Body W eight Gain (Tables 1-4, Appendix A) During the dosing phase of the study, exposure to both test substances produced statistically significant reductions (compared to control) in body weight and body weight gain in male rats. Recovery from these effects was demonstrated for both test substances. However, more complete recovery from the body weight effects was seen in male rats exposed to H-24648, compared to male rats exposed to H-24020. During recovery, mean body weight and body weight gain in the male H-24648 group exceeded that of controls, while mean body weight and body weight gain in the male H-24020 group remained below that of control. None of the differences during recovery was statistically significant. During the dosing phase of the study, exposure to both test substances produced similar effects on body weight and body weight gain in female rats. In both groups, mean body weight and body weight gain were slightly higher than in control but none of the differences was statistically significant compared to control, and no notable differences between the two test groups were observed. Females exposed to both test substances demonstrated increased body weight gain (relative to control) during recovery, but the differences were not statistically significant. Exposure to both test substances had similar effects on body weight and body weight gain. None of the body weight effects were considered to have affected the pharmacokinetic results. B. Clinical Observations and Mortality (Appendix B) No compound-related deaths occurred and no compound-related clinical signs were observed in any test group. Most observed clinical signs were attributed to the orbital sinus bleeding process. None of the clinical observations were considered to have affected the pharmacokinetic results. C. PFOA Data (Tables 5-6, Figures 1-3, Appendix D) 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. These considerations include (1) a single dose level was used and kinetics may or may not be linear with multiple dose levels, (2) the kinetics apply only to plasma, (3) steady-state may not have been achieved, (4) the small sample size may impact calculation of the terminal half-life, and (5) no analytical standard was available for the -nt contain - 16- C o m p a nSya,n^itae. Eo H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 branched chain molecules. For this analysis, it is assumed that the detector sensitivity is the same for all PFOA molecules. 2. Test Substances Concentrations of PFOA were measured in rat plasma by LC/MS. Rat plasma concentration data are shown in Figures 1 and 2. Individual animal data are in Appendix D. Plasma concentration vs. time course data presented in Figures 1 and 2 are also summarized in Table 5. No PFOA was detected in plasma collected during the pretest period (test day -3). PFOA was also not detected in the control group samples (Groups I and II). Rats were dosed for 20 days with the intent of achieving steady state plasma PFOA levels. Figures 1 and 2 show an apparent plateau in plasma PFOA levels between days 10 and 20. However, a larger than expected degree of variability was observed among the analyses of samples collected on days 1, 5, and 10. This variability is likely attributable to an additional dilution step that was required to bring the concentration within the limits of the standard curve and analytical accuracy. For this reason it is difficult to determine if steady-state condition was, in fact, achieved. Sample availability precluded any re-analysis. Difficulties extracting some samples collected on day 106 rendered them unanalyzable. These samples are indicated in the individual animal plasma data (Appendix D). Loss of these samples did not affect the interpretability of the data set or the conclusions drawn. Pharmacokinetic analysis of the plasma PFOA data is presented in Table 6. Biopersistence was evaluated by quantifying the half-life of total PFOA during the terminal elimination phase. The half-life for total PFOA in plasma of males was 9.6 1.5 days for group III (H-24648 males) and 10.4 1.6 days for group V (H-24020 males). These values were not statistically different from each other. The half-life for the females could not be estimated because the PFOA levels at the first post-dosing collection time (day 24) were below analytical detection. Maximal plasma concentration (Cmax) would be expected on the day (Tmax) steady state is achieved which was expected to be at the end of dosing. For all groups, except Group V (male, H-24020), Tmax values were similar (approximately 13-15 days). For group V, the Tmax estimate of 8 days is likely an artifact of the variability observed in the day 5 sample analysis. Cmax for females dosed with either test substance was lower than the corresponding males. Same sex Cmax differences were not statistically significant. Internal exposure was assessed by calculating AUC. Two means of expressing AUC were calculated: area under the curve for all points (AUCall); and AUC measured from time 0 and extrapolated to infinity (AUCINF). For these analyses, AUCall is the most appropriate measure of internal exposure because AUCINF could not be calculated for Groups IV and VI. A comparison of AUCall for the four test groups is presented in Figure 3. Differences in internal exposure were observed between compounds for males and females although these differences were not consistent. For males, dosing with H-24020 resulted in greater exposure to PFOA compared to dosing with H-24648. For females dosing with H-24648 0*061 -17- anV S aTV H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 resulted in greater exposure to PFOA compared to dosing with H-24020. For both test substances, exposure was approximately 2.5-4 fold higher for males compared to females. CONCLUSIONS Under the conditions of this study, dosing with either test substance caused mild reductions in body weight and body weight gain in male rats. There were no effects on body weight or body weight gain in females. The differences noted for males were not considered to have affected interpretation of the pharmacokinetic analyses. In rats of the same gender, no difference was observed in biopersistence of total PFOA from either test substance. For both test substances total internal exposure was higher in males compared to females. Males also had higher plasma Cmax values, compared to females when dosed with either test substance. For males, dosing with H-24020 resulted in greater exposure to PFOA compared to dosing with H-24648. For females dosing with H-24648 resulted in greater exposure to PFOA compared to dosing with H-24020. RECORDS AND SAMPLE STORAGE Specimens (if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware. - 18- H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 REFERENCES 1. Finlay, C. (2000). H-24018: Biopersistence Screening!0-Dose Oral Gavage Study in Rats. E. I. du Pont de Nemours and C o m p a n y M I H H H ^ 2. Levene, H. (1960). Robust test for equality of variances. In Contributions to Probability and Statistics, (J. Olkin, ed.), Stanford University Press, Palo Alto, CA. pp 278-292. 3. Shapiro, S.S. and M.B. Wilk (1965). An analysis of variance test for normality (complete samples). Biometrika 52:591-611. 4. Snedecor, G. W. and W. G. Cochran (1967). Statistical Methods, 6th ed. The Iowa State University Press, Iowa, pp 246-248,349-352. 5. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Statist. Assoc. 50:1096-1121. 6. Kruskal, W.H. and W.A. Wallis (1952). Use of ranks in one-criterion analysis of variance. J. Amer. Statist. Assoc. 47:583-621. 7. Dunn, O J. (1964). Multiple contrasts using rank sums. Technometrics 6:241-252. - 19- H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 TABLES - 20- .D o es icftoon\P'n SanWvzed H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period TABLE 1 MEAN BODY WEIGHTS (g) FOR MALES DuPont-5207 Test Substance Test Days Control H-24648 H-24020 1 214.6 219.1 211.4 2 216.5 218.8 210.4 3 226.5 227.2 217.9 4 236.2 224.9 218.5 5 242.1 223.8 220.3 6 246.1 218.1 219.0 7 253.9 221.8* 229.3 8 263.1 234.3 240.2 9 268.3 240.4 246.8 10 277.5 249.3 251.0 11 281.6 249.3* 253.1 12 288.1 258.3 260.0 13 295.3 265.6 266.7 14 298.3 269.1 269.4 # 15 305.4 16 306.7 275.3 276.0 272.3* 273.3* 17 313.7 279.2 . 276.7* 18 319.3 283.4* 281.9* 19 321.2 291.1 284.4* 20 323.5 290.9 286.4* 21 328.2 288.3* 286.2* 22 333.4 293.9 287.1* 32 384.6 362.0 342.9 39 409.8 399.7 369.2 46 443.0 435.8 397.4 53 451.5 445.5 400.6 60 470.8 466.1 418.6 67 494.9 494.1 440.4 74 502.8 506.4 453.7 81 521.0 521.7 468.6 88 534.1 ' 533.5 481.6 94 554.1 545.4 494.8 102 562.2 556.6 501.4 106 561.5 560.1 502.1 * Statistically significant difference from control by parametric comparison (Dunnett/Tamhane-Dunnett) (p < 0.05). 21 - eontPar,y no! con*tainTS D00S H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 TABLE 2 MEAN BODY WEIGHTS (g) FOR FEMALES Test Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 32 39 46 53 60 67 74 81 88 95 102 106 Control 173.3 173.4 177.8 183.3 185.6 185.9 188.6 195.6 197.4 199.2 199.8 204.2 208.2 208.1 210.4 213.1 215.8 216.2 216.6 219.7 221.6 223.5 243.6 252.0 261.1 262.5 270.9 278.1 277.3 285.5 292.0 297.5 297.8 298.7 Test Substance H-24648 H-24020 174.1 178.5 172.0 177.3 178.8 182.1 183.5 187.9 185.3 192.7 188.1 194.3 192.7 196.5 197.6 203.0 197.5 204.7 203.0 209.3 203.6 209.6 209.3 215.9 209.6 220.3 212.1 220.3 217.6 222.7 217.4 225.0 218.4 227.8 219.1 231.3 224.3 233.1 224.9 234.0 226.8 235.9 227.5 237.4 255.0 263.5 265.0 269.7 275.1 286.7 280.5 290.8 283.7 300.2 294.5 312.7 297.1 314.9 310.3 328.4 ' 320.7 333.3 329.5 339.8 332.5 347.4 333.7 347.5 There were no statistically significant differences from control at p < 0.05 by Dunnett/Tamhane-Dunnett. - 22- C o m P ^ * Sanl1' rtnlain tscacbi H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 TABLE 3 MEAN BODY WEIGHT GAINS (g) FOR MALES iesi Test Substance Days________ Control___________ H-24648__________ H-24020 1-21 113.6 69.2* 74.8* 21-106 233.3 271.8_____________215.9 * Statistically significant difference from control by parametric comparison (Dunnett/Tamhane-Dunnett) (p < 0.05). -23- rj. Dogs not contain t s c a c b i Cor.ipsny Sar.dv H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 TABLE 4 MEAN BODY WEIGHT GAINS (g) FOR FEMALES iesi Test Substance Days_________ Control___________ H-24648__________ H-24020 1-21 48.3 52.7 57.4 21-106 77.0 107.0 111.6 There were no statistically significant differences from control at p < 0.05 by Dunnett/Tamhane-Duimett. -24- not contain tSCACW Com^any Sam.s. ized. Doe: H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 TABLE 5 PFOA CONCENTRATION IN RAT PLASMA (/xmol/L) Mean Standard Deviation Group in days male, H-24648 1 61 59a 5 284 129 10 193 125 15 255 60 18 376 45 20 258 25 24 127 30 30 52 33 37 33 5a 51 15 8 106 0.5 0.4b,c Group V male, H-24020 129 31 513 151 295 142 332 49 279 55 348 49 161 24 74 15 49 22 20 8 0.2 b'd a N =4 b Only one sample above limit of detection, c N =3 d N=1 o O Group IV female, H-24648 82 35 115 28 144 35 174 91 147 19 141 19 0.4 0.9b 0.0 0.0 0.0 0.0 0.0 0.0 Note: N = 5 unless noted otherwise Group VI female, H-24020 92 10 108 11 88 14 123 22 128 25 117 23 0.3 0.7b 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.0C - 25- G evnpan y a r llcrtoontainT5 CACBl H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 TABLE RESULTS OF KINETIC ANALYSIS OF PFOA DATA Tm (days) C TM (/iM) Tmax (days) AUCall (/xM x days) AUCINF (/xM x days) Group III male, H-24648 9.6 1.5 379 44 15.4 5.8 6913 1329 6968 1337 Group V Group IV Group VI male, H-24020 female, H-24648 female, H-24020 10.4 1.6 <1 <1 519 139 200 78 134 21 8.0 6.7 14.0 4.2 13.4 7.1 9181 1839a 2932 306 2326 176b 9457 1988a _ _ Q ) ________ ___ HI________ Mean Standard Deviation (1) Values not calculated a Statistically significant difference from group III by Student t-test (p < 0.05). b Statistically significant difference from group IV by Student t-test (p < 0.05). Abbreviations: T 1/2 Terminal elimination half-life Cmax Maximum plasma concentration Tmax Time of maximum concentration AUCall Area under the curve of all data points AUCINF Area under the curve from 0 to infinity - 26- u- '___________ Bi H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 FIGURES - 27- . no\conlain ^ ;-s d .P 0' jotnpanv S sr H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period FIGURE 1 PFOA CONCENTRATION IN MALE RAT PLASMA DuPont-5207 0 10 20 30 40 50 60 70 80 90 100 110 Days Plasma PFOA concentration in male rats dosed with H-24648 or H-24020. Rats received single oral doses daily up to day 20. Error bars represent standard deviations of the mean. On test day 106, several plasma samples were unanalyzable. Plasma data shown for test day 106 are the mean of 3 or 1 sample for groups III and V, respectively. Plasma data for test days 1 and 37 are the means o f 4 samples for group III. All other data points are the means of 5 samples. -28- Does nol contain TSCAU^ Company Sanitized, % H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period % FIGURE 2 PFOA CONCENTRATION IN FEMALE RAT PLASMA # DuPont-5207 Plasma PFOA concentration in female rats dosed with H-24648 or H-24020. Rats received single oral doses daily up to day 20. Error bars represent standard deviations of the mean (N = 5). -29- no\ contain t s c a CW CotnpanVSa'v.ttized D oes H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period 12000 FIGURE 3 AUCall IN RAT PLASMA RESULTING FROM A 20-DAY ORAL GAVAGE 9 DuPont-5207 10000 TO 8000 X 3TO E<A Ja2 600 0 2 c 3 4000 < 2000 0 III - m ale, H -2 4 6 4 8 V - male, H-24020 IV - fern ale, H - 2 4 6 4 8 VI - female, H-24020 Summary o f area-under-the-curve (AUCall) for male and female rats dosed with H-24648 or H-24020. Error bars represent standard deviations (N = 5). tSCAc oSl -30- ,e&Sa' H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 APPENDICES 31 - . ,, j n o aS; nb l c O ^ H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 APPENDIX A Individual Body Weights -32- ^ T T scacbi Compaq,, s b Vh w 4- 00" "0' H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period INDIVIDUAL BODY WEIGHTS EXPLANATORY NOTES ABBREVIATIONS: SD - sacrificed by design DuPont-5207 fSCACBl -33- Ooss nclSanv^zeC H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS ANIMAL NUMBER 643111 643112 643113 643114 643115 Day 1 229.4 210.6 217.6 218.5 196.9 Day 2 230.0 213.0 218.1 222.3 199.1 Day 3 241.4 221.4 228.4 230.3 210.9 GROUP I (Control) Day 4 Day 5 249.3 234.0 239.4 240.1 218.1 259.7 238.2 244.4 247.6 220.6 Day 6 264.8 242.1 247.7 253.7 222.2 ANIMAL NUMBER 643111 643112 643113 643114 643115 Day 10 297.9 274.6 276.6 284.3 254.1 Day 11 300.7 280.0 280.9 288.8 257.6 Day 12 312.9 284.0 282.3 297.7 263.8 Day 13 318.9 292.6 290.4 303.8 270.6 Day 14 317.4 299.8 289.7 309.5 275.1 Day 15 329.0 307.0 296.7 314.2 280.0 ANIMAL NUMBER 643111 643112 643113 643114 643115 Day 19 346.4 324.3 309.9 334.6 290.6 Day 20 346.0 328.5 309.8 338.9 294.2 Day 21 353.2 331.7 314.8 342.7' 298.5 Day 22 356.7 341.4 317.0 348.8 303.2 Day 33 415.1 392.8 367.2 403.1 345.0 Day 39 443.3 420.2 389.7 430.8 364.8 ANIMAL NUMBER 643111 643112 643113 643114 643115 Day 67 526.0 494.6 492.5 508.1 453.4 Day 74 536.5 500.3 482.5 530.1 464.8 Day 81 547.4 513.0 512.3 548.3 483.9 Day 88 561.0 515.9 536.5 555.5 501.4 Day 95 573.0 534.4 565.2 580.4 517.7 Day 102 572.3 542.9 589.2 573.2 533.4 DuPont-5207 Day 7 270.1 252.0 255.5 259.3 232.4 Day 8 281.4 259.5 265.3 267.8 241.3 Day 9 285.9 267.3 269.4 273.1 245.9 Day 16 328.5 308.5 300.6 315.3 280.7 Day 17 338.4 317.0 303.0 322.0 288.0 Day 18 345.2 323.5 308.5 327.2 292.1 Day 46 477.5 454.3 424.4 463.7 395.3 Day 53 484.8 453.2 437.8 471.0 410.7 Day 60 505.4 466.3 460.2 493.6 428.5 Day 106 572.6 539.1 589.5 568.0 538.2 SD T e s t d a y 106 SD T e s t d a y 106 SD T e s t d a y 106 SD T e s t d a y 106 SD T e s t d a y 106 TSCA CB1, -34- Sanitized- P ss llul e"laln CompaRV H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS ANIMAL NUMBER 643116 643118 643119 643120 643126 Day 1 233.0 211.2 218.4 204.3 228.6 Day 2 231.1 211.4 217.8 202.2 231.3 Day 3 235.3 222.0 225.7 210.4 242.5 GROUP III (H-24648) Day 4 Day 5 219.0 222.5 223.7 214.5 244.7 210.0 225.6 214.8 216.9 251.6 Day 6 191.8 228.0 199.2 217.6 254.0 ANIMAL NUMBER 643116 643118 643119 643120 643126 Day 10 217.9 262.2 241.9 244.4 279.9 Day 11 224.3 254.8 239.4 245.7 282.2 Day 12 235.7 262.1 250.8 254.5 288.6 Day 13 251.0 273.2 258.6 253.8 291.2 Day 14 262.9 274.7 257.5 255.6 294.9 Day 15 274.8 281.1 261.6 259.7 299.5 ANIMAL NUMBER 643116 643118 643119 643120 643126 Day 19 305.3 298.7 266.7 274.1 310.5 Day 2 0 300.7 301.0 271.1 271.3 310.6 Day 21 290.3 304.7 261.1 273.4 312.0 Day 22 303.8 306.7 259.7 282.5 316.9 Day 33 384.7 369.0 329.7 341.4 385.0 Day 39 435.1 401.3 373.4 371.8 417.0 ANIMAL NUMBER 643116 643118 643119 643120 643126 Day 67 547.1 493.8 466.8 466.0 497.0 Day 74 561.7 504.7 477.6 483.8 504.4 Day 81 582.2 520.0 486.9 499.7 519.6 Day 88 598.5 : 532.7 495.7 511.1 529.5 Day 95 616.1 543.9 502.1 525.3 539.5 Day 102 625.5 551.6 511.9 539.2 554.7 DuPont-5207 Day 7 187.9 235.7 202.6 222.8 260.0 Day 8 196.2 250.8 216.7 234.6 273.0 Day 9 203.0 253.2 231.0 240.2 274.7 Day 16 277.1 280.8 253.8 266.0 302.2 Day 17 283.1 291.0 248.0 266.0 308.1 Day 18 293.5 290.1 255.6 269.9 307.9 Day 46 483.0 435.8 408.9 401.0 450.4 Day 53 488.8 451.0 416.2 414.6 456.7 Day 60 519.4 465.5 440.0 437.4 468.2 Day 106 628.1 556.9 517.8 542.8 555.0 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 tiovco' -35- 0 & S 2 } H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period ANIMAL NUMBER 643121 643122 643123 643124 643125 Day 1 230.0 201.9 215.3 215.0 194.7 Day 2 231.6 204.4 212.6 210.7 192.7 INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS GROUP V (H-24020) Day 3 239.8 208.7 221.9 218.0 201.1 Day 4 239.6 206.0 222.4 222.0 202.4 Day 5 252.8 202.6 228.1 221.4 196.4 Day 6 245.0 199.7 231.7 222.0 196.6 ANIMAL NUMBER 643121 643122 643123 643124 643125 Day 10 279.7 232.8 261.2 249.0 232.2 Day 11 285.7 238.3 264.0 243.8 233.9 Day 12 292.2 245.8 272.6 248.3 241.3 Day 13 302.3 253.2 279.2 251.9 247.0 Day 14 301.6 254.9 285.2 254.6 250.5 Day 15 306.4 260.7 287.4 252.9 253.9 ANIMAL NUMBER 643121 643122 643123 643124 643125 Day 19 326.2 269.4 298.0 258.5 270.0 Day 2 0 328.2 272.1 300.1 259.4 272.4 Day 21 328.8 274.0 302.6 254.8 270.6 Day 22 334.8 275.2 305.8 246.3 273.3 Day 33 397.8 327.3 365.3 316.2 307.8 Day 39 428.0 347.7 401.3 338.3 330.5 ANIMAL NUMBER 643121 643122 643123 643124 643125 Day 67 506.1 411.3 489.5 406.2 389.0 Day 74 521.2 419.9 499.0 426.2 402.4 Day 81 533.3 436.1 516.1 436.5 420.8 Day 88 550.3 447.3 531.5 446.1 433.0 Day 95 561.8 460.6 542.4 462.7 446.4 Day 102 575.8 466.1 542.3 461.4 461.2 # DuPont-5207 Day 7 242.6 213.7 240.8 236.3 212.9 Day 8 263.0 221.7 249.4 244.6 222.4 Day 9 270.7 230.1 256.0 252.6 224.8 Day 16 309.4 263.0 281.7 257.1 255.1 Day 17 311.5 264.8 292.8 253.7 260.6 Day 18 320.8 2.65.9 297.3 258.8 266.7 Day 46 464.5 378.9 428.9 363.1 351.6 Day 53 467.3 377.0 442.3 365.0 351.3 Day 60 486.5 390.0 467.1 386.5 363.0 Day 106 575.1 466.4 547.6 458.6 462.6 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 cotton tsca cw -36- 0<^3 0 0 ? ^ SaniBieA H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period INDIVIDUAL BODY WEIGHTS (g) OF FEMALE RATS ANIMAL NUMBER 643127 643128 643129 643130 643131 Day 1 175.1 179.0 177.0 167.9 167.7 Day 2 176.6 176.2 177.0 170.7 166.4 Day 3 178.5 181.4 181.8 176.5 170.9 GROUP II (Control) Day 4 Day 5 184.9 188.7 189.5 180.5 173.0 187.9 190.7 192.6 182.0 175.0 Day 6 189.7 189.1 191.7 180.9 178.2 ANIMAL NUMBER 643127 643128 643129 643130 643131 Day 10 204.2 201.1 206.2 195.1 189.6 Day 11 199.1 208.8 212.1 189.0 190.0 Day 12 205.2 213.0 215.1 196.2 191.7 Day 13 210.5 214.2 221.6 201.9 192.9 Day 14 211.2 211.9 218.7 204.0 194.5 Day 15 209.9 219.3 227.2 198.5 197.2 ANIMAL NUMBER 643127 643128 643129 643130 643131 Day 19 215.7 219.4 234.6 211.6 201.8 Day 20 223.0 224.6 240.3. 206.3 204.1 Day 21 221.9 229.3 240.6 210.3 206.0 Day 22 227.1 225.8 241.4 216.0 207.3 Day 33 233.8 257.4 271.2 230.2 225.5 Day 39 243.3 264.4 282.7 236.1 233.3 ANIMAL NUMBER 643127 643128 643129 643130 643131 Day 67 263.2 288.4 314.6 270.3 254.0 Day 74 265.6 284.5 313.4 269.8 253.1 Day 81 274.0 293.9 325.7 275.3 258.6 Day 88 279.3 300.5 338.0 280.2 261.8 Day 95 281.2 305.9 345.8 286.1 268.4 Day 102 282.2 304.7 352.8 281.7 267.4 DuPont-5207 Day 7 186.3 194.2 198.2 182.4 181.9 Day 8 198.1 201.7 203.5 188.8 185.9 Day 9 198.7 202.5 206.4 193.7 185.8 Day 16 213.4 219.2 229.9 204.6 198.3 Day 17 217.2 222.0 232.8 206.0 201.1 Day 18 218.9 218.9 232.0 211.1 200.1 Day 46 261.1 265.1 289.6 245.1 244.6 Day 53 258.0 274.9 295.9 245.5 238.0 Day 60 260.0 280.6 311.7 254.6 247.5 Day 106 286.8 304.5 351.6 282.2 268.2 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 _ contain TSCA GBji -37- H-24648 and H-24020: Biopersistence Screening ANIMAL NUMBER 643132 643133 643134 643135 643136 ANIMAL NUMBER 643132 643133 643134 643135 643136 ANIMAL NUMBER 643132 643133 643134 643135 643136 ANIMAL NUMBER 643132 643133 643134 643135 643136 Day 1 178.7 183.4 162.8 177.5 168.0 Day 10 213.6 219.1 188.9 206.7 186.5 Day 19 239.8 234.8 206.6 226.8 213.3 Day 67 330.2 316.4 252.2 297.8 275.9 Day 2 177.6 180.8 164.5 176.8 160.4 Day 11 216.1 213.8 188.5 207.6 192.1 Day 2 0 243.5 233.6 203.2. 227.0 217.0 Day 7 4 334.3 328.1 256.9 293.2 272.8 INDIVIDUAL BODY WEIGHTS (9) OF FEMALE RATS GROUP IV (H-- 2 4 6 4 8 ) Day 3 Day 4 / Day 5 Day 6 184.9 189.3 168.5 181.6 169.5 190.6 194.8 170.8 186.8 174.5 195.2 191.4 172.3 191.1 176.6 197.5 198.5 177.4 191.7 175.5 Day 12 222.4 223.1 192.1 210.5 198.6 Day 13 225.4 222.5 192.8 210.3 197.2 Day 14 224.1 231.3 194.0 214.2 197.1 Day 15 232.3 233.6 197.7 219.7 204.6 Day 21 247.2 237.9 203.7 227.1 218.0 Day 22 250.0 236.8 208.0 229.0 213.8 Day 33 277.1 271.0 221.3 257.9 247.8 Day 39 284.2 286.1 228.5 267.9 258.3 Day 81 349.5 350.8 259.5 302.5 289.0 Day 88 358.1 370.2 264.8 315.1 295.3 Day 95 369.8 383.3 277.7 316.8 300.0 Day 102 372.2 391.2 276.7 322.4 299.9 DuPont-5207 Day 7 200.0 203.9 181.5 197.1 180.8 Day 8 208.8 207.8 182.2 202.7 186.3 Day 9 210.4 206.1 183.4 199.7 187.8 Day 16 232.0 232.8 195.5 220.8 205.7 Day 17 236.0 232.4 196.2 219.9 207.6 Day 18 234.7 228.9 201.2 225.0 205.8 Day 46 304.3 306.5 227.8 280.3 256.8 Day 53 307.1 307.6 245.9 274.3 267.7 Day 60 319.6 300.8 243.0 283.3 271.8 Day 106 376.9 390.8 275.4 321.2 304.4 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 ------------ --............... . ---- -------- ----------------- ------- -- -- 7T.-- ... 1 ;; KL'AvwAt l i tmtai w TSClA CBt-- -38- H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS ANIMAL NUMBER 643137 643138 643139 643140 643141 Day 1 184.1 195.2 174.9 165.6 172.7 Day 2 183.1 195.2 170.4 164.4 173.6 Day 3 187.8 198.8 177.4 166.4 180.3 GROUP VI (H-24020) Day 4 Day 5 196.3 207.1 182.8 171.0 182.2 201.0 212.7 185.9 178.1 185.8 Day 6 198.9 216.0 188.1 181.2 187.4 ANIMAL NUMBER 643137 643138 643139 643140 643141 Day 10 220.6 230.8 198.2 197.2 199.8 Day 11 220.4 229.3 202.5 194.8 201.0 Day 12 225.9 239.1 210.4 200.0 204.3 Day 13 232.1 243.4 209.4 210.1 206.6 Day 14 230.7 245.3 208.0 209.6 208.0 Day 15 236.2 244.4 214.5 206.5 211.7 ANIMAL NUMBER 643137 643138 643139 643140 643141 Day 19 245.2 253.4 224.6 220.8 221.3 Day 20 247.5 256.8 225.1 220.0 220.7 Day 21 249.1 258.9 223.5 228.8 219.4 Day 22 248.7 259.3 221.3 230.4 227.3 Day 33 280.5 281.6 248.5 252.2 254.8 Day 39 284.7 288.9 256.0 251.6 267.5 ANIMAL NUMBER 643137 643138 643139 643140 643141 Day 67 326.4 359.5 291.0 285.4 301.2 Day 74 336.6 356.9 291.2 288.1 301.9 Day 81 351.2 378.2 297.8 305.4 309.3 Day 88 356.7 379.0 304.7 307.8 318.5 Day 95 358.6 394.7 311.3 308.3 326.1 Day 102 368.8 401.0 314.6 321.6 331.1 DuPont-5207 Day 7 202.4 216.4 192.5 179.9 191.3 Day 8 209.5 222.6 200.0 188.8 193.9 Day 9 212.7 225.4 201.1 190.4 193.9 Day 16 236.5 248.9 215.4 212.0 212.1 Day 17 238.8 249.4 219.4 215.0 216.5 Day 18 245.4 253.3 218.4 218.8 220.6 Day 46 293.2 315.4 261.8 277.0 286.2 Day 53 303.6 327.4 268.5 278.2 276.2 Day 60 312.8 339.2 280.4 281.3 287.1 Day 106 369.8 404.1 316.8 315.2 331.6 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 SD t e s t d a y 106 -39- H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 APPENDIX B Individual Clinical Observations mTSCACB* -40- Sanifeed.Does nut eontai ComPan^ H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period DuPont-5207 INDIVIDUAL CLINICAL OBSERVATIONS EXPLANATORY NOTES Any clinical sign observed on consecutive data collection days is assumed to have been present during the interim between observation days, and will be reported as having been observed over the period from the first-last day observed. noeslW*" 1^ -41 - Qsinpani San-'-' H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Sex Group Animal Observation MI 643111 General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Sacrificed by design MI 643112 General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Sacrificed by design MI 643113 General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Bilateral Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Sacrificed by design MI 643114 General observation. No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Bilateral Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Sacrificed by design DuPont-5207 Days 1-22,32,39-46,53-102 1.4.10.20.24.30.37.106 15.18.51 106 1-22,32,39-46,53-102 1.5.10.20.24.30.37.106 15.18.51 106 1-22,32,39-46,53-102 51.106 1,5,10,20,24,30,37 15,18 106 1-22,32,39-46,53-102 51 1.5.10.15.18.37.106 20,24,30 106 -42 - ;3 not contain TSCACBf Company Sanitized. Dc H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Sex Group Animal Observation MI 643115 General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Eye Observations, Bled via Orbital for Clin Path Discharge, Eye bilateral Discharge, Nose, Black D isch arg e, Eye r i g h t . B lack Hair Loss, Forelimb, Bilateral Hair Loss, Forepaw, Bilateral Hair Loss, Forepaw, Left Sacrificed by design DuPont-5207 Days 1-11 51 1,5,10,15,18,20,24, 30,37 106 21 21 19-20 74-106 18-22,32,39-46,53-67 12-17 106 -43- not containTscACBi Company Sanitized. UUw H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period Sex Group Animal M III 643116 INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Observation General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left M III 643118 Eye Observations, Bled via Orbital for Clin Path, Right Hair Loss, Abdomen, Medial Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left M III 643119 Eye Observations, Bled via Orbital for Clin Path, Right Eye Observations, Dark, Left Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Bilateral Eye Observations, Bled via Orbital for Clin Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Sacrificed by design DuPont-5207 Days 1-7,46,53-102 1.5.10.15.18.24.30, 37.51.106 20 8-22,32,39 106 I- 10,21-22,32,39-46, 53-102 1.5.10.15.18.24.30, 37.51.106 20 II- 20 106 1-22,32,39-46,53-102 10 1.5.15.18.24.30, 37.51.106 20 106 -44- Doss not contain TSCA CB` C om paq Sanitized H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Sex Group Animal Observation M III 643120 General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Bilateral Eye Observations, Bled via Orbital for Clin Path, Left M III 643126 Eye Observations, Bled via Orbital for Clin Path,. Right Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Bilateral Eye Observations, Bled via Orbital for Clin Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Discharge, Eye bilateral. Black Discharge, Eye left, Black Sacrificed by design DuPont-5207 Days 1-22,32,39-46,53-102 106 1,5,10,15,18,24,30, 37.51 20 106 1-18,20,22,32,39-46, 53-102 24,37 1.5.10.15.18.51 20,30,106 21 19 106 TSO^CBl not copain Doe eompan?-.' ian** H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Sex Group Animal Observation MV 643121 General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path Bilateral Eye Observations, Bled via Orbital for Clin Path Left Eye Observations, Bled via Orbital for Clin Path Right Sacrificed by design MV 643122 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path Left MV 643123 Eye Observations, Bled via Orbital for Clin Path, Right Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Bilateral Eye Observations, Bled via Orbital for Clin Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Sacrificed by design DuPont-5207 Days 1-22,32,39-46,53-102 37 1.5.10.15.18.24.30.51 20,106 106 1-22,32,39-46,53-102 1.5.10.15.18.24.30, 37.51 20,106 106 1-22,32,34-46,53-102 106 1.5.10.15.18.24.30, 37.51 20 106 Cov?aT^ %% H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period Sex Group Animal MV 643124 INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Observation General observation. No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left MV 643125 Eye Observations, Bledvia Orbital for Clin Path, Right Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Sacrificed by design # DuPont-5207 Days 1-22,32,39-46,53-102 1.5.10.15.18.24.30, 37.51 20,106 106 1-22,32,39-46,53-102 1.5.10.15.18.24.30, 37.51 20,106 106 -47 - no\ c o n ia i TSCA CE Compaq Sana: sd.Doss H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period INDIVIDUAL CLINICAL OBSERVATIONS IN FEMALE RATS Sex Group Animal Observation F II 643127 General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left F II 643128 Eye Observations, Bled via Orbital for Clin Path, Right Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left F II 643129 Eye Observations, Bled via Orbital for Clin Path, Right Discharge, Eye left. Black Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Eye Observations, Corneal Opacity, Right Sacrificed by design DuPont-5207 Days 1-22,32,39-46,53-102 1.5.10.15.18.24.30, 37.51 20,106 106 1-18,21-22,32,39-46, 53-81,95-102 1.5.10.15.18.24.30, 37.51 20,106 19-20,88 106 1-16 1.5.10.15.18.24.30, 37.51 20,106 17-22,32,39-46,53-106 106 novoon>a'"TSCAC*-s H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period INDIVIDUAL CLINICAL OBSERVATIONS IN FEMALE RATS Sex Group Animal Observation F II 643130 General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left F II Eye Observations, Bledvia Orbital for Clin Path, Right Discharge, Nose, Black Discharge, Eye left, Black Sacrificed by design 643131 General observation, No Abnormality Detected Eye Observations, Bledvia Orbital for Clin Path, Left Eye Observations, Bledvia Orbital for Clin Path, Right Eye Observations, Corneal Opacity, Left Sacrificed by design DuPont-5207 Days 1-22,39-46,53-102 1.5.10.15.18.24.30, 37.51 20,106 32 32 106 1-22,32,39 1.5.10.15.18.24.30, 37.51 20,106 46,53-106 106 n0\conW'n H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period INDIVIDUAL CLINICAL OBSERVATIONS IN FEMALE RATS Sex Group Animal Observation F IV 643132 General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left F IV 643133 Eye Observations, Bled via Orbital for Clin Path, Right Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left F IV 643134 Eye Observations, Bled via Orbital for Clin Path, Right Eye Observations, Dark, Left Hair Loss, Forelimb, Bilateral Stain Fur/Skin, Perinasal, Brown Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Discharge, Eye bilateral, Black Sacrificed by design DuPont-5207 Days 1-22,32,39-46,53-102 1.5.10.15.18.24.30, 37.51 20,106 106 I- 6,9-10,16-22,32,60-74 1.5.10.15.18.24.30, 37.51 20,106 II- 15,39-46,53 81-106 7-8 106 1-22,39-46,53-102 1.5.10.15.18.24.30, 37.51 20,106 32 106 ooKi H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period Sex Group Animal F IV 643135 INDIVIDUAL CLINICAL OBSERVATIONS IN FEMALE RATS Observation General observation. No Abnormality Detected Eye Observations, Exophthalmus, Left Eye Observations, Bled via Orbital for Clin Path, Left F IV 643136 Eye Observations, Bled via Orbital for Clin Path, Right Eye Observations, Corneal Opacity, Left Hair Loss, Forepaw, Bilateral Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Sacrificed by design DuPont-5207 Days 1-22,32,39-46,53-60 72-106 1.5.10.15.18.24.30, 37.51 20,106 67-106 81-106 106 1-22,32,39-46,53-102 1.5.10.15.18.24.30, 37.51 20,106 106 ColWf;;*-. 095 \O0 0 ^ H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period Sex Group Animal F VI 643137 F VI 643138 F VI 643139 INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Observation General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Bilateral Eye Observations, Bled via Orbital for Clin Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Bilateral Eye Observations, Bled via Orbital for Clin Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Sacrificed by design DuPont-5207 Days 1-22,32,39-46,53-102 24 1.5.10.15.18.30.37.51 20,106 106 1-22,32,39-46,53-102 24 1.5.10.15.18.30.37.51 20,106 106 1-22,32,39-46,53-102 1,5,10,15,18,24,30, 37.51 20,106 106 not contain TSCACJl Company Saniuzed. Does m% H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period_____________________ Sex Group Animal F VI 643140 INDIVIDUAL CLINICAL OBSERVATIONS IN MALE RATS Observation General observation, No Abnormality Detected Eye Observations, Partially Closed, Right Eye Observations, Enophthalmus, Right Eye Observations, Exophthalmus, Right Eye Observations, Bled via Orbital for Clin Path, Bilateral Eye Observations, Bled via Orbital for Clin Path, Left F VI 643141 Eye Observations, Bled via Orbital for Clin Path, Right Eye Observations, Corneal Opacity, Right Sacrificed by design General observation. No Abnormality Detected Eye O b serv atio n s, B led v ia O rb ita l fo r C lin Path, L e ft Eye Observations, Bled via Orbital for Clin Path, Right Sacrificed by design DuPont-5207 Days 1-22,32 74-106 46,53-106 39 37 1.5.10.15.18.24.30, 51.106 20 39-46,53-106 106 1-22,32,39-46,53-102 1.5.10.15.18.24.30, 37,51 20.106 106 , 0M 6r, t contain TSCACBt Company SanU.- -53 - H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period APPENDIX C ANALYTICAL METHODS -54- Company Sanitized. Doss net contain TSCA CBl H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period HPLC Method Column: Waters Xterra MS C18 2.1X30 mm, 2.5 fim Solvent A: 50mM ammonium acetate Solvent B: acetonitrile Gradient: Time (min) %A %B 0 80 20 12 61 39 12.1 80 20 14 80 20 Flow rate: 200 jul/min Column Temperature: 40 C Sample Temperature: 8 C Injection Volume: 5 il Mass spectrometer method Temperatures: Source: 125 C Desolvation: 350 C Gas Flows: Desolvation: 558 1/hr Cone: 144 1/hr Settings: Polarity: ESCone voltage: 20 V Aperture: 0 V LM 1 Resolution: 15.0 Ion energyl: 1.0 Exit: 50 HM 2 Resolution: 12.0 Capillary voltage: 2.5 kV Hexapole 1 : 0 V Hexapole 2:0 V HM 1 Resolution: 15.0 Entrance: 50 LM 2 Resolution: 12.0 Ion energyl: 1.0 Method: SIR of 2 channels Channel Mass 412.9 363.0 ' Dwell (sec) 0.25 0.25 Cone Voltage (V) 20.0 20.0 -55- ,,om nctcortW .SCACB1 H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period APPENDIX D INDIVIDUAL PFOA PLASMA CONCENTRATION DATA -56- H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period INDIVIDUAL PFOA PLASMA CONCENTRATION DATA EXPLANATORY NOTES All control rats had PFOA concentrations of 0 at all time points. Footnote "a" on each table represents data points where concentration could not be calculated due to sample processing error. - 57- ,tco^aV CotnPsn jS * A 00 H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period Individual PFOA Plasma Concentration Data for Male Rats Group m (H-24648) Animal Number 643116 643116 643116 643116 643116 643116 643116 643116 643116 643116 643116 643118 643118 643118 643118 643118 643118 643118 643118 643118 643118 643118 643119 643119 643119 643119 643119 643119 643119 643119 643119 643119 643119 Test Day 1 5 10 15 18 20 24 30 37 51 106 1 5 10 15 18 20 24 30 37 51 106 1 5 10 15 18 20 24 30 37 ' 51 106 Total /ig/mL 16.25 82.38 55.13 115.14 137.66 102.92 49.75 28.01 12.79 4.45 a 63.84 158.75 158.50 124.92 153.50 124.10 50.10 23.49 13.44 4.57 a. 9.63 166.38 55.75 122.76 168.32 113.58 75.14 38.75 a 12.12 0.44 Total HM 37.70 191.13 127.90 267.15 319.40 238.79 115.43 64.99 29.68 10.31 a 148.12 368.33 367.75 289.84 356.15 287.94 116.24 54.50 31.18 10.59 a 22.33 386.02 129.35 284.83 390.53 263.53 174.34 89.91 a 28.12 1.01 H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period Individual PFOA Plasma Concentration Data for Male Rats Group ID (H-24648) Animal Number Test Total Day /rg/mL 643120 643120 643120 643120 643120 643120 643120 643120 643120 643120 643120 643126 643126 643126 643126 643126 643126 643126 643126 643126 643126 643126 1 15.25 5 160.75 10 27.50 15 123.38 18 161.14 20 97.64 24 40.83 30 21.30 37 13.91 51 5.27 106 0.13 1a 5 44.75 10 118.50 15 64.28 18 189.80 20 117.28 24 58.39 30 0.00 37 17.27 51 5.47 106 0.10 All rats had pretest (test day --3) PFOA concentration of 0. Note - Onl' present in H-24648. Total jiM 35.38 372.97 63.81 286.26 373.87 226.54 94.73 49.42 32.27 12.23 0.29 a 103.83 274.94 149.14 440.37 272.11 135.48 0.00 40.07 12.69 0.23 - 59- CO no\1o r' G' H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period Individual PFOA Plasma Concentration Data for Male Rats Group V(H-24020) Animal Number Straight Branched Test Chain Chain Total Day ftg/mL /ig/mL /ig/mL 643121 643121 643121 643121 643121 643121 643121 643121 643121 643121 643121 643122 643122 643122 643122 643122 643122 643122. 643122 643122 643122 643122 643123 643123 643123 643123 643123 643123 643123 643123 643123 643123 643123 1 35.79 11.08 46.87 5 194.38 21.18 215.55 10 156.13 12.62 168.74 15 128.02 17.45 145.47 18 104.50 11.38 115.88 20 168.42 6.69 175.11 24 67.89 0.00 67.89 30 26.06 0.00 26.06 37 36.93 0.00 36.93 51 12.58 0.00 12.58 106 a a a 1 36.20 11.73 47.93 5 185.25 23.71 208.96 10 8 6 .8 8 13.65 100.52 15 104.86 13.96 118.82 18 117.62 3.93 121.55 20 115.98 4.55 120.53 24 61.19 0.00 61.19 30 35.39 0.00 35.39 37 15.01 0.00 15.01 51 4.99 0.00 4.99 106 0.07 0.00 0.07 1 35.95 10.95 46.90 5 100.63 22.93 123.56 10 21.38 16.21 37.58 15 108.56 15.59 124.15 18 123.88 5.14 129.02 20 131.24 6.33 137.57 24 58.32 0.00 58.32 30 37.19 0.00 37.19 37 17.19' 0.00 17.19 51 7.20 0.00 7.20 106 a a a Total fiM 108.74 500.12 391.52 337.52 268.87 406.29 157.52 60.46 85.68 29.18 a 111.20 484.82 233.23 275.69 282.01 279.65 141.97 82.11 34.83 11.58 0.16 108.82 286.67 87.20 288.06 299.34 319.19 135.31 86.29 39.88 16.71 a H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period Individual PFOA Plasma Concentration Data for Male Rats Group V (H-24020) Animal Number Straight Branched Test Chain Chain Total Day ig/mL jig/mL Ag/mL 643124 643124 643124 643124 643124 643124 643124 643124 643124 643124 643124 643125 643125 643125 643125 643125 643125 643125 643125 643125 643125 643125 1 61.57 5 271.00 10 172.50 15 144.80 18 145.50 20 154.94 24 76.37 30 37.14 37 23.30 51 11.72 106 a 1 46.88 5 235.25 10 118.50 15 148.74 18 82.46 20 148.94 24 82.77 30 24.41 37 13.29 51 6 .1 2 106 a All rats had pretest (test day -3) PFOA concentration of 0. 1 5 .6 2 2 5 .1 5 2 1 .9 2 1 8 .5 4 5 .0 9 7 .0 8 0 .0 0 0 .0 0 0 .0 0 0 .0 0 a 1 3 .0 0 2 5 .2 0 1 5 .8 8 1 5 .0 8 2 .5 7 5 .7 2 0 .0 0 0 .0 0 0 .0 0 0 .0 0 a 7 7 .1 9 2 9 6 .1 5 1 9 4 .4 2 1 6 3 .3 4 1 5 0 .5 9 1 6 2 .0 2 7 6 .3 7 3 7 .1 4 2 3 .3 0 1 1 .7 2 a 5 9 .8 8 2 6 0 .4 5 1 3 4 .3 8 1 6 3 .8 2 8 5 .0 3 1 5 4 .6 6 8 2 .7 7 2 4 .4 1 1 3 .2 9 6 .1 2 a Total HM 1 7 9 .0 9 6 8 7 .1 3 4 5 1 .0 9 3 7 8 .9 7 3 4 9 .4 0 3 7 5 .9 2 1 7 7 .1 9 8 6 .1 7 5 4 .0 6 2 7 .1 9 a 1 3 8 .9 3 6 0 4 .3 0 3 1 1 .7 8 3 8 0 .0 9 1 9 7 .2 9 3 5 8 .8 3 1 9 2 .0 4 5 6 .6 4 3 0 .8 4 1 4 .2 0 a -61 - Company Sanitized. Does not contain TSCACBI H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period Individual PFOA Plasma Concentration Data for Female Rats Group IV (H-24648) Animal Number 643132 643132 643132 643132 643132 643132 643132 643132 643132 643132 643132 643133 643133 643133 643133 643133 643133 643133 643133 643133 643133 643133 643134 643134 643134 643134 643134 643134 643134 643134 643134 643134 643134 . Test Day 1 5 10 15 18 20 24 30 37 51 106 1 5 10 15 18 20 24 30 37 51 106 1 5 10 15 18 20 24 30 37 ' 51 106 Total /tg/mL 45.52 35.88 60.47 144.70 68.98 52.94 0.82 0.00 0.00 0.04 a 37.92 60.33 73.63 53.62 53.10 53.08 0.00 0.00 0.00 0.00 0.00 9.13 37.75 80.13 56.10 72.70 69.04 0.00 0.00 0.00 0.00 a Total m 105.60 83.24 140.30 335.73 160.05 122.83 1.90 0.00 0.00 0.08 a 87.98 139.98 170.82 124.41 123.20 123.16 0.00 0.00 0.00 0.00 0.00 21.17 87.59 185.90 130.16 168.68 160.19 0.00 0.00 0.00 0.00 a - 62- aBd > u60WI H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period Individual PFOA Plasma Concentration Data for Female Rats Group IV (H-24648) Animal Number Test Total Day Itg/mL 643135 643135 643135 643135 643135 643135 643135 643135 643135 643135 643135 643136 643136 643136 643136 643136 643136 643136 643136 643136 643136 643136 1 41.37 5 51.50 10 41.55 15 59.22 18 65.56 20 69.68 24 0.00 30 0.00 37 0.00 51 0.00 106 a 1 43.35 5 61.63 10 54.78 15 61.88 18 57.28 20 58.72 24 0.00 30 0.00 37 0.00 51 0.00 106 a All rats had pretest (test day -3) PFOA concentration of 0. Note - Only present in H-24648. Total ilM 95.99 119.49 96.40 137.40 152.11 161.67 0.00 0.00 0.00 0.00 a 100.58 142.98 127.09 143.57 132.90 136.24 0.00 0.00 0.00 0.00 a - 63- Saniti: C o m p ly TSCACBI iB5neteonlgfo H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period Individual PFOA Plasma Concentration Data for Female Rats Group VI (H-24020) Animal Number Straight Branched Test Chain Chain Total Total Day iig/mL Rg/mL #lg/mL HM 643137 643137 643137 643137 643137 643137 643137 643137 643137 643137 643137 643138 643138 643138 643138 643138 643138 643138 643138 643138 643138 643138 643139 643139 643139 643139 643139 643139 643139 643139 643139 643139 643139 1 36.79 6.37 43.16 100.14 5 34.49 6.13 40.61 94.23 10 32.17 7.80 39.97 92.73 15 35.70 3.52 39.22 90.99 18 36.54 1.30 37.84 87.80 20 40.30 1.57 41.87 97.15 24 0.71 0.00 .0.71 1.65 30 0.00 0.00 0.00 0.00 37 0.00 0.00 0.00 0.00 51 0.09 0.00 0.09 0.20 106 0.00 0.00 0.00 0.00 1 36.38 6.73 43.11 100.02 5 43.76 7.76 51.52 119.53 10 27.99 6.21 34.20 79.34 15 47.56 4.19 51.75 120.08 18 60.12 3.96 64.08 148.68 20 43.70 1.20 44.90 104.17 24 0.00 0.00 0.00 0.00 30 0.00 0.00 0.00 0.00 37 0.00 0.00 0.00 0.00 51 0.00 0.00 0.00 0.00 106 a a a a 1 28.04 5.72 33.75 78.31 5 42.17 9.06 51.23 118.85 10 34.16 7.22 41.38 96.00 15 49.00 7.06 56.06 130.07 18 51.06 2.13 53.19 123.41 20 42.50 0.94 43.44 100.79 24 0.00 0.00 0.00 0.00 30 0.00 0.00 0.00 0.00 37 0.00 ` 0.00 0.00 0.00 51 0.02 0.00 0.02 0.05 106 0.00 0.00 0.00 0.00 -a.not P'Stfain TSCA ztl. Di - 6 4 - omP H-24648 and H-24020: Biopersistence Screening 20-Dose Oral Gavage Study in Rats with Recovery Period Individual PFOA Plasma Concentration Data for Female Rats Group VI (H-24020) Animal Number Straight Branched Test Chain Chain Total Total Day /tg/mL /tg/mL /tg/mL IlM 643140 643140 643140 643140 643140 643140 643140 643140 643140 643140 643140 643141 643141 643141 643141 643141 643141 643141 643141 643141 643141 643141 1 35.35 5 37.86 10 29.50 15 58.04 18 58.50 20 61.56 24 0.00 30 0.00 37 0.00 51 0.08 106 0.00 1 30.30 5 36.65 10 33.71 15 46.92 18 55.42 20 55.96 24 0.00 30 0.00 37 0.00 51 0.00 106 0.00 All rats had pretest (test day -3) PFOA concentration o f 0. 6.22 7.38 7.27 3.44 2.06 0.00 0.00 0.00 0.00 0.00 6.21 7.92 11.08 6.63 3.95 1.99 0.00 0.00 0.00 0.00 0.00 41.57 45.24 29.50 65.31 61.94 63.62 0.00 0.00 0.00 0.08 0.00 36.51 44.57 44.79 53.55 59.37 57.95 0.00 0.00 0.00 0.00 0.00 96.45 104.97 68.45 151.54 143.70 147.61 0.00 0.00 0.00 0.17 0.00 84.71 103.40 103.91 124.25 137.74 134.45 0.00 0.00 0.00 0.00 0.00 - 6 5 - c,& G O taP ' \' >>\cotv
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CUNY - The Graduate CenterColumbia University Mailman School of Public Health - Sociomedical Sciences